Frontiers in Medicine

Published by Frontiers Media SA
Online ISSN: 2296-858X
Publications
Kidney allograft rejection is associated with infiltration of inflammatory CD11b+ leukocytes. A CD11b agonist leukadherin-1 (LA1) increases leukocyte adhesion, preventing their transmigration and tissue recruitment in vivo. Here, we test the extent to which LA1-mediated activation of CD11b/CD18 enhances kidney allograft survival in a mouse model of fully MHC-mismatched orthotopic kidney transplantation, where C57BL/6J (H-2(b)) recipients received kidney allografts from Balb/c mice (H-2(d)). Isograft control recipients received a kidney from a littermate. Control isograft and allograft recipients were treated daily with cyclosporine (CsA) for 2 weeks, while the test group received CsA therapy and daily LA1 injections during week 1 and alternate days during weeks 2-8. LA1 treatment reduced interstitial leukocyte infiltration in the allograft, reduced neointimal hyperplasia and glomerular damage, and prolonged graft survival from 48.5% (CsA only) to 100% (CsA and LA1) on day 60. Serum creatinine levels showed significantly improved kidney function in LA1-treated mice compared to CsA-treated allograft controls [0.52 ± 0.18 mg/dL vs 0.24 ± 0.07 mg/dL (n = 5), respectively]. Furthermore, combination therapy reduced macrophage infiltration and increased the frequency of FoxP3 + Tregs in the allograft. These findings indicate a crucial role for CD11b/CD18 in the control of leukocyte migration to the transplanted kidney and identify integrin agonist LA1 as a novel potential therapeutic agent for kidney transplantation.
 
The varied nonpressor and nonantidiuretic actions of vasopressin are illustrated.
| Cells, receptors, and the effects of arginine vasopressin on blood glucose levels.
The pressor and antidiuretic actions of arginine vasopressin (AVP) have been well documented. This review focuses on the less widely appreciated actions of AVP which also have important physiologic functions and when better understood may provide important insights into common disease states. These actions include effects on pain perception and bone structure as well as important relationships to the varied components of metabolic syndrome. These include effects on blood glucose, lipid levels, and blood pressure. AVP may also play a role in the progression of chronic kidney disease and effect physiologic changes relating to aging, abnormal social behavior, and cognitive function. Important cellular responses including cell proliferation, inflammation, and control of infection and their relationship to AVP are described. Finally, the effects of AVP on hemostasis and the hypothalamic-pituitary-adrenal axis are noted. The goal of this summary of the various actions of AVP is to direct attention to the potential benefits of research in these underemphasized areas of importance.
 
STAT3 rs4796793 dependent endogeneous STAT3 mRNA expression and IFNα sensitivity. (A) STAT3 mRNA expression was measured by real-time PCR in peripheral blood lymphocytes (PBL) and melanoma cell lines (MM). A CG genotype PBL sample served as calibrator. ANOVA analyses did not show significant differences (PBL, p = 0.0863, Kruskal–Wallis; MM, p = 0.3127, parametric). (B) MM lines were subjected to 51200 IU IFNα/ml or not, after 4 days their metabolic activity was measured by MTS assay. Depicted are the means with standard error for each cell line measured in at least two independent experiments.
STAT3 SNP rs4796793 does not influence distant metastasis free survival (DMFS) nor overall survival (OS) in stage III melanoma patients. Patients were stratified according to their rs4796793 SNP. Kaplan–Meier plots for DMFS or OS of melanoma patients without (A,C) or with adjuvant IFNα therapy (B,D) in stage III. Below each graph, the patient numbers (pts.) at risk are given. Log-rank test was performed for statistical analysis.
Interferon alpha (IFNα) is approved for adjuvant treatment of stage III melanoma in Europe and the US. Its clinical efficacy, however, is restricted to a subpopulation of patients while side effects occur in most of treated patients. Thus, the identification of predictive biomarkers would be highly beneficial to improve the benefit to risk ratio. In this regard, STAT3 is important for signaling of the IFNα receptor. Moreover, the STAT3 single-nucleotide polymorphism (SNP) rs4796793 has recently been reported to be associated with IFNα sensitivity in metastatic renal cell carcinoma. To translate this notion to melanoma, we scrutinized the impact of rs4796793 functionally and clinically in this cancer. Interestingly, melanoma cells carrying the minor allele of rs4796793 were the most sensitive to IFNα in vitro. However, we did not detect a correlation between SNP genotype and STAT3 mRNA expression for either melanoma cells or for peripheral blood lymphocytes. Next, we analyzed the impact of rs4796793 on the clinical outcome of 259 stage III melanoma patients of which one-third had received adjuvant IFNα treatment. These analyses did not reveal a significant association between the STAT3 rs4796793 SNP and patients' progression free or overall survival when IFNα treated and untreated patients were compared. In conclusion, STAT3 rs4796793 SNP is no predictive marker for the efficacy of adjuvant IFNα treatment in melanoma patients.
 
Secondary bacterial infections following influenza infection are a pressing problem facing respiratory medicine. Although antibiotic treatment has been highly successful over recent decades, fatalities due to secondary bacterial infections remain one of the leading causes of death associated with influenza. We have assessed whether administration of a bacterial extract alone is sufficient to potentiate immune responses and protect against primary infection with influenza, and secondary infections with either Streptococcus pneumoniae or Klebsiella pneumoniae in mice. We show that oral administration with the bacterial extract, OM-85, leads to a maturation of dendritic cells and B-cells characterized by increases in MHC II, CD86, and CD40, and a reduction in ICOSL. Improved immune responsiveness against influenza virus reduced the threshold of susceptibility to secondary bacterial infections, and thus protected the mice. The protection was associated with enhanced polyclonal B-cell activation and release of antibodies that were effective at neutralizing the virus. Taken together, these data show that oral administration of bacterial extracts provides sufficient mucosal immune stimulation to protect mice against a respiratory tract viral infection and associated sequelae.
 
A) Periodic acid-Schiff stain shows one partially sclerotic glomerulus and two intact glomeruli; there is no tubulitis or interstitial fibrosis; minor tubular epithelial cell changes are noted (×200). (B) Electron microscopy shows foot process effacement (approximately 30% of the surface area) and reactive cytoplasmic changes in podocytes. Numerous red blood cells are present in the capillary loops and Bowman’s space (×3000).
Time course of events, treatments, and responses in serum albumin and urine protein excretion. The serum albumin level over time is depicted by the solid black line and the urine protein/creatinine ratio by the dashed gray line. The value at 40 weeks was imputed to be 0 because the patient was anuric.
| Interpretation of putative markers in FSGS.
Recurrent focal segmental glomerular sclerosis (rFSGS) in renal transplant recipients (RTR) is difficult to predict and treat. Early rFSGS is likely from circulating factors and preformed antibodies. We present the case of a 23-year-old white man who presented with rFSGS and acute renal failure, requiring dialysis 9-months after a 1-haplotype matched living-related transplant. We retrospectively analyzed serum samples from various clinical stages for rFSGS biomarkers: serum glomerular albumin permeability (Palb), soluble urokinase-type plasminogen activator receptor (suPAR) serum level with suPAR-β3 integrin signaling on human podocytes, and angiotensin II type I receptor-antibody (AT1R-Ab) titer. All biomarkers were abnormal at 1-year pre-transplant prior to initiation of dialysis and at the time of transplant. After initiation of hemodialysis, β3 integrin activity on human podocytes, in response to patient serum, as well as AT1R-Ab were further elevated. At the time of biopsy-proven recurrence, all biomarkers were abnormally high. One week after therapy with aborted plasmapheresis (secondary to intolerance), and high dose steroids, the Palb and suPAR-β3 integrin activity remained significantly positive. After 12-weeks of treatment with high-dose steroids, rituximab, and galactose, the patient remained hemodialysis-dependent. Three-months after his initial presentation, we commenced adrenocorticotropic hormone (ACTH, Acthar(®) Gel), 80 units subcutaneously twice weekly. Four-weeks later, he was able to discontinue dialysis. After 8-months of maintenance ACTH therapy, his serum creatinine stabilized at 1.79 mg/dL with <1 g of proteinuria. ACTH therapy was associated with improvement in renal function within 4 weeks. The use of rFSGS biomarkers may aid in predicting development of rFSGS.
 
Prevalence of use of psychotropic drugs by age groups.
| Characteristics of the study population according to age group.
Prevalence of osteopenia and osteoporosis by gender.
In the last decades, life expectancy of persons with Down syndrome (DS) has dramatically increased and it is estimated that they will be living as long as the general population within a generation. Despite being included among the progeroid syndromes, because of the presence of features typically observed in older adults, DS is still regarded as a disease of pediatric interest. Because limited knowledge is available on the clinical characteristics of adults with DS, this study aimed to assess clinical and non-clinical features of this population and to describe similarities to the geriatric population. In this study, we described 60 adults with DS evaluated at the Day Hospital of the Geriatric Department of the Policlinico A. Gemelli, Università Cattolica del Sacro Cuore in Rome. Individuals were assessed through a standardized protocol. The mean age of study participants was 38 years (range, 18-58 years) and 42 (70.0%) were women. Geriatric conditions were highly prevalent: severe cognitive impairment was diagnosed in 39 (65.0%) participants, behavioral symptoms were present in 25 (41.7%), and functional impairment in 23 (38.3%). Six (10.0%) participants lived in institutions and 11 (18.3%) were diagnosed as obese. The mean number of drugs used was 2.4; use of psychotropic drugs was highly prevalent. The most common chronic diseases were thyroid problems (44, 73.3%), followed by mood disorders (19, 31.7%), osteoporosis (18, 30.0%), and cardiac problems (10, 16.7%). Geriatric conditions and chronic diseases were more prevalent among participants aged ≥40 years. Several similarities between older adults and adults with DS were observed. Comorbidities, geriatric conditions, cognitive and functional deficits, and social problems are highly prevalent in both populations, contributing to the high complexity of these patients' assessment and treatment.
 
A progressive decrease in fertility, together with lengthening life expectancy, has driven a reshaping in the age distribution of the world population (1). The main consequence of this reshaping is a progressive increase in both the number and the relative proportion of older people in our society. Current fertility rates in virtually all developed countries are below replacement levels, reflecting the significant societal, cultural, and lifestyle changes over the last century. A faster decline in fertility is occurring in developing countries. The latter is anticipated to reduce global geographical differences in fertility rates. The increase in life expectancy is related to a number of factors such as improved socioeconomic conditions and access to health services, early detection of disease conditions, and improved short- and long-term outcomes after an illness. Mean global life expectancy has increased from 46.5 years in 1950–1955 to 66.0 years in 2000–2005. This increase has been more prominent in less developed countries although significant variation exists in these regions (2). Notably, the relative gain in life expectancy is also projected to increase at older age, i.e., by 27% at age 80, 19% at age 60, and only 9% at birth over the next 50 years. Therefore, specific subgroups within the older population, e.g., >80 years, are growing particularly fast.
 
A) Human placenta layers: amnion, chorion, and decidua. Amniotic layer is composed of a single-celled epithelial layer and a deeper mesodermal layer. Chorionic layer is composed of a mesodermal layer and a trophoblast layer. (B) Isolation of amnion membrane from placenta. The maternal side of placenta is placed face down and a shallow X-shaped incision is made through the center of the placenta. The thin, nearly transparent amnion membrane is then peeled starting at the center of the cut and progressing outward. (C) Morphology of amniotic epithelial cells in culture (×40).
As a unique source of stem cells, there is a growing interest in amniotic epithelial (AE) cells. Placenta is readily available; in fact, it is often discarded following delivery. As such, it is without the ethical concerns of embryonic stem cells. Further advantages to AE include that AE cells do not demonstrate tumorigenicity upon transplantation, and are gifted with immunomodulatory and anti-inflammatory properties. Thus, AE cells have exceptional features for use as cell-based therapies for liver disease.
 
Small-bowel mucosal immunofluorescence staining of IgA (green) and transglutaminase-2 (red) and co-localization of IgA and TG2 in yellow (arrow). In (A) a healthy control (no co-localization), in (B) a celiac patient with evidence of co-localization (arrow).
| Summary of the included studies evaluating the presence of intestinal TG2 deposits in overt celiac disease (CD).
| Summary of the included studies evaluating TG2 deposits in potential celiac disease (PCD).
To review the existing literature on the role and significance of intestinal transglutaminase 2 immunoglobulin A deposits (TG2 deposits) in patients with overt celiac disease (CD), potential celiac disease (PCD), and other autoimmune or gluten-related conditions. We conducted a systematic review of studies published in English, evaluating presence and characteristics of TG2 deposits in subjects with overt CD, PCD, gluten-related diseases [dermatitis herpetiformis (DH), gluten-ataxia (GA)], autoimmune disorders (type-1 diabetes), and other conditions. Studies were identified through a MEDLINE search (1950-2013). Twenty-three studies were included in the review. Eleven studies were performed in children. Overall TG2 deposits were present in 100% of adults with overt CD, while in children prevalence ranged from 73.2 to 100%. Six studies with an established definition of PCD were considered, prevalence of deposits ranging from 64.7 to 100%. A single study followed-up PCD patients with repeated biopsies and identified presence of intestinal deposits as the best marker to reveal progression toward villous atrophy. Two studies investigated presence of deposits in DH, reporting prevalence between 63 and 79%. A single study documented TG2 deposits in 100% of patients with GA. In children with type-1 diabetes (T1D), positivity of intestinal TG2 deposits ranged from 25 to 78%. Transglutaminase 2 IgA deposits seem to be a constant feature in overt CD patients and are frequently detectable in other gluten-related conditions (DH and GA). The vast majority of PCD patients express TG2 deposits at the intestinal level, but no sufficient data are available to exactly define their prognostic role as a marker of evolution toward overt CD. The frequent finding of TG2 deposits in the intestinal mucosa of patients with T1D is an interesting observation deserving further evaluation.
 
Selective delivery of radionuclides to tumors may be accomplished using a two-step approach, in which in the first step the tumor is pretargeted with an unlabeled antibody construct and in the second step the tumor is targeted with a radiolabeled small molecule. This results in a more rapid clearance of the radioactivity from normal tissues due to the fast pharmacokinetics of the small molecule as compared to antibodies. In the last decade, several pretargeting approaches have been tested, which have shown improved tumor-to-background ratios and thus improved imaging and therapy as compared to directly labeled antibodies. In this review, we will discuss the strategies and applications in (pre-)clinical studies of pretargeting concepts based on the use of bispecific antibodies, which are capable of binding to both a target antigen and a radiolabeled peptide. So far, three generations of the bispecific antibody-based pretargeting approach have been studied. The first clinical studies have shown the feasibility and potential for these pretargeting systems to detect and treat tumor lesions. However, to fully integrate the pretargeting approach in clinic, further research should focus on the best regime and pretargeting protocol. Additionally, recent developments in the use of bioorthogonal chemistry for pretargeting of tumors suggest that this chemical pretargeting approach is an attractive alternative strategy for the detection and treatment of tumor lesions.
 
An example of tumor budding (single tumor cells and small clusters of up to five tumor cells detached from the main tumor body). These can be seen on H&E [(A), arrows] but are far more readily recognized on the pancytokeratin immunostain of the corresponding tumor area [(B), arrows].
Simplified illustration of molecular pathways involved in the formation of tumor budding. Markers demonstrated to be overexpressed (yellow) and underexpressed (blue) in tumor buds by immunohistochemistry. Str, stromal cell, (c), cytoplasmic, (m) membranous, (n) nuclear.
In recent years, tumor budding in colorectal cancer has gained much attention as an indicator of lymph node metastasis, distant metastatic disease, local recurrence, worse overall and disease-free survival, and as an independent prognostic factor. Tumor buds, defined as the presence of single tumor cells or small clusters of up to five tumor cells at the peritumoral invasive front (peritumoral buds) or within the main tumor body (intratumoral buds), are thought to represent the morphological correlate of cancer cells having undergone epithelial-mesenchymal transition (EMT), an important mechanism for the progression of epithelial cancers. In contrast to their undisputed prognostic power and potential to influence clinical management, our current understanding of the biological background of tumor buds is less established. Most studies examining tumor buds have attempted to recapitulate findings of mechanistic EMT studies using immunohistochemical markers. The aim of this review is to provide a comprehensive summary of studies examining protein expression profiles of tumor buds and to illustrate the molecular pathways and crosstalk involved in their formation and maintenance.
 
Outline of the clinical trial set up. For details please see the Sections “Materials and Methods” and “Results” of the text.
Normalized SCORAD index (A) and normalized pruritus index (B) versus duration of treatment with either CsA or ECP. Data from all patients completing at least 2 months of treatment with CsA (3 mg/kg/day) (n = 16) or ECP (2 J/cm2, on two consecutive days/14 days) (n = 20) are included.
SCORAD score (A) and pruritus index (B) before and after 4 months of treatment with either CsA, 3 mg/kg/day or ECP, 2 J/cm2, on two consecutive days every second week. For details please confer the Section “Results” of the text.
Severe atopic dermatitis (AD) is a recurrent and debilitating disease often requiring systemic immunosuppressive treatment. The efficacy of cyclosporine A (CsA) is well proven but potential side effects are concerning. Several reports point at extracorporeal photopheresis (ECP) as an alternative treatment modality with few and mild side effects. However, no direct comparison between CsA and ECP in the treatment of AD has been performed so far. To compare the efficacy of CsA (3 mg/kg/day) and ECP (administered two consecutive days twice a month) in a cohort of patients with severe AD. A randomized cross-over study involving twenty patients with severe AD (SCORAD index 41-89) refractory to other treatments. The patients were allocated to a 4-month course of either of the two treatment modalities. Individual relapse periods (2-8 weeks) were interspersed before cross-over to the other treatment modality. Treatment efficacy was evaluated by SCORAD, PRURITUS (VAS-index 0-10), "overall global assessment" and serological biomarkers; sIL-2Rα, sE-selectin, eosinophilocytes, basophilocytes, and sIgE. 15 patients completed treatment. Both treatments lead to a marked and significant decrease in SCORAD and pruritus index. The average reduction of the SCORAD and pruritus index, respectively was a little higher for ECP treatment compared to CsA treatment; however, the differences did not reach statistical significance. The "overall global assessment" was significantly better in patients who underwent ECP therapy as compared to CsA treatment. None of the biomarkers showed significant changes after either treatment when compared to the initial values. ECP administered on two consecutive days twice a month to patients with severe AD has similar potency as CsA administered daily in a moderate dose. ECP is a treatment alternative in patients with severe AD that do not tolerate or are refractory to conventional immunosuppressants.
 
Atypical hemolytic uremic syndrome (aHUS) is a rare disorder characterized by over-activation and dysregulation of the alternative complement pathway. Its estimated prevalence is 1-2 per million. The disease is characterized by thrombotic microangiopathy, which causes anemia, thrombocytopenia, and acute renal failure. aHUS has more severe course compared to typical (infection-induced) HUS and is frequently characterized by relapses that leads to end stage renal disease. For a long time, kidney transplantation for these patients was contraindicated because of high rate of recurrence and subsequent renal graft loss. The post-kidney transplantation recurrence rate largely depends on the pathogenetic mechanisms involved. However, over the past several years, advancements in the understanding and therapeutics of aHUS have allowed successful kidney transplantation in these patients. Eculizumab, which is a complement C5 antibody that inhibits complement factor 5a and subsequent formation of the membrane-attack complex, has been used in prevention and treatment of post-transplant aHUS recurrence. In this paper, we present two new cases of aHUS patients who underwent successful kidney transplantation in our center with the use of prophylactic and maintenance eculizumab therapy that have not been published before. The purpose of reporting these two cases is to emphasize the importance of using eculizumab as a prophylactic therapy to prevent aHUS recurrence post-transplant in high-risk patients. We will also review the current understanding of the genetics of aHUS, the pathogenesis of its recurrence after kidney transplantation, and strategies for prevention and treatment of post-transplant aHUS recurrence.
 
I was greatly impressed by an article recently published in Nature Methods (1), in which intracellular autofluorescence was characterized as a biomarker for epithelial cancer stem cells (CSCs). Interestingly, this epithelial CSC-specific autofluorescence was also associated with a highly invasive and chemoresistant phenotype. Riboflavin (vitamin B2) – an ABCG2-selectively transported substrate – was identified, after autophagy had been ruled out, as the source of cell autofluorescence (1).
 
Schematic representation of current and suggested approach of chronic dizziness in older patients in general practice (D, diagnosis-oriented phase; P, prognosis-oriented phase).
Although the etiology of dizziness in older patients differs significantly from that of younger patients, most guidelines on dizziness advocate the same diagnosis-oriented approach for all patients regardless of their age. However, this diagnosis-oriented approach may be insufficient for older patients presenting with dizziness in general practice, because (1) general practitioners are often not able to identify an underlying cause of dizziness, (2) general practitioners regularly identify causes of dizziness that cannot be treated, and (3) general practitioners may identify causes of dizziness for which treatment is available but not desirable. In this article, the authors present a simultaneous diagnosis- and prognosis-oriented approach for older dizzy patients. This approach may enable general practitioners to improve their care for a voluminous group of impaired older patients, even if a diagnosis is not available (yet).
 
Flipchart summarizing the results of both culture and specific – 16S rDNA for 44 total hip and total knee samples.
Intraoperative conventional bacteriological cultures were compared with different polymerase chain reaction (PCR) methods in patients with total joint arthroplasties. The isolated bacteria were investigated for biofilm formation, and the biofilm forming strains, in their planktonic and biofilm forms, were further tested for their antimicrobial resistance against several clinically important antimicrobials. Forty four bone and joint samples were included and classified as infected or non-infected according to standard criteria for periprosthetic hip and knee infections. For the bacteriological diagnosis, conventional culture, two types of universal PCR and species specific PCR for three selected pathogens (Staphylococcus aureus, Staphylococcus epidermidis, and Pseudomonas aeruginosa) were applied. Biofilm formation determination was performed by the tissue culture plate method. Antimicrobial susceptibility of the planktonic bacteria was performed by the minimal inhibitory concentration determination and, of the biofilm forms, by the minimal inhibitory concentration for bacterial regrowth from the biofilm. Twenty samples were culture positive, with S. epidermidis, S. aureus, or P. aeruginosa. All PCR methods were very ineffective in detecting only one pathogen. All isolates were biofilm positive and their biofilm forms, were highly resistant. In this study, compared to PCR, culture remains the "gold standard." The biofilm formation by the causative bacteria and the concomitant manifold increased antimicrobial resistance may explain the clinical failure of treatment in some cases and should be considered in the future for therapeutic planning.
 
The author describes how he became a physician-scientist: difficulties he had to overcome coming from outside of the US (visa, funding, resident training), and his way back to Germany, while experiencing the thrill of actively participating in moving science. Setbacks, scientific success, adaptation to new developments, and the encounter of kindred spirits characterize this lifelong effort.
 
The self-standing turning transfer device. The frame is made of mild steel. The base is stabilized by the weight of the device and its two small feet. The rotating disk turns easily on the base. The handle is height adjustable.
| Demographic data and elderly mobility scores.
| Mean transfer-time for manual transfers and STurDi-assisted transfers.
| USE questionnaire scores for caregivers and patients.
Manual transfer of elderly patients remains commonplace in many developing countries because the use of lifting equipment, such as hoists, is often considered unaffordable luxuries. The aim of this study was, therefore, to evaluate the usage and potential benefits of a low-cost, mechanical turning transfer device among elderly patients and their caregivers on a geriatric ward in a developing country in South East Asia. Fifty-six inpatients, aged 66-92 years, on a geriatric ward, and their caregivers were recruited. Participants were asked to transfer from bed-to-chair transfer with manual assistance, and the task was repeated using the Self-standing Turning Transfer Device (STurDi). The time taken to perform manual transfers and STurDi-assisted transfers was recorded. Physical strain was assessed using the perceived physical stress-rating tool for caregivers with and without the use of the device. User satisfaction was evaluated using the usefulness, satisfaction, and ease of use questionnaire. There was a significant reduction in transfer-time with manual transfers compared to STurDi-assisted transfers [mean (SD) = 48.39 (13.98) vs. 36.23 (10.96); p ≤ 0.001]. The physical stress rating was significantly lower in STurDi-aided transfers compared to manual transfers, shoulder [median (interquartile range) = 0 (1) vs. 4 (3); p = 0.001], upper back [0 (0) vs. 5 (4); p = 0.001], lower back [0 (1) vs. 5 (3), p = 0.001], whole body [1 (2) vs. 4 (3), p = 0.001], and knee [0 (1) vs. 1 (4), p = 0.001]. In addition, majority of patients and caregivers definitely or strongly agreed that the device was useful, saved time, and was easy to use. We have therefore demonstrated in a setting where manual handling was commonly performed that a low-cost mechanical transfer device reduced caregiver strain and was well received by older patients and caregivers.
 
Schematic diagram of retinoids in podocyte injury. Retinoic acid (RA) has been demonstrated to play a critical role in attenuation of podocyte injury. The mechanism by which RA abrogates podocyte injury is dependent on the type of inciting injury. Podocyte apoptosis is improved with RA treatment in a murine model of adriamycin-induced nephropathy, focal segmental glomerulosclerosis (FSGS) model (green). Podocyte dedifferentiation is attenuated with RA treatment in models of HIV-associated nephropathy (HIVAN) (purple). In a murine model of crescentic glomerulonephritis, using nephrotoxic serum (NTS), RA treatment minimized parietal epithelial cell (PEC) proliferation (black) and restored podocytes by PEC trans differentiation (blue).
The primary etiology of CKD is a direct consequence of initial dysfunction and injury of the glomerulus, the main filtration system. Podocytes are terminally differentiated epithelial cells in the glomerulus, whose major function is the maintenance of this renal filtration barrier. Podocyte injury is implicated in many glomerular diseases including focal segmental glomerular sclerosis and HIV-associated nephropathy. In many of these diseased conditions, the podocyte can either undergo dedifferentiation and proliferation, apoptosis, or cell detachment. Regardless of the initial type of injury, the podocyte ultimately loses its functional capacity to maintain the glomerular filtration barrier. Significant injury resulting in a loss of the podocytes and failure to maintain the renal filtration barrier contributes to progressive kidney disease. Consequently, therapies that prevent podocyte injury and promote their regeneration will have a major clinical impact on glomerular disease. Retinoic acid (RA), which is a derivative of vitamin A, has many cellular functions including induction of cell differentiation, regulation of apoptosis, and inhibition of inflammation and proliferation. RA is required for kidney development and is essential for cellular differentiation in the setting of podocyte injury. The mechanism by which RA directs its beneficial effects is multifactorial, ranging from its anti-inflammatory and anti-fibrotic effects to a direct effect of upregulating podocyte differentiation markers in the podocyte. The focus of this review is to provide an overview of RA in kidney development and glomerular disease. We also highlight the key mechanism(s) by which RA restores podocyte differentiation markers and ameliorates glomerular disease.
 
| AGE expression. Immunofluorescence staining of podocytes to investigate the effect of ±benfotiamine after 48 h of incubation on the expression of AGE in the control, glucose, and PDF group. Highest AGE expression was found in the glucose and PDF group without benfotiamine; scale bar represents 50 µm (A). Quantitation of the AGE expression, highest AGE expression was present in the glucose and PDF group without benfotiamine (B). # P < 0.05 versus −benfotiamine. AGE, advanced glycation end-products; PDF, peritoneal dialysis fluid. 
| Actin cytoskeleton. Immunofluorescence staining of podocytes to investigate the effect of ±benfotiamine after 48 h of incubation on phalloidin in the control, glucose, and PDF group, magnification 400 x (A). Quantitation of the organization of the actin 
| Migration. Migration assay to investigate the effect of ±benfotiamine after 48 h of incubation on podocyte motility in the control, glucose, and PDF group, phase contrast microscopy, scale bar represents 
| Inflammation-NFκB activation. Immunofluorescence staining of podocytes to investigate the effect of ±benfotiamine after 48 h of incubation on inflammation in the control, glucose, and PDF group, representative images of NFκB-P65 staining, (Cy3) upper panel, and a merge of NFκB and nuclei (Hoechst), lower panel, scale bar represents 50 µm (A). Quantitation of NFκB activated cells, highest percentage of NFκB activation was present in the glucose and PDF group without benfotiamine (B). # P < 0.05 versus −benfotiamine. NFκB, nuclear factor kappa B; PDF, peritoneal dialysis fluid. 
| Apoptosis. Analysis of apoptosis in podocytes to investigate the effect of ±benfotiamine after 48 h of incubation in the control, glucose, and PDF group. Apoptosis was detected by fragmented nuclei and was highest in the glucose and PDF group. # P < 0.05 versus −benfotiamine, § P < 0.05 versus −benfotiamine. 
In peritoneal dialysis (PD), residual renal function (RRF) fundamentally contributes to improved quality of life and patient survival. High glucose and advanced glycation end-products (AGE) contribute locally to peritoneal and systemically to renal damage. Integrity of podocyte structure and function is of special importance to preserve RRF. Benfotiamine could counteract the glucose and AGE-mediated toxicity by blocking hyperglycemia-associated podocyte damage via the pentose-phosphate pathway. A human differentiated podocyte cell line was incubated with control solution (control), 2.5% glucose solution (glucose), and 2.5% peritoneal dialysis fluid (PDF) for 48 h either ±50 μM benfotiamine. Podocyte damage and potential benefit of benfotiamine were analyzed using immunofluorescence, western blot analysis, and a functional migration assay. For quantitation, a semiquantitative score was used. When incubating podocytes with benfotiamine, glucose, and PDF-mediated damage was reduced, resulting in lower expression of AGE and intact podocin and ZO-1 localization. The reorganization of the actin cytoskeleton was restored in the presence of benfotiamine as functional podocyte motility reached control level. Decreased level of inflammation could be shown as well as reduced podocyte apoptosis. These data suggest that benfotiamine protects podocytes from glucose and PDF-mediated dysfunction and damage, in particular, with regard to cytoskeletal reorganization, motility, inflammation, and podocyte survival.
 
The use of orthopedic implants in joints has revolutionized the treatment of patients with many debilitating chronic musculoskeletal diseases such as osteoarthritis. However, the introduction of foreign material into the human body predisposes the body to infection. The treatment of these infections has become very complicated since the orthopedic implants serve as a surface for multiple species of bacteria to grow at a time into a resistant biofilm layer. This biofilm layer serves as a protectant for the bacterial colonies on the implant making them more resistant and difficult to eradicate when using standard antibiotic treatment. In some cases, the use of antibiotics alone has even made the bacteria more resistant to treatment. Thus, there has been surge in the creation of non-antibiotic anti-biofilm agents to help disrupt the biofilms on the orthopedic implants to help eliminate the infections. In this study, we discuss infections of orthopedic implants in the shoulder then we review the main categories of anti-biofilm agents that have been used for the treatment of infections on orthopedic implants. Then, we introduce some of the newer biofilm disrupting technology that has been studied in the past few years that may advance the treatment options for orthopedic implants in the future.
 
Neonatal hyperoxia disrupts postnatal alveolar development in the lung. Representative tissue slides (H&E stains) of newborn mouse lung exposed to room air or 100% oxygen from birth to PN10. Thickened alveolar septae (thick arrow), inflammatory cells (thin arrow), and simplified alveoli (asterisks).
Summary of important pathophysiologic processes and long-term consequences following early pulmonary injury.
Neonatal chronic lung disease, i.e., bronchopulmonary dysplasia, is characterized by impaired pulmonary development resulting from the impact of different risk factors including infections, hyperoxia, and mechanical ventilation on the immature lung. Remodeling of the extracellular matrix, apoptosis as well as altered growth factor signaling characterize the disease. The immediate consequences of these early insults have been studied in different animal models supported by results from in vitro approaches leading to the successful application of some findings to the clinical setting in the past. Nonetheless, existing information about long-term consequences of the identified early and most likely sustained changes to the developing lung is limited. Interesting results point towards a tremendous impact of these early injuries on the pulmonary repair capacity as well as aging related processes in the adult lung.
 
Thirteen-year-old boy with stage III Burkitt’s lymphoma. (A,B)18FDG-PET and MRI at diagnosis showing oropharynx tumor. (C,D) Negative 18FDG-PET but residual disease on MRI after chemotherapy. Biopsy of the residual mass was negative.
Five-year-old boy with stage IV Burkitt’s lymphoma at relapse. (A)18FDG-PET after induction chemotherapy showing a nodular uptake on spleen whereas CI was negative. (B)18FDG-PET 12 weeks later, showing disease progression.
Kaplan–Meier survival graphs show 5-year PFS according to negative and positive post-induction chemotherapy 18FDG-PET using the Deauville criteria.
Kaplan–Meier survival graphs show 5-year PFS according to negative and positive post-induction chemotherapy CI results.
Burkitt lymphoma (BL) is a rare and aggressive form of B-cell lymphoma that is curable using intensive chemotherapy. Obtaining a complete response (CR) at the end of induction chemotherapy is a major prognostic factor. This study retrospectively evaluates the potential impact of (18)FDG-PET in the management of children with BL after induction chemotherapy, and the prognostic performance of the Deauville criteria. Nineteen children with BL treated according to the French LMB2001 protocol between 2005 and 2012 were included. (18)FDG-PET and conventional imaging (CI) were performed after induction chemotherapy to confirm CR. (18)FDG-PET was interpreted according to Deauville criteria with follow-up and/or histology as the gold standard. (18)FDG-PET was negative in 15 cases, in agreement with CI in 9/15 cases. The six discordant cases confirmed to be negative by histology, were considered as true negative for (18)FDG-PET. Negative predictive value (NPV) of CI and (18)FDG-PET were 73 and 93%, respectively. The 5-year progression-free survival (PFS) was significantly higher in patients with negative (18)FDG-PET than those with positive (18)FDG-PET (p = 0.011). (18)FDG-PET interpreted using Deauville criteria can help confirm CR at the end of induction chemotherapy, with a prognostic impact on 5-year PFS. Its high NPV could limit the use of residual mass biopsy. Given the small size of our population, these results need to be confirmed by future prospective studies on a larger population.
 
Microenvironmental stress causes ER stress and UPR activation in cancer cells. As a result, GRP78 is upregulated to enhance the folding capacity of the ER. A quote of the protein is transported to the cell membrane where it can bind different molecular partners and transduce either pro-survival or apoptotic signals.
| Different cancer types where GRP78 has been reported to play a role in proliferation, invasiveness, and/or chemoresistance along with representative references are listed.
Endometrial cancer (EC) is a common gynecologic malignancy often diagnosed at early stage. In spite of a huge advance in our understanding of EC biology, therapeutic modalities do not have significantly changed over the past 40 years. A restricted number of genes have been reported to be mutated in EC, mediating cell proliferation and invasiveness. However, besides these alterations, few other groups and ourselves recently identified the activation of the unfolded protein response (UPR) and GRP78 increase following endoplasmic reticulum (ER) stress as mechanisms favoring growth and invasion of EC cells. Here, a concise update on currently available data in the field is presented, analyzing the crosstalk between the UPR and the main signaling pathways regulating EC cell proliferation and survival. It is evident that this is a rapidly expanding and promising issue. However, more data are very likely to yield a better understanding on the mechanisms through which EC cells can survive the low oxygen and glucose tumor microenvironment. In this perspective, the UPR and, particularly, GRP78 might constitute a novel target for the treatment of EC in combination with traditional adjuvant therapy.
 
| Patient-reported process and outcomes of consultation by primary care doctor choice groups. 
| Relationships between patient-centered process of care and PRO of consultation. 
Hong Kong (HK) has pluralistic primary care that is provided by a variety of doctors. The aim of our study was to assess patient-reported outcomes of primary care consultations in HK and whether having a family doctor (FD) made any difference. We interviewed by telephone 3148 subjects from 5174 contacted households (response rate 60.8%) randomly selected from the general population of HK about the experience of their last primary care consultations in September 2007 and April 2008. We compared the patient-reported outcomes (PRO) and patient-centered process of care in those with a FD, those with other types of regular primary care doctors (ORD) and those without any regular primary care doctor (NRD). PRO included patient enablement, global improvement in health, overall satisfaction, and likelihood of recommending their doctors to family and friends. Patient-centered process of care indicators was explanations about the illness, and address of patient's concerns. One thousand one hundred fifty, 746, and 1157 reported to have FD, ORD, and NRD, respectively. Over 80% of those with FD consulted their usual primary care doctors in the last consultation compared with 27% of those with NRD. Compared with subjects having ORD or NRD, subjects with FD reported being more enabled after the consultation and were more likely to recommend their doctors to family and friends. Subjects with FD and ORD were more likely than those having NRD to report a global improvement in health and satisfaction. FD group was more likely than the other two groups to report receiving an explanation on the diagnosis, nature, and expected course of the illness, and having their concerns addressed. Patient enablement was associated with explanation of diagnosis, nature, and expected course of illness, and address of patient's concerns. People with a regular FD were more likely to feel being enabled and to experience patient-centered care in consultations.
 
The sick child of Gabriël Metsu.
Primary health care and family medicine at the core of health care: challenges and priorities in how to further strengthen their potential Chris van Weel 1,2* • ¹Radboud University Nijmegen, Nijmegen, Netherlands • ²Australian National University, Canberra, ACT, Australia Prognostication and risk assessment are a great good for health care, but at the same time there is a big problem. To a large extent, the generation of diagnostic cues is a subconscious process, which has hardly been formally researched. It is often linked to “intuition,” or “experience” and in Dutch family medicine jargon this has been coined as what can be best translated in English “a premonition of something being wrong” (pluis/niet-pluis gevoel). This may aptly summarize the inner-mind process but lends mythical dimensions to it that do little to come to an understanding of the process behind it. Therefore, the “premonition of something being wrong” presents itself as a high priority domain to gain a better understanding of professional performance in the complexity of primary health care. While its appropriate application may lead to substantial gains in health, unsuitable practice may lead to missed opportunities of prevention or diagnosis, delays in treatment, and medicalization. A major challenge of primary health care research is to get into the mechanisms of how the premonition of something being wrong is coming about and to develop methods to train professionals to apply this in an appropriate way.
 
Program of work and underpinning theory.
Background Clinical inertia, failure to intensify treatment according to evidence-based guidelines, leads to prolonged, avoidable hyperglycaemia in people with type 2 diabetes (T2D). This is a challenge for General Practice (GP) and Primary Care, where most people with T2D receive most of their care. Sustained, integrated translational research programs are needed to embed effective treatments in routine practice, yet many challenges exist to developing such programs. Objectives To explore challenges and facilitators to implementing a translational research program focused on insulin initiation and titration among people with T2D in GP and to identify key factors important to support and sustain such translation research in primary care.Operationalising a program of translational work in primary careWe describe a series of studies on insulin initiation and titration in GP including theory and qualitative work (Phase 1), a small feasibility and acceptability pilot (Phase 2), a large scale pilot (Phase 3), and a pragmatic cluster randomised trial currently under way (Phase 4). We used mixed methods to explore practice level implementation issues, and reflective investigator discussions to explore broader research program sustai
 
Cesarean section rates in some selected countries (10–14).
The framework for quality maternal and newborn care (QMNC): maternal and newborn health components of a health system needed by childbearing women and their infants. Reprinted from The Lancet, Vol. 384, Renfrew et al., Midwifery and quality care: findings from a new evidence-informed framework for maternal and newborn care, 129–45, Copyright 2014, with permission from Elsevier (6).
In most countries, maternal and newborn care is fragmented and focused on identification and treatment of pathology that affects only the minority of women and babies. Recently, a framework for quality maternal and newborn care was developed, which encourages a system-level shift to provide skilled care for all. This care includes preventive and supportive care that works to strengthen women's capabilities and focuses on promotion of normal reproductive processes while ensuring access to emergency treatment when needed. Midwifery care is pivotal in this framework, which contains several elements that resonate with the main dimensions of primary care. Primary health care is the first level of contact with the health system where most of the population's curative and preventive health needs can be fulfilled as close as possible to where people live and work. In this paper, we argue that midwifery as described in the framework requires the application of a primary care philosophy for all childbearing women and infants. Evaluation of the implementation of the framework should therefore include tools to monitor the performance of primary midwifery care.
 
Over the past few years, nuclear medicine has undergone impressive growth with the development of positron emission tomography (PET), especially using 18F-fluoro-deoxy-glucose (18FDG), and new approaches in targeted radionuclide therapy. These developments pave the way for personalized medicine by offering practical solutions, especially in oncology, neurology, and cardiology. Novel radiopharmaceuticals targeting relevant biomarkers are powerful patient selection tools for patients who may benefit from targeted therapies, and for early therapeutic response assessment. Moreover, once labeled with beta- or alpha-emitters, radiopharmaceuticals targeting relevant molecular markers expressed by different solid tumors, and hemopathies can be used for radionuclide therapy. The final objective here is to eradicate residual cancer disease by using cytotoxic mechanisms complementary to those of “non-radioactive” therapies. PET imaging and targeted radionuclide therapy then come together in the context of the theranostic approach to adapt injected activity for personalized therapy.
 
Eligible patients undergoing propensity-score matching. DIC, disseminated intravascular coagulation; rhTM, recombinant human soluble thrombomodulin.
Background: Anticoagulant therapy has been evaluated with respect to its potential usefulness in reducing the high mortality rates associated with severe sepsis, including sepsis-induced disseminated intravascular coagulation (DIC) after intestinal perforation. We examined the hypothesis that recombinant human soluble thrombomodulin (rhTM) is effective in the treatment of patients with septic shock with sepsis-induced DIC after laparotomy for intestinal perforation. Methods: We performed propensity-score and instrumental variable analyses of the Japanese Diagnosis Procedure Combination in-patient database, a nationwide administrative database. The main outcome was 28-day in-hospital all-cause mortality. Results: We categorized eligible patients (n = 2202) from 622 hospitals into the rhTM group (n = 726) and control group (n = 1476). Propensity-score matching created 621 matched pairs of patients with and without rhTM. There was neither significant difference in 28-day mortality between the two groups in the unmatched analysis (rhTM vs. control, 25.3 vs. 23.4%, respectively; difference, 1.9%; 95% CI, −1.9 to 5.7) nor in the propensity-score-matched analysis (rhTM vs. control, 26.1 vs. 24.8%, respectively; difference, 1.3%; 95% CI, −3.6 to 6.1). The logistic analysis showed no significant association between the use of rhTM and the mortality in propensity-score-matched patients (OR, 1.1; 95% CI, 0.82–1.4). The instrumental variable analyses, using the hospital rhTM-prescribing proportion as the variable, found that receipt of rhTM was not associated with the reduction in the mortality (risk difference, −6.7%; 95% CI, −16.4 to 3.0). Conclusion: We found no association between administration of rhTM and 28-day mortality in mechanically ventilated patients with septic shock and concurrent DIC after intestinal perforation.
 
| Examples of IncRNAs associated with liver diseases. 
The new landscape of human transcriptome along with the identification of numerous long non-coding RNAs (lncRNAs) has dramatically altered our approach to study diseases. It is now imperative to decipher the biological functions of these transcripts and how they impact on human cell and pathophysiology. Nonetheless, already at this very early stage of their study, the involvement of lncRNAs in cell transformation is emerging as a key aspect. Recently, researchers have started to explore the implications of lncRNAs alteration in hepatic pathophysiology. In this review, we will discuss in detail several examples of liver disease-relevant lncRNAs. Many lncRNAs have been shown to play a major role in hepatocellular carcinoma (HCC). For such type of tumor with an increasing incidence and a high mortality rate, it is crucial to identify new therapeutic targets and biomarkers to predict response to therapy. LncRNAs present as a promising new resource. One major challenge for the future would be to systematically address the lncRNAs expression among the different cellular components of the liver. To achieve this goal, a combination of clinically driven, genetically defined, morphologically classified, and molecular-based studies will have to be performed. In conclusion, lncRNAs will undoubtedly provide a rewarding field of study and most importantly a new resource to identify new disease associated biomarkers and molecular targets for therapy for liver diseases.
 
Models of lncRNA functions. Nuclear lncRNAs can regulate transcription by acting as enhancer RNA (eRNA) (A), by recruiting chromatin modifying complexes (B), or by regulating transcription factors activity (C). Moreover, they can regulate gene expression by acting on the spatial conformation of chromosomes (D) or by influencing pre-mRNA splicing (E). Cytoplasmic lncRNAs can regulate mRNA expression by regulating mRNA stability (F), mRNA translation (G), or by competing for microRNA binding (H). In addition, few lncRNAs contain small open reading frames (ORFs) that can be translated in biological active small peptides (I).
Long non-coding RNAs (lncRNAs) are important regulators of gene expression that influence almost every step in the life cycle of genes, from transcription to mRNA splicing, RNA decay, and translation. Besides their participation to normal physiology, lncRNA expression and function have been already associated to cancer development and progression. Here, we review the functional role and mechanisms of action of lncRNAs in normal hematopoiesis and how their misregulation may be implicated in the development of blood cell cancer, such as leukemia.
 
For centuries, skin diseases have been described according to their macromorphological appearance and classified according the morphological description. The system of grouping morphological features in skin diseases followed the same principles as defined by Carolus Linnaeus (1707–1778) in the taxonomy of plants and animals. The major development of the morphological description of skin diseases was following extensive application of dermatopathology on skin biopsies. By integrating macro- and micromorphology, a new system for description of skin diseases had been created the primary efflorescences. The primary efflorescences constitute a set of macromorphological characteristics, which are indicative for the most important general pathological features (1). This system has served and still serves the classification of skin diseases. The primary efflorescences are the essentials in descriptions, diagnosis, and treatment of dermatoses. Dermatoses are classified from the point of view of the fundamental pathologic process involved. In other words, the classification is made according to the essential lesions. During the last four decades important new insights in the genetics, pathophysiology, and cell biology have provided crucial information about the etiology and pathogenesis of skin diseases and have developed dermatology from a morphology driven discipline into an etiology based discipline. These observations have impacted the system of classification of skin diseases and the possibility for targeted treatments. The development of etiology based disease classification and targeted treatments have brought dermatology in better alignment with other medical disciplines such as internal medicine, rheumatology, and gastroenterology. In particular, the multidisciplinary approach in systemic diseases provides etiological concepts beyond the boundaries of the individual disciplines. Skin diseases are easily accessible for inspection and investigation. That is why skin diseases are at the frontiers for advancement of insights in the etiology and pathogenesis of diseases and for understanding the mode of action of treatments. A major question is whether classical dermatology in general practice can serve to the patients in the light of new developments? On one hand, there is a major challenge for teaching and continuing education. On the other hand, dermatology networks around centers of excellence are and will be of major importance in the future.
 
A schematic figure of the complement system. The figure shows the three complement activation pathways (yellow boxes), the components needed for activation (in black, like C3), the targets that activate complement (green), the different complement regulators (blue), and consequences of deficiencies of individual complement components leading either to infections (lilac boxes) or to complement deficiency syndromes (in red boxes). Explanations of the different arrow types are shown in the key box (bottom right). The classical pathway (top left) can be activated by C1q that binds to immune complexes or C-reactive protein. The lectin pathway (bottom left) becomes activated by mannan-binding lectin (MBL) or ficolins that bind to carbohydrates or acetylated moieties. The alternative pathway (top right) becomes activated spontaneously upon interaction with a foreign surface (e.g., microbes) that lacks complement inhibitors. After binding of C1q, MBL, or ficolins to their targets, the serine esterases attached to them (C1r, C1s, MASPs) become activated and cleave the subsequent components C4 and C2. C4b and C2a together generate the classical pathway C3/C5 convertase. Activation of C3 is central to complement activation. It can become activated by the alternative pathway C3/C5 convertase C3bBb composed of C3b and the activated factor B. Factor D activates factor B and properdin (P) stabilizes the C3bBb enzyme. Because of involvement of C3b in C3 cleavage, a positive feedback is created and the alternative pathway can amplify complement activation regardless of the initial activation route. C3 activation products, C3b and iC3b are important opsonins recognized by the phagocyte C3b (CR1) and iC3b (CR3) receptors. After activation of C5, the five terminal plasma glycoproteins (C5b, C6, C7, C8, and C9) bind sequentially to each other to generate the cytolytic membrane attack complex (MAC). Regulation of complement activation occurs at all key steps of the cascade. C1r and C1s are inhibited by the plasma protein C1-inhibitor (C1-INH). C1-INH also inhibits analogous MBL-associated serine protease, MASP-2. Activity of the classical pathway C3/C5 convertase, C4b2a, is inhibited by the plasma factor C4b-binding protein (C4bp). The activity of the alternative pathway C3/C5 convertase, C3bBb, is inhibited by the regulators factor H, DAF, and MCP. On human cell membranes, the main inhibitor of MAC is CD59. Because of the importance of complement as defense and inflammatory mediator system, its deficiencies can predispose to serious diseases. The deficiency in the clearance part (classical pathway) can predispose to SLE, whereas the alternative and terminal pathway deficiencies predispose to microbial infections. Deficiencies of complement regulators predispose to autoreactive disorders, where complement is either excessively activated (HAE, DDD) or misdirected against self cell surfaces (C3GN, aHUS, PNH). Leukocyte adhesion deficiency is a rare consequence of CR3 defect. Abbreviations: SLE, systemic lupus erythematosus; HAE, hereditary angioedema; C1-INH, C1-inhibitor; PNH, paroxysmal nocturnal hemoglobinuria; DDD, dense deposit disease; C3GN, C3 glomerulopathy; aHUS, hemolytic uremic syndrome; LAD, leukocyte adhesion deficiency; DAF, decay-accelerating factor; MASP, mannose-binding lectin-associated serine protease; CR, complement receptor; H, factor H; D, factor D; P, properdin; I, factor I; B, factor B; CD59, protectin; MCP, membrane cofactor protein.
Typical features of four distinct complement-related diseases with dermatological symptoms. (A) Hereditary angioedema, (B) SLE, (C) urticarial vasculitis, and (D) bullous pemphigoid. (A,C,D) are from the photogallery of the Clinic of Dermatology and Allergology, Helsinki University Central Hospital and (B) is from http://www.fightinglupus.org/sle-lupus.html
Activation and inhibition of the complement system on complement sensitive and resistant bacteria. The upper part shows the normal situation in complement activation, where a microbe becomes a target for complement attack. The lower part shows how borrelial OspE/CspA (or any other similar microbial protein) binds factor H to block complement activation on the bacterial surface. FH, factor H; B, factor B.
The complement system plays a key role in several dermatological diseases. Overactivation, deficiency, or abnormality of the control proteins are often related to a skin disease. Autoimmune mechanisms with autoantibodies and a cytotoxic effect of the complement membrane attack complex on epidermal or vascular cells can cause direct tissue damage and inflammation, e.g., in systemic lupus erythematosus (SLE), phospholipid antibody syndrome, and bullous skin diseases like pemphigoid. By evading complement attack, some microbes like Borrelia spirochetes and staphylococci can persist in the skin and cause prolonged symptoms. In this review, we present the most important skin diseases connected to abnormalities in the function of the complement system. Drugs having an effect on the complement system are also briefly described. On one hand, drugs with free hydroxyl on amino groups (e.g., hydralazine, procainamide) could interact with C4A, C4B, or C3 and cause an SLE-like disease. On the other hand, progress in studies on complement has led to novel anti-complement drugs (recombinant C1-inhibitor and anti-C5 antibody, eculizumab) that could alleviate symptoms in diseases associated with excessive complement activation. The main theme of the manuscript is to show how relevant the complement system is as an immune effector system in contributing to tissue injury and inflammation in a broad range of skin disorders.
 
Histology, immunohistochemistry, and molecular genetics of GISTs. (A,B) Histology. (A) Spindle cell tumor, with paranuclear vacuoles (so-called “leiomyoblastoma”). HE 40×. (B) Epitheloid tumor. Large, clear cytoplasm with central nucleus. HE 40×. (C) Spindle cells diffusely positive for CKIT (CD117). IHC 10×. (D) Epitheloid cells strongly and diffusely positive for DOG1, with evident membrane enhancement. IHC 40×. (E) Sanger sequencing with a duplication of GCC TAT in positions 502–503 (p.A502-Y503 dup). Mutation associated with sensitivity to imatinib. (F). Sanger sequencing with a substitution (A–C) in position 842, (p.D842V), imatinib resistant.
Structure of RTK III, with localization of the activating mutations in KIT and PDGFRA. EC, extracellular; JM, juxtamembrane; TK, tyrosine kinase.
Possible therapeutic targets (red) and targeted drugs in GISTs.
Evolution of the concept of GISTs since 70 years. EM, electron microscopy; IHC, immunohistochemistry; ICC, interstitial cells of Cajal; MB, molecular biology; SDH, succinil dehydrogenase; IGFR, insuline growth factor receptor; NGS, next generation sequencing.
Gastrointestinal stromal tumors (GISTs) are the most frequent mesenchymal tumors of the gastrointestinal tract. The discovery that these tumors, formerly thought of smooth muscle origin, are indeed better characterized by specific activating mutation in genes coding for the receptor tyrosine kinases (RTKs) CKIT and PDGFRA and that these mutations are strongly predictive for the response to targeted therapy with RTK inhibitors has made GISTs the typical example of the integration of basic molecular knowledge in the daily clinical activity. The information on the mutational status of these tumors is essential to predict (and subsequently to plan) the therapy. As resistant cases are frequently wild type, other possible oncogenic events, defining other "entities," have been discovered (e.g., succinil dehydrogenase mutation/dysregulation, insuline growth factor expression, and mutations in the RAS-RAF-MAPK pathway). The classification of disease must nowadays rely on the integration of the clinico-morphological characteristics with the molecular data.
 
Algorithm for rapid diagnosis and management of post-surgical spine infections.
| Rate of SSI following spine surgery by type of surgery.
| Surgical site infection pre-operative risk factors (28, 34-38).
Surgical site infection (SSI) following spine surgery is a dreaded complication with significant morbidity and economic burden. SSIs following spine surgery can be superficial, characterized by obvious wound drainage or deep-seated with a healed wound. Staphylococcus aureus remains the principal causal agent. There are certain pre-operative risk factors that increase the risk of SSI, mainly diabetes, smoking, steroids, and peri-operative transfusions. Additionally, intra-operative risk factors include surgical invasiveness, type of fusion, implant use, and traditional instead of minimally invasive approach. A high level of suspicion is crucial to attaining an early definitive diagnosis and initiating appropriate management. The most common presenting symptom is back pain, usually manifesting 2-4 weeks and up to 3 months after a spinal procedure. Scheduling a follow-up visit between weeks 2 and 4 after surgery is therefore necessary for early detection. Inflammatory markers are important diagnostic tools, and comparing pre-operative with post-operative levels should be done when suspecting SSIs following spine surgery. Particularly, serum amyloid A is a novel inflammatory marker that can expedite the diagnosis of SSIs. Magnetic resonance imaging remains the diagnostic modality of choice when suspecting a SSI following spine surgery. While 18F-fluorodeoxyglucose-positron emission tomography is not widely used, it may be useful in challenging cases. Despite their low yield, blood cultures should be collected before initiating antibiotic therapy. Samples from wound drainage should be sent for Gram stain and cultures. When there is a high clinical suspicion of SSI and in the absence of superficial wound drainage, computed tomography-guided aspiration of paraspinal collections is warranted. Unless the patient is hemodynamically compromised, antibiotics should be deferred until proper specimens for culture are secured.
 
Idiopathic pulmonary fibrosis (IPF) is characterized by progressive deposition of extracellular matrix, worsening dyspnea, and eventual mortality. Pathogenesis of IPF is poorly understood and the role inflammation and activated leukocytes play in the disease process is controversial. Previous studies demonstrated that activated leukocyte subsets characterize IPF patients. We sought to validate this observation in a well-defined cohort of 35 IPF patients and to correlate the observed leukocyte phenotypes with robust parameters of disease progression. We demonstrate that in univariate and multivariate analyses, increases in the CD14hi, CD16hi subset of monocytes measured at baseline correlated with disease progression, with a threshold value >0.5% of the total peripheral blood mononuclear cells being a significant predictor for worse outcome. In addition, several T cell subsets, including CD25 expressing CD4 cells, and CXCR3 expressing CD4 and CD8 subsets correlated with disease progression when found in increased percentages in the peripheral blood of IPF patients when sampled at baseline. Somewhat surprising in comparison to previous literature, the CD4 T cells did not appear to have lost expression of the co-stimulatory molecule, CD28, but the CD8 T cells did. Taken together, these results are consistent with the presence of an inflammatory process in IPF patients who eventually progress. However, when longitudinal measurements of these same markers were examined, there was significant heterogeneity of expression and these biomarkers did not necessarily remain elevated in IPF patients with progressive disease. We interpret this heterogeneity to suggest that IPF patients experience episodic inflammatory events that once triggered, may lead to disease progression. This longitudinal heterogeneity in biomarker analyses may explain why such markers are not consistently measured in all IPF cohorts.
 
Different clinical appearances such as Yellow nail syndrome and Lichen planus or lichenoid reactions can originate from close or identical etiologies. They may result from dental restorative materials or metal allergy. Interestingly, the nail sometimes returns to its normal condition, months after the withdrawal of the offending agents.
 
In this article, we give an update on recent findings regarding molecular pathology in cutaneous melanocytic tumors. The focus lies on use of genetics in the diagnosis of distinct subtypes of spitzoid tumors that are often characterized by specific phenotypic-genotypic alterations that can frequently be recognized by adequate histological examination. Typical illustrating cases are given in order to increase recognition of these lesions in daily dermatopathology practice. New molecular findings in the pathogenesis of congenital melanocytic tumors and neurocutaneous melanosis are reviewed. In addition, use of mutation analysis in the differential diagnosis of melanoma metastasis is discussed. Finally, application of mutation analysis in targeted therapy in advanced melanoma with advantages of new techniques such as next generation sequencing is described.
 
Histo)-pathological findings of cases tested positive for HEV RNA. (A) Case 1: macroscopy of liver explant (left picture, bar represents 1 cm), subtotal necrosis (low magnification, middle micrograph, scale bar: 2 mm), and lobular inflammation with confluent necrosis (high magnification, right micrograph, scale bar: 50 μm). (B) Case 2: pronounced necro-inflammatory activity (H&E and silver reticulin stain, left and middle micrograph, respectively, scale bar: 100 μm). Moderate portal and lobular inflammation with spotty necrosis (arrow; right micrograph, scale bar 50 μm). (C) Case 3: mild inflammation (H&E, silver reticulin stain and sirius red, from left to right, scale bar: 50 μm).
| Characteristics of study patients with suspected drug-induced liver injury. N (%)
| Characteristics of HEV RNA positive cases.
Hepatitis E virus (HEV) infection is increasingly recognized as a cause of acute hepatitis in the industrialized world. We aimed to determine the frequency of acute HEV infection in cases of suspected drug-induced liver injury (DILI), mainly a diagnosis of exclusion. To this aim, formalin-fixed paraffin-embedded (FFPE) liver tissues of all cases routinely processed in our institute during a 2 1/2 years period in which DILI was among the differential diagnoses (157 liver biopsies, 1 liver explant) were subjected to semi-nested RT-PCR for the detection of HEV RNA. Histopathology was re-evaluated on all cases tested positive. HEV RNA was detectable in 3 of 158 cases (2%) tested, comprising autochthonic as well as travel-related infections with genotypes 1, 3, and 4 each found once, respectively. Histopathologic findings comprised one case with subtotal hepatic necrosis and two cases of acute (cholestatic) hepatitis not distinguishable from acute hepatitis of other etiology. Thus, the overall frequency of acute HEV infection as determined by detection of HEV RNA in liver tissue is substantially increased in patients with suspected DILI compared to the healthy population, emphasizing the need to actively look for HEV infection in cases of suspected DILI. Molecular testing for HEV RNA in routinely processed FFPE liver tissues can be applied to cases with undetermined HEV status.
 
The 2014 epidemic of Ebola virus disease (EVD) in several West African countries has mortality rates of up to 70%, as reported by WHO. The exponential increase in the number of infections and deaths, coupled with the absence of specific preventive and therapeutic strategies, represents one of the biggest global health challenges of this millenium. Insights in the pathophysiology and treatment of EVD are thus urgently needed. In this paper, we postulate that EVD has the characteristics of hemophagocytic lymphohistiocytosis (HLH) syndrome (syn., macrophage activation syndrome). The identification of HLH as part of severe EVD, however, brings the possibility for a pathophysiologically targeted approach of therapy; special promise is represented by cytokine-directed therapy in the form of recombinant interleukin-1 receptor antagonist (anakinra). Treatment with anakinra has the advantage to interrupt the deleterious IL-1-mediated hyperinflammatory loop in macrophage activation syndrome, and it has been shown to be associated with remarkable effectiveness and an excellent safety record.
 
Confirmation of isolation of exosomal vesicles from human urine. (A) Western blot demonstrated significant enrichment of exosomal marker proteins in the retentate fraction. From the image analysis, there was more retention of intact protein in the urine with added protease inhibitors than without added protease inhibitors. (B) Electron micrograph (EM) of isolated exosomes in the exosome extract.
| AR exosomal proteins.
Relationship of total urine exosomal proteins (Ue), urine exosomal proteins specific to acute rejection (AR) when compared to soluble proteins in whole urine (Uw) and urine exosomal proteins previously published in literature (previously identified). We identified 59 novel urinary exosomal proteins that are exclusive to the exosomal fraction, including 3 (CLCA1, PROS1, and KIAA053) of which demonstrated an increase fold change in the AR samples only. Venn diagram created with VENNY (25).
Common proteins (e.g., albumin and tubulin) are not found in abundance in the exosomal fraction. Our findings show that the fold change of albumin and tubulin are much lower in the exosomal fraction than soluble fraction of urine.
A) Urine from patients in the acute rejection population enriched for eleven exosomal proteins with an increased fold change over the whole urine fraction. All, except CLCA1, have significantly (p-values <0.05) increased fold change in the Ue of AR when compared to Ue of nAR. (B) They are also enriched in Ue over Uw. CLCA1, PROS1, and KIAA0753 were detected in the exosomal fraction only, however, there is only significantly increased enrichment (*) was observed for ApoM (p = 0.02).
Urine exosomes are small vesicles exocytosed into the urine by all renal epithelial cell types under normal physiologic and disease states. Urine exosomal proteins may mirror disease specific proteome perturbations in kidney injury. Analysis methodologies for the exosomal fraction of the urinary proteome were developed for comparing the urinary exosomal fraction versus unfractionated proteome for biomarker discovery. Urine exosomes were isolated by centrifugal filtration of urine samples collected from kidney transplant patients with and without acute rejection (AR), which were biopsy matched. The proteomes of unfractionated whole urine (Uw) and urine exosomes (Ue) underwent mass spectroscopy-based quantitative proteomics analysis. The proteome data were analyzed for significant differential protein abundances in AR. A total of 1018 proteins were identified in Uw and 349 proteins in Ue. Two hundred seventy-nine overlapped between the two urinary compartments and 70 proteins were unique to the Ue compartment. Of 349 exosomal proteins identified from transplant patients, 220 had not been previously identified in the normal Ue fraction. Eleven Ue proteins, functionally involved in an inflammatory and stress response, were more abundant in urine samples from patients with AR, three of which are exclusive to the Ue fraction. Ue AR-specific biomarkers (1) were also detected in Uw, but since they were observed at significantly lower abundances in Uw, they were not significant for AR in Uw. A rapid urinary exosome isolation method and quantitative measurement of enriched Ue proteins was applied. Perturbed proteins in the exosomal compartment of urine collected from kidney transplant patients were specific to inflammatory responses, and were not observed in the Ue fraction from normal healthy subjects. Ue-specific protein alterations in renal disease provide potential mechanistic insights and offer a unique panel of sensitive biomarkers for monitoring AR.
 
Percent of normal weight (N = 182) and class II and III obese (N = 114) patients with occasional/frequent symptoms in each symptom group.
Several reports have shown an increased prevalence of gastrointestinal (GI) symptoms in obese subjects in community-based studies. To better understand the role of the GI tract in obesity, and because there are limited clinic-based studies, we documented the prevalence of upper and lower GI symptoms in morbidly obese individuals in a clinic setting. The aim of our study was to compare the prevalence of GI symptoms in morbidly obese individuals in a weight management clinic with non-obese individuals with similar comorbidities as morbidly obese individuals in an Internal Medicine clinic. Class II and III obese patients BMI >35 kg/m(2) (N = 114) and 182 non-obese patients (BMI <25 kg/m(2)) completed the GI symptoms survey between August 2011 and April 2012 were included in this study. The survey included 24 items pertaining to upper and lower GI symptoms. The participants rated the frequency of symptoms as absent (never, rarely) or present (occasionally, frequently). The symptoms were clustered into five categories: oral symptoms, dysphagia, gastroesophageal reflux, abdominal pain, and bowel habits. Responses to each symptom cluster were compared between obese group and normal weight groups using logistic regression. Of the 24 items, 18 had a higher frequency in the obese group (p < 0.005 for each). After adjusting for age and gender, the obese patients were more likely to have upper GI symptoms: any oral symptom (OR = 2.3, p = 0.0013), dysphagia (OR 2.9, p = 0.0006), and any gastroesophageal reflux (OR 3.8, p < 0.0001). Similarly, the obese patients were more likely to have lower GI symptoms: any abdominal pain (OR = 1.7, p = 0.042) and altered bowel habits (OR = 2.8, p < 0.0001). These observations suggest a statistically significant increase in frequency of both upper and lower GI symptoms in morbidly obese patients when compared to non-obese subjects.
 
PAR plasma levels above cut off of 3000 pg/ml in patients with eGFR >40 ml/min (blue line) as suggested by Li et al. applied to the patient cohort by Spinale et al. These values are likely not explained by reduced GFR alone. Elevated suPAR level in preserved renal function patients (orange line) is likely not dependent on eGFR.
Soluble urokinase receptor (suPAR) is proposed as circulating factor in focal and segmental glomerulosclerosis (FSGS) (1). Spinale et al. attempt to validate the role of suPAR in glomerular disease (2). Their mouse overexpression experiments of physiological suPAR forms are distinct from the studies by Wei et al. that expressed either alternate suPAR forms or used different mouse models (1). Additional experiments will help to further clarify the distinct roles of suPAR variants. Spinale et al. extend previous clinical studies indicating that glomerular filtration rate (GFR) is an important determinant of suPAR (3). This, however, does not imply that suPAR is only bystander, as illustrated by epidemiological studies linking elevated suPAR – independent of the eGFR – to cardiovascular disease in patients with CKD (4). As for most large protein plasma components, the balance between generation and clearance determines suPAR accumulation, adding complexity when studying the direct renal effects of suPAR, especially when possibly also causing kidney disease. Biopsy proven FSGS patients with GFR >40 ml/min have in 50% elevated suPAR levels (5), suggesting also suPAR production. In addition, suPAR fragments (measured and unmeasured) may cause podocyte injury, potentially contributing to a reduced GFR. The strong effect of a low GFR on serum suPAR levels in observational studies could obfuscate the effects of suPAR-induced glomerular pathology. In conclusion, dependence of serum suPAR levels on GFR precludes using suPAR as a single value biomarker for FSGS in conditions of low GFR, but this correlation does not serve as an explanation for elevated suPAR under preserved GFR (Figure (Figure11). Figure 1 suPAR plasma levels above cut off of 3000 pg/ml in patients with eGFR >40 ml/min (blue line) as suggested by Li et al. applied to the patient cohort by Spinale et al. These values are likely not explained by reduced GFR alone. ...
 
| Clinical taxonomy of HUS. 
| Inflammatory mediators in HUS. 
| Overall approach to the treatment of children with HUS. 
Hemolytic uremic syndrome (HUS) is characterized by thrombotic microangiopathy of the glomerular microcirculation and other vascular beds. Its defining clinical phenotype is acute kidney injury (AKI), microangiopathic anemia, and thrombocytopenia. There are many etiologies of HUS including infection by Shiga toxin-producing bacterial strains, medications, viral infections, malignancy, and mutations of genes coding for proteins involved in the alternative pathway of complement. In the aggregate, although HUS is a rare disease, it is one of the most common causes of AKI in previously healthy children and accounts for a sizable number of pediatric and adult patients who progress to end stage kidney disease. There has been great progress over the past 20 years in understanding the pathophysiology of HUS and its related disorders. There has been intense focus on vascular injury in HUS as the major mechanism of disease and target for effective therapies for this acute illness. In all forms of HUS, there is evidence of both systemic and intra-glomerular inflammation and perturbations in the immune system. Renewed investigation into these aspects of HUS may prove helpful in developing new interventions that can attenuate glomerular and tubular injury and improve clinical outcomes in patients with HUS.
 
In the present paper, we describe the facts that took place in the rat brain after a single injection of the enzyme neuraminidase from Clostridium perfringens into the right lateral ventricle. After injection, it diffused through the cerebrospinal fluid of the ipsilateral ventricle and the third ventricle, and about 400 μm into the periventricular brain parenchyma. The expression of ICAM1 in the endothelial cells of the periventricular vessels, IBA1 in microglia, and GFAP in astrocytes notably increased in the regions reached by the injected neuraminidase. The subependymal microglia and the ventricular macrophages begun to express IL1β and some appeared to cross the ependymal layer. After about 4 h of the injection, leukocytes migrated from large venules of the affected choroid plexus, the meninges and the local subependyma, and infiltrated the brain. The invading cells arrived orderly: first neutrophils, then macrophage-monocytes, and last CD8α-positive T-lymphocytes and B-lymphocytes. Leukocytes in the ventricles and the perivascular zones penetrated the brain parenchyma passing through the ependyma and the glia limitans. Thus, it is likely that a great part of the damage produced by microorganism invading the brain may be due to their neuraminidase content.
 
Targeted and non-targeted biological effects in conventional external beam radiotherapy. Targeted effects are caused by one or more particles traversing irradiated cells and can be divided in DNA and non-DNA-centered effects. Non-targeted effects describes the effects observed in cells that have not been directly traversed by particles but that are close to irradiated cells, as well as long-distance effects. DNA, mitochondria, and the cell membrane are the main sensitive targets of radiation. Following targeted and non-targeted effects, cells can survive (lesions are effectively repaired), they can die (lesions are not repaired) or they can be transformed. The dose–effect relationship of targeted effects is commonly fitted by linear or linear-quadratic models. A saturation of the response to non-targeted effects has been described. For more details, see the main text.
Targeted and non-targeted effects in targeted radionuclide therapy. Targeted effects are caused by one or more particles crossing irradiated cells and can be due to self-irradiation and cross-fire irradiation. Non-targeted effects include effects observed in cells close to irradiated cells and also long-distance effects. The nature of the dose–effect relationship resulting from targeted and non-targeted effects needs to be determined. For more details, see the main text.
Comparison of conventional external beam radiotherapy and targeted radionuclide therapy.
During the last decades, new radionuclide-based targeted therapies have emerged as efficient tools for cancer treatment. Targeted radionuclide therapies (TRT) are based on a multidisciplinary approach that involves the cooperation of specialists in several research fields. Among them, radiobiologists investigate the biological effects of ionizing radiation, specifically the molecular and cellular mechanisms involved in the radiation response. Most of the knowledge about radiation effects concerns external beam radiation therapy (EBRT) and radiobiology has then strongly contributed to the development of this therapeutic approach. Similarly, radiobiology and dosimetry are also assumed to be ways for improving TRT, in particular in the therapy of solid tumors which are radioresistant. However, extrapolation of EBRT radiobiology to TRT is not straightforward. Indeed, the specific physical characteristics of TRT (heterogeneous and mixed irradiation, protracted exposure and low absorbed dose rate) differ from those of conventional EBRT (homogeneous irradiation, short exposure and high absorbed dose rate), and consequently the response of irradiated tissues might be different. Therefore, specific TRT radiobiology needs to be explored. Determining dose-effect correlation is also a prerequisite for rigorous preclinical radiobiology studies because dosimetry provides the necessary referential to all TRT situations. It is required too for developing patient-tailored TRT in the clinic in order to estimate the best dose for tumor control, while protecting the healthy tissues, thereby improving therapeutic efficacy. Finally, it will allow to determine the relative contribution of targeted effects (assumed to be dose-related) and non-targeted effects (assumed to be non-dose-related) of ionizing radiation. However, conversely to EBRT where it is routinely used, dosimetry is still challenging in TRT. Therefore, it constitutes with radiobiology, one of the main challenges of TRT.
 
The network of HMGA regulatory mechanisms in human carcinomas. (A) In breast carcinoma, HMGA1 is able to simultaneously repress the expression of CBX7 and induce the expression of miR-181b. This latter, together with CBX7, takes part to a reciprocal regulation. (B) HMGA2, overexpressed in lung carcinomas, acts as competing endogenous RNA for let-7, allowing the activation of the TGF-beta signaling through the upregulation of TGFBR3. Decreased expression of TTF-1 in lung carcinomas allows the overexpression of HMGA2 protein directly, by releasing the transcriptional block on its promoter, and indirectly, by removing the translational block due to miR-33b. HMGA1 is able to induce the expression of miR-222, which in turn can target p27kip1 and PPP2R2A, then activating the AKT signaling. (C) The loss of miR-34b expression in cancer cells allows the overexpression of HMGA1, which in turn alters the miR-34b pathway by repressing it and its inducer p53. (D) The presence of several let-7 binding sites in the 3′ untranslated regions of HMGA1, HMGA2, and relative pseudogenes (HMGA1P, HMGA2P) alters the epigenetic modulation of HMGA2 and HMGA1 themselves (respectively), allowing their overexpression after decoy of let-7 microRNA. Dashed rectangles/ovals and lines represent decreased expression or loss of regulatory action, respectively.
Almost 30 years ago, overexpression of HMGA proteins was associated with malignant phenotype of rat thyroid cells transformed with murine retroviruses. Thereafter, several studies have analyzed HMGA expression in a wide range of human neoplasias. Here, we summarize all these results that, in the large majority of the cases, confirm the association of HMGA overexpression with high malignant phenotype as outlined by chemoresistance, spreading of metastases, and a global poor survival. Even though HMGA proteins' overexpression indicates a poor prognosis in almost all malignancies, their detection may be particularly useful in determining the prognosis of breast, lung, and colon carcinomas, suggesting for the treatment a more aggressive therapy. In particular, the expression of HMGA2 in lung carcinomas is frequently associated with the presence of metastases. Moreover, recent data revealed that often the cause for the high HMGA proteins levels detected in human malignancies is a deregulated expression of non-coding RNA. Therefore, the HMGA proteins represent tumor markers whose detection can be a valid tool for the diagnosis and prognosis of neoplastic diseases.
 
| Literature screening flow chart.
Background Induced abortion is a universal phenomenon and about 25% of pregnancies in the world end in induced abortion. Induced abortion refers to the use of artificial or drug methods to terminate the pregnancy in the early stage of pregnancy, which is a remedy for failed contraception and accidental pregnancy. Induced abortion means surgical abortion. There are two commonly used methods: negative pressure suction abortion and forceps curettage for induced abortion. Abortion is invasive and it will cause great harm to women's reproductive function. Clinically, there are also cases of re-pregnancy within 3 months after abortion or even re-pregnancy without recovery of menstruation. To improve symptoms and reduce these complications, antibiotics, motherwort, and Yasmin[Ethinylestradiol-Drospirenone (0.03/3 mg)] are clinically used alone or in combination after induced abortion. Methods Data were collected from six databases, including three English databases of Cochrane Library, PubMed and Embase, and three Chinese databases of CNKI, Wanfang, and Weipu. The original indicators of vaginal bleeding, menstrual recovery time, bleeding time, endometrial thickness 21 days after surgery and so on were included, and the incidence of postoperative bleeding less than menstrual volume, menstrual re-fluid time ≤ 37 days, bleeding time ≤ 7 days, re-pregnancy without menstruation, re-pregnancy within 3 months after the operation, the total incidence of postoperative complications were based on the ratio of the number of events in the group to the total number of people in the group reported in the literature. Review Manager 5.4 software was downloaded from the Cochrane website to evaluate the quality of the literature and analyze the results using random or fixed-effects models. The outcome of index data is divided into two types, one is dichotomy, and the other is measurement data. The binary data is expressed by odds ratio (OR), and the measurement data is expressed by mean difference (MD), and the confidence interval of both is 95%. Results After completing this meta-analysis, the results will be available. Conclusion The results will provide reliable data basis for the value of Yasmin combined with antibiotics and Motherwort in postoperative induced abortion. PROSPERO Registration Number CRD42021246764.
 
Top-cited authors
Claudio Franceschi
  • University of Bologna
Andrea Grignolio
  • Università Vita-Salute San Raffaele
Paolo Garagnani
  • University of Bologna
Maria Conte
  • University of Bologna
Cristina Morsiani
  • University of Bologna