Medical Hypotheses

Published by Elsevier
Online ISSN: 0306-9877
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Article
Electrophysiological findings in humans who are performing voluntary acts, indicate that the intention to act, follows brain activity rather than preceding it. This has implications for voluntary behavior and the doctrine of free will. This essay reviews the fields of human behavior, including medicine, in which this new thesis might have far-reaching significance.
 
Article
This case study demonstrates that the normal human body frequency, which can be disturbed by electromagnetic influences of the environment, can be modulated by 0.9% sodium chloride solutions (physiological saline) and that occurrence of allergic reactions have subsequently been suppressed as a result of this modulation. The use of distilled water as control showed no effect on occurrence of allergic reactions. Further observations on the growth of various plants in a greenhouse exposed to various geomagnetic fields support the previous observations on humans. The neutralization of electromagnetic influences on humans using 0.9% sodium chloride solution or by enclosure of plants within a copper wire Faraday cage resulting in a normal and uniform growth of plants as compared with disturbed and irregular growth in unenclosed controls, is demonstrated. These original observations propose a new strategy to suppress or prevent allergic reactions and possibly other effects observed in various human pathologies in relation to a disturbance of human body frequencies. It is hypothesized that the double helix structure of desoxyribonucleic acid (DNA) could be modified by environmental electromagnetic fields and that disresonance between the two chains of DNA could lead to the expression of specific pathology.
 
Article
To pose a new hypothesis of schizophrenia that affirms and unifies conventional hypotheses. Outside the brain, there are 5-HTP-containing argyrophil cells that have tryptophan hydroxylase 1 without l-aromatic amino acid decarboxylase. Monoamine oxidase in the liver and lung metabolize 5-HT, rather than 5-HTP, and 5-HTP freely crosses the blood-brain barrier, converting to 5-HT in the brain. Therefore I postulate that hyperfunction of 5-HTP-containing argyrophil cells may be a cause of schizophrenia. I investigate the consistency of this hypothesis with other hypotheses using a deductive method. Overactive 5-HTP-containing argyrophil cells produce excess amounts of 5-HTP. Abundant 5-HTP increases 5-HT within the brain (linking to the 5-HT hypothesis), and leads to negative feedback of 5-HT synthesis at the rate-limiting step catalysed by tryptophan hydroxylase 2. Owing to this negative feedback, brain tryptophan is further metabolized via the kynurenine pathway. Increased kynurenic acid contributes to deficiencies of glutamate function and dopamine activity, known causes of schizophrenia. The 5-HTP hypothesis affirms conventional hypotheses, as the metabolic condition caused by acceleration of tryptophan hydroxylase 1 and suppression of tryptophan hydroxylase 2, activates both 5-HT and kynurenic acid. In order to empirically test the theory, it will be useful to monitor serum 5-HTP and match it to different phases of schizophrenia. This hypothesis may signal a new era with schizophrenia treated as a brain-gut interaction.
 
Article
It is postulated that the immune reaction on chemical carcinogens can inhibit or stimulate the chemical-induced carcinogenesis depending on the individual peculiarities of the synthesis of antibodies. Critical events take place on the barriers between external and internal media. Antibodies to chemical carcinogens, which are secreted into the digestive or bronchial tract, bind the environmental carcinogens and prevent them from penetrating into the blood through the epithelium and thereby inhibit the beginning of the tumour growth in any organs. On the contrary, the serum antibodies promote the penetration of carcinogens through the digestive and bronchial epithelia and thereby stimulate carcinogenesis in the proper organs. The other events take place in the organs such as breast and prostate where carcinogens are transported from the blood. Secretory antibodies bind carcinogens in the blood and transport them through the epithelium of these glands and thereby stimulate the tumour origin in these organs. Antibodies, which are not secreted into the ducts of breast and prostate, hold carcinogens in the blood and thereby inhibit carcinogenesis in these organs. Antibodies to steroid hormones function in the same way, i.e., secretory antibodies stimulate, while the serum antibodies inhibit the genetoxic action of the hormones on breast and prostate. The stimulation of carcinogenesis in the lymphoid cells is realized owing to hapten-specific binding of carcinogens by the membrane receptors of the corresponding clones. Antibodies to the natural inhibitors of carcinogenesis (retinoids, tocopherole, etc.) stimulate the beginning of the tumour growth. Antibodies to carcinogens and antiidiotypic antibodies to the cytochromes p-450 may act as abzymes, i.e., as cytochromes p-450 and thereby increase the level of the carcinogen metabolites.
 
Article
Antitumour chemotherapy is nowadays a very active field of research, DNA targeting drugs being the most widely used group in therapy. The design, synthesis and anticancer activity of a new class of anticancer derivatives with pyrrolo-1,2-diazine and benzoquinone skeleton is presented. The synthesis is direct and efficient, involving an alkylation followed by a [3+2] dipolar cycloaddition. The penta- and tetra-cyclic pyrrolo-1,2-diazine were evaluated for their in vitro anticancer activity against an NCI 60 human tumour cell line panel. The pentacyclic-1,2-diazine exhibit a significant anticancer activity against Non-Small Cell Lung Cancer NCI-H460, Leukemia MOLT-4, Leukemia CCRF-CEM and Breast Cancer MCF7. We hypothesize that these molecules will exert their anticancer activity through multiple mechanisms of action: intercalating the DNA, inhibiting the topoisomerase enzymes and, destroying the DNA strands via electron transfer mechanism. However, the intercalation with the DNA seems to prevail in competition with the others mechanisms.
 
Article
A hypothesis is presented according to which the hypocalciuria in preeclamptic women is due to a decreased efficiency of intestinal calcium absorption as a consequence of diminished placental synthesis of 1,25-dihydroxyvitamin D related to lower circulating placental lactogen level and/or a possible reduction in the synthesis of insulin-like growth factor I.
 
Article
Aggressive fibromatosis (AF), also known as desmoid tumor is a monoclonal fibroblastic proliferation in a collagen matrix that arises in musculoaponeurotic structures. Though considered as benign, they are locally invasive and their propensity for recurrence after conservative surgery is well documented. Addition of postoperative adjuvant radiotherapy produces higher local control rates, although recurrence rates are still high in patients with positive margins. The antineoplastic activity of vitamin D has been demonstrated both in vitro and in vivo models of several cancers. The proposed mechanisms for antineoplastic activity include inhibition of proliferation associated with cell cycle arrest, induction of apoptosis and reduction in invasiveness and angiogenesis. It has also been shown that vitamin D has a negative impact on collagen homeostasis by inhibiting the formation and increasing its degradation. Since vitamin D has an antineoplastic activity and negative effect on collagen synthesis and deposition, it is proposed that 1,25-dihydroxy vitamin D3 can be a right therapeutic option for the management of desmoid tumors.
 
Effect of the addition of 7-DH, UVB-irradiated cholesterol and UVBirradiated 7-DH on human fibroblast cells. Cells were treated for 24 h with vehicle alone (A), 4 x 10-6 M UVB-irradiated cholesterol (B), 4 x 10-6 M 7-DH (C), 4 × 104 M UVB-irradiated 7-DHC (D). 
Article
Following solar ultraviolet radiation, epidermal 7-dehydrocholesterol is converted to previtamin D3, which then undergoes a thermal isomerization into vitamin D3. The metabolism of vitamin D3, which is usually considered as an inactive compound, gives rise to the active hormone 1,25-dihydroxyvitamin D3, following two hydroxylation steps occurring in liver and kidney. Here, we propose that this anabolic pathway can also be interpreted as a catabolic one leading to the degradation of the photoproducts of 7-dehydrocholesterol, for which a specific biological role in the skin is proposed.
 
Article
In Malignant Hyperthermia an increased open probability of the ryanodine Ca(2+)-channels in the SR-membrane primes a higher cytosolic Ca(2+)-concentration. This in turn accelerates ATP-hydrolysis culminating in a gradual decrease in ATP-levels. At low ATP-levels, IP3-synthesis is being stimulated and the ability of IP3 to release Ca2+ is enhanced. This results through the opening of IP3-dependent channels. Ca(2+)-release through the ryanodine channels and the IP3-dependent channels summate to increase the cytosol Ca(2+)-levels to such a high value that ATP is hydrolysed below a critical value causing rigor (contracture) of skeletal muscle. Since Ca(2+)-uptake by the SR is ATP-dependent, Ca(2+)-uptake will eventually also slow down and so contributes to the rise in cytosol Ca(2+)-concentration.
 
Article
Reduction of hepatic glucose output has been shown to be the chief basis for metformin's clinical benefit in diabetes, and the balance of the evidence suggests that this reflects inhibition of gluconeogenesis. Recent research with hepatocyte cell cultures demonstrates increased flux through pyruvate kinase in metformin-treated cells. An analysis of the conditions under which clinically relevant concentrations of metformin inhibit gluconeogenesis in hepatocyte cultures prompts the hypothesis that metformin potentiates the allosteric activation of pyruvate kinase by fructose-1,6-diphosphate. This model rationalizes several salient features of metformin's clinical activity: its ability to reduce hepatic triglyceride synthesis, its appetite-suppressant effect, and its failure to induce hypoglycemia.
 
Article
Extremely low frequencies, from 1 to 1.1 Hz, imprinted in water (imprinting was done by succussing a glass containing the water) led to a total abrogation of a facial seborrhoeic dermatitis, previously proposed as a visible model for the theory of 'memory of water'. This technique provides a new perspective on the enigma of homoeopathy and the treatment of allergic diseases and possibly all other inflammatory reactions.
 
Article
The Thomson Scientific Impact Factor (IF) for Medical Hypotheses has risen to 1.299 for 2006. This means that the IF has more than doubled since 2004, when it stood at 0.607. Using Elsevier's Scopus database; in 2004 there were 437 citations to Medical Hypotheses papers published in the previous two years--by 2006 this had trebled to 1216 citations. Monthly internet usage of Medical Hypotheses run at an average of about 26000 papers downloaded per month. An IF of 1.3 means that Medical Hypotheses has now entered the mainstream level of 'respectable' medical journals, in terms of its usage by other scientists. This is particularly pleasing given the aim of the journal is to publish radical and speculative ideas. A healthy IF is important to Medical Hypotheses because the journal deploys a system of editorial review, rather than peer review, for evaluation and selection of papers. Editorial review involves selection of a journal's content primarily by an editor who has broad experience and competence in the field, assisted by a relatively small editorial advisory board. The great advantage of editorial review is that it is able, by policy, to favour the publication of revolutionary science. But since editorial review relies on hard-to-quantify and non-transparent individual judgments, it is important for its outcomes to be open to objective evaluations. Scientometric measures of usage such as citations, impact factors and downloads constitute objective evidence concerning a journal's usefulness. Since Medical Hypotheses is performing adequately by such criteria, this provides a powerful answer to those who fetishize peer review and regard any other system of evaluation as suspect. Journal review procedures are merely a means to the end, and the end is a journal that serves a useful function in the dynamic process of science. Medical Hypotheses can now claim to perform such a role.
 
Article
Twenty years ago the fetal antigen hypothesis was proposed as a potential mechanism by which women are naturally immunized against cancer antigens by antigens from their fetus. Evidence from recent clinical studies shows that a high percentage of parous woman, but not nulliparous women, show evidence of immunization to antigens found on breast, ovarian and endometrial cancer cells. I suggest that this maternal immunization also affects the fetus, causing early immune rejection of fertilized ova that express cancer-related genotypes. Additional cancers, and perhaps even other types of genetic diseases, may be involved in this mechanism.
 
Article
The possibility that neuropeptides, in particular members of the tachykinin family are involved in inflammatory joint disease is widely disputed. Both clinical and experimental observations indicate that the tachykinin substance P (SP) may be involved in the pathogenesis of arthritis. We have studied the effects of tachykinins and the metabolites of SP on chondrocyte function. We have shown that the C-terminal pentapeptide sequence; H-Phe-Phe-Gly-Leu-Met-NH2 is biologically active in bovine chondrocyte cultures. The production of SP7-11 is limited by hydrolysis of the intact peptide by neutral endopeptidase (E.C. 3.4.24.11). The regulation of this enzyme would modulate the activity of substance P on articular cartilage chondrocytes.
 
Article
The Publisher regrets that this article is an accidental duplication of an article that has already been published in Medical Hypotheses, doi:10.1016/j.mehy.2007.08.005. The duplicate article has therefore been withdrawn.
 
Article
Chronic lymphocytic leukemia (CLL) is a common adult leukemia characterized by the accumulation of mature neoplastic B-lymphocytes. Typically, CLL follows an indolent course, with most patients surviving for many years. However, 10-20% of CLL patients carry 11q23 chromosomal deletions and often exhibit a more severe disease course, with earlier onset of symptoms, shortened lymphocyte doubling time, poor response to therapy, and shortened survival. The molecular basis for 11q23 deletions resulting in a poor prognosis is currently poorly understood. The tumor suppressor gene, ataxia-telangiectasia mutated (ATM, 11q22.3-23.1), is considered a likely candidate gene whose loss could result in the poor prognosis associated with 11q23 deletion and is mutated in a significant percentage of CLL cases. Recently, recombinant ATM expression in ATM-deficient cells was found to decrease transferrin receptor (TfR) expression, suggesting that deletion of the chromosomal region carrying ATM results in increased TfR expression. TfR imports iron into cells, an event necessary for DNA synthesis and cell growth. Additionally, rapidly growing malignant cells, including lymphomas and CLL, often express high TfR levels. Based on this, we propose that one molecular mechanism by which 11q23 deletions confer a poor prognosis in CLL is via increased TfR expression secondary to ATM loss, resulting in the increased cellular iron import, and hence increased capacity for malignant growth. Our hypothesis may also partially explain why gallium, an atomically iron-like toxic metal that binds to transferrin and the TfR is incorporated into cells and was previously demonstrated to have anti-tumor activity in patients with lymphomas refractory to other chemotherapeutic treatments.
 
Article
The adverse and beneficial effects of postmenopausal hormone replacement therapy include: ischemic heart disease, stroke, pulmonary embolism, breast cancer, an increased rate of onset of asthma as well as reductions in the incidence of diabetes in women with known coronary artery disease and osteoporotic fractures. These varied effects can be explained by the down regulation of 11beta-hydroxysteroid dehydrogenase by estradiol, which results in a reduction of tissue specific cortisol production. The reduction in local cortisol production which diminishes the endogenous anti-inflammatory effects, also allows for the progression of both vascular and pulmonary inflammation. The decrease in cortisol activation reduces insulin resistance and anti-proliferative effects thereby reducing the potential for diabetes but allowing for the emergence of malignancy. Furthermore, the decreased local tissue availability of cortisol reduces the tendency for the development of osteoporosis. New techniques and drugs are being developed to evaluate the modulation of 11beta-HSD1 activity. Further study should result in new ways to control both inflammation and metabolism.
 
Article
Tumor markers or tumor antigens are used for the monitoring of the response to treatment, follow-up, and potentially for diagnosis and screening. However, use of CA-125 serum assay as a single diagnostic tool is restricted by the fact that it is also produced by normal epithelia, not only by the ovarian cancer cells. Systemic lupus eryhtematosus (SLE) and related systemic autoimmune syndromes are associated with elevation of CA-125. In this group of patients antigen elevation had been tried to be linked with SLE disease activity. Although not found to be related with the disease activity, CA-125 serum levels were found to be related with the presence of nephrotic syndrome in the English literature. Although particularly important, the presence of ascites was not taken into consideration during the statistical analysis of the relationship between CA-125 elevation and nephrotic syndrome in SLE patients. However most of the SLE patients with nephrotic syndrome would have had accompanying ascites secondary to protein loss. Ascites itself could induce elevation in CA-125 serum levels. With this in mind we can hypothesize that the development of ascites was the primary cause for the elevation of CA-125 in SLE patients with nephrotic syndrome rather than the nephrotic syndrome itself. Probably the presence of ascites was the cause of observed relationship. Most likely ascites was a confounding variable biasing the results and statistical analysis. Failure to control for the presence of confounding variables such as ascites might lead to bias in all clinical trials. Otherwise a causative role for nephrotic syndrome in the elevation of serum CA-125 level seems somewhat inconsequential.
 
Article
Single amino-acid substitutions in the prion protein have been found to lead to resistance or susceptibility to amyloid fibril formation. In humans, the presence of methionine at position 129 in the prion protein results in increased susceptibility to prion disease, while the presence of valine at that position appears to be protective. It is hypothesized that the codon for M129 is an alternative initiation site for translation, which results in a truncated molecule that is missing the first 128 amino acids, including the signal peptide. This N-terminal truncated form of the prion molecule will not be transported to the extracellular space and thus will accumulate in the cytosol where it is more susceptible to fibril formation and aggregation; this aggregation could hinder normal degradation processes and cause disease. The results of experimental studies on truncated prion molecules support this hypothesis. To test the hypothesis, a gene segment, which when transcribed would result in a prion molecule starting at methionine 129, could be introduced into a convenient experimental animal to see if there is increased incidence of prion disease. Or, fibrils from the brains of affected M129/M129 homozygous individuals could be isolated and the molecules in the fibrils analyzed to determine the identity of the N-terminal amino acid(s). We predict that those isolates will have a preponderance of molecules that start with the methionine at position 129 in the intact protein.
 
Article
Several observations have led the author to conclude that massive injections of vitamin B-12b (hydroxocobalamin) will prove an excellent antidote for patients overdosed with sedatives/tranquilizers and/or alcohol.
 
Article
We hypothesize that the ratio of intracellular 13-hydroxy-octadeca-dienoic acid (13 HODE) and hydroxy-eicosatetraenoic acid (5-, 12- and/or 15-HETE) influences the expression or presentation of adhesive moieties on platelets, leukocytes, malignant cells and endothelial cells, thereby influencing their subsequent adhesive interactions. Thus, we demonstrate that under unstimulated conditions, these cells preferentially synthesize linoleic acid via their lipoxygenase enzymes into 13-HODE, the intracellular level of which is associated with limited or no cell adhesion, while following stimulation, the same cells preferentially metabolize arachidonic acid via the lipoxygenase enzyme into HETEs, the production of which is associated with enhanced adhesion. Which metabolite is synthesized by these cells and the subsequent adhesivity of these cells appear to be dependent upon both the intracellular level of cAMP and the ratio of linoleic and arachidonic acid substrates. This suggests that manipulation of this ratio will have significant effects on the adhesive events involved in the pathogenesis of thrombosis, inflammation and metastasis.
 
Article
Recent studies have proposed cell therapy as an alternative therapeutic strategy for many disease states such as diabetes mellitus. Among different cell types mesenchymal stem cells (MSC) have attracted a significant attention based on their intriguing potentials. However MSC therapy is limited as a large portion of transplanted cells undergo apoptosis after transplantation. Therefore, proposing a strategy to overcome this obstacle may be of great value. Recent studies have shown that hypoxia preconditioning (HPC) may improve cell viability after transplantation. Both HPC and hyperglycemia are reported to exert effects by different levels of ROS overproduction. Overdose of ROS in this case would trigger the apoptosis and thereby decreased cell viability after transplantation. Apelin; the endogenous ligand for the previously orphaned G protein-coupled receptor APJ is shown to exert anti apoptotic effects On oxidative stress-induced apoptosis in MSCs via MAPK/ERK1/2 and PI3K/AKT signaling pathways. Accordingly it has been hypothesized that pretreatment of HPC-MSC(s) with apelin 13 would be an effective approach to modify and possibly enhance the efficacy of MSCs in cell therapy of diabetes.
 
Article
Environmental and genetic factors contribute to familial chronic obstructive airways disease. The genetic component could be polygenic or in some families be associated with one or two major genes. It is assumed that most cases of familial chronic obstructive airways disease are polygenic, but this conclusion is based on insufficient data. The use of linkage analysis using DNA probes for specific genes that may have a direct role in the disease process should facilitate our understanding of the genetics. Genetic deficiency of alpha1-antitrypsin is associated with predisposition to pulmonary emphysema. In the absence of alpha 1-antitrypsin deficiency I suggest that a study of serine-proteinase inhibitors on chromosome 14 may identify a significant proportion of families where only one major gene is important.
 
Article
Here, we propose a novel hypothesis that 14-3-3 zeta might act as a sweeper of misfolded proteins by facilitating the formation of aggregates, which are referred to as inclusion bodies. Studies on the localization of the 14-3-3 proteins in different types of inclusion bodies in the brain including neurofibrillary tangle in Alzheimer's disease, pick bodies in Pick's disease, Lewy body-like hyaline inclusions in sporadic amyotrophic lateral sclerosis, prion/florid plaques in sporadic/variant Creutzfeldt-Jakob disease, nuclear inclusions in spinocerebellar ataxia-1, and possibly Lewy bodies in Parkinson's disease suggest a close association of these diseases with 14-3-3 zeta. The highly conserved hydrophobic surface of the amphipathic groove in 14-3-3 zeta represents a general mechanism with diverse cellular proteins, and it may also allow for the molecular recognition of misfolded proteins by hydrophobic interaction in disease conditions. When the abnormal processing of misfolded proteins overwhelms the quality control systems of the cell, it is likely that 14-3-3 zeta is recruited to form deposits of protein aggregates with nonnative, misfolded proteins in order to protect the cell against toxicity. Hence, 14-3-3 zeta may be considered as an auxiliary therapeutic tool in the protein aggregation disorders.
 
Article
Arthritis is inflammation in a joint often with joint damage, usually accompanied by pain, swelling and stiffness, resulting from infection, trauma, degenerative changes, metabolic disturbances, autoimmune or other causes. It occurs in various forms, including rheumatoid arthritis, osteoarthritis, bacterial arthritis and gout. Gallium III can inhibit the production of inflammatory cytokines, such as IL-1beta, produced by macrophage-like cells in vitro. A dose-dependent inhibition of IL-1beta and TPA stimulated MMP activity by gallium nitrate at increasing concentrations occurs, demonstrating that gallium nitrate can be a useful modulator of inflammation in arthritis. Gallium III is an inhibitor of bone resorption and is an effective treatment for hypercalcemia. Gallium III has been reported to be effective in the treatment of mycobacterium butycicum-induced arthritis in rats by antagonism of iron III. Long-term elimination of pain from arthritis by gallium III was first observed in horses primarily being treated for navicular disease. Several people treating their horses with gallium nitrate coincidentally found that arthritis pain in their fingers ended and did not return after soaking their hands in 14% gallium nitrate solution. Therefore, the severely arthritic hands of a 60-year-old woman were topically treated with a 14% aqueous solution of gallium nitrate for 90 min. Pain and inflammation from rheumatoid arthritis diminished rapidly, and neither pain nor inflammation returned during the following 2 years from that single treatment. A 61-year-old woman who had osteoarthritis in her left knee, shoulders and wrists was treated orally with 50 ml of a 1% gallium nitrate solution (120 mg elemental gallium) daily using a two week on and two week off protocol, resulting in almost total elimination of pain while on gallium nitrate, while pain partially returned during the two week off periods. Treatment of frozen shoulder with topical 40% gallium nitrate for 120 min resulted in greatly reduced pain and crepitus almost immediately with complete restoration of range of motion, with pain remaining essentially absent for over 1 year. Mechanisms of action are hypothesized to include anti-inflammatory, bone density improvements, antibacterial, anti-iron III and anti-aluminum III effects. Proper use of gallium III may be effective in terminating pain and inflammation of arthritis for years, often with a single treatment.
 
Article
Background: Numerous mutations in over 100 rod genes are the well-established cause of apoptotic death of these cells and development of night blindness in retinitis pigmentosa (RP). Cone death is either concomitant or follows rod death with resultant loss of critical peripheral and central day vision. As cones are generally not encumbered by genetic mutations, the causes of their death and its prevention are the central problems of RP research. Currently no FDA-approved medications are available for retarding RP progression. Hypothesis: It is proposed that cones, which are outnumbered 20:1 by rods, undergo apoptosis as a consequence of neurotrophic factor deficiencies and oxidative stresses accompanying massive rod death: increased retinal oxygen tension; leakage of lipid-peroxidation catalysts from disrupted membranes; reactive oxygen species from active/hyperactive microglia ingesting rod-apoptotic bodies. Accordingly we developed and tested a treatment regimen with a range of antioxidants in combination with the off-label use of deprenyl (1 mg/day), a safe antiapoptotic agent, which also upregulates eight neurotrophic factors. Since deprenyl inhibits only one of four mitochondrial apoptotic pathways, we added the antibiotic minocycline (100 mg/day) to our protocol at month 76. Minocycline complements deprenyl's therapeutic properties: it inhibits all four apoptotic pathways; inhibits apoptosis-initiating proteins; as phenol exerts powerful antioxidant properties; upregulates three antioxidant enzymes; downregulates oxidative/inflammatory microglia activities. Its safe long-term use for acne and rheumatoid arthritis received FDA approval; it passes the blood/brain and blood/retinal barriers readily; and because of its rapid and complete absorption causes no intestinal disturbances. The National Eye Institute has initiated in 2010 and 2011 clinical trials with minocycline (200 mg/day) for diabetic macular edema and retinal branch vein occlusion. Testing of hypothesis: The hypothesis was tested for 140 months with one RP patient monitored by Humphrey Perimetry, which was quantitated by two parameters: (a) sum of decibel units, (b) number of detected light sources (visual field). Although no decline was observed in these parameters during the first 50 months of treatment, they declined by 10-28% during months 50-65. These declines reversed upon introduction of minocycline: over the total 140-month treatment, the right eye visual field showed 0% decline and left eye 13.3% decline. Rate constants for logarithmic decline of visual field measured prior to treatment indicate that visual fields would have decreased by 64% and 70%, respectively by month 140 in the absence of treatment.
 
Article
Recently, there have been increasing evidences that microRNA-146 (miR-146) is related to up-regulated immune and inflammatory signaling through its target genes, such as IRAK1 and TRAF6. Additionally, abundant data continue to support the hypothesis that progressive up-regulation of inflammatory gene expression and elevated inflammatory signaling facilitate the development and progression of Alzheimer's disease (AD). This review focuses on the recent findings regarding the role of miR-146 in modulating immune response and its subsequent effects in the pathogenesis of AD.
 
Article
Herpes simplex virus type 1 (HSV-1) is latent in the nervous system of most humans. Ball [Can J Neurol Sci 9 (1982) 303] first suggested the hypothesis that HSV-1 could be involved in the pathogenesis of Alzheimer's Disease (AD) by noting that regions of the brain particularly and earliest affected in AD were the same as those most damaged during HSV encephalitis. Data from Itzhaki's research suggests that HSV-1 in the brain and the carriage of an apolipoprotein E allele 4 (ApoE e4) together confer risk for AD [J Pathol 97 (2002) 395], [Mol Chem Neuropathol 28 (1996) 135], [Alzheimer's Rep 1 (1998) 173], [Biochem Soc Trans 26 (1998) 273]. Of the two other studies based on Itzhaki's findings, one showed similar results [Lancet 349 (1997) 1102], and the other showed a similar trend [Lancet 351 (1998) 1330], [Lancet 352 (1998) 1312]. To further examine the role of HSV-1 in the etiology of AD, we have formulated a Neuroinvasive Score that quantifies the presence and viral load of HSV-1 in eight brain regions. These regions are: entorhinal cortex, hippocampus, pons, cerebellum, and neocortex (temporal, parietal, occipital, and frontal). We hypothesize that the Neuroinvasive Score that encompasses the presence, amount, and extent of HSV-1 spreading (neuroinvasiveness), will correlate with the genetic risk factor, ApoE e4, in the assessment of autopsy samples from AD patients. If the neuroinvasive score can be directly correlated to the different stages of AD (mild, moderate, severe), this will strengthen the hypothesis that HSV-1 is involved in AD and that ApoE e4 also confers risk for the development and progression of AD.
 
Article
Immune rejection of organ transplants has life-threatening implications. It is believed that allograft rejection is initiated by the activation of lymphocytes following recognition of donor antigens, leading to generation of effector T lymphocytes, alloantibody production, and graft infiltration by alloreactive cells. There is solid evidence that miRNAs are integral for maintaining immune homeostasis and self-tolerance. A deeper understanding of the regulation of the immune response by miRNAs could define new mechanisms for manipulating graft immunity and preventing rejection. The miRNA miR-155 is of particular interest due to its known roles in regulating the expression of genes relevant to allograft rejection and the induction of immune tolerance. Indeed, miR-155 has been shown to dramatically impact both innate and adaptive immune processes, including inflammation, antigen presentation, T-cell differentiation, cytokine production, and T regulatory cell (Treg) functions. The suppressor of cytokine signaling 1 (SOCS1) is a critical regulator of immune cell function and an evolutionarily conserved target of miR-155 in breast cancer cells. We propose that suppression of miR-155 could enhance SOCS1 expression in immune cells and suppress allograft rejection. Further studies on the specific role of miR-155 in allograft rejection may lead to the identification of new targets for therapeutic intervention.
 
Article
Preventive measures against infection by enterohaemorrhagic E. coli 0-157 are described. Eating yoghurt and Kefir supposedly induces more bifid bacteria and lactic acid bacteria to colonize in the intestines, thereby protecting humans from infection by E. coli 0-157. Some foods, such as plum extract, act as a mild antibiotic and produce an acidic environment within the intestine, thus interfering with growth of the E. coli 0-157. The natural colonization of harmless E. coli or other bacteria that are more powerful than E. coli 0-157 can possibly protect against infection. A vaccination against E. coli 0-157 H7 may also be effective. In addition, it has been suggested that the correct levels of nitric oxide and calcium in the blood may activate immunity and protect against infection by E. coli 0-157.
 
Article
The efficacy of reverse-electron-transport therapy of obesity should be promoted by agents which up-regulate hepatocyte enzymes that are potentially rate-limiting for mitochondrial fatty acid oxidation and electron shuttles. Peroxisome proliferator drugs, including the fibrates used to treat hyperlipidemia, may be useful in this regard, as they induce malic enzyme, the mitochondrial glycerol-3-phosphate dehydrogenase, and carnitine palmitoyl transferase I in rodent hepatocytes. An agent of this class, MEDICA 16, has the additional property of potently inhibiting both citrate lyase and acetyl-CoA carboxylase. As a result, methyl-substituted diacarboxylic acids (MEDICA) 16 can be expected to disinhibit hepatic fatty acid oxidation while up-regulating electron shuttle mechanisms, and thus should stimulate reverse electron transport. This may explain the remarkable 40% increase in basal metabolic rate observed in normal rats ingesting MEDICA 16--an effect not associated with any compensatory increase in food intake. Relative to controls, the MEDICA 16-treated rats achieved a 50% reduction in body fat and a modest increase in lean mass, such that weight and growth were not changed. In other rodent strains, MEDICA 16 has prevented obesity diabetes and atherogenesis. However, whether MEDICA 16 and other peroxisome proliferator drugs will have clinical utility in reverse-electron-transport therapy may hinge on their ability to induce key enzymes in human hepatocytes; cell culture studies to evaluate this are required.
 
Article
Human papillomavirus (HPV) type 16 is causally associated with a subset of oral cancers, predominantly those cancers arising in the oropharynx (OP). Increased HPV16 E6 and E7 oncogene expressions are responsible for the malignant transmission in these cancers. ErbB-2 is the family member most closely implicated in human cancer, where it is overexpressed in about 30% of carcinomas including head and neck squamous cell carcinoma. Coexpressions of E6/E7 and ErbB-2 downregulate E-cadherin and catenin expression, therefore induces metastatic process. Trastuzumab is a humanized monoclonal antibody that recognizes the ErbB-2 protein receptor and breakthrough in the treatment of metastatic breast cancer in combination with chemotherapeutic agents. This antibody is also in clinical testing for adjuvant treatment of breast cancer. We propose that trastuzumab as an adjuvant treatment may decrease process of tumor metastasis in oropharyngeal cancer patients who completed primary treatment (surgery and/or radiotherapy) and show expression of both HPV16 E6/E7 and erbB-2 oncoproteins. In vitro and in vivo studies with trastuzumab in these subgroup of patients may support our hypothesis.
 
Article
Egyptian medical papyri date the Santorini eruption, and reconcile the hitherto perceived dichotomy between archaeological/historical and scientific data. The medical documentation describes ailments, which can only have arisen from a volcanic source: ash fallout, rain acidified by ash, and a plume. Furthermore, the Egypt described by the medical texts matches the one in the series of so-called biblical plagues. This match in turn provides the length of time, 19 months, between the initial and final phases of the eruption, each phase contributing to the otherwise odd accumulation of sulfates spread over two consecutive biennia (1603-1600 BC) in Greenland's ice core. As a result, the initial phase of the eruption can be dated to August 21, 1603 BC, and the final one to March 1601 BC, in full agreement with the radiocarbon data (1627-1600 BC) based on the outermost ring on the branch of an olive tree killed by the eruption.
 
Article
We postulate that the short chain fatty acids, produced in the large gut by the microbial fermentation of dietary fiber, improve glucose tolerance and inhibit hepatic cholesterol and fibrinogen synthesis, probably by preventing an increase in serum levels of free fatty acids, and by improving insulin sensitivity. Since hypercholesterolemia, hyperfibrinogenemia and glucose intolerance are important risk factors for coronary heart disease, this could serve as a basis for recommendations that Western populations at risk should increase their dietary intake of substrates for short chain fatty acids.
 
Article
Natural stable isotope fractionation is a potential tool in investigation of metabolic process, since rigid mass balance considerations rule the changes in the isotopic ratio. As the natural changes in 13C/12C ratio of total CO2 between blood and urine served for studying renal bicarbonate reabsorption, studying changes in 18O/16O ratio of phosphate are suggested to investigate deranged phosphate metabolism. The 18O/16O ratio in serum phosphate is constant, determined by the ratio in the environmental drinking water. Therefore, measurements of this ratio in normal individuals, after modifications in phosphate metabolism and in diseases with high alkaline phosphatase activity are proposed. The main purpose of the proposed study is to assess whether measurements of 18O/16O ratio can detect malignant metastases in bones due to deranged phosphate metabolism. An assumption that these determinations might precede other tests for detecting bone metastases and can serve as an oncogenic marker is made.
 
Article
New functions of well-known genes have been revealed frequently. A new example is described in this report. Earlier we have detected an up-regulation of expression of the mitochondrial 16S rRNA gene in non-Hodgkin's lymphomas. Here we demonstrate that the human mitochondrial 16S rRNA gene encodes a potential oncopeptide, Humanin described recently. This peptide suppresses neuronal cell death induced by mutant genes responsible for familial Alzheimer's disease (AD). Analysis of the gene coding site structure showed that Humanin mRNA is translated most likely in the cytosol, but not in the mitochondrion in vivo. This led us to suppose that AD could be caused by a block of Humanin mRNA transport from mitochondria into the cytosol. Moreover, our data and reports by others an mitochondrial 16S rRNA transcription and characteristic of transcript structure suggests that Humanin is a potential oncopeptide. Thus, the use of Humanin for the treatment of AD may increase the risk for the development of malignant diseases.
 
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The concentrations of 16-hydroxylated steroids, especially 16 alpha-hydroxydehydroepiandrosterone (16 alpha-hydroxyDHEA) in amniotic fluid and infants' blood are elevated many fold at normal birth time as compared with mid-term concentrations and those found in prematurely born infants. It is logical to postulate that 16 alpha-hydroxyDHEA may be the natural inducer of lung maturation and preventor of respiratory distress syndrome. Because the infant born at normal gestational terminus has a very high concentration of blood 16 alpha-hydroxyDHEA, treating premature infants with amounts of this steroid to provide blood concentrations that are normal in full-term infants should be a well-tolerated procedure and should avoid the developmental problems associated with glucocorticoid treatments.
 
Article
The miR-17-92 cluster is an important microRNA cluster in the animals. It was mainly investigated as an oncogene in tumors but never studied in cardiovascular disease. On one aspect, miR-17-92 cluster is documented to play anti-apoptotic roles in tumor cells, including hypoxia-induced apoptosis. The families of miR-17, miR-19, and miR-92 promote resistance to apoptosis by directly inhibiting pro-apoptotic protein, and by the two major cell survival signaling pathways-PI3K/AKT, and MAPK/ERK. On the other aspect, the component members of miR-17-92 cluster are high expressed in the hearts of canine and mice, suggesting that there are effect targets of the cluster in the myocardium. So that, we hypothesized that the miR-17-92 cluster may protect the heart by diminishing the apoptosis and alleviating ischemia/reperfusion injury. This may be a new regulating target for patients with myocardial infarction and undergoing cardiac surgery.
 
Article
Interleukin (IL)-17 is a pro-inflammatory cytokine originally described in T lymphocytes. Increased production of IL-17 has been linked to the induction of cytokines, chemokines and adhesion molecules in various cell types, effects that likely contribute to a number of inflammatory diseases including rheumatoid arthritis. Importantly, in the same pathophysiological conditions production of TNFalpha is also up-regulated and recent studies suggest that cellular signaling pathways induced by IL-17 and TNFalpha converge. Recent studies showed that vascular endothelial and/or smooth muscle cells also express TNFalpha and IL-17, which can be up-regulated in pro-atherogenic pathophysiological conditions in the coronary arteries. TNFalpha has been shown to exert pro-inflammatory vascular effects (e.g., induction of oxidative stress, endothelial apoptosis, up-regulation of adhesion molecules and chemokines), however, the role of vascular IL-17 and its interaction with TNFalpha is much less understood. We propose that increased vascular IL-17 and TNFalpha levels can act synergistically to create a pro-inflammatory microenvironment promoting the development of atherosclerotic vascular disease.
 
Article
Bullous pemphigoid is an autoimmune blistering disease of the skin caused by autoantibodies directed against basement membrane zone adhesion molecules. Autoantibodies cannot fully explain several important features of the disease such as the difficulty transferring with the pathogenic autoantibodies, or the presence of heavy lesional infiltration of eosinophils and neutrophils that is necessary for disease production. There is increasing evidence that Th17 cells and the cytokines they release such as interleukin-17 are important regulators of innate and adaptive immune responses in many Th1 and/or Th2 mediated autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and allergic asthma. There is also evidence that Th17 cells have a role in pathogenesis of blistering skin diseases. Interleukin-17 is important in initiation and maintenance of many autoimmune reactions and it is involved in production of pro-inflammatory cytokines, matrix metalloproteinases, neutrophils, and eosinophils, all of which are important pathogenic factors in bullous pemphigoid. The hypothesis is that interleukin-17 has an important pathogenic role in BP and can describe features of the disease not explained by the autoantibody theory. This cytokine can be assessed in the blister fluid and sera of patients, and can be used as a marker of disease activity and response to therapy. The information obtained could also lead to the development of novel therapeutic strategies for this and other autoimmune blistering diseases.
 
Top-cited authors
Mark F McCarty
  • Calytic Longevity Foundation
Jian-Jun Li
  • Beijing Fuwai Hospital
Shih-Jen Tsai
  • Taipei Veterans General Hospital
Leo Sher
  • Icahn School of Medicine at Mount Sinai
Shaharyar Khan
  • Gencia Corporation