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Zinc and Manganese in the Schizophrenias
Abstract
The essential trace elements zinc and manganese have been noted as factors in brain disease since the Twenties. The combined use of zinc and manganese in schizophrenia is based on the following: increased urinary excretion of copper when both zinc and manganese are given orally; zinc alone causes a decrease in blood manganese; and the double deficiency of zinc and manganese frequently is found in patients with excess copper. The mauve factor (Kryptopyrrole) is known to increase the excretion of zinc and vitamin B6 (pyridoxine). Manganese is important in the building and breakdown cycles of protein and nucleic acid. For RNA chain initiation, manganese was found to be a better effector than magnesium. Manganese stimulates adenylate cyclase activity in brain tissue. Because cyclic-AMP plays a regulatory role in the action of several brain neurotransmitters, manganese is important in brain function. Owing to the fact that zinc is well absorbed from the gut but manganese is poorly absorbed all diagnostic categories may be harmed by large prolonged oral doses of zinc without manganese. In oral doses manganese occasionally elevates blood pressure in patients over 40 years of age. Zinc alone can lower blood pressure in some hypertensive patients. Prolonged use of phenothiazines causes tardive dyskinesia. Phenothiazines might chelate manganese making it unavailable for some presumed function as an enzyme activator.
... The remaining 57 publications were reviewed in detail. After detailed review, 27 additional studies were excluded for the following reasons: types of publications other than those of interest (review, letter, opinion, or meeting proceedings), [72][73][74] disease states other than schizophrenia, 75-77 lack of a mentally healthy control group, 78 measurement of trace elements in samples other than those of interest (eg, brain tissue, urine, tooth, or CSF), [79][80][81][82][83][84][85][86] insufficient data reported, 87,88 duplicate record, 89 and evaluation of outcomes other than those of interest (eg, dyskinesia, dystonia, akathisia, catatonia, or movement disorders). [90][91][92][93][94][95][96][97][98] Some abstracts or titles were likely to be related, but the full texts were not available to obtain sufficient data for analysis or to ensure they were relevant. ...
... Eleven studies were included in the meta-analysis of blood iron levels, 5 of which found lower levels of iron in patients with schizophrenia 26,36,44,57,58 and 6 of which found no significant difference in iron levels between patients and controls. 29,40,42,51,54,55 Lower levels of iron for patients with schizophrenia remained significant in subgroups of serum (SMD ¼ À0.54), patients in Asia (À0.56), drug-naive/drug-free patients (SMD ¼ À0.50), patients on antipsychotic drugs (SMD ¼ À0.71), inpatients (SMD ¼ À0.63), patients with acute or newly diagnosed schizophrenia (SMD ¼ À0.50), patients with chronic or previously diagnosed schizophrenia (SMD ¼ À0. 73), and male participants (SMD ¼ À0.38). Male patients had significantly higher levels of iron when compared with female patients (SMD ¼ 1.45). ...
Context:
The pathogenesis of schizophrenia appears to be multifaceted.
Objective:
The aim of this meta-analysis of studies that investigated blood and hair concentrations of trace elements in people diagnosed with schizophrenia was to determine whether levels of trace elements in patients with schizophrenia differ from those in healthy individuals.
Data sources:
The PubMed, Scopus, and Web of Science databases were searched to January 2018.
Study selection:
Studies that compared concentrations of trace elements in patients with schizophrenia with those in healthy controls, in patients with schizophrenia under different treatment regimens, or in patients with schizophrenia at different stages of disease were included.
Data extraction:
Data on study and sample characteristics and measures of trace elements were extracted.
Results:
Thirty-nine studies with a total of 5151 participants were included. Meta-analysis of combined plasma and serum data showed higher levels of copper, lower levels of iron, and lower levels of zinc among patients with schizophrenia vs controls without schizophrenia. Subgroup analyses confirmed the following: higher levels of copper in plasma, in users of typical antipsychotic drugs, and in males; lower levels of zinc in serum, in patients in Asia, in drug-naive/drug-free patients, and in inpatients; lower levels of iron in serum, in patients in Asia, in drug-naive/drug-free patients, in patients on antipsychotic drugs, in inpatients, in patients with acute or newly diagnosed schizophrenia, in patients with chronic or previously diagnosed schizophrenia, and in males; and lower levels of manganese in plasma and in patients with chronic or previously diagnosed schizophrenia.
Conclusions:
This meta-analysis provides evidence of an excess of copper, along with deficiencies of zinc, iron, and manganese, in patients with schizophrenia.
... The σ value was estimated by Microsoft office excel 2010 program. LoDs were found as follows (μg/L): 40 Ca-1.9, 24 Mg-0.24, 63 Cu-1.8, 56 Fe-0.13, 55 Mn-0.07, 77 Se-0.04, and 66 Zn-0.05. ...
... The current study found that the serum levels of Fe were reduced significantly in MDD patients which are supported by previous study results [39]. Low levels of Mn cause depression by increasing autoimmune reactions and macrocytosis [40]. In our present study, we found the significantly lower concentration of Mn in MDD patients compared with the control subjects (p < 0.05). ...
Background: Major depressive disorder (MDD) is a mixed disorder with the highly irregular course, inconsistent response to treatment and has no well-known mechanism for the pathophysiology. Major causes of depression are genetic, neurobiological, and environmental. However, over the past few years, altered serum levels of macro-minerals (MM) and trace elements (TE) have been recognized as major causative factors to the pathogenesis of many mental disorders. The purpose of this study was to determine the serum levels of MM (calcium and magnesium) and TE (copper, iron, manganese, selenium, and zinc) in MDD patients and find out their associations with depression risk.
Methods: This prospective case-control study recruited 247 patients and 248 healthy volunteers matched by age and sex. The serum levels of MM and TE were analyzed by atomic absorption spectroscopy (AAS). Statistical analysis was performed with independent sample t-tests and Pearson’s correlation test.
Results: We found significantly decreased concentrations of calcium and magnesium, iron, manganese, selenium, and zinc in MDD patients compared with control subjects (p<0.05). But the concentration of copper was significantly increased in the patients than control subjects (p<0.05). Data obtained from different inter-element relations in MDD patients and control subjects strongly suggest that there is a disturbance in the element homeostasis.
Conclusion: Our study suggests that altered serum concentrations of MM and TE are major contributing factors for the pathogenesis of MDD. Alterations of these elements in serum levels of MDD patients arise independently and they may provide a prognostic tool for the assessment of depression risk.
... This decrease of zinc content in brain favour findings by Harrison et al and Danscher et al.24,25 Cerebellar dysfunction has been associated with acute zinc loss.26 Rats, zinc deficient in prenatal and early postnatal periods develop abnormal brain.27 Decrease in zinc content affects the axonal transport, neuronal microtubule and tubulin synthesis and assembly.28 ...
... There was a significant decrease in Mn concentration in early age- control. Mn deficiency effects cerebral motor function.27 Huley et al demonstrated a relationship between seizure activity and Mn deficiency rats.38 Tanaka has presented a preliminary report on low blood Mn levels in epileptic patients.39 ...
Background:
In Indian traditional system of medicine Celastrus paniculatus extract has been used to improve intellect, memory and for the treatment of various mental disorders.
Purpose:
The present study was undertaken to evaluate the effectiveness of this medicinal plant on serum biochemistry.
Methods:
Ethanolic extract of seed of Celastrus paniculatus (2g/kg/body weight) was orally administrated for 16 days in 20 months old albino rats. The results were compared with 3 months, 12 months and 20 months old control rats. The concentration of trace elements was determined by atomic absorption spectrophotometer.
Results:
Significant variation was observed in the concentration of trace elements. In case of copper there was decrease in content in early aged (0.240 ± 0.004) control and age control (0.115 ± 0.004) rats whereas an increase in treated aged rats (0.124 ± 0.004) was observed. Non significant variation was observed in zinc content. Young control rats possessed 0.683 ± 0.004 (µg/ml) zinc contents in cerebellum. Age control animal showed the highest level of Zn 0.954 ± 0.002. Celastrus paniculatus treated rat show revealed the lowest level of zinc 0.457 ± 0.003 (µg/ml) in cerebellum. Young control rat had 0.066 ± 0 (µg/ml) manganese content which was significantly decreased in early age control (0.022 ± 0.0008) followed the significant increase in age control (0.087 ± 0.002). Treated rats possessed the decreased content than age control but higher than young and early age control. Non significant decrease in cobalt content was observed during ageing as in young control the highest cobalt content was 0.084 ± 0.0007 followed by decrease in early age control 0.83 ± 0 and age control 0.006 ± 0.0007 (µg/ml). Treated rats showed an increase in cobalt content up to 0.032 ± 0.0007.
Conclusion:
Results of the present study revealed that the determination of trace elements in blood and tissues has been widely used in the last two decades as a tool to understand their metabolic role in human and animals.
... Polymorphisms in the encoding gene of Mn-SOD have been reported to associate with the incidence risk of schizophrenia (Akyol et al. 2005). Early evidence conformed the role of manganese deficiency in the development of schizophrenia (Pfeiffer and LaMola 1983). Consistent with these findings, evaluating the trace elements in the serum of schizophrenic patients aged between 18 and 40 years has indicated decreased level of manganese (Cao et al. 2019). ...
This book reviews the role of trace elements in brain development, function, metabolism, and neurodegenerative disorders. It explores the molecular mechanisms of the effects of trace elements on metabolic pathways, mitochondrial nutrients, neurodegeneration, Central Nervous System (CNS) disorders, cell signaling, and neuronal functions. The book also discusses transport mechanisms of trace elements within CNS and their impact on neurotransmitter biology. Further, it examines the deleterious effects due to dyshomeostasis of trace elements in the central nervous system (CNS), resulting in damage to neurons and glial cells through the generation of reactive oxygen species and oxidative stress turn leading to neurodegeneration and neurological dysfunction. The book also explores the putative role of trace element deficiency in psychiatric disorders, including depression, and the imbalance of trace elements on neuronal genomic stability.
... Correction of Fe deficiency is of paramount importance to prevent exaggerated Mn uptake. There is evidence for dietary supplementation of antioxidants such as zinc, coenzyme Q10, resveratrol, magnesium, N-acetyl-L-cysteine, ascorbic acid, and omega-3 fatty acids to prevent or reverse psychotic symptoms in general and overall neurotoxicity [89][90][91][92][93][94]. Although dietary supplements may be promising, the only definitive solution for resolution of MA-induced persistent psychotic symptoms is cessation of drug use. ...
Purpose of Review
This review describes the increasing global problem of methamphetamine (MA) use and development of psychosis, the molecular and structural basis for this form of psychosis, and its treatment. The putative contribution of manganese (Mn), a common element found widely in nature and industry, to the development of MA-induced psychosis is discussed in relation to its shared toxicity with MA.
Recent Findings
Both MA and Mn cause damage to brain monoaminergic, glutaminergic, and GABAergic systems and to the blood brain barrier, leading to higher exposure to Mn. Iron (Fe) deficiency can also lead to Mn overexposure. Polymorphisms for genes encoding metabolic enzymes and transport proteins increase risk of toxicity and development of psychosis. Impaired hepatic Mn excretion from viral hepatitis also risks Mn toxicity.
Summary
It is possible that potential synergistic and/or additive effects of Mn in concert with MA may worsen, prolong, or shorten onset of psychosis.
... This element has a great interest of researchers in a variety of mental disorders, e.g. schizophrenia, wilson's disease and pick's disease [37]. Previous study has confirmed that excessive exposure to manganese stimulates neurotoxicity as a result of accumulation of this trace element in the mitochondria of brain [38]. ...
Schizophrenia is a mental disorder with abnormality in social behaviour and failure to understand what is real. It has been found that approximately 1% of the population worldwide is affected with schizophrenia. Although several studies have been conducted to assess and try to early detection of schizophrenia, however most of these studies still deficient. Therefore, this study was design to investigate and evaluate the expected association between the levels of trace elements (Se, Cu, Zn, Ni, Cr, Mn, Mg, Pb, Co, Fe and Al) and the risk of schizophrenia. Levels of these elements were determined in sera of 60 patients with schizophrenia using atomic absorption spectrophotometry technique and the alterations of these critical variables were analyzed in comparison with 60 healthy controls to try prediction of the occurrence and progression of disease. The results obtained showed a significant increase in the levels of Se, Cu, Ni, Cr and Mn, in contrast to significant decrease in the levels of Zn, Mg, Pb, Co and Al in schizophrenic patients compared to the healthy control group. The data analysis revealed the presence of valuable correlations between most of elements in schizophrenic patients. According to the finding of the present work, it can be suggested that these elements may have a vital role and prognostic significance in complex disorders leading to schizophrenia. The real mechanism responsible for the alterations in elements levels in patients with schizophrenia is unclear and requires additional evaluation. Therefore, further universal studies are wanted in order to advance understanding of the relationship between trace elements and their role in schizophrenia.
... Manganese is a cofactor with many cellular enzymes, especially those with antioxidant activity [40]. Several studies have attempted to examine the expected role of Mn in pathogeneses of a variety of mental disorders such as Wilson's disease, Pick's disease, and schizophrenia, whereas, it has been found that this element plays an important role in mental function [41,42]. It has also been found that Mn content in hair and nails was strongly associated with chronic depression [30]. ...
Major depressive disorder (MDD) is a common mental disorder worldwide; however, little is known about its etiology. It is well known that levels of certain trace elements are associated with the pathogenesis of some diseases. Accordingly, this study aims to evaluate the effect of trace elements and vitamins in the etiology of MDD. In this case–control study, sixty men patients with MDD and sixty, age and gender matched, control subjects were examined. Serum levels of Cu, Zn, Ni, Cr, Mn, Mg, and Al were determined by atomic absorption spectrometry as well as serum levels of vitamins E and A were determined using high-performance liquid chromatography. The results revealed that there were significantly higher levels (p < 0.001) of Cu, Cr, and Al in patients sera compared with control. While there were significantly lower levels (p < 0.001) of Zn, Ni, Mn, Mg, vitamin E, and vitamin A in MDD patients as compared with control. In addition, high Cu/Zn ratio (p < 0.05) was observed with the depressive disorder patients. The present study highlights some main indications: a significant relationship between the disturbances of element levels and vitamins (E and A) with MDD. Cu and Zn seemed to have a crucial role in understanding the pathogenesis of depressive disorders, where Cu/Zn ratio could have an important role in the diagnosis and monitoring of MDD. Moreover, the results suggest that the reduction in the antioxidant vitamin E leads to increased risk of MDD. Finally, more studies on using trace element supplementation would be suggested to clarify their effect, in order to improve the therapy of MDD.
... Chang et al., 1996;Kowalczyk et al., 2003;Fonte et al ., 2007 Pfeiffer & Lamola, 1983;Langhout et al., 1999;Ajayi, 2008 ...
... Furthermore, some papers were more likely to be reviews or opinion statements than articles. [115][116][117][118][119][120][121][122][123][124][125][126][127][128][129][130][131][132] Articles were excluded if they were published before January 1970, 133-135 if they did not mention specific values (mean 6 SD), [136][137][138][139][140][141][142] or if there was a lack of a control group meeting the inclusion criteria or using baseline references for concentrations of trace elements. [143][144][145][146][147][148][149] Some articles were excluded on the basis of the specific status of cases, e.g., pregnancy, severe mental retardation, alcoholism, Parkinson disease, participation in a nutritional dietary intervention, or categorization of cases based on nutritional status, [150][151][152][153][154][155][156][157][158][159][160][161] or because they were duplicate articles. ...
Seizures are among the most common causes of apparent life-threatening events. There are discrepancies among the published reports on the correlation between epilepsy/febrile seizures and deficiency or overload of trace elements. The objective of this review and meta-analysis was to examine the present knowledge on the concentrations of the most investigated trace metals, including zinc, copper, selenium, and magnesium, in patients with epilepsy and febrile seizures. The PubMed and Scopus databases were searched to identify case-control studies that compared the concentration of zinc, copper, magnesium, and selenium in serum, hair, or cerebrospinal fluid between patients with epilepsy/febrile seizures and controls. A total of 60 articles were included in the present study (40 pertaining to epilepsy and 25 pertaining to febrile seizures). The serum concentration of zinc in nontreated patients with epilepsy was significantly higher than in controls (P = 0.034). There were significantly reduced serum concentrations of zinc (P = 0.018) and selenium (P = 0.012) in patients with febrile seizures compared with controls. The concentrations of copper, magnesium, and zinc were all significantly altered in patients with epilepsy who received antiepileptic drugs compared with untreated patients with epilepsy. Designing treatments to selectively restore zinc levels may be a strategy for treating patients with epilepsy. It is still unclear whether these ions are causal to, or a cofactor in, the development of epilepsy. Knowledge of the effects of various antiepileptic drugs on trace element homeostasis could potentially be used to effectively guide appropriate therapeutic strategies in the future.
... of its highly restrictive nature and potential to cause significant adverse effects, its use is restricted to severe cases that fail to respond to other treatments. A less restrictive version of the ketogenic diet, the Atkins diet, has shown promise and deserves further study (Gaby. 2007;Joshi et al., 1999;Peled et al., 2001;Peterson et al., 1976;Pfeiffer and LaMola. 1983;Raju et al., 1994;Sullivan et al., 1990;Tamai et al., 1988;Gaby, 2007;Torres et al., 1999;Trimble et al., 1980;Turner et al., 1977). Several different nutrients (and two hormones) may also be beneficial in selected patients with epilepsy. The fact that nutritional factors are involved in the regulation of electrical activity in the brain ...
Certain dietary contents, biological supplements might influence the occurrence or treatment of epilepsy. Some studies have found that the supplementation with individual nutrients reduced seizure frequency or improved other aspects of health in patients with epilepsy. Potentially beneficial dietary interventions include treating blood glucose dysregulations. Identifying and avoiding allergenic foods, and avoiding suspected triggering agents such as alcohol, aspartame, and monosodium glutamate. The Atkins diet (very low in carbohydrates) is a less restrictive type diet that may be effective in some cases. Nutrients that may reduce seizure frequency include vitamin B6, magnesium, vitamin E, manganese, taurine, dimethylglycine, and omega-3 fatty acids. Administration of thiamine may improve cognitive function in patients with epilepsy. Supplementation with folic acid, vitamin B6, biotin, vitamin D, and L-carnitine may be needed to prevent or treat deficiencies resulting from the use of anticonvulsant drugs. Vitamin K1 has been recommended near the end of pregnancy for women taking anticonvulsants. Melatonin may reduce seizure frequency in some cases, and progesterone may be useful for women with cyclic exacerbations of seizures. In most cases, nutritional therapy is not a substitute for anticonvulsant medications. However, in selected cases, depending on the effectiveness of the interventions, dosage reductions or discontinuation of medications may be possible. However, nutrient supplementation may be necessary to prevent or reverse the effects of certain deficiencies that frequently result from the use of antiepileptic drugs.
... Manganese has been shown to accumulate in vivo in the mitochondria of brain areas associated with neurological symptoms[15]. A lower level of Mn plays a significant role in the development of schizophrenia possibly by interfering with the membrane stability[16]. Excessive exposure to airborne manganese can result in GAD[17]. ...
The purpose of the study was to determine the concentration of serum trace and other essential elements of generalized anxiety disorder patients and to find out the relationship between element levels and nutritional status or socioeconomic factors. The study was conducted among 50 generalized anxiety disorder patients and 51 healthy volunteers. Patients were selected and recruited in the study with the help of a clinical psychologist by random sampling. The concentrations of serum trace elements (Zn, Cu, Mn, and Fe) and other two essential elements (Ca and Mg) were determined by graphite furnace and flame atomic absorption spectroscopy. Data were analyzed by independent t test, Pearson’s correlation analysis, regression analysis, and analysis of variance. The serum concentrations of Zn, Cu, Mn, Fe, Ca, and Mg in generalized anxiety disorder patients were 1.069 ± 0.40, 1.738 ± 0.544, 1.374 ± 0.750, 3.203 ± 2.065, 108.65 ± 54.455, and 21 ± 4.055 mg/L, while those were 1.292 ± 0.621, 0.972 ± 0.427, 0.704 ± 0.527, 1.605 ± 1.1855, 101.849 ± 17.713, and 21.521 ± 3.659 mg/L in control subjects. Significantly decreased (p p p > 0.05). Socioeconomic data revealed that most of the patients were in the lower middle class group and middle-aged. Mean BMI of the control group (23.63 ± 3.91 kg/m2) and the patient group (23.62 ± 3.77 kg/m2) was within the normal range (18.5–25.0 kg/m2). The data obtained from different interelement relations in the generalized anxiety disorder patients and control group strongly suggest that there is a disturbance in the element homeostasis. So changes in the serum trace element level in generalized anxiety disorder patients occur independently and they may provide a prognostic tool for the diagnosis and treatment of this disease.
... Ca is also capable of inducing structural and cognitive deficits in schizophrenia, and it has been proposed that altered Ca signaling may constitute the central unifying molecular pathology in schizophrenia [13]. Lower level of Mn plays a significant role in the development of schizophrenia possibly by interfering the membrane stability [14]. No work with scalp hair samples of schizophrenic patients has been done to determine the concentrations of Zn, Mn, Ca, Cu, and Cd. ...
The purpose of the study was to determine the serum concentration of trace elements of panic disorder patients and to find out the relationship between trace element levels and nutritional status or socio-economic factors. The study was conducted among 54 panic disorder patients and 52 healthy volunteers. Patients were recruited from Bangabandhu Sheikh Mujib Medical University by random sampling. Serum trace element concentrations were determined by flame atomic absorption spectroscopy (for Mg, Zn, Ca, and Cu) as well as graphite furnace (for Mn). Data were analyzed by independent t test, Pearson’s correlation analysis, regression analysis, and ANOVA. The serum concentration of Mn, Zn, Ca, Cu, and Mg in panic disorder patients were 0.37 ± 0.30, 0.67 ± 0.20, 99.91 ± 15.15, 0.83 ± 0.23, and 21.14 ± 3.72 mg/L, while those were 0.4163 ± 0.2527, 0.86 ± 0.3, 106.6073 ± 18.6531, 0.8514 ± 0.3646, and 21.37 ± 2.03 mg/L in control subjects, respectively. The serum concentration of Zn decreased significantly (p = 0.001) in patient group. But the differences of the concentration of Mn, Ca, Cu, and Mg between patient and control group were not significant (p = 0.522, p = 0.065, p = 0.800, and p = 0.712, respectively). Socio-economic data reveal that most of the patients were very poor and middle aged. Mean BMIs of the control group (23.74 ± 2.71 kg/m2) and the patient group (22.62 ± 3.74 kg/m2) were within the normal range (18.5–25.0 kg/m2). There was no significant relationship between serum zinc level and BMI of patients (r = 0.038; p = 0.809). So the decreased level of serum zinc in panic disorder patients was not because of other reasons, but rather it may provide a prognostic tool for the diagnosis and treatment of this disease.
... Manganese has been shown to accumulate in vivo in the mitochondria of brain areas associated with neurological symptoms[24]. Lower level of Mn plays a significant role in the development of schizophrenia possibly by interfering with the membrane stability[25]. Magnesium is a natural calcium channel blocker and significant magnesium deficiency has been reported in depression[26]. ...
The purpose of the study was to determine the serum concentration of trace elements of panic disorder patients and to find out the relationship between trace element levels and nutritional status or socio-economic factors. The study was conducted among 54 panic disorder patients and 52 healthy volunteers. Patients were recruited from Bangabandhu Sheikh Mujib Medical University by random sampling. Serum trace element concentrations were determined by flame atomic absorption spectroscopy (for Mg, Zn, Ca, and Cu) as well as graphite furnace (for Mn). Data were analyzed by independent t test, Pearson's correlation analysis, regression analysis, and ANOVA. The serum concentration of Mn, Zn, Ca, Cu, and Mg in panic disorder patients were 0.37 +/- 0.30, 0.67 +/- 0.20, 99.91 +/- 15.15, 0.83 +/- 0.23, and 21.14 +/- 3.72 mg/L, while those were 0.4163 +/- 0.2527, 0.86 +/- 0.3, 106.6073 +/- 18.6531, 0.8514 +/- 0.3646, and 21.37 +/- 2.03 mg/L in control subjects, respectively. The serum concentration of Zn decreased significantly (p = 0.001) in patient group. But the differences of the concentration of Mn, Ca, Cu, and Mg between patient and control group were not significant (p = 0.522, p = 0.065, p = 0.800, and p = 0.712, respectively). Socio-economic data reveal that most of the patients were very poor and middle aged. Mean BMIs of the control group (23.74 +/- 2.71 kg/m(2)) and the patient group (22.62 +/- 3.74 kg/m(2)) were within the normal range (18.5-25.0 kg/m(2)). There was no significant relationship between serum zinc level and BMI of patients (r = 0.038; p = 0.809). So the decreased level of serum zinc in panic disorder patients was not because of other reasons, but rather it may provide a prognostic tool for the diagnosis and treatment of this disease.
... Ca is also capable of inducing structural and cognitive deficits in schizophrenia, and it has been proposed that altered Ca signaling may constitute the central unifying molecular pathology in schizophrenia [13]. Lower level of Mn plays a significant role in the development of schizophrenia possibly by interfering the membrane stability [14]. No work with scalp hair samples of schizophrenic patients has been done to determine the concentrations of Zn, Mn, Ca, Cu, and Cd. ...
The purpose of the study was to determine the concentration of trace elements present in scalp hair sample of schizophrenic patients and to find out the relationship between trace elements level and nutritional status or socioeconomic factors. The study was conducted among 30 schizophrenic male patients and 30 healthy male volunteers. Patients were recruited from Bangabandhu Sheikh Mujib Medical University by random sampling. Hair trace element concentrations were determined by flame atomic absorption spectroscopy and analyzed by independent t test, Pearson’s correlation analysis, regression analysis, and analysis of variance (ANOVA). Mn, Zn, Ca, Cu, and Cd concentrations of schizophrenic patients were 3.8 ± 2.31 μg/gm, 171.6 ± 59.04 μg/gm, 396.23 ± 157.83 μg/gm, 15.40 ± 5.68 μg/gm, and 1.14 ± 0.89 μg/gm of hair sample, while those of control subjects were 4.4 ± 2.32 μg/gm, 199.16 ± 27.85 μg/gm, 620.9 ± 181.55 μg/gm, 12.23 ± 4.56 μg/gm, and 0.47 ± 0.32 μg/gm of hair sample, respectively. The hair concentration of Zn and Ca decreased significantly (p = 0.024; p = 0.000, respectively) and the concentration of Cu and Cd increased significantly (p = 0.021; p = 0.000, respectively) in schizophrenic patients while the concentration of Mn (p = 0.321) remain unchanged. Socioeconomic data reveals that most of the patients were poor, middle-aged and divorced. Mean body mass indices (BMIs) of the control group (22.26 ± 1.91 kg/m2) and the patient group (20.42 ± 3.16 kg/m2) were within the normal range (18.5−25.0 kg/m2). Pearson’s correlation analysis suggested that only Ca concentration of patients had a significant positive correlation with the BMI (r = 0.597; p = 0.000) which was further justified from the regression analysis (R
2 = 44%; t = 3.59; p = 0.002) and one-way ANOVA test (F = 3.62; p = 0.015). A significant decrease in the hair concentration of Zn and Ca as well as a significant increase in the hair concentration of Cu and Cd in schizophrenic patients than that of its control group was observed which may provide prognostic tool for the diagnosis and treatment of this disease. However, further work with larger population is suggested to examine the exact correlation between trace element level and the degree of disorder.
... Elevated kryptopyrroles have been associated with an inborn error of pyrrole chemistry, but also can result from porphyria or exposure to heavy metals, toxic chemicals, and other conditions enhancing oxidative stress. This imbalance results in a striking deficiency of pyridoxine and zinc and is associated with poor stress control and explosive anger [13,14,16,28,29]. Treatment for this pyrrole disorder involved supplements of pyridoxine, pyridoxal-5-phos- phate, zinc, and Vitamins C and E. ...
Unlabelled:
Reduced violent behavior following biochemical therapy. We conducted an outcome study to measure the effectiveness of biochemical therapy for 207 consecutive patients presenting with a diagnosed behavior disorder. The treatment protocols were based on clinical evaluation and our past experience in the treatment of 8000 patients with behavior disorders at the Pfeiffer Treatment Center (PTC) over a 10-year period. Each test subject was screened for chemical imbalances previously found in high incidence in this population, including metal-metabolism disorders, methylation abnormalities, disordered pyrrole chemistry, heavy-metal overload, glucose dyscontrol, and malabsorption. The clinical procedure included a medical history, assay of 90 biochemical factors, and a physical examination. Standardized treatment protocols were applied for each imbalance that was identified. The frequencies of physical assaults and destructive episodes were determined using a standardized behavior scale before and after treatment, with follow-up ranging from 4 to 8 months.
Results:
Seventy-six percent of the test subjects achieved compliance during the treatment period. The remaining 24% were reported to have discontinued the therapy. A reduced frequency of assaults was reported by 92% of the compliant assaultive patients, with 58% achieving elimination of the behavior. A total of 88% of compliant destructive patients exhibited a reduced frequency of destructive incidents and 53% achieved elimination of the behavior. Statistical significance was found for reduced frequency of assaults (t=7.74, p<0.001) and destructive incidents (t= 8.77, p<0.001). The results of this outcome study strongly suggest that individualized biochemical therapy may be efficacious in achieving behavioral improvements in this patient population.
Trace elements are essential nutrients exist in all organisms in small amounts. They are involved in many physiological processes in the nervous system, but they have two faces; they may be beneficial and/or detrimental. Trace elements are mainly provided by diet, however, some of them exist in environment. Chronic exposure to high levels of some trace elements can lead to toxic effects on all parts of the body, especially the nervous system. Trace elements play important roles in mental health due to the involvement in learning and memory, mood, affective and social behaviors, cognitive processes, etc. Disturbance in their homeostasis is associated with pathogenesis of mental diseases and neuropsychiatric disorders. In this chapter, the role of trace elements in neuropsychiatric disorders including depression, anxiety, and schizophrenia will be reviewed.KeywordsTrace elementsZincCopperManganeseMagnesiumSeleniumNeuropsychiatric disordersDepressionAnxietySchizophrenia
Background: Numerous studies have shown that serum levels of trace elements including zinc play an essential role in regulation of hypertension. Objective: The objective of current study is to evaluate the differences in serum zinc levels among hypertensive and non-hypertensive male participants from Peshawar Khyber Pakhtun Khwa in Pakistan. Method: The study comprised of 140 adult males (70 hypertensive and 70 non-hypertensive). The subject’s age, weight, heights, and medical histories were acquired with informed consent on a well-designed proforma. Fresh blood samples were taken from 140 male participants in a Gel tube. The lipid profile test assessed total cholesterol, triglycerides, low-density lipoprotein, and high-density lipoprotein. An atomic absorption spectrophotometer with an acetylene flame was used for determination of serum zinc levels under normal conditions (Model Perkin Elmer AAS 700). Results: The mean serum zinc level (0.07115mg/dL) was lower in hypertensive subjects in comparison with non-hypertensive subjects (0.3428mg/dL).Conclusion: The mean serum zinc level in hypertensive subjects was lower than in non-hypertensive subjects.
Dosadašnja istraživanja koncentracija elemenata u tragovima u kosi i ostalim
biološkim matricama kod osoba sa shizofrenijom davala su kontradiktorne rezultate.
Mogući uzrok tome vjerojatno su nedovoljno osjetljivi analitički postupci i različite
metode mjerenja koje su upotrebljavane u istraživanjima.
Uvod
Bioelementi ili elementi u tragovima su sastavni dio enzima i
hormona koji reguliraju biološke funkcije. U ljudskom organizmu
u normalnim razinama bitni su za fiziološke procese, ali u stanju
deficijencije mogu stimulirati alternativne signalne putove te
uzrokovati različite bolesti. Stoga, neravnoteža u optimalnoj
razini elemenata u tragovima, ali i u njihovim međusobnim
omjerima može nepovoljno utjecati na biološke procese i pojavu
raznih poremećaja.
U ovom članku osvrnut ćemo se na njihovu, još uvijek nedovoljno razjašnjenu ulogu u patogenezi
shizofrenije. Shizofrenija je heterogena skupina psihotičnih kroničnih mentalnih poremećaja s
progredirajućim tijekom čija višefaktorska etiopatologija uključuje genetsku, organsku,socijalnu i
psihodinamsku komponentu nastanka i razvoja. Obzirom na navedeno, shizofreniju je ispravnije nazvati
kliničkim sindromom koji čini skupinu mentalnih i bihevioralnih fenomena.
In this review, we study the effect of various vitamins in the epileptic patients. These vitamins are generally may reduce seizure frequency and treating adverse effect of anticonvulsant drugs. Supplementation with folic acid, vitamin B6, vitamin E, biotin, vitamin D, may be needed to prevent or treat deficiencies resulting from the use of anticonvulsant drugs. Thiamine may improve cognitive function in the epileptic patients. Vitamin K1 has been recommended near the end of pregnancy for women taking anticonvulsant drugs. Vitamins therapy is not a substitute for anticonvulsant medications.
Even though manganese has been known for a long time to be officially an essential trace element, it is still greatly underrated. One of the reasons may be the assumption that as the trace mineral is fairly widely distributed in most foodstuffs so manganese deficiencies will not arise, therefore there is nothing to worry about. Unfortunately this assumption is not correct. Even if dietary manganese deficiency was not detrimental to healthy non-pregnant adults, an adequate amount of this trace mineral would be absolutely vital during gestation for normal foetal growth and development. This being the case, all would-be mothers should be informed about the importance of adequate dietary manganese before and during pregnancy. The medical profession is already stressing the importance of folic acid in the prevention of spina bifida. Similar action should be taken with manganese. In order to assess body manganese status, blood tests are unfortunately misleading, as normal human blood shows widely varying concentrations of the trace element, with higher concentrations in the red cells than in the serum. However, hair mineral analysis, when using correct measures and sample preparations, is an extremely valuable diagnostic tool for obtaining body manganese status. Hair mineral analysis is also an outstanding way to find out whether the would-be mother may also be suffering from heavy metal contamination, such as lead and/or cadmium, both known to lead to low birth-weight infants. Low birth-weight in turn has been associated, in later years, with a great variety of both neurological and physical defects. If hair mineral analysis records low manganese status, manganese supplementation should be prescribed. Fortunately manganese is well tolerated, due to its highly efficient excretory mechanism, its absorption not increasing above that which the body needs. However, it should be noted, that most trace metals exert an inhibitory effect on the absorption of others. Therefore, it would be prudent to prescribe a balanced vitamin/mineral combination, which includes sufficient manganese, in order to avoid creating deficiencies in others. Particularly, an adequate dietary zinc status is known to be absolutely vital both for reproduction and for healthy foetus development. In conclusion, manganese, with other trace elements and vitamins is absolutely essential in the development of a healthy babe. Therefore, all would-be mothers must be made immediately aware of this most important fact, as they have now been made aware of the importance of folic acid in the prevention of spina bifida. As seen from this discussion, the lack of manganese can also lead to a variety of foetal malformations. The sooner this point is put forward, the better, as the latest U.K. statistics reveal that out of every 100 live births, six babies are now born either with 'minor' or 'major' physical malformations. Furthermore, one in four babies are now born with some degree of learning disability and/or mental deficiency. These statistics are absolutely appalling! After all, our children are our future, so we must try our utmost to secure their future. Presently, because of our ignorance of basic reproductive biochemistry, we seem to be re-populating our world with the physically sick and the mentally infirm.
Psychological/behavioural treatmentsExerciseMusicHerbal medicineDietary measuresHomeopathyAcupunctureTranscranial magnetic stimulationChiropractic treatmentConclusions
References
Various dietary components, biological supplements might influence the incidence
or management of epilepsy. Some studies reported that the supplementation with
individual nutrients reduced seizure occurrence or improved other facets of health in
epileptic patients. The beneficial dietary involvement identifying and avoiding
allergenic foods, and avoiding suspected causing agents such as alcohol, aspartame,
and monosodium glutamate. The Atkins diet (very low in carbohydrates) is a less
preventive type diet that may be effective in some cases. Nutrients that may lessen
seizure occurrence include vitamin B6, magnesium, vitamin E, manganese, taurine,
dimethylglycine, and omega-3 fatty acids. Use of thiamine or vitamin B1 may
improve cognitive function in epileptic patients. Supplementation with folic acid,
vitamin B6, biotin or viatamine H, vitamin D, and L-carnitine may be needed to
prevent or treat deficiencies resulting from the use of antiepileptic drugs. Vitamin K1
is recommended near the end of pregnancy for women taking antiepileptic drugs.
Melatonin may reduce seizure occurrence in some cases, and progesterone may be
useful for women with cyclic exacerbations of seizures. In the majority of cases,
nutritional therapy is not a substitute for antiepileptic drugs. In some cases,
depending on the effectiveness of the involvement, dosage reduction or
discontinuation of drugs may be possible. However, nutrient supplementation may
be necessary to prevent or reverse the effects of certain deficiencies that regularly
result from the use of antiepileptic drugs.
Psychological treatmentsExerciseMusicHerbal medicineDietary measuresHomoeopathyAcupunctureTranscranial magnetic stimulationChiropractic treatmentConclusions
Acknowledgement
The authors have verified that retina dysfunction in patients suffering from chronic pancreatitis could be demonstrated by
the help of electroretinography and eliminated or significantly corrected by administration of pancreas enzyme preparations.
The retinograph may be applied successfully in the diagnosis of chronic pancreatitis and also in evaluation of the efficacy
of the substitution treatment. The insufficiency of zinc absorption may play a definite role in the development of these functional
disturbances. It has also been established that lower zinc values parallel with the decrease of the stool fat contents in
patients suffering from chronic pancreatitis and can be significantly improved by enzyme preparations.
Homeostasis of metal ions such as Zn(2+) is essential for proper brain function. Moreover, the list of psychiatric and neurodegenerative disorders involving a dysregulation of brain Zn(2+)-levels is long and steadily growing, including Parkinson's and Alzheimer's disease as well as schizophrenia, attention deficit and hyperactivity disorder, depression, amyotrophic lateral sclerosis, Down's syndrome, multiple sclerosis, Wilson's disease and Pick's disease. Furthermore, alterations in Zn(2+)-levels are seen in transient forebrain ischemia, seizures, traumatic brain injury and alcoholism. Thus, the possibility of altering Zn(2+)-levels within the brain is emerging as a new target for the prevention and treatment of psychiatric and neurological diseases. Although the role of Zn(2+) in the brain has been extensively studied over the past decades, methods for controlled regulation and manipulation of Zn(2+) concentrations within the brain are still in their infancy. Since the use of dietary Zn(2+) supplementation and restriction has major limitations, new methods and alternative approaches are currently under investigation, such as the use of intracranial infusion of Zn(2+) chelators or nanoparticle technologies to elevate or decrease intracellular Zn(2+) levels. Therefore, this review briefly summarizes the role of Zn(2+) in psychiatric and neurodegenerative diseases and highlights key findings and impediments of brain Zn(2+)-level manipulation. Furthermore, some methods and compounds, such as metal ion chelation, redistribution and supplementation that are used to control brain Zn(2+)-levels in order to treat brain disorders are evaluated.
This article reviews research on the use of diet, nutritional supplements, and hormones in the treatment of epilepsy. Potentially beneficial dietary interventions include identifying and treating blood glucose dysregulation, identifying and avoiding allergenic foods, and avoiding suspected triggering agents such as alcohol, aspartame, and monosodium glutamate. The ketogenic diet may be considered for severe, treatment-resistant cases. The Atkins diet (very low in carbohydrates) is a less restrictive type of ketogenic diet that may be effective in some cases. Nutrients that may reduce seizure frequency include vitamin B6, magnesium, vitamin E, manganese, taurine, dimethylglycine, and omega-3 fatty acids. Administration of thiamine may improve cognitive function in patients with epilepsy. Supplementation with folic acid, vitamin B6, biotin, vitamin D, and L-carnitine may be needed to prevent or treat deficiencies resulting from the use of anticonvulsant drugs. Vitamin K1 has been recommended near the end of pregnancy for women taking anticonvulsants. Melatonin may reduce seizure frequency in some cases, and progesterone may be useful for women with cyclic exacerbations of seizures. In most cases, nutritional therapy is not a substitute for anticonvulsant medications. However, in selected cases, depending on the effectiveness of the interventions, dosage reductions or discontinuation of medications may be possible.
Nutritional deprivation in the early stage of life increases the risk of developing schizophrenia. Oxidative stress, disturbed thinking and irrational behavior which are common to schizophrenic patients may be a result of changes in the levels of certain trace metals.
Twenty (20) healthy volunteers and a total of thirty-five (35) schizophrenic patients consisting of 20 on antipsychotic drugs for at least 2 weeks and 15 newly diagnosed but not taking antipsychotic drugs were considered. The plasma levels of trace metals were analyzed using atomic absorption spectrophotometer.
Fe and Se were significantly reduced in newly diagnosed and medicated-schizophrenic patients compared with controls. Pb, Cd and Cr were significantly raised in newly diagnosed drug free schizophrenic patients compared with controls. While Cr and Cd were significantly raised in schizophrenic patients on treatment compared with the controls.
Levels of certain nutritionally essential trace metals (Fe and Se) were reduced while levels of certain heavy metals (Pb, Cr and Cd) were raised in schizophrenic patients.
As an essential substance, zinc is involved in maintaining the functions and/or the structures of at least 200 metalloenzymes that participate in numerous biochemical reactions, including the metabolism of proteins and nucleic acids. The steady-state concentration of zinc in the brain must be regulated firmly since both an excess and a deficiency of zinc have been implicated in neurological disorders including epilepsy. Zinc-binding proteins have been detected in the bovine hippocampus, cerebellum, and pineal gland. A metallothionein-like protein has been identified recently in the rat brain which resembles in some but not all aspects a hepatic metallothionein. The synthesis of this protein is stimulated following the administration of zinc and copper but not of cadmium. The zinc-stimulated protein incorporates 35S cysteine 24-fold higher than the native, unstimulated protein; is blocked by actinomycin D; produces two isoforms by ion exchange chromatography on DEAE Sephadex A 25 columns; and by high performance liquid chromatography, depicts a similar but not identical profile to zinc-stimulated hepatic metallothionein. Since the synthesis of this protein is stimulated following the administration of zinc and is depressed in the brains of zinc-deficient rats, it is postulated that the unbound pool of zinc may serve as one of the factors involved in regulating the synthesis of this protein. Since zinc in physiological concentrations stimulates a number of pyridoxal phosphate-dependent reactions and in pharmacological doses inhibits an extensive number of SH-containing enzymes and receptor sites for neurotransmitters, we postulate that the metallothionein-like protein in the brain may have function(s) associated with zinc homeostasis and perhaps events related to synaptic functions.
It has long been accepted that schizophrenia is primarily a physical illness resulting from a chemical imbalance in the brain. This paper will review evidence supporting the hypothesis that histamine and prostaglandins are both linked and primary in the etiology of schizophrenia. Furthermore, their etiological significance supersedes the role of dopamine as a primary causative factor.
Non-Asian individuals with Down syndrome are much more likely to develop epileptic seizure disorders than individuals without Down syndrome. Examination of nutrient and metabolite levels in patients with these two seemingly disparate disorders reveals numerous similarities. Compared to individuals without these disorders, individuals with Down syndrome and individuals with seizures may have lower levels of vitamin A, vitamin B1, folate, vitamin B12, vitamin C, magnesium, manganese, selenium, zinc, carnitine, carnosine, choline, and possibly serine. Excesses of copper, cysteine, phenylalanine, and superoxide dismutase are also sometimes encountered in both disorders. In addition to common nutritional lower levels and excesses, disorders of metabolism involving vitamin B6, vitamin D, calcium, and tryptophan may play a common role. This paper hypothesizes that nutritional factors may account for the high joint occurrence of these conditions. Further examination of these data may provide insights into nutritional, metabolic and pharmacological treatments for both conditions.
Over the past 60 years there have been fundamental changes in the quality and quantity of food available to us as a nation. The character, growing method, preparation, source and ultimate presentation of basic staples have changed significantly to the extent that trace elements and micronutrient contents have been severely depleted. This trend, established in a review of the 5th Edition of McCance & Widdowson's The Composition of Foods, is still apparent in this review of the 6th edition of the same work. Concurrently there has been a precipitous change towards convenience and pre-prepared foods containing saturated fats, highly processed meats and refined carbohydrates, often devoid of vital micronutrients yet packed with a cocktail of chemical additives including colourings, flavourings and preservatives. It is proposed that these changes are significant contributors to rising levels of diet-induced ill health. Ongoing research clearly demonstrates a significant relationship between deficiencies in micronutrients and physical and mental ill health.
Serum pituitary levels of growth hormone (GH), thyrotropin (TSH), prolactin (PRL), luteinizing hormone (LH) and follicle stimulating hormone (FSH) were measured in sexually mature (adult) and sexually immature (juvenile) male rats who had been deprived of dietary zinc for 15 and 7 weeks, respectively. When compared to pair-fed control rats receiving a zinc supplemented diet, both the adult and juvenile zinc deficient rats had significantly lower body weights, tail lengths and ventral prostate weights. The testes of the sexually immature rats were also smaller than those of the pair-fed animals. In sexually mature, zinc deficient rats serum concentrations of GH and testosterone were significantly lower and serum LH levels significantly higher than in ad libitum fed control rats. Pituitary and hypothalamic levels of other hormones did not differ from values recorded in control animals. In sexually immature zinc deficient rats serum concentrations of GH were also significantly depressed; pituitary content and concentration of LH and pituitary and serum levels of FSH were significantly increased over control values. No discernible effects of zinc deficiency upon hyplthalamic content of LH-releasing hormone or serum concentrations of PRL or TSH were recorded in juvenile rats. Zinc deficiency has minimal effects upon the hypothalamic-pituitary axis of sexually mature rats. In sexually immature males, zinc deprivation leads to impairment of gonadal growth and increased synthesis and/or secretion of the pituitary gonadotropins.
High copper or low zinc levels of hair may indicate schizophrenia. Low manganese may indicate schizophrenia. High calcium and magnesium may indicate hypoglycemia. High lead indicates proximity to vehicular traffic, and high mercury may indicate poisoning or the use of mercury containing shampoos. A high zinc level may indicate vitamin B6 deficiency. Low sodium and potassium may indicate adrenal cortical stress.
Earlier work in the authors' laboratory showed that protein level in the diet of gravid rats affected the behavior of the offspring. The essential trace element zinc is importantly concerned with the process of RNA and protein synthesis in higher animals and man. Furthermore, varying degrees of zinc deficiency are felt to exist for a wide range of the world's population. Studies were begun to investigate the effects of a chronic mild zinc deficiency on maternal behavior in rats and the behavior of their offspring. Dams were studied over a period of three consecutive pregnancies and litters were sampled for measures of learning ability and level of emotionality. A zinc level of 15 ppm caused unequivocal trauma to parturition and postpartum maternal behavior. Offspring clearly manifested impaired behavior. Results are interpreted as reflecting a competition of mother and fetus for the marginal level of nutrient.
A twenty year old woman presented herself for routine examination after she had taken between 440 and 5700 mg elemental zinc or an average of 2300 mg every day for four months. The most striking laboratory findings were a serum zinc level of 1160 mcg/dl, a serum copper of 8 mcg/dl and undetectable ceruloplasmin. The patient was severly anemic and showed macrocytosis and neutropenia. Other abnormal parameters were a slightly elevated serum glucose, slightly depressed serum globulin and total protein, a very high alkaline phosphatase and low cholesterol. Polyamines were normal. Oral copper therapy and cessation of excess zinc produced remarkable reversal of all abnormal parameters beginning in the first week and virtual recovery of anemia and neutropenia by the fourth week post-treatment. Polyamine levels increased to between four and ten times normal during the period of accelerated blood formation, then reverted to normal. Macrocytosis rather than microcytosis in zinc toxicity or severe copper deficiency has been seen only in cases where generous supplements of vitamin C were supplied as in this case. There is a strong likelihood that the vitamin C fortuitously prevented even more severe anemia. The possible benefit of vitamin C and of zinc gluconate vs. zinc sulfate in zinc therapy is discussed. It appears that with proper monitoring, far larger doses of zinc than are now customary may be used if found to be therapeutically valuable.
The activity of thymidine kinase was found to be substantially reduced in brains and livers of zinc deficient rat fetuses after 20 days gestation. The levels of enzyme activity in the brain were reduced by 53% when compared with the restricted fed controls, and by 30% when compared with the ad lib fed group. The activities in the liver were reduced by 34% and 31%, respectively. In vitro addition of zinc did not alter the enzyme activity, even in the case of the zinc deficient preparation. The stability of the enzyme at 37°C was not affected by addition of zinc, however, preparations of the enzyme from the brain were considerably more stable than those from the liver.
This chapter discusses zinc deficiency and copper excess in the schizophrenias. Zinc and copper are well-known biological antagonists. Schizophrenics may have low levels of zinc, manganese, chromium, and molybdenum but may also contain high levels of copper, iron, cadmium, and mercury. Plasma zinc levels are significantly reduced in acute liver diseases, active tuberculosis, indolent ulcer, myocardial infarction, Down's syndrome, cystic fibrosis, growth retardation, pregnancy, and oral contraceptive therapies. Hypoglycemias occur frequently in psychic disorders and are misdiagnosed as schizophrenias. Human brain appears to contain more than one type of copper protein, and the one so far isolated has been designated as cerebrocuprein. Its physical properties are almost identical to the copper protein isolated from human liver and from human erythrocytes. Its physiological significance has not been assessed. Copper is an essential trace element and is necessary for supporting life, but an excess in the body can be toxic because the copper ions can inactivate enzymes by reacting with their sulfhydril groups. Porphorins act as chelating agents to increase urinary excretion of both copper and zinc.
A syndrome is described in the mauve-positive, urinary kryptopyrrole-ex-creting patient which has many distinguishing features, namely: (1) white spots in nails; (2) failure to remember dreams; (3) sweetish breath odor; (4) left upper quadrant abdominal pain; (5) dysperceptive schizophrenia and neurological-metabolical symptoms. These patients excrete urinary pyrroles at a level above 20 mcg percent. The usual age of onset is 15 to 20 years of age when the patient encounters the stress of senior year high school or first year of college. Kryptopyrrole has been shown to combine chemically with pyridoxal which then complexes with zinc to produce symptoms of vitamin B6 and zinc deficiency. The incidence is 30 to 40 percent in schizophrenics and 5 to 10 percent in normals. The disorder is familial and is responsible for the high incidence of "schizophrenia" in families. Adequate doses of 86 (up to 3.0 gm/day) and zinc will relieve the symptoms and reduce the urinary excretion of kryptopyrrole to the normal range. Discontinuation of the B6 -zinc results in a rapid return of serious symptoms within 48 hours. Work is progressing on the biochemical nature of stress-induced formation of kryptopyrrole.
Summary A direct method is presented for the determination of manganese in whole blood or serum by atomic absorption spectroscopy, using a graphite furnace with a temperature ramp controller. Blood or serum is diluted with an equal volume of a five percent solution of Triton-X100 containing heparin. This prevents the blood from coagulating and produces a solution with a viscosity suitable for injection into the furnace. The determination is linear in the range of 0-20 ppb with recoveries of around 100 percent. Blood levels from control subjects have a mean of 14.8 ppb, while serum levels are 1.2 ppb. A clinical application of the method is presented in a comparison of blood manganese levels in a group of patients with seizure activity as compared to a control
Used manganese chelate to treat drug-induced withdrawal and tardive dyskinesia in 15 18-70 yr old psychiatric inpatients; 10 patients also received niacin or niacinamide. After manganese, 4 cases showed dramatic and almost immediate cure, 9 showed definite improvement in 2-5 days, and only one case was unresponsive. The latter case demonstrated almost complete cure within a few hours after niacin therapy. In 8 other cases in which niacin was used, the drug significantly elevated mood and cleared the sensorium. In all 7 cases that received niacinamide, the sensorium was cleared, and in 2 of these there was significant improvement in extrapyramidal symptoms. It is concluded that manganese is of value in many cases of drug-induced withdrawal and tardive dyskinesia and may be of value in preventing these symptoms. It is suggested that niacin and niacinamide may be of some value in many cases of drug-induced extrapyramidal syndrome. The 15 case histories are appended. (55 ref) (PsycINFO Database Record (c) 2012 APA, all rights reserved)
A three-dimensional image of zinc-induced brain tubulin sheets has been reconstructed by computer from digitized electron microscope images of negatively stained specimens. Different views of the sheets were obtained by tilting the specimens in the microscope and also by sectioning normal to the plane of the sheets. The overall resolution of the data is about 2 nm. The features of the resulting three-dimensional model suggest an explanation for the somewhat variable appearance of tubulin subunits in electron microscope images of negatively stained intact and opened-out microtubules.
Abstract Mice given 64CuCl2 and 65ZnCl2 (10 μmol/kg) were treated with sodium diethyldithiocarbamate (0.5 mmol/kg). The treatment increased the brain level of radioactive copper five-fold and that of radioactive zinc three-fold. Such redistribution of metal ions may be explained from the formation of lipophilic metal chelates. The increased brain levels may involve neurotoxic effects.
At a recent panel on Otology, I asked the audience for a show of hands of those using Zinc for delayed healing and granulations. It was surprising to note that not more than 4 physicians out of 100 had tried Zinc. The need to report our encouraging results was apparent. From 1971 to 1975, 544 tympanoplasties and 122 mastoidectomies were studied for delayed healing due to granulations. Forty-six patients were found to have resistant granulations. Thirty-three of these healed within two weeks of therapy, 10 more required a total of four weeks for healing, and three did not respond well. Sixteen patients had recurrence when the medication was terminated as soon as healing had occurred but responded well when the medication was continued for four weeks after healing was complete. Five patients had nausea, which subsided when the dosage was reduced from the usual 200 mg. of Zinc Sulfate, three times daily with meals to 100 mg., t.i.d. or b.i.d. One patient developed mild urticaria.
Zinc therapy is apparently indicated in granulomata of the ear when healing does not occur with conventional therapy, especially in the postoperative patient; however, it will not suffice when there is massive involvement of the mastoid or middle ear, where surgical removal is indicated.
The three-dimensional structure of porcine brain tubulin in planar sheets formed in the presence of zinc has been determined to a resolution of approximately 20 Å by electron microscopy and image reconstruction on negatively stained samples. The samples were prepared with a mica floatation technique, which yields tubulin sheets with 36 reciprocal space maxima on lattice lines at 21, 28, 42 and 84 Å−1 in Fourier transforms of digitized images. In order to obtain three-dimensional data, sheets were tilted with the goniometer stage of the electron microscope to provide images at various angles between 0 ° and ± 60 °. Transforms of 33 tilted images plus the transform of untilted sheets based on an average of nine untilted images were combined to give the third dimension of reciprocal space (z∗). These data, were expressed in terms of the phases and amplitudes along the z∗ lattice line for each of the 36 maxima observed in untilted samples, as well as five additional lattice lines which have zero-amplitudes in the non-tilted central section of the three-dimensional transform. Home of these zero-amplitudes arise from systematic absences which are due to a 2-fold screw axis relating adjacent protofilaments of tubulin in the zinc-induced sheets. Thus in the three-dimensional reconstructions of the sheets a polarity of the protofilaments is apparent, with adjacent protofilaments aligned in opposite directions to give an antiparallel pattern, in contrast to normal microtubules composed of protofilaments in parallel alignment. Two classes of morphological units, each with a mass corresponding to a molecular weight of about 55,000, are found to alternate along the protofilaments. These distinct morphological units are identified as the α and β subunits of tubulin, confirming the representation of tubulin as an αβ heterodimer. Furthermore, the extensive internal contact between subunits within a dimer can readily be distinguished from the less extensive contact between dimer units. Such differences in contacts were not apparent in the earlier two-dimensional reconstructions. In addition, areas of excluded stain joining one class of subunits to the subunits of the other class in adjacent protofilaments have been resolved for tubulin polymerized in zinc-induced sheets. Of the two classes of subunits one is distinguished by a prominent cleft. Identification of which class of subunits is α and which is β is not yet possible.
Stripped human hemoglobin was shown to have a high apparent zinc association constant of 1.3 X 10(7) M-1 with a stoichiometry of one zinc for every two hemes. The saturation of this site produces a dramatic 3.7-fold increase in the oxygen affinity. The effect of zinc on the oxygen affinity is interrelated with the interaction of 2,3-diphosphoglyceric acid (2,3-DPG) and hemoglobin. Thus, a smaller zinc effect is observed in the presence of added 2,3-DPG. Information about the location of the zinc-binding site responsible for the increased oxygen affinity has been obtained by comparing the binding of zinc to various hemoglobins. Blocking the beta93 sulfhydryl group decreases the apparent zinc association constant by an order of magnitude. The substitution of histidine-beta143 in hemoglobin Abruzzo [beta143 (H21) His leads to Arg] and hemoglobin Little Rock [beta143 (H21) His leads to Gln] decreases the apparent zinc association constant by two orders of magnitude. The substitution of histidine-beta143 by other amino acids and the reaction of the beta93 sulfhydryl group are known to produce dramatic increases in the oxygen affinity. The binding of zinc to one or both of these amino acids can, therefore, explain the zinc-induced increase in the oxygen affinity.
Borderline and mildly retarded children attending the hospital developmental evaluation clinic were divided into two groups on the basis of the presence or absence of a pred with a paediatric control group using blood-lead concentration as the independent variable. Children with a history of diagnosed lead posisoning were excluded from the study. The group of mentally retarded children "aetiology unknown" had statistically significantly raised blood-lead concentrations but the mentally retarded sample with "probable aetiology" showed no significant difference in lead concentrations from those of the normal controls. It is concluded that the association between lead and mental retardation extends over a much wider range than hitherto suspected and that the nature of this association is independent of a history of "encephalopathic" lead poisoning. It is suggested that physicians should consider raised lead levels in their examination of all children suspected of mental retardation and that the numerical definition of lead toxicity should be re-evaluated.
Abstract— Endogenous protein phosphorylation has been studied during in vitro polymerization of microtubules by incubating a purified tubulin preparation at 37°C in the presence of radioactive ATP. At optimal conditions the rate of phosphorylation was found to follow the course of polymerization by a shift to a lower rate at the polymerization plateau.
Zn2+ at 0.5 mm was shown to stimulate phosphorylation, mainly of tubulin-associated proteins (mol wt 110,000 and 175,000,) and to a lesser extent of tubulin. The effect occurred at Zn2+-concentrations which induce formation of tubulin sheet polymers, which suggests that the state of aggregation of tubulin is of importance for the phosphorylation. In contrast to Zn2+, Mg2+ only increased phosphorylation of the high molecular weight proteins, and to a lesser degree. The stimulation by Zn2+ or Mg2+ was potentiated by cyclic AMP or cyclic GMP.
A low concentration of Zn2+ (5 μm) or cyclic GMP at 10 μm inhibited phosphorylation, possibly by interaction with a co-existing protein phosphatase.
The authors studied the adverse effects of zinc deprivation, limited to the latter third of pregnancy, on the brain and subsequent brain function. Observations made on rats are the subject of this report.
The role of zinc in some metabolic functions in man was investigated in 14 healthy male volunteers with primarily high or low serum zinc. In all the subjects, results of laboratory tests reflecting blood picture, metabolism of carbohydrates, fats and proteins and thyroid function as well as serum calcium and phosphate levels varied within the normal range. Significant differences between the subjects classified by serum zinc were found in alpha1-globulins. Serm thyroxins, effective thyroxine ratio and the immunoglobulins IgA showed a tendency to lower levels in subjects with low serum zinc. Substitution with zinc sulphate resulted in an increase of alpha 1-globulins, serum thyroxine and effective thyroxine ratio, and a decrease of albumin. Other tests remained by the therapy. The results suggest that there is a relationship between zinc and some metabolic functions in healthy subjects without symptoms of zinc deficiency.
The current studies were undertaken to examine the effects of the various prostaglandins (PG) on zinc transport across the rat small intestine. In in vitro studies using everted jejunal sacs, the addition of PGE2 to the mucosal media increased the transport of 65Zn from the mucosal surface to the serosal surface by 54%, whereas the addition of PGF2 decreased it by 40%. In contrast, addition of PGE2 to the serosal media decreased 65Zn transport from serosa to mucosa by 37% while the addition of PGF2 increased it by 36%. Our in vivo studies showed that oral administration of PGE2 caused a 2-fold increase in the 65Zn content of rat internal organs whereas PGF2 decreased it slightly but insignificantly. Pretreatment of rats with indomethacin resulted in a significant decrease in organ 65Zn content when compared to control, when the rats were administered 65Zn by the oral route. The decrease in organ 65Zn content was overcome by the administration of PGE2. Furthermore, the administration of PGF2 to indomethacin pretreated rats caused a further and significant decrease in the 65Zn content of liver and pancreas, the two organs that have a high zinc uptake. The fact that PG had no effect on the active transport of L-[3-3H]histidine and that PGE2 and PGF2 had opposing effects on zinc transport strongly suggests that PGE2 and PGF2 act as physiological regulators of zinc transport by the intestinal mucosa, and that their effects are specific.
Because the majority of hippocampal and cerebellar development occurs postnatally, these brain regions might be expected to be very sensitive to zinc deficiency during this period. Rat pups suckled for 21 days by dams fed a zinc-deficient diet demonstrated impaired body growth and had smaller cerebella compared to pups from pair-fed or ad libitum-fed controls given adequate zinc and had smaller hippocampi compared to the ad libitum-fed controls. In histologic preparations, there was a marked retention of the external granular layer of the cerebellum in response to zinc deficiency; the appearance of the hippocampus did not seem to be altered by the dietary treatments. Determinations of DNA, RNA, and protein indicated that both brain regions failed to maintain a normal rate of development. Pups from dams pair-fed with the zinc-deficient dams also displayed alterations in the morphology of the cerebellum and in the composition of both hippocampus and cerebellum, but those differences were not as severe as those seen in the zinc-deficient pups. The results indicate additional effects due to zinc deficiency which could not be explained solely on the basis of the undernutrition associated with zinc deficiency.
The urinary excretion of histamine and its metabolites methylhistamine (MeHi) and methylimidazoleacetic acid (MeImAA) was measured during the menstrual cycle in nine healthy women, one allergic woman and three non-pregnant women with anovulatory regular cycles. Simultaneous urinary analyses of luteinizing hormone (LH) and total estrogens were performed. The healthy women showed individual variations in the excretion of histamine, MeHi and MeImAA. This observation has been interpreted as an expression of minor individual differences in the catabolism of histamine. At midcycle an increase in the urinary excretion of histamine metabolites was sometimes evident and a statistically significant correlation could be established between MeHi and estrogen in urine. These results may support previous findings of histamine release by estrogens in uterine tissue but may also reflect an elevated histamine formation. The allergic woman excreted constantly increased amounts of histamine and its metabolites, especially when her allergic symptoms became aggravated pre-menstrually. She did not exhibit any change in MeImAA excretion at midcycle but the MeHi-excretion varied with the excretion of estrogens in the urine. The subjects with anovulatory menstrual cycles had low values of histamine and metabolites although within the normal variations.
Although Dilantin may cause an increase in serum copper and ceruloplasmin concentrations, there is no such increase in serum magnesium or zinc, nor is there any apparent correlation between Dilantin concentration in serum and copper, zinc, or magnesium concentrations. (Journal received July 1976)
A deficiency of dietary zinc during the suckling period of the rat results in a depression in normal growth, which is, in part, due to the inanition experienced by the dam. The pups from such zinc-deficient dams have smaller forebrains at all of the time intervals investigated in comparison with pups from both zinc-adequate controls. The cell number of the forebrain of the zinc-deficient pup was also reduced in comparison with the zinc-adequate pups. RNA concentration did not appear to be affected, although the total RNA content was reduced because of the smaller brain size. The amount of protein per cell was reduced at 6 and 15 days in the zinc-deficient forebrain and polysomal profiles displayed abnormal distribution of material between monosomes and polysomes in the zinc-deficient brain. Zinc deficiency during the suckling period thus appears to disadvantage the animal in terms of body, brain growth, accretion of cells into the forebrain, and normal protein metabolism.
The 7S nerve growth factor (7S NGF) is an oligomeric protein consisting of three distinct classes of subunits, alpha,beta, and gamma (A. P. Smith, S. Varon, and E. M. Shooter (1968), Biochemistry 7, 3259). The beta subunit contains the growth promoting activity while gamma is a potent esteropeptidase. The proteolytic activity of gamma is virtually completely inhibited in the 7S NGF aggregate (L. A. Greene, E. M. Shooter, and S. Varon (1969), Biochemistry 8, 3735). In this paper, we report that divalent metal ion chelating agents effect a seven- to tenfold increase in the esteropeptidase activity of 7S NGF at pH 7.40. Plots of esteropeptidase activity vs. chelator concentration give saturation curves which are either sigmoidal (EDTA) or hyperbolic (o-phenanthroline) depending on the chemical structure of the chelator. A survey of common divalent metal ions shows that only zinc ion (Ki = 8 times 10(7) M) and, to a lesser extent, cadmium ion are effective, reversible inhibitors of both 7S NGF and the gamma subunit esteropeptidase activities. We have found that during isolation of 7S NGF, Zn2+ is selectively associated with the oligomer in a ratio of approximately 1-2 g-atoms of zinc/mol of 7S NGF with an apparent affinity which is orders of magnitude tighter than is indicated by the Ki value for the gamma subunit. Dialysis to pH 4.0 where 7S NGF is known to undergo a reversible dissociation (A. P. Smith, S. Varon, and E. M. Shooter (1968), Biochemistry 7, 3259) brings about a tenfold reduction in the zinc ion content of the protein. This reduction is reversed on dialysis back to pH 7.4. In contrast, the isolated subunits contain only trace amounts of zinc ion at pH 7.4. Preliminary metal ion exchange experiments indicate that, of the common metal ions known to substitute for zinc in other zinc-metalloproteins, only cadmium ion is effective in substituting for zinc ion in 7S NGF. The fact that zinc ion is specifically bound to native 7S NGF, and that the zinc ion content of the system is critically dependent on the subunit aggregation state strongly suggests that zinc ion is an integral structural component of native 7S NGF.
VERY little is known about the endocrine regulation of amniotic fluid volume and composition1,2. Vizsolyi and Perks2 have described a technique for studying the transfer of fluid across the amniotic membrane of the guinea pig in vitro. They showed that arginine vasotocin and arginine vasopressin (antidiuretic hormone, ADH) could stimulate the movement of fluid from the maternal to the foetal side of the membrane. Because prolactin is found in remarkably high concentrations (up to 10 µg ml-1) in primate amniotic fluid3,4 and affects renal function5-8, we have investigated the effect of prolactin as well as of arginine vasopressin on the guinea pig amniotic membrane. Because cortisol can reverse the usual antidiuretic effect of ADH and because prolactin can restore this effect9, we have also investigated the action of cortisol. We have shown that ADH and prolactin have opposite effects on the amniotic membrane and that, in both cases, their actions can be reversed by cortisol. We suggest that fluid transfer across the amniotic membrane may provide an insight to the functioning of the kidneys, the ciliary body and the choroid plexus.
In the concentration range 1 n m to 1 μ m , lanthanum inhibited the calcium‐dependent component of anaphylactic histamine release, but was without effect on the component which was independent of calcium.
The inhibition of anaphylactic histamine release by lanthanum can be reversed by increasing the calcium ion concentration. The pA 2 for the lanthanum‐receptor interaction was found to be 7·6.
Lanthanum also inhibited the activation of anaphylactic histamine release by strontium ions.
The inhibition of anaphylactic histamine release by lanthanum was reversed by eluting the lanthanum from the cells.
In the concentration range 1 to 300 n m , lanthanum had no effect on the histamine release induced by compound 48/80 in a calcium‐free medium, but the effect of calcium on the histamine release by compound 48/80 was antagonized by lanthanum in this range of concentrations.
At concentrations of 10 μ m and greater, lanthanum induced a release of histamine in the absence of antigen.
In the concentration range 0·5 to 40 m m , manganese inhibited the calcium‐dependent component of anaphylactic histamine release, but was without effect on the component which is independent of calcium. The inhibition of anaphylactic histamine release by manganese could be reversed by increasing the calcium ion concentration.
After exposure of rabbits to tetraethyllead, each analyzed brain area (frontal cortex, cerebellum, hippocampus) contained approximately 33 μg of lead per gram dry weight. At the same time, there was a statistically significant loss in the same brain areas of the essential elements, copper, iron, and zinc. While the molar ratio between gain of lead and decrease of copper revealed an approximate proportionality of 1:1, the ratio between lead and iron was approximately 1:2. The decrease of zinc levels varied in these brain areas and was lowest in the inferior hippocampus. The potentiality of an interference of lead with essential trace metals of the brain, preferentially with the metal group of metalloenzymes, as the primary and dominant mechanism of the toxic action of lead in lead encephalopathy, is discussed.
A sudden and dramatic rise in the level of serum creatine phosphokinase (CPK) occurs at the haemolytic crisis period of chronic copper poisoning. This suggests that changes occur in the muscle cell membrane, as well as in the liver, erythrocyte, kidney and brain, which were previously recorded. There is no evidence for muscle lesions during the passive accumulating phase of copper toxicity, and once over the crisis, the serum CPK rapidly returns to normal levels.
Serum diamine oxidase levels are significantly elevated during normal pregnancy. In normal pregnancy the activity of this enzyme and the urinary excretion of gonadotropin are inversely related. As HCG starts to decline from the peak value, diamine oxidase appears in the blood and the level increases rapidly to high values while the HCG is declining and leveling off at a lower range. In 16 molar pregnancies the serum diamine oxidase values are comparable to those in normal pregnancy during the first trimester. In later stages of molar gestation (after the 15th week) the enzyme disappears from the blood, contrary to normal pregnancy, in which it continues to rise. In 80 other patients with trophoblastic disease, one had a significantly high diamine oxidase level similar to peak levels reached during normal pregnancy, 8 had slightly elevated serum diamine oxidase levels, and 71 had no serum diamine oxidase activity. One patient of the 5 with cancers of other than trophoblastic origin had only a slig...
Normal topographic brain zinc localization and the influence of three phenothiazine tranquilizers (chlorpromazine, thioridazine, perphenazine) were studied in vitro and in vivo in eight brain regions of 80 mice and 80 rats, from one hour till 21 days after injection of 5 and 15 microcuries of zinc chloride Zn 65, respectively. Brains of untreated animals took up 0.11%, 0.24% (maximum), and 0.16% of dose per gram, one hour, 7 and 21 days, respectively, after injection. Each of the phenothiazine compounds increases the total brain zinc uptake in all animals, more in rats than in mice. Regional changes were detected in rat brains: the occipitoemporal cortex, thalamus, and hippocampus are more zincophilic, the thalamus especially under chlorpromazine and the hippocampus under perphenazine treatment.
Zusammenfassung Bei der Albinoratte findet sich 48 h nach parenteraler Verabreichung von radioaktivem Zink (Zn65) ein hoher Anteil der Aktivität in den Gewebemastzellen. Nach Verabreichung des chemischen Histaminliberators, Compound 48/80, wird ein erheblicher Teil von Zn65 aus den Zellen frei.
1. The distribution of copper, zinc and manganese in seven regions of the brain, liver, heart, muscle from the abdominal wall, and skin of children was determined by means of atomic absorption spectrophotometry.
2. The results showed significantly lower levels of Cu, Zn and Mn in livers of children with kwashiorkor compared with control subjects. The concentrations of these three elements were higher in livers of children with marasmus than in livers of children suffering from kwashiorkor and not significantly different from those of control subjects.
3. The Cu concentration in muscle obtained from the abdominal wall of subjects with kwashiorkor and the Mn concentration in heart muscle of all groups with protein-calorie malnutrition were significantly lower than the respective values for the control group.
4. There was no significant difference between Cu, Zn or Mn concentration in brain tissues of control subjects and in those with protein-calorie malnutrition.
IN RECENT years there has been an increasing interest in the possible interplay between folic acid and anticonvulsive drugs. Subnormal serum folate levels have been found in a large number of patients treated with anticonvulsive drugs (Klipstein,1 Reynolds et al,2 Reynolds,3 and Ibbotson et al4). However, Weckman and Lehtovaara5 did not find any significant difference between the serum folate levels of a group of treated epileptics and a group of nontreated normal control subjects.
Furthermore, about 50 cases are reported in which antiepileptic drugs are stated as the causative agents of a folic acid deficiency resulting in megaloblastic anemia (review by Stokes and Fortune6).
In various reports, Reynolds7 has put forward the hypothesis that the presumed forlicacid deficiency may cause dementia and schizophrenia-like psychoses in patients with epilepsy. Also, Strachan and
Henderson8 maintain that folic acid deficiency may give rise to