Sex differences in amino acids lost via sweating could lead to differential susceptibilities to disturbances in nitrogen balance and collagen turnover.

Fluid collected during sweating is enriched with amino acids derived from the skin's natural moisturising factors and has been termed "faux" sweat. Little is known about sex differences in sweat amino acid composition or whether faux sweat amino acid losses affect nitrogen balance. Faux sweat collected by healthy adults (n = 47) after exercise, and at rest by chronic fatigue patients, was analysed for amino acid composition. Healthy females had higher total amino acid concentrations in sweat (10.5 ± 1.2 mM) compared with healthy males (6.9 ± 0.9 mM). Females had higher levels of 13 amino acids in sweat including serine, alanine and glycine. Higher hydroxyproline and proline levels suggested greater collagen turnover in females. Modelling indicated that with conservative levels of exercise, amino acid losses in females via faux sweat were triple than those predicted for urine, whereas in males they were double. It was concluded that females were more susceptible to key amino acid loss during exercise and/or hot conditions. Females reporting chronic fatigue had higher levels of methionine in faux sweat than healthy females. Males reporting chronic fatigue had higher levels of numerous amino acids in faux sweat compared to healthy males. Higher amino acid loss in faux sweat associated with chronic fatigue could contribute to a hypometabolic state. Depending on activity levels, climatic conditions and gender, amino acid losses in sweat and skin leachate could influence daily protein turnover where periods of continuously high turnover could lead to a negative net nitrogen balance.

Diverse characteristics of the urinary excretion of amino acids in humans and the use of amino acid supplementation to reduce fatigue and sub-health in adults.

BACKGROUND: The excretion of amino acids in urine represents an important avenue for the loss of key nutrients. Some amino acids such as glycine and histidine are lost in higher abundance than others. These two amino acids perform important physiological functions and are required for the synthesis of key proteins such as haemoglobin and collagen. METHODS: Stage 1 of this study involved healthy subjects (n = 151) who provided first of the morning urine samples and completed symptom questionnaires. Urine was analysed for amino acid composition by gas chromatography. Stage 2 involved a subset of the initial cohort (n = 37) who completed a 30 day trial of an amino acid supplement and subsequent symptom profile evaluation. RESULTS: Analyses of urinary amino acid profiles revealed that three groups could be objectively defined from the 151 participants using k-means clustering. The amino acid profiles were significantly different between each of the clusters (Wilks' Lambda = 0.13, p < 0.0001). Cluster 1 had the highest loss of amino acids with histidine being the most abundant component. Cluster 2 had glycine present as the most abundant urinary amino acid and cluster 3 had equivalent abundances of glycine and histidine. Strong associations were observed between urinary proline concentrations and fatigue/pain scores (r = .56 to .83) for females in cluster 1, with several other differential sets of associations observed for the other clusters. CONCLUSIONS: Different phenotypic subsets exist in the population based on amino acid excretion characteristics found in urine. Provision of the supplement resulted in significant improvements in reported fatigue and sleep for 81% of the trial cohort with all females reporting improvements in fatigue. TRIAL REGISTRATION: The study was registered on the 18th April 2011 with the Australian New Zealand Clinical Trials Registry ( ACTRN12611000403932 ).

CSF-methionine is elevated in psychotic patients.

Cerebrospinal fluid levels of methionine (MET), homocysteine (HCY) and cystathionine were studied in patients with psychotic disorders (n=36) and in healthy controls (n=25). Patients had significantly higher MET than controls (p<0.00001), and ten of the patients had MET levels above anyone of the controls. Moreover, three young male patients had HCY levels highly above any of the controls. There were no significant gender differences in any of the parameters. Neither ageing nor neuroleptic treatment offered an explanation for the increase of MET, because also young and drug-naive patients had significantly higher MET than the controls. We conclude that patients with psychotic disorders, at least in a phase of acute exacerbation, are often in a state of disturbed one-carbon metabolism.

Immune modulation with a staphylococcal preparation in fibromyalgia/chronic fatigue syndrome: relation between antibody levels and clinical improvement.

The aims of this study were to evaluate the serological response to treatment with staphylococcal vaccine in fibromyalgia/chronic fatigue syndrome patients and to explore the relationship between serological response and clinical effect. Twenty-eight patients, half of whom served as controls, were recruited from a 6-month randomised trial in which repeated administration of the staphylococcal toxoid vaccine Staphypan Berna (Berna Biotech, Switzerland) was tested against placebo. Antibody status against extracellular toxins/enzymes, cell-wall components, and enterotoxins was evaluated at baseline and at endpoint. The clinical response to treatment was recorded in rating scales. In the group receiving active treatment, significant serological changes were recorded, whereas no significant changes were found in controls. Treatment led to a significantly increased capacity of serum to neutralise alpha-toxin and a significant increase in serum IgG to alpha-toxin and lipase. Furthermore, the increase in these parameters combined paralleled the improvement in clinical outcome. Thus, the greater the serological response, the greater was the clinical effect. In conclusion, this explorative study has shown that repeated administration of the Staphypan Berna vaccine in patients with fibromyalgia/chronic fatigue syndrome causes a serological response to several staphylococcal antigens, particularly to certain extracellular toxins and enzymes. The results further show that this response is related to the clinical outcome of treatment.

Vitamin B12-B6-folate treatment improves blood-brain barrier function in patients with hyperhomocysteinaemia and mild cognitive impairment.

Thirty patients had mild cognitive impairment and increased homocysteine levels in serum. On average, they were supplemented orally with a high dose of a vitamin B12-B6-folate combination for 270 days. All patients had normal serum B12 and folate levels at baseline. Cerebrospinal fluid levels of the tau protein (CSF-tau) and the albumin ratio were measured before and after treatment. The serum homocysteine levels were normalised after treatment. The albumin ratio significantly correlated with vascular risk factors. At baseline, the ratio was higher in the patients in comparison with age-matched controls. After treatment, the ratio was significantly reduced, which may indicate a tightening of the blood-brain barrier. The CSF-tau levels did not change significantly although there was a numeric decline. None of the patients progressed into dementia during the treatment period. When treated with a vitamin B12-B6-folate combination, patients with mild cognitive impairment and hyperhomocysteinaemia appear to improve their blood-brain barrier function. They may also stabilise their cognitive status. Further investigations are warranted on the role of blood-brain barrier dysfunction in the pathogenesis of dementia.

Quality of life and standard of living in a randomly selected group of psychiatrically disabled people in Sweden 2 years after a psychiatry reform.

In Sweden, a psychiatry reform, aimed at improving the living conditions of the psychiatrically disabled, came into force in 1995. The aim of the present study was to evaluate the impact of the reform by investigating quality of life and standard of living 2 years later in a randomly selected group of people with longstanding psychiatric disability. Self-ratings and interviews were conducted in a study group and a control group. The study group consisted of 19 women and 18 men (mean age 46.1 years) diagnosed with neurosis, schizophrenia or affective disorder. The control group consisted of 19 women and 17 men (mean age 48.7 years). Self-rated quality of life was significantly poorer in the study group (P < 0.0001, unpaired t-test), and so was housing (P < 0.001, test of similar proportions in independent samples). We found no significant positive correlation between subjective quality of life and standard of living in either group but a significant negative correlation in the control group (P < 0.05; r = 0.40, Pearson correlation coefficient). The results suggest that, in 1997, people with longstanding psychiatric disability still had poorer quality of life than the general population. This may be due to factors other than outward standard of living.

Treatment of Alzheimer's disease with clioquinol.

As heavy metal ions may be implicated in the formation of senile plaques in Alzheimer-afflicted brains, treatment with clioquinol was tested in 20 patients with Alzheimer's disease. Clioquinol is a chelator that crosses the blood-brain barrier and has greater affinity for zinc and copper ions than for calcium and magnesium ions. Treatment was given for 21 days at doses of 20 mg/day to 10 patients and 80 mg/day to another 10 patients. The study was blind to the dosages but included no controls. Cerebrospinal fluid (CSF) investigations revealed a significant increase at day 7 and a decrease at day 21 in Tau protein and growth-associated protein (GAP43). These proteins are increased in Alzheimer's disease and considered as rather stable markers. The initial increase may indicate a temporary cytotoxicity to the brain and/or an increased release into the CSF from stores in the tissue, possibly from senile plaques where the proteins are accumulated. The levels of CSF-Tau protein correlated positively and significantly with the serum levels of copper and also with the serum copper/zinc ratio. Clinical ratings showed slight improvement after 3 weeks treatment with clioquinol in this open study.

One-carbon metabolism and other biochemical correlates of cognitive impairment as visualized by principal component analysis.

In the present report, 101 ambulatory elderly patients complaining about cognitive disturbances were investigated using the Mini-Mental State Examination (MMSE). Laboratory investigations, brain imaging, and electroencephalography were performed. Twelve patients were diagnosed with subjective memory complaints (SMC), 32 with mild cognitive impairment (MCI), 43 with dementia of the Alzheimer type (DAT), and 14 with vascular dementia (VAD). Thirty-three percent of the SMC group, 31% of the MCI group, 45% of the DAT group, and 62% of the VAD group had increased serum homocysteine (s-HCY). Principal component analysis of 19 variables showed 3 significant principal components by cross-validation. The cognitive impairment in the patients (MMSE) was explained to 50%. According to the principal component analysis, the population followed two different routes to cognitive impairment: one correlated with disturbance of one-carbon metabolism (cerebrospinal fluid vitamin B12, plasma B12, plasma folate, and s-HCY) and the other correlated with more classic dementia, as marked by cerebrospinal fluid tau, vascular risk factors, atrophy on brain imaging, possession of the apolipoprotein E4 allele, and age. There was poor discrimination between DAT and VAD.

The exfoliation syndrome in cognitive impairment of cerebrovascular or Alzheimer's type.

The prevalence of exfoliation syndrome was studied in 39 patients suffering from dementia and cognitive impairment; a positive finding of exfoliation was detected in 11/39 of these patients. A comparison with an age-matched population survey showed that the prevalence of ocular exfoliation and the relative risk were significantly elevated. These results suggested that lesions related to the exfoliative process might be located also in the brain of patients suffering from dementia and cognitive impairment.

[Depression and anxiety in the elderly still underdiagnosed. SSRI preparations in conjunction with psychotherapy provide effective treatment]. / Depression och ångest hos äldre fortfarande underdiagnostiserade. SSRI-preparat i förening med psykoterapi effektiv behandling.

Depression and anxiety disorders in the elderly are common and under-diagnosed. As depressed elderly people often present with more somatic than psychiatric symptoms, diagnosis is difficult for the general practitioner. The Geriatric Depression Scale can be used as a screening instrument for diagnosis in the elderly. The etiology of depression and anxiety disorders is multifactorial. Important risk factors are psychological stress, reduced absorption of essential nutrients such as folacin and vitamin B12, and biological changes in the brain associated with aging. Selective serotonin reuptake inhibitors (SSRIs) are the drugs of choice in the treatment of elderly people with depression and anxiety disorders. Currently, the most widely used SSRI is citalopram, which according to controlled trials has an effect not only on depressed mood but also on anxiety. The use of SSRIs combined with support and psychotherapy elicits a positive response in nearly 90% of elderly patients. In Sweden, the use of antidepressants is currently most common in the age group 75-80 years, expressed in DDD (defined daily doses/1,000 inhabitants). This indicates a fairly active treatment of the elderly in Sweden.

Hyperactivity in the hypothalamic-pituitary-adrenal axis in demented patients with delirium.

Occurrence of delirium is known to be related to, among other things, organic brain disorder, somatic disease and old age. It has been hypothesized that delirium is also associated with stress. Disturbances of the hypothalamic-pituitary-adrenal (HPA) system have been found in delirious patients in various studies. The aim of the present study was to determine the activity in the HPA axis in demented patients to ascertain whether the stress regulating system was more disturbed in patients with delirium than in those without delirium. Demented inpatients with no acute medical illness were included in the study. Basal cortisol levels in serum were measured and dexamethasone suppression test (DST) was performed. The most important finding of the study was a strong relationship between delirium and DST pathology irrespective of age and severity of dementia. It is suggested that certain demented individuals have an impaired HPA system and a low delirium threshold and respond to stress with delirium.

The Gottfries-Bråne-Steen scale: validity, reliability and application in anti-dementia drug trials.

Neuropsychological investigation using a comprehensive rating scale is important for the diagnosis and evaluation of dementia patients over time. Requirements for such a scale include accuracy, reliability, sensitivity of the scale over the disease course and simplicity for clinical use by a wide range of healthcare professionals. Ideally, the scale should also be capable of assessing the impact of pharmacological and non-pharmacological treatment regimens on the management of dementia patients. The Gottfries-Bråne-Steen (GBS) Scale is a comprehensive global assessment tool for evaluating dementia symptoms and is based on a semi-structured interview and observation of the patient. The scale consists of subscales measuring intellectual (12 items), emotional (3 items) and activities of daily living, primarily items of self-care (6 items); as well as 6 items of behavioral and psychological symptoms of dementia. This review describes the reliability, validity and sensitivity of the most recent version of the GBS scale since its original publication in 1982.

Late life depression.

Depression has an overall prevalence of 5-8%. The prevalence of late life depression is estimated among people 65 years of age to be 15%. There is a great under-diagnosis and under-treatment of late life depression with the most serious consequence being premature death. Depression is also an important and independent risk factor for mortality following myocardial infarction, while patients with stroke associated with depression also have a higher death rate. The suicide rate is increased in elderly especially elderly men with depression. The aetiology of depression is more heterogeneous than depression in younger adults. Obviously age-related changes in the brain increase the risk for depression. Patients with neurodegenerative disorders also run a higher risk for being depressed. In Alzheimer's disease the frequency is around 50%. Deficiency of essential nutrients like folic acid and vitamin B12 is an obvious risk factor for both disorders with cognitive impairment and depression. Treatment of depression in the elderly follows the same lines as treatment of depression in younger patients. Many different drugs may be prescribed; however, the risk of adverse events is greater in the elderly. The drugs of choice are the selective serotonin re-uptake inhibitors (SSRIs), which have a response rate of around 65%. Of interest is that emotional disturbances like irritability, aggressiveness and anxiety also respond to treatment with SSRIs. A comprehensive treatment of late life depression, which includes social and psychological support, has a response rate of 80-90%.

Changes in uptake of vitamin B(12) and trace metals in brains of mice treated with clioquinol.

Clioquinol is a hydroxyquinoline antibiotic that has been associated with severe side-effects in the CNS. The syndrome caused by clioquinol treatment, subacute myelo-optic neuropathy (SMON), is considered as one of the worst drug disasters of this century. The precise biochemical mechanism behind SMON is not fully understood. Clioquinol can form strong lipophilic chelates with divalent cations and therefore it has been speculated that the drug may disturb the retention of vitamin B(12) through chelation of Co(2+). In the present study, the tissue distribution and uptake capacity of [57Co]cyanocobalamin were estimated in mice treated with clioquinol or saline. The concentrations of some trace metals were also determined in brain tissue. Accumulation of vitamin B(12) in the brain and its concentration in blood were decreased by clioquinol treatment. The mean concentrations of several trace metals were also lowered in the brain while the concentration of cobalt in the brain was not affected, suggesting that clioquinol does not bind to the cobalt in vitamin B(12). Moreover, a significant decrease in the levels of S-adenosylmethionine (SAM) was observed in the brain after clioquinol treatment. This may be a consequence of decreased vitamin B(12) levels. From these results, it can be concluded that chronic treatment with clioquinol may alter the tissue homeostasis of vitamin B(12) in the brain.

Putamen mitochondrial energy metabolism is highly correlated to emotional and intellectual impairment in schizophrenics.

In a recent study, we demonstrated that cytochrome-c oxidase (COX), an indicator of neuronal activity, is increased in several brain regions from chronic, medicated schizophrenics. In the present study, to address the functional significance of those findings, we have measured COX activity in a group of schizophrenics in whom antemortem geriatric measures of motor, intellectual, and emotional impairment had been assessed. COX activity in the putamen was strongly negatively correlated with emotional (r = -.76; p < .005) and intellectual impairment (r = -0.76; p < .005), but not with motor impairment (r = 0.01). No significant correlations could be found in the frontal cortex, thalamus, caudate nucleus, globus pallidus, mesencephalon, or nucleus accumbens. Dopamine D2 receptor density in the putamen, measured with [3H]raclopride, was elevated in schizophrenics as compared to controls, as were Kd values. In contrast to COX activity, D2 receptor binding was moderately, but significantly positively correlated with intellectual impairment (r = 0.64; p < .05) but not with motor impairment. Results expose a unique anomaly in the effects of neuroleptics in terms of increasing neuronal signaling in the putamen, which may underlie a reversal of cognitive deficits in schizophrenics, while at the same time, elevating D2 receptor density that seems to be detrimental.

The synaptic-vesicle-specific proteins rab3a and synaptophysin are reduced in thalamus and related cortical brain regions in schizophrenic brains.

Two synaptic-vesicle proteins, rab3a and synaptophysin, have been studied on post-mortem brain tissues of schizophrenics and healthy controls. We found significantly reduced levels of rab3a in thalamus (p<0.001); for both proteins in gyrus cinguli and hippocampus (p<0.0001); for rab3a in frontal and parietal cortex (p<0.05); and no differences in temporal cortex or cerebellum in schizophrenics compared with controls. Reduced synaptic density may be a prominent feature of the molecular neuropathology of schizophrenia.

Mitochondrial function is differentially altered in the basal ganglia of chronic schizophrenics.

In the present study, we have applied a novel strategy involving the postmortem measurement of the mitochondrial respiratory chain enzyme cytochrome-c oxidase (COX; complex IV) to identify regional changes in energy metabolism in the basal ganglia of chronic, medicated schizophrenics. COX activity was decreased in the caudate nucleus but increased in the putamen and nucleus accumbens. An increase in succinate dehydrogenase (complex II) was evident in the putamen and nucleus accumbens, but changes were not seen with NADH dehydrogenase (complex I). An analysis of interregional correlations in energy metabolism revealed several anomalies in the connections between the caudate and putamen and the globus pallidus in schizophrenics. Results provide strong evidence that changes in baseline energy metabolism in specific regions of the basal ganglia may exist in the disease. Based upon the high degree of input it receives from associative cortical areas, results suggest that a defect in the caudate may underlie certain aspects of cognitive decline in schizophrenics. In contrast, an increase in COX in the putamen, which receives extensive projections from the sensorimotor cortex, may reflect an effect of chronic neuroleptic treatment on motor function.

Reduction of chromogranin A and B but not C in the cerebrospinal fluid in subjects with schizophrenia.

The granins (secretogranins/chromogranins) are a family of soluble proteins stored and released from the secretory large dense-core vesicles of the synapse. Schizophrenia is a common and devastating brain disorder. Although the aetiology of schizophrenia is unknown, data are accumulating that synaptic disturbance or damage may be of importance. The objective of this study was to compare the levels of chromogranin A, B and C in the cerebrospinal fluid (CSF) of patients with schizophrenia and healthy controls. CSF chromogranin levels were measured by RIA in 33 subsequent admissions of patients with psychotic disorder and in 31 healthy controls. The levels of CSF chromogranin A (11.8+/-3.0 vs 14.8+/-4.8 nmol/l, P=0.004), chromogranin B (3.4+/-0.49 vs 3.7+/-0.58 nmol/l, P=0.02), but not chromogranin C (70.2+/-15.7 vs 65.3+/-20.4 pmol/l, P=0.29) were lower in the schizophrenic patients than in the healthy controls. These data indicate that two widespread constituents of large dense-core vesicles, i.e. chromogranin A and chromogranin B, are altered in chronic schizophrenic patients.

The role of the polymorphic genes apolipoprotein E and methylene- tetrahydrofolate reductase in the development of dementia of the Alzheimer type.

The gene for apolipoprotein E (APOE) is polymorphic, and its variant APOE4 is a major risk factor for the development of Alzheimer-type dementia (AD). Another risk factor for AD appears to be negative cobalamin balance, which is very common in elderly people. Cobalamin and folate are interdependent and essential components of the one-carbon metabolism. Another important component is methylenetetrahydrofolate reductase (MTHFR), the gene for which is also polymorphic. Thermolabile MTHFR (tMTHFR), a gene variant that reduces the activity of its enzyme, is common in the general population. In the present study, 75% of 140 AD patients had at least one APOE4 allele. The numbers of APOE4 and tMTHFR alleles correlated significantly with the serum folate levels, however, in opposite directions. The significance of this was augmented by an inverse correlation between APOE4 and tMTHFR. Thus, not only MTHFR but also APOE appears to be related to the one-carbon metabolism, suggesting that APOE4 and insufficient one-carbon metabolism may be synergistic risk factors for AD.