Cage Environment Regulates Gut Microbiota Independent of Toll-Like Receptors.

The gut microbiome orchestrates epithelial homeostasis and both local and remote immunological responses. Critical to these regulatory interactions are innate immune receptors termed Toll-like receptors (TLRs). Studies to date have implicated innate immunity and Toll-like receptors in shaping key features of the gut microbiome. However, a variety of biological and environmental variables are also implicated in determining gut microbiota composition. In this report, we hypothesized that cohousing and environment dominated the regulation of the gut microbiota in animal models independent of innate immunity. To determine the importance of these variables, innate immunity, or environment in shaping gut microbiota, we used a randomized cohousing strategy and transgenic TLR-deficient mice. We have found that mice cohoused together by genotype exhibited limited changes over time in the composition of the gut microbiota. However, for mice randomized to cage, we report extensive changes in the gut microbiota, independent of TLR function, whereby the fecal microbiota of TLR-deficient mice converges with that of wild-type mice. TLR5-deficient mice in these experiments exhibit greater susceptibility to comparative changes in the microbiota than other TLR-deficient mice and wild-type mice. Our work has broad implications for the study of innate immunity and host-microbiota interactions. Given the profound impact that gut dysbiosis may have on immunity, this report highlights the potential impact of cohousing on the gut microbiota and indices of inflammation as outcomes in biological models of infectious or inflammatory disease.

[Internet search for counseling offers for older adults suffering from visual impairment]. / Internet-Recherche nach Beratungsangeboten für ältere Menschen mit Sehbehinderung.

BACKGROUND: Visual impairment is a relevant problem of aging. In many cases promising therapeutic options exist but patients are often left with visual deficits, which require a high degree of individualized counseling. This article analyzed which counseling offers can be found by patients and relatives using simple and routine searching via the internet. METHOD: Analyses were performed using colloquial search terms in the search engine Google in order to find counseling options for elderly people with visual impairments available via the internet. RESULTS: With this strategy 189 offers for counseling were found, which showed very heterogeneous regional differences in distribution. The counseling options found in the internet commonly address topics such as therapeutic interventions or topics on visual aids corresponding to the professions offering rehabilitation most present in the internet, such as ophthalmologists and opticians. Regarding contents addressing psychosocial and help in daily tasks, self-help and support groups offer the most differentiated and broadest spectrum. Support offers for daily living tasks and psychosocial counseling from social providers were more difficult to find with these search terms despite a high presence in the internet. DISCUSSION: There are a large number of providers of counseling and consulting for older persons with visual impairment. In order to be found more easily by patients and to be recommended more often by ophthalmologists and general practitioners, the presence of providers in the internet must be improved, especially providers of daily living and psychosocial support offers.

Diagnosis in schizophrenia and manic-depressive illness: a reassessment of the specificity of 'schizophrenic' symptoms in the light of current research.

Present clinical and research methods of differential diagnosis of schizophrenia and affective psychoses rely very heavily on presenting symptoms and signs, especially in acute psychosis. We have reviewed studies bearing on this issue, including studies of the phenomenology of psychotic illness, outcome, family history, response to treatment with lithium carbonate, and cross-national and historical diagnostic comparisons. We conclude that most so-called schizophrenic symptoms, taken alone and in cross section, have remarkably little, if any, demonstrated validity in determining diagnosis, prognosis, or treatment response in psychosis. In the United States, particularly, overreliance on such symptoms alone results in overdiagnosis of schizophrenia and underdiagnosis of affective illnesses, particularly mania. This compromises both clinical treatment and research.

Methylation hypothesis.

L-Methionine had no behavioral effects in normal humans and failed to increase concentrations of S-adenosylmethionine (methyl donor) in human or rat blood, while increasing rat liver levels more than fivefold. Methionine or S-adenosylmethionine in very high doses had almost no effect on methylation of tritiated levodopa in rodent tissues; various "methyl acceptor" molecules, including nicotinamide, guanidineacetic acid, and estradiol similarly had little effect. In rabbit lung, methionine and S-adenosylmethionine not only failed to increase production of dimethyltryptamine, but actually decreased it, possibly due to end-product inhibition by S-adenosylhomocysteine, which also strongly inhibited methylation of dopa in rat. These results fail to support several predictions of the "methylation hypothesis" concerning the pathophysiology and potential treatment of idiopathic psychotic disorders and leave the consistent clinical worsening effects of methionine in schizophrenia unexplained.

Electroencephalographic sleep in mania.

Electroencephalographic (EEG) sleep patterns were examined in nine unmedicated patients meeting DSM-III-R criteria for a current manic episode (four men and five women) for two to four consecutive nights. Compared with age- and sex-matched normal control subjects, manic patients exhibited significantly decreased total recording period, decreased time spent asleep, increased time awake in the last two hours of recording, shortened rapid eye movement (REM) latency, increased REM activity, and increased REM density. These results suggest that mania is associated with marked disturbances of sleep continuity and REM measures. Sleep continuity and REM sleep abnormalities of a similar nature and degree have been reported in major depression and psychotic depression. Thus, it is possible that various forms of affective disorders and psychotic disorders have pathophysiologic mechanisms in common.

Activities of types A and B MAO and catechol-o-methyltransferase in blood cells and skin fibroblasts of normal and chronic schizophrenic subjects.

We assayed activities of monoamine oxidase (MAO) type B in blood platelets and type A (and B) in fibroblasts cultured from punch biopsy specimens of skin, as well as of catechol-O-methyltransferase (COMT) in erythrocytes and fibroblasts. Fibroblasts contained moderate amounts of both forms of MAO (types A and B) found in human brain and large amounts of COMT activity. Activities of both enzymes correlated poorly between fibroblasts and blood cells. Comparing carefully diagnosed chronic schizophrenics with age-matched normal young men, we found no difference in these biochemical variables, nor could we distinguish patients with paranoid symptoms. In contrast, we confirmed markedly lower MAO activities in platelet samples from chronic patients provided by colleagues at the National Institute of Mental Health. Results concerning MAO and COMT activities are now sufficiently inconsistently characteristic of schizophrenics as to question their clinical applicability and to indicate a need for further critical evaluation, with special attention to diagnosis, matching of subjects, and effects of possible spurious environmental variables.

Polysomnographic characteristics of young manic patients. Comparison with unipolar depressed patients and normal control subjects.

Although sleep disturbance is a prominent feature of mania, its polysomnographic (PSG) features have received little study. To investigate more systematically the PSG characteristics of sleep in mania, all-night PSG evaluations were performed for two to four consecutive nights in 19 young manic patients (age range, 18 to 36 years), 19 age-matched patients with major depression, and 19 age-matched normal control subjects. Manic and depressed patients displayed nearly identical profiles of PSG abnormalities compared with normal control subjects, including disturbed sleep continuity, increased percentage of stage 1 sleep, shortened rapid eye movement latency, and increased rapid eye movement density. These results are similar to those reported in previous studies of major depression, and they are consistent with the possibility that the sleep disturbance in mania and major depression is caused by the same mechanism.

Sleep EEG in bulimia.

To evaluate the sleep electroencephalogram (EEG) characteristics of bulimia, all-night sleep EEGs were performed on 11 women meeting DSM-III criteria for bulimia. Comparison groups consisted of young women outpatients with major depression (n = 44) and young normal women (n = 20). The sleep EEGs of the bulimic patients were largely indistinguishable from those of the normal controls, except for a trend toward increased rapid eye movement (REM) density in the first REM period among the bulimic subjects. No differences in any sleep EEG measure were observed between bulimic patients with major depression and those without affective disorder. By contrast, the outpatients with major depression displayed marked sleep continuity disturbances, as well as significantly increased REM intensity and REM density, as compared to normal controls. Implications of these results with respect to the hypothesis that bulimia is related to major affective disorder are discussed.

Lecithin in the treatment of mania: double-blind, placebo-controlled trials.

The authors report double-blind, placebo-controlled trials of pure lecithin in the treatment of mania. As in preliminary trials, lecithin appeared to be nontoxic and effective. Improvement with lecithin was significantly greater than improvement with placebo in five of the six patients studied. The concurrent use of anticholinergic agents did not prevent the antimanic effect of lecithin. The authors discuss the possible mechanism of action of lecithin, including cholinergic and membrane-altering effects.

The dexamethasone suppression test in psychotic disorders.

Dexamethasone suppression tests were given to 69 consecutively admitted psychiatric patients. Nonsuppression rates for depression with or without melancholia and for schizophrenia were similar to those previously reported, but for mania and other psychoses the frequencies were higher than expected.

Propranolol in the treatment of neuroleptic-induced akathisia.

Fourteen patients with neuroleptic-induced akathisia were treated with propranolol in an open trial. All patients demonstrated substantial improvement of their akathisia; nine of the 14 obtained complete remission. Response was quite rapid, occurring within 24 hours in most cases. Doses required for improvement were low (30-80 mg/day), and side effects were few. Lithium-induced tremor improved considerably, but symptoms of parkinsonism and tardive dyskinesia showed little change. Preliminary results with certain other beta blockers suggest that they are less effective than propranolol in the treatment of akathisia.

"Schizoaffective disorder": an invalid diagnosis? A comparison of schizoaffective disorder, schizophrenia, and affective disorder.

The authors compared patients meeting widely accepted criteria for the diagnosis of schizoaffective disorder, manic type, with patients meeting rigorous criteria for manic disorder and schizophrenia, using three methods of validation: family history, short-term treatment response, and long-term outcome. No significant differences were found between patients with manic disorder and schizoaffective disorder. However, consistent and often highly significant differences separated patients with schizophrenia from those with manic disorder and schizoaffective disorder. The findings suggest that schizoaffective disorder, as currently defined, is not a valid and independent entity. The authors suggest that psychotic disorders not diagnosable as manic-depressive illness or schizophrenia and without apparent organic basis would best be called "undiagnosed" or "atypical" psychosis. Further, while proposals for new diagnoses or for subtyping of schizophrenia or manic-depressive illness should be encouraged, these should undergo rigorous screening for validity before being accepted into clinical use.

Failure to find evidence of schizophrenia in first-degree relatives of schizophrenic probands.

The first-degree relatives (N = 199) of DSM-III schizophrenic probands (N = 39) were diagnosed from chart data by a rater who was blind to proband diagnosis. No cases of even "possible" schizophrenia were found. This augments the growing evidence that the genetic component in schizophrenia may be less than was formerly suspected.

Clonidine in the treatment of mania and mixed bipolar disorder.

The symptoms of three bipolar patients remitted after clonidine treatment. One patient presented with mixed bipolar disorder, two were manic, and all were psychotic. One patient's akathisia also appeared to respond to clonidine. Clonidine's thymoleptic effect paralleled resulting cardiovascular changes.

Open trial of S-adenosylmethionine for treatment of depression.

Nine depressed inpatients completed trials with S-adenosylmethionine. Seven showed improvement or remission of their symptoms. As in European studies, no side effects were seen except the apparent induction of mania in two patients with bipolar disorder.

Lack of efficacy of d-propranolol in neuroleptic-induced akathisia.

d-Propranolol lacks clinically significant beta-adrenergic receptor blocking properties, but has the same membrane stabilizing effects as racemic (d,l) propranolol. To assess the role of beta-blockade versus membrane stabilization or other shared nonspecific effects in the therapeutic action of propranolol in neuroleptic-induced akathisia (NIA) we treated 11 patients with NIA in a crossover, double-blind study of d-propranolol versus placebo. Akathisia scores were unchanged after both d-propranolol and placebo. Eight patients were subsequently treated in a nonblind manner with racemic propranolol, with a significant reduction in akathisia scores. These findings suggest that beta-blockade, not membrane stabilization or other shared nonspecific effects, contributes to the efficacy of propranolol in NIA.

Fluoxetine-induced akathisia: clinical and theoretical implications.

Five patients receiving fluoxetine for the treatment of obsessive compulsive disorder or major depression developed akathisia. The typical fluoxetine-induced symptoms of restlessness, constant pacing, purposeless movements of the feet and legs, and marked anxiety were indistinguishable from those of neuroleptic-induced akathisia. Three patients who had experienced neuroleptic-induced akathisia in the past reported that the symptoms of fluoxetine-induced akathisia were identical, although somewhat milder. Akathisia appeared to be a common side effect of fluoxetine and generally responded well to treatment with the beta-adrenergic antagonist propranolol, dose reduction, or both. The authors suggest that fluoxetine-induced akathisia may be caused by serotonergically mediated inhibition of dopaminergic neurotransmission and that the pathophysiology of fluoxetine-induced akathisia and tricyclic antidepressant-induced "jitteriness" may be identical.

A fixed dose study of the plasma concentration and clinical effects of thioridazine and its major metabolites.

Fifty-three patients in an acute episode or exacerbation of psychosis were given thioridazine 200 or 400 mg daily for 2 weeks. Thioridazine and its active metabolites, mesoridazine and sulforidazine, were estimated in plasma by high performance liquid chromatography (HPLC) and radioreceptor assay (RRA). One week after institution of treatment, plasma concentrations of drug were stable in the morning 12h after dosing. Drug levels varied widely between patients, but in all patients the relative level of thioridazine to mesoridazine was about one half and thioridazine to sulforidazine was about two fold. Estimates of neuroleptic activity by RRA and the weighted sum of thioridazine, mesoridazine and sulforidazine by HPLC were very similar. Plasma concentration of parent compound, metabolites, or the sum of active substances as estimated by HPLC or RRA, showed only modest correlations (rs = 0.10-0.22, all NS) to the degree of improvement as measured by change on the Brief Psychiatric Rating Scale. Significant correlations were observed between plasma concentrations of drug and side effects, including dry mouth, blurred vision, or total rating on the Somatic Symptoms Scale. Even patients receiving the lowest dose and achieving the lowest plasma concentrations of drug showed considerable improvement. There was suggestive evidence that the patients achieving the highest plasma levels of drug did not have the best clinical outcome. These and similar observations from other studies suggest that currently used doses of neuroleptics may be excessive. Optimal drug effects as well as stronger relationships between dose, drug concentration, and clinical therapeutic effects might best be sought at doses below those in common use.

Neuroleptic blood levels and therapeutic effect.

Studies attempting to delineate a therapeutic range of blood levels for neuroleptics have yielded conflicting results. The reasons for this are briefly reviewed and a study is described in which a correlation is sought between blood levels of thioridazine and clinical efficacy. The study employs the radioreceptor assay for neuroleptics to detect both parent drug and active metabolites in blood. The results of the study indicate that while dose is a poor predictor of blood levels of medication, blood levels of neuroleptic activity in patients on thioridazine may be very highly correlated with antipsychotic effect.

Effect of glucose on antipsychotic drug-induced changes in dopamine neuronal activity.

The effect of glucose on antipsychotic drug-induced changes in the spontaneous activity of rat midbrain dopaminergic neurons was tested with the cells-per-track extracellular electrophysiology method. After daily s.c. treatment with vehicle, haloperidol (0.5 mg/kg), or clozapine (20 mg/kg) for 21 days, rats were anesthetized and recordings performed on one side of the brain. Then, glucose (250 mg/kg, i.v.) was administered and recordings were made from the contralateral midbrain. Glucose significantly reduced the number of spontaneously active A9 and A10 dopaminergic cells per track in control rats, but significantly attenuated the chronic haloperidol- and clozapine-induced reductions in dopaminergic cells per track. These results suggest that caloric intake may influence antipsychotic drug-induced changes in the population activity of midbrain dopaminergic neurons.