Prolonged hyperglycemia & hyperinsulinemia increases BDNF mRNA expression in the posterior ventromedial hypothalamus and the dorsomedial hypothalamus of fed female rats.

Brain-derived neurotrophic factor (BDNF) plays a key role in neuronal development, synaptic plasticity, and the central control of energy homeostasis. Peripheral metabolic signals such as leptin and glucose regulate hypothalamic BDNF gene expression. However, the effects of long-term hyperglycemia and/or hyperinsulinemia on BDNF mRNA levels in the hypothalamus and other brain regions where BDNF regulates physiological functions have not been investigated. Therefore, using in situ hybridization we examined whether high glucose, high insulin, or both affected BDNF gene expression in vivo. Ovariectomized, estrogen-replaced adult rats were fitted with indwelling jugular catheters and infused for 48 h with: saline (control), glucose (hyperglycemia-hyperinsulinemia), glucose with insulin (hyperinsulinemia only), diazoxide (Dzx) (control), or glucose with Dzx (hyperglycemia only). Glucose infusion (Hyperglycemia and hyperinsulinemia) significantly increased BDNF mRNA expression in the posterior ventromedial nucleus of the hypothalamus (pVMH) and in the dorsomedial nucleus of the hypothalamus (DMH). Unexpectedly, infusion of the KATP channel opener Dzx also increased BDNF mRNA expression in the pVMH and DMH. In contrast, no significant changes in BDNF mRNA expression were observed in the groups that were hyperinsulinemic only or hyperglycemic only. BDNF mRNA expression did not differ as a function of treatment in the anterior VMH, paraventricular nucleus of the hypothalamus, the hippocampus, or the amygdala. Hyperglycemia with and without hyperinsulinemia decreased BDNF mRNA levels in the pituitary. Plasma BDNF concentrations were not changed by any of the treatments. Our results suggest that hyperinsulinemia alone does not affect BDNF mRNA expression in the hypothalamus, hippocampus, or pituitary. Our study is the first to distinguish that within the hypothalamus, prolonged high glucose levels in non-fasted rats regulates BDNF gene expression in a brain nuclei-specific fashion.

Galanin-like peptide (GALP) neurone-specific phosphoinositide 3-kinase signalling regulates GALP mRNA levels in the hypothalamus of males and luteinising hormone levels in both sexes.

Galanin-like peptide (GALP) neurones participate in the metabolic control of reproduction and are targets of insulin and leptin regulation. Phosphoinositide 3-kinase (PI3K) is common to the signalling pathways utilised by both insulin and leptin. Therefore, we investigated whether PI3K signalling in neurones expressing GALP plays a role in the transcriptional regulation of the GALP gene and in the metabolic control of luteinising hormone (LH) release. Accordingly, we deleted PI3K catalytic subunits p110α and p110ß via conditional gene targeting (cKO) in mice (GALP-p110α/ß cKO). To monitor PI3K signalling in GALP neurones, these animals were also crossed with Cre-dependent FoxO1GFP reporter mice. Compared to insulin-infused control animals, the PI3K-Akt-dependent FoxO1GFP nuclear exclusion in GALP neurones was abolished in GALP-p110α/ß cKO mice. We next used food deprivation to investigate whether the GALP-neurone specific ablation of PI3K activity affected the susceptibility of the gonadotrophic axis to negative energy balance. Treatment did not affect LH levels in either sex. However, a significant genotype effect on LH levels was observed in females. By contrast, no genotype effect on LH levels was observed in males. A sex-specific genotype effect on hypothalamic GALP mRNA was observed, with fed and fasted GALP-p110α/ß cKO males having lower GALP mRNA expression compared to wild-type fed males. Finally, the effects of gonadectomy and steroid hormone replacement on GALP mRNA levels were investigated. Compared to vehicle-treated mice, steroid hormone replacement reduced mediobasal hypothalamus GALP expression in wild-type and GALP-p110α/ß cKO animals. In addition, within the castrated and vehicle-treated group and compared to wild-type mice, LH levels were lower in GALP-p110α/ß cKO males. Double immunofluorescence using GALP-Cre/R26-YFP mice showed androgen and oestrogen receptor co-localisation within GALP neurones. Our data demonstrate that GALP neurones are direct targets of steroid hormones and that PI3K signalling regulates hypothalamic GALP mRNA expression and LH levels in a sex-specific fashion.

Factors associated with metabolic syndrome in patients with systemic lupus erythematosus from Puerto Rico.

The aim of this study was to determine the factors associated with metabolic syndrome in patients with systemic lupus erythematosus from Puerto Rico. A total of 204 patients with systemic lupus erythematosus (per the American College of Rheumatology classification criteria) were evaluated. Metabolic syndrome was assessed using the American Heart Association and the National Heart, Lung, and Blood Institute classification. Socioeconomic-demographic parameters, health-related behaviours, clinical manifestations, autoantibodies, pharmacological treatments, disease activity (per the Systemic Lupus Activity Measure--Revised), and damage accrual (per the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index) were determined at study visit. Factors associated with metabolic syndrome were examined by univariable analyses and multivariable logistic regression models. A total of 196 (96.2%) were women. The mean age at study visit was 43.6 +/- 13.0 years, and the mean disease duration was 8.7 +/- 7.7 years. Seventy-eight patients (38.2%) had metabolic syndrome. In the multivariable analysis, age (odds ratio [OR] = 1.05; 95% confidence interval [CI] 1.02-1.09), government health insurance (OR = 2.06; 95% CI 1.07-4.22), exercise (OR = 0.33; 95% CI 0.14-0.92), thrombocytopenia (OR = 4.19; 95% CI 1.54-11.37), erythrocyte sedimentation rate (OR = 1.64; 95% CI 1.03-2.63), disease activity (OR = 1.14; 95% CI 1.00-1.30), and prednisone >10 mg/day (OR = 3.69; 95% CI 1.22-11.11) were associated with metabolic syndrome. In conclusion, older age, low socioeconomic status, lack of exercise, thrombocytopenia, increased erythrocyte sedimentation rate , higher disease activity, and prednisone >10 mg/day were independently associated with metabolic syndrome in patients with systemic lupus erythematosus from Puerto Rico.

Negative symptoms in the elderly patient with dementia.

Negative symptoms are a well-documented, intensively studied feature of schizophrenia. In recent years, however, increasing attention has been directed to the prominence of these symptoms in elderly patients suffering from dementia. Behavioral alterations such as avolition, apathy, social withdrawal and emotional disengagement appear to be commonly found in patients suffering from Alzheimer's disease. A consistent research finding is that negative symptoms in dementia cannot be solely accounted for by depression; they represent a separate symptomatic cluster. An area of ongoing investigation is the relationship of negative symptoms to the functional impairment of dementia. It has been hypothesized that negative symptoms may contribute to the functional impairment caused by cognitive deterioration. Recently, it was reported that negative symptoms in dementia are responsive to pharmacotherapy with an atypical antipsychotic agent. This treatment effect appeared to be independent of effects on positive symptoms. As dementia continues to be a major public health concern, the phenomenology of negative symptoms in the elderly and the treatment of these symptoms are likely to remain areas of active investigation.

Risperidone in the treatment of patients with Alzheimer's disease with negative symptoms.

INTRODUCTION: Negative symptoms such as diminished initiative, drive, motivation, and emotional reactivity have been described in patients with Alzheimer's disease (AD). The purpose of this study was to retrospectively analyze the efficacy and tolerability of risperidone for the treatment of clinically significant positive and negative symptoms in AD. METHODS: We reviewed the charts of 50 community-residing AD patients who had been treated in a specialized university-based dementia management clinic. Clinical data comparing baseline and 12 weeks of treatment were obtained by reviewing a series of rating scales that were recorded as part of a comprehensive behavioral assessment. RESULTS: Reviewed subjects had a mean age of 79.7 6 years and a mean of 12 +/- 3.6 years of school. Seventy percent of the subjects were female and the majority was White. The mean dose of risperidone prescribed was 1.3 +/- 0.6 mg per day (range from 0.5 mg to 3.0 mg). After 12 weeks of treatment, the severity of positive and negative symptoms was significantly reduced. Importantly, improvement in negative symptoms with the use of risperidone appeared to be independent of a positive treatment effect on positive symptoms. Risperidone had insignificant effects on both cognitive status and the emergence of extrapyramidal symptoms. CONCLUSION: This retrospective study demonstrates that risperidone appears to be efficacious in the treatment of clinically significant positive and negative symptoms in patients with AD.

Cognitive deficits and psychopathology in institutionalized versus community-dwelling elderly schizophrenia patients.

We evaluated psychiatric symptoms and neurocognitive functioning among 25 institutionalized and 25 outpatient DSM-IV-diagnosed schizophrenia patients, as well as 25 middle-aged and elderly normal comparison subjects. All subjects were assessed with the Positive and Negative Syndrome Scale, Hamilton Rating Scale for Depression, modified Simpson-Angus Extrapyramidal Symptom Scale, the Abnormal Involuntary Movement Scale, and the Mattis Dementia Rating Scale (DRS). The two patient groups had similar levels of depressive symptoms, but the institutionalized patients had more severe positive and negative symptoms and were on higher doses of neuroleptic medication. The institutionalized patients had significantly more cognitive impairment on the DRS than outpatients and normal comparison subjects, particularly on the subscales of initiation/perseveration, conceptualization, and memory. Results are discussed in terms of the possible neuropathology associated with cognitive impairment in chronic schizophrenia.

Risperidone in the treatment of elderly patients with psychotic disorders.

The authors evaluated the safety, tolerability, and efficacy of risperidone in 103 elderly patients (mean age, 71 years) with schizophrenia (75%) or schizoaffective disorder (25%). Using the Extrapyramidal Symptoms Rating Scale (ESRS), Positive and Negative Syndrome Scale (PANSS), and Clinical Global Impression (CGI) scale, they conducted a prospective, open-label, 12-week trial in 14 psychiatric centers in the United States. Patients' symptoms were assessed at baseline and over a 12-week period. At endpoint, ESRS scores were significantly reduced, as were PANSS total and subscale scores. There were no clinically significant changes in electrocardiograms, laboratory test results, or vital signs. Risperidone was well tolerated and efficacious in elderly patients with schizophrenia or schizoaffective disorder.

Psychiatric consultation in the nursing home. A survey of six states.

The authors examined availability, characteristics, and perceived adequacy of psychiatric consultation in nursing homes, as reported by directors of nursing, who returned 899 questionnaires. Thirty-eight percent of nursing home residents were judged to need a psychiatric evaluation; current frequency of consultation was rated as adequate by half of nursing directors. Nearly two-thirds reported that psychiatrists adequately provided diagnostic and medication recommendations; however, advice on nonpharmacologic management techniques, staff support, and dealing with staff stress and family conflicts was largely viewed as inadequate. Findings suggest that perceived need for psychiatric services is far greater than the level actually provided. Overall, more attention must be directed to identifying incentives for psychiatrists to practice in nursing homes, determining clinical effectiveness of mental health services, and examining effects of alternative payment mechanisms on level of care.

Cognitive deficits and psychopathology in elderly schizophrenic patients.

The authors investigated the syndromal and cognitive profiles of 25 DSM-III-R older schizophrenic inpatients with continuous acute psychotic symptoms and compared them with 20 younger schizophrenic patients by means of a multidimensional assessment battery. Subjects were medically well and without neurological comorbidity and were comparable in length of current hospitalization and medication regimens. There were no significant differences between the two groups on various symptom rating scores or on neurological variables. The older group's mean scores for various cognitive measures did not reach the value for senile dementia. They also scored significantly better on a memory test and on formal cognitive functions. These findings support the notion of a stable encephalopathy, rather than a dementia-like process, underlying the course of the illness. Authors discussed limitations and implications of these findings.

A naturalistic outcome study of risperidone treatment among hospital patients.

Risperidone, an atypical antipsychotic, was introduced into clinical use in New York State facilities in April 1994. In this chart review study, records were reviewed for the first 63 patients started on risperidone at the Bronx Psychiatric Center during 1994. Sixty percent of patients treated with risperidone had a positive outcome, indicated by clinical improvement either at discharge or in the hospital. Twenty-two percent required termination of risperidone treatment within the initial three months. Risperidone appeared to be associated with favorable outcome among chronic state hospital patients, including those not discharged within the first three months of treatment.

Altered GABAergic and glutamatergic transmission in audiogenic seizure-susceptible mice.

The C57BL/10 SPS/sps mouse mutant are audiogenic seizure-susceptible. The enzymatic activities of glutamate decarboxylase (GAD), GABA aminotransferase (GABA-T), alanine aminotransferase (ALA-T), aspartate aminotransferase (ASP-T), and glutamate dehydrogenase (GDH) of whole brain supernatant are significantly reduced in these epileptic mice. GABA uptake is decreased in cortex, midbrain, and pons medulla. Previous studies showed the presence of two sodium-dependent GLU uptake systems in normal (SPS/SP) mice. Glutamate Umax by System 1 is significantly decreased in these mice, whereas the Umax value for System 2 is significantly increased in the epileptic mice.

Inhibition of high-affinity [3H]L-proline binding to rat brain membranes by 2-amino-7-phosphonoheptanoic acid.

L-Glutamate and 2-amino-7-phosphonoheptanoic acid [corrected] (AP-7) (10(-9) to 10(-6) M), a competitive NMDA (N-methyl-D-aspartate) antagonist, inhibit approximately 60% of [3H]L-proline binding to rat membranes from midbrain. In hippocampal membranes, AP-7 inhibits proline binding by 80%, while in cerebellar membranes AP-7 had little effect. These results are indicative of the possible neuromodulatory role of proline in the central nervous system, possibly through the NMDA receptor(s).

GABAergic neurotransmission in the C57BL/10 sps/sps mouse mutant: a model of absence seizures.

The C57BL/10 sps/sps mouse mutant displays generalized absence seizure-like behavior. In these mice, glutamic acid decarboxylase activity is reduced in the cortex and hippocampus. Tritiated flunitrazepam binding (3H-flu) is reduced in these areas, as well as in midbrain, cerebellum, and pons-medulla. Quantitative [3H]-flunitrazepam binding autoradiography confirms these observations. GABA uptake by synaptosomes from sps/sps mice is also reduced in all the areas studied. Potassium-stimulated, Ca(2+)-dependent release of radioactivity from synaptosomes preloaded with [14C]-GABA is reduced in the hippocampus, increased in midbrain and pons-medulla, but remains unaltered in the cortex. These results suggest region-specific alterations in GABAergic neurotransmission that may be responsible for the absence-like seizures in C57BL/10 sps/sps mice.

The C57BL/10Bg sps/sps mouse: a mutant with absence-like seizures; neurochemical and behavioral correlates.

C57BL/10Bg sps/sps mice display behavioral arrest, similar to generalized absence seizures. Compared with the parent strain C57BL/10Bg SPS/SPS, the activities of glutamate decarboxylase (GAD, E. C. 2.6.1.15), GABA aminotransferase (GABA-T, E. C. 2.6.1.19), aspartate aminotransferase (ASP-T, E. C. 2.6.1.1), and glutamate dehydrogenase (GDH, E. C. 1.4.1.3) in whole brain crude supernatant were significantly reduced in the sps/sps mice. Alanine aminotransferase activity (ALA-T, E. C. 2.6.1.2), was not altered in any of the strains, and normalization of GAD, GABA-T and GDH activities by that of ALA-T, further revealed significant differences between the normal strain (SPS/SPS), the heterozygotes (SPS/sps), and behavioral arrest (sps/sps) mice. These results suggest the possible involvement of GABAergic and glutamatergic neurotransmission in the absence-like behavior displayed by sps/sps mice. Open field behavior of C57BL/10Bg sps/sps mice is characterized by periods of marked inactivity which easily distinguish affected homozygotes, from their heterozygotes littermates.

High-affinity binding of proline to mouse brain synaptic membranes.

There is evidence suggestive of the possible neuromodulatory role for L-proline in the mammalian brain. The binding of proline to whole mouse brain synaptic membranes has been partially characterized. Several binding sites for this imino acid have been identified; one in the nanomolar range and at least two in the submicromolar range. The binding of proline is inhibited by NaCl. Pipecolic acid (40 microM), ornithine, aminooxyacetic acid (AOAA), glycine, GABA, and glutamate were capable of significantly inhibiting proline binding. Although detailed pharmacological and functional studies are needed, these results are consistent with a brain-specific function for this imino acid, as well as, with the presence of specific binding site(s) for proline.

Proline binding to mouse brain synaptosomes.

L-proline has been shown to exert a variety of physiological and behavioral effects that are consistent with its possible role as a neuromodulator in the mammalian brain. The binding of l-proline to mouse brain synaptosomes has been partially characterized. Preliminary kinetic analysis shows the presence of at least two binding sites in the submicromolar range, and one in the nanomolar range. While more detailed studies are necessary as to determine the biological significance of proline binding to mouse brain synaptosomes, these results further support the possible role of proline as a neuromodulator.

Proline binding to mouse synaptosomes

La l-prolina ejerce unos efectos fisiológicos y conductúales los cuales sugieren su posible función como neuromodulador en el cerebro de los mamíferos. Se ha caracterizado parcialmente el enlazamiento de l-prolina a sinaptosomas de cerebro del ratón. Análisis preliminar de la cinética demustra la presencia de por lo menos dos sitios de enlazamiento en el rango submicromolar y de un sitio en el rango nanomolar. Aunque son necesarios estudios más detallados encaminados a esclarecer el significado biológico del enlazamiento de prolina a sinaptosomas de cerebro del ratón, estos resultados sirven de apoyo adicional a la posible función de prolina omo neuromodulador

Analysis of pure pancreatic juice in patients with chronic alcoholism.

To elucidate early biochemical changes of pancreatic juice and their reversibility in chronic alcoholics, pure pancreatic juice was collected from 23 chronic alcoholics by endoscopic retrograde catheterization of the papilla. Samples were collected at 1 minute intervals for 20 minutes after intravenous injection of secretin (Eisai, 1 U/kg) and for 10 minutes after CCK-PZ injection (Boots, 1 U/kg). Volume, bicarbonate concentration, protein concentration and three hydrolases were determined. Following results were obtained. (1) Five patients showed hypersecretory state. Four of the five patients showed hyperconcentration of protein. (2) Seventeen patients showed hyposecretory state. Lipase secretion was most frequently affected (94%). Maximal bicarbonate concentration was the next to be affected (82%). Amylase and chymotrypsinogen secretion were less frequently affected (65%). Flow rate was least frequently affected (24%). (3) It was suggested that exocrine dysfunction in chronic alcoholics is reversible in an early stage and that sequence of events with advancement of the stage is hypersecretion, hyperconcentration of protein, normalization of water secretion with a decrease in lipase secretion and maximal bicarbonate concentration, a decrease in amylase and chymotrypsinogen output, and finally a decrease in flow rate.

Analysis of human pure pancreatic juice in chronic pancreatitis and cancer of the pancreas.

Pure pancreatic juice was collected from 8 control subjects, 12 patients with chronic pancreatitis and 4 patients with cancer of the pancreas by endoscopic retrograde cannulation of the papilla. Samples were collected at 1 minute intervals for 20 minutes after rapid intravenous injection of secretin (Eisai, 1 U/kg) and for 10 minutes after rapid intravenous injection of CCK-PZ (Boots, 1 U/kg). Determinations of volume, bicarbonate concentration and three hydrolases (amylase, chymotrypsinogen and lipase) were made. Our tentative conclusions are (1) pancreatic enzymes are likely to be affected one after another, not in parallel fashing, in chronic pancreatitis and in cancer of the pancreas, (2) bicarbonate concentration and chymotrypsinogen or lipase are most susceptible in chronic pancreatitis and lipase secretion seems to be more susceptible than other parameters in cancer of the pancreas. Amylase is the least affected enzyme in both pancreatic diseases, and (3) determinations of chymotrypsinogen and/or lipase should be preferably performed among hydrolytic enzymes in the evaluation of exocrine pancreatic function in chronic pancreatitis and cancer of the pancreas.