Sex-dependent effects of social status on the regulation of arginine-vasopressin (AVP) V1a, oxytocin (OT), and serotonin (5-HT) 1A receptor binding and aggression in Syrian hamsters (Mesocricetus auratus).

Dominance status in hamsters is driven by interactions between arginine-vasopressin V1a, oxytocin (OT), and serotonin 1A (5-HT1A) receptors. Activation of V1a and OT receptors in the anterior hypothalamus (AH) increases aggression in males, while decreasing aggression in females. In contrast, activation of 5-HT1A receptors in the AH decreases aggression in males and increases aggression in females. The mechanism underlying these differences is not known. The purpose of this study was to determine if dominance status and sex interact to regulate V1a, OT, and 5-HT1A receptor binding. Same-sex hamsters (N = 47) were paired 12 times across six days in five min sessions. Brains from paired and unpaired (non-social control) hamsters were collected immediately after the last interaction and processed for receptor binding using autoradiography. Differences in V1a, OT, and 5-HT1A receptor binding densities were observed in several brain regions as a function of social status and sex. For example, in the AH, there was an interaction between sex and social status, such that V1a binding in subordinate males was lower than in subordinate females and V1a receptor density in dominant males was higher than in dominant females. There was also an interaction in 5-HT1A receptor binding, such that social pairing increased 5-HT1A binding in the AH of males but decreased 5-HT1A binding in females compared with unpaired controls. These results indicate that dominance status and sex play important roles in shaping the binding profiles of key receptor subtypes across the neural circuitry that regulates social behavior.

DIXDC1 contributes to psychiatric susceptibility by regulating dendritic spine and glutamatergic synapse density via GSK3 and Wnt/ß-catenin signaling.

Mice lacking DIX domain containing-1 (DIXDC1), an intracellular Wnt/ß-catenin signal pathway protein, have abnormal measures of anxiety, depression and social behavior. Pyramidal neurons in these animals' brains have reduced dendritic spines and glutamatergic synapses. Treatment with lithium or a glycogen synthase kinase-3 (GSK3) inhibitor corrects behavioral and neurodevelopmental phenotypes in these animals. Analysis of DIXDC1 in over 9000 cases of autism, bipolar disorder and schizophrenia reveals higher rates of rare inherited sequence-disrupting single-nucleotide variants (SNVs) in these individuals compared with psychiatrically unaffected controls. Many of these SNVs alter Wnt/ß-catenin signaling activity of the neurally predominant DIXDC1 isoform; a subset that hyperactivate this pathway cause dominant neurodevelopmental effects. We propose that rare missense SNVs in DIXDC1 contribute to psychiatric pathogenesis by reducing spine and glutamatergic synapse density downstream of GSK3 in the Wnt/ß-catenin pathway.

Predicting the effects of a high-energy diet on fatty liver and hippocampal-dependent memory in male rats.

OBJECTIVE: In rodents, diets exceeding nutritional requirements (i.e., high-energy diets; HED) impair hippocampal-dependent memory. Our research suggests that the effects likely involve HED-induced increases in liver lipids. In this experiment, rats were provided with diet choices to test whether voluntary consumption of a HED impairs spatial memory, whether differences in initial weight gain predict memory deficits, and whether increases in liver lipids are associated with the memory deficits. DESIGN AND METHODS: Adult male Sprague-Dawley rats were given a control diet or cafeteria-style HED for 8 weeks. Weight gain during the first 5 days on the diet was used to divide rats into a HED-Lean group and a HED-Obese group. Spatial water maze memory was tested 8 weeks later and postmortem liver lipid concentrations were quantified. RESULTS: Compared with the HED-Lean and control rats, the HED-Obese rats had impaired spatial memory and met the human diagnostic criterion of non-alcoholic fatty liver disease (>5% liver lipids relative to liver weight). Moreover, liver lipids were correlated with memory deficits. CONCLUSIONS: These findings show that voluntary consumption of a HED impairs memory, that initial weight gain predicts fatty liver and memory deficits, and that fatty liver may contribute to the memory-impairing effects of obesity.

Non-alcoholic fatty liver disease impairs hippocampal-dependent memory in male rats.

Non-alcoholic fatty liver disease (NAFLD) is a disorder observed in children and adults characterized by an accumulation of liver fat (>5% wet weight) in the absence of excessive alcohol intake. NAFLD affects 10 to 30% of the American population and is the most common cause of liver disease in the United States. NAFLD leads to serious disturbances in cardiovascular and hormonal function; however, possible effects on brain function have been overlooked. The aims of the present study were to test whether diet-induced NAFLD impairs hippocampal-dependent memory and to determine whether any observed deficits are associated with changes in hippocampal insulin signaling or concentrations of brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1). Post-weanling male Sprague-Dawley rats were fed a high fructose (60% of calories) or control diet for 12 weeks and then trained and tested in a spatial water maze. NAFLD was confirmed with postmortem measures of liver mass and liver lipid concentrations. NAFLD did not affect acquisition of the spatial water maze, but did impair retention tested 48 h later. Specifically, both groups demonstrated similar decreases in latency to swim to the escape platform over training trials, but on the memory test NAFLD rats took longer to reach the platform and made fewer visits to the platform location than control diet rats. There were no differences between the groups in terms of insulin-stimulated phosphorylation of insulin receptor ß subunit (IR-ß) and protein kinase B (PKB/AKT) in hippocampal slices or hippocampal BDNF or IGF-1 concentrations. Thus, these data indicate that NAFLD impairs hippocampal-dependent memory function and that the deficit does not appear attributable to alterations in hippocampal insulin signaling or hippocampal BDNF or IGF-1 concentrations.

Oral fingolimod for the treatment of patients with relapsing forms of multiple sclerosis.

Fingolimod, a sphingosine 1-phosphate receptor modulator, is the first oral treatment approved by the US Food and Drug Administration for the treatment of relapsing forms of multiple sclerosis (MS). The aim of this review was to provide a concise, comprehensive overview of the clinically relevant mechanism of action, efficacy and safety information available for fingolimod. Key data were derived from two international, Phase III, double-blind, randomised trials (TRANSFORMS and FREEDOMS) performed over 12 and 24 months, respectively, which evaluated fingolimod 0.5 and 1.25 mg daily in 1703 patients with relapsing forms of MS. In TRANSFORMS, there was a 52% reduction in the annualised relapse rate (ARR) with fingolimod 0.5 mg vs. 30 µg intramuscular interferon beta-1a (0.16 vs. 0.33; p < 0.001) at 1 year. In FREEDOMS, there was a 55% decrease in ARR at 2 years with fingolimod 0.5 mg vs. placebo (0.18 vs. 0.40; p < 0.001). Risk of disability progression, confirmed at 3 months, was also reduced by 30% over the 2-year study period with fingolimod vs. placebo (p = 0.02). Significantly fewer new or enlarged lesions on T(2) -weighted images were seen in both studies (TRANSFORMS, p = 0.002 vs. interferon beta-1a at 1 year; FREEDOMS, p < 0.001 vs. placebo at 2 years). Overall, fingolimod 0.5 mg was well tolerated by patients. Transient, generally asymptomatic bradycardia and infrequent atrioventricular block were seen with the administration of the first dose. Macular oedema and serious infections occurred infrequently. Reversible, asymptomatic elevations of liver enzymes could also occur. As the first approved oral disease-modifying treatment, fingolimod offers patients a convenient alternative to regular self-injection for the treatment of relapsing forms of MS. In addition to high efficacy with a relatively acceptable safety profile, fingolimod provides a therapy with a new mechanism of action.

A high fructose diet impairs spatial memory in male rats.

Over the past three decades there has been a substantial increase in the amount of fructose consumed by North Americans. Recent evidence from rodents indicates that hippocampal insulin signaling facilitates memory and excessive fructose consumption produces hippocampal insulin resistance. Based on this evidence, the present study tested the hypothesis that a high fructose diet would impair hippocampal-dependent memory. Adult male Sprague-Dawley rats (postnatal day 61) were fed either a control (0% fructose) or high fructose diet (60% of calories). Food intake and body mass were measured regularly. After 19 weeks, the rats were given 3 days of training (8 trials/day) in a spatial version of the water maze task, and retention performance was probed 48 h later. The high fructose diet did not affect acquisition of the task, but did impair performance on the retention test. Specifically, rats fed a high fructose diet displayed significantly longer latencies to reach the area where the platform had been located, made significantly fewer approaches to that area, and spent significantly less time in the target quadrant than did control diet rats. There was no difference in swim speed between the two groups. The retention deficits correlated significantly with fructose-induced elevations of plasma triglyceride concentrations. Consequently, the impaired spatial water maze retention performance seen with the high fructose diet may have been attributable, at least in part, to fructose-induced increases in plasma triglycerides.

Neurologic degenerative disorders.

Neurologic degenerative disorders pose challenges to patients, their families, and health care professionals who care for them. In recent years there have been many advances in the diagnosis and management of neurologic degenerative diseases. Multiple sclerosis, myasthenia gravis, Parkinson's disease, and amyotrophic lateral sclerosis are discussed.

Nursing interventions for persons receiving immunosuppressive therapies for demyelinating pathology.

The client receiving immunosuppressive therapy for demyelinating disorders faces many challenges. The nurse should be involved in the constant assessment of the client for potential complications of the therapy as well as changes in the underlying disease process. Many of the nursing interventions focus on comfort and symptom management as well as providing information for the client and family to use in understanding the therapy and minimizing the effects of immunosuppression. Involving the family in client management will only strengthen the overall plan and outcomes for client care.

Endoscopic biliary endoprosthesis in the palliation of malignant obstruction of the distal common bile duct: a randomized trial.

A total of 52 jaundiced elderly patients who had malignant obstruction of the distal common bile duct and who required palliative biliary decompression were randomized to receive either an endoscopically placed biliary endoprosthesis (10 French gauge) or conventional surgical bypass. Patients within the two treatment groups were well matched and 51 were followed until their death. Patients treated with endoprosthesis had a significantly shorter initial hospital stay than those treated surgically. In the long term, overall survival in the two groups was similar and jaundice was relieved in over 90 per cent of patients. Despite more re-admissions to hospital for those patients treated endoscopically, the total time spent in hospital still remained significantly shorter in this treatment group compared with those subjected to surgery. The endoscopically placed biliary endoprosthesis is a valuable alternative to conventional surgical bypass in the palliation of extrahepatic biliary obstruction.

The case against showing patients their records.

KIE: The author, a British consultant surgeon, expresses his reservations about patients' having access to their medical records. The nature of communication between doctors may change if it is known that patients will see the material; potentially helpful yet tentative diagnoses may be excluded while other information is watered down. Physicians will have additional, perhaps burdensome, demands placed on them to explain the records--including parts written by deceased or otherwise unavailable doctors, medical students, or nonphysicians. Persons other than patients may see the records, further complicating the issue. Ross asserts that, while patients do have the right to see records, full access could be more harmful than beneficial to patients and could be fraught with problems for physicians.^ieng

Extrahepatic biliary obstruction by a common bile duct inflammatory polyp in association with a gallstone, and treatment by endoscopic sphincterotomy.

After a two-year history of recurrent abdominal pain, an 84-year-old man presented with acute pancreatitis and obstructive jaundice. An endoscopic retrograde cholangiogram demonstrated two filling defects approximately 1.0 cm in diameter, in a dilated common bile duct. Endoscopic papillotomy was performed which resulted in a polypoid tumour delivering itself into the wound followed by a free flow of bile. In addition, a single 1.0 cm gallstone was removed from the common bile duct, above the tumour, using a Dormia basket. The patient recovered completely. Histological examination of biopsies of the tumour taken on three subsequent occasions showed it to consist only of inflammatory tissue (an inflammatory polyp) and later, regenerating bile duct mucosa. After six months this tumour had completely regressed.

A time-saving but effective approach to the follow-up of patients after curative surgery for carcinoma of the large bowel.

The traditional methods of follow-up of patients after curative surgery for large-bowel carcinoma have been shown to be time-consuming but largely ineffectual. A new approach is proposed which utilises laboratory investigations. A plea is made for controlled trials of cytotoxic regimens in patients with proven recurrent disease.