Norepinephrine applied in the paraventricular hypothalamic nucleus stimulates vasopressin release

The present experiments were designed to investigate the effect of norepinephrine (NE) applied directly in the area of the paraventricular nucleus (PVN) of the hypothalamus on arginine-vasopressin (AVP) release and blood pressure. A microinjection of 0.4 micrograms NE in the PNV produced a plasma AVP level of 26.3 +/- 5.3 pg/ml compared to 5.3 +/- 0.6 pg/ml in controls receiving dextrose (P less than 0.001). This rise was associated with blood pressure elevations varying between 10 and 13 mm Hg, lasting for about 5 min. Systemic injection of an antivasopressor AVP antagonist reversed or prevented the blood pressure rise induced by NE microinjection. The data suggest that locally applied NE in vasopressinergic neurons of the hypothalamus stimulates the release of AVP and induces an AVP-dependent rise in blood pressure.     

Patterns of hearing loss and psychiatric morbidity in elderly patients attending a hearing clinic

This study examines the relationship between hearing loss and psychiatric diagnosis in a geriatric population attending a hearing clinic. Major depression was the most frequent psychiatric disorder and was diagnosed in 30% of subjects. A sensorineural type hearing loss was diagnosed in 85% of the depressed subjects. More hearing loss was seen in subjects with onset of depression after age 55 years, in comparison to geriatric patients with depression onset before age 55 years, subjects with other psychiatric disorders and subjects without a psychiatric diagnosis (p <0.001). The audiogram and speech audiometry suggest involvement of auditory nerve and central auditory pathways in late onset depression.     

Effects of an Extract of Salmon Milt on Symptoms and Serum TNF and Substance P in Patients With Fibromyalgia Syndrome

PurposeThe aim of this study was to evaluate the effects of a dietary supplement containing primarily an extract of salmon's milt (semen) on symptoms and blood levels of proinflammatory molecules in patients with fibromyalgia syndrome (FMS), a chronic, painful musculoskeletal disease without a distinct pathogenesis or treatment. We recently reported increased serum levels of the proinflammatory molecules substance P (SP) and tumor necrosis factor (TNF) in patients with FMS as compared to those in normal controls.MethodsThis prospective, open-label study was conducted in patients with FMS (n = 87; 80 women, 7 men; age range, 18–80 years) selected from 2 clinical centers in Spain. Patients were administered the supplement and were evaluated at weeks 1 (before treatment), 4, 8, and 12 (end of treatment) for clinical parameters of functioning, fatigue, and pain, as well as overall impression. Patients were directed to take 1 capsule per day in the morning for the first 4 weeks, followed by 1 capsule in the morning and 1 capsule in the evening for the remaining 8 weeks. Differences in symptom scores in patients with FMS between weeks 1 and weeks 4, 8, and 12 were evaluated using ANOVA. Blood was obtained and serum separated in patients with FMS at 1 and 12 weeks and in a separate population of healthy controls (n = 20; 15 women, 5 men; age range, 25–65 years). Serum levels of SP and TNF were measured in patients with FMS at 1 and 12 weeks and in healthy controls by ELISA. TNF and SP levels in patients with FMS were compared between weeks 1 and 12, as well as between patients with FMS and untreated controls, using the Mann–Whitney U test.FindingsClinical parameters of functioning, fatigue, and pain, as well as overall impression, were improved significantly at 4 weeks as compared to 1 week and remained unchanged for the duration of the study (all, P < 0.0001). Serum TNF and SP levels were significantly elevated at 1 week in patients with FMS compared to controls and were decreased significantly at 12 weeks as compared to 1 week (all, P < 0.0001).ImplicationsOur findings indicate that this dietary supplement may significantly improve symptoms in patients with FMS. This is the first time to our knowledge that any molecule has been reported to be associated with a reduction in serum SP level. Consequently, the supplement or its hypothesized main active ingredient, spermine, may be developed as a novel treatment approach to FMS or other neuroinflammatory conditions. ClinicalTrials.gov identifier: NCT03911882.     

Synergistic drug-cytokine induction of hepatocellular death as an in vitro approach for the study of inflammation-associated idiosyncratic drug hepatotoxicity

Idiosyncratic drug hepatotoxicity represents a major problem in drug development due to inadequacy of current preclinical screening assays, but recently established rodent models utilizing bacterial LPS co-administration to induce an inflammatory background have successfully reproduced idiosyncratic hepatotoxicity signatures for certain drugs. However, the low-throughput nature of these models renders them problematic for employment as preclinical screening assays. Here, we present an analogous, but high-throughput, in vitro approach in which drugs are administered to a variety of cell types (primary human and rat hepatocytes and the human HepG2 cell line) across a landscape of inflammatory contexts containing LPS and cytokines TNF, IFNγ, IL-1α, and IL-6. Using this assay, we observed drug-cytokine hepatotoxicity synergies for multiple idiosyncratic hepatotoxicants (ranitidine, trovafloxacin, nefazodone, nimesulide, clarithromycin, and telithromycin) but not for their corresponding non-toxic control compounds (famotidine, levofloxacin, buspirone, and aspirin). A larger compendium of drug-cytokine mix hepatotoxicity data demonstrated that hepatotoxicity synergies were largely potentiated by TNF, IL-1α, and LPS within the context of multi-cytokine mixes. Then, we screened 90 drugs for cytokine synergy in human hepatocytes and found that a significantly larger fraction of the idiosyncratic hepatotoxicants (19%) synergized with a single cytokine mix than did the non-hepatotoxic drugs (3%). Finally, we used an information theoretic approach to ascertain especially informative subsets of cytokine treatments for most highly effective construction of regression models for drug- and cytokine mix-induced hepatotoxicities across these cell systems. Our results suggest that this drug-cytokine co-treatment approach could provide a useful preclinical tool for investigating inflammation-associated idiosyncratic drug hepatotoxicity.     

Impact of autonomic neuropathy on left ventricular function in normotensive type 1 diabetic patients: a tissue Doppler echocardiographic study

Cardiovascular autonomic neuropathy (CAN) is one of the most serious complications of diabetes and has been weakly linked with left ventricular (LV) diastolic dysfunction. Previous studies that explored this association either suffer from inadequate definition of CAN or have mainly used conventional Doppler or nuclear techniques to investigate LV diastolic function. Tissue Doppler imaging (TDI) has evolved as a new quantitative tool for the assessment of cardiac systolic function, diastolic function, and the hemodynamics of LV filling. We sought to investigate conventional and TDI-derived indexes of LV systolic and diastolic function in type 1 diabetic patients with and without CAN and also in normal control subjects. Our findings suggest that the presence of CAN seems to have an additive effect on LV diastolic dysfunction in type 1 diabetes.