Effects of serotonin and the serotonin blocker metergoline on meal patterns and macronutrient selection

Serotonin [5-hydroxytryptamine(5-HT)] in the paraventricular nucleus (PVN) of rats has a suppressive effect on feeding behavior and causes a selective decrease in carbohydrate ingestion, specifically at the onset of the natural (dark) feeding period. Studies conducted here provide further evidence for this phenomena, showing a similar dose-related decrease in carbohydrate ingestion at dark onset after PVN injection of 5-HT or of the agonists, d-norfenfluramine or fluoxetine, which act through endogenous 5-HT. To further characterize the effects of this indoleamine on the macrostructure of feeding, a computer-automated data acquisition system was used to analyze macronutrient feeding patterns in freely feeding animals maintained on the pure diets of protein, carbohydrate, and fat. Results indicate that PVN administration of 5-HT at dark onset decreases intake of the carbohydrate nutrient by decreasing meal size, feeding time, and feeding rate for this nutrient and increasing the satiating effect of carbohydrate. These effects, which occur specifically during the first meal after injection, are opposite those seen after peripheral administration of the 5-HT receptor antagonist, metergoline. This drug stimulates feeding through a selective increase in carbohydrate intake, characterized by an increase in meal size, percent composition, and feeding time for this nutrient and a decrease in the satiety ratio for carbohydrate. These results implicate the serotonergic system in the termination of carbohydrate-rich meals that are prevalent during the early hours of the natural feeding cycle.     

Neuronal pathways for activation of inhibitory interneurons in pyriform cortex of the rabbit

The neuronal pathways responsible for the fast inhibitory postsynaptic potentials (IPSPs) elicited in principal cells in the pyriform cortex (PC) by volleys from the olfactory bulb (OB), the lateral olfactory tract (LOT), the anterior commissure (AC), and the deep-lying structures of the PC (DPC) were studied in the rabbit. The central latencies of the fast IPSPs (measured from the onset of the monosynaptic excitatory postsynaptic potential (EPSP) elicited by volleys through the LOT) ranged between 3.0 and 9.3 ms (5.5 +/- 1.3 (SD) ms; n = 54) in the case of OB shocks and between 4.5 and 6.5 ms (5.1 +/- 0.7 (SD) ms; n = 7) in the case of LOT shocks. The onset latencies of the fast IPSPs were between 2.5 and 11.8 ms (5.1 +/- 1.8 (SD) ms; n = 66) in the case of DPC shocks and between 3.5 and 10.1 ms (5.8 +/- 1.5 (SD) ms; n = 61) in the case of AC shocks. The conditioning OB or LOT shocks almost completely eliminated the LOT-evoked fast IPSP when the testing shock was applied at the peak period of the conditioning slow IPSP. The conditioning OB shocks also eliminated the initial part of the OB-evoked fast IPSP, leaving the later part of the fast IPSP almost unchanged. Thus, the onset latency of the OB-evoked fast IPSP was lengthened by 7.1 +/- 2.9 (SD) ms (n = 35) by the conditioning OB shock. The conditioning OB or DPC shocks left the peak amplitude of the DPC-evoked fast IPSP almost unaffected. Similarly, the conditioning OB or AC shocks left the peak amplitude of the AC-evoked fast IPSP almost unaffected. The conditioning OB, DPC, or AC shocks had only a slight influence on the onset latency of the DPC- or AC-evoked fast IPSPs. Rhythmical steps at intervals of 3-5 ms were observed in the rising phase of the OB-evoked fast IPSP. This was interpreted as a result of a repetitive impingement of interneuronal discharges on the impaled cells. Spatial facilitation was observed among the fast IPSPs evoked by volleys from the OB, DPC, and AC when shocks were applied at suitable intervals. A slight facilitation was also seen between the LOT-evoked fast IPSP and the DPC- or AC-evoked fast IPSP. These results were interpreted as a result of the convergence of excitatory synaptic inputs onto the presumed inhibitory interneurons from the four structures of the brain. A temporal facilitation of the fast IPSPs was observed when the OB, DPC, or AC shocks were applied repetitively at short intervals. This suggests a temporal facilitation of the spike discharges of the presumed inhibitory interneurons under similar conditions. From these results, criteria were determined for identifying the inhibitory interneurons.     

Disposable contact lenses and their complications

Disposable soft contact lenses (DSCLs) have been marketed as a safer alternative to conventional soft lenses. Extended-wear DSCLs are designed for one or two weeks of continuous use before disposal. Those for daily wear are designed for use as conventional daily wear soft lenses, with daily removal and storage for 2 to 4 weeks before disposal. Beside minor complications, such as corneal abrasion, giant papillary conjunctivitis and toxic epithelial reactions to contact lens solutions, the most serious complication occurring in contact lens users is ulcerative keratitis. Several case-control studies performed over the last years, demonstrated that disposable contact lenses were associated with a 14-fold excess risk of ulcerative keratitis compared with that for patients wearing conventional daily-wear soft contact lenses and a 13-fold excess risk compared with that for wearers of rigid gas permeable contact lenses. However, the major risk factor for corneal ulceration in contact lens wearers is overnight lens wear of 1 to 3 nights. It was estimated that 49 to 74% of cases of contact lens associated ulcerative keratitis could be prevented by eliminating overnight wear.     

Thermal Effects and Small Signal Modulation of 1.3-μm InAs/GaAs Self-Assembled Quantum-Dot Lasers

We investigate the influence of thermal effects on the high-speed performance of 1.3-μm InAs/GaAs quantum-dot lasers in a wide temperature range (5–50°C). Ridge waveguide devices with 1.1 mm cavity length exhibit small signal modulation bandwidths of 7.51 GHz at 5°C and 3.98 GHz at 50°C. Temperature-dependent K-factor, differential gain, and gain compression factor are studied. While the intrinsic damping-limited modulation bandwidth is as high as 23 GHz, the actual modulation bandwidth is limited by carrier thermalization under continuous wave operation. Saturation of the resonance frequency was found to be the result of thermal reduction in the differential gain, which may originate from carrier thermalization.     

The thrombin receptor elevates intracellular calcium in adult rat ventricular myocytes

While there is evidence that thrombin receptor activation leads to contractile dysfunction and induces arrhythmias in ischemic/reperfused cardiac tissue, thrombin is variably reported to modulate intracellular calcium in cardiomyocytes. The present study demonstrates that thrombin receptor activation leads to a rise in intracellular calcium in adult ventricular myocytes and serves to reconcile previous discrepant findings. The thrombin receptor-derived agonist peptide (SFLLRN, a portion of the tethered ligand created by thrombin's proteolytic actions) increases cytosolic calcium and twitch amplitude in cardiomyocytes isolated from adult ventricles. The truncated control peptide FLLRN has no effect, establishing that the response to SFLLRN results from a specific agonist peptide-receptor interaction. However, the response to SFLLRN occurs only at high agonist peptide concentrations and thrombin itself is inactive. This result is not compatible with an action of SFLLRN at a distinct protease-activated receptor (PAR-2; which is activated by SFLLRN, but not by thrombin), since SLIGRL (a ligand which is selective for PAR-2, but not the thrombin receptor) has no effect. Rather, the enzyme-based cell isolation procedure may partially cleave the thrombin receptor and influence cell responses, since concentrations of SFLLRN which are sub-threshold in enzymatically disaggregated myocytes significantly increase the force of isometric contraction of intact rat papillary muscles. These studies provide the first evidence that thrombin receptor activation leads to a change in intracellular calcium and a positive inotropic response in adult ventricular myocardium.     

Homologous down-regulation of growth hormone-releasing hormone receptor messenger ribonucleic acid levels

Repeated stimulation of pituitary cell cultures with GH-releasing hormone (GHRH) results in diminished responsiveness, a phenomenon referred to as homologous desensitization. One component of GHRH-induced desensitization is a reduction in GHRH-binding sites, which is reflected by the decreased ability of GHRH to stimulate a rise in intracellular cAMP. In the present study, we sought to determine if homologous down-regulation of GHRH receptor number is due to a decrease in GHRH receptor synthesis. To this end, we developed and validated a quantitative RT-PCR assay system that was capable of assessing differences in GHRH-R messenger RNA (mRNA) levels in total RNA samples obtained from rat pituitary cell cultures. Treatment of pituitary cells with GHRH, for as little as 4 h, resulted in a dose-dependent decrease in GHRH-R mRNA levels. The maximum effect was observed with 0.1 and 1 nM GHRH, which reduced GHRH-R mRNA levels to 49 +/- 4% (mean +/- SEM) and 54 +/- 11% of control values, respectively (n = three separate experiments; P < 0.05). Accompanying the decline in GHRH-R mRNA levels was a rise in GH release; reaching 320 +/- 31% of control values (P < 0.01). Because of the possibility that the rise in medium GH level is the primary regulator of GHRH-R mRNA, we pretreated pituitary cultures for 4 h with GH to achieve a concentration comparable with that induced by a maximal stimulation with GHRH (8 micrograms GH/ml medium). Following pretreatment, cultures were stimulated for 15 min with GHRH and intracellular cAMP accumulation was measured by RIA. GH pretreatment did not impair the ability of GHRH to induce a rise in cAMP concentrations. However, as anticipated, GHRH pretreatment (10 nM) significantly reduced subsequent GHRH-stimulated cAMP to 46% of untreated controls. These data suggest that GHRH, but not GH, directly reduces GHRH-R mRNA levels. To determine whether this effect was mediated through cAMP, cultures were treated with forskolin, a direct stimulator of adenylate cyclase. Forskolin (10 microM) significantly reduced GHRH-R mRNA concentrations (37 +/- 6% of control values) indicating that GHRH acts through the cAMP-second messenger system cascade to regulate GHRH-R mRNA. The somatostatin analogue, octreotide (10 nM), which has been previously reported to decrease adenylate cyclase activity, did not affect GHRH-R mRNA levels. Taken together, these results indicate that GHRH inhibits the production of its own receptor by a receptor-mediated, cAMP-dependent reduction of GHRH-R mRNA accumulation.     

Bladder neck competency at rest in women with incontinence

PURPOSE: We determine the presence of an open bladder neck during video urodynamic studies and relate that finding to the presence of stress urinary incontinence. MATERIALS AND METHODS: Patients presenting with urinary incontinence, voiding dysfunction or pelvic floor prolapse underwent video urodynamics. With the patient upright and after 200 ml. contrast material had been instilled into the bladder the bladder neck was viewed to determine if it was open or closed. At that point the abdominal leak point pressure was measured. RESULTS: Of 102 women, average age 56.5 years (range 31 to 82), 13% had an open bladder neck and demonstrable stress incontinence on video urodynamics with an average abdominal leak point pressure of 45 cm. water (range 26 to 90). Of those with stress incontinence on urodynamics 23% had an open bladder neck. No continent patient had an open bladder neck. CONCLUSIONS: The presence of an open bladder neck with the bladder filled to 200 ml. correlates strongly with the presence of stress incontinence.     

HMG-CoA reductase regulation: use of structurally diverse first half-reaction squalene synthetase inhibitors to characterize the site of mevalonate-derived nonsterol regulator production in cultured IM-9 cells

Neuromuscular disease commonly affects the rearfoot as equinus, equinovarus, and equinovalgus deformity. Spastic hemiplegia caused by stroke, head injury, and cerebral palsy results in equinovarus deformity of the rearfoot. Spastic diplegia, most frequently caused by cerebral palsy, results in equinovalgus rearfoot deformity. Problems in ambulation, footwear, and bracing, as well as their orthopedic management, in patients with neuromuscular disease are discussed in a case-report format.     

Three distinct D-amino acid substitutions confer potent antiangiogenic activity on an inactive peptide derived from a thrombospondin-1 type 1 repeat

Mal II, a 19-residue peptide derived from the second type 1 properdin-like repeat of the antiangiogenic protein thrombospondin-1 (TSP-1), was inactive in angiogenesis assays. Yet the substitution of any one of three L-amino acids by their D-enantiomers conferred on this peptide a potent antiangiogenic activity approaching that of the intact 450-kDa TSP-1. Substituted peptides inhibited the migration of capillary endothelial cells with an ED50 of 8.5 nM for the D-Ile-15 substitution, 10 nM for the D-Ser-4 substitution, and 0.75 nM for the D-Ser-5 substitution. A peptide with D-Ile at position 15 could be shortened to its last seven amino acids with little loss in activity. Like whole TSP-1, the Mal II D-Ile derivative inhibited a broad range of angiogenic inducers, was selective for endothelial cells, and required CD36 receptor binding for activity. A variety of end modifications further improved peptide potency. An ethylamide-capped heptapeptide was also active systemically in that when injected i.p. it rendered mice unable to mount a corneal angiogenic response, suggesting the potential usefulness of such peptides as antiangiogenic therapeutics.     

Long-term inhalable particles and other air pollutants related to mortality in nonsmokers

Long-term ambient concentrations of inhalable particles less than 10 microm in diameter (PM10) (1973- 1992) and other air pollutants-total suspended sulfates, sulfur dioxide, ozone (O3), and nitrogen dioxide-were related to 1977-1992 mortality in a cohort of 6,338 nonsmoking California Seventh-day Adventists. In both sexes, PM10 showed a strong association with mortality for any mention of nonmalignant respiratory disease on the death certificate, adjusting for a wide range of potentially confounding factors, including occupational and indoor sources of air pollutants. The adjusted relative risk (RR) for this cause of death as associated with an interquartile range (IQR) difference of 43 d/yr when PM10 exceeded 100 microg/m3 was 1.18 (95% confidence interval [CI]: 1.02, 1.36). In males, PM10 showed a strong association with lung cancer deaths-RR for an IQR was 2.38 (95% CI: 1.42, 3.97). Ozone showed an even stronger association with lung cancer mortality for males with an RR of 4.19 (95% CI: 1.81, 9.69) for the IQR difference of 551 h/yr when O3 exceeded 100 parts per billion. Sulfur dioxide showed strong associations with lung cancer mortality for both sexes. Other pollutants showed weak or no association with mortality.