Effects of the phosphodiesterase inhibitor rolipram on the acoustic startle response in rats

Systemic administration of the phosphodiesterase inhibitor rolipram (0.05–10.0 mg/kg, IP) produced a rapid and dose-related increase in the amplitude of the acoustic startle response in rats. The (−) isomer was more potent than the (+) isomer in enhancing startle amplitude. Rolipram increased startle responses that were elicited by brief electrical stimulation of the ventral cochlear nucleus or nucleus reticularis pontis caudalis, two brainstem relay nuclei of the startle neural circuit. A low (5 μg) dose of rolipram produced an excitatory effect on startle following spinal (lumbar intrathecal) infusion but not following supraspinal (lateral ventricle) infusion. Rolipram (0.5 mg/kg, IP) excitation of startle was not blocked by drugs which differentially disrupt the release of monoamines (DSP4, reserpine + alpha-methylpara-tyrosine, reserpine + para-chloro-phenylalanine) or by drugs which differentially block monoamine receptors (haloperidol, prazosin, idazoxan, cinanserin, or cyproheptadine). The marked increase in startle seen following systemic rolipram injection is attributable, at least in part, on an action in the lumbar spinal cord that directly or indirectly facilitates neural transmission along the reticulospinal component of the startle reflex neural pathway. The startle reflex should be a useful behavioral test system for studying the mechanism of action of rolipram and related compounds purported to selectively inhibit calmodulin-independent forms of phosphodiesterase.     

Exercise training ameliorates progressive renal disease in rats with subtotal nephrectomy

To determine the effect of chronic exercise training on renal function in animals with moderate renal insufficiency, rats with 75% renal ablation were either exercise trained by swimming for two months or remained sedentary. Glomerular filtration rate was significantly higher in trained (1.89 +/- 0.07 ml/min) than in sedentary rats (1.52 +/- 0.11 ml/min). No change was observed in renal blood flow or the degree of hypertension. Proteinuria was reduced in trained (13.6 +/- 4.9 mg/24 hr) compared to sedentary animals (33.5 +/- 9.2 mg/24 hr). The degree of glomerulosclerosis was much less prominent in trained animals. Plasma, low-density lipoprotein cholesterol-levels and total triglycerides were reduced in trained compared to sedentary rats. This study suggests that chronic exercise training ameliorates the progression of renal disease and improves plasma lipids in rats with moderate renal insufficiency. The mechanism for this improvement in renal function appears to be independent of the influence of systemic blood pressure.     

Dendrotoxin-sensitive K+ currents contribute to accommodation in murine spiral ganglion neurons

We have previously identified two broad electrophysiological classes of spiral ganglion neuron that differ in their rate of accommodation ( Mo & Davis, 1997 a ). In order to understand the underlying ionic basis of these characteristic firing patterns, we used α-dendrotoxin (α-DTX) to eliminate the contribution of a class of voltage-gated K⁺ channels and assessed its effects on a variety of electrophysiological properties by using the whole-cell configuration of the patch-clamp technique. Exposure to α-DTX caused neurons that initially displayed rapid accommodation to fire continuously during 240 ms depolarizing test pulses within a restricted voltage range. We found a non-monotonic relationship between number of action potentials fired and membrane potential in the presence of α-DTX that peaked at voltages between –40 to –10 mV and declined at more depolarized and hyperpolarized test potentials. The α-DTX-sensitive current had two components that activated in different voltage ranges. Analysis of recordings made from acutely isolated neurons gave estimated half-maximal activation voltages of –63 and 12 mV for the two components. Because α-DTX blocks the Kv1.1, Kv1.2 and Kv1.6 subunits, we examined the action of the Kv1.1-selective blocker dendrotoxin K (DTX-K). We found that this antagonist reproduced the effects of α-DTX on neuronal firing, and that the DTX-K-sensitive current also had two separate components. These data suggest that the transformation from a rapidly adapting to a slowly adapting firing pattern was mediated by the low voltage-activated component of DTX-sensitive current with a potential contribution from the high voltage-activated component at more depolarized potentials. In addition, the effects of DTX-K indicate that Kv1.1 subunits are important constituents of the underlying voltage-gated potassium channels.     

Neuroendocrine and neurochemical measurements in depression

The authors performed dexamethasone suppression tests (DST), TRH infusions, 72-hour urine collections, and lumbar punctures on a group of male depressed patients. Approximately 60% of the patients were DST positive and 33% had a blunted TSH response. Two biologic variables, the 8 a.m. postdexamethasone cortisol and the postprobenecid CSF 5-hydroxyindoleacetic acid (5-HIAA), accounted for over half of the variance in the behavioral measure, the Hamilton score. Plasma cortisol elevation was associated with high 3-methoxy-4-hydroxyphenyl glycol (MHPG) excretion; TSH blunting was associated with low urinary MHPG excretion. Comprehensive biologic measures showed certain significant interrelationships and correlations with the severity of depression.     

Retrorenal colon: implications for percutaneous diskectomy

It has been recommended that computed tomography (CT) with the patient prone be performed in every patient undergoing percutaneous diskectomy; this would enable detection of a retrorenal location of the colon, which could interfere with the percutaneous procedure. In this evaluation of 346 prone CT studies, only one patient (0.29%) was found to have retrorenal or retropsoas bowel that would have been perforated at diskectomy. Because of this extremely low prevalence, the performance of prone CT in every patient undergoing percutaneous lumbar diskectomy is not believed to be necessary.     

Proton magnetic resonance spectroscopy of the brain in schizophrenic and affective patients.

Water-suppressed 1H magnetic resonance spectra were recorded from two brain regions of psychiatric patients and normal volunteers. The two regions studied were (a) the basal ganglia structures surrounding the anterior horn of the lateral ventricle and (b) the occipital cortex. N-Acetylaspartate (NAA), phosphocreatine-creatine (PCr-Cr), choline and inositol resonances were seen in both regions. Ratios of metabolite peak integrals to PCr-Cr peak integral were calculated for each spectrum. To control for partial volume effects, comparisons between patients and controls were made only from identical regions i.e. basal ganglia vs basal ganglia, and likewise for occipital cortex. Metabolite ratios from the occipital region of patients were similar to those from the occipital region of normal subjects. Bipolar patients being treated with lithium had elevated NAA/PCr-Cr in the basal ganglia region when compared to normals. These patients also demonstrated elevated choline/PCr-Cr and inositol/PCr-Cr ratios in the basal ganglia region.     

No-scalpel vasectomy: a technique for family physicians.

Family physicians frequently perform outpatient vasectomies. A new approach to exposing the vas deferens, called the no-scalpel vasectomy, results in fewer complications and, the authors believe, improved patient acceptance. This technique, which calls for two specialized instruments, is described, along with patient selection and education issues, vasal occlusion techniques and post-vasectomy follow-up.     

Pharmacological treatments that facilitate extinction of fear: Relevance to psychotherapy

A great deal is now known about the mechanisms of conditioned fear acquisition and expression. More recently, the mechanisms of inhibition of conditioned fear have become the subject of intensive study. The major model system for the study of fear inhibition in the laboratory is extinction, in which a previously fear conditioned organism is exposed repeatedly to the fear-eliciting cue in the absence of any aversive event and the fear conditioned response declines. It is well established that extinction is a form of new learning as opposed to forgetting or “unlearning” of conditioned fear, and it is hypothesized that extinction develops when sensory pathways conveying sensory information to the amygdala come to engage GABAergic interneurons through forms of experience-dependent plasticity such as long-term potentiation. Several laboratories currently are investigating methods of facilitating fear extinction in animals with the hope that such treatments might ultimately prove to be useful in facilitating exposure-based therapy for anxiety disorders in clinical populations. This review discusses the advances that have been made in this field and presents the findings of the first major clinical study to examine the therapeutic utility of a drug that facilitates extinction in animals. It is concluded that extinction is an excellent model system for the study of fear inhibition and an indispensable tool for the screening of putative pharmacotherapies for clinical use.     

Liver transplantation for erythropoietic protoporphyria liver disease.

In erythropoietic protoporphyria (EPP), there is excessive production of protoporphyrin, primarily in the bone marrow, resulting in increased biliary excretion of this heme precursor. Some patients will develop progressive liver disease that may ultimately require liver transplantation. However, excessive production of protoporphyrin by the bone marrow continues after transplantation, which may cause recurrent disease in the allograft. This study was performed to define post-transplant survival, the risk of recurrent disease, and specific management issues in patients transplanted for EPP liver disease. The patients studied consisted of twelve males and eight females, with an average age of 31 (range, 13-56) years at the time of transplantation. The estimated maximum MELD score prior to transplant was 21 (range, 15-29). Unique complications in the perioperative period were light induced tissue damage in four patients and neuropathy in six, requiring prolonged mechanical ventilation in four. Patient and graft survival rates were 85% at 1 year, 69% at 5 years, and 47% at 10 years. Recurrent EPP liver disease occurred in 11 of 17 patients (65%) who survived more than 2 months. Three patients were retransplanted at 1.8, 12.6, and 14.5 years after the initial transplant for recurrent EPP liver disease. In conclusion, the 5-year patient survival rate in patients transplanted for EPP liver disease is good, but the recurrence of EPP liver disease appears to diminish long term graft and patient survival.