Photoneural regulation of rat pineal nitric oxide synthase

We report here a photoneural regulation of nitric oxide synthase (NOS) activity in the rat pineal gland. In the absence of the adrenergic stimulation following constant light exposure (LL) or denervation, pineal NOS activity is markedly reduced. A maximal drop is measured after 8 days in LL. When rats are housed back in normal light:dark (LD) conditions (12:12), pineal NOS activity returns to normal after 4 days. A partial decrease in pineal NOS activity is also observed when rats are placed for 8 days in LD 18:6 or shorter dark phases, indicating that pineal NOS activity reflects the length of the dark phase. Because it is known that norepinephrine (NE) is released at night from the nerve endings in the pineal gland and this release is blocked by exposure to light, our data suggest that NOS is controlled by adrenergic mechanisms. Our observation may also explain the lack of cyclic GMP response to NE observed in animals housed in constant light.     

Phase I trial of intravenous carboplatin and cyclosporin A in refractory gynecologic cancer patients

Our objective was to determine the maximum tolerated dose of cyclosporin A (CsA) delivered as a loading dose (LD) and continuous i.v. infusion (CI) in combination with carboplatin in patients with refractory gynecologic cancers. Twenty-nine heavily pretreated patients (25 ovarian epithelial, 2 cervical, and 2 endometrial carcinomas) received 113 cycles of CsA and carboplatin from September 1989 to September 1991. Twenty-four of these 29 carcinomas were strictly defined to be platinum resistant. CsA was administered as a LD escalated from 6 to 10 mg/kg followed by a 24-h CI from 2.5 to 14.5 mg/kg/day. Carboplatin was targeted to an area under the time versus concentration curve (AUC) of 6 mg/ml x min and was not dose escalated. Whole-blood CsA concentrations (fluorescence polarization immunoassay) at the maximum tolerated dose (10 mg/kg LD, 14.5 mg/kg/day CI) ranged from 2.4 to 3.0 microgram/ml over 12 h. Estimated median carboplatin AUC, based on calculated carboplatin clearance, was 7.9 mg/ml x min. The dose-limiting toxicity of the combination of CsA and carboplatin was grade 4 thrombocytopenia. Grade 3 or 4 thrombocytopenia occurred in 35% of the patients, which could be explained by the effects of carboplatin (AUC of 6 mg/ml x min) alone. Overall, neutropenia occurred in 24% of the patients and anemia in 17% of the patients. Grade 3 or 4 nausea or vomiting was noted in 10 and 14% of the patients, respectively. Grade 3 hypertension during CsA administration occurred in 14% of the patients. No grade 3 or 4 nephrotoxicity was seen in this trial. Three objective responses were noted: one complete response (11 months) and one partial response (5 months), both in potentially platinum-sensitive patients with platinum-free intervals of only 9 months each. One platinum-resistant patient had a partial response for 21 months. Five additional patients experienced >75% reduction of CA-125 or a return to a normal CA-125 titer. We concluded that whole-blood CsA concentrations of >3.0 microgram/ml (as seen when CsA is used as a modulator of multidrug resistance) were not achievable in this combination with carboplatin in this population of heavily pretreated gynecologic cancer patients. However, because CsA is used in this trial as a chemosensitizer in platinum-sensitive tumors and as a chemomodulator of platinum resistance, we targeted a CsA concentration of >1.0 microgram/ml, which was achieved. The CsA dose recommended for a Phase II trial of this combination is 10 mg/kg LD and 11.6 mg/kg/day CI, which results in blood CsA concentrations ranging from 1.2 to 1.3 microgram/ml over 12 h. Responses in this population of refractory gynecologic cancer patients are unusual, and these encouraging results form the basis for a Phase II trial of this combination.     

Adult spinal deformity and respiratory failure. Surgical results in 35 patients

STUDY DESIGN: Retrospective chart and complementary study review. OBJECTIVES: To describe the features of adult patients with spinal deformity and respiratory failure and to analyze the results of surgical treatment. SUMMARY OF BACKGROUND DATA: Many authors have studied the relation between spinal deformities and cardiorespiratory failure, but there exists little information about the benefits of reconstructive surgery in severely compromised patients. METHODS: The charts and complementary studies of 35 adult patients surgically treated between January 1, 1978, and December 31, 1994, were reviewed. The patients were 18 years old or older (average age, 36 years). They had spinal deformity of any etiology with respiratory insufficiency as evidenced by vital capacity of less than 60% of predictive normal, PaO2 less than 80 mm Hg, or PaCO2 more than 45 mm Hg. All had reconstructive spinal surgery in an attempt to improve their respiratory problem. RESULTS: Seven patients died within the first postoperative year, and one patient was lost to follow-up at 6 months. The other 27 patients had a mean follow-up time of 72 months. The 34 patients were divided into three groups: good, fair, and poor evolution. The patients in the good evolution group had a better preoperative general condition, had more correction of their deformities, had more improvement in their respiratory function, and had fewer complications than those in the other groups. The patients in the poor evolution group were older, had more cardiac problems, and had less correction at surgery. CONCLUSION: The results of surgery varied from extremely good to extremely bad. The seven patients who died within the first year had no benefit, but the 27 others did very well, usually gaining significant improvement of their respiratory function. Because the alternative to surgical correction is death, this study shows that, under the right circumstances, correction of spinal deformity and, therefore, correction of respiratory function can be life-saving.     

Human biodistribution of an ultrasound contrast agent (Quantison) by radiolabelling and gamma scintigraphy

The biodistribution and kinetics of an air filled human serum albumin microcapsule formulation (Quantison) intended for use as an intravenous ultrasound contrast agent have been examined. 12 healthy subjects were administered with approximately 50 million microcapsules per kilogram body weight, radiolabelled with 50 MBq 123I. Imaging was performed over a period of 58 h using a large field-of-view gamma camera and the amount of labelled material present in the blood, urine and faeces measured. Imaging demonstrated that the liver was the organ with the highest uptake, with a mean uptake of 41.8% (SD 10.4%) of the administered dose 1 h following administration. The maximum uptake of the agent in the lungs was low, mean 4.0% (SD 3.4%). A small amount of uptake was visible in the bone marrow; however, this was not quantifiable. There was also evidence of minimal myocardial activity within 5 min of administration. No adverse events were observed and there were no changes in any of the individual post-study indices. The present study demonstrates the safety of Quantison. Gamma scintigraphy played a useful role in confirming the biodistribution of the agent with little lung uptake, high liver uptake and evidence of myocardial uptake.     

Kainate receptors mediate a slow postsynaptic current in hippocampal CA3 neurons

Glutamate, the neurotransmitter at most excitatory synapses in the brain, activates a variety of receptor subtypes that can broadly be divided into ionotropic (ligand-gated ion channels) and metabotropic (G-protein-coupled) receptors. Ionotropic receptors mediate fast excitatory synaptic transmission, and based on pharmacological and molecular biological studies are divided into NMDA and non-NMDA subtypes. The non-NMDA receptor group is further divided into AMPA and kainate subtypes. Virtually all fast excitatory postsynaptic currents studied so far in the central nervous system are mediated by the AMPA and NMDA subtypes of receptors. Surprisingly, despite extensive analysis of their structure, biophysical properties and anatomical distribution, a synaptic role for kainate receptors in the brain has not been found. Here we report that repetitive activation of the hippocampal mossy fibre pathway, which is associated with high-affinity kainate binding and many of the kainate receptor subtypes, generates a slow excitatory synaptic current with all of the properties expected of a kainate receptor. This activity-dependent synaptic current greatly augments the excitatory drive of CA3 pyramidal cells.     

Relationships between gastric emptying, intragastric meal distribution and blood glucose concentrations in diabetes mellitus

The aim of this study was to evaluate the prevalence of disordered intragastric meal distribution and the relationships between gastric emptying, intragastric distribution, glycemic control and gastrointestinal symptoms in diabetes mellitus. METHODS: Eighty-six patients with diabetes mellitus had measurements of gastric emptying and intragastric distribution of a radioisotopically labeled solid/liquid meal (100 g beef and 150 ml 10% dextrose), glycemic control (plasma glucose concentrations), upper gastrointestinal symptoms (questionnaire) and autonomic nerve function (cardiovascular reflexes). Results were compared to those obtained in 20 normal volunteers. RESULTS: Solid and liquid gastric emptying were delayed in the diabetic patients and correlated weakly. Intragastric meal distribution was also often abnormal, with increased retention of both solid and liquid in the proximal stomach and increased retention of solid but not liquid in the distal stomach. In all patients with increased retention of solid in the proximal stomach, emptying from the total stomach was delayed. Gastric emptying of liquid was slower in those subjects who had a mean plasma glucose > 15 mmol/liter during the gastric emptying measurement, when compared to the remainder of the group. CONCLUSION: In patients with diabetes mellitus, there is poor relationship between solid and liquid gastric emptying and intragastric meal distribution is frequently abnormal. Interpretation of the results of gastric emptying measurements should consider meal composition and plasma glucose concentrations.     

Risk of human immunodeficiency virus infection among pregnant crack cocaine users in a rural community

OBJECTIVE: To investigate why women who use crack cocaine are at increased risk of human immunodeficiency virus (HIV) infection. METHODS: One thousand one hundred fifty-two (99.7%) of 1155 consecutive prenatal patients attending a rural public health clinic were interviewed about drug use and sexual practices and tested for HIV infection and other sexually transmitted diseases. RESULTS: Fifty-one (4.7%) of 1096 pregnant women reported ever using crack cocaine, but only five (10%) of the crack cocaine users had ever injected drugs. Eighteen (35%) of the crack users were HIV infected compared with 22 (2%) of the 1045 women who reported never using crack (odds ratio 25, 95% confidence interval 12-52; P < .001). Crack users were more likely to have had a known HIV-infected sex partner, exchanged sex for money or drugs, and tested positive for syphilis than were non-crack users (for each comparison, P < .001). Before using crack, 18% of crack users had exchanged sex for money or drugs and 8% had averaged three or more sex partners per month; in contrast, after beginning to use crack, 76% of crack users exchanged sex for money or drugs and 63% averaged three or more sex partners per month (for both comparisons, P < .001). Crack users who were not HIV infected were more likely to have almost always used condoms and/or had fewer than three sex partners per month than were HIV-infected crack users (P < .01). CONCLUSION: Women who reported using crack cocaine were at an increased risk of HIV infection because crack use was associated with a significant increase in unprotected sexual contact.     

Smoking screening and management in primary care practices

This study examined how pain coping efficacy and pain coping strategies were related to reports of pain during mammography. Subjects were 125 women over the age of 50 undergoing screening mammograms. Prior to their mammogram, all subjects completed the Coping Strategies Questionnaire (CSQ) to assess how they cope with day-to-day pain experiences. Ratings of pain during the mammogram were collected using a 6-point pain/discomfort scale, a 100-mm Visual Analog Scale, the adjective checklist of the McGill Pain Questionnaire, and the Brief Pain Inventory. Up to 93% of the women reported the mammogram examination was painful. On average, women rated the mammography pain in the low to moderate range. Considerable variability in pain ratings was found, however, with some women reporting severe pain and others reporting little or no pain. Correlational analyses were conducted to examine how coping efficacy (CSQ ratings of ability to decrease pain and ability to control pain) and coping strategies (CSQ pain coping strategy subscales) related to variations in pain report. There was a pattern for ratings of ability to decrease pain to be related to lower ratings of current mammography pain. Women who rated their ability to decrease pain as high reported lower average levels of mammography pain, lower ratings on the mammography pain/discomfort scale, and were much more likely to report having had lower levels of pain during their last mammogram. These findings suggest that women who rate their coping efficacy in decreasing day-to-day pain as low may be at higher risk for having a painful mammogram. Individual pain coping strategies were not generally correlated with pain ratings. Behavioral interventions (e.g., patient controlled breast compression) and cognitive therapy interventions (e.g., training in the use of calming self-statements or distraction techniques) designed to increase coping efficacy potentially could be useful in reducing pain in women who are at risk for pain during mammography.