Hypotension and thirst in rats after isoproterenol treatment

Drinking induced in rats by systemic isoproterenol treatment is markedly attenuated after bilateral nephrectomy. The present experiments demonstrate that the hypotension produced by iso-proterenol treatment was more profound, and lasted much longer, in nephrectomized rats than in intact animals. When arterial blood pressure was partially elevated by central administration of angiotensin II or carbachol (Experiment 1) or by intraarterial infusion of epinephrine (Experiment 2), drinking behavior was restored in the nephrectomized animals and their water intakes approximated the amounts consumed by intact rats given isoproterenol. In general, an inverted U-shaped curve was found to define the relation between blood pressure and water intake in rats after isoproterenol treatment. Drinking was most probable when mean arterial blood pressures were in the range of 70–85 mm Hg, whereas rats were unlikely to drink when blood pressures were much below or above this range. These findings indicate that isoproterenol-induced thirst is not dependent on a renal dipsogen, and suggest instead that the hypersecretion of renin that occurs in intact rats is simply permissive of drinking behavior by modulating the hypotensive effects of the drug treatment.     

Efficacy response of inhaled beclomethasone dipropionate in asthma is proportional to dose and is improved by formulation with a new propellant

BACKGROUND: This study tested the hypothesis that there would be improved asthma control with increasing doses of beclomethasone dipropionate (BDP) formulated in hydrofluoroalkane-134a (HFA-BDP) and the standard chlorofluorocarbon propellants (CFC-BDP). Because HFA-BDP has improved lung deposition compared with CFC-BDP, this study also tested the hypothesis that HFA-BDP would provide more effective control of asthma than CFC-BDP. METHODS: In this multicenter, randomized, parallel-group blinded study, asthmatic subjects who had deterioration in asthma control after discontinuation of inhaled corticosteroids were randomized to receive one of 6 possible treatments: 100 microg/d, 400 microg/d, or 800 microg/d of HFA-BDP or 100 microg/d, 400 microg/d, or 800 microg/d of CFC-BDP for 6 weeks. Changes in spirometry, daytime asthma symptom and nighttime asthma-related sleep disturbance scores, morning and evening peak expiratory flows, and daily use of inhaled beta-agonist for symptom control on diary cards were assessed over 6 weeks of treatment. RESULTS: Three hundred twenty-three patients were randomized to the 6 treatment groups, which had similar demographics and baseline lung function. There were significantly larger changes from baseline at week 6 in FEV(1) percent predicted with increasing doses of both HFA-BDP and CFC-BDP. The FEV(1) percent predicted dose-response curve for HFA-BDP was shifted to the left compared with the dose-response curve for CFC-BDP. By using the Finney bioassay method, it was calculated that 2.6 times as much CFC-BDP would be required to achieve the same improvement in FEV(1) percent predicted as HFA-BDP (95% confidence interval, 1.1-11.6). All treatment groups except the 100 microg/d CFC-BDP group tolerated study drug well. Ten (17%) of 59 patients in this group reported an acute asthma episode, increased asthma symptoms (6 of the 8 reports of increased asthma symptoms were classified as severe), or both, and 8 patients withdrew from the study (3 for adverse events related to asthma). CONCLUSIONS: Increasing doses of inhaled corticosteroids lead to improved lung function and asthma control. Moreover, the reformulation of BDP in HFA enables effective asthma control at much lower doses than CFC-BDP.     

Controls of vasopressin secretion and thirst: similarities and dissimilarities in signals

RATS HAVE TWO PROMINENT RESPONSES TO DEHYDRATION: secretion of the antidiuretic hormone, vasopressin (VP), and thirst. Many signals directly affect both responses. These include two excitatory signals associated with increased plasma osmolality (pOsm) and two inhibitory signals associated with decreased pOsm (one each from cerebral and visceral osmoreceptors). In addition, both VP secretion and thirst during hypovolemia are stimulated by at least two signals, one neural (from cardiac baroreceptors) and one humoral (i.e., angiotensin II). In contrast to these evident similarities, there are definite dissimilarities in the signals for VP secretion and thirst. For example, acute hypervolemia inhibits VP secretion but not thirst, whereas acute hypertension inhibits thirst but not VP secretion. Thirst and VP secretion in rats each are stimulated by acute arterial hypotension, albeit not by the same signals; water intake is mediated by activation of the renin-angiotensin system but not by a neural signal from arterial baroreceptors, whereas the reverse may be true for the stimulation of VP secretion. These dissimilarities indicate that VP secretion and thirst in rats are neither invariably linked nor controlled by the same mechanisms.     

Identification and characterization of aquaporin-2 water channel mutations causing nephrogenic diabetes insipidus with partial vasopressin response

Congenital nephrogenic diabetes insipidus (NDI) is a rare disease caused most often by mutations in the vasopressin V2 receptor (AVPR2). We studied a family which included a female patient with NDI with symptoms dating from infancy. The patient responded to large doses of desmopressin (dDAVP) which decreased urine volume from 10 to 4 I/day. Neither the parents nor the three sisters were polyuric. The patient was found to be a compound heterozygote for two novel recessive point mutations in the aquaporin-2 (AQP2) gene: L22V in exon 1 and C181W in exon 3. Residue Cys181 in AQP2 is the site for inhibition of water permeation by mercurial compounds and is located near to the NPA motif conserved in all aquaporins. Osmotic water permeability (Pf) in Xenopus oocytes injected with cRNA encoding C181W-AQP2 was not increased over water control, while expression of L22V cRNA increased the Pf to approximately 60% of that for wild-type AQP2. Co-injection of the mutant cRNAs with the wild-type cRNA did not affect the function of the wild-type AQP2. Immunolocalization of AQP2-transfected CHO cells showed that the C181W mutant had an endoplasmic reticulum-like intracellular distribution, whereas L22V and wild-type AQP2 showed endosome and plasma membrane staining. Water permeability assays showed a high Pf in cells expressing wild-type and L22V AQP2. This study indicates that AQP2 mutations can confer partially responsive NDI.      

Multiple cerebral metastases: detectability with Gd-DTPA-enhanced MR imaging

Sixteen patients with suspected cerebral metastases were studied with magnetic resonance (MR) imaging before and after the intravenous administration of 0.1 mmol/kg of gadolinium diethylenetriaminepenta-acetic acid. The images were interpreted blindly by two neuroradiologists; all clinical, radiologic (computed tomographic and MR imaging), and pathologic data were reviewed to arrive at a final "best diagnosis," which was then compared with the prior blinded interpretations. Of seven patients found to have multiple metastases, six (86%) had at least one tumor nodule depicted by postinfusion MR imaging that was missed by one or both observers on review of preinfusion images alone. Lesions missed on preinfusion studies were usually small nodules hidden by or not detected next to regions of high-signal edema thought to be related to the adjacent tumor nodule. The authors believe that contrast enhancement improves detection of metastatic foci with MR imaging and that the findings indicate broader implications for the detection of multiple lesions from other causes.     

Surgery of labio-maxillo-palatal clefts during humanitarian mission in the Philippines

After describing the Philippines and the Comité de Soutien Enfance Philippines, a humanitarian association with a three-fold objective: to build, to educate and to treat, the authors present the organization and practical conduct of their missions abroad which have enabled them to treat almost 400 patients with cleft lip and palate between the ages of 3 months and 46 years.     

Mental health quality assurance. Development of the American Psychological Association/CHAMPUS program

In this article, quality assurance efforts in the field of mental health are discussed, especially concerning the reviews of outpatient clinical services. The recently established American Psychological Association APA/CHAMPUS program is described in detail, a national program of peer review that is illustrative of the major conceptual and professional issues inherent in the mental health quality assurance process. Throughout the article, comparisons are made between quality assurance in the medicine and mental health fields.     

Treatment of localized prostate cancer using a combination of high dose rate Iridium‐192 brachytherapy and external beam irradiation: Initial Australian experience

Combination high dose rate brachytherapy (HDRB) and external beam radiation therapy is technically and clinically feasible as definitive treatment for localized prostate cancer. We report the first large Australian experience using this technique of radiation dose escalation in 82 patients with intermediate‐ and high‐risk disease. With a median follow up of 3 years (156 weeks), complications were low and overall prostate‐specific antigen progression‐free survival was 91% using the American Society for Therapeutic Radiology and Oncology consensus definition. The delivery of hypofractionated radiation through the HDRB component shortens overall treatment time and is both biologically and logistically advantageous. As a radiation boost strategy, HDRB is easy to learn and could be introduced into most facilities with brachytherapy capability.