Inward rectifier potassium channels. Cloning, expression and structure-function studies

A PCR-based cloning strategy was used to identify novel subunits of the two-transmembrane domain inward rectifier potassium channel family from rat brain, heart, and skeletal muscle. When expressed in Xenopus oocytes, two of these clones (Kir4.1 and Kir2.3) gave rise to inwardly rectifying potassium currents. Two-electrode voltage clamp commands to potentials negative to EK evoked inward potassium-selective currents which rapidly reached a peak amplitude and then relaxed to a steady-state level. Differences in the extent of current relaxation, the degree of rectification, and the voltage-dependent block by external cesium were detected. Two other members of this family (Kir5.1 and Kir3.4) did not produce macroscopic currents, when expressed by themselves, yet both subunits modified the currents when coexpressed with other specific members of the Kir family. Expression of chimeric subunits between Kir4.1 and either Kir5.1 or Kir3.4 suggested that the transmembrane domains determine the specificity of subunit heteropolymerization, while the C-terminal domains contribute to alterations in activation kinetics and rectification. Expression of covalently linked subunits demonstrated that the relative subunit positions, as well as stoichiometry, affect heteromeric channel activity.     

The generation and maintenance of schedule-induced polydipsia in normal male rats without weight reduction

Experiment One demonstrated that two normal male Sprague-Dawley rats (approximately 60 days old) with free access to food and two control rats whose weights were held constant by dietary restriction acquired schedule-induced polydipsia (SIP) in daily 33-35 min sessions of fixed-time 60-s food delivery. Three of the rats showed rapid acquisition of SIP; the fourth acquired SIP more slowly and consumed less per session the other three rats. After a 36-40 day period without sessions, the constant-weight rats showed a 37% decrease in overall consumption due to reduced drinking bout length. The SIP of the free-feeding rats was not affected by the interruption. After 90-100 periodic food delivery sessions, all subjects consumed an average of 11.2-12.2 mL per session compared with 1.8-4.8 mL per session in baseline sessions with massed food presentations. Experiment Two replicated the acquisition phase of Experiment One using two non-weight-reduced rats of the age and size of those typically used in SIP studies (approximately 30 weeks old). Both acquired SIP, although one showed only a small average increase in consumption per session over baseline (2.8 mL/session under periodic food vs. 0.8 mL following massed-food presentations). Before weight reduction, the stronger drinker consumed approximately 8.8 mL per session compared with an average of 0.6 mL per session in baseline. After weight reduction, both exhibited strong SIP (18-19 mL per session in the final five sessions). This study demonstrates that weight reduction is not a necessary condition for the generation and maintenance of SIP in rats.     

Elderly patients with adult-onset growth hormone deficiency are not osteopenic

The age-related decline in GH secretion has been implicated in the development of osteoporosis. GH-deficient adults show a significant reduction in bone mineral density (BMD), which is greater in those with childhood-onset GH deficiency than in those with GH deficiency occurring in adult life. To determine whether GH deficiency in late adult life causes a reduction in BMD beyond the decline observed with increasing age, we studied 21 patients over the age of 60 yr with GH deficiency caused by organic pituitary disease and 23 controls of similar age and sex distribution and BMI. Dual energy x-ray absorptiometry was used to determine total bone mass and BMD at the hip and in the lumbar spine. Serum osteocalcin was determined in all subjects and urinary deoxypyridinoline/creatinine ratio in 19 patients and 21 controls. The median (range) known duration of GH deficiency in the patients was 8 yr (range, 4-41 yr). The median (range) total bone mass was 2774 g (range, 1534-3734) in the patients and 2717 g (range, 1235-3549) in the controls (P = 0.42). Specific measurements of BMD made at L2-L4, the right femoral neck, the right femoral trochanter, and Ward's triangle were 1.234 (range, 0.778-1.507) vs. 1.144 g/cm2 (range, 0.809-1.466; P = 0.48), 0.921 (range, 0.605-1.372) vs. 0.96 g/cm2 (range, 0.534-1.315; P = 0.62), 0.92 (range, 0.523-1.229) vs. 0.915 g/cm2 (range, 0.353-1.313; P = 0.68), and 0.773 (range, 0.408-1.289) vs. 0.806 g/cm2 (range, 0.353-1.154; P = 0.81) in the patients and controls, respectively. The median (range) serum osteocalcin was 11.5 (range, 3.6-23.0) vs. 15.1 ng/mL (range, 0.7-40.5; P = 0.019) in the patients and controls, respectively. The median (range) deoxypyridinoline cross-links/creatinine ratio was 3.5 micromol/mol (range, 0.8-8.3) in the patients and 4.9 micromol/mol (range, 3.0-9.7) in the controls (P 0.038). There was a significant correlation between serum insulin-like growth factor I and total bone mass in the controls, but not in the patients. These data demonstrate that BMD is not significantly altered in GH-deficient adults over the age of 60 yr. Markers of bone formation and resorption are decreased, however, suggesting that bone turnover is reduced. Further studies are required to determine whether the reduction in bone turnover in these patients is of benefit.     

The surgical procedure in the Mallory-Weiss syndrome

The authors dealt with treatment of 112 patients aged 27-70 years with the Mallory-Weiss syndrome. The diagnosis was confirmed by esophagogastroduodenoscopy. Diathermocoagulation was used in order to arrest bleeding. In profuse bleeding the margins of the mucosa fissures were first infiltrated with a solution of adrenaline. The Blakemore [correction of Bleikmorr] probe compression method was also used. Organ-saving operations were performed for continuing and recurrent bleedings. Two elderly patients with severe coexistent disease died. The authors consider that patients with the Mallory-Weiss syndrome must be treated by conservative methods. Operations for disruptions of the esophagus mucosa and acute blood loss will entail great risk.     

Postoperative analgesia with intramuscular morphine at fixed rate versus epidural morphine or sufentanil and bupivacaine in patients undergoing major abdominal surgery

Hydrofluoroalkane-134a (HFA) beclomethasone dipropionate (BDP) was formulated in a metered-dose inhaler (MDI) to deliver a particle size of 1.1 microm compared with 35 microns for currently marketed chlorofluorocarbon (CFC)-BDP products. Two phase I single-dose human deposition studies were conducted using technetium 99m-radiolabelled BDP in a press-and-breathe actuator without an add-on spacer. A healthy volunteer study (n=6) showed that 55-60% of the HFA-BDP ex-actuator dose was deposited in the lungs, with 29-30% deposited in the oropharynx. CFC-BDP deposition was 4-7% in the lungs and 90-94% in the oropharynx. The pattern of deposition within the lung showed that HFA-BDP was spread diffusely throughout the lung airways, whereas CFC-BDP was confined to the central airways with little, if any, peripheral airway deposition. A second study with asthmatics (n=16) confirmed that 56% of the HFA-BDP dose was deposited in the airways, with 33% in the oropharynx. In conclusion, hydrofluoroalkane-134a-beclomethasone dipropionate deposition was much greater in the airways than chlorofluorocarbon-beclomethasone dipropionate, with a concomitant reduction in oropharyngeal deposition. The increased lung deposition efficiency of the hydrofluoroalkane propellant has led to a reduction in the amount of beclomethasone dipropionate needed to achieve a similar efficacy. The penetration of the hydrofluoroalkane to the small airways may provide asthma treatment not afforded by conventional chlorofluorocarbons.