Functional consequences of ROMK mutants linked to antenatal Bartter's syndrome and implications for treatment

The antenatal variant of Bartter's syndrome is an autosomal recessive kidney disease characterized by polyhydramnios, premature delivery, hypokalemic alkalosis and hypercalciuria. It is genetically heterogeneous, having been linked recently to mutations in an ATP- sensitive, renal outer medullary K+channel, ROMK, and earlier to mutations in the Na-K-2Cl co-transporter, NKCC2. We characterized four of the mutations reported in three heterozygous ROMK variants of antenatal Bartter's and found that each expressed a distinct phenotype in Sf9 cells. One mutation expressed normal function and appears to be an allelic polymorphism. The other three mutations produced channels with significantly reduced K+fluxes. However, the mechanisms in each case were different and reflected abnormalities in phosphorylation, proteolytic processing or protein trafficking. The different mechanisms may be important in the design of appropriate therapy for patients with this disease.      

Determination of the parent of origin in nine cases of prenatally detected chromosome aberrations found after intracytoplasmic sperm injection

Prenatal cytogenetic analysis of 71 fetuses conceived by intracytoplasmic sperm injection (ICSI) resulted in the detection of nine (12.7%) chromosome aberrations including two cases of 47,XXY, four cases involving a 45,X cell line and three autosomal trisomies. Molecular analysis of the parental origin of the deleted or supernumerary chromosome was performed by using polymorphic microsatellite markers. Six cases involving a sex chromosome abnormality were found to be of paternal origin while the two trisomic cases that could be analysed were of maternal origin. Two cases involved the same infertile couple who had two consecutive ICSI pregnancies terminated because of a chromosome abnormality. The replaced embryos in both cases originated from a single batch of ICSI fertilized oocytes of which part was used to initiate the first pregnancy and part was cryopreserved and used to initiate the second pregnancy.      

Endoscopic retrograde cholangiopancreatography in postcholecystectomy syndrome

The study was aimed to determine the role of endoscopic retrograde cholangiopancreatography (ERCP) in patients with postcholecystectomy symptoms in respect to interval of presentation following cholecystectomy. 170 patients with postcholecystectomy symptoms and negative upper gastrointestinal endoscopy were evaluated using ERCP. One hundred and seventeen (75%) out of 156 patients with successful ERCP had one or more abnormalities seen at ERCP. Bile duct stones (55 patients), benign strictures of bile duct (27 patients) were the common lesions detected. A significantly higher (p < 0.001) positive diagnosis was possible at ERCP in patients presenting with jaundice (100%) as compared to those without jaundice (61.8%). Spectrum of causes among patients presenting in early post-operative period (< 1 month) was somewhat different from those presenting later. Bile duct ligature and biliary fistula were the predominant causes in the former group, while stones and benign strictures were commoner in the patients presenting late. Endoscopic sphincterotomy and stone removal was performed successfully in 25 out of 30 patients in whom it was attempted. ERCP was found to be a very useful procedure in the management of postcholecystectomy symptoms. Spectrum of underlying disease was different in patients presenting before 1 month following cholecystectomy as compared to those presenting later.     

Initial evaluation of a continuous speech recognition program for radiology

The aims of this work were to measure the accuracy of one continuous speech recognition product and dependence on the speaker's gender and status as a native or nonnative English speaker, and evaluate the product's potential for routine use in transcribing radiology reports. IBM MedSpeak/Radiology software, version 1.1 was evaluated by 6 speakers. Two were nonnative English speakers, and 3 were men. Each speaker dictated a set of 12 reports. The reports included neurologic and body imaging examinations performed with 6 different modalities. The dictated and original report texts were compared, and error rates for overall, significant, and subtle significant errors were computed. Error rate dependence on modality, native English speaker status, and gender were evaluated by performing ttests. The overall error rate was 10.3 +/- 3.3%. No difference in accuracy between men and women was found; however, significant differences were seen for overall and significant errors when comparing native and nonnative English speakers (P = .009 and P = .008, respectively). The speech recognition software is approximately 90% accurate, and while practical implementation issues (rather than accuracy) currently limit routine use of this product throughout a radiology practice, application in niche areas such as the emergency room currently is being pursued. This methodology provides a convenient way to compare the initial accuracy of different speech recognition products, and changes in accuracy over time, in a detailed and sensitive manner.     

The phorbol ester TPA strongly inhibits HIV-1-induced syncytia formation but enhances virus production: possible involvement of protein kinase C pathway

Cocultivation of MOLT-4 and MOLT-4/HIVHTLV-IIIB cells with more than 0.01 ng/ml of 12-O-tetradecanoylphorbol-13-acetate (TPA) for 20 hr strikingly inhibited HIV-induced syncytia formation resulting from cell to cell infection. Interestingly, the production of HIV-specific p24 antigen in the culture fluid was significantly enhanced by TPA. TPA down-modulated the expression of CD4. CD4 is essential for syncytia formation through interaction with viral envelope protein gp120 on the surface of MOLT-4 cells. The effects of TPA on syncytia formation and on CD4 expression were specifically interfered with by nontoxic doses of blockers of protein kinase C (PKC) such as staurosporine and H7. These data suggest that (1) TPA inhibits HIV-induced syncytia formation through down-modulation of CD4 molecules on the surface of MOLT-4 cells and (2) PKC may play an important role in cell to cell as well as in cell-free infection of HIV.     

A clinical study on injectable contraceptive Noristerat

Results of a clinical study involving 382 subjects using the injectable contraceptive Noristerat (norethisterone enanthate) is presented. The maximum number of acceptors were between 21-25 years of age and had been married for 6-10 years. 50% began their 1st injection within 1 year of the last childbirth. Continuation rates were very high and about 75% returned for their 2nd injection. Among the users, weight gain was seen more commonly than weight loss. There was no significant change in blood pressure. 52.2% reported a menstrual pattern which was within the acceptable range of normal, while only 12.7% had amenorrhea. 15% showed other types of menstrual disturbance. Only 1 woman in the series became pregnant. Menstrual abnormality was the most common cause for discontinuation among the 71 subjects available for interview.     

Quality of vaccination services and social demand for vaccinations in Africa and Asia.

For immunization to be effective in the long run as a major global disease control intervention it is important to provide good quality vaccination services. Studies carried out in three countries in Asia (Bangladesh, India, and the Philippines) and two countries in Africa (Ethiopia and Malawi), and reported on in this article, document the fact that parents are willing to invest considerable effort in having their children vaccinated; however, there are a number of serious shortcomings in the quality of the routine vaccination services and strains are apparent at the interface between the vaccination providers and the users. These shortcomings are detracting from the sustainability of routine vaccination programmes and are promoting the growth of pools of nonimmunized and partially immunized children. To safeguard the continued operation and to enhance the coverage of routine vaccination programmes it is crucial that these difficulties be addressed.     

Spread of bovine herpesvirus type 5 (BHV-5) in the rabbit brain after intranasal inoculation

Following intranasal inoculation of wild-type BHV-5 in rabbits, we studied the sequential transneuronal passage of the virus in the CNS by immunocytochemistry, histopathology, and virus isolation. At 4 and 6 days postinfection (d.p.i.), rabbits had no or mild neurological signs, and virus was isolated only from the olfactory bulbs. At 8 and 9 d.p.i., infected rabbits had severe neurological signs, and virus could be isolated from multiple regions of the brain segments. In these rabbits, high titers of virus were consistently present in the anterior and posterior cortices, including frontal, piriform/entorhinal, temporal, parietal, and occipital cortices, the hippocampus and the amygdala. Virus was isolated occasionally from the midbrain/diencephalon and pons/medulla. Virus was not isolated from the cerebellum and trigeminal ganglion of rabbits examined from 2-12 d.p.i. Immunocytochemistry revealed virus-specific antigens at 4 d.p.i. within the glomerular layer, external plexiform layer, and mitral cell layer of the main olfactory bulb. At 6 d.p.i., virus-specific antigens were also present within the inner granular layer of the main olfactory bulb. At 8 and 9 d.p.i., widespread BHV-5-specific staining occurred in the areas of the brain connected to the main olfactory bulb, including the frontal/cingulate cortex, anterior olfactory nucleus, lateral olfactory tubercle, piriform/entorhinal cortex, hippocampus, amygdala, dorsal raphe, and locus coeruleus. In the trigeminal ganglion, specific staining was detected within a few neurons at 2,4, 6, 8 d.p.i. However, further spread of the virus along the trigeminal pathway was not evident. These data indicate that BHV-5 replicates and spreads preferentially in the olfactory pathway following intranasal instillation and that this viral spread correlated with the severity of neurological symptoms and histopathological lesions.     

POSSIBLE INVOLVEMENT OF INOSITOL-LIPID METABOLISM IN MALIGNANT HYPERTHERMIA

-Adrenoceptor stimulation may induce malignant hyperthermia(MH) in vivo. Consequently, we have investigated the effectsof the -adrenoceptor agonist phenylephrine and, for comparison,the effects of the ß-adrenoceptor agonist isoproterenolon inositol-lipid metabolism of malignant hyperthermia susceptible(MHS) and healthy control (MHN) swine. The experiments wereperformed on electrically stimulated (frequency 0.2 Hz) trabeculaeisolated from the right ventricles of the hearts of MHS andMHN animals. After labelling with [³H] inositol for 6 h, differentinositol phosphates were measured by high pressure liquid chromatography,including inositol 1 - phosphate, inositol 1,4-bisphosphate,inositol 1,3,4-trisphosphate, inositol 1,4,5-trisphosphate (1,4,5-IP₃)and inositol 1,3,4,5 - tetrakisphosphate. After stimulationwith isoproterenol, the inositol phosphate content did not increaseor vary between muscle from MHS and MHN animals. In contrast,all inositol phosphates increased after stimulation with phenylephrinein both muscle types, the effects being greater in MHS thanin MHN, especially as regards 1,4,5-IP₃ content. As 1,4,5-IP₃,a presumed second messenger, has been shown to mobilize intracellularcalcium, it is concluded that an enhanced -adrenergic responseis involved in the development of MH. ^*Address for correspondence: Abteilung für Anästhesiologie,Universitäts-Krankenhaus Eppendorf, Martinistrasse52, D-2000Hamburg 20, Germany. Presented in part at the 1989 Meeting of the European Academyof Anaesthesiology in Bonn.