Functional and clinical characterization of a mutation in KCNJ2 associated with Andersen-Tawil syndrome.

BACKGROUND: Andersen-Tawil syndrome (ATS) is a rare inherited disorder, characterised by periodic paralysis, cardiac dysarrhythmias, and dysmorphic features, and is caused by mutations in the gene KCNJ2, which encodes the inward rectifier potassium channel, Kir2.1. This study sought to analyse KCNJ2 in patients with familial ATS and to determine the functional characteristics of the mutated gene. METHODS AND RESULTS: We screened a family with inherited ATS for the mutation in KCNJ2, using direct DNA sequencing. A missense mutation (T75R) of Kir2.1, located in the highly conserved cytoplasmic N-terminal domain, was identified in three affected members of this family. Using the Xenopus oocyte expression system and whole cell voltage clamp analyses, we found that the T75R mutant was non-functional and possessed a strong dominant negative effect when co-expressed with the same amount of wild type Kir2.1. Transgenic (Tg) mice expressing the mutated form of Kir2.1 in the heart had prolonged QTc intervals compared with mice expressing the wild type protein. Ventricular tachyarrhythmias were observed in 5 of 14 T75R-Tg mice compared with 1 of 7 Wt-Tg and none of 6 non-transgenic littermates. In three of five T75R-Tg mice with ventricular tachycardia, their ECG disclosed bidirectional tachycardia as in our proband. CONCLUSIONS: The in vitro studies revealed that the T75R mutant of Kir2.1 had a strong dominant negative effect in the Xenopus oocyte expression system. It still preserved the ability to co-assemble and traffic to the cell membrane in mammalian cells. For in vivo studies, the T75R-Tg mice had bidirectional ventricular tachycardia after induction and longer QT intervals.

Varicocele is associated with abnormal retention of cytoplasmic droplets by human spermatozoa.

OBJECTIVE: To determine whether varicocele is associated with retention of sperm cytoplasmic droplets in infertile men. DESIGN: Retrospective study. SETTING: University infertility clinic. PATIENT(S): Nonazoospermic men with idiopathic (n = 69) and varicocele-associated infertility (n = 73), and 20 fertile controls presenting for vasectomy. INTERVENTION(S): None. MAIN OUTCOME MEASURES(S): Standard semen parameters and percentage of spermatozoa with cytoplasmic droplets on Papanicolaou smears. RESULT(S): No statistically significant differences were found between the fertile and infertile groups with respect to semen volume. Fertile controls had significantly greater mean percent sperm motility and normal morphology than infertile men. The mean percentage of sperm with residual cytoplasm was statistically significantly different in all three groups. Infertile men with varicocele had the highest percentage of sperm with cytoplasmic droplets, the next highest level being in men with idiopathic infertility and the lowest level in fertile controls (11.7 +/- 1.0, 8.1 +/- 0.9 and 3.2 +/- 0.4%, respectively, P<.0001). CONCLUSION(S): Our data show that idiopathic and even moreso, varicocele-related male infertility are conditions associated with impaired disposal of residual sperm cytoplasm by the testis and/or epididymis. These data provide a possible mechanism for the observed semen abnormalities and reduced fertility potential associated with varicocele and idiopathic male infertility.

Bradycardia and the role of beta-blockade in the amelioration of left ventricular dysfunction.

BACKGROUND: It is clear that beta-blockers are effective for treatment of congestive heart failure, but their mechanism of action remains controversial. Hypothesized mechanisms include normalization of beta-receptor function and myocardial protection from the effects of catecholamines, possibly by the institution of bradycardia. We hypothesized that beta-blockade-induced bradycardia was an important mechanism by which these agents were effective for correction of LV dysfunction. METHODS AND RESULTS: In 2 groups of dogs with mitral regurgitation and LV dysfunction, beta-blockers were instituted. In 1 group that received beta-blockers and pacing (group beta+P), a pacemaker prevented the natural bradycardia that beta-blockers cause. In both groups, substantial LV dysfunction developed. Before beta-blockade, the end-systolic stiffness constant decreased from 3. 5+/-0.1 to 2.7+/-0.2 (P<0.01) at 3 months in group beta+P. A similar reduction occurred in the group that eventually received only beta-blockers (group betaB). In group betaB, end-systolic stiffness improved after 3 months of beta-blockade from 2.9+/-0.2 to 3.5+/-0.4 and was not different from baseline. However, in group beta+P, end-systolic stiffness failed to improve (2.7+/-0.2) after 3 months of mitral regurgitation, and was 2.9+/-0.2 at the end of the studies. The contractile function of cardiocytes isolated from the ventricles at the end of the studies confirmed these in vivo estimates of contractility. CONCLUSIONS: We conclude that institution of bradycardia is a major mechanism by which beta-blockers are effective for restoration of contractile function in a model of LV dysfunction.

Squamous cell carcinoma of the breast.

OBJECTIVE: To review the mammographic and ultrasonographic features of primary breast cancer containing squamous cell carcinoma. PATIENTS AND METHODS: From medical records for breast cancer patients seen over a 37-year period the authors identified 19 patients with squamous cell carcinoma, for 5 of whom histologic sections and imaging studies were available. The tumours were classified on the basis of histologic findings as pure (in two patients) or predominantly (in three patients) squamous cell carcinoma. Mammograms were available for four of the patients, and the mammographic report only was available for analysis for the fifth. Ultrasonography had been performed for four of the patients; the images were available for two of the patients and the reports only for two. RESULTS: The median age of the patients was 55 years. The mean size of the tumours, all of which were palpable, was 5.0 cm. None of the tumours was connected to the skin, arose in the nipple-areolar complex or was metastatic. On mammography, the margins of all five masses, which were oval in shape, were indistinct and partly well-circumscribed; in three cases, the tumour margin was also partly spiculated. No malignant microcalcifications were seen. The two "pure" squamous cell carcinoma tumours appeared on ultrasonography as solid hypoechoic masses, and two of the predominantly squamous cell carcinoma tumours had both cystic and solid components. At gross pathological examination, four of the tumours (two "pure" and two predominantly squamous cell carcinoma) were cystic, which reflected areas of necrosis and cyst formation. CONCLUSION: Although "pure" or predominantly squamous cell carcinoma is a rare histologic variant of breast cancer that lacks any typical mammographic features, this tumour can be added to the differential diagnosis of cystic breast masses seen on ultrasonography.

Economic effects of recent immigration on American workers.

PIP: DeFreitas examines the principal positions which have emerged among economists about immigration's impact, and reports results of his empirical analysis of the wage and employment effects of both recent undocumented aliens and settled migrants on native-born workers. A large 1980 census microdata bank is used to permit separate estimates for men and women, subdivided by race and Spanish origin. The sample used includes male and female respondents, ages 16-64, in the 79 largest metropolitan areas in the country. To test the segmented labor market model, the author acquired the detailed industrial/occupational matrix developed by Gerald Oster and David Gordon and applied it to the 1980 census microdata. A multivariate regression procedure was used to evaluate immigrant influence on employment and wage levels. The study shows that migrant workers today are disproportionately concentrated in low-wage jobs in distinct industries. Contrary to common belief, recent immigrants do not typically constitute a high-turnover labor pool with unemployment above that of similar natives. Results indicate that increased migration does not significantly affect the employment or wages of native-born Hispanics. Recent undocumented migration does reduce black men's employment and black women's wages; larger concentrations of settled immigrants are associated with lower Anglo wages, but the estimated magnitudes of these effects are not large. Empirical analysis raises questions about the direct applicability to modern immigration of the coreperiphery segmentation scheme used in the dual labor market literature. Nevertheless, the findings appear to be far less consistent with theories emphasizing migrant-native suitability over complementarity. Employment and training programs that provide upward mobility for natives, coupled with stepped-up unionization efforts among both the native and migrant unskilled seem more promising ameliorative measures than present policies focused on surveillance of the Mexican-American border and of millions of immigrant employers. A strong case could also be made for more progressive income redistribution programs. Short of these efforts, perhaps the most promising development in the near future is the decline in the supply of new native labor force entrants brought on by falling birth rates and the aging of the baby-boom cohort. If this continues at the forecasted rate, it is likely that the domestic costs of immigration will become smaller and its benefits more pronounced.^ieng