Janus kinase 2 influences growth hormone receptor metalloproteolysis

GH signals through the GH receptor (GHR), a cytokine receptor superfamily member that couples to the cytoplasmic tyrosine kinase, Janus kinase 2 (JAK2). In addition to its role in signaling, we recently implicated JAK2 in the regulation of cell surface GHR abundance by modulation of GHR trafficking and mature GHR stability. GHR is a target for constitutive and inducible metalloprotease-mediated cleavage that alters surface GHR levels and can modulate GH signaling. We previously found that metalloprotease cleavage of GHR is dramatically lessened in fibroblasts derived from mice with targeted deletion of the zinc-binding domain of TNF-alpha-cleaving enzyme [TACE; ADAM17 (a disintegrin and metalloprotease)], implicating this transmembrane ectoenzyme as a GHR metalloprotease. In this study we used a human fibrosarcoma reconstitution system to compare the effects of RNA interference-mediated knockdown of TACE vs. a related metalloprotease, ADAM10. We found that TACE knockdown dramatically reduced both the pace and the degree of inducible GHR proteolysis and augmented the abundance of mature GHR, suggesting a role for TACE in constitutive receptor proteolysis in this system as well. Notably, ADAM10 knockdown also reduced inducible GHR proteolysis, although to a lesser degree than TACE knockdown, suggesting a contribution from this metalloprotease also. To determine whether JAK2 affects GHR proteolysis, we compared JAK2-deficient vs. JAK2-replete cells and found that phorbol 12-methyl 13-acetate-induced GHR proteolysis was significantly diminished in cells that lacked JAK2. Reconstitution with a GHR mutant that lacks the box 1 region (which mediates JAK2 association) resulted in phorbol 12-methyl 13-acetate-induced proteolysis similar in degree to that of the wild-type GHR in JAK2-deficient cells. Introduction of JAK2 did not affect the proteolysis of this box 1-deleted GHR, suggesting GHR-JAK2 association is required for JAK2 to affect GHR proteolysis. Additionally, the inhibitory effect of anti-GHRext-mAb, a conformation-sensitive GHR antibody, on receptor proteolysis was lost in cells that lacked JAK2. Our data indicate that the susceptibility of GHR to proteolysis is substantially affected by JAK2, suggesting yet another role for this kinase in determining GH sensitivity.     

Lesional modulation of peripheral monocyte leucotactic responsiveness in leprosy.

Because the accumulation and activation of mononuclear phagocytes are critical to the host response to intracellular microbial pathogens, we evaluated mechanisms of peripheral monocyte leucotactic regulation in leprosy. Plasma from 53 of 67 patients was found to inhibit the locomotion of normal human monocytes. Neither the prevalence nor the magnitude of plasma leucotactic inhibitory activity correlated with disease histology or duration, type or duration of chemotherapy, or history of erythema nodosum leprosum. Plasma leucotactic inhibitory activity resided principally in a non-immunoglobulin, cell-directed inhibitor of 230,000 daltons molecular weight. Fractionation of plasma from patients with lepromatous leprosy revealed an additional, immunoglobulin-containing inhibitor of approximately 400,000 daltons weight, possibly an IgG-IgA immune complex. Production of leucotactic inhibitors by unstimulated and concanavalin A-stimulated peripheral mononuclear cells was normal; however, cutaneous explants from these patients spontaneously produced the 230,000 dalton leucotactic inhibitor in vitro. The ability of the lesions of leprosy to impede monocyte traffic may be an important pathogenetic mechanism.     

Differences in residency performances and specialty choices between graduates of three- and four-year curricula

This study identified differences in the specialty choices and residency program directors' performance ratings of residents graduated from two different curricula of the same medical school. One curriculum was three years long, and compressed two years of the basic sciences into one year of study. The other was a four-year program devoting two years each to the basic and clinical science, but with elements unifying the two areas. Using an 18-item form, the program directors rated the performance of 42-96% of the residents who had graduated in the classes of 1982, 1984, 1985, and 1986. (1982 was the only class of the three-year curriculum that was studied.) Graduates of the three-year program showed less strength in background medical knowledge and in their experience of using research data; their greatest strengths seemed to be in the sorts of skills that normally would be acquired during the course of residency experiences. Graduates of the four-year curriculum seemed more able to integrate background medical knowledge and effective care of patients. Their weaknesses appeared to be in those skills that would be developed during the course of the residency experience. The only marked differences between the two groups in terms of residency specialty choice were in surgery and medicine.     

盐酸丁咯地尔对家兔全血粘度、血小板聚集和红细胞压积的影响

研究盐酸丁咯尔地对血液流变学的影响。方法：测定盐酸丁咯地尔静脉给药对全血粘度、血小板聚集率和红细胞压积的影响。结果盐酸丁咯地尔１０ｍｇ／ｋｇ组可使全血粘度在高切变率８０Ｓ＾－１时下降了１７．１％,在低切变率时下降２１．９％,血小板最大聚集率下降了２８．２％。结论盐酸丁咯地尔能有效地改善血液流变指标。     

Relationship of birth weight and length with growth in height and body diameters from 5 years of age to maturity

Birth weight and birth length were compared with several growth measures, including body height and weight, linear measures of limbs, body diameters, and head circumference, in 726 Melbourne schoolchildren of both sexes age 5–18 years. The analysis of relationships between three categories of birth length, weight, and growth measures were based on z-scores and performed by using analysis of variance and partial correlation. The data showed that birth length was correlated with body height and birth weight was correlated with head circumference; the relationships were weak and were less clear around the age corresponding to the peak height velocity in either sex. Further studies are needed to determine the common underlying mechanisms responsible for these associations. Am. J. Hum. Biol. 11:772–778, 1999. © 1999 Wiley-Liss, Inc.     

Psychological status in female carriers of premutation FMR1 allele showing a complex relationship with the size of CGG expansion

We utilized a sample of 299 adult females aged between 19 and 86 years, carrying fragile X mental retardation (FMR1) alleles with small CCG expansions ranging from 50 to 141 repeats to analyse the relationships between psychological symptoms as assessed by the Symptom Checklist‐90‐Revised (SCL‐90‐R) and the size of the CGG repeat in the FMR1 gene. There were highly significant (negative) correlations between the size of the CGG repeat and a great majority of SCL‐90‐R subscale scores and all the global indices, suggesting that carriers of premutations in the mid‐size CGG repeat range may be at greatest risk for the development of psychiatric disorder.     

Phase II study of eribulin mesylate (E7389) in patients with metastatic castration-resistant prostate cancer stratified by prior taxane therapy

BackgroundTreatment options remain limited for patients with castration-resistant prostate cancer (CRPC). We evaluated eribulin mesylate (E7389), a nontaxane halichondrin B analog microtubule inhibitor, in patients with metastatic CRPC with or without previous taxane exposure.Patients and methodsMen with histologically proven CRPC, with or without prior taxane exposure, were enrolled in an open-label, single-arm phase II trial. Patients received eribulin mesylate 1.4 mg/m² as a 2- to 5-min i.v. bolus infusion on days 1 and 8 of a 21-day cycle. The primary efficacy end point was prostate-specific antigen (PSA) response rate.ResultsIn total, 108 patients were assessable for safety (50 were taxane-pretreated) and 105 for efficacy in the per-protocol population. The median age of patients was 71 years and median number of cycles was 4. PSA decreases of ≥50% were achieved in 22.4% and 8.5% of taxane-naive and taxane-pretreated patients, respectively. The most common grade 3/4 adverse event was neutropenia, seen in 22.4% of chemo-naive and 40% of taxane-pretreated men. Grade 3 peripheral neuropathy occurred in none of the taxane-naive patients and 6.0% of taxane-pretreated patients.ConclusionEribulin mesylate demonstrated activity and a relatively favorable toxicity profile in metastatic CRPC.     

Discriminant analysis of dermatoglyphic measurements in fragile X males and females

Two hundred and eight fragile X subjects (92 males and 116 females) and matched Australian (60 males and 32 females) and British (122 males and 118 females) normal samples were used to calculate 4 discriminant functions, based on dermatoglyphic measurements. The most efficient discriminating variables between fragile X and normal males, selected by means of the Wilk's stepwise method, included: ridge counts on fingers 1-3, the hallucal (f) count on soles, the atd angle, and pattern intensities in palmar areas 2, 4 and 5 as well as on fingers 4 and 5. In females, the ridge breadth, the hallucal (e) count, the atd angle and pattern intensities in palmar areas 3-5 as well as on fingers 1, 3 and 5 comprised the final discriminant. The misclassification rate based on distributions of individual discriminant scores in each pair of samples, and on prior probabilities, was lowest (16.8%) in fragile X males compared with the Australian normal subjects. In both female comparisons, this rate approached 44%. A bias to misclassification rates resulting from various analytical procedures and some properties of the data are discussed. We conclude that the discriminant function based on dermatoglyphic measured variables alone is not good enough for assessing carrier probabilities for fragile X, especially in females. However, we have been able to select the best discriminators which may be used, together with other measured body characteristics, to obtain a more powerful discriminant function. Moreover, a consideration of discriminant scores based on dermatoglyphic traits only may help in estimating carrier probabilities.(ABSTRACT TRUNCATED AT 250 WORDS)