RHAMM, a receptor for hyaluronan-mediated motility, compensates for CD44 in inflamed CD44-knockout mice: a different interpretation of redundancy

We report here that joint inflammation in collagen-induced arthritis is more aggravated in CD44-knockout mice than in WT mice, and we provide evidence for molecular redundancy as a causal factor. Furthermore, we show that under the inflammatory cascade, RHAMM (receptor for hyaluronan-mediated motility), a hyaluronan receptor distinct from CD44, compensates for the loss of CD44 in binding hyaluronic acid, supporting cell migration, up-regulating genes involved with inflammation (as assessed by microarrays containing 13,000 cDNA clones), and exacerbating collagen-induced arthritis. Interestingly, we further found that the compensation for loss of the CD44 gene does not occur because of enhanced expression of the redundant gene (RHAMM), but rather because the loss of CD44 allows increased accumulation of the hyaluronic acid substrate, with which both CD44 and RHAMM engage, thus enabling augmented signaling through RHAMM. This model enlightens several aspects of molecular redundancy, which is widely discussed in many scientific circles, but the processes are still ill defined.     

Do the recently modified pacemaker guidelines for neurocardiogenic syncope also apply to young patients? Analysis based on five-year follow-up of israeli soldiers with syncope and a positive tilt test

To assess the classification of neurocardiogenic syncope (NCS) as a IIA indication for pacemaker implantation in the recent American College of Cardiology/American Heart Association Task Force on Practice Guidelines/North American Society for Pacing and Electrophysiology guidelines, we performed chart reviews and follow-up interviews in a cohort of 45 consecutive young Israeli soldiers (age 18-24 years) with a history of syncope (mean of 9 prior syncopal episodes) and a positive tilt test treated with drug therapy. Asystole longer than 5 s during tilt testing occurred in 11 patients. Five years later, we found that only 2 patients were still taking medications, only 1 patient (2%) still reported frequent syncopal or near-syncopal episodes and 3 patients (7%) had rare symptoms (no more than one syncopal episode during the past 2 years), while the remaining 40 (89%) were symptom free off medications. Thus, NCS in young patients, even with prolonged asystole during tilt testing, a history of frequent syncopal episodes and other high- risk factors described in the guidelines, is often a self-limiting disorder, perhaps stress related or situational in nature; an overwhelming number of patients become asymptomatic and stop taking medications within 1-2 years. These patients do not require long-term therapy; thus, our data would suggest that the IIA pacing indication for NCS should be restricted to older patients.     

Recombinant α-Interferon May be Efficacious in Acute Hepatitis B

Whereas, in chronic type B hepatitis, the therapeutic effect of alpha-interferon has been studied extensively, data on the effect of interferon on the course and prognosis of acute hepatitis B are scarce in the literature. We report a case of acute type B hepatitis complicated by life-threatening extrahepatic manifestations where recombinant alpha-interferon facilitated clinical, biochemical, and serological recovery.     

The alopecias associated with vitamin D-dependent rickets type IIA and with hairless gene mutations: a comparative clinical, histologic, and immunohistochemical study

OBJECTIVE: To establish the unique and common clinical and microscopic characteristics of the alopecias associated with vitamin D-dependent rickets (VDDR) type IIA and with hairless gene mutations. DESIGN: A comparative clinical, histologic, and immunohistochemical study of the alopecias in 6 patients with VDDR IIA and 4 patients with atrichia with papular lesions (APL) and/or alopecia universalis congenita (AUC) (hereinafter "APL/AUC"). MAIN OUTCOME MEASURES: Clinical data were gathered from medical records, personal interviews, and physical examinations. Histologic and immunohistochemical studies were performed on 6 scalp punch biopsy specimens from each of the 2 studied groups. RESULTS: The alopecias in VDDR IIA and APL/AUC showed similar clinical, histologic, and immunohistochemical features. The clinical presentation of the VDDR alopecia resembled either the APL phenotype (ie, with papules and milia) or the AUC phenotype (without papules and milia). The main histologic findings included void infundibula; absence of the lower two thirds of the hair follicles, often replaced by vertically oriented irregular epithelial structures or epithelial cysts; irregular epithelial structures, often with small cysts in the middle and lower dermis; and small, medium, and large keratinizing cysts at all levels of the dermis. The larger epithelial cysts in the upper dermis stained positively for cytokeratin (CK) 10, which suggests an infundibular derivation, whereas the remaining irregular epithelial structures and cysts in the middle and lower dermis stained positively most frequently for CK17, CK19, and CD34, which suggests an outer root sheath derivation. CONCLUSIONS: The alopecias associated with VDDR IIA and with hairless gene mutations show striking clinical and microscopic similarities. Disintegration of the lower two thirds of the hair follicles seems to be the underlying defect, and a common pathogenetic pathway might be involved.     

MOB-1 and TNF-alpha interact to induce microvascular lung injury

We have recently identified the alpha-chemokine mob-1 as a highly inducible gene in several rat models of microvascular lung injury, whose expression was suppressed by inhibition of tumor necrosis TNF-alpha (TNF-alpha). This work provides further insight into the relationship between mob-1 and TNF-alpha in the development of lung injury assessed by pulmonary edema and leukosequestration. First, pulmonary mob-1 and TNF-alpha were upregulated in animals subjected to lung injury produced by the intratracheal administration of recombinant TNF-alpha and recombinant mob-1, respectively. Second, mob-1 inhibition by intratracheal anti-mob-1 antibody attenuated lung injury induced by recombinant TNF-alpha. Third, pretreatment with anti-TNF-alpha monoclonal antibody administered intratracheally abrogated recombinant mob-1-induced microvascular lung injury. In vitro, mob-1 and TNF-alpha increased each other's production in RAW 264.7 cells and mob-1 or TNF-alpha inhibition prevented endotoxin-induced upregulation of TNF-alpha or mob-1, respectively, from these cells. Together, these data suggest that mob-1 and TNF-alpha interact to promote lung inflammation.