Receptor-specific signaling for both the alternative and the canonical NF-kappaB activation pathways by NF-kappaB-inducing kinase

The NF-kappaB-inducing kinase (NIK) induces proteolytic processing of NF-kappaB2/p100 and, hence, the generation of NF-kappaB dimers such as p52:RelB but was suggested not to signal for the processing of IkappaB. Here, we show that although the induction of IkappaB degradation in lymphocytes by TNF is independent of NIK, its induction by CD70, CD40 ligand, and BLyS/BAFF, which all also induce NF-kappaB2/p100 processing, does depend on NIK function. Both CD70 and TNF induce recruitment of the IKK kinase complex to their receptors. In the case of CD70, but not TNF, this process is associated with NIK recruitment and is followed by prolonged receptor association of just IKK1 and NIK. Recruitment of the IKK complex to CD27, but not that of NIK, depends on NIK kinase function. Our findings indicate that NIK participates in a unique set of proximal signaling events initiated by specific inducers, which activate both canonical and noncanonical NF-kappaB dimers.     

A population-based study of the relationship between salt intake, bone resorption and bone mass

OBJECTIVE: To explore the relationship between urinary sodium (the best measure of salt intake), urinary calcium, urinary deoxypyridinoline (DPYR) and bone mass. DESIGN: Cross-sectional study. SETTING: Population based sample of healthy Hobart residents. SUBJECTS: One hundred and fifty-four (M = 34, F = 120) subjects invited to take part from a systematic sample of the electoral roll and a single newspaper advertisement. RESULTS: In both sexes, urinary sodium correlated moderately with urinary DPYR (r = 0.32, P < 0.0001) and urinary calcium (r = 0.37, P < 0.0001). In multivariate analysis, the combination of urinary sodium, total body bone area, age and sex explained 22% of the variation in log-transformed DPYR (P < 0.00001). In univariate analysis, both urinary sodium and urinary DPYR were strongly associated with bone mineral content and bone mineral density at all sites but this association disappeared after adjustment for confounders particularly body weight. CONCLUSIONS: This study has shown that salt intake is associated with markers of bone resorption in a population-based sample of males and females and appears likely to be a risk factor for osteoporosis despite the lack of a demonstrable association between bone mass and a single measure of urinary sodium excretion. Further studies are needed to define the effect of salt intake on bone mass and fractures more clearly. These studies will need to be either longitudinal or interventional in design with repeated measures of urinary sodium so that habitual sodium intake can be accurately assessed and regression dilution bias can be minimised.     

Concepts of establishing clinical bioequivalence of chlorofluorocarbon and hydrofluoroalkane beta-agonists

There are no established guidelines for judging equivalence between inhaled medications. The principles of establishing bioequivalence on the basis of bioavailability and pharmacokinetics may not be applicable to inhaled medications with predominantly topical and minimal systemic effects. For inhaled beta(2)-agonists, the most practical method of showing in vivo therapeutic equivalence is by comparing relative potencies (RPs) of pharmacodynamic effects (bronchodilation and bronchoprotection). A range of doses that includes placebo should be studied in an appropriate design with adequate sample size, and relative potency should be estimated. Hydrofluoroalkane and chlorofluorocarbon salbutamol are bioequivalent for both their bronchodilator (RP, 1.08; 90% confidence interval, 0.95%, 1.23%) and bronchoprotective effects (RP, 1.08; 90% confidence interval, 0.81%, 1.46%) with similar safety profile. Eighteen subjects are required in a cross-over design to demonstrate bronchoprotective bioequivalence with a confidence interval of 67% to 150% for the relative potency (80% power). For salbutamol, this can be achieved with a comparison of 100 and 200 microgram doses. Twelve subjects would suffice for a cumulative dose-response study for bronchodilator bioequivalence. For both outcomes, repeatability and quality control of measurements have to be ensured for an accurate interpretation of the results.     

Regulation of glomerular mesangial cell proliferation in culture by adrenomedullin.

Adrenomedullin is a recently discovered vasodilatory peptide that has been shown to be a potent activator of adenylate cyclase in a variety of cell systems, including rat mesangial cells. The major aim of the present study was to determine the regulation of rat mesangial cell proliferation (using [3H]thymidine incorporation as an index), apoptosis (using nucleosome-associated cytoplasmic DNA fragmentation as an index) and mitogen-activated protein kinase (MAPK) cascade, specifically extracellular signal-regulated kinase (ERK), jun-amino terminal kinase (JNK) and P38 mitogen-activated protein kinase (P38 MAPK) activities, by adrenomedullin-stimulated cyclic AMP-protein kinase-A pathway. Adrenomedullin increased cAMP levels significantly above basal and the response was inhibited by the adrenomedullin receptor antagonist, adrenomedullin-(22-52). Adrenomedullin also decreased [3H]thymidine incorporation and increased nucleosome-associated cytoplasmic DNA fragmentation, in a concentration-dependent fashion. Both these responses were receptor mediated as, adrenomedullin-(22-52) inhibited these effects. The decrease in proliferation and increase in apoptosis were both mimicked by forskolin, a direct adenylate cyclase activator. Adrenomedullin-mediated decrease in proliferation and increase in apoptosis were inhibited by H89 [[N-[2-((p-bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamide, hydrochloride]], a potent protein kinase-A inhibitor. Associated with the changes in proliferation and apoptosis, adrenomedullin decreased ERK2 activity, and increased JNK1 and P38 MAPK activities. All these kinase activities, except the increase in JNK1 activity could be simulated using forskolin. In addition, only adrenomedullin-mediated changes in ERK2 and P38 MAPK activities were inhibited by H89 while, adrenomedullin-stimulated JNK1 was not consistently inhibited by the protein kinase-A inhibitor. These results suggest that adrenomedullin might play an important role in mesangial cell turnover and that although adrenomedullin-mediated responses are primarily cAMP-dependent, it does not preclude the involvement of cAMP-independent pathways.     

Normal Anatomic Variants on Transthoracic Echocardiogram

Apart from their existence as medical curiosities, anatomic variants also double as diagnostic dilemmas. In the heart, more than in any other location in the body, misinterpretation of normal anatomic variants as pathologic entities can have a profound impact on treatment decisions and clinical consequences. Echocardiography is an easily accessible tool these days and is used routinely in most cardiac evaluations. Thus it becomes imperative for the echocardiographer to be cognizant of normal anatomic variants. Furthermore, echocardiographic findings should always be evaluated in their proper clinical context and diagnoses should never be entertained in a clinical vacuum. The literature is replete with numerous case reports and vignettes on these fascinating structures but is lacking in a formal review of normal anatomic variants. In this article, we have attempted a systemic review of normal variants, their embryologic origins, echocardiographic characteristics, and common pitfalls encountered in their evaluation.     

Sinus and A-V nodal dysfunction following myocardial infarction.

A patient in whom syncopal episodes occurred following an inferior myocardial infarction is described. Electrocardiographic monitoring revealed periods of profound sinus bradycardia and AV block during syncope. In addition, transient spontaneous prolongations of the PR interval due to AV nodal delay and episodes of atrial fibrillation also occurred. Sinus node recovery time following atrial overdrive was within normal limits. Symptoms disappeared following the insertion of a permanent, demand pacemaker. The onset of symptoms following myocardial infarction suggests that dysfunction of the sino-atrial and AV nodes may have been the result of ischemic damage during the infarction.     

Clinical profile of acute kidney injury in a pediatric intensive care unit from Southern India: A prospective observational study

Background:

Although the term acute renal failure was replaced by acute kidney injury (AKI) recently, there is a paucity of data on the incidence and profile of AKI in critically ill children from the developing world.

Objectives:

The objective of this study is to determine the incidence, etiology, short term outcome and predictors of fatality in critically ill children admitted to the pediatric intensive care unit (PICU) with AKI, aged 1 month to 13 years.

Materials and Methods:

In this prospective observational study, from June 2010 to March 2011, 215 children admitted to the PICU were screened for AKI, defined according to the AKI Network criteria. The patients with AKI were followed-up until discharge/death. Their clinical and biochemical data were recorded.

Results:

The incidence of AKI among 215 patients screened was 54 (25.1%). The common etiologies were infections, [34 (62.9%)], acute glomerulonephritis (7.6%), snake envenomation (5.7%), hemolytic uremic syndrome (3.8%) and congestive cardiac failures (3.8%). Among infections, pneumonia and septicemia constituted 26.5% each, meningoencephalitis accounted for 23.5%, and dengue, scrub typhus, tuberculosis and malaria constituted 9.3% of children with AKI. 27.8% of patients required dialysis. Overall mortality was 46.3%. On logistic regression analysis, requirement of mechanical ventilation was an independent predictor of fatality in AKI.

Conclusions:

Besides the high incidence of AKI in critically ill-children admitted to the PICU (25.1%), the condition was associated with adverse outcomes, including high mortality (46.3%) and need for dialysis (27.8%). Infections dominated the etiological profile. Requirement of mechanical ventilation predicted an adverse outcome in our patient population.