The amino-terminal region of Tyk2 sustains the level of interferon alpha receptor 1, a component of the interferon alpha/beta receptor

Tyk2 belongs to the Janus kinase (JAK) family of receptor associated tyrosine kinases, characterized by a large N-terminal region, a kinase-like domain and a tyrosine kinase domain. It was previously shown that Tyk2 contributes to interferon-alpha (IFN-alpha) signaling not only catalytically, but also as an essential intracellular component of the receptor complex, being required for high affinity binding of IFN-alpha. For this function the tyrosine kinase domain was found to be dispensable. Here, it is shown that mutant cells lacking Tyk2 have significantly reduced IFN-alpha receptor 1 (IFNAR1) protein level, whereas the mRNA level is unaltered. Expression of the N-terminal region of Tyk2 in these cells reconstituted wild-type IFNAR1 level, but did not restore the binding activity of the receptor. Studies of mutant Tyk2 forms deleted at the N terminus indicated that the integrity of the N-terminal region is required to sustain IFNAR1. These studies also showed that the N-terminal region does not directly modulate the basal autophosphorylation activity of Tyk2, but it is required for efficient in vitro IFNAR1 phosphorylation and for rendering the enzyme activatable by IFN-alpha. Overall, these results indicate that distinct Tyk2 domains provide different functions to the receptor complex: the N-terminal region sustains IFNAR1 level, whereas the kinase-like domain provides a function toward high affinity ligand binding.     

A case-control study of lung cancer among Vietnam veterans

Because of concerns among veterans over Agent Orange exposure, the Department of Veterans Affairs (VA) has conducted a series of studies of specific cancers among Vietnam veterans. Lung cancer is the topic of investigation in this report. The VA's Patient Treatment File (PTF) was used to identify 329 Vietnam era veterans with a diagnosis of lung cancer made between 1983 and 1990. The PTF is a computerized hospitalized database of inpatient records, including patients' demographic data, and diagnoses. A record is created for each patient discharged from any one of the VA's Medical Centers. Variables abstracted from the military record include education, race, branch of service, Military Occupational Specialty Code, rank, and units served within Vietnam. Two hundred sixty-nine controls were randomly selected from the PTF file of men hospitalized for a reason other than cancer. A second control group numbering 111 patients with colon cancer was also selected from the PTF file. Data were also gathered on exposure to Agent Orange through the location of each individual ground troop veteran's unit in relation to an area sprayed and the time elapsed since that area was sprayed. The crude odds ratio between service in Vietnam and lung cancer was of borderline significance (odds ratio = 1.39 with 95% confidence interval = 1.01-1.92). The relationship disappeared when the confounder year of birth was considered. We conclude from these data that there is no evidence of increased risk in lung cancer associated with service in Vietnam at this time.     

Restoration of T cell-independent type 2 induction of Ig secretion by neonatal B cells in vitro

The humoral immune response of neonates to T cell-independent type 2 (TI-2) Ags is markedly defective. We previously demonstrated that multivalent membrane Ig cross-linking, using dextran-conjugated anti-Ig Abs (anti-Ig-dextran), is an in vitro model for membrane Ig-dependent TI-2 induction of Ig secretion. In this work, we demonstrate that highly purified neonatal B cells are intrinsically defective in IgM secretion in response to anti-Ig-dextran and cytokines in vitro, as well as other modes of B cell activation, relative to adult B cells. However, costimulation of anti-Ig-dextran-activated neonatal B cells with either CD40-ligand, a recombinant bacterial lipoprotein, or LPS restores the IgM secretory response of neonatal B cells to adult levels. Analysis of Ig isotype secretion indicates that neonatal B cells have an enhanced capacity to secrete IgE and IgA relative to other Ig isotypes. These data suggest that neonatal B cells are competent to secrete Ig in response to TI-2 Ags if adequate costimuli are provided, and thus may have particular relevance for the design of vaccine strategies in the immunodeficient host. The data also suggest that neonatal B cells are programmed to secrete relatively enhanced amounts of IgE and IgA, which may be relevant for antimicrobial resistance at mucosal surfaces.     

Hypertension and pulmonary edema associated with subconjunctival phenylephrine in a 2-month-old child during cataract extraction

We have analysed trends in male:female ratios among newborns between 1950 and 1990 in 29 countries from five continents. The numbers of liveborn males and females over the period 1950-1994 were derived from the World Health Organization (WHO) database. Countries for which reliable data were available included 20 major European countries (excluding the former Soviet Union, Albania and a few small countries), Canada, the USA, selected countries of Central and South America, Japan, Australia and New Zealand. From the original numbers of males and females, we computed the proportion of males among liveborns for each country and for selected broader areas within Europe. In most countries the proportion of male liveborns was constant during the study period. In particular, the proportion of male newborns in the European Union was 0.515 in 1950-1954, 0.514 in 1970-1974 and 0.514 in 1990-1994. In the USA, corresponding values were 0.513, 0.513 and 0.512. In Japan the ratios were 0.513 in 1950-1954, 0.516 and 1970-1974 and 0.514 in 1990-1994. Decreasing ratios were observed in some northern and eastern European countries plus Greece and Portugal and, particularly, in Mexico. In contrast, the proportion of male liveborns tended to increase in southern Europe and Australia. Overall, among the 29 countries considered, the proportion of males declined in 16, increased in six, and remained stable in seven.     

Ulceration in necrobiosis lipoidica--a case report and study

A case of aggressive ulceration of necrobiosis lipoidica was successfully treated with oral prednisolone. A retrospective study of 23 cases of necrobiosis lipoidica revealed a 13% incidence of ulceration. The pathogenesis, clinical features and treatment of ulceration in necrobiosis lipoidica are discussed.     

Abrupt (< 1 day), acute (< 1 week), and early (< 1 month) vessel closure at the angioplasty site. Morphologic observations and causes of closure in 130 necropsy patients undergoing coronary angioplasty

While abundant clinical and angiographic data are available regarding features of acute or abrupt closure at the site of balloon angioplasty, little morphologic information is available. This study discusses morphologic-histologic causes for acute closure after angioplasty in 130 necropsy patients. Intimal-medial flaps, elastic recoil, and primary thrombosis were the three leading morphologic causes for closure. Data were subdivided into time categories: abrupt (< 1 day), acute (< 1 week), and early (< 1 month). Intimal-medial flaps remained the most common cause for angioplasty closure despite time from angioplasty to documented occlusion. Morphologic recognition of types and frequencies of angioplasty closure are discussed, and specific mechanical, pharmacologic, or combined treatments are reviewed.     

Purification and characterization of an alpha1,2,-L-fucosyltransferase, which modifies the cytosolic protein FP21,from the cytosol of Dictyostelium

A novel fucosyltransferase (cFTase) activity has been enriched over 10(6)-fold from the cytosolic compartment of Dictyostelium based on transfer of [3H]fucose from GDP-[3H]fucose to Galbeta1,3 GlcNAc beta-paranitrophenyl (paranitrophenyl-lacto-N-bioside or pNP-LNB). The activity behaved as a single component during purification over DEAE-, phenyl-, Reactive Blue-4-, GDP-adipate-, GDP-hexanolamine-, and Superdex gel filtration resins. The purified activity possessed an apparent Mr of 95 X 10(3), was Mg2+-dependent with a neutral pH optimum, and exhibited a Km for GDP-fucose of 0.34 microM, a Km for pNP-LNB of 0.6 mM, and a Vmax for pN-P-LNB of 620 nmol/min/mg protein. SDS-polyacrylamide gel electrophoresis analysis of the Superdex elution profile identified a polypeptide with an apparent Mr of 85 X 10(3), which coeluted with the cFTase activity and could be specifically photolabeled with the donor substrate inhibitor GDP-hexanolaminyl-azido-125I-salicylate. Based on substrate analogue studies, exoglycosidase digestions, and co-chromatography with fucosylated standards, the product of the reaction with pNP-LNB was Fucalpha1, 2Galbeta1,3GIcNAcbeta-pNP. The cFTase preferred substrates with a Galbeta1,3linkage, and thus its acceptor substrate specificity resembles the human Secretor-type alpha1,2- FTase. Afucosyl isoforms of the FP21 glycoprotein, GP21-I and GP21-II, were purified from the cytosol of a Dictyostelium mutant and found to be substrates for the cFTase, which exhibited an apparent K(m) of 0.21 microM and an apparent V(max) of 460 nmol/min/mg protein toward GP21-II. The highly purified cFTase was inhibited by the reaction products Fucalpha1,2Galbeta1,3GlcNAcbeta-pNP and FP21-II. FP21-I and recombinant FP21 were not inhibitory, suggesting that acceptor substrate specificity is based primarily on carbohydrate recognition. A cytosolic location for this step of FP21 glycosylation is implied by the isolation of the cFTase from the cytosolic fraction, its high affinity for its substrates, and its failure to be detected in crude membrane preparations.     

On the cramer-rao bound for carrier frequency estimation in the presence of phase noise

We consider the carrier frequency offset estimation in a digital burst-mode satellite transmission affected by phase noise. The corresponding Cramer-Rao lower bound is analyzed for linear modulations under a Wiener phase noise model and in the hypothesis of knowledge of the transmitted data. Even if we resort to a Monte Carlo average, from a computational point of view the evaluation of the Cramer-Rao bound is very hard. We introduce a simple but very accurate approximation that allows to carry out this task in a very easy way. As it will be shown, the presence of the phase noise produces a remarkable performance degradation of. the frequency estimation accuracy. In addition, we provide asymptotic expressions of the Cramer-Rao bound, from which the effect of the phase noise and the dependence on the system parameters of the frequency offset estimation accuracy clearly result. Finally, as a by-product of our derivations and approximations, we derive a couple of estimators specifically tailored for the phase noise channel that will be compared with the classical Rife and Boorstyn algorithm, gaining in this way some important hints on the estimators to be used in this scenario