Outbreak of adenovirus 35 pneumonia among adult residents and staff of a chronic care psychiatric facility

Outbreaks of acute respiratory disease caused by adenovirus are rarely documented in civilian populations, and adenovirus 35 is an uncommon serotype best recognized as a cause of serious disease in immunocompromised patients. An outbreak of adenovirus 35 pneumonia among residents and staff of a chronic care psychiatric facility was investigated. Fourteen (26%) of 53 residents and 4 (2%) of approximately 200 staff had radiographically confirmed pneumonia. Thirteen (93%) of 14 residents with pneumonia were hospitalized, 5 (36%) required mechanical ventilation, and 1 (7%) died. One staff member was hospitalized. Adenovirus infection was diagnosed in 17 (94%) persons with pneumonia by culture or serology and was confirmed as adenovirus 35 infection in 8 persons. Residents with pneumonia had resided at the facility longer than other residents. Chronic illness was not a risk factor for severe disease. Crowding and poor hygienic behaviors probably facilitated transmission among residents.     

Phosphorylation of activation functions AF-1 and AF-2 of RAR alpha and RAR gamma is indispensable for differentiation of F9 cells upon retinoic acid and cAMP treatment

The role of RAR alpha 1 and RAR gamma 2 AF-1 and AF-2 activation functions and of their phosphorylation was investigated during RA-induced primitive and parietal differentiation of F9 cells. We found that: (i) primitive endodermal differentiation requires RAR gamma 2, whereas parietal endodermal differentiation requires both RAR gamma 2 and RAR alpha 1, and in all cases AF-1 and AF-2 must synergize; (ii) primitive endodermal differentiation requires the proline-directed kinase site of RAR gamma 2-AF-1, whereas parietal endodermal differentiation additionally requires that of RAR alpha 1-AF-1; (iii) the cAMP-induced parietal endodermal differentiation also requires the protein kinase A site of RAR alpha-AF-2, but not that of RAR gamma; and (iv) the AF-1-AF-2 synergism and AF-1 phosphorylation site requirements for RA-responsive gene induction are promoter context-dependent. Thus, AF-1 and AF-2 of distinct RARs exert specific cellular and molecular functions in a cell-autonomous system mimicking physiological situations, and their phosphorylation by kinases belonging to two main signalling pathways is required to enable RARs to transduce the RA signal during F9 cell differentiation.     

The crystal structure of HIV-1 Nef protein bound to the Fyn kinase SH3 domain suggests a role for this complex in altered T cell receptor signaling

BACKGROUND: Human immunodeficiency virus (HIV) Nef protein accelerates virulent progression of acquired immunodeficiency syndrome (AIDS) by its interaction with specific cellular proteins involved in signal transduction and host cell activation. Nef has been shown to bind specifically to a subset of the Src family of kinases. The structures of free Nef and Nef bound to Src homology region 3 (SH3) domain are important for the elucidation of how the affinity and specificity for the Src kinase family SH3 domains are achieved, and also for the development of potential drugs and vaccines against AIDS. RESULTS: We have determined the crystal structures of the conserved core of HIV-1 Nef protein alone and in complex with the wild-type SH3 domain of the p59fyn protein tyrosine kinase (Fyn), at 3.0 A resolution. Comparison of the bound and unbound Nef structures revealed that a proline-rich motif (Pro-x-x-Pro), which is implicated in SH3 binding, is partially disordered in the absence of the binding partner; this motif only fully adopts a left-handed polyproline type II helix conformation upon complex formation with the Fyn SH3 domain. In addition, the structures show how an arginine residue (Arg77) of Nef interacts with Asp 100 of the so-called RT loop within the Fyn SH3 domain, and triggers a hydrogen-bond rearrangement which allows the loop to adapt to complement the Nef surface. The Arg96 residue of the Fyn SH3 domain is specifically accommodated in the same hydrophobic pocket of Nef as the isoleucine residue of a previously described Fyn SH3 (Arg96-->lle) mutant that binds to Nef with higher affinity than the wild type. CONCLUSIONS: The three-dimensional structures support evidence that the Nef-Fyn complex forms in vivo and may have a crucial role in the T cell perturbating action of Nef by altering T cell receptor signaling. The structures of bound and unbound Nef reveal that the multivalency of SH3 binding may be achieved by a ligand induced flexibility in the RT loop. The structures suggest possible targets for the design of inhibitors which specifically block Nef-SH3 interactions.     

Effects of gemfibrozil and ciprofibrate on plasma levels of tissue-type plasminogen activator, plasminogen activator inhibitor-1 and fibrinogen in hyperlipidaemic patients

Evaluation of fibrate treatment in humans has focused primarily on its anti-lipidaemic effects. A potentially favourable haemostasis-modulating activity of fibrates has also been recognized but the data are not consistent. We sought to learn more about this variability by examining the effects of gemfibrozil and ciprofibrate on plasma levels of tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1) and fibrinogen in primary hyperlipidaemic patients after six and twelve weeks of treatment using different assay systems for PAI-1 and fibrinogen. Although both fibrates effectively lowered triglyceride and cholesterol levels, no effect on the elevated baseline antigen levels of t-PA and PAI-1 was observed after fibrate treatment. However, both fibrates influenced plasma fibrinogen levels, albeit in a different way. Fibrinogen antigen levels were elevated by 17.6% (p <0.05) and 24.3% (p <0.001) with gemfibrozil after six and twelve weeks, respectively, whereas with ciprofibrate there was no effect. Using a Clauss functional assay with either a mechanical end point or a turbidity-based end point, no significant change in fibrinogen levels was seen after six weeks of gemfibrozil treatment. However, after twelve weeks, gemfibrozil enhanced functional fibrinogen levels by 7.2% (p <0.05) as assessed by the Clauss mechanical assay, but decreased functional fibrinogen levels by 12.5% (p <0.0001) when a Clauss assay based on turbidity was used. After six or twelve weeks of ciprofibrate treatment, functional fibrinogen levels were decreased by 10.1% (p <0.001) and 10.5% (p <0.0001), respectively on the basis of Clauss mechanical and by 14.2% (p <0.001) and 28.2% (p <0.0001), respectively with the Clauss turbidimetric assay. A remarkable and consistent finding with both fibrates was the decrease in functionality of fibrinogen as assessed by the ratio of functional fibrinogen (determined by either of the two Clauss assays) to fibrinogen antigen. Taken together, our results indicate that at least part of the variability in the effects of fibrates on haemostatic parameters can be explained by intrinsic differences between various fibrates, by differences in treatment period and/or by the different outcomes of various assay systems. Interestingly, the two fibrates tested both reduced the functionality of fibrinogen.     

Associations between ADHD and psychoactive substance use disorders. Findings from a longitudinal study of high-risk siblings of ADHD children

This article investigates the relationship between attention-deficit/hyperactivity disorder (ADHD) and psychoactive substance use disorders (PSUD) in siblings of ADHD and normal-control probands and addresses issues of psychiatric comorbidity and gender. Using DSM-III-R structured diagnostic interviews and blind raters, the authors conducted a 4-year follow-up of siblings. ADHD and male gender predicted higher rates and an earlier onset of PSUD after adjusting for high-risk status, other psychiatric disorders, and age. Risk was particularly high if the siblings had ADHD plus conduct disorder. This study's findings confirms the authors' prior report high-lighting the importance of drug and alcohol prevention and cessation programs aimed at ADHD youth and their siblings, particularly those with comorbid conduct disorder.     

Goodpasture syndrome involving overlap with Wegener's granulomatosis and anti-glomerular basement membrane disease

A 68-year-old Caucasian woman presented to the hospital with nodular pulmonary infiltrates and acute renal failure. Wegener's granulomatosis was initially considered to be most likely because of the presence of increased serum levels of c-anti-neutrophil cytoplasmic antibodies (c-ANCA). A consultation through the Internet after a renal biopsy demonstrated crescentic, necrotizing glomerulonephritis and linear deposits of immunoglobulin G (IgG) and complement C3, typical of anti-glomerular basement membrane (GBM) disease. Hemodialysis was instituted; however, the patient suddenly developed a massive cerebral hemorrhage and died before full therapy could take effect. Postmortem analysis of the patient's sera revealed high titers of IgG against the alpha 3 NC1 domain of type IV collagen. Serologic evidence of both p-ANCA and anti-GBM antibodies are becoming more frequently recognized in the setting of rapidly progressive glomerulonephritis. The patient reported here had the unusual combination of c-ANCA antibodies with anti-GBM disease, and this association raises complex questions regarding the pathogenesis of this type of renal injury.     

Drug rationalization: now for the hard part

In 1995 a national drug policy was finalized in Nepal. The authors outline the measures that were recommended for its implementation and the activities that have so far been undertaken. Much remains to be done, most notably in assisting, coordinating and supervising these activities.     

Study design of a total reference diet for a population in Northern Italy

A market based of 91 food items was purchased in Northern Italy, based on a list taken from a food survey previously conducted in the same area. The food items from the survey were grouped into 14 categories. Food samples were collected, homogenized, and frozen for the analysis of both the nutrient content and the levels of mineral contaminants. The study design and decision processes behind the choice of type and quantity of each food are explained. The relative quantities of each food group were compared with those from two similar studies. Finally, energy, nutrients, and mineral contaminants obtained by direct analysis were compared with the calculations given on the food composition tables. The comparison between the analyzed and calculated data only showed marked differences in phosphorus, sodium, potassium, and copper intakes.     

Lack of reactivation of cytomegalovirus (CMV) retinitis after stopping CMV maintenance therapy in AIDS patients with sustained elevations in CD4 T cells in response to highly active antiretroviral therapy

The suppression of human immunodeficiency virus (HIV) replication and elevation in CD4 cells observed with protease inhibitor combination regimens known as HAART (highly active antiretroviral therapy) may allow AIDS patients to undergo an immune recovery that allows them to suppress the progression of cytomegalovirus (CMV) retinitis. Eleven AIDS patients receiving HAART with healed CMV retinitis in whom CMV-specific maintenance therapy was discontinued were studied. Median CD4 cell counts were 42 before the initiation of HAART and 183 at discontinuation of anti-CMV therapy. While a median 1.1 log10 drop in plasma HIV-1 RNA was obtained between starting HAART and withdrawal of maintenance therapy for CMV, only 3 of 11 patients maintained plasma HIV RNA below the limits of detection. Reactivation of CMV retinitis after withdrawal of anti-CMV therapy did not occur in any of the patients observed for a median of 156 days (range, 92-558).