Dihydropteroate synthase gene mutations in Pneumocystis and sulfa resistance

Pneumocystis pneumonia (PCP) remains a major cause of illness and death in HIV-infected persons. Sulfa drugs, trimethoprim-sulfamethoxazole (TMP-SMX) and dapsone are mainstays of PCP treatment and prophylaxis. While prophylaxis has reduced the incidence of PCP, its use has raised concerns about development of resistant organisms. The inability to culture human Pneumocystis, Pneumocystis jirovecii, in a standardized culture system prevents routine susceptibility testing and detection of drug resistance. In other microorganisms, sulfa drug resistance has resulted from specific point mutations in the dihydropteroate synthase (DHPS) gene. Similar mutations have been observed in P. jirovecii. Studies have consistently demonstrated a significant association between the use of sulfa drugs for PCP prophylaxis and DHPS gene mutations. Whether these mutations confer resistance to TMP-SMX or dapsone plus trimethoprim for PCP treatment remains unclear. We review studies of DHPS mutations in P. jirovecii and summarize the evidence for resistance to sulfamethoxazole and dapsone

Origin of intermittent accretion-powered X-ray oscillations in neutron stars with millisecond spin periods

We have shown previously that many of the properties of persistent accretion-powered millisecond pulsars can be understood if their X-ray emitting areas are near their spin axes and move as the accretion rate and structure of the inner disk vary. Here we show that this "nearly aligned moving spot model" may also explain the intermittent accretion-powered pulsations that have been detected in three weakly magnetic accreting neutron stars. We show that movement of the emitting area from very close to the spin axis to about 10 degrees away can increase the fractional rms amplitude from less than about 0.5 percent, which is usually undetectable with current instruments, to a few percent, which is easily detectable. The second harmonic of the spin frequency usually would not be detected, in agreement with observations. The model produces intermittently detectable oscillations for a range of emitting area sizes and beaming patterns, stellar masses and radii, and viewing directions. Intermittent oscillations are more likely in stars that are more compact. In addition to explaining the sudden appearance of accretion-powered millisecond oscillations in some neutron stars with millisecond spin periods, the model explains why accretion-powered millisecond oscillations are relatively rare and predicts that the persistent accretion-powered millisecond oscillations of other stars may become undetectable for brief intervals. It suggests why millisecond oscillations are frequently detected during the X-ray bursts of some neutron stars but not others and suggests mechanisms that could explain the occasional temporal association of intermittent accretion-powered oscillations with thermonuclear X-ray bursts.Comment: 5 pages, 1 figure; includes additional discussion and updated references; accepted for publication in ApJ

A controlled trial of natalizumab for relapsing multiple sclerosis.

Background: In patients with multiple sclerosis, inflammatory brain lesions appear to arise from autoimmune responses involving activated lymphocytes and monocytes. The glycoprotein (alpha)(sub 4) integrin is expressed on the surface of these cells and plays a critical part in their adhesion to the vascular endothelium and migration into the parenchyma. Natalizumab is an (alpha)(sub 4) integrin antagonist that reduced the development of brain lesions in experimental models and in a preliminary study of patients with multiple sclerosis.Methods: In a randomized, double-blind trial, we randomly assigned a total of 213 patients with relapsing-remitting or relapsing secondary progressive multiple sclerosis to receive 3 mg of intravenous natalizumab per kilogram of body weight (68 patients), 6 mg per kilogram (74 patients), or placebo (71 patients) every 28 days for 6 months. The primary end point was the number of new brain lesions on monthly gadolinium-enhanced magnetic resonance imaging during the six-month treatment period. Clinical outcomes included relapses and self-reported well-being.Results: There were marked reductions in the mean number of new lesions in both natalizumab groups: 9.6 per patient in the placebo group, as compared with 0.7 in the group given 3 mg of natalizumab per kilogram (P<0.001) and 1.1 in the group given 6 mg of natalizumab per kilogram (P<0.001). Twenty-seven patients in the placebo group had relapses, as compared with 13 in the group given 3 mg of natalizumab per kilogram (P=0.02) and 14 in the group given 6 mg of natalizumab per kilogram (P=0.02). The placebo group reported a slight worsening in well-being (a mean decrease of 1.38 mm on a 100-mm visual-analogue scale), whereas the natalizumab groups reported an improvement (mean increase of 9.49 mm in the group given 3 mg of natalizumab per kilogram and 6.21 mm in the group given 6 mg of natalizumab per kilogram).Conclusions: In a placebo-controlled trial, treatment with natalizumab led to fewer inflammatory brain lesions and fewer relapses over a six-month period in patients with relapsing multiple sclerosis

Grey matter involvement by focal cervical spinal cord lesions is associated with progressive multiple sclerosis

BACKGROUND: The in vivo relationship of spinal cord lesion features with clinical course and function in multiple sclerosis (MS) is poorly defined. OBJECTIVE: The objective of this paper is to investigate the associations of spinal cord lesion features on MRI with MS subgroup and disability. METHODS: We recruited 120 people: 25 clinically isolated syndrome, 35 relapsing-remitting (RR), 30 secondary progressive (SP), and 30 primary progressive (PP) MS. Disability was measured using the Expanded Disability Status Scale. We performed 3T axial cervical cord MRI, using 3D-fast-field-echo and phase-sensitive-inversion-recovery sequences. Both focal lesions and diffuse abnormalities were recorded. Focal lesions were classified according to the number of white matter (WM) columns involved and whether they extended to grey matter (GM). RESULTS: The proportion of patients with focal lesions involving at least two WM columns and extending to GM was higher in SPMS than in RRMS (p = 0.03) and PPMS (p = 0.015). Diffuse abnormalities were more common in both PPMS and SPMS, compared with RRMS (OR 6.1 (p = 0.002) and 5.7 (p = 0.003), respectively). The number of lesions per patient involving both the lateral column and extending to GM was independently associated with disability (p < 0.001). CONCLUSIONS: More extensive focal cord lesions, extension of lesions to GM, and diffuse abnormalities are associated with progressive MS and disability

Pistons modeled by potentials

In this article we consider a piston modelled by a potential in the presence of extra dimensions. We analyze the functional determinant and the Casimir effect for this configuration. In order to compute the determinant and Casimir force we employ the zeta function scheme. Essentially, the computation reduces to the analysis of the zeta function associated with a scalar field living on an interval $[0,L]$ in a background potential. Although, as a model for a piston, it seems reasonable to assume a potential having compact support within $[0,L]$, we provide a formalism that can be applied to any sufficiently smooth potential.Comment: 10 pages, LaTeX. A typo in eq. (3.5) has been corrected. In "Cosmology, Quantum Vacuum and Zeta Functions: In Honour of Emilio Elizalde", Eds. S.D. Odintsov, D. Saez-Gomez, and S. Xambo-Descamps. (Springer 2011) pp 31