In vitro production of panton-valentine leukocidin among strains of methicillin-resistant Staphylococcus aureus causing diverse infections.

BACKGROUND: Community-acquired methicillin-resistant Staphylococcus aureus strains have recently been associated with severe necrotizing infections. Greater than 75% of these strains carry the genes for Panton-Valentine leukocidin (PVL), suggesting that this toxin may mediate these severe infections. However, to date, studies have not provided evidence of toxin production. METHODS: Twenty-nine community-acquired methicillin-resistant Staphylococcus aureus and 2 community-acquired methicillin-susceptible S. aureus strains were collected from patients with infections of varying severity. Strains were analyzed for the presence of lukF-PV and SCCmecA type. PVL production in lukF-PV gene-positive strains was measured by ELISA, and the amount produced was analyzed relative to severity of infection. RESULTS: Only 2 of the 31 strains tested, 1 methicillin-resistant Staphylococcus aureus abscess isolate and 1 nasal carriage methicillin-susceptible S. aureus isolate, were lukF-PV negative. All methicillin-resistant Staphylococcus aureus strains were SCCmec type IV. PVL was produced by all strains harboring lukF-PV, although a marked strain-to-strain variation was observed. Twenty-six (90%) of 29 strains produced 50-350 ng/mL of PVL; the remaining strains produced PVL in excess of 500 ng/mL. The quantity of PVL produced in vitro did not correlate with severity of infection. CONCLUSIONS: Although PVL likely plays an important role in the pathogenesis of these infections, its mere presence is not solely responsible for the increased severity. Factors that up-regulate toxin synthesis in vivo could contribute to more-severe disease and worse outcomes in patients with community-acquired methicillin-resistant Staphylococcus aureus infection.     

Increased glycogen particles in neutrophils in endotoxin-treated rats

Leukocyte glycogen in rats was investigated by electron microscopy during the development of endotoxin shock. Although all white blood cells were examined, only mature neutrophils exhibited an increase in cytoplasmic glycogen. Such neutrophils were observed in the vascular spaces of liver, spleen, lung, and bone marrow including the hematopoietic compartment. The increase in glycogen occurred as early as 30 minutes after endotoxin treatment and continued steadily for 16 hours. The increased glycogen content in neutrophils may be due to increased glycogen synthesis. The increase in glucose uptake by neutrophils may contribute to the causes of hypoglycemia in the late phase of endotoxic shock.     

STAT3 is required for IL-21-induced secretion of IgE from human naive B cells

The production of immunoglobulin E (IgE) is tightly regulated. This is evidenced by the fact that it comprises less than 0.0001% of serum Ig, and aberrant production causes atopic conditions, including allergy, rhinitis, and anaphylaxis. Interleukin-4 (IL-4) is a well-characterized inducer of IgE by human and murine B cells, whereas interferon-gamma can antagonize this effect. IL-21 has also been recognized for its ability to suppress IL-4-induced IgE production by murine B cells. Here, we identified IL-21 as an inducer of IgE production by CD40L-stimulated human naive B cells. Furthermore, there was a striking synergy between IL-4 and IL-21 on inducing IgE secretion by CD40L-stimulated human B cells, such that the levels detected under these conditions exceeded those induced by IL-4 or IL-21 alone by more than 10-fold. IL-21 induced activation of STAT3 and analysis of B cells from patients with loss-of-function STAT3 mutations revealed that the ability of IL-21 to induce IgE secretion, and augment that driven by IL-4, was STAT3-dependent. These findings highlight a fundamental difference between the regulation of IgE production by human and murine B cells and have implications for the dysregulated production of IgE in conditions characterized by extremely high levels of serum IgE.     

Neuroimaging and Cognitive Evidence for Combined HIV-Alcohol Effects on the Central Nervous System: A Review

Alcohol use disorder (AUD) among people living with HIV (PLWH) is a significant public health concern. Despite the advent of effective antiretroviral therapy, up to 50% of PLWH still experience worsened neurocognition, which comorbid AUD exacerbates. We report converging lines of neuroimaging and neuropsychological evidence linking comorbid HIV/AUD to dysfunction in brain regions linked to executive function, learning and memory, processing speed, and motor control, and consequently to impairment in daily life. The brain shrinkage, functional network alterations, and brain metabolite disruption seen in individuals with HIV/AUD have been attributed to several interacting pathways: viral proteins and EtOH are directly neurotoxic and exacerbate each other’s neurotoxic effects; EtOH reduces antiretroviral adherence and increases viral replication; AUD and HIV both increase gut microbial translocation, promoting systemic inflammation and HIV transport into the brain by immune cells; and HIV may compound alcohol’s damaging effects on the liver, further increasing inflammation. We additionally review the neurocognitive effects of aging, Hepatitis C coinfection, obesity, and cardiovascular disease, tobacco use, and nutritional deficiencies, all of which have been shown to compound cognitive changes in HIV, AUD, and in their comorbidity. Finally, we examine emerging questions in HIV/AUD research, including genetic and cognitive protective factors, the role of binge drinking in HIV/AUD-linked cognitive decline, and whether neurocognitive and brain functions normalize after drinking cessation.     

Bortezomib,Melphalan, and Prednisone (VMP) Regimen for Multiple Myeloma

The complexity of cancer chemotherapy requires pharmacists be familiar with the complicated regimens and highly toxic agents used. This column reviews various issues related to preparation, dispensing, and administration of antineoplastic therapy, and the agents, both commercially available and investigational, used to treat malignant diseases. Questions or suggestions for topics should be addressed to Dominic A. Solimando, Jr, President, Oncology Pharmacy Services, Inc., 4201 Wilson Blvd #110-545, Arlington, VA 22203, e-mail: ten.tsacmoc@cvSxRcnO; or J. Aubrey Waddell, Professor, University of Tennessee College of Pharmacy; Oncology Pharmacist, Pharmacy Department, Blount Memorial Hospital, 907 E. Lamar Alexander Parkway, Maryville, TN 37804, e-mail: ten.retrahc@ruofddaw.Regimen name: VMPOrigin of name: VMP is an acronym for the 3 drugs (bortezomib [Velcade], melphalan, and prednisone) in the regimen.     

Change in Alcohol Use Based on Self-Report and a Quantitative Biomarker,Phosphatidylethanol, in People With HIV

AIDS and Behavior - The timeline followback (TLFB) takes more resources to collect than the Alcohol Use Disorder Identification Test (AUDIT-C). We assessed agreement of TLFB and AUDIT-C with the...     

Extraction of Buried P Waves from Printed Electrocardiograms

Background: Morphologic identification of ectopic P‐waves from surface ECGs can be challenging, particularly when the P‐wave is buried in the QRST wave complex. Because ECGs are often available on paper and not digitally, we developed a method of subtracting the T‐wave from the buried P‐wave complex on paper ECGs. Methods: To validate our system, an atrial extrastimulus was introduced during and following the T‐wave. The ECGs were scanned and then transformed from an image format to a digital format. A computer algorithm digitally subtracted a QRST with no buried P‐wave from one with a buried P‐wave, thus resulting in an extracted P‐wave. The extracted P‐waves were compared to the nonburied P‐wave by determining correlation coefficients and by visual grading by two independent reviewers. Results: Visual grading comparing the buried P‐wave with the exposed paced P‐wave was 94%. The median correlation coefficient was 85%. Conclusions: An ectopic atrial P‐wave obscured by a coincident QRST wave complex can be accurately derived from printed ECG using this PC‐based system. Addition of this technique to the existing methods may aid in the localization and ablation of ectopic atrial foci.     

Involvement of endogenous opioid peptides in the neuroendocrine response of ewe lambs to the introduction of a ram

Prepubertal ewes can, under certain circumstances, be stimulated to ovulate by the novel introduction of a ram. The endocrine response to the presence of the ram is characterized by a rapid increase in the frequency of episodic release of LH. The purpose of this study was to investigate the effect of the presence of a ram on LH pulse frequency in vivo, gonadotrophin-releasing hormone (GnRH) and beta-endorphin concentrations in the median eminence, and on the influence of the endogenous opioid peptide agonist [D-Ala2,N-Phe4,Met(0)ol5]-enkephalin (FK 33-824) on basal and depolarization-induced release of GnRH from median eminence tissue superfused in vitro. The study was performed at two prepubertal ages in August and September. In September, the introduction of a ram resulted in an increase in pulsatile release of LH, which was associated with an increase in the rate of basal release of GnRH from median eminence tissue superfused in vitro, and the development of a marked ability of FK 33-824 to suppress depolarization-induced release of GnRH. The concentration of beta-endorphin in the median eminence was reduced in animals exposed to the ram at this time. In contrast, the introduction of a ram in August failed to stimulate an increase in LH pulse frequency, basal release of GnRH in vitro was not altered and FK 33-824 was ineffective in reducing depolarization-induced release of GnRH. These results suggest that the premature onset of reproductive activity induced by exposure to the ram may involve the participation of the endogenous opioid peptide system.