Boise VA Medical Center

Several interviews are available for assessing PTSD. These interviews vary in merit when compared on stringent psychometric and utility standards. Of all the interviews, the Clinician-Administered PTSD Scale (CAPS-1) appears to satisfy these standards most uniformly. The CAPS-1 is a structured interview for assessing core and associated symptoms of PTSD. It assesses the frequency and intensity of each symptom using standard prompt questions and explicit, behaviorally-anchored rating scales. The CAPS-1 yields both continuous and dichotomous scores for current and lifetime PTSD symptoms. Intended for use by experienced clinicians, it also can be administered by appropriately trained paraprofessionals. Data from a large scale psychometric study of the CAPS-1 have provided impressive evidence of its reliability and validity as a PTSD interview.

Abstract Several interviews are available for assessing PTSD. These interviews vary in merit when compared on stringent psychometric and utility standards. Of all the interviews, the Clinician‐Administered PTSD Scale (CAPS‐1) appears to satisfy these standards most uniformly. The CAPS‐1 is a structured interview for assessing core and associated symptoms of PTSD. It assesses the frequency and intensity of each symptom using standard prompt questions and explicit, behaviorally‐anchored rating scales. The CAPS‐1 yields both continuous and dichotomous scores for current and lifetime PTSD symptoms. Intended for use by experienced clinicians, it also can be administered by appropriately trained paraprofessionals. Data from a large scale psychometric study of the CAPS‐1 have provided impressive evidence of its reliability and validity as a PTSD interview.

A panel of national experts was convened by the Infectious Diseases Society of America (IDSA) to update the 2005 guidelines for the treatment of skin and soft tissue infections (SSTIs). The panel's recommendations were developed to be concordant with the recently published IDSA guidelines for the treatment of methicillin-resistant Staphylococcus aureus infections. The focus of this guideline is the diagnosis and appropriate treatment of diverse SSTIs ranging from minor superficial infections to life-threatening infections such as necrotizing fasciitis. In addition, because of an increasing number of immunocompromised hosts worldwide, the guideline addresses the wide array of SSTIs that occur in this population. These guidelines emphasize the importance of clinical skills in promptly diagnosing SSTIs, identifying the pathogen, and administering effective treatments in a timely fashion.

A panel of national experts was convened by the Infectious Diseases Society of America (IDSA) to update the 2005 guidelines for the treatment of skin and soft tissue infections (SSTIs). The panel's recommendations were developed to be concordant with the recently published IDSA guidelines for the treatment of methicillin-resistant Staphylococcus aureus infections. The focus of this guideline is the diagnosis and appropriate treatment of diverse SSTIs ranging from minor superficial infections to life-threatening infections such as necrotizing fasciitis. In addition, because of an increasing number of immunocompromised hosts worldwide, the guideline addresses the wide array of SSTIs that occur in this population. These guidelines emphasize the importance of clinical skills in promptly diagnosing SSTIs, identifying the pathogen, and administering effective treatments in a timely fashion.

The gut microbiome plays an important role in human health and influences the development of chronic diseases ranging from metabolic disease to gastrointestinal disorders and colorectal cancer. Of increasing prevalence in Western societies, these conditions carry a high burden of care. Dietary patterns and environmental factors have a profound effect on shaping gut microbiota in real time. Diverse populations of intestinal bacteria mediate their beneficial effects through the fermentation of dietary fiber to produce short-chain fatty acids, endogenous signals with important roles in lipid homeostasis and reducing inflammation. Recent progress shows that an individual’s starting microbial profile is a key determinant in predicting their response to intervention with live probiotics. The gut microbiota is complex and challenging to characterize. Enterotypes have been proposed using metrics such as alpha species diversity, the ratio of Firmicutes to Bacteroidetes phyla, and the relative abundance of beneficial genera (e.g., Bifidobacterium, Akkermansia) versus facultative anaerobes (E. coli), pro-inflammatory Ruminococcus, or nonbacterial microbes. Microbiota composition and relative populations of bacterial species are linked to physiologic health along different axes. We review the role of diet quality, carbohydrate intake, fermentable FODMAPs, and prebiotic fiber in maintaining healthy gut flora. The implications are discussed for various conditions including obesity, diabetes, irritable bowel syndrome, inflammatory bowel disease, depression, and cardiovascular disease.

Streptococcus pyogenes (group A in the Lancefield classification) is one of the most common human pathogens. Although this ubiquitous organism is responsible for a wide array of illnesses, most attention has focused on its relation to acute pharyngitis, because of the frequency of that condition and its potential for inciting acute rheumatic fever. The recent resurgence of invasive group A streptococcal infections,1,2 however, is a reminder that the pathogen can cause a variety of skin and soft-tissue infections, some of which are severe and even life-threatening.Streptococcal PyodermaPyoderma, or impetigo, is a localized, purulent infection of the . . .

The hallmarks of necrotizing fasciitis are friable superficial fascia, gray exudate without pus, and widespread tissue destruction. The infection is either polymicrobial or monomicrobial. Early surgical débridement and appropriate antibiotics are crucial for recovery.

Anthracyclines, such as doxorubicin and daunorubicin, are highly effective anticancer agents that produce a well-described but incompletely understood cardiac toxicity. According to a popular hypothesis, anthracyclines injure the heart by generating oxygen-centered free radicals. This free radical hypothesis, however, appears to be inconsistent with many observations, such as the frequent failure of anthracyclines at cardiotoxic doses to produce evidence of increased free radical generation. Other explanations of cardiotoxicity involve platelet-activating factor, prostaglandins, histamine, calcium, and C-13 hydroxy anthracycline metabolites. These C-13 hydroxy metabolites, on the basis of in vitro data, are considerably more potent than parent compounds as myocardial depressants and as inhibitors of ATPases of sarcoplasmic reticulum, mitochondria, and sarcolemma. Further studies will be required to determine whether metabolites or the other putative injurious agents discussed contribute substantially to the cardiomyopathy of anthracycline therapy. The hypotheses presented in this paper should provide a useful framework for subsequent investigations into the mechanisms of anthracycline cardiotoxicity.

Linezolid, the first available member of a new antibiotic class, the oxazolidinones, is broadly active against gram-positive bacteria, including drug-resistant strains. In this randomized, open-label trial, hospitalized adults with known or suspected methicillin-resistant Staphylococcus aureus (MRSA) infections were treated with linezolid (600 mg twice daily; n=240) or vancomycin (1 g twice daily; n=220) for 7-28 days. S. aureus was isolated from 53% of patients; 93% of these isolates were MRSA. Skin and soft-tissue infection was the most common diagnosis, followed by pneumonia and urinary tract infection. At the test-of-cure visit (15-21 days after the end of therapy), among evaluable patients with MRSA, there was no statistical difference between the 2 treatment groups with respect to clinical cure rates (73.2% of patients in the linezolid group and 73.1% in the vancomycin group) or microbiological success rates (58.9% in the linezolid group and 63.2% in the vancomycin group). Both regimens were well tolerated, with similar rates of adverse events.

Lymphocyte homing to normal tissues and recruitment to inflammatory tissue sites are controlled, in part, by the selective expression of chemokines, pro-inflammatory cytokines and mediators, and various adhesion proteins and molecules. In the mouse, mucosal addressin cell adhesion molecule-1 (MAdCAM-1) is selectively expressed on endothelium of high endothelial venules in gut and gut-associated lymphoid tissue. By interaction with its integrin ligand, alpha 4 beta 7, lymphocytes presumed to be involved in mucosal immunity are selectively recruited to these intestinal sites. After generating monoclonal antibodies against a murine cell line expressing recombinant human MAdCAM-1, we qualitatively and semiquantitatively assessed MAdCAM-1 expression in human tissue sections from various normal and inflammatory disorders. We found that human MAdCAM-1, as in the mouse, is expressed in a tissue-selective manner. In normal tissues, MAdCAM-1 is constitutively expressed to endothelium of venules of intestinal lamina propria. Interestingly, using computer-assisted morphometric analysis, the proportion of venular endothelium within lamina propria that expresses MAdCAM-1 is increased, compared with normal tissues, at inflammatory foci associated with ulcerative colitis and Crohn's disease. Moreover, for the most part, MAdCAM-1 is not detected in the majority of normal or inflamed extra-intestinal tissues, including those with mucosal surfaces. These results are consistent with a role, as originally defined in the mouse, for human MAdCAM-1 in the localization of alpha 4 beta 7+ lymphocytes in the gastrointestinal tract and associated lymphoid tissue. As such, the pathway defined by MAdCAM-1/alpha 4 beta 7 may be a relevant tissue-specific therapeutic target for the modulation of inflammatory bowel disease activity.

We investigated the relative efficacies of penicillin, clindamycin, and erythromycin in a mouse model of myositis due to Streptococcus pyogenes. Penicillin was ineffective unless given at the time of bacterial injection, and treatment delays of 2 h reduced its efficacy such that survival was no better than that of untreated control animals (P less than .05). Survival of erythromycin-treated mice was greater than that of both penicillin-treated mice and untreated controls, but only if treatment was begun within 2 h. Mice receiving clindamycin, however, had survival rates of 100%, 100%, 80%, and 70% even if treatment was delayed 0, 2, 6, and 16.5 h, respectively. Thus, clindamycin demonstrated superior efficacy to penicillin among all the various treatment groups (P less than .05). Our results corroborate the failure of penicillin in this model of streptococcal infection and suggest that, unlike penicillin, the efficacy of clindamycin is not adversely altered by the "Eagle effect."

Skin and soft tissue infections (SSTIs) are a common cause of morbidity in both the community and the hospital. An SSTI is classified as complicated if the infection has spread to the deeper soft tissues, if surgical intervention is necessary, or if the patient has a comorbid condition hindering treatment response (e.g., diabetes mellitus or human immunodeficiency virus). The purpose of this study was to compare linezolid to vancomycin in the treatment of suspected or proven methicillin-resistant gram-positive complicated SSTIs (CSSTIs) requiring hospitalization. This was a randomized, open-label, comparator-controlled, multicenter, multinational study that included patients with suspected or proven methicillin-resistant Staphylococcus aureus (MRSA) infections that involved substantial areas of skin or deeper soft tissues, such as cellulitis, abscesses, infected ulcers, or burns (<10% of total body surface area). Patients were randomized (1:1) to receive linezolid (600 mg) every 12 h either intravenously (i.v.) or orally or vancomycin (1 g) every 12 h i.v. In the intent-to-treat population, 92.2% and 88.5% of patients treated with linezolid and vancomycin, respectively, were clinically cured at the test-of-cure (TOC) visit (P=0.057). Linezolid outcomes (124/140 patients or 88.6%) were superior to vancomycin outcomes (97/145 patients or 66.9%) at the TOC visit for patients with MRSA infections (P<0.001). Drug-related adverse events were reported in similar numbers in both the linezolid and the vancomycin arms of the trial. The results of this study demonstrate that linezolid therapy is well tolerated, equivalent to vancomycin in treating CSSTIs, and superior to vancomycin in the treatment of CSSTIs due to MRSA.

Extracellular protein toxins contribute to the pathogenesis of a wide variety of Staphylococcus aureus infections. The present study investigated the effects that cell-wall active antibiotics and protein-synthesis inhibitors have on transcription and translation of genes for Panton-Valentine leukocidin, alpha-hemolysin, and toxic-shock syndrome toxin 1, in both methicillin-sensitive and methicillin-resistant S. aureus. Subinhibitory concentrations of nafcillin induced and prolonged mRNA for Panton-Valentine leukocidin, alpha-toxin, and toxic-shock syndrome toxin 1 and increased toxin production. In contrast, clindamycin and linezolid markedly suppressed translation, but not transcription, of toxin genes. These results suggest (1) that protein-synthesis inhibition is an important consideration in the selection of antimicrobial agents to treat serious infections caused by toxin-producing gram-positive pathogens and (2) that, by inducing and enhancing toxin production, inadvertent use of beta-lactam antibiotics to treat methicillin-resistant S. aureus infections may contribute to worse outcomes.

DRUG therapy in the elderly is complicated by many factors unique to this age group. Because it requires careful individualization, such therapy should be based on the principles of pharmacokinetics. Multiple disease processes, environmental influences, and genetic variation often combine with the physiologic effects of aging to affect the disposition of drugs in this heterogeneous population (Table 1). It is therefore difficult to generalize about the effects of age alone. Unfortunately, there has been relatively little investigation of the effects of age at the sites of drug action. In addition, little information is available about drug disposition and response in . . .

Doxorubicin (former generic name, adriamycin), a highly effective anticancer drug, produces cardiotoxicity, which limits its therapeutic potential. The mechanism of this cardiotoxicity has remained elusive. Our data suggest that this toxicity could involve doxorubicinol, the primary circulating metabolite of doxorubicin. Doxorubicinol was markedly more potent than doxorubicin at compromising both systolic and diastolic cardiac function. Similarly, doxorubicinol was much more potent than doxorubicin at inhibiting the calcium pump of sarcoplasmic reticulum [ATP phosphohydrolase (Ca2+-transporting), EC 3.6.1.38], the Na+/K+ pump of sarcolemma [ATP phosphohydrolase (Na+/K+-transporting), EC 3.6.1.37], and the F0F1 proton pump of mitochondria [ATP phosphohydrolase (H+-transporting, EC 3.6.1.34]. Our finding that this highly toxic metabolite was produced by cardiac tissue exposed to doxorubicin suggests that doxorubicinol could accumulate in the heart and contribute significantly to the chronic cumulative cardiotoxicity of doxorubicin therapy. Our observation that doxorubicin was more potent than doxorubicinol in inhibiting tumor cell growth in vitro suggests that the cardiotoxicity of doxorubicin is dissociable from its anticancer activity.

BACKGROUND: Asthma death rates are rising, with the greatest rise and highest death rates in old age. A reduced cardiovascular response in the elderly may lead to the underestimation by physicians of the severity of acute asthma attacks. This would be compounded if elderly patients had reduced awareness of bronchoconstriction. METHODS: Methacholine provoked bronchoconstriction was compared in 34 elderly (17 asthmatic, 17 normal; age 60-83, mean 68 years) and 33 young subjects (16 asthmatic, 17 normal; 20-46, mean 30 years). None were smokers. All underwent inhaled methacholine challenge by the Newcastle dosimeter method, monitored by maximal expiratory flow-volume loops (MEFVL). The endpoints were a 35% fall in forced expiratory flow at 50% vital capacity or cumulative inhalation of 6.4 mg methacholine. The one second forced expiratory volume (FEV1) was derived from MEFVL. After challenge and before bronchodilatation subjects graded awareness of respiratory discomfort from 1 (no symptoms) to 4 (pronounced symptoms needing immediate treatment). RESULTS: Despite a greater fall in FEV1 in elderly asthmatic patients (mean (SE) 27.4% (2.2%)) than in young asthmatic patients (21.5% (1.7%)) elderly patients were less aware of bronchoconstriction (awareness score 2.00 (SE 0.15) than young patients (3.06 (0.11)). Similar differences in awareness score were seen between elderly normal subjects (1.53 (0.17)) and young normal subjects (2.76 (0.22)), despite no difference in degree of bronchoconstriction. CONCLUSIONS: Reduced awareness of moderate acute bronchoconstriction in old age may delay self referral in acute asthma and contribute to higher asthma mortality in the elderly.

Anecdotal reports suggest an association between the use of nonsteroidal antiinflammatory drugs (NSAIDs) and the progression of invasive group A streptococcal infections to shock and multiorgan failure. There is a biochemical rationale that could support this theory. Though NSAIDs are frequently used to relieve pain or reduce fever, they also attenuate granulocyte functions such as chemotaxis, phagocytosis, and bacterial killing. In addition, findings in recent studies involving human volunteers injected with endotoxin suggest that pretreatment with NSAIDs enhances production of tumor necrosis factor, which leads to higher blood levels of this cytokine, probably by preventing feedback inhibition by prostaglandin E2. Thus, NSAIDs may contribute to the sudden onset of shock, organ failure, and aggressive infection by inhibiting neutrophil function, augmenting cytokine production, and attenuating the cardinal manifestations of inflammation.

Since the 1980s, there has been a marked increase in the recognition and reporting of highly invasive group A streptococcal (GAS) infections associated with shock and organ failure, with or without necrotizing fasciitis. Such dramatic cases have been defined as streptococcal toxic shock syndrome (StrepTSS). Strains of GAS isolated from patients with invasive disease have been predominantly M types 1 and 3, which produce either pyrogenic exotoxin A or B or both. The clinical and demographic features of streptococcal bacteremia, myositis, and necrotizing fasciitis are presented and compared with those of StrepTSS. Current concepts in the pathogenesis of invasive streptococcal infection will be presented, with emphasis on the interaction between GAS virulence factors and host defense mechanisms. Finally, new concepts in the treatment of StrepTSS will be discussed.

Resistance of Gram-positive bacterial pathogens, such as Staphylococcus aureus and Enterococcus faecium, to existing antibiotics continues to increase, and new antibiotics with activity against these pathogens are in demand. Linezolid (Zyvox, Pharmacia and Upjohn) is the first agent of a new class of antibiotics called the oxazolidinones. Linezolid possesses excellent microbial activity against a wide variety of Gram-positive pathogens including those resistant to methicillin and vancomycin (Vancocin, Eli Lilly). Linezolid is available for intravenous and oral administration and possesses excellent bioavailability. It exhibits good penetration into pulmonary, as well as skin and related structure tissues, and does not require dosage adjustment in hepatic or renal dysfunction. Linezolid is generally well-tolerated, with the predominant adverse effect manifesting as a duration dependent, reversible thrombocytopenia. Linezolid possesses monoamine oxidase inhibitor activity and caution is warranted with coadministration of adrenergic or seritonergic medications. Clinical trials conducted with linezolid in skin and structure infections, lower respiratory tract infections and vancomycin-resistant enterococcal infections demonstrate that linezolid is an effective therapy. Recent data suggest that linezolid may be superior to vancomycin for the treatment of infections caused by methicillin-resistant S. aureus. Linezolid is an excellent and promising new antibiotic for the treatment of resistant Gram-positive pathogens.

Although alcohol screening and brief intervention (SBI) reduces drinking in primary care patients with unhealthy alcohol use, incorporating SBI into clinical settings has been challenging. We systematically reviewed the literature on implementation studies of alcohol SBI using a broad conceptual model of implementation, the Consolidated Framework for Implementation Research (CFIR), to identify domains addressed by programs that achieved high rates of screening and/or brief intervention (BI). Seventeen articles from 8 implementation programs were included; studies were conducted in 9 countries and represented 533,903 patients (127,304 patients screened), 2,001 providers, and 1,805 clinics. Rates of SBI varied across articles (2-93% for screening and 0.9-73.1% for BI). Implementation programs described use of 7-25 of the 39 CFIR elements. Most programs used strategies that spanned all 5 domains of the CFIR with varying emphases on particular domains and sub-domains. Comparison of SBI rates was limited by most studies' being conducted by 2 implementation programs and by different outcome measures, scopes, and durations. However, one implementation program reported a high rate of screening relative to other programs (93%) and could be distinguished by its use of strategies that related to the Inner Setting, Outer Setting, and Process of Implementation domains of the CFIR. Future studies could assess whether focusing on Inner Setting, Outer Setting, and Process of Implementation elements of the CFIR during implementation is associated with successful implementation of alcohol screening, as well as which elements may be associated with successful, sustained implementation of BI.