US hospital care for patients with HIV infection and pneumonia: the role of public, private, and Veterans Affairs hospitals in the early highly active antiretroviral therapy era

STUDY OBJECTIVES: We evaluated differences in processes and outcomes of HIV-related pneumonia care among patients in Veterans Affairs (VA), public, and for-profit and not-for-profit private hospitals in the United States. We compared the results of our current study (1995 to 1997) with those of our previous study that included a sample of patients receiving care during the years 1987 to 1990 to determine how HIV-related pneumonia care had evolved over the last decade. SETTING/PATIENTS: The sample consisted of 1,231 patients with HIV infection who received care for Pneumocystis carinii pneumonia (PCP) and 750 patients with HIV infection who received care for community-acquired pneumonia (CAP) during the years 1995 to 1997. MEASUREMENT: We conducted a retrospective medical record review and evaluated patient and hospital characteristics, HIV-related processes of care (timely use of anti-PCP medications, adjunctive corticosteroids), non-HIV-related processes of care (timely use of CAP treatment medications, diagnostic testing, ICU utilization, rates of endotracheal ventilation, placement on respiratory isolation), length of inpatient hospital stay, and inpatient mortality. RESULTS: Rates of timely use of antibiotics and adjunctive corticosteroids for treating PCP were high and improved dramatically from the prior decade. However, compliance with consensus guidelines that recommend < 8 h as the optimal time window for initiation of antibiotics to treat CAP was lower. For both PCP and CAP, variations in processes of care and lengths of in-hospital stays, but not mortality rates, were noted at VA, public, private not-for-profit hospitals, and for-profit hospitals. CONCLUSIONS: This study provides the first overview of HIV-related pneumonia care in the early highly active antiretroviral therapy era, and contrasts current findings with those of a similarly conducted study from a decade earlier. Quality of care for patients with PCP improved, but further efforts are needed to facilitate the appropriate management of CAP. In the third decade of the epidemic, it will be important to monitor whether variations in processes of care for various HIV-related clinical diagnoses among different types of hospitals persist.     

Cannabinoid Modulation of Amygdala Subregion Functional Connectivity to Social Signals of Threat

Background:

Δ⁹-Tetrahydrocannabinol has been shown to modulate anxiety and facilitate the extinction of fear by inhibiting amygdala reactivity. Since functional coupling between the amygdala and prefrontal cortex is implicated in affective processes, it is possible that Δ⁹-tetrahydrocannabinol affects amygdala-prefrontal cortex functional connectivity in ways that differ across amygdala subregions: basolateral, centromedial, and superficial.

Methods:

The aim of the study was to examine the effects of Δ⁹-tetrahydrocannabinol on functional connectivity between amygdala subregions and the prefrontal cortex during socio-emotional threat in healthy adults using a double-blind, placebo-controlled, within-subjects design. Sixteen subjects completed a functional magnetic resonance imaging task designed to probe amygdala responses to social threat. Amygdala subregion-prefrontal cortex functional connectivity was compared between Δ⁹-tetrahydrocannabinol and placebo using generalized psychophysiological interaction analyses.

Results:

Findings indicated that Δ⁹-tetrahydrocannabinol enhanced basolateral and superficial amygdala connectivity to the rostral anterior cingulate/medial prefrontal cortex.

Conclusion:

These effects, including Δ⁹-tetrahydrocannabinol’s potential ability to reduce threat perception or enhance socio-emotional regulation, may help understand the neurocircuitry of affect.     

Novel antigens in non-small cell lung cancer: SP17, AKAP4, and PTTG1 are potential immunotherapeutic targets

Lung cancer is the leading cause of cancer deaths in both genders worldwide, with an incidence only second to prostate cancer in men and breast cancer in women. The lethality of the disease highlights the urgent need for innovative therapeutic options. Immunotherapy can afford efficient and specific targeting of tumor cells, improving efficacy and reducing the side effects of current therapies. We have previously reported the aberrant expression of cancer/testis antigens (CTAs) in tumors of unrelated histological origin. In this study we investigated the expression and immunogenicity of the CTAs, Sperm Protein 17 (SP17), A-kinase anchor protein 4 (AKAP4) and Pituitary Tumor Transforming Gene 1 (PTTG1) in human non-small cell lung cancer (NSCLC) cell lines and primary tumors. We found that SP17, AKAP4 and PTTG1 are aberrantly expressed in cancer samples, compared to normal lung cell lines and tissues. We established the immunogenicity of these CTAs by measuring CTA-specific autoantibodies in patients'' sera and generating CTA-specific autologous cytotoxic lymphocytes from patients'' peripheral blood mononuclear cells. Our results provide proof of principle that the CTAs SP17/AKAP4/PTTG1 are expressed in both human NSCLC cell lines and primary tumors and can elicit an immunogenic response in lung cancer patients.     

Insulin priming effect on estradiol-induced breast cancer metabolism and growth

Diabetes is a risk factor for breast cancer development and is associated with poor prognosis for breast cancer patients. However, the molecular and biochemical mechanisms underlying the association between diabetes and breast cancer have not been fully elucidated. Here, we investigated estradiol response in MCF-7 breast cancer cells with or without chronic exposure to insulin. We found that insulin priming is necessary and specific for estradiol-induced cancer cell growth, and induces anaplerotic shunting of glucose into macromolecule biosynthesis in the estradiol treated cells. Treatment with ERK or Akt specific inhibitors, U0126 or {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002, respectively, suppressed estradiol-induced growth. Interestingly, molecular analysis revealed that estradiol treatment markedly increases expression of cyclin A and B, and decreases p21 and p27 in the insulin-primed cells. In addition, estradiol treatment activated metabolic genes in pentose phosphate (PPP) and serine biosynthesis pathways in the insulin-primed cells while insulin priming decreased metabolic gene expression associated with glucose catabolism in the breast cancer cells. Finally, we found that anti-diabetic drug metformin and AMPK ligand AICAR, but not thiazolidinediones (TZDs), specifically suppress the estradiol-induced cellular growth in the insulin-primed cells. These findings suggest that estrogen receptor (ER) activation under chronic hyperinsulinemic condition increases breast cancer growth through the modulation of cell cycle and apoptotic factors and nutrient metabolism, and further provide a mechanistic evidence for the clinical benefit of metformin use for ER-positive breast cancer patients with diabetes.     

Safety and efficacy of quadrapeutics versus chemoradiation in head and neck carcinoma xenograft model

Chemoradiation is the strongest anti-tumor therapy but in resistant unresectable cancers it often lacks safety and efficacy. We compared our recently developed cell-level combination approach, quadrapeutics, to chemoradiation therapy to establish pre-clinical data for its biodistribution, safety and efficacy in head and neck squamous cell carcinoma (HNSCC), as a clinically challenging aggressive and resistant cancer. In vitro and in vivo models of four carcinomas were treated with standard chemoradiation and quadrapeutics using identical drug and radiation doses. We applied liposomal cisplatin or doxorubicin, colloidal gold, near-infrared laser pulses and radiation, all at low safe doses. The final evaluation used a xenograft model of HNSCC. Quadrapeutics enhanced standard chemoradiation in vitro by reducing head and neck cancer cell proliferation by 1000-fold, inhibiting tumor growth in vivo by 34-fold and improving animal survival by 5-fold, and reducing the side effects to a negligible level. In quadrapeutics, we observed an “inversion” of the drug efficacy of two standard drugs: doxorubicin, a low efficacy drug for the cancers studied, was two times more efficient than cisplatin, the first choice drug in clinic for HNSCC. The radical therapeutic gain of quadrapeutics resulted from the intracellular synergy of the four components employed which we administered in a specific sequence, while the reduction in the toxicity was due to the low doses of all four components. The biodistribution, safety and efficacy data for quadrapeutics in HNSCC ensure its high translational potential and justify the possibility of clinical trials.     

Bacteremic and nonbacteremic pneumococcal pneumonia. A prospective study

We prospectively identified cases of pneumococcal pneumonia and used stringent criteria to stratify them into bacteremic and nonbacteremic cases. Although patients were distributed among racial groups in proportion to all patients seen at this medical center, the proportion of African-Americans with bacteremic disease was significantly increased. All patients had at least 1 underlying condition predisposing to pneumococcal infection, and most had several. Although the mean number of predisposing factors was greater among bacteremic patients than nonbacteremic patients, only alcohol ingestion was significantly more common. Nearly one-third of patients had substantial anemia (hemoglobin < or = 10 g/dL) on admission, which may have predisposed to infection. In the case of other laboratory abnormalities, such as albumin, creatinine, and bilirubin, it was difficult to determine which abnormality might have predisposed to pneumococcal infection and which might have resulted from it. The radiologic appearance was varied. Airspace consolidation and air bronchogram on chest X-ray were highly associated with bacteremic disease, as was the presence of pleural effusion. Although the Pneumonia Patient Outcomes Research Team (PORT) risk score was a predictor of mortality, it did not help to predict the presence of bacteremia in an individual case. Most patients who died in the first week in hospital were bacteremic, and a high PORT risk score with bacteremia reliably predicted a high likelihood of a fatal outcome. Eleven patients had extrapulmonary disease with meningitis, empyema, and septic arthritis predominating; all of these patients were bacteremic. The antibiotic susceptibility of our strains correlated well with those that have been reported in the United States during the years of this study. The use of numerous antibiotics of different classes in many patients, especially those who were the most ill, precluded analysis of outcome based on antibiotic therapy. Only 17 patients had been vaccinated. Since nearly all patients had conditions for which pneumococcal vaccine is recommended and more than one-third had been hospitalized in the preceding 6 months, the low rate of vaccination can be regarded as a missed opportunity to administer a potentially beneficial vaccine.     

Ribavirin polarizes human T cell responses towards a Type 1 cytokine profile

BACKGROUND/AIMS: The therapeutic benefit of ribavirin, a nucleoside analog, in the treatment of chronic HCV infection is seen even in the absence of any apparent direct antiviral effect. We surmised that ribavirin may act by eliciting altered virus-specific immune responses. Because antiviral immunity is predominantly mediated by cytotoxic T cells and antiviral cytokines, we sought to determine whether ribavirin could promote antiviral (Type 1) cytokine expression in human T cells. METHODS: Isolated human T cells were activated in vitro with enterotoxin B or with phorbol ester plus ionomycin. Cytokine ELISAs were performed on culture supernatants, cytokine mRNA was detected following RT-polymerase chain reaction of T cell RNA, and T cell proliferation measured using MTT assay. RESULTS: Ribavirin enhanced a Type 1 (IL-2, IFNgamma, TNFalpha) while suppressing a Type 2 cytokine response (IL-4, IL-5 and IL-10), at the level of both protein and mRNA expression. Ribavirin mediated comparable effects on cytokine expression both following activation of specific T cell subpopulations with superantigen and following activation of a larger percentage of T cells via pharmacologic means. The in vitro effect on cytokine expression following ribavirin treatment was comparable in both CD4+ or CD8+ T cell subsets and was observed in a dose range that promoted T cell proliferation. CONCLUSIONS: These data support the view that ribavirin promotes a Type 1 cytokine-mediated immune response, a property which may account in part for its ability to enhance the antiviral activity of interferon-alpha in the treatment of chronic HCV infection.     

Protection from pulmonary fibrosis in leukotriene-deficient mice.

Although overproduction of proinflammatory 5-lipoxygenase (5-LO)-derived leukotrienes (LTs) has been demonstrated in the lungs of patients with pulmonary fibrosis, their causal involvement in this condition has not been established. Bleomycin-induced pulmonary fibrosis was studied in mice rendered LT deficient by knockout of the 5-LO gene (KO) and in wild-type (WT) control mice. Following administration of bleomycin, lung lavage fluid of WT mice demonstrated an approximately 5-fold increase in levels of cysteinyl-LTs over baseline levels at Day 1, with persistent elevation up to Day 21. As compared with WT mice, 5-LO KO mice demonstrated reduced amounts of histologically evident collagen as well as an approximately 60% reduction in lung hydroxyproline levels postbleomycin. Unlike WT mice, KO mice showed no increases in the numbers of lung inflammatory cells postbleomycin. Furthermore, in situ expression and stimulated production by mixed lung leukocytes of the antifibrotic cytokine interferon-gamma were significantly greater in cells from the 5-LO KO mice. Finally, lavage levels of the antiinflammatory and antifibrotic molecule, prostaglandin E(2), were significantly greater in the KO animals. These results provide strong evidence that LTs may participate in the pathogenesis of pulmonary fibrosis, and they may do so by direct effects as well as indirect effects occurring via their modulation of the synthesis of other inflammatory mediators.