Discovery of muscarinic acetylcholine receptor antagonist and beta 2 adrenoceptor agonist (MABA) dual pharmacology molecules.

We sought to design dual pharmacology bronchodilators targeting both the M(3) muscarinic acetylcholine and beta-2 adrenergic (ß(2)) receptors by applying our multivalent approach to drug discovery. Herein, we describe our initial discovery and the SAR of the first such compounds with matched potencies at both receptors.

Implementation of cervical cancer prevention services for HIV-infected women in Zambia: measuring program effectiveness.

BACKGROUND: Cervical cancer kills more women in low-income nations than any other malignancy. A variety of research and demonstration efforts have proven the efficacy and effectiveness of low-cost cervical cancer prevention methods but none in routine program implementation settings of the developing world, particularly in HIV-infected women. METHODS: In our public sector cervical cancer prevention program in Zambia, nurses conduct screening using visual inspection with acetic acid aided by digital cervicography. Women with visible lesions are offered same-visit cryotherapy or referred for histologic evaluation and clinical management. We analyzed clinical outcomes and modeled program effectiveness among HIV-infected women by estimating the total number of cervical cancer deaths prevented through screening and treatment. RESULTS: Between 2006 and 2008, 6572 HIV-infected women were screened, 53.6% (3523) had visible lesions, 58.5% (2062) were eligible for cryotherapy and 41.5% (1461) were referred for histologic evaluation. A total of 75% (1095 out of 1462) of patients who were referred for evaluation complied. Pathology results from 65% (715 out of 1095) of women revealed benign abnormalities in 21% (151), cervical intraepithelial neoplasia (CIN) I in 30% (214), CIN 2/3 in 33% (235) and invasive cervical cancer in 16.1% (115, of which 69% were early stage). Using a conditional probability model, we estimated that our program prevented 142 cervical cancer deaths (high/low range: 238-96) among the 6572 HIV-infected women screened, or one cervical cancer death prevented per 46 (corresponding range: 28-68) HIV-infected women screened. CONCLUSION: Our prevention efforts using setting-appropriate human resources and technology have reduced morbidity and mortality from cervical cancer among HIV-infected women in Zambia. Financial support for implementing cervical cancer prevention programs integrated within HIV/AIDS care programs is warranted. Our prevention model can serve as the implementation platform for future low-cost HPV-based screening methods, and our results may provide the basis for comparison of programmatic effectiveness of future prevention efforts.

The differential effects of thalamus and basal ganglia on facial emotion recognition.

This study examined if subcortical stroke was associated with impaired facial emotion recognition. Furthermore, the lateralization of the impairment and the differential profiles of facial emotion recognition deficits with localized thalamic or basal ganglia damage were also studied. Thirty-eight patients with subcortical strokes and 19 matched normal controls volunteered to participate. The participants were individually presented with morphed photographs of facial emotion expressions over multiple trials. They were requested to classify each of these morphed photographs according to Ekman's six basic emotion categories. The findings indicated that the clinical participants had impaired facial emotion recognition, though no clear lateralization pattern of impairment was observed. The patients with localized thalamic damage performed significantly worse in recognizing sadness than the controls. Longitudinal studies on patients with subcortical brain damage should be conducted to examine how cognitive reorganization post-stroke would affect emotion recognition.

Predictors of dyadic adjustment in multiple sclerosis.

Because multiple sclerosis (MS) is usually diagnosed between the ages of 20 and 50, a time during which most people begin serious relationships, dyadic adjustment for MS patients is a salient issue. However, little is known about factors that might contribute to dyadic adjustment problems in MS. In the present study, we predicted that MS patients showing evidence of three common sequelae of MS--depression symptoms, fatigue and cognitive dysfunction--would be most likely to display problems with dyadic adjustment. Sixty-four MS patients and 49 significant others were assessed. Patient-reported dyadic adjustment was significantly (P at least <0.05) associated with depression (r = -0.48) and fatigue (r = -0.31), but not cognitive functioning. Significant other-reported dyadic adjustment was significantly associated with patients' depression (r = -0.38), fatigue (r = -0.30) and executive functioning impairments (r = 0.37). Stepwise regression analyses revealed that depression was the only significant predictor of dyadic adjustment, regardless of whether significant other (r2 change = 0.16) or patient-reported (r2 change = 0.22) dyadic adjustment was used as the criterion variable. If depression leads to dyadic problems in MS patients, treatment of depression may result in improved dyadic adjustment. Conversely, if dyadic problems contribute to depression in MS, then treatment of dyadic problems may lead to relief from depression in these patients.