One-year expression from high-capacity adenoviral vectors in the brains of animals with pre-existing anti-adenoviral immunity: clinical implications.

The main challenge of gene therapy is to provide long-term, efficient transgene expression. Long-term transgene expression from first generation adenoviral vectors (Advs) delivered to the central nervous system (CNS) is elicited in animals not previously exposed to adenovirus (Ad). However, upon systemic immunization against Ad, transgene expression from a first generation Adv is abolished. High-capacity Advs (HC-Advs) provide sustained very long-term transgene expression in the brain, even in animals pre-immunized against Ad. In this study, we tested the hypothesis that a HC-Adv in the brain would allow for long-term transgene expression, for up to 1 year, in the brain of mice immunized against Ad prior to delivery of the vector to the striatum. In na?ve animals, the expression of beta-galactosidase from Adv or HC-Adv was sustained for 1 year. In animals immunized prior to vector delivery, expression from a first generation Adv was abolished. These results point to a very long-term HC-Adv-mediated transgene expression in the brain, even in animals that had been immunized systemically against Ad before the delivery of HC-Adv into the brain. This study therefore indicates the utility of HC-Adv as a powerful gene therapy vector for chronic neurological disorders, even in patients who had been pre-exposed to Ad prior to gene therapy.     

Activities of daily living and cognitive status: associations with urinary incontinence in Korea

Urinary incontinence (UI) is a prevalent condition among nursing home (NH) residents and a major cause of undesirable health outcomes and high costs of care. The overall aim is to determine the association between activities of daily living (ADL) and cognitive status among elderly residents with UI in NHs in Korea. Secondary analyses from a cross‐sectional study were performed in this study. Records of 221 elderly residents aged 65 or above who had no indwelling Foley catheter, were included. UI, ADL, cognitive status, depressive symptoms and co‐morbidities were measured through interviews with the residents and staff nurses. Logistic regression models were developed to assess the association between UI and ADL and cognitive status. The mean age of the participants was 80·3 (±7·2). Approximately 68% (n = 150) had UI based on information obtained from nurses. Age, gender, hypertension, arthritis, walking ability, ADL and cognitive status were significant factors in the univariate analyses. For the logistic regression model, ADL [odd ratio, 1·41; 95% confidence interval (CI), 1·26–1·57] and cognitive status (odd ratio, 1·10; 95% CI, 1·02–1·18) remained significant predictors for UI, after controlling for demographics and co‐morbidities. The ability to perform ADL and cognitive status are two factors that are strongly associated with UI. Future studies should examine the impact of environmental and organizational factors on UI in NH residents in Korea to develop a comprehensive and culturally sensitive intervention for this population.     

Morphological and functional alterations in ventricular myocytes from male transgenic mice with hypertrophic cardiomyopathy

Familial hypertrophic cardiomyopathy (FHC) is a human genetic disorder caused by mutations in sarcomeric proteins. It is generally characterized by cardiac hypertrophy, fibrosis, and myocyte disarray. A transgenic mouse model of FHC with mutations in the actin-binding domain of the alpha-myosin heavy chain (MyHC) gene displays many phenotypes similar to human FHC. At 4 months, male transgenic (TG) mice present with concentric cardiac hypertrophy that progresses to dilation with age. Accompanying this latter morphological change is systolic and diastolic dysfunction. Left ventricular (LV) myocytes from male TG and wild-type (WT) littermates at 5 and 12 months of age were isolated and used for morphological and functional studies. Myocytes from 5- and 12-month-old TG animals had shorter sarcomere lengths compared with WT. This sarcomere length difference was abolished in the presence of 2,3-butanedione monoxime, suggesting that the basal level of contractile element activation was increased in TG myocytes. Myocytes from 12-month-old TG mice were significantly longer than those from age-matched WT controls, and TG myocytes exhibited Z-band disorganization. When cells were paced at 0.5 Hz, TG myocyte relengthening and the fall in intracellular [Ca2+] were slowed when compared with cells from age-matched WT controls. Moreover, an increased amount of beta-myosin heavy chain protein was found in hearts from TG compared with WT. Thus, myocytes from the alpha-MyHC TG mouse model display many morphological and functional abnormalities that may help explain the LV dysfunction seen in this TG mouse model of FHC.     

Acculturation and the prevalence of pain amongst South Asian minority ethnic groups in the UK

BACKGROUND: Musculoskeletal pain is reported more commonly by South Asians in the UK than by white Europeans. This may result from a variety of factors, including cultural differences, and thus we investigated the extent to which differences in the prevalence of pain within the South Asian population could be explained by differences in acculturation (the extent to which immigrants take on the culture of their host population). METHODS: Nine hundred and thirty-three Europeans and 1914 South Asian (1165 Indian, 401 Pakistani and 348 Bangladeshi) subjects were recruited from the age-sex registers of 13 general practices in areas with high densities of South Asian populations (Bolton, Oldham, Ashton-under-Lyne and Birmingham). A 28-item acculturation scale was developed, based, on aspects including use of language, clothing style, and use of own-culture media. Principle component analysis generated a score (range 0-100), which was validated against constructs expected to relate to acculturation, such as years of full time education and time spent in the UK. The presence of widespread pain was assessed by the answer to the question 'Have you suffered from pain all over the body in the past month?' RESULTS: Widespread pain was more common in all three South Asian ethnic groups than in the white Europeans [odds ratio (OR) = 3.7, 95% confidence interval (CI) 2.9-4.9], with this increase ranging from 2.7 to 5.8 in the different South Asian subgroups. There was a similar increase in consultation rates for pain. Within the South Asians, pooling all three groups, there was a strong negative association between acculturation score and widespread pain, which remained after adjusting for age and sex: [OR (95% CI) per standard deviation decrease in acculturation score -1.2 (1.0-1.3)]. Adjusting for acculturation accounted for some, but not all, of the differences between the ethnic groups in the prevalence of widespread pain: OR 2.0 (95% CI 1.4-3.0). CONCLUSIONS: Widespread pain is more commonly reported in South Asians though there are interesting differences within the South Asian community. Lower acculturation has a strong influence on the reporting of pain, but cannot explain all of the difference between South Asian and European populations.     

Projected impacts of climate change on salmon habitat restoration

Throughout the world, efforts are under way to restore watersheds, but restoration planning rarely accounts for future climate change. Using a series of linked models of climate, land cover, hydrology, and salmon population dynamics, we investigated the impacts of climate change on the effectiveness of proposed habitat restoration efforts designed to recover depleted Chinook salmon populations in a Pacific Northwest river basin. Model results indicate a large negative impact of climate change on freshwater salmon habitat. Habitat restoration and protection can help to mitigate these effects and may allow populations to increase in the face of climate change. The habitat deterioration associated with climate change will, however, make salmon recovery targets much more difficult to attain. Because the negative impacts of climate change in this basin are projected to be most pronounced in relatively pristine, high-elevation streams where little restoration is possible, climate change and habitat restoration together are likely to cause a spatial shift in salmon abundance. River basins that span the current snow line appear especially vulnerable to climate change, and salmon recovery plans that enhance lower-elevation habitats are likely to be more successful over the next 50 years than those that target the higher-elevation basins likely to experience the greatest snow-rain transition.     

Insulin therapy in type 2 diabetes patients failing oral agents: cost-effectiveness of biphasic insulin aspart 70/30 vs. insulin glargine in the US

OBJECTIVES: To project the long-term clinical and economic outcomes of treatment with biphasic insulin aspart 30 (BIAsp 70/30, 30% soluble and 70% protaminated insulin aspart) vs. insulin glargine in insulin-na?ve type 2 diabetes patients failing to achieve glycemic control with oral antidiabetic agents alone (OADs). METHODS: Baseline patient characteristics and treatment effect data from the recent 'INITIATE' clinical trial served as input to a peer-reviewed, validated Markov/Monte-Carlo simulation model. INITIATE demonstrated improvements in HbA1c favouring BIAsp 70/30 vs. glargine (-0.43%; p < 0.005) and greater efficacy in reaching glycaemic targets among patients poorly controlled on OAD therapy. Effects on life expectancy (LE), quality-adjusted life expectancy (QALE), cumulative incidence of diabetes-related complications and direct medical costs (2004 USD) were projected over 35 years. Clinical outcomes and costs were discounted at a rate of 3.0% per annum. Sensitivity analyses were performed. RESULTS: Improvements in glycaemic control were projected to lead to gains in LE (0.19 +/- 0.24 years) and QALE (0.19 +/- 0.17 years) favouring BIAsp 70/30 vs. glargine. Treatment with BIAsp 70/30 was also associated with reductions in the cumulative incidences of diabetes-related complications, notably in renal and retinal conditions. The incremental cost-effectiveness ratio was $46 533 per quality-adjusted life year gained with BIAsp 70/30 vs. glargine (for patients with baseline HbA1c >/= 8.5%, it was $34 916). Total lifetime costs were compared to efficacy rates in both arms as a ratio, which revealed that the lifetime cost per patient treated successfully to target HbA1c levels of <7.0% and 相似文献   

Immunologic ignorance of vascular endothelial cells expressing minor histocompatibility antigen

Endothelial cells (ECs) presenting minor histocompatibility antigen (mhAg) are major target cells for alloreactive effector CD8⁺ T cells during chronic transplant rejection and graft-versus-host disease (GVHD). The contribution of ECs to T-cell activation, however, is still a controversial issue. In this study, we have assessed the antigen-presenting capacity of ECs in vivo using a transgenic mouse model with beta-galactosidase (β-gal) expression confined to the vascular endothelium (Tie2-LacZ mice). In a GVHD-like setting with adoptive transfer of β-gal–specific T-cell receptor–transgenic T cells, β-gal expression by ECs was not sufficient to either activate or tolerize CD8⁺ T cells. Likewise, transplantation of fully vascularized heart or liver grafts from Tie2-LacZ mice into nontransgenic recipients did not suffice to activate β-gal–specific CD8⁺ T cells, indicating that CD8⁺ T-cell responses against mhAg cannot be initiated by ECs. Moreover, we could show that spontaneous activation of β-gal–specific CD8⁺ T cells in Tie2-LacZ mice was exclusively dependent on CD11c⁺ dendritic cells (DCs), demonstrating that mhAgs presented by ECs remain immunologically ignored unless presentation by DCs is granted.     

Atypical nicotinic agonist bound conformations conferring subtype selectivity

The nicotinic acetylcholine (ACh) receptor (nAChR) plays a crucial role in excitatory neurotransmission and is an important target for drugs and insecticides. Diverse nAChR subtypes with various subunit combinations confer differential selectivity for nicotinic drugs. We investigated the subtype selectivity of nAChR agonists by comparing two ACh-binding proteins (AChBPs) as structural surrogates with distinct pharmacological profiles [i.e., Lymnaea stagnalis (Ls) AChBP of low neonicotinoid and high nicotinoid sensitivities and Aplysia californica (Ac) AChBP of high neonicotinoid sensitivity] mimicking vertebrate and insect nAChR subtypes, respectively. The structural basis of subtype selectivity was examined here by photoaffinity labeling. Two azidoneonicotinoid probes in the Ls-AChBP surprisingly modified two distinct and distant subunit interface sites: loop F Y164 of the complementary or (-)-face subunit and loop C Y192 of the principal or (+)-face subunit, whereas three azidonicotinoid probes derivatized only Y192. Both the neonicotinoid and nicotinoid probes labeled Ac-AChBP at only one position at the interface between loop C Y195 and loop E M116. These findings were used to establish structural models of the two AChBP subtypes. In the Ac-AChBP, the neonicotinoids and nicotinoids are nestled in similar bound conformations. Intriguingly, for the Ls-AChBP, the neonicotinoids have two bound conformations that are inverted relative to each other, whereas nicotinoids appear buried in only one conserved conformation as seen for the Ac-AChBP subtype. Accordingly, the subtype selectivity is based on two disparate bound conformations of nicotinic agonists, thereby establishing an atypical concept for neonicotinoid versus nicotinoid selectivity between insect and vertebrate nAChRs.     

Transiently elevated diastolic blood pressure is associated with a gender-dependent effect on cardiovascular risk

We assessed the morbidity and mortality of subjects with transiently elevated diastolic pressure in the General Practice Hypertension Study Group (GPHSG) population. A total of 23 578 patients (aged 18-65 years) from seven UK general practices were screened in 1974 for a diastolic blood pressure (DBP4) of > or = 90 mmHg. Two further readings of DBP4 determined hypertensive (either DBP4 > or = 90 mmHg) or transient hypertensive (both DBP4 < 90 mmHg) status. Transients (n = 850) were matched with normotensive controls (n = 824) and risk ratios calculated over a mean follow-up of 18.7 years. Rescreening was conducted in six of the practices (n = 20 942) after 7.7 years. Male transients had a higher relative hazard for cardiovascular mortality than controls (11.8%, 8.6%, adjusted relative hazard 1.59, P = 0.056). Female transients had a lower relative hazard for cardiovascular mortality than controls (3.6%, 5.4%, adjusted relative hazard 0.39, P = 0.018). In all, 422 patients with transient hypertension were rescreened along with 367 matched controls. Significantly more transients were on antihypertensive treatment compared with their controls (odds ratio (OR) [95% CI]) for both male (4.2 [1.6-11.1]) and female patients (2.4 [1.0-5.56]) and more untreated female transients developed hypertension. Male transients had a higher rates of diabetes mellitus (adj OR = 5.1, P = 0.04) and stroke (adj OR 15.9, P = 0.03). This study has shown that transiently elevated DBP in GPHSG is associated with a significantly higher risk of later hypertension in men and women and of diabetes, stroke and cardiovascular mortality in men. Women with this condition have a significantly lower cardiovascular mortality.     

Stable patients receiving prolonged mechanical ventilation have a high alveolar burden of bacteria

INTRODUCTION: In patients receiving prolonged mechanical ventilation (PMV), quantitative bronchoscopic culture has not been validated for the diagnosis of ventilator-associated pneumonia (VAP). OBJECTIVE: To measure the alveolar burden of bacteria in patients receiving PMV. SETTING: Respiratory care units of a university hospital and a long-term care facility. PATIENTS: Fourteen patients requiring PMV without clinical evidence of pneumonia. MEASUREMENTS: Quantitative culture of BAL from the right middle lobe and lingula. RESULTS: In 29 of 32 lobes, there was growth of at least one organism at > 10(4) cfu/mL. Most lobes had polymicrobial growth. CONCLUSIONS: Stable patients receiving PMV without clinical pneumonia have a high alveolar burden of bacteria. The bacterial burden in most patients exceeds the commonly accepted threshold for diagnosing VAP. The utility of quantitative bronchoscopic culture in the diagnosis of VAP in this patient population requires further study.