A neuronal model of Alzheimer's disease: an insight into the mechanisms of oxidative stress-mediated mitochondrial injury

Alzheimer's disease (AD) is associated with beta-amyloid accumulation, oxidative stress and mitochondrial dysfunction. However, the effects of genetic mutation of AD on oxidative status and mitochondrial manganese superoxide dismutase (MnSOD) production during neuronal development are unclear. To investigate the consequences of genetic mutation of AD on oxidative damages and production of MnSOD during neuronal development, we used primary neurons from new born wild-type (WT/WT) and amyloid precursor protein (APP) (NLh/NLh) and presenilin 1 (PS1) (P264L) knock-in mice (APP/PS1) which incorporated humanized mutations in the genome. Increasing levels of oxidative damages, including protein carbonyl, 4-hydroxynonenal (4-HNE) and 3-nitrotyrosine (3-NT), were accompanied by a reduction in mitochondrial membrane potential in both developing and mature APP/PS1 neurons compared with WT/WT neurons suggesting mitochondrial dysfunction under oxidative stress. Interestingly, developing APP/PS1 neurons were significantly more resistant to beta-amyloid 1-42 treatment, whereas mature APP/PS1 neurons were more vulnerable than WT/WT neurons of the same age. Consistent with the protective function of MnSOD, developing APP/PS1 neurons have increased MnSOD protein and activity, indicating an adaptive response to oxidative stress in developing neurons. In contrast, mature APP/PS1 neurons exhibited lower MnSOD levels compared with mature WT/WT neurons indicating that mature APP/PS1 neurons lost the adaptive response. Moreover, mature APP/PS1 neurons had more co-localization of MnSOD with nitrotyrosine indicating a greater inhibition of MnSOD by nitrotyrosine. Overexpression of MnSOD or addition of MnTE-2-PyP(5+) (SOD mimetic) protected against beta-amyloid-induced neuronal death and improved mitochondrial respiratory function. Together, the results demonstrate that compensatory induction of MnSOD in response to an early increase in oxidative stress protects developing neurons against beta-amyloid toxicity. However, continuing development of neurons under oxidative damage conditions may suppress the expression of MnSOD and enhance cell death in mature neurons.     

Developing a spatial-statistical model and map of historical malaria prevalence in Botswana using a staged variable selection procedure

Background  

Several malaria risk maps have been developed in recent years, many from the prevalence of infection data collated by the MARA (Mapping Malaria Risk in Africa) project, and using various environmental data sets as predictors. Variable selection is a major obstacle due to analytical problems caused by over-fitting, confounding and non-independence in the data. Testing and comparing every combination of explanatory variables in a Bayesian spatial framework remains unfeasible for most researchers. The aim of this study was to develop a malaria risk map using a systematic and practicable variable selection process for spatial analysis and mapping of historical malaria risk in Botswana.     

Long-term effects of nutrient intervention on markers of bone remodeling and calciotropic hormones in late-postmenopausal women

BACKGROUND: Adequate intakes of calcium and vitamin D reduce bone loss and fracture risk in the elderly. Other nutrients also affect bone health, and adequate intakes may influence bone turnover and balance. OBJECTIVE: We compared the long-term effects on bone turnover markers and calciotropic hormones of a multinutrient supplement, a calcium and vitamin D supplement, and dietary instruction aimed at increasing calcium intake through foods. DESIGN: Ninety-nine healthy postmenopausal women participated in a 3-y, randomized trial, receiving either 1) supplemental calcium (1450 mg/d) and vitamin D [10 microg (400 IU)/d], 2) calcium, vitamin D, and other nutrients (multinutrient supplement), or 3) dietary instruction (dietary control group). Data are from 83 subjects who completed the trial. RESULTS: Increases over baseline in calcium intakes and serum 25-hydroxyvitamin D concentrations were sustained over 3 y in all treatment groups. Circulating parathyroid hormone concentrations were reduced at year 1 in all treatment groups but trended toward baseline thereafter. Bone turnover markers followed a similar pattern, and none of the changes in biochemical concentrations differed significantly between groups. CONCLUSIONS: All 3 interventions offer long-term feasibility for increasing calcium intake and serum 25-hydroxyvitamin D concentrations. The dietary addition of micronutrients implicated in skeletal physiology confers no obvious bone-sparing effect in healthy postmenopausal women beyond that of calcium and vitamin D alone. The attenuation over time in suppression of parathyroid hormone and bone turnover might help explain why nutrient intervention tends to have less of a bone-sparing effect than do skeletally active medications such as estrogen or bisphosphonates.     

Post-traumatic stress disorder in women: current concepts and treatments

In the US, 13% of women develop post-traumatic stress disorder (PTSD) during their lifetime. An accurate diagnosis of PTSD requires screening for trauma and symptoms of PTSD. Current research in the neurobiologic and psychologic responses to traumatic stress supports the use of pharmacologic and psychosocial interventions. Selective serotonin reuptake inhibitors are the current first-line pharmacotherapy. Efficacious psychosocial interventions include exposure therapy and cognitive processing therapy.     

Intraocular pressure and acclimatization to 4300 M altitude

BACKGROUND: Studies were conducted to determine the effect of altitude exposure on intraocular pressure (IOP) and any relationship with the severity of acute mountain sickness (AMS). HYPOTHESES: a) IOP is decreased during exposure to 4300 m altitude; b) there is a positive correlation between IOP and AMS; and c) there is a correlation between changes in urinary catecholamines and IOP. METHODS: IOP (noncontact tonometry) was measured in 11 resting males during acute simulated altitude (446 mmHg, < 2 h, hypobaric chamber), during altitude acclimatization (15 d at 4300 m), and in 6 of the 11 volunteers during re-exposure in the chamber after 8 d at sea level (Study A). In a second study (Study B) of 12 females, IOP (contact tonometry) and 24-h urinary catecholamines were measured during a 50-h chamber exposure (446 mmHg). AMS severity was assessed using the Environmental Symptoms Questionnaire (ESQ-C). RESULTS: IOP decreased 25% after 2 d at altitude and returned toward sea level values by 15 d (Study A). IOP was reduced 13% after 5 h of exposure followed by return toward sea level values (Study B). Significant correlation was found between the sea level IOP and ESQ-C (Study A); significant correlation was found between the reduction in IOP and the ESQ-C and urinary epinephrine concentrations (Study B). CONCLUSIONS: Altitude exposure resulted in a reduction in IOP that occurred within hours and recovered during acclimatization. This reduction may be related to increases in epinephrine concentration. Measurement of IOP before and during altitude exposure may provide an objective method of assessing an individual's response to hypoxic stress.     

Dementia in rural primary care practices in Lake County, Oregon

Procedures used in assessing patients with dementia in rural settings are little studied. Among all patients aged 65 years and older in the four primary care practices in Lake County, Oregon, dementia cases were identified from computerized office databases using preselected International Classification of Diseases, Ninth Edition, codes. A semi-structured chart review determined (1) a dementia diagnosis, (2) cognitive and functional domains assessed, and (3) diagnostic studies performed. Of 1540 available records, 30 had dementia. Nineteen of them met National Institute of Neurological and Communicative Diseases and Stroke-Alzheimer's Disease and Related Disorders Association criteria for Alzheimer's disease (AD). Cognitive impairment was documented in 73% of the 51 identified charts and all with AD. Laboratory studies were recorded in 33% overall and in 42% with AD. Neuroimaging was documented in 18% overall and in 16% with AD. The prevalence of documented dementia in these rural practices may be low, possibly because cases of mild dementia may not be labeled as such. Laboratory studies were performed in a minority of cases of dementia.     

Contractile properties and fatigue of quadriceps muscles in multiple sclerosis

Functional characteristics of electrically stimulated quadriceps muscles of patients with multiple sclerosis (MS) were determined to investigate whether adaptations in muscle properties contribute to the higher fatigability of these patients. The estimated maximal isometric force generating capacity of MS patients was only 11.2% (P < 0.05) lower than control subjects. However, the patients were only able to voluntarily exert 75 +/- 22% (n = 12) of their maximal capacity, against 94 +/- 6% (n = 7) for the control subjects. There were no differences in muscle speed, suggesting that muscle fiber distribution was not different in the MS patients due to reduced muscle usage. During a series of repeated contractions, greater decrements occurred in isometric force and in maximal rate of force rise in the MS patients (by 31.3 +/- 10.3% and 50.1 +/- 10.0%, respectively; n = 13) than control subjects (23.8 +/- 6.6% and 39.0 +/- 8.1%, n = 15), suggesting a lower oxidative capacity. The results indicate that increasing the mass of their muscles by training may help to reduce the excessive muscle fatigue of MS patients.     

False negative biliary scintigraphy in gangrenous cholecystitis

Gangrenous cholecystitis is a serious complication of acute cholecystitis and is associated with increased morbidity and mortality rates. We report a case in which the diagnosis was suggested by ultrasound, but cholecystectomy delayed due to atypical clinical presentation and a false negative radionuclide biliary scan.     

Computed tomography fluoroscopy‐guided chemical lumbar sympathectomy: Simple,safe and effective

Demographic, clinical and laboratory data were retrospectively collected from records of 146 cases of CT fluoroscopy‐guided chemical lumbar sympathectomy for the palliation of inoperable peripheral vascular disease (PVD) between January 1997 and August 1999. Of these, 16% had claudication, 39% had rest pain and 44% had ischaemic ulcers or gangrene. Seventy‐three percent of elective cases were outpatients. At 3 months, 27 cases were lost to follow up, leaving 119 cases. Within 3 months, improvement, defined as doubling of the walking distance, cessation of rest pain or healing of ulcers, occurred in 30.3% of cases. No change was observed in 45.4% of cases and 24.3% of cases deteriorated. Patients with ulcers or gangrene had significantly poorer results than those without any ischaemic lesions, as only 19% versus 39% of patients improved (P < 0.05). The presence of hypertension, diabetes mellitus, hyperlipidaemia and smoking had no value in predicting clinical outcome (P > 0.05). There were no major complications noted. CT fluoroscopy‐guided chemical lumbar sympathectomy is safe and effective, with a complication rate of less than 1%, and efficacy of at least 30% measured within 3 months. It is a simple and minimally invasive procedure, easily performed on an outpatient basis. CT fluoroscopy‐guided chemical lumbar sympathectomy should be considered for all patients in the early stages of inoperable PVD.