Delayed onset of brain edema and mislocalization of aquaporin-4 in dystrophin-null transgenic mice

Cerebral water accumulation was studied during induction of brain edema in dystrophin-null transgenic mice (mdx-betageo) and control mice. Immunofluorescence and immunoelectron microscopic analyses of dystrophin-null brains revealed a dramatic reduction of AQP4 (aquaporin-4) in astroglial end-feet surrounding capillaries (blood-brain barrier) and at the glia limitans (cerebrospinal fluid-brain interface). The AQP4 protein is mislocalized, because immunoblotting showed that the total AQP4 protein abundance was unaltered. Brain edema was induced by i.p. injection of distilled water and 8-deamino-arginine vasopressin. Changes in cerebral water compartments were assessed by diffusion-weighted MRI with determination of the apparent diffusion coefficient (ADC). In dystrophin-null mice and control mice, ADC gradually decreased by 5-6% from baseline levels during the first 35 min, indicating the initial phase of intracellular water accumulation is similar in the two groups. At this point, the control mice sustained an abrupt, rapid decline in ADC to 58% +/- 2.2% of the baseline at 52.5 min, and all of the animals were dead by 56 min. After a consistent delay, the dystrophin-null mice sustained a similar decline in ADC to 55% +/- 3.4% at 66.5 min, when all of the mice were dead. These results demonstrate that dystrophin is necessary for polarized distribution of AQP4 protein in brain where facilitated movements of water occur across the blood-brain barrier and cerebrospinal fluid-brain interface. Moreover, these results predict that interference with the subcellular localization of AQP4 may have therapeutic potential for delaying the onset of impending brain edema.     

Blood pressure control during telemonitoring of home blood pressure. A randomized controlled trial during 6 months

AIM: To compare the effectiveness of antihypertensive treatment based on telemonitoring of home blood pressure (BP) and conventional monitoring of office BP. METHODS: Hypertensive patients (n = 236) participated in a randomized, controlled study. In the intervention group, antihypertensive treatment was based on home BP monitoring. BP readings were registered by a PDA and automatically transmitted to a server, by which the patient and doctor could communicate. In the control group, patients received usual care with office visits to adjust antihypertensive treatment as needed. Primary outcome was difference in systolic daytime ambulatory BP monitoring (ABPM) change between baseline and 6 months. RESULTS: In both groups, systolic daytime ABPM decreased significantly from baseline to follow-up. The decrease in systolic daytime ABPM was -11.9 mmHg in the intervention group and -9.6 mmHg in the control group (mean difference -2.3 [95% CI -6.1 to -1.5], p = 0.225). The likelihood of daytime ABPM normalization was similar in the two groups [32/113 (28%) vs 46/123 (37%), p = 0.139]. CONCLUSION: Antihypertensive treatment based on telemonitoring of home BP was as effective as usual monitoring of office BP with regards to reduction of BP.     

The relationship between gallbladder dynamics and the migrating motor complex in fasting healthy subjects

The relationship between gallbladder dynamics and the interdigestive migrating motor complex (MMC) was investigated in 10 healthy male volunteers by a hepatobiliary scintigraphy and gastroduodenal pressure recordings. Filling of the gallbladder commenced in late phase II or in phase III of the MMC and continued in a linear fashion during the following phase I. Simultaneously, an abrupt decrease in delivery of activity into the duodenum was encountered. Emptying of the gallbladder always occurred in phase II and lasted 14-46 min (median, 30 min). The transformation from filling to emptying of the gallbladder was closely related to changes from phase I to II on the motility curve.     

Gallbladder emptying and gastrointestinal cyclic motor activity in humans

The purpose of the present work was to answer two questions: does the human gallbladder empty in the fasting state, and, if so, is the emptying related to a specific phase of the activity in the gastrointestinal tract? The material consisted of nine healthy volunteers and the motility recordings were done with a perfused low-compliance system. Gallbladder emptying was recorded by the use of scintigraphy with 99mTc-HIDA. Eleven activity fronts were observed, and seven periods of gallbladder emptying were recorded. Reduction in counts over the gallbladder ranged from 8% to 32%. All emptyings took place in connection with phase-II activity in the intestine. Three were in close proximity to the following phase-III activity, and the other four occurred early in a phase II. Four activity fronts were not accompanied by output of bile. Conclusions: bile output from the gallbladder occurs in fasting humans, and gallbladder emptying takes place in connection with phase-II activity in the intestine but not always in close connection with the following phase-III activity.     

Relation of left ventricular geometry and function to systemic hemodynamics in hypertension: the LIFE Study. Losartan Intervention For Endpoint Reduction in Hypertension Study

OBJECTIVES: To clarify the relations of systemic hemodynamics to left ventricular (LV) geometric patterns in patients with moderate hypertension and target organ damage. BACKGROUND: LV geometry stratifies risk in hypertension, but relations of LV geometry to systemic hemodynamic patterns in moderately severe hypertension have not been fully elucidated. DESIGN: Cross-sectional case-control study. SETTING: Baseline findings in the echocardiographic substudy of the Losartan Intervention For Endpoint Reduction in Hypertension Study (LIFE) and in a normotensive reference group. PATIENTS/PARTICIPANTS: Nine hundred and sixty-four patients with Stage I-II hypertension and LV hypertrophy by Cornell voltage duration criteria ((SV3 + RaVL [+ 6 mm in women]) x QRS > 2440 mm x ms) or modified Sokolow- Lyon voltage criteria (SV1 + RV5/RV6 > 38 mm), and 366 apparently normal adults. INTERVENTIONS: None. METHODS: Two-dimensional and Doppler echocardiograms were used to classify hypertensive patients into groups with normal geometry, concentric remodelling and concentric and eccentric hypertrophy, and to measure stroke volume (SV), cardiac output, peripheral resistance and pulse pressure/SV as a measure of arterial stiffness. Comparisons were adjusted for covariates by general linear model with the Sidak post-hoc test RESULTS: Mean SV was higher in patients with eccentric hypertrophy (83 ml/beat) and lower with concentric remodeling (68 ml/beat) than in normal adults (73 ml/ beat). Cardiac output was highest in patients with eccentric LV hypertrophy and lower with concentric remodeling than eccentric hypertrophy; mean pressure and peripheral resistance were equally high in all hypertensive subgroups, whereas pulse pressure/SV was most elevated (by a mean of 47% versus reference subjects) with concentric remodeling and least so (mean + 15%) with eccentric hypertrophy. In multivariate analysis (Multiple R + 0.68), LV mass was independently related to higher systolic pressure, older age, SV, male gender and body mass index (all P< 0.001). Relative wall thickness was independently related (Multiple R + 0.50) to older age, higher systolic pressure, lower SV (all P< 0.001) and higher body mass index (P + 0.007). SV and cardiac output were lower in patients with low stress-corrected midwall shortening. CONCLUSION: In patients with moderate hypertension and ECG LV hypertrophy, the levels of SV and pulse pressure/ SV, are associated with, and may be stimuli to different LV geometric phenotypes.     

HIV neutralizing antibodies: development and association with HIV related disease

Serum neutralization was measured in 72 sera collected during a 5.5-year period from 10 HIV infected individuals. Neutralizing antibodies (NA) were present in all sera. NA titers ranging from greater than 40 to greater than 640 were detected in sera from 4 patients, who all remained healthy and further an increase with time of NA was observed in these 4 patients. Progression to disease was observed in 3 persons with NA titers less than or equal to 40 who also lacked or lost anti-gag antibodies. Two of these patients were HIV antigenaemic prior to development of disease, whereas antigen was not detected in the remaining 7 healthy persons. A weak positive correlation (R(S) = +0.643, p less than 0.001) was found between titers of NA and whole virus antibody (WVA), with the ratios between titers (NA titer/WVA titer) varying a 100-fold. The results suggest that the presence of NA in some cases might be related to a healthy carrier state and that a combination of low titer NA with decline of anti-gag antibodies and/or HIV antigenaemia is associated with progression to clinical disease.     

Updating prognosis and therapeutic effect evaluation in cirrhosis with Cox's multiple regression model for time-dependent variables

A multivariate Cox regression analysis with time-dependent variables has been performed on the data of 415 patients with cirrhosis included in a controlled clinical trial of 10-15 mg prednisone daily versus placebo. The analysis showed that a poor prognosis was associated with a low prothrombin index, marked ascites, GI bleeding, high age, high daily alcohol consumption, high bilirubin and alkaline phosphatase and low albumin values, little liver connective tissue inflammation, and poor nutritional status. Prothrombin index and ascites showed significant interaction with the treatment in such a manner that high prothrombin index and absence of ascites were associated with a beneficial effect of prednisone, whereas low prothrombin index and presence of ascites were associated with a harmful effect of prednisone treatment. The final model was validated in independent patients by comparing their actual survival with that predicted from the model, using a split-sample testing technique. The prognostic factors were combined with an index that can be used to update prognosis whenever changes occur in the clinical status of a patient during the course of the disease. The probability of surviving the next 3 or 6 months can be estimated from the prognostic index at any time during the course. The index may be of value for the correct timing of special therapeutic procedures such as liver transplantation.     

Immediate and prolonged clinical efficacy of ceftazidime versus ceftazidime plus tobramycin in chronic Pseudomonas aeruginosa infection in cystic fibrosis

20 patients with cystic fibrosis and chronic bronchopulmonary infection due to Pseudomonas aeruginosa entered a randomized cross-over study comparing ceftazidime (150 mg/kg body weight/24 h) plus tobramycin (10 mg/kg body weight/24 h) to ceftazidime alone (150 mg/kg body weight/24 h), both given intravenously for 2 weeks. 17 patients completed the study; both treatment regimens improved lung function and decreased the WBC count. No difference in clinical efficacy was found between the treatments. Pulmonary function returned to pre-treatment levels 3 months later with no difference between the treatments. No changes were seen in minimal inhibitory concentrations during treatment. None of the patients developed hypersensitivity or experienced serious adverse reactions to the drugs.