Pulmonary hypertension (PH) adversely affects outcome in sarcoidosis and is an important predictor of mortality in these patients. Early and accurate diagnosis of this complication may improve outcome. The current authors hypothesised that integration of 6-min walk test (6MWT) as part of the evaluation leads to an earlier diagnosis of this complication.A total of 162 patients with sarcoidosis underwent 6MWT. Demographic and pulmonary function results were analysed. Patients were further assessed by echocardiography and right heart catheterisation when clinically indicated.Patients with sarcoidosis-associated PH had significantly decreased results on pulmonary function testing. They also walked shorter distances and desaturated to lower levels on 6MWT. On logistic regression analyses, significant predictors of PH were oxygen saturation ,90% on 6MWT (odds ratio (OR) 12.1, 95% confidence interval (CI) 3.66-19.73) and diffusing capacity of the lung for carbon monoxide ,60% predicted (OR 7.3, 95% CI 1.98-24.82). Moreover, by combining the results of oxygen saturation at 6 min with those of echocardiography, the ability to correctly predict the presence of PH by right heart catheterisation was improved.Patients with diffusing capacity of the lung for carbon monoxide ,60% predicted and oxygen desaturation ,90% on 6-min walk test have a high likelihood of pulmonary hypertension and should undergo further evaluation for the presence of this disorder.

BackgroundSarcoidosis is a chronic disease with different phenotypic manifestations. Health-related quality of life is an important aspect in sarcoidosis, yet difficult to measure. The objective of this study was to identify clinical markers predictive of poor quality of life in sarcoidosis patients that can be followed over time and targeted for intervention.MethodsWe assessed the quality of life of 162 patients with confirmed sarcoidosis in a prospective, cross-sectional study using the Sarcoidosis Health Questionnaire (SHQ) and Short Form-36 Health Survey (SF-36). We evaluated the validity of these questionnaires and sought to identify variables that would best explain the performance scores of the patients.ResultsOn multivariate regression analyses, the very best composite model to predict total scores from both surveys was a model containing the distance-saturation product and Borg Dyspnea Scale score at the end of a 6-min walk test. This model could better predict SF-36 scores (R2 = 0.33) than SHQ scores (R2 = 0.24). Substitution of distanced walked in 6 min for the distance-saturation product in this model resulted in a lesser ability to predict both scores (R2 = 0.26 for SF-36; R2 = 0.22 for SHQ).ConclusionsBoth the SHQ and SF-36 surveys are valuable tools in the assessment of health-related quality of life in sarcoidosis patients. The best model to predict quality of life among these patients, as determined by regression analyses, included the distance-saturation product and Borg score after the 6-min walk test. Both variables represent easily obtainable clinical parameters that can be followed over time and targeted for intervention.

Our data indicate that both cigarette smoking and gender are important in shaping the clinical manifestations of sarcoidosis. The nature of the gender difference requires further study and may be related to differences in inflammatory response.

Despite an overall decline in the incidence of tuberculosis (TB), the percentage of cases representing miliary TB has remained stable. We report 2 cases of fatal miliary TB that remained unrecognized until autopsy, occurring within a 6-month period at 1 Detroit institution. These cases represent the wide range of presentation of miliary TB, from an acute fulminant course to a cryptic prolonged course with subtle clinical findings. Both cases shared a common end point with the development of adult respiratory distress syndrome.

Disinhibition during early stages of Alzheimer’s disease is postulated to cause network dysfunction and hyperexcitability leading to cognitive deficits. However, the underlying molecular mechanism remains unknown. Here we show that, in mouse lines carrying Alzheimer’s disease-related mutations, a loss of neuronal membrane potassium-chloride cotransporter KCC2, responsible for maintaining the robustness of GABAA-mediated inhibition, occurs pre-symptomatically in the hippocampus and prefrontal cortex. KCC2 downregulation was inversely correlated with the age-dependent increase in amyloid-β 42 (Aβ42). Acute administration of Aβ42 caused a downregulation of membrane KCC2. Loss of KCC2 resulted in impaired chloride homeostasis. Preventing the decrease in KCC2 using long term treatment with CLP290 protected against deterioration of learning and cortical hyperactivity. In addition, restoring KCC2, using short term CLP290 treatment, following the transporter reduction effectively reversed spatial memory deficits and social dysfunction, linking chloride dysregulation with Alzheimer’s disease-related cognitive decline. These results reveal KCC2 hypofunction as a viable target for treatment of Alzheimer’s disease-related cognitive decline, it confirms target engagement, where the therapeutic intervention takes place, and its effectiveness.

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