Gastric Emptying of Solid Meal in Male Chronic Alcoholics

Nausea and vomiting are common complaints in chronic alcoholics. Autonomic neuropathy and esophageal motor abnormalities are frequently observed in chronic alcoholics, but gastric emptying has not been studied in these patients. Gastric emptying of a solid meal was measured, using 99mTc-sulfur colloid cooked in a scrambled egg, in 10 male chronic alcoholics with upper gastrointestinal complaints of nausea and vomiting. All patients were adequately nourished, recently drinking, but just over withdrawal and free of clinical peripheral neuropathy. Gastric emptying in 10 alcoholics was similar to 5 normal controls (t 1/2 115 +/- 12 versus 107 +/- 8 min). These data suggest that upper gastrointestinal symptoms in chronic alcoholics are not related to gastric motor dysfunction.     

Measurements of pulmonary mechanics prior to the elective extubation of neonates

We measured total respiratory system compliance (CRS) and resistance (RRS) by the passive expiratory flow technique prior to the elective extubation of 61 neonates with a history of respiratory distress syndrome. Successful trials of extubation were characterized by a higher mean value of CRS when compared to trials that led to reintubation (1.52 vs. 1.10 mL/cm H2O, P = 0.004). Low values of CRS (0.9 mL/cm H2O or less) were invariably associated with extubation failure, whereas high values of CRS (1.3 mL/cm H2O or greater) were associated with extubation success in 94% of patients. A higher mean value of RRS was recorded in the group of infants who failed extubation when compared to those who were successful (0.22 vs. 0.17 cm H2O/mL/s, P = 0.042). We propose that measurements of pulmonary mechanics, particularly CRS, may be useful in identifying infants who will be at risk for extubation failure.     

Prevalence of Hypertension in Patients with Type II Diabetes in Referral versus Primary Care Clinics

We compared the prevalence of hypertension in patients with non–insulin-dependent diabetes mellitus (NIDDM) in referral and primary care practices using definitions of The Fifth Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC-V), while controlling for other risk factors such as hypertension, obesity, smoking, and age. Patients (n = 1443) were enrolled consecutively from a large referral practice at the Jackson Diabetes Center and four primary care clinics in the vicinity. Blood pressures were measured at three clinic visits after a 5-min rest in a sitting position using a standard clinical sphygmomanometer. Charts were reviewed to determine diabetes duration, insulin usage, height, weight, smoking history, use of antihypertensive and oral hypoglycemic medications, socioeconomic status, and race. Patients were classified as hypertensive based on JNC-V definitions or if they were on antihypertensive medication. Hypertension was termed uncontrolled if blood pressure was JNC-V Stage 2 or higher while on antihypertensive medication.

Seventy-eight percent of referral clinic and 55% of primary care clinic patients had either JNC-V State 1 or higher hypertension or were on antihypertensive medication. Actual blood pressures indicated that more patients had JNC-V Stage 1 (mild) or higher hypertension in referral compared to primary care clinics (62% versus 48% p = 0.01) but fewer had JNC-V Stage 2 or higher (moderate-severe) hypertension (12% versus 19% p = 0.002). Patients seen in the referral clinic were significantly more likely to have greater age, greater duration of diabetes, higher insulin dosage, longer smoking history, antihypertensive medication, and live outside the metropolitan area. By logistic regression, the odds of hypertension were significantly increased with age (OR 1.51/decade), BMI greater than 27 (OR 2.17), diabetes duration (OR 1.04/year), and insulin dosage (OR 1.74/U/kg). Current smoking and attending a referral clinic were not significantly related. The odds of moderate-severe hypertension were significantly increased with age (OR 1.23/decade), decreased by attending a referral clinic (OR 0.45), and not significantly related to other confounders in the model.

The prevalence of hypertension among patients with NIDDM was higher in referral than primary care clinics. The higher prevalence in the referral practice can be accounted for by the greater severity of associated risk factors in the referral practice patients; however, most patients will be diagnosed and treated for hypertension prior to referral. More patients in the referral practice were on hypertensive medication, which lowered the stage or severity of hypertension but still not to the normal range. The results suggest that the primary detection of hypertension in patients with type II diabetes resides with the primary care physician. Management of hypertension will require both a delineation and acceptance of responsibilities between the primary care physician and diabetes specialists.     

Calpains promote neutrophil recruitment and bacterial clearance in an acute bacterial peritonitis model

Activation of the innate immune system is critical for clearance of bacterial pathogens to limit systemic infections and host tissue damage. Here, we report a key role for calpain proteases in bacterial clearance in mice with acute peritonitis. Using transgenic mice expressing Cre recombinase primarily in innate immune cells (fes‐Cre), we generated conditional capns1 knockout mice. Consistent with capns1 being essential for stability and function of the ubiquitous calpains (calpain‐1, calpain‐2), peritoneal cells from these mice had reduced levels of calpain‐2/capns1, and reduced proteolysis of their substrate selenoprotein K. Using an acute bacterial peritonitis model, we observed impaired bacterial killing within the peritoneum and development of bacteremia in calpain knockout mice. These defects correlated with significant reductions in IL‐1α release, neutrophil recruitment, and generation of reactive oxygen species in calpain knockout mice with acute bacterial peritonitis. Peritoneal macrophages from calpain knockout mice infected with enterobacteria ex vivo, were competent in phagocytosis of bacteria, but showed impaired clearance of intracellular bacteria compared with control macrophages. Together, these results implicate calpains as key mediators of effective innate immune responses to acute bacterial infections, to prevent systemic dissemination of bacteria that can lead to sepsis.     

A calcium-dependent protease as a potential therapeutic target for Wolfram syndrome

Wolfram syndrome is a genetic disorder characterized by diabetes and neurodegeneration and considered as an endoplasmic reticulum (ER) disease. Despite the underlying importance of ER dysfunction in Wolfram syndrome and the identification of two causative genes, Wolfram syndrome 1 (WFS1) and Wolfram syndrome 2 (WFS2), a molecular mechanism linking the ER to death of neurons and β cells has not been elucidated. Here we implicate calpain 2 in the mechanism of cell death in Wolfram syndrome. Calpain 2 is negatively regulated by WFS2, and elevated activation of calpain 2 by WFS2-knockdown correlates with cell death. Calpain activation is also induced by high cytosolic calcium mediated by the loss of function of WFS1. Calpain hyperactivation is observed in the WFS1 knockout mouse as well as in neural progenitor cells derived from induced pluripotent stem (iPS) cells of Wolfram syndrome patients. A small-scale small-molecule screen targeting ER calcium homeostasis reveals that dantrolene can prevent cell death in neural progenitor cells derived from Wolfram syndrome iPS cells. Our results demonstrate that calpain and the pathway leading its activation provides potential therapeutic targets for Wolfram syndrome and other ER diseases.The endoplasmic reticulum (ER) takes center stage for protein production, redox regulation, calcium homeostasis, and cell death (1, 2). It follows that genetic or acquired ER dysfunction can trigger a variety of common diseases, including neurodegenerative diseases, metabolic disorders, and inflammatory bowel disease (3, 4). Breakdown in ER function is also associated with genetic disorders such as Wolfram syndrome (5–8). It is challenging to determine the exact effects of ER dysfunction on the fate of affected cells in common diseases with polygenic and multifactorial etiologies. In contrast, we reasoned that it should be possible to define the role of ER dysfunction in mechanistically homogenous patient populations, especially in rare diseases with a monogenic basis, such as Wolfram syndrome (9).Wolfram syndrome (OMIM 222300) is a rare autosomal recessive disorder characterized by juvenile-onset diabetes mellitus and bilateral optic atrophy (7). Insulin-dependent diabetes usually occurs as the initial manifestation during the first decade of life, whereas the diagnosis of Wolfram syndrome is invariably later, with onset of symptoms in the second and ensuing decades (7, 10, 11). Two causative genes for this genetic disorder have been identified and named Wolfram syndrome 1 (WFS1) and Wolfram syndrome 2 (WFS2) (12, 13). It has been shown that multiple mutations in the WFS1 gene, as well as a specific mutation in the WFS2 gene, lead to β cell death and neurodegeneration through ER and mitochondrial dysfunction (5, 6, 14–16). WFS1 gene variants are also associated with a risk of type 2 diabetes (17). Moreover, a specific WFS1 variant can cause autosomal dominant diabetes (18), raising the possibility that this rare disorder is relevant to common molecular mechanisms altered in diabetes and other human chronic diseases in which ER dysfunction is involved.Despite the underlying importance of ER malfunction in Wolfram syndrome, and the identification of WFS1 and WFS2 genes, a molecular mechanism linking the ER to death of neurons and β cells has not been elucidated. Here we show that the calpain protease provides a mechanistic link between the ER and death of neurons and β cells in Wolfram syndrome.