Platelet storage pool deficiency in pigs

We report a new bleeding disease--storage pool deficiency (SPD) of platelets--in pigs from the Mayo swine colony of homozygous von Willebrand's disease (vWD) and of heterozygous carriers of vWD. Levels of factor VIII, von Willebrand factor antigen (vWF:Ag), and ristocetin cofactor (RCof) were similar in the vWD carriers and SPD pigs. The latter pigs, however, had bleeding times of 15 minutes or more and were severe bleeders, in contrast to clinically normal vWD carriers. Platelet aggregation in response to collagen was reduced in most SPD pigs. Total platelet content of ADP, ATP, and serotonin was less than that of normal pigs. While the initial uptake of 14C-labeled serotonin into platelets was similar in SPD and normal pigs, retention of serotonin was reduced in platelets of SPD pigs. Transmission electron microscopy showed a large decrease of dense bodies in the platelets of SPD pigs. These findings support a diagnosis of SPD. Genetic analyses suggest an autosomal recessive mode of inheritance. A breeding program is under way to produce pigs affected only at the SPD gene, thus allowing further characterization of SPD and SPD-carrier pigs.     

Molecular basis of the heterogeneity of expression of glycosyl phosphatidylinositol anchored proteins in paroxysmal nocturnal hemoglobinuria

The purpose of these studies was to determine the molecular basis of the phenotypic mosaicism that is a defining feature of paroxysmal nocturnal hemoglobinuria (PNH). Analysis of T cell clones from a female patient revealed four distinct phenotypes based on surface expression of glycosyl phosphatidylinositol-anchored proteins (GPI-AP). When PIG-A (the gene that is mutant in PNH) from these clones was analyzed, four discrete somatic mutations were identified. Analysis of X chromosomal inactivation among the abnormal T cell clones was consistent with polyclonality. Together, these studies demonstrate that the phenotypic mosaicism that is characteristic of PNH is a consequence of genotypic mosaicism and that, at least in this case, PNH is a polyclonal rather than a monoclonal disease. That four distinct somatic mutations were present in a single patient suggests that in conditions that predispose to PNH PIG-A may be hypermutable.     

Alpha 4 beta 1-integrin expression on sickle reticulocytes: vascular cell adhesion molecule-1-dependent binding to endothelium

Important complications in sickle cell anemia occur secondary to vascular occlusion, which is postulated to be initiated by interactions of erythrocytes with vascular endothelial cells. In patients with sickle cell anemia, up to 25% of reticulocytes express the alpha 4 beta 1-integrin complex. Furthermore, erythrocytes from patients with sickle cell anemia bind to endothelial cells activated by tumor necrosis factor alpha via (TNF alpha) via interactions between erythrocyte alpha 4 beta 1 and endothelial cell vascular cell adhesion molecule-1 (VCAM- 1). Thus, binding of alpha 4 beta 1-expressing reticulocytes to cytokine-activated endothelial cells may initiate vascular complications in sickle cell anemia and perhaps other hemolytic anemias during episodes of infection and inflammation.     

Diabetic status and the relation of the three domains of glycemic control to mortality in critically ill patients: an international multicenter cohort study

Introduction

Hyperglycemia, hypoglycemia, and increased glycemic variability have each been independently associated with increased risk of mortality in critically ill patients. The role of diabetic status on modulating the relation of these three domains of glycemic control with mortality remains uncertain. The purpose of this investigation was to determine how diabetic status affects the relation of hyperglycemia, hypoglycemia, and increased glycemic variability with the risk of mortality in critically ill patients.

Methods

This is a retrospective analysis of prospectively collected data involving 44,964 patients admitted to 23 intensive care units (ICUs) from nine countries, between February 2001 and May 2012. We analyzed mean blood glucose concentration (BG), coefficient of variation (CV), and minimal BG and created multivariable models to analyze their independent association with mortality. Patients were stratified according to the diagnosis of diabetes.

Results

Among patients without diabetes, mean BG bands between 80 and 140 mg/dl were independently associated with decreased risk of mortality, and mean BG bands >140 mg/dl, with increased risk of mortality. Among patients with diabetes, mean BG from 80 to 110 mg/dl was associated with increased risk of mortality and mean BG from 110 to 180 mg/dl with decreased risk of mortality. An effect of center was noted on the relation between mean BG and mortality. Hypoglycemia, defined as minimum BG <70 mg/dl, was independently associated with increased risk of mortality among patients with and without diabetes and increased glycemic variability, defined as CV >20%, was independently associated with increased risk of mortality only among patients without diabetes. Derangements of more than one domain of glycemic control had a cumulative association with mortality, especially for patients without diabetes.

Conclusions

Although hyperglycemia, hypoglycemia, and increased glycemic variability is each independently associated with mortality in critically ill patients, diabetic status modulates these relations in clinically important ways. Our findings suggest that patients with diabetes may benefit from higher glucose target ranges than will those without diabetes. Additionally, hypoglycemia is independently associated with increased risk of mortality regardless of the patient''s diabetic status, and increased glycemic variability is independently associated with increased risk of mortality among patients without diabetes.See related commentary by Krinsley, http://ccforum.com/content/17/2/131See related commentary by Finfer and Billot, http://ccforum.com/content/17/2/134     

Postappendectomy fluid collections in children: incidence, nature, and evolution evaluated using US

At the authors' medical center, most patients with postappendectomy fluid collections are treated conservatively. Thirty-two (15%) of 216 children underwent postoperative sonography following appendectomies. In ten patients (31%), a total of 16 fluid collections were found on the initial postoperative sonogram. In the seven patients (70%) whose fluid collections were confined to the pelvis, the condition was treated conservatively and it resolved in 2-9 weeks. In three patients, fluid collections required surgical drainage and proved to be abscesses. In two of the three patients, abscesses were multiple and widely distributed in the abdomen, and the patients were clinically ill. The authors conclude that clinically symptomatic fluid collections develop postoperatively in approximately 5% of children who have undergone appendectomy for acute appendicitis and that the size and course of the fluid collection can be objectively monitored using sonography. Such fluid collections confined to the pelvis ultimately resolve with conservative, nonoperative therapy, although resolution may take up to 2 months.     

Folic acid nutrition in marasmic infants

To determine the prevalence of low folic acid levels in infants with marasmic malnutrition and to study its response to daily supplements of folic acid, a group of 80 malnourished infants 2 to 22 months of age were studied. In 12.5% of the group, serum folic acid levels were under 3ug/l and in 16.3%, red cell folic acid levels were under 140ug/l. In a sub group of 28 infants we determined the levels of folic acid on admission and discharge from a nutritional recovery center. During their hospital stay (median 117 days with a range of 94 to 130) infants received exclusively cow's milk with a daily supplement of 100ug of folic acid. On discharge, a significant increase of serum folic levels to normal values was observed. A similar improvement, but not to the same extent, was appreciated in red cell folates. Inadequate quantity of supplementation or short time of observation could explain the lack of complete correction in the erythrocyte folic concentration.     

A Third world international health elective for U.S. medical students. The 16-year experience of the State University of New York,Health Science Center at Brooklyn

The Department of Preventive Medicine and Community Health at the State University of New York, Health Science Center at Brooklyn (SUNY, HSCB) instituted an eight-week third world international health elective for fourth year medical students in 1980. Since that time, ninety students have participated. The purposes of this elective are to provide fourth year medical students with an opportunity to observe and study the structure and functions of a health care delivery system in a third world country, to provide medical service, and to have a crosscultural experience. The emphasis in this elective is on public health, preventive medicine, and primary care. There is a high level of student competition for this elective, with 46.9% of applicants having been accepted over a fifteen-year period. Although women comprise 40% of the average medical school class, they represent 50% of participants in this elective program. The percentage of African-American and Hispanic students has been 20%. These two minority groups represented from 8% to 10% of the student body during the period under study. Careful screening, including an examination of academic records and personal interviews, has resulted in the selection of highly motivated, adaptable, and dedicated students who have performed well at overseas sites. Student satisfaction levels with this elective are extremely high, with most rating it the best experience of their medical school years. Students undergo extensive preparation prior to going overseas. This covers issues related to individual health and safety, travel and lodging, and the nature of the host country culture, health care system, and assignment site. Our students are especially experienced at cross-cultural understanding because of the unusual diversity of the patients they treat in Brooklyn, and the ethnic diversity of local hospital staffs and the medical school class. This Brooklyn experience in cross-cultural understanding has been cited by many participants as having been the best preparation for functioning in a foreign culture. The Alumni Fund of the College of Medicine has strongly and consistently supported this elective both with philosophical commitment and financial grants to help defray travel costs. This type of support is unusual among medical schools in New York City. Overseas preceptors have willingly given of their time and institutional resources to make these experiences available and meaningful for students.