Factor V deficiency in Philadelphia-positive chronic myelogenous leukemia

Factor V deficiency has been identified in 8 of 8 patients 7--20 yr of age, with Philadelphia-positive (Ph1+) chronic myelogenous leukemia (CML). In these 8 patients, factor V deficiency was not due to hepatic dysfunction, factor V inhibitors, or disseminated intravascular coagulation. In 3 patients, factor V activity rose 10%--12% (0.10--0.12 U/ml) after the infusion of 28--31 ml/kg body weight of fresh frozen plasma (FFP). The rise persisted less than 14 hr. The mean measured postinfusion rise in factor V was 18% of the expected rise calculated from the volume of FFP infused in the patients' plasma volume. In 4 patients, a small transient rise in factor V activity occurred after splenectomy or plateletpheresis. Factor V deficiency was completely corrected after a marked reduction in bone marrow cellularity in 2 patients with Ph1+ CML treated with extensive chemotherapy, total body irradiation, and bone marrow transplantation. Factor V deficiency was retrospectively observed in 6 of 20 patients, ages 20--80 yr, with Ph1+ CML and 3 of 6 patients with other myeloproliferative disorders. The factor V deficiency appears to be associated with the large myeloid- megakaryocytic cell mass characteristic of CML and other myeloproliferative disorders.     

The immunobiology of colitis and cholangitis in interleukin-23p19 and interleukin-17a deleted dominant negative form of transforming growth factor beta receptor type ii mice

Dominant negative form of transforming growth factor beta receptor type II (dnTGFβRII) mice, expressing a dominant negative form of TGFβ receptor II under control of the CD4 promoter, develop autoimmune colitis and cholangitis. Deficiency in interleukin (IL)-12p40 lead to a marked diminution of inflammation in both the colon and the liver. To distinguish whether IL-12p40 mediates protection by the IL-12 or IL-23 pathways, we generated an IL-23p19(-/-) dnTGFβRII strain deficient in IL-23, but not in IL-12; mice were longitudinally followed for changes in the natural history of disease and immune responses. Interestingly, IL-23p19(-/-) mice demonstrate dramatic improvement in their colitis, but no changes in biliary pathology; mice also manifest reduced T-helper (Th)17 cell populations and unchanged IFN-γ levels. We submit that the IL-12/Th1 pathway is essential for biliary disease pathogenesis, whereas the IL-23/Th17 pathway mediates colitis. To further assess the mechanism of the IL-23-mediated protection from colitis, we generated an IL-17A(-/-) dnTGFβRII strain deficient in IL-17, a major effector cytokine produced by IL-23-dependent Th17 cells. Deletion of the IL-17A gene did not affect the severity of either cholangitis or colitis, suggesting that the IL-23/Th17 pathway contributes to colon disease in an IL-17-independent manner. These results affirm that the IL-12/Th1 pathway is critical to biliary pathology in dnTGFβRII mice, whereas colitis is caused by a direct effect of IL-23. (HEPATOLOGY 2012).     

Apnea Diving: Long-Term Neurocognitive Sequelae of Repeated Hypoxemia

ABSTRACT

This article examines the neurocognitive sequelae of repeated exposure to hypoxemia in apnea (breath-hold) divers. A brief review of the literature on the physiological and neurological adaptations involved in the “human diving reflex” is presented. The results from a neuropsychological investigation of N = 21 elite apnea divers are evaluated. Standard neuropsychological tests, with known sensitivity to mild brain insults, included speed of visuo-motor responding, speed of language comprehension, response inhibition, and visual and verbal attention and recall tasks. Results indicated that the breath-hold divers performed tasks within the average range compared to norms on all tests, suggesting that 1–20 years of repeated exposure to hypoxemia including multiple adverse neurological events did not impact on performance on standard neuropsychological tasks. The results are discussed in relation to implications for clinical conditions such as sleep apnea, respiratory disorders, altitude sickness, and recreational apnea activities.     

Metabolic clearance and secretion rates of subunits of human thyrotropin.

Metabolic clearance rates (MCR) of the alpha and beta subunits of human thyrotropin (hTSH-alpha and hTSH-beta) were determined by a constant infusion to equilibrium method. In 15 normal individuals (six men, six premenopausal women, and three post-menopausal women), the mean MCR of hTSH-alpha (68 ml/min per m2) was significantly faster than that of hTSH-beta (48 ml/min per m2) was significantly faster than that of hTSH-beta (48 ml/min per m2); both were two to three times more rapid than the previously determined MCR of hTSH. In patients with primary hypothyroidism, MCR were significantly slower with a mean value of 55 ml/min per m2 for hTSH-alpha and 37 ml/min per m2 for hTSH-beta. However, MCR of subunits were not significantly faster than normal in hyperthyroid patients. Serum concentrations of alpha subunits and hTSH-beta were measured by radioimmunoassay, and secretion rates of alpha and hTSH-beta from the pituitary were calculated using hTSH-alpha and hTSH-beta MCR, respectively. In the normal individuals, alpha secretion rates averaged 91 mug/day per m2, greater than those previously determined for hTSH and human follicle-stimulating hormone. Alpha secretion rates were significantly elevated in the normal postmenopausal women (211 mug/day per m2) and in the premenopausal hypothyroid women (202 mug/day per m2); they were also elevated in the postmenopausal hypothyroid women (277 mug/day per m2). Alpha secretion rates were significantly decreased in the premenopausal hyperthyroid women (66 mug/day per m2). Usually, the secretion rates of hTSH-beta could not be calculated in normal individuals, and the rates in hyperthyroid patients could never be calculated because serum hTSH-beta was not detected. Six normals had detectable hTSH-beta secretion rates (17 mug/day per m2); hTSH-beta secretion rates were significantly increased in patients with primary hypothyroidism (28 mug/day per m2). Although we had previously demonstrated a 50-fold increase in hTSH secretion rates in primary hypothyroidism, there was only a 2-fold increase in alpha and hTSH-beta secretion rates. Thus, increased subunit synthesis appears to be utilized predominantly for production of complete hTSH.     

The use of intermittent pneumatic compression of the thigh to affect arterial and venous blood flow proximal to a chronic wound site

Intermittent pneumatic compression of the lower limbs has been shown to have beneficial effects in patients with chronic ulceration. However, the intermittent compression cuff will normally be applied over the wound, which may produce discomfort or interfere with other treatments. Thigh‐only approaches to intermittent pneumatic compression could solve this problem. This study aimed to demonstrate if such a system would have positive effects on venous and arterial blood flow distal to the compression site, but proximal to wound sites. The distal venous and arterial effects of a prototype thigh‐only 3‐chamber sequential intermittent pneumatic compression system were tested in 20 healthy volunteers, and 13 patients with ulcers of various aetiologies using Doppler ultrasound. The system produced hyperaemic responses in the arterial flow of both test groups. The peak venous velocity on deflation of the first and second chambers of the cuff was also greater in the patients with ulceration than in the healthy volunteers (11.6 cm/s vs 8.3 cm/s, P = .1). This work demonstrates that compression of the thigh alone can produce positive haemodynamic effects in the calves of patients with chronic wounds, and that this approach should be investigated as a therapy to improve blood flow to wound sites.     

Natural killer T cells exacerbate liver injury in a transforming growth factor beta receptor II dominant-negative mouse model of primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is an organ-specific autoimmune liver disease characterized by the presence of antimitochondrial antibodies and the destruction of small intrahepatic bile ducts with portal inflammation. In previous studies, we reported that both CD1d expression and the frequency of CD1d-restricted natural killer T (NKT) cells were increased in the livers of patients with PBC. To define a specific role of CD1d-restricted NKT cells in the pathogenesis of PBC, particularly early events, we investigated the function of hepatic CD1d-restricted NKT cells in our transforming growth factor beta (TGF-beta) receptor II dominant-negative (dnTGFbetaRII) mouse model of PBC. We generated CD1d(-/-) and CD1d(+/-) dnTGFbetaRII mice and performed a comparative study of liver immunopathology. We report herein that these dnTGFbetaRII mice demonstrate a massive increase of hyperactive CD1d-restricted NKT cells within the hepatic tissues. CD1d(-/-)dnTGFbetaRII mice, which lack CD1d-restricted CD1d-restricted NKT cells, exhibit significantly decreased hepatic lymphoid cell infiltrates and milder cholangitis compared with CD1d(+/-)dnTGFbetaRII mice. Interestingly, there was a significant increase in the production of interferon-gamma in hepatic CD1d-restricted NKT cells activated by alpha-galactosylceramide in young but not older dnTGFbetaRII mice, suggesting an age-dependent role of CD1d-restricted NKT cells. CONCLUSION: These data demonstrate that CD1d-restricted NKT cells in dnTGFbetaRII mice are a critical factor in liver injury.     

Bleaching susceptibility and mortality of corals are determined by fine-scale differences in symbiont type

Coral bleaching has been identified as one of the major contributors to coral reef decline, and the occurrence of different symbionts determined by broad genetic groupings (clades A–H) is commonly used to explain thermal responses of reef-building corals. By using Stylophora pistillata as a model, we monitored individual tagged colonies in situ over a two-year period and show that fine level genetic variability within clade C is correlated to differences in bleaching susceptibility. Based on denaturing gradient gel electrophoresis of the internal transcribed spacer region 2, visual bleaching assessments, symbiont densities, host protein, and pulse amplitude modulated fluorometry, we show that subcladal types C78 and C8/a are more thermally tolerant than C79 and C35/a, which suffered significant bleaching and postbleaching mortality. Although additional symbiont types were detected during bleaching in colonies harboring types C79 and C35/a, all colonies reverted back to their original symbionts postbleaching. Most importantly, the data propose that the differential mortality of hosts harboring thermally sensitive versus resistant symbionts rather than symbiont shuffling/switching within a single host is responsible for the observed symbiont composition changes of coral communities after bleaching. This study therefore highlights that the use of broad cladal designations may not be suitable to describe differences in bleaching susceptibility, and that differential mortality results in a loss of both symbiont and host genetic diversity and therefore represents an important mechanism in explaining how coral reef communities may respond to changing conditions.