Undetectable bcr-abl rearrangements in some CML patients are due to a deletion mutation in the bcr gene

Most patients with chronic myelogenous leukemia (CML) have Philadelphia (Ph) chromosome. Breakpoints on chromosome 22 in CML occur in a small region designated as the breakpoint cluster region (bcr). More than 90 percent of CML patients have breakpoints in the bcr; the remaining patients had no detectable rearrangement. In our study, a commercially available 1.2 kb HindIII-BglII (1.2 HBg) bcr probe was used to locate breakpoints in the bcr, which were found in 22 of 24 patients. Furthermore, using a probe upstream from the 1.2 HBg probe, rearranged bands were clearly detected in the two patients in whom no extra bands had been found with the 1.2 HBg probe. These results strongly suggest that these two patients carry a deletion at the acr-abl recombination point encompassing the area of the 1.2 HBg probe. Therefore, in our series, all CML patients eventually had breakpoints in the bcr, and the involvement of rearrangement was demonstrated to be highly specific for CML. Our data indicate that hybridization of CML cellular DNA with several bcr probes is important in examining accurately the frequency of bcr-abl rearrangements in CML, as some cases contain a deletion within the region.     

Pharmacological LXR activation reduces presence of SR-B1 in liver membranes contributing to LXR-mediated induction of HDL-cholesterol

ObjectivePharmacological LXR activation has anti-atherosclerotic actions in animal models. Part of these beneficial effects may be explained by accelerated reverse cholesterol transport since both plasma high density lipoprotein (HDL) cholesterol and fecal neutral sterol secretion are higher upon LXR activation. Mechanisms underlying these LXR-mediated effects have not been fully elucidated.MethodsWe investigated the roles of the isoforms LXRα and LXRβ and the HDL cholesterol uptake receptor SR-B1 in modulation of cholesterol metabolism upon treatment of mice with the LXR ligand T0901317.ResultsHDL cholesterol was maximally 60% increased in a time-dependent fashion due to appearance of more and larger HDL particles. Fecal neutral sterol secretion was maximally induced after 1 week treatment. T0901317 treatment induced fecal neutral sterol secretion by ～300% in wild-type but not in Lxrα deficient mice. Surprisingly, LXR activation reduced SR-B1 protein amount in hepatic membranes, suggesting that this might contribute to elevated HDL cholesterol. However, T0901317 still elevated plasma HDL cholesterol in Sr-b1 deficient mice, suggesting that SR-B1 is not the only step involved in LXR-mediated induction of plasma HDL cholesterol. In addition, SR-B1 is not essential for LXR-induced cholesterol removal from the body.ConclusionInduction of fecal neutral sterol secretion by T0901317 critically depends on LXRα but not on LXRβ. LXR activation reduces SR-B1 in hepatic membranes, probably partly contributing to elevated HDL cholesterol. SR-B1 is not required to enhance fecal neutral sterol secretion.     

Importance of Dose Timing to Achieving Undetectable Viral Loads

Little is known about the importance of dose timing to successful antiretroviral therapy (ART). In a cohort comprised of Chinese HIV/AIDS patients, we measured adherence among subjects for 6 months using three methods in parallel: self-report using a visual analog scale (SR-VAS), pill count, and electronic drug monitors (EDM). We calculated two adherence metrics using the EDM data. The first metric used the proportion of doses taken; the second metric credited doses as adherent only if taken within a 1-h window of a pre-specified dose time (EDM ‘proportion taken within dose time’). Of the adherence measures, EDM had the strongest associations with viral suppression. Of the two EDM metrics, incorporating dose timing had a stronger association with viral suppression. We conclude that dose timing is also an important determinant of successful ART, and should be considered as an additional dimension to overall adherence.     

Therapeutic approaches to raising plasma HDL-cholesterol levels

Epidemiologic data from the Framingham and Prospective Cardiovascular Munster studies, demonstrating an inverse correlation between the plasma concentration of HDLs and the incidence of cardiovascular disease, have driven research to explore precisely how HDLs confer this cardioprotective effect. HDLs are anti-inflammatory, antithrombogenic and have vasoactive effects, as well as being efficient cholesterol acceptors enabling the removal of cholesterol from peripheral tissues, all functions that are likely to protect the vasculature. The first part of this article will review the clinical evidence in support of the pleiotropic effects of HDLs, along with laboratory-based investigations of the molecular mechanisms of action. As the evidence of clinical benefits of raising plasma HDL concentration has increased, so has the number of strategies currently being considered to achieve this goal. The second part of this article will review three current strategies: infusion of HDL-like products, comparing physicopharmacologic characteristics of the two commercial products currently under trial; the use of fibrates to raise plasma HDLs (although fibrates primarily reduce triglyceride levels, certain derivatives are able to induce significant increases in plasma HDLs); and the use of drugs that inhibit cholesterol ester transfer protein (these drugs increase plasma HDL concentration either alone or as an adjunct therapy with statins). The clinical efficacy and mechanism of action of fibrates and inhibitors of cholesterol ester transfer protein will be reviewed.     

Low HDL-cholesterol: a component of the metabolic syndrome only in the presence of fasting hypertriglyceridemia in type 2 diabetic patients

The relation between isolated low HDL-cholesterol and the components of the metabolic syndrome is poorly known in type 2 diabetes. We evaluated cardiovascular risk parameters in type 2 diabetic patients with low HDL-cholesterol, compared to those with low HDL-cholesterol and hypertriglyceridemia, isolated hypertriglyceridemia and normal lipid parameters. Patients with low HDL-cholesterol/high triglycerides had higher BMI (29.6 +/- 5.7 vs 27.9 +/- 4.4 or vs 28.1 +/- 5.2 kg/m(2) ), prevalence of obesity (69% vs 55% or vs 54%), higher levels of uric acid (339.0 +/- 83.3 vs 303.3 +/- 95.2 or vs 303.3 +/- 89.2 micromol/l) and C-peptide (0.76 +/- 0.40 vs 0.63 +/- 0.33 or vs 0.63 +/- 0.36 nmol/l) and number of components of the metabolic syndrome (27% patients with all the components) compared to patients with isolated low HDL-cholesterol or normal subjects, respectively. A similar pattern of values was evident in patients with isolated hypertriglyceridemia. With logistic regression analysis, BMI and uric acid levels were significantly associated with the presence of hypertriglyceridemia (both isolated or associated with low HDL-cholesterol), while patients with isolated low HDL-cholesterol and those without dyslipidemia displayed a similar more favourable metabolic pattern. These results indicate that low HDL-cholesterol is a component of the metabolic syndrome only in the presence of fasting hypertriglyceridemia in type 2 diabetic patients.     

Selection for Staphylococcus aureus small-colony variants due to growth in the presence of Pseudomonas aeruginosa

Opportunistic infections are often polymicrobial. Two of the most important bacterial opportunistic pathogens of humans, Pseudomonas aeruginosa and Staphylococcus aureus, frequently are coisolated from infections of catheters, endotracheal tubes, skin, eyes, and the respiratory tract, including the airways of people with cystic fibrosis (CF). Here, we show that suppression of S. aureus respiration by a P. aeruginosa exoproduct, 4-hydroxy-2-heptylquinoline-N-oxide (HQNO), protects S. aureus during coculture from killing by commonly used aminoglycoside antibiotics such as tobramycin. Furthermore, prolonged growth of S. aureus with either P. aeruginosa or with physiological concentrations of pure HQNO selects for typical S. aureus small-colony variants (SCVs), well known for stable aminoglycoside resistance and persistence in chronic infections, including those found in CF. We detected HQNO in the sputum of CF patients infected with P. aeruginosa, but not in uninfected patients, suggesting that this HQNO-mediated interspecies interaction occurs in CF airways. Thus, in all coinfections with P. aeruginosa, S. aureus may be underappreciated as a pathogen because of the formation of antibiotic-resistant and difficult to detect small-colony variants. Interspecies microbial interactions, analogous to those mediated by HQNO, commonly may alter not only the course of disease and the response to therapy, but also the population structure of bacterial communities that promote the health of host animals, plants, and ecosystems.     

Urinary incontinence due to the presence of necrotic adult Schistosoma haematobium parasite in the bladder following travel to Egypt

A case of seronegative urinary Schistosomiasis is reported in a 68-year-old Caucasian male presenting with urgency of micturition and incontinence several months after bathing in a chlorinated pool of a first class hotel in Egypt. The symptoms were initiated by a necrotic adult Schistosoma haematobium parasite found in the urinary bladder following a cystoscopic examination. The purpose of this report is to describe this probable and uncommon source of Schistosomiasis, to demonstrate that Schistosoma parasites can also be found in the urinary bladder and to emphasize the importance of travel history.     

Interdonor Incompatibility Due to Anti-Kell Antibody Undetectable by Automated Antibody Screening

A unit of whole donor blood, the plasma of which contained anti-Kell antibody, was transfused into a Kell-negative patient who had received a unit of Kell-positive blood 4 weeks previously. A haemolytic transfusion reaction ensued. The antibody had gone undetected in routine automated screening of the donor blood. Automated antibody detection techniques do not offer reliable detection of anti-Kell antibodies.     

Management of the patient with a low HDL-cholesterol

While there is epidemiologic evidence linking a low high-density lipoprotein (HDL) cholesterol level with coronary disease events, and interventions that raise HDL while lowering low-density lipoprotein (LDL) cholesterol levels have been shown to reduce subsequent coronary events, there are no studies showing benefit from raising HDL when a low HDL level is the sole lipid abnormality. HDL is thought to play a key role in reverse cholesterol transport, removing lipids from peripheral cells, but the precise role of HDL in cholesterol metabolism is not understood. The measurement of HDL levels has not been well standardized. Reliance on ratios relating HDL to LDL or to total cholesterol may be misleading in the management of patients. It has not been shown that measuring HDL subfractions or apolipoprotein levels is superior to measuring total HDL levels in predicting coronary risk. HDL levels may be raised by hygienic measures such as smoking cessation and exercise, but a considerable amount of exercise over a long period of time is required. Alcohol consumption and weight loss through dieting inconsistently raise HDL. Estrogen therapy raises and progestational agents lower HDL. Certain beta-blocking drugs lower HDL levels. For the patient with an isolated low HDL level the hygienic measures may be advised, but drug therapy such as nicotinic acid or gem-fibrozil should be prescribed only when low HDL is accompanied by elevated LDL levels that are unresponsive to diet and hygienic measures.