Pharmacogenetic comparison of CYP2D6 predictive and measured phenotypes in a South African cohort.

This corrects the article DOI: 10.1038/tpj.2015.76.

Pharmacogenetic comparison of CYP2D6 predictive and measured phenotypes in a South African cohort.

The relationship between genetic variation in CYP2D6 and variable drug response represents a potentially powerful pharmacogenetic tool. However, little is known regarding this relationship in the genetically diverse South African population. The aim was therefore to evaluate the relationship between predicted and measured CYP2D6 phenotype. An XL-PCR+Sequencing approach was used to determine CYP2D6 genotype in 100 healthy volunteers and phenotype was predicted using activity scores. With dextromethorphan as the probe drug, metabolic ratios served as a surrogate measure of in vivo CYP2D6 activity. Three-hour plasma metabolic ratios of dextrorphan/dextromethorphan were measured simultaneously using semi-automated online solid phase extraction coupled with tandem mass spectrometry. Partial adaptation of the activity score system demonstrated a strong association between genotype and phenotype, as illustrated by a kappa value of 0.792, inter-rater discrepancy of 0.051 and sensitivity of 72.7%. Predicted phenotype frequencies using the modified activity score were 1.3% for poor metabolisers (PM), 7.6% for intermediate metabolisers (IM) and 87.3% for extensive metabolisers (EM). Measured phenotype frequencies were 1.3% for PM, 13.9% for IM and 84.8% for EM. Comprehensive CYP2D6 genotyping reliably predicts CYP2D6 activity in this South African cohort and can be utilised as a valuable pharmacogenetic tool.

Chaotic particle heating due to an obliquely propagating wave in a magnetized plasma.

We study the dynamics of a relativistic charged particle in the presence of a uniform magnetic field and a stationary electrostatic wave that propagates at an arbitrary angle. The wave is considered as a series of periodic pulses which allows us to derive an exact map for the system. In particular, we investigate the heating process of an initially low-energy particle. It is found that abrupt changes in the maximum energy attained by the particle may occur as the angle between the wave propagation and the magnetic field varies. To determine what is the mechanism behind this phenomenon a reduced Hamiltonian that retains the important dynamical features is obtained. Using both Poincaré plots and perturbation theory, we identify that a separatrix reconnection is the key mechanism for the abrupt change in particle response.

Controlling chaos in wave-particle interactions.

We analyze the behavior of a relativistic particle moving under the influence of a uniform magnetic field and a stationary electrostatic wave. We work with a set of pulsed waves that allows us to obtain an exact map for the system. We also use a method of control for near-integrable Hamiltonians that consists of the addition of a small and simple control term to the system. This control term creates invariant tori in phase space that prevent chaos from spreading to large regions, making the controlled dynamics more regular. We show numerically that the control term just slightly modifies the system but is able to drastically reduce chaos with a low additional cost of energy. Moreover, we discuss how the control of chaos and the consequent recovery of regular trajectories in phase space are useful to improve regular particle acceleration.

Standard map in magnetized relativistic systems: fixed points and regular acceleration.

We investigate the concept of a standard map for the interaction of relativistic particles and electrostatic waves of arbitrary amplitudes, under the action of external magnetic fields. The map is adequate for physical settings where waves and particles interact impulsively, and allows for a series of analytical result to be exactly obtained. Unlike the traditional form of the standard map, the present map is nonlinear in the wave amplitude and displays a series of peculiar properties. Among these properties we discuss the relation involving fixed points of the maps and accelerator regimes.

Comparative 1H NMR-based metabonomic analysis of HIV-1 sera.

(1)H NMR spectroscopy of sera from HIV-1 infected and uninfected individuals was performed on 300 and 600 MHz instruments. The resultant spectra were automatically data reduced to 90 and 180 integral segments of equal length. Analysis of variance identified significant differences between the sample groups, especially for the samples analyzed on 600 MHz and reduced to fewer segments. Linear discriminant analysis correctly classified 100% of the samples analyzed on the 300 MHz NMR (reduced to 180 segments); an increase in instrument sensitivity resulted in lower percentages of correctly classified samples. Multinomial logistic regression (MLR) resulted in 100% correct classification of all samples from both instruments. Thus (1)H-NMR metabonomics on either instrument distinguishes HIV-positive individuals using or not using anti retroviral therapy, but the sensitivity of the instrument impacts on data reduction. Furthermore, MLR is a novel multivariate statistical technique for improved classification of biological data analyzed in NMR.

[Leptospirosis after a stay in Thailand]. / Leptospirose nach Thailand-Aufenthalt.

HISTORY AND ADMISSION FINDINGS: A 35-year-old man was admitted to our hospital with chills, headache, pain in the calves for five days and a bloody sputum. The day before he had returned from a 4-week trip to the north of Thailand. There he had participated in hiking trips and walked sometimes over wet fields with small skin injuries on his feet. The admission examination was uneventful except fever as high as 39 Celsius, particularly no rash, no conjunctivitis, no spleno- or hepatomegaly and no palpable lymph nodes could be noted. DIAGNOSTIC PROCEDURES: An x-ray of the chest showed confluent opacities, a bronchoscopy revealed diffuse alveolar hemorrhagy. Blood chemistry showed elevated liver enzymes, elevated kidney retention parameters and an increased C-reactive protein. An extended microbiological diagnostic procedure showed elevated antibody titers for leptospira and a PCR detected leptospira-DNA, representing acute leptospirosis. TREATMENT AND OUTCOME: After initiation of an antibiotic regimen including ceftriaxone and erythromycine the fever resolved immediately and the general condition improved. The patient could be discharged after two weeks in a good physical condition. CONCLUSION: The constellation of flu-like symptoms, hepatitis and nephritis, eventually escorted by bloody sputum, may suggest leptospirosis.

Applying biofluid 1H NMR-based metabonomic techniques to distinguish between HIV-1 positive/AIDS patients on antiretroviral treatment and HIV-1 negative individuals.

Metabonomics, the study of metabolites and their role in various physiological states, is a novel methodology arising from the post-genomics era and has extensive biomedical application. This technology has exhibited vast success in the identification and study of human diseases and may find further application in the study of HIV/AIDS. Specifically, the wide range of clinical and metabolic abnormalities associated with the use of antiretroviral (ARV) treatment may be investigated. To this end, this preliminary study evaluated whether metabonomic techniques could distinguish between HIV-1 positive/AIDS patients utilizing antiretroviral therapy and HIV-1 negative individuals. Serum metabolic profiles determined by 1H nuclear magnetic resonance (NMR) spectroscopy combined with pattern recognition analysis of the data showed that this distinction was attainable; suggesting that ARV-associated side-effects could be monitored utilizing NMR metabonomic techniques.

Comparison of body fluid distribution between chronic haemodialysis and peritoneal dialysis patients as assessed by biophysical and biochemical methods.

BACKGROUND: The control of extracellular volume is a key parameter for reducing hypertension and the incidence of cardiovascular mortality in dialysis patients. In recent years bioimpedance measurement (BIA) has been proven as a non-invasive and accurate method for measuring intracellular and extracellular fluid spaces in man. In addition, plasma atrial natriuretic peptide (ANP) and cyclic guanosine monophosphatase (cGMP) concentrations have been shown to reflect central venous filling. Using these methods, we compared body fluid status between stable patients on haemodialysis and peritoneal dialysis. METHODS: Thirty-nine chronic haemodialysis patients, 43 chronic peritoneal dialysis patients and 22 healthy controls were included in the study. Multifrequency BIA was performed using the Xitron BIS4000B device (frequencies from 5 to 500 kHz were scanned and fitted) in patients before and after haemodialysis. Peritoneal dialysis patients were measured after drainage of the dialysate. Plasma ANP and cGMP levels were measured in plasma using a (125)I solid phase RIA. Serum albumin concentrations and serum osmolality were measured in all patients. The body fluid data were analysed in relation with the clinical findings. RESULTS: Total body water (TBW) was 0.471+/-0.066 l/kg before haemodialysis and 0.466+/-0.054 l/kg after haemodialysis. Peritoneal dialysis patients had a TBW (0.498+/-0.063 l/kg) that was greater than the before and after dialysis values of haemodialysis patients. The extracellular body fluid (V(ecf)) was increased pre-haemodialysis. It was even greater in peritoneal dialysis patients compared with patients both pre- and post-haemodialysis (pre 0.276+/-0.037 l/kg; post 0.254+/-0.034 l/kg; peritoneal dialysis 0.293+/-0.042 l/kg, P<0.05). However, plasma ANP concentrations (representing intravascular filling) in peritoneal dialysis patients were comparable with post-haemodialysis values (284+/-191 pg/ml vs 286+/-144 pg/ml). The correlation coefficient between sysRR and V(ecf) was r=0.257 in haemodialysis (P=0.057) and r=0.258 in peritoneal dialysis (P<0.05). A significant negative correlation was found between serum albumin and V(ecf)/TBW in peritoneal dialysis patients (r= -0.624). CONCLUSION: Body fluid analysis by BIA demonstrated that TBW and V(ecf) were increased in peritoneal dialysis patients, and were comparable or even greater than values found before haemodialysis. However, plasma ANP levels indicated that intravascular filling was not increased in peritoneal dialysis. The ratio of V(ecf) to TBW was correlated to systolic pressure and negatively to serum albumin in peritoneal dialysis patients.

Dynamical symmetry breaking in the sea of the nucleon.

We derive the nonanalytic chiral behavior of the flavor asymmetry d - u. Such behavior is a unique characteristic of Goldstone boson loops in chiral theories, including QCD, and establishes the unambiguous role played by the Goldstone boson cloud in the sea of the proton. Generalizing the results to the SU(3) sector, we show that strange chiral loops require that the s - s distribution be nonzero.

Effect of blood vitamin A levels on the dark adaptation of mineworkers.

The average dark adaptation time for newly recruited Black mineworkers is longer than that reported for Whites. While this longer dark adaptation time may result from a number of pathological conditions, its most likely cause is a deficiency of vitamin A in the diet. A study was conducted in which the vitamin A level of the blood and the dark adaptation times were correlated in a group of Black mineworkers upon arrival and again after 4 - 6 months continuous work underground in a gold mine. The study indicated that a very marked decrease occurred in the miners' serum vitamin A level between the time of arrival at the mine and the second examination. This difference was found to be highly significant. This decrease was accompanied by an increase in mean dark adaptation time, which was significant at the 5% level. These observations accord with the findings of a previous study and are indicative of an inadequate dietary intake of vitamin A during the period when the miners were on the mine diet.