Asthma management: are GINA guidelines appropriate for daily clinical practice?

An international group of primary care asthma experts, as well as pulmonologists and allergists from Europe and the US, met to discuss asthma management focused on the primary care office. This paper summarizes their discussions. Accuracy of diagnosis and appropriateness of treatment is variable depending on the clinical circumstances and patient group. The value of classifying patients based on baseline or static asthma severity scores remains controversial, and asthma management decisions based on symptom control appear to have greater practical utility in a primary care setting. Furthermore, it must be recognized that patients, caregivers and physicians may have differing, and possibly conflicting, goals for therapy. There are many initiatives to improve the quality of asthma management, for example, primary care-focused guidelines being developed by the International Primary Care Respiratory Group, and several groups are working on asthma control scores. In addition, new therapies may improve the options available for increasing compliance and reducing side effects. In conclusion, asthma management should be patient-focused, with outcomes relevant to improving the quality of life for people with asthma.     

Possible mechanisms and gene involvement in speech problems in the 22q11.2 deletion syndrome.

SUMMARY: The 22q11.2 deletion syndrome represents a contiguous gene syndrome with a highly variable phenotype. To date, over 180 clinical features have been described. Studies have been done in order to identify the responsible genes. Several candidate genes such as TBX1 and COMT seem to be important in the development of the phenotype. One of the prevalent and serious problems encountered by patients with the 22q11.2 deletion is difficulty with speech. This may be due to a number of factors such as adenoid hypoplasia, muscle hypotonia, platybasia, upper airway asymmetry, and neuroanatomical abnormalities. The complex interaction of these factors leads to less favourable results after surgery to correct velopharyngeal insufficiency. This article offers a theoretical overview and proposes future research to investigate which factors are indeed responsible for the speech problems encountered by patients with the 22q11.2 deletion and identify responsible genes.     

Reduction of urinary bile alcohol excretion and serum cholestanol in patients with cerebrotendinous xanthomatosis after oral administration of deoxycholic acid

Deoxycholic acid and chenodeoxycholic acid were administered alternately to four patients with cerebrotendinous xanthomatosis. During this oral therapy serum cholestanol and urinary bile alcohols were determined. Both showed a marked decrease after the start of the two different therapies. It can be concluded that not only chenodeoxycholic acid but also deoxycholic acid is able to suppress endogenous human bile acid synthesis, which is in accordance with other experiments describing the effect of feeding of various bile acids on endogenous bile acid synthesis.     

Plasma free metanephrine measurement using automated online solid-phase extraction HPLC tandem mass spectrometry

BACKGROUND: Quantification of plasma free metanephrine (MN) and normetanephrine (NMN) is considered to be the most accurate test for the clinical chemical diagnosis of pheochromocytoma and follow-up of pheochromocytoma patients. Current methods involve laborious, time-consuming, offline sample preparation, coupled with relatively nonspecific detection. Our aim was to develop a rapid, sensitive, and highly selective automated method for plasma free MNs in the nanomole per liter range. METHODS: We used online solid-phase extraction coupled with HPLC-tandem mass spectrometric detection (XLC-MS/MS). Fifty microliters plasma equivalent was prepurified by automated online solid-phase extraction, using weak cation exchange cartridges. Chromatographic separation of the analytes and deuterated analogs was achieved by hydrophilic interaction chromatography. Mass spectrometric detection was performed in the multiple reaction monitoring mode using a quadrupole tandem mass spectrometer in positive electrospray ionization mode. RESULTS: Total run-time including sample cleanup was 8 min. Intra- and interassay analytical variation (CV) varied from 2.0% to 4.7% and 1.6% to 13.5%, respectively, whereas biological intra- and interday variation ranged from 9.4% to 45.0% and 8.4% to 23.2%. Linearity in the 0 to 20 nmol/L calibration range was excellent (R(2) > 0.99). For all compounds, recoveries ranged from 74.5% to 99.6%, and detection limits were <0.10 nmol/L. Reference intervals for 120 healthy adults were 0.07 to 0.33 nmol/L (MN), 0.23 to 1.07 nmol/L (NMN), and <0.17 nmol/L (3-methoxytyramine). CONCLUSIONS: This automated high-throughput XLC-MS/MS method for the measurement of plasma free MNs is precise and linear, with short analysis time and low variable costs. The method is attractive for routine diagnosis of pheochromocytoma because of its high analytical sensitivity, the analytical power of MS/MS, and the high diagnostic accuracy of free MNs.     

Reduced alpha and exaggerated theta power during the resting-state EEG in fragile X syndrome

This study characterizes the resting-state EEG in males with fragile X syndrome to reveal abnormalities in oscillatory brain dynamics. Analyses of the eyes-closed EEG epochs showed that the resting-state EEG in FXS can be characterized by elevated relative theta power (4–8 Hz) and reduced relative upper-alpha power (10–12 Hz). Although preliminary, these findings suggest that the well-documented imbalance in excitatory/inhibitory cortical circuit activity in FXS can be revealed the level of oscillatory behavior at the scalp. A next step for future studies is linking the EEG resting-state indices to cognitive and behavioral measures.     

Serious complications of umbilical venous catheterisation

Three male newborns, born at 30 weeks, 36 weeks and at term, respectively, developed serious complications related to umbilical venous catheters. The first patient had persistent bacteraemia due to a cardiac thrombus. He recovered after treatment. In the second patient, the umbilical venous catheter was placed in the pericardial sac, causing accumulation of parenteral nutrition and fatal cardiac tamponade. In the third patient, the umbilical catheter was positioned in the liver, leading to extravasation of parenteral nutrition in the liver and peritoneal cavity. At follow-up, he had developed an atrial septum defect, hypotonia and developmental retardation. Umbilical venous catheterisation has been used in neonatal intensive care units for more than 50 years to allow continuous infusion of medication, fluids and nutrition. However, the use of umbilical venous catheters can be associated with severe infectious, thrombotic and traumatic complications. Therefore, umbilical venous catheterisation requires a critical assessment of the need, alternatives and possible complications.     

Regulatory T cells contribute to the impaired immune response in patients with chronic hepatitis B virus infection

Chronic hepatitis B virus (HBV) infection is characterized by a weak immune response to HBV. Regulatory T cells (T(reg)) can suppress the function of effector T cells and may thus be key players in this impaired immune response. Changes in the functionality or number of T(reg) could explain the decreased antiviral response in chronic HBV patients. To investigate the role of T(reg) in chronic HBV infection, we compared the proportional frequency and functionality of T(reg) in peripheral blood of 50 chronic HBV patients, 23 healthy controls, and 9 individuals with a resolved HBV infection. A higher percentage of T(reg), defined as CD4, CD25, CD45RO, and cytotoxic T-lymphocyte-associated antigen 4-positive cells, was detected within the population of CD4(+) cells in peripheral blood of chronic HBV patients compared with healthy controls and individuals with a resolved HBV infection. Accordingly, chronic HBV patients displayed a higher FoxP3 messenger RNA level than healthy controls. Depletion of CD25(+) cells from peripheral blood mononuclear cells (PBMC) of chronic HBV patients resulted in an enhanced proliferation after stimulation with HBV core antigen. Reconstitution of these depleted PBMC with CD4(+)CD25(+) T(reg) resulted in a dose-dependent reduction of both HBV-specific proliferation and interferon gamma production. In conclusion, chronic HBV patients harbor an increased percentage of T(reg) in peripheral blood compared with controls. T(reg) have an immunosuppressive effect on HBV-specific T helper cells. The presence of HBV-specific T(reg) could contribute to an inadequate immune response against the virus, leading to chronic infection.     

Purification and characterization of Leydig cells from rat testes.

An LH-responsive Leydig cell preparation (containing 6+/-2% Leydig cells) was obtained by collagenase treatment of rat testis. Centrifugation of this cell preparation through a 13% Ficoll solution for 10 min at 1500 g resulted in a four times purification of the Leydig cells, with a concomitant increases in steroidogenic activity. Addition of 0-2% albumin to the 13% Ficoll solution, adjusted to 280 mosmol/l, resulted in a further twofold purification of the Leydig cells paralleled by a twofold increase in steroidogenic activity. Centrifugation of these Ficoll-albumin-purified Leydig cells through a 6% dextran solution for 2 min at 100 g resulted in a further 1-7 times purification of the Leydig cells. A combination of the two centrifugation steps resulted in a 12-5 times purification of Leydig cells compared with the original crude cell suspension, while an increase in steroidogenic activity of 22-5 times was obtained. This final cell preparation contained 59 +/- 17% Leydig cells (mean +/- S.D., n = 6). The recovery of Leydig cells was 29%. Collagenase treatment of testes deficient in spermatogenesis resulted in a cell preparation with the same steroidogenic activity as Ficoll-purified cells from normal testes. Centrifugation of these cells through a 13% Ficoll solution gave only a limited increase in the steroidogenic activity. Isopycnic centrifugation of the crude cell preparation on a discontinous Ficoll metrizoate gradient resulted in two discrete peaks of Leydig cells, one peak at a density of 1-039-1-055 g/ml and one at a density of 1-068-1-088 g/ml. Both types of cells produced testosterone. In the presence of LH, cyclic AMP production in both types of Leydig cells increased, but testosterone production was only increased by LH in the "denser" Leydig cells and not in the "light" Leydig cells. No difference in sensitivity to LH could be observed between the Leydig cell preparations of different purity. Using a 60 min pre-incubation period the highest testosterone response was obtained with 100-1000 ng LH/ml. The same maximum testosterone response was obtained with 10-100 ng LH/ml when the pre-incubation period was omitted.