Transgene expression of bcl-xL permits anti-immunoglobulin (Ig)-induced proliferation in xid B cells

Mutations in the tyrosine kinase, Btk, result in a mild immunodeficiency in mice (xid). While B lymphocytes from xid mice do not proliferate to anti-immunoglobulin (Ig), we show here induction of the complete complement of cell cycle regulatory molecules, though the level of induction is about half that detected in normal B cells. Cell cycle analysis reveals that anti-Ig stimulated xid B cells enter S phase, but fail to complete the cell cycle, exhibiting a high rate of apoptosis. This correlated with a decreased ability to induce the anti-apoptosis regulatory protein, Bcl-xL. Ectopic expression of Bcl-xL in xid B cells permitted anti-Ig induced cell cycle progression demonstrating dual requirements for induction of anti-apoptotic proteins plus cell cycle regulatory proteins during antigen receptor mediated proliferation. Furthermore, our results link one of the immunodeficient traits caused by mutant Btk with the failure to properly regulate Bcl-xL.     

Adrenocortical overexpression of gastric inhibitory polypeptide receptor underlies food-dependent Cushing's syndrome

Abnormal responsiveness of adrenocortical cells to gastric inhibitory polypeptide (GIP) in food-dependent Cushing's syndrome suggested that adrenal expression of ectopic, overexpressed, or mutated GIP receptor (GIPR) underlies this syndrome. The expression of GIPR was studied by RT-PCR in human adrenal tissues from two patients with GIP-dependent Cushing's syndrome (adenoma, bilateral hyperplasia), five fetal or adult controls, one patient with Cushing's disease, and four patients with non-food-dependent cortisol-secreting adenomas or bilateral hyperplasias and compared to that in normal pancreas. Hybridization of the RT-PCR-amplified ribonucleic acids with the human GIPR complementary DNA showed an overexpression of GIPR in the adrenals of the two GIP-dependent Cushing's syndrome patients compared to that in normal adrenal tissues (2-3 orders of magnitude) or pancreas (10-fold); no signal could be seen in adrenal adenomas or macronodular hyperplasia from cases of non-food-dependent Cushing's syndrome. No mutation of the GIPR was identified by sequencing the full-length receptor in GIP-dependent adrenal tissue. New alternative spliced isoforms of the GIPR were found, but are identical in GIP-dependent and normal adrenal tissues. Incubation of adrenal cells with GIP stimulates cortisol secretion in GIP-dependent, but not in normal fetal, adult, or non-food-dependent Cushing's syndrome, adrenals. We conclude that the GIPR overexpression and its coupling to steroidogenesis underlie GIP-dependent Cushing's syndrome.     

Growth of infants and young children born small or large for gestational age: findings from the Third National Health and Nutrition Examination Survey

An allele-specific polymerase chain reaction (ASPCR) assay for prenatal genotyping of the Kidd antigen system in order to identify pregnancies at risk for haemolytic disease of the newborn (HDN) was developed. Oligonucleotide primers were designed for ASPCR of JKA and JKB. A validation study was performed using DNA isolated from 54 serotyped whole blood samples and 8 amniocentesis samples. A concordance rate of 100 per cent was observed between serotyping and ASPCR detection of the JKA and JKB alleles. Experiments were conducted to quantify the maternal contamination that could be tolerated in Kidd ASPCR assays. The sensitivity of this assay ranged from 0.2 per cent when detecting the presence of JKB and JKA background, to 2 per cent for detecting the presence of JKA in a JKB background. This sensitive assay is particularly useful for rapid genotyping of fetal amniotic cells to identify pregnancies at risk for HDN due to incompatibilities within the Kidd blood group system.     

Influence of atipamezole on effects of midsacral subarachnoidally administered detomidine in mares

BACKGROUND: The reliable interpretation of the nasal provocation test in allergy diagnosis requires objective and measurable monitoring parameters for clinical practice. The clinical usefulness of the nasal provocation test has been limited by scanty knowledge of the specificity and sensitivity of the test and a lack of reference values. OBJECTIVE: To test and compare three objective monitoring parameters of a nasal provocation test in occupational allergic rhinitis. To evaluate the magnitude of the nasonasal effects in a unilateral allergen challenge. METHODS: The monitoring parameters of the nasal reaction were derived from the minimum cross-sectional area on acoustic rhinometry, the nasal resistance on active anterior rhinomanometry and the amount of nasal secretion measured at 15 min intervals for 60 min. Twenty-three bovine-allergic dairy and beef cattle farmers and 19 exposed, non-allergic control subjects were challenged first with a control solution and then with the cow allergen. RESULTS: All the three monitoring parameters showed high specificity and sensitivity in finding allergic and non-allergic subjects. The secretion parameter was found to be slightly superior to the acoustic rhinometry and rhinomanometry parameters. The side difference in the nasal response between the allergen-challenged and the contralateral diluent-challenged cavity was significant for all the parameters among the allergic subjects. The contralateral secretion amount was 1/3 of the ipsilateral secretion, indicating the magnitude of the contralateral nasonasal reflex. A nasonasal reflex was also noted in the nasal patency monitoring. The coefficient of variation was significantly lower for the acoustic rhinometry than for the rhinomanometry (P=0.0001). The optimal threshold values for a positive test were a secretion amount of 100 mg, a 15% decrease in the minimum cross-sectional area and a 50% increase in the resistance for the observation period of 30 min and correspondingly 210 mg, 30% and 100% for 60 min. CONCLUSION: The low-pressure aspiration of the nasal secretion from the anterior part of the nasal cavity was found to be a reliable and practical monitoring parameter to be used together with acoustic rhinometry or rhinomanometry in the nasal provocation test for clinical purposes. Although significant nasonasal effects took place in the unilateral allergen challenge, the response was more prominent in the allergen-challenged than in the contralateral diluent-challenged nasal cavity in most allergic subjects.     

Off-label dermatologic therapies. Usage, risks, and mechanisms

Off-label refers to the prescribing of Food and Drug Administration-approved drugs for a use not indicated on the package insert. The prescribing of off-label drugs may benefit patients with many dermatologic diseases including angiogenesis-related conditions. We surveyed 55 dermatologists from a single large academic program to assess their use of particular drugs for specific skin conditions, their perception of such use as being for Food and Drug Administration-approved or for off-label indications, and their attitudes towards off-label therapies. The practice of prescribing off-label drugs was common among the respondents, many of whom had misperceptions about which conditions are Food and Drug Administration-approved indications and about the legal ramifications of off-label therapies. We suggest that understanding the principles of off-label prescribing in conjunction with the mechanisms of drug action in diseases may help clinicians exercise their judgment in finding innovative therapies for their patients.     

Characterization of the ATP- and GTP-specific succinyl-CoA synthetases in pigeon. The enzymes incorporate the same alpha-subunit

Two succinyl-CoA synthetases, one highly specific for GTP/GDP and the other for ATP/ADP, have been purified to homogeneity from pigeon liver and breast muscle. The two enzymes are differentially distributed in pigeon, with only the GTP-specific enzyme detected in liver and the ATP-specific enzyme in breast muscle. Based on assays in the direction of CoA formation, the ratios of GTP-specific to ATP-specific activities in kidney, brain, and heart are approximately 7, 1, and 0.1, respectively. Both enzymes have the characteristic alpha- and beta-subunits found in other succinyl-CoA synthetases. Studies of the alpha-subunit by electrophoresis, mass spectrometry, reversed-phase high performance liquid chromatography, and peptide mapping showed that it was the same in the two enzymes. Characterization of the beta-subunits by the same methods indicated that they were different, with the tryptic peptide maps providing evidence that the beta-subunits likely differ along their entire sequences. Because the two succinyl-CoA synthetases incorporate the same alpha-subunit, the determinants of nucleotide specificity must reside within the beta-subunit. Determination of the apparent Michaelis constants showed that the affinity of the GTP-specific enzyme for GDP is greater than that of the ATP-specific enzyme for ADP (7 versus 250 microM). Rather large differences in apparent Km values were also observed for succinate and phosphate.     

The prevention pill

Eight children with the cyst of choledochus, ageing from 1 month to 15 years, were treated for the period of 20 years in clinic. Cystoduodenostomy is the method of choice for the treatment. All the patients have recovered.