Homozygous variant of UGT1A1 gene mutation and severe neonatal hyperbilirubinemia

Background: The aim of the present study was to compare, in a case–control study, the prevalence of nucleotide 211 guanine to adenine (G→A) mutation of uridine diphosphoglucuronosyl transferase (UGT1A1) gene in Malaysian Chinese newborns with and without severe hyperbilirubinemia (total serum bilirubin >250 µmol/L during first 48 h of life or ≥300 µmol/L thereafter), and to determine whether this mutation was a significant risk factor associated with severe hyperbilirubinemia. Methods: Seventy‐four term infants of Chinese descent admitted with severe hyperbilirubinemia were recruited. Infants without severe hyperbilirubinemia (n = 125) were randomly selected from among healthy Chinese term infants. UGT1A1 nucleotide 211 polymorphism was assayed using the Taqman single nucleotide polymorphism genotyping method. Using gestational age, types of feeds, G6PD mutation, G6PD enzyme levels, and UGT1A1 gene mutation status as independent variables, logistic regression analysis was carried out to determine the significant risk factors associated with severe hyperbilirubinemia. Results: UGT1A1 gene mutation was significantly more common among hyperbilirubinemic infants (39.2%) than controls (25.6%; P = 0.04). Gestational age (adjusted odds ratio [OR], 0.7; 95% confidence intervals [CI]: 0.5–0.9; P = 0.01), G6PD mutation (adjusted OR, 7.2; 95%CI: 2.7–19.0; P < 0.0001), exclusive breast‐feeding (adjusted OR, 11.7; 95%CI: 2.7–49.9; P = 0.001), and homozygous variant of UGT1A1 gene mutation (adjusted OR, 32.2; 95%CI: 3.8–273.2; P = 0.001) were significant risk factors. Heterozygous variant of UGT1A1 gene mutation, actual levels of G6PD enzyme, and mixed feeding were not. Conclusion: Homozygous variant of nucleotide 211 G→A mutation of UGT1A1 gene is a significant risk factor associated with severe hyperbilirubinemia among Malaysian Chinese newborns.     

Early pituitary-adrenal response and respiratory outcomes in preterm infants

OBJECTIVE: To assess the influence of circulating (basal) and stimulated plasma adrenocorticotrophin (ACTH) and serum cortisol on the duration of oxygen supplementation and development of chronic lung disease (CLD) in preterm, very low birthweight infants. METHODS: A total of 226 human corticotrophin releasing hormone stimulation tests were performed on 137 very low birthweight infants on days 7 and 14 in a tertiary neonatal centre. RESULTS: Multivariate regression analysis showed that the duration of oxygen supplementation was negatively associated with birth weight, but positively associated with alveolar-arterial oxygen gradient (A-aDO(2)) on the first day and with basal serum cortisol on day 14. In addition, the multivariate classification and regression trees model indicated that the two most useful indices for predicting CLD were clinical risk index for babies (CRIB) score (> 9) and peak serum cortisol (> 740 nmol/l) on day 14. The sensitivity, specificity, positive and negative predictive values of these factors for predicting CLD were 53%, 80%, 81%, and 70% respectively. CONCLUSIONS: The findings suggest that birth weight, severity of initial respiratory failure as reflected by the A-aDO(2) gradient, and continuing "stress" with persistent increase in serum cortisol on day 14 are significant risk factors associated with the duration of oxygen supplementation, whereas early pituitary-adrenal response (basal and peak plasma ACTH and serum cortisol on day 7) is not an independent risk factor. Although CRIB score in combination with peak serum cortisol on day 14 are useful predictors of CLD, the need to use a stimulation test and the relatively late timing of the forecast render these indices unattractive for routine clinical use.     

Introducing laparoscopic management of ectopic pregnancy to a busy gynaecology unit--is it worthwhile?

A review was carried out on 26 consecutive women undergoing surgery for ectopic pregnancy in the Limerick Regional Hospital, Ireland from April 2000 to April 2002. 13 were managed laparoscopically and 13 had laparotomy. There were no significant differences in age, parity or gestational age. 3 patients had previous ectopic pregnancy. 12/13 from the laparotomy group had a diagnostic laparoscopy prior to laparotomy. Anaesthetic time differed by 21.2 minutes with laparotomy being done faster than the laparoscopy group while operative time was 7.3 minutes longer in the laparoscopic group. The laparoscopic approach was associated with lower intraoperative blood loss (<50 ml vs 413.1 ml), less post operative analgesia requirement, shorter hospital stay (2.4 days vs 4.5 days), faster return to work (2 weeks vs 4 weeks) and less subsequent wound infection. Operative laparoscopy also has the advantage of being a diagnostic as well as a therapeutic tool in one procedure.     

Does concurrent in utero exposure to buprenorphine and antidepressant medications influence the course of neonatal abstinence syndrome?

Objective: To determine whether concurrent in utero exposure to buprenorphine and antidepressants impacts the course of neonatal abstinence syndrome (NAS) in infants.

Methods: A retrospective cohort study of 148 infants who were exposed to buprenorphine during pregnancy. Univariate and bivariate analyses were used to examine associations between concurrent maternal use of buprenorphine and antidepressants as compared to maternal use of buprenorphine alone.

Results: The time to onset of NAS resolution was significantly longer in infants exposed to both buprenorphine and antidepressants during pregnancy when compared to those exposed to buprenorphine alone (129.8?h versus 70.2?h, p?=?0.042).

Conclusions: Women who are prescribed both antidepressants and buprenorphine during pregnancy should be counseled about the possibility of a prolonged course of neonatal abstinence syndrome.     

Intimate relationships with their neighbors: tales of stem cells in Drosophila reproductive systems.

Stem cells have the unique potential to self-renew and to supply differentiated cells that replenish lost cells throughout an organism's lifetime. This unique property makes stem cells powerful therapeutic tools for future regenerative medicine. However, the molecular mechanisms of stem cell regulation are still poorly understood in many stem cell systems. Stem cell function has been shown recently to be controlled by concerted actions of extrinsic signals from its regulatory niche and intrinsic factors inside the stem cell. Stem cells in the Drosophila reproductive systems provide excellent models to understand the fundamental mechanisms underlying stem cell regulation, including the relationships between stem cells and their niches. Within the past few years, much progress in understanding stem cells in Drosophila has been made, and the knowledge gained from studying these stem cells greatly advances our understanding of stem cells in other systems, including humans. In this review, we summarize the recent progress and describe future challenges in understanding the molecular mechanisms controlling stem cell self-renewal, division, and differentiation in the Drosophila reproductive systems.     

Dectin-2 is predominantly myeloid restricted and exhibits unique activation-dependent expression on maturing inflammatory monocytes elicited in vivo

Dectin-2 is a recently described dendritic-cell-associated receptor, suggested to be involved in the initiation and maintenance of UV-induced tolerance. To understand the physiological relevance of the proposed functions of this C-type lectin-like receptor, we have generated monoclonal antibodies against its extracellular domain and performed a detailed study of its expression. In naive mice, Dectin-2 has a novel distribution pattern compared with other myeloid markers, but is predominantly expressed by a wide variety of tissue macrophages. Its expression was limited on dendritic cells and notably absent from brain microglia and choroid plexus or meningeal macrophages. On peripheral blood monocytes, Dectin-2 expression was very low on the surface but was transiently and markedly up-regulated on induction of inflammation in vivo using a variety of stimuli. This change in Dectin-2 expression occurs on 'inflammatory' monocytes after arrival at the inflammatory lesion as demonstrated by adoptive cell-transfer studies, and is independent of whether the macrophages elicited by the stimuli ultimately expressed Dectin-2. These observations show Dectin-2 expression to be characteristic of monocyte activation/maturation at an inflammatory lesion and provide a new perspective on the interpretation of Dectin-2 function in vivo.     

Bone morphogenetic protein receptor type II C-terminus interacts with c-Src: implication for a role in pulmonary arterial hypertension

Mutations of bone morphogenetic protein receptor type II (BMPR-II) have been associated with familial and idiopathic pulmonary arterial hypertension (PAH). BMPR-II is a member of the transforming growth factor-beta receptor superfamily. It consists of extracellular, transmembrane, and kinase domains, and a unique C-terminus with mostly unknown function. However, a number of PAH-causing mutations are predicted to truncate the C-terminus, suggesting that this domain plays an important role in the homeostasis of pulmonary vessels. In this study, we sought to elucidate the functional role of this C-terminus by seeking its interacting partners. Using yeast two-hybrid screening, we identified c-Src tyrosine kinase as a binding partner of this C-terminus. In vitro co-immunoprecipitation confirmed their interaction. Mutations truncating the C-terminus disrupted their interaction, while missense mutation within kinase domain reduced their interaction. In addition, BMPR-II and c-Src tyrosine kinase colocalized within intracellular aggregates when overexpressed in HEK293 cells. Moreover, mutations truncating the C-terminus disrupted their colocalization, whereas missense mutation within kinase domain had no effect on their colocalization. Furthermore, BMP ligand stimulation decreased c-Src-activating phosphorylation at Tyrosine 418 in pulmonary smooth muscle cells in both time- and concentration-dependent manners. Mutations that truncated the C-terminus abolished this response. Taken together, these results suggest a model in which proliferative effect of c-Src by vasoactive molecules is balanced by opposing effect of BMP signaling in basal state, and the loss of this balance due to BMPR2 mutations leads to increased c-Src activity and subsequently cell growth.     

Detection and calibration of microdeletions and microduplications by array-based comparative genomic hybridization and its applicability to clinical genetic testing.

PURPOSE: Genome-wide telomere screening by fluorescence in situ hybridization (FISH) has revealed that approximately 6% of unexplained mental retardation is due to submicroscopic telomere imbalances. However, the use of FISH for telomere screening is labor intensive and time consuming, given that 41 telomeres are interrogated. We have evaluated the use of array-based Comparative Genomic Hybridization (aCGH) as a more efficient tool for identifying telomere rearrangements. METHODS: In this study, 102 individuals with unexplained mental retardation, with either normal or abnormal FISH results, were selected for a blinded retrospective study using aCGH. Results between the two methodologies were compared to ascertain the ability of aCGH to be used in a clinical diagnostics setting. RESULTS: We detected 100% of all imbalances previously identified by FISH (n = 17) and identified two additional abnormalities, a 10q telomere duplication and an interstitial duplication of 22q11. Interphase FISH analysis verified all abnormal array results. We also demonstrated that aCGH can accurately calibrate the size of telomere imbalances by using an array with "molecular rulers" for the telomeric regions of 1p, 16p, 17p, and 22q. CONCLUSION: This study demonstrates that aCGH is an equivalent methodology to telomere FISH for detecting submicroscopic deletions. In addition, small duplications that are not easily visible by FISH can be accurately detected using aCGH. Because aCGH allows simultaneous interrogation of hundreds to thousands of DNA probes and is more amenable to automation, it offers an efficient and high-throughput alternative for detecting and calibrating unbalanced rearrangements, both of the telomere region, as well as other genomic locations.     

Participation of internal medicine department chairs in the internal medicine clerkship--results of a national survey.

PURPOSE: To characterize the involvement of internal medicine department chairs in the core third-year internal medicine clinical clerkship. METHOD: In 2003, the Clerkship Directors in Internal Medicine (CDIM) surveyed its membership. Along with demographics, clerkship directors were asked if the department's chair participated in the clerkship, the number of hours per month the clerkship director and chair discussed clerkship issues, and if published job expectations were discussed. RESULTS: The response rate was 62% (158/254): 103 responses (89 clerkship directors) represented unique medical schools, which formed the basis of the analysis. Eighty-two percent (84/103) reported the chair taught in the clerkship: 54% as teaching attending, 53% as ward attending, 13% as ambulatory attending, and 20% other (e.g., lectures, student rounds, morning report). Of them, 36% performed two activities; 14% three activities; and 2% four activities. Thirty-six percent of the clerkship directors discussed published expectations with their chair. They spent 1.7 (SD 2.2) hours per month with the chair discussing clerkship issues. However, 17% spent zero hours per month with the chair, and 29% spent zero hours per month with a dean's office representative. Chairs who taught spent more time each month with the clerkship director compared with chairs who did not teach (1.9 versus .82 hours, p = .01, Mann-Whitney). There was no association between the chairs' teaching and clerkship directors' demographics. CONCLUSIONS: Internal medicine department chairs are significantly involved in the clinical education of medical students, both administratively and through direct teaching. Chairs who teach spend more time discussing clerkship issues with the clerkship director. Chairs and clerkship directors should discuss expectations, and chairs should continue to visibly demonstrate their commitment to students' education.