Neonatal cholestasis: opportunities to increase early detection

ObjectiveTo describe primary care management of early and prolonged jaundice in otherwise-healthy term infants to identify opportunities to increase early diagnosis of cholestasis.MethodsCommunity-based pediatricians in St Louis, Missouri completed a mailed, anonymous, 29-item survey to assess practice demographics, timing of routine newborn office visits, and the management of early and prolonged neonatal jaundice.ResultsA total of 108 of 230 (47%) of eligible physicians responded (mean years in practice, 15.3, SD, 9.4). More respondents were very familiar with national guidelines for management of early (49%) than prolonged (16%) neonatal jaundice. Eighty-six percent reported all newborns were checked with transcutaneous bilirubin before hospital discharge. For transcutaneous bilirubin results at 48 hours of 7, 10, 12 and 15 mg/dL, 1%, 26%, 70%, and 74% of respondents, respectively, would order a fractionated bilirubin. Although the first routine visit usually occurred in the first week after discharge, 25% of physicians reported the 2nd visit was routinely scheduled after 4 weeks of age. Ninety-four percent reported they would obtain a fractionated bilirubin for infants jaundiced beyond 4 weeks of age. If cholestasis was identified at 6 weeks of age, 32% would obtain additional testing without referral to a subspecialist.ConclusionsManagement of early and prolonged neonatal jaundice is variable. Current practices appear to miss opportunities for early diagnosis of cholestasis and referral that are unlikely to be addressed without redesigning systems of care.     

Mapping of three novel loci for non‐syndromic autosomal recessive mental retardation (NS‐ARMR) in consanguineous families from Pakistan

Rafiq MA, Ansar M, Marshall CR, Noor A, Shaheen N, Mowjoodi A, Khan MA, Ali G, Amin‐ud‐Din M, Feuk L, Vincent JB, Scherer SW. Mapping of three novel loci for non‐syndromic autosomal recessive mental retardation (NS‐ARMR) in consanguineous families from Pakistan. To date, of 13 loci with linkage to non‐syndromic autosomal recessive mental retardation (NS‐ARMR), only six genes have been established with associated mutations. Here we present our study on NS‐ARMR among the Pakistani population, where people are traditionally bound to marry within the family or the wider clan. In an exceptional, far‐reaching genetic survey we have collected more than 50 consanguineous families exhibiting clinical symptoms/phenotypes of NS‐ARMR. In the first step, nine families (MR2‐9 and MR11) with multiple affected individuals were selected for molecular genetic studies. Two families (MR3, MR4) showed linkage to already know NS‐ARMR loci. Fifteen affected and 10 unaffected individuals from six (MR2, MR6, MR7, MR8, MR9 and MR11) families were genotyped by using Affymetrix 5.0 or 6.0 single‐nucleotide polymorphism (SNP) microarrays. SNP microarray data was visually inspected by dChip and genome‐wide homozygosity analysis was performed by HomozygosityMapper. Additional mapping was performed (to exclude false‐positive regions of homozygosity called by HomozygosityMapper and dChip) on all available affected and unaffected members in seven NS‐ARMR families, using microsatellite markers. In this manner we were able to map three novel loci in seven different families originating from different areas of Pakistan. Two families (MR2, MR5) showed linkage on chromosome 2p25.3‐p25.2. Three families (MR7, MR8, and MR9) that have been collected from the same village and belong to the same clan were mapped on chromosome 9q34.3. MR11 maps to a locus on 9p23‐p13.3. Analysis of MR6 showed two positive loci, on chromosome 1q23.2‐q23.3 and 8q24.21‐q24.23. Genotyping in additional family members has so far narrowed, but not excluded the 1q locus. In summary, through this study we have identified three new loci for NS‐ARMR, namely MRT14, 15 and 16.     

The effect of cyclic strain on embryonic stem cell-derived cardiomyocytes

Cardiomyocytes in the body are subjected to cyclic mechanical strain induced by the rhythmic heart beating. In this study, we tested the hypothesis that cyclic strain promotes cardiomyogenesis of embryonic stem cell-derived cardiomyocytes (ESCs). ESCs cultured on elastic polymer [poly(lactide-co-caprolactone), PLCL] scaffolds subjected to cyclic strain in vitro displayed elevated cardiac gene expression compared to unstrained controls. Six weeks after implantation into infarcted rat myocardium, the elastic cardiac patches (ESC-seeded PLCL scaffolds) showed reduced fibrotic tissue formation, likely due to a combination of lower apoptotic activity, higher vascular endothelial growth factor (VEGF) expression, and more extensive angiogenesis in the strained versus unstrained control [ESC-seeded, non-elastic poly(lactide-co-glycolide) scaffolds] patches. Importantly, cardiac gene expression was upregulated in the elastic patches compared to control, with evidence for cardiomyocyte-specific microstructures including myofibrillar bundles and Z-lines. This study shows that the use of an elastic polymer scaffold designed to permit mechanical strain transduction as a cell transplantation vehicle significantly increases cardiomyogenesis of the implanted ESCs.     

The use of poly(ethylene glycol) hydrogels to investigate the impact of ECM chemistry and mechanics on smooth muscle cells

Hydrogels based on poly(ethylene glycol) (PEG) are of increasing interest for regenerative medicine applications and are ideal materials to direct cell function due to the ability to confer key functionalities of native extracellular matrix (ECM) on PEG's otherwise inert backbone. Given extensive recent evidence that ECM compliance influences a variety of cell functions, PEG-based hydrogels are also attractive due to the ease with which their mechanical properties can be controlled. In these studies, we exploited the chemical and mechanical tunability of PEG-based gels to study the impact of ECM chemistry and mechanics on smooth muscle cells (SMCs) in both 2-D and 3-D model systems. First, by controlling the extent of crosslinking and therefore the mechanical properties of PEG-based hydrogels (tensile moduli from 13.7 to 423.9kPa), we report here that the assembly of F-actin stress fibers and focal adhesions, indicative of the state of actin contractility, were influenced by the compliance of 2-D PEG gels functionalized with either short adhesive peptides or full-length ECM proteins. Varying ECM ligand density and identity independent of gel compliance affected the physical properties of the focal adhesions, and also influenced SMC spreading in 2-D. Furthermore, SMCs proliferated to a greater extent as gel stiffness was increased. In contrast, the degree of SMC differentiation, which was qualitatively assessed by the extent of smooth muscle alpha-actin bundling and the association of calponin and caldesmon with the alpha-actin fibrils, was found to decrease with substrate stiffness in 2-D cultures. In 3-D, despite the fact that their viability and degree of spreading were greatly reduced, SMCs did express some contractile markers indicative of their differentiated phenotype when cultured within PEG-RGDS constructs. Combined, these data suggest that the mechanical and chemical properties of PEG hydrogels can be tuned to influence SMC phenotype in both 2-D and 3-D.     

Corticosteroid regulation of gonadotropin and prolactin secretion in the rat

The purpose of this study was to determine if glucocorticoids had any direct effects on the release of gonadotropin. In estrogen-primed ovariectomized immature rats, triamcinolone acetonide and deoxycorticosterone (1 mg/kg BW) caused a surge in both serum LH and FSH levels. Dexamethasone treatment (0.05 mg/kg BW) resulted in a highly significant selective release of FSH. Cortisol (1 mg/kg BW) suppressed serum FSH levels. A systematic dose-response study showed that triamcinolone acetonide significantly released LH and FSH and suppressed PRL at all doses tested (range, 0.25-4 mg/kg BW). Deoxycorticosterone was not as potent as triamcinolone acetonide and only doses greater than 0.8-1 mg/kg BW significantly released LH and FSH. Dexamethasone selectively released FSH at low doses (0.01, 0.02, 0.05, and 0.1 mg/kg BW) and inhibited LH at higher doses (0.5 and 1.0 mg/kg BW). A single low dose of dexamethasone (0.02 mg/kg BW) was found to significantly release LH. With respect to PRL secretion, a biphasic effect of dexamethasone was observed in that the lowest dose (0.01 mg/kg BW) stimulated PRL release while the highest dose (1.0 mg/kg BW) significantly inhibited PRL release. Triamicolone acetonide and deoxycorticosterone were found to require estrogen priming for their effects on gonadotropin secretion. The findings in this study raise the possibility that the beneficial effects seen with corticosteroids in inducing ovulation in polycystic ovarian syndrome may be due, in part, to their direct effects upon the release of gonadotropins.     

The chemotherapy of lymphoblastic lymphoma

Thirty-two patients treated on consecutive Southwest Oncology Group (SWOG) protocols for malignant lymphoma were subsequently diagnosed as having lymphoblastic lymphoma. Combination chemistry, usually adriamycin-based, produced complete responses (CR) in 17 patients (53%). Median survival was 15 mo. Patients achieving a CR survival significantly longer than patients with partial or no response (p < 0.01). Ten of 24 patients not receiving central nervous system (CNS) prophylaxis developed leptomeningeal lymphoma while none of the seven patients who received prophylactic intrathecal cytosine arabinoside or methotrexate developed CNS lymphoma (p = 0.04). Implications of these results for planning future treatment programs of lymphoblastic lymphoma are discussed.     

Perforation of the inferior vena cava with aortic and vertebral penetration by a suprarenal Greenfield filter

Various complications have been reported after insertion of the Greenfield filter. This report describes an unusual complication after suprarenal placement of this filter: spreading of the filter struts, with perforation of the inferior vena cava, and penetration of the aorta and a vertebral body, followed by fracture of one of the struts.     

Shoulder instability: impact of glenohumeral arthrotomography on treatment

We used arthrotomography to study the glenoid labrum in 114 patients. Sixty-nine of the patients had anatomic instability of the shoulder (including recurrent dislocation and subluxation of the shoulder), and 45 patients had functional instability of the shoulder (denoted by chronic pain, clicking of the joint, and the sensation that an unstable condition exists without the objective signs of it). Labral tears were revealed arthrotomographically in 86% of the patients with anatomic instability, while only 40% of the patients with functional instability had labral abnormalities, and these were primarily of minor severity. Fifty-six patients (44 of whom had anatomic instability; 12, functional instability) required surgery. The surgical findings were correlated with the arthrotomographic findings, and no false-positive results were revealed. However, arthrotomography demonstrated only part of the pathologic condition of two patients. These results confirm that there is a strong correlation between labral pathologic conditions and anatomic instability of the shoulder. Arthrotomographic studies have a great impact on the selection of therapy in cases of both anatomic and functional instability of the shoulder.     

Detecting Insufficient Effort Using the Seashore Rhythm and Speech-Sounds Perception Tests in Head Injury

This study examined the capacity of the Seashore Rhythm Test (SRT) and the Speech-Sounds Perception Test (SSPT) to detect insufficient effort in a clinical sample. Forty-six participants with financially compensable mild head injury who obtained scores indicative of insufficient effort on multiple measures were compared to 49 participants with brain injury who were not involved in litigation. Receiver operating characteristic (ROC) curve analysis indicated that both the SRT (AUC = .84) and SSPT (AUC = .80) were significant (p < .001) predictors of insufficient effort. Maximizing sensitivity and specificity, the optimal cutoff scores were 8 errors on the SRT and 10 errors on the SSPT. Combining both variables into a logistic regression function increased the diagnostic efficiency.     

Complete amino acid sequence of human plasma beta 2-glycoprotein I.

We have determined the complete amino acid sequence of beta 2-glycoprotein I (Mr, congruent to 50,000), a human plasma protein that is associated with lipids and binds to platelets but whose function is not yet known. The protein consists of 326 amino acids and has five attached glucosamine-containing oligosaccharides. The protein is rich in cysteine and proline, and the sequence is notable for the frequent occurrence of Cys-Pro linkages at regular intervals. Computerized analysis of the sequence reveals five consecutive homologous segments in which cysteine, proline, and tryptophan appear to be highly conserved. This suggests that beta 2-glycoprotein I may have evolved by repeated duplications of a gene coding for a 60-amino acid segment of protein.