Mutation database for the galactose-1-phosphate uridyltransferase (GALT) gene

Classical galactosemia is an autosomal recessive disorder caused by mutations in the galactose-1-phosphate uridyltransferase (GALT) gene. Our group developed a disease-specific database containing all of the reported sequence variants in GALT (Available at: http://arup.utah.edu/database/galactosemia/GALT_welcome.php; Last accessed: 13 April 2007). Currently the database contains a total of 229 sequence variants, of which 196 are mutations (including nine novel mutations identified in our laboratory), 31 polymorphisms in both introns and exons, and two variants of unknown or uncertain significance. All sequence variants have been verified for their position within the GALT gene and named following standard nomenclature. Sequence variants are reported with accompanying information on protein effect, classification of mutation vs. polymorphism, mutation type (when applicable) based on how each was first described in the literature, and accompanying link to pertinent publication. Unpublished variants are described with relevant clinical information that supports their classification as causative of the disease vs. polymorphisms. Other features of this database include disease information, relevant links for galactosemia and literature, reference sequences, ability to query by various criteria, and submit of novel variations to the database. This free online scientific resource was developed with the clinical laboratory in mind to serve as a reference and repository for novel findings that are periodically collected, verified, and updated into the database.     

Chlamydia trachomatis in women: antibody in cervical secretions as a possible indicator of genital infection.

One hundred eighty-five women college students were examined for genital infection with Chlamydia trachomatis. This organism was isolated from nine (5%) of the 185 women. Antibody was demonstrated in the genital secretions of 26 (14%) and in the serum of 70 (38%) of the women. None of the sexually inexperienced women was infected. Among those sexually experienced, the prevalence of isolation of C. trachomatis and of detection of local antibodies in cervical secretions and serum antibodies to C. trachomatis increased in relation to the number of life-time sexual partners. Local antibody appeared to be a more reliable indicator of infection with C. trachomatis than serum antibody in this college population.     

Transmission of Mycobacterium tuberculosis from an infant.

SETTING: This report investigates the unusual transmission of Mycobacterium tuberculosis from a 12-week-old infant with nosocomially acquired tuberculosis (TB). Compliance with recommendations on the post-exposure management of young children is described. DESIGN: Contacts of an infant case of TB were identified and recommended to undergo baseline and post-exposure tuberculin skin tests (TST) as per Canadian TB standards. TST conversion was measured at least 8 weeks post exposure. Children aged <6 years were recommended to initiate preventive treatment with isoniazid (INH) until their post-exposure TST. Information on TST results and adherence to therapy were analysed from existing medical records. RESULTS: Overall, 17 TST conversions were documented among 732 contacts: both parents, two health care workers (HCWs) who provided close care, and several patients, visitors and one staff member without obvious close contact. Of 65 eligible children, 46% completed post-exposure therapy as recommended. The most common reasons for treatment failure were concern about side effects, perception of low risk and lack of physician support. CONCLUSION: This investigation suggests that all children, including infants, with cough and numerous bacilli or extensive pulmonary disease should be considered infectious. Health care provider education is necessary to resolve the observed low compliance with current post-exposure management guidelines.     

Protease inhibitors and ectasia in coronary atherosclerosis

The possibility of elastase contributing to degradation of the arterial wall in atherosclerosis and to the formation of ectasia has prompted us to assay the main protease inhibitors, alpha 1-antitrypsin and alpha 2-macroglobulin, in patients with angiographic coronary disease with and without coronary ectasia. Serum concentrations of these two proteins were measured by immunonephelometry in 203 patients admitted for coronary arteriography. The results obtained were analyzed according to the presence of atheromatous lesions and their severity and to the presence or absence of ectasia. There was no correlation between the values observed and the presence or severity of coronary atherosclerosis, but the concentration of alpha 1-antitrypsin was significantly higher in patients with coronary ectasia (247.2 +/- 40.5 mg/ml) than in patients without ectasia (213.5 +/- 36.6 mg/100 ml; p less than 0.001). This study shows that coronary ectasia is associated with disturbances in the protease-antiprotease system, which may be consecutive to initial changes in elastase activity. Our results support the theory that elastase and protease inhibitors play a specific role in some atheromatous processes.     

Gastric inhibitory polypeptide (GIP) stimulated by fat ingestion in man.

Ten normal volunteers ingested emulsified corn oil and the immunoreactive GIP, insulin (IRI) and nonesterified fatty acid (NEFA) responses were measured. Serum GIP levels increased after the ingestion of corn oil in all subjects, rising from a mean fasting level of 272 pg/ml to 856 +/- 272 pg/ml (P less than 0.05) by 30 minutes. The peak mean serum GIP concentration of 1,345 +/- 291 pg/ml occurred at 60 minutes; and mean serum GIP levels at 180 minutes remained significantly elevated over fasting values. Serum IRI, glucose and NEFA concentrations did not change during the 180 minutes of study. No changes in serum GIP concentrations occurred when, for control purposes, six volunteers ingested water on another day. We conclude: 1) Fat is a potent stimulus for the release of GIP in normal individuals. 2) Endogenously released GIP is not insulinotropic under the conditions of this study.     

Metabolism of collagen in coronary patients

The alterations observed in connective tissue of the arterial wall and dermis in atherosclerosis incited us to investigate collagen metabolism in patients with coronary disease. We first studied collagen metabolism in fibroblast cultures, then measured serum levels of type III procollagen aminoterminal peptide. Fibroblast collagen metabolism was investigated in 12 consecutive patients of less than 45 years of age presenting with coronary disease and coronary atherosclerosis was found to be preserved in patients with atherosclerosis, but less type III type I procollagen was synthesized (14.6 +/- 6.6% versus 22.3 +/- 4.3%). This abnormality, found in 83% of our coronary patients, seemed to be unrelated to risk factors or to the severity of atherosclerosis. Serum type III procollagen aminoterminal peptide was assayed comparatively in 36 patients with coronary atherosclerosis confirmed at coronary-ventriculography and in 35 patients free from coronary disease as defined by the W.H.O. criteria. Serum levels of this peptide were significantly higher in patients with coronary atherosclerosis (26.76 +/- 16 ng/ml) than in controls (10.43 +/- 3.18 ng/ml). 61% of coronary patients had a peptide level higher than the normal value (17 ng/ml). No correlation was found between this rise in type III procollagen aminoterminal peptide and the severity of coronary lesions or the importance of risk factors. Thus, collagen metabolism is altered in coronary patients, and this alteration can be detected by a peripheral marker. However, the use of this marker to diagnose the presence or evaluate the course of atherosclerosis requires clarification.     

RANK-dependent autosomal recessive osteopetrosis: characterization of five new cases with novel mutations

Autosomal recessive osteopetrosis (ARO) is a genetically heterogeneous disorder attributed to reduced bone resorption by osteoclasts. Most human AROs are classified as osteoclast rich, but recently two subsets of osteoclast-poor ARO have been recognized as caused by defects in either TNFSF11 or TNFRSF11A genes, coding the RANKL and RANK proteins, respectively. The RANKL/RANK axis drives osteoclast differentiation and also plays a role in the immune system. In fact, we have recently reported that mutations in the TNFRSF11A gene lead to osteoclast-poor osteopetrosis associated with hypogammaglobulinemia. Here we present the characterization of five additional unpublished patients from four unrelated families in which we found five novel mutations in the TNFRSF11A gene, including two missense and two nonsense mutations and a single-nucleotide insertion. Immunological investigation in three of them showed that the previously described defect in the B cell compartment was present only in some patients and that its severity seemed to increase with age and the progression of the disease. HSCT performed in all five patients almost completely cured the disease even when carried out in late infancy. Hypercalcemia was the most important posttransplant complication. Overall, our results further underline the heterogeneity of human ARO also deriving from the interplay between bone and the immune system, and highlight the prognostic and therapeutic implications of the molecular diagnosis.     

Emergency care of esophageal foreign body impactions: timing,treatment modalities,and resource utilization

Esophageal foreign body impaction (EFBI) often requires urgent evaluation and treatment, but characteristics of emergency department (ED) care such as timing of presentation and therapeutic procedures and costs of care are unknown. We aimed to study health‐care utilization for patients with EFBI presenting to the ED. Cases of EFBI from 2002 to 2009 were identified by querying three different databases from the University of North Carolina Hospitals for all records with ICD‐9 CM code 935.1: ‘foreign body in the esophagus.’ Charts were reviewed to confirm EFBI and extract pertinent data related to the ED visit, including time of presentation, length of ED stay, medications administered, type of procedure performed, characteristics of procedures, and time to therapeutic procedure. Hospital charges for EFBI encounters and consult fees were determined from the Physicians' Fee Reference 2010, and were compiled to estimate costs. Of the 548 cases of EFBI identified, 351 subjects (64%) presented to the ED. A total of 118 (34%) patients received a medication to treat EFBI, which was only effective in 8% of those patients. Two hundred ninety (83%) subjects underwent a procedure including esophagogastroduodenoscopy (EGD) (n=206) or ear, nose, and throat surgery (ENT)‐performed laryngoscopy/esophagoscopy (n=138). Admission to the hospital occurred in 162 (46%) of cases. There was no relationship between ED arrival time and time‐to‐procedure or total time in ED. There was also no significant relationship between delivery of ED medications and likelihood of undergoing a procedure, or between ED arrival time and delivery of medications. The charges associated with a typical EFBI episode ranged from $2284–$6218. In conclusion, the majority of patients with EFBI at our institution presented to the ED. Medical management was largely ineffective. A therapeutic procedure was required to clear the EFBI in most patients. Time of ED arrival made no difference in time‐to‐procedure, indicating that gastroenterology and ENT specialists recognize the urgency of treating EFBI regardless of time of day.