Comparison of GENEHUNTER and MFLINK for analysis of COGA linkage data

We compared the NPLALL statistic from GENEHUNTER with two-point and three-point MALODs and MFLODs from MFLINK for all autosomal markers in the Collaborative Study on the Genetics of Alcoholism (COGA) data set. In general MFLINK produced more significant results than GENEHUNTER and implicated two regions containing candidate genes (ADH3 and DRD2). Many regions of interest identified in other studies reported at this workshop produced MALODs significant at p < or = 0.05, but these would not have been picked up by GENEHUNTER unless a less significant threshold were used.     

Second-generation peptidomimetic inhibitors of protein farnesyltransferase demonstrating improved cellular potency and significant in vivo efficacy.

The synthesis and evaluation of analogues of previously reported farnesyltransferase inhibitors, pyridyl benzyl ether 3 and pyridylbenzylamine 4, are described. Substitution of 3 at the 5-position of the core aryl ring resulted in inhibitors of equal or less potency against the enzyme and decreased efficacy in a cellular assay against Ras processing by the enzyme. Substitution of 4 at the benzyl nitrogen yielded 26, which showed improved efficacy and potency and yet presented a poor pharmacokinetic profile. Further modification afforded 30, which demonstrated a dramatically improved pharmacokinetic profile. Compounds 26 and 29 demonstrated significant in vivo efficacy in nude mice inoculated with MiaPaCa-2, a human pancreatic tumor-derived cell line.     

Donor to host transmission of disease via corneal transplantation

A literature search was conducted to report all cases of documented transmission of infectious diseases from donors to recipients of corneal transplants. Fourteen such cases have been reported. There is no experimental or clinical evidence to suggest the transmissions of either hepatitis or syphilis via corneal grafting. Available evidence regarding a number of neurologic and other disorders in which a slow virus etiology has been implicated were reviewed. On the basis of this review, we are able to draw certain conclusions and guidelines for selection or rejection of donor material for transplant surgery.     

Fat gram target to achieve high energy intake in cystic fibrosis

Higher fat and energy intakes confer a survival advantage in cystic fibrosis (CF). There is a need to develop effective nutrition programmes that ensure optimal energy intake in CF.

Methodology:

A cross-sectional measurement of clinical characteristics and energy and fat intakes in patients attending the CF outpatients clinic of the John Hunter Hospital, Newcastle was undertaken. Twenty-nine subjects, mean age 12 years (range 4.3–20.2), completed weighed food records to determine the contribution of fat to the percentage of the recommended energy intake obtained and to document use of pancreatic enzyme replacement therapy.

Results:

Diets with a high percentage of energy derived from fat did not guarantee that individuals with CF met their energy requirements. Subjects with total fat intakes of 100 g per day or greater, however, achieved in excess of 110% recommended daily intake (RDI) for energy. Up to 47% of subjects consumed more pancreatic enzyme replacement capsules than shown to give maximum effectiveness.

Conclusion:

Setting a 100 g daily fat target is a realistic way of ensuring high energy intakes in CF. Fat ready reckoners would identify the fat content of food and prescribe specific numbers of pancreatic enzyme replacement capsules to be consumed with each meal or food item.     

Intestinal permeability in kwashiorkor

Intestinal permeability can be assessed non-invasively using the lactulose-rhamnose (L-R) test, which is a reliable measure of small intestinal integrity. AIMS: To determine risk factors for abnormal intestinal permeability in kwashiorkor, and to measure changes in L-R ratios with inpatient rehabilitation. DESIGN: A case-control study of 149 kwashiorkor cases and 45 hospital controls. The L-R test was adapted to study kwashiorkor in Malawi, with testing at weekly intervals during nutritional rehabilitation. Urine sugars were measured by thin layer chromatography in London. RESULTS: The initial geometric mean L-R ratios (x100) (with 95% confidence interval) in kwashiorkor were 17.3 (15.0 to 19.8) compared with 7.0 (5.6 to 8.7) for controls. Normal ratios are < 5, so the high ratios in controls indicate tropical enteropathy syndrome. Abnormal permeability in kwashiorkor was associated with death, oliguria, sepsis, diarrhoea, wasting and young age. Diarrhoea and death were associated with both decreased L-rhamnose absorption (diminished absorptive surface area) and increased lactulose permeation (impaired barrier function) whereas nutritional wasting affected only L-rhamnose absorption. Despite, clinical recovery, mean L-R ratios improved little on treatment, with mean weekly ratios of 16.3 (14.0 to 19.0), 13.3 (11.1 to 15.9) and 14.4 (11.0 to 18.8). CONCLUSION: Abnormal intestinal permeability in kwashiorkor correlates with disease severity, and improves only slowly with nutritional rehabilitation.     

Respiratory syncytial virus genotypes and disease severity among children in hospital

OBJECTIVES: To determine the spectrum of N and G genotypes of respiratory syncytial virus (RSV) causing respiratory tract infection and whether particular genotypes are associated with severity of infection. PATIENTS AND METHODS: Nasopharyngeal aspirates (NPAs) were obtained from 114 infants with acute respiratory tract infection due to RSV over two seasons. Viral mRNA was extracted from NPAs or cultured virus, reverse transcribed, and the cDNA amplified by the polymerase chain reaction using primers directed to parts of the N and G gene respectively. Amplicons were separately digested with four different restriction endonucleases for each gene. The fragments were separated by agarose gel, electrophoresis, and the electrophoretic patterns used to assign the various genotypes. Disease severity was assessed as very mild (upper respiratory tract signs only), mild (coryza and signs of lower respiratory tract infection), moderate (requiring nasogastric or intravenous fluids), and severe (requiring oxygen or ventilation). RESULTS: Five of the six known N genotypes were detected, but NP4 and NP2 were found most frequently. There was no association between N genotype and disease severity. Six G (SHL) genotypes were detected. Significantly (p = 0.04) more of the infants infected with the SHL2 genotype had severe or moderate disease. CONCLUSIONS: During the seasonal peaks of RSV respiratory tract infection at least 10 different RSV genotypes cocirculated. While there is no association between N genotypes and disease severity, infection with the SHL2 G genotype appears to result in moderate to severe disease.     

Factors associated with osteoarthritis of the hip and knee in Hong Kong Chinese: obesity, joint injury, and occupational activities

In 1998, a case-control study was conducted in Hong Kong on hospital patients with osteoarthritis of the hip (n = 138) and osteoarthritis of the knee (n = 658). Age- and sex-matched controls were recruited consecutively from general practice clinics in the same region. The following three risk factors were found to be associated with osteoarthritis of both the hip and the knee: first, a history of joint injury: for osteoarthritis of the hip, the odds ratio = 25.1 (95% confidence interval (CI): 3.5, 181) in men and 43.3 (95% CI: 11.7, 161) in women; for osteoarthritis of the knee, the odds ratio = 12.1 (95% CI: 3.4, 42.5) in men and 7.6 (95% CI: 3.8, 15.2) in women; second, climbing stairs frequently: for osteoarthritis of the hip, the odds ratio = 12.5 (95% CI: 1.5, 104.3) in men and 2.3 (95% CI: 0.6, 8.1) in women; for osteoarthritis of the knee, the odds ratio = 2.5 (95% CI: 1.0, 6.4) in men and 5.1 (95% CI: 2.5, 10.2) in women; third, lifting heavy weight frequently: for osteoarthritis of the hip, the odds ratio = 3.1 (95% CI: 0.7, 14.3) in men and 2.4 (95% CI: 1.1, 5.3) in women; for osteoarthritis of the knee, the odds ratio = 5.4 (95% CI: 2.4, 12.4) in men and 2.0 (95% CI: 1.2, 3.1) in women. In addition, subjects whose height and weight were in the highest quartile were at increased risk of osteoarthritis of the hip and knee, respectively (p < 0.05).