Segregation analysis of microcephaly.

Microcephaly is a heterogeneous disorder with genetic and environmental causes. However, there is little information on what proportion of cases are caused by inherited susceptibility, or the mode of inheritance in familial cases. To address these questions, we have performed classical and complex segregation analyses for microcephaly on 2 sets of family data collected from genetic counseling clinics in Vancouver and Jerusalem. These samples consisted of 143 affected individuals in 127 families ascertained from Vancouver, and 101 affected individuals in 59 families ascertained from Jerusalem. The results of the segregation analyses for the Vancouver sample indicated that approximately half of all microcephaly cases were due to highly penetrant recessive mutant alleles, with the remainder being sporadic. Although a recessive model allowing for the occurrence of sporadic cases fit the data from Vancouver best, a dominant model could not be statistically rejected. The classical segregation analysis on the Jerusalem sample suggested that both a dominant model with 29% of the cases being sporadic and a purely recessive model provided adequate fit to the data. Although the complex segregation analysis of this sample indicated that a dominant model provided a more parsimonious explanation for the observed familial variation, a recessive model was only marginally rejected. It should be noted that in the Jerusalem sample, families tended to be ascertained in the genetic counseling clinic only after the birth of a second affected child. This could be a potential bias which could inflate the segregation ratio, thus giving the impression of dominant inheritance. Our analyses, while confirming the complex nature of the cause of microcephaly, indicate that it may be necessary to await the results of genetic linkage analysis before a definitive mode of inheritance can be determined.

Age, sex, and the familial risk of rheumatoid arthritis.

The familial aggregation of rheumatoid arthritis was examined to determine factors modifying the risk of rheumatoid arthritis in first degree relatives of 165 cases ascertained from January 1, 1987, through March 31, 1987, using the Saint Margaret Memorial Hospital Rheumatoid Arthritis Registry, Pittsburgh, Pennsylvania, without regard to previous information concerning the occurrence of rheumatoid arthritis among their family members. The reported affection status of first degree relatives, verified through a structured clinical evaluation, revealed a false-positive reporting rate for family members of 61%. In contrast, there were no false-negative cases detected. There were no differences in average family size or total number of years at risk between 135 simplex and 30 multiplex families; however, aggregation analysis revealed that only 18 of 30 confirmed multiplex families had significant excess risk of rheumatoid arthritis. Significant differences were found when probands from multiplex families were compared with those from simplex families with regard to female to male ratio for probands (1:1 in multiplex families vs. 3:1 in simplex families) and average age of onset for probands (41 years in multiplex families vs. 48 years in simplex families). The familial risk for rheumatoid arthritis was similar in parents (4.2%) and siblings (4.6%) and lowest for children (0.7%) of probands. The authors assert that the affection status of first degree relatives of patients with rheumatoid arthritis is often falsely reported as positive. The familiality of rheumatoid arthritis may be more accurately related to the sex and age at onset of the affected family member.

Genetic epidemiology of rheumatoid arthritis.

We conducted family studies and segregation analyses of rheumatoid arthritis (RA) that were based on consecutive patients with RA ascertained without regard to family history or known risk factors. First-degree relatives from 135 simplex and 30 multiplex families were included in the analyses. A highly penetrant recessive major gene, with a mutant allele frequency of .005, was identified as the most parsimonious genetic risk factor. Significant evidence for heterogeneity in risk for RA was observed for proband gender but not for proband age at onset. Kaplan-Meier risk analysis demonstrated significant evidence for differences in the distribution of risk among first-degree relatives. These analyses demonstrated that both proband gender and age at onset are important risk factors but that proband gender appears to be the more important determinant of risk, with relatives of male probands having the greatest cumulative risk for RA. In addition, log-linear modeling identified proband gender, familiality (multiplex or simplex), and an interaction term between these two variables as being adequate to define the distribution of risk in families. The pattern of risk for RA among susceptible individuals and its inheritance is thus heterogeneous. For future genetic analyses, families with an excess of affected males having a young age at onset may be the most informative in identifying the putative recessive gene and its modifiers.

A comparison of paralysing agents in double-contrast barium meal examinations.

One hundred and fourteen patients attending for barium meal examination were randomly allocated to receive Buscopan (hyoscine N-butylbromide, Boehringer Ingelheim; 20 mg) or glucagon (0.5 mg) as paralysing agents, or sterile water as control. The radiographs were analysed with regard to (a) gastric and duodenal distension and coating and (b) early or delayed filling of the duodenum with barium, in order to assess claims that paralysing agents influence radiographic quality. It was found that both duodenal distension and coating were better with Buscopan and glucagon than with water but there was no difference between Buscopan and glucagon in producing these effects. Relaxants produced no significant effect on distension or coating of the stomach. Glucagon prolonged the time of some examinations but gave better visualisation of the stomach, which was less frequently obscured by contrast in the duodenum.

Echo-free renal masses on ultrasound: the stethoscope as an adjunct to their diagnosis.

A patient with an intrarenal arteriovenous malformation is described. Ultrasound suggested this to be a renal cyst but auscultation revealed a loud bruit and, on the basis of this, arteriography rather than cyst puncture was carried out.

Clinical trial of microcrystalline hydroxyapatite compound ('Ossopan') in the prevention of osteoporosis due to corticosteroid therapy.

A controlled clinical trial was carried out in 40 patients at risk of osteoporosis because of long-term treatment with prednisolone (5 to 20 mg/day) to determine the efficacy and tolerance of microcrystalline hydroxyapatite compound (MCHC) when used to prevent the appearance or progression of osteoporosis: 32 patients were treated with 6 to 8 g MCHC for 12 months and 8 served as an untreated control group. The two groups were well matched as regards age, sex and underlying disease; 37 patients (29 MCHC, 8 control) successfully completed the trial. The majority (68%) of the patients had back pain prior to the trial, the severity of which was graded at 3-monthly intervals. In the MCHC-treated group, there was a dramatic and significant (p less than 0.001) reduction in pain during the trial, almost to the point of its disappearance. Of 19 patients with initial back pain only 2 still reported any pain at all after 12-months' MCHC treatment. In the control group, back pain severity increased during the trial in 3 patients and was unchanged in the fourth. Neither MCHC-treated nor control group patients showed any significant change in standing or stem height during the 12-months' trial period. Both mean cortical thickness and mean metacarpal index figures showed small, insignificant decreases during 12-months' MCHC treatment but much more marked decreases in the control group which, despite the small number of patients, came close to being statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)