Serum pseudocholinesterase and very-low-density lipoprotein metabolism.

Serum pseudocholinesterase (PChE) was discovered in 1932. Since this protein mimics many of the catalytic properties of acetylcholinesterase, it has traditionally been referred to as PChE, even though its true biological function is unknown. Serum PChE is synthesized in the liver and secreted into the circulation as a sialated glycoprotein. Although no convincing evidence of biological function exists, a significant number of obese and diabetic patients have elevated levels of PChE. The same phenomenon is found in experimental animal models of obesity, diabetes and hyperlipoproteinemia. Streptozotocin-induced diabetic mice showed increased serum PChE activity concomitant with increased serum triacylglycerol and PChE activity declined with treatment. Iso-OMPA, a nontoxic inhibitor of serum PChE, reduced serum and liver triacylglycerols and serum VLDL in streptozotocin-induced rodent diabetes. These findings suggest that PChE may have a role in VLDL metabolism.

Congenital contractural deformities of the fingers and arthropathy.

Four patients are described who presented with congenital finger contractures and arthropathy. There was synovial cell hyperplasia and giant cells but no inflammatory process. Radiographs showed flattening of the metacarpal and metatarsal heads and the proximal femoral ossification centres. In the oldest patient the process had subsided leaving slight contractures but severe impairment of hip mobility. In another the arthropathy was still prominent in the early teens. In a third, finger contractures had failed to respond to conservative or surgical measures.

Congenital contractural deformities of the fingers and arthropathy

Four patients are described who presented with congenital finger contractures and arthropathy. There was synovial cell hyperplasia and giant cells but no inflammatory process. Radiographs showed flattening of the metacarpal and metatarsal heads and the proximal femoral ossification centres. In the oldest patient the process had subsided leaving slight contractures but severe impairment of hip mobility. In another the arthropathy was still prominent in the early teens. In a third, finger contractures had failed to respond to conservative or surgical measures.

Prognosis of adult onset polycystic kidney disease re-evaluated.

To appraise the prognosis of adult onset polycystic kidney disease (APKD), an inception cohort containing 140 subjects from 17 kindreds was assembled. Multiple renal cysts, demonstrable by ultrasonography, or clinical APKD, or both were present in 100 subjects. APKD was predicted in 32 subjects unavailable for ultrasonography and could not be excluded in eight deceased subjects. All had been at risk for endstage renal disease (ESRD) since birth. The probability of either developing ESRD, requiring dialysis or transplantation, or dying was estimated using a time-to-event analysis. The earliest age at which ESRD occurred was 36 years. For those with APKD, the probability of being alive and not having ESRD was 77% by age 50, 57% by age 58, and 52% by age 73 years. Excluding those predicted to have APKD changes these probabilities to 75, 53, and 47%, respectively. The serum creatinine values were less than 1.5 mg/dl for most subjects who had not developed ESRD. The prognosis for subjects with APKD is much better than most reports suggest and can be estimated from the time-to-event data presented.

Age at clinical onset and at ultrasonographic detection of adult polycystic kidney disease: data for genetic counselling.

Few reports are available on the age-related risk of relatives of affected persons to manifest adult polycystic kidney disease (APKD). For 371 persons in 17 kindreds, at risk for APKD by virtue of having an affected first degree relative, we calculated the estimated probability of clinical diagnosis of APKD to be 0.011 by age 20, 0.041 by age 30, 0.115 by age 40, 0.299 by age 50, and 0.404 by age 60 years (expected = 0.50). Ultrasonographic examination of 172 asymptomatic persons at risk showed definite APKD in 60. The probability of ultrasonographic detection of asymptomatic APKD is estimated as 0.222, 0.657, and 0.855 at age 5, 15, and 25 years, respectively. The probability of having APKD following normal ultrasonogram results (conservatively assuming 90% specificity) is estimated as 0.46, 0.28, and 0.14 for persons at 50% risk in their first, second, or third decade. The marginal benefit of ultrasound as a diagnostic test for APKD for persons in the second or third decade is estimated as 0.37 and 0.41, respectively for a "positive" test and 0.22 and 0.37 for a "negative" test.

Study of alleles of the second complement component (C2) on Canadian HLA haplotypes.

Typing for genetic variation in the second complement component C2 was performed on sera from HLA haplotyped Canadian families. Part of the data has been studied and analysed as a population; in addition there is a further random collection of haplotypes bearing the C2*2 allele. In the population data there were 444 separate haplotypes from unrelated parents or other founders: 4.7% of the haplotypes carried the uncommon allele C2*2; one haplotype carried the rare C2*3. Study of C2 2-1 heterozygotes in the population data revealed 59 haplotypes which carried the common C2*1 allele and one which carried a deficiency allele C2*0. The remaining haplotypes carried either C2*1 or else an undetectable C2*0 allele. In the entire data there were 281 meioses informative for C2. The only recombinant between HLA-B and C2 showed the C2 locus to be on the DR side of the B locus. Strong allelic association between C2 *2 and Bw22 and less strong association between C2 *2 and B15 suggested the possibility of two ancestral C2 mutants. Examination of other markers on these and subsequently collected haplotypes do not conflict with this idea since the B15 haplotypes mostly carry C4A *4, C4B *2 whilst the Bw22 haplotypes mostly carry C4A *4, C4B *4. The alternative idea, that there was one original mutant which crossed over from a B15 to a Bw22 haplotype or vice versa is not excluded, however. Since approximate equilibrium has been reached between Bw22 and the HLA-A locus alleles on these C2 *2 bearing haplotypes, we conclude that this mutation is at least 5000 years old. Other haplotypes carrying C2 *2 are assumed to be ancestral recombinants; if this is true, the C2 locus map position between HLA-B and HLA-DR is confirmed. Study of C2 mutation may provide a model for understanding the genetics of some disease susceptibility genes in the HLA region.

HLA-B27 haplotypes in family studies of ankylosing spondylitis.

Although HLA-B27 carries a high relative risk for development of ankylosing spondylitis (AS), most B27 positive individuals do not have spondylitis. One interpretation of this observation is that there may be 2 types of B27, 1 which carries the risk factor and 1 which does not. If this were the case, then with the help of markers closely linked to HLA-B, it might be possible to detect differences between the B27 haplotypes in AS patients and those in healthy probands. We studied 197 members of 18 families with known AS and 110 members of 19 families in which HLA-B27 was present without any known inflammatory spinal disease. HLA antigens A, B, and C and alleles of complement components C2, C4, and Factor B and glyoxalase-1 were determined in all cases. Detailed haplotypes were assigned and their associations with development of the disease were examined. We were unable to identify any distinct HLA-B27 haplotype associated with AS; 2 common haplotypes and several miscellaneous ones were found in both groups. Thinking that the development of AS might be influenced by the other, non-B27 haplotype, we analyzed this and found that there was no detectable influence. The data do not contradict the notion that B27 in whites is a single entity and is itself the susceptibility factor predisposing to the development of ankylosing spondylitis.

Familial, EsD-linked, retinoblastoma with reduced penetrance and variable expressivity.

We report an example of four generation familial retinoblastoma in which there are three distinct categories of RB gene expression: frank retinoblastoma, unilateral or bilateral; retinoma; and no visible evidence of retinal pathology other than normal degeneration with age. Two large sibships derived from matings informative for RB and EsD provide strong confirmatory evidence for tight linkage between these loci (P = 0.0002), and thus assignment of RB to chromosome 13q14. There is a striking difference (P less than 2%) in RB penetrance between the two principal generations, which suggests that an additional epistatic, host-resistance gene may also be segregating within the family.

Electrophoretic evidence that GLO2 is the ancestral allele at the glyoxalase-I locus in humans.

Glyoxalase-I (EC 4.4.1.5) is polymorphic in humans but not in the closely related hominoid species, Pan troglodytes (the common chimpanzee). The electrophoretic mobility of chimpanzee glyoxalase-I is identical to that of human GLO2, as is that of another Old World primate, Macaca fasicularis. These evidences suggest that GLO2 may be the ancestral allele at this locus in hominoids. The significance of the human GLO variation is discussed in the light of other recent findings showing balanced polymorphism at this locus.

Human infections with thymine-requiring bacteria.

Clinical details are presented of 16 patients from whom thymine-requiring (thy-) mutants of pathogenic organisms were isolated; all had been treated with co-trimoxazole. The urine of six patients infected with thy- mutants contained levels of a thymine-like compound sufficient to support their growth. This might be the result either of the breakdown of pus cells or of thymine production by living bacteria that persist in stones or scar tissue, a suggestion supported by the observation of mutant growth "in satellitism" in vitro. Since 1975 we have isolated mutants from patients who have had short courses of co-trimoxazole, in contrast to those we reported upon previously, all except one of whom had had long courses. We are now isolating thy- mutants more frequently than hitherto. Secondary mutations to a low thymine requirement may now be occurring more rapidly, thereby allowing more mutant organisms to survive. The clinical significance of infection with thy- mutants is not yet clear, but evidence is accumulating that they are pathogenic. Alternative chemotherapy is suggested for patients from whom such mutants have been isolated.

Thymine-requiring bacteria associated with co-trimoxazole therapy.

Since 1971 thymine-requiring (thy-) pathogens have been isolated from the urine of 8 patients with renal calculi, and from the sputum of 1 patient with chronic chest infection. The patients had been treated with co-trimoxazole for several months before the isolation of the mutant pathogens. There was persistent pyuria in the patients with renal calculi, and purulent sputum in the patient with chronic chest infection. The mutants were identified by their inability to grow on diagnostic sensitivity test agar (D.S.T., Oxoid) which is deficient in thymine. It was found that wild-type bacteria can produce growth factors for the metabolism of the mutants in vitro, and the urine of the patients contained by thymine-like compounds. These findings indicate that thy- mutants may develop in renal calculi during co-trimoxazole therapy. Therapy should be changed to a more suitable antimicrobial as soon as possible after diagnosis of mutant infection.