Biomedical subjects
Publications and source records attributed to C A Morris.
In a series of 48 patients with Williams syndrome examined from 1984 to 1988, 3 physical manifestations were noted which have not been emphasized in previous reports of this condition. Unusual sacral creases were found in 25/48 patients, a linear array of hemangiomas (nevus flammeus) on the back in 3/48, and limitation of supination in 5/48.
Reports of adults with Williams syndrome (WS) have been rare. We have evaluated 13 adult WS patients and reviewed 16 case reports of WS in patients older than age 16 years. Adults in our study had progressive multisystem medical problems. Cardiovascular complications were common (12/13) including hypertension (8), supravalvular aortic stenosis (9), aortic hypoplasia (3), pulmonic artery stenosis (4), peripheral stenoses (3), and mitral valve prolapse (2). Joint limitation (12/13) was progressive, often accompanied by kyphoscoliosis and lordosis. Recurrent urinary tract infections in 6 individuals led to radiologic studies showing urethral stenosis in 2, and bladder diverticula and vesicoureteral reflux in 3. Gastrointestinal problems included obesity (5), chronic constipation (7), diverticulosis (3), and cholelithiasis (4). Hypercalcemia was documented in 5 patients, although others had hypercalcemic symptoms (abdominal pain, polyuria, and constipation). One 45-year-old man had parathyroid hyperplasia. Previous reports likewise document significant morbidity. Thus, Williams syndrome in an adult appears to dictate aggressive evaluation and monitoring. Investigation of calcium metabolism should be undertaken in each adult WS patient.
We investigated the natural history of Williams syndrome (WS), including physical characteristics and cognitive, academic language, sensory integration, and adaptive and maladaptive behavior in 32 patients (age 3 to 30 years). These patients were available for psychoeducational testing, parent interview, medical and educational record review, and behavioral observation. Thirty-seven nonlocal individuals (age 8 months to 31 years) were not tested but data on history and development, sensory integration, adaptive and maladaptive behavior were collected resulting in a total sample of 69. The unique constellation of physical manifestations and associated clinical problems in WS contributes to a characteristic behavioral phenotype of 6 factors beginning in infancy with development of salient attachment behaviors. Later a key issue affecting the learning abilities of both the school-aged child and adult with WS was an inadequate development in the use of tools. Theoretical constructs from developmental behavioral genetics, attachment theory, operant conditioning, neuropsychology, and psychosocial theory considered interactively offer explanations for these characteristics.
The enzyme carbonic anhydrase has been suggested as a critical participant in osteoclast-mediated bone resorption. In humoral hypercalcemia of malignancy (HHM) intense osteoclastic bone resorption is principally responsible for the observed hypercalcemia. We therefore undertook to examine the effect of the carbonic anhydrase inhibitor acetazolamide on the hypercalcemia induced by the H500 Leydig cell tumor in Fisher rats, a well-described model of HHM. Acetazolamide treatment for 10 h at 10 mg/h resulted in a significant fall in serum calcium in the five drug-treated animals (14.2 +/- 0.9 to 11.5 +/- 0.1 mg/dl, p less than 0.05). Conversely, the six animals infused with vehicle alone showed a significant rise in serum calcium (12.5 +/- 0.5 to 13.8 +/- 0.1 mg/dl, p less than 0.05). At the end of the infusion, the acetazolamide-treated animals had a significantly lower mean serum calcium than those receiving vehicle alone (11.5 +/- 0.1 versus 13.8 +/- 0.1, p less than 0.05). There was no significant change in serum phosphorus, urine calcium, urine phosphorus, or nephrogenous cyclic AMP excretion between the two groups. Acetazaolamide and HTS 5-(3-hydroxybenzoyl)-2-thiophenesulfonamide, another carbonic anhydrase inhibitor, both significantly inhibited in vitro bone resorption induced by 5 X 10(-9) M 36Tyr(1-36)-PTHrP-amide (PTHrP, parathyroid hormone-related protein). Acetazolamide also inhibited the resorption induced by 10(-8) M (1-141)-PTHrP and 2.5 X 10(-9) M (1-74)-PTHrP. We conclude that acetazolamide is effective in lowering the serum calcium in animals with humoral hypercalcemia of malignancy. The data are consistent with the hypothesis that the mechanism of action for this effect is direct inhibition of osteoclast-mediated bone resorption.
The mechanism by which parathyroid hormone-related protein (PTH-RP) stimulates bone resorption is not known. Like certain other resorbing agents it may act to release bone-resorbing cytokines from the osteoblast. To examine this hypothesis, we used serum-free conditioned media (CM) from SAOS II cells incubated with 10(-8) M h(1-74) PTH-RP for 48 h. Treated CM contained substantially more bone-resorbing activity (BRA) in the fetal-rat long-bone assay than CM from untreated cells (2.17 +/- 0.21 vs 1.38 +/- 0.16 fold stimulation over basal [f]; p less than 0.05]. After centrifugation and dialysis, 1 liter of treated CM contained a total BRA of 7102 ngeq b(1-34) PTH with a specific activity (SA) of 447 ngeq b(1-34) PTH/mg protein. Treated CM did not stimulate the ROS assay and the cytokines PGE2, TGF-alpha, EGF, GM-CSF and IL-1 were present in low concentrations. The BRA was heat sensitive. Ultrafiltration revealed that 97% of the BRA was in a 3-30 kD fraction. Further purification was achieved by sequential reverse phase HPLC and size exclusion-HPLC (SE-HPLC). A single fraction containing BRA from SE-HPLC was purified 277-fold to a SA of 123,810 ngeq b(1-34) PTH/mg protein and had an apparent MW of 9 kD. SDS-PAGE revealed 4 bands in this SE-HPLC fraction with 1 band at 9 kD unique to that fraction. PTH-RP may cause bone resorption in part by stimulating the release of a 9 kD protein from osteoblasts which is responsible for activating osteoclasts.
A retrospective analysis was undertaken on patients undergoing liver transplantation between April 1985 and May 1980 at Baylor University Medical Center, Dallas, Texas. A total of 358 patients were evaluated, 416 of whom received liver transplants, including 15 simultaneous liver/kidney transplants. The overall patient survival in this group was 82% at 1 year and 75% at 3 years, using Kaplan-Meier life tables.
The efficacy and acceptability of yeast-derived recombinant hepatitis B vaccine given by the intradermal route was investigated in 221 health care volunteers. Two hundred and sixteen received a full course of three doses of vaccine. Only one subject was withdrawn because of a significant adverse reaction (psoriasis). The vaccine stimulated an antibody response in 81%. The response to the vaccine was better in women than in men (87% compared with 71%, p = 0.007) and in women below the age of 40 years compared with older women (94% compared with 76%, p = 0.01). For men the response showed a sequential decline with age for each decade (90% responders from age 29 or less, 72% aged 30-39 and 65% aged 40 or more, p = 0.04). Retrospective enquiry showed that over 90% had found the intradermal route acceptable and 59% would prefer vaccine by the intradermal route in preference to intramuscular notwithstanding local reactions. Although the seroconversion rate was of a high order in younger women the antibody titres were not high with only 9 of 215 recipients developing titres greater than 1000 mIU/ml, a level which could be expected to ensure prolonged immunity. A fourth intradermal dose of vaccine given to 60 volunteers who had shown a low response (less than 38 mIU/ml) or no serological response to a three-dose course stimulated a good booster effect (to 150-600 mIU/ml) in only 5 (8%).
A human parathyroid-like protein (PLP) has recently been isolated and cloned from human tumors associated with the paraneoplastic syndrome, humoral hypercalcemia of malignancy. PLP shares NH2-terminal amino acid sequence similarity with PTH but has a unique primary structure thereafter. Studies reported to date have indicated that both native and synthetic amino-terminal PLP polypeptides display actions in vivo and in vitro that are similar to those of PTH. We report here that purified native PLP and synthetic 36Tyr(1-36)amide human PLP induce epidermal growth factor-dependent transformation of NRK 49F cells in soft agar. Further, the synthetic peptide induces a significant increase in the biosynthesis of fibronectin by human dermal fibroblasts. (1-34)PTH does not display either of these biological activities. These data indicate that there are qualitative differences between PTH and the recently identified PLP. The latter hormone appears to possess transforming growth factor-like properties that may be relevant to its physiological actions.
PTH-like proteins (PTHLP), which are associated with humoral hypercalcemia of malignancy, have recently been purified. Isolation of their corresponding cDNAs has revealed that they are derived from a single gene. In this report a synthetic gene encoding PTHLP-(1-141), a 141-amino acid protein corresponding to the most abundant PTHLP cDNA detected in human tumors, was expressed in bacteria and purified to homogeneity. Recombinant (r) PTHLP-(1-141) migrates with an aberrantly high mol wt on sodium dodecyl sulfate-polyacrylamide gel electrophoresis, presumably as a result of its unusually basic pI. rPTHLP-(1-141), like PTH, induced hypercalcemia in rats, caused release of 45Ca from fetal rat bones, and stimulated the synthesis of cAMP by rat osteosarcoma cells and canine renal membrane preparations. A comparison of the abilities of rPTHLP-(1-141) and bovine PTH-(1-34) to stimulate cAMP synthesis indicated rPTHLP-(1-141) to be 5-fold more potent in the osteosarcoma assay, while nearly 30-fold less active in the renal membrane adenylate cyclase assay. Although 100-fold less potent than bovine PTH-(1-34) in promoting bone resorption, rPTHLP-(1-141) was a potent calcemic factor in vivo, inducing a rise in serum calcium from 10.4 to 14.5 mg/dl when infused into rats at 1.3 micrograms/h. These results support previous assumptions that PTHLP is the humoral factor responsible for humoral hypercalcemia of malignancy. In addition, they suggest substantial differences between PTHLP and PTH in the regulation of calcium homeostasis.
The natural history of Williams syndrome, including medical complications, growth patterns, and problems in adulthood, was investigated. A growth pattern characterized by delay in the first 4 years of life, catch-up growth in childhood, and low ultimate adult height was found. Despite multiple medical problems in infancy, including feeding problems, failure to thrive, colic, and otitis media, mean age at diagnosis was 6.4 years. Developmental disabilities and cardiovascular disease were the major concerns in childhood. The older children developed progressive joint limitation and hypertonia. Adult patients were handicapped by their developmental disabilities. Hypertension, and gastrointestinal and genitourinary problems occurred frequently. Independent living and competitive employment were limited less by the individual's physical problems than by the psychologic and adaptive limitations. Williams syndrome is a progressive disorder with multisystem involvement.
Fifteen mature cows and 12 two-year-old heifers were superovulated with purified follicle stimulating hormone (FSH-P) to study the relationship between FSH-P dose level and response (measured as number of palpated corpora lutea (CL) and plasma progesterone concentration). The cattle came from a high prolificacy breeding herd for which cows were originally purchased after producing at least two sets of twins; the heifers were bred in the herd. At dose levels of 8,16, 24 and 28 mg FSH-P in cows, averages respectively of 2.3, 3.5, 6.9 and 11.1 palpable CLs were found. There was an average difference in response of two CLs between heifers and cows (higher in heifers, though not significantly so). The relationship found between progesterone concentration and CL number could be a useful indicator of superovulation success in future experiments. The regression for cows was 1.25 +/- 0.11 ng/ml progesterone per unit increase in CL number, with a correlation of 0.92 between the two variables over the CL range 1 to 25. The corresponding value for heifers was 2.74 +/- 0.24 ng/ml per CL (correlation 0.94), or 2.50 +/- 0.40 ng/ml per CL (correlation 0.83) if one record (29 CL, 84 ng progesterone/ml) was excluded.
In a multicentre, prospective, randomised, placebo controlled study of 55 patients with histories of genital warts for at least one year, a four week course of inosine pranobex 3 g a day improved the clinical response to conventional treatment (primarily podophyllin or trichloroacetic (now called trichlorethanoic) acid). Although more patients given inosine pranobex improved than those given placebo, the difference in general response between the two groups was not significant. When other variables (numbers of warts and extent of lesions) were considered, however, the patients given inosine pranobex fared significantly better. These results suggest that inosine pranobex may be worth considering as adjunct to treatment of patients with refractory genital warts.
A 16K PTH-like protein with a unique primary structure has recently been isolated from several human tumors associated with the syndrome of humoral hypercalcemia of malignancy. Certain spontaneous and transplantable animal tumors also cause this syndrome. The responsible mediator in these animal tumors is not known. We report the isolation of 16K proteins from the rat H500 Leydig cell tumor and the canine apocrine cell adenocarcinoma of the anal sac. Both proteins are potent activators of PTH receptor-coupled adenylate cyclase in bone cells. Both proteins demonstrate similarities in amino acid composition to one another and to the human PTH-like protein. Limited amino-terminal sequence information from the canine protein demonstrates homology with the human PTH-like protein. Antibodies raised to a synthetic human PTH-(1-36)-like peptide cross-react with both the rat and canine proteins in an immunoradiometric assay. These data demonstrate that by physical and immunological criteria PTH-like peptides are present in these animal tumors that appear to be closely related to the human PTH-like peptide. These data further suggest that this protein is not unique to humans, but has an evolutionary origin which extends back at least 65-80 million yr.
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We are reporting on a 4-generation family in which 6 individuals had frontonasal dysplasia with variable extracranial abnormalities. All affected persons had hypertelorism, bifid or broad nose, and highly arched palate. Associated abnormalities included cleft lip and palate (1/6), webbed neck (2/6), Sprengel anomaly (2/6), pseudoarthrosis of the clavicle (2/6), pectus excavatum (3/6), narrow, sloping shoulders (3/6), diaphragmatic hernia (2/6), broad first toe (4/6), brachydactyly (3/6), fifth finger clinodactyly (5/6), longitudinal grooves of nails (5/6), shawl scrotum (2/3 males), first degree hypospadias (1/3), and mild mental retardation (1/6). Only one affected female had brachycephaly and right coronal synostosis. Four other affected relatives had varying degrees of facial asymmetry, but normal skull contour. No male to male transmission is observed, and both daughters of an affected male were affected. Based on the phenotype of the 3 affected females, craniofrontonasal syndrome (CFNS) is the likely diagnosis. However, there are 3 affected males in this kindred, and 2 of the 3 had significant anomalies. Affected males also had genital abnormalities and pectus deformity of the chest, not previously reported in this condition. Two of the 3 males have posterolateral diaphragmatic hernia. This family expands the phenotype of affected males.
Calf mortality data were summarized from four experiments, including a total of 15,694 birth records over 39 herd-years. Two experiments at Waikite and Waikeria were long-term, straightbred Angus and Hereford selection trials and the other two, at Goudies and Tokanui stations, were comparisons of 11 sire breeds mated to Angus and Herefore cows. The objective of the analyses was to study the relationship between birth weight (BW) and calf mortality for both calf sexes and for different dam age or parity groups. Overall calf death rates from birth to weaning were greater (P less than .01) from 2-yr-old than from older dams at Waikite (13.4 vs 5.3%) and Waikeria (14.7 vs 5.2%). Sex differences in death rate within 2 d of birth were small for calves from older dams. Death rate of males vs females from 2-yr-old dams were 9.1 vs 3.2% (Waikite) and 17.7 vs 10.5% (Waikeria). Mature Angus dams at Goudies had 3.7% calf deaths at birth (4.9 vs 2.4% for males vs females), a further 1.8% calf deaths to weaning and 4.6% assisted births. The BW of calves at Waikite from Angus 2-yr-old vs older dams averaged, respectively, 6.8 and 6.5% of their dam's precalving live weights. Corresponding figures for Waikeria Angus were 7.8 and 6.6% and for Waikite Herefords, 7.3 and 6.9%. Quadratic regressions revealed that, on a whole-herd basis, a small increase in BW would have no effect on total mortality at Waikeria and would decrease total mortality at Waikite; regression lines were different in shape and minimum value for calves from the two dam age groups. Quadratic models also provided an adequate fit to data from Goudies and Tokanui. There was no particular threshold BW.
A study of a modified Canadian unit system of measuring laboratory workload was undertaken in five joint Public Health Laboratory Service and hospital microbiology laboratories. Ten percent of the specimens received over six months were sampled, the number of units expended on each was recorded, and the results were analysed on a central computer. The process of gathering information in the absence of laboratory computers was time consuming and, despite careful planning, differences were found in the recording practices of the laboratories. The analysis of results did not lead to major changes in data gathering techniques because the same information about laboratory workload could be obtained by collecting numbers of clearly defined specimens. Analysis of workload units could be useful for particular purposes, such as comparing differences between laboratories using different techniques for the same investigation or assessing the possible benefits of automation. It must be appreciated, however, that workload units are measures of quantity not of laboratory performance.
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