Expanding allelic and phenotypic spectrum of ZC4H2-related disorder: A novel hypomorphic variant and high prevalence of tethered cord

ZC4H2 (MIM# 300897) is a nuclear factor involved in various cellular processes including proliferation and differentiation of neural stem cells, ventral spinal patterning and osteogenic and myogenic processes. Pathogenic variants in ZC4H2 have been associated with Wieacker-Wolff syndrome (MIM# 314580), an X-linked neurodevelopmental disorder characterized by arthrogryposis, development delay, hypotonia, feeding difficulties, poor growth, skeletal abnormalities, and dysmorphic features. Zebrafish zc4h2 null mutants recapitulated the human phenotype, showed complete loss of vsx2 expression in brain, and exhibited abnormal swimming and balance problems. Here we report 7 new patients (four males and three females) with ZC4H2-related disorder from six unrelated families. Four of the 6 ZC4H2 variants are novel: three missense variants, designated as c.142T>A (p.Tyr48Asn), c.558G>A (p.Met186Ile) and c.602C>T (p.Pro201Leu), and a nonsense variant, c.618C>A (p.Cys206*). Two variants were previously reported : a nonsense variant c.199C>T (p.Arg67*) and a splice site variant (c.225+5G>A). Five patients were on the severe spectrum of clinical findings, two of whom had early death. The male patient harboring the p.Met186Ile variant and the female patient that carries the p.Pro201Leu variant have a relatively mild phenotype. Of note, 4/7 patients had a tethered cord that required a surgical repair. We also demonstrate and discuss previously under-recognized phenotypic features including sleep apnea, arrhythmia, hypoglycemia, and unexpected early death. To study the effect of the missense variants, we performed microinjection of human ZC4H2 wild-type or variant mRNAs into zc4h2 null mutant zebrafish embryos. The p.Met186Ile mRNA variant was able to partially rescue vsx2 expression while p.Tyr48Asn and p.Pro201Leu mRNA variants were not. However, swimming and balance problems could not be rescued by any of these variants. These results suggest that the p.Met186Ile is a hypomorphic allele. Our work expands the genotypes and phenotypes associated with ZC4H2-related disorder and demonstrates that the zebrafish system is a reliable method to determine the pathogenicity of ZC4H2 variants.     

An evaluation of three methods for determining colloid osmotic pressure

Plasma colloid osmotic pressure (COP) is an important determinant in edema formation. Three methods for assessing the COP were evaluated. Direct measurement of COP using the 4420 Wescor Colloid Osmometer was compared to the estimation of COP from both serum total protein and total serum solids (TSS) determinations. Blood samples from twenty adult patients (mean age = 64 years) undergoing cardiopulmonary bypass surgery were collected for COP assessment. Sample collection was performed prior to heparinization/hemodilution, during hypothermic bypass and at the conclusion of bypass following protamine administration. The results obtained from each method were analyzed by a two-way analysis of variance. The Bonferroni technique was used for comparison of sample means when the difference was significant (p less than 0.05). Correlations were reported by linear regression analysis. A statistically significant difference (p less than 0.01) was found between the three methods. A regression equation for the estimation of COP from total serum solids is offered: COP = (3.02 * TSS) + 0.65. Prospective clinical testing between the direct COP measurement and the estimation of COP from TSS using the equation (n = 38) revealed a significant correlation (R2 = .932) and no significant difference between the two (p greater than 0.05).     

Comparison of gaseous microemboli counts in arterial, simultaneous and venous heat exchange with a hollow fiber membrane oxygenator

Potential sources of gaseous microemboli during cardiopulmonary bypass are varied. However, it is known that membrane oxygenators generate fewer gaseous microemboli than bubble oxygenators and that bubblers cannot utilize arterial heat exchange without generating significant gaseous microemboli during rewarming. A membrane oxygenator utilizing simultaneous gas and heat exchange raises the concern that concurrent gas and heat exchange would result in a higher production of gaseous microemboli compared to conventional venous heat exchange devices. This in vitro study compared venous, simultaneous, arterial and control (venous) heat exchanger gaseous microemboli counts during rewarming. No significant difference was found between the four heat exchangers when comparing inlet and outlet gaseous microemboli counts. This in vitro study suggests that there is no difference in gaseous microemboli generation when varying the position of the heat exchanger in the extracorporeal circuit incorporating a microporous membrane oxygenator.     

Hydrolysis of the Prodrug, 2′, 3′, 5′ -Triacetyl-6-azauridine

Purpose. The purposes were to study the kinetics of hydrolysis of 2,3,5-triacetyl-6-azauridine ( 1 ) in aqueous solution (µ = 0.5) and to identify the main intermediates and products of the reaction. Methods. A stability indicating isocratic LC assay was used to study the rate of degradation of 1 A gradient LC assay was used to study the time courses of the degradants. The products of hydrolysis were isolated by preparative liquid chromatography and identified by ¹H-NMR and CI-MS. The pK_a value was obtained by potentiometric titration. Results. At 36.8°C, the pH-rate profile of 1 in water was adequately described by a four-term rate equation. The intermediates were identified as the primary and secondary di-acetates, and the primary and secondary mono-acetates. The final product was 6-azauridine. Conclusions. A simplified kinetic scheme could be used to describe the concentration-time profiles of 1, the intermediates and the final product.     

Life-long absence of sexual drive in a woman associated with 5-dihydrotestosterone deficiency

A case of a woman who presented with life-long absence of sexual drive is reported. Although her history contained psychological factors that might have been etiologic in her presentation, she had not responded to sex therapy or cognitive-behavior psychotherapy undertaken at other clinics. When seen by the author, she was found to have poorly developed external genitalia. The only abnormality discovered on endocrinological evaluation was a reduced level of 5 dihydrotestosterone. Treatment with dihydrotestosterone gel applied to her vulva generated sexual drive and her ability to become sexually aroused.     

Prostate cancer treatment and ten-year survival among group/staff HMO and fee-for-service Medicare patients.

OBJECTIVE: To compare treatment patterns and the ten-year survival of prostate cancer patients in two large, nonprofit, group/staff HMOs to those of patients receiving care in the fee-for-service health setting. DATA SOURCES/STUDY DESIGN: A cohort of men age 65 and over diagnosed with prostate cancer between 1985 and the end of 1992 and followed through 1994. Subjects (n = 21,741) were ascertained by two population-based tumor registries covering the greater San Francisco-Oakland and Seattle-Puget Sound areas. Linkage of registry data with Medicare claims data and with HMO inpatient utilization data allowed the determination of health plan enrollment and the measurement of comorbid conditions. Multivariate regression models were used to examine HMO versus FFS treatment and survival differences adjusting for sociodemographic and clinical characteristics. PRINCIPAL FINDINGS: Among cases with non-metastatic prostate cancer, HMO patients were more likely than FFS patients to receive aggressive therapy (either prostatectomy or radiation) in San Francisco-Oakland (odds ratio [OR] = 1.69, 95% CI = 1.46-1.96) but not in Seattle (OR = 1.15, 0.93-1.43). Among men receiving aggressive therapy, HMO cases were three to five times more likely to receive radiation therapy than prostatectomy. Overall mortality was equivalent over ten years (HMO versus FFS mortality risk ratio [RR] = 1.01, 0.94-1.08), but prostate cancer mortality was higher for HMO cases than for FFS cases (RR = 1.25, 1.13-1.39). CONCLUSION: Despite marked treatment differences for clinically localized prostate cancer, overall ten-year survival for patients enrolled in two nonprofit group/staff HMOs was equivalent to survival among patients receiving care in the FFS setting, even after adjustment for sociodemographic and clinical characteristics. Similar overall but better prostate cancer-specific survival among FFS patients is most plausibly explained by differences between the HMO and FFS patients in both tumor characteristics and unmeasured patient selection factors.     

Commercialization of health services: implications for the laboratories

The commercialization of health services has wide ranging implications for all medical specialties as well as for patients. Factors that must be considered include not only the financial implications, but also questions of quality and academic interests such as teaching and training. Laboratories must provide a service that the purchaser wishes to buy and must be successful in overcoming competition from the private sector. Each component part of the overall service must be analyzed in order that the laboratory is efficiently structured to provide an optimum service. A good understanding of management issues and a flexible approach are paramount in the provision of efficient, cost-effective and quality service for the ultimate benefit of the patient.