Congenital disorder of glycosylation type Ia presenting as early-onset cerebellar ataxia in an adult

Congenital disorders of glycosylation (CDG) are a recently described, underrecognized group of syndromes characterized biochemically by abnormal glycosylation of serum and cellular glycoproteins. We report a previously undiagnosed adult male who presented with early-onset cerebellar ataxia in the context of mental impairment, peripheral neuropathy, retinopathy, body dysmorphism, cardiomyopathy, and hypogonadism. Newly available screening and genetic testing confirmed the diagnosis as CDG type Ia. This case emphasizes that CDG should be considered as a differential diagnosis for adults with early-onset cerebellar ataxia, particularly in those persons with the aforementioned features, and that undiagnosed cases of childhood ataxia may require reassessment now that testing is available. © 2006 Movement Disorder Society

The development of a new measure of quality of life for children with congenital cardiac disease

The purpose of the study was to develop a questionnaire measuring health-related R1 quality of life for children and adolescents with congenital heart disease, the ConQol, that would have both clinical and research applications. We describe here the process of construction of a questionnaire, the piloting and the development of a weighted scoring system, and data on the psychometric performance of the measure in a sample of 640 children and young people recruited via 6 regional centres for paediatric cardiology from across the United Kingdom. The ConQol has two versions, one designed for children aged from 8 to 11 years, and the other for young people aged from 12 to 16 years. Initial findings suggest that it is a valid and reliable instrument, is acceptable to respondents, and is simple to administer in both a research and clinical context.

Impact on perinatal mortality of missed opportunities to treat maternal syphilis in rural South Africa: baseline results from a clinic randomized controlled trial

OBJECTIVE To demonstrate the impact on perinatal mortality of inadequate treatment for maternal syphilis despite adequate screening. METHOD In 12 clinics providing antenatal care in Hlabisa, South Africa 1783 pregnant women were screened for syphilis at their first antenatal visit between June and October 1998. Pregnancy outcome was determined among those with syphilis. RESULTS A total of 158 women were diagnosed with syphilis: prevalence 9% (95% CI 8-10%). Mean gestation at first antenatal visit was 24 weeks. Thirty women (19%) received no treatment and 96 (61%) received all three recommended doses of penicillin. Among those receiving at least one dose, mean delay to the first dose was 20 days. Among those fully treated mean delay to treatment completion was 34 days. Pregnancy outcome was known for 142 women (90%) and there were 17 perinatal deaths among 15 women (11%). Eleven of 43 women (26%) who received one or fewer doses of penicillin experienced ii perinatal death whilst only four of 99 women (4%) who received two or more doses of penicillin did so (P = 0.0001). Protection from perinatal death increased with the number of doses of penicillin: linear modelling suggests that one dose reduced the risk by 41%, two doses by 65% and three doses by 79%, compared with no doses. A dose-specific, categorical model confirmed reduction in risk by 79% for all three doses. CONCLUSION Despite effective screening, many pregnant women with syphilis remain inadequately treated, resulting in avoidable perinatal mortality. Delays in starting and finishing treatment, as well as incomplete treatment occur. Near-patient syphilis testing in the antenatal clinic with early treatment could improve treatment of syphilis and reduce perinatal mortality, and a randomized trial to test this is underway.

Impact of on-site testing for maternal syphilis on treatment delays, treatment rates, and perinatal mortality in rural South Africa: a randomised controlled trial

Background: Syphilis remains a significant cause of preventable perinatal death in developing countries with many women remaining untested and thus untreated. Syphilis testing in the clinic (on-site testing) may be a useful strategy to overcome this. We studied the impact of on-site syphilis testing on treatment delays and rates, and perinatal mortality. Methods: We conducted a cluster randomised controlled trial among seven pairs of primary healthcare clinics in rural South Africa, comparing on-site testing complemented by laboratory confirmation versus laboratory testing alone. Intervention clinics used the on-site test conducted by primary care nurses, with results and treatment available within an hour. Control clinics sent blood samples to the provincial laboratory, with results returned 2 weeks later. Results: Of 7134 women seeking antenatal care with available test results, 793 (11.1%) tested positive for syphilis. Women at intervention clinics completed treatment 16 days sooner on average (95% confidence interval: 11 to 21), though there was no significant difference in the proportion receiving adequate treatment at intervention (64%) and control (69%) clinics. There was also no significant difference in the proportion experiencing perinatal loss (3.3% v 5.1%; adjusted risk difference: -0.9%; 95% Cl -4.4 to 2.7). Conclusions: Despite reducing treatment delays, the addition of on-site syphilis testing to existing laboratory testing services did not lead to higher treatment rates or reduce perinatal mortality. However on-site testing for syphilis may remain an important option for improving antenatal care in settings where laboratory facilities are not available.

A transgenic mouse model that recapitulates the clinical features of both neonatal and adult forms of the skin disease epidermolytic hyperkeratosis

Keratins are the major structural proteins of keratinocytes, which are the most abundant cell type in the mammalian epidermis. Mutations in epidermal keratin genes have been shown to cause severe blistering skin abnormalities. One such disease, epidermolytic hyperkeratosis (EHK), also known as bullous congenital ichthyosiform erythroderma, occurs as a result of mutations in highly conserved regions of keratins K1 and K10. Patients with EHK first exhibit erythroderma with severe blistering, which later is replaced by thick patches of scaly skin. To assess the effect of a mutated K1 gene on skin biology and to produce an animal model for EHK, we removed 60 residues from the 2B segment of HK1 and observed the effects of its expression in the epidermis of transgenic mice. Phenotypes of the resultant mice closely resembled those observed in the human disease, first with epidermal blisters, then later with hyperkeratotic lesions. In neonatal mice homozygous for the transgene, the skin was thicker, with an increased labeling index, and the spinous cells showed a collapse of the keratin filament network around the nuclei, suggesting that a critical concentration of the mutant HK1, over the endogenous MK1, was required to disrupt the structural integrity of the spinous cells. Additionally, footpad epithelium, which is devoid of hair follicles, showed blistering in the spinous layer, suggesting that hair follicles can stabilize or protect the epidermis from trauma. Blisters were not evident in adult mice, but instead they showed a thick, scaly hyperkeratotic skin with increased mitosis, resulting in an increased number of corneocytes and granular cells. Irregularly shaped keratohyalin granules were also observed. To date, this is the only transgenic model to show the typical morphology found in the adult form of EHK.

Pulmonary vascular remodeling: a target for therapeutic intervention in pulmonary hypertension

Pulmonary vascular remodeling is an important pathological feature of pulmonary hypertension, leading to increased pulmonary vascular resistance and reduced compliance. It involves thickening of all three layers of the blood vessel wall (due to hypertrophy and/or hyperplasia of the predominant cell type within each layer), as well as extracellular matrix deposition. Neomuscularisation of non-muscular arteries and formation of plexiform and neointimal lesions also occur. Stimuli responsible for remodeling involve transmural pressure, stretch, shear stress, hypoxia, various mediators [angiotensin II, endothelin (ET)-1, 5-hydroxytryptamine, growth factors, and inflammatory cytokines], increased serine elastase activity, and tenascin-C. In addition, there are reductions in the endothelium-derived antimitogenic substances, nitric oxide, and prostacyclin. Intracellular signalling mechanisms involved in pulmonary vascular remodeling include elevations in intracellular Ca2+ and activation of the phosphatidylinositol pathway, protein kinase C, and mitogen-activated protein kinase. In animal models of pulmonary hypertension, various drugs have been shown to attenuate pulmonary vascular remodeling. These include angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, ET receptor antagonists, ET-converting enzyme inhibitors, nitric oxide, phosphodiesterase 5 inhibitors, prostacyclin, Ca2+-channel antagonists, heparin, and serine elastase inhibitors. Inhibition of remodeling is generally accompanied by reductions in pulmonary artery pressure. The efficacy of some of the drugs varies, depending on the animal model of the disease. In view of the complexity of the remodeling process and the diverse aetiology of pulmonary hypertension in humans, it is to be anticipated that successful anti-remodeling therapy in the clinic will require a range of different drug options. (C) 2001 Elsevier Science Inc. All rights reserved.

Physiological roles and regulation of mammalian sulfate transporters

All cells require inorganic sulfate for normal function. Sulfate is among the most important macronutrients; in cells and is the fourth most abundant anion in human plasma (300 muM). Sulfate is the major sulfur source in many organisms, and because it is a hydrophilic anion that cannot passively cross the lipid bilayer of cell membranes, all cells require a mechanism for sulfate influx and efflux to ensure an optimal supply of sulfate in the body. The class of proteins involved in moving sulfate into or out of cells is called sulfate transporters. To date, numerous sulfate transporters have been identified in tissues and cells from many origins. These include the renal sulfate transporters NaSi-1 and sat-1, the ubiquitously expressed diastrophic dysplasia sulfate transporter DTDST, the intestinal sulfate transporter DRA that is linked to congenital chloride diarrhea, and the erythrocyte anion exchanger AE1. These transporters have only been isolated in the last 10-15 years, and their physiological roles and contributions to body sulfate homeostasis are just now beginning to be determined. This review focuses on the structural and functional properties of mammalian sulfate transporters and highlights some of regulatory mechanisms that control their expression in vivo, under normal physiological and pathophysiological states.

The child of uncertain sex: 17 years of experience

Objective: To review the common clinical presentations, investigations and final diagnosis of children presenting with genital ambiguity. Methodology: Retrospective search of the Royal Children's Hospital, Brisbane, Australia, medical records and personal medical database of one of the authors (MJT) between 1982 and 1999. Results: Fifty-one children aged 0.1-;14 (mean 3.9) years were identified. Twenty-two cases had a 46XX karyotype, and commonly presented with an enlarged phallus (77.2%), urogenital sinus (63.6%) and labioscrotal fold(s) (40.9%). Congenital adrenal hyperplasia (CAH) was the most common final diagnosis (72.7%) . Twenty-nine cases of genital ambiguity had a 46XY karyotype and commonly presented with palpable gonad(s) (75.8%), undescended testes (51.7%), penoscrotal hypospadias (51.7%) and a small phallus (41.3%). Androgen insensitivity and gonadal dysgenesis were the commonest final diagnosis both occurring at a frequency of 17.2%. Conclusions: The results emphasize the importance of CAH as the most common diagnosis in 46XX cases presenting with ambiguous genitalia. Those with 46XY had a wider range of diagnoses. Despite thorough investigation, 23.5% had no definite final diagnosis made.

Rapid transplacental infection with bovine pestivirus following intranasal inoculation of ewes in early pregnancy

Despite the importance of congenital viral infections in both veterinary and human medicine, only limited experimental work has been carried out to elucidate the mechanisms involved in transplacental virus infections. To further an understanding of fetal infection with pestiviruses, the distribution of bovine pestivirus in the uterine and fetal tissues of ewes in early pregnancy, following a natural route of infection, was investigated. On the 18th day of pregnancy, nine ewes were inoculated by the intranasal route with 1 X 10(5) 50% tissue culture infective doses of an Australian isolate of noncytopathic bovine pestivirus (bovine viral diarrhea virus genotype 1). All ewes were ovariohysterectomized at approximately 100 hours postinfection. Samples from the reproductive tract and conceptus were examined histologically and tested for bovine pestivirus by nested reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry and for interferon-tau mRNA expression by nonnested RT-PCR. Although no histopathologic changes were observed in the maternal or fetal tissues, virus was detected in the reproductive tract of all nine ewes and in all of the conceptuses examined. Al; the time of surgery, only two of the nine ewes were demonstrably viremic. This study demonstrates that bovine pestivirus can spread from a natural site of infection to the ovine fetus within 4 days in the absence of maternal immunity and despite the presence of interferon expression in the reproductive tract.

Specificity of 17 beta-oestradiol and benzo[a] pyrene oxidation by polymorphic human cytochrome P4501B1 variants substituted at residues 48, 119 and 432

1. Eight human cytochrome P4501B1 (CYP1B1) allelic variants, namely Arg(48)Ala(119)Leu(432), Arg(48)Ala(119)Val(432), Gly(48)Ala(119)Leu(432), Gly(48)Ala(119)Val(432), Arg(48)Ser(119)Leu(432), Arg(48)Ser(119)Val(432), Gly(48)Ser(119)Leu(432) and Gly(48)Ser(119)Val(432) (all with Asn(453)), were expressed in Escherichia coli together with human NADPH-P450 reductase and their catalytic specificities towards oxidation of 17 beta -oestradiol and benzo[a]pyrene were determined. 2. All of the CYP1B1 variants expressed in bacterial membranes showed Fe2+. CO versus Fe2+ difference spectra with wavelength maxima at 446 nm and they reacted with antibodies raised against recombinant human CYP1B1 in immunoblots. The ratio of expression of the reductase to CYP1B1 in these eight preparations ranged from 0.2 to 0.5. 3. CYP1B1 Arg(48) variants tended to have higher activities for 17 beta -oestradiol 4-hydroxylation than Gly(48) variants, although there were no significant variations in 17 beta -oestradiol 2-hydroxylation activity in these eight CYP1B1 variants. Interestingly, ratios of formation of 17 beta -oestradiol 4-hydroxylation to 2-hydroxylation by these CYP1B1 variants were higher in all of the Val(432) forms than the corresponding Leu(432) forms. 4. In contrast, Leu(432) forms of CYP1B1 showed higher rates of oxidation of benzo[a]pyrene (to the 7, 8-dihydoxy-7,8-dihydrodiol in the presence of epoxide hydrolase) than did the Val(432) forms. 5. These results suggest that polymorphic human CYP1B1 variants may cause some altered catalytic specificity with 17 beta -oestradiol and benzo[a]pyrene and may influence susceptibilities of individuals towards endogenous and exogenous carcinogens.

Adipose tissue as an endocrine organ

Adipose tissue is a highly active endocrine organ secreting a range of soluble products with both local and distant actions. These hormones have important roles in metabolism, reproduction, cardiovascular function and immunity. It is now evident that adipose endocrine function directly influences other organ systems, including the brain, liver and skeletal muscle. The endocrine function of adipose tissue is significantly regulated by nutritional status, and both are inextricably linked to the energy storage role of adipose tissue. This chapter highlights the endocrinology of adipose tissue by concentrating on functional aspects of the secreted products. The data of particular relevance to humans are highlighted, and areas in need of future research are suggested.