Aetiological bases of 46,XY disorders of sex development in the Hong Kong Chinese population.

OBJECTIVE: Disorders of sex development are due to congenital defects in chromosomal, gonadal, or anatomical sex development. The objective of this study was to determine the aetiology of this group of disorders in the Hong Kong Chinese population. SETTING: Five public hospitals in Hong Kong. PATIENTS: Patients with 46,XY disorders of sex development under the care of paediatric endocrinologists between July 2009 and June 2011. MAIN OUTCOME MEASURES: Measurement of serum gonadotropins, adrenal and testicular hormones, and urinary steroid profiling. Mutational analysis of genes involved in sexual differentiation by direct DNA sequencing and multiplex ligation-dependent probe amplification. RESULTS: Overall, 64 patients were recruited for the study. Their age at presentation ranged from birth to 17 years. The majority presented with ambiguous external genitalia including micropenis and severe hypospadias. A few presented with delayed puberty and primary amenorrhea. Baseline and post-human chorionic gonadotropin-stimulated testosterone and dihydrotestosterone levels were not discriminatory in patients with or without AR gene mutations. Of the patients, 22 had a confirmed genetic disease, with 11 having 5α-reductase 2 deficiency, seven with androgen insensitivity syndrome, one each with cholesterol side-chain cleavage enzyme deficiency, Frasier syndrome, NR5A1-related sex reversal, and persistent Müllerian duct syndrome. CONCLUSIONS: Our findings suggest that 5α-reductase 2 deficiency and androgen insensitivity syndrome are possibly the two most common causes of 46,XY disorders of sex development in the Hong Kong Chinese population. Since hormonal findings can be unreliable, mutational analysis of the SRD5A2 and AR genes should be considered the first-line tests for these patients.

Enzyme replacement therapy for mucopolysaccharidosis VI (Maroteaux-Lamy syndrome): experience in Hong Kong.

Mucopolysaccharidosis VI (Maroteaux-Lamy syndrome) is a very rare inherited lysosomal storage disease. We evaluated the efficacy and safety of weekly infusions of recombinant human arylsulfatase B as enzyme replacement therapy for two patients in whom this condition was advanced. The primary outcome variables were the distance walked in a 6-minute walk test, forced vital capacity, and ejection fraction. The secondary outcome variables were the number of stairs climbed in a 3-minute stair climbing test, joint mobility, urinary glycosaminoglycan excretion, auto-continuous positive airway pressure study and liver size. After 24 weeks of treatment, patient A walked 40 m (36%) and patient B walked 66 m (58%) more in the walk test than at baseline. After 48 weeks, in patient A the corresponding improvements were 142 m (129%) in the walk test and 33 stairs (60%) in the 3-minute stair climbing test, and in patient B the respective improvements were 198 m (174%) and 77 stairs (140%). There was a significant decline in urinary glycosaminoglycan excretion and improvement in range of motion of joints in both patients. The auto-continuous positive airway pressure study revealed improvements in patient A, while other efficacy variables remained static. There were no drug-related adverse events or allergic reactions reported during and after the infusions of recombinant human arylsulfatase B. Recombinant human arylsulfatase B significantly improves endurance and reduces urinary glycosaminoglycan excretion. The drug is generally safe and well tolerated.

Wilson Sims Fall Risk Assessment Tool Versus Morse Fall Scale in Psychogeriatric Inpatients: a Multicentre Study.

OBJECTIVE: To compare predictive validity of the Wilson Sims Fall Risk Assessment Tool (WSFRAT) with that of the Morse Fall Scale (MFS) in psychogeriatric inpatients. METHODS: Psychogeriatric patients from Shatin Hospital, Tai Po Hospital, Castle Peak Hospital, and United Christian Hospital who had fall incident between April 2019 and April 2020 were identified. Their fall risks were assessed by the WSFRAT and the MFS, and their falls incidents during hospitalisation were recorded. Patients were classified as having high fall risk when their MFS score was ≥45 and when their WSFRAT score was ≥7. Sensitivity, specificity, and positive and negative predictive values of the two scales were calculated. RESULTS: We identified 183 (90 male and 93 female) psychogeriatric patients aged ≥65 years who had fall incident and were assessed by both the WSFRAT and the MFS during the study period. Among the 183 patients, four sustained a fall during hospital stay, giving a prevalence of 2.19%. All four patients were classified as having high risk of fall by WSFRAT, but only two of them were classified so by MFS. The sensitivity of WSFRAT was 100%, which was higher than the 50% by MFS, but specificity of MFS was higher than that of WSFRAT (45.81% vs 54.75%). CONCLUSION: WSFRAT is a better fall risk assessment scale for psychiatric inpatients than MFS, because of higher sensitivity (100% vs 50%). It has items specific to psychiatric patients and should replace MFS in psychiatric settings.

Ambiguous genitalia, impaired steroidogenesis, and Antley-Bixler syndrome in a patient with P450 oxidoreductase deficiency.

Cytochrome P450 oxidoreductase deficiency is a recently established autosomal recessive disease characterised by ambiguous genitalia, impaired steroidogenesis, and skeletal malformations, referred to as Antley-Bixler syndrome. Clinical manifestations in affected patients are highly variable. We report on a girl with P450 oxidoreductase deficiency who presented with virilisation at birth. There was transient maternal virilisation during pregnancy as well. She was initially diagnosed with congenital adrenal hyperplasia caused by 21-hydroxylase deficiency and/or aromatase deficiency. At 1 year of age, skeletal abnormalities suggestive of Antley-Bixler syndrome were detected. Molecular analysis of the fibroblast growth factor receptor 2 (FGFR2) gene was normal but POR gene analysis showed that she was homozygous for an R457H missense mutation. The diagnosis, P450 oxidoreductase deficiency, was confirmed. Results of her endocrine studies and urinary steroid profiling are also presented.

The value of serum neopterin, interferon-gamma levels and interleukin-12B polymorphisms in predicting acute renal allograft rejection.

Acute rejection remains a poor predictor of graft outcome. In this study, we measured serum levels of interferon (IFN)-gamma and neopterin by enzyme-linked immunosorbent assay and a single nucleotide polymorphism (SNP) within the 3' untranslated region of the interleukin (IL)-12 B gene (1188 A/C) to determine whether either of these factors could predict acute rejection in renal transplantation. Significantly higher early post-transplant neopterin levels (days 5-7; 35.7 versus 19.9 nmol/l) were observed in recipients who subsequently rejected their grafts. Post-transplant neopterin levels showed a strong positive correlation with 1-month creatinine levels (Spearman's correlation 0.62, P < 0.001), suggesting macrophage activation early after transplantation. Pretransplant neopterin and IFN-gamma levels and the IL-12B gene SNP did not predict acute rejection in this small retrospective study. The ability to predict acute rejection non-invasively early after transplantation could lead to individual tailoring of immunosuppressive regimens and perhaps lead eventually to longer graft survival.

Uterine crowding in the sow affects litter sex ratio, placental development and embryonic myogenin expression in early gestation.

Uterine crowding in the pig results in intrauterine growth restriction (IUGR), and permanently affects fetal muscle fibre development, representing production losses for the commercial pig herd. The present study sought to understand how different levels of uterine crowding in sows affects muscle fibre development in the early embryo at the time of muscle fibre differentiation and proliferation. Sows either underwent surgical, unilateral oviduct ligation (LIG; n = 10) to reduce the number of embryos in the uterus, or remained as intact, relatively-crowded controls (CTR; n = 10). Embryos and placentae were collected at Day 30 of gestation, and myogenic regulatory factor (MRF) transcript abundance was determined using real-time PCR for both myogenin (MYOG) and myoblast differentiation 1 (MYOD1). Unilateral tubal ligation resulted in lower numbers of embryos in utero, higher placental weights and a higher male : female sex ratio (P < 0.05). Relative MYOD1 expression was not different, but MYOG expression was higher (P < 0.05) in the LIG group embryos; predominantly due to effects on the male embryos. Relatively modest uterine crowding therefore affects MRF expression, even at very early stages of embryonic development, and could contribute to reported differences in fetal muscle fibre development, birthweight and thus post-natal growth performance in swine.

Macroenvironment effects on oocytes and embryos in swine.

As in other domestic mammals, the interaction between genotype and environment in swine has profound effects on the ultimate phenotype of the individual born. Interactions within the litter in utero add an additional level of complexity in a litter-bearing species like the pig. Nutritional manipulations during the preovulatory period affect the maturity of the follicle and enclosed oocyte, and the metabolic and endocrine mechanisms potentially mediating these effects have been described. Extensive research on lactational catabolism in the first parity sow has established an association between the development of immature follicles and oocytes, and the reduced fertility of these sows when bred at the first postweaning estrus. This negative impact of lactational catabolism appears to be exaggerated in contemporary dam-lines by a minimal delay between weaning and first estrus, further limiting the maturity of the follicle and oocyte at the time of ovulation. Metabolic programming may induce gender-specific loss of embryos by Day 30 and affects embryonic development directly, without significant effects on placental size. In contrast, inadvertent crowding of embryos in utero, particularly evident in a sub-population of mature sows with high ovulation rates and moderate to high embryonic survival to Day 30, significantly limits placental development of crowded litters. However, even at Day 30, moderate crowding in utero also appears to affect myogenesis in the embryo in a gender-specific manner. In the absence of compensatory placental growth after Day 30, classic measures of IUGR are evident in surviving fetuses at Day 90 and at term.

Bacterial meningitis--complication from a dialysis catheter.

Various infective complications associated with dialysis catheter infection have been reported in the literature previously. We report a case of a hemodialysis patient presented with confusion and dysarthria secondary to Staphylococcus aureus septicemia and meningitis originating from a tunneled catheter used for providing dialysis. Blood cultures from the periphery, central venous catheter and culture of the line tip grew methicillin-sensitive Staphylococcus aureus. Lumbar puncture after CT brain confirmed Staphylococcus aureus. He was treated with high dose of an appropriate parenteral antibiotic and also removal of the infected line. In spite of optimal treatment, he died 15 days following his admission. The ideal option will be to use a definitive access like a fistula or AV graft, but in practice a significant proportion of hemodialysis patients is dialyzed with temporary or tunneled catheters all over the world, and infection poses a serious threat to dialysis patients resulting in significant mortality and morbidity. In patients with dialysis catheter-related sepsis, removal of the infected catheters and appropriate antibiotic treatment will prevent serious metastatic complications. Planning definitive access well ahead in chronic kidney disease patients and minimizing the use of temporary access is the only way forward.

Molecular characterisation of the 22q13 deletion syndrome supports the role of haploinsufficiency of SHANK3/PROSAP2 in the major neurological symptoms.

METHODS: The 22q13 deletion syndrome (MIM 606232) is characterised by moderate to profound mental retardation, delay/absence of expressive speech, hypotonia, normal to accelerated growth, and mild dysmorphic features. We have determined the deletion size and parent of origin in 56 patients with this syndrome. RESULTS: Similar to other terminal deletion syndromes, there was an overabundance of paternal deletions. The deletions vary widely in size, from 130 kb to over 9 Mb; however all 45 cases that could be specifically tested for the terminal region at the site of SHANK3 were deleted for this gene. The molecular structure of SHANK3 was further characterised. Comparison of clinical features to deletion size showed few correlations. Some measures of developmental assessment did correlate to deletion size; however, all patients showed some degree of mental retardation and severe delay or absence of expressive speech, regardless of deletion size. CONCLUSION: Our analysis therefore supports haploinsufficiency of the gene SHANK3, which codes for a structural protein of the postsynaptic density, as a major causative factor in the neurological symptoms of 22q13 deletion syndrome.

Antioxidant status in controlled and uncontrolled hypertension and its relationship to endothelial damage.

Hypertension is associated with an increased risk of atherosclerosis. Free radical oxidative damage has been implicated in the atherogenic process. We measured levels of the antioxidants uric acid, thiols, vitamins C, A and E as well as the total antioxidant capacity in 21 normotensive controls, 22 patients whose hypertension was controlled on drugs and 30 patients with uncontrolled hypertension. Mean BPs in the groups were 125/76, 132/80 and 181/98 mmHg, respectively. When compared with controls, both hypertensive groups had significantly lower serum ascorbic acid (54 +/- 5 vs. 37 +/- 6 vs. 38 +/- 5 mumol/l, P < 0.05) and albumin-corrected thiol levels (9.91 +/- 0.18 vs. 8.69 +/- 0.20 vs. 8.92 +/- 0.19 mumol/g, P < 0.05). The levels of the other antioxidants did not differ significantly between the groups. Levels of von Willebrand factor, a marker of endothelial damage, were correlated with SBP but not with antioxidant status. We conclude that hypertensive subjects have lower levels of the antioxidants vitamin C and thiols and this may reflect greater oxidative consumption. The implications for atherogenesis and endothelial function and integrity in hypertension are discussed.

Managing serum phosphate in haemodialysis patients: time for an innovative approach?

BACKGROUND/OBJECTIVES: Hyperphosphataemia, a common biochemical abnormality in chronic kidney disease, poses significant management challenges. This study aims to determine whether the reasons for this are multifactorial; including poor dietary knowledge, poor adherence to a low phosphate diet and phosphate-binding medications and the impact of age on these parameters. SUBJECTS/METHODS: In order to compare serum phosphate and other associated parameters to the UK Renal Association Clinical Practice Guidelines 2010 an audit and service evaluation questionnaire was carried out in May 2011 on 130 haemodialysis outpatients attending the Plymouth Dialysis Unit. RESULTS: Fifty-three percent of patients had serum phosphate within the target range of 1.1-1.7 mmol/l, 77% and 85% had serum calcium and parathyroid hormone within target ranges, respectively. Younger patients (18-45 years) were significantly less likely to have serum phosphate within range χ(2) (2, n=124)=18.77, P<0.001. Despite better knowledge of their own phosphate levels (P=0.005), phosphorus-rich foods (P<0.001), symptoms of hyperphosphataemia (P<0.001) and increased use of Renal Patient View (P=0.002), <65 years old had significantly higher phosphate levels than those >65 years (P<0.001). No significant associations were found between phosphate control and the following factors: gender, timing of dialysis shift, years on dialysis or dialysis adequacy. CONCLUSIONS: In this population, despite better knowledge, younger patients have worse phosphate control than older patients. Using the same dietary education techniques may not be suitable for all ages, more innovative approaches supported by skilled health professionals are needed to motivate and engage with younger patients to promote self-management and adherence.

Molecular analysis of congenital adrenal hyperplasia due to 21-hydroxylase deficiency in Hong Kong Chinese patients.

BACKGROUND: Congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency (21OHD) is an autosomal recessive disorder due to mutation in the CYP21A2 gene. OBJECTIVE: To elucidate the genetic basis of 21-hydroxylase-deficient CAH in Hong Kong Chinese patients. PATIENTS AND METHODS: Mutational analysis of the CYP21A2 gene was performed on 35 Hong Kong Chinese patients with 21OHD using direct DNA sequencing and multiplex ligation-dependent probe amplification (MLPA). RESULTS: The genetic findings of 21 male and 14 female patients are the following: c.293-13A/C>G (intron 2 splice site; 20 alleles), p.I172N (13), p.R356W (7), p.Q318X (4). A total of 20 mutant alleles contained gross deletion/conversion of all or part of the CYP21A2 gene. A novel mutation, c.1367delA (p.D456fs), was detected in one patient. One patient had only a heterozygous mutation detected. Out of 35 patients, 16 would have been incorrectly genotyped if either DNA sequencing or MLPA alone was used for molecular analysis. CONCLUSIONS: The frequency of various mutations in the studied patients differs from those reported in other Asian populations. Gross deletion/conversion accounts for nearly one-third of the genetic defects. Therefore, laboratories must include methods for detecting point mutations as well as gross deletions/conversions to avoid misinterpretation of genotype. Genotyping has increasingly been proven to be a useful tool for supplementing, if not replacing, hormonal profiling for the diagnosis of 21OHD.

Is there a role for beta-blockers in hypertensive diabetic patients?

Clinical trials have not yet produced long-term primary prevention data on the effects of angiotensin converting enzyme inhibitors, calcium antagonists or alpha-blockers on cardiovascular complications and sudden death in hypertensive patients. Large-scale secondary preventive studies on calcium antagonists have been disappointing. In contrast, beta-blockers have an established role in cardioprotection both in primary and secondary preventive studies and there is evidence to show that the cardioprotective effect of beta-blockers is even greater in the diabetic population. Furthermore, this favourable impact of beta-blockers was achieved despite diabetic patients having a worse risk factor profile and poorer prognosis. In this review the use of beta-blockers in diabetic patients will be discussed and their impact on coronary artery disease described.

The treatment of elderly hypertensive patients.

Treatment of hypertension in the elderly has hitherto been considered to be potentially dangerous. Three recent studies have clearly shown that in selected elderly hypertensives, blood pressure reduction very effectively reduces cardiovascular complications without causing unacceptable adverse effects. The impact on non-fatal stroke was most striking although a reduction in coronary events was also achieved. Thiazide diuretics were used in all three trials, and beta-blockers were used in two. Thiazide diuretics had a major beneficial effect. In this review the applicability of these results to the whole unselected population of elderly hypertensives is considered, and the choice of therapy in different subgroups of patients discussed.

The infancy-childhood-puberty model of growth: clinical aspects.

The infancy-childhood-puberty (ICP) growth model describes human growth from the latter half of the intrauterine life to maturity as three additive and partly superimposed components--infancy, childhood and puberty. Each component can be analysed mathematically and appears to be controlled by distinct biological mechanisms. The infancy component is largely nutrition dependent, the childhood component is mostly dependent on growth hormone (GH) and the pubertal component depends on the synergism between sex steroids and GH. The ICP model offers a method for detecting abnormalities in the three components, so that early intervention can be targeted and therapy monitored.

Activation of endothelial cells in thrombosis and vasculitis.

The endothelium participates actively in homeostatic mechanisms such as the regulation of vascular tone and maintenance of a nonthrombotic environment, as well as directing biological responses such as leukocyte trafficking to inflammatory sites. Disruption of these processes leads to disease. In the antiphospholipid antibody syndrome autoantibodies provoke the endothelium to develop a prothrombotic surface. In systemic vasculitides associated with presence of antineutrophil cytoplasm antibodies, it is likely that the autoantibodies incite premature neutrophil activation, disrupted neutrophil-endothelium interactions and endothelial damage. This review considers how normal endothelial functions may be subverted in disease and how active endothelial responses may contribute to disease.

Assessment of disease activity in systemic vasculitis.

The systemic vasculitides are a group of inflammatory disorders characterised by relapses and remission. Before the introduction of immunosuppressive drugs, mortality was unacceptably high. Immunosuppressive therapy has had a therapeutic impact, but at the cost of increased risk of infection and other adverse effects. Differentiating infection from active disease can be difficult, and the inappropriate prescription of immunosuppressive drugs can be fatal. Hence disease indices which can aid physicians to identify the active phase of disease and enable early treatment, will be valuable in the management of this group of disorders.

Antineutrophil cytoplasm antibody-induced neutrophil nitric oxide production is nitric oxide synthase independent.

BACKGROUND: Antineutrophil cytoplasm antibodies (ANCAs) are implicated in the pathogenesis of systemic vasculitis. We asked whether ANCA could induce nitric oxide (NO) release from human neutrophils and, if so, whether this NO production was dependent on NO synthase (NOS) activity. METHODS: Neutrophil NO production was measured using a chemiluminescence assay, and NOS activity was determined by the conversion of [(14)C] L-arginine to [(14)C] L-citrulline and NOS mRNA expression by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Human neutrophils isolated from healthy donors were incubated at 37 degrees C with human ANCA, normal human IgG, murine monoclonal myeloperoxidase ANCA, murine proteinase-3 ANCA, or their respective isotypic controls for 6 to 12 hours in RPMI. Both human and monoclonal ANCA led to a dose-dependent increase of NO compared with control IgG. Neutrophils, either freshly isolated or incubated for seven hours with murine monoclonal myeloperoxidase ANCA, proteinase-3 ANCA, or a mixture of interleukin-1 beta, tumor necrosis factor-alpha, interferon-gamma plus lipopolysaccharide showed no NOS activity with low conversion rates of [(14)C] L-arginine to [(14)C] L-citrulline, which could not be inhibited by N(G)-monomethyl-L-arginine (NOS inhibitor). To detect NOS mRNA expression, RT-PCR was performed using oligonucleotide primers derived from mRNA sequences of either human constitutive endothelial NOS (eNOS), constitutive neuroneal NOS (nNOS), or human hepatocyte inducible NOS (iNOS). There was no expression of either eNOS, nNOS, or iNOS in untreated, human and murine monoclonal ANCA-treated, or cytokine-treated neutrophils. CONCLUSION: These data suggest that human neutrophils produce NO in response to ANCA but in a NOS-independent way. NO can be generated from a nonenzymatic interaction between hydrogen peroxide and arginine. We postulate that this is the predominant pathway of NO synthesis in neutrophils, since ANCAs are capable of inducing reactive oxygen species production from neutrophils.

Neutrophil FcgammaRIIIb allelic polymorphism in anti-neutrophil cytoplasmic antibody (ANCA)-positive systemic vasculitis.

Neutrophils constitutively express FcgammaRIIa and FcgammaRIIIb receptors. Both receptors exhibit allelic variants which have different quantitative functional capacities: the biallelic FcgammaRIIa-R131 and -H131 alleles, and the neutrophil antigen (NA) NA1/NA2 alleles. ANCA activation of neutrophils requires ligation of FcgammaRIIa receptor, but recent data have shown that ANCA can also bind FcgammaRIIIb receptor. The aim of this study was to determine whether the FcgammaRIIIb polymorphism was a risk factor for the development of ANCA-associated systemic vasculitis, or the associated nephritis. FcgammaRIIIb receptor genotyping was determined by allele-specific polymerase chain reaction. Genomic DNA was extracted from 101 Caucasian patients with ANCA+ vasculitis (of whom 84 had renal disease) and 100 ethnically matched controls. Of the patients with ANCA+ systemic vasculitis, 71 had ANCA with specificity for proteinase 3 and 30 with specificity for myeloperoxidase (MPO). Overall no significant difference in genotype distribution or allele frequencies was found between patients and controls, or between patients with renal disease and controls. However, there was a trend for an increase in homozygosity for the NA1 allele in patients with a vasculitis and this was significant in patients who had anti-MPO antibodies. The FcgammaRIIIb receptor polymorphism is not a major factor predisposing to the development of ANCA+ systemic vasculitis or the associated nephritis. The over-representation of the FcgammaRIIIb homozygous NA1 allele in patients with anti-MPO antibodies may have implications for disease susceptibility.