Chinese normotensive and essential hypertensive reference intervals for plasma aldosterone and renin activity by liquid chromatography-tandem mass spectrometry.

OBJECTIVES: The renin-angiotensin-aldosterone system (RAAS) regulates blood pressure. Plasma renin activities (PRA) and plasma aldosterone concentrations (PAC) are biomarkers related to RAAS. Liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based measurements for PRA and PAC have become popular. Method-specific reference intervals (RIs) are required. METHODS: Routine PRA and PAC services in a Hong Kong teaching hospital were based on LC-MS/MS methods. PRA and PAC RIs were developed for normotensive subjects and essential hypertensive (EH) patients. Healthy volunteers were recruited to establish normotensive RIs. PRA and PAC results of hypertensive patients with urine aldosterone tests for primary aldosteronism (PA) screening were retrieved from the laboratory information system. Patients without PA were included. Patients with secondary hypertension and patients on medications affecting the RAAS were excluded. The central 95% RIs were established based on the recommendations of the Clinical and Laboratory Standards Institute guideline C28-A3. RESULTS: PRA and PAC of 170 normotensive volunteers and 362 EH patients were analysed. There was no sex-specific difference in PRA and PAC for normotensive and EH reference subjects. Differences for PRA and PAC were noted between normotensive subjects aged below 45 and their older counterparts. However, such a difference was only identified for PRA but not PAC in EH patients. Age-specific RIs were established accordingly. CONCLUSIONS: This study presented age-specific LC-MS/MS RIs of PRA and PAC for both normotensive and EH populations for local Chinese in Hong Kong.

Fatal pancytopenia in a hemodialysis patient after treatment with low-dose methotrexate.

We report a 56-year-old male hemodialysis patient who developed fatal pancytopenia after treatment with low-dose methotrexate for psoriasis and psoriatic arthropathy. Risk factors identified included impaired renal function, concurrent use of nonsteroidal anti-inflammatory drugs, low serum albumin, and relatively low serum folate level. Literature review found similar risk factors in 12 other cases. Therefore, methotrexate, even as a single dose, should not be used to treat rheumatic conditions in dialysis patients.

IgM Antibodies Can Access Cryptic Antigens Denied to IgG: Hypothesis on Novel Binding Mechanism.

Antibodies are well-known protein mediators of immunity. IgM is the primordial member and the neglected sibling of the later-evolved and more proficient IgG in regard to their therapeutic and diagnostic use. Serendipitously, however, we found a paradox: While murine IgM antibodies specific for guanosine triphosphate (GTP) were able to recognize native guanylyl antigens found in primate or rat muscle tissues by immunofluorescence assays (which mimicked the auto-antibodies from autoimmune patients to skeletal or smooth muscle), the murine and human IgG counterparts failed. The results were replicated in cell-free direct binding assays using small latex microspheres decorated densely with GTP. The IgG antibodies could bind, however, if GTP was presented more spaciously on larger particles or as a univalent hapten. Accordingly, oligomerization of GTP (30-mer) destroyed the binding of the IgG antibodies but enhanced that of the IgMs in inhibition ELISA. We reason that, contrary to current belief, IgM does not bind in a lock-and-key manner like IgG. We hypothesize that whereas the intact and rigid antigen-binding site of IgG hinders the antibody from docking with antigens that are obstructed, in IgM, the two component polypeptides of the antigen-binding site can dissociate from each other and navigate individually through obstacles like the ancestral single-polypeptide antibodies found in sharks and camelids, both components eventually re-grouping around the antigen. We further speculate that polyreactive IgMs, which enigmatically bind to more than one type of antigen, use the same modus operandi. These findings call for a re-look at the clinical potential of IgM antibodies particularly in specific areas of cancer therapy, tissue pathology and vaccine design, where IgG antibodies have failed due to target inaccessibility.

Low testosterone and clinical outcomes in Chinese men with type 2 diabetes mellitus - Hong Kong Diabetes Registry.

AIMS: To assess the implications of low testosterone on cardiovascular risk factors, metabolic syndrome (MES) and clinical outcomes in Chinese men with Type 2 Diabetes (T2D). METHODS: A prospective cohort study carried out in a university hospital involving a consecutive cohort of 1239 Chinese men with T2D and a median disease duration of 9years followed up for 4.8years. Clinical characteristics, frequency of MES, serum total testosterone and clinical events were analyzed. Multivariate logistic regression was performed to examine the independent association of low testosterone with MES after adjustment for confounding covariates. Cox proportional hazards regression analysis was used to derive hazard ratio for clinical outcomes. RESULTS: More men with low testosterone had cardiovascular-renal disease and MES than those with normal testosterone. The adjusted odds ratio (OR) of low testosterone for MES was 2.63 (95% Confidence Interval [CI] 1.56-4.61). After a median follow-up of 4.8years, the hazard ratio (HR) of low testosterone was 2.22 (95% CI 1.23-4.01) for incident non-prostate cancer. In a multivariate Cox-regression model, the HRs were attenuated but remained significant with adjustment for MES and renal parameters. CONCLUSIONS: Chinese men with low testosterone had high prevalence of cardiovascular disease and MES with high incidence non-prostate cancer.

Tacrolimus toxicity in islet transplantation due to interaction with macrolides.

BACKGROUND: Drug interactions are an important risk in transplant patients. Case presentation: This case describes an incident where a patient with islet transplantation, who was using tacrolimus as part of the immunosuppressant regime, was started on a course of clarithromycin and experienced nephrotoxicity and neurotoxicity. He was an outpatient at that time and was managed with temporary cessation of tacrolimus until the tacrolimus level returned to target and his symptoms resolved. He recovered well and was resumed on his usual dosage of tacrolimus to prevent rejection of islets. CONCLUSION: Care should be taken with commonly used antibiotics to avoid potentially dangerous interactions with immunosuppressant drugs.

'Open-and-close' pituitary surgery in an acromegalic man presenting with excessive sweatiness.

Ectopic-acromegaly is rare. Diagnosing ectopic-acromegaly is challenging given that the clinical and biochemical manifestations can be almost indistinguishable from those of patients with growth hormone secreting pituitary adenomas. This case report highlights the importance of clinical vigilance in differentiating between the two conditions. A 41-year-old Caucasian man presented with typical features of acromegaly with an enlarged pituitary and a lung lesion. Although excision of the lung mass showed a carcinoid tumour, normalisation of growth hormone factors did not occur soon enough. This led to a presumed diagnosis of a pituitary adenoma. However, no pituitary tumour was identified during trans-sphenoidal surgery. Postoperatively, the patient improved clinically and biochemically. Retrospective histological examination of the excised lung lesion showed a small proportion of tumour cells containing growth hormone releasing hormone (GHRH), suggesting ectopic-GHRH production from the lung neuroendocrine tumour. An open-and-close trans-sphenoidal surgery could have been avoided in this patient with ectopic-GHRH acromegaly.

DNA-based diagnosis of xeroderma pigmentosum group C by Whole-genome scan using single-nucleotide polymorphism microarray.

In this study, we have established the molecular basis of xeroderma pigmentosum (XP) in two unrelated Chinese families. In the first patient with consanguineous parents, we mapped the disease-causing locus XPC using single-nucleotide polymorphism microarray. Mutational analysis of the XPC gene showed that the patient is homozygous for a nonsense mutation, E149X. After developing DNA-based diagnosis of XPC, we screened another XP patient for XPC mutations. We found that the second patient is a compound heterozygote of 1209delG and Q554X in this gene. These are the first XPC-causing mutations identified in Chinese patients.

Testosterone level in men with type 2 diabetes mellitus and related metabolic effects: A review of current evidence.

A significant proportion of patients with type 2 diabetes mellitus have a low testosterone level relative to reference ranges based on healthy young men. Only a small number of these patients suffer from classical hypogonadism as a result of recognizable hypothalamic-pituitary-gonadal axis pathology. The cut-off value of the serum testosterone level in men without obvious hypothalamic-pituitary-gonadal axis pathology is controversial. It is unclear to what extent a low serum testosterone level causally leads to type 2 diabetes and/or the metabolic syndrome. From a theoretical standpoint, there can be complex interactions among the hypothalamic-pituitary-gonadal axis, body composition and insulin resistance, which can be further influenced by intrinsic and extrinsic factors to give rise to metabolic syndrome, glucose intolerance, and low-grade inflammation to increase the risk of cardiovascular disease. Although a low serum testosterone level frequently coexists with cardiometabolic risk factors and might serve as a biomarker, more studies are required to clarify the causal, mediating or modifying roles of low serum testosterone level in the development of adverse clinical outcomes. Currently, there are insufficient randomized clinical trial data to evaluate the effects of testosterone replacement therapy on meaningful clinical outcomes. The risk-to-benefit ratio of testosterone therapy in high-risk subjects, such as those with type 2 diabetes, also requires elucidation. The present article aims to review the current evidence on low serum testosterone levels in patients with type 2 diabetes, and its implications on cardiovascular risk factors, metabolic syndrome and adverse clinical outcomes.

Predictive value of dialysate cell counts in peritonitis complicating peritoneal dialysis.

Early prediction of outcomes has major potential implications regarding the management of dialysis-related peritonitis. The outcomes of 565 consecutive episodes of peritonitis complicating peritoneal dialysis between August 2001 and July 2005 were evaluated in relation to the dialysate cell counts. Discriminatory power, based on the area under the receiver-operating characteristic (ROC) curves, of the cell counts was assessed. The findings then were validated externally in a cohort of 217 peritonitis episodes from another dialysis unit. During the study period, 565 episodes of peritonitis were included for analysis, 465 of which had treatment success defined as complete resolution of peritonitis without the need for Tenckhoff catheter removal. Of the remaining 100 episodes (treatment failure), 70 required Tenckhoff catheter removal and 30 had peritonitis-related death. The peritoneal dialysate total white blood cell count on day 3 of peritonitis predicted treatment failure independent of standard risk factors, and it had a higher area under the ROC curve than the dialysate white cell count on day 1 (0.80 versus 0.58; P < 0.0001). Using a peritoneal dialysate white count cut point > or = 1090/mm3 on day 3, the sensitivity was 75% and the specificity was 74% for the prediction of treatment failure (defined as catheter loss or peritonitis-related death). In multiple logistic regression analyses, peritoneal dialysate white count > or = 1090/mm3 on day 3 was an independent prognostic marker for treatment failure after adjustment for conventional risk factors (hazard ratio 9.03; 95% confidence interval 4.40 to 18.6; P < 0.0001). Number of years on peritoneal dialysis; diabetes; gram-negative organisms; and Pseudomonas, fungal, or Mycobacterium species were other independent risk factors that were predictive of treatment failure. Findings from an independent validation set of peritonitis (217 episodes after exclusion of Mycobacterium and fungal causes) also favored the peritoneal dialysate white count on day 3, as compared with day 1 and day 2, to predict treatment failure. Area under the ROC curve for the white counts on day 3 was 0.98 (95% confidence interval 0.95 to 0.99) in the validation set. This study demonstrated and cross-validated the superiority of peritoneal dialysate white cell count on day 3 to predict outcomes of dialysis-related peritonitis. These results call attention to the value of validating prognostic factors of peritonitis complicating peritoneal dialysis.

The p11 subunit of annexin II heterotetramer is regulated by basic carboxypeptidase.

The Ca(2+)-dependent phospholipid-binding protein annexin II heterotetramer (AIIt) is composed of two copies of annexin II and a p11 dimer. The interaction of the carboxyl-terminal lysine residues of the p11 subunit of AIIt with the lysine-binding kringle domains of plasminogen is believed to play a key role in plasminogen binding and stimulation of the tPA-catalyzed cleavage of plasminogen to plasmin. In the current report, we show that AIIt-stimulated plasminogen activation is regulated by basic carboxypeptidases, in vitro. The incubation of AIIt with a 1/400 molar ratio of carboxypeptidase B for periods as short as 2 min resulted in a significant loss in AIIt-stimulated plasminogen activation. Carboxypeptidase B (CpB) as well as thrombin-activated fibrinolysis inhibitor (TAFIa) and carboxypeptidase N (CpN) rapidly reduced AIIt-stimulated plasminogen activation by 80%. The molar ratio of carboxypeptidase/AIIt for half-maximal inhibition of AIIt was 1/4700, 1/700, and 1/500 for CpB, TAFIa, and CpN, respectively. Treatment of AIIt with carboxypeptidase resulted in loss of both carboxyl-terminal lysine residues from the p11 subunit, which correlated with a decrease in the k(cat) and an increase in the K(m) for plasminogen activation. The data reveal a novel mechanism for the regulation of AIIt-stimulated plasminogen activation.