Modulating monocyte-derived macrophage polarization in cerebral ischemic injury with hyperglycemia.

Ischemic stroke (IS), characterized by high mortality rate, occurs owing to diminished or blocked blood flow to the brain. Hyperglycemia (HG) is a major contributor to the risk of IS. HG induces augmented oxidative stress and Blood-Brain Barrier breakdown, which increases the influx of blood-derived myeloid cells into the brain parenchyma. In cerebral ischemia, infiltrating monocytes undergo differentiation into pro-inflammatory or anti-inflammatory macrophages, having a large effect on outcomes of ischemic stroke. In addition, interleukin-4 (IL-4) and interleukin-13 (IL-13) engage in post-ischemia repair by polarizing the infiltrating monocytes into an anti-inflammatory phenotype. In this study, we aimed to determine the effect of phenotypic polarization of monocyte-derived macrophages on the prognosis of IS with HG (HG-IS). We first established a hyperglycemic mouse model using streptozotocin (150 mg/kg) and induced transient middle cerebral artery occlusion. We observed that blood-brain barrier permeability increased in HG-IS mice, as per two-photon live imaging and Evans blue staining. We also confirmed the increased infiltration of monocyte-derived macrophages and the downregulation of anti-inflammatory macrophages related to tissue remodeling after inflammation in HG-IS mice through immunohistochemistry, western blotting, and flow cytometry. We observed phenotypic changes in monocyte-derived macrophages, alleviated infarct volume, and improved motor function in HG-IS mice treated with IL-4 and IL-13. These findings suggest that the modulation of phenotypic changes in monocyte-derived macrophages following IS in hyperglycemic mice may influence ischemic recovery.

Clinical characteristic and management of haemophilia patients in Malaysia: A single centre experience.

INTRODUCTION: Haemophilia is one of the commonest inherited bleeding disorders which may lead to long term disabilities if not treated properly. Our aim of study is to understand the clinical characteristic, treatment and complications of adult haemophilia patients in our centre. MATERIALS AND METHODS: A retrospective cross-sectional review of all adult haemophilia A (HA) or haemophilia B (HB) patients who received treatment in Hospital Pulau Pinang from January 2021 to December 2022 was conducted. Data was retrieved from patients' medical records. RESULTS: A total of 75 haemophilia patients (64 HA and 11 HB) were included in this study with median age of 37 years (range 19 70). 42 of them had severe haemophilia (50% of HA, 91% of HB). All HB and 93.8% of severe HA patients were on prophylaxis. Six severe and one mild HA patients developed inhibitor with four of them currently on non-factor prophylaxis. 24 patients (32%) had prior hepatitis C infection and all of them have been successfully treated. The mean annual bleeding rate for severe haemophilia patients were 1.77 (SD ±3.6). Target joints were observed in 9.3% of patients with ankle joint (71.4%) being the most affected joint. More than one quarter (26.7%) of our patients have comorbidities with majority of them having hypertension (17/20), followed by diabetes mellitus (5/20) and ischemic heart disease (5/20). CONCLUSION: Our study showed that a significant number of adult patients with haemophilia have comorbidities. Apart from optimising factor replacement therapy, future planning should include improvement in screening, risk modification and prevention of cardiovascular disease.

SGLT2 and DPP4 inhibitors improve Alzheimer's disease-like pathology and cognitive function through distinct mechanisms in a T2D-AD mouse model.

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2D) share common features, including insulin resistance. Brain insulin resistance has been implicated as a key factor in the pathogenesis of AD. Recent studies have demonstrated that anti-diabetic drugs sodium-glucose cotransporter-2 inhibitor (SGLT2-i) and dipeptidyl peptidase-4 inhibitor (DPP4-i) improve insulin sensitivity and provide neuroprotection. However, the effects of these two inhibitors on the brain metabolism and insulin resistance remain uninvestigated. We developed a T2D-AD mouse model using a high-fat diet (HFD) for 19 weeks along with a single dose of streptozotocin (100 mg/kg, intraperitoneally) at the fourth week of HFD initiation. Subsequently, the animals were treated with SGLT2-i (empagliflozin, 25 mg/kg/day orally [p.o.]) and DPP4-i (sitagliptin, 100 mg/kg/day p.o.) for 7 weeks. Subsequently, behavioral tests were performed, and the expression of insulin signaling, AD-related, and other signaling pathway proteins in the brain were examined. T2D-AD mice not only showed increased blood glucose levels and body weight but also insulin resistance. SGLT2-i and DPP4-i effectively ameliorated insulin sensitivity and reduced body weight in these mice. Furthermore, SGLT2-i and DPP4-i significantly improved hippocampal-dependent learning, memory, and cognitive functions in the T2D-AD mouse model. Interestingly, SGLT2-i and DPP4-i reduced the hyperphosphorylated tau (pTau) levels and amyloid ß (Aß) accumulation and enhanced brain insulin signaling. SGLT2-i reduced pTau accumulation through the angiotensin converting enzyme-2/angiotensin (1-7)/ mitochondrial assembly receptor axis, whereas DPP4-i reduced Aß accumulation by increasing insulin-degrading enzyme levels. These findings suggest that SGLT2-i and DPP4-i prevent AD-like pathology and cognitive dysfunction in T2D mice potentially through affecting brain insulin signaling via different mechanisms.

Cauda equina thickening: an approach to MRI findings.

There are many causes of cauda equina (CE) thickening on neuroimaging of the lumbar spine. The imaging features of CE thickening for the various conditions often overlap and are non-specific to clinch a definite diagnosis. Hence, the imaging findings have to be discerned in accordance with the patient's presenting history, clinical examination findings, and results from electrophysiology and laboratory studies. In this review, the authors aim to supplement the existing literature on imaging findings of CE thickening with a diagnostic framework for clinical workup. The authors also aim to familiarise readers with the interpretation of CE thickening on magnetic resonance imaging (MRI) and would like to illustrate the normal variants and pitfalls that could be mistaken for abnormal results.

Impact of food texture modifications on oral processing behaviour, bolus properties and postprandial glucose responses.

Several studies have demonstrated food texture manipulation on oral processing behaviour (OPB). We explored the effect of texture-differences of equivalent carbohydrate load on OPB, bolus properties and postprandial glycaemic responses (PPG). In a randomised cross-over, within-subjects, non-blinded design, healthy male participants (N = 39) consumed fixed portions of white rice (WR) and rice cake (RC) while being video recorded to measure microstructural eating behaviours. PPG was compared between test foods over a period of 120-min, and the bolus properties and saliva uptake at swallow were measured for both test foods. RC displayed higher instrumental hardness, chewiness and Young's modulus than WR (p = 0.01), and participants perceived RC as more springy and sticky than WR (p < 0.001). The RC meal was chewed more per bite (p < 0.001) and consumed at a faster eating rate (p = 0.033) than WR. WR bolus particles were smaller at swallow (p < 0.001) with a larger total surface area (p < 0.001), compared to RC. The glucose response for RC was significantly higher during the first 30-min postprandial period (p = 0.010), and lower in the later (30-120 min) postprandial period (p = 0.031) compared to WR. Total blood glucose iAUC did not differ significantly between WR and RC meals despite their large differences in texture, OPB and bolus properties. Oro-sensory exposure time was a significant predictor of glucose iAUC30min for both test meals (RC, p = 0.003; WR, p = 0.029). Saliva uptake in the bolus was significantly positively associated with blood glucose during the first 30-min postprandial period for the RC meal (p = 0.008), but not for WR. We conclude that food texture modifications can influence OPB and bolus properties which are key contributors to the dynamic evolution of the glycaemic response. Total blood glucose responses were the same for both test foods, though differences in oral processing and bolus properties influenced temporal changes in PPG.

High prevalence of central hypothyroidism among patients with transfusion dependent thalassemia in Hospital Pulau Pinang: A cross sectional study.

INTRODUCTION: Thalassemia is the most common heritable haematological disorder in Malaysia. Hypothyroidism is one of the complications of the transfusion dependent thalassemia (TDT) patients as a result of iron overload. MATERIALS AND METHODS: All registered TDT patients attending Haematology day care, Hospital Pulau Pinang from January 2019 to January 2020 were included in the study. Hypothyroidism was defined according to TSH and FT4, or based on the history of treatment for diagnosed hypothyroidism. RESULTS: There were 51 TDT patients, with 24 (47%) males and 27 (53%) females. Most of the patients were Malays (27, 53%) followed with Chinese (23, 45%) and Indonesian (1, 2%). Beta thalassemia major and HbE beta thalassaemia accounted for 35 (68.8%) and 14 (27.5%) TDT patients respectively, while two (3.9%) were HbH Constant Spring. Eleven (21.6%) had hypothyroidism; of which seven (63.6%) had central hypothyroidism, three (27.3%) had subclinical hypothyroidism, the remaining one (9.1%) had primary hypothyroidism. Three (27.3%) had concomitant hypogonadism, one (9.1%) had hypocortisolism and another (9.1%) had both diabetes mellitus and hypogonadism. There was no statistical relationship between the prevalence of hypothyroidism and age, serum ferritin, splenectomy history and iron chelation therapy. CONCLUSION: High prevalence of central hypothyroidism is reported. Measurement of both TSH and FT4 is recommended as initial screening for thyroid dysfunction among patient with TDT.

Local adenoviral delivery of soluble CD200R-Ig enhances antitumor immunity by inhibiting CD200-ß-catenin-driven M2 macrophage.

CD200 is known as an immune checkpoint molecule that inhibits innate immune cell activation. Using a head and neck squamous cell carcinoma (HNSCC) model, we sought to determine whether localized delivery of adenovirus-expressing sCD200R1-Ig, the soluble extracellular domain of CD200R1, enhances antitumor immunity. Mouse-derived bone marrow cells and M1/M2-like macrophages were cocultured with tumor cells and analyzed for macrophage polarization. As an in vivo model, C57BL/6 mice were subcutaneously injected with MEER/CD200High cells, CD200-overexpressing mouse HNSCC cells. Adenovirus-expressing sCD200R1-Ig (Ad5sCD200R1) was designed, and its effect was tested. Components in the tumor-immune microenvironment (TIME) were quantified using flow cytometry. CD200 promoted tumor growth and induced the expression of immune-related genes, especially macrophage colony-stimulating factor (M-CSF). Interestingly, CD200 induced M2-like polarization both in vitro and in vivo. Consequently, CD200 recruited more regulatory T (Treg) cells and fewer CD8+ effector T cells. These effects were effectively abolished by local injection of Ad5sCD200R1. These protumor effects of CD200 were driven through the ß-catenin/NF-κB/M-CSF axis. CD200 upregulated PD-L1, and the combined targeting of CD200 and PD-1 thus showed synergy. The immune checkpoint CD200 upregulated immune-related genes through ß-catenin signaling, reprogrammed the TIME, and exerted protumor effects. Ad5sCD200R1 injection could be an effective targeted strategy to enhance antitumor immunoediting.

Presence and prevalence of UV related genetic mutations in uveal melanoma: similarities with cutaneous melanoma.

Ultraviolet (UV) radiation is an accepted etiological factor in cutaneous melanoma (CM), however its role in uveal melanoma (UM) is controversial. Partly as a consequence, CM and UM are often considered to be separate conditions, and advances in the treatment of CM have not led to joint clinical trials or parallel improvements in survival of UM. This study hypothesized that a subset of UM tumors displays evidence of genetic changes consistent with UV-related damage similar to that shown in CM. Analysis of the Broad Institute's Firebrowse depository of 80 UM samples and 343 CM samples, together with the Sanger Institute's Catalogue of Somatic Mutations in Cancer depository of 995 UM and 12,447 CM samples was undertaken to identify the most frequently mutated genes, mutation types, and specific nucleotide variants (SNVs) in each condition. Somatic mutation data were cross-correlated and shared mutations assessed against known effects of UV radiation. The proportion of samples with C>T substitutions (a classic genetic marker of UV-related damage) was higher in UM than CM on both DNA strands (17.0% vs 13.1%, p=0.038). The most frequently encountered cross-correlated mutated genes between UM and CM were, in order, BRAF, NRAS, TP53, CDKN2A, TERT, PTEN, ARID2, and KMT2C, with multiple common BRAF point mutations. Each cross-correlated mutation, and each common point mutation in BRAF, was associated with UV-related mechanistic changes. These findings support the hypothesis that the etiology of a substantial minority of UMs may be more UV dependent than previously recognized.

Prevalence of endocrine complications in transfusion dependent thalassemia in Hospital Pulau Pinang: A pilot study.

INTRODUCTION: Frequent blood transfusions results in iron overload and lead to multiple endocrine complications. In spite of improvements in iron chelation therapy, a significant number of transfusion dependent thalassaemia (TDT) patients still develop endocrine complications. The aim of this study is to evaluate the prevalence of various endocrine complications in our adult TDT patients and to study the correlation with serum ferritin and liver iron concentration (LIC). METHODS: A retrospective review of all TDT patients treated in Haematology Unit, Hospital Pulau Pinang (HPP) was conducted. RESULTS: Of the 45 adult TDT patients, 22 were males and 23 were females with mean age of 28.8±6.9 years old. Majority of TDT in HPP were beta thalassemia major (71.1%), followed by E-Beta thalassemia (24.4%) and HbH-Constant Spring (4.4%). Frequency of transfusion was 3-4 weekly. 40.0% of adult TDT suffered from at least one endocrine complication. Among the adult TDT patients with endocrine complication, 50% have one endocrinopathy, 38.9% with two types of endocrinopathies and 11.1% of them have three or more types of endocrinopathies. Hypogonadism (22.2%) was the commonest endocrine complication, followed by osteoporosis (20%), hypothyroidism (13.3%), diabetes mellitus (6.7%) and hypocortisolism (4.4%). Patients with endocrine complications were significantly older. Mean serum ferritin level and LIC was higher among patients with endocrine complications but both were not statistically significant. CONCLUSION: Endocrinopathy is still prevalent in 40% of adult TDT patients. This leads to higher health-care resource utilization, cost and significant morbidities among patients with TDT. Therefore, regular monitoring and early detection with intensification of chelation therapy is essential.

CD200 Induces Epithelial-to-Mesenchymal Transition in Head and Neck Squamous Cell Carcinoma via ß-Catenin-Mediated Nuclear Translocation.

The membrane glycoprotein CD200 binds to its receptor CD200R1 and induces tolerance, mainly in cells of the myeloid lineage; however, information regarding its role in solid tumors is limited. Here, we investigated whether CD200 expression, which is enriched mainly in high-grade head and neck squamous cell carcinoma (HNSCC), correlates with cancer progression, particularly the epithelial-to-mesenchymal transition (EMT). The forced overexpression of CD200 in the HNSCC cell line, UMSCC84, not only increased the expression of EMT-related genes, but also enhanced invasiveness. The cleaved cytoplasmic domain of CD200 interacted with ß-catenin in the cytosol, was translocated to the nucleus, and eventually enhanced EMT-related gene expression. CD200 increased the invasiveness of mouse tonsillar epithelium immortalized with E6, E7, and Ras (MEER), a model of tonsillar squamous cell carcinoma. siRNA inhibition of CD200 or extracellular domain of CD200R1 down-regulated the expression of EMT-related genes and decreased invasiveness. Consistently, compared to CD200-null MEER tumors, subcutaneous CD200-expressing MEER tumors showed significantly increased metastatic migration into draining lymph nodes. Our study demonstrates a novel and unique role of CD200 in inducing EMT, suggesting the potential therapeutic target for blocking solid cancer progression.

Amino acids disrupt calcium-dependent adhesion of stratum corneum.

In the stratum corneum, the intercellular junction made up of cadherin proteins provides the structural integrity of the framework. Ca2+ ions are known to play a key role in maintaining this junction. In this study, we hypothesized that Ca2+ chelation in stratum corneum will weaken the bond of the tissue and consequently promote exfoliation. Amino acids, ubiquitously existing as metabolites and building blocks of the body, have the molecular property to chelate Ca2+ ions. In the current study, we verified the Ca2+ chelating property of amino acids and demonstrated that amino acids can interfere with the interaction of cadherins, separate stratum corneum into pieces, and thereby stimulate the exfoliation process of skin. These results validate the importance of Ca2+ ion in the skin exfoliation process. Importantly, our findings indicate that amino acids may be efficiently used for improving skin conditions.

Cost-Effectiveness Analysis for the Treatment of Hyperphosphatemia in Predialysis Patients: Calcium-Based versus Noncalcium-Based Phosphate Binders.

BACKGROUND: Hyperphosphatemia in chronic kidney disease (CKD) patients is often treated with calcium carbonate (CaCO3) despite the fact that CaCO3 is associated with increased calcium load and potentially increased cardiovascular risk. Alternative treatments with noncalcium-based phosphate binders do not increase the calcium load but are more costly. This study analyzes the cost-effectiveness of sevelamer versus CaCO3 for the treatment of hyperphosphatemia in stage III-V predialysis CKD patients in Malaysia. METHODS: A Markov decision model was adapted to simulate a hypothetical cohort of CKD patients requiring treatment for hyperphosphatemia. Survival was estimated by using efficacy data from the INDEPENDENT-CKD clinical trial. Cost data was obtained from Malaysian studies while health state utilities were derived from literature. Analysis was performed over lifetime duration from the perspective of the Ministry of Health Malaysia with 2013 as reference year. RESULTS: In the base case analysis, sevelamer treatment gained 6.37 life years (5.27 QALY) compared to 4.25 life years (3.54 QALY) with CaCO3. At 3% discount, lifetime costs were RM159,901 ($48,750) and RM77,139 ($23,518) on sevelamer and CaCO3, respectively. Incremental cost-effectiveness (ICER) of sevelamer versus CaCO3 was RM47,679 ($14,536) per QALY, which is less than the WHO threshold of three times GDP per capita (RM99,395) per QALY. Sensitivity analyses, both using scenario sensitivity analysis and probabilistic sensitivity analysis, showed the result to be robust. CONCLUSIONS: Our study finds that sevelamer is potentially cost-effective compared to CaCO3, for the treatment of hyperphosphatemia in predialysis CKD III-V. We propose that sevelamer should be an option in the treatment of Malaysian predialysis patients with hyperphosphatemia, particularly those with high calcium load.

What are the direct medical costs of managing Type 2 Diabetes Mellitus in Malaysia?

INTRODUCTION: An economic analysis was performed to estimate the annual cost of diabetes mellitus to Malaysia. METHODS: We combined published data and clinical pathways to estimate cost of follow-up and complications, then calculated the overall national cost. Costs consisted of diabetes follow-up and complications costs. RESULTS: Patient follow-up was estimated at RM459 per year. Complications cost were RM42,362 per patient per year for nephropathy, RM4,817 for myocardial infarction, RM5,345 for stroke, RM3,880 for heart failure, RM5,519 for foot amputation, RM479 for retinopathy and RM4,812 for cataract extraction. CONCLUSION: Overall, we estimated the total cost of diabetes as RM2.04 billion per year for year 2011 (both public and private sector). Of this, RM1.40 billion per year was incurred by the government. Despite some limitations, we believe our study provides insight to the actual cost of diabetes to the country. The high cost to the nation highlights the importance of primary and secondary prevention.

Ratio of Klebsiella/Bifidobacterium in early life correlates with later development of paediatric allergy.

Several studies have reported that intestinal microbial colonisation patterns differ between non-allergic and allergic infants. However, the microbial signature underlying the pathogenesis of allergies remains unclear. We aim to gain insight into the development of the intestinal microbiota of healthy infants and infants who develop allergy in early life, and identify potential microbiota biomarkers of later allergic disease. Using a case-control design in a Chinese sub-cohort of a Singaporean birth cohort (GUSTO), we utilised 16S rRNA gene sequencing to assess intestinal microbial composition and diversity of 21 allergic and 18 healthy infants at 3 weeks, 3 months and 6 months of age, and correlated the microbiota with allergy at ages 18 and 36 months. Pronounced differences in intestinal microbiota composition between allergic and healthy infants were observed at 3 months of age. The intestine of healthy infants was colonised with higher abundance of commensal Bifidobacterium. Conversely, Klebsiella, an opportunistic pathogen, was significantly enriched in the allergic infants. Interestingly, infants with a high Klebsiella/Bifidobacterium (K/B) ratio (above the population median K/B ratio) at age 3 months had an odds ratio of developing allergy by 3 years of age of 9.00 (95% confidence interval 1.46-55.50) compared to those with low K/B ratio. This study demonstrated a relationship between the ratio of genera Klebsiella and Bifidobacterium during early infancy and development of paediatric allergy in childhood. Our study postulates that an elevated K/B ratio in early infancy could be a potential indicator of an increased risk of allergy development. This line of research might enable future intervention strategies in early life to prevent or treat allergy. Our study provides new insights into microbial signatures associated with childhood allergy, in particular, suggests that an elevated K/B ratio could be a potential early-life microbiota biomarker of allergic disease.

Tobacco smoke exposure and respiratory morbidity in young children.

OBJECTIVE: Secondhand smoke exposure is a potentially preventable cause of significant respiratory morbidity in young children. Our study aimed to quantify respiratory morbidity in young children exposed to secondhand smoke to identify potentially modifiable factors. MATERIALS AND METHODS: This study was embedded in a prospective birth cohort study of pregnant women and their children from fetal life onwards in Singapore (Growing Up in Singapore Towards healthy Outcomes, or GUSTO). Data on prenatal, antenatal and postnatal active and secondhand tobacco smoke exposure were obtained by an investigator-administered questionnaire for the periods before pregnancy, at 26-28 weeks' gestation and 24 months after delivery. Data on respiratory morbidity (wheezing episodes, croupy cough, nebuliser use, snoring) and other morbidity (fever, hospitalisation, ear infection) of the child was collected at week 3 and at months 3, 6, 9, 12, 15, 18 and 24 after delivery. Information on parental atopy and potential confounders such as socioeconomic status and maternal educational level were also obtained. Statistical analysis of the data was performed to quantify any significant differences in incidence of respiratory morbidity in children exposed to tobacco smoke in utero and postdelivery, compared with those in smoke-free environments. RESULTS: Women who smoked regularly prior to pregnancy comprised 12.5% (n=155) of the study population; this number fell to 2.3% (n=29) during pregnancy. Mothers exposed to secondhand smoke in the household before pregnancy comprised 35.7% of the study population (n=441) and 31.5% (n=389) were exposed during pregnancy. Postnatally, the prevalence of secondhand tobacco smoke exposure from birth to 2 years of age was 29% (n=359). Participants of Malay ethnicity (p<0.001), mothers with no or primary level education (p<0.001) and mothers with low socioeconomic status (p<0.001) had the highest exposure to tobacco smoke. Offspring secondhand smoke exposure at home by 12 months and by 24 months of age was associated with an increase in hospital admissions due to respiratory disease (RR 1.89, 95% CI 1.02 to 3.50, p=0.04 by 12 months and RR 1.64, 95% CI 1.05 to 2.55, p=0.03 by 24 months) as well as all-cause hospitalisation (RR 1.57, 95% CI 1.14 to 2.17, p=0.01 by 12 months and RR 1.49, 95% CI 1.17 to 1.90, p=0.001 by 24 months), adjusting for parental atopy and child atopic dermatitis. Participants exposed to secondhand smoke by 12 months postdelivery had a significantly increased risk of having at least one wheezing episode (RR 1.71, 95% CI 1.38 to 2.11, p<0.001). CONCLUSIONS: Secondhand smoke exposure during the prenatal and postnatal periods is associated with increased respiratory morbidity in children. Opportunistic screening and targeted smoking cessation counselling for parents at child hospital admissions and well-child outpatient visits, as well as preconception smoking cessation counselling for future pregnancies, may be beneficial to protect the child from negative health impacts.

A unique role for p53 in the regulation of M2 macrophage polarization.

P53 is critically important in preventing oncogenesis but its role in inflammation in general and in the function of inflammatory macrophages in particular is not clear. Here, we show that bone marrow-derived macrophages exhibit endogenous p53 activity, which is increased when macrophages are polarized to the M2 (alternatively activated macrophage) subtype. This leads to reduced expression of M2 genes. Nutlin-3a, which destabilizes the p53/MDM2 (mouse double minute 2 homolog) complex, promotes p53 activation and further downregulates M2 gene expression. In contrast, increased expression of M2 genes was apparent in M2-polarized macrophages from p53-deficient and p53 mutant mice. Furthermore, we show, in mice, that p53 also regulates M2 polarization in peritoneal macrophages from interleukin-4-challenged animals and that nutlin-3a retards the development of tolerance to Escherichia coli lipopolysaccharide. P53 acts via transcriptional repression of expression of c-Myc (v-myc avian myelocytomatosis viral oncogene homolog) gene by directly associating with its promoter. These data establish a role for the p53/MDM2/c-MYC axis as a physiological 'brake' to the M2 polarization process. This work reveals a hitherto unknown role for p53 in macrophages, provides further insight into the complexities of macrophage plasticity and raises the possibility that p53-activating drugs, many of which are currently being trialled clinically, may have unforeseen effects on macrophage function.

A necessary step toward kidney donor safety: the transition from locking polymer clips to transfixion techniques in laparoscopic donor nephrectomy.

Donor safety is of paramount importance in addressing end-stage renal failure through living kidney transplantation. The United States Food and Drug Administration (FDA) issued a Class II recall on the use of Hem-o-lok (Teleflex, Limerick, Pennsylvania, United States) polymer clips on the renal artery in laparoscopic donor nephrectomy (LDN) in June 2006 following 3 reported cases of donor deaths secondary to slipped ligature. The National University Hospital of Singapore made the transition regarding hilar control in minimally invasive donor nephrectomy, from using polymer and titanium clips to transfixion techniques (pure or hand-assisted laparoscopic) via laparoscopic staples or intracorporeal suturing, respectively. This study assessed safety during the transition in arterial transfixion techniques in minimally invasive donor nephrectomy for both donors and recipients. Forty-five consecutive kidney donors underwent donor nephrectomy over a 2-year period starting from June 2010. A total of 37 donors who underwent LDN (pure laparoscopic or hand-assisted laparoscopic) were included in the analysis. Of the 37 patients, 23 kidney donors had renal arterial control using Hem-o-lok while 14 patients from November 2011 onward underwent transfixion of the renal artery. The 2 groups of donor who underwent renal arterial control by either clips ligature or transfixion technique were comparable. The outcomes for the recipients in each group were similar with no statistical difference between postoperative creatinine level, incidence of delayed graft function, or graft survival at 1 year. We conclude that the transition in renal arterial control technique to transfixion techniques in LDN in line with FDA recommendation is feasible and affords equivalent donor and recipient outcomes.

A positive anti-nuclear antibody result does not contraindicate living kidney donation.

Autoantibodies may precede the clinical onset of disease in up to two-thirds of patients with systemic lupus erythematosus (SLE). There is thus concern that antinuclear antibody (ANA) positivity in living kidney donors may eventuate in development of lupus nephritis post-uninephrectomy. Post-uninephrectomy, we routinely examine living kidney donors at 6 weeks, 6 months, 12 months, and annually thereafter. We performed a retrospective review of living kidney donors who had undergone uninephrectomy between July 1, 1999, and December 1, 2008. Data were collected for pre- and post-uninephrectomy renal function, proteinuria, hematuria, ANA, and anti-double stranded deoxyribonucleic acid (anti-dsDNA) antibodies. Among 68 living donor uninephrectomies performed during the study period, we excluded patients with no pre- uninephrectomy ANA or defaulted postoperative follow-up (n = 2). Twelve (18.2%) living donors were ANA-positive (M:F = 4:8) with a median titer of 1:100 (range, 1:100-1:800); 1 was transiently anti-dsDNA-positive. There were no significant differences between ANA-positive and ANA-negative donors in baseline demographics or pre-uninephrectomy creatinine clearance (median 108.0, range 79-179 mL/min vs. 106, range 58-172 mL/min, P = NS). Only 1 ANA-positive patient displayed transient microscopic hematuria (8 red blood cells); none had proteinuria pre-nephrectomy. Median follow-up was 63.5 (range, 21.2-139.3) months. At last clinic review, none of the ANA-positive donors had developed clinical symptoms or signs of SLE. Comparing ANA-positive and ANA-negative live donors at 5 years post-uninephrectomy, there were no significant differences in creatinine clearance (median 86.5, range 67-112 mL/min vs. 85.0, range 35-154 mL/min, P = NS), total urine protein (median 0, range 0-0.196 g/24 h vs 0, range 0-0.190 g/24 h, P = NS), or presence of hematuria (16.7% vs 33.3%, P = NS). Isolated ANA positivity does not contraindicate living kidney donation. Up to 5 years post- uninephrectomy, the risk of developing clinical lupus among low-titer ANA-positive individuals remains low.