Constitutive Glycolytic Metabolism Supports CD8+ T Cell Effector Memory Differentiation during Viral Infection.

Extensive metabolic changes accompany T cell activation, including a switch to glycolytic energy production and increased biosynthesis. Recent studies suggest that subsequent return to reliance on oxidative phosphorylation and increasing spare respiratory capacity are essential for the differentiation of memory CD8+ T cells. In contrast, we found that constitutive glycolytic metabolism and suppression of oxidative phosphorylation in CD8+ T cells, achieved by conditional deletion of hypoxia-inducible factor regulator Vhl, accelerated CD8+ memory cell differentiation during viral infection. Despite sustained glycolysis, CD8+ memory cells emerged that upregulated key memory-associated cytokine receptors and transcription factors and showed a heightened response to secondary challenge. In addition, increased glycolysis not only permitted memory formation, but it also favored the formation of long-lived effector-memory CD8+ T cells. These data redefine the role of cellular metabolism in memory cell differentiation, showing that reliance on glycolytic metabolism does not hinder formation of a protective memory population.

Microbiota engraftment after faecal microbiota transplantation in obese subjects with type 2 diabetes: a 24-week, double-blind, randomised controlled trial.

OBJECTIVE: The impact of faecal microbiota transplantation (FMT) on microbiota engraftment in patients with metabolic syndrome is uncertain. We aimed to study whether combining FMT with lifestyle modification could enhance the engraftment of favourable microbiota in obese patients with type 2 diabetes mellitus (T2DM). DESIGN: In this double-blind, randomised, placebo-controlled trial, 61 obese subjects with T2DM were randomly assigned to three parallel groups: FMT plus lifestyle intervention (LSI), FMT alone, or sham transplantation plus LSI every 4 weeks for up to week 12. FMT solution was prepared from six healthy lean donors. Faecal metagenomic sequencing was performed at baseline, weeks 4, 16 and 24. The primary outcome was the proportion of subjects acquiring ≥20% of microbiota from lean donors at week 24. RESULTS: Proportions of subjects acquiring ≥20% of lean-associated microbiota at week 24 were 100%, 88.2% and 22% in the FMT plus LSI, FMT alone, and sham plus LSI groups, respectively (p<0.0001). Repeated FMTs significantly increased the engraftment of lean-associated microbiota (p<0.05). FMT with or without LSI increased butyrate-producing bacteria. Combining LSI and FMT led to increase in Bifidobacterium and Lactobacillus compared with FMT alone (p<0.05). FMT plus LSI group had reduced total and low-density lipoprotein cholesterol and liver stiffness at week 24 compared with baseline (p<0.05). CONCLUSION: Repeated FMTs enhance the level and duration of microbiota engraftment in obese patients with T2DM. Combining lifestyle intervention with FMT led to more favourable changes in recipients' microbiota and improvement in lipid profile and liver stiffness. TRIAL REGISTRATION NUMBER: NCT03127696.

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.

Obesity Modulates Intestinal Intraepithelial T Cell Persistence, CD103 and CCR9 Expression, and Outcome in Dextran Sulfate Sodium-Induced Colitis.

Obesity impacts over 30% of the United States population, resulting in a wide array of complications. Included among these is the deterioration of the intestinal barrier, which has been implicated in type 2 diabetes and susceptibility to bacterial transepithelial migration. The intestinal epithelium is maintained by αß and γδ intraepithelial T lymphocytes, which migrate along the epithelia, support epithelial homeostasis, and protect from infection. In this study, we investigate how obesity impacts intraepithelial lymphocyte (IEL) persistence and function in intestinal homeostasis and repair. Mice were fed a high-fat diet to induce obesity and to study immunomodulation in the intestine. There is a striking reduction in αß and γδ IEL persistence as obesity progresses with a different mechanism in αß versus γδ IEL populations. CD4+ and CD4+CD8+ αß intraepithelial T lymphocytes exhibit reduced homeostatic proliferation in obesity, whereas both αß and γδ IELs downregulate CD103 and CCR9. The reduction in intraepithelial T lymphocytes occurs within 7 wk of high-fat diet administration and is not dependent on chronic inflammation via TNF-α. Young mice administered a high-fat diet upon weaning exhibit the most dramatic phenotype, showing that childhood obesity has consequences on intestinal IEL seeding. Together, this dysfunction in the intestinal epithelium renders obese mice more susceptible to dextran sulfate sodium-induced colitis. Diet-induced weight loss restores IEL number and CD103/CCR9 expression and improves outcome in colitis. Together, these data confirm that obesity has immunomodulatory consequences in intestinal tissues that can be improved with weight loss.

Association of technologically assisted integrated care with clinical outcomes in type 2 diabetes in Hong Kong using the prospective JADE Program: A retrospective cohort analysis.

BACKGROUND: Diabetes outcomes are influenced by host factors, settings, and care processes. We examined the association of data-driven integrated care assisted by information and communications technology (ICT) with clinical outcomes in type 2 diabetes in public and private healthcare settings. METHODS AND FINDINGS: The web-based Joint Asia Diabetes Evaluation (JADE) platform provides a protocol to guide data collection for issuing a personalized JADE report including risk categories (1-4, low-high), 5-year probabilities of cardiovascular-renal events, and trends and targets of 4 risk factors with tailored decision support. The JADE program is a prospective cohort study implemented in a naturalistic environment where patients underwent nurse-led structured evaluation (blood/urine/eye/feet) in public and private outpatient clinics and diabetes centers in Hong Kong. We retrospectively analyzed the data of 16,624 Han Chinese patients with type 2 diabetes who were enrolled in 2007-2015. In the public setting, the non-JADE group (n = 3,587) underwent structured evaluation for risk factors and complications only, while the JADE (n = 9,601) group received a JADE report with group empowerment by nurses. In a community-based, nurse-led, university-affiliated diabetes center (UDC), the JADE-Personalized (JADE-P) group (n = 3,436) received a JADE report, personalized empowerment, and annual telephone reminder for reevaluation and engagement. The primary composite outcome was time to the first occurrence of cardiovascular-renal diseases, all-site cancer, and/or death, based on hospitalization data censored on 30 June 2017. During 94,311 person-years of follow-up in 2007-2017, 7,779 primary events occurred. Compared with the JADE group (136.22 cases per 1,000 patient-years [95% CI 132.35-140.18]), the non-JADE group had higher (145.32 [95% CI 138.68-152.20]; P = 0.020) while the JADE-P group had lower event rates (70.94 [95% CI 67.12-74.91]; P < 0.001). The adjusted hazard ratios (aHRs) for the primary composite outcome were 1.22 (95% CI 1.15-1.30) and 0.70 (95% CI 0.66-0.75), respectively, independent of risk profiles, education levels, drug usage, self-care, and comorbidities at baseline. We reported consistent results in propensity-score-matched analyses and after accounting for loss to follow-up. Potential limitations include its nonrandomized design that precludes causal inference, residual confounding, and participation bias. CONCLUSIONS: ICT-assisted integrated care was associated with a reduction in clinical events, including death in type 2 diabetes in public and private healthcare settings.

Sudomotor dysfunction independently predicts incident cardiovascular-renal events and all-cause death in type 2 diabetes: the Joint Asia Diabetes Evaluation register.

BACKGROUND: Early detection and risk factor control prevent chronic kidney disease (CKD) progression. Evaluation of peripheral autonomic dysfunction may detect incident cardiovascular-renal events in type 2 diabetes (T2D). METHODS: SUDOSCAN, a non-invasive tool, provides an age-adjusted electrochemical skin conductance (ESC) composite score incorporating hands/feet ESC measurements, with a score ≤53 indicating sudomotor dysfunction. A consecutive cohort of 2833 Chinese adults underwent structured diabetes assessment in 2012-13; 2028 participants without preexisting cardiovascular disease (CVD) and CKD were monitored for incident cardiovascular-renal events until 2015. RESULTS: In this prospective cohort {mean age 57.0 [standard deviation (SD) 10.0] years; median T2D duration 7.0 [interquartile range (IQR) 3.0-13.0] years; 56.1% men; 72.5% never-smokers; baseline ESC composite score 60.7 (SD 14.5)}, 163 (8.0%) and 25 (1.2%) participants developed incident CKD and CVD, respectively, after 2.3 years of follow-up. The adjusted hazard ratios (aHRs) per 1-unit decrease in the ESC composite score for incident CKD, CVD and all-cause death were 1.02 [95% confidence interval (CI) 1.01-1.04], 1.04 (1.00-1.07) and 1.04 (1.00-1.08), respectively. Compared with participants with an ESC composite score >53, those with a score ≤53 had an aHR of 1.56 (95% CI 1.09-2.23) for CKD and 3.11 (95% CI 1.27-7.62) for CVD, independent of common risk markers. When added to clinical variables (sex and duration of diabetes), the ESC composite score improved discrimination of all outcomes with appropriate reclassification of CKD risk. CONCLUSIONS: A low ESC composite score independently predicts incident cardiovascular-renal events and death in T2D, which may improve the screening strategy for early intervention.

Bacteriophage transfer during faecal microbiota transplantation in Clostridium difficile infection is associated with treatment outcome.

OBJECTIVE: Faecal microbiota transplantation (FMT) is effective for the treatment of recurrent Clostridium difficile infection (CDI). Studies have shown bacterial colonisation after FMT, but data on viral alterations in CDI are scarce. We investigated enteric virome alterations in CDI and the association between viral transfer and clinical outcome in patients with CDI. DESIGN: Ultra-deep metagenomic sequencing of virus-like particle preparations and bacterial 16S rRNA sequencing were performed on stool samples from 24 subjects with CDI and 20 healthy controls. We longitudinally assessed the virome and bacterial microbiome changes in nine CDI subjects treated with FMT and five treated with vancomycin. Enteric virome alterations were assessed in association with treatment response. RESULTS: Subjects with CDI demonstrated a significantly higher abundance of bacteriophage Caudovirales and a lower Caudovirales diversity, richness and evenness compared with healthy household controls. Significant correlations were observed between bacterial families Proteobacteria, Actinobacteria and Caudovirales taxa in CDI. FMT treatment resulted in a significant decrease in the abundance of Caudovirales in CDI. Cure after FMT was observed when donor-derived Caudovirales contigs occupied a larger fraction of the enteric virome in the recipients (p=0.024). In treatment responders, FMT was associated with alterations in the virome and the bacterial microbiome, while vancomycin treatment led to alterations in the bacterial community alone. CONCLUSIONS: In a preliminary study, CDI is characterised by enteric virome dysbiosis. Treatment response in FMT was associated with a high colonisation level of donor-derived Caudovirales taxa in the recipient. Caudovirales bacteriophages may play a role in the efficacy of FMT in CDI. TRIAL REGISTRATION NUMBER: NCT02570477.

Glycaemia control and the risk of hospitalisation for infection in patients with type 2 diabetes: Hong Kong Diabetes Registry.

BACKGROUND: Infection occurs more commonly in diabetic patients compared with the general population and is an under-recognised but important morbidity in patients with diabetes. We examined the impact of glycaemic control on hospitalisation for infection in a large prospective cohort of Chinese adults with type 2 diabetes. METHODS: Between July 1994 and June 2014, 22 846 patients with type 2 diabetes underwent detailed assessment of metabolic control and diabetes complications. Patients were followed for occurrence of infection requiring hospitalisation as identified using discharge diagnosis codes. RESULTS: Over a median follow-up of 4.8 years, 20.3% of patients were hospitalised for any infection type, with respiratory tract, genitourinary tract, and skin being the most commonly affected sites. In multivariate Cox regression, time-dependent HbA1c was associated with all-site infection (hazard ratio [HR] 1.07 [95% confidence interval {CI}:1.05-1.09, P < 0.001]), genitourinary tract infection (HR 1.09 [95% CI: 1.04-1.14], P < 0.001), and skin infection (HR 1.16 [95% CI 1.12-1.21]. P < 0.001), but not infection of respiratory tract, and was independent of age, gender, disease duration, smoking, body mass index, glomerular filtration rate, haemoglobin, history of stroke, congestive heart failure, coronary heart disease, peripheral artery disease, diabetic neuropathy and cancer, and baseline drug use. Against an arbitrary HbA1c interval of >7.0-8.0% (53-64 mmol/mol), patients with HbA1c ≤6.0% (42 mmol/mol) and >8.0% (64 mmol/mol) had excess risks of infection-related hospitalisation adjusted for other factors. CONCLUSIONS: In patients with type 2 diabetes, burden of serious infection is high. In the diabetic population, a U-shape relationship between glycaemia and infection-related hospitalisation was detected.

Id2 regulates hyporesponsive invariant natural killer T cells.

While the invariant natural killer T (iNKT)-cell response to primary stimulation with the glycolipid, α-galactosylceramide (αGalCer), is robust, the secondary response to this stimulus is muted resulting in a hyporesponsive state characterized by anti-inflammatory interleukin-10 (IL-10) production and high expression of programmed cell death 1 (PD1) and neuropilin 1 (NRP1). The E protein transcription factors and their negative regulators, the Id proteins, have previously been shown to regulate iNKT cell thymic development, subset differentiation and peripheral survival. Here, we provide evidence that the expression of the transcriptional regulator Id2 is downregulated upon stimulation of iNKT cells with their cognate antigen. Moreover, loss of Id2 expression by iNKT cells resulted in a hyporesponsive state, with splenic Id2-deficient iNKT cells expressing low levels of TBET, high levels of PD1 and NRP1 and production of IL-10 upon stimulation. We propose that downregulation of Id2 expression is an essential component of induction of the anti-inflammatory, hyporesponsive state in iNKT cells.

Additive effects of blood glucose lowering drugs, statins and renin-angiotensin system blockers on all-site cancer risk in patients with type 2 diabetes.

BACKGROUND: Hyperglycemia is associated with increased risk of all-site cancer that may be mediated through activation of the renin-angiotensin-system (RAS) and 3-hydroxy-3-methyl-glutaryl-coenzyme-A-reductase (HMGCR) pathways. We examined the joint associations of optimal glycemic control (HbA1c <7%), RAS inhibitors and HMGCR inhibitors on cancer incidence in patients with type 2 diabetes. METHODS: Patients with type 2 diabetes, with or without a history of cancer or prior exposure to RAS or HMGCR inhibitors at baseline were observed between 1996 and 2005. All patients underwent a comprehensive assessment at baseline and were followed until the censored date at 2005 or their death. RESULTS: After a median follow-up period of 4.91 years (interquartile range, 2.81 to 6.98), 271 out of 6,103 patients developed all-site cancer. At baseline, patients with incident cancers were older, had longer disease duration of diabetes, higher alcohol and tobacco use, and higher systolic blood pressure and albuminuria, but lower triglyceride levels and estimated glomerular filtration rate (P <0.05). Patients who developed cancers during follow-up were less likely to have started using statins (22.5% versus 38.6%, P <0.001), fibrates (5.9% versus 10.2%, P = 0.02), metformin (63.8% versus 74.5%, P <0.001) or thiazolidinedione (0.7% versus 6.8%, P <0.001) than those who remained cancer-free. After adjusting for co-variables, new treatment with metformin (hazard ratio: 0.39; 95% confidence interval: 0.25, 0.61; P <0.001), thiazolidinedione (0.18; 0.04, 0.72; P = 0.015), sulphonylurea (0.44; 0.27, 0.73; P = 0.014), insulin (0.58; 0.38, 0.89; P = 0.01), statins (0.47; 0.31, 0.70; P <0.001) and RAS inhibitors (0.55; 0.39, 0.78; P <0.001) were associated with reduced cancer risk. Patients with all three risk factors of HbA1c ≥7%, non-use of RAS inhibitors and non-use of statins had four-fold adjusted higher risk of cancer than those without any risk factors (incidence per 1,000-person-years for no risk factors: 3.40 (0.07, 6.72); one risk factor: 6.34 (4.19, 8.50); two risk factors: 8.40 (6.60, 10.20); three risk factors: 13.08 (9.82, 16.34); P <0.001). CONCLUSIONS: Hyperglycemia may promote cancer growth that can be attenuated by optimal glycemic control and inhibition of the RAS and HMGCR pathways.

Hypoglycaemia, chronic kidney disease and death in type 2 diabetes: the Hong Kong diabetes registry.

BACKGROUND: In patients with type 2 diabetes, chronic kidney disease (CKD) is associated with increased risk of hypoglycaemia and death. Yet, it remains uncertain whether hypoglycaemia-associated mortality is modified by CKD. METHODS: Type 2 diabetic patients, with or without CKD at enrolment were observed between 1995 and 2007, and followed up till 2009 at hospital medical clinics. We used additive interaction, estimated by relative excess risk due to interaction (RERI) and attributable proportion due to interaction (AP) to examine possible synergistic effects between CKD and severe hypoglycaemia (defined as hospitalisations due to hypoglycaemia in the 12 months prior to enrolment) on the risk of death. RESULTS: In this cohort of 8,767 type 2 diabetic patients [median age: 58 (interquartile range: 48 to 68) years; disease duration: 5 (1 to 11) years, men: 47.0%], 1,070 (12.2%) had died during a median follow-up period of 6.66 years (3.42-10.36) with 60,379 person-years.Upon enrolment, 209 patients had severe hypoglycaemia and 194 developed severe hypoglycaemia during follow-up (15 patients had both). In multivariable analysis and using patients without severe hypoglycaemia nor CKD as the referent group (683 deaths in 7,598 patients), severe hypoglycaemia alone (61 deaths in 272 patients) or CKD alone (267 death in 781 patients) were associated with increased risk of death [Hazard ratio, HR: 1.81(95%CI: 1.38 to 2.37) and 1.63 (1.38 to 1.93) respectively]. Having both risk factors (59 deaths in 116 patients) greatly enhanced the HR of death to 3.91 (2.93 to 5.21) with significant interaction (RERI: 1.46 and AP: 0.37, both p-values < 0.05). CONCLUSIONS: Severe hypoglycaemia and CKD interact to increase risk of death in type 2 diabetes patients.

An uncommon cause of Cushing's syndrome in a 70-year-old man.

Cushing's syndrome due to exogenous steroids is common, as about 1% of the general populations use exogenous steroids for various indications. Although endogenous Cushing's syndrome due to ectopic adrenocorticotropic hormone from a pancreatic neuroendocrine tumour is rare, a correct and early diagnosis is important. The diagnosis and management require high clinical acumen and collaboration between different specialists. We report a case of ectopic adrenocorticotropic hormone Cushing's syndrome due to pancreatic neuroendocrine tumour with liver metastasis. Early recognition by endocrinologists with timely surgical resection followed by referral to oncologists led to a favourable outcome for the patient up to 12 months after initial presentation.

Functional Diversity of Memory CD8 T Cells is Spatiotemporally Imprinted.

Tissue-resident memory CD8 T cells (TRM) kill infected cells and recruit additional immune cells to limit pathogen invasion at barrier sites. Small intestinal (SI) TRM cells consist of distinct subpopulations with higher expression of effector molecules or greater memory potential. We hypothesized that occupancy of diverse anatomical niches imprints these distinct TRM transcriptional programs. We leveraged human samples and a murine model of acute systemic viral infection to profile the location and transcriptome of pathogen-specific TRM cell differentiation at single-transcript resolution. We developed computational approaches to capture cellular locations along three anatomical axes of the small intestine and to visualize the spatiotemporal distribution of cell types and gene expression. TRM populations were spatially segregated: with more effector- and memory-like TRM preferentially localized at the villus tip or crypt, respectively. Modeling ligand-receptor activity revealed patterns of key cellular interactions and cytokine signaling pathways that initiate and maintain TRM differentiation and functional diversity, including different TGFß sources. Alterations in the cellular networks induced by loss of TGFßRII expression revealed a model consistent with TGFß promoting progressive TRM maturation towards the villus tip. Ultimately, we have developed a framework for the study of immune cell interactions with the spectrum of tissue cell types, revealing that T cell location and functional state are fundamentally intertwined.

Intrarenal arterial resistance is associated with microvascular complications in Chinese type 2 diabetic patients.

BACKGROUND: Increased renal arterial resistance is associated with various types of chronic renal parenchymal diseases. A resistance index (RI) > 0.8 predicts deterioration in renal function in diabetic subjects. However, the association between renal RI and other diabetic complications has not been investigated. In this study, we examined the association between intrarenal arterial RI and diabetic complications in Chinese type 2 diabetic subjects. METHODS: Three hundred and eighty-seven Chinese type 2 diabetic patients were recruited from a structured assessment programme to evaluate their risk factors and complications as a part of the quality improvement programme at the Prince of Wales Hospital. All subjects underwent ultrasound examinations for the assessment of intrarenal arterial RI of both kidneys. Clinical and biochemical parameters, including diabetes-related microvascular complications (nephropathy, retinopathy and sensory neuropathy) and macrovascular diseases, were examined. RESULTS: The mean RI of patients with any microvascular complications (0.70 ± 0.09 versus 0.65 ± 0.06) such as nephropathy (0.71 ± 0.09 versus 0.66 ± 0.06), retinopathy (0.71 ± 0.08 versus 0.67 ± 0.08) and sensory neuropathy (0.75 ± 0.07 versus 0.68 ± 0.08) and with any macrovascular complications (0.71 ± 0.09 versus 0.68 ± 0.08) was higher than those without (P < 0.05). On multivariate analysis, after controlling for confounding variables, an RI ≥0.75 was associated with microvascular complications, nephropathy, retinopathy and sensory neuropathy, with odds ratio of 4.02 [95% confidence interval (CI) 1.72-9.4], 4.99 (2.61-9.56), 2.78 (1.52-5.09) and 5.74 (1.8-18.3), respectively. The association of RI with macrovascular complications was not significant in multivariate analysis. CONCLUSION: Increased intrarenal arterial resistance was independently associated with an increased risk of microvascular complications including diabetic nephropathy, diabetic retinopathy and diabetic sensory neuropathy in Chinese type 2 diabetic patients.

Innate immunity in donor procurement.

PURPOSE OF REVIEW: Ischaemic kidney injury occurs during organ procurement and can lead to delayed graft function or nonviable grafts. The innate immune system is a key trigger of inflammation in renal ischaemia. This review discusses the components of innate immunity known to be involved in renal ischaemic reperfusion injury (IRI). Understanding how inflammatory damage is initiated in renal IRI is important for the development of targeted therapies aimed at preserving the donor organ. RECENT FINDINGS: Much remains to be determined about the role of innate immune signalling in renal ischaemia/reperfusion injury. Recently, discoveries about complement receptors, Toll-like receptors (TLRs), NOD-like receptors (NLRs) and inflammasomes have opened new avenues of exploration. We are also now learning that macrophages, complement and TLR activation may have additional roles in renal repair following IRI. SUMMARY: A greater understanding of the mechanisms that contribute to innate immune-mediated renal ischaemic damage will allow for the development of therapeutics targeted to the donor organ. New data suggest that treatment limited to specific receptors on specific cells, or localized to specific regions within the kidney, may provide novel approaches to maximize our use of donor organs, particularly those that may have been discarded due to prolonged preimplantation ischaemia.

Memory-like CD8+ T cells generated during homeostatic proliferation defer to antigen-experienced memory cells.

Naive T cells proliferate in response to lymphopenia and acquire the phenotypic and functional qualities of memory T cells, providing enhanced protection against infection. How well memory-like T cells generated during lymphopenia-induced homeostatic proliferation (HP)-memory differentiate into secondary memory cells and compete with Ag-experienced true-memory cells is unknown. We found that CD8(+) HP-memory T cells generated robust responses upon infection and produced a secondary memory population comparable to true-memory cells in the absence of competition. However, when true-memory and HP-memory T cells competed during infection, HP-memory cells contributed less to the effector population, contracted earlier, and formed fewer secondary memory cells. Furthermore, HP- and true-memory cells demonstrated distinct chemokine receptor expression and localization within the spleen during infection, indicating differential access to signals necessary for secondary memory formation. Thus, HP-memory T cells provide protection without compromising the true-memory population. Differences in HP- and true-memory T cells may reveal the basis of competition for limited resources within the memory-T cell compartment.

Longitudinal dynamics of gut bacteriome, mycobiome and virome after fecal microbiota transplantation in graft-versus-host disease.

Fecal microbiota transplant (FMT) has emerged as a potential treatment for severe colitis associated with graft-versus-host disease (GvHD) following hematopoietic stem cell transplant. Bacterial engraftment from FMT donor to recipient has been reported, however the fate of fungi and viruses after FMT remains unclear. Here we report longitudinal dynamics of the gut bacteriome, mycobiome and virome in a teenager with GvHD after receiving four doses of FMT at weekly interval. After serial FMTs, the gut bacteriome, mycobiome and virome of the patient differ from compositions before FMT with variable temporal dynamics. Diversity of the gut bacterial community increases after each FMT. Gut fungal community initially shows expansion of several species followed by a decrease in diversity after multiple FMTs. In contrast, gut virome community varies substantially over time with a stable rise in diversity. The bacterium, Corynebacterium jeikeium, and Torque teno viruses, decrease after FMTs in parallel with an increase in the relative abundance of Caudovirales bacteriophages. Collectively, FMT may simultaneously impact on the various components of the gut microbiome with distinct effects.

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.

Evolution of Diabetes Care in Hong Kong: From the Hong Kong Diabetes Register to JADE-PEARL Program to RAMP and PEP Program.

The rapid increase in diabetes prevalence globally has contributed to large increases in health care expenditure on diabetic complications, posing a major health burden to countries worldwide. Asians are commonly observed to have poorer ß-cell function and greater insulin resistance compared to the Caucasian population, which is attributed by their lower lean body mass and central obesity. This "double phenotype" as well as the rising prevalence of young onset diabetes in Asia has placed Asians with diabetes at high risk of cardiovascular and renal complications, with cancer emerging as an important cause of morbidity and mortality. The experience from Hong Kong had demonstrated that a multifaceted approach, involving team-based integrated care, information technological advances, and patient empowerment programs were able to reduce the incidence of diabetic complications, hospitalizations, and mortality. System change and public policies to enhance implementation of such programs may provide solutions to combat the burgeoning health problem of diabetes at a societal level.