Recent progress in the treatment of proliferative lupus nephritis

The recent decades have witnessed significant progress in the treatment of lupus nephritis. Existing immunosuppressive regimens have been refined to enhance efficacy and reduce adverse effects, resulting in improvements in renal and patient survival and patients' quality of life. This review focuses on the new treatments that have emerged over the past 2 decades. The data and methodology of important clinical trials are discussed to highlight the important findings and their limitations. The role of mycophenolate mofetil as induction or maintenance immunosuppressive treatment is discussed in detail. Racial variations in prognosis and treatment response are evident. With increasing treatment options and better appreciation of patient characteristics that impact on response and tolerance, the management of lupus nephritis has become more individualized. The choice and the dosing regimen of immunosuppressive agents should take into account factors such as race, type of lupus nephritis, disease severity, renal reserve, and prior disease course, to aim for an optimal balance of benefit and risk.     

Sleep apnea and risk of deep vein thrombosis: a non-randomized, pair-matched cohort study

BackgroundPatients with sleep apnea have been reported to be associated with increased prevalence of deep vein thrombosis (DVT) in some papers, which were criticized for either a small sample size or lack of a prospective control. Our study strived to explore the relationship of sleep apnea and the subsequent development of DVT using a nationwide, population-based database.MethodsFrom 2000 to 2007, we identified a study cohort consisting of newly diagnosed sleep apnea cases in the National Health Insurance Research Database. A control cohort without sleep apnea, matched for age, sex, comorbidities, major operation, and fractures, was selected for comparison. The 2 cohorts were followed-up, and we observed the occurrence of DVT by registry of DVT diagnosis.ResultsOf the 10,185 sampled patients (5680 sleep apnea patients vs. 4505 control), 40 (0.39%) cases developed DVT during a mean follow-up period of 3.56 years, including 30 (0.53%) from the sleep apnea cohort and 10 (0.22 %) from the control group. Subjects with sleep apnea experienced a 3.113-fold (95% confidence interval, 1.516-6.390; P = .002) increase in incident DVT, which was independent of age, sex, and comorbidities. Kaplan-Meier analysis also revealed the tendency of sleep apnea patients toward DVT development (log-rank test, P = .001). The risk of DVT was even higher in sleep apnea cases who needed continuous positive airway pressure treatment (hazard ratio 9.575; 95% confidence interval, 3.181-28.818; P <.001).ConclusionSleep apnea may be an independent risk factor for DVT.     

Ankle-brachial index as an indicator of arterial stiffness in patients without peripheral artery disease

We tested the hypothesis that the Ankle-Brachial Index (ABI) in patients without peripheral arterial disease ([PAD] ABI > 1.0) is an indicator of arterial stiffness. Fifty-five patients had measurement of carotid pulse wave contour, pulse wave velocity (PWV), and ABI. Vascular stiffness as assessed by augmentation index (AIx) showed a significant (P = .002) inverse correlation with ABI. Dichotomizing ABI into groups above and below the median showed that persons with a lower ABI, >1.0 to 1.5 (n = 27) had a significantly (P < .01) higher AIx than those with a higher ABI > 1.5 (n = 28). In contrast, vascular stiffness assessed by brachial-ankle or carotid femoral PWV did not correlate with ABI. In summary, ABI is an indicator of arterial stiffness assessed by AIx. Vascular changes detected by AIx are not the same as those detected by PWV. Assessment of ABI may have utility in cardiovascular risk assessment in patients without PAD.     

Self‐perceived preparedness for dental practice amongst graduates of The University of Hong Kong’s integrated PBL dental curriculum

Objectives: To determine how prepared for dental practice graduates from the integrated problem‐based learning (PBL) dental undergraduate curriculum at The University of Hong Kong (HKU) perceive themselves to be and to identify factors associated with self‐perceived preparedness. Materials and methods: A postal questionnaire was sent to five cohorts of dentists who had graduated from HKU’s integrated PBL curriculum between 2004 and 2008. Using a 4‐point Likert scale, the questionnaire assessed the self‐perceived level of preparedness in 59 competencies grouped in nine domains. Responses were dichotomised into ‘poorly prepared’ and ‘well prepared’. Results: The response rate was 66% (159/241). The mean proportion (± standard deviation) of respondents indicating well‐preparedness was 72.0 ± 15.1% overall, and for each domain was as follows: general patient management, 93.1 ± 12.1%; practice management, 81.0 ± 22.2%; periodontology and dental public health, 73.5 ± 19.3%; conservative dentistry, 92.5 ± 13.1%; oral rehabilitation, 62.8 ± 24.0%; orthodontics, 23.0 ± 32.9%; managing children and special‐needs patients, 64.8 ± 28.9%; oral and maxillofacial surgery, 52.2 ± 25.2%; and drug and emergency management, 84.7 ± 22.6%. The odds of self‐perceived well‐preparedness were increased for cohorts graduating in 2004 and 2005 and graduates working in a non‐solo dental practice. Conclusions: Dental graduates of HKU’s integrated PBL curriculum felt well prepared for the most fundamental aspects of dental practice. However, apparent deficiencies of training in orthodontics and oral and maxillofacial surgery will need to be addressed by continuing education, postgraduate training and planning for the new 6‐year undergraduate curriculum in 2012.     

IDH2 mutations are frequent in angioimmunoblastic T-cell lymphoma

Mutations in isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) occur in most grade 2 and 3 gliomas, secondary glioblastomas, and a subset of acute myelogenous leukemias but have not been detected in other tumor types. The mutations occur at specific arginine residues and result in the acquisition of a novel enzymatic activity that converts 2-oxoglutarate to D-2-hydroxyglutarate. This study reports IDH1 and IDH2 genotyping results from a set of lymphomas, which included a large set of peripheral T-cell lymphomas. IDH2 mutations were identified in approximately 20% of angioimmunoblastic T-cell lymphomas (AITLs), but not in other peripheral T-cell lymphoma entities. These results were confirmed in an independent set of AITL patients, where the IDH2 mutation rate was approximately 45%. This is the second common genetic lesion identified in AITL after TET2 and extends the number of neoplastic diseases where IDH1 and IDH2 mutations may play a role.     

Functional STAT3 deficiency compromises the generation of human T follicular helper cells

T follicular helper (Tfh) cells are critical for providing the necessary signals to induce differentiation of B cells into memory and Ab-secreting cells. Accordingly, it is important to identify the molecular requirements for Tfh cell development and function. We previously found that IL-12 mediates the differentiation of human CD4(+) T cells to the Tfh lineage, because IL-12 induces naive human CD4(+) T cells to acquire expression of IL-21, BCL6, ICOS, and CXCR5, which typify Tfh cells. We have now examined CD4(+) T cells from patients deficient in IL-12Rβ1, TYK2, STAT1, and STAT3 to further explore the pathways involved in human Tfh cell differentiation. Although STAT1 was dispensable, mutations in IL12RB1, TYK2, or STAT3 compromised IL-12-induced expression of IL-21 by human CD4(+) T cells. Defective expression of IL-21 by STAT3-deficient CD4(+) T cells resulted in diminished B-cell helper activity in vitro. Importantly, mutations in STAT3, but not IL12RB1 or TYK2, also reduced Tfh cell generation in vivo, evidenced by decreased circulating CD4(+)CXCR5(+) T cells. These results highlight the nonredundant role of STAT3 in human Tfh cell differentiation and suggest that defective Tfh cell development and/or function contributes to the humoral defects observed in STAT3-deficient patients.     

The folliculin-FNIP1 pathway deleted in human Birt-Hogg-Dube syndrome is required for murine B-cell development

Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disorder characterized by cutaneous fibrofolliculomas, pulmonary cysts, and kidney malignancies. Affected individuals carry germ line mutations in folliculin (FLCN), a tumor suppressor gene that becomes biallelically inactivated in kidney tumors by second-hit mutations. Similar to other factors implicated in kidney cancer, FLCN has been shown to modulate activation of mammalian target of rapamycin (mTOR). However, its precise in vivo function is largely unknown because germ line deletion of Flcn results in early embryonic lethality in animal models. Here, we describe mice deficient in the newly characterized folliculin-interacting protein 1 (Fnip1). In contrast to Flcn, Fnip1(-/-) mice develop normally, are not susceptible to kidney neoplasia, but display a striking pro-B cell block that is entirely independent of mTOR activity. We show that this developmental arrest results from rapid caspase-induced pre-B cell death, and that a Bcl2 transgene reconstitutes mature B-cell populations, respectively. We also demonstrate that conditional deletion of Flcn recapitulates the pro-B cell arrest of Fnip1(-/-) mice. Our studies thus demonstrate that the FLCN-FNIP complex deregulated in BHD syndrome is absolutely required for B-cell differentiation, and that it functions through both mTOR-dependent and independent pathways.