Spontaneous retrotransposon insertion into TNF 3′UTR causes heart valve disease and chronic polyarthritis

Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) are chronic inflammatory diseases that together affect 2–3% of the population. RA and AS predominantly involve joints, but heart disease is also a common feature in RA and AS patients. Here we have studied a new spontaneous mutation that causes severe polyarthritis in bone phenotype spontaneous mutation 1 (BPSM1) mice. In addition to joint destruction, mutant mice also develop aortic root aneurism and aorto-mitral valve disease that can be fatal depending on the genetic background. The cause of the disease is the spontaneous insertion of a retrotransposon into the 3′ untranslated region (3′UTR) of the tumor necrosis factor (TNF), which triggers its strong overexpression in myeloid cells. We found that several members of a family of RNA-binding, CCCH-containing zinc-finger proteins control TNF expression through its 3′UTR, and we identified a previously unidentified regulatory element in the UTR. The disease in BPSM1 mice is independent of the adaptive immune system and does not appear to involve inflammatory cytokines other than TNF. To our knowledge, this is the first animal model showing both polyarthritis and heart disease as a direct result of TNF deregulation. These results emphasize the therapeutic potential of anti-TNF drugs for the treatment of heart valve disease and identify potential therapeutic targets to control TNF expression and inflammation.Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) are related and overlapping chronic inflammatory diseases that affect joints and severely impair mobility of the patients (1, 2). RA patients generally present with a symmetric polyarthritis of the peripheral joints. RA affects more women than men, typically leads to bone and cartilage erosion, and is often associated with the presence of rheumatoid factor in the serum. By contrast, AS is a disease of the sacroiliac joint and the spine with variable involvement of peripheral joints. AS is more prevalent in men than women, generally rheumatoid factor-negative, and characterized by new cartilage and bone formation that leads to ankylosis of the spine. The causes of RA and AS are ill-defined, but genetic influences have a major role in both diseases. It is generally accepted that RA and AS are auto-inflammatory diseases that involve many inflammatory cytokines. Interestingly, although disease-modifying antirheumatic drugs have been useful in the treatment of RA, they have shown limited effect in AS. However, anti-TNF therapies have shown a high efficacy in both diseases. Both RA and AS are systemic diseases that can also affect several other organs. Extra-articular manifestations of RA include vasculitis, lung inflammation, formation of s.c. nodules, and heart disease (3), whereas psoriasis, inflammatory bowel disease (IBD), and heart valve disease are commonly associated with AS (4–6). We describe here a new mouse model with characteristics of both RA and AS.     

Cost-Utility Analysis of a Collaborative Care Intervention for Major Depressive Disorder in an Occupational Healthcare Setting

Purpose Major depression is associated with high levels of absence and reduced productivity. Therefore the costs to society are high. The aim of this study was to evaluate the cost-utility of collaborative care for major depressive disorder (MDD) compared to care as usual in an occupational healthcare setting. A societal perspective was taken. Methods In this randomised controlled trial, 126 sick-listed workers with MDD were included (65 collaborative care, 61 care as usual). Baseline measurements and follow up measures (3, 6, 9 and 12 months) were assessed by questionnaire. We applied the Trimbos/iMTA questionnaire for costs associated with psychiatric illness, the SF-HQL and the EQ-5D respectively measuring the health care utilization, production losses and general health related quality of life. Results The average annual healthcare costs in the collaborative care group were €3,874 (95 % CI €2,778–€5,718) compared to €4,583 (95 % CI €3,108–€6,794) in the care as usual group. The average quality of life years (QALY’s) gained were lower in the collaborative care group, 0.05 QALY. The majority of the ICERS (69 %) indicate that collaborative care is less costly but also less effective than care as usual. Including the productivity costs did not change this result. Conclusions The cost-utility analysis showed that collaborative care generated reduced costs and a reduction in effects compared to care as usual and was therefore not a cost-effective intervention.     

Variation in the Human Leukocyte Antigen system and risk for endemic Burkitt lymphoma in northern Uganda

Endemic Burkitt lymphoma (eBL) is an aggressive childhood B-cell lymphoma associated with Plasmodium falciparum (Pf) malaria and Epstein–Barr virus (EBV) infections. Variation in the Human Leukocyte Antigen (HLA) system is suspected to play a role, but assessments using less accurate serology-based HLA typing techniques in small studies yielded conflicting results. We studied 200 eBL cases and 400 controls aged 0–15 years enrolled in northern Uganda and typed by accurate high-resolution HLA sequencing methods. HLA results were analyzed at one- or two-field resolution. Odds ratios and 95% confidence intervals (aOR, 95% CI) for eBL risk associated with common HLA alleles versus alleles that were rare (<1%) or differed by <2% between the cases and controls as the reference category, were estimated using multiple logistic regression adjusting for age, sex, microgeography, region, malaria positivity and treatment history, and genetic variants associated with eBL. Compared to the controls, eBL cases had a lower frequency of HLA-A*02 (aOR = 0·59, 95% CI 0·38–0·91), HLA-B*41 (aOR = 0·36, 95% CI 0·13–1·00), and HLA-B*58 alleles (aOR = 0·59, 95% CI 0·36–0·97). eBL cases had a lower frequency of HLA-DPB1 homozygosity (aOR = 0·57, 95% CI 0·40–0·82) but a higher frequency of HLA-DQA1 homozygosity (aOR = 2·19, 95% CI 1·42–3·37). Our results suggest that variation in HLA may be associated with eBL risk.     

Mean platelet counts are relatively decreased with malaria but relatively increased with endemic Burkitt Lymphoma in Uganda,Tanzania, and Kenya

Platelet counts are decreased in Plasmodium falciparum malaria, which is aetiologically linked with endemic Burkitt lymphoma (eBL). However, the pattern of platelet counts in eBL cases is unknown. We studied platelet counts in 582 eBL cases and 2 248 controls enrolled in a case-control study in Uganda, Tanzania and Kenya (2010–2016). Mean platelet counts in controls or eBL cases with or without malaria-infection in controls versus eBLcases were compared using Student’s t-test. Odds ratios (ORs) and two-sided 95% confidence intervals (95% CIs) were estimated using multiple logistic regression, controlling for age, sex, haemoglobin and white blood cell counts. Platelets were decreased with malaria infection in the controls [263 vs. 339 × 10⁹ platelets/l, P < 0·0001; adjusted OR (aOR) = 3·42, 95% CI: 2·79–4·18] and eBL cases (314 vs. 367 × 10⁹ platelets/l, P-value = 0·002; aOR = 2·36, 95% CI: 1·49–3·73). Unexpectedly, platelets were elevated in eBL cases versus  controls in overall analyses (mean: 353 vs. 307 × 10⁹ platelets/l, P < 0·0001; aOR = 1·41; 95% CI: 1·12–1·77), and when restricted to malaria-positive (mean 314 vs. 263 × 10⁹ platelets/l, P < 0·0001; OR = 2·26; 95% CI: 1·56–3·27) or malaria-negative (mean 367 vs. 339 × 10⁹ platelets/l, P < 0·001; OR = 1·46; 95% CI: 1·17–1·83) subjects. Platelets were decreased with malaria infection in controls and eBL cases but elevated with eBL.     

Clinic HIV-focused features and prevention of Pneumocystis carinii pneumonia

OBJECTIVE: To examine the association of clinic HIV-focused features and advanced HIV care experience with Pneumocystis carinii pneumonia (PCP) prophylaxis and development of PCP as the initial AIDS diagnosis. DESIGN: Nonconcurrent prospective study. SETTING: New York State Medicaid Program. PARTICIPANTS: Medicaid enrollees diagnosed with AIDS in 1990–1992. MEASUREMENTS AND MAIN RESULTS: We collected patient clinical and health care data from Medicaid files, conducted telephone interviews of directors of 125 clinics serving as the usual source of care for study patients, and measured AIDS experience as the cumulative number of AIDS patients treated by the study clinics since 1986. Pneumocystis carinii pneumonia prophylaxis in the 6 months before AIDS diagnosis and PCP at AIDS diagnosis were the main outcome measures. Bivariate and multivariate analyses adjusted for clustering of patients within clinics. Of 1,876 HIV-infected persons, 44% had PCP prophylaxis and 38% had primary PCP. Persons on prophylaxis had 20% lower adjusted odds of developing PCP (95% confidence interval [CI] 0.64, 0.99). The adjusted odds of receiving prophylaxis rose monotonically with the number of HIV-focused features offered by the clinic, with threefold higher odds (95% CI 1.6, 5.7) for six versus two or fewer such features. Patients in clinics with three HIV-focused features had 36% lower adjusted odds of PCP than those in clinics with one or none. Neither clinic experience nor specialty had a significant association with prophylaxis or PCP. CONCLUSIONS: PCP prevention in our study cohort appears to be more successful in clinics offering an array of HIV-focused features. Presented in part at the 19th Annual Meeting of the Society of General Internal Medicine, Washington, DC, May 1996, and the Eleventh International Conference on AIDS, Vancouver, BC, Canada, July 1996. Funded by the Agency for Health Care Policy and Research (RO1 HS06465-04).     

Management of hypertriglyceridaemia-induced acute pancreatitis in pregnancy

Introduction: Acute pancreatitis is a recognised rare complication in pregnancy. The reported incidence varies between 3 and 7 in 10?000 pregnancies and is higher in the third trimester. The commonest causes in pregnancy include gallstones, alcohol and hypertriglyceridaemia. Non-gallstone pancreatitis is associated with more complications and poorer outcome with hypertriglyceridaemia-induced acute pancreatitis having mortality rates ranging from 7.5 to 9.0% and 10.0 to 17.5% for mother and foetus, respectively.

Case history: A 40-year-old para 4 woman, who presented at 15⁺⁴ weeks’ gestation, was diagnosed with acute pancreatitis. Past medical history included Graves’ disease and hypertriglyceridaemia. Fenofibrate was discontinued immediately after discovery of the pregnancy. Initial investigations showed elevated amylase (475.0?µ/L) and triglycerides (46.6?mmol/L). Imaging revealed an inflamed pancreas without evidence of biliary obstruction/gallstones hence confirming the diagnosis of hypertriglyceridaemia-induced acute pancreatitis. Laboratory tests gradually improved (triglyceride 5.2?mmol/L on day 17). On day 18, ultrasound confirmed foetal demise (18⁺¹ weeks) and a hysterotomy was performed as she had had four previous caesarean sections.

Conclusion: Management of acute pancreatitis in pregnancy requires a multi-disciplinary approach. Hypertriglyceridaemia-induced acute pancreatitis has poor outcomes when diagnosed in early pregnancy. Identifying those at risk pre-pregnancy and antenatally can allow close monitoring through pregnancy to optimise care.