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BACKGROUND: Patients with systemic lupus erythematosus have T-cell dysfunction that has been attributed to the activation of the mammalian target of rapamycin (mTOR). Rapamycin inhibits antigen-induced T-cell proliferation and has been developed as a medication under the generic designation of sirolimus. We assessed safety, tolerance, and efficacy of sirolimus in a prospective, biomarker-driven, open-label clinical trial. METHODS: We did a single-arm, open-label, phase 1/2 trial of sirolimus in patients with active systemic lupus erythematosus disease unresponsive to, or intolerant of, conventional medications at the State University of New York Upstate Medical University (Syracuse, NY, USA). Eligible participants (aged ≥18 years) had active systemic lupus erythematosus fulfilling four or more of 11 diagnostic criteria defined by the American College of Rheumatology. We excluded patients with allergy or intolerance to sirolimus, patients with life-threatening manifestations of systemic lupus erythematosus, proteinuria, a urine protein to creatinine ratio higher than 0·5, anaemia, leucopenia, or thrombocytopenia. Patients received oral sirolimus at a starting dose of 2 mg per day, with dose adjusted according to tolerance and to maintain a therapeutic range of 6–15 ng/mL. Patients were treated with sirolimus for 12 months. Safety outcomes included tolerance as assessed by the occurrence of common side-effects. The primary efficacy endpoint was decrease in disease activity, assessed using the British Isles Lupus Assessment Group (BILAG) index and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Blood samples of 56 matched healthy individuals were obtained as controls for immunobiological outcomes monitored at each visit. The primary efficacy endpoint was assessed in all patients who completed 12 months of treatment, and all patients who received at least one dose of treatment were included in the safety analyses. This trial is registered with ClinicalTrials.gov, number NCT00779194. FINDINGS: Between March 9, 2009, and Dec 8, 2014, 43 patients were enrolled, three of whom did not meet eligibility criteria. 11 of the 40 eligible patients discontinued study treatment because of intolerance (n=2) or non-compliance (n=9). SLEDAI and BILAG disease activity scores were reduced during 12 months of treatment in 16 (55%) of 29 patients who completed treatment. Mean SLEDAI score decreased from 10·2 (SD 5·6) at enrolment to 4·8 (4·5) after 12 months of treatment (p

Inferior alveolar nerve blocks are commonly performed for dental anaesthesia. The procedure is generally safe with a low rate of complications. We report a patient with a reproducible, delayed-onset sensory deficit associated with contrast-enhancing lesions in the trigeminal nerve, pons and medulla following inferior alveolar nerve local anaesthesia. We propose that this previously undescribed condition is a form of Type IV hypersensitivity reaction.

It is often uncertain whether deaths that occur during active treatment for complications of AIDS result from diagnostic or therapeutic failure. Accurate diagnosis of infections is particularly important, and has relevance not only for the patient but also to partners, relatives, hospital staff and other patients. In the absence of adequate physical facilities and in view of the lack of success in obtaining formal autopsies in patients dying with AIDS, a limited autopsy protocol was devised for routine application at our hospital, beginning in 1989. The major aim of this protocol was to enable the safe collection of diagnostic material from patients who died despite active therapy, to ascertain unrecognized conditions and confirm existing diagnoses. We present findings from the first 16 limited autopsies which resulted in 12 additional diagnoses and a revision of the principal cause of death in 7 cases.

Background and Aims: Autopsy studies suggest that cardiac inflammation is associated with increased mortality in systemic lupus erythematosus (SLE). Echocardiography has traditionally been the primary cardiac screening modality in SLE; however there are often limitations indetectingmyocardial andpericardial inflammation.We investigate theutilityofdelayed-enhancement cardiac magnetic resonance (CMR) compared to echocardiography in a group of 37 SLE patients – the largest SLE cohort yet investigated with CMR. Methods: Echocardiography and cardiac magnetic resonance (1.5 T) with gadolinium contrast were performed in 37 consecutive SLE patients (mean age 39.9± 12.5 years; 80% female; mean SLEDAI score 3.8± 3.5). Mean exercise capacity was 97.5± 24.5% predicted METS. Results: Of the 37 patients, echocardiography was abnormal in 13 (35%), with 10 cases of valvular incompetence, four of LV wall abnormalities, and three of pericardial pathology. CMR revealed inflammation in 12 patients (32%), of which five had a normal echocardiogram. The presence of CMR-detectable inflammation did not correlate with (i) any immunological markers (dsDNA, C3/C4, CRP, ESR, antibodies to cardiolipin, SSA, SSB or Rho-52), (ii) immunosuppressive regimen, or (iii) exercise tolerance. Conclusions: Echocardiography has a high yield for valvular disease in SLE, whereas CMR detects significant rates of myocardial and pericardial inflammation, often in patients with no detectable echo abnormality. CMR may thus be a worthwhile addition to the cardiac monitoring algorithm in SLE. However, as no immunological or functional correlatesofCMR-detectable inflammationhaveyet been identified, further study is warranted to determine the clinical relevance of this phenomenon.

Australia’s response to HIV/AIDS has contained the local epidemic. Centres of HIV epidemiology, clinical, social and virology research have contributed greatly to the understanding of clinical, pathophysiological, treatment and behavioural aspects of HIV/AIDS in those living with, and at risk for, HIV. Also underpinning the success in fighting HIV/AIDS is a highly regulated, quality assured public/private pathology enterprise interacting with the biomedical industry, pharmaceutical industry innovators and international research groups. Features of the Australian response to HIV have been partnerships of stakeholders, including researchers and pathologists, which have led to a series of formal, bipartisan, National HIV/AIDS Strategy documents and implementation programs operating in a universal access to health care environment. Innovation, such as in politically difficult harm reduction models of prevention, have been adopted and the documented success of the Australian needle and syringe program (NSP), human rights based legislative frameworks and evidenced-based public health policy decision-making has demonstrated that HIV epidemics in intravenous drug use (IVDU) and heterosexual populations can be largely prevented. Recent increases in HIV transmission in gay men reflected in rising rates of new HIV diagnoses, demand innovative approaches in prevention, testing and treatment. Findings from the Australian experience have relevance to other jurisdictions embarking on national strategy development in the HIV/AIDS domain.