IRGQ-mediated autophagy in MHC class I quality control promotes tumor immune evasion.

The autophagy-lysosome system directs the degradation of a wide variety of cargo and is also involved in tumor progression. Here, we show that the immunity-related GTPase family Q protein (IRGQ), an uncharacterized protein to date, acts in the quality control of major histocompatibility complex class I (MHC class I) molecules. IRGQ directs misfolded MHC class I toward lysosomal degradation through its binding mode to GABARAPL2 and LC3B. In the absence of IRGQ, free MHC class I heavy chains do not only accumulate in the cell but are also transported to the cell surface, thereby promoting an immune response. Mice and human patients suffering from hepatocellular carcinoma show improved survival rates with reduced IRGQ levels due to increased reactivity of CD8+ T cells toward IRGQ knockout tumor cells. Thus, we reveal IRGQ as a regulator of MHC class I quality control, mediating tumor immune evasion.

Human MCTS1-dependent translation of JAK2 is essential for IFN-γ immunity to mycobacteria.

Human inherited disorders of interferon-gamma (IFN-γ) immunity underlie severe mycobacterial diseases. We report X-linked recessive MCTS1 deficiency in men with mycobacterial disease from kindreds of different ancestries (from China, Finland, Iran, and Saudi Arabia). Complete deficiency of this translation re-initiation factor impairs the translation of a subset of proteins, including the kinase JAK2 in all cell types tested, including T lymphocytes and phagocytes. JAK2 expression is sufficiently low to impair cellular responses to interleukin-23 (IL-23) and partially IL-12, but not other JAK2-dependent cytokines. Defective responses to IL-23 preferentially impair the production of IFN-γ by innate-like adaptive mucosal-associated invariant T cells (MAIT) and γδ T lymphocytes upon mycobacterial challenge. Surprisingly, the lack of MCTS1-dependent translation re-initiation and ribosome recycling seems to be otherwise physiologically redundant in these patients. These findings suggest that X-linked recessive human MCTS1 deficiency underlies isolated mycobacterial disease by impairing JAK2 translation in innate-like adaptive T lymphocytes, thereby impairing the IL-23-dependent induction of IFN-γ.

Primary total hip arthroplasty: health related quality of life outcomes.

PURPOSE: The health related quality of life (HRQoL) outcomes of total hip arthroplasty (THA) present a pertinent and clinically important problem in modern orthopaedics. Our goal was to report and compare the health-related outcomes after THA in respect to type of fixation in patients with hip osteoarthritis (H-OA) one year after operation. METHODS: A total of 145 patients with H-OA who received THA were evaluated. Uncemented and cemented subjects were evaluated using generic measures, i.e. the EQ-5D questionnaire, and the disease-specific measures designed by the authors, i.e. the Total Hip Arthroplasty Questionnaire (THAQ). Obtained data was statistically processed at the level of pain, functionality and general health perception. Patient-reported outcomes were measured differences between pre-operative measures and those at one-year follow-up visit. RESULTS: Significant improvement in health outcomes was reached in both groups regardless of the type of fixation (p < 0.001). Uncemented fixation exhibited better results for EQ-5DINDEX, pain (p = 0.004) and self-care on EQ-5D (p = 0.043), as well as increased magnitude of change for functionality on THAQ (p = 0.002). However, additional analysis of the subset did not reveal a significant difference between cemented vs. uncemented groups with regard to function on THAQ, but the significant difference on self-care and pain dimensions of EQ-5D remained. CONCLUSIONS: Uncemented endoprosthesis generally achieved better short-term outcomes in some dimensions. However, painless mobility has been restored in most of the patients, regardless of the fixation type. Both methods reached good clinical outcomes in their respective domains; therefore, we would emphasise prevention of osteoarthritis and the quality of care as the more important predictors of good clinical outcomes.

Autoinflammation in patients with leukocytic CBL loss of heterozygosity is caused by constitutive ERK-mediated monocyte activation.

Patients heterozygous for germline CBL loss-of-function (LOF) variants can develop myeloid malignancy, autoinflammation, or both, if some or all of their leukocytes become homozygous for these variants through somatic loss of heterozygosity (LOH) via uniparental isodisomy. We observed an upregulation of the inflammatory gene expression signature in whole blood from these patients, mimicking monogenic inborn errors underlying autoinflammation. Remarkably, these patients had constitutively activated monocytes that secreted 10 to 100 times more inflammatory cytokines than those of healthy individuals and CBL LOF heterozygotes without LOH. CBL-LOH hematopoietic stem and progenitor cells (HSPCs) outgrew the other cells, accounting for the persistence of peripheral monocytes homozygous for the CBL LOF variant. ERK pathway activation was required for the excessive production of cytokines by both resting and stimulated CBL-LOF monocytes, as shown in monocytic cell lines. Finally, we found that about 1 in 10,000 individuals in the UK Biobank were heterozygous for CBL LOF variants and that these carriers were at high risk of hematological and inflammatory conditions.

Alimentary infections during war conditions: Mostar and Tomislavgrad, Bosnia and Herzegovina, 1992-1995.

The aim of this study was to assess the outcome of sanitary and epidemiologic measures undertaken in relation to alimentary infections in the military corps of the Croatian Defense Council (Hrvatsko vjece obrane) and civilian population in Mostar and Tomislavgrad regions during the 1992-1995 War in Bosnia and Herzegovina. A total of 25 (4.8%) of soldiers and 7 (7.1%) of non-military personnel were not being granted medical clearance to be employed in the food provision services. We recorded a total of 68 alimentary infections cases in military personnel (with an incidence of 536.2 per 100,000 persons), and 436 in civilian population (573.9 per 100,000 person), without significant difference between them (p=0.647). We did not record any alimentary infection outbreak in the military personnel, while two smaller epidemics of the abdominal typhus were recorded among civilian populations, but without lethal outcomes. The results of this study suggest that even the most basic adherence to the principle of standard sanitary and epidemiologic preventive measures may substantially reduce the probability of alimentary infections outbreaks, even in the highly disruptive, warfare environment.

Croatian Medical Corps in Bosnia and Herzegovina during the 1992-1995 war.

OBJECTIVE: The purpose of this study was to review the establishment and operation of the Croatian Medical Corps in Bosnia and Herzegovina in the 1992-1995 war. METHODS: We analyzed pertinent documents available to one of the authors (B.I.) who served on the Headquarter of the Corps, the study of the 17 published articles describing medical activities in various parts of Bosnia and Herzegovina during the war, as well as other relevant medical-military literature. RESULTS: The Corps functioned effectively and, in fact, served as a new health care system for the Croats in Bosnia and Herzegovina. It was initiated, planned, and operated voluntarily by members of the medical community, established before the defense forces, and later incorporated within them, but retaining its autonomy. CONCLUSIONS: The development of the Corps represents a unique phenomenon in the history of military medicine.