Genetically programmed alternative splicing of NEMO mediates an autoinflammatory disease phenotype.

Host defense and inflammation are regulated by the NF-κB essential modulator (NEMO), a scaffolding protein with a broad immune cell and tissue expression profile. Hypomorphic mutations in inhibitor of NF-κB kinase regulatory subunit gamma (IKBKG) encoding NEMO typically present with immunodeficiency. Here, we characterized a pediatric autoinflammatory syndrome in 3 unrelated male patients with distinct X-linked IKBKG germline mutations that led to overexpression of a NEMO protein isoform lacking the domain encoded by exon 5 (NEMO-Δex5). This isoform failed to associate with TANK binding kinase 1 (TBK1), and dermal fibroblasts from affected patients activated NF-κB in response to TNF but not TLR3 or RIG-I-like receptor (RLR) stimulation when isoform levels were high. By contrast, T cells, monocytes, and macrophages that expressed NEMO-Δex5 exhibited increased NF-κB activation and IFN production, and blood cells from these patients expressed a strong IFN and NF-κB transcriptional signature. Immune cells and TNF-stimulated dermal fibroblasts upregulated the inducible IKK protein (IKKi) that was stabilized by NEMO-Δex5, promoting type I IFN induction and antiviral responses. These data revealed how IKBKG mutations that lead to alternative splicing of skipping exon 5 cause a clinical phenotype we have named NEMO deleted exon 5 autoinflammatory syndrome (NDAS), distinct from the immune deficiency syndrome resulting from loss-of-function IKBKG mutations.

Age-Related Retinal Changes in Wild-Type C57BL/6J Mice Between 2 and 32 Months.

Purpose: The purpose of this study was to extend our understanding of how aging affects normal retina function and morphology in wild-type C57BL/6J mice, by analyzing electrophysiological recordings and in vivo and post mortem anatomy. Methods: Electroretinograms (ERGs), spectral domain optical coherence tomography (SD-OCT), and confocal scanning laser ophthalmoscope (cSLO) in vivo images were obtained from mice between the ages of 2 and 32 months in four groups: group 1 (<0.5 years), group 2 (1.0-1.5 years), group 3 (1.5-2.0 years), and group 4 (>2.0 years). Afterward, mouse bodies and eyes were weighed. Eyes were stained with hematoxylin and eosin (H&E) and cell nuclei were quantified. Results: With aging, mice showed a significant reduction in both a- and b-wave ERG amplitudes in scotopic and photopic conditions. Additionally, total retina and outer nuclear layer (ONL) thickness, as measured by SD-OCT images, were significantly reduced in older groups. The cSLO images showed an increase in auto-fluorescence at the photoreceptor-RPE interface as age increases. H&E cell nuclei quantification showed significant reduction in the ONL in older ages, but no differences in the inner nuclear layer (INL) or ganglion cell layer (GCL). Conclusions: By using multiple age groups and extending the upper age limit of our animals to approximately 2.65 years (P970), we found that natural aging causes negative effects on retinal function and morphology in a gradual, rather than abrupt, process. Future studies should investigate the exact mechanisms that contribute to these gradual declines in order to discover pathways that could potentially serve as therapeutic targets.

[First experience of application of assist circulation device using biventricular type "excor"].

The frequency of use of assist blood device as the "bridge" to the heart transplantation increased in last years. An assessment of results of first 7 implantations of assist circulation device using biventricular type "Excor" was made. The implantations were performed in Federal Almazov centre of the heart, blood and endocrinology. An observation period after implantation was since 11 till 301 days. The heart transplantation of 4 patients was carried out in different terms after implantation. One of the patients passed away on the fifth day due to the pulmonary embolism. Another patient died on the eleventh day after the implantation because of multiple organ failure against the background of severe chronic cardiac failure. The waiting list of heart transplantation includes 2 patients.

Cardiac tamponade as a manifestation of tuberculosis.

Tuberculosis has been increasing in incidence in recent years. Pericardial involvement and pericardial effusions are well-documented and may result in pericardial tamponade. Despite this, large pericardial effusions are uncommon, and manifestation as cardiac tamponade is rare. We report two cases of tuberculous pericarditis in which the initial feature was tamponade. Since the diagnosis of tuberculosis may be delayed due to the slow-growing nature of the bacterium, physicians need to be aware of this possibility and consider the use of modern diagnostic techniques that may permit an earlier diagnosis.

[Purulent pericarditis].

Purulent pericarditis is diagnosed when pus is drained from the pericardial space or when bacteria are cultured from the pericardial fluid. This rare disease is often diagnosed late, when severe hemodynamic compromise develops due to pericardial tamponade. It is usually a complication of pneumonia, especially if there is empyema as well, and often follows chest surgery or chest wall infections. It sometimes appears in patients with septicemia, especially when they are debilitated or immuno-compromised. Diagnosis is aided by echocardiography. Pericardiocentesis and drainage of the pus, as well as prolonged antibiotic treatment, are mandatory. Delay in diagnosis and treatment often results in death. Some surviving patients may develop constrictive pericarditis and require pericardiectomy. We report a 73-year-old man with pulmonary lymphoma who suffered from purulent pericarditis secondary to sepsis with methicillin-resistant Staphylococcus aureus. Pericardial drainage and appropriate antibiotic treatment eventually resulted in complete recovery.

[Functional-cost approach to the evaluation of methods used in postgraduate education of public health administrators]. / Funktsional'no-stoimostnyi podkhod k otsenke metodov poslediplomnogo obucheniia organizatorov zdravookhraneniia.

The article: "Functional and Cost Approach to the Evaluation of Methods of Postgraduate Training of Public Health Administrators" raises a number of issues concerning the use of methodology of cost analysis for assessing the methods used in the system of postgraduate training of public health administrators. The emphasis is placed on the analysis of teaching staff functions and the expenditures allocated for their realization. A question of developing a functional model and also a functional and cost diagram is considered. An example is found in the method of group dynamics as one of the variants of active training. An evaluation has been made of advantages and disadvantages as compared with a classical variant of training. It has been noted that the approach suggested is of major importance while introducing the cost-accountable relations into the system of postgraduate training.

[Ways to improve the management of hospitals]. / Puti sovershenstvovaniia upravleniia statsionarnym uchrezhdeniem.

The article "Ways of improving the management of in-patient facilities" examines the organizational structure of management in respect to hospitals. A systems approach is used for management analysis. A hospital facility is defined as an hierarchical multilevel system of management. In this connection some problems concerning hospital management are considered: the multi-level character of management system, the specificity of management at each echelon of decision making process, the development of curative and diagnostic process technology, the problem of assessing management effectiveness at each hierarchical level. Attention is given to the training of hospital staff. Ways of improving the management of hospitals are determined for the purpose of raising the quality and effectiveness of in-patient care.