Hypomorphic RAG deficiency: impact of disease burden on survival and thymic recovery argues for early diagnosis and HSCT.

Patients with hypomorphic mutations in the RAG1 or RAG2 gene present with either Omenn syndrome or atypical combined immunodeficiency with a wide phenotypic range. Hematopoietic stem cell transplantation (HSCT) is potentially curative, but data are scarce. We report on a worldwide cohort of 60 patients with hypomorphic RAG variants who underwent HSCT, 78% of whom experienced infections (29% active at HSCT), 72% had autoimmunity, and 18% had granulomas pretransplant. These complications are frequently associated with organ damage. Eight individuals (13%) were diagnosed by newborn screening or family history. HSCT was performed at a median of 3.4 years (range 0.3-42.9 years) from matched unrelated donors, matched sibling or matched family donors, or mismatched donors in 48%, 22%, and 30% of the patients, respectively. Grafts were T-cell depleted in 15 cases (25%). Overall survival at 1 and 4 years was 77.5% and 67.5% (median follow-up of 39 months). Infection was the main cause of death. In univariable analysis, active infection, organ damage pre-HSCT, T-cell depletion of the graft, and transplant from a mismatched family donor were predictive of worse outcome, whereas organ damage and T-cell depletion remained significant in multivariable analysis (hazard ratio [HR] = 6.01, HR = 8.46, respectively). All patients diagnosed by newborn screening or family history survived. Cumulative incidences of acute and chronic graft-versus-host disease were 35% and 22%, respectively. Cumulative incidences of new-onset autoimmunity was 15%. Immune reconstitution, particularly recovery of naïve CD4+ T cells, was faster and more robust in patients transplanted before 3.5 years of age, and without organ damage. These findings support the indication for early transplantation.

Recent thymic emigrants, T regulatory cells, and BAFF level in children with X-linked agammaglobulinaemia in association with chronic respiratory disease.

BACKGROUND: X-linked agammaglobulinaemia (XLA) is a genetic disorder affecting B cell maturation, which is characterised by a low number of B cells, agammaglobulinaemia and increased susceptibility to a variety of bacterial infections. This study was performed to assess T cell subpopulations in a group of children with XLA in association with chronic respiratory disease (CRD). METHODS: Numbers of T cell subpopulations (CD3+, CD4+, CD8+, CD3+DR+, naïve, memory, recent thymic emigrants (RTE), regulatory T cells, follicular T helpers) were measured by eight-colour flow cytometry in 22 XLA patients and 50 controls. BAFF level was measured by ELISA. RESULTS: XLA patients with CRD had a significantly lower percentage of RTE numbers and Tregs, while significantly higher absolute counts of lymphocytes, CD3+, CD8+, CD3+DR+ and CD4+CD45RO+ T cells were detected as compared with healthy controls. In patients with XLA without CRD, the number of follicular T helper cells was altered significantly (percentage and absolute), as compared with healthy controls. Additionally, they had significantly higher counts (percentage and absolute) of CD4+CD45RA+ cells and lower percentage of CD4+CD45RO+ cells in comparison with healthy controls. CONCLUSIONS: Our study affords new information concerning CRD and T cell subsets that differentiate or are maintained in the absence of B cells in children with XLA. T cell's homeostasis depends on the presence of chronic respiratory disease that may be caused by the delay in diagnosis.

[Effect of toll-like receptors (TLR) ligands on in vitro synthesis of proinflammatory cytokines by peripheral blood mononuclear cells from healthy persons and from patients with common variable immunodeficiency].

Production of citokines of tumor-necrosis factor (TNF)-alpha and interferon (IFN)-alpha by peripheral blood mononuclear cells (PBMC) from healthy men and from patients with common variable immunodeficiency (CVID) after stimulation with zymosan, lypopolysaccharides, flagellin and CpG, which are ligands of TLR 2/6, TLR 4, TLR 5, TLR 9 respectively, was studied in vitro. In healthy men production of TNF-alpha varied between individuals, whereas synthesis of IFN-alpha was similar. Spontaneous production of TNF-alpha by PBMC in patients with CVID was increased and accompanied by decrease in TNF-alpha production stimulated by each analyzed ligands except CpG. Observed changes in TLR-dependent TNF-alpha production can play important role in pathogenesis of CVID.

Analysis of toll-like receptor-dependent production of proinflammatory cytokines in vitro by human peripheral blood mononuclears of donors and patients with primary immunodeficiency.

The production of TNF-alpha and IFN-alpha cytokines by peripheral blood mononuclears in response to stimulation by TLR2/6, TLR4, TLR5, TLR9 ligands (zymosan, LPS, flagellin, and CpG-oligodeoxynucleotide, respectively) was studied in donors and patients with common variable immunodeficiency. Individual characteristics of TNF-alpha production by mononuclears were revealed in donors. Reduced stimulated production of TNF-alpha in response to stimulation with TLR4 and TLR5 ligands in vitro was detected in patients with common variable immunodeficiency.

["Silent" pheochromocytomas]. / "Nemye" feokhromotsitomy.

The results of surgical treatment of 126 patients with "hormonally inactive" and catecholamine secreting tumors of the adrenals were studied. Among them 2 cases (1.6%) of "dumb" pheochromocytoma were diagnosed. The clinical observations have shown the difficulties in the diagnosis of "dumb" pheochromocytoma before operation, risk of performing adrenalectomy and necessity to correct hemodynamic disorders during anesthesia in connection with latent catecholamine activity. The laboratory and instrumental means of examination of patients with suspected "hormonally inactive" tumor of the medullary substance of the adrenal are proposed. The variants of prevention and arrest of hemodynamic disorders during ablation of the "dumb" pheochromocytoma were considered. When the "dumb" pheochromocytoma had the diameter less than 5 cm and the adequate preparation was conducted the authors propose a laparoscopic access for adrenalectomy on the right, and retroperitoneoscopic access on the left. The detection of the catecholamine secreting tumor of more than 5 cm diameter, when problems with the clipping of the central vein of the adrenal take place, open accesses should be preferred--mainly thoracophrenotomy in the X intercostal space. If it was not possible to prove "dumb" pheochromocytoma before operation and it was started with endovideosurgical intervention during which it was not possible to first clip the central vein of the adrenal and the risk of hemodynamic disorders was high, the early transition to open operative intervention is thought to be expedient.

[Ganglionic blockers in abdominal surgery: facts and hypotheses. 2.Clinical, pathophysiological and pharmacological aspects of ganglionic blocker use]. / Ganglioblokatory v abdominal'noi khirurgii: fakty i gipotezy. Soobshchenie 2. Klinicheskie, patofiziologicheskie i farmakologicheskie aspekty primeneniia ganglioblokatorov.

The authors discuss facts and hypotheses on the effects of benzohexonium upon the motor activity of the intestine and the significance of N-cholinolytics for prophylactics and treatment of postoperative pareses of the gastrointestinal tract. The ganglioblockers possess antistress effect, reduce the degree of pathological vegetative reactions and facilitate realization of the mechanisms of selfregulation of functions of the small and large intestine. Using benzohexonium during operation and in the first days after it makes the intestinal pareses less frequent. N-cholinolytics however do not have a considerable stimulating influence on the contracting activity of the gastrointestinal tract that accounts for their not high effectiveness in treatment of early functional motor evacuatory disorders. The points of action of gangliolytics, those at the level of the intestinal wall included, can not be considered to be completely established, as well as the mechanisms of their indirect effect. The ganglionic blockade should be considered as the basic method of prophylactics of the postoperative paresis of the intestine.

[Early diagnosis and intensive care of acute postoperative pancreatitis]. / Ranniaia diagnostika i intensivnaia terapiia ostrogo posleoperatsionnogo pankreatita.

Diagnostic algorithm developed on the basis of multifactorial regression analysis is suggested for more objective diagnosis of acute pancreatitis after operations on the hepatopancreatoduodenal organs. This algorithm helps differentiate the strategy of intensive care in patients with pancreatitis, pancreatic disease, and uneventful postoperative period. It is impossible to single out the specific (pathognomonic) clinical signs of this complication during the immediate postoperative period. Hyperamylasemia and changes in other enzymes are important but not absolute markers of unfavorable course of disease.

[Rendering anesthesiological and resuscitation care to wounded by a medical reinforcement group in an armed conflict]. / Okazanie anesteziologicheskoi i reanimatologicheskoi pomoshchi gruppoi meditsinskogo usileniia ranenym v vooruzhennom konflikte.

The authors describe the aims and content of anesthesiologic and reanimatologic care of the medical reinforcement group in the medical institution of the 1st echelon of specialized care. Basing on the experience of treatment of 825 casualties with gunshot injuries the rational methods of anesthesia and intensive care are shown including the prolonged controlled ventilation, infusion-transfusion therapy, early enteral nutrition. The main causes of lethal outcomes are analyzed. The conclusion was made that during counter-terrorist operations it is reasonable to include anesthesiologists and reanimatologists into the medical reinforcement group.

[Prognostication and prevention of acute postoperative pancreatitis]. / Prognozirovanie i profilaktika ostrogo posleoperatsionnogo pankreatita.

Equations for accurate prediction of the course of postoperative pancreatitis are developed by multifactorial regression analysis for purposeful prevention of this condition. An injury to the pancreas and the "readiness" of hepatoduodenal organs to a degenerative destructive process are significant for the development of pancreatitis. A differentiated strategy is developed for preventing this complication during the post- and intraoperative period by protease inhibitors, cytostatics, and other nonspecific methods.

[Fractional analysis of urinary alpha-amylase as a probe-free method of diagnosis of biliary dyskinesia in children]. / Fraktsionnoe opredelenie alpha-amilazy mochi kak bezzondovyi metod diagnostiki diskinezii zhelchevyvodiashchikh putei v detskom vozraste.

To diagnose biliary dyskinesia (BD) in children, a method of urine alpha-amylase measurement is offered. It is based on the presence of a direct and close correlation between amylase activity and the amount of endogenous cholecystokinin-pancreozymin in the same portion of the urine. It is concluded that fractional measurement of urine alpha-amylase can be used for diagnosing BD in childhood as a tentative test. It is advisable that it may be used for examining younger children and in cases where the employment of other methods of examination is not feasible.