Safety and pharmacodynamics of venetoclax (ABT-199) in a randomized single and multiple ascending dose study in women with systemic lupus erythematosus.

Objective The anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) may contribute to the pathogenesis of systemic lupus erythematosus. The safety, tolerability, and pharmacodynamics of the selective Bcl-2 inhibitor venetoclax (ABT-199) were assessed in women with systemic lupus erythematosus. Methods A phase 1, double-blind, randomized, placebo controlled study evaluated single ascending doses (10, 30, 90, 180, 300, and 500 mg) and multiple ascending doses (2 cycles; 30, 60, 120, 240, 400, and 600 mg for 1 week, and then 3 weeks off per cycle) of orally administered venetoclax. Eligible participants were aged 18-65 years with a diagnosis of systemic lupus erythematosus for 6 months or more receiving stable therapy for systemic lupus erythematosus (which could have included corticosteroids and/or stable antimalarials). Results All patients (48/48) completed the single ascending dose, 25 continued into the multiple ascending dose, and 44/50 completed the multiple ascending dose; two of the withdrawals (venetoclax 60 mg and 600 mg cohorts) were due to adverse events. Adverse event incidences were slightly higher in the venetoclax groups compared with the placebo groups, with no dose dependence. There were no serious adverse events with venetoclax. The most common adverse events were headache, nausea, and fatigue. Venetoclax 600 mg multiple ascending dose treatment depleted total lymphocytes and B cells by approximately 50% and 80%, respectively. Naive, switched memory, and memory B-cell subsets enriched in autoreactive B cells exhibited dose-dependent reduction of up to approximately 80%. There were no consistent or marked changes in neutrophils, natural killer cells, hemoglobin, or platelets. Conclusions Venetoclax was generally well tolerated in women with systemic lupus erythematosus and reduced total lymphocytes and disease-relevant subsets of antigen-experienced B cells. Registration ClinicalTrials.gov: NCT01686555.

The Use of Autologous Mesenchymal Stem Cells for Cell Therapy of Patients with Amyotrophic Lateral Sclerosis in Belarus.

We studied a new method of treatment of amyotrophic lateral sclerosis with autologous mesenchymal stem cells. Autologous mesenchymal stem cells were injected intravenously (intact cells) or via lumbar puncture (cells committed to neuronal differentiation). Evaluation of the results of cell therapy after 12-month follow-up revealed slowing down of the disease progression in 10 patients in comparison with the control group consisting of 15 patients. The cell therapy was safe for the patients.

[Evidence-based choice and antidepressants treatment in psychiatry]. / Ratsional'nyi vybor i primenenie antidepressantov v psikhiatricheskoi praktike.

Depression is a severe and usually recurrent mental disorder which leads to a prominent impairment of physical and social functioning, a reduced quality of life of the patients, implies as well an increased morbidity and mortality. Reducing the social-economic depression burden is possible in the optimization of decision-making process of antidepressant choice (including SSRIs and SNRIs) based on the evidence-based risk/benefit ratio and resource saving potential treatment involving target psychosocial interventions and monitoring of long-term treatment adherence.

Effect of platelet releasate on osteogenic differentiation of human mesenchymal bone marrow stem cells.

We studied the effect of platelet releasate on osteogenic differentiation of human mesenchymal BM stem cells. Histological staining and reverse transcription PCR analysis showed that addition of platelet releasate to osteogenic differentiation medium stimulated the formation of calcium ossificates and alkaline phosphatase and increased expression of osteopontin and alkaline phosphatase genes.

[Scaling of the process of biosynthesis of surfactants by Rhodococcus erythropolis EK-1 on hexadecane].

Peculiarities of synthesis of surface-active substances (SAS) are studied at periodical cultivation of Rhodococcus erythropolis EK-1 in the AK-210 fermenter on medium containing n-hexadecane. Maximum indicators of SAS synthesis (concentration of extra cellular SAS is 7.2 g/l; factor of emulsification of the cultural liquid 50%; SAS yield from the substrate 50%) have been observed at 60-70% concentration of dissolved oxygen from the saturation level with aerial oxygen (pH 8.0) fractional supply of the substrate by portions each being 0.3-0.4% every 5-6 h to a final volume concentration of 2.4% and with the use of 10% inoculate grown until mid-exponential phase on the medium with 1.0 vol % of n-hexadecane. Implementation of the process of SAS biosynthesis with the fermentation equipment provided the possibility to increase almost two-fold the amount of the synthesized SAS and reduce 3.5-fold the time of cultivation of the producer strain compared with the growth in flasks at shake-flask propagator.

[Tumor necrosis factor in blood plasma and morphofunctional parameters of the hart in patients with chronic heart failure complicated by a course of ischemic heart disease. Dynamics under effect of treatment]. / Faktor nekroza opukholei v plazme krovi i morfofunktsional'nye parametry serdtsa u bol'nykh s khronicheskoi serdechnoi nedostatochnost'iu oslozhnivshei techenie ishemicheskoi bolezni serdtsa. Dinamika pod vliianiem lecheni.

AIM: To examine the course of chronic cardiac failure (CCF), morphofunctional parameters of the heart in correlation with activity of cytokine system; to evaluate effectiveness, tolerance and safety of combined CCF treatment including a cardioselective beta-adrenoblocker bisoprolol in patients with CCF FC I-IV having a high plasm level of tumor necrosis factor alpha (TNF-alpha). MATERIAL AND METHODS: The concentration of TNF-alpha in plasm of 40 patients with IHD complicated by CCF of FC I-IV and ejection fraction under 45% was measured at enzyme immunoassay. The treatment included combined therapy with diuretics, cardiac glycosides, peripheral vasodilators, ACE inhibitors, bisoprolol (group I) or no bisoprolol (group II). RESULTS: CCF patients with TNF-alpha had a significantly reduced IMT, more frequent episodes of CCF decompensation, longer CCF history, lower EF and threshold exercise intensity. In group I patients all these parameters improved. CONCLUSION: CCF patients with elevated plasm levels of TNF-alpha showed a severe course of the disease, low IMT, abnormal myocardial contraction and exercise tolerance. The addition of bisoprolol to combined treatment of the above patients improves their clinical condition, morphological parameters of the heart and exercise tolerance.

[Ultrasonic diagnosis of abdominal foreign bodies]. / Ul'trazvukovaia diagnostika inorodnykh tel briushnoi polosti.

Experience with ultrasonic examination (USE) in diagnosis of foreign abdominal bodies in 23 patients is reviewed. Foreign abdominal bodies have specific echosemiotics. It is demonstrated that USE provides maximal information about sizes, structure, location of foreign abdominal bodies, their depth of location and relationship with abdominal organs. It makes sense to make in some cases a differential diagnosis with inflammatory infiltrates and abdominal abscesses, fetus, gastric bezoar. It is necessary for this to use additional X-ray and endoscopic methods. USE helps to decide on optimal surgical approach and gives information for repeated surgery that permits to reduce the time of relaparotomy.

Effects of radiation on the production of immunoglobulins in children subsequent to the Chernobyl disaster.

Studies on the immediate and long-term effects of radiation on the B-system immunity of children who were affected by radiation after the Chernobyl disaster (from 1986-1992) are summarized in this paper. Complete clinical and immunological examination of more than 6000 children have been carried out. The dynamics of the immune system, with ongoing reactions of cell proliferation and differentiation, gene amplification, transcription, translation, biosynthesis and switching production of isotypes and subclasses of immunoglobulins, as well as specific and nonspecific (natural) antibodies, make it highly susceptible to the action of radiation in addition to other ecological factors. B-system of immunity (B-cel level, concentration of immunoglobulins-M, G, A, E; subclasses of IgG (IgG1-IgG4) in the serum and saliva, and the level of nonspecific heterophilic autoantibodies (RF, antithyroglobulin) were investigated in children of differing ages and sex living in the territories of the Republic of Belarus contaminated with radionuclides. Research showed decreased levels of B-cell and IgM and IgG isotopes 40-50 days after the disaster and increased levels of IgA immunoglobulins at that time. Long-term effects of low doses of radiation showed increased concentrations of IgM and IgG, correlating changes in the B-system of immunity with the level of 137Cs contamination in the territory of residence and also with the amount of 137Cs found in the children.

[The use of the carbon dioxide laser in acute surgical infection of the soft tissues]. / Ispol'zovanie uglekislotnogo lazera pri ostroi khirurgicheskoi infektsii miagkikh tkanei.

Clinico-laboratory studies were conducted in 46 patients with wound infection for the treatment of which carbon-dioxide laser was used, and in 78 patients who were operated on with a metal scalpel (control). It is shown that "excision" and "evaporation" of tissues took 15-45 minutes. Repeated interventions were performed in 15% of cases due to bleeding from vessels measuring 1.0-1.5 mm in diameter. After surgical debridement with a scalpel the number of microbes reduced from 10(7)-10(9) to 10(3)-10(4) per g. After exposure to the laser beam this value was 10(1) but on day 3-4 it was 10(5)-10(6). The extent of the zone of coagulation necrosis in the zone exposed to the laser beams measured up to 500 microns, and began diminishing only on day 7-9 of postoperation. Suppuration of the wounds in 56% of patients of the main group treated by operation was in conformity with the results of bacteriological and morphological studies. In the control group this index was 15.4%. It is concluded that the use of carbon-dioxide laser as a "light scalpel" with subsequent primary closure of the wound is inexpedient. Its use in preparing a wound for closure with secondary sutures has no advantages over radical surgical debridement.

[Kidney and pancreas transplantation in patients with insulin-dependent diabetes mellitus]. / Transplantatsiia pochki i podzheludochnoi zhelezy bol'nym insulinzavisimym sakharnym diabetom.

The article analyses the results of one-stage transplantation of the kidney and pancreas in three patients suffering from insulin-dependent diabetes mellitus with diabetic nephropathy in the stage of terminal renal failure which called for programmed hemodialysis. The specific features of early postoperative management of patients are described, particularly the various routes of drug administration.

[Interactions of mononuclear cells of peripheral blood with islet cells in vitro]. / Vzaimodeistvie mononuklearov perifericheskoi krovi s ostrovkovymi kletkami in vitro.

Peripheral blood mononuclear cells from Type I diabetic patients health donors or Wistar rats were cultured with rat islet cells for 18 h. Then TNF content of the medium and basal and stimulated insulin release were determined. Mononuclear cells from both healthy donors and diabetic patients could inhibit the insulin release with no correlation to TNF content. Addition of lipopolysaccharide resulted in a 5-7 times increase of TNF content of the medium followed by a more pronounced inhibition of insulin release. Rat mononuclear cells inhibited the beta-cell function almost completely and initially produced large amounts of TNF. The data indicate that inhibition of insulin release by blood mononuclear cells in vitro does not reflect anti beta-cell specific cellular immunity, involves cytokines and, probably depends upon the initial properties of the cells.

Islet cell transplantation in type I diabetes mellitus: evaluation of humoral immune response.

Four males and three females ranging in age from 20 to 35 years and afflicted with complicated Type 1-diabetes for more than 8 years underwent islet cell allotransplantation (ATx, 6 cases) and xenotransplantation (XTx, 1 case). Precultured islet cells derived from human or bovine fetal pancreata were injected into the m. rectus abdominis. Immunosuppression was not applied. Plasma C-peptide and islet cell surface antibodies (ICSA) were continually measured both before and until the twentienth week following islet cell transplantation. All recipients were subdivided as "responsive" (RR, 3 males) or "non-responsive" (NRR, 1 male and 3 females), according to the dynamics of their ICSA levels. All 3 RR (1XTx and 2 ATx) showed a peak of ICSA two weeks after cell injection. Subsequent ICSA levels had the tendency to either diminish or increase. Heterogeneity of preoperative antibody level, especially in NRR, was also observed. No associations between ICSA and ATx or XTx, age at diabetes onset, or duration of the disease was found. Only one RR with XTx had a reduced daily insulin requirement and a significant C-peptide response similar to the dynamics of ICSA levels. A greater mass of available bovine islet cells might be responsible for this effect.