Circulating Microparticles Are Differentially Increased in Lowlanders and Highlanders with High Altitude Induced Pulmonary Hypertension during the Cold Season.

The role of microparticles (MPs) and cold in high altitude pulmonary hypertension (HAPH) remains unexplored. We investigated the impact of long-term cold exposure on the pulmonary circulation in lowlanders and high-altitude natives and the role of MPs. Pulmonary hemodynamics were evaluated using Doppler echocardiography at the end of the colder and warmer seasons. We further examined the miRNA content of MPs isolated from the study participants and studied their effects on human pulmonary artery smooth muscle (hPASMCs) and endothelial cells (hPAECs). Long-term exposure to cold environment was associated with an enhanced pulmonary artery pressure in highlanders. Plasma levels of CD62E-positive and CD68-positive MPs increased in response to cold in lowlanders and HAPH highlanders. The miRNA-210 expression contained in MPs differentially changed in response to cold in lowlanders and highlanders. MPs isolated from lowlanders and highlanders increased proliferation and reduced apoptosis of hPASMCs. Further, MPs isolated from warm-exposed HAPH highlanders and cold-exposed highlanders exerted the most pronounced effects on VEGF expression in hPAECs. We demonstrated that prolonged exposure to cold is associated with elevated pulmonary artery pressures, which are most pronounced in high-altitude residents. Further, the numbers of circulating MPs are differentially increased in lowlanders and HAPH highlanders during the colder season.

Pulmonary Vascular Pressure Response to Acute Cold Exposure in Kyrgyz Highlanders.

Background/Aims: Long-term high altitude residence leads to a sustained increase in pulmonary vascular resistance and elevation of pulmonary artery pressure due to chronic alveolar hypoxia. However, living at high altitude is also associated with other environmental factors such as cold. There is still little experimental evidence suggesting detrimental effects of low temperatures on the pulmonary vasculature. Therefore, our objective was to investigate acute effects of cold exposure on the pulmonary circulation in Kyrgyz high altitude natives. Methods: Responses of the pulmonary circulation during acute exposure to controlled cold conditions (4°C-6°C) for 60 minutes were measured in highlanders using Doppler echocardiography. Based on the Doppler echocardiography-derived tricuspid regurgitant systolic pressure gradient (TRG), subjects with TRG ≥40 mmHg were allocated into the pulmonary hypertension (PH) group. Participants from the PH group were compared with volunteer control subjects with TRG <40 mmHg. All baseline measurements were evaluated in a warm room during 60 minutes (22°C-28°C). Following baseline echocardiography, the subjects were assigned to either warm or cold exposure for an additional 60 minutes. Results: Acute cold exposure significantly increased TRG both in the control (ΔTRG, 4.93 mmHg) and in the PH (ΔTRG, 8.15 mmHg) group, compared to the respective warm exposure conditions (ΔTRG, -0.14 and -0.05 mmHg). No changes in cardiac output were observed upon cold exposure. Conclusion: Thus, acute exposure to cold leads to elevation of pulmonary artery pressure in high altitude residents.

Circulating Apoptotic Signals During Acute and Chronic Exposure to High Altitude in Kyrgyz Population.

Background: Circulating apoptotic signals (CASs) have been described in the pathologies associated with dysregulated apoptosis, such as cancer, heart diseases, and pulmonary hypertension (PH). However, nothing is known about the expression profiles of these markers in the circulation of humans exposed to acute and chronic effects of high altitude (HA). Methods: Gene expression levels of different apoptotic signals (ASs) were analyzed in human pulmonary artery smooth muscle cells (PASMCs) upon hypoxia incubation. In addition, we measured the plasma values of relevant CAS in Kyrgyz volunteers during acute and chronic exposure to HA. Finally, we analyzed the effects of pro-apoptotic mediator Fas ligand (FasL) on apoptosis and proliferation of human PASMCs. Results: Several cellular AS were increased in PASMCs exposed to hypoxia, in comparison to normoxia condition. Among analyzed CAS, there was a prominent reduction of FasL in lowlanders exposed to HA environment. Furthermore, decreased circulatory levels of FasL were found in highlanders with HA-induced PH (HAPH), as compared to the lowland controls. Furthermore, FasL concentration in plasma negatively correlated with tricuspid regurgitant gradient values. Finally, FasL exerted pro-apoptotic and anti-proliferative effects on PASMCs. Conclusion: Our data demonstrated that circulating levels of FasL are reduced during acute and chronic exposure to HA environment. In addition, dysregulated FasL may play a role in the context of HAPH due to its relevant functions on apoptosis and proliferation of PASMCs.

Prevalence of Group A b-Hemolytic Streptococcus Among Children with Tonsillopharyngitis in Kyrgyzstan: The Difficulty of Diagnostics and Therapy.

OBJECTIVE: Rheumatic fever (RF) is well known disease as a result of frequent complication of the group A b-hemolytic streptococcal (GABHS) tonsillopharyngitis, have noticeably grown for the last 15 years among young generation in the Kyrgyz Republic. It is important to hold a study about the prevalence of RF and GABHS and their susceptibility to antibiotics in the Kyrgyz Republic. MATERIALS AND METHODS: We have studied 200 children with chronic tonsillopharyngitis at the National Center of Pediatrics and Child Surgery in Bishkek (the Kyrgyz Republic) from August till September 2008. 188 (48 out of them are with RF) out of total 200 children are Kyrgyz and 12 are Russian (2 out of them are with RF). 111 out of total are female (34 out of them are with RF) and 89 are male (17 out of them are with RF). The average age of the subjects is 10.9±6.0 (from 3 to 17 years old). The presence of GABHS was assessed using two ways: by the rapid antigen detection test (RADT) for outcrop of streptococcus antigen in smear from mucosal surface of tonsils, and by bacterial culture analysis (BA). RADT was used to determine its specificity and sensitivity in order to recommend practitioners its further wide use. Furthermore, the discovered culture of GABHS have been investigated on susceptibility to antibiotics by disc-diffusion method. RESEARCH RESULTS: GABHS antigen was positive in 72 (36.0 %) subjects from RADT and in 80 (40.0%) subjects from BA out of 200 total subjects. In the patients with RF (n=51), GABHS was positive in 18 (35.2%) subjects by RADT and in 24 (47.0%) subjects by BA. In the subjects without RF (n=149), GABHS was positive in 54 (36.2%) subjects by RADT and in 56 (37.5%) by BA. Among 80 GABHS positive results sensitive to antibiotics were: to penicillin only 10 (12.5%), to ampicillin-29 (36.2%), to amoxicillin-36 (45.0%), to ceftriaxon - 31 (38.7%), to roxithromycin - 21 (26.2%), to erythromycin- 19 (23.7%). It is noted that 21 (26.2%) GABHS positive results were absolutely resistant for all these tested antibiotics. RADT showed that its specificity is 85% as well as its sensitivity is equal to 67.5%. CONCLUSION: In this study the sensitivity of RADT was low; therefore, the negative results of RADT don't exclude presence of GABHS. High prevalence of GABHS antigen demonstrates not only in patients with RF, but also among healthy children (without RF) of the Kyrgyz Republic. The high prevalence of GABHS at children with RF (47.0%), probably, presents a low sensitivity to antibiotics and irregular secondary prophylaxis. Significant presence of GABHS among healthy children (37.5%) requires improvement of primary prevention to prevent further spread of RF and Rheumatic Heart Disease (RHD) in the country.

Rheumatologic services in Central Asian countries: current state of development of rheumatology in Central Asia.

Rheumatologic and public health services of Central Asia's republics have suffered hugely as a result of social and economic declines following the dissolution of the Union of Soviet Socialist Republics (USSR) and transition of these republics to market economies. Between 1990 and 2000 there was a mass outflow of highly skilled rheumatologists and teachers and researchers in rheumatology to countries abroad, leading to significant deprivation of rheumatological service in Central Asian countries. During this time, there was continued growth of various rheumatic diseases (RDs) including rheumatic fever, and musculoskeletal and connective tissue disorders. The medical and social burden of RDs imposed on society was strongly underestimated until recent times. There is an urgent need to define the epidemiology of RDs and their impact on the quality of life of people afflicted by these conditions, and to improve the diagnostics and treatment of these conditions.

High incidence of rheumatic fever and rheumatic heart disease in the republics of Central Asia.

The epidemiological situation involving rheumatic fever (RF) and rheumatic heart disease (RHD) not only remains unresolved but is also a cause of serious concern due to the rapid increase in the incidence of RF/RHD in many developing countries. After the collapse of the Soviet Union, the republics of Central Asia experienced an economic decline that directly affected the public health sector of this region. This is the main cause of the high prevalence of many infectious diseases in Central Asia, including streptococcal tonsillopharyngitis, which carries the risk of complications such as RF. The difficulty involved in early diagnosis of RF and the development of RHD among children and adolescents causes early mortality and sudden death, leading to economic damage in these countries due to the loss of the young working population. Among all the developing countries, Kyrgyzstan, which is located in the heart of Central Asia, has the highest prevalence of RF/RHD. The increase in the prevalence of RF in Central Asia can be attributed to factors such as the low standard of living and changes in the virulence of streptococci and their sensitivity to antibiotics.

Increased prevalence of group A ß-hemolytic streptococcus among an ethnic population in Kyrgyzstan detected by the rapid antigen detection test.

The incidence of rheumatic fever (RF) has markedly increased in the last 10 years in Kyrgyzstan. Therefore, investigating the prevalence of group A ß-hemolytic streptococcus (GABHS), which is the cause of RF, in the Kyrgyzstan population is crucial. We studied 189 subjects: 59 children [29 with RF and/or rheumatic heart disease (RHD)] and 130 adults (15 with RHD). The average age of the subjects was 41.0±10.0 years (range 8 months to 72 years). A general clinical examination and medical history including eating habits was carried out. The prevalence of GABHS was tested using the highly sensitive rapid antigen detection test (RADT) to detect the outcrop of streptococcus antigen in smears taken from the mucosal surface of the tonsils or the back of the throat. GABHS antigen was positive in 70 of a total 189 subjects [37.0%; 22/59 children (37.2%), 48/130 adults (36.9%)]. In patients with RF/RHD (n=44), GABHS was positive in 14 subjects [31.8%; 8/29 children (27.6%), 6/15 adults (40.0%)]. Thirty-two subjects with RF/RHD had frequent episodes of tonsillopharyngitis. In subjects without RF/RHD (n=145), GABHS was positive in 56 subjects [38.6%; 14/30 children (46.6%), 42/115 adults (36.5%)]. Thirty of these subjects had frequent episodes of tonsillopharyngitis. Of the 130 adults, the most-consumed dairy products included yoghurt (n=115; 88.4%), milk kasha (n=75; 57.7%) and milk (n=40; 30.7%). Of the 115 subjects in the yoghurt-consuming group, 44 (38.2%) had positive results for GABHS. In the non-yoghurt-consuming group, 4/15 subjects (26.6%) had positive results for GABHS. Using RADT for GABHS, a high prevalence of GABHS antigen was detected not only in patients with RF/RHD, but also in the healthy population (without RF/RHD). The low GABHS prevalence in children with RF/RHD (27.6%) was probably due to corresponding antibiotic therapy. In conclusion, the high prevalence of GABHS is one of the main reasons for the rapid increase in RF/RHD in Kyrgyzstan, and RADT would be an effective tool for its detection.