Therapeutic granulocyte and monocyte apheresis (GMA) for treatment refractory sarcoidosis: a pilot study of clinical effects and possible mechanisms of action.

Sarcoidosis is a systemic, inflammatory disorder, which in a proportion of patients runs a chronic progressive course despite immunosuppressive treatment. Therapeutic granulocyte and monocyte apheresis (GMA) has been shown to be an effective treatment option for other systemic inflammatory disorders, but has not yet been investigated in sarcoidosis. The aim of this study was to evaluate the response to GMA in sarcoidosis. Seven patients with sarcoidosis refractory to standard immunosuppressive therapy received 10 GMA sessions. All patients underwent chest X-ray, spirometry, a Chronic Respiratory Disease Questionnaire (CRQ-SAS), blood tests and bronchoscopy with bronchoalveolar lavage (BAL) before treatment and at 2-4 weeks and 3 months (except bronchoscopy) after the last treatment session. Bronchoalveolar lavage fluid (BALF) cell differential counts were recorded and T cells from blood and BALF were analysed for markers of activity, differentiation and T regulatory function. Compared to baseline, five of seven patients reported an improvement in dyspnoea score. In BALF there was an increase in the percentage of macrophages and a decrease in the percentage of lymphocytes and CD4(+) /FoxP3(+) T cells. Furthermore, the decrease in BALF CD4(+) /FoxP3(+) T cells correlated significantly with an improvement in dyspnoea score. In peripheral blood there was a statistically significant increase in the percentage of CD4(+) /CD27(-) T cells and a trend towards an initial increase in the percentage of CD4(+) /FoxP3(+) T cells, followed by a statistically significant decrease. The effects of GMA on regulatory T cells are consistent with those observed in other inflammatory disorders and could potentially translate into a clinical benefit.

Kinetics of the soluble IL-1 receptor type I during treatment with an LCAP filter in patients with inflammatory bowel disease.

Leukocyte apheresis primarily used for treatment of inflammatory diseases such as inflammatory bowel disease (IBD). Beside an effect of the apheresis column, the plastic lines in the apheresis system might also have an effect due to interaction between the plastic surfaces and circulating leukocytes and plasma proteins. We recently reported generation of LL-37 in the plastic lines during leukocyte adsorbing apheresis. This generation might have a positive impact on the immunologic tolerance and therefore be one operational mechanism by which the apheresis treatment executes its effect. In the present study, we report a significant generation of sIL-1RI in the apheresis lines that is initially absorbed by the LCAP device. This finding, together with our previous data on IL-1Ra indicate that important members of the IL-1 family are significantly altered during the LCAP treatment of patients with IBD. Since IL-1 and its antagonists are important for regulation of inflammatory processes in IBD, we speculate that the LCAP related changes in sIL-1RI and IL-1Ra might impact the clinical outcome. These findings have to be taken into consideration when designing new apheresis techniques as well as sham-controlled studies.

[Monitoring of the medicodemographic situation in Moscow].

There has been recently a trend in declining mortality rates in all population groups. Higher birth rates and lower mortality have been responsible for a reduction in natural population loss in Moscow. At the same time, 14 of the 123 Moscow municipal districts show a positive natural population growth largely due to higher birth rates. Better social and economic living conditions, the effective activities of health care bodies and sanitary and epidemiological well-being services of the city have caused recent positive changes in the demographic situation.

[Impact of chemical ambient air pollution in Moscow on its population's health].

The ambient atmosphere of Moscow is appraised as unbeneficial to the health of the population, that of children and adolescents in particular. Motor transport is a powerful source of the ambient air pollution of Moscow. The average annual level of atmospheric pollution in 2008 is considered to be moderate. Scientific-and-practical studies using the risk assessment methodology also suggest that the ambient air in Moscow is the leading habitat posing a carcinogenic and non-carcinogenic risk to Muscovites' health.

Down-regulation of interferon-gamma parallels clinical response to selective leukocyte apheresis in patients with inflammatory bowel disease: a 12-month follow-up study.

BACKGROUND & AIMS: Pilot studies have indicated a therapeutic role for an apheresis device (Adacolumn) that selectively adsorbs leukocytes in patients with inflammatory bowel diseases. It may also exert immunoregulatory effects contributing to its clinical efficacy. This study aimed to correlate the clinical response to leukocyte apheresis with the expression of key cytokines in mucosal tissue, in peripheral leukocytes, and in plasma. METHODS: Ten patients (seven with Crohn's disease and three with ulcerative colitis, median age: 31 years) with mild to moderately chronic activity were recruited to an open study. Patients were refractory to or had a relapse despite conventional treatment including azathioprine. Leukocyte apheresis was performed once a week for five consecutive weeks. Clinical efficacy was assessed on week 7 and after 12 months. Colonoscopy with multiple biopsies was performed at the start of the study and after 7 weeks for semiquantitative immunohistochemical analyses of cytokines. Cytokine levels in blood and the proportion of cytokine producing CD4+ and CD8+ lymphocytes were determined. RESULTS: The apheresis procedures were well tolerated and no major adverse events were encountered. The median clinical activity score decreased from 12 to 7 on week 7 (P=0.031, n=9) and to 4 after 12 months (P=0.004, n=9). Five patients were in clinical remission at the 12th month. Tissue interferon (IFN)-gamma-positive T-cells decreased in clinical responders (P=0.027) after apheresis. In parallel, significantly lower levels of IFN-gamma-producing lymphocytes were detected in peripheral blood. IFN-gamma-positive cells in pretreatment biopsies completely disappeared or decreased in posttreatment biopsies sampled on week 7 in responders (P=0.027) and appeared to predict the maintenance of long-term remission or response after 12 months. CONCLUSIONS: Leukocyte apheresis is a novel and safe nonpharmacological adjunct therapy that may prove useful in steroid refractory or dependent patients when conventional drugs have failed. Down-regulation of IFN-gamma in mucosal biopsies and in peripheral leukocytes may be a predictive marker for sustained, long-term response.

Allergen challenge alters intracellular cytokine expression.

The pathophysiology of asthma is complex and engages cascades of events in the cytokine network. We, therefore, investigated the impact of bronchial allergen challenge in humans on the cytokine profile of circulating lymphocytes. Peripheral blood samples from 10 patients with allergic asthma were collected before and 24 h after allergen provocation. Patients who mounted a late-phase reaction were designated dual responders opposite to single responders. Whole blood cells were stimulated by mitogen and intracellular interleukin (IL)-4 and interferon (IFN)-gamma were detected by flow cytometry. The allergen challenge induced a decrease in IL-4+CD4+ cells in the patients (P = 0.05), and a significant decrease (P < 0.05) in IFN-gamma+CD4+ cells was noted in single, but not dual, responders. In addition, there was a significant difference (P < 0.01) with respect to the changes in the IFN-gamma+CD4+ cells comparing dual and single responders. No corresponding changes were observed in CD8+ cells. The data suggest a possible on-going traffic of IFN-gamma and IL-4+CD4+ lymphocytes into the bronchial mucosa in relation to an allergen challenge and generate the hypothesis that a difference exists between single and dual responders in this respect. Because the CD4+IFN-gamma-producing cells have the capacity to downregulate the T-helper type 2 response, a reduced capacity in this aspect might contribute to the pathophysiology in dual responders.

Virulence characteristics of Escherichia coli strains causing acute cystitis in young adults in Iran.

BACKGROUND: Escherichia coli strains that cause cystitis posses virulence properties that facilitate their colonisation and persistence in the bladder. In Iran, despite the high number of the urinary tract infections, very few studies has been done to determine the role of these virulence properties in the pathogenesis of E. coli cyctitis. PATIENTS AND METHODS: Eighty-seven strains of E. coli, isolated from young adults with cystitis in Shiraz, Iran, were examined for the expression of type 1 and P-fimbriae, mannose resistant haemagglutination, haemolysin production, aerobactin-mediated iron uptake, O:K serotypes, biochemical phenotypes (BPTs) and their antibiotic susceptibility patterns. RESULTS: Seventy-six percent of the strains expressed multiple virulence properties. There was a significant correlation between the presence of aerobactin and the expression of type 1 fimbriae. All P-fimbriated strains produced aerobactin with 50% of them also coexpressing haemolysin. Of the 29 different O:K serotypes identified, 42% belonged to serotypes not commonly found among European serotypes associated with UTI. Strains of O groups 4 and 6 expressed more virulence factors than the others. A high resistance against ampicillin, trimethoprim and cotrimoxasol was observed among the isolates with 53% of the isolates showing multiresistance to these three antibiotics. Certain BPTs were also found among O:K serotypes with some containing strains of the same virulence profile. CONCLUSION: We conclude that certain colonal groups of E. coli are commonly associated with cystitis in young adults in Iran with strains possessing a combination of aerobactin and type 1 fimbriae being the dominant ones and belonging to serotypes not commonly found in Europe. We also conclude that the multiple antibiotic resistant E. coli strains causing cyctitis are highly prevalent in this part of the country.

[Sanitary assessment of iodine levels in the environment and their impact on children's health]. / Gigienicheskaia otsenka soderzhaniia ioda v okruzhaiushchei srede i vliianie na zdorov'e detei.

The Irkutsk province and the Republic of Buryatia which are a part of the Baikal Region (Siberia) were studied for environmental iodine balance. The water and local foodstuffs were found to show low iodine levels (they being 0.2 to 6.9 micrograms/l). In children, iodine deficiency was detected in 60-87% of the total number examined. There was a relationship between of the severity of neurological symptoms, the onset of thyroid diseases, general morbidity, physical development, iodine levels in the body. It is concluded that iodine deficiency has a great impact on the development of the regional pathology in children.

Selective translocation of coliform bacteria adhering to caecal epithelium of rats during catabolic stress.

Adult conventional rats were starved for 48 h with or without haemorrhage at 24 h, and translocation of caecal coliforms to mesenteric lymph nodes (MLNs) was measured. Translocation was detected in three of 11 rats without haemorrhage, in 6 of 11 starved and sham-operated rats and in 12 of 22 rats after haemorrhage. In contrast, only one of 13 non-instrumented and fed control rats showed translocation. Translocation was associated with more coliforms adhering to caecal epithelium in rats. Coliform isolates from caecum, caecal epithelium and MLNs were characterised and grouped into different biochemical phenotypes (BPTs) by a biochemical fingerprinting method. Of 291 BPTs detected in the caecum of all rats, 108 were also found on caecal epithelium; 36 BPTs were detected in MLNs, of which 17 were not detected either in the caecum or on the caecal epithelium of the corresponding rats. One isolate from each of these 36 BPTs was selected and compared to the others. Four common (C) BPTs (i.e., C1-C4) were identified among them. Strains of C1 formed the majority of isolates from the caecum (79%), caecal epithelium (71%) and MLNs (91%). In contrast, C2-C4 had a significantly lower incidence both in the caecum and on the caecal epithelium, but not in the MLNs. These findings indicate that not all caecal coliforms adhere to the epithelium during catabolic stress and that for translocation to occur, other bacterial properties besides adhesion are needed. It is also concluded that coliforms with a low incidence in the caecum can translocate with the same efficiency as those with a high incidence.

Starvation increases the number of coliform bacteria in the caecum and induces bacterial adherence to caecal epithelium in rats.

OBJECTIVE: To investigate the impact of starvation for 24 and 48 h on the number of coliform bacteria in the caecal contents, on the mucosal adherence of coliform bacteria, and on bacterial translocation in rats. DESIGN: Open prospective study. SETTING: University departments of surgery and microbiology, Sweden. MATERIAL: 46 adult male Sprague-Dawley rats. INTERVENTIONS: 19 rats served as controls, and were fed until samples were taken. Six animals were starved for 24 h and another 15 for 48 h, with free access to water, and then anaesthetised before blood, mesenteric lymph nodes (MLN), caecum, and caecal contents were sampled. To verify bacterial translocation in this strain of rats, another six rats underwent controlled haemorrhage for 60 min to reduce the blood pressure to 55 mm Hg mean arterial pressure (MAP). These rats had free access to food and water before haemorrhage but were allowed only water until samples were taken 24 h after haemorrhage. MAIN OUTCOME MEASURES: Presence and number of coliform bacteria in samples taken from caecal contents, caecal epithelium, MLN, and blood. RESULTS: Starvation for 24 h increased the number of coliform bacteria (colony forming units (CFU)/g) in the caecal contents 25-fold (p < 0.05). Starvation for 48 h further increased the number by a factor of 100. The number of coliform bacteria that adhered to the caecal epithelium increased 3,000 times in rats that had been starved for 48 h (p < 0.001). There was no significant difference in translocation (as indicated by cultures from MLN) between rats that had been fed and those that had been starved for 48 h. In 4 of the 6 rats that were bled and then starved for 24 h there were signs of bacterial translocation, which was significantly more than the 1/19 in fed rats (p < 0.05). CONCLUSION: Starvation increases the number of bacteria in the caecal contents and increases bacterial adherence to the caecal epithelium. These changes may contribute to the previously reported increase in bacterial translocation in starved compared wit fed rats that were subjected to stress. The same changes in the gut were observed in animals subjected to haemorrhagic stress in addition to starvation, and in which bacterial translocation was evident.

Hyperosmotic glucose infusion during hemorrhage does not reduce bacterial translocation in 24 hour-starved rats.

Food deprivation 24 h before stress increases bacterial translocation in hemorrhage. Presently it tested whether hyperosmolality, induced by exogenous glucose infusion to improve plasma refill, prevents or reduces bacterial translocation after experimental hemorrhage in 24 h food-deprived rats. Rats were given an i.v. infusion of either 2 mL of 30% glucose (G) or the same volume of .9% NaCl (C) while simultaneously being submitted to a standardized 60 min hemorrhage period, of moderate or more severe hemorrhage. Blood was not reinfused. Despite development of marked hyperglycemia (p < .001, G vs. C) resulting in significantly greater reductions in packed cell volume (p < .001, G vs. C), bacterial translocation was detected similarly in both groups regardless of whether moderate (10/12-G, 9/12-C) or severe (15/19-G, 15/18-C) hemorrhage was inflicted. It was concluded that hyperglycemic hyperosmolality did not prevent bacterial translocation in these models of hemorrhagic stress in 24 h-starved rats.

[Epidemiological risks of tuberculous infection foci in patients discharging L forms of Mycobacterium tuberculosis]. / Epidemicheskaia opasnost' ochagov tuberkuleznoi infektsii s nalichiem lits, vydeliaiushchikh L-formy mikobakterii tuberkuleza.

It is shown that patients from dispensary follow-up groups II, III and VII who discharge M. Tuberculosis L-forms demonstrable after repeated (two) examinations are epidemiologically dangerous to surrounding people. Preventive measures in the families should be based on the duration of the contact with the carrier, social and household conditions, stability and frequency of L-forms isolation. Unstable L-forms are found reversible. In new cases of the above infection from the families at risk the disease runs with scarce symptoms, predominance of respiratory infiltration and solitary destructive lesions, slowly regressive inflammation.

[Prostaglandin-like inhibitors of prostaglandin-H-synthase]. / Prostaglandinopodobnye ingibitory prostaglandin-H-sintazy.

The effect of none prostaglandin-like cyclopentanone derivatives on the prostaglandin H synthase activity was studied. Seven substances proved to be inhibitors of the enzyme, some of the being similar to the well-known nonsteroid antiinflammatory drugs with respect to their inhibitory activity.

[2-component inhibition of prostaglandin H synthetase by nonsteroidal anti-inflammatory preparations]. / Dvukhkomponentnoe ingibirovanie prostaglandin-H-sintetazy nesteroidnymi protivovospalitel'nymi preparatami.

A combined effect on the irreversible inhibitor aspirin and fast reversible inhibitors ibuprofen, naproxen and sodium salicylate on prostaglandin-H-synthetase was studied on microsomal fractions from ram vesicular glands. The fast reversible inhibitors were shown to bind to prostaglandin-H-synthetase at the same site as aspirin and thereby to protect the enzyme against irreversible inactivation by aspirin.

[Gas chromatographic determination of amino acid configuration in the optically active stationary phase]. / Gazokhromatograficheskoe opredelenie konfiguratsii aminokislot na opticheski aktivnoi statsionarnoi faze.

The synthesis and physico-chemical properties of a novel optically active stationary phase--N-stearoyl-L-valyl-t-butylamide (I) applied for GLC separation of enantiomeric alpha-amino acids are described. The optical purity of the compound (I) is not less than 85%. The efficiency of the phase is shown on analyses of the configuration of amino acids in peptidolipids and glycopeptidolipids produced by the paraffin-oxidizing bacterium Mycobacterium paraffinicum.

[Nature of the interaction of voltaren and other pyrazolone and aniline derivatives with prostaglandin endoperoxide synthetase]. / O kharaktere vzaimodeistviia vol'tarena i nekotorykh proizvodnykh pirazolona i anilina s éndoperoksiprostaglandinsintetazoi.

A study was made of the nature and mechanism of interaction of voltaren, butadion, analgin, phenacetin and paracetamol with endoperoxide prostaglandin synthetase (PGH-synthetase) of sheep vesicular glands. Activity of the enzyme was measured by polarography with the aid of a Clark's electrode. Butadion and analgin reversibly inhibited PGH-synthetase at concentrations of the order of 10(-4) M, whereas voltaren at those of the order of 10(-6) M. As regards the mechanism of action, butadion and analgin are competitive inhibitors of PGH-synthetase in respect to arachidonic acid and uncompetitive inhibitors in respect to the electron donor adrenaline. Phenacetin administered at concentrations up to 4 X 10(-2) M did not inhibit PGH-synthetase, whereas paracetamol (10(-3)-10(-2) M) increased its catalytic activity, apparently due to the electron donor properties.

[Mechanism of ibuprofen and naproxen interaction with endoperoxide prostaglandin synthetase]. / O mekhanizme vzaimodeistviia ibuprofena i naproksena s éndoperoksidprostaglandinsintetazoi.

The authors studied the pattern and mechanism of ibuprophen and naproxen interaction with endoperoxideprostaglandin synthetase (PGH synthetase) of sheep vesicular glands. The enzymatic activity of PGH synthetase was determined polarographically with the aid of a Clark electrode. Ibuprophen and naproxen were found to inhibit completely PGH synthetase at concentrations of the order of 1 X 10(-5) M. As regards the mechanism of action both the drugs are competitive inhibitors of this enzyme with reference to arachidonic acid and incompetitive inhibitors with reference to adrenaline, an electron donor.

[Mechanisms of interaction of acetylsalicylic acid and indomethacin with endoperoxide prostaglandin synthetase]. / O mekhanizmakh vzaimodeistviia atsetilsalitsilovoi kisloty i indometatsina s éndoperoksidprostaglandinsintetazoi.

A study was made of the character and kinetics of interaction of acetylsalicylic acid and indomethacin with endoperoxide prostaglandin synthetase (PGH-synthetase) of sheep vesicular glands and human platelets. Enzymatic activity of PGH-synthetase was determined polarographically with the aid of Clark's electrodes. Acetylsalicylic acid was found to inhibit PGH-synthetase of sheep vesicular glands and human platelets at concentrations of the order of 1 x 10(-6) and 1 x 10(-4) M, whereas indomethacin at concentrations of 1 x 10(-6) and 1 x 10(-7) M, respectively. Acetylsalicylic acid inhibited PGH-synthetase from sheep vesicular glands and that from human platelets at an equal rate. Indomethacin inhibited the enzyme from sheep vesicular glands to a higher degree. Indomethacin reversibly interacted with PGH-synthetase. Meanwhile acetylsalicylic acid inhibited this enzyme irreversibly.