Oral immune regulation using colitis extracted proteins for treatment of Crohn＇s disease： Results of a phase I clinical trial

AIM: To evaluate safety and possible efficacy of induction of oral immune regulation using colitis extracted proteins(CEP) in Crohn‘s disease (CD) subjects.METHODS: Ten CDs were treated orally with autologous CEP thrice weekly for 16 wk. Subjects were monitored for CDAI and IBDQ. Immune modulatory effect was assessed by T-lymphocyte FACS analysis, CEP-specific IFNγ ELISPOT assay and cytokine levels.RESULTS: Induction of oral immune regulation significantly ameliorated disease activity. All (10/10) subjects had clinical response (CDAI≤70) and 7/10 achieved clinical remission (CDAI≤150). Significant increase in mean IBDQ score was noted (134±9vs 164±12). No treatment-related adverse events were noted. High levels of CEP-specific IFNγ spot forming colonies were detected in five subjects prior to treatment and in all five, a marked decrease was observed. The CD4+/CDS+ lymphocyte ratio and peripheral NKT cell numbers increased significantly, in 7/10 and in 5/10 subjects, respectively. Significant increase in serum IL-10 and IL-4 levels was observed in 7/10 subjects during treatment period.CONCLUSION: Immune regulation via oral administration of CEP is a safe and possibly effective treatment for subjects with moderate CD and may provide means of antigen-specific immune modulation.     

Is it time to reassess the categorization of disease burdens in low-income countries?

The classification of disease burdens is an important topic that receives little attention or debate. One common classification scheme, the broad cause grouping, is based on etiology and health transition theory and is mainly concerned with distinguishing communicable from noncommunicable diseases. This may be of limited utility to policymakers and planners. We propose a broad care needs framework to complement the broad cause grouping. This alternative scheme may be of equal or greater value to planners. We apply these schemes to disability-adjusted life year estimates for 2000 and to mortality data from Tanzania. The results suggest that a broad care needs approach could shift the priorities of health planners and policymakers and deserves further evaluation.     

Pharmacokinetics of First-Line Tuberculosis Drugs in Tanzanian Patients

East Africa has a high tuberculosis (TB) incidence and mortality, yet there are very limited data on exposure to TB drugs in patients from this region. We therefore determined the pharmacokinetic characteristics of first-line TB drugs in Tanzanian patients using intensive pharmacokinetic sampling. In 20 adult TB patients, plasma concentrations were determined just before and at 1, 2, 3, 4, 6, 8, 10, and 24 h after observed drug intake with food to estimate the areas under the curve from 0 to 24 h (AUC_0–24) and peak plasma concentrations (C_max) of isoniazid, rifampin, pyrazinamide, and ethambutol. Acetylator status for isoniazid was assessed phenotypically using the isoniazid elimination half-life and the acetylisoniazid/isoniazid metabolic ratio at 3 h postdose. The geometric mean AUC_0–24s were as follows: isoniazid, 11.0 h · mg/liter; rifampin, 39.9 h · mg/liter; pyrazinamide, 344 h · mg/liter; and ethambutol, 20.2 h · mg/liter. The C_max was below the reference range for isoniazid in 10/19 patients and for rifampin in 7/20 patients. In none of the patients were the C_maxs for pyrazinamide and ethambutol below the reference range. Elimination half-life and metabolic ratio of isoniazid gave discordant phenotyping results in only 2/19 patients. A substantial proportion of patients had an isoniazid and/or rifampin C_max below the reference range. Intake of TB drugs with food may partly explain these low drug levels, but such a drug intake reflects common practice. The finding of low TB drug concentrations is concerning because low concentrations have been associated with worse treatment outcome in several other studies.     

Establishment of a GM-CSF-dependent megakaryoblastic cell line with the potential to differentiate into an eosinophilic lineage in response to retinoic acids

We recently established a human granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent cell line (HML) from colony-constituent cells grown by peripheral blood cells of a patient with acute megakaryoblastic leukaemia. The HML cells possessed megakaryocytic features, as determined by cytochemical, electron microscopic and flow cytometric analysis. In the present study we examined the effects of retinoic acid (RA) on the development of HML cells. All- trans -RA, 13- cis -RA and 9- cis -RA at 10⁻⁸ mol/l to 10⁻⁵ mol/l inhibited the GM-CSF-dependent cell growth. Some of the RA-treated cells contained prominent azurophilic granules and were positive for peroxidase. They also reacted with Biebrich scarlet, Luxol fast blue and a monoclonal antibody against eosinophil peroxidase. In addition, exposure to RA increased the frequency and the intensity of major basic protein-positive cells. However, eosinophil-derived neurotoxin and eosinophil cationic protein were not detected or were only detected at a low level in the lysates of the HML cells treated with RA. Although IL-5 alone could not stimulate cell growth, the addition of IL-5 to the cultures containing stem cell factor + all- trans -RA was required for the expression of the eosinophilic phenotype. These results suggest that the HML cell line is a megakaryoblastic cell line with the potential to differentiate into the eosinophilic lineage. HML cells may be a useful model for elucidating the eosinophilic differentiation programme.     

Antioxidant therapy for chronic hepatitis C after failure of interferon: Results of phase Ⅱ randomized, double-blind placebo controlled clinical trial

AIM: To assess the safety and efficacy of antioxidant therapy for patients with chronic hepatitis C virus (HCV) infection. METHODS: One hundred chronic HCV infection patients failed in interferon treatment were enrolled and randomly assigned to receive combined intravenous and oral antioxidants or placebo, or oral treatment alone. Primary end points were liver enzymes, HCV-RNA levels and histology. RESULTS: Combined oral and intravenous antioxidant therapy was associated with a significant decline in ALT levels in 52% of patients who received antioxidant therapy vs 20% of patients who received placebo (P = 0.05). Histology activity index (HAI) score at the end of treatment was reduced in 48% of patients who received antioxidant therapy vs 26% of patients who received placebo (P = 0.21). HCV-RNA levels decreased by 1-log or more in 28% of patients who received antioxidant therapy vs 12% who received placebo (P = NS). In part Ⅱ of the trial, oral administration of antioxidants was not associated with significant alterations in any of the end points. CONCLUSION: Antioxidant therapy has a mild beneficial effect on the inflammatory response of chronic HCV infection patients who are non-responders to interferon. Combined antiviral and antioxidant therapy may be beneficial for these patients.     

The impact of the HIV epidemic on tuberculosis transmission in Tanzania

OBJECTIVE: To assess the impact of the HIV epidemic on tuberculosis transmission in Tanzania by estimating the trend in annual risk of tuberculosis infection (ARTI) over the period 1983-2003. DESIGN: Tuberculin survey among school children aged 6-14 years, randomly selected by cluster sampling. METHODS: Primary outcome was the ARTI among children without a BCG vaccination scar. To obtain time trends, data were reanalysed from three previous surveys carried out at intervals of 5 years since 1983, using identical methods and definitions. RESULTS: Of 96,226 children included in the analysis (74% of those enrolled), 10,239 (11%) had no BCG scar. The ARTI was 0.68% (95% confidence interval 0.55-0.81). Despite a doubling of notification rates of smear-positive tuberculosis since 1983, this represents an average annual decline since the first survey of 2.7% (P < 0.001). The declining trend in ARTI was observed in 17 of 20 regions, with no association between this trend and region-specific prevalence of HIV infection among patients with tuberculosis (P = 0.575). A similar decline in ARTI was observed among children with a BCG scar and for various ways of estimating the prevalence of tuberculosis infection from the distribution of skin test reactions. CONCLUSION: Despite substantial increases in tuberculosis incidence, the overall population-level effect of the HIV epidemic on tuberculosis transmission in Tanzania has been limited. This suggests that in the presence of a strong control programme, the HIV epidemic has limited impact on tuberculosis transmission.     

Thrombopoietin augments stem cell factor-dependent growth of human mast cells from bone marrow multipotential hematopoietic progenitors.

The effects of thrombopoietin (TPO) and/or stem cell factor (SCF) on the development of human mast cells from CD34(+) bone marrow (BM) cells were investigated using a serum-deprived liquid culture system. Mast cells were identified by measurement of intracellular histamine content, immunocytochemical staining, and flow cytometric analysis. Whereas SCF alone generated only a small number of tryptase+ cells, the addition of TPO to the culture containing SCF resulted in an apparent production of mast cells from 3 weeks until at least 15 weeks. Some of the cells reacted with an antichymase monoclonal antibody as well. Based on the effects of growth factor(s) on a later phase of the mast cell growth, TPO may stimulate an early stage of mast cell development in combination with SCF, whereas subsequent growth seems to be supported by SCF alone. Single-cell culture studies indicated that the CD34(+)CD38(-)c-kit+ cells and CD34(+)CD38(+)c-kit+ cells were responsible for the SCF + TPO-dependent mast cell production. Two-step culture assays clearly showed that mast cells originated from multilineage colony-forming cells that had potential to differentiate into neutrophil/mast cell lineages, neutrophil/macrophage/mast cell lineages, or neutrophil/macrophage/mast cell/erythroid lineages. These results suggest that TPO plays an important role in the development of human mast cells from CD34(+) BM cells in concert with SCF, and provide direct evidence of the differentiation into the mast cell lineage of human multipotential BM-derived progenitors.     

Mobile phones as a health communication tool to improve skilled attendance at delivery in Zanzibar: a cluster-randomised controlled trial

Please cite this paper as: Lund S, Hemed M, Nielsen B, Said A, Said K, Makungu M, Rasch V. Mobile phones as a health communication tool to improve skilled attendance at delivery in Zanzibar: a cluster-randomised controlled trial. BJOG 2012;119:1256-1264. Objective To examine the association between a mobile phone intervention and skilled delivery attendance in a resource-limited setting. Design Pragmatic cluster-randomised controlled trial with primary healthcare facilities as the unit of randomisation. Setting Primary healthcare facilities in Zanzibar. Population Two thousand, five hundred and fifty pregnant women (1311 interventions and 1239 controls) who attended antenatal care at one of the selected primary healthcare facilities were included at their first antenatal care visit and followed until 42?days after delivery. All pregnant women were eligible for study participation. Methods Twenty-four primary healthcare facilities in six districts in Zanzibar were allocated by simple randomisation to either mobile phone intervention (n?=?12) or standard care (n?=?12). The intervention consisted of a short messaging service (SMS) and mobile phone voucher component. Main outcome measures Skilled delivery attendance. Results The mobile phone intervention was associated with an increase in skilled delivery attendance: 60% of the women in the intervention group versus 47% in the control group delivered with skilled attendance. The intervention produced a significant increase in skilled delivery attendance amongst urban women (odds ratio, 5.73; 95% confidence interval, 1.51-21.81), but did not reach rural women. Conclusions The mobile phone intervention significantly increased skilled delivery attendance amongst women of urban residence. Mobile phone solutions may contribute to the saving of lives of women and their newborns and the achievement of Millennium Development Goals 4 and 5, and should be considered by maternal and child health policy makers in developing countries.     

Oral immune regulation using colitis extracted proteins for treatment of Crohn''s disease: Results of a phase Ⅰ clinical trial

AIM: To evaluate safety and possible efficacy of induction of oral immune regulation using colitis extracted proteins (CEP) in Crohn's disease (CD) subjects. METHODS: Ten CDs were treated orally with autologous CEP thrice weekly for 16 wk. Subjects were monitored for CDAI and IBDQ. Immune modulatory effect was assessed by T-lymphocyte FACS analysis, CEP-specific IFNγ ELISPOT assay and cytokine levels. RESULTS: Induction of oral immune regulation significantly ameliorated disease activity. All (10/10) subjects had clinical response (CDAI ≤ 70) and 7/10 achieved clinical remission (CDAI ≤ 150). Significant increase in mean IBDQ score was noted (134±9 vs 164±12). No treatment-related adverse events were noted. High levels of CEP-specific IFNγ spot forming colonies were detected in five subjects prior to treatment and in all five, a marked decrease was observed. The CD4+/CD8+ lymphocyte ratio and peripheral NKT cell numbers increased significantly, in 7/10 and in 5/10 subjects, respectively. Significant increase in serum IL-10 and IL-4 levels was observed in 7/10 subjects during treatment period.CONCLUSION: Immune regulation via oral administration of CEP is a safe and possibly effective treatment for subjects with moderate CD and may provide means of antigen-specific immune modulation.