GH administration rescues fatty liver regeneration impairment by restoring GH/EGFR pathway deficiency.

GH pathway has been shown to play a major role in liver regeneration through the control of epidermal growth factor receptor (EGFR) activation. This pathway is down-regulated in nonalcoholic fatty liver disease. Because regeneration is known to be impaired in fatty livers, we wondered whether a deregulation of the GH/EGFR pathway could explain this deficiency. Hepatic EGFR expression and triglyceride levels were quantified in liver biopsies of 32 obese patients with different degrees of steatosis. We showed a significant inverse correlation between liver EGFR expression and the level of hepatic steatosis. GH/EGFR down-regulation was also demonstrated in 2 steatosis mouse models, a genetic (ob/ob) and a methionine and choline-deficient diet mouse model, in correlation with liver regeneration defect. ob/ob mice exhibited a more severe liver regeneration defect after partial hepatectomy (PH) than methionine and choline-deficient diet-fed mice, a difference that could be explained by a decrease in signal transducer and activator of transcription 3 phosphorylation 32 hours after PH. Having checked that GH deficiency accounted for the GH signaling pathway down-regulation in the liver of ob/ob mice, we showed that GH administration in these mice led to a partial rescue in hepatocyte proliferation after PH associated with a concomitant restoration of liver EGFR expression and signal transducer and activator of trnascription 3 activation. In conclusion, we propose that the GH/EGFR pathway down-regulation is a general mechanism responsible for liver regeneration deficiency associated with steatosis, which could be partially rescued by GH administration.

Program Note: Using UN process indicators to assess needs in emergency obstetric services: Gabon, Guinea-Bissau, and The Gambia.

PURPOSE: We report on assessments of the needs for emergency obstetric care in 3 West African countries. METHODS: All (or almost all) medical facilities were visited to determine whether there are sufficient facilities of adequate quality to manage the expected number of obstetric emergencies. RESULTS: Medical facilities able to provide emergency obstetric care were poorly distributed and often were unable to provide needed procedures. Too few obstetricians and other providers, lack of on-the-job training and supervision were among the challenges faced in these countries.

"Good obstetrics" revisited: too many evidence-based practices and devices are not used.

INTRODUCTION: As countries are designing and implementing strategies to address maternal and newborn mortality and morbidity (Millennium Development Goals 5 and 4), it appears that a large number of evidence-based obstetric practices are not used in many settings, and this is a major obstacle to the improvement of quality obstetric care. OBJECTIVES: To remind readers of the existing, relatively easy-to-implement, evidence-based interventions that are currently not being universally applied in obstetric care and, second, to foster research to expand the evidence base further for obstetric care practices and devices, especially those that could be used in resource-poor settings. METHODS: We review possible reasons why changes into practices are difficult to obtain, and we list the key evidence-based interventions known to effectively deal with the main obstetric complications, with supporting references and sources of documentation. We also list some promising interventions that require more research before being recommended. CONCLUSION: Professionals and health services managers have a crucial role in producing the best quality obstetric and neonatal care through implementing the listed evidence-based interventions and make them accessible to all pregnant women and their newborns without delay, even in poor settings. Reasons for which progress is slow should be addressed. One of these reasons being the lack of access to scientific knowledge from the part of professionals in developing countries, we give the key references and also websites which are freely accessible through the Internet. It is hoped that this paper will stimulate the discussion on the dissemination and use of good obstetric practices, and contribute to better maternal and newborn health.

Is vacuum extraction still known, taught and practiced? A worldwide KAP survey.

OBJECTIVE: Is vacuum extraction-the method of first choice for assisting vaginal delivery in case of prolonged labor-losing ground in the developing world? And if it is, why? The paper tries to answer these disturbing questions, and examine their consequences. METHODS: A rapid Knowledge-Attitude-Practice (KAP) survey was conducted during 2003-2004 on the question of assisted vaginal delivery (AVD) by the use of the vacuum extractor. Public health specialists and obstetricians from 121 developing countries were consulted about their knowledge of the method in their country, its reputation (i.e. their attitude) and its use (practice). RESULTS: Overall 48% of the respondent countries have confirmed knowledge, positive attitude, teaching and countrywide use of the method, while 37% said the method is known and used by only a limited number of specialists who do not teach it, and 15% admitted no knowledge and therefore no use. CONCLUSION: Given the evidence-based international recognition of the benefits of vacuum extraction (if practiced correctly and for appropriate indications), it is unjust to deprive women with prolonged labor (and their fetuses) of a simple intervention that can contribute to reducing life threatening complications. This unsophisticated worldwide survey, while not providing in-depth explanations, calls for rehabilitation of vacuum extraction in countries where it is disappearing and surgical extraction is not yet readily accessible to all women with prolonged labor.

Can the process indicators for emergency obstetric care assess the progress of maternal mortality reduction programs? An examination of UNFPA Projects 2000-2004.

BACKGROUND: In view of the disappointing progress made in the last 20 years in reducing maternal mortality in low-income countries and before going to scale in implementing the new evidence-based strategies, it is crucial to review and assess the progress made in pilot countries where maternal mortality reduction programs focused on emergency obstetric care. OBJECTIVE: To review the process indicators recommended for monitoring emergency obstetric care and their application in field situations, examining the conditions under which they can be used to assess the progress of maternal mortality reduction programs. METHODS: Five of the six UN recommended process indicators were monitored annually for 5 years in selected districts of Morocco, Mozambique, India and Nicaragua. Trends are presented and discussed. RESULTS: With specific variations due to different local situations in the four countries and in spite of variations in quality of data collection, all indicators showed a consistent positive trend, in response to the inputs of the programs. CONCLUSIONS: The UN process indicators for emergency obstetric care should continue to be promoted, but with two important conditions: (1) data collection is carefully checked for quality and coverage; (2) efforts are made to match process and outcome indicators (maternal and perinatal mortality, incidence of complications).

The cumulative occurrence of resistance mutations in the HIV-1 protease gene is associated with failure of salvage therapy with ritonavir and saquinavir in protease inhibitor-experienced patients.

Salvage therapy with ritonavir (RTV) and saquinavir (SQV) failed to achieve virological and immunological improvement in 24 HIV-infected patients who discontinued triple therapy with RTV or indinavir (IDV) because of failure or intolerance to treatment. Changes in the HIV-1 protease gene sequence were analyzed prospectively in 14 patients. No primary protease mutation was found prior to the use of protease inhibitors. After 7 months of treatment with IDV or RTV, primary resistance mutations at codons pol 46 and/or pol 82 were observed in 11 of 13 patients. After 16 weeks on RTV-SQV, novel primary mutations related to SQV emerged in 7 of 13 patients, together with an increase in the number of secondary resistance mutations. Our observations indicate that the cumulative occurrence of resistance mutations in the protease gene was associated with failure of antiretroviral therapy. The presence of mutations to a first protease inhibitor may represent a risk factor for the failure of a subsequent treatment with a second line protease inhibitor.

[Prevention of intestinal allograft rejection by anti-adhesion molecule antibodies in a mouse model]. / Prévention du rejet d'allogreffe intestinale par des anticorps antimolécules d'adhésion dans un modèle murin.

STUDY AIM: Small bowel transplantation is still hampered by a high morbidity and mortality linked to the heavy non specific immunosuppression which is required by the transplantation of this lymphoid organ. Adhesion molecules appear to be potential targets for specific immunosuppression. The aim of the study was to investigate the effect of a transitory administration of anti-LFA-1 or anti-alpha 4 monoclonal antibodies (mAb) in the prevention of rejection in a model of fetal small-bowel transplantation in mice. MATERIALS AND METHODS: The small bowel of C57BL/6 (H-2b) fetus (16 to 20 days of gestation) was transplanted into adult C3H/He mice (H-2k) or C57BL/6 recipient mice. Recipients were treated with a short course of either anti-LFA-1 mAb alone, either with anti-alpha 4 mAb alone, or with both mAb. Biopsies with histological study of the grafts were performed between post-operative day 5 and 60. A score of development and rejection was assigned to each sample. RESULTS: Normal intestinal development with no sign of rejection was observed in 24/28 syngenic grafts till post-operative day 45. In the absence of treatment, intense rejection was observed as soon as day 5 and all allogenic grafts were rejected (n = 22). In contrast, in anti-LFA-1 mAb treated mice, 18/20 allogenic grafts developed normally with minimal signs of rejection. In anti-alpha 4 treated mice, a transient protective effect on small bowel allograft survival was observed on day 7 but thereafter, all grafts were massively rejected within a few days (n = 18). The combination of both mAb didn't improve the survival of the grafts when compared to anti-LFA-1 mAb treated grafts (n = 10). CONCLUSION: These results demonstrate that a transitory administration of anti-LFA-1 mAb, but not of anti-alpha 4 mAb, is able to prolong significantly the survival of non vascularized small bowel fetal grafts in mice. Our results are promising for the possible use of the anti-LFA-1 mAb in clinical intestinal transplantation.

HIV-1 viral load, phenotype, and resistance in a subset of drug-naive participants from the Delta trial. The National Virology Groups. Delta Virology Working Group and Coordinating Committee.

BACKGROUND: The Delta trial showed that combination therapy (zidovudine plus didanosine and zidovudine plus zalcitabine) substantially lengthened life and reduced disease progression compared with zidovudine monotherapy. We did a nested virological study in three countries (France, the Netherlands, and the UK) to investigate changes in markers for viral load and antiretroviral-drug resistance during therapy. METHODS: 240 zidovudine-naive HIV-1-infected patients were randomly assigned zidovudine only (n = 87), zidovudine plus didanosine (n = 80), or zidovudine plus zalcitabine (n = 73). Viral load in peripheral-blood mononuclear cells and plasma was measured by quantitative culture. Plasma HIV-1 RNA was measured by reverse-transcriptase PCR amplification, and serum p24 antigen by ELISA. Resistance to antiretroviral drugs was measured phenotypically by culture and genotypically by detection and quantification of drug-related point mutations in the pol gene. Analyses were done by intention to treat. FINDINGS: The reduction in viral load was greatest 4-12 weeks after the start of therapy and was most pronounced in the combination-therapy study groups (median reductions of RNA at 4 weeks 1.58, 1.28, and 0.49 log10 copies/mL for zidovudine plus didanosine, zidovudine plus zalcitabine, and zidovudine only, respectively). RNA levels at 8 weeks were predictive of disease progression and death after allowance for baseline values. At 48 weeks, the proportion of participants with phenotypic zidovudine resistance was similar in all three groups: didanosine and zalcitabine resistance were rare; zidovudine genomic resistance correlated with phenotypic resistance (r = 0.54, p < 0.0001) and developed earlier in the combined-therapy groups. However, participants in the zidovudine monotherapy group had higher circulating loads of resistant virus than those in the combined-therapy groups. INTERPRETATION: Combined antiretroviral therapy was more efficient at lowering virus load than monotherapy. Although zidovudine resistance was common in monotherapy and combined-therapy groups, circulating concentrations of resistant virus were substantially lower in the combination groups, which is likely to be a result of the continued antiviral activity of didanosine or zalcitabine.

In vivo semen-associated pH neutralization of cervicovaginal secretions.

Physiological cervicovaginal acidity can partly inactivate human immunodeficiency virus (HIV). Basic semen components should be able to partially neutralize in vivo cervicovaginal pH. The goals of the study were to evaluate the relationship between cervicovaginal pH and presence of semen components in sexually active African women and to assess whether vaginal douching with water performed just after sexual intercourse could significantly reduce semen components and restore physiological cervicovaginal pH. Cervicovaginal secretion (CVS) from 56 heterosexual African women (19 to 45 years old), living in Bangui, Central African Republic, were evaluated for pH, semen components (prostatic acid phosphatase [PAP] and prostatic specific antigen [PSA]), cellularity, and hemoglobin at inclusion and after vaginal douching with 100 ml of water by using a bock. Before douching, semen components were found in 46 of 56 CVS (82%). The mean vaginal pH was 5.2 (range, 3.6 to 7.7), and concentrations of both PAP and PSA correlated positively and strongly with cervicovaginal pH (P < 0.001). After douching, semen components were found in 35 of 56 CVS (62%) (P = 0.03). Cervicovaginal PAP and PSA levels were significantly decreased (respectively, P < 0.0001 and P < 0.01; PAP, -72%; PSA, -87%), as was the total cell count (-60%; P < 0.0001). Furthermore, in CVS previously positive for both PAP and PSA, the mean vaginal pH was significantly decreased (6.5 versus 5.3, P < 0.01); no genital bleeding was observed. Frequent persistence of semen in CVS from heterosexually active African women leads to a shift from acidity to neutrality that could favor male to female HIV transmission. Vaginal douching provides significant elimination of semen after sexual intercourse; it should be considered for study as a supplementary means for the prevention of heterosexual HIV transmission.

Nutritional status of children in the Lao PDR.

The results of the first nationally representative survey of nutritional status of children in the Lao PDR, focusing on the assessment of protein-energy malnutrition are described. Among children under 5 years of age, the prevalence of stunting (children of short stature, below -2 Z-scores height-for-age) is 48 per cent, which is classified by WHO as a 'very high' prevalence, greater than the average of developing countries in the world and in South-East Asia. The prevalence of wasting (children too thin, below -2 Z-scores weight-for-height) is 10 per cent, also 'very high', and slightly greater than the average of South-East Asian children. The prevalence of children underweight (below -2 Z-scores weight-for-age) is 44 per cent, again 'very high' and significantly greater than the average of developing countries in the world and in South-East Asia. Significant differences are observed in the prevalence of both stunting and wasting when comparing subgroups of children: urban children are less stunted and wasted than rural children, children of the lowland majority less than children of ethnic minorities, and children whose mothers had completed primary education less than children whose mothers had never been to school. Girls are less malnourished than boys, but not significantly so. Similar prevalences of stunted and underweight children are noted when comparing with the results of a national survey made in the Lao PDR 10 years ago, although the sampling was not the same.

Rate of detection of human herpesvirus-6 at different stages of HIV infection.

In a cross-sectional study, human herpesvirus-6 (HHV-6) infection was analysed by means of polymerase chain reaction in peripheral blood mononuclear cells (PBMCs) and saliva from 125 HIV-seropositive subjects and 29 HIV-seronegative controls. HHV-6 was detected in saliva significantly more frequently in HIV-seronegative subjects than in HIV-seropositive subjects (p = 0.023), with no significant difference between HIV-seropositive subgroups. The HIV proviral copy number in PBMCs differed significantly according to HIV subgroup, as expected, but did not differ according to either the presence of HHV-6 or the number of HHV-6 copies in PBMCs. All the HHV-6 identified were variant B except for one variant A strain detected in saliva from a healthy subject. These results do not support the hypothesis that there is synergistic activation of HHV-6 infection in the course of HIV infection.

A prospective evaluation of clinical criteria and polymerase chain reaction assay of cerebrospinal fluid for the diagnosis of cytomegalovirus-related neurological diseases during AIDS.

OBJECTIVE: To study the predictive value of clinical criteria and polymerase chain reaction (PCR) assay of cerebrospinal fluid (CSF) for the diagnosis of cytomegalovirus (CMV)-related neurological disorders during AIDS. SETTING: Four infectious diseases departments in two tertiary referral teaching hospitals in Paris, France. DESIGN AND PARTICIPANTS: One-year prospective study involving 164 consecutive immunosuppressed HIV-seropositive patients undergoing lumbar puncture (LP). METHODS: A tentative diagnostic classification, based on strict operational criteria and PCR assay of CSF, was performed at the time of LP. At the end of the study, tentative diagnoses and PCR results were blindly and independently compared with the firm diagnoses, based on central nervous system histology, clinical outcome and/or viral culture of CSF. RESULTS: The tentative diagnosis showed CMV-related neurological disease in 38 patients, and CMV DNA was detected in 42. Among the 88 patients for whom a firm diagnosis was possible, 26 had a diagnosis of CMV-related neurological disease. The concordance between the tentative and firm diagnoses was 61%, with a kappa index of 0.40. In contrast, the sensitivity and specificity of PCR were respectively 92 and 94%, with positive and negative predictive values of 86 and 97%. The presence of CMV DNA in CSF was associated with an increased risk of death (P < 0.0001). CONCLUSIONS: Unlike clinical criteria, PCR detection of viral DNA in CSF can be used reliably for antemortem diagnosis of CMV-related neurological disease, a frequent complication of AIDS in this study. This rapid method should make a major impact on the management of these patients.

The influence of socio-biological factors on perinatal mortality in a rural area of Bangladesh.

"The present study considers data on all pregnancies that ended in a stillbirth or live birth in a rural area of Bangladesh during the years 1982 to 1984. It considers the relationships of both biological and socio-economic factors to perinatal mortality....[Results show a] lack of association with any measure of socio-economic status.... Our study has confirmed that survival of the perinatal period is separately related to both maternal age and primiparity. Once maternal age is taken into account, high parity shows no evidence of decreasing survival chances."

The Lao People's Democratic Republic: maternal mortality and female mortality: determining causes of deaths.

A sample of 380 female deaths in the age group 15-49 years from 16 provinces of the Lao People's Democratic Republic were analyzed to determine the most likely cause of death. 127 deaths were classified as maternal, 28% occurred during pregnancy and the remaining 72% within six weeks of the termination of pregnancy. Almost three quarters of all maternal deaths were directly related to obstetrical complications during pregnancy or childbirth. Many of these deaths could probably have been avoided, if appropriate obstetric care had been available. The level of attention to problems related to maternity and childbirth needs to be raised at all responsible levels of the health service system. This must start at the health facility where attending nurses and midwives should be oriented towards pregnancy-related problems and early detection of high-risk women, with appropriate supervisory support. District and national administrations should also focus more on maternity services within their Primary Health Care programme.

PIP: During April-August 1993 a study was conducted with the aim of ascertaining the causes and determinants of maternal deaths in Laos. The findings are based on 380 cases identified among women 15-49 years old for 16 out of 17 provinces. 33.4% of deaths (127 cases) were identified by verbal autopsy as pregnancy related. 72% of deaths occurred postnatally, and almost 40% were due to postpartum hemorrhage. The majority of deaths were to poor women and occurred in rural areas. Almost 75% of deaths were related to obstetrical complications during pregnancy or childbirth. 26.0% of deaths were due to a retained placenta and postpartum hemorrhage, 11.0% were due to induced abortion, and 7.1% were due to uterine inertia and postpartum hemorrhage. 5.5% had hemorrhage during the pregnancy, and 5.5% had a uterine rupture. 6.3% died of complications from spontaneous abortion. 7.1% died of infection. Among deaths at home and home deliveries, 71% were poor, 55% well-off, 70% rural, and 50% urban. Deaths at home after a hospital delivery were to 10% of poor women, 10% of well-off women, 10% of rural women, and 14% of urban women. 14% of poor women, 28% of well-off women, 16% of rural women, and 29% of urban women died in a hospital. Deaths on the way to the hospital involved 3% of poor women and 3% of rural women.

Socio-cultural and economic determinants of contraceptive use in the Lao People's Democratic Republic.

PIP: There is a lack of detailed information about population issues in the Lao People's Democratic Republic. Available estimates are based upon the results of the most recent national census, taken in 1985, and a multi-round survey of a subsample of the population conducted during 1988-91. No contraceptive prevalence survey has ever been undertaken on a large scale. It is clear, however, that with a total fertility rate of 6.7 and an annual population growth rate of 2.9%, fertility in the country is among the highest in the world. Despite resource limitations in the country and the already rapid population growth rate, however, the Lao government has a pronatalist population policy supporting birth spacing, but not fertility limitation. In an attempt to explore the demand for contraceptive services, this article presents the results of household surveys of 4154 currently married women of mean age 30.4 years and their husbands about their actual and ideal family size, their knowledge of contraceptive methods and sources of supplies, and their current and potential use of contraception. The researchers considered the following six indicators to analyze the sociocultural and economic determinants of contraception: place of residence, ethnic group, perception of economic status by the interviewer, years spent at school, possession of items of communication with the modern world, and personal experience. The distribution of these factors is examined with regard to knowledge of the fecund period during the menstrual cycle, knowledge of various contraceptive methods and their source of supply, ideal family size and composition, demand for limitation or spacing of births, ever- and current use of contraception, reasons for non-use or for stopping use, satisfaction with the currently used method, and readiness to pay for contraception.^ieng

Measles in rural Bangladesh: issues of validation and age distribution.

In the Third World, scientists have described thoroughly the pattern of measles in Africa. In Asia, however, the epidemiology of measles has been poorly described. In 1989, a measles surveillance system was initiated in Matlab, rural Bangladesh in order to monitor measles incidence in the area. The population (100,000), which has relatively low immunization coverage, has an excellent demographic surveillance system which allows accurate follow-up. The system works through trained community health workers who visit all households every fortnight and report possible cases of measles. Medical doctors review a proportion of index cases and cases in infants soon after the appearance of the rash. Of the 4673 cases reported in all age groups, 18% were visited by medics. Confirmation of diagnosis was related to the age at onset and overreporting by community health workers is documented. The incidence of measles was estimated at 43% of children < 5 years old. Of cases < 5 years of age, 14% occurred below the age at vaccination (incidence rate = 5.5%). A strong seasonal pattern is reported. Case-fatality rates are low. This is the first report which shows the effect of age on reliability of reported measles. It shows the misclassification likely to occur when reporting measles in large-scale surveys, particularly in infants. It also shows that the pattern of measles in this community resembles the pattern reported for African communities and calls for a review of immunization strategies with vaccination below 9 months of age.

Introducing the low-dose pill to Bangladesh; issues of continuation and failure.

In response to government plans to introduce a low-dose pill to the national family planning program of Bangladesh, a comparison of the performance of low-dose and standard-dose pills among a rural Bangladeshi population was conducted. Continuation rates were found to be better among users of the low-dose pill and there was no evidence that failure rates were higher. The relative risk (standard-dose vs. low-dose) over the first 30 months following adoption was 1.25 for first method continuation, and 1.29 for extended use failure. This paper, thus, provides evidence that low-dose pills may be a suitable method of contraception for rural Bangladeshi women.

Gender and age differentials in risk factors for childhood malnutrition in Bangladesh.

A case-control study of risk factors of clinical marasmus was undertaken to determine which factors differed according to gender and age groups. Case patients were children whose mid-upper arm circumference measured less than 110 mm and control subjects were children matched for age and sex with an arm circumference more than 120 mm. Between June 1988 and June 1989, 164 such pairs of children aged 1 to 4 years were studied. The effect of various demographic, socioeconomic, environmental, and health factors was investigated in a multivariate analysis using conditional logistic regression. Results showed an increased risk of marasmus among children with siblings under 5 years old. This increased risk was observed irrespective of gender or age. Children who consumed formula foods also had an increased risk of marasmus. Again, this elevated risk was maintained for boys and girls. Overall, higher maternal education was associated with a reduced risk of marasmus; however, this was only statistically significant for boys and for children 18 months or older. Religion was also associated with marasmus but only in older children (> or = 18 months). These results indicate that better strategic planning is necessary to formulate effective interventions to reduce severe malnutrition, particularly in societies where strong age- and sex-preferential behavior exists.

PIP: Between June 1988 and June 1989, a study of 164 case-control pairs, 1-4 years mold, in the Maternal and Child Health-Family (MCH-FP) area in the Matlab of Bangladesh was conducted to examine risk factors of clinical marasmus within gender and age groups. 73% of marasmus cases were females 12-23 months old. For all the children, presence of siblings younger than 5 years old (odds ratio [OR] = 2.84; p .001), maternal education (OR = 0.29 for = or 5 years; p .001 for the trend), and ingestion of formula food (OR = 18.4; p .001) were significant risk factors for marasmus. Religion bordered on significance (OR = 0.49 for Hindu; p = .06). Both boys and girls faced an increased risk of marasmus if they had a sibling younger than 5 years old living in the same household (OR = 2.85; p = .05 and OR = 3.07; p .001, respectively). They both were also at increased risk of marasmus if they consumed formula (OR = 12.4; p = .01 and OR = 25.7; p .001). Boys were significantly less likely to develop marasmus if their mothers had any education (OR = 0.51 for 5 years and 0.12 for = 5 years; p .001). Yet, maternal education had only a weak effect on reducing the risk of developing marasmus in girls. Younger (18 months) and older children were both likely to develop marasmus if they had a sibling younger than 5 years old at home (OR = 2.37 and 3.27; p = .01 and .005, respectively). The risk of marasmus was much lower in older children if they had educated mothers and if they lived in Hindu families (OR = 0.2 for = or 5 years education and 1.19; p = .007 and .01, respectively). These findings suggest that the free services of the MCH program may not reach the disadvantaged due to age and sex biases and that maternal education does not benefit the nutritional status of the most vulnerable age group to marasmus, the very young.