Preclinical modeling of EGFR-specific antibody resistance: oncogenic and immune-associated escape mechanisms.

To define the molecular basis of secondary resistance to epidermal growth factor receptor (EGFR)-specific antibodies is crucial to increase clinical benefit in patients. The limited access to posttreatment tumor samples constitutes the major barrier to conduct these studies, representing preclinical experimentation as a useful alternative. Anti-EGFR antibody-based therapy has been reported to mediate tumor regression by interrupting oncogenic signals and, more recently, by inducing antitumor immunological responses. However, resistance models have been focused only on tumor escape associated with EGFR blockade, whereas studies describing immune-associated escape mechanisms have not been reported thus far. To address this idea, we modeled resistance induction in D122 metastasis-bearing C57BL/6 mice treated with 7A7 (an anti-murine EGFR antibody). Similarly to patients receiving EGFR-specific antibodies, 7A7 resistance promotion represents an important drawback to successful therapy. Characterization of primary cultures derived from metastasis in 7A7-treated mice revealed a high frequency of tumor variants resistant to in vivo and in vitro antibody treatment. We showed, for the first time, the convergence of alterations in oncogenic and immunological pathways in 7A7-resistant variants. To identify key molecules behind resistance, seven 7A7-resistant variants were screened. HER3 overexpression and PTEN deficiency leading to hyperactivation of protumoral downstream signaling were found in these variants as a consequence of 7A7-mediated EGFR inhibition. Concomitantly, we found a high percentage of resistant variants carrying abnormalities in the constitutive and/or interferon gamma (IFN-γ)-inducible major histocompatibility complex I (MHC-I) expression. A significant decrease in mRNA levels for MHC-I heavy chains, ß2-microglogulin and antigen processing machinery genes as well as transcriptional alterations in IFN-γ pathway components were identified as the main mechanisms underlying MHC-I expression defects in 7A7-resistant variants. Notably, these defects have not been previously associated with EGFR-specific antibody resistance, providing novel immunological escape mechanisms. This study has strong implications for the development of new combination strategies to overcome anti-EGFR antibodies refractoriness.

Body weight loss by very-low-calorie diet program improves small artery reactive hyperemia in severely obese patients.

BACKGROUND: Endothelial dysfunction is a major underlying mechanism for the elevated cardiovascular risk associated with increased body weight. We aimed to assess the impact of weight loss induced by an intensive very-low-calorie diet (VLCD) on arterial wall function in severely obese patients (SOP). METHODS: Thirty-four SOP were admitted to the metabolic ward of the hospital for a 3-week period. A VLCD characterized by a liquid diet providing 800 kcal/day was administered. The small artery reactivity to postischemic hyperemia index (saRHI), a surrogate marker of endothelial function, was assessed before and 1 week after hospital discharge. Anthropometry and biochemical parameters were also measured. Obese and non-obese age- and gender-matched groups were recruited for baseline comparisons. RESULTS: SOP had significantly lower saRHI compared with obese and non-obese individuals. SaRHI significantly increased after the intervention in SOP (1.595 ± 0.236 vs. 1.737 ± 0.417, p = 0.015). A significant improvement in glucose (p = 0.026), systolic blood pressure (p = 0.049), LDLc (p < 0.001), and inflammatory parameters was observed. Body weight loss was associated with a higher saRHI (r = -0.385, p = 0.033), and it was the main determinant of saRHI variation independently of confounders (ß -0.049, IC 95 % -0.091-0.008, p = 0.021). CONCLUSIONS: Weight loss induced by a VLCD in SOP improved small artery reactivity, and it was associated with the amelioration of metabolic and inflammation markers. Endothelial dysfunction may be softened by body weight loss interventions and useful in the management of cardiovascular risk factors in SOP.

Impact of simultaneous pancreas-kidney transplantation: patients' perspectives.

BACKGROUND: Few qualitative studies of simultaneous pancreas-kidney transplantation (SPK Tx) have been published. The aims of this study were to explore from the perspective of patients, the experience of living with diabetes mellitus type 1 (T1DM), suffering from complications, and undergoing SPK Tx with good outcome; and to determine the impact of SPK Tx on patients and their social and cultural environment. METHODS: We performed a focused ethnographic study. Twenty patients were interviewed. Data were analyzed using content analysis and constant comparison following the method proposed by Miles and Huberman. RESULTS: A functioning SPK Tx allowed renal replacement therapy and insulin to be discontinued. To describe their new situation, patients used words and phrases such as "miracle", "being reborn" or "coming back to life". Although the complications of T1DM, its surgery and treatment, and associated psychological problems did not disappear after SPK Tx, these were minimized when compared with the pretransplantation situation. CONCLUSION: For patients, SPK Tx represents a recovery of their health and autonomy despite remaining problems associated with the complications of T1DM and SPK Tx. The understanding of patients' existential framework and their experience of disease are key factors for planning new intervention and improvement strategies.

Passive measles immunity in a Nigerian tertiary health care facility: the influence of human immunodeficiency virus infection on measles antibody levels in mother-infant pairs at birth.

BACKGROUND: Infants are protected from measles infection by maternal measles antibodies (MMA). The level of these MMA at birth in newborn children depends on the levels in their mother and the extent of placental transfer. We investigated maternal HIV infection as a predictor of levels of MMA in mother-infant pairs in Maiduguri. METHODS: A total of 180 mother-infant pairs were tested for MMA between 15th January and 29th March 2010. Levels of MMA were measured using enzyme linked immunosorbent assay (ELISA) test. RESULTS: Fifteen (8.3%) mothers were found with HIV infection and all were on antiretroviral treatment for HIV, and all of them had protective MMA. Of these mothers with HIV infection, only one (0.6%) of their newborn infants had un-protective level of maternal measles antibody. Maternal measles antibodies in mother-infant pairs had significant correlation (p = 0.005) for both HIV-infected and HIV-uninfected groups. The mean MMA of the newborn children was lower in infants of HIV-infected mothers than in HIV-uninfected mothers (p = 0.37). Linear regression analysis showed no significant association between maternal HIV infection and MMA in mother-infant pairs (p = 0.72) for mothers and (p = 0.37) for newborn infants. CONCLUSION: Maternal HIV infection was not associated with significantly reduced MMA in mother-infant pairs, as high protective levels were evident in both mother-infant pairs at birth.

Clinical staging of HIV infection as a surrogate for CD4 count in HIV-infected children.

BACKGROUND: Human immunodeficiency virus (HIV) infection is a major cause of infant and childhood mortality and morbidity; without treatment about 50% of them will succumb to HIV/AIDS before the age of two years. OBJECTIVE: to evaluate the usefulness of clinical manifestations of HIV infection as a surrogate for CD4 counts in antiretroviral-naive HIV-infected children. METHODS: newly diagnosed HIV-infected children, antiretroviral-naive attending a paediatric infectious diseases unit were enrolled. The clinical manifesta-tions, age, sex, and WHO clinical stage of each patient were determined. CD4 count and CD4% were estimated at presentation and correlated with various clinical manifestations of HIV disease. RESULTS: the study population consisted of 126 children, aged four months to 14 years with a mean of 3.2 ± 2.7 years and a male to female ratio of 1.2:1. Eighty-one percent of the children acquired HIV infection through mother-to-child transmission (MTCT). The CD4% was higher in infants (p < 0.000) and lower in children over five years of age. Eighty-six percent of them in stage 4 were children less than 24 months of age. CD4% showed a modest correlation with WHO paediatric clinical staging (r=0.62, p=0.002). Patients with lymphadenopathy (stage 1) had a high absolute CD4 count whereas patients with failure to thrive had a relatively low absolute CD4 count. CONCLUSION: WHO Paediatric clinical staging for HIV infection correlates with CD4% and can be used as a surrogate to CD4. CD4 count and CD4% vary with age and complications of the disease.

[The monitoring of dialysis dose by ionic dialysance-based Kt reveals less dialysis adequacy than the Kt/V(UREA)-based measurement in critically ill patients with acute renal failure]. / La medida de la dosis de diálisis mediante Kt por dialisancia iónica revela una menor adecuación que la medida por Kt/V(UREA) en la insificiencia renal aguda de pacientes críticos.

INTRODUCTION: Measurement of dialysis dose by methods based on urea kinetics (Kt/VUREA) are hardly applicable to critical ill patients with acute renal failure (ARF). However, it is the base of the ADQI consensus recommendation for the target minimum dose. OBJECTIVE: To evaluate the usefulness of the real-time measurement of delivered dialysis dose (Kt) by means of the ionic dialysance (KtID) in the critically ill patient and to compare adequacy of dialysis dose between KtID and traditional Kt/V(UREA). MATERIAL AND METHODS: Prospective observational study in 17 critically ill patients with ARF requiring acute hemodialysis with a predefined prescription for the study (51 measures). RESULTS: The mean delivered Kt/V(UREA) was 1.19 +/- 0.14, with 59% of the sessions with values equal or above the ADQI recommendation. On the contrary, the mean KtID values obtained was 37.6 +/- 1 l, with only 29.4% of the sessions being equal or greater than the recommended values. CONCLUSIONS: Dialysis dose monitoring by means of KtID reveals a lower degree of adequacy as compared to the traditional Kt/V(UREA) method. The dynamic character of KtID monitoring can allow the adaptation of each dialysis session ("K" and/or "t") in order to achieve the recommended dose.

La medida de la dosis de diálisis mediante Kt por dialisancia iónica revela una menor adecuación que la medida por Kt/VUREA en la insuficiencia renal agudade pacientes críticos / Dialysis dose measurements of Kt by ionic dialisance reveals less dialysis adequacy than the Kt/VUREA-based method in critically ill patients with acute renal failure

Introducción: La medida de la dosis de hemodiálisis basada en la cinética de la urea (Kt/VUREA) adolece de problemas de aplicabilidad en el paciente crítico con insuficiencia renal aguda (IRA). No obstante, las recomendaciones de consenso sobre la dosis se basan en el Kt/VUREA. Objetivo: Evaluarla utilidad de la medida en tiempo real de la dosis de diálisis suministrada (Kt) mediante dialisancia iónica (KtDI)en el paciente crítico y el grado de adecuación de la dosis en comparación con la medida estándar del Kt/VUREA. Materialy métodos: Estudio prospectivo observacional de medida de dosis en 17 pacientes críticos con IRA sometidos a3 sesiones de diálisis intermitente con prescripción predefinida para este estudio (en total 51 medidas). Resultados: El Kt/VUREA medio suministrado por sesión fue de 1,19 ±0,14, con un 59% de sesiones consideradas adecuadas por lo recomendado por la ADQI. Por el contrario, la media de KtDI obtenida fue de 37,6 ± 1 l, con sólo un 29,4% igual o por encima del valor mínimo recomendado. Conclusiones: La monitorización de la dosis mediante KtDI revela un menor grado de adecuación en comparación con el Kt/VUREA. El carácter dinámico de la medida de KtDI puede permitirla adaptación de cada sesión de diálisis («K» y/o «t») con el fin de lograr el objetivo de dosis mínima (AU)

Introduction: Measurement of dialysis dose by methods based on urea kinetics (Kt/VUREA) are hardly applicable to critical ill patients with acute renal failure (ARF). However, it is the base of the ADQI consensus recommendation for the target minimum dose. Objetive: To evaluate the usefulness of the real-time measurement of delivered dialysis dose (Kt) by means of the ionic dialysance (KtID) in the critically ill patient and to compare adequacy of dialysis dose between KtID and traditional Kt/VUREA. Material and methods: Prospective observational study in 17 critically ill patients with ARF requiring acute hemodialysis with a predefined prescription for the study (51 measures). Results: The mean delivered Kt/VUREA was 1.19 ± 0.14, with 59% of the sessions with values equal or above the ADQI recommendation. On the contrary, the mean KtID values obtained was 37.6 ± 1 l, with only 29.4%of the sessions being equal or greater than the recommended values. Conclusions: Dialysis dose monitoring by means of KtI Dreveals a lower degree of adequacy as compared to the traditional Kt/VUREA method. The dynamic character of KtID monitoring can allow the adaptation of each dialysis sessions(«K» and/or «t») in order to achieve the recommended dose (AU)

Urinary tract infection in febrile children in Maiduguri north eastern Nigeria.

One hundred and forty five children aged 1 month to sixty months who had fever at presentation to the paediatric department of University of Maiduguri Teaching Hospital were investigated for urinary tract infection in this prospective study from November 2004 to October 2005. Prevalence of urinary tract infection was found to be 13.7 per cent. While the female sex and malnutrition were found to be significantly associated with urinary tract infection, height of temperature and symptoms referable to urinary system were not. Ninety per cent of the isolates were Gram negative; mainly coliform Spp, the remaining 10 per cent were due to staphylococcus aureus. Gentamicin was still found to be effective against most of the urinary pathogens. However, clavulinic acid potentiated amoxicillin, ampicillin, nalidixic acid and cotrimoxazole were found to be poorly effective. We therefore conclude that all ill children especially younger ones presenting with fever be screened for urinary tract infection. A regular surveillance of urinary tract infection pathogens and their antibiotic sensitivity pattern is recommended.

Study of hepatic functions and prevalence of hepatitis B surface antigenaemia in Nigerian children with human immunodeficiency virus infection.

BACKGROUND: HIV and hepatitis B virus (HBV) co-infected patients have a significantly increased risk of dying from liver disease especially after starting treatment with highly active antiretroviral therapy. We aim to determine the prevalence of hepatitis B surface antigenaemia in HIV-infected children and their significance in relation to hepatic functions. METHOD: Two hundred and eighty four HIV-infected children aged between 4 mouths to 15 years attending the Paediatric infectious disease clinic of University of Maiduguri Teaching Hospital (UMTH) Maiduguri, Nigeria from September 2007 to December 2007 were the subject for this study. Two hundred and seventy six HIV-negative children with served as age and sex-matched controls. They underwent investigations to evaluate the liver function (serum alanine transferase (ALT), alkaline phosphotase (ALP) and bilirubin) and the prevalence of hepatitis B surface antigen (HBsAg) using ELISA technique. RESULTS: Prevalence of HBsAg of 19% and 9.4% was observed among HIV-infected children controls (p = 0.004). Serum ALT and bilirubin concentrations were significantly higher in the HIV-infected group compared to the controls, (p < 0.05). HIV-infected children with HBs antigenaemia had significantly higher ALT and ALP concentrations compared to those without HBs antigenaemia (p < 0.05). CONCLUSION: These findings point to the high risk of HBV infection and continual paranchymal damage in HIV-infected children before commencing ART. Vaccination against HBV should eliminate this risk. Ideally HBV serology should be evaluated before starting ART to help guide therapeutic decision-making.

QTL detection for milk production traits in goats using a longitudinal model.

Eight paternal half-sib families were used to identify chromosomal regions associated with variation in the lactation curves of dairy goats. DNA samples from 162 animals were amplified by PCR for 37 microsatellite markers, from Capra hircus autosomes CHI3, CHI6, CHI14 and CHI20. Milk samples were collected during 6 years, and there were 897 records for milk yield (MY) and 814 for fat (FP) and protein percentage (PP). The analysis was conducted in two stages. First, a random regression model with several fixed effects was fitted to describe the lactation function, using a scale (alpha) plus four shape parameters: beta and gamma, both associated with a decrease in the slope of the curve, and delta and phi that are related to the increase in slope. Predictions of alpha, beta, gamma, delta and phi were regressed using an interval mapping model, and F-tests were used to test for quantitative trait loci (QTL) effects. Significant (p < 0.05) QTLs were found for: (i) MY: CHI6 at 70-80 cM for all parameters; CHI14 at 14 cM for delta and phi; (ii) FP: CHI14, at 63 cM was associated with beta; CHI20, at 72 cM, showed association with alpha; (iii) PP: chromosomal regions associated with beta were found at 59 cM in CHI3 and at 55 cM in CHI20 with alpha and gamma. Analyses using more families and more animals will be useful to confirm or to reject these findings.

[Mixed hereditary polyposis with atypical extracolonic manifestations]. / Poliposis hereditaria mixta con manifestaciones extracolónicas atípicas.

We present the case of a 31 year-old-man with mixed hereditary polyposis and atypical extracolonic manifestations, as patent ductus arteriosus and mental retardation, with cranial hyperostosis. This is an extremely uncommon polyposis syndrome and has a moderate risk to progress to colon cancer.

Poliposis hereditaria mixta con manifestaciones extracolónicas atípicas / Mixed hereditary polyposis with atypical extracolonic manifestations

Presentamos un varón de 31 años con poliposis hereditaria mixta y manifestaciones extracolónicas atípicas como ductus arterioso persistente y retraso mental, con hiperostosis craneal. Se trata de un síndrome polipósico extremadamente infrecuente y con riesgo moderado de progresión a desarrollar cáncer de colon

We present the case of a 31 year-old-man with mixed hereditary polyposis and atypical extracolonic manifestations, as patent ductus arteriosus and mental retardation, with cranial hyperostosis. This is an extremely uncommon polyposis syndrome and has a moderate risk to progress to colon cancer

More reliable data for diarrhoeal intervention programmes: rethinking on knowledge, attitude and practice studies.

The aim of this study was to propose an alternative approach to traditional knowledge, attitude and practice (KAP) studies to enhance the quality of data on which educational health programmes are based. The methodology proposed and illustrated involved a triangulation of approaches derived from linguistics, cognitive science, and medical laboratory sciences. Three diarrhoeal health talks (educational messages) as given to mothers in three primary-care facilities in Borno State (Northeast Nigeria) were subjected to a linguistics analysis. Relationships were then sought between the ontology of knowledge in the health talks as revealed by the text analysis and two other kinds of data, namely: (a) mothers' answers to a set of ecologically-sensitive reasoning questions that test how much relevant inferential knowledge the health talks allow for and (b) results of microbiological and biochemical analyses of salt-sugar rehydration solutions prepared by mothers participating in the study. The findings of the study show a relationship between contents/formatting of the health talks and the extent to which relevant inferential competence was supported or demonstrated by mothers. It was also evident that the laboratory analyses could be related either directly to the health talks or indirectly in terms of what the health talks need to emphasize on. The conclusion shows how the methodology proposed addresses shortcomings of traditional KAP studies in respect of the gap between health knowledge and practice.

Bioelectrical impedance analysis of the body composition of Nigerian children with sickle cell disease.

We used bioelectrical impedance (BIA) to investigate the body composition of children with sickle cell disease (SCD) in northern Nigeria. A total of 48 children with SCD and 51 controls between 3 and 20 years of age were studied. A significant difference was found in the weights of male subjects over the age of 10 years compared to controls (p = 0.01), but not in height. Significant differences were also observed for SCD males in the 10-18-year-old age range in body mass index (p = 0.001), fat free mass (p = 0.001), per cent fat free mass, (p = 0.02), body fat (p = 0.02), and per cent body fat (p = 0.02). No significant differences in any of these parameters between SCD subjects and controls were obtained for males under the age of 10 years. There were no significant differences in the height, weight, body mass index, or fat free mass for female SCD subjects compared to controls over the age range we studied. However, there were significant differences in the per cent fat free mass (p = 0.006), body fat (p = 0.025), and per cent body fat (p = 0.01) for female SCD subjects over the age of 10 years compared to controls. In addition to documenting differences in the body composition of adolescent boys with sickle cell disease in Nigeria, this study also demonstrated the feasibility of using bioelectrical impedance to analyse the body composition of individuals under the hot, arid conditions which prevail in sub-Saharan Africa.

Increased serum levels of N-telopeptides (NTx) of bone collagen in postmenopausal Nigerian women.

Serum levels of cross-linked N-telopeptides (NTx) of bone collagen, alkaline phosphatase (ALP), and intact parathyroid hormone (PTH) were determined in 64 premenopausal (PRM) and 86 postmenopausal (PSM) women living in northern Nigeria. Serum NTx values were correlated with ALP activity (r = 0.31-0.58, P < 0.01) and PTH (0. 32-0.35, P < 0.01)) in all of the subjects studied, and were also related to age (-0.47, P < 0.001) and body mass index (-0.45, P < 0. 001) in PRM women. Menopause had the effect of increasing the circulating concentrations of NTx and ALP activity by 15% (P = 0. 001) and 11% (P = 0.02), respectively; however, serum levels of PTH were not different between these two groups of women. Compared with Caucasian counterparts matched for age and body mass index, PSM Nigerian women had significantly increased circulating concentrations of NTx (21.7 versus 16.2 nmol BCE/liter, P = 0.01) and demonstrated a trend towards higher ALP activities and PTH levels. These results indicate that (1) discrete reference intervals should be defined for biochemical markers of bone metabolism in African populations, (2) Nigerian women have relatively higher rates of bone turnover, and (3) further investigation of the implications of increased serum NTx should be undertaken using physical methods such as dual X-ray absorptiometry (DXA) and bone ultrasound attenuation.