Clinical and mutational features of X-linked agammaglobulinemia in Mexico.

X-linked agammaglobulinemia (XLA) is caused by BTK mutations, patients typically show <2% of peripheral B cells and reduced levels of all immunoglobulins; they suffer from recurrent infections of bacterial origin; however, viral infections, autoimmune-like diseases, and an increased risk of developing gastric cancer are also reported. In this work, we report the BTK mutations and clinical features of 12 patients diagnosed with XLA. Furthermore, a clinical revision is also presented for an additional cohort of previously reported patients with XLA. Four novel mutations were identified, one of these located in the previously reported mutation refractory SH3 domain. Clinical data support previous reports accounting for frequent respiratory, gastrointestinal tract infections and other symptoms such as the occurrence of reactive arthritis in 19.2% of the patients. An equal proportion of patients developed septic arthritis; missense mutations and mutations in SH1, SH2 and PH domains predominated in patients who developed arthritis.

Variations of B cell subpopulations in peripheral blood of healthy Mexican population according to age: Relevance for diagnosis of primary immunodeficiencies.

BACKGROUND: Peripheral blood B cells include lymphocytes at various stages of differentiation, each with a specific function in the immune response. All these stages show variations in percentage and absolute number throughout human life. The numbers and proportions of B subpopulation are influenced by factors such as gender, age, ethnicity, and lifestyle. This study establishes reference values according to age of peripheral blood B cell subtypes in healthy Mexican population. METHODS: Peripheral blood from healthy new-borns and adults were analysed for total B cell subpopulations, using surface markers such as CD19, IgM, IgD, CD21, CD24, CD27, and CD38, to identify naïve, memory with and without isotype switch, double-negative, transitional, and plasmablast cells. RESULTS: We observed a significant variation in terms of frequency and absolute counts between all groups analysed. Values from each B cell subpopulation show variations according to age. CONCLUSIONS: In order to attempt to elucidate reference values for B cell subpopulation, the present study evaluated a population sample of healthy blood donors from this region. Values reported here can also be used as a tool for diagnosis of diseases in which B cell maturation is affected.

Longitudinal growth and health outcomes in nutritionally at-risk children who received long-term nutritional intervention.

BACKGROUND: The benefits of short-term oral nutritional supplementation (ONS) in undernourished children are well-established. The benefits of long-term ONS in promoting longitudinal growth and health in children who are at risk of undernutrition have not been reported previously. METHODS: In this 48-week prospective, single-arm, multicentre trial, 200 Filipino children aged 3-4 years with weight-for-height percentiles from 5th to 25th (WHO Child Growth Standards) were enrolled. Parents received dietary counselling at baseline, and at weeks 4 and 8. Two servings of ONS (450 mL) were consumed daily, providing 450 kcal, 13.5 g protein and micronutrients. Weight, height, dietary intake using 24-h dietary recalls, and physical activity and appetite using the visual analogue scales were assessed at baseline and weeks 4, 8, 16, 24, 32, 40 and 48. The number of sick days for acute illnesses was collected over the study period. RESULTS: At baseline, mean age was 41.2 months with 50% being male. Weight-for-height percentiles showed the greatest increase in the first 4 weeks (12.1 and 12.8 percentiles, respectively, P < 0.0001) and remained significantly higher than baseline (P < 0.0001) but were relatively stable from week 4 onwards. Height-for-age percentiles increased steadily over time and became significantly higher than baseline from week 24 onwards (P < 0.0001). Appetite and physical activity scores at all post-baseline visits improved from baseline (P < 0.0001), and a reduction in the number of sick days from week 16 onwards was also observed (P < 0.0001). Higher parental education level, being male and higher baseline weight-for-height percentiles were significantly associated with higher ponderal and linear growth over time in repeated measures analysis of covariance. CONCLUSIONS: Intervention consisting of initial dietary counselling and continued ONS helped sustain normal growth after a catch-up growth in nutritionally at-risk children.

Effects of oral nutritional supplementation in the management of malnutrition in hospital and post-hospital discharged patients in India: a randomised, open-label, controlled trial.

BACKGROUND: Hospital malnutrition is a significant problem that still remains under-recognised and under-treated in India. The present study assessed the effects of oral nutritional supplementation (ONS) in conjunction with dietary counselling versus dietary counselling (control) alone in malnourished patients when given in hospital and post-hospital discharge. METHODS: The present study was conducted in nine private and four public hospitals. Patients from various medical wards were screened for malnutrition using modified Subjective Global Assessment (mSGA) and randomised to control (n = 106) or ONS (n = 106) for 12 weeks. Two servings (460 mL) of ONS were prescribed daily, providing 432 kcal, 16 g of protein and 28 micronutrients. The primary outcome was weight gain over 12 weeks. Other outcomes included change in body mass index (BMI), serum pre-albumin, albumin and C-reactive protein levels, energy and nutrient intakes, and handgrip strength at weeks 4, 8 and 12, as well as mSGA score at week 12. RESULTS: The mean age of patients was 39 years. Fifty-five percent were males and 90.3% were moderately malnourished (mSGA score B) at baseline. At week 12, ONS significantly improved certain parameters compared to control: weight (2.0 versus 0.9 kg; P < 0.001), BMI (0.76 versus 0.37 kg m(-2) ; P < 0.001) and energy intake per day (560 versus 230 kcal; P < 0.05). There were no differences in biochemical parameters and mSGA score between groups. Additionally, patients on ONS who were more functionally impaired at baseline had significantly greater weight gain and improved handgrip strength scores than controls. CONCLUSIONS: ONS use throughout hospital stay and post-hospital discharge significantly improved energy intake and weight in malnourished Indian patients. Those patients with poorer functional status at baseline demonstrated the most benefit.

Current state and future perspectives of the Latin American Society for Immunodeficiencies (LASID).

Primary immunodeficiencies (PID) are genetic diseases that affect the immune system and for the last 20 years, the Latin American Society for Immunodeficiencies (LASID) has been promoting initiatives in awareness, research, diagnosis, and treatment for the affected patients in Latin America. These initiatives have resulted in the development of programmes such as the LASID Registry (with 4900 patients registered as of January 2014), fellowships in basic and clinical research, PID summer schools, biannual meetings, and scientific reports, amongst others. These achievements highlight the critical role that LASID plays as a scientific organisation in promoting science, research and education in this field in Latin America. However, challenges remain in some of these areas and the Society must envision additional strategies to tackle them for the benefit of the patients. In June 2013, a group of experts in the field met to discuss the contributions of LASID to the initiatives of PID in Latin America, and this article summarises the current state and future perspectives of this society and its role in the advance of PIDs in Latin America.

Lymphocytes and B-cell abnormalities in patients with common variable immunodeficiency (CVID).

BACKGROUND AND AIMS: Common variable immunodeficiency (CVID) is a primary antibody deficiency characterised by decreased antibody production and low or normal B-cell numbers. To elucidate the clinical and immunological heterogeneity of CVID, we studied 16 patients diagnosed with CVID. METHODS: We analysed B, T and NK cell populations. We also assessed CD27 expression to define B-cell subsets and examined the expression of molecules important in B-cell proliferation and differentiation, such as the transmembrane activator and CALM interactor (TACI), inducible costimulator (ICOS), CD154 and CD40. RESULTS: We observed reduced B and T-cell numbers in CVID patients; this reduction was more pronounced in adults. While one group of patients (group I) showed a significant reduction in CD27+ memory B-cells, another group (group II) of patients exhibited numbers of CD27+ memory B-cells similar to the healthy donor. The frequency of B-cells and T-cells expressing CD40 and ICOS, respectively, was significantly lower in all CVID patients compared with healthy donors. Finally, a correlation between the frequency of CD27+ memory B-cells and clinical features was observed in CVID patients. CONCLUSION: These results suggest that in some patients, the combined defects in both T and B-cells may account for CVID. Additionally, patients in group I exhibited an increased frequency of pneumonia and chronic diarrhoea.

Guidelines for the use of human immunoglobulin therapy in patients with primary immunodeficiencies in Latin America.

Antibodies are an essential component of the adaptative immune response and hold long-term memory of the immunological experiences throughout life. Antibody defects represent approximately half of the well-known primary immunodeficiencies requiring immunoglobulin replacement therapy. In this article, the authors review the current indications and therapeutic protocols in the Latin American environment. Immunoglobulin replacement therapy has been a safe procedure that induces dramatic positive changes in the clinical outcome of patients who carry antibody defects.

Clinical and immunological features of common variable immunodeficiency in Mexican patients.

BACKGROUND: Common variable immunodeficiency (CVID) is characterised by hypogammaglobulinaemia and a broad clinical spectrum, mainly showing recurrent bacterial infections accompanied sometimes by increased susceptibility to chronic lung disease, autoimmunity, and neoplastic diseases. OBJECTIVES: To evaluate the clinical and immunological characteristics of patients with CVID in Mexico. METHODS: This is a retrospective analysis of 43 patients with CVID from the Immunology Division of seven different reference centres in Mexico. Patients were diagnosed according to the diagnostic criteria of the European Society for Immunodeficiency Diseases. We collected demographics, clinical and immunological data from each patient and a statistical analysis was performed. RESULTS: There were 23 (53.5%) male and 20 (46.5%) female patients. Median age at onset of disease was 13.7 years, and median age at diagnosis was 19 years. Average delay in diagnosis was 12.5 years. The median total serum levels of IgG, IgM, and IgA at diagnosis were 175, 18, and 17.8mg/dL, respectively. The mean percentage of CD19+ B cells was 8.15%. Sinusitis (83%), pneumonia (83%), gastrointestinal infection (70%), and acute otitis media (49%) were the most common manifestations. Bronchiectasis was present in 51% of the patients, 44% manifested non-infectious chronic diarrhoea, and 70% experienced weight loss. Autoimmunity was present in 23% of the patients; haemolytic anaemia and autoimmune thrombocytopenic purpura were the most common presentations. Allergy was present in 30.2% of patients, with allergic rhinitis and asthma being the most frequent types. Two patients developed malignancy. All the patients received Intravenous immunoglobulin (IVIG) as a fundamental part of the treatment at a mean dose of 408mg/kg. CONCLUSION: This is the first cohort of CVID reported in Mexico We found that infection diseases were the most frequent presentations at onset. Moreover, patients had an average diagnosis delay of twelve years and thus a major prevalence of bronchiectasis. We suggest performing an extended analysis of patients with CVID patients in other Latin American countries.

Survival of Mexican patients with paediatric-onset systemic lupus erythematosus and abnormal electroencephalogram.

BACKGROUND: Over the past three decades, there has been a remarkable improvement in the outcome of children diagnosed with systemic lupus erythematosus (SLE). In general, paediatric-onset SLE has been associated with higher mortality rates and more disease damage than adults with SLE. The objective was to determinate the impact of clinical, laboratory, and electroencephalographic findings on survival amongst patients with paediatric-onset SLE. METHODS: Charts of Mexican patients with paediatric-onset SLE diagnosed between 1970 and 2001 were analysed retrospectively; univariate and multivariate analyses were used for analysing associations between clinical and laboratory features and death; Kaplan-Meier tests were used to estimate survival curves. RESULTS: 159 patients were included, 105 were female, with a median age of 12.7 years at diagnosis and a median duration of symptoms prior to diagnosis of 8.4 months. Univariate analysis showed that haematuria, leukocyturia, proteinuria, presence of urine cast, <60% glomerular filtration rate, haemolytic anaemia, and abnormal electroencephalogram, were all poor prognostic factors (p<0.05). Multivariate analysis showed that the presence of proteinuria and abnormal electroencephalograms (p<0.05) were independent factors associated with death. The overall survival rate was 82.9% at five years and 77.4% at ten years upon follow-up. Infection and high disease activity were the most common causes of death. CONCLUSIONS: Survival of paediatric-onset SLE patients was lower compared to that reported for patients in wealthier countries. Amongst the patients who died, the presence of proteinuria and abnormal electroencephalograms were found to be determinant for survival. Infection and activity were the most common causes of death.

Advancing the management of primary immunodeficiency diseases in Latin America: Latin American Society for Immunodeficiencies (LASID) Initiatives.

Primary immunodeficiency diseases (PIDD) are associated with significant morbidity and mortality and result in a significant public health burden. This is in part due to the lack of appropriate diagnosis and treatment of these patients. It is critical that governments become aware of this problem and provide necessary resources to reduce this impact on health care systems. Leading physicians in their respective countries must be supported by their own governments in order to implement tools and provide education and thus improve the diagnosis and treatment of PIDD. The Latin American Society of Primary Immunodeficiencies (LASID) has initiated a large number of activities aimed at achieving these goals, including the establishment of a PIDD registry, development of educational programmes and guidelines, and the introduction of a PIDD fellowship programme. These initiatives are positively impacting the identification and appropriate treatment of patients with PIDD in Latin America. Nevertheless, much remains to be done to ensure that every person with PIDD receives proper therapy.

Critical issues and needs in management of primary immunodeficiency diseases in Latin America.

Experts from six Latin American countries met to discuss critical issues and needs in the diagnosis and management of primary immunodeficiency diseases (PIDD). The diagnosis of PIDD is generally made following referral to an immunology centre located in a major city, but many paediatricians and general practitioners are not sufficiently trained to suspect PIDD in the first place. Access to laboratory testing is generally limited, and only some screening tests are typically covered by government health programmes. Specialised diagnostic tests are generally not reimbursed. Access to treatment varies by country reflecting differences in healthcare systems and reimbursement policies. An online PIDD Registry Programme for Latin America has been available since 2009, which will provide information about PIDD epidemiology in the region. Additional collaboration across countries appears feasible in at least two areas: a laboratory network to facilitate the diagnosis of PIDD, and educational programmes to improve PIDD awareness. In total, these collaborations should make it possible to advance the diagnosis and management of PIDD in Latin America.

Primary immunodeficiency diseases in Latin America: proceedings of the Second Latin American Society for Immunodeficiencies (LASID) Advisory Board.

Early diagnosis and appropriate therapy are essential for the best prognosis and quality of life in patients with primary immunodeficiency diseases (PIDDs). Experts from several Latin American countries have been meeting on a regular basis as part of an ongoing effort to improve the diagnosis and treatment of PIDD in this region. Three programmes are in development that will expand education and training and improve access to testing facilities throughout Latin America. These programmes are: an educational outreach programme (The L-Project); an immunology fellowship programme; and the establishment of a laboratory network to expand access to testing facilities. This report provides the status of these programmes based on the most recent discussions and describes the next steps toward full implementation of these programmes.

The Hamaker constant of anatase aqueous suspensions.

The linear relationship of the yield stress with the square zeta potential may be used to determine the Hamaker constants in suspensions. In this work we have obtained the Hamaker constant for the attractive forces between anatase particles in aqueous suspensions using this method and compared them with those obtained by contact angle measurement. The results show excellent agreement.

Intrinsic viscosity of SiO2, Al2O3 and TiO2 aqueous suspensions.

The viscosity of dilute suspensions of several metal oxides (SiO2, Al2O3 and TiO2) was measured at different pH values. The intrinsic viscosity, [eta], was derived from the concentration dependence of the viscosity. This magnitude was pH-dependent. A correlation with the shape of the kinetic unity has been proposed.

Relation of serum retinol to acute phase proteins and malarial morbidity in Papua New Guinea children.

BACKGROUND: Acute phase proteins (APPs) are associated with malaria-induced hyporetinemia (serum retinol <0.70 micromol/L); however, the degree of the association is not well documented. OBJECTIVE: The association between malaria-induced hyporetinemia and APPs was assessed. DESIGN: In a cross-sectional study, 90 children with serum retinol concentrations from <0.35 to >1.05 micromol/L were selected from children in a clinical trial of vitamin A supplementation. Serum was collected before treatment allocation. Retinol binding protein (RBP) concentrations were determined by radioimmunoassays, and transthyretin, alpha(1)-acid glycoprotein (AGP), alpha(1)-antichymotrypsin, C-reactive protein (CRP), haptoglobin, and albumin concentrations by radial immunodiffusion assays. RESULTS: Children in the subsample had high rates of splenomegaly and Plasmodium-positive blood-smear slides (P < 0.01); AGP (Pearson's r = -0.40, P < 0.001) and CRP (r = -0.21, P = 0.04) were inversely correlated with retinol. The negative APPs RBP, transthyretin, and albumin were positively and significantly associated with retinol. All APPs, except alpha(1)-antichymotrypsin, were significantly correlated with splenomegaly. Of the positive APPs, AGP correlated with CRP (r = 0.37, P < 0.001), indicating chronic inflammation. In a stepwise regression analysis, 73% of retinol's variability was explained by RBP and transthyretin. The model predicted that a 1-SD increase in RBP or transthyretin increases retinol by approximately 0.38 or 0.47 micromol/L, respectively, whereas an equivalent increase in AGP decreases retinol by 0.12 micromol/L. CONCLUSIONS: The RBP-transthyretin transport complex of retinol is not altered by inflammation. Positive APPs are useful markers of type and severity of inflammation; however, except for AGP, it is unlikely that they can correct for malaria-induced hyporetinemia.

A single 210-mumol oral dose of retinol does not enhance the immune response in children with measles.

This trial assessed the effect of vitamin A on reversing measles-induced unresponsiveness to recall antigens and on enhancing measles antibody production. These assessments were part of a randomized, double-masked clinical trial of the efficacy of 210 mumol of retinol as retinyl palmitate for reducing measles-associated morbidity. Two hundred children between 5 mo and 17 y of age with acute measles were enrolled at the Urban Health Centers in Ndola, Zambia; 110 subjects received a placebo and 90 received vitamin A. At enrollment and 2 wk later, blood samples were collected to determine measles hemagglutinin antibody titer and, at 1 and 2 wk post-enrollment, cutaneous delayed-type hypersensitivity tests (DTH) for seven antigens were applied. Both groups of subjects showed marked DTH unresponsiveness, but vitamin A-treated subjects had a significant prolongation of unresponsiveness to tuberculin [odds ratio (OR) 3.22 and 95% confidence interval (CI) 1.27-8.2], Candida (OR 5.43, CI 1.13-25.9) and Proteus (OR 5.17, CI 1.14-28.4), after adjustment for previous vaccination and age. DTH unresponsiveness was antigen specific, reflecting prior vaccination history, and was not associated with acute respiratory infection status. In addition, children in both treatment groups showed a significant increase in measles antibody titer from baseline to wk 2, but this increment was not significantly different between the groups (P = 0.25). These results indicate that a single oral dose of 210 mumol of retinol as retinyl palmitate in oil does not enhance the immune system during measles.

Multiple high dose vitamin A supplementation. A report on five cases.

Vitamin A toxicity is a concern among health care providers, especially when present recommendations for vitamin A may result in multiple dosing during a short period of time. We observed no vitamin A toxicity in 5 children who received multiple high doses of vitamin A. These 8-month to 5-year-old children were part of a community trial of vitamin A during acute measles, and were being treated at a local hospital for severe acute respiratory infection, malaria, and/or diarrhoea. One 12-month-old who received 1,612,500 I.U. within a period of three weeks showed elevated serum retinol (3.42 mumol/l), but none of the five showed signs of toxicity. These cases illustrate the confusion surrounding the correct use of vitamin A for infants and children with multiple morbid conditions. A plea is made to report similar situations since clinical trials are unethical.

Acute inflammation induces hyporetinemia and modifies the plasma and tissue response to vitamin A supplementation in marginally vitamin A-deficient rats.

Plasma retinol is reduced during numerous infections, and inflammation alters the hepatic synthesis of retinol-binding protein (RBP). In this study, we have investigated the effects of endotoxin-induced inflammation on vitamin A (VA) supplementation in a rat model of marginal VA deficiency. Marginally VA-deficient rats received an intraperitoneal dose of lipopolysaccharide (LPS, n = 14) or saline (n = 10); 6 h later, six LPS + VA and six saline + VA rats received 7.1 micromol VA orally. Twenty-four hours after endotoxin administration, rats with inflammation (LPS) had lower plasma retinol, RBP, and hepatic RBP than saline rats (37, 31 and 44%, respectively, P < 0.05). Inflammation did not affect VA concentrations in liver and perirenal adipose tissue, although kidney VA was reduced relative to saline rats. However, urinary VA was not detected. Eighteen hours after VA supplementation, inflammation reduced the plasma unesterified retinol response (P < 0. 05) in LPS + VA relative to saline + VA rats, although total VA increased as a result of the presence of retinyl esters in LPS + VA rats. Hepatic esterified retinol concentration was reduced (P < 0. 01) in LPS + VA compared with saline + VA rats; however, hepatic unesterified retinol did not differ. Renal total retinol increased in VA-supplemented rats, but urinary retinol excretion, when observed, was low, independently of inflammation. These findings indicate that inflammation-induced hyporetinemia does not necessarily imply a loss of VA, but rather represents a redistribution of tissue VA brought about by a reduced hepatic synthesis of RBP. Practical implications from these collective results are to recommend the determination of both unesterified and esterified retinol to fully assess the plasma response to VA supplementation and to caution the use of VA assessment methodologies that depend on the hepatic synthesis of RBP during acute inflammation.

A low molar ratio of retinol binding protein to transthyretin indicates vitamin A deficiency during inflammation: studies in rats and a posterior analysis of vitamin A-supplemented children with measles.

To assess whether the molar ratio of retinol-binding protein (RBP) to transthyretin (TTR) is of utility in detecting vitamin A (VA) deficiency during inflammation, we analyzed data from a rat model of endotoxin-induced inflammation and from a previously reported randomized, placebo-controlled trial of VA supplementation in children with acute measles. In rats, both marginal VA deficiency and inflammation were independent causes of low plasma RBP (two-way ANOVA, P < 0.001), whereas plasma TTR concentration was reduced only by inflammation (P < 0.001). The molar ratio of plasma RBP to TTR was reduced (by approximately 50%) only in rats with marginal VA deficiency and inflammation (two-way ANOVA interaction, P < 0.01). Serum retinol concentration, C-reactive protein (CRP, an indicator of inflammation) and the RBP:TTR molar ratio were determined in children with acute measles at baseline and 2 wk after subgroups received a placebo or a 210 micromol VA supplement. The ratio of RBP:TTR was selectively reduced in children in the placebo group with low plasma retinol (<0.35 micromol/L) and elevated CRP (>40 mg/L). In children with a low RBP:TTR molar ratio (<0.30) at baseline, the RBP:TTR ratio increased significantly 2 wk later only in the VA-treated subgroup. These analyses provide evidence that, because RBP is differentially reduced in comparison to TTR during VA deficiency, the combined determination of the concentrations of serum RBP and TTR may provide a promising means of detecting VA deficiency during inflammation.