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.

Functional characterization of two new STAT3 mutations associated with hyper-IgE syndrome in a Mexican cohort.

Hyper-IgE syndrome (HIES) is an immunodeficiency disorder that is characterized by distinctive immunologic and non-immunologic manifestations. Although mutations in signal transducer and activator of transcription 3 (STAT3) have been associated with HIES, the exact nature of the relationship is unknown. Here, we characterized the functional activity of STAT3 and its mutations in 11 Mexican patients with autosomal dominant HIES. STAT3 phosphorylation was evaluated by flow cytometry, and in silico analyses were performed to estimate the impact of allelic mutations on the DNA binding and SH2 domains of the STAT3 protein. Electrophoretic mobility shift assays were used to assess whether the STAT3 mutants could bind to the consensus oligonucleotide target in vitro. Two novel mutations [g.58891A>T (Asn395Tyr) and g.59078A>T (Asn425Tyr)] as well as one possible somatic mosaicism were found in several of the patients who bore some remarkable features. However, there were no direct correlations between genotypes and HIES clinical features. STAT3 phosphorylation was found to be lower in the patient cohort than in healthy controls. Moreover, the mutated STAT3 proteins could bind to the Sp1, but not to the STAT3, consensus sequence. From these functional studies, the STAT3 mutations found in our patient cohort were concluded to be deleterious for normal STAT3 function.

Vaginal progesterone as maintenance treatment after an episode of preterm labour (PROMISE) study: a multicentre, double-blind, randomised, placebo-controlled trial.

OBJECTIVE: To evaluate whether maintenance treatment with vaginal progesterone after an arrested preterm labour reduces the incidence of preterm delivery. DESIGN: Multicentre, randomised, double-blind, placebo-controlled trial. SETTING: Twelve tertiary care centres in Spain. POPULATION: A total of 265 women with singleton pregnancy, preterm labour successfully arrested with tocolytic treatment, and cervical length of <25 mm. METHODS: Randomisation was stratified by gestational age (from 24.0 to <31.0 weeks of gestation and from 31.0 to <34.0 weeks of gestation) and centre. Patients were randomly assigned, in a 1 : 1 ratio, to either daily vaginal capsules of 200 mg progesterone or placebo until delivery or 36.6 weeks of gestation, whichever occurred first. MAIN OUTCOME MEASURES: Primary outcome was delivery before 34.0 and 37.0 weeks of gestation. Secondary outcomes were discharge-to-delivery time, readmissions because of preterm labour, emergency service use, and neonatal morbidity and mortality. RESULTS: From June 2008 through June 2012, 1419 women were screened: 472 met the inclusion criteria and 265 were randomised. The final analysis included 258 women: 126 in the progesterone group and 132 in the placebo group. There were no significant differences between the progesterone and placebo groups in terms of delivery at <34 weeks of gestation [9/126 (7.1%) versus 10/132 (7.6%), P = 0.91] or <37 weeks of gestation [36/126 (28.6%) versus 29/132 (22.0%), P = 0.22]. There were no differences observed between groups when considering the two strata of gestational age at inclusion. CONCLUSIONS: A maintenance treatment of 200 mg of daily vaginal progesterone capsules in women discharged home after an episode of arrested preterm labour did not significantly reduce the rate of preterm delivery. TWEETABLE ABSTRACT: Maintenance progesterone in 258 women after arrested PTL showed no benefit.

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.

Molecular analysis for patients with IL-12 receptor ß1 deficiency.

Autosomal recessive interleukin-12 receptor ß1 (IL-12Rß1) deficiency has been described as the most common cause of Mendelian susceptibility to mycobacterial disease (MSMD), characterized by clinical disease due to weakly virulent mycobacteria such as Bacille Calmette-Guérin (BCG) vaccines and environmental mycobacteria (EM) in children who are normally resistant to most infectious agents. Here, we report the cases of five patients with mycobacterial infection, including one with systemic lupus erythematosus (SLE). Blood samples from patients and healthy controls were activated in vitro with BCG, BCG+IL-12, and BCG+IFN-γ. The results showed reduced or no production of IFN-γ after IL-12 stimulation in all samples. IL-12Rß1 expression on the cell surface was negligible or absent. Genetic analysis showed five novel mutations.

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.

Detection of inheritance pattern in thirty-three Mexican males with chronic granulomatous disease through 123 dihydrorhodamine assay.

BACKGROUND: There are two inheritance patterns, the X-linked recessive (XL) pattern and the autosomal recessive pattern. There is no information on the predominant inheritance pattern of male patients with chronic granulomatous disease (CGD) in Mexico. OBJECTIVE: The aim of this study was to determine the inheritance pattern in a cohort of Mexican male patients with CGD by means of the detection of an XL status carrier among their female relatives, and to describe the frequency of discoid lupus (DL) among carriers. METHODS: We detected the female relatives within the families of male patients with CGD, and carried out the 123 dihydrorhodamine (DHR) assay in all female participants. All carriers were questioned for current or past established DL diagnosis. RESULTS: We detected 33 families with one or more CGD male patients; we found an XL-CGD in 79% of the relatives from at least one female relative with a bimodal pattern. For the remaining seven relatives we were not able to confirm a carrier status by means of a DHR assay. Moreover, we detected one mother with CGD secondary to skewed X-chromosome inactivation. We also found 47 carriers, and only one carrier with DL among them. CONCLUSION: We concluded that XL-CGD is the most frequent form of CGD in a cohort of CGD male patients in Mexico. DHR assay is a fast and practical tool to determine the CGD form in the Latin-American countries. Finally, DL frequency in Mexico is lower than that reported in the literature for other regions of the world.

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.

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.

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.

Retraction Note: Insomnia, sleepiness, anxiety and depression among different types of gamers in African countries.

This Article has been retracted.

Insomnia, sleepiness, anxiety and depression among different types of gamers in African countries.

Gaming has increasingly become a part of life in Africa. Currently, no data on gaming disorders or their association with mental disorders exist for African countries. This study for the first time investigated (1) the prevalence of insomnia, excessive daytime sleepiness, anxiety and depression among African gamers, (2) the association between these conditions and gamer types (i.e., non-problematic, engaged, problematic and addicted) and (3) the predictive power of socioeconomic markers (education, age, income, marital status, employment status) on these conditions. 10,566 people from 2 low- (Rwanda, Gabon), 6 lower-middle (Cameroon, Nigeria, Morocco, Tunisia, Senegal, Ivory Coast) and 1 upper-middle income countries (South Africa) completed online questionnaires containing validated measures on insomnia, sleepiness, anxiety, depression and gaming addiction. Results showed our sample of gamers (24 ± 2.8 yrs; 88.64% Male), 30% were addicted, 30% were problematic, 8% were engaged and 32% were non-problematic. Gaming significantly contributed to 86.9% of the variance in insomnia, 82.7% of the variance in daytime sleepiness and 82.3% of the variance in anxiety [p < 0.001]. This study establishes the prevalence of gaming, mood and sleep disorders, in a large African sample. Our results corroborate previous studies, reporting problematic and addicted gamers show poorer health outcomes compared with non-problematic gamers.

Characterization of Bruton's tyrosine kinase mutations in Mexican patients with X-linked agammaglobulinemia.

X-linked agammaglobulinemia (XLA) is a humoral primary immunodeficiency in which affected patients have very low levels of peripheral B cells and a profound deficiency of all immunoglobulin isotypes. Mutations in the gene encoding for Bruton's tyrosine kinase (Btk) are responsible for most of the agammaglobulinemia. In this work, 14 Btk mutations responsible of causing XLA are described; eight of which are novel and six are mutations previously reported. Seven of the mutations were due to deletions and insertions of exons and introns, respectively, which suggest splicing defects. The others were missense mutations, five of which affect arginine residues and have been described, and two new which affect leucine and glutamine residues (L111P and E605G). Most of these mutations were located at the kinase domain of Btk and, less frequently, they were found in PH and SH2 domains. Protein expression was also affected since most of the patients did not express or express very low Btk.