Chediak-Higashi syndrome: Lessons from a single-centre case series

Background: Chediak-Higashi syndrome (CHS) is a rare and potentially fatal autosomal recessive disease characterized by frequent bacterial infections, bleeding tendency, oculocutaneous albinism, photosensitivity and progressive neurologic dysfunction. Owing to the rarity of this condition, the objective of this study was to describe patients with CHS. Methods: Retrospective evaluation of patients followed in a paediatric tertiary centre of Allergy and Immunology of São Paulo, Brazil, between 1986 and 2018 with a confirmed diagnosis of CHS. Data were obtained from medical records. Demographic aspects, family history, clinical findings, laboratory data, diagnosis, treatment and outcome were described. Results: A total of 14 patients (five male) were included. Clinical manifestations were first recognized at a median age of two months (at birth-20 months). Median age at diagnosis was 1.7 years (0-5 years). All patients had recurrent infections. Albinism was present in 13 patients and silvery or light hair was present in 14. Seven patients developed hemophagocytic lymphohistiocytosis (HLH); the median age at the diagnosis of HLH was 5.7 years (2.6-6.7 years) and the median interval between the diagnosis of CHS and HLH was 3.3 years (0-5 years). Four of the most recently diagnosed patients underwent bone marrow transplantation (BMT). Nine patients are deceased, and one was lost to follow-up. The median age of death was 6.7 years (3.8-22 years). Five patients died of HLH, one of lymphoma, and three of infection. All the patients who had HLH before the year of 2000 died of HLH. The two most recently diagnosed patients with HLH were able to cure the HLH, although they died of other causes. Four patients are alive, three of them after successful BMT. Conclusion: Thirty years of follow up showed an improvement in the prognosis in patients with CHS. The better understanding of the underlying biological mechanisms of HLH allowed the standardization of management protocols, resulting in survival improvement. BMT is the only treatment that can change CHS prognosis, which emphasizes the need for early identification of the disease

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Chediak-Higashi syndrome: Lessons from a single-centre case series.

BACKGROUND: Chediak-Higashi syndrome (CHS) is a rare and potentially fatal autosomal recessive disease characterized by frequent bacterial infections, bleeding tendency, oculocutaneous albinism, photosensitivity and progressive neurologic dysfunction. Owing to the rarity of this condition, the objective of this study was to describe patients with CHS. METHODS: Retrospective evaluation of patients followed in a paediatric tertiary centre of Allergy and Immunology of São Paulo, Brazil, between 1986 and 2018 with a confirmed diagnosis of CHS. Data were obtained from medical records. Demographic aspects, family history, clinical findings, laboratory data, diagnosis, treatment and outcome were described. RESULTS: A total of 14 patients (five male) were included. Clinical manifestations were first recognized at a median age of two months (at birth-20 months). Median age at diagnosis was 1.7 years (0-5 years). All patients had recurrent infections. Albinism was present in 13 patients and silvery or light hair was present in 14. Seven patients developed hemophagocytic lymphohistiocytosis (HLH); the median age at the diagnosis of HLH was 5.7 years (2.6-6.7 years) and the median interval between the diagnosis of CHS and HLH was 3.3 years (0-5 years). Four of the most recently diagnosed patients underwent bone marrow transplantation (BMT). Nine patients are deceased, and one was lost to follow-up. The median age of death was 6.7 years (3.8-22 years). Five patients died of HLH, one of lymphoma, and three of infection. All the patients who had HLH before the year of 2000 died of HLH. The two most recently diagnosed patients with HLH were able to cure the HLH, although they died of other causes. Four patients are alive, three of them after successful BMT. CONCLUSION: Thirty years of follow up showed an improvement in the prognosis in patients with CHS. The better understanding of the underlying biological mechanisms of HLH allowed the standardization of management protocols, resulting in survival improvement. BMT is the only treatment that can change CHS prognosis, which emphasizes the need for early identification of the disease.

Collagen type IV-related nephropathies in Portugal: pathogenic COL4A3 and COL4A4 mutations and clinical characterization of 25 families.

Pathogenic mutations in genes COL4A3/COL4A4 are responsible for autosomal Alport syndrome (AS) and thin basement membrane nephropathy (TBMN). We used Sanger sequencing to analyze all exons and splice site regions of COL4A3/COL4A4, in 40 unrelated Portuguese probands with clinical suspicion of AS/TBMN. To assess genotype-phenotype correlations, we compared clinically relevant phenotypes/outcomes between homozygous/compound heterozygous and apparently heterozygous patients. Seventeen novel and four reportedly pathogenic COL4A3/COL4A4 mutations were identified in 62.5% (25/40) of the probands. Regardless of the mutated gene, all patients with ARAS manifested chronic renal failure (CRF) and hearing loss, whereas a minority of the apparently heterozygous patients had CRF or extrarenal symptoms. CRF was diagnosed at a significantly younger age in patients with ARAS. In our families, the occurrence of COL4A3/COL4A4 mutations was higher, while the prevalence of XLAS was lower than expected. Overall, a pathogenic COL4A3/COL4A4/COL4A5 mutation was identified in >50% of patients with fewer than three of the standard diagnostic criteria of AS. With such a population background, simultaneous next-generation sequencing of all three genes may be recommended as the most expedite approach to diagnose collagen IV-related glomerular basement membrane nephropathies.

Management practices associated with the bulk tank milk prevalence of Mycoplasma spp. in dairy herds in Northwestern Portugal.

The objective of this study was to evaluate the effect of some management practices on the prevalence of Mycoplasma spp. in Northwestern Portuguese dairy farms from bulk tank milk (BTM) samples. Additionally, the within-herd prevalence of Mycoplasma spp. was also determined, but only in BTM positive herds. From May 2007 to November 2008, 492 BTM samples from 164 dairies randomly chosen in a population of 1234 dairy farms were analyzed. Five herds (3.0%) had positive mycoplasmal culture results, from which 4 out of 164 (2.4%) were Mycoplasma bovis, with simultaneous presence of Mycoplasma bovigenitalium or Mycoplasma canadense in two of those samples. In one out of 164 (0.6%) herds Mycoplasma capricolum subsp. capricolum was also found. In BTM positive Mycoplasma spp. herds, the apparent intra-herd prevalence was low and varied between 2.5% and 4.5%. Multiple locus variable-number of tandem-repeat analysis was conducted in order to compare the genetic relationship between the isolates. Mycoplasma spp. was found to be present in cows with subclinical mastitis with or without California Mastitis Test positive results, hence all cows should be tested when the agent is isolated from bulk tank rather than selecting suspected cows. A multivariable logistic regression using the Firth's penalized maximum likelihood estimation was performed showing that increasing number of lactating cows (OR=1.05; P<0.01) was associated with a higher probability of isolating Mycoplasma spp. On the other hand, identifying problem cows was associated with a lower probability (OR=0.06; P<0.05). Particular importance was given to the prevalence of M. bovis, and the results obtained highlight the need to include this agent in mastitis control protocols in national dairies and in sanitary controls of transitioned animals between European countries.

Effects of protein sources on concentrations of hydrogen sulphide in the rumen headspace gas of dairy cows.

Two Latin square design experiments investigated the relationship between hydrogen sulphide concentration in the rumen headspace gas of dairy cows and the early stages of protein degradation in the rumen. In Expt 1, three protein sources differing in rumen N (nitrogen) degradability (maize gluten feed (MGF); sunflower meal (SFM); and soyabean meal (SBM)) were used, whereas in Expt 2 four different batches of the same feed (MGF) differing in colour (CIE L*, a*, b* (CIELAB) scale) were used. After allowing the concentration of hydrogen sulphide in rumen gas to decline close to zero, a fixed amount of protein sources was offered to cows and the concentrations of hydrogen sulphide were recorded in rumen headspace gas at 30-min intervals. In Expt 1, the concentration of hydrogen sulphide showed considerable variation between protein sources, with MGF having the highest concentration followed by SFM and SBM resulting in very low concentrations. The N wash losses (zero time measurements with nylon bags) ranked the feeds in the same way, from MGF (highest; 61%) to SBM (lowest; 26%). There were marked differences in the degradation of cystine and methionine between protein sources, although the degradation of cystine was always higher than for methionine. MGF (Expt 2) led to increased concentrations of hydrogen sulphide, with peak concentrations achieved between 1 and 2 h after feeding. The concentrations of hydrogen sulphide were higher for MGF1, intermediate for MGF2 and lower for MGF3 and MGF4, agreeing with colour scale. Differences in the early stages of dietary sulphur degradation corresponded with differences in hydrogen sulphide concentrations in rumen gas. The results suggest that hydrogen sulphide concentrations in the rumen headspace gas could be useful to evaluate nutritional parameters not measured by the in sacco technique, contributing to a better understanding of the response of dairy cows to different protein supplements.

Consumo de crack: repercusiones en la estructura y en la dinámica de las relaciones familiares / No disponible

Este estudio tiene como objetivo conocer el impacto del uso continuo de crack en la estructura y dinámica de las relaciones familiares. Se trata de un estudio de caso de abordaje cualitativo que utilizó entrevistas semi-estructuradas e instrumentos construidos con base en el Modelo Calgary de Evaluación e Intervención de la Familia (genograma y ecomapa). Él estudio se realizó con un miembro de una familia designada por la Unidad de Salud de la Familia de un barrio, en una cuidad del Estado del Río Grande do Sul. Se identificó que el consumo de crack provoca un distanciamiento entre los miembros de la familia, además de comportamientos adoptados para preservar la integridad del grupo familiar. Somos conscientes de las limitaciones impuestas por la red de servicios de salud y servicios sociales, los cuales se constituyen en factores que influyen en la dinámica del mundo de la familia. Se concluye que el fenómeno del consumo de drogas en el mundo contemporáneo y el papel de los servicios de salud y de la sociedad en este contexto es un desafío claro y constante, y debe sentar las bases del debate de la política de salud tanto a nivel local como nacional (AU)

This study aimed to ascertain the impact of the continued use of crack in the structure and dynamics of family relationships. .It is a case study of qualitative approach. We used semi-structured interviews and instruments aimed at the Calgary Assessment Model Intervention in Family (ecomap and genogram). The study was conducted with a member of a family designated by the Family Health Unit in a neighborhood in a municipality of Rio Grande do Sul. Crack consumption leads to alienation among children due to behavioral changes, aggressiveness, sometimes accompanied by physical violence, fear, sense of danger to the family, adoption of more cautious behavior, in order to protect the integrity of its members, passivity and powerlessness, and the harsh effects of crack brings the family a sense of resignation. However, we realize the limitations imposed by the limited network of health services and social facilities, and factors that influence the dynamics of the familial world. So, rethinking the phenomenon of drug use in the contemporary world and the role of society in this context is a challenging course and one that should be discussed by all (AU)

Cinacalcet in the treatment of persistent hyperparathyroidism after kidney transplantation.

BACKGROUND: Secondary hyperparathyroidism persists in 30 - 50% of patients after a successful kidney transplant and it is the most frequent cause of hypercalcemia after transplant, contributing to graft loss and mortality. Several medical therapies have been studied for the treatment of this condition without clear benefit. Recently, interest has grown in the use of cinacalcet in kidney transplant recipients. METHODS: We describe the efficacy of cinacalcet in 18 kidney transplant patients with persistent hyperparathyroidism and progressive hypercalcemia treated for a period of 12-months. We analyzed serum calcium, phosphorus and parathyroid hormone levels every 6 months, and cinacalcet was titrated if necessary. Statistical analysis was performed using ANOVA. RESULTS: With therapy, all patients exhibited significant reduction in parathyroid hormone levels, from a mean value of 242.04 ± 105.82 pg/ml to a mean value of 145.62 ± 54.99 pg/ml (p < 0.001) 12 months later. In addition, serum calcium levels normalized during the study period, from 11.16 mg/d to 9.95 mg/dl (mean values) (p < 0.001). No significant change in serum creatinine was found in this group of patients. Cinacalcet was well tolerated, with no side effects documented. CONCLUSION: This preliminary experience suggests that cinacalcet may be useful in the treatment of persistent hyperparathyroidism after kidney transplant. In addition, cinacalcet controlled hypercalcemia, which has well known adverse effects after transplant. This was accomplished with no evidence of declining kidney function or limiting side effects.

Mycobacterium gordonae urinary infection in a renal transplant recipient.

The authors present a case of urinary infection by a non-tuberculous mycobacteria (NTM) species, Mycobacterium gordonae, in a renal transplant recipient. A 29-year-old female patient had persistent sterile pyuria after her second kidney transplant. An NTM, M. gordonae, was isolated, and the patient was started on antituberculous treatment, with resolution of leukocyturia. Ureteral stenosis with hydronephrosis and deterioration of allograft function was diagnosed later on and, despite the introduction of intraureteral catheter and resolution of hydronephrosis, there was no recovery of baseline renal function. She ultimately resumed dialysis after a severe pyelonephritis. The authors discuss the problems of establishing diagnosis of infection (versus colonization) by NTM and highlight the difficulty of treating these infections, especially because of the possible interaction with immunosuppressant agents, facilitating anti-allograft immune response.

Avaliação isocinetica da função muscular do quadril e do tornozelo em idosos que sofrem quedas / Isokinetic evaluation of hip and ankle muscle function among elderly people who suffer falls

Analisar o impacto da funcao muscular dos membros inferiores sobre as quedas em uma populacao de idosos. Metodos: os participantes foram 30 idosos, 14 que nao haviam sofrido quedas e 16 que ja haviam sofrido quedas no ultimo 6 meses, selecionados aleatoriamente no ambulatorio de geriatria de um hospital universitario. Todos foram submetidos a avaliacao demografica e clinica e ao teste de funcao muscular no Dinamometro Isocientico Biodex. Os avaliadores nao foram informados sobre o grupo a que pertencia cada idoso ate o final do estudo. Foram feitas analises estatisticas descritivas para todas as variaveis e para a comparacao entre os grupos foram utilizados o test t-Student, Mann-whitney, qui-quadrado ou teste exato de fisher, no nivel de significancia < 0,05. Resultados Em relacao a funcao muscular do tornozelo, os idosos que ja cairam apresentaram menor potencia media (p variado entre 0,005 e 0,001), menor trabalho propocional ao peso corporal (p variado entre 0,046 e 0,028) e o menor pico de torque propocional ao peso corporal( p=0.23). Para a articulacao do quadril nao houve diferencas estatisticamente significativas entre os grupos em nenhuma das variaveis testadas.Conclusoes: idosos que ja cairam apresentaram menores valores de pico de torque, trabalho proporcional ao peso corporal e potencia media para a articulacao de tornozelo em relacao aos que nao cairam. Nao houve diferencas estatisticamente significatyivas para a funcao muscular do quadril. Nossos achados mostram que na abordagem fisioterapeutica do idoso e necessario incluir rxercicios de fortalecimento para o tornozelo, contribuindo para a prevencao de quedas

Immunophenotypic aberrations, DNA content, and cell cycle analysis of plasma cells in patients with myeloma and monoclonal gammopathies.

We describe the immunophenotypic and gross DNA defects in 55 patients with myeloma and 50 patients with monoclonal gammopathy and review the literature on this subject (MedLine, 1994-2000). Our data confirmed previous reports indicating that in myeloma nearly all marrow plasma cells are abnormal (98.7 +/- 8.1%). In monoclonal gammopathy the fraction of abnormal plasma cells was 35.0 +/- 32.8%. In both myeloma and monoclonal gammopathy, the most frequent aberrant phenotypic features consisted of absence of expression of CD19, strong expression of CD56, and decreased intensity of expression of CD38; aberrant expression of CD10, CD20, CD22, or CD28 was observed in less than one-third of myeloma cases. The vast majority of cases had two or more phenotypic aberrations. In the DNA studies, 7% of myeloma cases were biclonal and 93% of cases were monoclonal. In those studies with only one plasma cell mitotic cycle, 37% had normal DNA content and 63% were aneuploid (hyperploid, 61%; hypoploid, 2%). The mean percentages of plasma cells in S- and G2M phases were 4.9 +/- 8.5 and 4.4 +/- 6.9%, respectively. Thirty-eight percent of cases had more than 3% of plasma cells in S phase. In monoclonal gammopathy, the DNA index of abnormal plasma cells ranged from 0.89 to 1.30 and the percentage of diploid (31%) and aneuploid (69%) cases was not different from the results found in myeloma. The differences in percentage of abnormal plasma cells in S- (7.4 +/- 8.6%) and G2M-phases (2.4 +/- 1.7%) in patients with monoclonal gammopathy were not statistically significant.

Unexpected pattern of beta-globin mutations in beta-thalassaemia patients from northern Portugal.

We characterized the genetic nature of beta-thalassaemia in northern Portugal. Of the 164 patients studied three were beta-thalassaemia major cases (one IVS-1-6/beta degrees 39 and two homozygous IVS-1-110). The analysis of the frequency of each mutation in the families revealed that the codon 6(-A) mutation was unexpectedly frequent (40%) and associated with the beta-globin haplotype E, and not with the usual European and North African CD6(-A) haplotypes. In contrast, the frequency of IVS-1-6 (8%) and beta degrees 39 (19%) was found to be lower than in the rest of the country. The frequency of all other mutations was similar to previous reports for central/southern Portugal. Six families carried none of the most frequent mutations in the Mediterranean area. These families were studied by gene sequencing, revealing that three families carried a previously described mutation (CD16 G --> A). The remaining families carried previously unidentified mutations: one showed an 86 bp insertion in exon 2 (named HGSA) and two showed a deletion of a cytidine in codon 11 (CD11(-C)). The results, showing a high frequency (82%) of beta degrees mutations, strongly indicates that genetic counselling should be intensified as a means of preventing the spread of the severe mutations found.

Hepatitis C virus genotypes and the influence of the induction of immunosuppression with anti-thymocyte globulin (ATG) on chronic hepatitis in renal graft recipients.

Hepatitis C virus (HCV) exhibits a dramatic genetic variability and several mechanisms of immunological response are unable to control hepatic and extrahepatic replication. Genotype 1 b is associated with more severe clinical manifestations and is less responsive to interferon. In addition, we have reported an increase of HCV RNA viral load after renal transplantation. Anti-thymocyte globulin (ATG) is supposed to increase viral replication and liver dysfunction in chronically infected renal graft recipients. We evaluated the genotype profile in HCV+ patients of our Renal Transplant Unit and studied the effects of ATG, as part of the induction of immunosuppression, on viral load and liver enzymes abnormalities. From 726 renal graft recipients, 104 patients, with a mean follow up of 3.9 +/- 2.9 years, were anti-HCV+ by ELISA II. HCV RNA was measured by quantitative PCR. We correlated the viral load and biochemical liver parameters with genotype, exposure to ATG as induction therapy, early acute rejection episode and the duration of infection. Of the 81 patients tested, 72% were viraemic and genotype 1 b was the predominant viral strain (66%). The majority of these patients (65%) were coinfected by two or more strains. There was no correlation between HCV RNA blood levels and liver enzymes. We did not find higher viral load with genotype 1 b infection (68 +/- 88 mEq/ml vs 75.8 +/- 123 mEq/ml in the others) nor with ATG induction therapy (43.5 +/- 71.3 mEq/ml vs 64.1 +/- 110.5 mEq/ml). Early acute rejection and longer follow up were not associated with higher levels of HCV RNA. The biochemical liver profile showed no relationship with the variables studied. We concluded that genotype 1 b is the predominant strain in our HCV+ population and there is a great prevalence of coinfection with several genotypes. Our results did not confirm a deleterious effect of the use of ATG as induction therapy in these HCV-infected patients. Prospective randomised studies with liver biopsy evaluation are needed to answer more fully the remaining questions about the best immunosuppressive therapy in renal graft recipients with chronic HCV infection.

Immunophenotypic characteristics of acute leukaemia after myelodysplastic syndromes.

PURPOSE: To analyse the immunophenotype of acute leukaemia (AL) after myelodysplastic syndromes (MDS) (MDS-AL) and to compare the immunophenotypic profile of acute myeloblastic leukaemia (AML) secondary to MDS (MDS-AML) with that of "de novo"-AML. PATIENTS AND METHODS: Twenty patients with MDS-AL and 29 patients with "de novo"-AML were studied. Morphocytochemical and flow cytometric studies were done in each case. RESULTS: All the MDS-AL studied displayed a myeloid phenotype (MDS-AML). The main difference between MDS-AML and "de novo"-AML was a significantly higher frequency of CD34 expression in the first group. Differences concerning the expression of other non-lineage related or myeloid-associated markers were not statistically significant, although the percentage of cases CD15(+) was lower in MDS-AML. The overall frequency of expression of lymphoid-associated markers was similar in both groups, T-cell markers being more frequently detected. CONCLUSIONS: Our findings support the usefulness of immunophenotyping studies to characterize MDS-AL and suggest some immunophenotyping differences between MDS-AML and "de novo"-AML which might have biological and prognostic significance.