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"Missing heritability" is a current problem in human genetics. I previously reported a method to estimate heritability of a polymorphism (hp2) for a common disease without calculating the genetic variance under dominant and the recessive models. Here, I extend the method to the co-dominant model and carry out trial calculations of hp2. I also calculate hp2 applying the allele distribution model originally reported by Pawitan et al. for comparison as a conventional method. But unexpectedly, hp2 calculated for rare variants with high odds ratios was much higher than the calculated values with the allele distribution model. Also, while examining the basis for the difference in calculated hp2, I noticed that conventional methods use the allele frequency (AF) of a variant in the general population to calculate the genetic variance of that variant. However, this implicitly assumes that the unaffected are included among the phenotypes of the disease - an assumption that is inconsistent with case-control studies in which unaffected individuals belong to the control (unaffected) group. Therefore, I modified the allele distribution model by using the AF in the patient population. Consequently, the hp2 of rare variants calculated with the modified allele distribution model was quite high. Recalculating hp2 of several rare variants reported in the literature with the modified allele distribution model yielded results were 3.2 - 53.7 times higher than the hp2 calculated with the original allele distribution model. These results suggest that the contribution of rare variants to heritability of a disease has been considerably underestimated.
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Cancers are genetically categorized into common diseases showing a so-called multifactorial inheritance except for rare familial cancers. And as a measure to estimate the strength of genetic factors in the multifactorial diseases, heritability (h2) is generally used. However, there have been few reports on the estimation of heritability for cancers. We calculated the heritability from the incidence in subject population and the familial recurrence rate in first-degree relatives of the affected for cancers quoting the data from a large-scale prospective cohort study by Hidaka et al. published in 2020. This is the first report for heritability of any cancers in Japanese population. The results showed that heritability of overall cancers in Japanese population is 0.064, which is much lower than Nordic population reported by Mucci et al. that was 0.33. For individual cancers, stomach cancer (h2 = 0.14), colorectum cancer (0.006), lung cancer (0.08) and uterine cancer (0.16) accounted for half of the total patients, and each heritability tends to be lower than previously reported for the European descent. The results of this study suggest that heritability of cancers varies greatly by ethnicity. And these results should be important in terms of cancer genetics and in the genetic counseling for cancers.
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Predisposição Genética para Doença , Neoplasias , Humanos , Neoplasias/genética , Neoplasias/epidemiologia , Feminino , Japão/epidemiologia , Masculino , Incidência , Estudos de Coortes , Estudos Prospectivos , Pessoa de Meia-Idade , Povo Asiático/genética , Adulto , Idoso , População do Leste AsiáticoRESUMO
A next-generation sequencing (NGS) study identified a very high viral load of Torquetenovirus (TTV) in KD patients. We aimed to evaluate the feasibility of a newly developed quantitative species-specific TTV-PCR (ssTTV-PCR) method to identify the etiology of KD. We applied ssTTV-PCR to samples collected from 11 KD patients and 22 matched control subjects who participated in our previous prospective study. We used the NGS dataset from the previous study to validate ssTTV-PCR. The TTV loads in whole blood and nasopharyngeal aspirates correlated highly (Spearman's R = 0.8931, p < 0.0001, n = 33), supporting the validity of ssTTV-PCR. The ssTTV-PCR and NGS results were largely consistent. However, inconsistencies occurred when ssTTV-PCR was more sensitive than NGS, when the PCR primer sequences mismatched the viral sequences in the participants, and when the NGS quality score was low. Interpretation of NGS requires complex procedures. ssTTV-PCR is more sensitive than NGS but may fail to detect a fast-evolving TTV species. It would be prudent to update primer sets using NGS data. With this precaution, ssTTV-PCR can be used reliably in a future large-scale etiological study for KD.
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Infecções por Vírus de DNA , Síndrome de Linfonodos Mucocutâneos , Reação em Cadeia da Polimerase , Torque teno virus , Torque teno virus/genética , Torque teno virus/isolamento & purificação , Síndrome de Linfonodos Mucocutâneos/virologia , Reação em Cadeia da Polimerase/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Conjuntos de Dados como Assunto , Humanos , Masculino , Feminino , Lactente , Pré-Escolar , Criança , Estudos Prospectivos , DNA Viral/genética , DNA Viral/isolamento & purificação , Infecções por Vírus de DNA/virologiaRESUMO
Apart from some Mendelian-inherited tumors, malignancies are multifactorial diseases, and reported data are often the only sources to estimate familial recurrence risk. Edwards' approximation formula has provided one way forward, but it uses estimates only from incidence in the general population, and is thus too simple to be widely utilized for complex individual instances. On the other hand, the heritability of malignancies has been estimated from twin studies, and it has been found that different tumors have rather different heritability. In the present study, I report a method to estimate the familial recurrence risk from the population incidence and the heritability of each malignancy, applying Falconer's liability threshold model. Trial calculations with this method using literature data support its potential use. For example, the calculation indicated that the relative risk of developing stomach cancer is 2.1 times in the first-degree relatives than in the general population whereas for leukemia the risks were estimated to be 7.4 times and 2.9 times for the first- and the second-degree relatives, respectively. Thus, the proposed method could be a useful tool in genetic counseling for risk of malignancies.
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Aconselhamento Genético , Neoplasias , Família , Predisposição Genética para Doença , Humanos , Neoplasias/epidemiologia , Neoplasias/genética , RiscoRESUMO
Key Clinical Message: COVID may manifest multisystem inflammatory syndrome in children (MIS-C) which mimics Kawasaki disease (KD). Differentiating KD and MIS-C is difficult. Immunomodulatory treatment should be initiated promptly without accurate diagnosis. Abstract: A febrile Ukrainian infant developed giant aneurysms in coronary arteries. Differentiating between Kawasaki disease and multisystem inflammatory syndrome in children was difficult. In both illnesses, coronary aneurysm may develop unless treated promptly. Therefore, guidelines should synthesize these clinical entities so that treatment can be initiated before rigorous diagnosis.
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Cause of Kawasaki disease (KD) is unknown. KD is often resistant to treatment with intravenous immunoglobulin (IVIG). Sano's score, which is derived from total bilirubin (TBIL), aspartate aminotransferase (AST) and C-reactive protein (CRP), is predictive of IVIG resistance in Japan. A recent study reported that Torquetenovirus (TTV), especially TTV7, was present at a high viral load in the patients with KD. We used PCR to quantify TTV load and amplicon next generation sequencing to detect individual TTV species. We used serum samples that were collected between 2002 and 2005 from 57 Japanese KD patients before IVIG treatment. Correlations between TTV load and Sano's score, the biomarkers that constitute this score, and IVIG resistance were examined. TTV load was positively correlated with Sano's score (P = 0.0248), TBIL (P = 0.0004), and AST (P = 0.0385), but not with CRP (P = 0.6178). TTV load was marginally correlated with IVIG resistance (P = 0.1544). Presence of TTV7 was correlated with total TTV load significantly (P = 0.0231). The correlations between biomarkers for KD and TTV load suggested that TTV may play a role in the pathophysiology of KD. We hypothesize that TTV7 may be associated with a higher total viral load in KD.
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Síndrome de Linfonodos Mucocutâneos , Torque teno virus , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Torque teno virus/genética , Síndrome de Linfonodos Mucocutâneos/complicações , Aspartato Aminotransferases , Carga Viral , Bilirrubina , Biomarcadores , Proteína C-Reativa , Estudos RetrospectivosRESUMO
BACKGROUND: Due to the coronavirus disease 2019 (COVID-19) pandemic, hygienic behaviors became a new norm since January 2020. The hygiene hypothesis predicts that an excessively hygienic environment may adversely affect human health. OBJECTIVE: We quantified the effect of COVID-19 on immunological parameters linked to the hygiene hypothesis. METHODS: We examined age-specific levels of total nonspecific immunoglobulin G (IgG) and IgE in individuals who visited Fukuoka Tokushukai Hospital between 2010 and 2021. Pre-COVID (2010-2019) and COVID (2020-2021) periods were compared. RESULTS: IgG levels steadily decreased throughout Pre-COVID period. IgG levels fell abruptly from the pre-COVID period to the COVID period in all age groups (P = 0.0271, < 0.3 years; P = 0.0096, 0.3-5 years; P = 0.0074, ≥ 5 years). The declines in IgG in < 0.3 years and that in ≥ 5 years accelerated during the COVID period. IgE levels were seasonal, but did not change noticeably from the pre-COVID to COVID period. IgG levels recorded for patients with Kawasaki disease (KD) (mean 709 mg/dL) were significantly lower than for matched control subjects (826 mg/dL) (P<0.0001). DISCUSSION: Hygienic behaviors during the COVID-19 outbreak decreased the chance of infection, which may explain the decreases in IgG levels in children and adults. Neonatal IgG declined, possibly because of the decrease in maternal IgG. CONCLUSION: Hygienic behaviors decreased the IgG levels in all age groups, from neonates to adults. This downturn in IgG may lead to vulnerability to infections as well as to KD.
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COVID-19 , Síndrome de Linfonodos Mucocutâneos , Adulto , Anticorpos Antivirais , COVID-19/epidemiologia , Criança , Humanos , Imunoglobulina E , Imunoglobulina G , Lactente , Recém-Nascido , Síndrome de Linfonodos Mucocutâneos/epidemiologia , PandemiasRESUMO
Dengue hemorrhagic fever (DHF) is a potentially fatal manifestation of an infection with the mosquito-borne dengue virus. Because of the social and economic costs of DHF, many countries in Asia and South America have initiated public health measures aimed at vector control. Despite these measures, DHF incidence rates do not appear to be declining. The effectiveness of vector control in reducing dengue transmissibility has thereby been questioned. Here, we revisit this conclusion using epidemiological data from Thailand. We first show, with age incidence data, that dengue transmission rates have fallen since 1981; surprisingly, however, these declines are not associated with decreases in DHF incidence. Instead, district-level analyses indicate a nonmonotonic relationship between the basic reproductive number R0 and DHF incidence. To understand this relationship, we formulated three mathematical models, which differ in their assumptions of transient between-serotype cross-protection. Unlike the first two models, the previously unconsidered third model with clinical cross-protection can reproduce this nonmonotonic relationship. Simulation of this model with nonstationary R0 reproduces several previously unexplained patterns of dengue dynamics, including a transition from a approximately 2-year cycle to a approximately 4-year cycle and a transient trough in DHF incidence in provinces with rapid R0 declines. These results imply that DHF incidence can be effectively controlled with a sufficiently large reduction in R0 but that moderate reductions may be counterproductive. More broadly, these results show that assuming parameter stationarity in systems with approximate stationarity in disease incidence is unjustified and may result in missed opportunities to understand the drivers of disease variability.
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Dengue/transmissão , Dengue/epidemiologia , Dengue/imunologia , Humanos , Incidência , Especificidade da EspécieRESUMO
AIM: To investigate why breastfed infants are more likely to have prolonged jaundice than formula-fed infants. METHODS: Serum unconjugated bilirubin (UCB), total cholesterol (TC) and triglyceride (TG) were measured for 102 infants of 1 month. Enrolled infants were 42 breastfed, 40 mixed-fed and 20 bottle-fed infants. Statistic analyses for relationship among UCB, TC, TG, perinatal factors and post-natal factors were performed for these infants. RESULTS: In correlation analyses UCB was correlated with peak transcutaneous bilirubin value in neonatal period (TcBn) (r = 0.612, P < 0.0001) and with TC (r = 0.383, P < 0.0001). When analyses of covariance (ANCOVA) for UCB were performed using TcBn as the covariate, the results indicated that there was neither significant main nor interaction effect of feeding method on UCB, and that main and interaction effects of TC on UCB were significant when TC was categorised into two groups (≤150 mg/dL and >150 mg/dL). CONCLUSIONS: It is suggested that both neonatal hyperbilirubinemia and subsequent higher plasma TC are associated factors for prolonged jaundice.
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Antioxidantes/análise , Bilirrubina/sangue , Colesterol/sangue , Aleitamento Materno , Feminino , Humanos , Recém-Nascido , Icterícia/etiologia , MasculinoRESUMO
INTRODUCTION: Urolithiasis in children is often due to metabolic abnormalities (e.g. hypocitraturia) and hence recurs frequently. CASE PRESENTATION: A 3-year-old boy presented with gross hematuria. Computed tomography detected a urethral calculus. The calculus was removed surgically. The stone was composed of calcium oxalate. Although oxalate and uric acid levels in the urine were within normal ranges, urine calcium was moderately elevated and urine citrate was substantially low. Urinalyses of the parents revealed that the father had acidic hypocitraturic urine, containing oxalate crystals, and the mother had hypercalciuria. Administration of oral citrate acid normalized urine citrate levels and eliminated the oxalate crystals, from the boy and his father. CONCLUSION: Although preventing urolithiasis using oral citrate is common in the adult population, this preventive measure is not well recognized in children, thus warranting further study.
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BACKGROUND: Maternally inherited diabetes and deafness, and mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes are examples of mitochondrial diseases that are relatively common in the adult population. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes are assumed to be associated with decreases in arginine and citrulline. Biomarkers, such as growth differentiation factor-15, were developed to assist in the diagnosis of mitochondrial diseases. CASE PRESENTATION: A 55-year-old Japanese man, an insulin user, presented after a loss of consciousness. A laboratory test showed diabetic ketoacidosis. He and his mother had severe hearing difficulty. Bilateral lesions on magnetic resonance imaging, the presence of seizure, and an elevated ratio of lactate to pyruvate, altogether suggested a diagnosis of mitochondrial disease. Mitochondrial DNA in our patient's peripheral blood was positive with a 3243A>G mutation, which is the most frequent cause of maternally inherited diabetes and deafness, and mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. As a result, maternally inherited diabetes and deafness/mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes was diagnosed. We measured growth differentiation factor-15 and multiple amino acids in his blood, longitudinally during and after the stroke-like episode. Growth differentiation factor-15 was increased to an immeasurably high level on the day of the stroke-like episode. Although his diabetes improved with an increased dose of insulin, the growth differentiation factor-15 level gradually increased, suggesting that his mitochondrial insufficiency did not improve. Multiple amino acid species, including arginine, citrulline, and taurine, showed a decreased level on the day of the episode and a sharp increase the next day. In contrast, the level of aspartic acid increased to an extremely high level on the day of the episode, and decreased gradually thereafter. CONCLUSIONS: Growth differentiation factor-15 can be used not only for the diagnosis of mitochondrial disease, but as an indicator of its acute exacerbation. A stroke-like episode of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes reflects a drastic derangement of multiple amino acids. The involvement of aspartic acid in the episodes should be explored in future studies.
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Surdez/diagnóstico , Diabetes Mellitus Tipo 2/diagnóstico , Síndrome MELAS/diagnóstico , Doenças Mitocondriais/diagnóstico , Arginina/sangue , Ácido Aspártico/sangue , Biomarcadores/sangue , DNA Mitocondrial/genética , Surdez/genética , Diabetes Mellitus Tipo 2/genética , Fator 15 de Diferenciação de Crescimento/sangue , Humanos , Síndrome MELAS/genética , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/genética , MutaçãoRESUMO
The profile of antimicrobial resistance (ie, antibiogram) may be disparate between children and adults. An infant developed severe deep neck infection with a multidrug-resistant microbe. The microbe was more drug-resistant in children than in adults, in our hospital. Treatment of a child should be guided by the antibiogram obtained from children.
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BACKGROUND: It has frequently been reported that Plasmodium vivax suppressed Plasmodium falciparum and ameliorated disease severity in patients infected with these two species simultaneously. The authors investigate the hypothesis that immunological responses stimulated by P. vivax may play a role in suppressing co-infecting P. falciparum. METHODS: Sera, taken sequentially from one of the authors (YN) during experimental infection with P. vivax, were added to in vitro cultures of P. falciparum. Cross-reactive antibodies against P. falciparum antigens, and cytokines were measured in the sera. RESULTS: Significant growth inhibitory effects upon P. falciparum cultures (maximally 68% inhibition as compared to pre-illness average) were observed in the sera collected during an acute episode. Such inhibitory effects showed a strong positive temporal correlation with cross-reactive antibodies, especially IgM against P. falciparum schizont extract and, to a lesser degree, IgM against Merozoite Surface Protein (MSP)-119. Interleukin (IL)-12 showed the highest temporal correlation with P. vivax parasitaemia and with body temperatures in the volunteer. CONCLUSION: These results suggest the involvement by cross-reactive antibodies, especially IgM, in the interplay between plasmodial species. IL-12 may be one of direct mediators of fever induction by rupturing P. vivax schizonts, at least in some subjects. Future studies, preferably of epidemiological design, to reveal the association between cross-reactive IgM and cross-plasmodial interaction, are warranted.
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Malária Vivax/imunologia , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/imunologia , Plasmodium vivax/imunologia , Soro/imunologia , Adulto , Animais , Anticorpos Antiprotozoários/sangue , Antígenos de Protozoários/imunologia , Reações Cruzadas , Humanos , Imunoglobulina M/sangue , Interleucina-12/sangue , Masculino , Plasmodium falciparum/crescimento & desenvolvimentoRESUMO
Kawasaki disease (KD), first identified in 1967, is a pediatric vasculitis of unknown etiology that has an increasing incidence in Japan and many other countries. KD can cause coronary artery aneurysms. Its epidemiological characteristics, such as seasonality and clinical picture of acute systemic inflammation with prodromal intestinal/respiratory symptoms, suggest an infectious etiology for KD. Interestingly, multiple host genotypes have been identified as predisposing factors for KD. To explore experimental methodology for identifying etiological agent(s) for KD and to optimize epidemiological study design (particularly the sample size) for future studies, we conducted a pilot study. For a 1-year period, we prospectively enrolled 11 patients with KD. To each KD patient, we assigned two control individuals (one with diarrhea and the other with respiratory infections), matched for age, sex, and season of diagnosis. During the acute phase of disease, we collected peripheral blood, nasopharyngeal aspirate, and feces. We also determined genotypes, to identify those that confer susceptibility to KD. There was no statistically significant difference in the frequency of the risk genotypes between KD patients and control subjects. We also used unbiased metagenomic sequencing to analyze these samples. Metagenomic sequencing and PCR detected torque teno virus 7 (TTV7) in two patients with KD (18%), but not in control subjects (P = 0.111). Sanger sequencing revealed that the TTV7 found in the two KD patients contained almost identical variants in nucleotide and identical changes in resulting amino acid, relative to the reference sequence. Additionally, we estimated the sample size that would be required to demonstrate a statistical correlation between TTV7 and KD. Future larger scale studies with carefully optimized metagenomic sequencing experiments and adequate sample size are warranted to further examine the association between KD and potential pathogens, including TTV7.
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Infecções por Vírus de DNA/complicações , Infecções por Vírus de DNA/virologia , Síndrome de Linfonodos Mucocutâneos/etiologia , Torque teno virus/fisiologia , Alelos , Biomarcadores , Pré-Escolar , Suscetibilidade a Doenças , Evolução Molecular , Feminino , Genoma Viral , Genômica/métodos , Genótipo , Humanos , Lactente , Masculino , Metagenoma , Metagenômica , Razão de Chances , Estações do AnoRESUMO
We report a family with complex febrile seizures (FS). The proband is a 15-year-old boy with seizures that persisted beyond 6 years of age. His father, aunt, and cousin also have the histories of FS until 8, 9, and 8 years old, respectively. A base substitution 5569G-->T of voltage-gated sodium channel alpha-1 subunit gene was found in DNA derived from the affected members of this family.
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Epilepsia Generalizada/genética , Saúde da Família , Mutação de Sentido Incorreto , Proteínas do Tecido Nervoso/genética , Convulsões Febris/genética , Canais de Sódio/genética , Análise Mutacional de DNA/métodos , Epilepsia Generalizada/complicações , Humanos , Masculino , Canal de Sódio Disparado por Voltagem NAV1.1 , Proteínas do Tecido Nervoso/sangue , Linhagem , Convulsões Febris/sangue , Convulsões Febris/complicações , Homologia de Sequência , Canais de Sódio/sangueRESUMO
"Missing heritability" in genome wide association studies, the failure to account for a considerable fraction of heritability by the variants detected, is a current puzzle in human genetics. For solving this puzzle the involvement of genetic variants like rare single nucleotide polymorphisms (SNPs) and copy number variations (CNVs) has been proposed. Many papers have published estimating the heritability of sets of polymorphisms, however, there has been no paper discussing the estimation of a heritability of a single polymorphism. Here I show a simple but rational method to calculate heritability of an individual polymorphism, hp(2). Using this method, I carried out a trial calculation of hp(2) of CNVs and SNPs using published data. It turned out that hp(2) of some CNVs is quite large. Noteworthy examples were that about 25% of the heritability of type 2 diabetes mellitus and about 15% of the heritability of schizophrenia could be accounted for by one CNV and by four CNVs, respectively. The results suggest that a large part of missing heritability could be accounted for by re-evaluating the CNVs which have been already found and by searching novel CNVs with large hp(2).
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Variações do Número de Cópias de DNA/genética , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Alelos , Transtorno do Espectro Autista/genética , Transtorno Depressivo/genética , Diabetes Mellitus Tipo 2/genética , Genótipo , Hereditariedade , Humanos , Razão de Chances , Esquizofrenia/genéticaRESUMO
Charcot-Marie-Tooth disease type 4C (CMT4C) is an autosomal recessive peripheral neuropathy reported in several Algerian families. The gene locus of this disease has been narrowed to 5q31-33. Recently, a missense mutation in the gene for the kinesin superfamily KIF1B was reported as the cause of Charcot Marie Tooth disease type 2A (CMT2A). We suspected that Rab6KIFL, one of the kinesin superfamily proteins, might be involved in the pathophysiology of CMT4C, because Rab6KIFL gene is located in 5q31. The coding regions of the Rab6KIFL gene of genomic DNA derived from one Algerian family with CMT4C were analyzed by direct sequencing. No mutation in Rab6KIFL gene was found in this family. Further investigation is necessary to identify the causative gene for CMT4C.
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Doença de Charcot-Marie-Tooth/genética , Cromossomos Humanos Par 5 , Cinesinas/genética , Sequência de Bases , Doença de Charcot-Marie-Tooth/fisiopatologia , Mapeamento Cromossômico , Primers do DNA , Éxons , Feminino , Humanos , Masculino , LinhagemRESUMO
Episodic ataxia type 2 (EA2) has been reported to result from mutations in the CACNA1A gene, located on chromosome 19p13. We describe a family with episodic ataxia, clinically indistinguishable from EA2, that was not caused by CACNA1A gene mutation. The proband is an 11-year-old boy, who has had 6 cerebellar ataxic attacks since 8 years of age. His attacks occurred almost monthly, lasting for 2 to 3 days. He was treated successfully with acetazolamide. His identical twin, mother and grandmother developed ataxic attacks at age 10, 34, and 50, respectively. The symptoms in his grandmother improved gradually without medication. His mother and identical twin took acetazolamide with a good response. We examined the CACNA1A gene for this family but did not detect any mutations. Furthermore, there was no evidence of genetic linkage between the CACNA1A gene and the symptomatic patients in this family. This suggests that the cause of EA2 can be heterogeneous, that is, defects of genes other than CACNA1A might be the cause of EA2.
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Canais de Cálcio/genética , Ataxia Cerebelar/genética , Criança , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Repetições Minissatélites , Linhagem , Análise de Sequência de DNARESUMO
Medical and entomological surveys were conducted to determine the risk factors of Plasmodium falciparum and P. vivax infections on Lombok Island, Indonesia, to find the risk factors and the main mosquito vectors for each malaria. Multivariate longitudinal analysis demonstrated two significant risk factors for infection with P. falciparum: disappearance of P. vivax parasitemia (p<0.001) and a specific study site (p<0.001). In contrast, younger age (p=0.024) and the interpolated virtual density of An. subpictus (p=0.041) were significantly associated with increased risk of infection with P. vivax. Thus, it seems that the distribution of P. vivax was determined largely by the presence of An. subpictus, whilst that of P. falciparum was influenced by antagonism with P. vivax. This result shows the importance of following-up treated P. vivax patients to identify recrudescence of P. falciparum in this area.
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Anopheles , Insetos Vetores , Malária Falciparum/epidemiologia , Malária Vivax/epidemiologia , Adolescente , Adulto , Distribuição por Idade , Idoso , Animais , Criança , Pré-Escolar , Humanos , Indonésia/epidemiologia , Lactente , Recém-Nascido , Larva , Modelos Logísticos , Estudos Longitudinais , Malária Falciparum/parasitologia , Malária Falciparum/transmissão , Malária Vivax/parasitologia , Malária Vivax/transmissão , Pessoa de Meia-Idade , Análise Multivariada , Densidade Demográfica , Fatores de Risco , Análise de Pequenas ÁreasRESUMO
BACKGROUND: Kawasaki disease (KD) is a common cause of acquired paediatric heart disease in developed countries. KD was first identified in the 1960s in Japan, and has been steadily increasing since it was first reported. The aetiology of KD has not been defined, but is assumed to be infection-related. The present study sought to identify the factor(s) that mediate the geographical variation and chronological increase of KD in Japan. METHODS AND FINDINGS: Based upon data reported between 1979 and 2010 from all 47 prefectures in Japan, the incidence and mean patient age at the onset of KD were estimated. Using spatial and time-series analyses, incidence and mean age were regressed against climatic/socioeconomic variables. Both incidence and mean age of KD were inversely correlated with the total fertility rate (TFR; i.e., the number of children that would be born to one woman). The extrapolation of a time-series regressive model suggested that KD emerged in the 1960s because of a dramatic decrease in TFR in the 1940s through the 1950s. CONCLUSIONS: Mean patient age is an inverse surrogate for the hazard of contracting the aetiologic agent. Therefore, the observed negative correlation between mean patient age and TFR suggests that a higher TFR is associated with KD transmission. This relationship may be because a higher TFR facilitates sibling-to-sibling transmission. Additionally, the observed inverse correlation between incidence and TFR implies a paradoxical "negative" correlation between the incidence and the hazard of contracting the aetiologic agent. It was hypothesized that a decreasing TFR resulted in a reduced hazard of contracting the agent for KD, thereby increasing KD incidence.