Heritability of cancers in Japanese population: Estimation from recent cohort data.

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.

Viral load of Torquetenovirus correlates with Sano's score and levels of total bilirubin and aspartate aminotransferase in Kawasaki disease.

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.

A Ukrainian infant with giant coronary aneurysms: A case report and literature review.

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.

Identification of Torquetenovirus Species in Patients with Kawasaki Disease Using a Newly Developed Species-Specific PCR Method.

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.

Hygienic behaviors during the COVID-19 pandemic may decrease immunoglobulin G levels: Implications for Kawasaki disease.

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.

Estimation of familial recurrence risk of malignancy: Application of liability threshold model in genetic counseling.

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.

Formation of a calcium oxalate urethral stone in a 3-year-old boy due to hypocitraturia.

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.

Dynamic derangement in amino acid profile during and after a stroke-like episode in adult-onset mitochondrial disease: a case report.

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.

An intubated 7-month-old infant with a retropharyngeal abscess and multidrug-resistant Streptococcus mitis.

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.

A novel variant of torque teno virus 7 identified in patients with Kawasaki disease.

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.

Copy number variations play important roles in heredity of common diseases: a novel method to calculate heritability of a polymorphism.

"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).

Decreasing fertility rate correlates with the chronological increase and geographical variation in incidence of Kawasaki disease in Japan.

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.

A patient with hypereosinophilic syndrome that manifested with acquired hemophilia and elevated IgG4: a case report.

INTRODUCTION: Hypereosinophilic syndrome is defined as a prolonged state (more than six months) of eosinophilia (greater than 1500 cells/µL), without an apparent etiology and with end-organ damage. Hypereosinophilic syndrome can cause coagulation abnormalities. Among hypereosinophilic syndrome types, the lymphocytic variant (lymphocytic hypereosinophilic syndrome) is derived from a monoclonal proliferation of T lymphocytes. Here, we describe the case of a patient with lymphocytic hypereosinophilic syndrome who presented with a coagulation abnormality. To the best of our knowledge, this is the first such report including a detailed clinical picture and temporal cytokine profile. CASE PRESENTATION: A 77-year-old Japanese man presented to our facility with massive hematuria and hypereosinophilia (greater than 2600 cells/µl). His eosinophilia first appeared five years earlier when he developed femoral artery occlusion. He manifested with multiple hematomas and prolonged activated partial thromboplastin time. His IgG4 level was remarkably elevated (greater than 2000 mg/dL). Polymerase chain reaction tests of peripheral blood and bone marrow identified lymphocytic hypereosinophilic syndrome. His prolonged activated partial thromboplastin time was found to be due to acquired hemophilia. Glucocorticoids suppressed both the hypereosinophilia and coagulation abnormality. However, tapering of glucocorticoids led to a relapse of the coagulation abnormality alone, without eosinophilia. Tumor necrosis factor α, interleukin-5, and/or eotaxin-3 may have caused the hypereosinophilia, and interleukin-10 was correlated with the coagulation abnormality. CONCLUSIONS: To the best of our knowledge, this is the first case in which lymphocytic hypereosinophilic syndrome and IgG4-related disease have overlapped. In addition, our patient is only the second case of hypereosinophilic disease that manifested with acquired hemophilia. Our patient relapsed with the coagulation abnormality alone, without eosinophilia. This report shows that the link between eosinophilia, IgG4, and clinical manifestations is not simple and provides useful insight into the immunopathology of hypereosinophilic syndrome and IgG4-related disease.

Geographical association between socioeconomics and age of dengue haemorrhagic fever patients in Surabaya, Indonesia.

A study was designed to correlate the ages of dengue patients to the geographical and temporal demographic structure in 28 districts in Surabaya, Indonesia, between 1996 and 2005. The geographical distribution of the mean patient age was stable throughout the study period. The mean patient age did not correlate with the demographic structure but was related to the prevalence of poor housing where mosquito density was high. These results suggested that socioeconomic factors which affect mosquito abundance are more important determinants of the mean age of DHF patients than the demographic variables.

Correlation between unconjugated bilirubin and total cholesterol in the sera of 1-month-old infants.

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.

Relationship between transmission intensity and incidence of dengue hemorrhagic fever in Thailand.

BACKGROUND: Dengue is the most prevalent mosquito-borne virus, and potentially fatal dengue hemorrhagic fever (DHF) occurs mainly in secondary infections. It recently was hypothesized that, due to the presence of cross-immunity, the relationship between the incidence of DHF and transmission intensity may be negative at areas of intense transmission. We tested this hypothesis empirically, using vector abundance as a surrogate of transmission intensity. METHODOLOGY/PRINCIPAL FINDINGS: House Index (HI), which is defined as the percentage of households infested with vector larvae/pupae, was obtained from surveys conducted on one million houses in Thailand, between 2002 and 2004. First, the utility of HI as a surrogate of transmission intensity was confirmed because HI was correlated negatively with mean age of DHF in the population. Next, the relationship between DHF incidence and HI was investigated. DHF incidence increased only up to an HI of about 30, but declined thereafter. Reduction of HI from the currently maximal level to 30 would increase the incidence by more than 40%. Simulations, which implemented a recently proposed model for cross-immunity, generated results that resembled actual epidemiological data. It was predicted that cross-immunity generates a wide variation in incidence, thereby obscuring the relationship between incidence and transmission intensity. The relationship would become obvious only if data collected over a long duration (e.g., >10 years) was averaged. CONCLUSION: The negative relationship between DHF incidence and dengue transmission intensity implies that in regions of intense transmission, insufficient reduction of vector abundance may increase long-term DHF incidence. Further studies of a duration much longer than the present study, are warranted.

Suppression of Plasmodium falciparum by serum collected from a case of Plasmodium vivax infection.

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.

Decreases in dengue transmission may act to increase the incidence of dengue hemorrhagic fever.

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.

Decreased expression of hypothalamic neuropeptides in Huntington disease transgenic mice with expanded polyglutamine-EGFP fluorescent aggregates.

Huntington disease is caused by polyglutamine (polyQ) expansion in huntingtin. Selective and progressive neuronal loss is observed in the striatum and cerebral cortex in Huntington disease. We have addressed whether expanded polyQ aggregates appear in regions of the brain apart from the striatum and cortex and whether there is a correlation between expanded polyQ aggregate formation and dysregulated transcription. We generated transgenic mouse lines expressing mutant truncated N-terminal huntingtin (expanded polyQ) fused with enhanced green fluorescent protein (EGFP) and carried out a high-density oligonucleotide array analysis using mRNA extracted from the cerebrum, followed by TaqMan RT-PCR and in situ hybridization. The transgenic mice formed expanded polyQ-EGFP fluorescent aggregates and this system allowed us to directly visualize expanded polyQ aggregates in various regions of the brain without performing immunohistochemical studies. We show here that polyQ-EGFP aggregates were intense in the hypothalamus, where the expression of six hypothalamic neuropeptide mRNAs, such as oxytocin, vasopressin and cocaine-amphetamine-regulated transcript, was down-regulated in the transgenic mouse brain without observing a significant loss of hypothalamic neurons. These results indicate that the hypothalamus is susceptible to aggregate formation in these mice and this may result in the down-regulation of specific genes in this region of the brain.