Japanese Public Health Insurance System's new genomic strategic action to shorten the "diagnostic odyssey" for patients with rare and intractable diseases.

In June 2024, the Japanese government introduced a new genomic strategic action to shorten the "diagnostic odyssey" for patients with rare and intractable diseases: Six groups of rare diseases, (i) Muscle weakness group, (ii) Growth retardation, intellectual disability, and characteristic facial features group, (iii) Intellectual disability/epilepsy group, (iv) Cardiomyopathy group (mainly adult onset) (v) Proteinuria group, (vi) Fever, inflammation, skin rash, osteoarthritis group, have been newly recognized as "difficult-to-differentiate disorders" and comprehensive genomic testing can be reimbursed when patients belong to one of the six groups and certain requirements are met. The introduction of comprehensive genomic testing will improve the diagnosis rate of diseases and have significant potential to enhance Japan's rare and intractable disease policy. The new strategy in Japan and its rationale will be a reference for insurance reimbursement of comprehensive genomic testing in other countries that have universal health coverage supported by the public health insurance system.

Dose-dependent mortality involving convulsions due to subarachnoid Urografin® injection in rats.

An ionically hypertonic contrast medium Urografin® was inadvertently administered into the subarachnoid space of an individual and this resulted in convulsions and acute respiratory failure. We examined the effects of subarachnoid Urografin® injections on the rat central nervous system. The onset and frequency of the convulsions, as well as fatality, were dependent on the amount of Urografin® administered. No convulsions were observed in rats receiving injections of hypertonic NaCl solution or saline. The results confirmed that subarachnoid injections of Urografin® cause convulsions and death, as previously reported in human cases, and our study ascertained the causal relationship between the above malpractice and fatal outcomes.

Laparoscopically Removed Streak Gonad Revealed Gonadoblastoma in Frasier Syndrome.

BACKGROUND: Frasier syndrome (FS) is characterized by gonadal dysgenesis and progressive nephropathy caused by mutation in the Wilm's tumor gene (WT1). We report a case of FS in which diagnosis was based on amenorrhea with nephropathy, and laparoscopically-removed streak gonad which revealed gonadoblastoma. CASE REPORT: At the age of 3 years, the patient developed nephrotic syndrome. This later became steroid-resistant and, by the age of 16 years, had progressed to end-stage renal failure with peritoneal dialysis. At the age of 17 years, the patient presented primary amenorrhea and was referred to our department. Physical examination was consistent with Tanner 1 development and external genitalia were female phenotype. Speculum examination showed uterine cervix and uterine body and bilateral ovaries were not palpable on pelvic examination. Multi-sliced computed tomography of abdomen and pelvis revealed streaked structure along the bilateral external iliac artery at pelvic wall and hypoplastic uterus. Serum testing revealed primary hypogonadism pattern, elevated follicle-stimulating hormone and luteinizing hormone with low concentrations of estradiol and testosterone. The patient underwent genetic counseling with her parents. Chromosomal status was 46XY karyotype and DNA sequencing confirmed FS due to a heterozygous WT1 mutation (IVS9+5G>A). Elective laparoscopic bilateral salpingo-oophorectomy was performed to avoid increased risk for gonadoblastoma. Pathological examination revealed gonadoblastoma in the right gonad. CONCLUSION: Although a rare disease, the diagnosis of FS should be considered in the case of primary amenorrhea with nephropathy. Prophylatic gonadectomy is recommended due to the high risk of gonadoblastoma in the dysgenetic gonad.

Hippocampal neuronal degeneration in the traumatic brain injury mouse: non-trivial effect of scalp incision.

OBJECTIVES: In experimental models of traumatic brain injury (TBI), posttraumatic hippocampal neuronal degeneration in the cornu ammonis 1 (CA1), and/or the cornu ammonis 3 (CA3) regions are regarded as the most notable phenotypic appearances relating to the pathophysiology of human post-concussion syndrome. However, these morphological changes are often also seen in subjects without TBI, namely 'sham' groups. The frequencies and reasons of appearance of hippocampal neuronal degeneration in mice with TBI and/or sham are not clear. METHODS: We compared the frequencies of hippocampal neuronal degeneration among three groups: TBI (mice with external force impact performed by Marmarou's weight drop model after scalp incision), sham (mice with scalp incision alone), and control (mice with neither external force impact nor scalp incision), using hematoxylin and eosin stain in day 6 (n = 5 in each group.) Isoflurane was used for anesthesia in all mice. RESULTS: The frequencies were 80, 100, and 20% in CA1, and 20, 40, and 60% in CA3, for TBI, sham, and control, respectively. In CA1, a significant difference of the frequency was observed between sham and control (p = 0.048), but not, between TBI and sham (p = 1.000) in Fisher's exact test. In CA3, no significant difference in the frequency was observed between the three groups. CONCLUSION: Scalp incision, rather than external impact force, might affect the CA1 hippocampal neuronal degeneration in mice with TBI. In addition, factor(s) other than external impact force or scalp incision may also cause hippocampal neuronal degeneration in both CA1 and CA3. Careful interpretation is needed concerning hippocampal neuronal degeneration induced by a weight drop device observed in mice with TBI.

The histopathological structures of the extrapleural hematoma wall: A case report.

Extrapleural hematoma is a rare condition in which blood is present in the extrapleural space, which sometimes causes death due to respiratory failure. Although a single low-density stripe, called a "displaced extrapleural fat sign," can be detected in chest computed tomographic (CT) scans, no reports have confirmed this structure histopathologically. We performed an autopsy on a patient with extrapleural hematoma who died of respiratory failure. An extrapleural fat sign was detected on the antemortem CT. We investigated the wall structure histopathologically. The hematoma wall was composed of parietal pleura, a sub-pleural layer, an extrapleural fat layer and endothoracic fascia. The case indicated that extrapleural hematoma occurs at the endothoracic fascia.

Fatal overdose from synthetic cannabinoids and cathinones in Japan: demographics and autopsy findings.

BACKGROUND: Sixty-one autopsy cases involving cathinones and/or cannabinoids (synthetic cathinones/cannabinoids) use have been reported. However, little is known about the demographics and autopsy findings in fatal synthetic cathinones/cannabinoids users. OBJECTIVES: To elucidate demographic and autopsy findings (i.e. major organ pathology and causes of death) in synthetic cathinones/cannabinoids cases. METHODS: We reviewed forensic autopsy reports in Department of Legal Medicine of Tokyo Women's Medical University (Tokyo, Japan) between 2011 and 2015 (a total of 359). We compared demographic and autopsy findings between synthetic cathinones/cannabinoids and methamphetamine cases (as control subjects). RESULTS: There were 12 synthetic cathinones/cannabinoids cases and 10 methamphetamine cases. Synthetic cathinones/cannabinoids users were significantly younger than methamphetamine users (p < 0.01), and there were no cases that used both synthetic cathinones/cannabinoids and methamphetamine. Acute intoxication and cardiac ischemia were the two most prominent causes of death in both synthetic cathinones/cannabinoids users and methamphetamine users. Excited delirium syndrome and pulmonary aspiration were found only in synthetic cathinones/cannabinoids cases. CONCLUSIONS: The populations of synthetic cathinones/cannabinoids and methamphetamine users who died of an overdose are different in Japan. Acute intoxication, cardiac ischemia, excited delirium syndrome, pulmonary aspiration, and drowning are the major autopsy findings in synthetic cathinones/cannabinoids-related death. Clinicians shuld be aware of these potentially fatal complications in the medical management of synthetic cathinones/cannabinoids users.

Gonadal tumor in Frasier syndrome: a review and classification.

Frasier syndrome is a rare inherited disease characterized by steroid-resistant nephrotic syndrome, gonadal tumor, and male pseudohermaphroditism (female external genitalia with sex chromosomes XY), which is based on a splice site mutation of Wilms tumor-suppressor gene 1 (WT1). Several unusual Frasier syndrome cases have been reported in which male pseudohermaphroditism was absent. We reviewed 88 Frasier syndrome cases in the literature and classified them into three types (type 1-3) according to external genitalia and sex chromosomes, and described their clinical phenotypes. Type 1 Frasier syndrome is characterized by female external genitalia with 46,XY (n = 72); type 2 by male external genitalia with 46,XY (n = 8); and type 3 by female external genitalia with 46,XX (n = 8). Clinical course differs markedly among the types. Although type 1 is noticed at the mean age of 16 due to mainly primary amenorrhea, type 2 and 3 do not present delayed secondary sex characteristics, making diagnosis difficult. The prevalence of gonadal tumor is high in type 1 (67%) and also found in 3 of the 8 type 2 cases, but not in any type 3 cases, which emphasize that preventive gonadectomy is unnecessary in type 3. On the basis of our findings, we propose a new diagnostic algorithm for Frasier syndrome.

Gender differences in D-aspartic acid content in skull bone.

In forensic medicine, the personal identification of cadavers is one of the most important tasks. One method of estimating age at death relies on the high correlation between racemization rates in teeth and actual age, and this method has been applied successfully in forensic odontology for several years. In this study, we attempt to facilitate the analysis of racemized amino acids and examine the determination of age at death on the basis of the extent of aspartic acid (Asp) racemization in skull bones. The specimens were obtained from 61 human skull bones (19 females and 42 males) that underwent judicial autopsy from October 2010 to May 2012. The amount of D-Asp and L-Asp, total protein, osteocalcin, and collagen I in the skull bones was measured. Logistic regression analysis was performed for age, sex, and each measured protein. The amount of D-Asp in the female skull bones was significantly different from that in the male skull bones (p = 0.021), whereas the amount of L-Asp was similar. Thus, our study indicates that the amount of D-Asp in skull bones is different between the sexes.