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Blood biomarkers are minimally invasive, are available at a relatively low cost, and are easily accessible; therefore, they are expected to play a pivotal role in the diagnosis of dementia. Measurement of the amyloid-β ratio and phosphorylated tau in plasma has shown high potential for accurate detection of brain pathology in patients with Alzheimer's disease. Studies have investigated blood biomarkers that reflect neurodegeneration and neuroinflammation in patients with dementia. Challenges associated with blood biomarker use include the lack of robustness of the test and the role of confounders that potentially prevent their immediate clinical application. Further real-world studies are warranted to validate the usefulness of blood biomarkers in dementia management. Appropriate recommendations for the use of blood biomarkers for dementia have been published for physicians and investigators, both in Japan and overseas. Considering the versatility of blood biomarkers, they should be cautiously introduced for clinical use.

This study aimed to clarify associations of clinical and neuropsychological features and change in regional cerebral blood flow (rCBF) on 123 I-IMP-SPECT in patients with Parkinson's disease (PD) who developed dementia. Sixty-one PD patients (mean age, 65.9 ± 8.6 years; mean disease duration, 11.0 ± 11.0 years) were recruited and followed-up for two years. Clinical and neuropsychological characteristics, and rCBF from SPECT were compared between PD patients who developed dementia (PDD+) and those who remained undemented (PDD-). Thirty-eight PD patients (62.3%) were diagnosed with PD-MCI at baseline. During follow-up, 22 PD patients (36%) developed dementia (PDD+). Univariate logistic regression models showed that Hoehn and Yahr scale 4 (odds ratio [OR] 5.85; 95% confidence interval [CI] 1.35-30.75]), visual hallucination (OR 5.95; 95%CI 1.67-25.4]), and PD-MCI (OR 6.47; 95%CI 1.57-39.63]) represented a significant risk factor for PDD+. Among neuropsychological parameters, WAIS (Wechsler Adult Intelligence Scale)-III block design (OR 6.55; 95%CI 1.66-29.84), letter number sequencing (OR 7.01; 95%CI 1.65-36.64), digit-symbol coding (OR 3.90; 95%CI 1.13-14.2), Wechsler Memory Scale, revised (WMS-R) visual paired associates II (delayed recall) (OR 4.68; 95%CI 1.36-17.36), Logical memory I (immediate recall) (OR 8.30; 95%CI 1.37-90.89), Logical memory II (delayed recall) (OR 6.61; 95%CI 1.35-44.33), Visual reproduction I (immediate recall) (OR 7.67; 95%CI 2.11-31.40), and Visual reproduction II (delayed recall) (OR 5.64; 95%CI 1.62-21.47) were significant risk factors. Decreased rCBF assessed using the general linear model (two-sample t-test) by SPM8 was observed in the left precuneus (0, -66, 16), right cuneus (6, -76, 30), and left angular gyrus (-46, -74, 32) in PDD+ compared with PDD- patients. Collectively, we have here shown that clinical and neuropsychological characteristics as well as changes to rCBF in PD patients who converted to PDD+. These features should be carefully monitored to detect the development of dementia in PD patients.

At the Department of Pharmacy of Fukuoka University Hospital, hepatitis B virus(HBV)screening tests, and HBV-DNA quantitative monitoring, are conducted before starting chemotherapy with injectable anticancer drugs. If certain tests have not been performed, the pharmacists order them as part of the protocol based pharmacotherapy management(PBPM)system. However, the status of HBV-related testing among patients taking oral anticancer drugs is unclear. Therefore, we surveyed the status of HBV-related testing in patients, who were prescribed oral anticancer drugs with a label warning regarding HBV reactivation, at our hospital between August 1 and September 30, 2021. We examined the effect of pharmacist support for HBV reactivation measures based on the PBPM. During the study, 247 patients were prescribed oral anticancer drugs, and 36% did not undergo HBV screening or HBV-DNA quantitative monitoring. Screening or monitoring was performed in most cases after they were ordered by the pharmacists or after informing the physicians. These results suggest that HBV-related testing in patients taking oral anticancer drugs is inadequate, and pharmacist support based on the PBPM may help prevent the development of hepatitis and facilitate the continuation of anticancer drug treatment for underlying diseases.

This study aimed to clarify associations between neuropsychological scales and regional cerebral blood flow (rCBF) of on ‍ 123 I-IMP-SPECT in patients with Parkinson's disease with mild cognitive impairment (PD-MCI). Forty-two participants (mean age, 65.5 ± 8.9 years; mean disease duration, 11.1 ±5.7 years) were evaluated using the Wechsler Adult Intelligence Scale, third edition (WAIS-III), Wechsler Memory Scale, revised (WMS-R), Stroop test, Category word fluency, Auditory verbal learning test, Raven colored progressive matrices, Trail Making Test-B, and Clock drawing test. Participants were classified into PD-MCI and PD non-demented (PD-ND) using ten of these scales or its subtests. The rCBF of the posterior cingulate gyrus, precuneus, and parietal lobes was evaluated by ‍ 123 I-IMP-SPECT using the easy Z-‍score imaging system (eZIS analysis). Extent was the extent index of voxels showing z-score > 2, and Severity was mean z-score in those regions on eZIS analysis. Cingulate island sign score (CIScore) was the ratio of integrated z-scores of the posterior cingulate gyrus to those of the posterior cortex.Twenty-three participants were diagnosed with PD-MCI (55%). The rCBF indices were significantly increased in the PD-MCI group compared to the PD-ND group (Extent: P = 0.047; CIScore: P = 0.006). These indices were significantly correlated with WAIS-III Processing Speed (Extent: P = 0.041, R = -0.317; Severity: P = 0.047, R = -0.309), Stroop effect (Extent: P = 0.003, R = 0.443; Severity: P = 0.004, R = 0.437), WMS-R Visual memory (Extent: P = 0.019, R = -0.361; Severity: P = 0.014, R = -0.375), and Delayed memory score (Extent: P = 0.005, R = -0.423; Severity: P = 0.044, R = -0.312). The rCBF indices showed no correlations with the number of impaired cognitive domains. Collectively, decreased posterior parietal area rCBF and lower scores on selective neuropsychological scales might be helpful to detect a transition period from PD-MCI to PD-D.

Microglia originating from yolk sac exert various functions to maintain the homeostasis in the brain, and their functional breakdown appears to be involved in the pathophysiology of various neurological diseases. In this review article, loss of homeostatic microglia and new therapeutic approaches for rare neurological disorders are discussed. ASLP (adult-onset leukoencephalopathy with axonal spheroids and pigmented glia) known as a primary microgliopathy is an adult-onset leukoencephalopathy caused by CSF1R mutation. CSF1 receptor encoded by CSF1R plays an important role in the function of microglia. In brain of ALSP patients, homeostatic microglia are significantly reduced. The biallelic mutations for CSF1R cause childhood-onset severe phenotype and elimination of microglia from the brain parenchyma. Since microglia also almost disappear in CSF1R-deficient mice and rats, CSF1R deficiency and loss of microglia appear to be tightly associated across species. Based on the underlying mechanism of homeostatic microglia loss, novel approaches using cell transplantation of normal microglia-like cells have been attempted. Transplantation of wild-type bone marrow cells into Csf1r-/- mice results in replacement by donor-derived microglial-like cells in the recipient's brain. The concept of "microglial niche" may explain the rationale behind the microglial cell transplantation in disease condition(s). Hematopoietic stem cell transplantation (HSCT) has been attempted in 4 patients with ALSP. Beneficial effects by showing stabilization of the disease course have been observed. Although the effectiveness of HSCT for ALSP patients warrants further investigation, the approach of cell transplantation that replaces ruptured homeostatic microglia with normal microglia-like cells seems to be promising.

Objectives　This study aimed to determine risk factors for frailty and lifestyle-related diseases impacting the incidence of loss of independence among Japanese community-dwelling older adults, and to measure the magnitude of these associations.Methods　We conducted an 8.1-year prospective study involving 1,214 residents of the town of Kusatsu, aged 65 years and over, who were initially free of disability and underwent the comprehensive geriatric assessment between 2002 and 2011. Loss of independence was defined as the incidence of disability or having died before the occurrence of disability was certified by the Long-Term Care Insurance program in Japan. Risk factors for lifestyle-related diseases and health status comprised hypertension, diabetes mellitus, overweight, chronic kidney disease, current smoking, past history of stroke, heart disease and cancer, frailty, underweight, anemia, hypoalbuminemia, and cognitive decline. Frailty was defined as the presence of three or more of the following criteria: Weight loss, weakness, exhaustion, slowness, and low levels of physical activity. Prefrailty was defined as the presence of one or two of these same criteria. Cox proportional-hazard regression model was used to estimate hazard ratios (HR) and the population attributable fraction (PAF) of loss of independence.Results　During the follow-up, 475 cases, including 372 disabilities and 103 deaths, were identified as having experienced loss of independence. The multivariable HRs for the loss of independence were 1.3 to 2.2-fold higher for the presence of frailty, past history of stroke, cognitive decline, prefrailty, and smoking. The PAF of loss of independence was the greatest for prefrailty (19%), followed by frailty (12%). The PAF was relatively large for prefrailty (19%) and smoking (11%) in men, and frailty (18%), prefrailty (18%), and chronic kidney disease (11%) in women. Stratified by age category, participants aged 65-74 years having frailty and several lifestyle-related diseases showed significantly higher HRs for loss of independence and greater PAFs for prefrailty (18%), frailty (13%), and smoking (11%).Conclusions　Loss of independence among Japanese community-dwelling older adults who underwent screening examinations was largely attributed to frailty and prefrailty. Our findings suggest that the screening and the intervention for frailty and lifestyle-related diseases in the early stages of old age might be beneficial in prolonging healthy life expectancy of Japanese community-dwelling older adults.

During the past 20 years, genome studies for Alzheimer's disease (AD) have elucidated the pathogenesis of AD including the amyloid hypothesis. However, clinical trials of the disease modifying drugs for AD developed based on the amyloid hypothesis have been largely unsuccessful. New genes associated with AD have been identified through comprehensive genome analyses such as genome-wide association studies and whole genome/exome sequencing using next-generation sequencers. With these efforts, new therapeutic targets to AD have been explored. This review summarizes the genetic make-up of AD in terms of both risk and protective factors from the viewpoint of novel therapeutic targets to AD.

The Dominantly Inherited Alzheimer's Network (DIAN) observational study compared pathophysiological markers between mutation carriers and non-carriers in autosomal dominant Alzheimer's disease. This study revealed that changes in the biomarkers in the mutation carrier's brain start as early as 20 or even 25 years prior to the onset of symptoms. Doctors of the DIAN-Japan team have successfully implemented the DIAN study in Japan (DIAN-J) with effort and enthusiasm. The DIAN-J study is completely compatible with the DIAN study. All members of the DIAN-J team were certified by the NIH and Washington University. The DIAN researchers started a prevention trial (DIAN-TU) testing two monoclonal antibodies in 2013. Together with the DIAN global members including the Japanese team, they will start the new DIAN-TU NexGen Trial testing a BACE inhibitor in 2017. The API study is another clinical trial of anti-amyloid monoclonal antibody therapy for family members of patients with early-onset familial AD who carry the PSEN1 E280A mutation. This study has shown the same biomarker changes that were reported in the DIAN study.

Cutting-edge genomics technologies have substantially improved our understanding of the pathogenesis of Alzheimer's disease (AD). The identification of mutations in APP, PSEN1, and PSEN2 causative for autosomal dominant AD (ADAD) has provided the basis of the "amyloid cascade" hypothesis of the pathogenetic mechanism of AD. While a number of therapeutic candidates targeting amyloid-β were developed using genetically engineered mouse models of ADAD, none have proven successful in mitigating the symptoms of AD in phase III clinical trials. Thus, we must reconsider the modification of AD pathogenesis by targets within the amyloid cascade, and explore new targets for AD therapy. This review provides a comprehensive summary of the recent genetic studies of AD from this perspective, and discusses prospective and emerging therapeutic interventions for patients with AD.

Numerous epidemiological studies have shown that the apolipoprotein E gene (APOE) is a strong genetic risk factor for Alzheimer's disease (AD) among people from various ethnic backgrounds. ApoE occurs as three isoforms that differ at two amino acids residues (112 and 158): ApoE ε2, ε3, and ε4. The ε4 allele is responsible for a genetic predisposition to AD, increasing the risk of AD by approximately 4-fold compared to the common ε3 allele. In contrast, the ε2 allele shows a protective effect against AD. APOE ε4 is known to affect the age at onset of AD in a dose-dependent manner. In addition to the role of genetic risk, increasing evidence suggests that the substantial effects of APOE genotypes on cognitive function, imaging and biomarker findings, have been reported in cognitively normal individuals in an age-dependent manner. A high frequency of amyloid deposition among cognitively normal, aged individuals carrying the APOE ε4 allele has been demonstrated. This suggests that APOE ε4 facilitates amyloid deposition during the very early phase of AD pathogenesis. Preventive intervention by using disease-modifying drugs is now being investigated through an exploratory clinical trial for the cognitively normal, aged individuals with the APOE ε4 allele.

The Alzheimer's Disease Cooperative Study (ADCS) started in 1991 as part of an agreement between the National Institute on Aging (NIA) and the University of California, San Diego, is a major clinical activity for treating Alzheimer's disease (AD). As part of the NIA Division, the ADCS supports all activities for AD treatment, including the discovery and evaluation of new diagnostic methods, drugs, and devices for patients with AD, as well as the prevention of AD.

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an early-onset dementia that predominantly affects the cerebral white matter. After the discovery of a gene encoding the colony stimulating factor 1 receptor (CSF-1R) as a causative gene in patients with HDLS, gene analysis of CSF-1R enabled the diagnosis of HDLS without histopathological evidence. To clarify the genetic and clinical characteristics of HDLS, here, we reviewed the characteristics of patients with HDLS with CSF-1R mutations in the literature. Seventy-three patients from 54 pedigrees with HDLS from various ethnic backgrounds have been reported. Among them, Japanese patients account for 22% (16 patients from 15 pedigrees). Mean age at onset was 45 years (18 to 78 years). A wide range of clinical features including cognitive decline, behavioral changes, seizures, pyramidal signs, and parkinsonism have been described in these patients. Various kinds of mutations were found in the tyrosine kinase domain of CSF-1R. A frameshift mutation causing nonsense-mediated mRNA decay was also described. This suggests that haploinsufficiency of CSF-1R is sufficient to cause HDLS. Neuropathological analysis revealed that microglia in the brains of patients demonstrated distinct morphology and distribution. These results suggest that primary microglial dysfunction due to CSF-1R signaling perturbation may underlie the pathogenesis of HDLS.

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal dominant early-onset dementia that affects the cerebral white matter predominantly. Mutations in colony stimulating factor-1 receptor (CSF-1R) were identified as the genetic cause of HDLS, and this enabled the antemorterm diagnosis of HDLS by genetic testing. This review paper describes clinical and neuroimaging findings in genetically-proven HDLS cases. The mean age at onset was 45 years ranging from 18 to 78 years. The most frequent initial symptom was cognitive decline. A wide range of clinical features including intellectual decline, behavioral and character changes, convulsion, pyramidal signs and motor symptoms have been described. Series of brain MRI study exhibit the white matter changes on FLAIR images, which were occasionally asymmetric in the early phase of the disease. Early MRI features are alteration of corpus callosum and dilatation of lateral ventricles showing central atrophy. Hyperintensity lesions detected by diffusion weighted images were detectable in some cases with HDLS. Brain CT study showed spotty calcification in the affected white matter. HDLS is not rare disease and should be considered as differential diagnosis of early-onset dementia exhibiting the white matter disease.

Dementia with Lewy bodies (DLB) is the second most common cause of neurodegenerative dementia in the elderly. DLB is clinically characterized by fluctuating cognitive dysfunction, visual hallucinations, and parkinsonism. It is sometimes difficult to clinically diagnose patients with DLB because of the overlap of the clinical and pathological findings of this disease with those of Alzheimer's disease. Precise clinical diagnosis is important for determining the drug therapy appropriate for improving DLB symptoms. Biomarkers that enable more accurate diagnosis of DLB and reflect its complex clinical progression are highly desired. Cognitive impairment frequently occurs in patients with Parkinson's disease (PD). The common pathological features of DLB and PD are Lewy bodies and Lewy neurites, both of which are composed of α-synuclein. DLB and PD are now considered to belong to a common spectrum of disorders designated as Lewy body disease (LBD). We have previously reported that the α-synuclein levels in cerebrospinal fluid (CSF) are significantly lower in patients with DLB than in patients with other types of dementia. However, the significance of quantifying the CSF α-synuclein levels as a biomarker for DLB has been a matter of debate because the results for these levels have been inconsistent among different studies. Similar inconsistency has been observed in studies on the plasma α-synuclein levels in patients with LBD. Here, we review the recent progress on biomarkers of LBD, especially in DLB, and discuss their application to clinical diagnosis.

Adult-onset leukoencephalopathy involving the white matter of the brain is a heterogeneous disorder that exhibits a wide range of clinical manifestations. Recent advances in molecular genetics enable gene-based diagnosis of some forms of adult-onset leukoencephalopathy. In this review, the classification of adult-onset leukoencephalopathy based on molecular genetic findings is proposed. The autosomal dominant forms of adult-onset leukoencephalopathy include hereditary diffuse leukoencephalopathy with spheroids (HDLS), autosomal dominant adult-onset leukoencephalopathy (ALDL), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and Alexander disease. The autosomal recessive forms of adult-onset leukoencephalopathy include cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), vanishing white matter (VWM) with leukoencephalopathy, Nasu-Hakola disease, and metachromatic leukodystrophy (MDL). X-chromosome-linked disorders include fragile X-associated tremor and ataxia syndrome (FXTAS) and adrenoleukodystrophy (ALD). Identification of the genes responsible for adult-onset leukoencephalopathy provides an important clue for elucidation of molecular pathophysiology underlying white matter disorders. One example is the identification of mutations in colony stimulating factor 1 receptor (CSF-1R) in patients with HDLS. Missense and splice site mutations have been found in the tyrosine kinase domain of CSF-1R. CSF-1R is highly expressed in microglia in the brain. It has been demonstrated that mice depleted of CSF-1R exhibit loss of microglia in the brain. In addition, stimulation of IL-34, a ligand of CSF-1R, induces proliferation and activation of microglia. These findings raise an intriguing possibility that dysfunction of microglia may play a role in the pathogenesis of white matter lesions occurring in patients with HDLS.

We report the case of a 76-year-old man with apraxia of eyelid opening (AEO) and amyotrophic lateral sclerosis with dementia (ALS-D)/frontotemporal lobar degeneration with motor neuron disease (FTLD-MND). The initial symptom was AEO. Neurological examination revealed mainly bulbar symptoms with a neurogenic pattern on needle electromyograms of the tongue muscles and the biceps muscles. Furthermore, he developed severe dementia with frontal lobe dysfunction and progressive non-fluent aphasia. Brain magnetic resonance imaging revealed severe cerebral atrophy and leukoaraiosis in the bilateral frontal lobes and the anterior part of the bilateral temporal lobes; brain 99mTc ethyl cysteinate dimer single photon emission computed tomography (ECD SPECT) showed hypoperfusion in the same areas. The patient showed improvement in stereotyped behavior and AEO after treatment with 50 mg/day of fluvoxamine maleate (the initial dose was 25 mg/day). Because serotonin receptors are markedly reduced in the frontal and temporal cortexes of patients with FTLD, we considered that dysfunction of the serotonergic system in the frontotemporal lobe caused AEO. Considering the findings of this case along with those of previous reports, we propose that there is a relatively homogeneous development of ALS-D/FTLD-MND with AEO.

We report a sporadic case of a female patient with oculopharyngeal muscular dystrophy (OPMD). Her father died at age 86 and mother at age 74. There was no familial occurrence of the disease. The patient initially developed a nasal voice at age 66. Neurological examinations on admission at age 72 revealed bilateral ptosis, a limitation of ocular movement without diplopia, dysphagia, and proximal muscle weakness. Serum creatine kinase level was slightly increased. Biopsied muscle specimens showed variation in fiber size as well as the occasional presence of rimmed vacuoles. On the basis of these clinical and laboratory findings, we suspected a diagnosis of OPMD, although a family history was absent. To confirm the diagnosis of OPMD, we performed a gene analysis for poly A binding protein, nuclear 1 (PABPN1; PABP2), which revealed a mild expansion of GCG repeat (8 repeats) as a heterozygous state. Clinical features of the patient were consistent with those in a previous literature reporting that patients carrying (GCG)8 repeat as a heterozygous state show a relatively late onset and a mild phenotype. The case of this patient emphasizes the importance of the PABPN1 gene analysis for patients showing muscular weakness involving oculopharyngeal and proximal limb muscles even when a familial occurrence of the disease is not apparent.

A 42-year-old man complained of severe left orbital pain for 7 months. The diagnosis of cluster headache was made on the basis of diagnostic criteria formed by the International Headache Society. Sumatriptan was effective in relieving pain to a certain degree, but the frequency of the occurrence of pain gradually increased. Subsequently, he presented sensory disturbances in the left trigeminal nerve, and was admitted to our hospital. On admission, his neurological examination revealed left miosis and paresthesia in the first branch of the left trigeminal nerve. Neither anhidrosis nor ptosis was noted. His autonomic failure was consistent with post-synaptic disturbance as determined by pharmacological analysis for pupil's function. On the basis of the unique combination of neurological sings and symptoms including the unilateral headache, partial Horner's syndrome, and V1 sensory disturbance, we diagnosed him as having Raeder's syndrome. To exclude the possibility of a lesion in the Gasser ganglion of the middle fossa of the cranium or carotid artery causing symptomatic Raeder's syndrome, imaging studies including brain MRI, cervical MRA, and Doppler ultrasonography were performed, which revealed normal findings. We started him on oral prednisolone at 1 mg/kg once a day, which resulted in a rapid and dramatic suppression of pain. Thus, this case showed a progression from cluster headache to idiopathic Raeder's syndrome, which suggests that these two disorders might share common pathological and anatomical lesions.

The effects of simulated microgravity on mammalian reproduction were studied using tail-suspended mice, during parabolic flight in a jet plane and in a horizontal clinostat device. In the tail-suspended mouse, which is a model of the shift of body fluid in a microgravity environment, atrophy of the testis and decrease of serum testosterone level were observed. The sperm motility decreased in the muG condition produced by the parabolic flight. There were no statistically significant differences in the efficiency of achieving normal fertilization in vitro, but there was a statistically significant decrease in the number of embryos reaching the morula and blastocyst stages after 96 hours in culture under clinostat rotation. These results suggest that the process of fertilization in vitro is not sensitive to the gravitational vector. However, the possibility exists that microgravity increases the disturbance of spermatogenesis and sperm motility or the frequency of early embryonic lethality. On the possibility of reproduction in space, there are some problems such as the cosmic radiation besides gravity. It is necessary to carry out further experiments in outer space.

Spinocerebellar ataxia type 6 (SCA6, MIM 183086) is an autosomal dominant spinocerebellar degeneration. Mild expansion of a CAG repeat in voltage-dependent Ca2+ channel alpha 1A subunit (CACNL1A) gene, which was predicted to encode a polyglutamine tract, has been identified as a causative mutation for SCA6. SCA6 is one of the common subtypes of spinocerebellar degeneration, accounting for approximately 12% in the dominantly inherited ataxias in Japan. Mean age at onset in the SCA6 patients is 52 years, which is much later than those reported for other autosomal dominant ataxias including SCA1, SCA2, Machado-Joseph disease, and dentatorubral-pallidoluysian atrophy. Anticipation in SCA6 is quite mild. The size of expanded CAG repeats ranged 21 to 26 repeats and was found to be correlated inversely with age at onset in patients with SCA6. Ataxia is most common and cardinal clinical features in SCA6. Patients with a prolonged clinical course, however, show other accompanying clinical features including dystonic postures, involuntary movements, and abnormalities in tendon reflexes. Investigations of the mechanisms of neuronal death in the cerebellum, in particular relation to the impaired function of the voltage-dependent Ca2+ channel and the toxic effects of expanded polyglutamine tracts, will be indispensable for the development of therapeutic measures for SCA6.

Bloody urine was grossly observed and multinodular shadow confirmed in both lungs of an 81-year-old male, who had been referred to our department. The diagnosis was bladder cancer (TCC, G3, T4N3M1) from detailed examination. With his advanced age and lowered ADL, the family did not wish for aggressive treatment, so no combination multidrug chemotherapy was attempted. Instead he was given 300 mg/day UFT per os. After 4 weeks administration, the metastatic focus decreased and tended to contract; at the same time gross observation revealed no more bloody urine. Moreover, following 7 weeks of administration, the bladder tumor disappeared, the lung metastatic focus showed overall shrinkage of over 50%, the lymph node metastasis also was more than 50% less, and the case was considered to be PR. The literature reveals UFT was efficacious in only 2 other cases of progressive bladder carcinoma. Since UFT has fewer complications, such as myelosuppression, among antitumor agent, it is considered worth trying in cases where intensive treatment is not feasible.

Twenty-four previously untreated patients with a diagnosis of prostatic cancer were treated with chlormadinone acetate (CMA) alone (100 mg/day) for 4 weeks, and luteinizing hormone-releasing hormone analogue (LH-RHa) was added for the next 24 weeks. Marked decreases in blood LH, testosterone (T), prostate specific antigen (PSA), gamma-seminoprotein (gamma-Sm), and prostatic acid phosphatase (PAP) were observed after a single dose of CMA. T levels were significantly increased 3 days after the initial dose of LH-RHa, and did not return to the pretreatment level. There were no significant increases in any of the markers, nor were there any flare-up cases. Triglyceride levels, which were slightly elevated before the start of treatment, were significantly decreased 24 weeks after the completion of combined therapy. PSA was evaluated as partial response (PR) or better in 86.7% of the patients. Overall evaluation showed PR or better in 75.0% of the patients. These findings suggest that prior administration of CMA followed by combined administration with LH-RHa is useful in the treatment of prostatic cancer. No negative effects on lipid metabolism were observed at any time during the treatment period.

A 58-year-old man was admitted with a swelling in the frontal region. Computerized tomography scan, magnetic resonance imaging and angiography revealed a tumor in the right frontal sinus. The surgically extirpated specimen showed clear cell carcinoma which was suspected to be a metastasis from renal cell carcinoma. Subsequent urologic examination disclosed the right renal tumor. Since there were no other systemic metastases, right nephrectomy was performed. Pathologically, the renal tumor was clear cell subtype renal cell carcinoma and had the same histology as the frontal sinus tumor.

Distal myopathy with rimmed vacuoles (DMRV) is an autosomal recessive muscular disorder that has been predominantly reported to occur in Japanese population. This disease is characterized clinically by weakness of the distal muscles in the lower limbs in early adulthood, most typically in the tibialis anterior muscle presenting with footdrop. Recently, the gene locus for familial vacuolar myopathy sparing quadriceps muscle with autosomal recessive inheritance (hereditary inclusion body myopathy, HIBM), which was reported to occur in Jews of Persian origin, was mapped to chromosome 9. Since DMRV and HIBM share similar clinical, genetic, and histopathological features, we performed linkage analysis on seven DMRV families. Detection of obligate recombination events as well as pairwise and multipoint linkage analyses revealed that the most likely location of the DMRV gene is in a 23.3 cM interval defined by D9S319 and D9S276 on chromosome 9, which overlap the critical region for HIBM locus. The results raise the possibility that DMRV and HIBM are allelic disease. Identification of the gene(s) for DMRV and HIBM using positional cloning strategy will lead to clarification of the genetic homogeniety for these diseases as well as the understanding in common pathways causing muscle degeneration with vacuolar formation.

We developed a Hotwire for use in percutaneous transcatheter thermotherapy (PTCT) for local tumor control. The Hotwire has a temperature sensor and a heater, and is inserted into the hepatic artery through a Y-connector and an angiocatheter. It can then warm fluid from the Y-connector to 45 degrees C under electorical control PTCT was performed on liver tumors using 4 mg of MMC and 10 mg Epirubicin. The antitumor effects and indications for PTCT were investigated in patients with unresectable liver tumors, including 3 patients who had hepatocellular carcinoma (HCC) with intraportal invasion and collateral vessels, one patient with liver metastasis of rectal cancer, and two gastric cancer patients. In all patients, tumor marker levels decreased (PIVKA-II; 8.5-->0.9, 2.9-->0.9, AFP; 1154-->753, CEA; 300-->226, TPA; 6319-->4227, 3312-->943), and CRP levels were markedly elevated with tumor fever. The only adverse reaction to PTCT was nausea and vomiting in one female patient. We repeated PTCT 6 times for giant HCC, and performance status was improved (2-->0). In conclusion, PTCT using the Hotwire is useful for treating hypervascular tumors limited to the liver, especially HCC with intraportal invasion and collateral vessels.

The rapid development in human chromosome studies during the past 2 decades has opened up a variety of new avenues in both basic and clinical human genetics. This has been due to the extended resolution of chromosome analysis especially by the introduction of high-resolution banding and fluorescence in situ hybridization (FISH) techniques. High-resolution banding methods using elongated chromosomes from cells at early mitotic stage can be divided into two main categories: one involves S-phase synchronization using methotrexate or thymidine with subsequent release from the block, and the other involves the application of DNA-binding agents, such as ethidium bromide, which inhibit mitotic chromosome condensation. High-resolution band analysis facilitates refined determination of the breakpoints on rearranged chromosomes, and thus minute deletions, small translocations and other subtle chromosome mutations can readily be detected and identified. It has also proved to be valuable for accurate gene mapping and comparative cytogenetics. Each of the high-resolution bands consists of DNA molecules as long as approximately 3Mb on the average, and this resolution limitation has been overcome by the introduction of the FISH method, which enables chromosome and genomic analyses to be carried out at the DNA molecule level. For FISH analysis, appropriate DNA probes of various insert sizes can be chosen for different purposes, and FISH with specific probes permits high-resolution analysis of chromosome DNA constitution at particular loci. For instance, it is possible to detect and map unique sequences more than 1 kb in size on mitotic chromosomes, and to identify cryptic chromosome rearrangements not recognizable even by high-resolution band analysis. Better resolution of breakpoint determination can also be expected by FISH using an adequate series of DNA clones arrayed on the physical map within the relevant chromosome region. An even better genomic resolution by FISH can be obtained by utilizing free chromatin DNA fibers released from interphase nuclei as a hybrization target. The FISH signals on the chromatin fiber preparations are shown to be "linear", unlike the standard FISH signals that have a "dot" appearance, and the resolution attainable should be comparable to analysis of a straight DNA double helix itself. The degree of resolution in the so-called fiber-FISH method ranges from a few to 300 kb, and thus the method can readily be applied to the high-resolution assessment of ordering and overlapping of isolated DNA clones from a specific chromosome region, as well as sizing of gaps between the clones. Fiber-FISH may prove most valuable for the precise determination of breakpoints at the kilobase level, and also for identifying minute deletions and duplications. By presenting some examples of our own recent works, this review attempts to summarize the current contribution of the above strategies in mediating the two separate ranges of resolution achieved by the classical chromosome and molecular DNA analyses.

Background: The anti-androgen therapy usually used to manage prostatic cancer is effective because the growth of adenocarcinoma of the prostate is influenced by androgens. However, some prostatic cancers do not respond to hormone therapy. Many studies have been conducted with the objective being to assess the responsiveness of prostatic cancer tissues by measuring the amount of androgen receptors (AR). The present study investigates the expression of AR in adenocarcinoma and in benign adenoma of the human prostate., Methods: Formaline fixed paraffin sections of adenocarcinoma were prepared using 86 patients with primary prostatic cancer, seven patients with relapsed prostatic cancer, and 26 patients with BPH (as the control). Specimens were obtained by needle biopsy and immunohistochemical staining was performed., Results: The benign adenoma AR were stained in the nuclei of the glandular epithelial cells. The receptor-positive and receptor-negative cells were intermingled with the malignant prostatic cells. The labelling indexes (LI) of the androgen receptor stain values in adenocarcinoma of the prostate (57.8 +/- 14.5%) in 86 patients were significantly lower than benign adenoma (86.4 +/- 6.3%) (p = 0.0001). And the LI were decreased with the progress of grades in malignancy: 72.8 +/- 7.5% in well differentiated; 58.7 +/- 7.3% in moderately differentiated; and 41.4 +/- 8.2% in poorly differentiated adenocarcinoma (p = 0.0001). Moreover, LI in relapsed case, all of which were poorly differentiated (22.9 +/- 13.6%), were significantly lower than the LI values of the primary cancer cases with poorly differentiated adenocarcinoma (p = 0.0004). Responders to anti-androgen therapy had high AR positive rate (p = 0.0001) and weakly stained cases had a lower survival rate than strongly stained cases (p = 0.03)., Conclusion: These results suggest that the detection of AR with immunohistochemical study is useful for estimating the prognosis of the patients undergone anti-androgen therapy. And prostatic cancer cells are heterogeneously composed of clones of both androgen dependent and independent cancer cells before hormonal therapy is begun. And one reason why these tumors easily relapse with the progress of grades in hormonal therapy.

A 54-year-old male was referred to our outpatient clinic because of milky urine. He had lived in Kumamoto, an area of endemic filariasis. There were no microfilaria found in his blood smear. Lymphangiography showed dilation of the retroperitoneal lymphatics and bilateral renal refluxes. The thoracic duct was obvious. The initial treatment consisted of irrigating the bilateral renal pelvis with silver nitrate solution, but was not successful and recurrent acute urinary retention developed. Therefore, we performed stripping and ligation of the bilateral renal lymphatics. Chyluria disappeared immediately after surgery. The etiology and various treatments for chyluria are discussed.

Background: We studied the relationship between the recurrence rate of primary superficial bladder cancer and random biopsy., Methods: We performed transurethral resection of primary superficial bladder cancer in 144 patients, and in 55 of those cases a random biopsy was also performed. The non-recurrence rate was examined in many recurrence facters., Results: The non-recurrence rate in the group with random biopsy was not significantly different from that observed in the group (100 patients) without random biopsy (chi 2 test, Generalized Wilcoxon test and multivariate analysis). Because the intravesical instillation therapy is an important inhibition factor in the recurrence rate of the primary superficial bladder cancer, we further analysed the recurrence rate in two non treated groups with or without random biopsy (13 and 35 patients respectively). No significant difference in the rate of recurrence between the two groups was observed. However, we noted recurrence of bladder cancer at biopsy positions in 8/13 patients., Conclusion: It appears that random biopsy may have an effect on the recurrence or the implantation of tumor cells. Further studies are needed to clarify whether random biopsy is a risk factor in the recurrence rate of primary superficial bladder cancer.

We reported two siblings with slowly progressive muscle weakness in proximal and peroneal muscles without atrophy, myalgia, cramps, or episodic weakness. The serum creatine kinase level was moderately elevated. The prominent features of their muscle pathology were accumulation of tubular aggregates in type 2 fibers, predominantly in type 2B fibers, and marked type 1 fiber atrophy. Three to eleven % of muscle fibers contained tubular aggregates. Electron microscopic examination revealed accumulation of double-walled tubular structures. Familial myopathy with tubular aggregates as a hallmark of muscle pathology is considered to be a new clinical form of childhood-onset familial myopathies.

It is important to know the proliferating ability and the malignant potential of tumor tissues. We have examined the expression of PCNA/cyclin, p53 and C-erbB-2 in transitional cell carcinoma of the human urinary bladder by an immunohistochemical method, and compared the results with the histological grade, stage and survival rate. Immunohistochemical studies, using monoclonal and polyclonal antibodies, on these proteins were performed with formaline fixed-paraffin sections of tumor tissue from 40 patients with bladder cancer. Generally, a higher grade and higher stage tumors expressed PCNA/cyclin, p53 and C-erbB-2 with a greater frequency than the tumors with a lower grade and lower stage and strongly stained cases had a lower survival rate than weakly stained cases. These findings suggest that the detection of each antigen is useful for estimating the malignant potential of transitional cell carcinoma as the adjuvant studies, because of its applicability to paraffin-embedded tissue sections and its simple, rapid technique.

We report a 48-year-old woman with dentatorubral-pallidoluysian atrophy (DRPLA). She is the only patient in her 15 family members in two generations. She developed cerebellar ataxia and epilepsy at age 43. On admission at 48, she showed mild dementia and choreic movement in her face and extremities as well as truncal and limb ataxia. Routine laboratory examinations were normal. The point mutations in the tRNALys gene of mitochondrial DNA specific for MERRF were not found. A cranial CT scan and MRI showed mild atrophy of the cerebellum and prominent atrophy in the pons, especially in the tegmentum. Although she was thought to have DRPLA from the clinical point of view, absence of family history made the diagnosis difficult. Her parents were healthy until their 80's and died of cerebrovascular diseases and her 5 siblings had no symptoms. Hereditary DRPLA is known as an autosomal dominant disorder, with a high rate of penetrance and low rate of new mutation. According to our recent findings of a CAG repeat expansion in the DRPLA gene, this patient was diagnosed as a sporadic DRPLA. Considering the wide varieties of clinical manifestations, it is essential to examine this gene abnormality for diagnosing sporadic DRPLA.

Seventeen patients with prostatodynia (chronic prostatitis-like syndrome) refractory to conventional medical treatment were treated with electric acupuncture at a low-wave frequency. All of them had had a complicated clinical course and pelvic hypertonicity. This therapy was administered to mitigate the congestion of pelvic circulation, especially around the prostate. The clinical efficacy of longterm treatment was considered excellent in 30% and moderate in 70% of the patients, with an overall efficacy rate of 100%. Treatment with Chinese medicines and chemical agents could be withdrawn completely in 50% of the patients, treatment with chemical agents could be withdrawn in 30% of the patients, and the dose of either type of medication could be reduced in 20% of the patients. To examine whether the efficacy of electric acupuncture was related to the induction of cytokines we also examined the serum levels of INF-gamma, IL-1 beta and IL-6, but, no significant elevation of either of them was detected.

The degree of damage on the peristomal skin of 42 patients who accepted the urostomy was visually and histologically evaluated. The incidence of damages on the areas of the skin where the materials was applied was 85.7%. The occurrence of non-active lesions (mainly permanent pigment change) was statistically more significant than the active lesions (mainly redness) [p < 0.05]. The incidence of skin lesions using the skin barrier agents was significantly lower statistically than the incidence with the adhesive medication indicating a superior treatment for the skin condition [p < 0.05]. Although the gross appearances were normal, the microscopic and electron microscopic evaluations detected chronic damages indicating comparatively evident changes. The results suggest that these histological evaluations are useful in examining the damage on peristomal skin.

Antiandrogen therapy has an important role in the treatment of patients with benign prostatic hypertrophy who lack indication for surgery. Herein, the effects on lipid metabolism of administration of antiandrogen agents for benign prostatic hypertrophy are reported. Eighty patients with benign prostatic hypertrophy were each treated with the antiandrogen agents, chlormadinone acetate, allylestrenol, gestonolone caproate and oxendolone for 12 months. The levels of total cholesterol (TC), triglyceride (TG), high density lipoprotein (HDL), low density lipoprotein (LDL), alpha-lipoprotein, apoprotein, and maronediardehyde (MDA) were measured every 4 weeks after initiation of antiandrogen treatment. In the chlormadinone acetate group, the TG level was significantly decreased between 3 and 6 months after treatment (p < 0.05). In the oxendolone group, the alpha-lipoprotein level was also elevated between 3 and 6 months and between 6 to 12 months after treatment (p < 0.05). The MDA level was also significantly elevated 6 and 12 months after treatment. However, the levels of the other lipids were within the normal range. In conclusion, the changes in the levels of plasma lipoprotein, apoprotein and MDA resulting from antiandrogen therapy were unlikely to be a cause of ischemic coronary disease.

A 46-year-old man was admitted to our hospital with the complaint of gross hematuria and renal failure. The patient had undergone right nephrectomy 10 years earlier suffering from nephrotuberculosis, and the remaining left side manifested severe hydronephrosis and vesicoureteral reflux (VUR). After the immediate nephrostomy, renal function was recovered and hematuria was improved preservatively. By the rectal examination, a goose egg size and stony hard prostate was detected. The needle biopsy of the prostate revealed pathologically transitional cell carcinoma (TCC) G2, and the image findings showed stage of T4N0M0 of the prostatic carcinoma. Modified pelvic exenteration was performed, and specimens were examined by the step section method. The diagnosis was TCC, G2 > G3 and stage of pT4N0 in the right lobe of the prostate. This case is she 20th reported case in Japan. We emphasize the importance of the mapping of dissected specimens and the reviewed literature.