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The use of azacitidine (AZA) has been known to lead to a high incidence of hematotoxic adverse events. The aims of this study were to identify the risk factors for thrombocytopenia after the administration of AZA and to analyze time to the initial platelet transfusion. Sixty-two patients with myelodysplastic syndrome (MDS), who were treated with AZA in Gifu Municipal Hospital between March 2012 and June 2020, were included in this study. The risk factors for thrombocytopenia were identified using univariate analysis of patient characteristics, disease type, and laboratory values immediately before the start of treatment. Variables with p0.2 identified in the univariate analysis were used as independent variables in the multivariate analysis. This analysis identified "creatinine clearance (CCr)60 mL/min" as a significant factor (odds ratio, 4.790; 95% confidence interval [CI], 1.380-16.70; p=0.014). Subsequently, time in days to the initial platelet transfusion after the initial administration of AZA was analyzed using the log-rank test. The overall median time in days to platelet transfusion was 370 days. The log-rank test was used to determine the influence of patient characteristics, disease type, and laboratory values immediately before the start of treatment. The subsequent Cox proportional hazard regression analysis using variables with p0.2 as independent variables identified "hemoglobin (Hb)8.0 g/dL" as a significant factor (hazard ratio, 2.143; 95% CI, 1.001-4.573; p=0.048). The results of this study led to the following clinical implications: first, patients with CCr of60 mL/min at the start of treatment should be treated with caution due to the risk of thrombocytopenia. Second, patients with Hb of8.0 g/dL at the start of treatment may require platelet transfusion in the early stage of treatment.

Congenital Zika virus (ZIKV) infection can cause lifelong medical and developmental conditions and management needs. There is limited information on the strengths and weaknesses of the systems of care for addressing ZIKV and other neurodevelopmental disabilities (NRD) in the United States (US) Affiliated Pacific Island Territories. Therefore, the purpose of the study was to assess the quality of the chronic illness systems of care for children with congenital ZIKV and other NRD in the US Pacific Island Territories. A cross-sectional study was conducted among health professionals from American Samoa, Guam, and Commonwealth of the Northern Mariana Islands. Participants completed an adapted version of the Assessment of Chronic Illness Care 3.5 (ACIC), which is based on the Chronic Care Model. The median Total Program Score was calculated, which ranged from limited support (0–2), basic support (3–5), reasonably good support (6–8), to fully developed support for care (9–11). Among the 17 health professionals who completed the survey, 47% were Guamanian/Chamorro, 24% were Samoan, 12% were Filipino, and 6% were Other Pacific Islanders. The median (25th percentile, 75th percentile [interquartile range]) Total Program Score was 5 (3, 6 [3]), indicating basic support for ZIKV and other NRD care for children. As more is learned about the full spectrum of clinical findings related to ZIKV, it is critical to continue to build an interdisciplinary maternal and child health workforce with the capacity and preparation to adequately address the special needs of children with ZIKV and other NRD.

Cardiovascular surgery is a highly invasive intervention that is often performed in elderly patients at risks of complications because of malnutrition and reduced immunity. This study investigated nutritional factors that affected length of hospital stay in patients undergoing cardiovascular surgery. Among 68 patients who underwent surgery at the Department of Cardiovascular Surgery of Gifu Municipal Hospital between April 2013 and March 2015, 55 with complete data were included in the analysis. Data on serum albumin (ALB), transferrin (Tf), pre-albumin (PA) and retinol binding protein (RBP) levels were collected. The median length of hospital stay was 29 days (stays of ≥30 days were considered long-term hospitalization). Multivariate analysis (multiple logistic regression) included age (≥ 65 years), sex (female), and ALB (≤ 3.0 g/dL), Tf (≤ 150.0 mg/dL), PA (≤ 10.0 mg/dL) and RBP (≤ 1.5 mg/dL) levels. ALB [odds ratio (OR) 10.37, 95% CI (confidence interval): 1.185-90.80

Chemotherapy for cancer is increasingly implemented in the outpatient setting. Pharmacists contribute to cancer treatment by conducting counseling during outpatient chemotherapy visits. They provide guidance on drug treatment, side effects, and side effect countermeasures on every visit. However, there have been few economic evaluations of pharmacist involvement in outpatient chemotherapy. Therefore, we performed a cost utility analysis. We assigned usual care (control) and pharmacist counseling to two groups of 19 patients receiving outpatient chemotherapy for breast cancer at Gifu Municipal hospital. Quality of life was measured at three timepoints before and during chemotherapy treatment using the EuroQol 5 dimension instrument (EQ-5D). EQ-5D values across the timepoints were 0.831, 0.757, and 0.791 for the control group, and 0.882, 0.883, and 0.921 for the pharmacist counseling group. The additional cost in the pharmacist counseling group was 2,227 yen per counseling session. The change in quality-adjusted life years (QALY) was a maximum of -0.021±0.186 in the control group and 0.007±0.199 in the pharmacist counseling group. The maximum cost for one QALY was 1,360,558 yen (≈12,460 US dollars). Pharmacists' counseling in outpatient cancer chemotherapy for breast cancer patients had an acceptable incremental cost-effect ratio, contributing to improved patient quality of life without significant additional expenditure to healthcare.

We retrospectively investigated the renal function index of patients with type 2 diabetes mellitus (T2DM) to examine the influence of dipeptidyl peptidase-4 (DPP-4) inhibitors on renal function between patients up to early nephropathy and after overt nephropathy. Patients with T2DM (18 years old) who had been prescribed hypoglycemic agents for ≥3 months at Gifu Municipal Hospital between March 2010 and April 2014 were included in the study. Renal function was evaluated as the estimated glomerular filtration rate (eGFR) decline from baseline at 12 months. Patients in the DPP-4 inhibitor-treated and untreated groups with an eGFR ≥60 (358 [58.2 %] and 257 [41.8 %], respectively) and eGFR60 (115 [60.2 %] and 76 [39.8 %], respectively) were subjected to multiple logistic regression analysis. Among patients with an eGFR ≥60, no significant differences were observed in eGFR decline rates over time. However, among patients with an eGFR60, significant decreases were observed in eGFR decline rates10 % (6 months; odds ratio, 0.476

Over-the-counter (OTC) drugs and health foods/supplements are used as means of self-medication with the aim of preventing diseases and maintaining health. No reports have yet addressed the relationship between healthcare systems and self-medication. Here, we carried out a retrospective survey to identify healthcare system factors affecting OTC drug and health food/supplement usage. Patients hospitalized at Gifu Municipal Hospital between October 1, 2014 and March 31, 2015 were given a survey. The items surveyed were age, gender, disease, alcohol intake/smoking status, insurance classification, and medical pharmaceuticals, OTC drugs, and health foods/supplements used immediately before hospitalization. We performed multiple logistic regression analysis using OTC drugs and health foods/supplements as dependent variables with patient attributes, medical insurance, etc. as independent variables. A total of 5,965 patients were analyzed. OTC users comprised 2.6 % (156 people) of the total. The use of OTC drugs was significantly higher for females and alcohol consumers than in other categories. In contrast, the use of OTC drugs was significantly lower for participants in public expense/medical subsidy programs. Health foods/supplements were used by 4.0 % of all subjects (240 people); their use was significantly higher among females and users of medical pharmaceuticals. On the other hand, the use of health foods/supplements was significantly lower for smokers, users of the latter-stage elderly healthcare system, and users of public expense/medical subsidy programs.

The relationship between depressive symptoms and glycemic control in youth with type 2 diabetes was assessed at baseline (n = 682), 6, and/or 24 months (n = 576). Neither baseline nor persistence of depressive symptoms was significantly associated with maintenance of glycemic control. Nevertheless, depressive symptoms were common, suggesting the importance of repeated screening.

Aims Examine barriers for taking glucose-lowering oral medications, associated baseline characteristics, strategies used, and the adherence impact in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. Methods We studied youth prescribed oral diabetes medications over two years (N = 611, 583, and 525 at 6, 12, and 24 months). Clinicians documented barriers (e.g. forgetting, routines, other concerns) in the subsample that reported missed doses (N = 423 [69.2%], 422 [72.4%], and 414 [78.9%] at 6, 12, and 24 months, respectively). Adherence strategies were also assessed (e.g. family, schedule, reminder device) using standard questions. Logistic regression was used to analyze associations with medication adherence. Results Those missing doses were not different from the total sample (61.5% female, 13.9 ± 2.0 years, >80% racial/ethnic minorities). No baseline demographic or clinical predictors of barriers to medication adherence were identified. Among those for whom barriers were assessed, “forgetting” with no reason named (39.3%) and disruptions to mealtime, sleep, and schedule (21.9%) accounted for the largest proportion of responses. Family support was the primary adherence strategy identified by most youth (≥50%), followed by pairing the medication regimen with daily routines (>40%); the latter strategy was associated with significantly higher adherence rates (p = 0.009). Conclusions Family supported medication adherence was common in this mid-adolescent cohort, but self-management strategies were also in evidence. Findings are similar to those reported among youth with other serious chronic diseases. Prospective studies of multi-component family support and self-management interventions for improving medication adherence are warranted. Trial registration: ClinicalTrials.gov NCT00081328 .

We report the results of 28 patients with scaphoid nonunion treated with curettage and biconcave cancellous bone grafting from the distal radius using a volar approach and pin fixation. This study consisted of 28 patients (24 males and 4 females). The mean age at surgery was 28 years. The mean interval from injury to surgery was 22 months. The mean follow-up period was 20 months. By Russe classification, there were 6 distal third nonunions, 19 middle third nonunions and 3 proximal third nonunions. We reviewed final function and radiographic appearance. Bony union was achieved in all cases. Pins were removed at a mean of 7 weeks after surgery. Post-activity pain resolved in all cases. Mean wrist extension was 79 degrees and mean flexion 77 degrees. Mean grip strength was 35.8 kgf. The mean postoperative radio-lunate angle was 4.9 degrees (-21-28.8) compared to -5.9 degrees (-37.5-17.5) preoperatively. No complications were encountered. Our procedure is straightforward and not technically demanding. An STT arthrotomy is not necessary and the technique allows for concurrent correction of carpal instability. Bony union was achieved in all cases with no complications.

Objectives To characterize, during a 2-year period, the proportion of youth with type 2 diabetes (T2D) enrolled in the Treatment Options for Type 2 Diabetes in Adolescents and Youth study that reported ever at least trying smoking cigarettes and/or drinking alcohol. Study design Longitudinal data were examined for participants with T2D ages 10-18 years at baseline. Youth psychosocial, parent/family, environmental, and biological correlates of trying health risk behaviors were tested via cross-sectional multivariate models at each time point. Longitudinal models were explored for selected factors. Results Data were obtained from the Treatment Options for Type 2 Diabetes in Adolescents and Youth study's ethnically diverse participants at baseline (N = 644), 6-month (N = 616), and 24-month (N = 543) assessments. The percentage of youth ever trying only smoking remained stable at 4%; only drinking alcohol increased from 17% to 26%, and both smoking and drinking increased from 10% to 18% during the 2-year period. Factors related to trying health risk behaviors were older age, male sex, non-Hispanic white race-ethnicity, lower grades, more depressive symptoms, and stressful life events. Depressive symptoms, stressful life events, and body mass index Z-score (the latter with smoking only) were related to engagement in health risk behaviors over time. Conclusions Youth with T2D who are already at risk for health complications and who reported engaging in activities that further increase the likelihood of life-threatening morbidities were characterized. Although most correlates of trying these risk behaviors are nonmodifiable, intervention efforts may need to focus on potentially modifiable factors, such as depressive symptoms and lower grades.

To establish a correlation between a reliable subjective measure, the Sedation-Agitation Scale (SAS), and an objective tool, the Bispectral Index (BIS), for monitoring critically ill patients with a decreased level of consciousness.Prospective, comparative, single-blinded observer study.Surgical and medical intensive care units of the Tufts-New England Medical Center, a 349-bed tertiary care, academic medical center.A convenience sample of 20 adult, critically ill patients with a decreased level of consciousness. The data from one patient were excluded because the patient did not meet inclusion criteria.Patients were prospectively evaluated by a blinded observer using the SAS to subjectively determine their level of consciousness. Sedation levels varied from unarousable (SAS score of 1), to very sedated (SAS score of 2), to mildly sedated (SAS score of 3). Simultaneously, the patients were continuously monitored for 4-6 hrs with the BIS device. There was wide variability in BIS scores for any given level of consciousness as compared with the SAS. Unarousable patients had BIS scores ranging from 23 to 97, with a median score of 50 and an interquartile range of 24. Very sedated patients had BIS scores ranging from 35 to 98, with a median score of 68 and an interquartile range of 36. Mildly sedated patients had BIS scores ranging from 67 to 91, with a median score of 76 and an interquartile range of 8. Overall, there was a less than satisfactory correlation between BIS values and SAS scores (r =.36, p.001). However, the correlation improved with subgroup analysis when BIS values associated with excessive muscle movement were excluded (r =.50, p.001).The correlation between SAS and BIS scores was suboptimal and inconsistent in a heterogeneous group of critically ill patients. The generation of BIS hardware and software, studied herein, is neither reliable nor valid for routinely monitoring the level of consciousness in the critically ill patient. Excessive muscle movement by the patient is an important and spurious influence on BIS values and seriously undermines BIS reliability.

To gain a better understanding of how mutations of the prion protein (PrP) gene are responsible for progressive dementia syndrome and to clarify the correlation between genotype and phenotype, which should help to explain how the prion promotes neurological symptoms.Genetic prion diseases are associated with point or insertional mutations in the PrP gene. The insertional mutations described so far consist of one to nine extra octapeptide repeats, except three repeats. Insertions of one to four extra octapeptide repeats cause Creutzfeldt-Jakob disease (CJD) in patients without a family history of neurological disorders. CJD generally presents as progressive dementia.Routine clinical assessment and sequence analysis of the PrP gene of DNA from a 56 year old Japanese man with progressive dementia syndrome.Sequence analysis disclosed a novel four octapeptide repeat insertion within the PrP gene. The patient was initially affected by progressive cerebellar and brainstem signs; a few months later myoclonus and rapidly progressive dementia appeared. These symptoms were similar to those of sporadic CJD.Taken together with previous investigations of CJD patients with insertional mutations, the current observation strengthens the notion that small octapeptide insertions from one to four extra repeats within the PrP gene cause CJD, which is characterised by late onset after the sixth decade, rapid progression, death within a few months, and lack of a family history of neurological disorders, the latter suggesting incomplete penetrance. Different patients with four extra octapeptide repeats have different patterns of extra insertions, suggesting that progression of the disease depends on the number of extra repeats.

OBJECTIVE The study objective was to examine the prevalence of depressive symptoms and relationships to quality of life and demographics in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study’s large, ethnically diverse youth with type 2 diabetes. RESEARCH DESIGN AND METHODS A total of 704 youth with type 2 diabetes RESULTS Some 14.8% reported clinically significant depressive symptoms, and older girls had significantly higher rates than older boys. CONCLUSIONS Rates of significant depressive symptoms were similar to those of healthy adolescents and lower than those of teens with type 1 diabetes. Elevated depressive symptoms, particularly in older girls, suggest clinicians assess vulnerability.

OBJECTIVE This study examined parental factors associated with outcomes of youth in the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) clinical trial. RESEARCH DESIGN AND METHODS Of 699 youth with type 2 diabetes in the TODAY cohort, 623 (89.1%) had a parent participate and provide data at baseline, including weight, HbA1c, blood pressure, symptoms of depression, binge eating (BE), and medical history. Youth were followed 2–6.5 years. Data were analyzed using regression models and survival curve methods. RESULTS Parental diabetes (43.6% of parents) was associated with higher baseline HbA1c (P < 0.0001) and failure of youths to maintain glycemic control on study treatment (53.6% vs. 38.2% failure rate among those without a diabetic parent, P = 0.0002). Parental hypertension (40.6% of parents) was associated with hypertension in youth during TODAY (40.4% vs. 27.4% of youth with and without parental hypertension had hypertension, P = 0.0008) and with higher youth baseline BMI z scores (P = 0.0038). Parents had a mean baseline BMI of 33.6 kg/m2. Parental obesity (BMI >30 kg/m2) was associated with higher baseline BMI z scores in the youth (P < 0.0001). Depressive symptoms in parents (20.6% of parents) were related to youth depressive symptoms at baseline only (P = 0.0430); subclinical BE in parents was related to the presence of subclinical BE (P = 0.0354) and depressive symptoms (P = 0.0326) in youth throughout the study period. CONCLUSIONS Parental diabetes and hypertension were associated with lack of glycemic control, hypertension, and higher BMI z scores in youth. Further research is needed to better understand and address parental biological and behavioral factors to improve youth health outcomes.

Squamous epithelial dysplasia is often observed multifocally in the cancerous oesophagus and is presumably considered to be a pre-cancerous lesion. A mutation of the p53 tumour suppressor gene is commonly identified in oesophageal cancer and dysplasia. p53 mutations can be anticipated immunohistochemically. In order to confirm the biological and clinical significance of p53 expressions in oesophageal field carcinogenesis, immunostaining for p53 in cancerous and multifocal precancerous lesions from resected human oesophagus was systematically investigated, while paying special attention to the contiguity of these lesions. Lesions expressing p53 were detected in 46.5% (20 of 43 lesions) of the invasive carcinoma, and in 51.0% (46 of 90 lesions) of the carcinoma in situ, and in 51.4% (92 of 179 lesions) of the dysplasia. Next, the p53 expression in dysplasia was compared with that in carcinoma for the same case. 37 of 39 (94.8%) dysplasias contiguous to p53-positive carcinomas also expressed p53 (P < 0.0001). On the other hand, the isolated dysplasias without contiguity to p53-positive carcinomas, only expressed p53 protein in 44.0% (11 of 25 lesions). No significant correlations were found between the p53 staining and either the clinicopathological features or prognosis. Discordant p53 alterations, such as those seen in cancerous and isolated precancerous lesions, may thus demonstrate further evidence for a multicentric or field carcinogenesis of the human oesophagus. © 2000 Cancer Research Campaign

BAG-1 is a Bcl-2-binding protein that functions as an anti-apoptotic molecule. In this report we show a possible correlation between BAG-1 expression levels and the probability of oral squamous cell carcinoma (SCC) progression. We investigated BAG-1 expression levels in 22 patients diagnosed with early lesions (T1 and T2) of oral SCCs using immunohistochemistry and western blotting. High steady-state levels of BAG-1 were detected in 13 out of 22 cases (59%). High BAG-1 expression was observed more frequently in cases with nodal metastasis (89%) than in those without nodal metastasis (38%) (P

Recent studies have indicated that deposition of beta amyloid peptide in the brains of patients with senile dementia of the Alzheimer type (SDAT) is a consequence of abnormal processing of the beta amyloid protein precursor. In addition, reduced concentrations of various peptides have been measured in post-mortem brain tissue and cerebrospinal fluid (CSF) of patients with SDAT. We determined concentrations of the peptides derived from prepro-vasoactive intestinal peptide (VIP)--peptide histidine methionine-27 (PHM-27), peptide histidine valine (PHV) and VIP--and peptides derived from prepro-somatostatin (prepro-SS), SS-14 and SS-28, in CSF of patients with SDAT by radioimmunoassay combined with high performance liquid chromatography. We found significantly reduced levels of total PHM-immunoreactivity (IR) and PHV, and unaltered levels of PHM-27 and VIP in SDAT, compared with those in controls. Total SS-IR and SS-28 concentrations were significantly reduced in SDAT, while SS-14 levels did not differ from those of controls. These results suggest that an altered processing of the prepro-peptides of VIP and SS may occur in SDAT and that these alterations might have a significant role in the pathogenesis of SDAT.

Various forms of adrenocortical insufficiency can cause musculoskeletal symptoms such as muscle pain, tautness of the limbs, arthralgia, and flexion contractures. However, the findings of neurological investigations are inconclusive and have not been well summarized.We report the case of a 61-year-old man with isolated adrenocorticotropic hormone deficiency who presented with musculoskeletal symptoms, including flexion contractures. We performed three neurological investigations: nerve conduction studies, electromyography, and muscle biopsy analysis. Further, we reviewed reports of 16 patients with various forms of adrenocortical insufficiency and musculoskeletal symptoms by considering the findings of these three investigations.From the literature review, we found that (a) analysis of muscle biopsy is the most sensitive technique, followed by electromyography and then nerve conduction studies; and (b) the longer the duration of the musculoskeletal symptoms, the greater the incidence of abnormal findings with all three techniques.Physicians may prioritize neurological investigations, depending on these findings.

Symptom management in palliative care requires reliable symptom assessment. We assessed the inter-rater reliability of a simple proxy symptom-assessment scale using the Japanese version of the Support Team Assessment Schedule (STAS-J) in a hospital-based palliative care team (HPCT) setting. By doing this, we assessed symptoms in a series of consecutive patients at two university hospitals with certified HPCTs within 2 days of referral and 7 days after. A physician and nurse assessed 20 symptoms. In total, 120 patients were assessed within 2 days of referral and 92 patients at 7 days after referral. As a result, we find that the intra-class correlation coefficients were 0.02-0.89 at referral and 0.20-0.92 at 7 days after. The perfect concordance rates were 37-89% at referral and 53-96% at 7 days after. The perfect or +/-1 concordance rates were 71-97% at referral and 73-100% at 7 days after. In conclusion, the symptom item of the STAS-J had high inter-rater reliability.

Multidrug-resistant uropathogenic Escherichia coli (UPEC) is increasing gradually on a worldwide scale. We therefore examined the possibility of bacteriophage (phage) therapy for urinary tract infections (UTIs) caused by the UPEC strains as an alternative to chemotherapy. In addition to the well-known T4 phage, KEP10, which was newly isolated, was used as a therapeutic phage candidate. KEP10 showed a broader bacteriolytic spectrum (67%) for UPEC strains than T4 (14%). Morphological and genetic analyses showed that KEP10 resembles phage T4. Phages T4 and KEP10 injected into the peritoneal cavity of mice were distributed immediately to all organs examined and maintained a high titer for at least 24 h. They were stable in the urine of both mice and humans for 24 h at 37 degrees C. Administration of these phages into the peritoneal cavity caused a marked decrease in the mortality of mice inoculated transurethrally with a UPEC strain, whereas most of the control mice died within a few days of bacterial infection. Inoculation with phage alone produced no adverse effects attributable to the phage per se. The present study experimentally demonstrated the therapeutic potential of phage for E. coli-induced UTIs, and T-even-related phages may be suitable candidates with which to treat them.

Human skin shows various morphological characteristics, depending on the body site. As these distinct phenotypes have been explained on the basis of the variance in epidermal keratinocytes and the presence of skin appendages, the spatial distinction of the dermal components has not been fully elucidated.To identify and characterize the profiles of mRNAs that are abundantly or specifically expressed by fibroblasts derived from trunk skin, but not from palmoplantar skin or oral mucosa.In order to identify the distinct mRNA expression by trunk skin fibroblasts, a subtraction cDNA screening was performed first, followed by Northern blotting, Western blotting and immunohistochemistry for cultured human and rat dermal fibroblasts and those skin tissues. Finally, whole mount in situ hybridization (WISH) was performed to examine the differences in the expression of the corresponding gene during the developmental stage of mouse embryos.We identified three cDNA clones encoding fibronectin (FN), pregnancy-specific beta1-glycoprotein 5 and beta-actin, respectively, whose mRNAs were abundantly or specifically expressed by trunk skin fibroblasts. FN and some integrins were further confirmed to be expressed more selectively in human and rat trunk skin fibroblasts, both in terms of the RNA and the protein levels, compared with the fibroblasts derived from plamoplantar skin and oral mucosa. WISH demonstrated that FN was localized around the hair follicles of mouse embryos.FN, one of most potent extracellular matrix molecules, was demonstrated to be spatially transcribed depending on the body sites. The distinct expression of FN was suggestive of the essential commitment in the process of cutaneous development and morphogenesis of appendages originated from hair germ. The paucity of FN in palmoplantar skin and oral mucosa might explain the characteristics of these skin phenotypes.

Although adherence clearly influences response to antiretroviral therapy (ART), accurate assessment of adherence is problematic. The objective of this analysis was to assess the independent predictive value of protease inhibitor (PI) concentrations as a supplement to self-report as markers of medication adherence.This retrospective analysis was conducted from a prospective clinical trial designed to compare the outcomes of frequent versus infrequent HIV RNA measurement used to manage antiretroviral therapy. For 131 patients, self-reported medication adherence, HIV RNA levels, CD4 counts and PI concentrations (unannounced, random samples) were measured at baseline (when patients changed to a new regimen) and every 2 months thereafter. The change in HIV RNA from baseline to month 6 (area-based measure) was used to evaluate overall response. The proportion of measured PI concentrations below the detection limit was used as an alternative marker of adherence. An undetectable concentration would be expected after missing a single dose.The mean baseline CD4 count was 125 cells/mm3 and the mean HIV RNA level was 4.7 log10 copies/ml. The mean change in log10 HIV RNA was -0.73 copies/ml. The mean percentage of self-reported adherence was 91% (range: 15-100%) and the mean proportion of undetectable PI concentrations was 27% (range: 0-100%, mean 2.5 samples/patient). The correlation between the two measures was -0.23 (P=0.009). In a multivariate model, percentage of visits with undetectable PI concentrations (P=0.02), percentage of medication adherence (P=0.02), baseline HIV RNA level (P=0.005), prior PI use (P=0.0004), prior lamivudine (3TC) use (P=0.0009) and randomization to the frequent HIV RNA measurement group (P0.0001) were all related to change in HIV RNA. After accounting for adherence, patients who always had detectable PI concentrations had an average of 0.4 log10 additional HIV RNA reduction compared with those who had no detectable concentrations.Repeated, random PI concentration values are independently predictive of virological response and may add to self-report of adherence in understanding the response to ART.

Background and aim: The diagnosis of submucosal fundal varices is challenging. Currently, endoscopy and endoscopic ultrasound (EUS) are considered most useful for this purpose. The aim of this study was to evaluate if multi-detector row CT (MDCT) angiography contributes to the diagnosis of submucosal fundal varices.

CD44 is a principal cell surface receptor for hyaluronan, a major component of extracellular matrices. Cells are surrounded by and encounter matrix in vivo, which in turn serves a variety of cell functions through the direct adhesion via their receptors. CD44 communicates cell-matrix interactions into the cell via "outside-in signaling" and has an important role in biological activities. The interaction of CD44 with fragmented hyaluronan on rheumatoid synovial cells induces expression of VCAM-1 and Fas on the cells, which leads to Fas-mediated apoptosis of synovial cells by the interaction of T cells bearing FasL. On the other hand, engagement of CD44 on tumor cells derived from lung cancer reduces Fas expression and Fas-mediated apoptosis, resulting in less susceptibility of the cells to CTL-mediated cytotoxicity through Fas-FasL pathway. Thus, although the CD44-mediated signaling differs among cells and circumstances, we here propose the functional role of CD44 in inflammatory processes and tumor susceptibility and the rational design of future therapeutic strategies including the exploitation of CD44-mediated pathway in vivo.

It is well known that the 5-year survival rate of advanced ovarian cancer patients greatly improved after the appearance of cisplatin. Recently, paclitaxel has been reported to be effective in the treatment of cisplatin-resistant ovarian cancer. However, control of intraperitoneal lesions is still the biggest problem in this treatment, and attention is focused on the development of effective approaches. Intraperitoneal chemotherapy is considered to be a mode of administration expected to have a direct effect on ovarian cancer by penetrating the tumor and an indirect effect via blood vessels. We examined the outcome and adverse drug reactions in 102 ovarian cancer patients who underwent repeated intraperitoneal administration of cisplatin in our hospital between April 1987 and April 1999. We confirmed that this method may greatly improve the five-year survival rate compared to intravenous administration.

We performed meta-analysis using the data in literatures of the clinical study related to pharmacotherapies for allergic rhinitis in Japan as evidences. We extracted double-blind studies which used first-generation antihistamines, early-stage second-generation antihistamines, late-stage second-generation antihistamines and arachidonic acid metabolite-receptor antagonists as investigational drugs. In meta-analysis of first-generation antihistamines and early-stage second-generation antihistamines, significant differences between them were detected in final overall improvement and usefulness. In meta-analysis of early-stage second-generation antihistamines and late-stage second-generation antihistamines, significant differences between them were detected in usefulness and sleepiness as an adverse effect. In meta-analysis of late-stage second-generation antihistamines and arachidonic acid metabolite-receptor antagonists, significant differences between them were detected in final overall improvement and usefulness. These results indicate a historical trend in the development of drugs including measures to deal with sleepiness as an adverse effect. The arachidonic acid metabolite antagonists appeared to be promising among the oral drugs for allergic rhinitis, although data related to the arachidonic acid metabolite antagonists are still few and further collection of them is necessary.

Based on the previous report showing that mitochondrial (MT) alteration is associated with platinum (Pt) resistance, we have determined how the alternative MT function is involved in Pt cell cytotoxicity particularly in relation to the apoptosis. MT membrane potential (delta psi m) semi-quantitatively assessed by rhodamin 123 (Rh) sensitivity was significantly elevated in acquired Pt-resistant 2008/C13*5.25 cells (C13) established from its parental 2008 cells or known intrinsic Pt-resistant JHOC cells established from ovarian clear cell adenocarcinoma. Laser confocal microscopy of these cells stained with Rh revealed that MT in Pt-resistant cells were distributed in whole cytoplasm with relatively higher fluorescent intensity whereas MT in Pt-sensitive cells were localized in perinuclear space with lower fluorescent intensity. Electron microscopy showed the predominantly condensed MT in which crestal structure was not observed clearly in Pt-resistant cells. Western blot analysis using murine monoclonal anti-Bcl-2 antibody showed more than 5-fold Bcl-2 overexpression in Pt-resistant cells in response to cisplatin treatment. Cytochrome C (CytC) in MT was released from MT into cytoplasm in response to cisplatin treatment in Pt-sensitive cells, whereas up-regulation of CytC level in MT rather than CytC release from MT was observed in Pt-resistant cells. These data are strongly suggesting that changes at MT level would impact on the relative resistance of malignant cells to undergo drug-induced apoptosis.

The factors influencing the development of small intestinal obstruction following gastric surgery are controversial.Univariate and multivariate analyses were carried out on data from 48 patients with gastric cancer who underwent total gastrectomy and Roux-en-Y reconstruction for a potential cure.Of these 48 patients, 11 (22.9%) presented with mechanical obstruction in the small intestine postoperatively. There were no statistically significant differences with regard to age, sex, and the presenting pathology. The development of obstruction was not related to a longer operation time, a greater estimated blood loss during surgery, an extensive lymph node dissection and a combined resection of adjacent organs. The probability that the antecolic anastomosis would cause obstruction was significant when compared with findings in case of the retrocolic anastomosis (P0.05). In the multivariate logistic regression analysis, the significant risk factors related to the development of small intestinal obstruction proved to be reconstructive route of jejunal loop.In potentially curative patients undergoing total gastrectomy, retrocolic anastomosis should be attempted to prevent the development of postoperative intestinal obstruction.

We report a case of basal subarachnoid hemorrhage in a child. The etiology of this lesion was difficult to diagnose. The patient was a 9-year-old boy. He sustained minor head injury followed by loss of consciousness and cardiopulmonary arrest. He was brought to our emergency room by ambulance. On arrival, he presented with cardiopulmonary arrest and deep comatose state. Basal subarachnoid hemorrhage was revealed on CAT scan. 3D-CTA documented two bulging portions: one was at the junction between the left vertebral artery and the left posterior inferior cerebellar artery. The other one was shown at the basilar artery. He died on the 7th hospital day. The autopsy revealed a laceration of the left vertebral artery. Microscopically, the wall around the laceration showed a defect in the internal elastic membrane and a decrease of smooth muscle cells with moderate fibrosis in the tunica media. These findings were compatible with the structure of a congenital aneurysm. Hence, the patient was strongly suspected to have had a congenital aneurysm whose rupture was triggered by minor head injury.

To present a case of fluoroquinolone treatment failure in urinary tract infection caused by Pseudomonas aeruginosa, accompanied by in vivo selection of the post-treatment isolate that showed decreased susceptibilities to fluoroquinolones, and to report fluoroquinolone resistance mechanisms in the post-treatment isolate.A patient with urinary tract infection was treated with a suboptimal dose of a fluorinated quinolone, gatifloxacin. P. aeruginosa strains were isolated before and after fluoroquinolone treatment. The pretreatment and post-treatment isolates were examined for relatedness by arbitrarily primed polymerase chain reaction. For these isolates, the minimum inhibitory concentration of antimicrobial agents was determined and mutations in the target genes (gyrA and parC) and regulatory genes (mexR and nfxB) for drug efflux pumps were analyzed.Failure of fluoroquinolone treatment of urinary tract infection was observed. The post-treatment isolate, which was assumed to be isogenic to the pretreatment isolate, exhibited fourfold to 16-fold increases in the MIC of fluoroquinolones. In this isolate, a new mutation, not observed in the pretreatment isolate, was found only in the gyrA gene, resulting in an amino acid change of aspartic acid to asparagine in codon 87 of GyrA.The P. aeruginosa isolate that was initially susceptible to fluoroquinolones showed decreased susceptibility to fluoroquinolones after treatment with a suboptimal dose of one fluoroquinolone. In the post-treatment isolate, the alteration of GyrA would be responsible for the decreased susceptibility to fluoroquinolones. We should be aware that inappropriate use of fluoroquinolones could select such a strain harboring a quinolone resistance-associated alteration of DNA gyrase.

Production of guanidinoacetic acid, a precursor of creatinine is known to be reduced by metabolic disturbance when kidney function is damaged, and thus it may be a sensitive marker of renal damage. Therefore, the urinary levels of guanidinoacetic acid, creatinine and creatine from patients with urinary tract neoplasm who received cisplatin treatment were measured by liquid chromatography-mass spectrometry. Following the administration of cisplatin, the urinary excretion of guanidinoacetic acid decreased significantly, and the low concentration was maintained for at least five days. The concentrations of creatinine and creatine gradually decreased until the third day after cisplatin administration, and slightly increased on the fifth day. As superoxide might be concerned in renal damage by cisplatin, the effect of cisplatin on superoxide generation was also investigated using human neutrophils. Cisplatin significantly enhanced phorbol 12-myristate 13-acetate-induced superoxide generation in a concentration-dependent manner, but had no effect on the superoxide generation induced by N-formyl-methionyl-leucyl-phenylalanine and arachidonic acid. The superoxide generation increased by cisplatin was inhibited by staurosporine, an inhibitor of protein kinase C, but was rather enhanced by genistein, an inhibitor of protein tyrosine kinase.

We experienced a case of paraurethral cyst in a 42-year-old woman. A paraurethral cyst, the diameter of which was about 2 cm, was observed in the septum between urethra and vagina. No communication between the cyst and urthra or vagina was detected. The resected cyst did not reveal malignant findings. Sixty-one cases of paraurethral cyst in the Japanese literature are also reviewed.

We conducted a dose-finding study for combination therapy of paclitaxel (Taxol; TXL) and carboplatin (Paraplatin; CBDCA). TXL is a novel plant-derived anticancer agent that is a diterpene derivative possessing the taxane ring. The subjects were patients with ovarian carcinoma, who were evaluated by a modified Fibonacci method. The dosage of TXL was 150 to 180 mg/m2. CBDCA was administered by dose escalation from AUC = 4 to 7. The administration schedule was as follows. Pre-medication was administered before TXL was given. TXL was then administered by intravenous infusion over 3 hours, followed by CBDCA. The dose of CBDCA was determined using the Calvert formula: [AUCX (GFR + 25)]. GFR was calculated with the Jelliffe equation. The non-hematological toxicities observed in 15 eligible cases were mainly grade 1, with no grade 3 or above, and no increase in severity was observed with stepping up. The hematological toxicities were grade 3 leukopenia in 5 of 15 cases, neutropenia in 5 cases and thrombocytopenia in 0 cases. No grade 4 toxicity was observed. The lowest counts of leukocytes and neutrophils were reached after 10.8 and 11.7 days, respectively. The toxicities were reversible in most cases with subsequent recovery. The above findings indicate that the recommended dosages for TJ therapy for Japanese ovarian cancer patients should be TXL 180 mg/m2 and CBDCA at a target of AUC = 6.

Adhesion molecules are involved in intracellular signaling in various physiological and pathological processes including metastasis and growth of tumor cells. Tumor cells interact with various host cells as well as with extracellular matrices through certain adhesion molecules such as integrins. We here propose that stimulation of beta1 integrin reduces intercellular adhesion molecule (ICAM)-1-mediated interaction of lung cancer cells with CTLs. This concept is based on the following findings: (a) engagement of beta1 integrins on certain lung cancer cells by a specific antibody or by ligand matrices such as fibronectin and collagen markedly reduced ICAM-1 expression on the cell surface and induced sICAM-1; (b) down-regulation of ICAM-1 by stimulation of beta1 integrins was abrogated by tyrosine kinase inhibitors or by transfection of dominant negative truncations of focal adhesion kinase (FAK); (c) engagement of beta1 integrins also reduced ICAM-1-dependent adhesion of lung cancer cells to T cells, a process completely inhibited by tyrosine kinase inhibitors and by transfection of dominant negative forms of FAK; and (d) stimulation of beta1 integrins prevented killing of lung cancer cells by autologous CTLs. In malignant tumors, cancer cells, including lung cancer cells, are surrounded by extracellular matrix proteins such as fibronectin and collagen. This suggests that the engagement of beta1 integrins by matrix proteins potentially occurs in cancer cells in vivo and that continuous stimulation via beta1 integrins reduces ICAM-1-expression, ICAM-1-mediated adhesion of cancer cells to CTLs and their killing by CTLs. Our results suggest that such processes can lead to the escape of lung cancer cells in vivo from immunological surveillance.

The prognostic value of tumor apoptosis was studied in patients with oropharyngeal squamous cell carcinoma treated with radical radiotherapy. Forty-eight patients with oropharyngeal squamous cell carcinoma who received radical radiotherapy between 1990 and 1995 were enrolled in the study. The radiation treatment for all patients involved the administration of 65 Gy in 26 fractions over a 6.5-week period. The apoptotic index (AI; the apoptotic cell count per 1000 tumor cells ) was distributed from 0 to 10 with a median at 2 and a mode of 1. There was a significant linear correlation between the AI and mitotic index (MI) (r=0.393, 95% confidence interval: 0.129‐0.605). The cause-specific 5-year survival for patients with AI greater than the median was 46% and for the counterpart was 41%. There was no diAerence in cause-specific survival between AI/MI greater than the median (50%) and AI/MI smaller than the median (36%). The number of patients was too small to draw definite conclusions, but the AI and the AI/MI before treatment were not shown to have a prognostic value for oropharyngeal squamous cell carcinoma in our study. The primary sites and treatment methods may influence the prognostic value of AI even for the same histological types. # 2001 Elsevier Science Ltd. All rights reserved.

The genome of the model plant Arabidopsis thaliana has been sequenced by an international collaboration, The Arabidopsis Genome Initiative. Here we report the complete sequence of chromosome 5. This chromosome is 26 megabases long; it is the second largest Arabidopsis chromosome and represents 21% of the sequenced regions of the genome. The sequence of chromosomes 2 and 4 have been reported previously and that of chromosomes 1 and 3, together with an analysis of the complete genome sequence, are reported in this issue. Analysis of the sequence of chromosome 5 yields further insights into centromere structure and the sequence determinants of heterochromatin condensation. The 5,874 genes encoded on chromosome 5 reveal several new functions in plants, and the patterns of gene organization provide insights into the mechanisms and extent of genome evolution in plants.

Article abstract The authors report a patient carrying a missense mutation in exon 10 of tau that causes a substitution at codon 301 (P301S). Although the patient shares the rapidly progressive frontotemporal dementia of the other reported pedigrees with P301S, the clinical phenotype is unique in that parkinsonism was a major symptom in the early stage and because behavioral symptoms with dementia became prominent 2 years after the onset of the disease. This study substantiates the notion that tau mutations at codon 301 can show various phenotypes.

Primary small cell carcinoma (SCC) of the bladder is a rare but important entity. We report two cases of SCC of the bladder diagnosed by urinary cytology.A 71-year-old male (case 1) and a 79-year-old female (case 2) presented with asymptomatic gross hematuria. Urinary cytology in case 1 showed the presence of a few undifferentiated malignant small cells and many transitional cell carcinoma (TCC) cells with a bloody and necrotic background. The former cells were small and round, with naked, hyperchromatic nuclei and finely granular chromatin. Pathologic diagnosis after total cystectomy was TCCSCCadenocarcinoma, T2M0N0. Urinary cytology of case 2 showed the presence of many undifferentiated malignant small cells and many TCC cells with or without squamous metaplasia. Cytologic features of the former cells were almost the same as those in case 1. Moreover, these cells were neuroendocrine marker positive by immunocytochemistry. Pathologic diagnosis after tumor resection was SCC and TCCsquamous cell carcinoma, T1b.The prognosis of primary SCC of the bladder is usually poor. Because our cases were found by urinary cytology at a relatively early stage, both have been well, without any evidence of recurrence, 30 and 25 months after surgery even without adjuvant therapy.

The oral active vitamin D pulse therapy was performed for 20 chronic hemodialysis patients with secondary hyperparathyroidism (2 degrees HPT). Before pulse therapy, all patients showed high-turnover bone diseases, elevated serum alkaline phosphatase (Alp) and elevated serum parathyroid hormone (PTH). They had at least one parathyroid gland detected by ultrasonography. In one patient, serum PTH level did not decrease during three months. In five patients, hypercalcemia was observed so that the pulse therapy was with drawn. Another patient was resistant to the second pulse therapy for recurrence of 2 degrees HPT. Total parathyroidectomy and autotransplantation was performed in these seven patients. The size of parathyroid gland in patients undergoing surgical treatment was significantly larger than those estimated by ultrasonography in patients successfully treated with pulse therapy (p0.005). In all patients with surgical treatment, the conventional oral active vitamin D therapy was performed with caution to hypercalcemia preoperatively. The preoperative Alp levels decreased compared with those of at the beginning of the pulse therapy. Postoperatively, the total amount of intravenous administered calcium decreased, and serum calcium levels were easily controlled.

Exonic and intronic mutations in the tau gene cause familial frontotemporal dementia and parkinsonism linked to chromosome 17. Here, we describe a new mutation, consisting of a C-to-T transition at position +12 of the intron following exon 10 of the tau gene in the Kumamoto pedigree, showing frontotemporal dementia. The mutation caused a marked reduction in melting temperature of the tau exon 10-splicing regulatory element RNA and a large increase in exon 10-containing transcripts. Brain tissue from affected individuals showed an abnormal preponderance of exon 10-containing transcripts that was reflected at the protein level by an overproduction of tau isoforms with four microtubule-binding repeats. Immunostaining revealed the presence of tau aggregates in degenerating neurons and glial cells. Isolated tau filaments had a twisted ribbon-like morphology and were made of hyperphosphorylated four-repeat tau isoforms. The additional mutation located dose to the splice-donor site of the intron following exon 10 of the tau gene supports the view that intronic mutations exercize their pathogenic effect by destabilizing RNA secondary structure.

The cell lines designated JHOS-2, JHOC-5 and JHOC-6 were established from epithelial ovarian carcinomas. JHOS-2 was established from a serous adenocarcinoma of a 45-year-old Japanese woman, JHOC-5 from a recurrent tumor of a clear cell adenocarcinoma of a 47-year-old Japanese woman and JHOC-6 from a tumor of a clear cell adenocarcinoma of a 43-year-old Japanese woman. These cell lines have grown well and serial passages were successively carried out more than 20 times. The monolayer cultured cells revealed neoplastic and pleomorphic features, and grew in multilayers. Electron micrographs revealed epithelial origins that had desmosomes and tonofilaments.

We performed a retrospective long-term study to evaluate the efficacy of intravesical instillation of Tokyo 172 strain Bacillus Calmette-Guerin (BCG) on carcinoma in situ (CIS) of the bladder. Between 1989 and 1998, 42 patients with CIS of bladder underwent intravesical instillation of BCG. In the follow-up period from 6 to 116 months (mean: 37.3 months), the efficacy rate of intravesical BCG instillation for CIS of the bladder was 81.0%. Two patients died from the bladder cancer. The non-recurrence rate in patients with grade 2 carcinoma (19 cases) was not significantly different from that in those with grade 3 carcinoma (23 cases). However, the recurrence rate in patients with secondary CIS (15 cases) was significantly higher than in those with primary CIS (27 cases). The recurrence of CIS was observed in 7 of 42 cases. In 6 of 7 patients, CIS recurred within one year after treatment. Total cystectomy was performed in 10 of 42 patients, and pathological findings of muscle layer invasion were detected in 8 patients. Although side effects occurred in 33 patients (77.5%), no clinically significant side effects were observed. Our results suggest that intravesical BCG therapy may be useful for the treatment of CIS of the bladder.

In order to clarify the expression of prohormone convertase (PC) 1/3 and PC2 in various carcinoids and non-carcinoid endocrine tumors, we performed indirect immunoperoxidase staining on total of 19 cases of carcinoids (9 cases of bronchial carcinoids, 4 cases of rectal carcinoids, 4 cases of gastric carcinoids and 2 cases of bile duct carcinoids). Our study also included 7 non-carcinoid endocrine tumors. Seventy-nine% and 26% of carcinoids highly or strongly expressed positive staining for PC1/3 and PC2, respectively. High and strong expressions (3+ or 4+) of both PC1/3 and PC2 were noted in only bronchial carcinoids. Strong expressions for only PC1/3 were noted in rectal carcinoids. Bile duct carcinoids also demonstrated higher expressions of PC1/3 than those of PC2. These results suggested that high expressions of both PC1/3 and PC2 in bronchial carcinoids might reflect their diverse and frequent peptide production. The expressions of PC1/3 mRNA and PC2 mRNA detected by in situ hybridization in the bronchial carcinoids and rectal carcinoids were correlated with immunoexpressions of both of the antigens. The granular immunoexpression pattern of PC1/3 and PC2 visualized by confocal laser scanning microscopy would suggest the site of post-translational processing in the secretory granules. Non-carcinoid endocrine tumors showed low expressions (+ or 2+) of PC1/3 and PC2, except for thyroid medullary carcinoma showing high immunoexpression of PC1/3. Other non-carcinoid endocrine tumors (parathyroid adenomas and adrenal pheochromocytomas) revealed low immunoexpressions for both PC1/3 and PC2.

We summarized and reviewed published reports, including our studies, on the reverse transcription-polymerase chain reaction (RT-PCR) detection of micrometastatic prostate cancer cells in lymph nodes, bone marrow and peripheral blood. Some published data preliminarily suggest that the RT-PCR assay of micrometastatic prostate cancer cells may allow a more accurate assessment of lymph node and bone metastases of prostate cancer, and offer a presurgical prediction of the pathological stage of clinically localized disease. In addition, the RT-PCR assay may have a unique prognostic value in prostate cancer. However, controversy remains over the clinical significance of the RT-PCR assay. This assay could potentially develop into a diagnostic procedure for the clinical decision making in patients with prostate cancer. To establish the clinical significance of the RT-PCR assay, further optimized and standardized RT-PCR assay studies are needed, investigating large populations and involving long-term follow-up for the determination of any association between the results of the RT-PCR assay and specific clinical outcome.

The specificity of cytoarchitectural abnormalities in limbic structures of patients with schizophrenia and their contributions towards the etiology of schizophrenia remain unknown. We have recently reported an increased breakdown of nonerythroid alpha-spectrin (fodrin), a major component of neuronal cytoskeletal proteins, in schizophrenic left superior temporal cortices [Kitamura et al., 1998: Biol Psychiatry 43:254-262], suggesting that polymorphisms of the alpha-spectrin gene might contribute to the vulnerability to schizophrenia. We screened for genetic variations associated with schizophrenia through the C-terminus sequences of the human nonerythroid alpha-spectrin gene (SPTAN1) spanning two EF-hands and also tested a possible contribution of the polymorphism to the development of schizophrenia by an association study. We found a polymorphic region of an intron located in the second EF-hand of SPTAN1 gene. There was no significant difference between patients with schizophrenia and controls in allele frequencies or genotype distribution. There is evidence that the Psh BI SPTAN1 gene polymorphism does not play a major role in the genetic component of schizophrenia.