Impact of menopausal symptoms on presenteeism in Japanese women.

BACKGROUND: Menopausal symptoms are common among middle-aged women. Working women with severe menopausal symptoms are more likely to experience presenteeism-a condition where employees continue to work despite feeling unwell. However, it remains unclear as to which specific symptoms women experience during the menopausal transition and postmenopausal periods that primarily contribute to presenteeism. AIMS: To evaluate the associations between types of menopausal symptoms and presenteeism among Japanese women. METHODS: A cross-sectional study of 4000 women aged 40-59 years who were currently working was conducted in Japan in September 2022. We used an online self-administered questionnaire that included items on demographic characteristics, the Menopause Rating Scale for measuring menopausal symptoms and the Work Functioning Impairment Scale for measuring presenteeism. Logistic regression analysis was performed. RESULTS: Women with severe overall menopausal symptoms had 12.18-fold (95% confidence interval [CI] 9.09-16.33, P < 0.001) increased odds of presenteeism compared with those without symptoms. Participants with psychological symptoms also had significantly higher presenteeism (severe: odds ratio: 9.18, 95% CI 6.60-12.78, P < 0.001). However, after controlling for psychological symptoms, there were no significant associations between somatic and urogenital symptoms and presenteeism. CONCLUSIONS: The results indicate that menopausal symptoms, especially psychological symptoms, have a significant impact on presenteeism among Japanese women. Organizations need to address menopausal symptoms in the workplace, with an emphasis on reducing work-related stress for women with menopausal symptoms.

Rapid nongenomic modulation by neurosteroids of dendritic spines in the hippocampus: Androgen, oestrogen and corticosteroid.

Memories are stored in synapses that consist of axon terminals and dendritic spines. Dendritic spines are postsynaptic structures of synapses and are essential for synaptic plasticity and cognition. Therefore, extensive investigations concerning the functions and structures of spines have been performed. Sex steroids and stress steroids have been shown to modulate hippocampal synapses. Although the rapid modulatory action of sex steroids on synapses has been studied in hippocampal neurones over several decades, the essential molecular mechanisms have not been fully understood. Here, a description of kinase-dependent signalling mechanisms is provided that can explain the rapid nongenomic modulation of dendritic spinogenesis in rat and mouse hippocampal slices by the application of sex steroids, including dihydrotestosterone, testosterone, oestradiol and progesterone. We also indicate the role of synaptic (classic) sex steroid receptors that trigger these rapid synaptic modulations. Moreover, we describe rapid nongenomic spine modulation by applying corticosterone, which is an acute stress model of the hippocampus. The explanations for the results obtained are mainly based on the optical imaging of dendritic spines. Comparisons are also performed with results obtained from other types of imaging, including electron microscopic imaging. Relationships between spine modulation and modulation of cognition are discussed. We recognise that most of rapid effects of exogenously applied oestrogen and androgen were observed in steroid-depleted conditions, including acute slices of the hippocampus, castrated male animals and ovariectomised female animals. Therefore, the previously observed effects can be considered as a type of recovery event, which may be essentially similar to hormone replacement therapy under hormone-decreased conditions. On the other hand, in gonadally intact young animals with high levels of endogenous sex hormones, further supplementation of sex hormones might not be effective, whereas the infusion of blockers for steroid receptors or kinases may be effective, with respect to suppressing sex hormone functions, thus providing useful information regarding molecular mechanisms.

Sexuality education in Japanese medical schools.

The present study aimed to investigate current sexuality education in Japanese medical schools and the impact of position title in the Japanese Society for Sexual Medicine (JSSM). Questionnaires were mailed to urology departments in all Japanese medical schools. The responses were evaluated according to four factors: the number of lecture components, curriculum hours, degree of satisfaction with the components and degree of satisfaction with the curriculum hours. We also investigated differences in these four factors among three groups: Directors, Council members and non-members of the JSSM. The medians of curriculum hours and the number of the lecture components were 90.0 min and 7.0, respectively. The curriculum hours of the Directors (140.0 min) were significantly longer than those of the non-members (90.0 min; P<0.05). The number of lecture components taught by Directors (9.5) was significantly higher than that of the Council (4.0; P<0.01) and non-members (7.0; P<0.05). More than half of the faculties were not satisfied with the lecture components and curriculum hours. This is the first study on sexuality education in Japanese medical schools. It showed the inadequacy of both curriculum hours and lecture components, and that the position title of department chair affects sexuality education in medical schools.

Distinctive role of vasohibin-1A and its splicing variant vasohibin-1B in tumor angiogenesis.

Vasohibin-1 (VASH1) was isolated as a negative-feedback regulator of angiogenesis expressed in endothelial cells (ECs). There are two transcripts of VASH1, that is, the full-length VASH1A consisting of seven exons and the splicing variant VASH1B consisting of four exons. Here, we compared the effects of VASH1A and VASH1B on tumor angiogenesis. When ECs were transfected with VASH1A or VASH1B cDNAs, VASH1B transfectants, but not VASH1A ones, induced autophagic cell death of ECs. With sonoporation, the VASH1A or VASH1B gene were transfected specifically in ECs of tumor vessels in mice. Both VASH1A and VASH1B decreased tumor vessel density and inhibited tumor growth. VASH1A normalized the remaining tumor vessels, increased their rate of perfusion, decreased tumor hypoxia and enhanced the efficacy of anticancer chemotherapy, whereas VASH1B pruned tumor vessels without causing normalization, increased tumor hypoxia and tumor necrosis and did not enhance the efficacy of anticancer chemotherapy. The alternate transfection of mice with the VASH1A and VASH1B gene showed the highest effects on antitumor activity and normalization of tumor vessels. Our present findings on VASH1A and VASH1B should provide an innovative approach that would improve the efficacy of antiangiogenic cancer therapy by balancing vascular normalization and pruning.

Circular muscle contraction in the mice rectum plays a key role in morphine-induced constipation.

BACKGROUND: Although opioids induce intestinal muscle contraction and provoke constipation, the intestinal region(s) that contribute to the constipation have remained unclear. We report here a region-specific response of intestinal muscle contraction to morphine and its correlation with in vivo constipation. METHODS: Regions of mice small and large intestines were dissected histologically and circular muscle contractile responses were measured using isometric transducers. Bead expulsion assays were performed to assess in vivo constipation. KEY RESULTS: The strongest contraction in response to morphine was detected in the rectum. The distal and transverse colon also showed strong contractions, whereas weak responses were detected in the proximal colon, jejunum, and ileum. Regarding the sustainability of muscle contractions during morphine exposure, prolonged waves were detected only in the rectum, while the waves diminished gradually in other regions. To identify the mechanism(s) underlying this difference, we focused on nitric oxide synthase (NOS). In the distal colon, decreased contraction during morphine exposure was recovered by application of a NOS inhibitor (L-NAME), while a NOS substrate (L-arginine) enhanced contractile degradation. In contrast L-NAME and L-arginine modestly affected the sustained contraction in the rectum. To confirm the correlation with constipation, beads were inserted into the transverse colon, distal colon, or rectum after morphine administration and expulsion times were examined. Beads tended to stop at the rectum even when inserted in the deeper colonic regions. CONCLUSIONS & INFERENCES: The rectum showed the greatest response to morphine in both in vitro and in vivo analyses, therefore it may play a key role for opioid-induced constipation.

TRPM8 has a key role in experimental colitis-induced visceral hyperalgesia in mice.

BACKGROUND: Transient receptor potential channel melastatin 8 (TRPM8) is activated by cold temperatures and cooling agents (menthol and icilin). Recent studies showed TRPM8 is expressed in visceral organs and peripheral sensory pathways. However, the role of TRPM8 in visceral hyperalgesia is poorly understood in pathological states such as inflammatory bowel disease. Hence, we investigated the distribution of TRPM8 and its involvement in visceral hyperalgesia in experimental colitis mice. METHODS: TRPM8 immunoreactivity was detected using immunohistochemical staining with fluorescein-conjugated tyramide amplification. Visceral hyperalgesia was measured by the intracolonic administration of TRPM8 agonist, WS-12, in control and dextran sodium sulfate (DSS)-induced colitis mice. KEY RESULTS: TRPM8 immunoreactivity in the distal colon was much higher than in the transverse and proximal colon under physiological conditions. TRPM8 immunoreactivity markedly increased in the distal colon mucosa of DSS-induced colitis mice compared with control mice. The number of TRPM8 nerve fibers in mucosa of DSS- or 2,4,6-trinitrobenzene sulfonic acid-induced colitis model mice drastically increased compared with control mice. TRPM8 immunoreactivities colocalized with the calcitonin gene-related peptide- and substance P-immunoreactive nerve fibers in the mucosa. Intracolonic administration of WS-12 induced behavioral visceral pain-like responses. The numbers of these responses in the colitis model mice were 3 times higher than in control mice, and were decreased by pretreatment with the TRPM8 channel blocker AMTB. CONCLUSIONS & INFERENCES: Increased expression of TRPM8 may contribute to the visceral hyperalgesia of experimental colitis.

The combination of strong expression of ZNF143 and high MIB-1 labelling index independently predicts shorter disease-specific survival in lung adenocarcinoma.

BACKGROUND: The transcription factor, zinc finger protein 143 (ZNF143), positively regulates many cell-cycle-related genes. The ZNF143 would show high expression of multiple solid tumours related closely to cancer cell growth, similar to the widely accepted Ki67 (MIB-1) protein, but the underlying mechanisms for ZNF143 remain unclear. We investigated the association of ZNF143 expression with clinicopathological features and prognoses of patients with lung adenocarcinoma. METHODS: Expressions of ZNF143 and MIB-1 were immunohistochemically analysed in 183 paraffin-embedded tumour samples of patients with lung adenocarcinoma. The ZNF143 expression was considered to be strong when >30% of the cancer cells demonstrated positive staining. RESULTS: Strong ZNF143+ expression showed a significantly close relationship to pathologically moderate to poor differentiation and highly invasive characteristics. The ZNF143 positivity potentially induced cell growth of lung adenocarcinoma, correlated significantly with high MIB-1 labelling index (⩾10%). Univariate and multivariate analyses demonstrated that both strong ZNF143+ and the high MIB-1 index group have only and significantly worse survival rates. CONCLUSIONS: The combination of strong ZNF143 expression and high MIB-1 index potentially predicts high proliferating activity and poor prognosis in patients with lung adenocarcinoma, and may offer a therapeutic target against ZNF143.

5-HT3 receptor antagonists ameliorate 5-fluorouracil-induced intestinal mucositis by suppression of apoptosis in murine intestinal crypt cells.

BACKGROUND AND PURPOSE: Chemotherapeutic agents, including 5-fluorouracil (5-FU), frequently cause intestinal mucositis resulting in severe diarrhoea and morphological mucosal damage. 5-HT3 receptor antagonists are clinically effective in the treatment of nausea and emesis during cancer chemotherapy. Therefore we here have examined the effects of 5-HT3 receptor antagonists on 5-FU-induced intestinal mucositis in mice. EXPERIMENTAL APPROACH: Intestinal mucositis was induced in male C57BL/6 mice by daily administration of 5-FU (50 mg·kg⁻¹) for 5 days. Effects of 5-HT3 receptor antagonists, ramosetron (0.01-0.1 mg·kg⁻¹) and ondansetron (5 mg·kg⁻¹), on the accompanying histology, cytokine production and apoptosis were assessed. KEY RESULTS: Continuous administration of 5-FU to mice caused severe intestinal mucositis, which was histologically characterized by the shortening of villi and destruction of intestinal crypts, accompanied by body weight loss and diarrhoea. Daily ramosetron administration dose-dependently reduced the severity of intestinal mucositis, body weight loss and diarrhoea. Similar beneficial effects were observed with ondansetron. The number of apoptotic, caspase-3- and caspase-8-activated cells increased 24 h after the first 5-FU administration, and these responses were reduced by ramosetron. The up-regulation of TNF-α, IL-1ß and IL-6 following 5-FU treatment was also attenuated by ramosetron. CONCLUSIONS AND IMPLICATIONS: 5-HT3 receptor antagonists ameliorated 5-FU-induced intestinal mucositis in mice, and this action could result from suppression of apoptotic responses in the intestinal crypt cells via inhibition of cytokine expression. Thus, 5-HT3 receptor antagonists may be useful for preventing not only nausea and emesis but also intestinal mucositis during 5-FU chemotherapy.

Clinical and safety profiles of bipolar transurethral vaporization of the prostate in saline: a preliminary report.

Transurethral vaporization of the prostate in saline (TURisV) is an innovative endoscopic surgical modality for the treatment of benign prostatic hyperplasia (BPH) that vaporizes prostate tissue using a uniquely designed mushroom electrode. TURisV promises instant hemostatic tissue ablation under saline irrigation and offers clinical advantages for endoscopic BPH operations. From July 2008 to February 2009, TURisV was performed in 17 cases with clinically significant BPH. Median operation time was 127.0 min and median volume of vaporized prostate tissue was 41.1 g. Median International Prostate Symptom Score improved from 20 to 4 after 12 months. Median maximum flow rate increased from 5.3 mL/s to 13.8 mL/s after 12 months. Postoperative median residual urine improved from 48.0 mL to 7.0 mL after 12 months. No changes in hemoglobin or electrolyte levels were seen postoperatively. Our results suggest that TURisV is a safe and efficacious treatment for BPH.

Distribution of transient receptor potential vanilloid 1 channel-expressing nerve fibers in mouse rectal and colonic enteric nervous system: relationship to peptidergic and nitrergic neurons.

In the gut, transient receptor potential vanilloid (TRPV) 1 activation leads to release of neurotransmitters such as neuropeptides and nitric oxide. However, the distribution of TRPV1 nerve fibers and neurotransmitters released form sensory nerve endings in the enteric nervous system are currently not well understood. The present study investigated the immunohistochemical distribution of TRPV1 channels, sensory neuropeptides, and nitric oxide and their co-localization in mouse large intestine. Numerous TRPV1 and calcitonin gene-related peptide (CGRP) immunoreactivities were detected, mainly in the mucosa, submucosal layer, and myenteric plexus. Abundant substance P (SP), neurokinin A (NKA), and neuronal nitric oxide synthase (nNOS)-immunoreactivity were revealed in muscle layers. Motor function studies of circular and longitudinal muscles found that contractile responses to capsaicin in the rectum were most sensitive among the rectum, and distal, transverse, and proximal colon. Double labeling studies were carried out in horizontal sections of mouse rectum. TRPV1/protein gene product (PGP)9.5 double labeled axons were observed, but PGP9.5 and neuronal nuclear protein immunopositive cell bodies did not express TRPV1 immunoreactivity in the myenteric plexus. In the mucosa, submucosal layer, deep muscular plexus, circular muscle, myenteric plexus and longitudinal muscle layer, TRPV1 nerve fibers were found to contain CGRP, SP and nNOS. SP and NKA were almost entirely colocalized at the axons and cell bodies in all layers. Double labeling with c-Kit revealed that TRPV1 nerve fibers localized adjacent to the interstitial cells of Cajal (ICC). These results suggest that the TRPV1-expressing nerve and its neurotransmitters regulate various functions of the large intestine.

Subdiaphragmatic vagotomy promotes nociceptive sensitivity of deep tissue in rats.

To verify whether vagal dysfunction is associated with chronic pain, we evaluated the effects of subdiaphragmatic vagotomy (vgx) on the sensitivity toward noxious stimuli in rats. Vgx rats showed sustained hyperalgesia in the gastrocnemius muscle without tissue damage (no increase in vgx-induced plasma creatine phosphokinase or lactose dehydrogenase levels) accompanied by hypersensitivity to colonic distension. We found a dramatic increase in the levels of metabotropic glutamate receptor 5, protein kinase C (PKC) gamma and phosphorylated-PKCgamma within the spinal cord dorsal horn in vgx rats, which suggests that vgx may evoke sensory nerve plasticity. Morphine produced a dose-dependent increase in the withdrawal threshold in both vgx and sham-operated rats, but the effect of a lower dose in vgx rats was weaker than that in sham-operated rats. Muscle hyperalgesia in vgx rats was also attenuated by gabapentin and amitriptyline, but was not affected by diclofenac, dexamethasone or diazepam. These findings indicate that subdiaphragmatic vagal dysfunction caused chronic muscle hyperalgesia accompanied by visceral pain and both gabapentin and amitriptyline were effective for subdiaphragmatic vagotomy-induced pain, which are partially similar to fibromyalgia syndrome. Furthermore, this chronic muscle pain may result from nociceptive neuroplasticity of the spinal cord dorsal horn.

Association of varicella zoster virus load in the aqueous humor with clinical manifestations of anterior uveitis in herpes zoster ophthalmicus and zoster sine herpete.

AIM: To investigative whether clinical manifestations of anterior uveitis are associated with the viral load of varicella zoster virus (VZV) in the aqueous humor in patients with herpes zoster ophthalmicus (HZO) and zoster sine herpete (ZSH). METHODS: After informed consent was given, an aliquot of aqueous humor was collected from patients with VZV anterior uveitis (n = 8). Genomic DNA of the human herpes viruses was measured in the aqueous humor by two PCR assays: a qualitative multiplex PCR and a quantitative real-time PCR. RESULTS: All patients had unilateral acute anterior uveitis with high intraocular pressure, mutton fat keratic precipitates with some pigmentation, and trabecular meshwork pigmentation. Multiplex PCR demonstrated VZV genomic DNA in all of the samples, but not in other human herpes virus samples (human simplex virus types 1 and 2, Epstein-Barr virus, cytomegalovirus and human herpes virus types 6, 7 and 8). Real-time PCR revealed a high copy number of VZV DNA in the aqueous humor. After the initial onset of anterior uveitis, iris atrophy and distorted pupil with paralytic mydriasis developed. The intensity of iris atrophy and pupil distortion, but not ocular hypertension, correlated with the viral load of VZV in the aqueous humor. CONCLUSION: VZV viral load in the aqueous humor correlated significantly with damage to the iris (iris atrophy and pupil distortion) in patients with HZO and ZSH.

Circadian clock molecules CLOCK and CRYs modulate fibrinolytic activity by regulating the PAI-1 gene expression.

Disruptions of circadian rhythms are associated with the development of many disorders. However, whether a disruption of the circadian clock can cause anomalies of the hemostatic balance remains unknown. The present study examines coagulation and fibrinolytic activities in circadian clock mutants, a homozygous Clock mutant and Cry1/Cry2 double knockout (Cry1/2-deficient) mice. The euglobulin clot lysis time (ELT) showed circadian variations that peaked at 21:00 (early night) in wild-type mice, suggesting that fibrinolytic activity is lowest at this time. The ELT was continuously reduced in Clock mutants, while the ELT was significantly increased and did not differ between day and night (9:00 and 21:00) in Cry1/2-deficient mice. The prothrombin time (PT) and activated partial prothrombin time (APTT) were constant in all genotypes. To identify which factors cause the loss of ELT rhythm, we measured fibrinolytic parameters in Clock mutant and Cry1/2-deficient mice. The robust circadian fluctuation of plasma plasminogen activator inhibitor 1 (PAI-1) that peaked at early night was damped to trough levels in Clock mutant mice. On the other hand, PAI-1 levels in Cry1/2-deficient mice remained equivalent to the peak levels of those in wild-type mice at both 9:00 and 21:00. Circadian changes in plasma PAI-1 levels seemed to be regulated at the level of gene expression, because the plasma PAI-1 levels in Clock mutant and Cry1/2-deficient mice were closely correlated with the level of PAI-1 mRNA transcript in these mice. Plasma plasminogen and hepatic mRNA levels were not rhythmic in wild-type mice, and continuously higher in Clock mutant than in wild-type or Cry1/2-deficient mice. In contrast, the activity and mRNA levels of tissue type plasminogen activator (t-PA), plasma levels and mRNA levels of plasminogen, and plasma levels of alpha2 plasmin inhibitor (alpha2PI) in all genotypes were constant throughout the day. Coagulation parameters such as factor VII, factor X, prothrombin and fibrinogen remained constant throughout the day, and were not affected by clock gene mutations. These results suggest that circadian clock molecules play an important role in hemostatic balance by regulating the fibrinolytic systems.

Immunohistochemical co-localization of transient receptor potential vanilloid (TRPV)1 and sensory neuropeptides in the guinea-pig respiratory system.

Electrophysiological studies within the lung have documented the presence of heterogenous groups of afferent fibers composed of Adelta and C-fibers and studies of somatosensory nerves within the skin reveal a complex pattern of distribution of sensory neuropeptides and transient receptor potential vanilloid (TRPV)1 positive nerves. However, the anatomical location of these different subpopulations of nerves within the lung has not been extensively studied. In the present study we have demonstrated that TRPV1 axons represented only a small proportion of the total number of PGP9.5 staining nerves within guinea-pig tracheal epithelium and only half the number of TRPV1 axons was immunopositive for substance P. In contrast, most TRPV1 positive neurones found within guinea-pig intrapulmonary airways were found to co-localize with sensory neuropeptides substance P and calcitonin gene-related peptide within and beneath the epithelium, around blood vessels, within airway smooth muscle and alveoli, indicative of heterogeneity of TRPV1 positive axons throughout the airways. However, in the smooth muscle layer of the trachea there was evidence of substance P and calcitonin gene-related peptide containing nerves that did not stain for TRPV1. We also demonstrated a complete loss of TRVP1 positive axons in the trachea and intrapulmonary airways and associated loss of bronchoconstriction induced by capsaicin, in animals chronically treated with capsaicin. However, some neuropeptide immunoreactive axons remained in the smooth muscle layer of capsaicin-treated animals which could represent the small subset of neuropeptide containing fibers which do not co-localize with TRPV1. We have provided evidence of heterogeneity of TRPV1 positive nerve fibers, including fibers characterized by lack of co-localization with neuropeptides in various regions of the airways and the existence of neuropeptide containing fibers that were not TRPV1 positive in guinea-pigs.

Protective role of vanilloid receptor type 1 in HCl-induced gastric mucosal lesions in rats.

BACKGROUND: Effects of vanilloid-receptor agonists and antagonists on HCl-induced gastric lesions in rats were investigated to elucidate the role of vanilloid receptor type 1 (VR1) in gastric mucosal defense mechanisms. METHODS: Gastric lesions in rats were evaluated after intragastric administration of 0.6 N HCl. The localization of VR1 in the stomach was investigated immunohistochemically. RESULTS: Intragastric administration of capsaicin inhibited the formation of gastric lesions in a dose-dependent manner (0.1-2.5 mg/kg). The functional VR1 antagonists ruthenium red and capsazepine markedly aggravated HCl-induced gastric lesions in rats. The gastroprotective effect of capsaicin was attenuated by ruthenium red or capsazepine. It is reported that resiniferatoxin, [6]-gingerol and lafutidine are compounds that activate VR1 and/or capsaicin-sensitive afferent neurons. These compounds significantly inhibited the formation of HCl-induced gastric lesions, and their gastroprotective effects were inhibited by treatment with ruthenium red. The immunohistochemical studies revealed that nerve fibers expressing VR1 exist along gastric glands in the mucosa, around blood vessels in the submucosa, in the myenteric plexus, and in the smooth muscle layers, especially the circular muscle layer. CONCLUSION: The results of this study suggest that VR1 plays a protective role in the gastric defensive mechanism in rats.

High proliferative potential colony-forming cells (HPP-CFCs) in the peripheral blood of rheumatoid arthritis patients with interstitial lung disease.

OBJECTIVE: To examine the presence of high proliferative potential colony-forming cells (HPP-CFCs) in the peripheral blood of rheumatoid arthritis (RA) patients with and without interstitial lung disease (ILD). METHODS: Peripheral blood mononuclear cells from 35 RA patients with and without ILD, 12 patients with infectious pulmonary diseases, 10 patients with idiopathic pulmonary fibrosis (IPF), and 20 healthy volunteers, were assayed for in vitro colony formation. RESULTS: HPP-CFCs were detected significantly more frequently in the peripheral blood of patients with ILD (11/14: 78%, p<0.05) than in that of patients without ILD (4/21: 19%). HPP-CFCs were not detected in the peripheral blood of patients with infectious pulmonary diseases, those with IPF or healthy volunteers. CONCLUSIONS: HPP-CFCs were frequently found in the peripheral blood of RA patients with ILD compared with those without ILD, suggesting the mobilization of HPP-CFCs from the bone marrow into the peripheral blood in association with ILD in RA.

Modifier effect of ENOS in autosomal dominant polycystic kidney disease.

A significant phenotypical variability is observed in autosomal dominant polycystic kidney disease (ADPKD). ADPKD is associated with altered endothelial-dependent vasodilation and decreased vascular production of nitric oxide (NO). Thus, ENOS, the gene coding for the endothelial nitric oxide synthase (eNOS), could have a modifier effect in ADPKD. In order to test this hypothesis, we genotyped 173 unrelated ADPKD patients from Belgium and the north of France for the Glu298Asp, intron 4 VNTR and T-786C polymorphisms of ENOS and looked for their influence on the age at end-stage renal disease (ESRD). In males (n = 93), the Glu298Asp polymorphism was associated with a lower age at ESRD (Glu/Asp + Asp/Asp: 49.0 +/- 1.2 years, n = 53; Glu/Glu: 53.5 +/- 1.5 years, n = 40; simple regression, P = 0.02; multiple regression, P = 0.006). This effect was confirmed in a subset of males linked to PKD1 and reaching ESRD before age 45, and by a cumulative renal survival analysis in PKD1-linked families. Further studies demonstrated that NO synthase (NOS) activity was decreased in renal artery samples from ADPKD males harbouring the Asp298 allele, in association with post-translational modifications and partial cleavage of eNOS. No significant effect of the other polymorphisms was found in males, and no polymorphism influenced the age at ESRD in females. In conclusion, the frequent Glu298Asp polymorphism of ENOS is associated with a 5 year lower mean age at ESRD in this subset of ADPKD males. This effect could be due to a decreased NOS activity and a partial cleavage of eNOS, leading to a further decrease in the vascular production of NO.

Dramatic efficacy of cyclophosphamide pulsed therapy combined with double-filtration plasmapheresis for treating severe massive pulmonary hemorrhage associated with systemic lupus erythematosus.

Abstract Pulmonary hemorrhage (PH) is a rare but fatal complication of systemic lupus erythematosus (SLE). We report a patient with SLE and a massive PH who was treated with double-filtration plasmapheresis synchronized with cyclophosphamide pulsed therapy. The patient showed dramatic improvement immediately and was followed for 3 years without recurrence. Prompt treatment during the acute phase of PH with this short-term intensive combination therapy may offer the best chance of success. There are few reports of long-term followup, especially in Japan.

Effects of vanilloid receptor agonists and antagonists on gastric antral ulcers in rats.

Defunctionalization of capsaicin-sensitive afferent nerves by pretreatment with a neurotoxic dose of capsaicin aggravates gastric ulcers in rats. In the present study, we investigated the roles of vanilloid receptors in gastric antral ulcers, using vanilloid receptor agonists and antagonists. Gastric antral ulcers were induced by a combination of diethyldithiocarbamate and 1 N HCl in refed rats. The administration of ruthenium red (1.5 mg/kg, s.c., twice daily) aggravated gastric antral ulcers (ulcer index: control, 33.7+/-13.7 mm(2); ruthenium red, 99.9+/-11.0 mm(2)). A similar result was observed in rats pretreated with a neurotoxic dose of capsaicin. On the other hand, capsaicin (1-10 mg/kg, p.o., twice daily) inhibited antral ulcer formation (ulcer index: control, 99.2+/-20.6 mm(2); capsaicin 10 mg/kg, 37.0+/-11.7 mm(2)). A similar effect was obtained in rats treated with the novel antiulcer drug, lafutidine (3-10 mg/kg, p.o., twice daily), which has gastroprotective activity mediated by capsaicin-sensitive afferent nerves. The antiulcer effects of capsaicin and lafutidine were abolished by ruthenium red and by pretreatment with a neurotoxic dose of capsaicin. These results suggest that vanilloid receptors play a gastroprotective role in gastric antral ulcers. In addition, treatment with ruthenium red may be an alternative tool for defunctionalization of capsaicin-sensitive afferent nerves.

Absence of mutations in the beta-catenin and adenomatous polyposis coli genes in papillary and follicular thyroid carcinomas.

beta-Catenin has multiple functions both in intercellular adhesion and in signal transduction. As a signaling molecule, mutations in exon 3 of the beta-catenin gene stabilize this protein in the cytoplasm. Subsequently, accumulated beta-catenin protein translocates to nuclei with T-cell factor-4, and upregulates transcriptional activity of the target genes involved in carcinogenesis. Mutations in exon 3 of the beta-catenin gene have been detected in various carcinomas. We examined immunolocalization of beta-catenin protein and mutations in the beta-catenin and adenomatous polyposis coli (APC) genes in papillary carcinoma (25 cases), follicular carcinoma (two cases), and benign thyroid tumor (29 cases). We detected no mutation in exon 3 of the beta-catenin gene in both malignant and benign thyroid tumors by polymerase chain reaction (PCR) and direct sequencing. No mutations in the mutation cluster region of APC were found in any tumor samples analyzed. Immunohistochemically, beta-catenin showed membranous localization in most specimens. These results suggest that mutations of the beta-catenin and APC genes are rare and that activation of the Wnt signaling pathway may not contribute to pathogenesis in human papillary and follicular thyroid carcinomas.