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The relationship between the white-coat effect (WCE), defined as white-coat hypertension under treatment, and the frequency of orthostatic hypotension (OH) is not known. We conducted an orthostatic test in patients with WCE to determine the frequency of OH.This was a cross-sectional study of 5631 patients with hypertension visiting general practitioners nationwide, in which 4305 patients with hypertension recorded their home blood pressure (BP) and consented to the orthostatic test. Patients with hypertension were divided into four groups: controlled hypertension (CHT), masked hypertension (MHT), sustained hypertension (SHT), and WCE. The orthostatic test was performed, and BP and pulse rate were measured immediately and 1 min after orthostasis.The OH frequencies immediately after standing in CHT, WCE, SHT, and MHT patients were 7, 11.7, 12.1, and 6.6%, respectively, and those at 1 min after standing were 7.1, 13.1, 11.6 and 6.9%, respectively (Chi-square test, P0.01, respectively). Logistic regression analysis was performed to examine the relationship between WCE and the frequency of OH. The frequency of OH immediately after standing was significantly increased [adjusted odds ratio (AOR), 1.702; 95% confidence interval (CI), 1.246-2.326; P0.01]. The frequency of OH at 1 min after standing was also significantly higher (AOR, 1.897; 95% CI, 1.396-2.578; P0.01).When the standing test was performed for patients with WCE, the frequency of OH increased. Thus, it is important to recognize the possibility of OH in patients with WCE to avoid adverse events associated with excessive hypotension.

Aim: Sodium–glucose cotransporter 2 inhibitors (SGLT2is) provide renal protection in patients with type 2 diabetes mellitus (T2DM). The aim of this study was to elucidate the renal effects of long-...

Aims/Introduction Sodium–glucose cotransporter 2 inhibitors (SGLT2i) improve renal outcome in patients with type 2 diabetes mellitus, but the mechanism is not fully understood. The aim of this retrospective study was to assess the association of achieved blood pressure with renal outcomes in Japanese type 2 diabetes mellitus patients with chronic kidney disease. Materials and Methods We assessed 624 Japanese type 2 diabetes mellitus patients with chronic kidney disease taking SGLT2i for >1 year. The patients were classified as those with post‐treatment mean arterial pressure (MAP) of ≥92 mmHg (n = 344) and those with MAP of, Incidence of renal composite outcome and changes in logarithmic value of the albumin‐to‐creatinine ratio and estimated glomerular filtration rate.

The stratum corneum (SC), the outermost epidermal layer, consists of nonviable anuclear keratinocytes, called corneocytes, which function as a protective barrier. The exact modes of cell death executed by keratinocytes of the upper stratum granulosum (SG1 cells) remain largely unknown. Here, using intravital imaging combined with intracellular Ca(2+)- and pH-responsive fluorescent probes, we aimed to dissect the SG1 death process in vivo. We found that SG1 cell death was preceded by prolonged (∼60 min) Ca(2+) elevation and rapid induction of intracellular acidification. Once such intracellular ionic changes were initiated, they became sustained, irreversibly committing the SG1 cells to corneocyte conversion. Time-lapse imaging of isolated murine SG1 cells revealed that intracellular acidification was essential for the degradation of keratohyalin granules and nuclear DNA, phenomena specific to SC corneocyte formation. Furthermore, intravital imaging showed that the number of SG1 cells exhibiting Ca(2+) elevation and the timing of intracellular acidification were both tightly regulated by the transient receptor potential cation channel V3. The functional activity of this protein was confirmed in isolated SG1 cells using whole-cell patch-clamp analysis. These findings provide a theoretical framework for improved understanding of the unique molecular mechanisms underlying keratinocyte-specific death mode, namely corneoptosis.

FK506 (tacrolimus) is an immunosuppressant widely used as an ointment in the treatment of atopic dermatitis. However, local application of FK506 can evoke burning sensations in atopic dermatitis patients, and its mechanisms are unknown. In this study, we found that FK506 activates transient receptor potential ankyrin 1 (TRPA1) channels. In Ca2+-imaging experiments, increases in intracellular Ca2+ concentrations ([Ca2+]i) by FK506 were observed in HEK293T cells expressing hTRPA1 or hTRPM8. FK506-induced currents were observed in HEK293T cells expressing hTRPA1 or mTRPA1, but less or not at all in cells expressing hTRPV1 or hTRPM8 using a patch-clamp technique. FK506 also evoked single-channel opening of hTRPA1 in an inside-out configuration. FK506-induced [Ca2+]i increases were also observed in TRPA1-expressing mouse primary sensory neurons. Furthermore, injection of FK506 evoked licking or biting behaviors and these behaviors were almost abolished in TRPA1 knockout mice. These results indicate that FK506 might cause pain sensations through TRPA1 activation.

Maternal–fetal calcium (Ca2+) transport in the placenta plays a critical role in maintaining fetal bone mineralization. Mutations in the gene encoding the transient receptor potential cation channel, subfamily V, member 6 (TRPV6) have been identified as causative mutations of transient neonatal hyperparathyroidism due to insufficient maternal–fetal Ca2+ transport in the placenta. In this study, we found two novel mutations in subjects that have transient neonatal hyperparathyroidism. TRPV6 carrying the mutation p.Arg390His that localizes to the outer edge of the first transmembrane domain (S1) showed impaired trafficking to the plasma membrane, whereas TRPV6 having the mutation p.Gly291Ser in the sixth ankyrin repeat (AR) domain had channel properties that were comparable those of WT channels, although the increases in steady-state intracellular Ca2+ concentration could have led to Ca2+ overload and subsequent death of cells expressing this mutant channel. These results indicate that the AR6 domain contributes to TRPV6-mediated maintenance of intracellular Ca2+ concentrations, and that this region could play a novel role in regulating the activity of TRPV6 Ca2+-selective channels.

The role of TRP channels in the ventilatory response to CO

The placenta is required to transport calcium (Ca2+) from mother to fetus during fetal bone mineralization. In an attempt to clarify the molecular basis of Ca2+ entry for this transport, we identified TRPM6 as a candidate for apical Ca2+ entry pathway. TRPM6 mRNA increased during the last 4 days of pregnancy, coinciding with fetal bone mineralization in mice. TRPM6 mRNA and protein was localized in the trophoblasts in labyrinth where the maternal–fetal Ca2+ transport occurs. In patch-clamp recordings, we observed TRPM6/TRPM7-like currents in mouse trophoblasts after starting fetal bone mineralization but not before mineralization. Plasma membrane Ca2+ permeability was significantly increased in TRPM6/TRPM7 expressed HEK293 cells under physiological Mg2+ and ATP concentration but not in TRPM6 or TRPM7 homomer-expressing cells. These results suggest that TRPM6 is functionally expressed in mouse placental trophoblasts, implicating in maternal–fetal Ca2+ transport likely with TRPM7, which might enable to sustain fetal bone mineralization.

Purpose: Calcium entry channels in the plasma membrane are thought to play a major role in maintaining cellular Ca2+ levels, crucial for growth and survival of normal and cancer cells. The calcium-selective channel TRPV6 is expressed in prostate, breast, and other cancer cells. Its expression coincides with cancer progression, suggesting that it drives cancer cell growth. However, no specific inhibitors for TRPV6 have been identified thus far. Methods: To develop specific TRPV6 inhibitors, we synthesized molecules based on the lead compound TH-1177, reported to inhibit calcium entry channels in prostate cancer cells in vitro and in vivo. Results: We found that one of our compounds (#03) selectively inhibited TRPV6 over five times better than TRPV5, whereas TH-1177 and the other synthesized compounds preferentially inhibited TRPV5. The IC50 value for growth inhibition by blocking endogenous Ca2+ entry channels in the LNCaP human prostate cancer cell line was 0.44 ± 0.07 μM compared to TH-1177 (50 ± 0.4 μM). Conclusions: These results suggest that compound #03 is a relatively selective and potent inhibitor for TRPV6 and that it is an interesting lead compound for the treatment of prostate cancer and other cancers of epithelial origin.

Transient neonatal hyperparathyroidism (TNHP) is etiologically a heterogeneous condition. One of the etiologies is an insufficient maternal-fetal calcium transport through the placenta. We report six subjects with homozygous and/or compound-heterozygous mutations in the gene encoding the transient receptor potential cation channel, subfamily V, member 6 (TRPV6), an epithelial Ca2+-selective channel associated with this condition. Exome sequencing on two neonates with skeletal findings consistent with neonatal hyperparathyroidism identified homozygous frameshift mutations before the first transmembrane domain in a subject born to first-cousins parents of Pakistani descent as well as compound-heterozygous mutations (a combination of a frameshift mutation and an intronic mutation that alters mRNA splicing) in an individual born to a non-consanguineous couple of African descent. Subsequently, targeted mutation analysis of TRPV6 performed on four other individuals (born to non-consanguineous Japanese parents) with similar X-rays findings identified compound-heterozygous mutations. The skeletal findings improved or resolved in most subjects during the first few months of life. We identified three missense variants (at the outer edges of the second and third transmembrane domains) that alter the localization of the TRPV6: one recurrent variant at the S2-S3 loop and two recurrent variants (in the fourth ankyrin repeat domain) that impair TRPV6 stability. Compound heterozygous loss-of-function mutations for the pathogenic frameshift allele and the allele with an intronic c.607+5G>A mutation resulted in the most severe phenotype. These results suggest that TNHP is an autosomal-recessive disease caused by TRPV6 mutations that affect maternal-fetal calcium transport.

The article Hypotonicity-induced cell swelling activates TRPA1, written by Fumitaka Fujita, Kunitoshi Uchida, Yasunori Takayama, Yoshiro Suzuki, Masayuki Takaishi and Makoto Tominaga, was originally published electronically on the publisher’s internet portal (currently SpringerLink) on 16 June 2017 without open access.

This study attempted to clarify the differences in blood pressure (BP) between the office (clinic) and home settings in patients with controlled, sustained, masked or white-coat hypertension. The following formula was used: office mean systolic BP (omSBP)-mean morning home SBP (mmhSBP)/office mean diastolic BP (omDBP)-mean morning home DBP (mmhDBP). The paired t-test was used for statistical analysis. The omSBP-mmhSBP/omDBP-mmhDBP calculation yielded the following results: among normotensive subjects, -1.1±11.2/-1.7±8.5 mm Hg (mean SBP and mean DBP were higher at home than in the office; n=451, P=0.038 in SBP, P=0.000 in DBP); in controlled hypertensive patients, -0.42±10.9/-2.2±8.2 mm Hg (n=1362, P=0.160 in SBP, P=0.000 in DBP); among sustained hypertensive patients, 5.6±14.7/0.048±9.9 mm Hg (n=1370, P=0.000 in SBP, P=0.857 in DBP); in masked hypertensive patients, -15.3±12.9/-9.3±9.5 mm Hg (n=1308, both P=0.000); and among white-coat hypertensive patients, 23.7±13.2/8.2±9.1 mm Hg (n=580, both P=0.000). Our results showed a difference of 5 mm Hg in SBP among sustained hypertensive patients, as recommended by the Japanese Society of Hypertension Guidelines for the Management of Hypertension; however, in other hypertensive patient types, the differences in SBP and DBP between office and home measurements differed by >5 mm Hg. Office and home BP measurements should be interpreted cautiously, keeping in mind the clinical setting.

TRPV6 belongs to the vanilloid family of the transient receptor potential channel (TRP) superfamily. This calcium-selective channel is highly expressed in the duodenum and the placenta, being responsible for calcium absorption in the body and fetus. Previous observations have suggested that TRPV6 is not only permeable to calcium but also to other divalent cations in epithelial tissues. In this study, we tested whether TRPV6 is indeed also permeable to cations such as zinc and cadmium. We found that the basal intracellular calcium concentration was higher in HEK293 cells transfected with hTRPV6 than in non-transfected cells, and that this difference almost disappeared in nominally calcium-free solution. Live cell imaging experiments with Fura-2 and NewPort Green DCF showed that overexpression of human TRPV6 increased the permeability for Ca(2+), Ba(2+), Sr(2+), Mn(2+), Zn(2+), Cd(2+), and interestingly also for La(3+) and Gd(3+). These results were confirmed using the patch clamp technique. (45)Ca uptake experiments showed that cadmium, lanthanum and gadolinium were also highly efficient inhibitors of TRPV6-mediated calcium influx at higher micromolar concentrations. Our results suggest that TRPV6 is not only involved in calcium transport but also in the transport of other divalent cations, including heavy metal ions, which may have toxicological implications.

The rate-limiting step of dietary calcium absorption in the intestine requires the brush border calcium entry channel TRPV6. The TRPV6 gene was completely sequenced in 170 renal calcium stone patients. The frequency of an ancestral TRPV6 haplotype consisting of three non-synonymous polymorphisms (C157R, M378V, M681T) was significantly higher (P = 0.039) in calcium stone formers (8.4%; derived = 502, ancestral = 46) compared to non-stone-forming individuals (5.4%; derived = 645, ancestral = 37). Mineral metabolism was investigated on four different calcium regimens: (i) free-choice diet, (ii) low calcium diet, (iii) fasting and (iv) after a 1 g oral calcium load. When patients homozygous for the derived haplotype were compared with heterozygous patients, no differences were found with respect to the plasma concentrations of 1,25-vitamin D, PTH and calcium, and the urinary excretion of calcium. In one stone-forming patient, the ancestral haplotype was found to be homozygous. This patient had absorptive hypercalciuria. We therefore expressed the ancestral protein (157R+378V+681T) in Xenopus oocytes and found a significantly enhanced calcium permeability when tested by a (45)Ca(2+) uptake assay (7.11 +/- 1.93 versus 3.61 +/- 1.01 pmol/min/oocyte for ancestral versus derived haplotype, P < 0.01). These results suggest that the ancestral gain-of-function haplotype in TRPV6 plays a role in calcium stone formation in certain forms of absorptive hypercalciuria.

The removal of unwanted body fat using a noninvasive technique is desirable to patients and physicians. The authors describe a controlled, multicenter, clinical trial assessing the safety and efficacy of a focused therapeutic ultrasound device for noninvasive body contouring.Eligible healthy adult subjects were enrolled to the experimental group or the control group at five sites. The experimental group received one treatment with the Contour I device (UltraShape Ltd., Tel Aviv, Israel) in the abdomen, thighs, or flanks and were evaluated over a 12-week period. Efficacy outcomes were reduction of circumference and fat thickness. Circumference reduction was compared with the untreated group and with an untreated area (thigh) within the treated group. Safety monitoring included laboratory testing (including serum lipids), pulse oximetry, and liver ultrasound.One hundred sixty-four subjects participated in the study (137 subjects in the experimental group and 27 in the control, untreated group). A single Contour I treatment was safe and well tolerated and produced a mean reduction of approximately 2 cm in treatment area circumference and approximately 2.9 mm in skin fat thickness. The majority of the effect was achieved within 2 weeks and was sustained at 12 weeks. No clinically significant changes in the measured safety parameters were recorded. Seven adverse events were reported, all of which were anticipated, mild, and resolved within the study period.The Contour I device provides a safe and effective noninvasive technology for body contouring.

Background and Purpose— We investigated the factors influencing inpatient convalescent rehabilitation outcomes in patients with ischemic stroke, particularly severity of leukoaraiosis on magnetic resonance imaging. Methods— Participants included 520 patients with ischemic stroke (317 men and 203 women; mean age, 72.8±8.4 years) who were transferred from acute care hospitals for inpatient convalescent rehabilitation. Ischemic stroke subtypes included lacunar infarction (n=41), atherothrombosis (n=223), artery-to-artery embolism (n=67), cardiogenic embolism (n=97), undetermined embolism (n=76), and uncategorized ischemic stroke (n=16). Leukoaraiosis was graded according to periventricular hyperintensity (PVH) and deep white matter hyperintensity on magnetic resonance imaging. Functional Independence Measure scores were assessed on admission and at discharge. Results— Multiple regression analysis revealed that rehabilitation outcomes, measured as total Functional Independence Measure scores, were significantly associated with leukoaraiosis estimated by PVH grade. This association was observed after adjustment for factors such as severity, age, and poststroke history. In all patients, PVH grades were associated with Functional Independence Measure motor scores ( P P Conclusions— Our study revealed that the degree of leukoaraiosis was associated with inpatient convalescent rehabilitation outcome in patients with ischemic stroke. Furthermore, the PVH grade was associated with motor function outcome, whereas the deep white matter hyperintensity grade correlated with cognitive function outcome, likely because the progression patterns and anatomic backgrounds of PVH and deep white matter hyperintensity differ according to ischemic stroke subtype.

Amino acid homeostasis depends on specific amino acid transport systems, many of which have been characterized at the molecular level. However, the classical System IMINO, defined as the Na+-dependent proline transport activity that escapes inhibition by alanine, had not been identified at the molecular level. We report here the functional characteristics and tissue distribution of Sodium/Imino-acid Transporter 1 (SIT1), which exhibits the properties of classical System IMINO. SIT1, the product of the slc6a20 gene, is a member of the SLC6 Na+- and Cl--dependent neurotransmitter transporter family whose function has remained unknown. When expressed in Xenopus oocytes, rat SIT1 mediated the uptake of imino acids such as proline (K0.5 approximately 0.2 mM) and pipecolate, as well as N-methylated amino acids (e.g. MeAIB, sarcosine). SIT1-mediated proline transport was pH-independent and insensitive to inhibition by alanine or lysine. Proline transport was Na+-dependent, Cl--stimulated, and voltage-dependent. Li+, but not H+, could substitute for Na+. Human SIT1 also functioned as a Na+-dependent proline transporter. Rat SIT1 mRNA was expressed in epithelial cells of duodenum, jejunum, ileum, stomach, cecum, colon, and kidney proximal tubule S 3 segments. SIT1 mRNA was also expressed in the choroid plexus, microglia, and meninges of the brain and in the ovary. Previous reports have documented the marked urinary hyperexcretion of proline in newborn rodents and man. We found that SIT1 was dramatically up-regulated in the kidneys of 3-day-old mice, accounting for the maturation of proline reabsorption in the mouse. The human slc6a20 gene coding SIT1 is an appropriate target for investigation of hereditary forms of iminoaciduria in man.

Traditionally, Asians have been thought to age more gracefully than Caucasians. The resistance to aging in the Asian patient was credited to the thicker dermis of Asian skin that contains greater collagen and the darker pigment that protects against photoaging. Although these statements are true, the authors propose a new paradigm that explains how the illusion of Asian youthfulness may be understood. The "baby model" purports that the Asian face has many attributes similar to an infant, including a wider and rounder face, higher eyebrow, fuller upper lid, lower nasal bridge, flatter midface, apparently more protuberant lips, and more receded chin. These commonalities between the infant and the Asian compel the viewer to perceive the Asian face as more youthful. However, the Asian face is subjected to a greater amount of gravitational force due to weaker skeletal support, heavier soft tissue, larger amount of malar fat, thicker skin, and a weaker chin. Facial rejuvenative surgery should always be cognizant of the propensity of the Asian skin to unfavorable healing, need for greater tissue suspension, and more conspicuous temporal alopecia. Asian aesthetics that differ and converge with Western ideals are reviewed so that the Western surgeon in particular can comprehend the Asian conception of youthful beauty.

Transient receptor potential vanilloid 4 (TRPV4), a calcium-permeable channel, is highly expressed in the apical membrane of choroid plexus epithelial cells (CPECs) in the brain. The function of TRPV4 is unknown. Here, we show physical and functional interaction between TRPV4 and anoctamin 1 (ANO1) in HEK293T cells and CPECs. Chloride currents induced by a TRPV4 activator (GSK1016790A) were markedly increased in an extracellular calcium-dependent manner in HEK293T cells expressing TRPV4 with ANO1, but not with ANO4, ANO6, or ANO10, the mRNAs of which were expressed in the choroid plexus. We also found physical interaction between TRPV4 and ANO1 in both HEK293T cells and choroid plexus. We observed that ANO1 was activated at a warm temperature (37°C) in HEK293T cells and that the heat-evoked chloride currents were markedly enhanced after GSK1016790A application in CPECs. Simultaneous stimulation by warmth and hyposmosis induced chloride current activation in wild-type, but not in TRPV4-deficient, CPECs. Cell volume changes were induced by ANO1-mediated chloride currents in parallel with membrane potential changes, and the cell volume was significantly decreased at negative membrane potentials by TRPV4-induced ANO1 activation. Thus, physical and functional interactions between TRPV4 and ANO1 can modulate water transport in the choroid plexus.

A novel inwardly rectifying K+ channel, Kir7.1, with unique pore properties, was cloned recently. Working in the field of osmoregulation, we have also identified the same human and rat channel and found that the channel is unique not only in its pore sequence but also in its dense localization in the follicular cells of the thyroid gland. Northern blot analysis revealed that the channel message was abundantly expressed in the thyroid gland and small intestine, and moderately in the kidney, stomach, spinal cord and brain. Immunohistochemistry of the rat thyroid, intestine and choroid plexus demonstrated the expression of the channel protein in the follicular cells and epithelial cells, suggesting a role in the regulation of the ion-transporting functions of these specialized cells. The unique pore properties of Kir7.1 make it a strong candidate for the hypothetical low-conductance K+ channel that is functionally coupled with Na+,K+-ATPase by recycling K+. We therefore further examined the co-localization of Kir7.1 and Na+,K+-ATPase and found that both are localized in the basolateral membrane of the thyroid follicular cell; in the choroid plexus, which is known to be unique in having Na+,K+-ATPase in the apical side of the epithelial cells, Kir7.1 was found in the apical membrane, implying a close functional coupling between the channel and Na+,K+-ATPase.

Transient receptor potential ankyrin 1 (TRPA1) protein is a nonselective cation channel. Although many studies suggest that TRPA1 is involved in inflammatory and neuropathic pain, its mechanism remains unclear. Here we identify an alternative splice variant of the mouse Trpa1 gene. TRPA1a (full-length) and TRPA1b (splice variant) physically interact with each other and TRPA1b increases the expression of TRPA1a in the plasma membrane. TRPA1a and TRPA1b co-expression significantly increases current density in response to different agonists without affecting their single-channel conductance. Exogenous overexpression of Trpa1b gene in wild-type and TRPA1KO DRG neurons also increases TRPA1a-mediated AITC responses. Moreover, expression levels of Trpa1a and Trpa1b mRNAs change dynamically in two pain models (complete Freund's adjuvant-induced inflammatory pain and partial sciatic nerve ligation-induced neuropathic pain models). These results suggest that TRPA1 may be regulated through alternative splicing under these pathological conditions.

Prostate cancer is a major health concern as it has the second highest incidence rate among cancers in men. Despite progress in tumor diagnostics and therapeutic approaches, prognosis for men with advanced disease remains poor. In this review we provide insight into the changes of the intermediary metabolism in normal prostate and prostate cancer. In contrast to normal cells, prostate cancer cells are reprogrammed for optimal energy-efficiency with a functional Krebs cycle and minimal apoptosis rates. A key element in this relationship is the uniquely high zinc level of normal prostate epithelial cells. Zinc is transported by the SLC30 and SLC39 families of zinc transporters. However, in prostate cancer the intracellular zinc content is remarkably reduced and expression levels of certain zinc transporters are altered. Here, we summarize the role of different zinc transporters in the development of prostate cancer.

Transporters for vitamin C and its oxidized form dehydroascorbic acid (DHA) are crucial to maintain physiological concentrations of this important vitamin that is used in a variety of biochemical processes. The human SLC23 family consists of the Na(+)-dependent vitamin C transporters SVCT1 (encoded by the SLC23A1 gene) and SVCT2 (SLC23A2) as well as an orphan transporter SVCT3 (SLC23A3). Phylogenetically, the SLC23 family belongs to the nucleobase-ascorbate transporter (NAT) family, although no nucleobase transport has yet been demonstrated for the human members of this family. The SVCT1 and SVCT2 transporters are rather specific for ascorbic acid, which is an important antioxidant and plays a crucial role in a many metal-containing enzymes. SVCT1 is expressed predominantly in epithelial tissues such as intestine where it contributes to the supply and maintenance of whole-body ascorbic acid levels. In contrast to various other mammals, humans are not capable of synthesizing ascorbic acid from glucose and therefore the uptake of ascorbic acid from the diet via SVCT1 is essential for maintaining appropriate concentrations of vitamin C in the human body. The expression of SVCT2 is relatively widespread, where it serves to either deliver ascorbic acid to tissues with high demand of the vitamin for enzymatic reactions or to protect metabolically highly active cells or specialized tissues from oxidative stress. The murine Slc23a3 gene encoding the orphan transporter SVCT3 was originally cloned from mouse yolk sac, and subsequent studies showed that it is expressed in the kidney. However, the function of SVCT3 has not been reported and it remains speculative as to whether SVCT3 is a nucleobase transporter.

Capsiate is produced by 'CH-19 Sweet' (Capsicum annuun L.), a non-pungent cultivar of red pepper. Like capsaicin, capsiate is thought to enhance energy metabolism by activating the sympathetic nervous system and suppressing inflammation, but the underlying mechanisms for this are uncertain. We previously reported that capsiate could activate transient receptor potential vanilloid 1 (TRPV1), a capsaicin receptor. The purpose of the present study is to investigate whether capsinoids activate other TRP channels.Using Ca(2+) imaging and whole-cell patch-clamp methods, we analysed the response of TRP channels to three kinds of capsinoids, capsiate, dihydrocapsiate and nordihydrocapsiate, in HEK293T cells expressing TRP channels or in primary cultures of mouse dorsal root ganglion neurons.We found that in both cell types TRP ankyrin 1 (TRPA1) had a slightly weaker response to capsinoids compared with TRPV1, with the capsiate EC(50) for TRPA1 activation being more than that for TRPV1 activation, and that the capsinoid-evoked action was blocked by a specific TRPA1 antagonist. TRPA1 was activated by capsinoids, but not by their degradation products. Amino acids known to participate in TRPA1 activation following cysteine covalent modification or zinc treatment were not involved in the activation of TRPA1 by capsinoid.Taken together, these results indicate that capsinoids activate TRPA1 by an as yet unknown mechanism, and TRPA1 could be involved in physiological phenomena associated with capsinoid treatment.

A 75-year-old male who with type 3 gastric cardia cancer with multiple liver metastases was initially treated with S-1 in July of 2005. After 4 courses of the treatment, the liver metastases became undetectable on abdominal CT scan, with reduction in size of the primary tumor of the stomach. After 7 months of S-1 treatment, however, the progression of the primary lesion was endoscopically detected, and irinotecan was administered, demonstrating primary tumor regression. When re-growth of the primary tumor was observed, 3 courses of paclitaxel treatment showed little effect and was replaced by docetaxel treatment for 5 months, which had a grade 3 adverse effect. The next 10 courses of 5-FU combined with methotrexate were applied for one year until the primary tumor showed enlargement. Then 12 courses of CDDP with S-1 were administered until now, and the size of the primary carcinoma is under control. The patient is being followed on an outpatient basis without any surgical treatment, while the liver metastases have not relapsed on abdominal imaging.

Ca2+ is essential for numerous physiological functions in our bodies. Therefore, its homeostasis is finely maintained through the coordination of intestinal absorption, renal reabsorption, and bone resorption. The Ca2+-selective epithelial channels TRPV5 and TRPV6 have been identified, and their physiological roles have been revealed: TRPV5 is important in final renal Ca2+ reabsorption, and TRPV6 has a key role in intestinal Ca2+ absorption. The TRPV5 knockout mice exhibit renal leak hypercalciuria and accordingly upregulate their intestinal TRPV6 expression to compensate for their negative Ca2+ balance. In contrast, despite their severe negative Ca2+ balance, TRPV6-null mice do not display any compensatory mechanism, thus resulting in secondary hyperparathyroidism. These results indicate that the genes for TRPV5 and TRPV6 are differentially regulated in human diseases associated with disturbed Ca2+ balance such as hypercalciuria, osteoporosis, and vitamin D–resistant rickets.

Objective To estimate asymmetry in normal and pathological facial functions using an established computer generated objective evaluation technique. Methods Analysis was performed on three-dimensional (3-D) data captured using a specially designed 3-D face shape measurement system. Six healthy volunteers and six patients with Bell's palsy were analyzed for forced eye closure and grinning actions. The asymmetry was computed at locations that had the greatest effect in each action on both the left and right sides of the face, in reference to a relaxed condition. The patients' data were captured and analyzed repeatedly for a period of three days for an average interval of four weeks, and the results were compared with the Yanagihara scale. Results The control set of a normal sample exhibited a low standard deviation and a high correlation coefficient in both facial actions, and this contributed to a robust evaluation. The patients showed a higher standard deviation than the healthy subjects because of the larger degree of scatter of the data points in their respective data distributions. During the three clinical examinations, our proposed quantification method produced a continuous grading scheme, as opposed to the discrete scheme of the House-Brackmann grading. Conclusion Our proposed system shows advantages over the existing methods in that it does not rely on reference points nor does it use markers to analyze facial deformation. In addition, our estimations are very robust and accurate because our approach directly evaluates 3-D spatial variations in normal and pathological facial functions.

Permanent isolated proximal renal tubular acidosis (pRTA) with ocular abnormalities is a systemic disease with isolated pRTA, short stature and ocular abnormalities. We identified a novel homozygous deletion of nucleotide 2,311 adenine in the kidney type Na+/HCO3 − cotransporter (kNBC1) cDNA in a patient with permanent isolated pRTA. This mutation is predicted to result in a frame shift at codon 721 forming a stop codon after 29 amino acids anomalously transcribed from the SLC4A4 gene. Cosegregation of this mutation with the disease was supported by heterozygosity in the parents of the affected patient. The absence of this mutation in 156 alleles of 78 normal individuals indicates that this mutation is related to the disease and is not a common DNA sequence polymorphism. When injected into Xenopus oocytes, the mutant cRNA failed to induce electrogenic transport activity. In addition, immunofluorescence and Western blot analysis failed to detect the expression of the full-length protein in mutant-injected oocytes. Our results expand the spectrum of kNBC1 mutations in permanent isolated pRTA with ocular abnormalities and increase our understanding of the renal tubular mechanism that is essential for acid-base homeostasis.

Two Japanese sibs with the Meckel syndrome are reported. Both babies showed the classical triad of this condition : occipital encephalocele, cystic kidneys, and postaxial polydactyly of all four limbs. The diagnostic criteria and differential diagnosis were reviewed.

Transient receptor potential vanilloid 1 (TRPV1) is activated by elevated temperature (>42 °C), and it has been reported that cold temperature decreases capsaicin-induced TRPV1 activity. In contrast, transient receptor potential melastatin 8 (TRPM8) is activated by low temperatures and menthol, and heat stimulation suppresses menthol-evoked TRPM8 currents. These findings suggest that the effects of specific agents on TRPV1 and TRPM8 channels are intricately interrelated. We examined the effects of menthol on human (h)TRPV1 and of capsaicin on hTRPM8. hTRPV1 currents activated by heat and capsaicin were inhibited by menthol, whereas hTRPM8 currents activated by cold and menthol were similarly inhibited by capsaicin. An in vivo sensory irritation test showed that menthol conferred an analgesic effect on the sensory irritation evoked by a capsaicin analogue. These results indicate that in our study the agonists of TRPV1 and TRPM8 interacted with both of these channels and suggest that the anti-nociceptive effects of menthol can be partially explained by this phenomenon. Electronic supplementary material The online version of this article (doi:10.1007/s12576-015-0427-y) contains supplementary material, which is available to authorized users.

Claudins are major components of tight junctions and contribute to the epithelial-harrier function by restricting free diffusion of solutes through the paracellular pathway. We have mapped a new locus for recessive renal magnesium loss on chromosome 1p34.2 and have identified mutations in CLDN19, a member of the claudin multigene family, in patients affected by hypomagnesemia, renal failure, and severe ocular abnormalities. CLDN19 encodes the tight-junction protein claudin-19, and we demonstrate high expression of CLDN19 in renal tubules and the retina. The identified mutations interfere severely with either cell-membrane trafficking or the assembly of the claudin-19 protein. The identification of CLDN19 mutations in patients with chronic renal failure and severe visual impairment supports the fundamental role of claudln-19 for normal renal tubular function and undisturbed organization and development of the retina. © 2006 by The American Society of Human Genetics. All rights reserved., published_or_final_version

In early stages of osteoarthritis, osteotomy produced a satisfactory result with no adverse effects and significant improvement in the nonoperated-on contralateral hip. In many cases of unilateral osteotomy in a group with preoperative radiologic scores above 70, the function was either improved or unchanged in the nonoperated-on hip. In many cases with scores below 70, there was deterioration of joint structure. Bilateral osteotomy is recommended only in the cases with preoperative radiologic scores below 70. Osteotomy was prescribed on the contralateral hip within a short period of time after aarthroplasty. Deterioration occurred in some contralateral nonoperated-on hips when the preoperative clinical scores were high, while improvement generally occurred when preoperative scores were low.

Two cases of stress fracture of the ulna in athletes are presented and the mechanism of injury discussed.