Fact-finding survey of doctors at the departments of pediatrics and pediatric surgery on the transition of patients with childhood-onset chronic disease from pediatric to adult healthcare.

BACKGROUND: The number of adult patients with childhood-onset chronic diseases is increasing. However, the process of transitioning these patients from child- to adult-centered medical services faces many difficulties. Despite the key role that doctors in the pediatric field are considered to play in transition, few fact-finding surveys about transition have been conducted among these doctors. OBJECTIVE: The aim of this study was to demonstrate the current status and challenges in the transition of patients with childhood-onset chronic diseases by a fact-finding survey of pediatricians and pediatric surgeons at a university hospital. METHODS: A cross-sectional survey was performed using an anonymous self-administered questionnaire. Seventy-six doctors of pediatrics and pediatric surgery (excluding junior residents) in a university hospital were asked to answer an anonymous self-report questionnaire. A multidisciplinary research team selected items related to the transitional process. RESULTS: Sixty (79%) doctors participated, of whom 52 (87%) showed awareness of transition. No doctor answered that "Transition is conducted smoothly." Doctors with shorter pediatric department experience had lower awareness and poorer experience with transition. In contrast to pediatric surgeons, pediatricians explained "job-seeking activities" and "contraceptive methods" to the patient, and reported a higher patient age at which to initiate explanation of transition to the patient and his/her family. Among factors inhibiting transition, 39 (65%) respondents selected "The patient's family members do not desire transition" and 34 (57%) selected "Although a relevant adult healthcare department is available, it will not accept the patient." The medical providers most frequently considered to have responsibility for playing a central role in the transition process were "pediatrician/pediatric surgeon," "medical social worker," and "regional medical liaison office." DISCUSSION: To promote transition, pediatric and adult healthcare departments should share concerns about and cooperate in the establishment of more effective methods of transition, and provide multidisciplinary collaboration to support patients and their families.

miR-515-5p suppresses trophoblast cell invasion and proliferation through XIAP regulation in preeclampsia.

MicroRNAs (miRNAs) are non-coding small RNA molecules that can be secreted into the circulation and which exist in remarkably stable forms. Circulating miRNAs regulate numerous biological process and are aberrantly expressed in pathological conditions. Differentially expressed circulating miRNAs have received attention as potential biomarkers for many diseases. In this study, we revealed that miR-515-5p was significantly upregulated in maternal serum from preeclampsia patients in comparison to normal pregnant women. Bioinformatics prediction and a dual-luciferase reporter gene assay revealed that miR-515-5p directly targets the X-linked inhibitor of apoptosis protein (XIAP) 3'-untranslated region. In addition, the overexpression of miR-515-5p inhibited the proliferation and invasion of HTR-8/SVneo trophoblast cells. The decreased XIAP expression and reduced epithelial-mesenchymal transition (EMT) were observed in the preeclamptic placenta. Collectively, miR-515-5p may play critical roles in the pathogenesis of preeclampsia through suppression of XIAP, and serum miR-515-5p may act as a potential biomarker for preeclampsia.

Molecular characterization and antimicrobial resistance of Streptococcus agalactiae isolated from pregnant women in Japan, 2017-2021.

Objectives: This study aimed to elucidate the molecular characteristics and antimicrobial resistance of Streptococcus agalactiae (group B streptococcus, GBS) colonizing pregnant women in Japan. Methods: GBS isolates obtained from screening of pregnant women from 2017 to 2021 were analyzed for capsular serotype, sequence type (ST), and antimicrobial susceptibility. For levofloxacin-resistant isolates, mutations in the quinolone resistance-determining regions (QRDRs) of the gyrA, gyrB, and parC genes were analyzed. Results: Seventy-six GBS isolates were recovered from 1090 women (isolation rate: 7.0%). Of the 76 isolates, serotype III (31.6%) was the most prevalent, followed by V (19.7%), Ia (17.1%), and Ib (10.5%). Among the 22 STs identified, capsular serotype III/ST335-clonal complex (CC) 19 lineage was dominant (13.2%), followed by Ia/ST23, III/ST17, and V/ST1. Levofloxacin resistance was detected in 15.8% (n=12) of all the isolates, with serotype Ib being the most common. Most levofloxacin resistant isolates belonged to serotype Ib/CC10 or serotype V/CC19, with double mutations in the QRDRs, Ser81Leu in GyrA and Ser79Phe in ParC. Conclusions: The present study indicates the prevalence of the serotype III/ST335 (CC19) lineage, and the spread of serotype Ib/CC10 and serotype V/CC19 lineages, which are responsible for levofloxacin resistance in colonizing GBS in pregnant women in Japan.

Efficacy of a Transitional Support Program Among Adolescent Patients With Childhood-Onset Chronic Diseases: A Randomized Controlled Trial.

It is recommended that patients with childhood-onset chronic diseases (CCD) be transferred from pediatric to adult healthcare systems when they reach adulthood. Transitional support helps adolescents with CCD transition smoothly. Transition readiness is one of the key concepts to assess the efficacy of transitional support programs. This study aims to investigate the effect of a transitional support program on transition readiness, self-esteem, and independent consciousness among Japanese adolescents with various CCD using a randomized controlled trial. Adolescents with CCD aged 12-18 years participated in a randomized controlled trial evaluating the efficacy of a transitional support program. The patients in the intervention group visited transitional support outpatient clinics twice. They answered questionnaires regarding their disease and future perspectives to healthcare professionals and independently made a short summary of their disease. All the participants answered the questionnaires four times. Eighty patients participated in this study. Among those in the intervention group, transition readiness within one, three, and 6 months after interventions, and self-esteem within 1 month after interventions were higher than that of the control group. The scores on the "dependence on parents" subscale at 6 months after interventions were lower for the intervention group as compared to the control group. This program is expected to help patients transition smoothly from pediatric to adult healthcare systems.

Progression of age-related macular degeneration in eyes with abnormal fundus autofluorescence in a Japanese population: JFAM study report 3.

PURPOSE: To evaluate the progression of early age-related macular degeneration to neovascular age-related macular degeneration (nAMD), and identify the abnormal fundus autofluorescence (FAF) patterns and markers of choroidal neovascularization (CNV) in fellow eyes of patients with unilateral nAMD. METHODS: Sixty-six patients with unilateral nAMD who developed abnormal FAF in the fellow eyes were enrolled in this multicenter, prospective, observational study, and followed-up for 5 years. FAF images on Heidelberg Retina Angiogram Digital Angiography System (HRA) or HRA2 were classified into eight patterns based on the International Fundus Autofluorescence Classification Group system. The patients in which the fellow eyes progressed to advanced nAMD, including those who did not develop nAMD, were assessed based on the following factors: baseline FAF patterns, age, sex, visual acuity, drusen, retinal pigmentation, baseline retinal sensitivity, family history, smoking, supplement intake, hypertension, body mass index, and hematological parameters. RESULTS: Of the 66 patients, 20 dropped out of the study. Of the remaining 46 patients, 14 (30.42%, male: 9, female: 5) progressed to nAMD during the 5-year follow-up. The most common (50% eyes) FAF pattern in the fellow eyes was the patchy pattern. According to the univariate analysis, CNV development was significantly associated with age, supplement intake, and low-density lipoprotein levels (p<0.05). Multivariable analysis revealed that patients who showed non-compliance with the supplement intake were more likely to develop nAMD (p<0.05). No significant association was found between the patchy pattern and CNV development (p = 0.86). CONCLUSION: The fellow eyes (with abnormal FAF) of patients with unilateral nAMD may progress from early to advanced nAMD. However, no FAF pattern was found that predicted progression in nAMD.

Clonal diversity of Clostridium perfringens human clinical isolates with various toxin gene profiles based on multilocus sequence typing and alpha-toxin (PLC) typing.

OBJECTIVES: Clostridium perfringens is a common anaerobic pathogen causing enteritis/enterocolitis and wound infections in humans. We analyzed clonal diversity and toxin gene prevalence in C. perfringens clinical isolates from humans in northern Japan. METHODS: Prevalence of nine toxin genes was analyzed for 585 C. perfringens isolates from patients collected for 20-month period between May 2019 and December 2020 by molecular methods. Sequence type (ST) based on multilocus sequence typing (Xiao's scheme) and alpha-toxin (PLC) sequence type were determined for a total of 124 isolates selected in the present study along with those in our previous study (2017-2018). RESULTS: Toxinotypes A (68.2%) was the most frequent, followed by F (31.6%), and G (0.2%), while additional toxin genes encoding binary enterotoxin (BEC/CPILE) and beta2 toxin were identified in one and six isolates, respectively. Among the 124 isolates with various toxin gene profiles, 62 STs including 53 novel types were identified, revealing the presence of six clonal complexes (CCs) consisting of 27 STs. Most of enterotoxin gene (cpe)-positive isolates belonged to CC36, CC41, and CC117. Based on 22 key amino acids in alpha toxin sequence, four PLC types (I-IV) including 21 subtypes were classified, and their relation to individual STs/CCs was clarified. Two isolates harboring bec/cpile belonged to different STs (ST95, ST131) and PLC types (If, IVb), indicating distribution of this toxin gene to distinct lineages. CONCLUSIONS: The present study revealed the diversity in C. perfringens clones of human origin with various toxin gene profiles represented by ST/CC and PLC type.

Development and validation of a Japanese version of the TRANSITION-Q.

BACKGROUND: The evaluation of transition readiness is indispensable for long-term follow-ups of adolescent patients with childhood-onset chronic diseases (CCD). We developed a Japanese version of the TRANSITION-Q (TRANSITION-Q-J) and used it to assess Japanese patients with CCD. METHODS: The TRANSITION-Q-J was developed through forward and backward translations followed by cognitive interviews with five adolescent patients. The field test was conducted with 125 adolescent patients, and a retest was conducted with 113 adolescent patients. RESULTS: Confirmatory factor analysis supported the two-factor analysis model including F1 (communication and self-management) and F2 (examination behavior). Sufficient internal consistency and test-retest reliability were demonstrated among the total 14 items, F1, and F2 (Cronbach's α > 0.80, intraclass correlation coefficient > 0.85). Convergent and discriminant validity for the 14 items and F1 were acceptable; however, F2 did not correlate significantly with the Rosenberg Self-Esteem Scale and Independent Consciousness Scale. Regarding known-groups validity, the older group had a significantly higher mean TRANSITION-Q-J score (50.05) than the younger group (43.28; P = 0.04). The same results were found for both F1 and F2. CONCLUSIONS: The TRANSITION-Q-J for adolescent patients with CCD was developed and its reliability and validity were verified. This scale is easy to administer. In addition to being a tool for transition period support, it could be used to verify effective factors and in program outcome evaluation, including intervention studies.

The therapeutic potential of exosomal miR-22 for cervical cancer radiotherapy.

Cervical cancer is the fourth-most prevalent malignancy in women. For advanced cervical cancer, radiotherapy is a major treatment. Micro RNAs (miRNAs) are small, noncoding RNAs that negatively regulate the target gene expression posttranscriptionally. miR-22 is frequently downregulated in various cancers including cervical cancer, and is associated with a poor prognosis in cervical cancer. Exosomes are small endosomally secreted vesicles that carry components such as proteins, messenger RNA (mRNA), DNA and miRNA. We investigated whether or not exosomes can efficiently deliver miR-22 to recipient cervical cancer cells and affect the gene expression in the cells, as well as assessed the role of exosomal miR-22 in radiosensitivity. Exosomes containing high levels of miR-22 were extracted by ultracentrifugation and then characterized by Western blotting, a nanoparticle tracking analysis and electron microscopy. The high presence of miR-22 in the exosome was confirmed by real-time polymerase chain reaction. After the administration of the collected exosomal miR-22 to SKG-II and C4-I cervical cancer cells, the level of miR-22 in the cells was significantly increased, indicating the absorption of the exosomal miR-22. When miR-22 encapsulated in exosomes was administered to the SKG-II cells, the level of c-Myc binding protein (MYCBP) and human telomerase reverse transcriptase (hTERT) was significantly decreased in correlation with increased radiosensitivity determined by a clonogenic assay. Taken together, these results suggest that the administration of exosomal miR-22 may be a novel drug delivery system for cervical cancer radiotherapy.

The differential expression of miRNAs between ovarian endometrioma and endometriosis-associated ovarian cancer.

BACKGROUND: MicroRNAs (miRNAs) have been implicated to play a vital role in development, differentiation, cell proliferation and apoptosis. However, which miRNAs are actually associated with endometriosis-associated ovarian cancer remains controversial. METHODS: Serum and ascites samples were obtained from all patients. Serum samples from 5 cases of ovarian endometrioma and endometriosis-associated ovarian cancer each were submitted for comprehensive miRNA microarray profiling. We investigated the differential expression of miRNAs between the two groups to confirm the pivotal role of miRNAs. Quantitative reverse transcription-polymerase chain reaction validation of five selected miRNAs [miR-92a-3p, miR-486-5p, miR-4484, miR-6821-5p, and miR-7108-5p] was performed, and miR-486-5p expression analysis was followed by proliferation and wound healing assays, depending on the expression of miR-486-5p. RESULT: miR-486-5p expression in serum and ascites samples from endometriosis-associated ovarian cancer patients was significantly higher than that from ovarian endometrioma patients. Moreover, the miR-486-5p level in serum and ascites samples was significantly correlated with the severity of the endometriosis. The upregulation of miR-486-5p in immortalized ovarian endometrioma cells significantly increased proliferation and migration. In contrast, the downregulation of miR-486-5p in these cells significantly decreased proliferation and migration. CONCLUSION: miR-486-5p might function as an oncogenic miRNA in endometriosis-associated ovarian cancer and could be a noninvasive biomarker to prospect the severity of ovarian endometrioma.

MicroRNA-22 enhances radiosensitivity in cervical cancer cell lines via direct inhibition of c-Myc binding protein, and the subsequent reduction in hTERT expression.

MicroRNAs (miRs) influence the expression of their target genes post-transcriptionally and serve an important role in multiple cellular processes. The downregulation of miR-22 is associated with a poor prognosis in cervical cancer. However, the mechanisms underlying miR-22-mediated gene regulation and its function are yet to be elucidated. In the present study, the effect of miR-22 expression on the radiosensitivity of cervical cancer was investigated. First, miR-22 was either up- or downregulated to evaluate the regulation of the MYC-binding protein (MYCBP) in four cervical cancer cell lines (C-4I, SKG-II and SiHa). Notably, MYCBP expression was inversely associated with miR-22 induction. A dual-luciferase reporter gene assay revealed that miR-22 directly targets the MYCBP 3'-untranslated region. Subsequently, the level of human telomerase reverse transcriptase component (hTERT; an E-box-containing c-Myc target gene) was analyzed after the up- or downregulation of miR-22. Notably, miR-22-mediated repression of MYCBP reduced hTERT expression. In addition, the influence of miR-22 on radiosensitivity in C-4I, SKG-II and SiHa cells was examined using a clonogenic assay and in mouse xenograft models. Upregulation of miR-22 was associated with increased radiosensitivity. Furthermore, lentiviral transduction of miR-22 reduced the Ki-67 index while increasing the TUNEL index in xenograft tissue. The current findings indicate the potential utility of miR-22 in radiotherapy for cervical cancer.

Five-year follow-up of fundus autofluorescence and retinal sensitivity in the fellow eye in exudative age-related macular degeneration in Japan.

PURPOSE: To assess the 5-year change in abnormal fundus autofluorescence (FAF) patterns and retinal sensitivity in the fellow eye of Japanese patients with unilateral exudative age-related macular degeneration (AMD). METHODS: Patients with unilateral exudative AMD who developed abnormal FAF in the fellow eyes were enrolled. FAF imaging and microperimetry were performed at baseline and follow-ups. FAF findings were classified into 8 patterns based on the International Fundus Autofluorescence Classification Group to assess retinal sensitivity. Forty-five points covering the central 12 degrees on microperimetry were superimposed onto the FAF images. Each point was classified depending on the distance from the abnormal FAF. "Close" was defined as the portion within 1 degree from the border of any abnormal FAF, and "Distant" was defined as the portion over 1 degree from the border of abnormal FAF. To investigate the association between the retinal sensitivity and distance from the abnormal FAF, hierarchical linear mixed-effect models were used with the distance, time and time squared from baseline (months), and angle (degrees) as fixed effects. Differences among patients, eyes, and test point locations were considered successively nested random effects. RESULTS: We studied 66 fellow eyes with abnormal FAF. Twenty-seven eyes were followed-up during the 5 years. In the 13 of 27 eyes (48%), the abnormal FAF patterns had changed during the 5 years. We found retinal sensitivity was associated significantly with the distance from the abnormal FAF ("Distant": p<0.001, time2 from baseline: p<0.001, angle: p<0.001). The mean retinal sensitivity of the "Close" tended to deteriorate after the third year and eventually showed the similar sensitivity as the portion within the abnormal FAF. CONCLUSION: FAF patterns can change about half during the 5 years and the retinal sensitivity near abnormal FAF tends to deteriorate after the third year.

Prevalence and Genetic Diversity of Toxin Genes in Clinical Isolates of Clostridium perfringens: Coexistence of Alpha-Toxin Variant and Binary Enterotoxin Genes (bec/cpile).

Clostridium perfringens (C. perfringens) is responsible for food-borne gastroenteritis and other infectious diseases, and toxins produced by this bacterium play a key role in pathogenesis. Although various toxins have been described for C. perfringens isolates from humans and animals, prevalence of individual toxins among clinical isolates has not yet been well explored. In the present study, a total of 798 C. perfringens clinical isolates were investigated for prevalence of eight toxin genes and their genetic diversity by PCR, nucleotide sequencing, and phylogenetic analysis. Besides the alpha-toxin gene (plc) present in all the isolates, the most common toxin gene was cpe (enterotoxin) (34.2%), followed by cpb2 (beta2 toxin) (1.4%), netB (NetB) (0.3%), and bec/cpile (binary enterotoxin BEC/CPILE) (0.1%), while beta-, epsilon-, and iota-toxin genes were not detected. Genetic analysis of toxin genes indicated a high level of conservation of plc, cpe, and netB. In contrast, cpb2 was revealed to be considerably divergent, containing at least two lineages. Alpha-toxin among 46 isolates was classified into ten sequence types, among which common types were distinct from those reported for avian isolates. A single isolate with bec/cpile harbored a plc variant containing an insertion of 834-bp sequence, suggesting its putative origin from chickens.

Fundus autofluorescence and retinal sensitivity in fellow eyes of age-related macular degeneration in Japan.

PURPOSE: Abnormal fundus autofluorescence (FAF) potentially precedes onset of late age-related macular degeneration (AMD) in Caucasian patients. Many differences exist between Asian and Caucasian patients regarding AMD types and severity, gender, and genetic backgrounds. We investigated the characteristics of abnormal FAF and retinal sensitivity in the fellow eyes of Japanese patients with unilateral neovascular AMD. METHODS: Sixty-six patients with unilateral neovascular AMD and abnormal FAF in the fellow eye were enrolled in this multicenter, prospective, observational study. The best-corrected visual acuity, fundus photographs, FAF images, and retinal sensitivity on microperimetry were measured periodically for 12 months. The FAF images were classified into eight patterns based on the International Fundus Autofluorescence Classification Group. The points measured by microperimetry were superimposed onto the FAF images and fundus photographs and classified as "within," "close," and "distant," based on the distance from the abnormal FAF and other findings. The relationship between the location of the baseline abnormal FAF and retinal sensitivity was investigated. RESULTS: In Japanese patients, patchy (33.3%) and focally increased (30.3%) patterns predominated in the abnormal FAF. Intermediate-to-large drusen was associated predominantly with hyperfluorescence and hypofluorescence. Neovascular AMD developed within 1 year in six (9.1%) eyes, the mean baseline retinal sensitivity of which was 12.8 ± 4.7 dB, significantly (p<0.002) lower than the other eyes. In 44 of the other 60 eyes, microperimetry was measurable at baseline and month 12 and the mean retinal sensitivity improved significantly from 13.5 ± 4.4 to 13.9 ± 4.8 dB (p<0.001), possibly associated with lifestyle changes (e.g., smoking cessation, antioxidant and zinc supplementation). The mean retinal sensitivities of points within and close to the abnormal FAF were 9.9 and 11.7 dB, respectively, which were significantly lower than the 14.0 dB of the points distant from the abnormal FAF. CONCLUSION: In Japanese patients, patchy and focally increased patterns predominated in the abnormal FAF. The retinal sensitivity was lower close to/within the abnormal FAF. FAF and microperimetry are useful to assess macular function before development of neovascular AMD or geographic atrophy.

A Qualitative Assessment of Adolescent Girls' Perception of Living with Congenital Heart Disease: Focusing on Future Pregnancies and Childbirth.

PURPOSE: Congenital heart disease (CHD) is the most common birth anomaly in Japan, occurring in approximately 10.6 of every 1,000 live births. Advancements in medical and surgical care have increased births by women diagnosed with CHD. The study's purpose was to examine the perceptions of pregnancy and childbirth among adolescent girls with CHD. DESIGN AND METHODS: Twelve semi-structured interviews were conducted, and the data were analyzed using a modified grounded-theory approach. RESULTS: Three categories and 16 subcategories were extracted. Adolescent girls with CHD reported feelings of distress and anxiety while struggling with their disease, and feared how their disease might negatively influence their future pregnancy. These concerns were related to a desire to become familiar with CHD. The girls also explored how their disease would be managed during pregnancy and childbirth. Overall, these perceptions were influenced by the girls' acceptance of their disease, and support from family, friends, and healthcare professionals. CONCLUSIONS: Healthcare professionals might assess adolescent girls' awareness of their disease before discussing pregnancy and childbirth risks. To encourage them to understand and cope with their disease, healthcare professionals might provide interventions tailored to the timing, stage, and degree of pregnancy and childbirth awareness. This could allow safer life planning, especially concerning pregnancy and childbirth decisions. PRACTICE IMPLICATIONS: To address adolescent girls' needs, healthcare professionals should continuously assess their awareness of pregnancy and childbirth as well as their psychological status, alongside CHD issues.

Analyzing the risk factors for a diminished oocyte retrieval rate under controlled ovarian stimulation.

Aim: To investigate which risk factors contribute to a lower oocyte retrieval ratio in women who are receiving controlled ovarian hyperstimulation. Methods: The authors retrospectively analyzed 329 in vitro fertilization (IVF) cycles under controlled ovarian hyperstimulation by using a gonadotropin-releasing hormone antagonist or agonist at Osaka Medical College, Japan. The patients were classified into five groups: advanced age, male infertility, severe endometriosis, tubal infertility, and unexplained infertility. The primary outcomes were the patients' age, oocyte retrieval ratio, serum basal follicle-stimulating hormone, total dose of gonadotropin, and the clinical outcome. A secondary outcome was the stepwise multivariate logistic regression analysis to assess the factors associated with the failure of oocyte retrieval. Results: The oocyte retrieval ratio declined significantly with the patient's age. The ratio of endometriosis in unsuccessful cases was significantly higher than that in successful cycles. Advanced age and endometriosis were the factors that were significantly associated with a lowered oocyte retrieval rate. Conclusion: Advanced age and endometriosis are high-risk factors that contribute to oocyte retrieval failure in infertile patients who are receiving IVF treatment.

Increased EphA4-ephexin1 signaling in the medial prefrontal cortex plays a role in depression-like phenotype.

Accumulating evidence suggests a role of the ephrin receptor EphA4 and the downstream protein ephexin1 in synaptic plasticity, which is implicated in depression. We examined whether EphA4-ephexin1 signaling plays a role in the pathophysiology of depression, and the antidepressant-like effect of EphA4 inhibitor rhynchophylline. We found increased ratios of p-EphA4/EphA4 and p-ephexin1/ephexin1 in the prefrontal cortex (PFC) and hippocampus but not in the nucleus accumbens (NAc), of susceptible mice after social defeat stress. Furthermore, the p-EphA4/EphA4 ratio was higher in the parietal cortex of depressed patients compared with controls. Systemic administration of rhynchophylline, produced a rapid antidepressant-like effect in a social defeat stress model by inhibiting EphA4-ephexin1 signaling and activating brain-derived neurotrophic factor-TrkB signaling in the PFC and hippocampus. Pretreatment with rhynchophylline before each social defeat stress could prevent the onset of the depression-like phenotype after repeated social defeat stress. Overexpression of EphA4 in the medial PFC owing to infection with an EphA4 adeno-associated virus caused the depression-like phenotype 3 weeks later and rhynchophylline had a rapid antidepressant-like effect in these mice. These findings suggest that increased EphA4-ephexin1 signaling in the PFC plays a role in the pathophysiology of depression.

Evaluation of the artificial membrane permeability of drugs by digital simulation.

A digital simulation method has been developed for evaluating the membrane permeability of drugs in the parallel artificial membrane permeation assay (PAMPA). The simulation results have shown that the permeability coefficient (log Ppampa) of drugs is linearly increased with increasing their distribution coefficient (log KD,M) to the lipid membrane, i.e., the hydrophobicity of the drug molecules. However, log Ppampa shows signs of leveling off for highly hydrophobic drugs. Such a dependence of log Ppampa is in harmony with the reported experimental data, and has been well explained in terms of the change in the rate-determining step from the diffusion in the membrane to that in the unstirred water layer (UWL) on both sides of the membrane. Additionally, the effects of several factors, including lag time, diffusion coefficient, pH, and pKa, on the permeability coefficient have been well simulated. It has thus been suggested that the proposed method should be promising for in silico evaluation of the membrane permeability of drugs.

Influence of osmotic stress on thermal perception and thermoregulation in heat is different between sedentary and trained men.

Hyperosmolality in extracellular fluid in humans attenuates autonomic thermoregulation in heat, such as sweating and blood flow in the skin. However, exercise training minimizes the attenuation. The aim of the present study was to clarify the influence of hyperosmolality on thermal perception and to assess the training effect of exercise. Ten sedentary (SED) and 10 endurance-trained (TR) healthy young men were infused with 0.9% (normal saline [NS]) or 3% NaCl (hypertonic saline [HS]) for 120min on two separate days. After infusion for 20min, heat stimulus to the skin of the whole body was produced by a gradual increase in hot water-perfused suit temperature (33°C, 36°C, and 39°C), which was first used in the normothermic condition and then in the mild hyperthermic condition (0.5-0.6°C increase in esophageal temperature) and controlled by immersion of the lower legs in a water bath at 34.5°C and 42°C, respectively. Thermal sensation and comfort were rated at the time of each thermal condition. Plasma osmolality increased by ~10mosmL/kg·H2O in the HS trial. In the mild hyperthermic condition, increases in sweat rate and cutaneous vascular conductance were lower in the HS than in the NS trial in both the SED and TR groups (p<0.05). In the SED group, thermal sensation in the mild hyperthermic condition was lower in the HS than in the NS trial (p<0.05); there was no significant difference between the trials in the TR group. These results might indicate that hyperosmolality attenuates thermal sensation with heat and that exercise training eliminates the attenuation.

Interactions of mean body and local skin temperatures in the modulation of human forearm and calf blood flows: a three-dimensional description.

AIM: The inter-relationships between mean body and local skin temperatures have previously been established for controlling hand and foot blood flows. Since glabrous skin contains many arteriovenous anastomoses, it was important to repeat those experiments on non-glabrous regions using the same sample and experimental conditions. METHODS: Mild hypothermia (mean body temperature 31.4 °C), normothermia (control: 36.0 °C) and moderate hyperthermia (38.3 °C) were induced and clamped (climate chamber and water-perfusion garment) in eight males. Within each condition, five localised thermal treatments (5, 15, 25, 33, 40 °C) were applied to the left forearm and right calf. Steady-state forearm and calf blood flows were measured (venous occlusion plethysmography) for each of the resulting 15 combinations of clamped mean body and local skin temperatures. RESULTS: Under the normothermic clamp, cutaneous blood flows averaged 4.2 mL 100 mL(-1) min(-1) (±0.28: forearm) and 5.4 mL 100 mL(-1) min(-1) (±0.27: calf). When mildly hypothermic, these segments were unresponsive to localised thermal stimuli, but tracked those changes when normothermic and moderately hyperthermic. For deep-body (oesophageal) temperature elevations, forearm blood flow increased by 5.1 mL 100 mL(-1) min(-1) °C(-1) (±0.9) relative to normothermia, while the calf was much less responsive: 3.3 mL 100 mL(-1) min(-1) °C(-1) (±1.5). Three-dimensional surfaces revealed a qualitative divergence in the control of calf blood flow, with vasoconstrictor tone apparently being released more gradually. CONCLUSION: These descriptions reinforce the importance of deep-tissue temperatures in controlling cutaneous perfusion, with this modulation being non-linear at the forearm and appearing linear for the calf.