Endometrial epithelial-mesenchymal transition (EMT) by menstruation-related inflammatory factors during hypoxia.

Endometriosis is characterised by inflammation and fibrotic changes. Our previous study using a mouse model showed that proinflammatory factors present in peritoneal haemorrhage exacerbated inflammation in endometriosis-like grafts, at least in part through the activation of prostaglandin (PG) E2 receptor and protease-activated receptor (PAR). In addition, hypoxia is a well-known inducer of fibrosis that may be associated with epithelial-mesenchymal transition (EMT). However, the complex molecular interactions between hypoxia and proinflammatory menstruation-related factors, PGE2 and thrombin, a PAR1 agonist, on EMT in endometriosis have not been fully characterised. To explore the effects of hypoxia and proinflammatory factors on EMT-like changes in endometrial cells, we determined the effects of PGE2 and thrombin (P/T) on EMT marker expression and cell migration in three dimensional cultured human endometrial epithelial cells (EECs) and endometrial stromal cells (ESCs). Treatment of EECs with P/T under hypoxia stimulated cell migration, increased the expression of mesenchymal N-cadherin, vimentin and C-X-C chemokine receptor type 4 (CXCR4), and reduced the expression of epithelial E-cadherin. Furthermore, treatment with C-X-C motif chemokine ligand 12 (CXCL12), a ligand for CXCR4, increased EMT marker expression and cell migration. In ESCs, P/T or oestrogen treatment under hypoxic conditions increased the expression and secretion of CXCL12. Taken together, our data show that hypoxic and proinflammatory stimuli induce EMT, cell migration and inflammation in EECs, which was increased by CXCL12 derived from ESCs. These data imply that inflammatory mediators in retrograde menstrual fluid contribute to ectopic endometrial EMT and migration in the presence of peritoneal hypoxia.

Facial skin photo-aging and development of hyperpigmented spots from children to middle-aged Japanese woman.

BACKGROUND/PURPOSE: Facial skin hyperpigmention caused by chronic sun exposure is a major skin complaint, however, its characteristics and influential factors are still limitedly known. METHODS: A cross-sectional survey in healthy Japanese women aged from 6 to 62 years (n=169) was conducted using a facial image analyzer VISIA™ for knowing onset age of hyperpigmented spot formation, its chronological changes, and influence of environmental factors. RESULTS: UV Pigmented Spot (PS) Score was positively correlated with age (R=.487, P=.000). Hyperpigmented spots appeared first around 18 years old in most subjects, and PS score remarkably increased at 20s then gradually increased by ages. The subjects with Skin Type I, one of the three grades of Japanese Skin Type (JST), whose melanin formation is genetically lower, showed higher PS score. A woman aged 31 years was subjected a weekly VISIA measurement for 2 years, and found no changes in the number, place, size and intensity of the pigment spots in this duration. CONCLUSION: Hyperpigmented spots developed in women over 20 years of age due to chronic sun exposure without sun protection during childhood and adolescent and it was stable afterwards, whose intensity was influenced by age and skin type.

Hip fracture incidence in Japan: Estimates of new patients in 2012 and 25-year trends.

UNLABELLED: We estimated the number of hip fracture patients in 2012 in Japan and investigated the trends in incidence during a 25-year period from 1987 to 2012. Despite the increasing number of patients, the incidence of hip fracture in both men and women aged 70-79 years showed the possibility of decline. INTRODUCTION: The objectives of this study were to estimate the number of hip fracture patients in 2012, to investigate the trends in incidence during a 25-year period from 1987 to 2012, and to determine the regional differences in Japan. METHODS: Data were collected through a nationwide survey based on hospitals by a mail-in survey. Hip fracture incidences by sex and age and standardized incidence ratios by region were calculated. RESULTS: The estimated numbers of new hip fracture patients in 2012 were 175,700 in total (95 % CI 170,300-181,100), 37,600 (36,600-38,600) for men and 138,100 (134,300-141,900) for women. The incidence rates in both men and women aged 70-79 years were the lowest in the 20-year period from 1992 to 2012. The incidence was higher in western areas of Japan than that in eastern areas in both men and women; however, the difference in the incidence of hip fracture between western and eastern areas is becoming smaller. CONCLUSIONS: Despite the increasing number of new patients, the incidence of hip fracture in both men and women aged 70-79 years showed the possibility of decline. The exact reasons for this are unknown, but various drugs for improving bone mineral density or preventing hip fracture might have influenced the results. A decrease in the differences in nutrient intake levels might explain some of the change in regional differences in Japan.

p.E66Q mutation in the GLA gene is associated with a high risk of cerebral small-vessel occlusion in elderly Japanese males.

BACKGROUND AND PURPOSE: GLA is the causative gene of Fabry disease, an X-linked lysosomal storage disorder resulting from α-galactosidase A (α-GAL) deficiency. Stroke is an important manifestation of Fabry disease, and recent epidemiological studies have indicated that up to 4.9% of young male cryptogenic stroke patients have GLA mutations. To determine the importance of GLA mutations in the general stroke population, the frequency of GLA mutations in Japanese male ischaemic stroke (IS) patients with various risk factors and ages was measured. METHODS: A total of 475 male IS patients (mean age 69.7 ± 12.5 years), were enrolled in this study. A blood sample was obtained to produce blood spots for measurement of α-GAL activity. Blood samples with decreased enzymatic activity were reassayed and the entire GLA gene was analyzed by direct DNA sequencing if α-Gal A activity was consistently low. RESULTS: α-Gal A activity was decreased in 10 men, five of whom (1.1%) had the GLA gene mutation, p.E66Q. All IS patients with p.E66Q mutation had substantial residual α-Gal A activity, in contrast to patients with classic-type Fabry disease. Clinically, all patients with p.E66Q mutation were > 50 years old and had multiple small-vessel occlusions (lacunar infarctions). Statistical analysis using Fisher's exact test showed the allele frequency of GLA p.E66Q in patients with small-vessel occlusion to be significantly higher than that in the general Japanese population [odds ratio (OR) = 3.34, P = 0.025). CONCLUSIONS: GLA p.E66Q mutation is a genetic risk factor for cerebral small-vessel occlusion in elderly Japanese males.

Safety and factors contributing to the difficulty of laparoscopic surgery for rectal cancer treated with preoperative chemoradiotherapy.

BACKGROUND: The safety of laparoscopic surgery for rectal cancer following chemoradiotherapy (CRT) has not been fully established. The aim of our retrospective study was to examine the outcomes and the factors contributing to the difficulty of laparoscopic surgery after CRT. METHODS: Eighty-seven consecutive rectal cancer patients treated with CRT were analyzed. Clinicopathological factors were compared between laparoscopic surgery (n = 57) and open surgery (n = 30) groups, and factors that correlated with operation time and blood loss were analyzed in low anterior resection (LAR) cases in the laparoscopic surgery group (n = 46). RESULTS: There was less blood loss in the laparoscopic surgery group than in the open surgery group (191 vs. 1,043 ml, p = 0.0001), and the operation time in the two groups was similar (329 vs. 322 min, p = 0.8). The rate of conversion from laparoscopic surgery to open surgery was 1.8 %. There was no significant difference in the morbidity rate (laparoscopic surgery 22.8 % vs. open surgery 33.3 %, p = 0.3). All circumferential resection margins were clear. Three-year cumulative rates of local recurrence were as follows: laparoscopic surgery: 1.9 % vs. open surgery: 8.4 % (p = 0.4), and distant recurrence was 28.5 % in laparoscopic surgery vs. 22.7 % in open surgery (p = 0.8) and these rates were not significantly different. In laparoscopic LAR cases, a shorter distance of the tumor from the anal verge was associated with a longer operation time. A high computed tomography Hounsfield units value of the mesorectum (CTV) was associated with increased blood loss in the first 23 cases, but not in the other 23 cases. CONCLUSIONS: Laparoscopic surgery following CRT was safe and feasible. A shorter anal verge was associated with a longer operation time. Blood loss increased in cases with high CTV, but this can likely be mitigated by experience.

Exome sequencing in a family with an X-linked lethal malformation syndrome: clinical consequences of hemizygous truncating OFD1 mutations in male patients.

Oral-facial-digital syndrome type 1 (OFD1; OMIM #311200) is an X-linked dominant disorder, caused by heterozygous mutations in the OFD1 gene and characterized by facial anomalies, abnormalities in oral tissues, digits, brain, and kidney; and male lethality in the first or second trimester pregnancy. We encountered a family with three affected male neonates having an 'unclassified' X-linked lethal congenital malformation syndrome. Exome sequencing of entire transcripts of the whole X chromosome has identified a novel splicing mutation (c.2388+1G > C) in intron 17 of OFD1, resulting in a premature stop codon at amino acid position 796. The affected males manifested severe multisystem complications in addition to the cardinal features of OFD1 and the carrier female showed only subtle features of OFD1. The present patients and the previously reported male patients from four families (clinical OFD1; Simpson-Golabi-Behmel syndrome, type 2 with an OFD1 mutation; Joubert syndrome-10 with OFD1 mutations) would belong to a single syndrome spectrum caused by truncating OFD1 mutations, presenting with craniofacial features (macrocephaly, depressed or broad nasal bridge, and lip abnormalities), postaxial polydactyly, respiratory insufficiency with recurrent respiratory tract infections in survivors, severe mental or developmental retardation, and brain malformations (hypoplasia or agenesis of corpus callosum and/or cerebellar vermis and posterior fossa abnormalities).

An imprinted gene p57KIP2 is mutated in Beckwith-Wiedemann syndrome.

p57KIP2 is a potent tight-binding inhibitor of several G1 cyclin/Cdk complexes, and is a negative regulator of cell proliferation. The gene encoding p57KIP2 is located at 11p15.5 (ref. 2), a region implicated in both sporadic cancers and Beckwith-Wiedemann syndrome, a cancer-predisposing syndrome, making it a tumour-suppressor candidate. Several types of childhood tumours including Wilms' tumour, adrenocortical carcinoma and rhabdomyosarcoma exhibit a specific loss of maternal 11p15 alleles, suggesting that genomic imprinting is involved. Genetic analysis of the Beckwith-Wiedemann syndrome indicated maternal carriers, as well as suggesting a role of genomic imprinting. Previously, we and others demonstrated that p57KIP2 is imprinted and that only the maternal allele is expressed in both mice and humans. Here we describe p57KIP2 mutations in patients with Beckwith-Wiedemann syndrome. Among nine patients we examined, two were heterozygous for different mutations in this gene-a missense mutation in the Cdk inhibitory domain resulting in loss of most of the protein, and a frameshift resulting in disruption of the QT domain. The missense mutation was transmitted from the patient's carrier mother, indicating that the expressed maternal allele was mutant and that the repressed paternal allele was normal. Consequently, little or no active p57KIP2 should exist and this probably causes the overgrowth in this BWS patient.

Domain-specific mutations in TGFB1 result in Camurati-Engelmann disease.

Camurati-Engelmann disease (CED, MIM 131300) is an autosomal dominant, progressive diaphyseal dysplasia characterized by hyperosteosis and sclerosis of the diaphyses of long bones. We recently assigned the CED locus to an interval between D19S422 and D19S606 at chromosome 19q13.1-q13.3, which two other groups confirmed. As the human transforming growth factor-1 gene (TGFB1) is located within this interval, we considered it a candidate gene for CED.

Time-, spin-, and angle-resolved photoemission spectroscopy with a 1-MHz 10.7-eV pulse laser.

We describe a setup of time-, spin-, and angle-resolved photoemission spectroscopy (tr-SARPES) employing a 10.7 eV (λ = 115.6 nm) pulse laser at a 1 MHz repetition rate as a probe photon source. This equipment effectively combines the technologies of a high-power Yb:fiber laser, ultraviolet-driven harmonic generation in Xe gas, and a SARPES apparatus equipped with very-low-energy-electron-diffraction spin detectors. A high repetition rate (1 MHz) of the probe laser allows experiments with the photoemission space-charge effects significantly reduced, despite a high flux of 1013 photons/s on the sample. The relatively high photon energy (10.7 eV) also brings the capability of observing a wide momentum range that covers the entire Brillouin zone of many materials while ensuring high momentum resolution. The experimental setup overcomes the low efficiency of spin-resolved measurements, which gets even more severe for the pump-probed unoccupied states, and affords the opportunity to investigate ultrafast electron and spin dynamics of modern quantum materials with energy and time resolutions of 25 meV and 360 fs, respectively.

Citizen seismology helps decipher the 2021 Haiti earthquake.

On 14 August 2021, the moment magnitude (Mw) 7.2 Nippes earthquake in Haiti occurred within the same fault zone as its devastating 2010 Mw 7.0 predecessor, but struck the country when field access was limited by insecurity and conventional seismometers from the national network were inoperative. A network of citizen seismometers installed in 2019 provided near-field data critical to rapidly understand the mechanism of the mainshock and monitor its aftershock sequence. Their real-time data defined two aftershock clusters that coincide with two areas of coseismic slip derived from inversions of conventional seismological and geodetic data. Machine learning applied to data from the citizen seismometer closest to the mainshock allows us to forecast aftershocks as accurately as with the network-derived catalog. This shows the utility of citizen science contributing to our understanding of a major earthquake.

Over-expression of the LTC4 synthase gene in mice reproduces human aspirin-induced asthma.

BACKGROUND: The pathogenesis of aspirin-induced asthma (AIA) is presumed to involve the aspirin/non-steroidal anti-inflammatory drug (NSAID)-induced abnormal metabolism of arachidonic acid, resulting in an increase in 5-lipoxygenase (5-LO) metabolites, particularly leukotriene C(4) (LTC(4) ). However, the role of LTC(4) in the development of AIA has yet to be conclusively demonstrated. OBJECTIVE: The aim of this study was to evaluate the contribution of the lipid product LTC(4) secreted by the 5-LO pathway to the pathogenesis of AIA. METHODS: To evaluate antigen-induced airway inflammation, the concentrations of T-helper type 2 cytokine in bronchoalveolar lavage fluid (BALF) obtained from LTC(4) synthase-transgenic (Tg) and wild-type (WT) mice after challenge with ovalbumin were measured. Subsequently, the ex vivo and in vivo effects of the NSAID sulpyrine were investigated in these Tg and WT mice by measuring the secretion of LTC(4) from sulpyrine-treated BAL cells and the levels of LTC(4) in BALF following challenge with sulpyrine. Finally, the sulpyrine-induced airway response by the administration of pranlukast, an antagonist of the cysteinyl (cs)-LT1 receptor, was analysed. RESULTS: The concentrations of IL-4, -5, and -13 in BALF from Tg mice were significantly higher than those in WT mice. In addition, sulpyrine augmented the secretion of LTC(4) in BALF and by BAL cells in Tg mice, but not in WT mice. Additionally, the increased airway resistance induced by sulpyrine could be reduced by treatment with pranlukast. Furthermore, the secretion of LTC(4) from mast cells, eosinophils, and macrophages was increased in the allergen-stimulated LTC(4) synthase gene Tg mice, even in the absence of sulpyrine, as well as in BAL cells after sulpyrine. CONCLUSION AND CLINICAL RELEVANCE: The over-expression of the LTC(4) synthase in a mouse asthma model also replicates the key features of AIA. And our study supports that cys-LTs play a major role in the pathogenesis of AIA in patients with chronic asthma.

Endoscopic submucosal dissection for early gastric cancer performed by supervised residents: assessment of feasibility and learning curve.

BACKGROUND AND AIM: Endoscopic submucosal dissection (ESD) is feasible as a treatment for early gastric cancer (EGC) when it is performed by an experienced endoscopist. We investigated whether it was feasible for novice endoscopists to perform ESD for EGC, and how difficult it was to learn the procedure. METHODS: This case series study was performed in a cancer referral center. Three resident endoscopists, who had already learned basic procedures, performed ESD under supervision for 30 consecutive lesions, and their procedures were analyzed. The procedure was divided for assessment into (i) mucosal incision and (ii) submucosal dissection by completion of the circumferential mucosal cut. An insulated-tip knife was used for mucosal incision and submucosal dissection. A total of 90 mucosal EGCs (< or = 2 cm) without ulcers or scars in 87 patients were included. Outcomes were: rates of complete resection, complications, and self-completion; operation time; learning curve; and reasons for change of supervisor as an indicator of difficulty. RESULTS: Among the 90 procedures, there was a good overall complete resection rate of 93 %, with an acceptable complication rate of 4.4 %; the complications were delayed hemorrhage in two patients, and perforations in another two patients that were repaired successfully by endoscopic clipping. The self-completion rate and operation time were significantly worse for submucosal dissection than for mucosal incision. Two of the three operators showed a flat learning curve for submucosal dissection. Difficulty with the procedure was related mainly to uncontrollable hemorrhage. CONCLUSIONS: With appropriate supervision, gastric ESD by residents is feasible, with equivalent complete resection rates and acceptable complication rates compared with those of experienced endoscopists, although there was difficulty in achieving sufficient self-completion rates in submucosal dissection. Better control of bleeding during submucosal dissection may be a key to improving the procedure.

A randomized controlled trial assessing the effectiveness of professional oral care by dental hygienists.

OBJECTIVES: This study was designed to compare professional oral care (POC) by a dental hygienist with tooth brushing and mouth rinsing by patients themselves according to the instructions of a nurse (control). METHODS: Forty patients were randomly assigned to either the POC group (n = 20) or control group (n = 20). The presence of plaque and bacteria was assessed clinically. RESULTS: One patient in the POC group and three patients in the control group dropped out because of exacerbation of underlying disease or death. Plaque control record scores were significantly lower in the POC group than in the control group on the fifth hospital day and the day of discharge. There was no significant difference between the groups in the detection rate of Candida species; and nosocomial pathogens on either day. CONCLUSIONS: Professional oral care by a dental hygienist is more effective than tooth brushing and mouth rinsing by patients themselves according to the instructions of a nurse.

A two-year follow-up of surgical and non-surgical treatments in patients with masticatory muscle tendon-aponeurosis hyperplasia.

This study re-examined the usefulness of surgery for the management of masticatory muscle tendon-aponeurosis hyperplasia (MMTAH) through a comparison of the outcomes between patients who underwent surgery and those who did not. The duration of follow-up was 2 years. Twenty-eight patients who attended the study hospital and were given a diagnosis of MMTAH were included. Nineteen patients underwent surgery (surgical group) and nine patients were instructed to open their mouths wide once a day and did not undergo surgery (non-surgical group). Maximum mouth opening, impairment of daily activities, satisfaction, and the status of mouth opening training were evaluated after surgery. The mean increase in mouth opening after 2 years was 20.2mm in the surgical group and 2.4mm in the non-surgical group. Adequate mouth opening training led to satisfactory results 2 years postoperative, and sustained mouth opening training for 6 months after surgery was a key factor for obtaining good outcomes. The general condition and personality of individual patients should be evaluated carefully before surgery to estimate whether or not they can endure the pain associated with postoperative mouth opening training. The results of this study suggest that the surgical procedure is useful for the management of MMTAH.

Molecular cloning and chromosomal mapping of DNA rearranged with the parathyroid hormone gene in a parathyroid adenoma.

Parathyroid adenomas are common benign neoplasms for which no chromosomal defects have been described. We recently found two parathyroid adenomas bearing clonal restriction fragment abnormalities involving the PTH locus, and now show that in one of these tumors: (a) a DNA rearrangement occurred at the PTH locus; (b) the rearrangement separated the PTH gene's 5' flanking region from its coding exons, conceivably placing a newly adjacent gene under the influence of PTH regulatory elements; (c) the DNA that recombined with PTH normally maps to 11q13, the known chromosomal location of several oncogenes and the gene for multiple endocrine neoplasia type I; and (d) the rearrangement was a reciprocal, conservative recombination of the locus on 11q13 (Human Gene Mapping Library assignment D11S287) with PTH (on 11p15). These data provide molecular cytogenetic evidence for the clonal occurrence of a major chromosome 11 aberrancy in this benign parathyroid tumor. The D11S287 clone could prove useful in genetic linkage analyses, in determining precise 11q13 breakpoints in other neoplasms, and in identifying a gene on chromosome 11 that may participate in parathyroid tumor development.

The relation between spike-timing dependent plasticity and Ca2+ dynamics in the hippocampal CA1 network.

In our previous study, spike timing dependent synaptic plasticity (STDP) was investigated in the CA1 area of rat hippocampal slices using optical imaging. It was revealed that the profiles of STDP could be classified into two types depending upon layer specific location along the dendrite. The first was characterized by a symmetric time window observed in the proximal region of the stratum radiatum (SR), and the second by an asymmetric time window in the distal region of the SR. Our methods involved the bath-application of bicuculline (GABA(A) receptor antagonist) to hippocampal slices, which revealed that GABAergic interneuron projections were responsible for the symmetry of a time window. In this study, the intracellular Ca2+ increase of hippocampal CA1 neurons, induced by the protocol of timing between pre- and post-synaptic excitation (i.e. STDP protocol), was measured spatially by using optical imaging to investigate how the triggering of STDP is dependent on intracellular calcium concentration. We found that the magnitude of STDP was closely related to the rate of Ca2+ increase ("velocity") of calcium transient during application of induction stimuli. Location dependency was also analyzed in terms of Ca2+ influx. Furthermore, it was shown that decay time constant of Ca2+ dynamics during the application of STDP-inducing stimuli was also significantly correlated with STDP.

Primary malignant lymphoma of the cranial vault.

A 60-year-old woman presented with a subcutaneous mass on her scalp. Computed tomography (CT) showed a homogeneously enhanced mass of the parietal bone with both intra- and extra-calvarial extension and having destroyed the right parietal bone. The mass was hypointense on the T1-weighted magnetic resonance image, slightly hyperintense on the T2-weighted image and homogenously enhanced with Gd-DTPA. Bone scintigraphy showed prominent accumulation of radioisotopes in the scalp lesion. The tumour was removed, including the involved bone and dura mater. Histologic diagnosis was non-Hodgkin's B-cell lymphoma, and tumour cells had infiltrated into the dura mater. The patient was treated with radiotherapy and chemotherapy. She returned to ordinary daily life and has been well without recurrence for 3 years. Although primary malignant lymphoma of the cranial vault is rare, it should be considered in the differential diagnosis when a mass is encountered in the cranial vault. We have found only fourteen such cases in the literature, and we review these cases.

Tuberculosis Caused by Mycobacterium orygis in Dairy Cattle and Captured Monkeys in Bangladesh: a New Scenario of Tuberculosis in South Asia.

Mycobacterium orygis, commonly known as the oryx bacillus and a newly proposed Mycobacterium tuberculosis complex subspecies, was isolated from 18 cattle in a dairy farm and two captured rhesus monkeys in a zoo in Bangladesh. All the infected animals had tuberculosis lesions in their lungs, suggesting transmission and infection with M. orygis by an airborne route. The 20 isolates were analysed using a range of conventional and molecular typing methods, and RD-deletion typing and sequencing of selected genes confirmed the isolates as M. orygis. Multiple-locus variable-number tandem repeat analysis (MLVA) allowed the isolates to be divided into three clusters based on the relatedness of their MLVA profiles. The two monkey isolates shared the same MLVA pattern with 15 of the cattle isolates, whereas the remaining three cattle isolates had different patterns, even though the latter animals had been kept in the same dairy farm. The diversity observed among isolates may suggest the bacteria have been established in this area for a long period. This study along with other recent findings that report the detection of M. orygis from animals as well as humans originating from South Asia potentially indicate endemic distribution of M. orygis in South Asia.