Fukuoka University

BACKGROUND: Although many studies have found an association between Helicobacter pylori infection and the development of gastric cancer, many aspects of this relation remain uncertain. METHODS: We prospectively studied 1526 Japanese patients who had duodenal ulcers, gastric ulcers, gastric hyperplasia, or nonulcer dyspepsia at the time of enrollment; 1246 had H. pylori infection and 280 did not. The mean follow-up was 7.8 years (range, 1.0 to 10.6). Patients underwent endoscopy with biopsy at enrollment and then between one and three years after enrollment. H. pylori infection was assessed by histologic examination, serologic testing, and rapid urease tests and was defined by a positive result on any of these tests. RESULTS: Gastric cancers developed in 36 (2.9 percent) of the infected and none of the uninfected patients. There were 23 intestinal-type and 13 diffuse-type cancers. Among the patients with H. pylori infection, those with severe gastric atrophy, corpus-predominant gastritis, and intestinal metaplasia were at significantly higher risk for gastric cancer. We detected gastric cancers in 21 (4.7 percent) of the 445 patients with nonulcer dyspepsia, 10 (3.4 percent) of the 297 with gastric ulcers, 5 (2.2 percent) of the 229 with gastric hyperplastic polyps, and none of the 275 with duodenal ulcers. CONCLUSIONS: Gastric cancer develops in persons infected with H. pylori but not in uninfected persons. Those with histologic findings of severe gastric atrophy, corpus-predominant gastritis, or intestinal metaplasia are at increased risk. Persons with H. pylori infection and nonulcer dyspepsia, gastric ulcers, or gastric hyperplastic polyps are also at risk, but those with duodenal ulcers are not.

autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

BACKGROUND: Use of the conventional Western and Japanese classification systems of gastrointestinal epithelial neoplasia results in large differences among pathologists in the diagnosis of oesophageal, gastric, and colorectal neoplastic lesions. AIM: To develop common worldwide terminology for gastrointestinal epithelial neoplasia. METHODS: Thirty one pathologists from 12 countries reviewed 35 gastric, 20 colorectal, and 21 oesophageal biopsy and resection specimens. The extent of diagnostic agreement between those with Western and Japanese viewpoints was assessed by kappa statistics. The pathologists met in Vienna to discuss the results and to develop a new consensus terminology. RESULTS: The large differences between the conventional Western and Japanese diagnoses were confirmed (percentage of specimens for which there was agreement and kappa values: 37% and 0.16 for gastric; 45% and 0.27 for colorectal; and 14% and 0.01 for oesophageal lesions). There was much better agreement among pathologists (71% and 0.55 for gastric; 65% and 0.47 for colorectal; and 62% and 0.31 for oesophageal lesions) when the original assessments of the specimens were regrouped into the categories of the proposed Vienna classification of gastrointestinal epithelial neoplasia: (1) negative for neoplasia/dysplasia, (2) indefinite for neoplasia/dysplasia, (3) non-invasive low grade neoplasia (low grade adenoma/dysplasia), (4) non-invasive high grade neoplasia (high grade adenoma/dysplasia, non-invasive carcinoma and suspicion of invasive carcinoma), and (5) invasive neoplasia (intramucosal carcinoma, submucosal carcinoma or beyond). CONCLUSION: The differences between Western and Japanese pathologists in the diagnostic classification of gastrointestinal epithelial neoplastic lesions can be resolved largely by adopting the proposed terminology, which is based on cytological and architectural severity and invasion status.

We present possible observing scenarios for the Advanced LIGO, Advanced Virgo and KAGRA gravitational-wave detectors over the next decade, with the intention of providing information to the astronomy community to facilitate planning for multi-messenger astronomy with gravitational waves. We estimate the sensitivity of the network to transient gravitational-wave signals, and study the capability of the network to determine the sky location of the source. We report our findings for gravitational-wave transients, with particular focus on gravitational-wave signals from the inspiral of binary neutron star systems, which are the most promising targets for multi-messenger astronomy. The ability to localize the sources of the detected signals depends on the geographical distribution of the detectors and their relative sensitivity, and [Formula: see text] credible regions can be as large as thousands of square degrees when only two sensitive detectors are operational. Determining the sky position of a significant fraction of detected signals to areas of 5-[Formula: see text] requires at least three detectors of sensitivity within a factor of [Formula: see text] of each other and with a broad frequency bandwidth. When all detectors, including KAGRA and the third LIGO detector in India, reach design sensitivity, a significant fraction of gravitational-wave signals will be localized to a few square degrees by gravitational-wave observations alone.

Abstract The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

Non-motor symptoms (NMS) in Parkinson's disease (PD) are common, significantly reduce quality of life and at present there is no validated clinical tool to assess the progress or potential response to treatment of NMS. A new 30-item scale for the assessment of NMS in PD (NMSS) was developed. NMSS contains nine dimensions: cardiovascular, sleep/fatigue, mood/cognition, perceptual problems, attention/memory, gastrointestinal, urinary, sexual function, and miscellany. The metric attributes of this instrument were analyzed. Data from 242 patients mean age 67.2 +/- 11 years, duration of disease 6.4 +/- 6 years, and 57.3% male across all stages of PD were collected from the centers in Europe, USA, and Japan. The mean NMSS score was 56.5 +/- 40.7, (range: 0-243) and only one declared no NMS. The scale provided 99.2% complete data for the analysis with the total score being free of floor and ceiling effect. Satisfactory scaling assumptions (multitrait scaling success rate >95% for all domains except miscellany) and internal consistency were reported for most of the domains (mean alpha, 0.61). Factor analysis supported the a prori nine domain structure (63% of the variance) while a small test-retest study showed satisfactory reproducibility (ICC > 0.80) for all domains except cardiovascular (ICC = 0.45). In terms of validity, the scale showed modest association with indicators of motor symptom severity and disease progression but a high correlation with other measures of NMS (NMSQuest) and health-related quality of life measure (PDQ-8) (both, rS = 0.70). In conclusion, NMSS can be used to assess the frequency and severity of NMS in PD patients across all stages in conjunction with the recently validated non-motor questionnaire.

Skin wounds greatly affect the global healthcare system, creating a substantial burden on the economy and society. Moreover, the situation is exacerbated by low healing rates, which in fact are overestimated in reports. Cutaneous wounds are generally classified into acute and chronic. The immune response plays an important role during acute wound healing. The activation of immune cells and factors initiate the inflammatory process, facilitate wound cleansing and promote subsequent tissue healing. However, dysregulation of the immune system during the wound healing process leads to persistent inflammation and delayed healing, which ultimately result in chronic wounds. The microenvironment of a chronic wound is characterized by high quantities of pro-inflammatory macrophages, overexpression of inflammatory mediators such as TNF-α and IL-1β, increased activity of matrix metalloproteinases and abundance of reactive oxygen species. Moreover, chronic wounds are frequently complicated by bacterial biofilms, which perpetuate the inflammatory phase. Continuous inflammation and microbial biofilms make it very difficult for the chronic wounds to heal. In this review, we discuss the role of innate and adaptive immunity in the pathogenesis of acute and chronic wounds. Furthermore, we review the latest immunomodulatory therapeutic strategies, including modifying macrophage phenotype, regulating miRNA expression and targeting pro- and anti-inflammatory factors to improve wound healing.

The antiviral antibiotic brefeldin A (BFA) strongly inhibits the protein secretion in cultured rat hepatocytes (Misumi, Y., Misumi, Y., Miki, K., Takatsuki, A., Tamura, G., and Ikehara, Y. (1986) J. Biol. Chem. 261, 11398-11403). We have further examined the inhibitory effect of the drug on intracellular transport of albumin by an immunocytochemical technique with peroxidase-conjugated Fab fragments of anti-rat albumin IgG. In hepatocytes treated with BFA (2.5 micrograms/ml) for 1 h at 37 degrees C, no characteristic structures of the Golgi complex could be observed, and albumin was diffusely distributed in the endoplasmic reticulum (ER), nuclear envelope, and small vesicles around, in contrast to its condensed localization in the Golgi complex in the control cells. Such an unusual distribution of the secretory protein, however, was rearranged to the normal localization in the Golgi complex after 4 h even in the presence of the drug, possibly due to a metabolism of the drug to an inert form. Exposure of the cells to BFA with constant renewals (2.5 micrograms/ml at 1-h intervals) or at a higher concentration (10 micrograms/ml) caused a prolonged accumulation of albumin in the ER, resulting in its dilation. These results indicate that BFA primarily blocks the protein transport from the ER to the Golgi complex, consistent with the biochemical data previously reported.

We report on the population properties of compact binary mergers inferred from gravitational-wave observations of these systems during the first three LIGO-Virgo observing runs. The Gravitational-Wave Transient Catalog 3 (GWTC-3) contains signals consistent with three classes of binary mergers: binary black hole, binary neutron star, and neutron star–black hole mergers. We infer the binary neutron star merger rate to be between 10 and <a:math xmlns:a="http://www.w3.org/1998/Math/MathML" display="inline"><a:mrow><a:mn>1700</a:mn><a:mtext> </a:mtext><a:mtext> </a:mtext><a:msup><a:mrow><a:mi>Gpc</a:mi></a:mrow><a:mrow><a:mo>−</a:mo><a:mn>3</a:mn></a:mrow></a:msup><a:mtext> </a:mtext><a:msup><a:mrow><a:mi>yr</a:mi></a:mrow><a:mrow><a:mo>−</a:mo><a:mn>1</a:mn></a:mrow></a:msup></a:mrow></a:math> and the neutron star–black hole merger rate to be between 7.8 and <c:math xmlns:c="http://www.w3.org/1998/Math/MathML" display="inline"><c:mrow><c:mn>140</c:mn><c:mtext> </c:mtext><c:mtext> </c:mtext><c:msup><c:mrow><c:mi>Gpc</c:mi></c:mrow><c:mrow><c:mo>−</c:mo><c:mn>3</c:mn></c:mrow></c:msup><c:mtext> </c:mtext><c:msup><c:mrow><c:mi>yr</c:mi></c:mrow><c:mrow><c:mo>−</c:mo><c:mn>1</c:mn></c:mrow></c:msup></c:mrow></c:math>, assuming a constant rate density in the comoving frame and taking the union of 90% credible intervals for methods used in this work. We infer the binary black hole merger rate, allowing for evolution with redshift, to be between 17.9 and <e:math xmlns:e="http://www.w3.org/1998/Math/MathML" display="inline"><e:mrow><e:mn>44</e:mn><e:mtext> </e:mtext><e:mtext> </e:mtext><e:msup><e:mrow><e:mi>Gpc</e:mi></e:mrow><e:mrow><e:mo>−</e:mo><e:mn>3</e:mn></e:mrow></e:msup><e:mtext> </e:mtext><e:msup><e:mrow><e:mi>yr</e:mi></e:mrow><e:mrow><e:mo>−</e:mo><e:mn>1</e:mn></e:mrow></e:msup></e:mrow></e:math> at a fiducial redshift (<g:math xmlns:g="http://www.w3.org/1998/Math/MathML" display="inline"><g:mi>z</g:mi><g:mo>=</g:mo><g:mn>0.2</g:mn></g:math>). The rate of binary black hole mergers is observed to increase with redshift at a rate proportional to <i:math xmlns:i="http://www.w3.org/1998/Math/MathML" display="inline"><i:mo stretchy="false">(</i:mo><i:mn>1</i:mn><i:mo>+</i:mo><i:mi>z</i:mi><i:msup><i:mo stretchy="false">)</i:mo><i:mi>κ</i:mi></i:msup></i:math> with <m:math xmlns:m="http://www.w3.org/1998/Math/MathML" display="inline"><m:mi>κ</m:mi><m:mo>=</m:mo><m:mn>2.</m:mn><m:msubsup><m:mn>9</m:mn><m:mrow><m:mo>−</m:mo><m:mn>1.8</m:mn></m:mrow><m:mrow><m:mo>+</m:mo><m:mn>1.7</m:mn></m:mrow></m:msubsup></m:math> for <o:math xmlns:o="http://www.w3.org/1998/Math/MathML" display="inline"><o:mi>z</o:mi><o:mo>≲</o:mo><o:mn>1</o:mn></o:math>. Using both binary neutron star and neutron star–black hole binaries, we obtain a broad, relatively flat neutron star mass distribution extending from <q:math xmlns:q="http://www.w3.org/1998/Math/MathML" display="inline"><q:msubsup><q:mn>1.2</q:mn><q:mrow><q:mo>−</q:mo><q:mn>0.2</q:mn></q:mrow><q:mrow><q:mo>+</q:mo><q:mn>0.1</q:mn></q:mrow></q:msubsup></q:math> to <s:math xmlns:s="http://www.w3.org/1998/Math/MathML" display="inline"><s:msubsup><s:mn>2.0</s:mn><s:mrow><s:mo>−</s:mo><s:mn>0.3</s:mn></s:mrow><s:mrow><s:mo>+</s:mo><s:mn>0.3</s:mn></s:mrow></s:msubsup><s:msub><s:mi>M</s:mi><s:mo stretchy="false">⊙</s:mo></s:msub></s:math>. We confidently determine that the merger rate as a function of mass sharply declines after the expected maximum neutron star mass, but cannot yet confirm or rule out the existence of a lower mass gap between neutron stars and black holes. We also find the binary black hole mass distribution has localized over- and underdensities relative to a power-law distribution, with peaks emerging at chirp masses of <v:math xmlns:v="http://www.w3.org/1998/Math/MathML" display="inline"><v:msubsup><v:mn>8.3</v:mn><v:mrow><v:mo>−</v:mo><v:mn>0.5</v:mn></v:mrow><v:mrow><v:mo>+</v:mo><v:mn>0.3</v:mn></v:mrow></v:msubsup></v:math> and <x:math xmlns:x="http://www.w3.org/1998/Math/MathML" display="inline"><x:msubsup><x:mn>27.9</x:mn><x:mrow><x:mo>−</x:mo><x:mn>1.8</x:mn></x:mrow><x:mrow><x:mo>+</x:mo><x:mn>1.9</x:mn></x:mrow></x:msubsup><x:msub><x:mi>M</x:mi><x:mo stretchy="false">⊙</x:mo></x:msub></x:math>. While we continue to find that the mass distribution of a binary’s more massive component strongly decreases as a function of primary mass, we observe no evidence of a strongly suppressed merger rate above approximately <ab:math xmlns:ab="http://www.w3.org/1998/Math/MathML" display="inline"><ab:mn>60</ab:mn><ab:msub><ab:mi>M</ab:mi><ab:mo stretchy="false">⊙</ab:mo></ab:msub></ab:math>, which would indicate the presence of a upper mass gap. Observed black hole spins are small, with half of spin magnitudes below <db:math xmlns:db="http://www.w3.org/1998/Math/MathML" display="inline"><db:msub><db:mi>χ</db:mi><db:mi>i</db:mi></db:msub><db:mo>≈</db:mo><db:mn>0.25</db:mn></db:math>. While the majority of spins are preferentially aligned with the orbital angular momentum, we infer evidence of antialigned spins among the binary population. We observe an increase in spin magnitude for systems with more unequal-mass ratio. We also observe evidence of misalignment of spins relative to the orbital angular momentum. Published by the American Physical Society 2023

We examined the effect of brefeldin A, an antiviral antibiotic, on protein synthesis, intracellular processing, and secretion in primary culture of rat hepatocytes. The secretion was strongly blocked by the drug at 1 microgram/ml and higher concentrations, while the protein synthesis was maintained fairly well. Pulse-chase experiments with [35S]methionine demonstrated that brefeldin A completely blocked the proteolytic conversion of proalbumin to serum albumin up to 60 min of chase, although its conversion was observed as early as 20 min in the control cells. The drug also inhibited the terminal glycosylation of oligosaccharide chains of alpha 1-protease inhibitor and haptoglobin. These two modifications have been shown to occur at the trans region of the Golgi complex. The drug, however, had no effect on the proteolytic processing of the haptoglobin proform which takes place within the endoplasmic reticulum. Such an effect by brefeldin A is very similar with that induced by the carboxylic ionophore monensin. However, in contrast to evidence that monensin causes a delayed secretion of the unprocessed forms of these proteins, brefeldin A allowed the completely processed forms to be secreted after a prolonged accumulation of the unprocessed forms. Morphological observations demonstrated that the endoplasmic reticulum was markedly dilated by treatment with the drug at 10 micrograms/ml which continuously blocked the secretion. On the other hand, brefeldin A caused no inhibitory effect on the endocytic pathway as judged by cellular uptake and degradation of 125I-asialofetuin. These results indicate that brefeldin A is a unique agent which primarily impedes protein transport from the endoplasmic reticulum to the Golgi complex by a mechanism different from those considered for other secretion-blocking agents so far reported.

Hematopoietic progenitor cells (HPCs) normally reside in the bone marrow (BM) but can be mobilized into the peripheral blood (PB) after treatment with GCSF or chemotherapy. In previous studies, we showed that granulocyte precursors accumulate in the BM during mobilization induced by either GCSF or cyclophosphamide (CY), leading to the accumulation of active neutrophil proteases in this tissue. We now report that mobilization of HPCs by GCSF coincides in vivo with the cleavage of the N-terminus of the chemokine receptor CXCR4 on HPCs resident in the BM and mobilized into the PB. This cleavage of CXCR4 on mobilized HPCs results in the loss of chemotaxis in response to the CXCR4 ligand, the chemokine stromal cell-derived factor-1 (SDF-1/CXCL12). Furthermore, the concentration of SDF-1 decreased in vivo in the BM of mobilized mice, and this decrease coincided with the accumulation of serine proteases able to directly cleave and inactivate SDF-1. Since both SDF-1 and its receptor, CXCR4, are essential for the homing and retention of HPCs in the BM, the proteolytic degradation of SDF-1, together with that of CXCR4, could represent a critical step leading to the mobilization of HPCs into the PB in response to GCSF or CY.

We report the observation of gravitational waves from two compact binary coalescences in LIGO's and Virgo's third observing run with properties consistent with neutron star-black hole (NSBH) binaries. The two events are named GW200105_162426 and GW200115_042309, abbreviated as GW200105 and GW200115; the first was observed by LIGO Livingston and Virgo and the second by all three LIGO-Virgo detectors. The source of GW200105 has component masses, whereas the source of GW200115 has component masses and (all measurements quoted at the 90% credible level). The probability that the secondary's mass is below the maximal mass of a neutron star is 89%-96% and 87%-98%, respectively, for GW200105 and GW200115, with the ranges arising from different astrophysical assumptions. The source luminosity distances are and, respectively. The magnitude of the primary spin of GW200105 is less than 0.23 at the 90% credible level, and its orientation is unconstrained. For GW200115, the primary spin has a negative spin projection onto the orbital angular momentum at 88% probability. We are unable to constrain the spin or tidal deformation of the secondary component for either event. We infer an NSBH merger rate density of when assuming that GW200105 and GW200115 are representative of the NSBH population or under the assumption of a broader distribution of component masses. © 2021. The Author(s). Published by the American Astronomical Society.

BACKGROUND AND PURPOSE: About one half of those who develop adult-onset moyamoya disease experience intracranial hemorrhage. Despite the extremely high frequency of rebleeding attacks and poor prognosis, measures to prevent rebleeding have not been established. The purpose of this study is to determine whether extracranial-intracranial bypass can reduce incidence of rebleeding and improve patient prognosis. METHODS: This study was a multicentered, prospective, randomized, controlled trial conducted by 22 institutes in Japan. Adult patients with moyamoya disease who had experienced intracranial hemorrhage within the preceding year were given either conservative care or bilateral extracranial-intracranial direct bypass and were observed for 5 years. Primary and secondary end points were defined as all adverse events and rebleeding attacks, respectively. RESULTS: Eighty patients were enrolled (surgical, 42; nonsurgical, 38). Adverse events causing significant morbidity were observed in 6 patients in the surgical group (14.3%) and 13 patients in the nonsurgical group (34.2%). Kaplan-Meier survival analysis revealed significant differences between the 2 groups (3.2%/y versus 8.2%/y; P=0.048). The hazard ratio of the surgical group calculated by Cox regression analysis was 0.391 (95% confidence interval, 0.148-1.029). Rebleeding attacks were observed in 5 patients in the surgical group (11.9%) and 12 in the nonsurgical group (31.6%), significantly different in the Kaplan-Meier survival analysis (2.7%/y versus 7.6%/y; P=0.042). The hazard ratio of the surgical group was 0.355 (95% confidence interval, 0.125-1.009). CONCLUSIONS: Although statistically marginal, Kaplan-Meier analysis revealed the significant difference between surgical and nonsurgical group, suggesting the preventive effect of direct bypass against rebleeding. CLINICAL TRIAL REGISTRATION URL: http://www.umin.ac.jp/ctr/index.htm. Unique identifier: C000000166.

The human estrogen receptor (hER) exists as two subtypes, hER alpha and hER beta, that differ in the C-terminal ligand-binding domain and in the N-terminal transactivation domain. In this study, we investigated the estrogenic activities of soy isoflavones after digestion with enteric bacteria in competition binding assays with hER alpha or hER beta protein, and in a gene expression assay using a yeast system. The estrogenic activities of these isoflavones were also investigated by the growth of MCF-7 breast cancer cells. Isoflavone glycoside binds weakly to both receptors and estrogen receptor-dependent transcriptional expression is poor. The aglycones bind more strongly to hER beta than to hER alpha. The binding affinities of genistein, dihydrogenistein and equol are comparable to the binding affinity of 17 beta-estradiol. Equol induces transcription most strongly with hER alpha and hER beta. The concentration required for maximal gene expression is much higher than expected from the binding affinities of the compounds, and the maximal activity induced by these compounds is about half the activity of 17 beta-estradiol. Although genistin binds more weakly to the receptors and induces transcription less than does genistein, it stimulates the growth of MCF-7 cells more strongly than does genistein.

Neuroinflammation is involved in the onset or progression of various neurodegenerative diseases. Initiation of neuroinflammation is triggered by endogenous substances (damage-associated molecular patterns) and/or exogenous pathogens. Activation of glial cells (microglia and astrocytes) is widely recognized as a hallmark of neuroinflammation and triggers the release of proinflammatory cytokines, leading to neurotoxicity and neuronal dysfunction. Another feature associated with neuroinflammatory diseases is impairment of the blood-brain barrier (BBB). The BBB, which is composed of brain endothelial cells connected by tight junctions, maintains brain homeostasis and protects neurons. Impairment of this barrier allows trafficking of immune cells or plasma proteins into the brain parenchyma and subsequent inflammatory processes in the brain. Besides neurons, activated glial cells also affect BBB integrity. Therefore, BBB dysfunction can amplify neuroinflammation and act as a key process in the development of neuroinflammation. BBB integrity is determined by the integration of multiple signaling pathways within brain endothelial cells through intercellular communication between brain endothelial cells and brain perivascular cells (pericytes, astrocytes, microglia, and oligodendrocytes). For prevention of BBB disruption, both cellular components, such as signaling molecules in brain endothelial cells, and non-cellular components, such as inflammatory mediators released by perivascular cells, should be considered. Thus, understanding of intracellular signaling pathways that disrupt the BBB can provide novel treatments for neurological diseases associated with neuroinflammation. In this review, we discuss current knowledge regarding the underlying mechanisms involved in BBB impairment by inflammatory mediators released by perivascular cells.

BACKGROUND: Excessive myocardial fibrosis impairs cardiac function in hypertensive hearts. Roles of transforming growth factor (TGF)-beta in myocardial remodeling and cardiac dysfunction were examined in pressure-overloaded rats. METHODS AND RESULTS: Pressure overload was induced by a suprarenal aortic constriction in Wistar rats. Fibroblast activation (proliferation and phenotype transition to myofibroblasts) was observed after day 3 and peaked at days 3 to 7. Thereafter, myocyte hypertrophy and myocardial fibrosis developed by day 28. At day 28, echocardiography showed normal left ventricular fractional shortening, but the decreased ratio of early to late filling velocity of the transmitral Doppler velocity and hemodynamic measurement revealed left ventricular end-diastolic pressure elevation, indicating normal systolic but abnormal diastolic function. Myocardial TGF-beta mRNA expression was induced after day 3, peaked at day 7, and remained modestly increased at day 28. An anti-TGF-beta neutralizing antibody, which was administered intraperitoneally daily from 1 day before operation, inhibited fibroblast activation and subsequently prevented collagen mRNA induction and myocardial fibrosis, but not myocyte hypertrophy. Neutralizing antibody reversed diastolic dysfunction without affecting blood pressure and systolic function. CONCLUSIONS: TGF-beta plays a causal role in myocardial fibrosis and diastolic dysfunction through fibroblast activation in pressure-overloaded hearts. Our findings may provide an insight into a new therapeutic strategy to prevent myocardial fibrosis and diastolic dysfunction in pressure-overloaded hearts.

Abstract A nation‐wide sero‐epidemiologic survey of adult T‐cell leukemia virus (ATLV), detected es anti‐ATLA (ATLV‐associated antigen), was made in Japan. Sera from adult donors in 15 different locations were screened for anti‐ATLA. High incidences (6 to 37%) of antibody‐positive donors were found in seven regions, one in northern Japan, and the others in southwestern regions. These areas are ATLV‐endemic areas corresponding to ATL‐endemic areas. Examination of sera from healthy donors aged 6 to 80 years in ATL‐endemic areas showed an age‐dependent increase of seropositive donors with a maximum of about 30% at 40 years of age. Anti‐ATLA was found in all but two of 142 patients with ATL Anti‐ATLA‐positive patients with ATL were mainly found in ATLV‐endemic areas, and only a few in ATL‐nonendemic areas. Six patients with cutaneous T‐cell lymphoma in ATLV‐nonendemic areas gave a negative reaction for anti‐ATLA. The geometric mean titer of anti‐ATLA of patients with ATL was higher than that of healthy donors.

The paper is devoted to the study of the function E γ ρ,μ(z) defined for complex ρ, μ, γ (Re(ρ) > 0) by which is a generalization of the classical Mittag-Leffler function E ρ,μ(z) and the Kummer confluent hypergeometric function Φ(γ, μ; z). The properties of E γ ρ,μ(z) including usual differentiation and integration, and fractional ones are proved. Further the integral operator with such a function kernel is studied in the space L(a, b). Compositions of the Riemann–Liouville fractional integration and differentiation operators with E γ ρ,μ,ω;a+ are established. An analogy of the semigroup property for the composition of two such operators with different indices is proved, and the results obtained are applied to construct the left inversion operator to the operator E γ ρ,μ,ω;a+. Since, for γ = 0, E 0 ρ,μ,ω;a+ coincides with the Riemann–Liouville fractional integral of order μ, the above operator and its inversion can be considered as generalized fractional calculus operators involving the generalized Mittag-Leffler function E γ ρ,μ(z) in the kernels. Similar assertions are presented for the integral operators containing the Mittag-Leffler and Kummer functions, E ρ,μ(z) and Φ(γ, μ; z), in the kernels, and applications are given to obtain solutions in closed form of the integral equations of the first kind.

Abstract 2006, there was, no single instrument (questionnaire or scale) for attempting a comprehensive assessment of the wide range of nonmotor symptoms (NMS) of Parkinson's disease (PD). The PD nonmotor group, a multidisciplinary group of experts including patient group representatives developed and validated the NMS screening questionnaire (NMSQuest) comprising 30 items. The NMSQuest is a self completed screening tool designed to draw attention to the presence of NMS. In this paper, we present the results gathered from 545 patients using the definitive version of the NMSQuest highlighting the prevalence of the wide range of NMS flagged in the NMSQuest from consecutive PD patients in an international setting. © 2007 Movement Disorder Society

Pairs of enantiomers of nine aldoses were separated by gas-liquid chromatography on an OV-17 capillary column as the trimethylsilyl ethers of methyl 2- (polyhydroxyalkyl) -thiazolidine-4 (R) -carboxylates, which were obtained by the reaction of aldoses with L-cysteine methyl ester. This method was applied to the determination of the absolute configurations of the component monosaccharides of a Thladiantha saponin.