The 2018 ISDE achalasia guidelines.

Achalasia is a relatively rare primary motor esophageal disorder, characterized by absence of relaxations of the lower esophageal sphincter and of peristalsis along the esophageal body. As a result, patients typically present with dysphagia, regurgitation and occasionally chest pain, pulmonary complication and malnutrition. New diagnostic methodologies and therapeutic techniques have been recently added to the armamentarium for treating achalasia. With the aim to offer clinicians and patients an up-to-date framework for making informed decisions on the management of this disease, the International Society for Diseases of the Esophagus Guidelines proposed and endorsed the Esophageal Achalasia Guidelines (I-GOAL). The guidelines were prepared according the Appraisal of Guidelines for Research and Evaluation (AGREE-REX) tool, accredited for guideline production by NICE UK. A systematic literature search was performed and the quality of evidence and the strength of recommendations were graded according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE). Given the relative rarity of this disease and the paucity of high-level evidence in the literature, this process was integrated with a three-step process of anonymous voting on each statement (DELPHI). Only statements with an approval rate >80% were accepted in the guidelines. Fifty-one experts from 11 countries and 3 representatives from patient support associations participated to the preparations of the guidelines. These guidelines deal specifically with the following achalasia issues: Diagnostic workup, Definition of the disease, Severity of presentation, Medical treatment, Botulinum Toxin injection, Pneumatic dilatation, POEM, Other endoscopic treatments, Laparoscopic myotomy, Definition of recurrence, Follow up and risk of cancer, Management of end stage achalasia, Treatment options for failure, Achalasia in children, Achalasia secondary to Chagas' disease.

Comparison of spinal alignment, muscular strength, and quality of life between women with postmenopausal osteoporosis and healthy volunteers.

This study compared spinal alignment, muscular strength, and quality of life (QOL) between women with postmenopausal osteoporosis and healthy volunteers. The results indicated that lower QOL in osteoporosis patients may be associated with increased thoracic kyphosis, reduced lean muscle mass, and generalized muscle weakness. INTRODUCTION: Increased spinal kyphosis is common in patients with osteoporosis and negatively impacts quality of life (QOL). Muscular strength is also important for QOL in patients with osteoporosis. However, spinal kyphosis and muscle weakness also occur in healthy individuals with advancing age. The purposes of this study were thus to compare spinal alignment, muscular strength, and QOL between women with postmenopausal osteoporosis and healthy volunteers. METHODS: Participants comprised 236 female patients with postmenopausal osteoporosis (mean age, 68.7 years) and 93 healthy volunteer women (mean age, 71.0 years). Body mass index (BMI), angles of spinal kyphosis, back extensor strength, grip strength, and QOL were compared between groups. RESULTS: BMI, back extensor strength, and grip strength were significantly higher in the volunteer group than in the osteoporosis group (p < 0.01). Both thoracic kyphosis and lumbar lordosis were significantly greater in the osteoporosis group than in the volunteer group (p < 0.01). With regard to QOL, the 36-Item Short-Form Health Survey (SF-36) subscale scores of role physical, bodily pain, general health, and role emotional were all significantly lower in the osteoporosis group than in the volunteer group (p < 0.05 each). SF-36 physical component summary (PCS) score was significantly lower in the osteoporosis group than in the volunteer group (p < 0.001). SF-36 PCS score correlated positively with thoracic kyphosis and negatively with BMI only in the osteoporosis group (p < 0.05 each). CONCLUSIONS: These results indicated that lower QOL in osteoporosis patients may be associated with increased thoracic kyphosis, reduced lean muscle mass, and generalized muscle weakness.

Improvement of spinal alignment and quality of life after corrective surgery for spinal kyphosis in patients with osteoporosis: a comparative study with non-operated patients.

UNLABELLED: This study evaluated changes in spinal alignment and quality of life (QOL) after corrective spinal surgery for patients with postmenopausal osteoporosis and spinal kyphosis. Spinal global alignment and QOL were significantly improved after corrective spinal surgery but did not reach the level of non-operated controls. INTRODUCTION: With the increased aging of society, the demand for corrective spinal instrumentation for spinal kyphosis in osteoporotic patients is increasing. However, previous studies have not focused on the improvement of quality of life (QOL) after corrective spinal surgery in patients with osteoporosis, compared to non-operated control patients. The purposes of this study were thus to evaluate changes in spinal alignment and QOL after corrective spinal instrumentation for patients with osteoporosis and spinal kyphosis and to compare these results with non-operated patients. METHODS: Participants comprised 39 patients with postmenopausal osteoporosis ≥50 years old who underwent corrective spinal surgery using multilevel posterior lumbar interbody fusion (PLIF) for symptomatic thoracolumbar or lumbar kyphosis, and 82 age-matched patients with postmenopausal osteoporosis without prevalent vertebral fractures. Spinopelvic parameters were evaluated with standing lateral spine radiography, and QOL was evaluated with the Japanese Osteoporosis QOL Questionnaire (JOQOL), SF-36, and Roland-Morris Disability Questionnaire (RDQ). RESULTS: Lumbar kyphosis angle, sagittal vertical axis, and pelvic tilt were significantly improved postoperatively. QOL evaluated with all three questionnaires also significantly improved after 6 months postoperatively, particularly in domain and subscale scores for pain and general/mental health. However, these radiographic parameters, total JOQOL score, SF-36 physical component summary score, and RDQ score were significantly inferior compared with non-operated controls. CONCLUSIONS: The results indicate that spinal global alignment and QOL were significantly improved after corrective spinal surgery using multilevel PLIF for patients with osteoporosis and spinal kyphosis but did not reach the level of non-operated controls.

Association of spinal curve deformity and back extensor strength in elderly women with osteoporosis in Japan and the United States.

UNLABELLED: The difference in the shape of sagittal spinal curvature and distribution of vertebral fractures in women of comparable age with osteoporosis from Japan and the United States with different cultures and lifestyles was identified. Back extensor strength was significantly associated with lumbar lordosis in Akita group, indicating the potential importance of strengthening the back extensor. INTRODUCTION: The purpose of the study was to assess the association of osteoporotic spinal deformities with back strength in elderly women in Japan and the United States. METHODS: Subjects diagnosed with osteoporosis were selected to participate prospectively. In both groups, we measured the angles of thoracic kyphosis and lumbar lordosis with plain lateral radiographs and back extensor strength. The number of vertebral fractures and the ratio of lumbar fractures to thoracic fractures are also evaluated. The level of participants' daily activities was assessed with use of comparable tests in Akita (quality-of-life score) and Minnesota (physical activity score). RESULTS: A total of 102 Japanese women residing in Akita, Japan (Akita group), and 104 white women evaluated in Rochester, MN, USA (Minnesota group), participated in this study. The angle of thoracic kyphosis and lumbar lordosis was higher in the Minnesota group than in the Akita group. The ratio of lumbar fractures to thoracic fractures was higher in the Akita group than in the Minnesota group. In the Akita group, multiple regression analysis revealed that the angle of lumbar lordosis correlated significantly with back extensor strength. CONCLUSIONS: We identified the difference in the shape of sagittal spinal curvature and distribution of vertebral fractures in women of comparable age with osteoporosis from two geographic areas of the world with different cultures and lifestyles. Back extensor strength was significantly associated with lumbar lordosis in Akita group, indicating the potential importance of strengthening the back extensor for improving or maintaining lumbar lordosis.

A long-term study of acotiamide in patients with functional dyspepsia: results from an open-label phase III trial in Japan on efficacy, safety and pattern of administration.

BACKGROUND: This long-term 48-week study of acotiamide was carried out to investigate the efficacy, safety and administration pattern in patients with functional dyspepsia (FD). METHODS: This was a multicenter, open-label, single-arm, long-term phase III study in which patients with FD were given acotiamide, 100 mg t.i.d., for 48 weeks. The two major efficacy endpoints were global overall treatment efficacy (OTE) and the elimination rate of three cardinal symptoms (i.e. postprandial fullness, early satiation and upper abdominal bloating), which were evaluated weekly and daily by the patients, respectively. The long-term administration patterns were investigated by following the patients based on cessation and readministration criteria. RESULTS: Efficacy was analyzed in 405 patients. The OTE improvement rate was 26.1% at week 1 and increased with time. It was 60.6% at week 8 and subsequently maintained. Similarly, the symptom elimination rate increased up to week 8. Many patients who met the cessation criterion achieved remission of FD symptoms after experiencing dose interruption and readministration. The incidence rate of adverse drug reactions was 11.5% and most of the adverse drug reactions were mild in severity except increased ALT in 1 patient. CONCLUSION: FD symptoms were controlled by intermittent administration of acotiamide even in patients with relapsing FD.

Unsedated transnasal ultrathin esophagogastroduodenoscopy may provide better diagnostic performance in gastroesophageal reflux disease.

Transnasal ultrathin esophagogastroduodenoscopy (N-EGD) with less gagging reflexes under non-sedation is likely suitable for the diagnosis of gastroesophageal reflux disease (GERD), however, N-EGD might have drawbacks, including its low image resolution. Limited information is available regarding the diagnosability of N-EGD for GERD. We compared the utility and gagging reflexes of three different endoscopies, including N-EGD, ultrathin transoral EGD (UTO-EGD) and conventional oral EGD (CO-EGD), in the diagnosis of GERD. We performed screening endoscopy in 1580 patients (N-EGD n=727, UTO-EGD n=599, CO-EGD n=254) and compared the frequency distributions of the severity of reflux esophagitis, hiatus hernia, and Barrett's epithelium to estimate the diagnostic performance of each endoscopy. We also analyzed patients' tolerability of endoscopy by the subjective evaluation of gagging reflexes. In the diagnosis of reflux esophagitis and Barrett's epithelium, there was no significant difference in the frequency distributions of the severity of the diseases among three EGDs. However, the incidence of Barrett's epithelium was higher than that in the previous nationwide survey of GERD in Japan. The evaluated size of hiatus hernia was smaller in N-EGD than in two other peroral endoscopies. The size of hiatus hernia correlated significantly with severity of gagging reflexes that was also lowest when diagnosed with N-EGD. N-EGD had an equivalent performance in the diagnosis of reflux esophagitis and Barrett's epithelium compared with CO-EGD. Enlargement of hiatus hernia induced by gagging reflexes was minimal in N-EGD, resulting in its better performance in the diagnosis of Barrett's epithelium.

Impact of serotonin transporter gene polymorphism on brain activation by colorectal distention.

BACKGROUND AND AIMS: Determining the gene that plays a key role in brain-gut interactions is a crucial step for clarifying the pathophysiology of irritable bowel syndrome (IBS). We previously reported that the 5-hydroxytryptamine transporter gene-linked polymorphic region (5-HTTLPR) is related to anxiety in subjects with IBS. The amygdala is more activated during fearful face recognition in individuals with the s allele of 5-HTTLPR. Here, we tested our hypothesis that 5-HTTLPR differentially activates brain regions with colorectal distention in humans. METHODS: We enrolled 28 subjects without any organic disease. The study was approved by the Ethics Committee and all subjects gave written informed consent. DNA was extracted from the peripheral blood. The genotype of 5-HTTLPR was determined using polymerase chain reaction. Age, sex, diagnosis-matched individuals with the s/s genotype (n=14) and individuals with the l allele (genotypes l/s, l/l, l/extra-l, n=14) were compared. A barostat bag was inserted to the colorectum and was intermittently inflated with no (0 mm Hg), mild (20 mm Hg), or intense (40 mm Hg) stimulation on a random order. Radioactive H2[(15-)O] saline was injected at bag inflation and then positron emission tomography was performed. Changes in rCBF were analyzed using statistical parametric mapping. RESULTS: Individuals with the s/s genotype showed a significantly larger increase in rCBF by colorectal distention from 0 mm Hg to 40 mm Hg than individuals with the l allele. The significantly more activated brain regions in individuals with the s/s genotype were the left anterior cingulate cortex and right parahippocampal gyrus (p<0.0001). The increase in rCBF by colorectal distention of 20 mm Hg compared with 0 mm Hg was significantly larger in the left orbitofrontal cortex of individuals with the s/s genotype than that of individuals with the l allele (p<0.0001). CONCLUSION: These data suggest that individuals with a weak function of serotonin transporter respond to gut signals more in emotion-regulating brain regions. Functional gene polymorphism may partially predict the individual effect of a selective serotonin reuptake inhibitor on visceral pain.

Spinal curvature and postural balance in patients with osteoporosis.

SUMMARY: Postural deformity might represent another risk factor for postural instability and falls. Relation between spinal curvatures and postural sway were evaluated. Lumbar (not thoracic) kyphosis and spinal inclination have a statistical correlation with postural sway. Postural deformity with lumber kyphosis may represent as a risk factor for falls. INTRODUCTION: Postural instability has been considered as a risk factor for falls and osteoporotic fractures. Previous studies have demonstrated that several factors display significant relationships with postural instability. Postural deformity might represent another risk factor for postural instability and falls. This study evaluates the influence of spinal curvature on postural instability in patients with osteoporosis. METHODS: Subjects comprised 93 patients with a mean age of 70 years. Angles of thoracic and lumbar kyphosis and spinal inclination that reflected a forward stooped posture were evaluated using a computer-assisted device. Sway and postural instability were evaluated using a computerized stabilometer showing seven parameters. Relationships among parameters of postural deformity and postural balance were analyzed using Pearson's correlation coefficients. RESULTS: No significant correlations were observed between any parameters of postural balance and angle of thoracic kyphosis. However, all parameters showed significant positive correlations with angle of lumbar kyphosis (r = 0.251-0.334; p < 0.05-0.001). Moreover, lumbar kyphosis, but not thoracic kyphosis, showed a positive correlation with spinal inclination (r = 0.692, p < 0.001), and all parameters of postural balance showed significant positive correlations with spinal inclination (r = 0.417-0.551, p < 0.001). CONCLUSION: Lumbar kyphosis, but not thoracic kyphosis, affecting spinal inclination and postural balance may represent a risk factor for falls.

A phase II trial of the novel serotonin type 3 receptor antagonist ramosetron in Japanese male and female patients with diarrhea-predominant irritable bowel syndrome.

BACKGROUND: Irritable bowel syndrome (IBS) is a common gastrointestinal disorder. Serotonin type 3 (5-HT3) receptor antagonist alosetron hydrochloride is indicated for women with chronic, severe diarrhea-predominant IBS who have not responded adequately to conventional therapy. However, whether or not the therapeutic efficacy of 5-HT3 receptor antagonists has gender difference is uncertain. METHODS: A double-blind, placebo-controlled, parallel-group, comparative study was conducted to evaluate the effect of novel 5-HT3 receptor antagonist, ramosetron hydrochloride, in male and female patients with diarrhea-predominant IBS. 418 subjects were randomized (109 subjects: placebo, 105 subjects: 1 microg, 103 subjects: 5 microg, and 101 subjects: 10 microg) and administered the study drug once daily. RESULTS: The monthly responder rates of 'Patient-reported global assessment of relief of irritable bowel syndrome symptoms' in the 5- and 10-microg ramosetron hydrochloride-administered groups were higher than the placebo group (26.92, 42.57, and 43.01% for placebo, 5 and 10 microg). Moreover, the difference of the responder rate in comparison with the placebo group was similar in males and females. As for safety, there was tolerability at doses up to 10 microg. CONCLUSION: Ramosetron is an effective and well-tolerated treatment not only for female IBS patients but also for male patients.

Bradykinin system is involved in endometriosis-related pain through endothelin-1 production.

BACKGROUND: Endometriosis is a gynaecological disease exhibiting severe pelvic pain, but the mechanism of pain production remains unknown. Bradykinin (BK) is known as an inflammatory mediator, and shows elevated levels in inflammatory diseases such as rheumatoid arthritis. In the present study, we evaluated whether BK is involved in endometriosis-related pain. METHODS: Endometriotic lesions were used for immunohistochemistry. Primary cultures of endometriotic stromal cells (ESC) were stimulated with IL-1ß and/or BK. Quantitative RT-PCR was used to evaluate the mRNA expressions of BK receptors (BKR) and endothelin-1 in ESC. The concentration of endothelin-1 in cystic fluid of endometrioma or non-endometrioma was measured with ELISA. The conditioned medium of ESC stimulated with IL-1ß and/or BK was injected intraplantarly in mice, and evaluated whether pain-related licking behaviour was elicited. RESULTS: The expressions of BK and BKR in endometriotic lesions were observed by immunohistochemistry. In vitro experiments showed that IL-1ß induced BKR-B1 and B2 on ESC. Activation of these receptors by BK significantly induced endothelin-1 expression in ESC, which was negated completely by HOE-140, a BKR-B2 antagonist. The cystic fluid of endometrioma contained higher amount of endothelin-1 compared to non-endometrioma. Intraplantar injection of the conditioned medium of ESC treated with IL-1ß and BK significantly induced licking behaviour, which was suppressed with BQ-123, an endothelin type-A receptor antagonist. CONCLUSIONS: The present study demonstrated the presence and the function of the BK axis in endometriosis, and established a potential new therapy target for endometriosis-related pain. SIGNIFICANCE: The present study demonstrated (1) the presence and the function of the BK system in endometriosis, (2) activation of BKR induced endothelin-1 in endometriotic lesion and (3) blocking endothelin-1 was effective to decrease pain.

Transgenic expression of replication-restricted enteroviral genomes in heart muscle induces defective excitation-contraction coupling and dilated cardiomyopathy.

Numerous studies have implicated Coxsackievirus in acute and chronic heart failure. Although enteroviral nucleic acids have been detected in selected patients with dilated cardiomyopathy, the significance of such persistent nucleic acids is unknown. To investigate the mechanisms by which restricted viral replication with low level expression of Coxsackieviral proteins may be able to induce cardiomyopathy, we generated transgenic mice which express a replication-restricted full-length Coxsackievirus B3 (CVB3) cDNA mutant (CVB3DeltaVP0) in the heart driven by the cardiac myocyte-specific myosin light chain-2v (MLC-2v) promoter. CVB3DeltaVP0 was generated by mutating infectious CVB3 cDNA at the VP4/VP2 autocatalytic cleavage site from Asn-Ser to Lys-Ala. Cardiac-specific expression of this cDNA leads to synthesis of positive- and negative-strand viral RNA in the heart without formation of infectious viral progeny. Histopathologic analysis of transgenic hearts revealed typical morphologic features of myocardial interstitial fibrosis and in some cases degeneration of myocytes, thus resembling dilated cardiomyopathy in humans. There was also an increase in ventricular atrial natriuretic factor mRNA levels, demonstrating activation of the embryonic program of gene expression typical of ventricular hypertrophy and failure. Echocardiographic analysis demonstrated the presence of left ventricular dilation and decreased systolic function in the transgenic mice compared with wild-type littermates, evidenced by increased ventricular end-diastolic and end-systolic dimensions and decreased fractional shortening. Analysis of isolated myocytes from transgenic mice demonstrate that there is defective excitation-contraction coupling and a decrease in the magnitude of isolated cell shortening. These data demonstrate that restricted replication of enteroviral genomes in the heart can induce dilated cardiomyopathy with excitation-contraction coupling abnormalities similar to pressure overload models of dilated cardiomyopathy.

Efficacy of rabeprazole on heartburn symptom resolution in patients with non-erosive and erosive gastro-oesophageal reflux disease: a multicenter study from Japan.

BACKGROUND: Few studies have compared the efficacy of proton pump inhibitors in resolving the symptoms of non-erosive reflux disease (NERD) and of erosive gastro-oesophageal reflux disease (GERD) in Japan. AIM: To investigate and compare the efficacy of 4-week course of rabeprazole 10 mg/day on symptom resolution in NERD and erosive GERD in Japan. METHODS: The modified Los Angeles classification was used to grade endoscopically GERD in patients with heartburn (Grades N and M: NERD, Grades A and B: mild reflux oesophagitis (RO), and Grades C and D: severe RO). Rabeprazole 10 mg/day was administered for 4 weeks to 180 patients who kept symptom diaries. RESULTS: Complete relief of the symptoms was achieved in 35.8% of the NERD group and 55.4% of the erosive GERD group (mild RO: 51.1% and severe RO: 77.8%). Rabeprazole was significantly more effective in erosive GERD than in NERD patients. Among the NERD subgroups (Grades N and M), no difference in symptom improvement was observed. CONCLUSIONS: Four-week, rabeprazole 10 mg/day acid suppression therapy was effective in resolving symptoms in Japanese GERD patients. This therapy was more effective in erosive GERD than in NERD patients, and in those with severe RO than in those with mild RO.

Effect of alpha-helical CRH on quantitative electroencephalogram in patients with irritable bowel syndrome.

Patients with irritable bowel syndrome (IBS) may have a higher tone of corticotropin-releasing hormone (CRH) in the brain. We tested our hypothesis that peripheral administration of CRH antagonist, alpha-helical CRH(9-41) (alphahCRH), improves decreased alpha power spectra and increased beta power spectra of electroencephalogram (EEG) in IBS patients. A barostat bag was inserted to the descending colon of 10 normal controls and 10 IBS patients. The EEG power spectra and topography were measured during baseline period and colonic distention period with the administration of saline followed by the administration of 10 microg kg(-1) of alphahCRH. IBS patients showed a significantly lower alpha power percentage and a higher beta power percentage than normal controls during baseline. Colonic distention induced a decrease in the alpha power percentage and an increase in the beta power percentage in both groups without difference between groups. After the administration of alphahCRH, changes in the EEG power spectra in response to colonic distention were blunted and the differences in the EEG power spectra between IBS patients and controls vanished. Peripheral administration of alphahCRH almost normalized EEG activities in IBS patients. Our data strongly suggest that CRH plays an important role in IBS.

Optimal dose of ramosetron in female patients with irritable bowel syndrome with diarrhea: A randomized, placebo-controlled phase II study.

BACKGROUND: Previous studies showed that 5 µg of ramosetron, a serotonin (5-hydroxytryptamine: 5-HT)-3 receptor antagonist, is only effective in male patients with irritable bowel syndrome (IBS) with diarrhea (IBS-D). We hypothesized that either dose 1.25, 2.5, or 5 µg of ramosetron would be effective in female patients with IBS-D. METHODS: This randomized, double-blind, placebo-controlled, phase II dose-finding exploratory trial included 409 female outpatients with IBS-D treated in Japan. They were administered oral placebo (n=102), or 1.25 µg (n=104), 2.5 µg (n=104), or 5 µg (n=99) of ramosetron once daily for 12 weeks after a 1-week baseline period. The primary endpoint was monthly responder rates of global improvement of IBS symptoms in the first month. Secondary endpoints included global improvement in the other months, abdominal pain/discomfort, weekly mean changes in the Bristol Stool Form Scale (BSFS), and IBS-QOL. KEY RESULTS: Middle dose (2.5 µg) of ramosetron significantly improved abdominal pain/discomfort at second month (62.5%, P=.002), third month (60.6%, P=.005), and the last evaluation point (63.5%, P=.002) and weekly BSFS (P<.05) except at Week 8, 11, and 12 than placebo. IBS-QOL did not change. Ramosetron induced more constipation than placebo. CONCLUSIONS & INFERENCES: The trial suggested that 2.5 µg of ramosetron is the most effective and least harmful option for treating female patients with IBS-D (Clinicaltrials.gov ID: NCT01274000).

Progressive cardiac dysfunction and fibrosis in the cardiomyopathic hamster and effects of growth hormone and angiotensin-converting enzyme inhibition.

BACKGROUND: Growth hormone (GH) improves cardiac function in the rat with myocardial infarction, but its effects in a model of primary dilated cardiomyopathy have not been reported. GH effects were examined at early (4 months) and late (10 months) phases of disease in the cardiomyopathic (CM) hamster, and the combination of GH with chronic ACE inhibition was assessed in late-phase heart failure. METHODS AND RESULTS: CM hamsters (CHF 147 line) at 4 months showed severe systolic left ventricular (LV) dysfunction with normal LV filling pressure, and at 10 months there was more severe systolic as well as diastolic dysfunction with increasing myocardial fibrosis. Recombinant human GH alone for 3 weeks at age 4 months increased LV wall thickness and reduced systolic wall stress without altering diastolic wall stress, whereas at 10 months, wall stress and fractional shortening did not improve. The LV dP/dt(max) was enhanced at both ages by GH, which at 4 months reflected increased contractility, but at 10 months was most likely caused by elevation of the LV filling pressure. The increasing degree of fibrosis correlated inversely with LV function but was unaffected by GH. In other CM hamsters, high-dose ACE inhibition alone (quinapril), started at 8 months and continued for 11 weeks, improved LV function and inhibited unfavorable remodeling, but the addition of GH for 3 weeks at age 10 months produced increased wall thickness with little additional functional benefit and increased the LV filling pressure and diastolic wall stress. CONCLUSIONS: GH treatment alone improved LV dysfunction at 4 months of age in CM hamsters by increasing contractility and reducing wall stress but had few beneficial effects at 10 months in severe LV failure. After chronic ACE inhibition, addition of GH at 10 months had no additional beneficial effects and further increased LV diastolic pressure. These differing effects of GH may relate to the progressive increase of LV fibrosis in the CM hamster.

Radionuclide angiographic assessment of left ventricular diastolic filling in amyloid heart disease: a study of patients with familial amyloid polyneuropathy.

To assess left ventricular diastolic filling in amyloid heart disease, 17 patients with familial amyloid polyneuropathy and 20 normal subjects were examined by radionuclide angiography. None of the patients showed clinical evidence of restrictive cardiomyopathy. All but two patients had normal left ventricular ejection fraction. Peak filling rate was significantly lower and time to peak filling rate was significantly greater in patients than in normal subjects (2.60 +/- 0.52 versus 3.10 +/- 0.44 EDV/s, p less than 0.001, and 215 +/- 53 versus 147 +/- 18 ms, p less than 0.001, respectively). The mean left ventricular filling volume during rapid diastolic filling and atrial systole in patients was 54.5 +/- 19.5% and 44.2 +/- 21.6% of the stroke volume, respectively, compared with 83.8 +/- 6.6% (p less than 0.001) and 20.0 +/- 6.0% (p less than 0.001), respectively, in normal subjects. Although 10 of the 14 patients without clinical evidence of overt heart disease had normal ventricular wall thickness as well as normal ejection fraction, 8 of the 10 showed abnormal diastolic filling. In patients with familial amyloid polyneuropathy, indexes of diastolic filling were significantly related to ventricular wall thickness alone. The incidence and magnitude of abnormalities in time to peak filling rate and contribution of rapid filling as well as atrial systole to ventricular filling increased with age and duration of illness. Thus, abnormal diastolic filling can be seen even in the early stage of familial amyloid polyneuropathy and may be related to myocardial amyloid deposition as well as to fibrosis. Careful consideration should be given to age and duration of illness when diastolic filling is assessed in this disorder.

Iodine-123 metaiodobenzylguanidine scintigraphic assessment of myocardial sympathetic innervation in patients with familial amyloid polyneuropathy.

OBJECTIVES: This study attempted to assess myocardial sympathetic innervation using iodine-123 (I-123) metaidobenzylguanidine (MIBG) imaging in patients with familial amyloid polyneuropathy. BACKGROUND: Signs and symptoms of cardiac autonomic dysfunction are commonly seen in patients with cardiac amyloidosis. However, the incidence and magnitude of abnormalities in myocardial sympathetic nerve function by means of I-123 MIBG imaging and their relation to clinical findings, cardiac function and the results of thallium-201 (Tl-201) and technetium-99m pyrophosphate (Tc-99m PYP) myocardial scanning have not yet been clarified. METHODS: We performed M-mode, two-dimensional and Doppler echocardiography and I-123 MIBG, Tl-201 and Tc-99m PYP imaging of the heart in 12 patients with familial amyloid polyneuropathy and biopsy-proved cardiac amyloidosis. RESULTS: Ten of 12 patients had no clinical evidence of overt heart disease, but left ventricular (LV) wall thickening was observed in 4 of these 10. Left ventricular percent fractional shortening and Doppler transmitral flow velocity patterns were found to be normal in all 12 patients. Eight of 12 patients showed no myocardial MIBG accumulation, with limited uptake in the remaining 4 demonstrated only in the LV anterior wall. Diffuse but mild myocardial uptake of Tc-99m PYP occurred in only 4 of 12 patients, and all 12 had normal results on Tl-201 myocardial scanning. Complete defects on myocardial MIBG scans were found in five of eight patients with negative findings on Tc-99m PYP myocardial scanning. The incidence and magnitude of myocardial uptake of MIBG were independent of clinical findings, extent of endomyocardial amyloid deposition, electrocardiographic QRS voltage and ventricular wall thickness. CONCLUSIONS: Patients with familial amyloid polyneuropathy show a high incidence of myocardial adrenergic denervation with viable myocardium that can be identified very early in cardiac amyloidosis, before the development of clinically apparent heart disease, ventricular wall thickening, significant LV systolic and diastolic dysfunction and positive findings on Tc-99m PYP myocardial scanning.

Primary care in the treatment of functional gastrointestinal symptoms in Japan: prescription preferences and impression of results.

BACKGROUND: Functional gastrointestinal (GI) disorders are common in primary care. However, proper pharmacological approaches have not yet been established. The reason for a lack of proper approaches may be attributable to the lack in clarity of their pathogenesis and pathophysiology. Meta-analysis of pharmacological approaches to functional GI disorders failed to identify the solid cluster of patients' symptoms. AIM: The aim of this study is to assess the perspective of primary care doctors concerning prescriptions for functional GI symptoms, evaluate the efficacy of the drugs prescribed, and the need for medication for these symptoms. METHOD: Questionnaires were sent to primary care doctors, and a total of 149 responses were obtained. Efficacy of each medication was evaluated by the number of doctors favouring the category, and the respective impressions of prescriptions given. RESULTS: Symptoms of heartburn were well controlled by anti-secretory drugs (H2RAs and PPIs), while appetite loss and abdominal gurgling were not controlled by any medications. CONCLUSIONS: This survey reveals differences in need for various prescription drugs in functional GI symptoms.

Animal models of heart failure recent developments and perspectives.

Heart failure is a complex syndrome characterized by inability of the heart to supply sufficient cardiac output to meet the metabolic needs of the body. Over the past few decades, a number of animal models of heart failure have been developed to study questions that cannot be readily studied in the clinical setting. Because the syndrome of heart failure in humans has many underlying causes, ranging from primary myocardial disease (often of unknown etiology) to myocardial failure consequent to ventricular overload with secondary cardiac hypertrophy (as in hypertension, valvular heart disease, or myocardial infarction), no single animal model can successfully mimic the pathophysiology of these clinical settings. Regardless of the original cardiac abnormality, however, the end-stage heart failure syndrome generally presents a picture of cardiac dilation and circulatory congestion associated with maladaptive neurohumoral responses affecting the heart and peripheral circulation, which provide prime targets for new treatment strategies. An ideal animal model of heart failure should mimic the clinical setting as closely as possible, be accessible and reproducible, relatively stable under chronic conditions, and sufficiently economical to permit experiments in a large number of animals. In this review, we discuss the advantages and disadvantages of naturally occurring models of heart failure and models in which heart failure is induced in normal animals, focusing in particular on models that are useful for exploring disease mechanisms and interventions to prevent or treat heart failure. Much is being learned from large animals such as the dog and pig, although small animal models (rat and hamster) have many favorable features, and as genetic methods and miniaturized physiologic techniques mature, the mouse is beginning to provide gene-based models of cardiac failure aimed at better understanding of molecular mechanisms. (Trends Cardiovasc Med 1997;7:161-167). © 1997, Elsevier Science Inc.

Urocortin and corticotropin-releasing factor receptor expression in normal cycling human ovaries.

Urocortin is a member of the CRF neuropeptide family and has a 43% homology to CRF in amino acid sequence. Urocortin has been found to bind with high affinity to CRF receptors. CRF has been detected in the human ovary and has been demonstrated to suppress ovarian steroidogenesis in vitro. In this study we examined urocortin and CRF receptor expression in normal cycling human ovaries, using immunohistochemistry and RT-PCR. Normal cycling human ovaries were obtained at oophorectomy and hysterectomy from patients who underwent surgery for cervical cancer or myoma uteri. Intense urocortin immunoreactivity was detected in luteinized thecal cells of regressing corpora lutea, in which only luteinized thecal cells have the capacity for steroidogenesis. Immunoreactive urocortin was also detected in luteinized granulosa and thecal cells of functioning corpora lutea, in which both cell components are capable of producing steroids. RT-PCR analyses revealed that messenger ribonucleic acid levels for urocortin, CRF, and CRF receptor type 1 and type 2alpha were significantly higher in the regressing corpus luteum than in the functioning corpus luteum. The spatial and temporal immunolocalization patterns of CRF receptor were similar to those of urocortin. These results suggest that urocortin is locally synthesized in steroidogenic luteal cells and acts on them as an autocrine and/or paracrine regulator of ovarian steroidogenesis, especially during luteal regression.