Genomic and clinical characterization of a familial GIST kindred intolerant to imatinib.

Familial gastrointestinal stromal tumors (GIST) are rare. We present a kindred with multiple family members affected with multifocal GIST who underwent whole genome sequencing of the germline and tumor. Affected individuals with GIST harbored a germline variant found within exon 13 of the KIT gene (c.1965T>G; p.Asn655Lys, p.N655K) and a variant in the MSR1 gene (c.877 C > T; p.Arg293*, pR293X). Multifocal GISTs in the proband and her mother were treated with preoperative imatinib, which resulted in severe intolerance. The clinical features of multifocal GIST, cutaneous mastocytosis, allergies, and gut motility disorders seen in the affected individuals may represent manifestations of the multifunctional roles of KIT in interstitial cells of Cajal or mast cells and/or may be suggestive of additional molecular pathways which can contribute to tumorigenesis.

Street-level diplomacy and local enforcement for meat safety in northern Tanzania: knowledge, pragmatism and trust.

BACKGROUND: With increasing demand for red meat in Tanzania comes heightened potential for zoonotic infections in animals and humans that disproportionately affect poor communities. A range of frontline government employees work to protect public health, providing services for people engaged in animal-based livelihoods (livestock owners and butchers), and enforcing meat safety and food premises standards. In contrast to literature which emphasises the inadequacy of extension support and food safety policy implementation in low- and middle-income countries, this paper foregrounds the 'street-level diplomacy' deployed by frontline actors operating in challenging contexts. METHODS: This research is based on semi-structured interviews with 61 government employees, including livestock extension officers/meat inspectors and health officers, across 10 randomly-selected rural and urban wards. RESULTS: Frontline actors combined formal and informal strategies including the leveraging of formal policy texts and relationships with other state employees, remaining flexible and recognising that poverty constrained people's ability to comply with health regulations. They emphasised the need to work with livestock keepers and butchers to build their knowledge to self-regulate and to work collaboratively to ensure meat safety. Remaining adaptive and being hesitant to act punitively unless absolutely necessary cultivated trust and positive relations, making those engaged in animal-based livelihoods more open to learning from and cooperating with extension officers and inspectors. This may result in higher levels of meat safety than might be the case if frontline actors stringently enforced regulations. CONCLUSION: The current tendency to view frontline actors' partial enforcement of meat safety regulations as a failure obscures the creative and proactive ways in which they seek to ensure meat safety in a context of limited resources. Their application of 'street-level diplomacy' enables them to be sensitive to local socio-economic realities, to respect local social norms and expectations and to build support for health safety interventions when necessary. More explicitly acknowledging the role of trust and positive state-society relations and the diplomatic skills deployed by frontline actors as a formal part of their inspection duties offers new perspectives and enhanced understandings on the complicated nature of their work and what might be done to support them.

Measuring Glymphatic Flow in Man Using Quantitative Contrast-Enhanced MRI.

On the basis of animal models, glymphatic flow disruption is hypothesized to be a factor in the development of Alzheimer's disease. We report the first quantitative study of glymphatic flow in man, combining intrathecal administration of gadobutrol with serial T1 mapping to produce contrast concentration maps up to 3 days postinjection, demonstrating performing a quantitative study using the techniques described feasibility and providing data on pharmacokinetics.

One Health contributions towards more effective and equitable approaches to health in low- and middle-income countries.

Emerging zoonoses with pandemic potential are a stated priority for the global health security agenda, but endemic zoonoses also have a major societal impact in low-resource settings. Although many endemic zoonoses can be treated, timely diagnosis and appropriate clinical management of human cases is often challenging. Preventive 'One Health' interventions, e.g. interventions in animal populations that generate human health benefits, may provide a useful approach to overcoming some of these challenges. Effective strategies, such as animal vaccination, already exist for the prevention, control and elimination of many endemic zoonoses, including rabies, and several livestock zoonoses (e.g. brucellosis, leptospirosis, Q fever) that are important causes of human febrile illness and livestock productivity losses in low- and middle-income countries. We make the case that, for these diseases, One Health interventions have the potential to be more effective and generate more equitable benefits for human health and livelihoods, particularly in rural areas, than approaches that rely exclusively on treatment of human cases. We hypothesize that applying One Health interventions to tackle these health challenges will help to build trust, community engagement and cross-sectoral collaboration, which will in turn strengthen the capacity of fragile health systems to respond to the threat of emerging zoonoses and other future health challenges. One Health interventions thus have the potential to align the ongoing needs of disadvantaged communities with the concerns of the broader global community, providing a pragmatic and equitable approach to meeting the global goals for sustainable development and supporting the global health security agenda.This article is part of the themed issue 'One Health for a changing world: zoonoses, ecosystems and human well-being'.

Straelensiosis in two cats and ten dogs from Israel.

Straelensiosis is uncommonly described outside Europe. This report describes straelensiosis in two cats and in ten dogs diagnosed with the disease outside Europe. Both cats displayed erythematous macules or nodules on the abdominal skin. One cat was extremely pruritic, while in the other the lesions were incidental findings when the cat was presented for neutering. The mites were noted in skin scrapings in both cats and histopathologically in one cat. All dogs showed a general distribution of papules, and intense pruritus was noted in six dogs. The diagnosis in all dogs was based on histopathology. Treatment of the animals in this study varied, and among the various administrated treatments, amitraz showed promising results.

Qualitative development of a patient-reported outcome symptom measure in diarrhea-predominant irritable bowel syndrome.

OBJECTIVES: Despite a documented clinical need, no patient reported outcome (PRO) symptom measure meeting current regulatory requirements for clinically relevant end points is available for the evaluation of treatment benefit in diarrhea-predominant IBS (IBS-D). METHODS: Patients (N=113) with IBS-D participated in five study phases: (1) eight concept elicitation focus groups (N=34), from which a 17-item IBS-D Daily Symptom Diary and four-item IBS-D Symptom Event Log (Diary and Event Log) were developed; (2) one-on-one cognitive interviews (N=11) to assess the instrument's comprehensiveness, understandability, appropriateness, and readability; (3) four data triangulation focus groups (N=32) to confirm the concepts elicited; (4) two hybrid (concept elicitation and cognitive interview) focus groups (N=16); and (5) two iterative sets of one-on-one cognitive interviews (N=20) to further clarify the symptoms of IBS-D and debrief a revised seven-item Diary and four-item Event Log. RESULTS: Of thirty-six concepts initially identified, 22 were excluded because they were not saturated, not clinically relevant, not critical symptoms of IBS-D, considered upper GI symptoms, or too broad or vaguely defined. The remaining concepts were diarrhea, immediate need (urgency), bloating/pressure, frequency of bowel movements, cramps, abdominal/stomach pain, gas, completely emptied bowels/incomplete evacuation, accidents, bubbling in intestines (bowel sounds), rectal burning, stool consistency, rectal spasm, and pain while wiping. The final instrument included a daily diary with separate items for abdominal and stomach pain and an event log with four items completed after each bowel movement as follows: (1) a record of the bowel movement/event and an assessment of (2) severity of immediacy of need/bowel urgency, (3) incomplete evacuation, and (4) stool consistency (evaluated using the newly developed Astellas Stool Form Scale). Based on rounds of interviews and clinical input, items considered secondary or nonspecific to IBS-D (rectal burning, bubbling in intestines, spasms, and pain while wiping) were excluded. CONCLUSIONS: The IBS-D Symptom Diary and Event Log represent a rigorously developed PRO instrument for the measurement of the IBS-D symptom experience from the perspective of the patient. Its content validity has been supported, and future work should evaluate the instrument's psychometric properties.

Emergency contraception: prescribing practices of general internists compared with other primary care physicians.

Primary care physicians of all specialties should be familiar with prescribing emergency contraception (EC). We conducted a mail survey of 282 randomly sampled physicians in general internal medicine (31%), family medicine (34%) and obstetrics-gynecology (35%). Experience with prescribing EC significantly differed by specialty (63% of general internists, 76% of family physicians, and 94% of obstetrician-gynecologists, p < 0.0001). Controlling for year of graduation, gender, religion and practice location, family physicians [adjusted odds ratio (OR): 2.5, 95% confidence interval (CI): 1.2-5.2] and obstetrician-gynecologists (adjusted OR: 11.2, 95% CI: 4.0-31.3) were still significantly more likely to have ever prescribed EC than general internists. Efforts to increase awareness and knowledge of EC should be aimed at general internists since they provide primary care for many reproductive age women.

Potential novel targets for Alzheimer pharmacotherapy: I. Secretases.

The prevailing major theory of Alzheimer's disease (AD) is that insoluble amyloid beta-peptide (Abeta) found in the cerebral plaques characteristic of the disease is causative or is at least a contributing factor. According to this theory, inhibition of aberrant Abeta production should prevent or at least limit the extent of AD pathophysiology. As three 'secretase' enzymes (alpha, beta and gamma) catalyse the proteolytic cleavage of amyloid precursor protein (APP) (the precursor protein of Abeta), one or more secretases have become targets for potential novel AD pharmacotherapy. Secretase inhibitors have been designed and are in various stages of development. The clinical trials of these compounds will, if positive, result in drugs with dramatically better clinical efficacy or, if negative, will force a reassessment of the theory about the role of Abeta in AD.

Myomectomy fever: testing the dogma.

OBJECTIVE: To test the hypothesis that elevated temperature is more common after abdominal myomectomy than after hysterectomy. DESIGN: Retrospective cohort study. SETTING: Academic medical center. PATIENT(S): One hundred one women who underwent abdominal myomectomy and 160 women who underwent total abdominal hysterectomy for benign disease from 1988-1993. INTERVENTION(S): Abdominal myomectomy. MAIN OUTCOME MEASURE(S): Temperature of > or = 38.5 degrees C within 48 hours after operation. RESULT(S): Although univariate analysis showed that the incidence of elevated temperature was slightly greater among patients who underwent myomectomy (33% versus 26%, relative risk 1.29, 95% confidence interval 0.88-1.90), multivariate logistic regression analysis showed a 3.29 relative risk of elevated temperature (95% confidence interval 1.56-6.96) with myomectomy after controlling for age, parity, estimated blood loss, and treatment by the general gynecology service. CONCLUSION(S): After controlling for confounders, myomectomy was found to be an independent predictor for fever in the first 48 hours after operation.

Regional myocardial perfusion and mechanics: a model-based method of analysis.

A new parametric model-based method has been developed that allows epicardial strain distributions to be computed on the left ventricular free wall in normal and ischemic myocardium and integrated with the regional distributions of anatomic and physiological measurements so that underlying relationships can be explored. An array of radiopaque markers was sewn on the anterior wall of the left ventricle (LV) in three anesthetized open-chest canines, and their positions were recorded using biplane video fluoroscopy before and 2 min after occlusion of the left anterior descending coronary artery. The three-dimensional (3D) anatomy of the LV and epicardial fiber angles were measured post-mortem using a 3D probe. A prolate spheroidal finite element model was fitted to the epicardial surface points (with <0.2 mm accuracy) and fiber angles (<5 degrees error). Regional myocardial blood flows (MBFs) were measured using fluorescent microspheres and fitted into the model (<0.3 ml min(-1) g(-1) error). Epicardial fiber and cross-fiber strain distributions were computed by allowing the model to deform from end-diastole to end-systole according to the recorded motion of the surface markers. Systolic fiber strain varied from -0.05 to 0.01 within the region of the markers during baseline, and regional MBF varied from 1.5 to 2.0 ml min(-1) g(-1). During 2 min ischemia, regional MBF was less than 0.3 ml min(-1) g(-1) in the ischemic region and 1.0 ml min(-1) g(-1) in the nonischemic region, and fiber strain ranged from 0.05 in the central ischemic zone to -0.025 in the remote nonischemic tissue. This analysis revealed a zone of impaired fiber shortening extending into the normally perfused myocardium that was significantly wider at the base than the apex. A validation analysis showed that a regularizing function can be optimized to minimize both fitting errors and numerical oscillations in the computed strain fields.

A three-dimensional finite element method for large elastic deformations of ventricular myocardium: I--Cylindrical and spherical polar coordinates.

A three-dimensional Galerkin finite element method was developed for large deformations of ventricular myocardium and other incompressible, nonlinear elastic, anisotropic materials. Cylindrical and spherical elements were used to solve axisymmetric problems with r.m.s. errors typically less than 2 percent. Isochoric interpolation and pressure boundary constraint equations enhanced low-order curvilinear elements under special circumstances (69 percent savings in degrees of freedom, 78 percent savings in solution time for inflation of a thick-walled cylinder). Generalized tensor products of linear Lagrange and cubic Hermite polynomials permitted custom elements with improved performance, including 52 percent savings in degrees of freedom and 66 percent savings in solution time for compression of a circular disk. Such computational efficiencies become significant for large scale problems such as modeling the heart.

A three-dimensional finite element method for large elastic deformations of ventricular myocardium: II--Prolate spheroidal coordinates.

A three-dimensional finite element method for nonlinear finite elasticity is presented using prolate spheroidal coordinates. For a thick-walled ellipsoidal model of passive anisotropic left ventricle, a high-order (cubic Hermite) mesh with 3 elements gave accurate continuous stresses and strains, with a 69 percent savings in degrees of freedom (dof) versus a 70-element standard low-order model. A custom mixed-order model offered 55 percent savings in dof and 39 percent savings in solution time compared with the low-order model. A nonsymmetric 3D model of the passive canine LV was solved using 16 high-order elements. Continuous nonhomogeneous stresses and strains were obtained within 1 hour on a laboratory workstation, with an estimated solution time of less than 4 hours to model end-systole. This method represents the first practical opportunity to solve large-scale anatomically detailed models for cardiac stress analysis.

An equibiaxial strain system for cultured cells.

We developed a device that applies homogeneous equibiaxial strains of 0-10% to a cell culture substrate and quantitatively verified transmission of substrate deformation to cultured cardiac cells. Clamped elastic membranes in both single-well and multiwell versions of the device are uniformly stretched by indentation with a plastic ring, resulting in strain that is directly proportional to the pitch-to-radius ratio. Two-dimensional deformations were measured by tracking fluorescent microspheres attached to the substrate and to cultured adult rat cardiac fibroblasts. For nominal stretches up to 18%, strains along circumferential and radial axes were equal in magnitude and homogeneously distributed with negligible shear. For 5% stretch, circumferential and radial strains in the substrate were 0.046 +/- 0.005 and 0.048 +/- 0.004 [not significant (NS)], respectively, and shear strain was 0.001 +/- 0.003 (NS). Calibration of both single-well and multiwell versions permits strain selection by device rotation. The reproducible application and quantification of homogeneous equibiaxial strain in cultured cells provides a quantitative approach for correlating mechanical stimuli to cellular transduction mechanisms.

Relative morbidity of abdominal hysterectomy and myomectomy for management of uterine leiomyomas.

OBJECTIVE: To compare the morbidity of total abdominal hysterectomy and abdominal myomectomy in the surgical management of uterine leiomyomas. METHODS: Hospital records were reviewed for all women who underwent hysterectomy (n = 89) or myomectomy (n = 103) between May 1, 1988, and May 1, 1993, for the preoperative diagnosis of leiomyoma. RESULTS: There were significant differences between the two groups for average age (hysterectomy 39.2 years, myomectomy 34.4 years; mean difference 4.8, 95% confidence interval [CI] of difference 3.7-5.9), uterine size (hysterectomy 15.2, myomectomy 11.5 weeks; mean difference 3.8, 95% CI of difference 2.0-5.4) and use of a GnRH agonist (hysterectomy 23.6%, myomectomy 55.3%; relative risk [RR] 0.4, 95% CI 0.3-0.6). Myomectomy was associated with decreased estimated blood loss (hysterectomy 796 mL, myomectomy 464 mL; mean difference 331, 95% CI 121-542) and febrile morbidity (risk of temperature 38C or 48 or more hours postoperatively: for hysterectomy 49.4%, for myomectomy 32%; RR 1.5, 95% CI 1.1-2.2). Using multivariate linear regression, estimated blood loss was similar between the groups after controlling for uterine size. There was no difference in blood transfusion rates. There were two ureteral, one bladder, one bowel, and one femoral nerve injury in the hysterectomy group, and there were no intraoperative visceral injuries in the myomectomy group. CONCLUSION: Myomectomy compares favorably to hysterectomy in the surgical management of leiomyomas, with a possible decreased risk for visceral injury and infection.

Comparison of two techniques for measuring two-dimensional strain in rat left ventricles.

Measurements of regional deformation in the left ventricle are needed to understand the structural basis of ventricular function. Two techniques were employed to measure two-dimensional strain in the intact, beating rat heart. Rats were anesthetized and ventilated, and the chest of each rat was opened. Homogeneous two-dimensional strains were measured during the cardiac cycle relative to end diastole with either a triangle of miniature (0.3-0.5 mm) piezoelectric crystals implanted at midwall or with three epicardial surface markers imaged with a 60-Hz video system. Average heart rate was 303 +/- 37 beats/min, end-diastolic pressure was 2 +/- 2 mmHg, and peak-systolic pressure was 106 +/- 31 mmHg in all of the hearts. In general, strains during the cardiac cycle showed similar trends to those previously reported in the dog. The magnitudes of peak systolic cardiac strains on the epicardium and at midwall were -0.076 +/- 0.055, -0.068 +/- 0.014 (circumferential), -0.102 +/- 0.040, -0.082 +/- 0.039 (longitudinal), and 0.065 +/- 0.016, 0.064 +/- 0.043 (in-plane shear). There were mechanical side effects due to the crystal implantation that may limit the usefulness of this technique in its present form in the contracting rat heart. The epicardial surface technique does not have these side effects and will allow measurements of regional systolic cardiac function in rats with pathological interventions or genetic modifications that may alter regional ventricular function.

Distributed mechanics of the canine right ventricle: effects of varying preload.

Fundamental questions in the mechanics of the right ventricle (RV) include: what are the distributions of diastolic and systolic strains across the RV epicardium and how do these strains change with increasing preload? Arrays (approximately 4 x 4 cm) of 25 to 30 lead markers were sutured to the epicardium of the RV anterior free wall in 6 open-chest, anesthetized dogs. Biplane cinéradiography (16 mm, 120 fps) was used to track marker positions throughout the cardiac cycle as loading conditions were altered by intravenous volume infusion. Continuous two-dimensional nonhomogeneous deformations were estimated across the region by fitting high-order finite element surfaces to the three-dimensional marker coordinates in successive ciné frames. End-systolic strains referred to end-diastole did not change with increasing preload, but did exhibit considerable longitudinal variation, e.g. the principal strain associated with maximal shortening (E1) was more than twice as great nearer the apex (E1 = -0.18 +/- 0.08) than in more basal (E1 = -0.09 +/- 0.05) regions. However, large amounts of lengthening occurred during diastolic inflation. End-diastolic extensional strains referred to an unloaded configuration were moderate at low pressure (E2 = 0.13 +/- 0.08) but increased to large values at high preloads (E2 = 0.28 +/- 0.11). End-diastolic strains also showed considerable longitudinal variation, i.e. near the base lengthening (E2 = 0.31 +/- 0.13) tended to be much greater than near the apex (E2 = 0.15 +/- 0.12). These results indicate that both diastolic sarcomere lengths and systolic sarcomere shortening increase in proportion to diastolic loading leaving end-systolic sarcomere strains unchanged.

Seasonal flank alopecia in affenpinschers.

Two intact, distantly related, female affenpinschers, belonging to a breeder, were referred in March 1993 for the investigation of bilateral, symmetrical flank alopecia in one bitch and bilateral, symmetrical flank, dorsum and tail alopecia in the other; the alopecia occurred from November to May and January to May, respectively. During that period the bitches were kept in a conservatory without artificial heating or lighting. The owner reported that the mother of one bitch had had bilateral, symmetrical flank alopecia during one winter when kept in the conservatory, but was normal the following winter when kept in the house. Three other females and a male exhibited the same clinical signs when kept in the conservatory during the winter. Seasonal flank alopecia has not previously been reported in affenpinschers.

Effect of coronary artery reperfusion on transmural myocardial remodeling in dogs.

BACKGROUND: The effects of reperfusion after coronary occlusion on transmural remodeling of the ischemic region early and late after nontransmural infarction must importantly affect the recovery of regional function. Accordingly, analysis of local volume and three-dimensional strain was performed using a finite element method to determine regional remodeling. Systolic and remodeling strains were measured using radiographic imaging of three columns (approximately 1 cm apart) of four to six gold beads implanted across the left ventricular posterior wall in 6 dogs. METHODS AND RESULTS: After a control study, infarction was produced by 2 to 4 hours of proximal left circumflex coronary artery occlusion followed by reperfusion. Follow-up studies were performed at 2 days, 3 weeks, and 12 weeks with the dogs under anesthesia and in closed-chest conditions. Biplane cineradiography was performed to obtain the three-dimensional coordinates of the beads. At 2 days, end-systolic strains were akinetic with loss of normal transmural gradients of shortening and thickening. Remodeling strains (RS) were determined by use of a nonhomogeneous finite element method by referring the end-diastolic configuration during follow-up studies to its control state at matched end-diastolic pressures and heart rates. Tissue volume at 2 days increased substantially, more at the endocardium (30 +/- 7%) than at the epicardium (5 +/- 12%, P < .01); the increase was associated with an average RS in the wall-thickening direction of 0.18 +/- 0.15 (P < .01) with all other RS near zero. At 12 weeks systolic function partially recovered, with normal wall thickening in the epicardium (radial strain, 0.081 +/- 0.056 [control] versus 0.113 +/- 0.088 [12 weeks]) but with dysfunction in the endocardium (0.245 +/- 0.108 [control] versus 0.111 +/- 0.074 [P < .01] [12 weeks]). This inability of the inner wall to recover function may be related to increased transmural torsional shear and negative longitudinal-radial transverse shear in the inner wall. Volume loss occurred at 12 weeks in the endocardium (-36 +/- 16%) corresponding to transmural gradients in longitudinal RS and both transverse shear RS. Negative longitudinal RS was greater at the endocardium (-0.20 +/- 0.10) than at the epicardium (-0.06 +/- 0.05, P < .01). CONCLUSIONS: These results indicate the presence of marked subendocardial edema 2 days after reperfusion following 2 to 4 hours of coronary occlusion. At 3 months after reperfusion, however, there was volume loss in the inner wall due to shrinkage along the myofiber direction with reduced transmural function and loss of longitudinal shortening, while both tissue volume and function recovered completely in the outer wall.

Gradients of epicardial strain across the perfusion boundary during acute myocardial ischemia.

To study the mechanical interaction between acutely ischemic and adjacent perfused myocardium, nonhomogeneous distributions of end-systolic epicardial strain were measured using an array of radiopaque beads sewn on the left ventricular free wall of the pig during complete left circumflex coronary artery occlusion. The midwall perfusion boundary, demarcated by postmortem dye injection, was reconstructed over the span of the epicardial array. During ischemia, circumferential and longitudinal shortening remained significantly depressed up to 13 mm outside the ischemic region near the base of the ventricle, up to 8-9 mm at the midventricle, but only 0-1 mm near the apex (P < 0.05). Gradients of circumferential and longitudinal strain across the boundary were significantly different during both baseline conditions and acute ischemia (P = 0.0001). However, gradients of the change in the strain from baseline to ischemia were not different for the two components. These results support the concept that direction-dependent differences in the strain gradients across the boundary during ischemia were due to the preservation of the baseline regional variations of strain combined with a loss of systolic function in the ischemic region.

Scar remodeling and transmural deformation after infarction in the pig.

BACKGROUND: Changes in stress and tissue material properties have been proposed as important mechanical factors that may influence infarct expansion and subsequent healing. Because such changes will be reflected by alterations in the finite deformation of the tissue, we examined the direction and magnitude of myocardial deformation after coronary ligation in the pig. METHODS AND RESULTS: Gold beads were implanted in the left ventricular free wall of five pigs. After ligation of the coronary supply to the region containing the markers, we used biplane cineradiography to reconstruct the three-dimensional deformations of the myocardium during single cardiac cycles as well as the remodeling deformations that occurred over time. Deformations were studied at 1 and 3 weeks after infarction. The analysis of single cardiac cycles revealed permanent loss of systolic shortening immediately after ligation. However, significant passive systolic wall thickening (P < .001) and large shears were observed at 3 weeks in regions composed almost entirely of collagen. The analysis of remodeling deformations at 1 week revealed infarct expansion with a predominant axis that varied widely. At 3 weeks, a 30% to 60% reduction in local tissue volume was measured in the infarct region, with the principal direction of scar shrinkage nearly circumferential in all animals (range, -2 degrees to 35 degrees). CONCLUSIONS: We conclude that infarct expansion and scar shrinkage may be controlled by different factors. In addition, we conclude that measurement of systolic wall thickening alone is not always adequate to assess postinfarction regional contractile function.