Latent Rheumatic Heart Disease: Outcomes 2 Years After Echocardiographic Detection

Screening with portable echocardiography has uncovered a large burden of latent rheumatic heart disease (RHD) among asymptomatic children in endemic regions, the significance of which remains unclear. This study aimed to determine the 2-year outcomes for children with latent RHD diagnosed by echocardiographic screening. Children identified with latent RHD enrolled in a biannual follow-up program. Risk factors for disease persistence and progression were examined. Of 62 children, 51 (82 %) with latent RHD had a median follow-up period of 25 months. Of these 51 children, 17 (33.3 %) reported an interval sore throat or symptoms consistent with acute rheumatic fever (ARF). Of 43 children initially classified as having borderline RHD, 21 (49 %) remained stable, 18 (42 %) improved (to no RHD) and 4 (10 %) worsened to definite RHD. Of the 8 children initially classified as having definite RHD, 6 (75 %) remained stable, and 2 (25 %) improved to borderline RHD. Two children had confirmed episodes of recurrent ARF, one of which represented the sole case of clinical worsening. The risk factors for disease persistence or progression included younger age (p = 0.05), higher antistreptolysin O titers at diagnosis (p = 0.05), and more morphologic valve abnormalities (p = 0.01). After 2 years, most of the children had a benign course, with 91 % remaining stable or showing improvement. Education may improve recognition of streptococcal sore throat. Longer-term follow-up evaluation, however, is warranted to confirm disease progression and risk factor profile. This could help tailor screening protocols for those at highest risk.     

Spatial aspects of oncogenic signalling determine the response to combination therapy in slice explants from Kras‐driven lung tumours

A key question in precision medicine is how functional heterogeneity in solid tumours informs therapeutic sensitivity. We demonstrate that spatial characteristics of oncogenic signalling and therapy response can be modelled in precision‐cut slices from Kras‐driven non‐small‐cell lung cancer with varying histopathologies. Unexpectedly, profiling of in situ tumours demonstrated that signalling stratifies mostly according to histopathology, showing enhanced AKT and SRC activity in adenosquamous carcinoma, and mitogen‐activated protein kinase (MAPK) activity in adenocarcinoma. In addition, high intertumour and intratumour variability was detected, particularly of MAPK and mammalian target of rapamycin (mTOR) complex 1 activity. Using short‐term treatment of slice explants, we showed that cytotoxic responses to combination MAPK and phosphoinositide 3‐kinase–mTOR inhibition correlate with the spatially defined activities of both pathways. Thus, whereas genetic drivers determine histopathology spectra, histopathology‐associated and spatially variable signalling activities determine drug sensitivity. Our study is in support of spatial aspects of signalling heterogeneity being considered in clinical diagnostic settings, particularly to guide the selection of drug combinations. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

Sonographic evaluation of the size of Achilles tendon: the effect of exercise and dominance of the ankle

This study was undertaken to measure and compare the thickness and cross-sectional area of the Achilles tendon between frequent- and infrequent-exercise subjects, and between the dominant and nondominant ankles in an asymptomatic Chinese population. Interobserver variability in the measurement of the size of Achilles tendon was also evaluated. High-resolution ultrasound (US) examination of Achilles tendons was performed in 40 healthy subjects (20 who frequently exercised, had exercise at least 3 days per week and at least 2 h per session; and 20 who infrequently exercised); their age range was 19 to 25 years. The thickness and cross-sectional area of the Achilles tendons were measured in a transverse scan at the level of medial malleolus. For each subject, the Achilles tendons were measured by five operators to evaluate the interobserver variability in the measurements. The mean thickness and cross-sectional areas of the Achilles tendon in a healthy Chinese population are 5.23 mm(2) and 56.91 mm(2)(2), respectively. The mean thickness of the Achilles tendon of frequent-exercise subjects (dominant ankle 5.43 mm, nondominant ankle 5.38 mm) was significantly greater than that of infrequent-exercise subjects (dominant ankle 5.08 mm, nondominant ankle 5.04 mm) (p < 0.05). The cross-sectional area of the tendons was also larger in frequent-exercise subjects but, whereas a significant result was found in dominant ankles (frequent-exercise subjects 60.46 mm(2)(2), infrequent-exercise subjects 54.71 mm(2)(2)) (p < 0.05), this was not the case for the nondominant ankles (frequent-exercise subjects 57.09 mm(2)(2), infrequent-exercise subjects 55.4 mm(2)(2)) (p > 0.05). In both frequent- and infrequent-exercise subjects, there was no significant difference in the mean thickness and cross-sectional area of Achilles tendon between dominant and nondominant ankles (p > 0.05). There was a high reproducibility in the sonographic measurement of the thickness (68%) and cross-sectional area (81%) of Achilles tendons. Results suggested that exercise would cause increase in the thickness and cross-sectional area of Achilles tendon. Interobserver variability is not significant in the sonographic measurement of Achilles tendons.     

Contractile Dysfunction of Left Ventricular Cardiomyocytes in Patients With Pulmonary Arterial Hypertension

Background

After lung transplantation, increased left ventricular (LV) filling can lead to LV failure, increasing the risk of post-operative complications and mortality. LV dysfunction in pulmonary arterial hypertension (PAH) is characterized by a reduced LV ejection fraction and impaired diastolic function.

Objectives

The pathophysiology of LV dysfunction in PAH is incompletely understood. This study sought to assess the contribution of atrophy and contractility of cardiomyocytes to LV dysfunction in PAH patients.

Methods

LV function was assessed by cardiac magnetic resonance imaging. In addition, LV biopsies were obtained in 9 PAH patients and 10 donors. The cross-sectional area (CSA) and force-generating capacity of isolated single cardiomyocytes was investigated.

Results

Magnetic resonance imaging analysis revealed a significant reduction in LV ejection fraction in PAH patients, indicating a reduction in LV contractility. The CSA of LV cardiomyocytes of PAH patients was significantly reduced (∼30%), indicating LV cardiomyocyte atrophy. The maximal force-generating capacity, normalized to cardiomyocyte CSA, was significantly reduced (∼25%). Also, a reduction in the number of available myosin-based cross-bridges was found to cause the contractile weakness of cardiomyocytes. This finding was supported by protein analyses, which showed an ∼30% reduction in the myosin/actin ratio in cardiomyocytes from PAH patients. Finally, the phosphorylation level of sarcomeric proteins was reduced in PAH patients, which was accompanied by increased calcium sensitivity of force generation.

Conclusions

The contractile function and the CSA of LV cardiomyocytes is substantially reduced in PAH patients. We propose that these changes contribute to the reduced in vivo contractility of the LV in PAH patients.     

Impact of Baby‐Friendly Hospital Practices on Breastfeeding in Hong Kong

Abstract: Background: The World Health Organization (WHO) developed the Baby‐Friendly Hospital Initiative to improve hospital maternity care practices that support breastfeeding. In Hong Kong, although no hospitals have yet received the Baby‐Friendly status, efforts have been made to improve breastfeeding support. The aim of this study was to examine the impact of Baby‐Friendly hospital practices on breastfeeding duration. Methods: A sample of 1,242 breastfeeding mother‐infant pairs was recruited from four public hospitals in Hong Kong and followed up prospectively for up to 12 months. The primary outcome variable was defined as breastfeeding for 8 weeks or less. Predictor variables included six Baby‐Friendly practices: breastfeeding initiation within 1 hour of birth, exclusive breastfeeding while in hospital, rooming‐in, breastfeeding on demand, no pacifiers or artificial nipples, and information on breastfeeding support groups provided on discharge. Results: Only 46.6 percent of women breastfed for more than 8 weeks, and only 4.8 percent of mothers experienced all six Baby‐Friendly practices. After controlling for all other Baby‐Friendly practices and possible confounding variables, exclusive breastfeeding while in hospital was protective against early breastfeeding cessation (OR: 0.61; 95% CI: 0.42–0.88). Compared with mothers who experienced all six Baby‐Friendly practices, those who experienced one or fewer Baby‐Friendly practices were almost three times more likely to discontinue breastfeeding (OR: 3.13; 95% CI: 1.41–6.95). Conclusions: Greater exposure to Baby‐Friendly practices would substantially increase new mothers’ chances of breastfeeding beyond 8 weeks postpartum. To further improve maternity care practices in hospitals, institutional and administrative support are required to ensure all mothers receive adequate breastfeeding support in accordance with WHO guidelines. (BIRTH 38:3 September 2011)     

Pharmacogenomics of metabotropic glutamate receptor subtype 1 and in vivo malignant melanoma formation

We have previously shown that ectopic expression of metabotropic glutamate receptor subtype 1 in melanocytes is essential for both development and in vivo growth of melanoma using newly developed transgenic mice which conditionally express metabotropic glutamate receptor subtype 1 (mGluR1). In this study, we developed conditional transgenic mice, which harbor melanocytes not only in the dermis and hair follicles but also in the epidermis using stem cell factor transgenic mice. Pigmented plaques on the backs, tails, ears or groins of the transgenic mice began to appear 13 weeks after activation of the mGluR1 transgene, and the transgenic mice produced melanomas at a frequency of 100% 36 weeks after transgene activation. Although this transgenic mouse harbors melanocytes in the epidermis, proliferation of melanoma cells took place in the dermis. To elucidate the signals involved in development and growth of melanoma, inhibitors to phospholipase C, protein kinase C and mitogen‐activated protein kinase kinase 1/2, and antagonists to Ca²⁺ and calmodulin were administrated to transgenic mice. Each signal inhibitor to phospholipase, protein kinase C, Ca²⁺ release, calmodulin and mitogen‐activated protein kinase kinase 1/2 inhibited melanoma development. However, once melanoma was developed, the growth of melanoma was dramatically inhibited only by the inhibitor to mitogen‐activated protein kinase kinase 1/2 with partial inhibition by inhibitors to protein kinase C and phospholipase C. This inhibition of melanoma growth was well correlated with the expression of phosphorylated extracellular signal‐regulated kinase 1/2 and Ki‐67. These results indicate that for development of melanoma, activation of every signaling pathway from mGluR1 is required. However, for growth of melanoma, the extracellular signal‐regulated kinase pathway plays a key role.