WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited

Cholangiocarcinoma (CC) is typically diagnosed at an advanced stage and is refractory to surgical intervention and chemotherapy. Despite a global increase in the incidence of CC, little progress has been made toward the development of treatments for this cancer. Here we utilized human tissue; CC cell xenografts; a p53-deficient transgenic mouse model; and a non-transgenic, chemically induced rat model of CC that accurately reflects both the inflammatory and regenerative background associated with human CC pathology. Using these systems, we determined that the WNT pathway is highly activated in CCs and that inflammatory macrophages are required to establish this WNT-high state in vivo. Moreover, depletion of macrophages or inhibition of WNT signaling with one of two small molecule WNT inhibitors in mouse and rat CC models markedly reduced CC proliferation and increased apoptosis, resulting in tumor regression. Together, these results demonstrate that enhanced WNT signaling is a characteristic of CC and suggest that targeting WNT signaling pathways has potential as a therapeutic strategy for CC.     

Transcervical submandibular sialoadenectomy

The submandibular glands are subject to several pathologies that require excision. The most common problem that affects these salivary glands is sialadenitis combined with sialolithiasis. This problem occurs in the submandibular gland 10 times more frequently than it does in the parotid gland. Other illnesses frequently involving the submandibular glands are represented by sialadenosis and benign, malign, and intermediate neoplasms.Diagnosis of any disturbance in the submandibular gland involves both a clinical and instrumental (echography, traditional radiography [ortopantomography] and eventually computed tomography (CT) or magnetic resonance imaging) assessment. Surgery is the usual method of treatment of both chronic sialadenitis and neoplasms in the submandibular gland. A submandibular gland surgical approach can be cervical, intraoral, or endoscopic.The authors present their clinical experience with a total of 40 patients with illnesses involving the submandibular gland treated with submandibular gland excision by a transcervical approach. Their experience suggests that this approach entails a relatively simple procedure, involves low risks for the nerve structure around the gland, permits wide resection margins for neoplasms, and incurs little aesthetic damage.     

Refractory Heart Failure Dependent on Short‐Term Mechanical Circulatory Support: What Next? Heart Transplant or Long‐Term Ventricular Assist Device

Chronic heart failure is a progressive and eventually fatal illness. Although the disease cannot be cured and treatment is symptom oriented, most of the patients benefit from optimum medical treatment. Patients with rapid deterioration in chronic advanced heart failure refractory to medical treatment need inotropic support and may need intra‐aortic balloon pump to maintain circulatory support, which of course cannot be prolonged beyond a certain limit. The outcome of heart transplant and long‐term ventricular assist device (VAD) in such patients is poor. The short‐term mechanical circulatory support (MCS) offered to such patients not only provides effective circulatory support and stabilizes them hemodynamically, but also halts the ensuing or reverts the established end‐organ failure. As the name suggests, the short‐term MCS offers support for the short term, usually less than a month. Although some patients with acute heart failure experience recovery of myocardial function with short‐term MCS support, others become dependent. These patients, stabilized and “stuck” with short‐term MCS, can be “rescued” with long‐term VAD or heart transplantation. Both the procedures, when done in this special situation, have their inherent advantages, disadvantages, and complications and hence need the careful consideration about the choice of the procedure. We have tried to elucidate this situation by considering the advantages and disadvantages of both options.     

A UK Single Centre Retrospective Analysis of the Relationship between Haemodynamic Changes and Outcome in Patients Undergoing Prolonged Left Ventricular Assist Device Support

Purpose: Despite their efficacy, LVADs remain associated with serious complications. The relationship between haemodynamic changes during support and outcome remains inadequately characterised. This association was investigated in LVAD recipients undergoing prolonged support.Methods: Forty patients receiving LVAD therapy for >2 years were reviewed retrospectively (mean support duration was 38.62 ± 15.28). Pre- and on-LVAD haemodynamic data were assessed in three groups: (1) those receiving ongoing support (n = 24); (2) those who underwent cardiac transplantation (n = 4); (3) those who died during support (n = 12).Results: For group 1 and 2, LVAD support achieved a decrease in mean PAP, mean PCWP, TPG, and PVR and an increase in thermodilution blood flow (TBF) with significance at ≤5% level. For group 3, there were non-significant changes in TPG and PVR at the 5% level but for mean PAP, mean PCWP, and TBF the changes were similar to Groups 1 and 2 with significance at ≤5% level. Aggregated data from all three groups showed a 58% increase in TBF on LVAD support.Conclusion: Highly significant and favourable haemodynamic changes were found. However, group 3 did not undergo decrease in TPG and PVR possibly because of suboptimal LVAD flow, right heart dysfunction and unavoidable prolongation of support.     

Comparative effects of cuff size and tightness of fit on accuracy of blood pressure measurements

To determine the effect of snugness of cuff wrap on the accuracy of blood pressure (BP) measurements, we performed two studies on 6 healthy volunteers. In both studies, control values were obtained from the right upper arm with cuffs of appropriate size and snug fit. Study 1 had two phases. In the first, cuffs of appropriate size were wrapped snugly around the upper left arm of seated subjects. The effects of two other degrees of cuff snugness on the measurement of BP were evaluated by placing a filled 250-mL intravenous fluid bag between the cuff and arm over the triceps, measuring BP, then draining the same bag of half its contents and then all of its contents without rewrapping the cuff (loose, very loose fit), each time measuring BP. The second phase of study 1 was identical in procedure, except that the cuffs used on the left arm were one size too small. In study 2, the experimental cuffs were placed just above the right ankle. To alter the signal-to-noise ratio, BP was raised or lowered: the standing position elevated mean BP by an average of 90 mm Hg, and elevation of the legs decreased mean BP by an average of 43 mm Hg. In study 1, we found that appropriately sized cuffs, whether wrapped tightly or loosely, gave correct BP readings. Cuffs snugly wrapped, but too small for the subject, gave high BP readings, on the average by approximately 10 mm Hg. Loose wrapping of small cuffs gave variable results in individual subjects that exaggerated systolic BP from 2 to 80 mm Hg. In study 2, elevating the legs or standing decreased or increased BP consistently. Loose wrapping of appropriately sized cuffs around the ankles of the subjects had no additional significant effect on BP.     

Unified treatment algorithm for the management of crotaline snakebite in the United States: results of an evidence-informed consensus workshop

Background

Injuries represent a significant and growing public health concern in China. This Review was conducted to document the characteristics of injured patients presenting to the emergency department of Chinese hospitals and to assess of the nature of information collected and reported in published surveillance studies.

Methods

A systematic search of MEDLINE and China Academic Journals supplemented with a hand search of journals was performed. Studies published in the period 1997 to 2007 were included and research published in Chinese was the focus. Search terms included emergency, injury, medical care.

Results

Of the 268 studies identified, 13 were injury surveillance studies set in the emergency department. Nine were collaborative studies of which eight were prospective studies. Of the five single centre studies only one was of a prospective design. Transport, falls and industrial injuries were common mechanisms of injury. Study strengths were large patient sample sizes and for the collaborative studies a large number of participating hospitals. There was however limited use of internationally recognised injury classification and severity coding indices.

Conclusion

Despite the limited number of studies identified, the scope of each highlights the willingness and the capacity to conduct surveillance studies in the emergency department. This Review highlights the need for the adoption of standardized injury coding indices in the collection and reporting of patient health data. While high level injury surveillance systems focus on population-based priority setting, this Review demonstrates the need to establish an internationally comparable trauma registry that would permit monitoring of the trauma system and would by extension facilitate the optimal care of the injured patient through the development of informed quality assurance programs and the implementation of evidence-based health policy.     

Adverse events associated with pediatric exposures to dextromethorphan

Study objective: Dextromethorphan is the most common over-the-counter (OTC) antitussive medication. We sought to characterize adverse events associated with dextromethorphan in children <12 years old from a surveillance program of OTC cough/cold medication exposures.

Methods: This is a retrospective case series of oral exposures to dextromethorphan with ≥1 adverse event from multiple U.S. sources (National Poison Data System, FDA Adverse Event Reporting System, manufacturer safety reports, news/media, medical literature) reported between 2008 and 2014. An expert panel determined the relationship between exposure and adverse events, estimated dose ingested, intent of exposure, and identified contributing factors to exposure.

Results: 1716 cases contained ≥1 adverse event deemed at least potentially related to dextromethorphan; 1417 were single product exposures. 773/1417 (55%) involved only one single-ingredient dextromethorphan product (dextromethorphan-only). Among dextromethorphan-only cases, 3% followed ingestion of a therapeutic dose; 78% followed an overdose. 69% involved unsupervised self-administration and 60% occurred in children <4 years old. No deaths or pathologic dysrhythmias occurred. Central nervous system [e.g., ataxia (N?=?420)] and autonomic symptoms [e.g., tachycardia (N?=?224)] were the most common adverse events. Flushing and/or urticarial rash occurred in 18.1% of patients. Dystonia occurred in 5.4%.

Conclusions: No fatalities were identified in this multifaceted surveillance program following a dextromethorphan-only ingestion. Adverse events were predominantly associated with overdose, most commonly affecting the central nervous and autonomic systems.     

Complex Caring Trajectories in Community Mental Health: Contingencies, Divisions of Labor and Care Coordination

The concept of ‘trajectory’ refers to the unfolding of individual service users’ health and illness experiences, the organization of health and social care work surrounding them and the impact this work has on people involved. Using qualitative data from a study completed in two sites in Wales we first reveal the complex character of trajectories encountered in the community mental health field. We show how these can be shaped by features peculiar to mental ill-health per se, and by features with organizational origins. We then use our data to lay bare true divisions of labor. Mental health professionals featured prominently in our study. We also reveal relatively invisible contributions made by professionals on the periphery, support workers, unpaid lay carers and service users. In examining the significance of our findings we identify particular lessons for mental health practitioners, managers and policymakers sharing concerns for the coordination of care.     

The effect of polymer molecular weight and cell seeding density on viability of cells entrapped within PEGDA hydrogel microspheres

Abstract

Cell microencapsulation can be used in tissue engineering as a scaffold or physical barrier that provides immunoisolation for donor cells. When used as a barrier, microencapsulation shields donor cells from the host immune system when implanted for cell therapies. Maximizing therapeutic product delivery per volume of microencapsulated cells necessitates first optimising the viability of entrapped cells. Although cell microencapsulation within alginate is well described, best practices for cell microencapsulation within polyethylene glycol is still being elucidated. In this study we microencapsulate mouse preosteoblast cells within polyethylene glycol diacrylate (PEGDA) hydrogel microspheres of varying molecular weight or seeding densities to assess cell viability in relation to cell density and polymer molecular weight. Diffusion studies revealed molecule size permissible by each molecular weight PEGDA towards correlating viability with polymer mesh size. Results demonstrated higher cell viability in higher molecular weight PEGDA microspheres and when cells were seeded at higher cell densities.