Transplantation of human amnion epithelial cells reduces hepatic fibrosis in immunocompetent CCl4-treated mice

Chronic liver injury and inflammation lead to hepatic fibrosis, cirrhosis, and liver failure. Embryonic and mesenchymal stem cells have been shown to reduce experimental liver fibrosis but have potential limitations, including the formation of dysplastic precursors, tumors, and profibrogenic cells. Other stem-like cells may reduce hepatic inflammation and fibrosis without tumor and profibrogenic cell formation. To test this hypothesis we transplanted human amnion epithelial cells (hAEC), isolated from term delivered placenta, into immunocompetent C57/BL6 mice at week 2 of a 4-week regimen of carbon tetrachloride (CCl4) exposure to induce liver fibrosis. Two weeks following hAEC infusion, intact cells expressing the human-specific markers inner mitochondrial membrane protein and human leukocyte antigen-G were found in mouse liver without evidence of host rejection of the transplanted cells. Human albumin, known to be produced by hAEC, was detected in sera of hAEC-treated mice. Human DNA was detected in mouse liver and also spleen, lungs, and heart of some animals. Following hAEC transplantation, CCl4-treated animals showed decreased serum ALT levels and reduced hepatocyte apoptosis, compared to controls. hAEC-treated mouse liver had lower TNF-α and IL-6 protein levels and higher IL-10 compared to animals given CCl4 alone. Compared to CCl4 controls, hAEC-treated mice showed fewer activated collagen-producing hepatic stellate cells and less fibrosis area and collagen content. Reduced hepatic TGF-β levels in conjunction with a twofold increase in the active form of the collagen-degrading enzyme matrix metalloproteinase-2 in hAEC-treated mice compared to CCl4 controls may account for the reduction in fibrosis. hAEC transplantation into immunocompetent mice leads to cell engraftment, reduced hepatocyte apoptosis, and decreased hepatic inflammation and fibrosis.

Outcomes in gastric and junctional cancer using neoadjuvant and adjuvant chemotherapy (epirubicin, oxaliplatin, and capecitabine) and radical surgery

Background The MAGIC/UK Medical Research Council (MRC) trial set the standard of care for treatment of resectable gastric and junctional adenocarcinoma, demonstrating that perioperative chemotherapy with epirubicin, cisplatin and 5-fluorouracil (ECF) confers a survival benefit over surgery alone. The randomized ECF for advanced and locally advanced esophagogastric cancer (REAL-2) trial showed that, in the metastatic setting, the EOX regimen (epirubicin, oxaliplatin and capecitabine) is as effective as ECF, with a favourable toxicity profile. Methods Consecutive patients with resectable gastric or junctional adenocarcinoma treated with perioperative EOX, between 2007 and 2012, were retrospectively analysed. Results Fifty-nine patients (12 female, 47 male), commenced EOX therapy; 47 underwent surgery. A good pathological response was seen in 34 %, (16/47). Disease recurrence occurred in 19 patients (19/47, 40 %). Median overall survival was 22 months, with 4-year survival of 47 %. Chemotoxicities were consistent with those previously reported for this regimen. Conclusion This study in a high-volume centre demonstrates that EOX in resectable gastric and junctional adenocarcinoma is associated with a reasonable safety profile, and efficacy consistent with that reported for ECF.

Clinical outcomes, not clinical utility, should be the major consideration for saxagliptin with or without metformin

A recent review by Panagoulias and Doupis, published in Patient Preference and Adherence, concerned the saxagliptin/metformin fixed combination (SAXA/MET FDC), and was titled "Clinical utility in the treatment of type 2 diabetes with the saxagliptin/metformin fixed combination."1 This review concluded that "The SAXA/MET FDC is a patient-friendly, dosage-flexible, and hypoglycemia-safe regimen with very few adverse events and a neutral or even favorable effect on body weight. It achieves significant glycosylated hemoglobin A1c reduction helping the patient to achieve his/her individual glycemic goals."1

Late reactivation of herpes zoster keratitis results in band keratopathy

Purpose To report an unusual case of a late-stage reactivation of immune stromal keratitis associated with herpes zoster ophthalmicus (HZO), occurring without any apparent predisposing factors, more than 4 years after an acute zoster dermatomal rash. Significant corneal hypoesthesia and a central band keratopathy developed within 6 months of the late-stage reactivation. The clinical case management, issues associated with management, and management options are discussed, including the use of standardized, regulatory approved, antibacterial medical honey. Case Report An 83-year-old woman presented for routine review with a reactivation of right anterior stromal keratitis and mild anterior uveitis, occurring more than 4 years after an acute HZO dermatomal rash and an associated initial episode of anterior stromal keratitis. Corneal sensation became markedly impaired, and over the subsequent 6 months, a right central band keratopathy developed despite oral antiviral and topical steroid therapy. Visual acuity with pinhole was reduced to 20/100 in the affected eye and moderate irritation and epiphora were experienced. The patient declined the surgical intervention options of chelation, lamellar keratectomy, and phototherapeutic keratectomy to treat the band keratopathy. Longer-term management has involved preservative-free artificial tears, eyelid hygiene, standardized antibacterial medical honey, topical nonpreserved steroid, and UV-protective wraparound sunglasses. The clinical condition has improved over 14 months with this ocular surface management regimen, and visual acuity of 20/30 is currently achieved in a comfortable eye. Conclusions The chronic and recurrent nature of HZO can be associated with significant corneal morbidity, even many years after the initial zoster episode. Long-term review and management of patients with a history of herpes zoster stromal keratitis are indicated following the initial corneal involvement. Standardized antibacterial medical honey can be considered in the management of the chronic ocular surface disease associated with HZO and warrants further evaluation in clinical trials.

Institutionalization

During the 18th and 19th centuries, prostitution came to be understood as a potentially disruptive element in the management of society. New forms of social control developed that sought to transform the souls of prostitutes to better control their bodies. Institutions for managing prostitutes, such as Magdalen Homes and lock hospitals, were introduced or increased in number throughout the British Empire, North America, and Western Europe. Often these institutions had as their stated objective the physical purification and moral reform of prostitutes, appearing to make a dramatic break with earlier methods of social control that had relied on practices of physical punishment and spatial segregation. Emergent institutions for the social control of prostitutes used a regimen of religious training, hard labor, and medical expertise. The objective of the Magdalen Home was not to punish sin but to absolve it, while the function of the lock hospital was not simply to confine the ill, but to confine the ill to "cure" them. The role of these institutions was not only symbolic, mirroring in some way the operation of earlier forms of social control, but was also practical and transformative. The mass institutionalization of prostitutes that occurred during the 18th and 19th centuries produced and emphasized sexual, class, and gender boundaries, grounded in the broad distinction between "pure" and "impure" women. Because of its association with sin, prostitution before the 18th century had been constructed as a religious problem relating to salvation and penitence. Throughout Western Europe during the Middle Ages, prostitutes, like the medieval leper and the Jew, were subject to restrictions designed to distinguish and isolate them from other members of their communities. The repression of prostitution during the Middle Ages was neither systematic nor highly organized, although it reinforced the image of the prostitute as sinful "other".

Afterschool MediaClub: Critical literacy in a high diversity, high poverty urban setting

In this chapter we present analyses of data produced with young people in an afterschool digital literacy program for 9 – 12 year olds. The young people were students at a high diversity, high poverty outer suburban elementary school in Queensland, Australia. The club was part of the URLearning research project (2010-14). In the classroom-based component of the project we worked with teachers to develop intellectually substantive and critical digital literacy practice. MediaClub was in some ways complementary to the classroom component; it was designed to skill up interested kids as digital media experts not only for their families and communities, but also for the classroom. Given the critical literacy traditions established in Australian schools, we approached MediaClub with certain critical expectations. In this chapter we look at what ensued, highlighting unanticipated critical outcomes at a time of heightened struggle over English curriculum. Critical literacy has been part of official English curriculum in Queensland since the early 1990s. The approach has been primarily text analytic, concerned with giving students access to genres of power and tools for understanding the ideological work of language through text. Many ideas for translating this normative critical project into classroom practice have been developed for use from the earliest elementary grades onwards. However, curricular space for critical literacy is under pressure. Amongst other things, this reflects both the development of Australia’s first national curriculum and the construction of a regimen of national literacy testing. At MediaClub we found a certain resistance to learning activities which were “too much like school”. However, in a context of increased control of teachers’ and students’ work in the classroom, MediaClub evolved as a learning space that can be understood in critical terms. Our experience in this regard might be of interest to teachers and researchers in high diversity high poverty settings that are strongly controlled through increasingly prescriptive – even scripted – pedagogies.

Environmental conditions are important for establishing and evaluating pre-clinical models of GVHD

GVHD remains the major complication of allo-HSCT. Murine models are the primary system used to understand GVHD, and to develop potential therapies. Several factors are critical for GVHD in these models; including histo- compatibility, conditioning regimen, and T-cell number. We serendipitously found that environmental factors such as the caging system and bedding also significantly impact the kinetics of GVHD in these models. This is important because such factors may influence the experimental conditions required to cause GVHD and how mice respond to various treatments. Consequently, this is likely to alter interpretation of results between research groups, and the perceived effectiveness of experimental therapies.

Inadvertent hypothermia after procedural sedation and analgesia in a cardiac catheterisation laboratory: A prospective observational study

Objective To identify the prevalence of and risk factors for inadvertent hypothermia after procedures performed with procedural sedation and analgesia in a cardiac catheterisation laboratory. Design Single-centre, prospective observational study. Setting Tertiary care private hospital in Australia. Participants A convenience sample of 399 patients undergoing elective procedures with procedural sedation and analgesia were included. Propofol infusions were used when an anaesthetist was present. Otherwise, bolus doses of either midazolam or fentanyl or a combination of these medications was used. Interventions None Measurements and main results Hypothermia was defined as a temperature <36.0° Celsius. Multivariate logistic regression was used to identify risk factors. Hypothermia was present after 23.3% (n=93; 95% confidence interval [CI] 19.2%-27.4%) of 399 procedures. Sedative regimens with the highest prevalence of hypothermia were any regimen that included propofol (n=35; 40.2%; 95% CI 29.9%-50.5%) and the use of fentanyl combined with midazolam (n=23; 20.3%; 95% CI 12.9%-27.7%). Difference in mean temperature from pre to post-procedure was -0.27°C (Standard deviation [SD] 0.45). Receiving propofol (odds ratio [OR] OR 4.6 95% CI 2.5-8.6), percutaneous coronary intervention (OR 3.2 95% CI 1.7-5.9), body mass index <25 (OR 2.5 95% CI 1.4-4.4) and being hypothermic prior to the procedure (OR 4.9; 95% CI 2.3-10.8) were independent predictors of post-procedural hypothermia. Conclusions A moderate prevalence of hypothermia was observed. The small absolute change in temperature observed may not be a clinically important amount. More research is needed to increase confidence in our estimates of hypothermia in sedated patients and its impact on clinical outcomes.

Parkinson's disease, nutrition, and surgery in context of critical care

Parkinson’s disease is a common neurodegenerative disorder with a higher risk of hospitalization than the general population. Therefore, there is a high likelihood of encountering a person with Parkinson’s disease in acute or critical care. Most people with Parkinson’s disease are over the age of 60 years and are likely to have other concurrent medical conditions. Parkinson’s disease is more likely to be the secondary diagnosis during hospital admission. The primary diagnosis may be due to other medical conditions or as a result of complications from Parkinson’s disease symptoms. Symptoms include motor symptoms, such as slowness of movement and tremor, and non-motor symptoms, such as depression, dysphagia, and constipation. There is a large degree of variation in the presence and degree of symptoms as well as in the rate of progression. There is a range of medications that can be used to manage the motor or non-motor symptoms, and side effects can occur. Improper administration of medications can result in deterioration of the patient’s condition and potentially a life-threatening condition called neuroleptic malignant-like syndrome. Nutrients and delayed gastric emptying may also interfere with intestinal absorption of levodopa, the primary medication used for motor symptom management. Rates of protein-energy malnutrition can be up to 15 % in people with Parkinson’s disease in the community, and this is likely to be higher in the acute or critical care setting. Nutrition-related care in this setting should utilize the Nutrition Care Process and take into account each individual’s Parkinson’s disease motor and non-motor symptoms, the severity of disease, limitations due to the disease, medical management regimen, and nutritional status when planning nutrition interventions. Special considerations may need to be taken into account in relation to meal and medication times and the administration of enteral feeding. Nutrition screening, assessment, and monitoring should occur during admission to minimize the effects of Parkinson's disease symptoms and to optimise nutrition-related outcomes.

South Asians' cardiac medication adherence

Aim This paper is a report of a narrative review examining the current state of knowledge regarding adherence with cardiac medication among South Asian cardiac patients. Background South Asians experience higher rates of cardiovascular disease than any other ethnic group. South Asians may be less adherent with a cardiac medication regimen than Caucasians. The factors contributing to adherence are important to discover to assist South Asians to optimize their cardiac health. Data sources CINAHL, Medline (Ovid), PsychINFO, EMB Reviews-(Cochrane), and EMBASE were accessed using the key words: 'South Asian', 'Asia', 'East India', 'India', 'Pakistan', 'Bangladesh', 'Sri Lanka', 'medication compliance', 'medication noncompliance' and 'medication adherence'. English language papers published from January 1980 to January 2013 were eligible for inclusion. Review methods Abstracts were reviewed for redundancy and eligibility by the primary author. Manuscripts were then retrieved and reviewed for eligibility and validity by the first and last authors. Content analysis strategies were used for the synthesis. Results Thirteen papers were in the final data set; most were conducted in India and Pakistan. Medication side-effects, cost, forgetfulness and higher frequency of dosing contributed to non-adherence. South Asian immigrants also faced language barriers, which contributed to non-adherence. Knowledge regarding the medications prescribed was a factor that increased adherence. Conclusion South Asians' non-adherence to cardiac medications is multifaceted. How South Asians who newly immigrate to Western countries make decisions regarding their cardiac medication adherence ought to be explored in greater detail.

EVERSUN: A phase 2 trial of alternating sunitinib and everolimus as first-line therapy for advanced renal cell carcinoma

Background We hypothesised that alternating inhibitors of the vascular endothelial growth factor receptor (VEGFR) and mammalian target of rapamycin pathways would delay the development of resistance in advanced renal cell carcinoma (aRCC). Patients and methods A single-arm, two-stage, multicentre, phase 2 trial to determine the activity, feasibility, and safety of 12-week cycles of sunitinib 50 mg daily 4 weeks on / 2 weeks off, alternating with everolimus 10 mg daily for 5 weeks on / 1 week off, until disease progression or prohibitive toxicity in favourable or intermediate-risk aRCC. The primary end point was proportion alive and progression-free at 6 months (PFS6m). The secondary end points were feasibility, tumour response, overall survival (OS), and adverse events (AEs). The correlative objective was to assess biomarkers and correlate with clinical outcome. Results We recruited 55 eligible participants from September 2010 to August 2012. Demographics: mean age 61, 71% male, favourable risk 16%, intermediate risk 84%. Cycle 2 commenced within 14 weeks for 80% of participants; 64% received ≥22 weeks of alternating therapy; 78% received ≥22 weeks of any treatment. PFS6m was 29/55 (53%; 95% confidence interval [CI] 40% to 66%). Tumour response rate was 7/55 (13%; 95% CI 4% to 22%, all partial responses). After median follow-up of 20 months, 47 of 55 (86%) had progressed with a median progression-free survival of 8 months (95% CI 5–10), and 30 of 55 (55%) had died with a median OS of 17 months (95% CI 12–undefined). AEs were consistent with those expected for each single agent. No convincing prognostic biomarkers were identified. Conclusions The EVERSUN regimen was feasible and safe, but its activity did not meet pre-specified values to warrant further research. This supports the current approach of continuing anti-VEGF therapy until progression or prohibitive toxicity before changing treatment.

Vaccination of koalas (Phascolarctos cinereus) with a recombinant chlamydial major outer membrane protein adjuvanted with poly I:C, a host defense peptide and polyphosphazine, elicits strong and long lasting cellular and humoral immune responses

Chlamydial infections are wide spread in koalas across their range and a solution to this debilitating disease has been sought for over a decade. Antibiotics are the currently accepted therapeutic measure, but are not an effective treatment due to the asymptomatic nature of some infections and a low efficacy rate. Thus, a vaccine would be an ideal way to address this infectious disease threat in the wild. Previous vaccine trials have used a three-dose regimen; however this is very difficult to apply in the field as it would require multiple capture events, which are stressful and invasive processes for the koala. In addition, it requires skilled koala handlers and a significant monetary investment. To overcome these challenges, in this study we utilized a polyphosphazine based poly I:C and a host defense peptide adjuvant combined with recombinant chlamydial major outer membrane protein (rMOMP) antigen to induce long lasting (54 weeks) cellular and humoral immunity in female koalas with a novel single immunizing dose. Immunized koalas produced a strong IgG response in plasma, as well as at mucosal sites. Moreover, they showed high levels of C. pecorum specific neutralizing antibodies in the plasma as well as vaginal and conjunctival secretions. Lastly, Chlamydia-specific lymphocyte proliferation responses were produced against both whole chlamydial elementary bodies and rMOMP protein, over the 12-month period. The results of this study suggest that a single dose rMOMP vaccine incorporating a poly I:C, host defense peptide and polyphosphazine adjuvant is able to stimulate both arms of the immune system in koalas, thereby providing an alternative to antibiotic treatment and/or a three-dose vaccine regime.

The ATHEROMA (Atorvastatin Therapy: Effects on Reduction of Macrophage Activity) Study. Evaluation using ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging in carotid disease

Objectives: The aim of this study was to evaluate the effects of low-dose (10 mg) and high-dose (80 mg) atorvastatin on carotid plaque inflammation as determined by ultrasmall superparamagnetic iron oxide (USPIO)-enhanced carotid magnetic resonance imaging (MRI). The hypothesis was that treatment with 80 mg atorvastatin would demonstrate quantifiable changes in USPIO-enhanced MRI-defined inflammation within the first 3 months of therapy. Background: Preliminary studies indicate that USPIO-enhanced MRI can identify macrophage infiltration in human carotid atheroma in vivo and hence may be a surrogate marker of plaque inflammation. Methods: Forty-seven patients with carotid stenosis >40% on duplex ultrasonography and who demonstrated intraplaque accumulation of USPIO on MRI at baseline were randomly assigned in a balanced, double-blind manner to either 10 or 80 mg atorvastatin daily for 12 weeks. Baseline statin therapy was equivalent to 10 mg of atorvastatin or less. The primary end point was change from baseline in signal intensity (ΔSI) on USPIO-enhanced MRI in carotid plaque at 6 and 12 weeks. Results: Twenty patients completed 12 weeks of treatment in each group. A significant reduction from baseline in USPIO-defined inflammation was observed in the 80-mg group at both 6 weeks (ΔSI 0.13; p = 0.0003) and at 12 weeks (ΔSI 0.20; p < 0.0001). No difference was observed with the low-dose regimen. The 80-mg atorvastatin dose significantly reduced total cholesterol by 15% (p = 0.0003) and low-density lipoprotein cholesterol by 29% (p = 0.0001) at 12 weeks. Conclusions: Aggressive lipid-lowering therapy over a 3-month period is associated with significant reduction in USPIO-defined inflammation. USPIO-enhanced MRI methodology may be a useful imaging biomarker for the screening and assessment of therapeutic response to "anti-inflammatory" interventions in patients with atherosclerotic lesions. (Effects of Atorvastatin on Macrophage Activity and Plaque Inflammation Using Magnetic Resonance Imaging [ATHEROMA]; NCT00368589).

Analysis of human immunodeficiency virus type 1 drug resistance in children receiving nucleoside analogue reverse-transcriptase inhibitors plus nevirapine, nelfinavir, or ritonavir (Pediatric AIDS Clinical Trials Group 377)

In Pediatric AIDS Clinical Trials Group 377, antiretroviral therapy-experienced children were randomized to 4 treatment arms that included different combinations of stavudine, lamivudine (3TC), nevirapine (Nvp), nelfinavir (Nfv), and ritonavir (Rtv). Previous treatment with zidovudine (Zdv), didanosine (ddI), or zalcitabine (ddC) was acceptable. Drug resistance ((R)) mutations were assessed before study treatment (baseline) and at virologic failure. Zdv(R), ddI(R), and ddC(R) mutations were detected frequently at baseline but were not associated with virologic failure. Children with drug resistance mutations at baseline had greater reductions in virus load over time than did children who did not. Nvp(R) and 3TC(R) mutations were detected frequently at virologic failure, and Nvp(R) mutations were more common among children receiving 3-drug versus 4-drug Nvp-containing regimens. Children who were maintained on their study regimen after virologic failure accumulated additional Nvp(R) and 3TC(R) mutations plus Rtv(R) and Nfv(R) mutations. However, Rtv(R) and Nfv(R) mutations were detected at unexpectedly low rates.

Development of a cognitive framework for pharmaceutical care

Pharmaceutical Care is defined as “the responsible provision of drug therapy for the purpose of achieving definite outcomes that improve a patient’s quality of life”. One of the fundamental concepts in understanding needs for pharmaceutical care are Drug-Related Problems (DRPs). As the complexity of medication treatment increases, identification of drug-related problems (DRPs) by healthcare professionals remains vital to patient safety and Quality Use of Medicines(QUM). DRPs have been used by many researchers to evaluate the QUM in different settings. DRPs present, however, a list of potential problems not a strategic framework for assessing a medication regimen.