Nanocomposite liposomes for pH-controlled porphyrin release into human prostate cancer cells

It is both challenging and desirable to have drug sensitizers released at acidic tumor pH for photodynamic therapy in cancer treatment. A pH-responsive carrier was prepared, in which fumed silica-attached 5,10,15,20-tetrakis(4-trimethylammoniophenyl)porphyrin (TTMAPP) was encapsulated into 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) nanocomposite liposomes. The sizes of agglomerates were determined by dynamic light scattering to be 115 nm for silica and 295 nm for silica-TTMAPP-DOPC liposomes. Morphological changes were also found in TEM images, showing liposome formation at pH 8.5 but collapse upon silanol protonation. TTMAPP release is enhanced from 13% at pH 7.5 to 80% at pH 2.3, as determined spectrophotometrically through dialysis membranes. Fluorescence emission of TTMAPP encapsulated in the dry film of liposomes was reduced to half at pH 8.6 when compared to that at pH 5.4, while the production of singlet oxygen was quintupled at pH 5.0 compared to pH 7.6. Upon treatment of human prostate cancer cells with liposomes containing 6.7 μM, 13 μM, 17 μM and 20 μM TTMAPP, the cell viabilities were determined to be 60%, 18%, 20% and 5% at pH 5.4; 58%, 30%, 25% and 10% at pH 6.3; and 90%, 82%, 68% and 35% at pH 7.4, respectively. Light-induced apoptosis in cancerous cells was only observed in the presence of liposomes at pH 6.3 and pH 5.4 but not at pH 7.4, as indicated by chromatin condensation.

Nanocomposite liposomes are relatively stable in weak basic solutions but effectively release porphyrins at acidic pH, as indicated by the difference in fluorescence.     

The incidence and natural course of occult inguinal hernias during TAPP repair

Background

One of the proposed advantages of laparoscopic inguinal hernia repair is complimentary inspection of the contralateral side and possible detection of occult hernias. Incidence of occult contralateral hernias is as high as 50 %. The natural course of such occult defects is unknown and therefore operative rationale is lacking. This study was designed to analyze the incidence of occult contralateral inguinal hernias and its natural course.

Methods

A total of 1,681 patients were diagnosed preoperatively with unilateral inguinal hernia. None of these patients had complaints of the contralateral side preoperatively. All patients underwent laparoscopic inguinal hernia transabdominal preperitoneal (TAPP) repair. Operative details were analyzed retrospectively. Patients with occult contralateral defects were identified and tracked. Patients with an evident occult hernia received immediate repair. Patients with a smaller beginning or incipient hernia were followed.

Results

In 218 (13 %) patients, an occult hernia was found at the contralateral side during preoperative exploration. In 129 (8 %) patients, an occult true hernia was found. In 89 (5 %) patients, an occult incipient hernia was found. An incipient hernia was defined as a beginning hernia. All patients with an incipient hernia were followed. The mean follow-up was 112 (range 16–218) months. Twenty-eight (32 %) patients were lost to follow-up. In the 61 remaining patients, 13 (21 %) occult incipient hernias became symptomatic requiring repair. The mean time between primary repair and development of a symptomatic hernia on the contralateral side was 88 (range 24–210) months.

Conclusions

This study shows that the incidence of occult contralateral hernias is 13 % during TAPP repair of unilateral diagnosed inguinal hernias. In 5 % of the cases, the occult hernia consisted of a beginning hernia. Eventually, one of five will become symptomatic and require repair. These outcomes support immediate repair of occult defects, no matter its size.     

Sodium Thiosulfate in the Treatment of Calciphylaxis

The authors review the presentation, diagnosis, and treatment of calciphylaxis and also describe applications of a novel therapeutic option, sodium thiosulfate. Two cases of advanced uremic calciphylaxis from both clinic and hospital settings are presented. One patient, a 57-year-old woman with end-stage renal disease, was treated with surgical debridement and sodium thiosulfate 25g three times a week. After introducing sodium thiosulfate treatment, the affected sites continue to heal with encouraging improvement of ulcer depth. Sodium thiosulfate was well-tolerated and facilitated wound healing. The patient did not develop sepsis. Sodium thiosulfate appears to be a viable first-line treatment for calciphylaxis and should be seriously considered early in the course of treatment.Calciphylaxis is an obliterative vasculopathy that causes ischemia and necrosis of the skin, subcutaneous fat, visceral organs, and skeletal muscle.1 Early lesions resemble livedo reticularis and can appear as indurated, erythematous papules, nodules, plaques, or bullae. As the lesions grow, they become more stellate and develop necrotic foci, eventually becoming painful ulcerations. Proximal involvement at high-trauma sites (thighs, abdomen, buttocks, and breasts) is most common and associated with a higher mortality rate.While the pathogenesis of calciphylaxis is poorly understood, it is theorized to be a two-stage process. The first stage involves vascular injury in the form of mural calcification, intimal hyperplasia, and endovascular fibrosis. This vessel damage sensitizes the supplied tissue areas to ischemia. In the second stage, additional vascular damage is triggered by clinical events, such as local trauma, hypotension, or thrombosis and leads to the development of an ischemic infarct, dystrophic calcification, or ulceration.1 Histological findings include a mixed inflammatory infiltrate, a giant cell reaction, and panniculitis with subcutaneous calcium deposits, and fat necrosis.Calciphylaxis affects 1 to 4 percent of patients with end-stage renal disease (ESRD),1,2 but can also impact patients with normal calcium levels and renal function. In addition to renal impairment and dialysis dependency, predisposing factors that increase a patient’s risk for developing calciphylaxis include female gender, Caucasian race, obesity, warfarin use, systemic steroid use, hypercoagulable states, diabetes mellitus, liver disease, protein malnutrition, calcium salts and vitamin D treatment, raised serum calcium phosphate product (>70mg/m²), raised serum phosphate, and raised serum aluminium.1 Prognosis for calciphylaxis generally remains poor due to the high risk of complications, namely sepsis. The estimated one-year survival rate is 45.8 percent.3Sodium thiosulfate (STS) is a powerful antioxidant and chelating agent, which has been traditionally used for cyanide poisoning and cisplatin toxicity. There are increasing reports of STS being used off-label to successfully treat both uremic4-11 and nonuremic12-15 calciphylaxis.     

Impaired longitudinal deformation measured by speckle-tracking echocardiography in children with end-stage renal disease

Background

Left ventricular dysfunction is an important co-morbidity of end-stage renal disease (ESRD) and is associated with a poor prognosis in the adult population. In pediatric ESRD, left ventricular function is generally well preserved, but limited information is available on early changes in myocardial function. The aim of this study was to investigate myocardial mechanics in pediatric patients with ESRD using speckle-tracking echocardiography (STE).

Methods

Echocardiographic studies, including M-mode, tissue Doppler imaging (TDI) and STE, were performed in 19 children on dialysis, 17 transplant patients and 33 age-matched controls. Strain measurements were performed from the apical four-chamber and the short axis view, respectively.

Results

The interventricular and left ventricular posterior wall thickness was significantly increased in dialysis and transplant patients compared to healthy controls. No significant differences were found in shortening fraction, ejection fraction and systolic tissue Doppler velocities. Dialysis and transplant patients had a decreased mean longitudinal strain compared to healthy controls, with a mean difference of 3.1 [95 % confidence interval (CI) 2.0–4.4] and 2.7 (95 % CI 1.2–4.2), respectively. No differences were found for radial and circumferential strain.

Conclusions

Speckle-tracking echocardiography may reveal early myocardial dysfunction in the absence of systolic dysfunction measured by conventional ultrasound or TDI in children with ESRD.

     

The influence of MCAT and GPA preadmission academic metrics on interview scores

Medical school admissions interviews are used to assess applicants’ nonacademic characteristics as advocated by the Association of American Medical Colleges’ Advancing Holistic Review Initiative. The objective of this study is to determine whether academic metrics continue to significantly influence interviewers’ scores in holistic processes by blinding interviewers to applicants’ undergraduate grade point averages (uGPA) and Medical College Admission Test (MCAT). This study examines academic and demographic predictors of interview scores for two applicant cohorts at the University of Michigan Medical School. In 2012, interviewers were provided applicants’ uGPA and MCAT scores; in 2013, these academic metrics were withheld from interviewers’ files. Hierarchical regression analysis was conducted to examine the influence of academic and demographic variables on overall cohort interview scores. When interviewers were provided uGPA and MCAT scores, academic metrics explained more variation in interview scores (7.9%) than when interviewers were blinded to these metrics (4.1%). Further analysis showed a statistically significant interaction between cohort and uGPA, indicating that the association between uGPA and interview scores was significantly stronger for the 2012 unblinded cohort compared to the 2013 blinded cohort (β = .573, P < .05). By contrast, MCAT scores had no interactive effects on interviewer scores. While MCAT scores accounted for some variation in interview scores for both cohorts, only access to uGPA significantly influenced interviewers’ scores when looking at interaction effects. Withholding academic metrics from interviewers’ files may promote assessment of nonacademic characteristics independently from academic metrics.     

Online scan of FASD prevention and health promotion resources for Aboriginal and Torres Strait Islander communities

Issue addressed

Foetal Alcohol Spectrum Disorder (FASD) includes a range of life‐long impairments caused by alcohol exposure in utero. Health professionals are vital to preventing FASD but many are hesitant to discuss FASD with clients due to their need for additional resources to aid the conversation. This scan sought to identify the scope and gaps in publicly available FASD prevention and health promotion resources, and assess their cultural appropriateness for use among five key groups of Indigenous Australian people including: (i) pregnant women, (ii) women of childbearing age, (iii) grandmothers and aunties, (iv) men, and (v) health professionals.

Methods

Relevant resources published 1995‐2017 were identified through the Australian Indigenous HealthInfoNet, FASD organisation websites, grey literature, Google searches, and field experts. Results were screened by inclusion and cultural appropriateness criteria developed and piloted by the research team, and further screened by health professionals attending FASD training workshops.

Results

115 of the 2146 identified resources were eligible. Relevant resources were found for all five key groups; however, no resources were specifically designed for men, grandmothers or aunties.

Conclusions

A range of high‐quality, culturally appropriate resources were identified, however, health professionals attending the training workshops were not aware of their availability. Further resource development is suggested for men, grandmothers and aunties.

So what?

Prioritisation of active dissemination and implementation strategies is suggested to increase awareness and use of future resource developments. The inclusion of a resource trial among health professionals is a recommended strategy to increase awareness and use of newly developed resources.