Single-cell mapping of focused ultrasound-transfected brain.

Gene delivery via focused ultrasound (FUS) mediated blood-brain barrier (BBB) opening is a disruptive therapeutic modality. Unlocking its full potential will require an understanding of how FUS parameters (e.g., peak-negative pressure (PNP)) affect transfected cell populations. Following plasmid (mRuby) delivery across the BBB with 1 MHz FUS, we used single-cell RNA-sequencing to ascertain that distributions of transfected cell types were highly dependent on PNP. Cells of the BBB (i.e., endothelial cells, pericytes, and astrocytes) were enriched at 0.2 MPa PNP, while transfection of cells distal to the BBB (i.e., neurons, oligodendrocytes, and microglia) was augmented at 0.4 MPa PNP. PNP-dependent differential gene expression was observed for multiple cell types. Cell stress genes were upregulated proportional to PNP, independent of cell type. Our results underscore how FUS may be tuned to bias transfection toward specific brain cell types in vivo and predict how those cells will respond to transfection.

Evaluation of 278 New Bluephase Style Light Curing Units Purchased Over Six Years.

OBJECTIVE: This study measured 278 new curing lights (LCUs) to determine if they met the manufacturer's specifications. MATERIALS AND METHODS: Over a 6-year period, the light output from 278 Bluephase Style LCUs was measured before the LCUs were given to students (41 in 2017, 44 in 2018, 46 in 2019, 48 in 2020, 50 in 2021, and 49 in 2022). The radiant exitance (mW/cm²) from each year was compared using ANOVA and Tukey- Kramer multiple comparisons test with adjustment for the unequal sample sizes (α=0.05). The results were also compared against the manufacturer's stated radiant exitance of 1200 mW/cm². RESULTS: The 278 LCUs delivered an average (± standard deviation) radiant exitance of 1203 ± 16.7 mW/cm². The lowest radiant exitance was 1149 mW/cm² and the highest was 1257 mW/cm². Although there were statistically significant differences in the LCUs from each year, these values were within the manufacturer's tolerance of values of ± 10%. Approximately 13% of the emitted light was below 420 nm, and 87% was above 420 nm. CONCLUSION: These new LCUs were all multiple peak LCUs that emitted an average radiant exitance of 1,203 mW/cm² (range 1149 to 1257 mW/cm². Purchasers of the Style LCU can be confident that their new LCU will meet the manufacturer's specifications.

Three-dimensional beam profiling used to characterize dental light-curing units.

Two-dimensional (2D) beam profiling is an emerging technique used to characterize the beam homogeneity in dental light-curing units (LCUs). This project developed a method to combine multiple 2D beam profiles that had been measured along the beam path to create a 3D profile of the beam. This allowed a quantitative investigation of beam divergence and homogeneity at different distances from the source. To illustrate the use of this technique, four representative dental LCUs were measured. In addition, the selected dental LCUs demonstrated the effects of LCU design, particularly that of fiber optic light guides, on beam quality. The results show the value of a program that can recombine multiple beam profile images made at different distances from the source to create a 3D beam profile of a light beam.

Trauma Care in Mongolia: INTACT Evaluation and Recommendations for Improvement.

INTRODUCTION: Injury is the third leading cause of death in Mongolia, with a 29% increase in motor vehicle fatalities over the past decade. Half of the population lives outside the urbanized capital of Ulaanbaatar, where access to care is limited. This study evaluates and describes the Mongolian trauma system and makes recommendations for improvements. METHODS: Hospital-level data were collected, and an International Assessment of Capacity for Trauma (INTACT) score (0-10) was calculated. INTACT is a validated measure for evaluating trauma capacity in developing countries based on resource availability; a score of 10 reflects ideal staffing and equipment. The survey was administered to key staff members at 10 rural and urban hospitals in spring 2016. INTACT scores were calculated for each hospital and compared to expected INTACT scores based on the World Health Organization Guidelines for Essential Trauma Care (GETC). RESULTS: Ulaanbaatar enjoys a centralized prehospital transportation service and two appropriately resourced tertiary hospitals. Rural Mongolians rely upon regionally located tertiary facilities with similar capabilities. INTACT scores for secondary-level hospitals (n = 2) failed to meet expected GETC minimums, as did 2 of 4 primary facilities. There are no national standards guiding prehospital care, triage, or transfer. No outpatient rehabilitation facilities exist within Mongolia. CONCLUSION: The Mongolian trauma system utilizes regionalized care to provide emergency services. Among surveyed hospitals, 60% met GETC standards. Areas for improvement include increased resourcing of primary and secondary facilities, development of rural prehospital systems, adoption of universal standards for patient care, and creation of post-acute rehabilitation facilities.

Contribution of common non-synonymous variants in PCSK1 to body mass index variation and risk of obesity: a systematic review and meta-analysis with evidence from up to 331 175 individuals.

Polymorphisms rs6232 and rs6234/rs6235 in PCSK1 have been associated with extreme obesity [e.g. body mass index (BMI) ≥ 40 kg/m(2)], but their contribution to common obesity (BMI ≥ 30 kg/m(2)) and BMI variation in a multi-ethnic context is unclear. To fill this gap, we collected phenotypic and genetic data in up to 331 175 individuals from diverse ethnic groups. This process involved a systematic review of the literature in PubMed, Web of Science, Embase and the NIH GWAS catalog complemented by data extraction from pre-existing GWAS or custom-arrays in consortia and single studies. We employed recently developed global meta-analytic random-effects methods to calculate summary odds ratios (OR) and 95% confidence intervals (CIs) or beta estimates and standard errors (SE) for the obesity status and BMI analyses, respectively. Significant associations were found with binary obesity status for rs6232 (OR = 1.15, 95% CI 1.06-1.24, P = 6.08 × 10(-6)) and rs6234/rs6235 (OR = 1.07, 95% CI 1.04-1.10, P = 3.00 × 10(-7)). Similarly, significant associations were found with continuous BMI for rs6232 (ß = 0.03, 95% CI 0.00-0.07; P = 0.047) and rs6234/rs6235 (ß = 0.02, 95% CI 0.00-0.03; P = 5.57 × 10(-4)). Ethnicity, age and study ascertainment significantly modulated the association of PCSK1 polymorphisms with obesity. In summary, we demonstrate evidence that common gene variation in PCSK1 contributes to BMI variation and susceptibility to common obesity in the largest known meta-analysis published to date in genetic epidemiology.

The reliability of the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) among dermatologists, rheumatologists and neurologists.

BACKGROUND: Previous studies have shown that skin disease in dermatomyositis (DM) is best assessed using the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI). Although the CDASI has been validated for use by dermatologists, it has not been validated for use by other physicians such as rheumatologists and neurologists, who also manage patients with DM and assess skin activity in clinical trials. OBJECTIVES: To assess the reliability of the CDASI among dermatologists, rheumatologists and neurologists. METHODS: Fifteen patients with cutaneous DM were assessed using the CDASI and the Physician Global Assessment (PGA) by five dermatologists, five rheumatologists and five neurologists. RESULTS: The mean CDASI activity scores for dermatologists, rheumatologists and neurologists were 21·0, 21·8 and 20·8, respectively. These mean scores were not different among the specialists. The CDASI damage score means for dermatologists, rheumatologists and neurologists were 5·3, 7·0 and 4·8, respectively. The mean scores between dermatologists and rheumatologists were significantly different, but the means between dermatologists and neurologists were not. The intraclass correlation coefficients (ICCs) for interrater reliability for CDASI activity and damage were good to excellent for dermatologists and rheumatologists, and moderate to excellent for neurologists. The ICCs for intrarater reliability for CDASI activity and damage were excellent for dermatologists and rheumatologists and moderate to excellent for neurologists. The PGA displayed lower interrater and intrarater reliability relative to the CDASI. CONCLUSIONS: Our results confirm the reliability of the CDASI when used by dermatologists and rheumatologists. The data for its use by neurologists were not as robust.

Silibinin Reduces the Impact of Obesity on Invasive Liver Cancer.

Obesity is associated with non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). Obesity and metabolic abnormalities resulting in low-grade inflammation can increase the risk of developing NASH and HCC. NASH, a risk factor for HCC, is characterized by increased inflammation, lipid accumulation, and liver injury. Obesogenic proteins modulate signaling pathways that induce physiological changes including lipogenesis, ROS, and inflammation. Silibinin, a polyphenol in milk thistle seed, has been shown to have anti-inflammatory properties. Studies have yet to determine whether silibinin can be used to dissect the obesity-cancer link to delay progression of liver cancer. Using an in vitro model, sera from obese (OB), overweight (OW), or normal weight (NW) males (based on BMI) were used to determine the efficacy of silibinin to reduce the pro-tumorigenic properties of obesity. HepG2 cells were exposed to OB, OW, NW ± silibinin and tested for growth, ROS, lipogenesis, MMP-9, invasion and protein expression. Silibinin suppressed obesity-induced growth, ROS, lipogenesis, MMP-9, and cell invasion. These physiological changes corresponded with decreased FASN, IL-6, IL-1B, and phosphorylated Erk. We describe the differential effect of sera from OB, OW, and NW males on characteristics relevant for liver cancer and the potential use of silibinin to mitigate these effects.

Effects of Obesity on the Regulation of Macrophage Population in the Prostate Tumor Microenvironment.

Obesity is associated with a greater risk of prostate cancer mortality. However, the mechanisms connecting obesity to the progression of prostate cancer remain unknown. This study determined the impact of obesity on macrophage recruitment and tumor-associated macrophage (TAM) polarization in the prostate tumor microenvironment, since a high concentration of TAMs in tumors has been linked to progression in prostate cancer. We utilized an in vitro model in which pre-adipocytes, prostate cancer cells, and macrophages were exposed to sera from obese or nonobese men, or conditioned media generated under obese or nonobese conditions. Matrigel invasion chambers were used to assess macrophage recruitment in vitro, and immunohistochemical analysis evaluated recruitment in a PTEN knockout mouse model. qPCR was used to measure mRNA levels of CCL2, COX-2, IL-10, TGF-beta, VEGF-A, arginase-1, and MMP-9. PGE2 production was measured by ELISA. Obesity increased macrophage and TAM recruitment, and increased mRNA levels of TAM markers in macrophages. Similarly, obese conditions increased CCL2 and COX-2 expression, as well as PGE2 levels in prostate cancer cells. COX-2 inhibition resulted in lower expression of obesity-induced TAM markers. Our data suggest that obesity promotes macrophage infiltration into the prostate tumor microenvironment, and induces TAM polarization through the COX-2/PGE2 pathway.

Mobile gastrointestinal and endoscopic surgery in rural Ecuador: 20 years' experience of Cinterandes.

INTRODUCTION: Five billion people worldwide do not have timely access to surgical care. Cinterandes is one of the only mobile surgical units in low- and middle-income countries. This paper examines the methodology that Cinterandes uses to deliver mobile surgery. METHODS: Founding and core staff were interviewed, four missions were participated in, and internal documents and records were analysed between 1 May and 1 July 2014. RESULTS: Cinterandes performed 7641 operations over the last 20 years (60% gastrointestinal/laparoscopic), travelling 300,000 km to remote areas of Ecuador. The mobile surgery programme was initiated by a local Ecuadorian surgeon in 1980. Funding was acquired from businesses, private hospitals, and individuals, to fund a low-cost surgical truck, simple equipment, and running costs. The mobile surgical unit is a 24-foot modified Isuzu truck containing a preparation room with general equipment storage and running water, together with an operating room including the operating table, anaesthetic and surgical equipment. Mission structure includes: patient identification by a network of local medical personnel in remote regions; pre-operative assessment at 1 week by core team via teleconsultations; four-day surgical missions; post-operative recovery in tents or a local clinic; post-operative follow-up care by local personnel and remote teleconsultations. The permanent core team includes seven members; lead surgeon, lead anaesthetist, operating-room technician, medical coordinator, driver, general coordinator, and receptionist. Additional support members include seven regular surgeons, residents, medical students, and volunteers. CONCLUSION: Surgery is a very effective way to gain the trust of the community, due to immediate results. Trust opens doors to other programmes (e.g. family medicine). Surgery can be incorporated with all other aspects of health care, which can in turn be incorporated with all other aspects of human development, education, food production and nutrition, housing, work and productivity, communication, and recreation.

Reassessment of the succession of lactic acid bacteria in commercial cucumber fermentations and physiological and genomic features associated with their dominance.

A compositional re-assessment of the microbiota present in commercial cucumber fermentation using culture independent and dependent methods was conducted, with emphasis on lactic acid bacteria (LAB). Two commercial cucumber fermentation tanks were monitored by measuring pH, dissolved oxygen and temperature, and used as sources of samples for microbial plating, genomic DNA extraction and measurement of organic acids and carbohydrates by HPLC. Six additional commercial tanks were included to identify the dominant microorganisms using molecular methods. A comparative analysis of the publically available genome sequences corresponding to the LAB found in cucumber fermentations was completed to gain an understanding of genomic features possibly enabling dominance. Analyses of the microbiota suggest Lactobacillales prevail in cucumber fermentations, including in order of prevalence Lactobacillus pentosus, Lb. plantarum, Lb. brevis, Weissella spp., Pediococcus ethanolidurans, Leuconostoc spp. and Lactococcus spp. It was observed that Lb. pentosus and Lb. plantarum have comparatively larger genomes, higher gene counts, uniquely distribute the ribosomal clusters across the genome as opposed to close to the origin of replication, and possess more predicted amino acids prototrophies and selected biosynthesis related genes. It is theorized that Lb. pentosus and Lb. plantarum dominance in cucumber fermentations is the result of their genetic make-up.

Treatment response with mepolizumab in severe eosinophilic asthma patients with previous omalizumab treatment.

BACKGROUND: We performed post hoc analyses to evaluate the effect of humanized monoclonal antibody mepolizumab in patients with severe eosinophilic asthma previously treated with omalizumab. METHODS: Data were collected from two randomized double-blind, placebo-controlled studies: MENSA (NCT01691521: 32-week treatment phase) and SIRIUS (NCT01691508: 24-week treatment phase). Active treatment was 75 mg intravenous mepolizumab (MENSA) or 100 mg subcutaneous mepolizumab (MENSA, SIRIUS). Patients had evidence of eosinophilic inflammation ≥150 cells/µl (at screening) or ≥300 cells/µl (during the previous year). Primary outcomes were the rate of exacerbations (MENSA) and the percentage reduction in oral corticosteroid (OCS) dose (SIRIUS). Other outcomes included lung function (forced expiratory volume in 1 s and morning peak expiratory flow), Asthma Control Questionnaire (ACQ-5), St George's Respiratory Questionnaire (SGRQ) scores, and safety. RESULTS: Overall, 576 patients were included from MENSA and 135 from SIRIUS, with 13% and 33% previously receiving omalizumab, respectively. In MENSA, mepolizumab reduced the rate of exacerbations by 57% (prior omalizumab) and 47% (no prior omalizumab) vs placebo. In SIRIUS, reductions in OCS use were comparable regardless of prior omalizumab use. Despite reducing chronic OCS use, mepolizumab also resulted in similar reductions in exacerbation rate relative to placebo in both subgroups. Asthma control and quality of life improved with mepolizumab vs placebo in both studies independent of prior omalizumab use, as shown by ACQ-5 and SGRQ scores. Adverse events were also comparable irrespective of prior omalizumab use. CONCLUSIONS: These post hoc analyses indicate that patients with severe eosinophilic asthma respond positively to mepolizumab regardless of prior use of omalizumab.

Patient and Physician Perceptions of Changes in Surgical Care in Mongolia 9 Years After Roll-out of a National Training Program for Laparoscopy.

INTRODUCTION: In 2005, the general population of Mongolia was not aware of laparoscopic surgery and was skeptical about the safety of surgical care. A 9-year initiative to expand laparoscopic surgery was initiated by Mongolian surgeons. This study examines the current barriers to and perceptions of surgical care following laparoscopic surgical expansion countrywide. MATERIALS AND METHODS: In September 2013, interviews were conducted with 71 patients, and 39 physicians in Mongolia. Patients and physicians were interviewed using separate sets of interview questions. Questions were designed to gauge perceptions of surgical care in Mongolia evaluating for access, affordability, sustainability, barriers to care, quality, and knowledge of laparoscopy. Responses were fine coded for statistical analysis. RESULTS: 79 % of patients felt surgical care was improving in Mongolia, and 76 % would choose laparoscopy if available. Physicians (100 %) felt laparoscopic surgery had improved surgical care in Mongolia. Barriers to care for patients were time to work up and diagnosis (37 %), and funding an operation (39 %). None of the 36 % of patients who stated funding an operation would be difficult identified government sources of funding (p < 0.001). Physicians identified insufficient equipment supply (69 %), insufficient training (41 %), and cost (38 %) as barriers for laparoscopy. 74 % of physicians felt that Mongolian physicians return or stay in Mongolia after training, defying the trend of migration in low-resource settings. DISCUSSION: Improved local patient and physician perception of laparoscopy is propelling the expansion of laparoscopy in Mongolia.

Normative spino-pelvic parameters in patients with the lumbarization of S1 compared to a normal asymptomatic population.

INTRODUCTION: Normal spino-pelvic values for patients with lumbarization of S1 have not been described in the literature. Presented are the normal values for this population group, the prevalence of S1 lumbarization, and the correlation between pelvic incidence (PI) and lumbar lordosis (LL) in this group. METHODS: Two databases of asymptomatic patients were combined to identify 11 patients with the lumbarization of S1. The whole spine images were used to measure the true prevalence rate. Lumbar 3D EOS models were built to measure spino-pelvic parameters for the lumbarization group compared to the asymptomatic population. Seven patients appeared at first to have six lumbar vertebrae, but counting caudally from C2 showed this was not the case. RESULTS: 11/268 patients demonstrated the lumbarization of S1 to give a true prevalence rate of 4.1 %. The lumbarization group demonstrated a statistically significant difference with regard to PI, PT, and SS, and total lordosis measured from superior endplate of L1 to the superior endplate of the first fixed sacral segment. L6I was not significantly correlated to lordosis; however, PI did have a significant correlation with lordosis. Lordosis could be estimated in this group by the equation: [Formula: see text]. CONCLUSION: Incomplete imaging of the spine may lead to false estimation of the prevalence of lumbarization. Patients with lumbarization have higher lordosis values and lordosis can now be estimated during pre-operative planning for this group.

Variations in survival time for amalgam and resin composite restorations: a population based cohort analysis.

OBJECTIVE: To estimate the association between the restorative material used and time to further treatment across population cohorts with universal coverage for dental treatment. BASIC RESEARCH DESIGN: Cohort study of variation in survival time for tooth restorations over time and by restoration material used based on an Accelerated Failure Time model. CLINICAL SETTING: Primary dental care clinics. PARTICIPANTS: Members of Canada's First Nations and Inuit population covered by the Non-Insured Health Benefits program of Health Canada for the period April 1, 1999 to March 31, 2012. INTERVENTION: Tooth restorations using resin composite or amalgam material. MAIN OUTCOME: Survival time of restoration to further treatment. RESULTS: Median survival time for resin composite was 51 days longer than amalgam, for restorations placed in 1999-2000. This difference was not statistically significant (p⟩0.05). Median survival times were lower for females, older subjects. Those visiting the dentist annually, and decreased monotonically over time from 11.2 and 11.3 years for resin composite and amalgam restorations respectively placed in 1999-2000 to 6.9 and 7.0 years for those placed in 2009-10. CONCLUSIONS: Resin composite restorations performed no better than amalgams over the study period, but cost considerably more. With the combination of the overall decrease in survival times for both resin composite and amalgam restorations and the increase in use of resin composite, the costs of serving Health Canada's Non-Insured Health Benefits population will rise considerably, even without any increase in the incidence of caries.

Factors associated with neurocognitive test performance at baseline: a substudy of the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial.

OBJECTIVES: We describe neuropsychological test performance (NP) in antiretroviral treatment (ART)-naïve HIV-positive individuals with CD4 cell counts above 500 cells/µL. METHODS: In a neurology substudy of the International Network for Strategic Initiatives in Global HIV Trials (INSIGHT) Strategic Timing of AntiRetroviral Treatment (START) study, eight neurocognitive tests were administered. The primary measure of NP was the quantitative NP z-score (QNPZ-8), the average of the z-scores for the eight tests. Associations of baseline factors with QNPZ-8 scores were assessed by multiple regression. Mild neurocognitive impairment (NCI) was defined as z-scores < -1 in at least two of six cognitive domains. RESULTS: A total of 608 participants had a median age of 34 years; 11% were women and 15% were black; the median time since HIV diagnosis was 0.9 years; the median CD4 cell count was 633 cells/µL; 19.9% had mild NCI. Better NP was independently associated with younger age, being white, higher body mass index (0.10 per 10 kg/m(2) higher), and higher haematocrit percentage (0.19 per 10% higher). Worse NP was associated with longer time since HIV diagnosis (-0.17 per 10 years), diabetes (-0.29) and higher Framingham risk score (-0.15 per 10 points higher). QNPZ-8 scores differed significantly between geographical locations, with the lowest scores in Brazil and Argentina/Chile. CONCLUSIONS: This is the largest study of NP in ART-naïve HIV-positive adults with CD4 counts > 500 cells/µL. Demographic factors and diabetes were most strongly associated with NP. Unmeasured educational/sociocultural factors may explain geographical differences. Poorer NP was independently associated with longer time since HIV diagnosis, suggesting that untreated HIV infection might deleteriously affect NP, but the effect was small.

Ketamine for rapid reduction of suicidal ideation: a randomized controlled trial.

BACKGROUND: Suicide is a devastating public health problem and very few biological treatments have been found to be effective for quickly reducing the intensity of suicidal ideation (SI). We have previously shown that a single dose of ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, is associated with a rapid reduction in depressive symptom severity and SI in patients with treatment-resistant depression. METHOD: We conducted a randomized, controlled trial of ketamine in patients with mood and anxiety spectrum disorders who presented with clinically significant SI (n = 24). Patients received a single infusion of ketamine or midazolam (as an active placebo) in addition to standard of care. SI measured using the Beck Scale for Suicidal Ideation (BSI) 24 h post-treatment represented the primary outcome. Secondary outcomes included the Montgomery-Asberg Depression Rating Scale--Suicidal Ideation (MADRS-SI) score at 24 h and additional measures beyond the 24-h time-point. RESULTS: The intervention was well tolerated and no dropouts occurred during the primary 7-day assessment period. BSI score was not different between the treatment groups at 24 h (p = 0.32); however, a significant difference emerged at 48 h (p = 0.047). MADRS-SI score was lower in the ketamine group compared to midazolam group at 24 h (p = 0.05). The treatment effect was no longer significant at the end of the 7-day assessment period. CONCLUSIONS: The current findings provide initial support for the safety and tolerability of ketamine as an intervention for SI in patients who are at elevated risk for suicidal behavior. Larger, well-powered studies are warranted.

Depletion of Uhrf1 inhibits chromosomal DNA replication in Xenopus egg extracts.

UHRF1 (ubiquitin-like, containing PHD and RING finger domains 1) has a well-established role in epigenetic regulation through the recognition of various histone marks and interaction with chromatin-modifying proteins. However, its function in regulating cell cycle progression remains poorly understood and has been largely attributed to a role in transcriptional regulation. In this study we have used Xenopus laevis egg extracts to analyse Uhrf1 function in DNA replication in the absence of transcriptional influences. We demonstrate that removal of Uhrf1 inhibits chromosomal replication in this system. We further show that this requirement for Uhrf1, or an associated factor, occurs at an early stage of DNA replication and that the consequences of Uhrf1 depletion are not solely due to its role in loading Dnmt1 onto newly replicated DNA. We describe the pattern of Uhrf1 chromatin association before the initiation of DNA replication and show that this reflects functional requirements both before and after origin licensing. Our data demonstrate that the removal of Xenopus Uhrf1 influences the chromatin association of key replication proteins and reveal Uhrf1 as an important new factor required for metazoan DNA replication.

Free tissue transfer in head and neck reconstruction: 100 consecutive cases.

OBJECTIVES: Free flap reconstruction of head and neck defects is a rapidly changing field. We present a case series in this field in which we critically assess our survival rates and complications, and we highlight specific technical variables that may be associated with improved outcomes. METHODOLOGY: This case series from a tertiary medical centre comprises 100 consecutive head and neck microvascular free flap reconstructions. Medical notes were reviewed specifically for indications, adjuvant and neoadjuvant chemoradiotherapy, complications, and outcome of the free flap. RESULTS: The overall flap survival rate was 99%, with a 6% return-to-theatre rate. Three cases had a general complication in the form of a non-flap compromising haematoma that necessitated a return to theatre for an evacuation. Specific microvascular anastomosis-related complication rate was 2% requiring salvage revision. One flap was lost due to infection. Of the 100 cases, 87% were fasciocutaneous free flaps, 7% were musculocutaneous, 5% were osseocutaneous, and one was a skin/cartilage free flap. With regard to indications for reconstruction, oncological resection accounted for 86% of cases; a total of 12% had mandibular bone involvement that required osseocutaneous reconstruction. CONCLUSIONS: We have highlighted specific technical steps we used that may have contributed to our positive results. Moreover, we encourage the use of standardised postoperative monitoring guidelines for all multidisciplinary surgical teams involved in head and neck patients; they facilitate communication and increase early detection of complications, permitting timely intervention, which may be critical for flap survival.

Re-engineered p53 activates apoptosis in vivo and causes primary tumor regression in a dominant negative breast cancer xenograft model.

Inactivation of p53 pathway is reported in more than half of all human tumors and can be correlated to malignant development. Missense mutation in the DNA binding region of p53 is the most common mechanism of p53 inactivation in cancer cells. The resulting tumor-derived p53 variants, similar to wild-type (wt) p53, retain their ability to oligomerize via the tetramerization domain. Upon hetero-oligomerization, mutant p53 enforces a dominant negative effect over active wt-p53 in cancer cells. To overcome this barrier, we have previously designed a chimeric superactive p53 (p53-CC) with an alternative oligomerization domain capable of escaping transdominant inhibition by mutant p53 in vitro. In this report, we demonstrate the superior tumor suppressor activity of p53-CC and its ability to cause tumor regression of the MDA-MB-468 aggressive p53-dominant negative breast cancer tumor model in vivo. In addition, we illustrate the profound effects of the dominant negative effect of endogenous mutant p53 over wt-p53 in cancer cells. Finally, we investigate the underlying differential mechanisms of activity for p53-CC and wt-p53 delivered using viral-mediated gene therapy approach in the MDA-MB-468 tumor model.

STARTING A LAPAROSCOPIC SURGERY PROGRAMME IN THE SECOND LARGEST TEACHING HOSPITAL IN GHANA.

BACKGROUND: Komfo Anokye Teaching Hospital (KATH) is the second largest hospital in Ghana. Two years have elapsed after performance of the first laparoscopic cholecystectomy. OBJECTIVES: To examine our experience and lessons learned. DESIGN: Retrospective review. SETTING: Komfo Anokye Teaching Hospital (KATH). SUBJECTS: We reviewed leadership support, the role of a surgeon champion, training of physician and OR staff, influence of surgeons from outside Ghana and equipment status. The results of laparoscopic cholecystectomies performed from 2010-2012 were compared with information available from open cholecystectomies over the same period. RESULTS: Evidence of leadership support included equipment purchase and invitation of outside experts yearly from 2008. A KATH surgeon champion was identified in 2010. A dedicated OR team received training and exhibited excellent ownership of equipment preparation. Since 2010, 25 laparoscopic cholecystectomies have been performed, 17 independently by a single surgeon. Average operative time was 1.41 hours and length of stay (LOS) 1.5 days. Conversion rate was 4.0% (1/25). Complication rate was 20.0% (5/25), none involving haemorrhage or injuries to bile ducts or bowel. Median patient satisfaction score was 5 on a scale of 1-5 where 5 is most satisfied. Complication rates and hospital stay were lower than for open cholecystectomy (20.0% vs 34.5%, p > 0.05 and 1.5 days vs 6.6 days, p < 0.001 respectively). Operative times were on average 27 min onger for laparoscopic cholecystectomy (p < 0.01). CONCLUSION: Laparoscopic cholecystectomy at KATH has become a reality with less complications rates, shorter LOS, and trends towards improved patient satisfaction. Expanding laparoscopic surgery in Ghana requires its inclusion into residency training programmes and public education about its benefits for both patients and physicians.