A novel approach in breast reconstruction: The extended lateral thoracic flip-over flap combined with loops and lipofilling (ELT FOLL).

INTRODUCTION: The use of the thoracodorsal musculocutaneous flap has been limited to donor site complications, whereas the thoracodorsal fasciocutaneous flap spares the muscle and limits morbidities. Our objective is to describe a new technique of breast reconstruction using an extended lateral thoracic (ELT) flip-over flap combined with loops and lipofilling (ELT FOLL) to achieve better breast remodeling. METHODS: Between 2013 and 2018, 64 patients underwent breast reconstruction using an ELT FOLL. The flap is designed in an elliptical transverse pattern and extends 2 cm lateral to the back midline up to the breast axis at the level of the inframammary fold. The surgical technique consists of an infiltration and tunnelization of the breast recipient site and surrounding area, deepithelialization of the skin paddle, and additional preparation of the flaps and loops. Liposuction is performed using the power-assisted liposuction and lipofilling technique, and lipofilling is achieved throughout the thoracic cutaneous surface of the reconstructed site, particularly into the lower quadrant of the breast. RESULTS: Among the reconstructions, 73.4% was delayed and 92.2% was unilateral. A fourth of the patients were smokers, and 39.1% received radiotherapy. The total complication rate was 8.7%, the patient's shoulder function was not affected at long term, with the DASH score rising from 6.53 preoperatively to 11.32 at 6 weeks and 7.52 at 6 months. The average operative time was 57 min, and drains were removed at day one after surgery. CONCLUSION: The ELT FOLL should be considered a simple, safe, and reliable alternative for breast reconstruction.

Development of a Resonant Microwave Sensor for Sediment Density Characterization.

In this study, a sensor based on the development of a planar antenna immersed in sediments dedicated to water content monitoring in this type of material is proposed and experimentally validated. It is produced by a conventional Printed Circuit Board (PCB) manufacturing process on a double-sided metalized FR4 substrate. The sensitivity of the sensor is ensured by the variation of the real part of the complex dielectric permittivity of sediments with water content at around 1 GHz. As shown, in this frequency range, electrode polarization and Maxwell-Wagner polarization effects become negligible, leading to only a bulk water polarization sensitivity. The sensor operates in the reflection mode by monitoring the variation of the resonant frequency as a function of the sediment density through the S11 reflection measurements. An experimental sensitivity of 820   MHz . g - 1 . cm 3 was achieved. Despite the simplification of data interpretation at the considered frequency, the influence of ionic species such as NaCl in sediments on the real part of the relative complex dielectric permittivity is highlighted. This demonstrates the importance of considering a second parameter such as the S11 level at low frequency or the electrical conductivity to extract the density from the frequency measurements.

Non-competitive cyclic peptides for targeting enzyme-substrate complexes.

Affinity reagents are of central importance for selectively identifying proteins and investigating their interactions. We report on the development and use of cyclic peptides, identified by mRNA display-based RaPID methodology, that are selective for, and tight binders of, the human hypoxia inducible factor prolyl hydroxylases (PHDs) - enzymes crucial in hypoxia sensing. Biophysical analyses reveal the cyclic peptides to bind in a distinct site, away from the enzyme active site pocket, enabling conservation of substrate binding and catalysis. A biotinylated cyclic peptide captures not only the PHDs, but also their primary substrate hypoxia inducible factor HIF1-α. Our work highlights the potential for tight, non-active site binding cyclic peptides to act as promising affinity reagents for studying protein-protein interactions.

Wnt ligands influence tumour initiation by controlling the number of intestinal stem cells.

Many epithelial stem cell populations follow a pattern of stochastic stem cell divisions called 'neutral drift'. It is hypothesised that neutral competition between stem cells protects against the acquisition of deleterious mutations. Here we use a Porcupine inhibitor to reduce Wnt secretion at a dose where intestinal homoeostasis is maintained despite a reduction of Lgr5+ stem cells. Functionally, there is a marked acceleration in monoclonal conversion, so that crypts become rapidly derived from a single stem cell. Stem cells located further from the base are lost and the pool of competing stem cells is reduced. We tested whether this loss of stem cell competition would modify tumorigenesis. Reduction of Wnt ligand secretion accelerates fixation of Apc-deficient cells within the crypt leading to accelerated tumorigenesis. Therefore, ligand-based Wnt signalling influences the number of stem cells, fixation speed of Apc mutations and the speed and likelihood of adenoma formation.

1,25-Dihydroxycholecalciferol (calcitriol) modifies uptake and release of 25-hydroxycholecalciferol in skeletal muscle cells in culture.

The major circulating metabolite of vitamin D3, 25-hydroxycholecalciferol [25(OH)D], has a remarkably long half-life in blood for a (seco)steroid. Data from our studies and others are consistent with the hypothesis that there is a role for skeletal muscle in the maintenance of vitamin D status. Muscle cells internalise vitamin D-binding protein (DBP) from the circulation by means of a megalin/cubilin plasma membrane transport mechanism. The internalised DBP molecules then bind to actin and thus provide an intracellular array of high affinity binding sites for its specific ligand, 25(OH)D. There is evidence that the residence time for DBP in muscle cells is short and that it undergoes proteolytic degradation, releasing bound 25(OH)D. The processes of internalisation of DBP and its intracellular residence time, bound to actin, appear to be regulated. To explore whether 1,25-dihydroxycholecalciferol (calcitriol) has any effect on this process, cell cultures of myotubes and primary skeletal muscle fibers were incubated in a medium containing 10-10M calcitriol but with no added DBP. After 3h pre-incubation with calcitriol, the net uptake of 25(OH)D by these calcitriol-treated cells over a further 4h was significantly greater than that in vehicle-treated control cells. This was accompanied by a significant increase in intracellular DBP protein. However, after 16h of pre-incubation with calcitriol, the muscle cells showed a significantly depressed ability to accumulate 25(OH)D compared to control cells over a further 4 or 16hours. These effects of pre-incubation with calcitriol were abolished in fibers from VDR-knockout mice. The effect was also abolished by the addition of 4,4'-diisothiocyano-2,2'-stilbenedisulfonic acid (DIDS), which inhibits chloride channel opening. Incubation of C2 myotubes with calcitriol also significantly reduced retention of previously accumulated 25(OH)D after 4 or 8h. It is concluded from these in vitro studies that calcitriol can modify the DBP-dependent uptake and release of 25(OH)D by skeletal muscle cells in a manner that suggests some inducible change in the function of these cells.

Fludarabine-based reduced intensity regimen for matched related donor hematopoietic stem cell transplantation in acquired severe aplastic anemia.

Different conditioning regimens have been evaluated in matched-related donor allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acquired severe aplastic anemia (SAA) with varying results. In this manuscript, we report our experience with fludarabine (120mg/m2), very low dose cyclophosphamide (1200mg/m2) and antithymocyte globulin (7.5mg/kg). Low dose total body irradiation (2Gy) was added to the conditioning regimen for patients older than 15 years. Nineteen patients (median age 23years) underwent transplant between 2008 and 2015. The majority (89%) were younger than 40 years. Stem cell source was BM (n=11) or PBSC (n=8). GvHD prophylaxis consisted of cyclosporine and either a short course of methotrexate (n=9) or mycophenolate mofetil (n=10). Eighteen (94.7%) patients achieved sustained engraftment. The median times to neutrophil and platelet engraftments were 19 (range: 14-34) and 17.1 (range: 12-25) days, respectively. The day-30 cumulative incidence of neutrophil and platelet engraftment was 89.4% and 94.7%, respectively. No secondary graft rejection was observed. The 1-year cumulative incidence of aGvHD (grade II-IV) and cGvHD was 11.7% and 0%, respectively. The 2-year GvHD-free survival rate was 78.6% (95% CI: 52.5-91.4%). Fludarabine-based reduced intensity regimen for MRD allo-HSCT in SAA compares favorably to other available regimens. This regimen deserves further investigations with larger cohort of patients.

[Treatment of macular hematoma complicating AMD by vitrectomy, subretinal r-TPA injection, intravitreal injection of bevacizumab combined with gas tamponade: Report of 4 cases]. / Traitement des hématomes maculaires compliquant la DMLA par vitrectomie, injection sous-rétinienne r-TPA, injection intravitréenne de bévacizumab associé à un tamponnement par gaz : à propos de 4 cas.

INTRODUCTION: The occurrence of a subretinal hematoma in age-related macular degeneration (AMD) is a serious complication that can impact the visual prognosis with a poor functional recovery. The management of this complication remains controversial. Several therapeutic methods have been described. We report the results of four patients treated with a protocol combining: vitrectomy, subretinal injection of r-TPA 0.025mg/0.3ml, intravitreal injection of 0.05ml of bevacizumab and retinal tamponade with 20% SF6 gas. PATIENTS AND METHODS: Our series consists of four patients with a submacular hematoma complicating AMD, included in succession between October 2013 and October 2014 and treated with the same treatment protocol and by the same surgeon. All patients underwent surgery within eight days after the onset of the macular hematoma. Patients with a consultation period longer than eight days did not undergo this treatment. Face down postoperative positioning was then carried out for seven days by the patients. RESULTS: We observed a shift in the macular hematoma in the four patients, which allowed the identification of secondary neovascularization responsible for the bleeding. The visual acuity improved in three patients from hand motion (HM) preoperatively to 2/10 at one month postoperatively. One patient maintained visual acuity 1/20 during the entire follow-up despite almost complete resorption of the subretinal hematoma. These visual acuities were stable at 6 months postoperatively. DISCUSSION: Macular subretinal hematoma can cause severe visual loss by several mechanisms. The blood accumulates between the neurosensory retina and the retinal pigment epithelium, which causes a toxic effect on the surrounding tissues, thus resulting in a loss of photoreceptors and cellular destruction in the pigment epithelium and choriocapillaris, evolving into a fibroglial scar. CONCLUSION: The therapeutic evaluation of this protocol in our series of four patients gives a favorable result. We observed an improvement in visual acuity in 3/4 of cases. This surgical technique appears to be effective in the treatment of this complication of AMD. However, a study on a larger scale is needed to confirm these results.

Sunlight exposure is just one of the factors which influence vitamin D status.

Studies on the determinants of vitamin D status have tended to concentrate on input - exposure to ultraviolet B radiation and the limited sources in food. Yet, vitamin D status, determined by circulating concentrations of 25-hydroxyvitamin D (25(OH)D), can vary quite markedly in groups of people with apparently similar inputs of vitamin D. There are small effects of polymorphisms in the genes for key proteins involved in vitamin D production and metabolism, including 7-dehydrocholesterol reductase, which converts 7-dehydrocholesterol, the precursor of vitamin D, to cholesterol, CYP2R1, the main 25-hydroxylase of vitamin D, GC, coding for the vitamin D binding protein which transports 25(OH)D and other metabolites in blood and CYP24A1, which 24-hydroxylates both 25(OH)D and the hormone, 1,25-dihydroxyvitamin D. 25(OH)D has a highly variable half-life in blood. There is evidence that the half-life of 25(OH)D is affected by calcium intake and some therapeutic agents. Fat tissue seems to serve as a sink for the parent vitamin D, which is released mainly when there are reductions in adiposity. Some evidence is presented to support the proposal that skeletal muscle provides a substantial site of sequestration of 25(OH)D, protecting this metabolite from degradation by the liver, which may help to explain why exercise, not just outdoors, is usually associated with better vitamin D status.

The effect of parathyroid hormone on the uptake and retention of 25-hydroxyvitamin D in skeletal muscle cells.

Data from our studies, and those of others, support the proposal that there is a role for skeletal muscle in the maintenance of vitamin D status. We demonstrated that skeletal muscle is able to internalise extracellular vitamin D binding protein, which then binds to actin in the cytoplasm, to provide high affinity binding sites which accumulate 25-hydroxyvitamin D3 (25(OH)D3) [1]. This study investigated the concentration- and time-dependent effects of parathyroid hormone (PTH) on the capacity of muscle cells to take up and release 3H-25(OH)D3. Uptake and retention studies for 3H-25(OH)D3 were carried out with C2C12 cells differentiated into myotubes and with primary mouse muscle fibers as described [1]. The presence of PTH receptors on mouse muscle fibers was demonstrated by immunohistochemistry and PTH receptors were detected in differentiated myotubes, but not myoblasts, and on muscle fibers by Western blot. Addition of low concentrations of vitamin D binding protein to the incubation media did not alter uptake of 25(OH)D3. Pre-incubation of C2 myotubes or primary mouse muscle fibers with PTH (0.1 to 100 pM) for 3h resulted in a concentration-dependent decrease in 25(OH)D3 uptake after 4 or 16h. These effects were significant at 0.1 or 1pM PTH (p<0.001) and plateaued at 10pM, with 25(OH)D3 uptake reduced by over 60% (p<0.001) in both cell types. In C2 myotubes, retention of 25(OH)D3 was decreased after addition of PTH (0.1 to 100pM) in a concentration-dependent manner by up to 80% (p<0.001) compared to non-PTH treated-C2 myotubes. These data show that muscle uptake and retention of 25(OH)D3 are modulated by PTH, a physiological regulator of mineral homeostasis, but the cell culture model may not be a comprehensive reflection of vitamin D homeostatic mechanisms in whole animals.

First report of pediatric hematopoietic stem cell transplantation activities in the eastern mediterranean region from 1984 to 2011: on behalf of the pediatric cancer working committee of the eastern mediterranean blood and marrow transplantation group.

To describe the hematopoietic stem cell transplantation (HSCT) activities for children in the Eastern Mediterranean (EM) region, data on transplants performed for children less than 18 years of age between 1984 and 2011 in eight EM countries (Egypt, Iran, Jordan, Lebanon, Oman, Pakistan, Saudi Arabia and Tunisia) were collected. A total of 5187 transplants were performed, of which 4513 (87%) were allogeneic and 674 (13%) were autologous. Overall, the indications for transplantation were malignant diseases in 1736 (38.5%) and non-malignant in 2777 (61.5%) patients. A myeloablative conditioning regimen was used in 88% of the allografts. Bone marrow (BM) was the most frequent source of stem cells (56.2%), although an increasing use of PBSC was observed in the last decade. The stem cell source of autologous HSCT has shifted over time from BM to PBSC, and 80.9% of autologous HSCTs were from PBSCs. The donors for allogeneic transplants were matched-related in 94.5% of the cases, and unrelated transplants, mainly cord blood (99%) in 239 (5.5%) cases. This is the first report to describe the pediatric HSCT activities in EM countries. Non-malignant disorders are the main indication for allogeneic transplantation. Frequency of alternate donor transplantation is low.

[Analysis of the quality of data issued from Beirut's hospitals in order to measure short-term health effects of air pollution]. / Analyse de la qualité des données issues des hôpitaux de Beyrouth Municipe pour mesurer les effets à court terme de la pollution atmosphérique.

BACKGROUND: The effects of air pollution on human health have been the subject of much public health research. Several techniques and methods of analysis have been developed. Thus, Beirut Air Pollution and Health Effects (BAPHE) was designed to develop a methodology adapted to the context of the city of Beirut in order to quantify the short-term health effects of air pollution. METHODS: The quality of data collected from emergency units was analyzed in order to properly estimate hospitalizations via these units. This study examined the process of selecting and validating health and pollution indicators. RESULTS: The different sources of data from emergency units were not correlated. BAPHE was therefore reoriented towards collecting health data from the emergency registry of each hospital. A pilot study determined the appropriate health indicators for BAPHE and created a classification methodology for data collection. CONCLUSION: In Lebanon, several studies have attempted to indirectly assess the impact of air pollution on health. They had limitations and weaknesses and offered no recommendations regarding the sources and quality of data. The present analysis will be useful for BAPHE and for planning further studies.

Evidence for a specific uptake and retention mechanism for 25-hydroxyvitamin D (25OHD) in skeletal muscle cells.

Little is known about the mechanism for the prolonged residence time of 25-hydroxyvitamin D (25OHD) in blood. Several lines of evidence led us to propose that skeletal muscle could function as the site of an extravascular pool of 25OHD. In vitro studies investigated the capacity of differentiated C2 murine muscle cells to take up and release 25OHD, in comparison with other cell types and the involvement of the membrane protein megalin in these mechanisms. When C2 cells are differentiated into myotubes, the time-dependent uptake of labeled 25OHD is 2-3 times higher than in undifferentiated myoblasts or nonmuscle osteoblastic MG63 cells (P < .001). During in vitro release experiments (after 25OHD uptake), myotubes released only 32% ± 6% stored 25OHD after 4 hours, whereas this figure was 60% ± 2% for osteoblasts (P < .01). Using immunofluorescence, C2 myotubes and primary rat muscle fibers were, for the first time, shown to express megalin and cubilin, endocytotic receptors for the vitamin D binding protein (DBP), which binds nearly all 25OHD in the blood. DBP has a high affinity for actin in skeletal muscle. A time-dependent uptake of Alexafluor-488-labeled DBP into mature muscle cells was observed by confocal microscopy. Incubation of C2 myotubes (for 24 hours) with receptor-associated protein, a megalin inhibitor, led to a 40% decrease in 25OHD uptake (P < .01). These data support the proposal that 25OHD, after uptake into mature muscle cells, is held there by DBP, which has been internalized via membrane megalin and is retained by binding to actin.

Complete heart block in a patient with acute lymphoblastic leukaemia: teicoplanin as a possible cause and review of literature.

WHAT IS KNOWN AND OBJECTIVE: Teicoplanin is a glycopeptide antibiotic used against documented or presumed methicillin-resistant infections. We report a 31-month-old boy with acute lymphocytic leukaemia who developed permanent complete atrioventricular block (CAVB) necessitating pacemaker insertion after receiving teicoplanin for Staphylococcus epidermidis bacteremia. CASE SUMMARY: Clinical assessment of the child revealed febrile neutropenia. After thorough assessment and work-up, the patient was started on teicoplanin intravenously after which he had sudden onset of bradycardia. Electrocardiography showed CAVB that eventually required permanent pacemaker insertion. Twenty-nine months from the incident, the patient is doing well. WHAT IS NEW AND CONCLUSION: We report on a case of teicoplanin-associated CAVB in a child with acute lymphoblastic leukaemia (ALL). This is one of only two similar cases reported in the literature. Teicoplanin remains the most probable cause. The use of teicoplanin should be approached cautiously in the setting of immunosuppression. Whether VZV contributed and teicoplanin triggered remains speculative. Physicians should be aware of this possible complication.

A preliminary investigation of Beta-hCG expression in patients with osteosarcoma.

There are eight reported cases in the literature of osteosarcomas secreting ß-hCG. Our primary aim was to investigate the rate of ß-hCG expression in osteosarcoma and attempt to understand the characteristics of osteosarcomas that secrete ß-hCG. We reviewed 37 histopathology slides (14 biopsies and 23 surgical specimens) from 32 patients with osteosarcoma. The slides were retrospectively stained for ß-hCG expression. Patient and tumour characteristics, including age, gender, tumour location, subtype, proportion of necrosis, presence of metastases and recurrence were recorded. A total of five of the 32 tumours were found to be positive for ß-hCG expression (one strongly and four weakly). This incidence of this expression was found in tumours with poor histological response to neoadjuvant chemotherapy. The use of ß-hCG expression as a diagnostic, prognostic or follow-up marker is questionable and needs further investigation with a larger sample size.

Predictors of bone loss in childhood hematologic malignancies: a prospective study.

SUMMARY: Twenty-nine children with malignancies and age, gender-matched controls were prospectively studied over 14 months. Patients had higher parathyroid hormone (PTH) levels and fat mass, lower bone mass, and bone mass increments at follow-up than controls. Lean mass, age at diagnosis, systemic and intrathecal therapy were predictors of bone mass changes on adjusted analyses. INTRODUCTION: Children with hematologic malignances have low bone mass. We prospectively investigated anthropometric, clinical, and hormonal predictors of changes in bone mass in children receiving cancer therapy. METHODS: Twenty-nine children, mean age of 9 ± 2.9 years and 32 age and gender-matched controls, were studied. Seven had completed their course 40 ± 22 weeks prior, while 22 were still receiving therapy for 80 ± 28 weeks. Age at diagnosis, calcium intake, exercise activity, systemic corticosteroids in dexamethasone (Dex) dose, and methotrexate (MTX), and intrathecal MTX therapy received within follow-up period were assessed. Routine chemistries, PTH, 25-hydroxy vitamin D (25-OHD), bone remodeling markers, bone mass, and body composition were measured at baseline and 14 months. RESULTS: Patients had lower exercise activity, sun exposure, and bone markers levels than controls. They had higher PTH levels and fat mass, lower bone mass at the spine, hip, and total body, and lower increments at these sites on follow-up. Predictors of bone mass changes on univariate analyses were: age at diagnosis (R = -0.50 to -0.44, p < 0.05), Dex-MTX doses (R = -0.58 to -0.41, p < 0.05), intrathecal therapy (p < 0.03),% changes in lean mass (R = 0.37 to 0.54, p < 0.04), 25-OHD levels (R = 0.39, p < 0.03), and PTH levels (R = -0.47 to -0.41, p < 0.05). Lean mass, age at diagnosis, systemic and intrathecal therapy were predictors of bone mass changes on adjusted analyses. CONCLUSION: This study provides insight into the pathophysiology of bone loss in children receiving cancer therapy and possible interventions to optimize their skeletal health.

Zinc and biotin deficiencies after pancreaticoduodenectomy.

We report zinc and biotin deficiencies after pancreaticoduodenectomy in a 16 year old female presenting clinically with marked alopecia, total body hair loss, dry skin with scales, and maculopathy with significant vision loss. These micronutrient deficiencies likely occurred due to resection of the duodenum and proximal jejunum, sites of primary absorption of several micronutrients and their protein carriers, including zinc and biotin. Early diagnosis is essential to prevent irreversible sequelae. Adequate supplementation of zinc and biotin as well as dietary advice is needed for clinical improvement.

Correlation of plasma resistin with obesity and insulin resistance in type 2 diabetic patients.

AIM: The aim of this case-control study was to assess the relationship between resistin levels and obesity and insulin resistance in type 2 diabetic patients. METHODS: The study involved a sample of the Jordanian population that included 140 type 2 diabetic patients and 125 control subjects. RESULTS: Serum resistin levels were higher in type 2 diabetic patients compared with the controls (P<0.01). Markers of adiposity [body mass index (BMI) and waist circumference (WC)] and insulin resistance, as well as fasting blood glucose, glycated haemoglobin, urea and blood pressure were considerably higher among the studied diabetics than in the controls. When diabetic patients were subdivided into age-group categories of 10-year intervals, resistin levels significantly increased with increased age, with a significant proportion in the group aged>60 years (P<0.01). Similarly, there was a significant association between plasma resistin and blood urea with growing older in diabetic patients. Pearson's analysis revealed positive correlations between plasma resistin and age, urea, creatinine, insulin, BMI, WC, body-fat content and homoeostasis model assessment (HOMA). Furthermore, plasma resistin concentrations were higher in type 2 diabetic obese patients than in non-diabetic obese subjects (P<0.01), whereas no such difference was found between overweight and normal-weight controls. CONCLUSION: These results suggest that variations in resistin concentrations are not directly related to susceptibility to type 2 diabetes. However, it may be that resistin plays a role in the pathogenesis of obesity and insulin resistance, both of which could, indirectly, contribute to the development of type 2 diabetes.