No benefit of vitamin D supplementation on muscle function and health-related quality of life in primary cardiovascular prevention patients with statin-associated muscle symptoms: A randomized controlled trial.

BACKGROUND: Statins are the leading lipid-lowering drugs, reducing blood cholesterol by controlling its synthesis. Side effects are linked to the use of statins, in particular statin-associated muscle symptoms (SAMS). Some data suggest that vitamin D supplementation could reduce SAMS. OBJECTIVE: The purpose of this study was to evaluate the potential benefits of vitamin D supplementation in a randomized controlled trial. METHODS: Men (n = 23) and women (n = 15) (50.5 ± 7.7 years [mean ± SD]) in primary cardiovascular prevention, self-reporting or not SAMS, were recruited. Following 2 months of statin withdrawal, patients were randomized to supplementation (vitamin D or placebo). After 1 month of supplementation, statins were reintroduced. Before and 2 months after drug reintroduction, muscle damage (creatine kinase and myoglobin) was measured. Force (F), endurance (E) and power (P) of the leg extensors (ext) and flexors (fle) and handgrip strength (FHG) were also measured with isokinetic and handheld dynamometers, respectively. The Short Form 36 Health Survey (SF-36) questionnaire and a visual analog scale (VAS) were administrated to assess participants' self-reported health-related quality of life and SAMS intensity, respectively. Repeated-measures analysis was used to investigate the effects of time, supplementation, and their interaction, according to the presence of SAMS. RESULTS: Despite no change for objective measures, subjective measures worsened after reintroduction of statins, independent of supplementation (VAS, SF-36 mental component score, all p < 0.05). However, no interaction between time and supplementation according to the presence of SAMS was observed for any variables. CONCLUSIONS: Vitamin D supplementation does not appear to mitigate SAMS.

Impact of statin withdrawal on perceived and objective muscle function.

BACKGROUND AND AIMS: Statin-associated muscle symptoms (SAMS) are frequently reported. Nevertheless, few data on objective measures of muscle function are available. Recent data suggesting an important nocebo effect with statin use could confound such effects. The objective was to assess if subjective and objective measures of muscle function improve after drug withdrawal in SAMS reporters. METHODS: Patients (59 men, 33 women, 50.3±9.6 yrs.) in primary cardiovascular prevention composed three cohorts: statin users with (SAMS, n = 61) or without symptoms (No SAMS, n = 15), and controls (n = 16) (registered at clinicaltrials.gov, NCT01493648). Force (F), endurance (E) and power (P) of the leg extensors (ext) and flexors (fle) and handgrip strength (Fhg) were measured using isokinetic and handheld dynamometers, respectively. A 10-point visual analogue scale (VAS) was used to self-assess SAMS intensity. Measures were taken before and after two months of withdrawal. RESULTS: Following withdrawal, repeated-measures analyses show improvements for the entire cohort in Eext, Efle, Ffle, Pext and Pfle (range +7.2 to +13.3%, all p≤0.02). Post-hoc analyses show these changes to occur notably in SAMS (+8.8 to +16.6%), concurrent with a decrease in subjective perception of effects in SAMS (VAS, from 5.09 to 1.85). Fhg was also improved in SAMS (+4.0 to +6.2%) when compared to No SAMS (-1.7 to -4.2%) (all p = 0.02). CONCLUSIONS: Whether suffering from "true" SAMS or nocebo, those who reported SAMS had modest but relevant improvements in muscle function concurrent with a decrease in subjective symptoms intensity after drug withdrawal. Greater attention by clinicians to muscle function in frail statin users appears warranted. TRIAL REGISTRATION: This study is registered in clinicaltrials.gov (NCT01493648).

Influence of the LDL-Receptor Genotype on Statin Response in Heterozygous Familial Hypercholesterolemia: Insights From the Canadian FH Registry.

BACKGROUND: Whether low-density lipoprotein (LDL) receptor (LDLR) residual activity influences the LDL-lowering effect of statins in heterozygous familial hypercholesterolemia (HeFH) remains unclear. The objective of this study was to investigate the relationship between the LDLR genotype and statin-induced LDL cholesterol (LDL-C) reductions in HeFH. METHODS: A total of 615 individuals with HeFH (receptor-defective [RD] genotype: n = 226; receptor-negative [RN] genotype: n = 389) from 7 lipid clinics across Canada who initiated statin monotherapy were included in this retrospective longitudinal study. Statin-induced reductions in LDL-C among individuals with RD and RN genotypes were compared with the use of linear models. RESULTS: There were 334 women and 281 men with a mean untreated LDL-C concentrations of 6.97 ± 1.65 mmol/L. Untreated and on-statin LDL-C levels where higher among patients with an RN genotype: untreated: RN 7.24 (95% confidence interval [CI] 6.98-7.50) mmol/L vs RD 6.70 (95% CI 6.41-6.98) mmol/L (P = 0.0002); on-statin: RN 4.50 (95% CI 4.31-4.70) vs RD 4.05 (95% CI 3.84-4.26) mmol/L (P = 0.0004). After adjustments for age, sex, smoking status, untreated LDL-C concentrations, statin type and dose, as well as the clinic where the patients were treated, the LDL-C-lowering effect of statins was significantly weaker for individuals with an RN mutation than for individuals with an RD mutation: RN: -31.1% (95% CI -34.7% to -27.4) vs RD -36.5% (95% CI -40.4% to -32.6%); P < 0.0001. The LDLR genotype was the strongest nonmodifiable independent correlate of statin-induced LDL-C reductions (R2 = 2.3%; P = 0.0001). CONCLUSION: The LDLR genotype is significantly associated with statin-induced reductions in LDL-C concentrations in HeFH.

A Homozygous Deep Intronic Mutation Alters the Splicing of Nebulin Gene in a Patient With Nemaline Myopathy.

Nemaline myopathy is a rare disorder affecting the muscle sarcomere. Mutations in nebulin gene (NEB) are known to be responsible for about 50% of nemaline myopathy cases. Nebulin is a giant protein which is formed integrally with the sarcomeric thin filament. This complex gene is under extensive alternative splicing giving rise to multiple isoforms. In this study, we report a 6-year-old boy presenting with general muscular weaknesses. Identification of rod-shaped structures in the patient' biopsy raised doubt about the presence of a nemaline myopathy. Next-generation sequencing was used to identify a causative mutation for the patient syndrome. A homozygous deep intronic substitution was found in the intron 144 of the NEB. The variant was predicted by in silico tools to create a new donor splice site. Molecular analysis has shown that the mutation could alter splicing events of the nebulin gene leading to a significant decrease of isoforms level. This change in the expression level of nebulin could give rise to functional consequences in the sarcomere. These results are consistent with the phenotypes observed in the patient. Such a discovery of variants in this gene will allow a better understanding of the involvement of nebulin in neuromuscular diseases and help find new treatments for the nemaline myopathy.

A founder mutation in the PLPBP gene in families from Saguenay-Lac-St-Jean region affected by a pyridoxine-dependent epilepsy.

Pyridoxine-dependent epilepsy (PDE) is a relatively rare subgroup of epileptic disorders. They generally present in infancy as an early onset epileptic encephalopathy or seizures, refractory to standard treatments, with rapid and variable responses to vitamin B6 treatment. Whole exome sequencing of three unrelated families identified homozygous pathogenic mutation c.370_373del, p.Asp124fs in PLPBP gene in five persons. Haplotype analysis showed a single shared profile for the affected persons and their parents, leading to a hypothesis about founder effect of the mutation in Saguenay-Lac-St-Jean region of French Canadians. All affected probands also shared one single mitochondrial haplotype T2b3 and two rare variations in the mitochondrial genome m.801A>G and m.5166A>G suggesting that a single individual female introduced PLPBP mutation c.370_373del, p.Asp124fs in Quebec. The mutation p.Asp124fs causes a severe disease phenotype with delayed myelination and cortical/subcortical brain atrophy. The most noteworthy radiological finding in this Quebec founder mutation is the presence of the temporal cysts that can be used as a marker of the disease. Also, both patients, who are alive, had a history of prenatal supplements taken by their mothers as antiemetic medication with high doses of pyridoxine. In the context of suspected PDE in patients with neonatal refractory seizures, treatment with pyridoxine and/or Pyridoxal-5-phophate has to be started immediately and continued until the results of genetic analysis received. Even with early appropriate treatment, neurological outcome of our patient is still poor.

Bone Marrow Chimeras to Study Neuroinflammation.

Bone marrow transplantation is the standard of care for a host of diseases such as leukemia and multiple myeloma, as well as genetically inherited metabolic diseases affecting the central nervous system. In mouse models, bone marrow transplantation has proven a valuable tool for understanding the hematopoietic system and the homing of hematopoietic cells to their target organs. Many techniques have been developed to create chimeric mice, animals with a hematopoietic system derived from a genetic background that differs from the rest of the body. Current genetic tools allow for virtually limitless possibilities in the choice of donor mice. This protocol describes methods of bone marrow transplantation in mouse models for studies of the brain under basal and pathological conditions. Specific points to be addressed include the preparation of recipient mice by irradiation or chemotherapy; the choice, isolation, and injection of donor cells; and analytical methods such as fluorescence-activated cell sorting and immunostaining. © 2018 by John Wiley & Sons, Inc.

The fecal immunochemical test (fit): Selected aspects regarding its effectiveness for colorectal cancer screening in Quebec City.

BACKGROUND AND AIMS: FIT's value has been ascertained across Canada and worldwide, but still needs to be assessed within the province of Quebec. There also remains a gap between formal indications for FIT, and its actual use in clinical practice. This research aims to evaluate some aspects of FIT's effectiveness in our setting, and its application by prescribers. METHODS: We retrospectively identified and reviewed all the colonoscopies conducted for a positive FIT in 2014 at 2 hospitals located in Quebec City. RESULTS: Five hundred and fifty-nine (559) colonoscopies were reviewed. We obtained PPVs of 6.8% and 46.9% for the detection of CRC and AA, respectively. The PPV for the detection of SCL was higher in men compared to women (OR 1.56, 95%CI 1.11-2.20) and among justified FITs compared to unwarranted ones (OR 1.88, 95%CI 1.34-2.63). The PPV for CRC detection was 25.0% in the presence of unexplained iron deficiency anemia and 6.5% when anemia was absent (p = 0.0058). In 49.9% of cases, the prescription of a FIT was inappropriate. CONCLUSION: The FIT holds a better PPV for detecting SCL among men and when it is indicated. Anemia is associated with a higher CRC detection rate. Half of the FITs were not initially indicated.

mCSF-Induced Microglial Activation Prevents Myelin Loss and Promotes Its Repair in a Mouse Model of Multiple Sclerosis.

A pathological hallmark of multiple sclerosis (MS) is myelin loss in brain white matter accompanied by compromised remyelination. Demyelinated lesions are deeply associated with oligodendrocyte apoptosis and a robust inflammatory response. Although various studies point towards a noxious role of inflammation in MS, others emphasize a positive role for the innate immune cells in disease progression. A cytokine well-known to stimulate cell survival, proliferation and differentiation of myeloid cells, macrophage colony-stimulating factor (mCSF), was administered to mice during a 5 week-long cuprizone diet. Treated mice exhibited reduced myelin loss during the demyelination phase, together with an increased number of microglia and oligodendrocyte precursor cells in lesion sites. Tamoxifen-induced conditional deletion of the mCSF receptor in microglia from cuprizone-fed mice caused aberrant myelin debris accumulation in the corpus callosum and reduced microglial phagocytic response. mCSF therefore plays a key role in stimulating myelin clearance by the brain innate immune cells, which is a prerequisite for proper remyelination and myelin repair processes.

Sex-based differences in apnoea of prematurity: A retrospective cohort study.

NEW FINDINGS: What is the central question of the study? Is there a sex-based difference in the incidence of apnoea of prematurity and the success or failure of caffeine therapy in preterm infants? What is the main finding and its importance? Our data show that females received fewer days of caffeine treatment than males. This was most noticeable in infants born between 260/7 and 276/7  weeks of gestational age. These results highlight the importance of considering sex in clinical and basic research investigating the pathophysiology of apnoea of prematurity. ABSTRACT: This retrospective cohort study assessed whether sex influences the occurrence of apnoea of prematurity (AOP) in preterm infants. The analysis included a cohort of 24,387 preterm infants born between the gestational ages (GA) of 240/7 and 336/7  weeks that were admitted to tertiary neonatal care units participating in the Canadian Neonatal Network from January 2011 to December 2015. Of those, 13,983 (57%) were diagnosed with AOP. More females were diagnosed with AOP than males, but the difference in the male/female ratio was marginal (P = 0.058). The majority (89%) of infants diagnosed with AOP received caffeine (89% of males; 89% of females). By using the discontinuation of caffeine therapy as a proxy for the resolution of significant AOP, data analysis showed that females born before 336/7 weeks of GA stopped caffeine treatment earlier than males whether the caffeine was discontinued before 34 or 37 weeks of GA. Consequently, females had fewer days of caffeine therapy than males, especially infants born between 260/7 and 276/7  weeks (P < 0.004), 280/7 and 296/7  weeks (P < 0.03), and 320/7 and 336/7  weeks of GA (P < 0.04). Similar trends were observed when the corrected GA at discontinuation of caffeine was used. Given that AOP is indicative of an immature respiratory system, our data suggest that the maturation of the respiratory system might occur more rapidly in females than males. We conclude that sex needs to be considered in future studies on AOP.

Risk Factors for Removal of Calcaneus Screws: A Retrospective Study.

Although techniques using calcaneus screws have shown high union rates, posterior heel pain due to prominent hardware at the posterior and plantar aspect of the calcaneal tuberosity seems to be a significant complaint that often leads to hardware removal. The purpose of the present study was to identify the clinical and radiologic risk factors associated with calcaneus screw removal. A retrospective study of adult patients who required calcaneus screw fixation from January 2008 to December 2016 was conducted. We reviewed the medical records and radiographs to evaluate the risk factors for screw removal. Of the 123 patients included in the present study, 63 were male and 60 were female. The mean age was 55.0 ± 6.0 years, and the mean body mass index was 31.0 ± 6.0 kg/m2. The removal rate was 8.8% (10 of 114 evaluated) at the 1-year follow-up point and 13.6% (12 of 88 evaluated) at the 2-year follow-up point. The mean interval to removal was 1.23 ± 1.22 years. A total of 16 screws (72.7%) were removed for heel pain. At the 1-year follow-up examination, the removal rate due to inflammatory arthritis was 25.0% (p = .07). Moreover, the proportion of screw removal was greater at 2 years in illicit drug users (p = .008). Screw sizes ≤6.5 mm showed a tendency (p = .12) toward a lower rate of removal at the 2-year follow-up point. Calcaneus screws should be used with caution in specific patient populations such as illicit drug users and those with inflammatory arthritis. The use of smaller diameter calcaneus screws might be an option to lower the rate of screw removal due to heel pain.

Impact of lipoprotein apheresis with dextran-sulfate adsorption on the expression of genes involved in cardiovascular health in the blood of patients with homozygous familial hypercholesterolemia.

Lipoprotein apheresis (LA) with dextran sulfate adsorption (DSA) is a reliable method to decrease LDL-cholesterol (C) concentrations in patients with homozygous familial hypercholesterolemia (HoFH). The objective of the present study was to investigate the impact of LA with DSA on the mRNA expression of genes associated with cardiovascular health in the whole blood of HoFH patients. Blood samples were collected before and after LA treatment with DSA in 9 HoFH patients. Microarray analyses were performed to measure the whole blood expression of >30 000 annotated genes pre- and post-LA. Concomitant reductions in LDL-C (median -73.8%, range: -55.9 to -82.0, P = .0001) and lipoprotein (a) concentrations (median -74.1%, range -65.6 to -84.1, P = .003) were induced with LA treatment. LA with DSA did not impact the whole blood mRNA expression of most key genes involved in cardiovascular health, including those associated with cholesterol, fatty acid and lipoprotein metabolism. However, LA with DSA significantly upregulated the whole blood expression of early growth response protein (EGR)1 (1.94-fold, P = .02), EGR3 (1.56-fold, P = .0008) and B-cell lymphoma 3-encoded protein (BCL3; 1.25-fold, P = .03). In conclusion, this study demonstrated that a single LA treatment with DSA has very limited impact on the whole blood expression of a broad spectrum of genes associated with cardiovascular health. Our results suggest that contact between blood cells and the primary membrane or extracorporeal circulation could upregulate the expression of EGR1, EGR3, BCL3, and MMP9 in blood cells.

Distinct Subtypes of Microparticle-containing Immune Complexes Are Associated with Disease Activity, Damage, and Carotid Intima-media Thickness in Systemic Lupus Erythematosus.

OBJECTIVE: Microparticles (MP) are small extracellular vesicles present in body fluids. MP originate from different cellular lineages, principally from platelets in blood, and may expose phosphatidylserine (PS). In systemic lupus erythematosus (SLE), MP harbor immunoglobulin G (IgG), thereby forming MP-containing immune complexes (mpIC). We aimed to verify an association between SLE disease activity, damage, and surrogate markers of atherosclerosis and MP harboring IgG, taking into account the platelet origin and PS exposure of MP. METHODS: MP expressing surface IgG, platelet antigen (CD41+), and PS were quantified using flow cytometry in plasma of 191 women with SLE. Carotid ultrasounds (US) were available in 113 patients. Spearman correlation analysis was used to analyze whether levels of MP were associated with the following outcomes: SLE Disease Activity Index 2000 (SLEDAI-2K), Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI), and carotid US plaques and intima-media thickness (CIMT) as surrogates for vascular damage. RESULTS: We found CD41+ MP harboring IgG present in SLE. A positive correlation was found between SLEDAI-2K and levels of CD41+ MP harboring IgG and exposing (p = 0.027) and non-exposing PS (p = 0.001). Conversely, SDI (p = 0.024) and CIMT (p = 0.016) correlated with concentrations of CD41- MP harboring IgG and exposing PS. Associations were independent of low-density lipoprotein cholesterol level, body mass index, and antimalarial drug use. CONCLUSION: Different subtypes of mpIC are produced in SLE and are associated with distinct clinical characteristics such as disease activity and vascular damage. The assessment of MP subtypes might serve for the design of predictive markers of disease activity and vascular damage in patients.

Comparison of two low-density lipoprotein apheresis systems in patients with homozygous familial hypercholesterolemia.

Low-density lipoprotein (LDL) apheresis (LA) is a reliable method to decrease LDL-C concentrations and remains the gold standard therapy in homozygous familial hypercholesterolemia (HoFH). The objective of this study was to compare the efficacy of two LA systems [heparin-induced extracorporeal LDL precipitation (HELP) vs. dextran sulfate adsorption (DS) on the reduction of lipids, inflammatory markers, and adhesion molecules in a sample of genetically defined HoFH subjects (n = 9)]. Fasting blood samples were collected before and after LA. All subjects served as their own control and were first treated with the HELP system then with DS in this single sequence study. Compared with HELP, DS led to significantly greater reductions in total cholesterol (-63.3% vs. -59.9%; P = 0.05), LDL-C (-70.5% vs. -63.0%; P = 0.02), CRP (-75.3% vs. -48.8%; P < 0.0001), and TNF-α (-23.7% vs. +14.7%; P = 0.003). Reductions in the plasma levels of PCSK9 (-45.3% vs. -63.4%; P = 0.31), lipoprotein (a) (-70.6% vs. -65.0%; P = 0.30), E-selectin (-16.6% vs. -18.3%; P = 0.65), ICAM-1 (-4.0 vs. 5.6%; P = 0.56), and VCAM-1 (8.3% vs. -1.8%; P = 0.08) were not different between the two systems. For the same volume of filtered plasma (3,000 mL), however, HELP led to greater reductions in plasma apoB (-63.1% vs. -58.3%; P = 0.04), HDL-C (-20.6% vs. -6.5%; P = 0.003), and PCSK9 (-63.4% vs. -28.5%; P = 0.02) levels. These results suggest that both LA systems are effective in reducing plasma lipids and inflammatory markers in HoFH. Compared with HELP, greater reductions in lipid levels and inflammatory markers were achieved with DS, most likely because this method allows for a larger plasma volume to be filtered. J. Clin. Apheresis 31:359-367, 2016. © 2015 Wiley Periodicals, Inc.

Inefficient clearance of myelin debris by microglia impairs remyelinating processes.

An imbalance between remyelinating and demyelinating rates underlies degenerative processes in demyelinating diseases such as multiple sclerosis. An optimal therapeutic strategy would be to stimulate remyelination while limiting demyelination. Although accumulation of myelin debris impairs remyelination, the mechanisms regulating the clearance of such debris by mononuclear phagocytic cells are poorly understood. We demonstrate that after cuprizone intoxication, CCR2-dependent infiltration of mouse bone marrow-derived cells is abundant in demyelinating areas, but that these cells do not impact demyelination. However, in CX3CR1-deficient mice, the clearance of myelin debris by microglia was blocked greatly, affecting the integrity of the axon and myelin sheaths and thus preventing proper remyelination. These results highlight the crucial role played by CX3CR1 in myelin removal and show that there can be no efficient remyelination after a primary demyelinating insult if myelin clearance by microglia is impaired.

Hearing outcomes in functional surgery for middle ear malformations.

OBJECTIVES: To standardize the information for families of children having functional surgery for middle ear malformations, we describe the audiometric results of the subgroup of patients with the most favorable anatomic conditions: viable auditory canal, intact tympanic membrane, mobile stapes, and corresponding to a Jahrsdoerfer score of 8 or higher. STUDY DESIGN: Case series, tertiary referral center. METHODS: Charts of patients undergoing functional surgery for congenital middle ear malformations were reviewed for demographic data, preoperative Jahrsdoerfer score, ossicular chain status, type of ossiculoplasty, and audiometric data before and 6 months postsurgery. RESULTS: Eighteen consecutive interventions were performed on 13 patients (average age of 9 years, 8 girls and 5 boys) between 2004 and 2011. The ossiculoplasties performed were as follows: incus repositioning (4), double-layer tragal cartilage (5), intact native chain reconstruction (3), and partial ossicular prosthesis (6). Mean air bone gap (ABG) was 40.8 ± 12.4 dB preoperatively and 20.9 ± 12.9 dB postoperatively (p < 0.0001). Preoperative and postoperatively mean air conduction PTA thresholds were 49.9 ± 9.5 and 30.0 ± 14.1 dB, respectively (p < 0.0001). All ears operated on except one had air conduction improvement. There were no complications. CONCLUSION: Functional surgery for congenital middle ear malformations gives variable hearing outcomes. In this study, with the most favorable anatomic conditions, 12 ears (67%) of 18 had air conduction improvement below 30 dB.

Cysteine-rich secretory protein 1 in seminal plasma: potential biomarker for the distinction between obstructive and nonobstructive azoospermia.

OBJECTIVE: To investigate the presence of cysteine-rich secretory protein 1 (CRISP1) in seminal plasma as a means of distinguishing between obstructive azoospermia (OA) and nonobstructive azoospermia (NOA). DESIGN: Seminal plasma from normospermic donors (n = 45) and azoospermic donors (n = 80) was examined to determine CRISP1 levels. Neutral alpha-glucosidase (NAG) enzymatic activity was measured for comparison with CRISP1 levels. SETTING: Research unit of an academic medical center. PATIENT(S): Normospermic and azoospermic donors from the clinical andrology laboratory of the centre hospitalier universitaire de Québec and from Mount Sinai Hospital. INTERVENTION(S): Seminal CRISP1 measurement by Western blot analysis. Neutral alpha-glucosidase activity was evaluated by a photometric method. MAIN OUTCOME MEASURE(S): Seminal plasma CRISP1 levels, NAG activity, cutoff value, sensitivity, and specificity. RESULT(S): All seminal plasma samples from normospermic and nonobstructive azoospermic donors were CRISP1 positive, whereas CRISP1 was absent or present at low levels in samples from patients with OA. A significant correlation between seminal CRISP1 levels and NAG activity was found in azoospermic semen samples. The cutoff point to distinguish between donors with NOA or OA was established at 0.655 (relative intensity). At this threshold, specificity was 85% and sensitivity was 92%. CONCLUSION(S): Seminal CRISP1 combined with NAG activity can potentially distinguish between OA and NOA.

Management of Bartholin's gland carcinoma using high-dose-rate interstitial brachytherapy boost.

PURPOSE: To describe the patterns of use, clinical outcomes, and dose-volume histogram parameters of high-dose-rate interstitial brachytherapy (HDR-ISBT) in the management of Bartholin's gland cancer. METHODS AND MATERIALS: Five patients with Stage II-III Bartholin's gland carcinoma treated with CT-based HDR-ISBT boost were reviewed. Plans were generated using an inverse planning simulated annealing algorithm. Dose-volume histogram parameters were assessed. The total doses of HDR-ISBT and EBRT were converted to total equivalent dose in 2Gy (EQD2). RESULTS: All 5 patients received HDR-ISBT as a boost (median dose, 30Gy) after EBRT (median dose, 45Gy). Three patients received postoperative irradiation for gross residual tumor or positive surgical margins and 2 patients were treated by primary chemoradiotherapy. The median V100, D90, and D100 for the CTV were 98.3%, 89Gy10, and 64Gy10 (EQD2), respectively. A complete response was observed in all patients. No local recurrence occurred. All patients remain alive and free of disease (median followup, 78 months; range, 8-93). Severe vaginal toxicities were observed, including vaginal necrosis that resolved with hyperbaric oxygen therapy. CONCLUSIONS: HDR-ISBT boost after EBRT offers excellent long-term local control in patients with Bartholin's gland carcinoma. HDR-ISBT should be considered for positive surgical margins or residual tumor after surgery and for locally advanced malignancies treated by primary chemoradiotherapy.

Inverse-planned gynecologic high-dose-rate interstitial brachytherapy: clinical outcomes and dose--volume histogram analysis.

PURPOSE: To present clinical outcomes and dose-volume histogram parameters of three-dimensional image-based high-dose-rate interstitial brachytherapy (HDR-ISBT) in patients with primary or recurrent gynecologic cancer unsuitable for intracavitary brachytherapy (ICB). METHODS AND MATERIALS: Records of 43 women treated between 2001 and 2009 with iridium-192 gynecologic HDR-ISBT boost, using a Syed-Neblett template and inverse planning simulated annealing dose optimization, were reviewed. Median HDR-ISBT dose was 30Gy, delivered in 4-6Gy/fraction. Dose-volume histogram parameters recommended by the Groupe Européen de Curiethérapie-European Society for Therapeutic Radiology and Oncology for image-based ICB were analyzed. Total doses were normalized to 2Gy fractions (biologically equivalent dose in 2Gy fractions). Local control (LC) and survival were calculated using Kaplan-Meier method. Toxicities were defined according to Common Terminology Criteria for Adverse Events v3.0. RESULTS: There were 34 primary malignancies (cervix=12, vagina=15, Bartholin's gland=5, and vulva=2) and 9 recurrences. International Federation of Gynecology and Obstetrics stage distribution for primary cancers was I=2, II=13, III=15, and IV=4. Median followup was 19.3 months (range, 0-92.2). Two-year LC was 87% for primary cancers, and 45% for recurrent cancers, respectively (p=0.0175). Median V(100), D(90), and D(100) for clinical target volume were 97.6%, 90.2, and 68.7Gy(10), respectively. Median bladder and rectal D(2)(cc) were 76.6 and 79.5Gy(3), respectively. Median urethral D(10) was 80.6Gy(3). Twelve patients experienced Grades 3 and 4 late morbidity, but toxicities were transient. Only 2 patients had persistent severe toxicities. A trend toward increased risk for vaginal necrosis was observed with a clinical target volume >84cc. CONCLUSIONS: HDR-ISBT may achieve good LC in gynecologic cancer unsuitable for ICB, especially in primary malignancies with a 2-year LC rate higher than 85%. Delivery of such high doses has potential advantages but may predispose to adverse effects, reversible in most cases.

[Not Available]. / L'opinion des étudiants en médecine de Québec sur les punitions corporelles.

OBJECTIVE: To determine the opinion of medical students attending Laval University (Québec, Québec) regarding the controversial subject of corporal punishment in children. METHOD: For five consecutive years, from the 2006/2007 through to the 2010/2011 school year, an opinion poll was completed by the fourth year medical students at Laval University during a seminar concerning the maltreatment of children. RESULTS: Of the 712 students questioned, 91% were younger than 30 years of age and 74% were female. With respect to the use of corporal punishment on children, 22% of the respondents declared they were in favour of it. More men than women were in favour of this disciplinary practice, with 31% of the men in favour compared with 18% of the woman (adjusted RC 2.2 [95% CI 1.4 to 3.4]; P=0.0003). Approximately 36% of the students who had experienced corporal punishment were in favour of it, compared with only 4% of those who had not experienced this form of discipline (adjusted RC 16.5 [95%CI 8.6 to 31.4]; P<0.0001). Among those who stated that they had been victims of physical abuse, 25% declared themselves in favour of this practice, which was a similar proportion to those who had not been victims of physical abuse (21%) (P=0.52). CONCLUSION: While several medical organizations have declared opposition to the use of corporal punishment, greater than one in five future Quebec doctors are in favour of this disciplinary method and could influence the behaviour of parents in this regard.

Association with replication between estrogen-related receptor gamma (ESRRgamma) polymorphisms and bone phenotypes in women of European ancestry.

Osteoporosis is a bone disease characterized by low bone mineral density (BMD), a highly heritable polygenic trait. Women are more prone than men to develop osteoporosis owing to a lower peak bone mass and accelerated bone loss at menopause. Lack of estrogen thus is a major risk factor for osteoporosis. In addition to having strong similarity to the estrogen receptor 1 (ESR1), the orphan nuclear estrogen-related receptor gamma (ESRRgamma) is widely expressed and shows overlap with ESR1 expression in tissues where estrogen has important physiologic functions. For these reasons, we have undertaken a study of ESRRgamma sequence variants in association with bone measurements [heel quantitative ultrasound (QUS) by measurements of broadband ultrasound attenuation (BUA), speed of sound (SOS), and stiffness index (SI) and dual-energy X-ray absorptiometry (DXA) at the femoral neck (FN) and lumbar spine (LS)]. A silent variant was found to be associated with multiple bone measurements (LS, BUA, SOS, and SI), the p values ranging from .006 to .04 in a sample of 5144 Quebec women. The region of this variant was analyzed using the HapMap database and the Gabriel method to define a block of 20 kb. Using the Tagger method, eight TagSNPs were identified and genotyped in a sample of 1335 women. Four of these SNPs capture the five major block haplotypes. One SNP (rs2818964) and one haplotype were significantly associated with multiple bone measures. All SNPs involved in the associations were analyzed in two other sample sets with significant results in the same direction. These results suggest involvement of ESRRgamma in the determination of bone density in women.