Prescription Practices Regarding the use of Systemic Drugs in the Management of Patients with Chronic Pruritus amongst Indian Dermatologists - A Questionnaire Based Survey.

Background: Chronic pruritus poses a significant challenge to treating physicians due to multitude of underlying causes and varying treatment strategies. Several topical, systemic, and physical modalities have been tried with variable success. Prescription practices in chronic pruritus are influenced by differential knowledge and experience of physicians, patient-related factors, and resource availability. Aim: The purpose of this survey was to observe the current pattern of practice in Indian dermatologists in the management of chronic pruritus and to identify practice gaps particularly regarding the use of various systemic agents as antipruritics. Materials and Methods: A previously validated questionnaire was sent to consultant dermatologists across India between January 2020 and July 2020. The questionnaire was comprised of six questions (multiple-choice questions as well as open-ended questions) regarding the use of antidepressants, cyclic gamma-aminobutyric acid (GABA) analogues, opioid antagonists, antihistamines, and alternate therapies in the management of chronic pruritus. Results: A total of 700 dermatologists completed the questionnaire (response rate 70%). Overall, antihistamines were the most common drug prescribed in chronic pruritus (more than 95% respondents). Other systemic agents such as opioid antagonists, gabapentinoids, and antidepressants were prescribed by 22.42%, 71.85%, and 75.29% respondents, respectively, in chronic pruritus as either monotherapy or in combination with antihistamines in specific types of itches. Among antidepressants, tricyclic antidepressants (TCAs) (69.29%) were prescribed most often, followed by selective serotonin reuptake inhibitors (SSRIs) (32.29%) and serotonin and norepinephrine reuptake inhibitors (SNRIs) (9.14%). Other treatment options such as omalizumab, thalidomide, ondansetron, ursodeoxycholic acid (UDCA), and rifampicin were used by 10% respondents to alleviate pruritus in special situations. Conclusion: This survey revealed the redundant practice of prescribing antihistamines in chronic pruritus irrespective of etiology among Indian dermatologists. It also revealed a differential approach regarding use of systemic agents such as gabapentinoids, opioid antagonists, and antidepressants, in academic and non-academic institutions. The survey emphasized a barrier in writing prescription of systemic agents such as opioid antagonist and SNRIs due to lack of knowledge and experience, fear of side effects, and inadequate available evidence.

Acute superficial and deep necrosis of lower limb following femoral arterial cannulation in a neonate undergoing arterial switch operation for transposition of great arteries.

Arterial lines are routinely used for hemodynamic monitoring and blood sampling in the operating room and in cardiac surgery intensive care unit. The complications related to arterial line insertion are very low; the knowledge of the relevant artery anatomy, skills and the experience of the operator and selection of a right size cannula plays a vital role in reducing morbidity related to arterial line insertion. We describe extensive superficial and deep necrosis of lower limb following arterial cannula insertion in a preterm neonate undergoing arterial switch procedure and discuss measures to prevent such a complication.

Pre-medication with simethicone and N-acetyl cysteine for improving mucosal visibility during upper gastrointestinal endoscopy: A randomized controlled trial.

BACKGROUND AND AIM: Diagnostic performance of esophagogastroduodenoscopy (EGD) may be compromized due to adherent mucus and foam. In this study, we aimed at assessing the impact of premedication on mucosal visibility during endoscopy. METHODS: This is a double-blinded (patient and investigator), randomized trial conducted at a tertiary care centre. Patients were randomized into four groups: A (water), B (simethicone [S]), C (N-acetyl cysteine [NAC]), D (S + NAC). Premedication solutions were administered 10-30 minutes before endoscopy and mucosal visibility graded from 1 (best) to 4 (worst) (1 best, 4 worst). Total mucosal visibility scores (TMVS) from six sites ranged from 6 (best) to 24 (worst) points. The primary outcome of study was comparison of TMVS between simethicone and combination (S + NAC) premedication groups. Secondary outcomes were adverse events and impact of endoscopy timing on TMVS. RESULTS: Total 800 patients (39 years, 68.8% males) were randomized into four groups. Median TMVS were significantly lower in groups B (7 [6-8]) and D (8 [6-9]) as compared to A (11 [9-13]) and C (10 [8-12]). Proportion of cases with adequate gastric mucosal visibility (score < 7) was 26% in group A, 71% in group B, 36% in group C and 79% in group D. There was no difference in TMVS in groups A and C (p = 0.137). TMVS were significantly lower in late (> 20-30 minutes) vs. early (10-20 minutes) endoscopy sub-group (8 [7-11] vs, 9 ([7-11], p = 0.001). However, TMVS were similar between group B and group D in early endoscopy group (p = 0.451). There was no significant difference in the lesion detection rate among the different premedication drugs (p > 0.05). CONCLUSIONS: Premedication with simethicone or combination (simethicone and NAC) significantly improves mucosal visibility during EGD. If early endoscopy is indicated, simethicone provides similar mucosal visibility and may be an effective alternative to combined premedication. TRIAL REGISTRATION: NCT05951712.

Mitochondrial Deoxyribonucleic Acid (mtDNA), Maternal Inheritance, and Their Role in the Development of Cancers: A Scoping Review.

Mitochondrial DNA (mtDNA) is a small, circular, double-stranded DNA inherited from the mother during fertilization. Evolutionary evidence supported by the endosymbiotic theory identifies mitochondria as an organelle that could have descended from prokaryotes. This may be the reason for the independent function and inheritance pattern shown by mtDNA. The unstable nature of mtDNA due to the lack of protective histones, and effective repair systems make it more vulnerable to mutations. The mtDNA and its mutations could be maternally inherited thereby predisposing the offspring to various cancers like breast and ovarian cancers among others. Although mitochondria are considered heteroplasmic wherein variations among the multiple mtDNA genomes are noticed, mothers can have mitochondrial populations that are homoplasmic for a given mitochondrial mutation. Homoplasmic mitochondrial mutations may be transmitted to all maternal offspring. However, due to the complex interplay between the mitochondrial and nuclear genomes, it is often difficult to predict disease outcomes, even with homoplasmic mitochondrial populations. Heteroplasmic mtDNA mutations can be maternally inherited, but the proportion of mutated alleles differs markedly between offspring within one generation. This led to the genetic bottleneck hypothesis, explaining the rapid changes in allele frequency witnessed during the transmission of mtDNA from one generation to the next. Although a physical reduction in mtDNA has been demonstrated in several species, a comprehensive understanding of the molecular mechanisms is yet to be demonstrated. Despite initially thought to be limited to the germline, there is evidence that blockages exist in different cell types during development, perhaps explaining why different tissues in the same organism contain different levels of mutated mtDNA. In this review, we comprehensively discuss the potential mechanisms through which mtDNA undergoes mutations and the maternal mode of transmission that contributes to the development of tumors, especially breast and ovarian cancers.

Rational design of novel microtubule targeting anticancer drugs N-imidazopyridine noscapinoids: Chemical synthesis and experimental evaluation based on in vitro using breast cancer cells and in vivo using xenograft mice model.

We present N-imidazopyridine-noscapinoids, a new class of noscapine derivatives that bind to tubulin and exhibit antiproliferative activity against triple positive (MCF-7) and triple negative (MDA-MB-231) breast cancer cells. The N-atom of the isoquinoline ring of noscapine scaffold was altered in silico by coupling the imidazo [(Ye et al., 1998; Ke et al., 2000) 1,21,2-a] pyridine pharmacophore to rationally develop a series of N-imidazopyridine-noscapinoids (7-11) with high tubulin binding affinity. The predicted ΔGbinding of the N-imidazopyridine-noscapinoids 7-11 varied from -27.45 to -36.15 kcal/mol, a much lower value than noscapine with ΔGbinding -22.49 kcal/mol. The cytotoxicity of N-imidazopyridine-noscapinoids was evaluated using hormone dependent MCF-7, triple negative MDA-MB-231 breast cancer cell lines and primary breast cancer cells. The cytotoxicity of these compounds (represented as IC50 concentration) ranges between 4.04 and 33.93 µM against breast cancer cells without affecting normal cells (IC50 value > 952 µM). All the compounds (7-11) perturbed the cell cycle progression at G2/M phase and triggered apoptosis. Among all the N-imidazopyridine-noscapinoids, N-5-Bromoimidazopyridine-noscapine (9) showed promising antiproliferative activity and was selected for detailed investigation. The onset of apoptosis treated with 9 using MDA-MB-231 revealed morphological changes like cellular shrinkage, chromatin condensation, membrane blebbing, and apoptotic bodies formation. Along with elevated reactive oxygen species (ROS), there was a loss of mitochondrial membrane potential, suggesting induction of apoptosis to cancer cells. Compound 9 was also found to significantly regress the implanted tumour in nude mice as xenografts of MCF-7 cells without any apparent side effects after drug administration. We conclude that N-imidazopyridine-noscapinoids possess excellent potential as a promising drug for treating breast cancers.

Development of 1,3-diynyl derivatives of noscapine as potent tubulin binding anticancer agents for the management of breast cancer.

We developed 1,3-diynyl derivatives of noscapine (an opium alkaloid) through in silico combinatorial approach and screened out a panel of promising derivatives that bind tubulin and display anticancer activity. The selected derivatives such as 9-4-tBu-Ph-Diyne (20p), 9-3,4-Di-Cl-Diyne (20k) and 9-3,4-Di-F-Diyne (22s) noscapinoids revealed improved predicted binding energy of -6.676 kcal/mol for 20p, -7.294 kcal/mol for 20k and -7.750 kcal/mol for 20s respectively in comparison to noscapine (-5.246 kcal/mol). These 1,3-diynyl derivatives (20p, 29k and 20s) were strategically synthesized in high yields by regioselective modification of noscapine scaffold and HPLC purified (purity is >96%). The decrease in intrinsic fluorescence of purified tubulin to 8.39%, 17.39% and 25.47% by 20p, 20k and 20s respectively, compared to control suggests their binding capability to tubulin. Their cytotoxicity activity was validated based on cellular studies using two human breast adenocarcinoma (MCF-7 and MDA-MB-231), a panel of primary breast tumor cells and one normal human embryonic kidney cell (293 T). The 1,3-diynyl noscapinoids, 20p, 20k and 20s inhibited cellular proliferation in all the cancer cells that ranged between 6.2 and 38.9 µM, without affecting the normal healthy cells (cytotoxicity is <5% at 100 µM). Further, these novel derivatives arrest cell cycle in the G2/M-phase, followed by induction of apoptosis to cancer cells. Thus, we conclude that 1,3-diynyl-noscapinoids have great potential to be a novel therapeutic agent for breast cancers.Communicated by Ramaswamy H. Sarma.

Ameloblastic fibro-odontoma or complex odontoma masquerading as gingival enlargement.

Ameloblastic fibro-odontoma is a rare tumor affecting the pediatric population and young adults. The World Health Organization (WHO) in 2005 defined it as "A neoplasm composed of proliferating odontogenic epithelium in a cellular ectomesenchymal tissue with varying degrees of inductive changes and dental hard tissue formation." There exists a controversy on its histogenesis designating it as a hamartoma (developing complex odontoma [CO]) or a true neoplasm since both the lesions appear similar histologically. Recently, the WHO in 2017 has clubbed both these lesions as the same entity. Most cases are reported in males and in mandible, while cases in maxilla are scarce. This article describes a recurrence of a previously reported case of ameloblastic fibroma which showed maturation into AFO or CO in a girl aged 6 years in the posterior maxilla. This case is reported due to its rarity and a brief review with differential diagnosis is also discussed.

Rational design, chemical synthesis and cellular evaluation of novel 1,3-diynyl derivatives of noscapine as potent tubulin binding anticancer agents.

We present a new class of derivatives of noscapine, 1,3-diynyl-noscapinoids of an antitussive plant alkaloid, noscapine based on our in silico efforts that binds tubulin and displays anticancer activity against a panel of breast cancer cells. Structure-activity analyses pointed the C-9 position of the isoquinoline ring which was modified by coupling of 1,3-diynyl structural motifs to rationally design and screened a series of novel 1,3-diynyl-noscapinoids (20-22) with robust binding affinity with tubulin. The selected 1,3-diynyl-noscapinoids, 20-22 revealed improved predicted binding energy of -6.568 kcal/mol for 20, -7.367 kcal/mol for 21 and -7.922 kcal/mol for 22, respectively in comparison to the lead molecule (-5.246 kcal/mol). These novel derivatives were chemically synthesized and validated their anticancer activity based on cellular studies using two human breast adenocarcinoma, MCF-7 and MDAMB-231, as well as with a panel of primary breast cancer cells isolated from patients. Interestingly, all these derivatives inhibited cellular proliferation in all the cancer cells that ranged between 6.2 to 38.9 µM, which is 6.7 to 1.5 fold lower than that of noscapine. Unlike previously reported derivatives of noscapine that arrests cells in the S-phase, these novel derivatives effectively inhibit proliferation of cancer cells, arrests cell cycle in the G2/M-phase followed by apoptosis and appearance of apoptotic cells. Thus, we conclude that 1,3-diynyl-noscapinoids have great potential to be a novel therapeutic agent for breast cancers.

CSU57 encodes a novel repressor of sorbose utilization in opportunistic human fungal pathogen Candida albicans.

Human fungal pathogen Candida albicans cannot utilize L-sorbose as a sole carbon source. However, chromosome 5 monosomic strains can grow on sorbose as repressors present on this chromosome get diminished allowing the expression of sorbose utilization gene (SOU1) located on chromosome 4. Functional identification of these repressors has been a difficult task as they are scattered on a large portion of the right arm of chromosome 5. Herein, we have applied the telomere-mediated chromosomal truncation approach to identify a novel repressor for sorbose utilization in this pathogen. Multiple systematic chromosomal truncations were performed on the right arm of Chr5 in the background of csu51∆/CSU51 to minimize the functional region to 6-kb chromosomal stretch. Further, truncation that removes the part of Orf19.3942 strongly suggested its role in sorbose utilization. However, compelling evidence comes from the observation that truncation at 1,044.288-kb position of Chr5 in the strain csu51∆/CSU51 orf19.3942∆/Orf.19.3942 produced Sou+ phenotype; otherwise, the strain remains Sou- . This confirms beyond doubt the role of Orf.19.3942 in the regulation of sorbose utilization and designated as CSU57. Comparison of SOU1 gene expression of Sou+ strains with wild type suggested its role at transcriptional level. Strain carrying double disruption of CSU57 remains Sou- . Co-overexpression of SOU1 and CSU57 together does not make the recipient strain Sou- ; however, multiple tandem copies of CSU57 produced diminished growth compared with control suggesting that it is a weak repressor. Taken together, we report that CSU57 encodes a novel repressor of L-sorbose utilization in this pathogen. TAKE AWAY: CSU57 encodes a repressor for L-sorbose utilization in Candida albicans. Csu57p acts in combination with Csu51p and other regulators. Csu57p exerts its repressing effect at transcriptional level of SOU1 gene. Utilization of sorbose positively correlates to the expression of SOU1 gene. Multiple copies of CSU57 can partially suppress Sou+ phenotype.

Sulforaphane in broccoli: The green chemoprevention!! Role in cancer prevention and therapy.

Isothicyanates present in cruciferous vegetables are known to exhibit chemoprevention by various mechanisms. Presently, there is growing evidence that a phytochemical compound known as sulforaphane in these green leafy vegetables is found to be effective in preventing and treating various cancers such as prostate cancer, breast cancer, colon cancer, skin, urinary bladder and oral cancers. This component is naturally present in the broccoli sprouts, kale, cabbage, cauliflower and garden cress and is available as a commercial supplementary pill called Broccoli extract. Availability of many bioactive substances such as vitamins, polyphenols, sulfides, glucosinolates and antioxidants makes broccoli consumption important in daily diet regularly. Researchers have named it as "Green chemoprevention." It is easily affordable and more cost-effective than the traditional chemopreventive drugs. Results from the epidemiological and experimental studies have emphasized the role of sulforophane as a complementary or alternative chemopreventive agent.

Foot loading pattern and hind foot alignment are corrected in varus knees following total knee arthroplasty: a pedobarographic analysis.

PURPOSE: Osteoarthritis of knees with varus deformity is associated with a compensatory valgus deformity of the hindfoot and a lateral loading foot pressure pattern. However, whether this abnormal loading pattern is corrected in total knee arthroplasty (TKA) is unclear. METHODS: The alignment and loading pattern of 91 consecutive patients (121 knees) undergoing TKA with pre-operative varus more than 10° were evaluated prospectively with functional outcome scores, static conventional radiography and dynamic pedobarogaphy pre-operatively and 1-year post-operatively. Outcomes assessed were Oxford Knee Scores, American Orthopaedic Foot and Ankle Scores, femorotibial mechanical angle, tibia-hindfoot angle, hindfoot valgus/varus index (VVI), foot line of pressure (LOP) laterality and peak pressure (PP) at both time points. RESULTS: Of 121 knees, 98 (81%) regained normal alignment of the knee and 114 (92%) of the hindfoot. Similarly, PP (p < 0.001), VVI (pre-operative: - 0.29 ± 0.22, post-operative: - 0.04 ± 0.23, p < 0.001) and LOP laterality (pre-operative: 7% medial, post-operative: 96% medial, p < 0.001) all medialised post-operatively. All patients had improved functional outcomes at the knee (pre-operative: 20 ± 2, post-operative: 40 ± 2, p < 0.001) and ankle (pre-operative: 59 ± 10, post-operative: 89 ± 6, p < 0.001). CONCLUSION: The present study shows, following the correction of knee varus with TKA, hindfoot alignment and foot loading pattern are both restored in the majority of patients. TKA offers both static and dynamic correction as seen in the hindfoot and loading pattern, respectively. LEVEL OF EVIDENCE: Level III: prospective case-control study.

Description and Initial Experience with the "LIFT" (Less Incisions but Four Trocars) Technique for Laparoscopic Cholecystectomy.

Background: Modifications to conventional laparoscopic cholecystectomy (LC) aim to reduce trauma to the abdominal wall and improve cosmetic outcomes. Although single-incision laparoscopic surgery (SILS) provides excellent cosmetic results, the procedure is technically demanding. Herein, we describe the LIFT technique ("Less Incisions but Four Trocars"), with four trocars but only one 3-mm visible incision, using conventional instruments. Methods: Retrospective study with the LIFT technique for cholecystectomy during 2017. Access to the abdomen is obtained with two trocars (11 and 5 mm) through the same intraumbilical skin incision, and two extraumbilical 3-mm trocars for a correct triangulation (one of them concealed below the bikini line). The results are compared with a series of patients operated on with LC by the same surgical team during 2016. Results: During the study period, 90 procedures were performed. Both techniques showed similar results in terms of surgical time, conversion rate, complications, and hospital length of stay. The patients operated on with the LIFT technique reported better cosmetic evaluation and less postoperative pain at 3 months compared with LC. Conclusion: The LIFT technique is a safe and feasible alternative for cholecystectomy that can provide a significant improvement from the cosmetical point of view, mostly for those patients who are especially concerned with their body image.

Enterically delivered insulin tregopil exhibits rapid absorption characteristics and a pharmacodynamic effect similar to human insulin in conscious dogs.

AIMS: Current therapy fails to emulate rapid (first-phase) insulin release in relation to a meal, a key defect in types 1 and 2 diabetes. We aimed to quantify the pharmacokinetic (PK) and pharmacodynamic (PD) profile of insulin tregopil, an enterically-absorbed insulin analog that restores the normal distribution of insulin between the hepatic portal and peripheral circulations. MATERIALS AND METHODS: The PK and PD profiles of insulin tregopil were studied in overnight-fasted, catheterized, conscious canines using four approaches: (1) equimolar intraportal infusions of tregopil vs human insulin; (2) escalating doses of oral tregopil; (3) identical, consecutive enteric doses of tregopil; and (4) comparison of oral tregopil to inhaled and subcutaneous human insulin administration. RESULTS: Equimolar intraportal infusions of tregopil and human insulin resulted in very similar PK profiles and PD profiles were nearly identical. Enteric delivery of tregopil brought about rapid absorption with tmax = 20 minutes in most cases. Median tmax was 20 minutes for oral tregopil and inhaled insulin and 88 minutes for subcutaneous human insulin. The time required for arterial plasma insulin levels to return to baseline was approximately 90, 210 and 360 minutes for oral tregopil, inhaled insulin and subcutaneous insulin, respectively. CONCLUSIONS: Enterically delivered tregopil is rapidly absorbed and restores a portal-to-peripheral vascular distribution. These characteristics should improve postprandial hyperglycaemia in types 1 and 2 diabetes.

Cryosurgery: A Simple Tool to Address Oral Lesions.

AIM: The study was aimed at evaluating the efficacy of cryosurgery in the management of oral mucosal lesions. Time taken for healing, postoperative pain, secondary infection, and recurrence of lesion was evaluated. MATERIALS AND METHODS: A total of 30 patients with oral mucosal lesions were included in the study. The patients were evaluated for pain and postoperative infection which was documented on the 1st, 3rd, 7th, 21st day after the procedure. Other parameters such as healing time and scarring were assessed at 21st day. Recurrence of the lesion was evaluated in the 3rd and 6th postoperative month. All these data were statistically evaluated. RESULTS: The pain and swelling which reduced mainly during the 7th postoperative day which was highly significant. The discomfort of the patient was relatively less. Only three patients showed delayed healing out of all patients. Recurrence of lesion was noted in two cases which conclude to about 6.7%. CONCLUSION: The cryosurgery is overall a better modality for treatment of oral lesions as it is more reasonable with adequate success. The procedure is relatively more acceptable and has shown to have a faster recovery.

Ixabepilone and Carboplatin for Hormone Receptor Positive/HER2-neu Negative and Triple Negative Metastatic Breast Cancer.

BACKGROUND: Hormonal therapies and single-agent sequential chemotherapeutic regimens are the standards of care for HER2- metastatic breast cancer (MBC). However, treating patients with hormone-refractory and triple negative (TN) MBC remains challenging. We report the results of combined ixabepilone and carboplatin in a single-arm phase II trial. PATIENTS AND METHODS: In the present prospective analysis of hormone receptor-positive (HR+)/HER2- and TN MBC cohorts, patients could have received 0 to 2 chemotherapy regimens for MBC before enrollment. All patients received ixabepilone 20 mg/m2 and carboplatin (area under the curve, 2.5) on days 1 and 8 every 21 days. The primary endpoint was the objective response rate (ORR). The secondary objectives included progression-free survival (PFS), clinical benefit rate (CBR), overall survival (OS), and toxicity. RESULTS: We enrolled 54 HR+ and 49 TN patients (median, 1 previous chemotherapy regimen for metastatic disease; most in addition to adjuvant chemotherapy). The ORR was 34% and 30.4% for the HR+ and TN patients, respectively, with a corresponding CBR of 56.6% and 41.3%. The ORRs were similar in taxane-pretreated patients (ORR, 31.4% and 28.6% for HR+ and TN patients, respectively). The median OS was 17.9 months for HR+ patients and 12.5 months for TN patients. The median PFS was similar for both groups at 7.6 months. Grade 3/4 nonhematologic toxicities included neuropathy (9%) and fatigue (8%). Nine patients developed grade 3/4 neuropathy, 7 of whom had received previous taxane treatment. CONCLUSION: Ixabepilone plus carboplatin is active even in later-line HR+ and TN disease. Toxicities were manageable without cumulative myelosuppression. This combination is a reasonable option for those patients with MBC who require combination chemotherapy.

Benign chondroid syringoma affecting the upper lip: Report of a rare case and review of literature.

Chondroid syringoma (CS) (mixed tumor of the skin) is a rare neoplasm of the sweat glands, which presents itself as a slow-growing, painless, nonulcerated, subcutaneous or intracutaneous mass often occurring in the head and neck region. The clinician may miss the diagnosis of this lesion due to its rarity. CS should be considered in the differential diagnosis of any subcutaneous nodules, especially in the head and neck region. The diagnosis of CS is mainly based on the histopathologic examination. This article presents a 35-year-old male with a mass on the upper lip that was histopathologically diagnosed as an apocrine variant of benign CS with squamous metaplasia after surgical excision. No sign of recurrence is evident till date during the follow-up. We report this case because of its rarity. A brief literature review and all the reported cases in the lip have been listed.

Silence of male child sexual abuse in India: Qualitative analysis of barriers for seeking psychiatric help in a multidisciplinary unit in a general hospital.

INTRODUCTION: In 2007, Ministry of Women and Child Welfare, supported by United Nations Children's Fund, save the children and Prayas conducted a study to understand the magnitude of child abuse in India, they found that 53.22% children faced one or more forms of sexual abuse; among them, the number of boys abused was 52.94%. AIM: The aim of this study was to explore the barriers for seeking psychiatric help by qualitative analysis of stake holders of male victims of child abuse. MATERIALS AND METHODS: All the statements made by the stakeholders regarding psychiatric assessment and treatment were recorded in each referral made to the psychiatrist. Semistructured interviews and in-depth interviews were conducted to explore the topic of understanding the need for psychiatric treatment to the victims. RESULTS: Collaborative child response unit, a multidisciplinary team, to tackle child sexual abuse in a general hospital received three referrals of male child abuse among the 27 referrals in 20 months. The main theme of the barrier that was generated by interviewing the stakeholders of male child victims of abuse was the misconception of superiority of a male victim due to gender (patriarchy) an expectation that he will outgrow the experience. In-depth interviews of three cases of homosexual abuse explored the theme. CONCLUSION: Patriarchy is oppressing male children and acts as a barrier to seek psychiatric help in collaborative child response unit.

Defects in Protein Folding Machinery Affect Cell Wall Integrity and Reduce Ethanol Tolerance in S. cerevisiae.

The chaperonin complex CCT/TRiC (chaperonin containing TCP-1/TCP-1 ring complex) participates in the folding of many crucial proteins including actin and tubulin in eukaryotes. Mutations in genes encoding its subunits can affect protein folding and in turn, the physiology of the organism. Stress response in Saccharomyces cerevisiae is important in fermentation reactions and operates through overexpression and underexpression of genes, thus altering the protein profile. Defective protein folding machinery can disturb this process. In this study, the response of cct mutants to stress conditions in general and ethanol in specific was investigated. CCT1 mutants showed decreased resistance to different conditions tested including osmotic stress, metal ions, surfactants, reducing and oxidising agents. Cct1-3 mutant with the mutation in the conserved ATP-binding region showed irreversible defects than other mutants. These mutants were found to have inherent cell wall defects and showed decreased ethanol tolerance. This study reveals that cell wall defects and ethanol sensitivity are linked. Genetic and proteomic analyses showed that the yeast genes RPS6A (ribosomal protein), SCL1 (proteasomal subunit) and TDH3 (glyceraldehyde-3-phosphate dehydrogenase) on overexpression, improved the growth of cct1-3 mutant on ethanol. We propose the breakdown of common stress response pathways caused by mutations in CCT complex and the resulting scarcity of functional stress-responsive proteins, affecting the cell's defence against different stress agents in cct mutants. Defective cytoskeleton and perturbed cell wall integrity reduce the ethanol tolerance in the mutants which are rescued by the extragenic suppressors.

Incidence and Predictive Factors for Recovery of Ovarian Function in Amenorrheic Women in Their 40s Treated With Letrozole.

PURPOSE: This prospective study assessed the impact of 2 years of aromatase inhibitor (AI) therapy on the incidence of ovarian function recovery (OFR) in women age 40 to 49 with estrogen receptor-positive breast cancer who were premenopausal at diagnosis and who underwent chemotherapy-induced amenorrhea during adjuvant treatment. PATIENTS AND METHODS: Women age 40 to 49 with estrogen receptor-positive breast cancer who had ceased menstruating with adjuvant cyclophosphamide-based chemotherapy, had postmenopausal serum estradiol (E2), and had received tamoxifen for ≥ 1 year were treated with letrozole (2.5 mg) daily for ≥ 2 years. Serum follicle-stimulating hormone (FSH) and E2 were measured at baseline and over 2 years. A general linear model was used to assess serial FSH by OFR. Logistic regression was used to assess baseline predictors and OFR. RESULTS: The study enrolled 177 women (145 women age 45 to 49 years and 32 women age 40 to 44 years). Of 173 evaluable patients, 67 (39%; 95% CI, 31% to 46%) regained ovarian function; 11 of these patients (6%; 95% CI, 3% to 10%) resumed menses, and 56 of these patients (32%; 95% CI, 25% to 39%) developed premenopausal E2 without menses. Among AI-naïve patients, serial FSH significantly increased over time (P < .001), did not vary significantly by OFR status (P = .55), but showed mild evidence of a decrease after month 12 for those who resumed menses (P = .0989). Age less than 45 years and inhibin B were significant multivariable baseline predictors of OFR. CONCLUSION: These results emphasize the challenge in determining definitive menopause in women with chemotherapy-induced amenorrhea. The risk of OFR during treatment with AIs in amenorrheic women in their 40s is high, and AI therapy should be avoided in these patients.

Waiving in vivo studies for monoclonal antibody biosimilar development: National and global challenges.

Biosimilars are biological medicinal products that contain a version of the active substance of an already authorised original biological medicinal product (the innovator or reference product). The first approved biosimilar medicines were small proteins, and more recently biosimilar versions of innovator monoclonal antibody (mAb) drugs have entered development as patents on these more complex proteins expire. In September 2013, the first biosimilar mAb, infliximab, was authorised in Europe. In March 2015, the first biosimilar (Zarxio™, filgrastim-sndz, Sandoz) was approved by the US Food and Drug Administration; however, to date no mAb biosimilars have been approved in the US. There are currently major differences between how biosimilars are regulated in different parts of the world, leading to substantial variability in the amount of in vivo nonclinical toxicity testing required to support clinical development and marketing of biosimilars. There are approximately 30 national and international guidelines on biosimilar development and this number is growing. The European Union's guidance describes an approach that enables biosimilars to enter clinical trials based on robust in vitro data alone; in contrast, the World Health Organization's guidance is interpreted globally to mean in vivo toxicity studies are mandatory. We reviewed our own experience working in the global regulatory environment, surveyed current practice, determined drivers for nonclinical in vivo studies with biosimilar mAbs and shared data on practice and study design for 25 marketed and as yet unmarketed biosimilar mAbs that have been in development in the past 5y. These data showed a variety of nonclinical in vivo approaches, and also demonstrated the practical challenges faced in obtaining regulatory approval for clinical trials based on in vitro data alone. The majority of reasons for carrying out nonclinical in vivo studies were not based on scientific rationale, and therefore the authors have made recommendations for a data-driven approach to the toxicological assessment of mAb biosimilars that minimises unnecessary use of animals and can be used across all regions of the world.