A proof-of-concept study of growth hormone in children with Phelan-McDermid syndrome.

BACKGROUND: Phelan-McDermid syndrome (PMS) is caused by 22q13 deletions including SHANK3 or pathogenic sequence variants in SHANK3 and is among the more common rare genetic findings in autism spectrum disorder (ASD). SHANK3 is critical for synaptic function, and preclinical and clinical studies suggest that insulin-like growth factor-1 (IGF-1) can reverse a range of deficits in PMS. IGF-1 release is stimulated by growth hormone secretion from the anterior pituitary gland, and this study sought to assess the feasibility of increasing IGF-1 levels through recombinant human growth hormone (rhGH) treatment, in addition to establishing safety and exploring efficacy of rhGH in children with PMS. METHODS: rhGH was administered once daily for 12 weeks to six children with PMS using an open-label design. IGF-1 levels, safety, and efficacy assessments were measured every 4 weeks throughout the study. RESULTS: rhGH administration increased levels of IGF-1 by at least 2 standard deviations and was well tolerated without serious adverse events. rhGH treatment was also associated with clinical improvement in social withdrawal, hyperactivity, and sensory symptoms. LIMITATIONS: Results should be interpreted with caution given the small sample size and lack of a placebo control. CONCLUSIONS: Overall, findings are promising and indicate the need for larger studies with rhGH in PMS. Trial registration NCT04003207. Registered July 1, 2019, https://clinicaltrials.gov/ct2/show/NCT04003207 .

Supporting new graduate physiotherapists in their first year of private practice with a structured professional development program; a qualitative study.

BACKGROUND: The transition from physiotherapy student to working in private practice has been identified as challenging. However, very little is known about whether structured professional development programs impact on this transition. OBJECTIVES: To describe new graduates' perceptions of a structured professional development program, termed the Recent Graduate Program (RGP), designed to support their transition into physiotherapy private practice. DESIGN: Qualitative analysis of data from a one-year longitudinal mixed methods study. METHOD: A total of 72 interviews were conducted over a one-year period with 20 new graduates from 19 private practices within one publicly listed allied health organisation. Semi-structured interviews were conducted before commencing work and at three, nine and 12 months. Interviews were recorded and transcribed verbatim prior to a conventional content analysis that aimed to acquire direct information from new graduates without imposing preconceived categories or theoretical perspectives. FINDINGS: New graduates reported that the RGP supported their growth as a practitioner and facilitated their learning, particularly when complemented by the experiential learning from client interactions. The RGP met their expectations with the formal education program and regular mentoring sessions highly valued. Informal support from peers and senior clinicians, while not part of the RGP, was also perceived to facilitate their growth and confidence as a physiotherapist. CONCLUSIONS: This study demonstrates that the provision of a structured transition program by a private practice employer was perceived by new graduates to facilitate their learning, confidence and self-efficacy. The RGP provides a useful model by which other practices may support new graduates.

Batzelladine D and norbatzelladine L purified from marine sponge Monanchora arbuscula induce the reversal of fluconazole.

ATP-Binding Cassette (ABC) transporters are the main class of transmembrane transporters involved in pathogenic fungal resistance against chemotherapeutic agents. Herein we report results which show that batzelladine D (1) and norbatzelladine L (2) reverse the fluconazole resistance phenotype mediated by Pdr5p transporter on Saccharomyces cerevisiae. Both alkaloids were able to chemosensitize the Pdr5p-overexpressing strain by synergistic interaction with fluconazole. Both compounds also showed an inhibitory effect on the catalytic activity and on the intracellular accumulation of rhodamine 6G, and did not show significant in vitro mammalian cells toxicity.

Long-term safety in patients with recurrent ovarian cancer treated with niraparib versus placebo: Results from the phase III ENGOT-OV16/NOVA trial.

OBJECTIVE: Niraparib is a poly(ADP-ribose) polymerase (PARP) inhibitor approved for use in heavily pretreated patients and as maintenance treatment in patients with newly-diagnosed or recurrent ovarian cancer following a response to platinum-based chemotherapy. We present long-term safety data for niraparib from the ENGOT-OV16/NOVA trial. METHODS: This multicenter, double-blind, randomized, controlled phase III trial evaluated the efficacy and safety of niraparib for the treatment of recurrent ovarian cancer. Patients were randomly assigned 2:1 to receive either once-daily niraparib 300 mg or placebo. Two independent cohorts were enrolled based on germline BRCA mutation status. The primary endpoint was progression-free survival, reported previously. Long-term safety data were from the most recent data cutoff (September 2017). RESULTS: Overall, 367 patients received niraparib 300 mg once daily. Dose reductions due to TEAEs were highest in month 1 (34%) and declined every month thereafter. Incidence of any-grade and grade ≥ 3 hematologic and symptomatic TEAEs was also highest in month 1 and subsequently declined. Incidence of grade ≥ 3 thrombocytopenia decreased from 28% (month 1) to 9% and 5% (months 2 and 3, respectively), with protocol-directed dose interruptions and/or reductions. Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) were reported in 2 and 6 niraparib-treated patients, respectively, and in 1 placebo patient each. Treatment discontinuations due to TEAEs were <5% in each month and time interval measured. CONCLUSION: These data demonstrate the importance of appropriate dose reduction according to toxicity criteria and support the safe long-term use of niraparib for maintenance treatment in patients with recurrent ovarian cancer. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01847274.

Retroperitoneal lymph node recurrence of epithelial ovarian cancer: Prognostic factors and treatment outcome.

OBJECTIVE: To evaluate the treatment outcome and survival of patients with epithelial ovarian cancer recurrence isolated to the retroperitoneal lymph nodes compared to intraperitoneal spread. METHODS: A retrospective cohort study including women with recurrence of epithelial ovarian, cancer, who were treated at a single medical center, between 2000 and 2015. Patients were classified into three groups according to the site of recurrence: intraperitoneal only, retroperitoneal lymph nodes only, and both. Response to treatment was assessed by the RECIST criteria. RESULTS: Out of 135 patients in our cohort, 66 were diagnosed with intraperitoneal recurrence, 30 with retroperitoneal lymph node recurrence and 39 with combined site recurrence. The clinical, pathological and surgical characteristics were similar among all groups, besides CA-125 which was significantly lower in the retroperitoneal recurrence group at diagnosis, end of treatment and recurrence. The median follow-up period was 45.8 months. Overall survival (OS) and post relapse survival (PRS) were significantly higher in the retroperitoneal recurrence group vs. the intraperitoneal and combined site recurrence groups. (OS - 93.07, 47.9 and 41.7 months, respectively, p < .001, PRS - 68.57, 29.67 and 19.7 months, respectively, p < .001). On cox's regression analysis, retroperitoneal recurrence was found to be an independent prognostic factor for survival. CONCLUSIONS: The site of recurrence has significant prognostic value regarding PRS and OS. Patients with recurrence limited to the retroperitoneal lymph nodes have a favourable prognosis with median survival longer than 5 years.

Antifungal activities of the essential oil and its fractions rich in sesquiterpenes from leaves of Casearia sylvestris Sw.

Casearia genus (Salicaceae) is found in sub-tropical and tropical regions of the world and comprises about 160-200 species. It is a medicinal plant used in South America, also known as "guaçatonga", "erva-de-tiú", "cafezinho-do-mato". In Brazil, there are about 48 species and 12 are registered in the State of Rio de Janeiro, including Casearia sylvestris Sw. There are many studies related to the chemical profile and cytotoxic activities of extracts from these plants, although few studies about the antifungal potential of the essential oil have been reported. In this work, we have studied the antifungal properties of the essential oil of C. sylvestris leaves, as well as of their fractions, against four yeasts (Saccharomyces cerevisae, Candida albicans, C. glabrata and C. krusei) for the first time. The chemical analysis of the essential oil revealed a very diversified (n = 21 compounds) volatile fraction composed mainly of non-oxygenated sesquiterpenes (72.1%). These sesquiterpenes included α-humulene (17.8%) and α-copaene (8.5%) and the oxygenated sesquiterpene spathulenol (11.8%) were also identified. Monoterpenes were not identified. The fractions are mainly composed of oxygenated sesquiterpenes, and the most active fraction is rich in the sesquiterpene 14-hydroxy -9-epi-ß-caryophyllene. This fraction was the most effective in inhibiting the growth of three yeast strains.

Antifungal activities of the essential oil and its fractions rich in sesquiterpenes from leaves of Casearia sylvestris Sw

ABSTRACT Casearia genus (Salicaceae) is found in sub-tropical and tropical regions of the world and comprises about 160-200 species. It is a medicinal plant used in South America, also known as "guaçatonga", "erva-de-tiú", "cafezinho-do-mato". In Brazil, there are about 48 species and 12 are registered in the State of Rio de Janeiro, including Casearia sylvestris Sw. There are many studies related to the chemical profile and cytotoxic activities of extracts from these plants, although few studies about the antifungal potential of the essential oil have been reported. In this work, we have studied the antifungal properties of the essential oil of C. sylvestris leaves, as well as of their fractions, against four yeasts (Saccharomyces cerevisae, Candida albicans, C. glabrata and C. krusei) for the first time. The chemical analysis of the essential oil revealed a very diversified (n = 21 compounds) volatile fraction composed mainly of non-oxygenated sesquiterpenes (72.1%). These sesquiterpenes included α-humulene (17.8%) and α-copaene (8.5%) and the oxygenated sesquiterpene spathulenol (11.8%) were also identified. Monoterpenes were not identified. The fractions are mainly composed of oxygenated sesquiterpenes, and the most active fraction is rich in the sesquiterpene 14-hydroxy -9-epi-β-caryophyllene. This fraction was the most effective in inhibiting the growth of three yeast strains.

Fifth Ovarian Cancer Consensus Conference: individualized therapy and patient factors.

This manuscript reports the consensus statements regarding the design and conduct of clinical trials in patients with newly diagnosed and recurrent epithelial ovarian cancer (EOC), following deliberation at the Fifth Ovarian Cancer Consensus Conference (OCCC), held in Tokyo in November 2015. Three important questions were identified for discussion prior to the meeting and achieved consensus during the meeting: (i) What are the most important factors to be evaluated prior to initial therapy? (ii) What are the most important factors to be evaluated specifically in recurrent disease? (iii) Are there specific considerations for special patient subpopulations? In addition, we report a list of important unmet needs compiled during the consensus process, which is intended to guide future research initiatives.

Immunohistochemical c-kit expression in uterine serous carcinoma tissue.

AIM: Uterine serous carcinoma (USC) is an aggressive tumor that represents only 10% of endometrial cancer cases but accounts for a disproportionate number of deaths due to uterine cancer. Advances in the development of specific c-kit receptor-targeted drugs have promoted its potential therapeutic application as a target in tumor-related diseases. The aim of the present study was to evaluate imunohistochemical expression of c-kit in USC tissue in order to assess whether positive cases can be candidates for targeted therapy. MATERIALS AND METHODS: C-kit expression assessment by immunohistochemistry was performed on deparaffinized sections of paraffin-embedded tissue blocks of confirmed consecutive available USC uterine specimens of patients diagnosed from 2000 to 2014. Sections of gastrointestinal stromal tumor (GIST) tissue known to contain c-kit served as positive controls. RESULTS: Immunohisto- chemical c-kit staining was not observed in any of 31 USC tissue samples examined. Intense staining was observed in the sections of GIST tissue. CONCLUSION: The present results may indicate that primary USC is not a candidate for c-kit targeted therapy.

Identification and Characterization of an Insulin-Like Receptor Involved in Crustacean Reproduction.

Sexual differentiation and maintenance of masculinity in crustaceans has been suggested as being regulated by a single androgenic gland (AG) insulin-like peptide (IAG). However, downstream elements involved in the signaling cascade remain unknown. Here we identified and characterized a gene encoding an insulin-like receptor in the prawn Macrobrachium rosenbergii (Mr-IR), the first such gene detected in a decapod crustacean. In mining for IRs and other insulin signaling-related genes, we constructed a comprehensive M. rosenbergii transcriptomic library from multiple sources. In parallel we sequenced the complete Mr-IR cDNA, confirmed in the wide transcriptomic library. Mr-IR expression was detected in most tissues in both males and females, including the AG and gonads. To study Mr-IR function, we performed long-term RNA interference (RNAi) silencing in young male prawns. Although having no effect on growth, Mr-IR silencing advanced the appearance of a male-specific secondary trait. The most noted effects of Mr-IR silencing were hypertrophy of the AG and the associated increased production of Mr-IAG, with an unusual abundance of immature sperm cells being seen in the distal sperm duct. A ligand blot assay using de novo recombinant Mr-IAG confirmed the existence of a ligand-receptor interaction. Whereas these results suggest a role for Mr-IR in the regulation of the AG, we did not see any sexual shift after silencing of Mr-IR, as occurred when the ligand-encoding Mr-IAG gene was silenced. This suggests that sexual differentiation in crustaceans involve more than a single Mr-IAG receptor, emphasizing the complexity of sexual differentiation and maintenance.

Extensive heterosis in growth of yeast hybrids is explained by a combination of genetic models.

Heterosis, also known as hybrid vigor, is the superior performance of a heterozygous hybrid relative to its homozygous parents. Despite the scientific curiosity of this phenotypic phenomenon and its significance for food production in agriculture, its genetic basis is insufficiently understood. Studying heterosis in yeast can potentially yield insights into its genetic basis, can allow one to test the different hypotheses that have been proposed to explain the phenomenon and allows better understanding of how to take advantage of this phenomenon to enhance food production. We therefore crossed 16 parental yeast strains to form 120 yeast hybrids, and measured their growth rates under five environmental conditions. A considerable amount of dominant genetic variation was found in growth performance, and heterosis was measured in 35% of the hybrid-condition combinations. Despite previous reports of correlations between heterosis and measures of sequence divergence between parents, we detected no such relationship. We used several analyses to examine which genetic model might explain heterosis. We found that dominance complementation of recessive alleles, overdominant interactions within loci and epistatic interactions among loci each contribute to heterosis. We concluded that in yeast heterosis is a complex phenotype created by the combined contribution of different genetic interactions.

Can parametrectomy be avoided in early cervical cancer? An algorithm for the identification of patients at low risk for parametrial involvement.

AIMS: To assess the rate of parametrial involvement in a large cohort of patients who underwent radical hysterectomy for cervical cancer and to suggest an algorithm for the triage of patients to simple hysterectomy or simple trachelectomy. METHODS: Multicenter retrospective study of patients with cervical cancer stage I through IIA who underwent radical hysterectomy and pelvic lymphadenectomy. The patients were divided into 2 groups according to whether or not the parametrium was involved. The two groups were compared with regard to the clinical and histopathological variables. Logistic regression of the variables potentially assessable prior to definitive hysterectomy such as age, tumor size, lymph-vascular space invasion (LVSI) and nodal involvement was performed. RESULTS: Five hundred and thirty patients had specific histological data on parametrial involvement and in 58 (10.9%) patients, parametria was involved. Parametrial involvement was significantly associated with older age, tumors larger than 2 cm, deeper invasion, LVSI, involved surgical margins, and the presence of nodal metastasis. By triaging patients with a tumor ≤ 2 cm and no LVSI, the parametrial involvement rate was 1.8% (2/112 patients). With further triage of patients with negative nodes, the rate of parametrial involvement was 0% (0/107 patients). CONCLUSION: Using a pre-operative triage algorithm, patients with early small lesions, no LVSI and no nodal involvement may be spared radical surgical procedures and parametrectomy. Further prospective data are urgently needed.

Profile of the Health and Nutritional Status of Older Adults in Mexico. 2012 National Health and Nutrition Survey.

BACKGROUND: The health and nutritional conditions of older adults in Mexico are heterogeneous. The prevalence of chronic noncommunicable diseases is elevated with disparities in functionality and socioeconomic inequities. OBJECTIVES: To obtain updated information of the health and nutritional profile of older adults in Mexico in a national representative sample. METHODS: Information was obtained from 6,687 60 years and older adults from the 2012 National Health and Nutrition Survey (ENSANUT 2012). An index defining the status of «healthy adult¼ was constructed taking into account the variables of independence in performing activities of daily living (ADL), based on the development by Katz, instrumental ADL, no chronic diseases, nonsmoker and no active use of alcohol. Tables of frequencies and proportions were constructed and expanded to describe the general characteristics and nutritional status of the adult Mexican population. A logistic regression model was used to study changes in the probability of being classified as a healthy adult with respect to different variables of interest. Probabilities using the delta method were estimated to establish 95% confidence intervals. RESULTS: In this study 12.2% of the older adults, were classified as healthy. The logistic regression model adjusted for the variables included in the study shows that the interaction of age and gender is significant (P = 0.068), where the probability of healthy adult status decreases in women with ageing and remains stable for men. Also, living in the southern region of the country significantly decreases the probability of healthy adult status (P = 0.001). Gender of the older adult was not significant. CONCLUSIONS: In Mexico, the health conditions of older adults are deficient. Public policies need to be generated that are directed at this population group and will translate into self-care actions in the early stages of life so as to guarantee a healthy future.

The effect of coexisting uterine myomas on clinico-pathological variables of endometrial carcinoma.

PURPOSE: To assess the prevalence of leiomyomas in patients with endometrial carcinoma (EC) and the association of their presence with clinico-pathological variables and with survival. MATERIALS AND METHODS: A retrospective chart review was conducted of all endometrial carcinoma (EC) patients diagnosed and treated in the present institution between 2002 and 2008. Selected clinical data were abstracted from medical records. Pathological data such as the presence of myomas (any size), tumor grade, depth of myometrial invasion presence of lymphovascular space involvement (LVSI), and the presence of metastases, are based on the original pathology report. RESULTS: Coexisting myomas were found in 74 (56.9%) of 130 EC patients diagnosed during the study period. No significant difference with regard to age, histological type, stage, grade, depth of myometrial invasion, LVSI, lymph node involvement, and presence of metastases (other than lymph node involvement) was found between patients without and with myomas. There was also no significant difference in survival of EC patients without and with coexistent myomas. CONCLUSION: The present data seem to indicate that the presence of myomas does not affect clinico-pathological variables of EC patients nor their survival.

Temporal pattern of recurrence of stage I endometrial cancer in relation to histological risk factors.

OBJECTIVE: To study the temporal pattern of endometrial cancer recurrence in relation to histological risk factors in a large multicenter setting. METHODS: 843 patients with apparent stage I endometrial cancer were followed for a median time of 38 months, documenting all recurrences. Patients were stratified as high risk based on the presence of at least one of the established histological risk factors: high tumor grade, penetration to the outer half of the myometrium, lymphvascular space involvement, lower uterine segment involvement and non endometroid histology. Survival analysis, including Kaplan-Meier curves, log-rank tests and multi-variate Cox proportional hazard regression were used to evaluate the equality of recurrence-free distributions for different levels of risk. RESULTS: Recurrence was documented in 66 cases. The presence of one or more of the histological risk factors was associated with significantly shorter recurrence free survival, not attenuating over time (p < 0.001). Age-adjusted Cox regression model demonstrated a significantly decreased recurrence-free survival (HR = 2.8 95% CI 1.5, 5.1) in the presence of risk factors. CONCLUSIONS: In patients with stage I endometrial cancer, the presence of histological risk factors is associated with a significantly higher recurrence rate, which does not attenuate over follow up time. This may allow for a selective approach in the follow- up of endometrial cancer patients.