Removal of uterine polyps: clinical management and surgical approach.

Endometrial polyps have a reported prevalence from 7.8% up to 30% and are one of the most cost-consuming gynecological conditions for our specialty. There are strong practitioner beliefs that surgical removal of endometrial polyps is highly beneficial, particularly for those with abnormal uterine bleeding and infertility. Additionally, polypectomy is indicated to reduce the risk of malignancy. Transvaginal ultrasound is the first-line diagnostic option for detection of endometrial polyps, while sonohysterography has similar accuracy as hysteroscopy in the diagnostic confirmation. Blind dilatation and curettage is not recommended for polyp removal; rather, hysteroscopy in the operating room and office setting using small-diameter hysteroscopic equipment is the standard approach. This can be performed without anesthesia in most women. While hysteroscopy is an effective method for polypectomy with a low complication rate, it is unknown whether this is truly beneficial for reproductive-age women with infertility and prior assisted reproduction therapy. The risk of malignancy in women with postmenopausal bleeding justifies the necessity of polypectomy with histologic tissue examination. In asymptomatic women, the risk of malignancy is low, and there are no known benefits of polyp removal in the prevention of malignant transformation. Cost-effective studies remain to be done to provide us with the optimal approach to endometrial polyps including the management of asymptomatic and/or infertile women, ideal location including office-based or the operating room setting, complication prevention including intrauterine adhesions, and recurrence issues.

The role of intra-operative cell salvage in patient blood management for revision hip arthroplasty: a prospective cohort study.

Cell salvage is an important component of blood management in patients undergoing revision hip arthroplasty surgery. However concerns regarding efficacy and patient selection remain. The aims of this study were to describe intra-operative blood loss, cell salvage re-infusion volumes and red blood cell transfusion rates for revision hip procedures and to identify factors associated with the ability to salvage sufficient blood intra-operatively to permit processing and re-infusion. Data were collected from a prospective cohort of 664 consecutive patients undergoing revision hip surgery at a single tertiary centre from 31 March 2015 to 1 April 2018. Indications for revision surgery were aseptic (n = 393 (59%)) fracture (n = 160 (24%)) and infection (n = 111 (17%)). Salvaged blood was processed and re-infused when blood loss exceeded 500 ml. Mean (SD) intra-operative blood loss was 1038 (778) ml across all procedures. Salvaged blood was re-infused in 505 of 664 (76%) patients. Mean (SD) re-infusion volume was 253 (169) ml. In total, 246 of 664 (37%) patients received an allogeneic red blood cell transfusion within 72 h of surgery. Patients undergoing femoral component revision only (OR (95%CI) 0.41 (0.23-0.73)) or acetabular component revision only (0.53 (0.32-0.87)) were less likely to generate sufficient blood salvage volume for re-infusion compared with revision of both components. Compared with aseptic indications, patients undergoing revision surgery for infection (1.87 (1.04-3.36)) or fracture (4.43 (2.30-8.55)) were more likely to generate sufficient blood salvage volume for re-infusion. Our data suggest that cell salvage is efficacious in this population. Cases where the indication is infection or fracture and where both femoral and acetabular components are to be revised should be prioritised.

Inflation of 430-parsec bipolar radio bubbles in the Galactic Centre by an energetic event.

The Galactic Centre contains a supermassive black hole with a mass of four million Suns1 within an environment that differs markedly from that of the Galactic disk. Although the black hole is essentially quiescent in the broader context of active galactic nuclei, X-ray observations have provided evidence for energetic outbursts from its surroundings2. Also, although the levels of star formation in the Galactic Centre have been approximately constant over the past few hundred million years, there is evidence of increased short-duration bursts3, strongly influenced by the interaction of the black hole with the enhanced gas density present within the ring-like central molecular zone4 at Galactic longitude |l| < 0.7 degrees and latitude |b| < 0.2 degrees. The inner 200-parsec region is characterized by large amounts of warm molecular gas5, a high cosmic-ray ionization rate6, unusual gas chemistry, enhanced synchrotron emission7,8, and a multitude of radio-emitting magnetized filaments9, the origin of which has not been established. Here we report radio imaging that reveals a bipolar bubble structure, with an overall span of 1 degree by 3 degrees (140 parsecs × 430 parsecs), extending above and below the Galactic plane and apparently associated with the Galactic Centre. The structure is edge-brightened and bounded, with symmetry implying creation by an energetic event in the Galactic Centre. We estimate the age of the bubbles to be a few million years, with a total energy of 7 × 1052 ergs. We postulate that the progenitor event was a major contributor to the increased cosmic-ray density in the Galactic Centre, and is in turn the principal source of the relativistic particles required to power the synchrotron emission of the radio filaments within and in the vicinity of the bubble cavities.

Risk factors and mitigation of influenza among Indigenous children in Australia, Canada, United States, and New Zealand: a scoping review.

AIM: This review considers prominent risk factors and mitigation strategies of influenza among Indigenous children. METHODS: Seven electronic databases were searched from the period of 2004-2017 to locate articles discussing influenza among Indigenous children in the developed circumpolar nations of Australia, Canada, United States, and New Zealand. Articles selected for inclusion discussed influenza among Indigenous children as either individuals or as a part of a community. Ancestry searches of articles meeting the review criteria were also undertaken to discern seminal research in this topic area. RESULTS: From the 39 primary research studies included, marked risk factors and mitigation strategies of influenza among Indigenous children were identified using inductive analysis. Notable risk factors included age under 2 years, cigarette smoke exposure, presence of a chronic illness, and crowded living conditions. Successful mitigation of influenza for Indigenous children included strategies to improve vaccine coverage, provision of health education, and policy change. CONCLUSION: In the past, the impact of influenza upon Indigenous communities has been devastating for both children and their families. By utilizing existing public health infrastructure and collaborating with culturally unique Indigenous groups, preventive action for Indigenous children at significant risk of contracting influenza can be realized.

Altiratinib Inhibits Tumor Growth, Invasion, Angiogenesis, and Microenvironment-Mediated Drug Resistance via Balanced Inhibition of MET, TIE2, and VEGFR2.

Altiratinib (DCC-2701) was designed based on the rationale of engineering a single therapeutic agent able to address multiple hallmarks of cancer (1). Specifically, altiratinib inhibits not only mechanisms of tumor initiation and progression, but also drug resistance mechanisms in the tumor and microenvironment through balanced inhibition of MET, TIE2 (TEK), and VEGFR2 (KDR) kinases. This profile was achieved by optimizing binding into the switch control pocket of all three kinases, inducing type II inactive conformations. Altiratinib durably inhibits MET, both wild-type and mutated forms, in vitro and in vivo. Through its balanced inhibitory potency versus MET, TIE2, and VEGFR2, altiratinib provides an agent that inhibits three major evasive (re)vascularization and resistance pathways (HGF, ANG, and VEGF) and blocks tumor invasion and metastasis. Altiratinib exhibits properties amenable to oral administration and exhibits substantial blood-brain barrier penetration, an attribute of significance for eventual treatment of brain cancers and brain metastases.

Alternative lengthening of telomeres in cancer stem cells in vivo.

Chromosome ends are protected by telomeres that prevent DNA damage response and degradation. Telomerase expression extends telomeres and inhibits DNA damage response. Telomeres are also maintained by the recombination-based alternative lengthening pathway. Telomerase is believed to be the sole mechanism for telomere maintenance in the epidermis. We show that basal cells in the epidermis maintain telomeres both by telomerase and alternative lengthening of telomere (ALT) mechanisms in vivo. ALT was detected in epidermal stem cells in Terc(-/-) mice, and normal human epidermal keratinocytes are also ALT-positive. The ALT pathway is suppressed in primary, but not metastatic, epidermal squamous cell carcinomas (SCC) in Terc(+/+) mice. The ALT pathway is expressed in stem cells and basal cells in epidermal SCC in Terc(-/-) mice, and in some telomerase-positive human SCC lines. Telomeres shorten markedly in stem cells and basal cells in epidermal SCC in vivo. Telomere shortening is associated with telomeric DNA damage response and apoptosis in stem cells and basal cells. Stem cells were transformed in both primary and metastatic epidermal SCC. Genetic ablation of this small cell population resulted in significant tumor regression in vivo. We concluded that alternative lengthening of telomeres is important in epidermal homeostasis and tumorigenesis in vivo.

Contraception in sea-going service personnel.

The right to make an informed choice about contraception should be afforded to every individual serving within the United Kingdom (UK) Armed Forces. This article looks at the responsibilities and approach that healthcare professionals should take within a Primary Care setting, summarises the common contraceptive options available, discusses the associated advantages and disadvantages of each technique, and considers operational factors in a military environment that combine to influence the final contraceptive choice an individual makes. Case Study. A 19-year old Able Rate joined the Royal Navy (RN) and at her joining medical it was noted that she had been on Microgynon™ combined oral contraceptive pill for approximately three years. During this time, her menstrual periods remained light; she never experienced adverse effects, demonstrated good compliance, and was happy to remain on this contraceptive regimen. Over the course of the next eighteen months, she was reviewed by a number of Medical Officers and Civilian Medical Practitioners on a quarterly basis, with Microgynon™ re-prescribed on each occasion. The appropriate Defence Medical Information Capability Programme (DMICP) template was used, with weight, smoking status, compliance and any issues or comments documented accordingly. In December 2010, a discussion regarding long-acting reversible contraception (LARC) was documented for the first time. The patient agreed to give LARC some thought and a review appointment was made for one month. She was subsequently started on the progestogen-only pill Cerazette™. It was noted by the consulting doctor that both the patient's mother and grandmother had a positive history of cerebrovascular events and the combined oral contraceptive pill was discontinued. Upon review at two months, the patient reported that she was content on Cerazette™ and wished to continue with this medication. She was amenorrhoeic, highly compliant, had given up smoking and her weight and blood pressure were stable. However, due to supply issues, it was explained that Cerazette™ was no longer a viable option for her. She had no plans to start a family, and was keen to investigate other contraceptive options. Furthermore, she expressed a particular desire to remain amenorrhoeic, as she was due to deploy overseas in the coming months, and not only wanted to avoid the inconvenience of having her period, but also felt it preferable not to have to take a daily pill when considering the constantly changing time zones. She subsequently had the etonogestrel-releasing subdermal implant Nexplanon™ fitted without complication. She has remained amenorrhoeic throughout and this form of long-acting reversible contraception has particularly suited her busy working role and active lifestyle.

The guidance of stem cell differentiation by substrate alignment and mechanical stimulation.

Mesenchymal stem cells (MSC) represent a promising and clinically relevant cell source for tissue engineering applications. As such, guiding MSCs toward specific lineages and maintaining these phenotypes have been particularly challenging as the contributions of mechanical, chemical and structural cues to the complex differentiation process are largely unknown. To fully harness the potential of MSCs for regenerative medicine, a systematic investigation into the individual and combined effects of these stimuli is needed. In addition, unlike chemical stimulation, for which temporal and concentration gradients are difficult to control, mechanical stimulation and scaffold-based cues may be relatively more biomimetic and can be applied with greater control to ensure fidelity in MSC differentiation. The objective of this study is to investigate the role of nanofiber matrix alignment and mechanical stimulation on MSC differentiation, focusing on elucidating the relative contribution of each parameter in guided regeneration of functional connective tissues. It is observed that nanofiber alignment directs MSC response to physiological loading and that fibroblastic differentiation requires a combination of physiologically-relevant cell-material interactions in conjunction with mechanical stimulation. Importantly, the results of this study reveal that systemic and readily controllable cues, such as scaffold alignment and optimized mechanical stimulation, are sufficient to drive MSC differentiation, without the need for additional chemical stimuli. Moreover, these findings yield a set of fundamental design rules that can be readily applied to connective tissue regeneration strategies.

Docetaxel pharmacokinetics and its correlation with two in vivo probes for cytochrome P450 enzymes: the C(14)-erythromycin breath test and the antipyrine clearance test.

BACKGROUND: Docetaxel has marked inter-patient PK variability, and metabolic phenotypic probes may enable individualised dosing. This is the first report directly comparing the erythromycin breath test (EBT) (a CYP3A4 probe) with the antipyrine clearance test (ACT), (a general CYP-P450/predominant CYP3A4 probe) for the correlation with docetaxel PK and toxicity. METHODS: Patients pretherapy underwent: (A) EBT: IV C(14)[N-methyl]-erythromycin was administered and breath samples analysed for (14)CO(2), derived parameters included (1) (14)CO(2) flux at 10-min (CO(2)f(10)), (2) 20-min (CO(2)f(20)), (3) terminal rate constant k(CO2) and (4) AUC(CO2,(0-∞)) and AUC(CO2,(0-60).) (B) ACL test: patients were given oral antipyrine 10 mg/kg, blood samples were taken for PK, and the clearance (CL(Ant)) was derived. Docetaxel was then given at 75 mg/m(2)/3-weekly or 35 mg/m(2)/weekly. Samples taken for docetaxel PK in first course on day 1 and PK parameters included clearance (CL(Doc)). RESULTS: Twenty patients accrued, docetaxel: 3-weekly/weekly = 13:7. EBT parameters (N = 19) (mean, [CV%]): CO(2)f(10) (%/min) 0.051 (106), CO(2)f(20) 0.052 (82), k(CO2) (min(-1)) 0.007 (22), AUC(CO2,(0-∞)) 7.9 (85), AUC(CO2,(0-60)) 2.64 (81). CL(Ant) (N = 19) (ml/min); 35.8 (37). Docetaxel PK parameters (N = 19): CL(Doc) (l/h) = 57.2 (36), t(Doc1/2) (h) = 12.7 (33). No correlations were observed between the docetaxel PK and EBT parameters. For docetaxel weekly patients, a significant linear relationship was observed between CL(Doc) and CL(Ant) (P = 0.007, R (2) = 79.47%). CONCLUSIONS: The utility of EBT for the prediction of docetaxel PK was not confirmed in this study. The antipyrine clearance test may be superior in this regard for docetaxel, but regimen dependent and hence warrants further evaluation.

Metabolic adaptations of oxidative muscle during spawning migration in the Atlantic salmon Salmo salar L.

The adaptability/plasticity of the highly oxidative red muscle in Atlantic salmon was demonstrated during spawning migration. Substrate concentrations and the enzymatic pathways of ATP production were examined in red muscle obtained from Atlantic salmon at different sites along their migratory route in the Exploits River, Newfoundland, Canada. Individuals were chronologically sampled from a seawater site, two sites upstream, and at spawning. The 20% decrease in salmon body weight during the later stages of migration was accompanied by large decreases (mg dry weight(-1)) in both glycogen (P < 0.01) and total muscle lipid (P < 0.01). In contrast, water content and protein concentration (mg dry weight(-1)) of the red muscle increased by 25 and 34%, respectively, at spawning. Enzymes of the glycolytic pathways demonstrated a significant (P < 0.001) decrease in maximal activity as migration proceeded whereas enzymes of the oxidative phosphorylation pathways, specifically the citric acid cycle enzymes, exhibited an increase (P < 0.001) in maximal activity at spawning. The antioxidant enzyme superoxide dismutase also demonstrated an increase (P < 0.001) in maximal activity during the latter stages of migration. These adaptations imply that the red epaxial muscle of Atlantic salmon has a more efficient means of oxidizing lipids, while minimizing free radical damage, during the later stages of migration and spawning, thereby potentially increasing post spawning survival.

Oestrus in the Julia Creek dunnart (Sminthopsis douglasi) is associated with wheel running behaviour but not necessarily changes in body weight, food consumption or pouch morphology.

The Julia Creek dunnart (Sminthopsis douglasi) is an endangered carnivorous marsupial belonging to the family Dasyuridae. This study investigated the oestrous cycle of this species in terms of its reproductive physiology and behaviour to explore more efficient methods of oestrus detection. Ten sexually mature captive female dunnarts were monitored daily at David Fleay Wildlife Park, Burleigh Heads, Australia, from mid September to late December 2006 for changes in urogenital cytology within the urine (0, 1+, 2+ and 3+), running wheel activity, body weight, uneaten food, faecal steroid metabolites (progesterone and oestradiol) and pouch development. Periods of increased running wheel activity were associated (p=0.004) with an increase in the proportion of cornified urogenital epithelial cells found in the urine; periods of decreasing weight (p<0.001) and uneaten food (p<0.001) were also associated with changes in urogenital cytology but not to the point where they would be useful for oestrus detection. Between 60.3% and 92.0% of peak distances (confidence interval 95%) occurred when the epithelial cell index was 2+ or 3+. Only 15.5-37.5% of peak weights (CI: 95%) and 28.1-49.9% of incidences of uneaten food (CI: 95%) occurred when the epithelial cell index was 2+ or 3+. There was no significant difference in the mean length of the oestrous cycle when measured by urogenital cytology (mean+/-SD: 25.0+/-5.7 days; n=20) or peak distance travelled (mean+/-SD: 25.4+/-5.7 days; n=20). Changes in the concentration of oestradiol metabolites in Julia Creek Dunnart faeces were not useful in characterising the oestrous cycle. Wheel running activity declined markedly with increased faecal progestagen concentration. The majority of the pouch variables examined showed maximum development during the inter-oestrus period but as there was considerable variation between animals, the pouch was not considered a useful index of oestrus.

Gemcitabine sensitization by checkpoint kinase 1 inhibition correlates with inhibition of a Rad51 DNA damage response in pancreatic cancer cells.

The protein kinase checkpoint kinase 1 (Chk1) has been implicated as a key regulator of cell cycle progression and DNA repair, and inhibitors of Chk1 (e.g., UCN-01 and EXEL-9844) potentiate the cytotoxic actions of chemotherapeutic drugs in tumor cells. We have examined the ability of PD-321852, a small-molecule Chk1 inhibitor, to potentiate gemcitabine-induced clonogenic death in a panel of pancreatic cancer cell lines and evaluated the relationship between endpoints associated with Chk1 inhibition and chemosensitization. Gemcitabine chemosensitization by minimally toxic concentrations of PD-321852 ranged from minimal (<3-fold change in survival) in Panc1 cells to >30-fold in MiaPaCa2 cells. PD-321852 inhibited Chk1 in all cell lines as evidenced by stabilization of Cdc25A; in combination with gemcitabine, a synergistic loss of Chk1 protein was observed in the more sensitized cell lines. Gemcitabine chemosensitization, however, did not correlate with abrogation of the S-M or G2-M checkpoint; PD-321852 did not induce premature mitotic entry in gemcitabine-treated BxPC3 or M-Panc96 cells, which were sensitized to gemcitabine 6.2- and 4.6-fold, respectively. In the more sensitized cells lines, PD-321852 not only inhibited gemcitabine-induced Rad51 focus formation and the recovery from gemcitabine-induced replication stress, as evidenced by persistence of gamma-H2AX, but also depleted these cells of Rad51 protein. Our data suggest the inhibition of this Chk1-mediated Rad51 response to gemcitabine-induced replication stress is an important factor in determining gemcitabine chemosensitization by Chk1 inhibition in pancreatic cancer cells.

4-Phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione inhibitors of the checkpoint kinase Wee1. Structure-activity relationships for chromophore modification and phenyl ring substitution.

High-throughput screening has identified a novel class of inhibitors of the checkpoint kinase Wee1, which have potential for use in cancer chemotherapy. These inhibitors are based on a 4-phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione template and have been shown by X-ray crystallography to bind at the ATP site of the enzyme. An extensive study of the effects of substitution around this template has been carried out, which has identified substituents which lead to improvements in potency and selectivity for Wee1. While retention of the maleimide ring and pendant 4-phenyl group is necessary for potency, replacement of the carbazole nitrogen by oxygen is well tolerated and results in improved Wee1 selectivity against the related checkpoint kinase Chk1. Wee1 potency and selectivity are also enhanced by the incorporation of lipophilic functionality at the 2'-position of the 4-phenyl ring, and Wee1 selectivity against Chk1 is favored by C3-C5 alkyl substitution of the carbazole nitrogen. These studies provide a basis for the design of active analogues of the pyrrolocarbazole lead with improved physical properties.

Pyrido[2,3-d]pyrimidin-7-ones as specific inhibitors of cyclin-dependent kinase 4.

Inhibition of the cell cycle kinase, cyclin-dependent kinase-4 (Cdk4), is expected to provide an effective method for the treatment of proliferative diseases such as cancer. The pyrido[2,3-d]pyrimidin-7-one template has been identified previously as a privileged structure for the inhibition of ATP-dependent kinases, and good potency against Cdks has been reported for representative examples. Obtaining selectivity for individual Cdk enzymes, particularly Cdk4, has been challenging. Here, we report that the introduction of a methyl substituent at the C-5 position of the pyrido[2,3-d]pyrimidin-7-one template is sufficient to confer excellent selectivity for Cdk4 vs other Cdks and representative tyrosine kinases. Further optimization led to the identification of highly potent and selective inhibitors of Cdk4 that exhibit potent antiproliferative activity against human tumor cells in vitro. The most selective Cdk4 inhibitors were evaluated for antitumor activity against MDA-MB-435 human breast carcinoma xenografts in mice.

Screening of some Australian Flacourtiaceae species for in vitro antioxidant, cytotoxic and antimicrobial activity.

A total of 27 methanol extracts obtained from different plant parts of 10 species of rain forest trees belonging to four genera of the Flacourtiaceae and originating from Australia were investigated. In vitro cytotoxicity was measured by an ATP Lite-M assay method against the mouse P388 lymphocytic leukemia cell line. The total antioxidant activity has been assessed based on scavenging activity of stable ABTS free radicals. The minimum inhibition concentration (MIC) was determined by the dilution method performed in 96 well plates against four different microbes. The leaf extract of Casearia sp. (RB 3051), mature stem extract of Casearia grayi and stem extract of Scolopia braunii were found to have most antioxidant activity (IC50 = 2.9 microg/ml), cytotoxic activity (LC50 = 0.89 microg/ml) and antimicrobial activity against all four different microbes, respectively. The results obtained suggested that among the four genera studied Casearia is the most promising in respect of finding significant antioxidant, cytotoxic and also antimicrobial activity.