Juvenile hormones direct primordial germ cell migration to the embryonic gonad.

Germ cells are essential to sexual reproduction. Across the animal kingdom, extracellular signaling isoprenoids, such as retinoic acids (RAs) in vertebrates and juvenile hormones (JHs) in invertebrates, facilitate multiple processes in reproduction. Here we investigated the role of these potent signaling molecules in embryonic germ cell development, using JHs in Drosophila melanogaster as a model system. In contrast to their established endocrine roles during larval and adult germline development, we found that JH signaling acts locally during embryonic development. Using an in vivo biosensor, we observed active JH signaling first within and near primordial germ cells (PGCs) as they migrate to the developing gonad. Through in vivo and in vitro assays, we determined that JHs are both necessary and sufficient for PGC migration. Analysis into the mechanisms of this newly uncovered paracrine JH function revealed that PGC migration was compromised when JHs were decreased or increased, suggesting that specific titers or spatiotemporal JH dynamics are required for robust PGC colonization of the gonad. Compromised PGC migration can impair fertility and cause germ cell tumors in many species, including humans. In mammals, retinoids have many roles in development and reproduction. We found that like JHs in Drosophila, RA was sufficient to impact mouse PGC migration in vitro. Together, our study reveals a previously unanticipated role of isoprenoids as local effectors of pre-gonadal PGC development and suggests a broadly shared mechanism in PGC migration.

Malnutrition risk, outcomes, and costs among older adults undergoing elective surgical procedures: A retrospective cohort study.

BACKGROUND: We examine here the association between malnutrition risk and adverse health outcomes among older adult patients undergoing elective surgical procedures. METHODS: We conducted a retrospective study using linked clinical and administrative databases. Malnutrition risk was assessed prior to surgery, defined by unintentional weight loss and decreased food intake. We performed a logistic regression analysis of the primary outcome, a composite adverse outcome measure, including death, bleeding, pneumonia, and other surgical complications. We conducted Fine-Gray proportional hazard regression analysis of hospital length of stay (LOS). We performed a generalized linear regression analysis of in-hospital cost data. All regression analyses controlled for frailty, age, sex, surgical category, and comorbidities. RESULTS: Of a total of 3457 older adult elective surgical patients (65-102 years), 310 (9.0%) screened positive for malnutrition risk. In multivariable regression analyses, malnutrition risk was associated with an increased risk of the composite adverse outcome (odds ratio [OR] = 1.74; 95% CI = 1.25-2.39), higher hospitalization costs (relative cost = 1.84; 95% CI = 1.59-2.13), and a decreased risk of discharge from the hospital (hazard ratio = 0.67; 95% CI = 0.59-0.77) compared with those who screened negative. CONCLUSION: Older adult patients with malnutrition risk were at an increased risk of adverse surgical outcomes, had longer LOS in the hospital, and incurred higher costs of care. It is important to screen for malnutrition risk and refer older adults for dietetic consults prior to elective surgery.

Patient perspectives on the use of indwelling pleural catheters in malignant pleural effusions.

BACKGROUND: Indwelling pleural catheters are an effective treatment option for patients with malignant pleural effusions. Despite their popularity, there remains a paucity of data on the patient experience and key patient-centred outcomes. OBJECTIVE: To investigate the experience of patients receiving an indwelling pleural catheter to better inform and identify potential areas for improvement in care. METHODS: This was a multicentre survey study at three academic, tertiary-care centres in Canada. Patients with a diagnosis of malignant pleural effusion who had an indwelling pleural catheter inserted were included. An adapted questionnaire specific to indwelling pleural catheters was used with responses recorded on a 4-point Likert scale. Patients completed the questionnaire in-person or by phone at 2-week and 3-month follow-up appointments. RESULTS: A total of 105 patients were enrolled in the study with 84 patients included in the final analysis. At the 2-week follow-up, patient-reported improvements in dyspnoea and quality of life from indwelling pleural catheter were high at 93% and 87%, respectively. The predominant issues identified were discomfort at time of insertion (58%), itching (49%), difficulty with sleeping (39%), discomfort with home drainage (36%) and the pleural catheter reminding patients of their disease (63%). Avoiding hospitalisation for the management of dyspnoea was important to 95% of patients. Findings were similar at 3 months. CONCLUSIONS: Indwelling pleural catheters are an effective intervention to directly improve dyspnoea and quality of life but have important disadvantages for some; clinicians and patients should be aware of these when making an informed decision regarding treatment.

Comparison of Outcomes Following Glaucoma Drainage Tube Surgery Between Primary and Secondary Glaucomas, and Between Phakic and Pseudophakic eyes.

PURPOSE: To report outcomes of glaucoma drainage device (GDD) surgery based on primary or secondary glaucoma diagnosis and lens status. DESIGN: Single-center, retrospective, consecutive cohort study. METHODS: University of Florida patients aged 18 to 93 years who underwent nonvalved GDD surgery between 1996 and 2015 with a minimum of 1-year follow-up were examined. Of the 186 eyes of 186 patients enrolled, 108 had a primary glaucoma and 78 a secondary glaucoma diagnosis. Excluding 13 aphakic patients, 57 eyes were phakic and 116 pseudophakic. Mean intraocular pressure (IOP), mean number of medications, visual acuity (VA), surgical complications, and failure (IOP ≥18 mm Hg, IOP <6 mm Hg, reoperation for glaucoma, or loss of light perception) were the main outcome measures. RESULTS: No significant difference was noted in mean IOP and mean medication use (12.8 ±â€Š4.5 and 13.0 ±â€Š6.6 mm Hg on 2.0 ±â€Š1.2 and 1.5 ±â€Š1.1 medication classes, respectively), mean VA (1.08 ±â€Š0.98 and 0.94 ±â€Š0.89, respectively), failure, or numbers of complications and reoperations (P > 0.05) between eyes with primary and secondary glaucomas at up to 5 years postoperatively. Comparison of phakic and pseudophakic eyes showed a statistically significant higher success rate for the pseudophakic patient group at the ≥18 mm Hg upper limit and <6 mm Hg lower limit (P = 0.01), and significantly fewer eyes required reoperation to lower IOP (6.9% vs 23%). CONCLUSIONS: GDD surgery appears equally effective for secondary glaucomas as for primary glaucomas, and has a better outcome for pseudophakic eyes than phakic eyes.

Comparison of Outcomes of Glaucoma Drainage Implant Surgery With or Without Prior Failed Trabeculectomy.

PRECIS: A comparison of 186 glaucoma patients with mixed diagnoses who underwent nonvalved glaucoma drainage device (GDD) implant surgery showed similar long-term intraocular pressure (IOP), medication, and visual acuity (VA) outcomes between those with prior failed trabeculectomy surgery versus those without. PURPOSE: The purpose of this study was to evaluate whether prior failed trabeculectomy adversely affects the outcome of glaucoma tube surgery. PATIENTS AND METHODS: A total of 186 eyes of 186 patients who underwent a nonvalved GDD implant surgery by a single surgeon between 1996 and 2015 at a University practice were included. Patients were of mixed diagnoses and over 18 years old. Before the GDD surgery, 65 had a previous failed glaucoma filtering surgery and 121 had no prior glaucoma surgery. Demographic information, preoperative and postoperative IOP, medication, VA, and complications were collected from chart review. RESULTS: No significant difference was noted in mean IOP and mean medication use (13.0 and 12.6 mm Hg on 2.0 and 1.7 medication classes at 5 y postoperatively, respectively), mean VA and change in VA from baseline, or numbers of complications (P>0.05), between eyes that had a prior failed filtration surgery and those that had not. Kaplan-Meier plots for failure over 5 years using a lower limit of <5 mm Hg and an upper limit of ≥18, ≥15, or ≥12 mm Hg did not show a significant difference between groups. Subanalyses were performed to examine only primary glaucoma eyes and results were similar. Further group subanalyses comparing those with baseline IOP ≥25 or <25 mm Hg, age 65 and above or below 65 years and those specifically with Baerveldt 350 mm2 implants also did not show significant differences. CONCLUSION: Prior failed filtration surgery does not appear to affect the outcome of future GDD surgery.

Testicular germ cell tumors arise in the absence of sex-specific differentiation.

In response to signals from the embryonic testis, the germ cell intrinsic factor NANOS2 coordinates a transcriptional program necessary for the differentiation of pluripotent-like primordial germ cells toward a unipotent spermatogonial stem cell fate. Emerging evidence indicates that genetic risk factors contribute to testicular germ cell tumor initiation by disrupting sex-specific differentiation. Here, using the 129.MOLF-Chr19 mouse model of testicular teratomas and a NANOS2 reporter allele, we report that the developmental phenotypes required for tumorigenesis, including failure to enter mitotic arrest, retention of pluripotency and delayed sex-specific differentiation, were exclusive to a subpopulation of germ cells failing to express NANOS2. Single-cell RNA sequencing revealed that embryonic day 15.5 NANOS2-deficient germ cells and embryonal carcinoma cells developed a transcriptional profile enriched for MYC signaling, NODAL signaling and primed pluripotency. Moreover, lineage-tracing experiments demonstrated that embryonal carcinoma cells arose exclusively from germ cells failing to express NANOS2. Our results indicate that NANOS2 is the nexus through which several genetic risk factors influence tumor susceptibility. We propose that, in the absence of sex specification, signals native to the developing testis drive germ cell transformation.

Measurement and prognosis of frail patients undergoing transcatheter aortic valve implantation: a systematic review and meta-analysis.

OBJECTIVES: Our objectives were to review the literature to identify frailty instruments in use for transcatheter aortic valve implantation (TAVI) recipients and synthesise prognostic data from these studies, in order to inform clinical management of frail patients undergoing TAVI. METHODS: We systematically reviewed the literature published in 2006 or later. We included studies of patients with aortic stenosis, diagnosed as frail, who underwent a TAVI procedure that reported mortality or clinical outcomes. We categorised the frailty instruments and reported on the prevalence of frailty in each study. We summarised the frequency of clinical outcomes and pooled outcomes from multiple studies. We explored heterogeneity and performed subgroup analysis, where possible. We also used Grading of Recommendations, Assessment, Development and Evaluation (GRADE) to assess the overall certainty of the estimates. RESULTS: Of 49 included studies, 21 used single-dimension measures to assess frailty, 3 used administrative data-based measures, and 25 used multidimensional measures. Prevalence of frailty ranged from 5.67% to 90.07%. Albumin was the most commonly used single-dimension frailty measure and the Fried or modified Fried phenotype were the most commonly used multidimensional measures. Meta-analyses of studies that used either the Fried or modified Fried phenotype showed a 30-day mortality of 7.86% (95% CI 5.20% to 11.70%) and a 1-year mortality of 26.91% (95% CI 21.50% to 33.11%). The GRADE system suggests very low certainty of the respective estimates. CONCLUSIONS: Frailty instruments varied across studies, leading to a wide range of frailty prevalence estimates for TAVI recipients and substantial heterogeneity. The results provide clinicians, patients and healthcare administrators, with potentially useful information on the prognosis of frail patients undergoing TAVI. This review highlights the need for standardisation of frailty measurement to promote consistency. PROSPERO REGISTRATION NUMBER: CRD42018090597.

Delayed male germ cell sex-specification permits transition into embryonal carcinoma cells with features of primed pluripotency.

Testicular teratomas result from anomalies in embryonic germ cell development. In 129 inbred mice, teratoma initiation coincides with germ cell sex-specific differentiation and the mitotic-meiotic switch: XX and XY germ cells repress pluripotency, XX germ cells initiate meiosis, and XY germ cells activate male-specific differentiation and mitotic arrest. Here, we report that expression of Nanos2, a gene that is crucial to male sex specification, is delayed in teratoma-susceptible germ cells. Decreased expression of Nanos2 was found to be due, in part, to the Nanos2 allele present in 129 mice. In teratoma-susceptible germ cells, diminished expression of genes downstream of Nanos2 disrupted processes that were crucial to male germ cell differentiation. Deficiency for Nanos2 increased teratoma incidence in 129 mice and induced developmental abnormalities associated with tumor initiation in teratoma-resistant germ cells. Finally, in the absence of commitment to the male germ cell fate, we discovered that a subpopulation of teratoma-susceptible germ cells transition into embryonal carcinoma (EC) cells with primed pluripotent features. We conclude that delayed male germ cell sex-specification facilitates the transformation of germ cells with naïve pluripotent features into primed pluripotent EC cells.

Germ cell tumors: Insights from the Drosophila ovary and the mouse testis.

Ovarian and testicular germ cell tumors of young adults are thought to arise from defects in germ cell development, but the molecular mechanisms underlying malignant transformation are poorly understood. In this review, we focus on the biology of germ cell tumor formation in the Drosophila ovary and the mouse testis, for which evidence supports common underlying mechanisms, such as blocking initiation into the differentiation pathway, impaired lineage progression, and sexual identity instability. We then discuss how these concepts inform our understanding of the disease in humans. Mol. Reprod. Dev. 84: 200-211, 2017. © 2017 Wiley Periodicals, Inc.

Misexpression of cyclin D1 in embryonic germ cells promotes testicular teratoma initiation.

Testicular teratomas result from anomalies in embryonic germ cell development. In the 129 family of inbred mouse strains, teratomas arise during the same developmental period that male germ cells normally enter G1/G0 mitotic arrest and female germ cells initiate meiosis (the mitotic:meiotic switch). Dysregulation of this switch associates with teratoma susceptibility and involves three germ cell developmental abnormalities seemingly critical for tumor initiation: delayed G1/G0 mitotic arrest, retention of pluripotency, and misexpression of genes normally restricted to embryonic female and adult male germ cells. One misexpressed gene, cyclin D1 (Ccnd1), is a known regulator of cell cycle progression and an oncogene in many tissues. Here, we investigated whether Ccnd1 misexpression in embryonic germ cells is a determinant of teratoma susceptibility in mice. We found that CCND1 localizes to teratoma-susceptible germ cells that fail to enter G1/G0 arrest during the mitotic:meiotic switch and is the only D-type cyclin misexpressed during this critical developmental time frame. We discovered that Ccnd1 deficiency in teratoma-susceptible mice significantly reduced teratoma incidence and suppressed the germ cell proliferation and pluripotency abnormalities associated with tumor initiation. Importantly, Ccnd1 expression was dispensable for somatic cell development and male germ cell specification and maturation in tumor-susceptible mice, implying that the mechanisms by which Ccnd1 deficiency reduced teratoma incidence were germ cell autonomous and specific to tumorigenesis. We conclude that misexpression of Ccnd1 in male germ cells is a key component of a larger pro-proliferative program that disrupts the mitotic:meiotic switch and predisposes 129 inbred mice to testicular teratocarcinogenesis.

IL-33 activates tumor stroma to promote intestinal polyposis.

Tumor epithelial cells develop within a microenvironment consisting of extracellular matrix, growth factors, and cytokines produced by nonepithelial stromal cells. In response to paracrine signals from tumor epithelia, stromal cells modify the microenvironment to promote tumor growth and metastasis. Here, we identify interleukin 33 (IL-33) as a regulator of tumor stromal cell activation and mediator of intestinal polyposis. In human colorectal cancer, IL-33 expression was induced in the tumor epithelium of adenomas and carcinomas, and expression of the IL-33 receptor, IL1RL1 (also referred to as IL1-R4 or ST2), localized predominantly to the stroma of adenoma and both the stroma and epithelium of carcinoma. Genetic and antibody abrogation of responsiveness to IL-33 in the Apc(Min/+) mouse model of intestinal tumorigenesis inhibited proliferation, induced apoptosis, and suppressed angiogenesis in adenomatous polyps, which reduced both tumor number and size. Similar to human adenomas, IL-33 expression localized to tumor epithelial cells and expression of IL1RL1 associated with two stromal cell types, subepithelial myofibroblasts and mast cells, in Apc(Min/+) polyps. In vitro, IL-33 stimulation of human subepithelial myofibroblasts induced the expression of extracellular matrix components and growth factors associated with intestinal tumor progression. IL-33 deficiency reduced mast cell accumulation in Apc(Min/+) polyps and suppressed the expression of mast cell-derived proteases and cytokines known to promote polyposis. Based on these findings, we propose that IL-33 derived from the tumor epithelium promotes polyposis through the coordinated activation of stromal cells and the formation of a protumorigenic microenvironment.

A 16-year-old male with dizziness, parasthesias, and ataxia.

A 16-year-old African-American male with no past medical history presented with gait instability and somnolence. He had intermittent neurological complaints during the prior 4 months, including dizziness, left arm paresthesias, decreased hearing, and inability to control his hands. After an initial diagnosis of vertigo, his symptoms progressed, leading to reevaluation and a second emergency department head computed tomography (CT) scan, which revealed a large area of hypodensity in the cerebellum. Repeat head CT on arrival to the intensive care unit showed a large, left cerebellar hemispheric stroke. This case study discusses the findings of the patient's cerebral angiogram, the diagnosis of fibromuscular dysplasia, and the aggressive treatment that likely prevented further devastating strokes in the brainstem, thalamus, and occipital lobe. This case serves as a reminder that strokes are not just an adult disease and that classic presentations can occur even in unconventional patients.