Parkinson disease affects more than 1% of the population over 60 y old. The dominant models for Parkinson disease are based on the use of chemical toxins to kill dopamine neurons, but do not address ...the risk factors that normally increase with age. Forkhead transcription factors are critical regulators of survival and longevity. The forkhead transcription factor, foxa2, is specifically expressed in adult dopamine neurons and their precursors in the medial floor plate. Gain- and loss-of-function experiments show this gene, foxa2, is required to generate dopamine neurons during fetal development and from embryonic stem cells. Mice carrying only one copy of the foxa2 gene show abnormalities in motor behavior in old age and an associated progressive loss of dopamine neurons. Manipulating forkhead function may regulate both the birth of dopamine neurons and their spontaneous death, two major goals of regenerative medicine.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The floor plate, an essential ventral midline organizing center that produces the morphogen Shh, has distinct properties along the neuraxis. The neurogenic potential of the floor plate and its ...underlying mechanisms remain unknown. Using Shh as a driver for lineage analysis, we found that the mouse midbrain, but not the hindbrain, floor plate is neurogenic, giving rise to dopamine (DA) neurons. Distinct spatiotemporal Shh and Wnt expression may distinguish the neurogenetic potential of these structures. We discovered an inhibitory role for Shh: removal of Shh resulted in neurogenesis from the hindbrain midline and, conversely, high doses of Shh inhibited proliferation and DA neuron production in midbrain cultures. We found that Wnt/beta-catenin signaling is necessary and sufficient for antagonizing Shh, DA progenitor marker induction and promotion of dopaminergic neurogenesis. These findings demonstrate how the dynamic interplay of canonical Wnt/beta-catenin signaling and Shh may orchestrate floor plate neurogenesis or a lack thereof.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The Ewing sarcoma family of tumors (EFT) is a group of highly malignant small round blue cell tumors occurring in children and young adults. We report here the largest genomic survey to date of 101 ...EFT (65 tumors and 36 cell lines). Using a combination of whole genome sequencing and targeted sequencing approaches, we discover that EFT has a very low mutational burden (0.15 mutations/Mb) but frequent deleterious mutations in the cohesin complex subunit STAG2 (21.5% tumors, 44.4% cell lines), homozygous deletion of CDKN2A (13.8% and 50%) and mutations of TP53 (6.2% and 71.9%). We additionally note an increased prevalence of the BRCA2 K3326X polymorphism in EFT patient samples (7.3%) compared to population data (OR 7.1, p = 0.006). Using whole transcriptome sequencing, we find that 11% of tumors pathologically diagnosed as EFT lack a typical EWSR1 fusion oncogene and that these tumors do not have a characteristic Ewing sarcoma gene expression signature. We identify samples harboring novel fusion genes including FUS-NCATc2 and CIC-FOXO4 that may represent distinct small round blue cell tumor variants. In an independent EFT tissue microarray cohort, we show that STAG2 loss as detected by immunohistochemistry may be associated with more advanced disease (p = 0.15) and a modest decrease in overall survival (p = 0.10). These results significantly advance our understanding of the genomic and molecular underpinnings of Ewing sarcoma and provide a foundation towards further efforts to improve diagnosis, prognosis, and precision therapeutics testing.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Purpose
To determine the utility of the endometrial receptivity analysis (ERA) in women with prior failed embryo transfers (ET).
Methods
This was a retrospective study of patients who underwent an ...ERA test with a subsequent frozen ET. Women were classified based on their indication for an ERA test: (1) ≥ 1 prior failed ET (cases), or (2) as a prophylactic measure (controls). A subset analysis of women with ≥ 3 prior failed transfers was performed. Pregnancy outcomes of the subsequent cycle were examined, including conception, clinical pregnancy, and ongoing pregnancy/live birth.
Results
A total of 222 women were included, 131 (59%) women with ≥ 1 prior failed ET and 91 (41%) controls. Among the 131 women with ≥ 1 prior failed ET, 20 women (9%) had ≥ 3 prior failed ETs. The proportion of non-receptive ERA tests in the three groups were the following: 45% (≥ 1 prior failed ET), 40% (≥ 3 prior failed ETs), and 52% (controls). The results did not differ between cases and controls. The pregnancy outcomes did not differ between women with ≥ 1 prior failed ET and controls. In women with ≥ 3 prior failed ETs, there was a lower ongoing pregnancy/live birth rate (28% vs 54%,
P
= 0.046).
Conclusion
Women with ≥ 1 prior failed ET and ≥ 3 prior failed ETs had a similar prevalence of non-receptive endometrium compared to controls. Women with ≥ 3 prior failed ETs had a lower ongoing pregnancy/live birth rate despite a personalized FET, suggesting that there are additional factors in implantation failure beyond an adjustment in progesterone exposure.
We tested the hypothesis that the three clinical phenotypes of polycystic ovary syndrome (PCOS) represent forms of the same metabolic disorder.
Prospective cohort analysis.
University-based tertiary ...care.
Three-hundred sixteen untreated consecutive women diagnosed as having PCOS.
None.
Each subject underwent an evaluation of ovulatory function, body habitus, acne, and hirsutism; serum free and total testosterone (T), 17-hydroxyprogesterone (17-HP), and DHEAS; and fasting plasma glucose and insulin levels. Insulin resistance and β-cell function were assessed using the homeostatic assessment model equation (HOMA-IR and HOMA-β-cell, respectively).
The Oligo+HA+Hirsutism phenotype was present in 48% of subjects, Oligo+HA in 29%, and Oligo+Hirsutism in 23%. The three phenotypes did not differ in mean body mass index, waist-to-hip ratio, racial composition, degree of oligo-ovulation, prevalence of acne, or family history of hyperandrogenic symptomatology. However, subjects demonstrating the Oligo+HA+Hirsutism phenotype were the youngest and had the greatest degrees of hyperandrogenemia, hyperinsulinemia, and β-cell function; patients with the Oligo+Hirsutism phenotype where the oldest and had the mildest degrees of hyperandrogenemia, hyperinsulinemia, and β-cell function. Subjects with the Oligo+HA phenotype demonstrated intermediate degrees of hyperandrogenemia and metabolic dysfunction.
We conclude that the three clinical phenotypes of PCOS do not represent forms of the same metabolic disorder and may be the result of varying degrees of metabolic dysfunction; greater degrees of β-cell function and circulating insulin levels favored the development of hirsutism and frank hyperandrogenemia.
OBJECTIVE Type II odontoid fracture is a common injury among elderly patients, particularly given their predisposition toward low-energy falls. Previous studies have demonstrated a survival advantage ...following early surgery among patients older than 65 years, yet octogenarians represent a medically distinct and rapidly growing population. The authors compared operative and nonoperative management in patients older than 79 years. METHODS A single-center prospectively maintained trauma database was reviewed using ICD-9 codes to identify octogenarians with C-2 cervical fractures between 1998 and 2014. Cervical CT images were independently reviewed by blinded neurosurgeons to confirm a Type II fracture pattern. Prospectively recorded outcomes included Glasgow Coma Scale (GCS) score, Abbreviated Injury Scale (AIS) score, Injury Severity Score (ISS), additional cervical fracture, and cord injury. Primary end points were mortality at 30 days and at 1 year. Statistical tests included the Student t-test, chi-square test, Fisher's exact test, Kaplan-Meier test, and Cox proportional hazard. RESULTS A total of 111 patients met inclusion criteria (94 nonoperative and 17 operative 15 posterior and 2 anterior). Mortality data were available for 100% of patients. The mean age was 87 years (range 80-104 years). Additional cervical fracture, spinal cord injury, GCS score, AIS score, and ISS were not associated with either management strategy at the time of presentation. The mean time to death or last follow-up was 22 months (range 0-129 months) and was nonsignificant between operative and nonoperative groups (p = 0.3). Overall mortality was 13% in-hospital, 26% at 30 days, and 41% at 1 year. Nonoperative and operative mortality rates were not significant at any time point (12% vs 18%, p = 0.5 in-hospital; 27% vs 24%, p = 0.8 30-day; and 41% vs 41%, p = 1.0 1-year). Kaplan-Meier analysis did not demonstrate a survival advantage for either management strategy. Spinal cord injury, GCS score, AIS score, and ISS were significantly associated with 30-day and 1-year mortality; however, Cox modeling was not significant for any variable. Additional cervical fracture was not associated with increased mortality. The rate of nonhome disposition was not significant between the groups. CONCLUSIONS Type II odontoid fracture is associated with high morbidity among octogenarians, with 41% 1-year mortality independent of intervention-a dramatic decrease from actuarial survival rates for all 80-, 90-, and 100-year-old Americans. Poor outcome is associated with spinal cord injury, GCS score, AIS score, and ISS.
Objective To determine the impact of ovary-secreted products on adrenocortical function in women with PCOS by studying the adrenocortical response to acute adrenocorticotropic-stimulating hormone ...(ACTH) stimulation before and after bilateral oophorectomy. Design Prospective study. Setting Tertiary care medical center. Patient(s) Fourteen women with PCOS, scheduled for bilateral oophorectomy for benign indications, on postoperative transdermal estradiol (E2 ). Intervention(s) Physical examination, blood sampling before and after oophorectomy, measurement of hormone levels; assessment of basal (Steroid0 ), maximum stimulated (Steroid60 ), and net increment (ΔSteroid) levels of androstenedione (A4), dehydroepiandrosterone (DHEA), and cortisol (F) before and after ACTH 1–24 stimulation. Main Outcome Measure(s) Preoperative and postoperative basal and ACTH (1–24) stimulated hormone levels. Result(s) Total testosterone, free testosterone, and estrone levels decreased, and follicle-stimulating hormone levels statistically significantly increased after oophorectomy. No statistically significant differences in E2 , DHEA sulfate (DHEAS), or sex hormone-binding globulin levels were detected. Basal and ACTH-stimulated A4 levels statistically significantly decreased after oophorectomy, and ΔA4 was statistically significantly increased. No statistically significant differences in DHEA0 , DHEA60 , or F0 levels were detected. The F60 and ΔF levels tended to increase after oophorectomy, but the differences did not reach statistical significance. Conclusion(s) Ovarian factors do not appear to contribute significantly to the adrenocortical dysfunction of PCOS.
Subarachnoid Hemorrhage Abraham, Michael K; Chang, Wan-Tsu Wendy
Emergency medicine clinics of North America,
11/2016, Letnik:
34, Številka:
4
Journal Article
Recenzirano
Aneurysmal subarachnoid hemorrhage (SAH) is a neurological emergency with high risk of neurological decline and death. Although the presentation of a thunderclap headache or the worst headache of a ...patient's life easily triggers the evaluation for SAH, subtle presentations are still missed. The gold standard for diagnostic evaluation of SAH remains noncontrast head computed tomography (CT) followed by lumbar puncture if the CT is negative for SAH. Management of patients with SAH follows standard resuscitation of critically ill patients with the emphasis on reducing risks of rebleeding and avoiding secondary brain injuries.
Summary Background Accurate electrocardiographic (ECG) differentiation of ventricular tachycardia (VT) from supraventricular tachycardia with aberrancy (SVT-A) on ECG is key to therapeutic ...decision-making in the emergency department (ED) setting. Objective The goal of this study was to test the accuracy and agreement of emergency medicine residents to differentiate VT from SVT-A using the Vereckei criteria. Methods Six emergency medicine residents volunteered to participate in the review of 114 ECGs from 86 patients with a diagnosis of either VT or SVT-A based on an electrophysiology study. The resident reviewers initially read 12-lead ECGs blinded to clinical information, and then one week later reviewed a subset of the same 12-lead ECGs unblinded to clinical information. Results One reviewer was excluded for failing to follow study protocol and one reviewer was excluded for reviewing less than 50 blinded ECGs. The remaining four reviewers each read 114 common ECGs blinded to clinical data and their diagnostic accuracy for VT was 74% (sensitivity 70%, specificity 80%), 75% (sensitivity 76%, specificity 73%), 61% (sensitivity 81%, specificity 25%), and 68% (sensitivity 84%, specificity 40%). The intraclass correlation coefficient (ICC) was 0.31 (95% CI 0.22–0.42). Eliminating two of the four reviewers who left a disproportionately high number of ECGs unclassified resulted in an increase in overall mean diagnostic accuracy (70–74%) and agreement (0.31–0.50) in the two remaining reviewers. Three reviewers read 45 common ECGs unblinded to clinical information and had accuracies for VT 93%, 93% and 78%. Conclusion The new single lead Vereckei criteria, when applied by emergency medicine residents achieved only fair-to-good individual accuracy and moderate agreement. The addition of clinical information resulted in substantial improvement in test characteristics. Further improvements (accuracy and simplification) of algorithms for differentiating VT from SVT-A would be helpful prior to clinical implementation.
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