Using CAHPS patient experience data for patient-centered medical home transformation.
To examine how primary care practices use the Consumer Assessment of Healthcare Providers and Systems (CAHPS) survey and its patient-centered medical home (PCMH) items during their PCMH transition. Qualitative study of practices' use of patient experience data during PCMH transformation, based on a random sample of primary care practices engaged in PCMH transformation, stratified by region, practice size, PCMH recognition history, and use of the CAHPS PCMH survey. We interviewed 105 practice leaders from 294 sampled practices (36% response rate) and used content analysis to identify themes about uses of patient experience data for practice improvement during PCMH transformation. Patient experience data were used primarily to assess and track improvements toward PCMH goals and as quality improvement (QI) metrics. CAHPS measures were used most often to discuss best practices, share data with patient advisory councils, and improve provider performance. The CAHPS PCMH survey helped practices improve patient-centeredness, particularly in coordinating care and supporting patient self-management and communication. The CAHPS PCMH items that assisted practices most were about patient self-management and provider referrals. Most practice leaders using the CAHPS PCMH survey felt that its items were actionable for standardizing PCMH changes or making structural changes. Practices administering CAHPS surveys focused on a more diverse set of QI areas. CAHPS surveys were considered actionable for PCMH transformation and used in standardizing and coordinating care. The CAHPS PCMH items were considered integral to the continuous QI needed for moving beyond formal PCMH recognition and maximizing transformation. This supports the National Committee for Quality Assurance's recommendation to administer the CAHPS or CAHPS PCMH survey for PCMH transformation.


Unrecognized severe postoperative hypercapnia: a case of apneic oxygenation.
Transcutaneous pulse oximetry is increasingly being used to supplant arterial blood gas measurement as a means to monitor oxygenation. Previous studies have demonstrated that, despite inadequate ventilation, oxygenation can be maintained during delivery of supplemental oxygen by a process known as diffusion respiration. In this setting, severe hypercapnia and acidosis rapidly develop. This case report demonstrates that pulse oximetry is an unreliable means to monitor adequacy of ventilation. A 75-year-old woman in good health suffered a fracture of the right hip that necessitated arthroplasty. During postoperative recovery, she remained unresponsive while receiving 100% oxygen through an endotracheal tube; mechanical ventilation was not used. Pulse oximetry indicated a blood oxygen saturation of 94 to 96%; however, results of blood gas studies 3 1/2 hours postoperatively revealed profound hypercapnia (arterial carbon dioxide tension, 265 mm Hg) and acidosis (pH, 6.65) but confirmed normal oxygen levels (arterial oxygen tension, 213 mm Hg). Assisted ventilation resulted in normalization of the blood gases and an improved level of consciousness. The patient was then transferred to Mayo Clinic Rochester and had an uneventful recovery.


The effect of modeled absolute timing variability and relative timing variability on observational learning.
There is much evidence to suggest that skill learning is enhanced by skill observation. Recent research on this phenomenon indicates a benefit of observing variable/erred demonstrations. In this study, we explore whether it is variability within the relative organization or absolute parameterization of a movement that facilitates skill learning through observation. To do so, participants were randomly allocated into groups that observed a model with no variability, absolute timing variability, relative timing variability, or variability in both absolute and relative timing. All participants performed a four-segment movement pattern with specific absolute and relative timing goals prior to and following the observational intervention, as well as in a 24h retention test and transfers tests that featured new relative and absolute timing goals. Absolute timing error indicated that all groups initially acquired the absolute timing, maintained their performance at 24h retention, and exhibited performance deterioration in both transfer tests. Relative timing error revealed that the observation of no variability and relative timing variability produced greater performance at the post-test, 24h retention and relative timing transfer tests, but for the no variability group, deteriorated at absolute timing transfer test. The results suggest that the learning of absolute timing following observation unfolds irrespective of model variability. However, the learning of relative timing benefits from holding the absolute features constant, while the observation of no variability partially fails in transfer. We suggest learning by observing no variability and variable/erred models unfolds via similar neural mechanisms, although the latter benefits from the additional coding of information pertaining to movements that require a correction.


[Placement of permanent epicardial pacemaker in a newborn with congenital complete AV block].
Isolated congenital atrioventricular block is reported in one out of 20,000 live births. The optimistic view on the prognosis and indications for permanent pacing have been modified in the last 35 years. The purpose of this report is to present a prenatally diagnosed case, outlining the surgical technique for permanent pacing. The infant was a male born by cesarean section, weighted 3030 grs and had a structurally normal heart. His ECG showed complete AV block with narrow QRS, atrial rate was 140 and ventricular rate was 55. We implanted a epicardial pacemaker VVIR by midline laparatomy. The lead was unipolar 35 cms long screw-in type and was placed in the right ventricle through the xiphoid process. The pacemaker was placed in a GoreTex bag and fixed intraperitoneal to the abdominal wall. The infant did well after the procedure and he was discharged in good condition one week later. We conclude that it is appropriate to implant a permanent pacemaker in these patients with low ventricular rate thus reducing the risk of sudden cardiac death. The surgical technique is safe and makes easy the generator replacement.


Short term performance evaluation of a perfluorocopolymer coated gas exchanger for arteriovenous CO2 removal.
A new perfluorocopolymer coating for micropore hollow fiber gas exchangers was developed to improve gas exchange, reduce plasma leakage, and reduce blood-surface interactions. The present authors evaluated gas exchanger performance using this new coating in a prospective, randomized, controlled, unblinded, large animal model of CO2 retention. Adult sheep (30-40 kg), under general anesthesia, underwent cannulation of the carotid artery (12 F) and jugular vein (14 F). The perfluorocopolymer coated (n = 5) and uncoated (n = 5) gas exchangers were attached to an arteriovenous CO2 removal (AVCO2R) circuit. Blood gases, CO2 removal, and hemodynamics were monitored throughout the 6 hour study. Average CO2 removal was 107.6 +/- 15.6 ml/min (coated) vs. 93.0 +/- 13.9 ml/min (uncoated; p < 0.01). PaCO2 and CO2 removal for both coated and uncoated did not deteriorate significantly over the study. Average AVCO2R blood flow was 1,130 +/- 25 ml/min (coated) versus 1,101 +/- 79 ml/min (uncoated; p = not significant). Likewise, cardiac output and AVCO2R blood flow did not change over the duration of the study. No significant differences in the pressure gradient or resistance between devices (coated, 6.89 +/- 1.14 mm Hg/L/min; uncoated, 6.42 +/- 0.23 mm Hg/L/min) was noted. The authors concluded that the new perfluorocopolymer coated gas exchanger improved CO2 removal without compromising hemodynamics in an acute performance evaluation.


How to keep up with the critical care literature and avoid being buried alive.
To provide practical suggestions for accessing, utilizing, and storing the rapidly expanding literature on critical care. Original research on information sources for clinicians and techniques for keeping up with the literature, found through bibliographic searches, our personal files, and consultation with critical care colleagues. Suggestions for keeping up with the critical care literature include: 1) focus the clinical question; 2) locate literature using bibliographic databases; 3) use original journal articles; 4) use systematic reviews with confidence; 5) use text-books with caution; 6) read the preappraised literature; 7) abandon advertisements; 8) throw away the throwaways; 9) teach yourself critical appraisal; 10) be wary of overinterpretation of substitute end points; 11) teach yourself basic clinical statistics; 12) engage in effective browsing; 13) store useful articles; 14) invest in informatics; and 15) implement evidence-based practice guidelines. Efficient access, appraisal, and application of the literature on intensive care are basic skills for intensivists, who have adopted a variety of resourceful and pragmatic methods for "keeping up."


[Angioma-like liver lesions in patients with chronic liver disease].
The aim of this study was to evaluate in our healthcare area the clinical, ultrasonographic, and evolutionary features of patients with chronic liver disease and angioma-like liver lesions on ultrasonography. We conducted a retrospective study amongst patients seen at the Ultrasonography Unit, Gastroenterology Department between January 2000 and June 2004. Included in the study were patients that presented with clinical and/or laboratory complaints consistent with chronic liver disease of any etiology, and those in which abdominal ultrasounds revealed the existence of at least one angioma-like liver lesion. All relevant epidemiological, clinical, ultrasonographic, and evolutionary data were carefully collected and recorded. In the course of our study, 58 patients were diagnosed with chronic liver disease and angioma-like liver lesions, of which 13 showed clinical, laboratory, ultrasonographic, and/or histological signs of liver cirrhosis. In 50% of patients these lesions were less than 10 mm in diameter, and in most cases were located in the right hepatic lobe. During an average follow-up period of 35 months (6-168 months) we verified that, in two patients, these lesions, initially interpreted as angiomas were in fact malignancies (one hepatocellular carcinoma and one metastatic adenocarcinoma of the gallbladder). In both cases, the patients were cirrhotic. Thus, our study revealed that 15% of lesions found in cirrhotic patients initially interpreted as angiomas were actually malignant. Our study revealed that, in patients with chronic liver disease, particularly in cirrhotic patients, a considerable percentage of ultrasonographic lesions originally interpreted as angiomas are in fact malignant tumors.


Historical background: patellofemoral pain in young people.
This article examines the evolution of the current understanding of what patellofemoral pain is, or is not, in young people. It focuses on the articular cartilage of the patella because chondromalacia patellae (softened articular cartilage) was almost unanimously presumed to be the primary cause of patellofemoral pain in young people until recently.


A monoclonal antibody against the c-erbB-2 protein enhances the cytotoxicity of cis-diamminedichloroplatinum against human breast and ovarian tumor cell lines.
A monoclonal antibody (TAb 250) specific to an extracellular epitope of the c-erbB-2 protein (gp185) inhibited the in vitro proliferation of human breast tumor cell lines that overexpress c-erbB-2 in a dose-dependent manner. Treatment of cells with combinations of cis-diammedichloroplatinum (CDDP) and TAb 250 resulted in a significantly enhanced cytotoxic effect. This synergistic cytotoxicity was apparent over a wide range of antibody concentrations (200 pg/ml-100 micrograms/ml) including concentrations that showed no inhibitory effect alone. TAb 250 did not increase the cytotoxic effect of CDDP in a cell line exhibiting no detectable level of gp185. Athymic mice bearing s.c. xenografts of human tumor cells expressing high levels of gp185 showed a greatly enhanced inhibition of tumor growth when treated with TAb 250 and CDDP compared to treatment with the antibody or CDDP alone. This effect was specific inasmuch as TAb 250 did not enhance the growth-inhibitory effect of CDDP on tumor xenografts which were not expressing gp185.


[The practice of forensic psychiatry in England and Brazil: a brief comparison].
The authors make a comparative analysis between the practice of forensic psychiatry in England and in Brazil. The purpose is to stimulate the debate about the conduction of this psychiatric specialization in both countries. It is a study specifically addressed to the criminal area and its approach is carried out based on the legal, clinical, and ethical points of view. The observations made in England may be also applied to Wales, but not to the United Kingdom as a whole, since different legislation is adopted in Scotland and Northern Ireland. It concludes that while in Brazil there is a need for a closer and more integrated relationship between Psychiatry and Law, it is equally significant to clearly define the scope and the boundaries of each of these areas, as ignoring the boundaries between the two specialties could result in the risk of their relationship becoming confused, as appears to be the case in the English context.


Jun activation domain binding protein 1 expression is associated with low p27(Kip1)levels in node-negative breast cancer.
The purpose is to evaluate expression levels of Jun activation domain-binding protein 1 (JAB1) in breast cancer tissue and adjacent normal tissue, to determine whether JAB1 expression is associated with p27(Kip1) expression in invasive breast carcinomas, and to evaluate the prognostic significance of JAB1 and p27(Kip1) in node-negative breast cancer. JAB1 levels were measured in 10 matched pairs of invasive breast tumor tissue and adjacent normal tissue using Western blot analysis. We also investigated the immunoreactivity of JAB1 and p27(Kip1) levels in paraffin-embedded tissue specimens from 220 patients with node-negative breast cancer who had not received adjuvant systemic therapy. The median follow-up was 15 years. JAB1 was expressed at higher levels in invasive tumors than in adjacent normal tissue (P = 0.01). JAB1 overexpression was observed in 57% of invasive breast cancers. Low levels of p27(Kip1) were noted in 70% of the tumor specimens. We found an inverse correlation between JAB1 and p27(Kip1) expression levels (P = 0.01). JAB1 overexpression was associated with patient age of at least 50 years (P = 0.03) and tumor size of </=2 cm (P = 0.01). Elevated levels of p27(Kip1) were associated with low nuclear grade (P = 0.01). At 5 years of follow-up, neither JAB1 nor p27(Kip1) expression was related to disease-free survival. These data indicate that JAB1 is commonly overexpressed in invasive breast carcinomas. JAB1 overexpression is associated with low levels of p27(Kip1) in node-negative breast cancer. In this study, JAB1 and p27(Kip1) were not independent prognostic factors.


[Inhibitive effect of soybean isoflavone on prostate hyperplasia in rats].
To explore the inhibitive effect of soybean isoflavone on benign prostatic hyperplasia in rats. By subcutaneously injecting testosterone propionate to induce prostate hyperplasia in rats, the changes of prostate wet weight, prostatic index, morphological change, prostate-specific acid phosphatase (PAP), acid phosphatase in the control, the model, low, moderate, high dose of soybean isoflavone groups were observed. The ventral prostate wet weight, prostatic index, and PAP in the low, moderate, and high dose groups were significantly lower than those in the models (P < 0.05). The ventral prostate wet weight, prostatic index, and PAP in the moderate, and high dose groups were significantly lower than those in the low dose group (P < 0.05). Soybean isoflavone inhibits prostate hyperplasia and the increase of acid phosphatase and PAP in a dose-dependent manner in rats. Soybean isoflavone may serve as supplementary therapy and prevent benign prostatic hyperplasia.


Induction of Ly-6A/E expression by murine lymphocytes after in vivo immunization is strictly dependent upon the action of IFN-alpha/beta and/or IFN-gamma.
Ly-6A/E is a phosphatidylinositol-linked membrane protein which mediates murine T and B cell signalling. IFN-gamma, IFB-alpha/beta, LPS, and IL-4 have all been reported to induce or upregulate Ly-6A/E by normal lymphocytes. Since no systematic study has addressed the stimulant selectivity of Ly-6A/E expression by murine lymphocytes nor investigated its induction and regulation during primary in vivo immune responses we analyzed in vitro Ly-6A/E expression after murine stimuli and during a number of distinct in vivo immunizations. We show that LPS induces B cell Ly-6A/E in vitro by stimulating the release of IFN-alpha/beta by 'contaminating' adherent cells. In the presence of anti-IFN-gamma + anti-IFN-alpha/beta antibodies, no Ly-6A/E was induced upon addition of multiple cytokines, including IL-4, or mitogenic doses of anti-Ig antibody. Furthermore, IFN-gamma-containing, CD4+ T cell (Th1) supernatants potently induced Ly-6A/E by murine B cells whereas IL-4-containing (Th2) supernatants were either weak or ineffective; anti-IFN-gamma + anti-IFN-alpha/beta inhibited Ly-6A/E induction by both Th1 and Th2 supernatants. Immunization of mice with Brucella abortus or poly (I).poly (C) resulted in induction of Ly-6A/E expression by virtually all B and T cells, whereas injection of G alpha M delta led to peak induction of Ly-6A/E by approximately 50% of both B and T cells. Lymphocytes from mice infected with the nematode parasites Nippostrongylus brasiliensis or Heligmosomoides polygyrus expressed no Ly-6A/E.(ABSTRACT TRUNCATED AT 250 WORDS)


Frequent Sugar-Sweetened Beverage Consumption and the Onset of Cardiometabolic Diseases: Cause for Concern?
The incidence of noncommunicable diseases is on the rise and poses a major threat to global public health. This is in parallel to a steady increase in worldwide intake of sugar-sweetened beverages (SSBs) among all age groups. As several studies demonstrated a controversial relationship between SSB consumption and the metabolic syndrome (MetS), this mini-review focuses on links between its intake and (1) MetS, (2) prediabetes/type 2 diabetes mellitus (T2DM), and (3) hypertension. A detailed search for clinical and observational studies published during the past 10 years was conducted using key terms that link SSBs to the MetS, T2DM, and hypertension. Here we excluded all meta-analyses and also literature that solely focused on obesity. The analysis revealed that most epidemiological studies strongly show that frequent SSB intake contributes to the onset of the MetS in the longer term. Some of the findings also show that regular SSB intake can alter glucose handling and insulin sensitivity, thereby contributing to the development of the MetS and T2DM. There is also evidence that frequent SSB intake (and particularly fructose) is linked to hypertension and well-known cardiovascular disease risk factors. However, some studies report on the lack of negative effects as a result of SSB consumption. Because of this discrepancy, we propose that well-designed long-term clinical studies should further enhance our understanding regarding the links between SSB consumption and the onset of cardiometabolic diseases.


Tobacco use in adult long-term survivors of retinoblastoma.
A significant risk of lung cancer was identified among hereditary, but not nonhereditary, retinoblastoma (Rb) patients. Tobacco use was investigated to determine whether differences in smoking prevalence might explain the lung cancer excess and to characterize smoking patterns in adult survivors of Rb. Subjects were 441 hereditary and 395 nonhereditary 1-year survivors of Rb, age >or=18 years, who responded to a telephone survey about current health behavior, including tobacco use. Response rates were 76% for hereditary and 73% for nonhereditary survivors. We compared patterns and predictors of current tobacco use among hereditary and nonhereditary survivors with other childhood cancer survivor studies and the U.S. population. Hereditary Rb survivors currently smoke cigarettes significantly less frequently than nonhereditary survivors (16. 8% versus 24.3%), although among current smokers, age at smoking initiation (17 years old) and average cigarettes (1.5 packs) smoked daily are similar. Predictors of current and ever cigarette smoking include nonhereditary Rb, older age, being female, less education, and use of other tobacco products. Rb survivors smoke cigarettes significantly less than the U.S. population (rate ratio, 0.63; 95% confidence interval, 0.5-0.8 for males; rate ratio, 0.75; 95% confidence interval, 0.6-0.9 for females), but Rb survivors have comparable smoking rates with other childhood cancer survivors. Smoking did not account for the increased risk of lung cancer among hereditary Rb patients, and this may point to an enhanced sensitivity to the carcinogenic effects of tobacco. Adult survivors of Rb should be encouraged to stop smoking.


Stress-induced enhancement of colitis in rats: CRF and arginine vasopressin are not involved.
Because exacerbation of colitis seems to be associated with stress, we proposed evaluating the influence of stress and the involvement of corticotropin-releasing factor (CRF) and arginine vasopressin (AVP) on experimental colitis in rats. Partial restraint stress was applied during 4 consecutive days, before or after intracolonic 2,4,6-trinitrobenzenesulfonic acid (TNB) instillation (15 mg) in rats. Finally, two groups of rats were centrally injected with alpha-helical CRF-(9-41) (5 micrograms) or AVP antagonist (5 micrograms) before each session of stress. Stress was applied before or right after TNB enhanced colitis, with an increase in macroscopic and histological scores and myeloperoxidase activity, alpha-Helical CRF-(9-41) or AVP antagonist had no effect on TNB-induced colitis but enhanced the effects of stress on colitis. These results show that stress may exacerbate experimental colitis in rats and that CRF and AVP are not responsible for this effect.


A novel method for measuring gaze orientation in space in unrestrained head conditions.
Investigation of eye movement strategies often requires the measurement of gaze orientation without restraining the head. However, most commercial eye-trackers have low tolerance for head movements. Here we present a novel geometry-based method to estimate gaze orientation in space in unrestricted head conditions. The method combines the measurement of eye-in-head orientation-provided by a head-mounted video-based eye-tracker-and head-in-space position and orientation-provided by a motion capture system. The method does not rely on specific assumptions on the configuration of the eye-tracker camera with respect to the eye and uses a central projection to estimate the pupil position from the camera image, thus improving upon previously proposed geometry-based procedures. The geometrical parameters for the mapping between pupil image and gaze orientation are derived with a calibration procedure based on nonlinear constrained optimization. Additionally, the method includes a procedure to correct for possible slippages of the tracker helmet based on a geometrical representation of the pupil-to-gaze mapping. We tested and validated our method on seven subjects in the context of a one-handed catching experiment. We obtained accuracy better than 0.8° and precision better than 0.5° in the measurement of gaze orientation. Our method can be used with any video-based eye-tracking system to investigate eye movement strategies in a broad range of naturalistic experimental scenarios.


Pyruvate Kinase Differentially Alters Metabolic Signatures during Head and Neck Carcinogenesis.
During glycolysis, the muscle isoform of pyruvate kinase PKM2 produces ATP in exchange for dephosphorylation of phosphoenolpyruvate (PEP) into pyruvate. PKM2 has been considered as a tumor-promoting factor in most cancers, whereas the regulatory role of PKM2 during head and neck carcinogenesis remained to be delineated. PKM2 mRNA and protein expression was examined in head and neck tumorous specimens. The role of PKM2 in controlling cellular malignancy was determined in shRNA-mediated PKM2-deficient head and neck squamous cell carcinoma (HNSC) cells. In agreement with the results in other cancers, PKM2 expression is enriched in both mouse and human HNSC tissues. Nevertheless, PKM2 mRNA expression reversely correlated with tumor stage, and greater recurrence-free survival rates are evident in the PKM2high HNSC population, arguing that PKM2 may be tumor-suppressive. Multifaceted analyses showed a greater in vivo xenografic tumor growth and an enhanced cisplatin resistance in response to PKM2 loss, whereas PKM2 silencing led to reduced cell motility. At the molecular level, metabolic shifts towards mitochondrial metabolism and activation of oncogenic Protein kinase B (PKB/Akt) and extracellular signal-regulated kinase (ERK) signals were detected in PKM2-silencing HNSC cells. In sum, our findings demonstrated that PKM2 differentially modulated head and neck tumorigenicity via metabolic reprogramming.


Implementation of an enhanced recovery program in pediatric laparoscopic colorectal patients does not worsen analgesia despite reduced perioperative opioids: a retrospective, matched, non-inferiority study.
Enhanced recovery protocols (ERPs) decrease length of stay and postoperative morbidity, but it is important that these benefits do not come at a cost of sacrificing proper perioperative analgesia. In this retrospective, matched cohort study, we evaluated postoperative pain intensity in pediatric patients who underwent laparoscopic colorectal surgeries before and after ERP implementation. Patients in each cohort were randomly matched based on age, diagnosis, American Society of Anesthesiologists classification, and surgical procedure. The primary outcome was average daily postoperative pain score, while the secondary outcomes included postoperative hospital length of stay, complication rate, and 30-day readmissions. Since our hypothesis was non-inferior analgesia in the postprotocol cohort, a non-inferiority study design was used. After matching, 36 pairs of preprotocol and postprotocol patients were evaluated. ERP patients had non-inferior recovery room pain scores (difference 0 (-1.19, 0) points, 95% CI -0.22 to 0.26 points, p valuenon-inferiority <0.001) and 4-day postoperative pain scores (difference -0.3±1.9 points, 95% CI -0.82 to 0.48 points, p valuenon-inferiority <0.001) while receiving less postoperative opioids (difference -0.15 [-0.21, -0.05] intravenous morphine equivalents/kg/day, p<0.001). ERP patients also had reduced postoperative hospital stays (difference -1.5 [-4.5, 0] days, p<0.001) and 30-day readmissions (2.8% vs 27.8%, p=0.008). Implementation of our ERP for pediatric laparoscopic colorectal patients was associated with less perioperative opioids without worsening postoperative pain scores. In addition, patients who received the protocol had faster return of bowel function, shorter postoperative hospital stays, and a lower rate of 30-day hospital readmissions. In pediatric laparoscopic colorectal patients, the incorporation of an ERP was associated with a pronounced decrease in perioperative morbidity without sacrificing postoperative analgesia.


Functional regions of human telomerase reverse transcriptase and human telomerase RNA required for telomerase activity and RNA-protein interactions.
Telomerase is a specialized reverse transcriptase (RT) that is minimally composed of a protein catalytic subunit and an RNA component. The RNA subunit contains a short template sequence that directs the synthesis of DNA repeats at the ends of chromosomes. Human telomerase activity can be reconstituted in vitro by the expression of the human telomerase protein catalytic subunit (hTERT) in the presence of recombinant human telomerase RNA (hTR) in a rabbit reticulocyte lysate (RRL) system. We analyzed telomerase activity and binding of hTR to hTERT in RRL by expressing different hTERT and hTR variants. hTRs containing nucleotide substitutions that are predicted to disrupt base pairing in the P3 helix of the pseudoknot weakly reconstituted human telomerase activity yet retained their ability to bind hTERT. Our results also identified two distinct regions of hTR that can independently bind hTERT in vitro. Furthermore, sequences or structures between nucleotides 208 and 330 of hTR (which include the conserved CR4-CR5 domain) were found to be important for hTERT-hTR interactions and for telomerase activity reconstitution. Human TERT carboxy-terminal amino acid deletions extending to motif E or the deletion of the first 280 amino acids abolished human telomerase activity without affecting the ability of hTERT to associate with hTR, suggesting that the RT and RNA binding functions of hTERT are separable. These results indicate that the reconstitution of human telomerase activity in vitro requires regions of hTERT that (i) are distinct from the conserved RT motifs and (ii) bind nucleotides distal to the hTR template sequence.


Simplified rheumatic heart disease screening criteria for handheld echocardiography.
Using 2012 World Heart Federation criteria, standard portable echocardiography (STAND) reveals a high burden of rheumatic heart disease (RHD) in resource-poor settings, but widespread screening is limited by cost and physician availability. Handheld echocardiography (HAND) may decrease costs, but World Heart Federation criteria are complicated for rapid field screening, particularly for nonphysician screeners. The aim of this study was to determine the best simplified screening strategy for RHD detection using HAND. In this prospective study, STAND (GE Vivid q or i or Philips CX-50) was performed in five schools in Gulu, Uganda; a random subset plus all children with detectable mitral regurgitation or aortic insufficiency also underwent HAND (GE Vscan). Borderline or definite RHD cases were defined by 2012 World Heart Federation criteria on STAND images, by two experienced readers. HAND studies were reviewed by cardiologists blinded to STAND results. Single and combined HAND parameters were evaluated to determine the simplified screening strategy that maximized sensitivity and specificity for case detection. In 1,439 children (mean age, 10.8 ± 2.6 years; 47% male) with HAND and STAND studies, morphologic criteria and the presence of any mitral regurgitation by HAND had poor specificity. The presence of aortic insufficiency was specific but not sensitive. Combined criteria of mitral regurgitation jet length ≥ 1.5 cm or any aortic insufficiency best balanced sensitivity (73.3%) and specificity (82.4%), with excellent sensitivity for definite RHD (97.9%). With a prevalence of 4% and subsequent STAND screening of positive HAND studies, this would reduce STAND studies by 80% from a STAND-based screening strategy. In resource-limited settings, HAND with simplified criteria can detect RHD with good sensitivity and specificity and decrease the need for standard echocardiography. Further study is needed to validate screening by local practitioners and long-term outcomes.


[Contrast-Enhanced Ultrasound of Fibrolamellar Hepatocellular Carcinoma].
We present the case of a 24-year-old male patient, who was admitted for endoscopy due to sustained pain in the upper abdomen with nausea and postprandial fullness without vomiting for more than 5 months. In the physical examination, an epigastric induration was found. Endoscopy revealed an external impression of the proximal duodenum. Beyond that, normal findings could be ascertained in gastroscopy and ileo-colonoscopy. Abdominal ultrasound identified a large hypoechoic lesion in the left liver lobe with a sharp delineation. Along the upper mesenteric vessels, enlarged lymphnodes were visible with contact to the proximal duodenum. Contrast-enhanced ultrasound (CE-US) was conducted and revealed the typical perfusion pattern of hepatocellular carcinoma. For further assessment, an ultrasound-guided core-biopsy of the lesion was performed. The histopathological evaluations resulted in the diagnosis of a hepatocellular carcinoma of fibrolamellar subtype.With the present case, we want to illustrate the perfusion pattern of a fibrolamellar hepatocellular carcinoma in contrast-enhanced ultrasound. Even though the tumor tissue is surrounded by lamellar bands of fibrosis with collagen-rich fibers, the perfusion pattern is consistent with the previously known appearance of HCC in CE-US.


Regional myocardial wall thinning at multidetector computed tomography correlates to arrhythmogenic substrate in postinfarction ventricular tachycardia: assessment of structural and electrical substrate.
A majority of patients undergoing ablation of ventricular tachycardia have implanted devices precluding substrate imaging with delayed-enhancement MRI. Contrast-enhanced multidetector computed tomography (MDCT) can depict myocardial wall thickness with submillimetric resolution. We evaluated the relationship between regional myocardial wall thinning (WT) imaged by MDCT and arrhythmogenic substrate in postinfarction ventricular tachycardia. We studied 13 consecutive postinfarction patients undergoing MDCT before ablation. MDCT data were integrated with high-density 3-dimensional electroanatomic maps acquired during sinus rhythm (endocardium, 509±291 points/map; epicardium, 716±323 points/map). Low-voltage areas (<1.5 mV) and local abnormal ventricular activities (LAVA) during sinus rhythm were assessed with regard to the WT. A significant correlation was found between the areas of WT <5 mm and endocardial low voltage (correlation-R=0.82; P=0.001), but no such correlation was found in the epicardium. The WT <5 mm area was smaller than the endocardial low-voltage area (54 cm(2) [Q1-Q3, 46-92] versus 71 cm(2) [Q1-Q3, 59-124]; P=0.001). Among a total of 13 060 electrograms reviewed in the whole study population, 538 LAVA were detected and analyzed. LAVA were located within the WT <5 mm (469/538 [87%]) or at its border (100% within 23 mm). Very late LAVA (>100 ms after QRS complex) were almost exclusively detected within the thinnest area (93% in the WT<3 mm). Regional myocardial WT correlates to low-voltage regions and distribution of LAVA critical for the generation and maintenance of postinfarction ventricular tachycardia. The integration of MDCT WT with 3-dimensional electroanatomic maps can help focus mapping and ablation on the culprit regions, even when MRI is precluded by the presence of implanted devices.


Variceal bleeding and portal hypertensive gastropathy.
Cirrhosis can be the end stage of any chronic liver disease. At the time of diagnosis of cirrhosis varices are present in about 60% of decompensated and 30% of compensated patients. The risk factors for the first episode of variceal bleeding in cirrhotic patients are the severity of liver dysfunction, large size of varices and the presence of endoscopic red colour signs but only one-third of patients who have variceal haemorrhage have the above risk factors. Recent interest has been directed at identifying haemodynamic factors that may reflect the pathophysiological changes which lead to variceal bleeding, e.g. it has been confirmed that no bleeding occurs if HVPG falls below 12 mmHg and also a hypothesis has been put forward in which bacterial infection is considered a trigger for bleeding. Pharmacological treatment with beta-blockers is safe, effective and is the standard long-term treatment for the prevention of recurrence of variceal bleeding. Combination of beta-blockers with isosorbide-5-mononitrate needs further testing in randomized controlled trials. The use of haemodynamic targets for reduction in HVPG response needs further study, and surrogate markers of pressure response need evaluation. If endoscopic treatment is chosen, variceal ligation is the modality of choice. The combination of simultaneous variceal ligation and sclerotherapy does not offer any benefit. However, the use of additional sclerotherapy for the complete eradication of small varices after variceal ligation needs to be evaluated. The results of current prospective randomized controlled trials comparing variceal ligation with pharmacological treatment are awaited with great interest. Finally, the use of transjugular intrahepatic portosystemic shunt (TIPS) for the secondary prevention of variceal bleeding is not substantiated by current data, as survival is not improved and because of its worse cost-benefit profile compared to other treatments. In contrast, there still is a role for the selective surgical shunts in the modern management of portal hypertension. The ideal patients should be well compensated cirrhotics, who have had troublesome bleeding - either who have failed at least one other modality of therapy (drugs or ligation), have bled from gastric varices despite medical or endoscopic therapy, or live far from suitable medical services. Recently, ligation has been compared to beta-blockers for primary prophylaxis but so far there is no good evidence to recommend banding for primary prophylaxis, if beta-blockers can be given.


Colorectal polyp outcomes after participation in the seAFOod polyp prevention trial: Evidence of rebound elevated colorectal polyp risk after short-term aspirin use.
The seAFOod polyp prevention trial was a randomised, placebo-controlled, 2 × 2 factorial trial of aspirin 300 mg and eicosapentaenoic acid (EPA) 2000 mg daily in individuals who had a screening colonoscopy in the English Bowel Cancer Screening Programme (BCSP). Aspirin treatment was associated with a 20% reduction in colorectal polyp number at BCSP surveillance colonoscopy 12 months later. It is unclear what happens to colorectal polyp risk after short-term aspirin use. To investigate colorectal polyp risk according to the original trial treatment allocation, up to 6 years after trial participation. All seAFOod trial participants were scheduled for further BCSP surveillance and provided informed consent for the collection of colonoscopy outcomes. We linked BCSP colonoscopy data to trial outcomes data. In total, 507 individuals underwent one or more colonoscopies after trial participation. Individuals grouped by treatment allocation were well matched for clinical characteristics, follow-up duration and number of surveillance colonoscopies. The polyp detection rate (PDR; the number of individuals who had ≥1 colorectal polyp detected) after randomization to placebo aspirin was 71.1%. The PDR was 80.1% for individuals who had received aspirin (odds ratio [OR] 1.13 [95% confidence interval 1.02, 1.24]; p = 0.02). There was no difference in colorectal polyp outcomes between individuals who had been allocated to EPA compared with its placebo (OR for PDR 1.00 [0.91, 1.10]; p = 0.92). Individuals who received aspirin in the seAFOod trial demonstrated increased colorectal polyp risk during post-trial surveillance. Rebound elevated neoplastic risk after short-term aspirin use has important implications for aspirin cessation driven by age-related bleeding risk. ISRCTN05926847.


Glucocorticoid-induced muscle atrophy prevention by exercise in fast-twitch fibers.
Exercise has been shown to be effective in preventing glucocorticoid-induced atrophy in muscles containing high proportions of type II or fast-twitch fibers. This investigation was undertaken to further evaluate this response in type IIa and IIb fibers, determined by histochemical staining for myofibrillar adenosinetriphosphatase with alkaline and acid preincubation. Steroid [cortisol acetate (CA), 100 mg/kg body wt] and exercise (running 90 min/day, 29 m/min) treatments were initiated simultaneously for 11 consecutive days in female rats. Fiber distribution and area measurements were performed in a deep and superficial region of plantaris muscle. The exercise regimen spared approximately 40% of the CA-induced plantaris muscle atrophy. In the deep region, the fiber population, which contained approximately 13% type I (slow-twitch), 24% type IIa, and 63% IIb fibers, was not affected by either treatment. In the superficial section, which consisted solely of type II fibers, the proportion of type IIa fibers was higher (27 vs. 9%, P less than 0.01) in the steroid- than in the vehicle-treated groups. Within each region, type IIa fibers were less susceptible to atrophy than type IIb fibers, and within each fiber type, the deep region had less atrophy than the superficial region. Type I fibers were unchanged by steroid treatment. For type IIa fibers, exercise prevented 100% of the atrophy in the deep region and 50% in the superficial region. For type IIb fibers, the activity spared 67 and 40% of the atrophy in these same regions, respectively. These results show that glucocorticoids are capable of changing the myosin phenotype.(ABSTRACT TRUNCATED AT 250 WORDS)


Interactions between lonidamine and beta- or hydroxypropyl-beta-cyclodextrin.
The possibility of obtaining inclusion complexes between lonidamine and beta- or hydroxypropyl-beta-cyclodextrin have been evaluated by phase solubility diagram, differential scanning calorimetry (DSC), and x-ray diffractometry. The applied complexation methods were spray-drying, kneading, and solid dispersion. DSC and x-ray analyses of the powders revealed an external interaction between lonidamine and cyclodextrins. Dissolution profiles of the obtained powders were also studied to define the most appropriate preparation method and molar ratio to use in attempts to increase lonidamine water solubility.


The influence of dietary marine oil (Polepa) and evening primrose oil (Efamol) on prostaglandin production by the rat mesenteric vasculature.
The interactions of n-6 and n-3 fatty acids on prostaglandin metabolism in the isolated rat mesenteric vessels were studied. Sprague-Dawley rats (200-220 g) were fed for two weeks a fat-free semi-synthetic diet supplemented with 10% by weight of different combinations of Evening Primrose Oil (Efamol), a rich source of linoleic acid (LA) and gamma-linolenic acid (GLA), the immediate precursor of dihomo-gamma-linolenic acid (DGLA), and Polepa (POL), a marine oil rich in eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids. The combinations of supplement were as follows: 9% Efamol - 1% POL, 8% Efamol - 2% POL, 7% Efamol - 3% POL, 6% Efamol - 4% POL, 5% Efamol - 5% POL. The outflow of thromboxane (TxB2), prostacyclin (6-keto-PGF1 alpha), PGE2, and PGE1 was decreased in relation to the proportion of marine oil in the diet, except for the group which received 8% Efamol - 2% POL, and which showed an increase in 6-keto-PGF1 alpha, PGE2, and PGE1. The decrease in TxB2 was much greater than those of 6-keto-PGF1 alpha or PGE2, while PGE1 followed the same pattern as prostacyclin and PGE2. These results suggest that n-3 fatty acids, at high concentrations, inhibits conversion of both DGLA and AA to eicosanoids. Low concentrations of fish oil may, in contrast, increase formation of desirable 1 and 2 series eicosanoids.


Causal Association of Haptoglobin With Obesity in Mexican Children: A Mendelian Randomization Study.
Little is known about the association between haptoglobin level and cardiometabolic traits. A previous genome-wide association study identified rs2000999 in the HP gene as the stronger genetic contributor to serum haptoglobin level in European populations. We investigated the association of HP rs2000999 with serum haptoglobin and childhood and adult obesity in up to 540/697 and 592/691 Mexican cases and controls, respectively. Anthropometric and biochemical data were collected. Serum haptoglobin was measured by an immunoturbidimetry assay. HP rs2000999 was genotyped using the TaqMan technology. Mendelian randomization analysis was performed using the Wald and inverse variance weighting methods. Haptoglobin level was positively associated with childhood and adult obesity. HP rs2000999 G allele was positively associated with haptoglobin level in children and adults. HP rs2000999 G allele was positively associated with childhood but not adult obesity. The association between HP rs2000999 and childhood obesity was removed after adjusting for haptoglobin level. In a Mendelian randomization analysis, haptoglobin level genetically predicted by HP rs2000999 showed a significant causal effect on childhood obesity by the Wald and inverse variance weighting methods. Our data provide evidence for the first time for a causal positive association between serum haptoglobin level and childhood obesity in the Mexican population. Our study contributes to the genetic elucidation of childhood obesity and proposes haptoglobin as an important biomarker and treatment target for obesity.


A qualitative study showing women's participation and empowerment in instrumental vaginal births.
An instrumental birth with a ventouse or forceps is a complicated birth, possibly resulting in fear of childbirth which could influence the entire birth experience negatively. Patients who are actively involved in their care have a stronger sense of satisfaction and a sense of participation can contribute to shorter hospital stays. To describe the experience of participation for women involved in an instrumental delivery with ventouse or forceps. Qualitative semi-structured interviews with 16 women who gave birth aided by a ventouse or forceps. Their answers were analyzed through qualitative content analysis. In addition the women were asked to evaluate their experience during the delivery. Using a numerical scale (NRS) the birth experience was graded by choosing a number between 0 (worst possible experience) and 10 (best conceivable experience). Two themes were extracted from the data: To be part of a team and To feel empowered. Five categories were identified from the women's descriptions of the experience of involvement during the instrumental delivery: to cooperate; to understand; to have contact; to participate, and to not be involved. Those women who rated their experience as low grade, described a lack of involvement in their childbirth compared to those women who rated their experience as high. This study shows how cooperation and empowerment of the woman are two key factors in order for the women to have a positive experience of their instrumental vaginal births. The study also shows that empowerment is created when the woman is actively engaged and participates in the birth process which gives her the feeling of being part of the team, creating an environment based on mutual understanding.


Longitudinal associations between smoking cessation medications and alcohol consumption among smokers in the International Tobacco Control Four Country survey.
Available evidence suggests that quitting smoking does not alter alcohol consumption. However, smoking cessation medications may have a direct impact on alcohol consumption independent of any effects on smoking cessation. Using an international longitudinal epidemiological sample of smokers, we evaluated whether smoking cessation medications altered alcohol consumption independent of quitting smoking. Longitudinal data were analyzed from the International Tobacco Control Four Country (ITC-4) Survey between 2007 and 2008, a telephone survey of nationally representative samples of smokers from the United Kingdom, Australia, Canada, and the United States (n = 4,995). Quantity and frequency of alcohol consumption, use of smoking cessation medications (varenicline, nicotine replacement [NRT], and no medications), and smoking behavior were assessed across 2 yearly waves. Controlling for baseline drinking and changes in smoking status, we evaluated whether smoking cessation medications were associated with reduced alcohol consumption. Varenicline was associated with a reduced likelihood of any drinking compared with nicotine replacement (OR = 0.56; 95% CI = 0.34 to 0.94), and consuming alcohol once a month or more compared to nicotine replacement (OR = 0.43; 95% CI = 0.27 to 0.69) or no medication (OR = 0.63; 95% CI = 0.41 to 0.99). Nicotine replacement was associated with an increased likelihood of consuming alcohol once a month or more compared to no medication (OR = 1.14; 95% CI = 1.03 to 1.25). Smoking cessation medications were not associated with more frequent drinking (once a week or more) or typical quantity consumed per episode. Medication effects on drinking frequency were independent of smoking cessation. This epidemiological investigation demonstrated that varenicline was associated with a reduced frequency of alcohol consumption. Continued work should clarify under what conditions nicotine replacement therapies may increase or decrease patterns of alcohol consumption.


Hemangioma of the spleen: presentation, diagnosis, and management.
Splenic hemangioma is a rare disorder but remains the most common benign neoplasm of the spleen. It often has a latent clinical picture; however, spontaneous rupture has been reported to occur in as many as 25% of this patient population.1 Treatment most often consists of splenectomy. This report reviews an 8-year experience with splenic hemangioma at Mayo Clinic. Thirty-two patients were identified with SH during the 8-year study period. The average age was 63 years (range 23 to 94 years) with 17 women and 15 men. Six patients presented with symptoms potentially related to the SH. The remainder (80%) were asymptomatic, and the SH was discovered incidentally during evaluation for other disorders. A mass or palpable spleen was appreciated in only four patients (12.5%). SHs ranged in size from 0.3 to 7 cm maximum diameter. A diagnosis of SH was made in 11 patients based on the findings of a splenic mass on computed tomography or ultrasound. Each of these SHs was < or =4 cm. Three of the 11 patients had multiple SHs. All 11 patients were managed successfully with observation. All but one of the patients remains asymptomatic, and no complications have developed during follow-up (range 0.6 to 7 years, mean 2.9 years). The diagnosis of splenic hemangioma was made at the time of surgery in the remaining 21 patients (65%). Splenectomy was performed for suspicion of primary or secondary splenic pathology. There were no instances of spontaneous rupture of the SH. Small splenic lesions, which meet the radiologic criteria for hemangiomas, may be safely observed.


Conformational behavior of simple furanosides studied by optical rotation.
Experimental and theoretical specific optical rotations (OR) of anhydro, epithio, and epiminoderivatives of methyl tetrofuranosides in chloroform solutions have been compared and used as a tool for exploring their conformational behavior. The potential energy surfaces of these saccharides with reduced flexibility were examined with the density functional theory and the MP2 and CCSD(T) wavefunctions methods. Theoretical ORs were obtained by Boltzmann averaging of values calculated for local minima. Resultant rotations could be used to assess the quality of the DFT and MP2 relative conformer energies. OR values calculated for equilibrium geometries in vacuum were significantly improved when the solvent was accounted for by a polarizable continuum model and first and diagonal second OR derivatives were used for an anharmonic vibrational averaging. The DFT used as a default method reproduced the experimental data fairly well. A modified B3LYP functional containing 70% of HF exchange further improved the results. Because of the strong dependence of OR on the conformation, not only the absolute configuration could be determined, but also the conformational populations were estimated. Likewise, the predicted dependence of OR on the light wavelength well agreed with experiment. The increasing precision of the contemporary computational methods thus makes it possible to relate the specific rotation to more detailed features in molecular structure.


Direct vasodilatory effect of insulin on isolated retinal arterioles.
To test the hypothesis that insulin has a direct vasodilatory effect on retinal arteries and their branches and to investigate the mechanisms involved. Segments of porcine retinal arteries were dissected, cannulated, and perfused. Vessel diameter was measured continuously on-line. Vessels were precontracted to 66% +/- 0.9% (SEM, n = 148) of their original diameter by perfusing with 124 mM K(+)-Krebs solution. Dose-response curves to insulin (2 to 2000 microU/ml) were compared for extraluminal (EL), intraluminal (IL), and combined IL-EL application. The effect of cyclooxygenase and nitric oxide synthase inhibition on the insulin response was determined, as was Ca2+ channel involvement. EL insulin alone had no significant effect on vessel diameter. IL insulin produced a dose-dependent dilatation of 5.6% +/- 2.9% (n = 22) of the K+ contracted diameter at 200 microU/ml and up to 12.4% +/- 3.6% (n = 22) by 2000 microU/ml, whereas combined IL-EL insulin application caused dilatation at all concentrations, rising to 15.1% +/- 2.9% (n = 44) at 200 microU/ml and 19.7% +/- 3% (n = 44) at 2000 microU/ml. IL indomethacin (5 x 10(-5) M) had no significant effect on the insulin-induced dilatation, whereas IL L-NAME (10(-4) M) inhibited insulin dilatation completely. The addition of EL verapamil (10(-6) M) during insulin-induced dilatation resulted in further dilatation to 37.8% +/- 4.2% (n = 18). However, the addition of insulin to verapamil-dilated vessels caused no further dilatation. Exposure to EL insulin while the IL K+ contraction dose-response curve was measured had no effect. Results in main arteries and branches did not differ. The IL application of insulin dilates potassium-contracted pig retinal arteries. This effect was enhanced by the EL presence of insulin, which did not result in dilatation when it was administered alone. The dilatation response was mediated by nitric oxide but not by prostaglandins. There was some evidence for the involvement of Ca2+ channels in insulin-induced dilatation. These results imply that insulin is a vascular regulator in normal conditions and may have relevance to the vascular changes occurring in diabetes and hypertension in the retina.


Physicians' perspectives on the informational needs of low-risk prostate cancer patients.
Despite the evidence indicating that decision aids (DA) improve informed treatment decision making for prostate cancer (PCa), physicians do not routinely recommend DAs to their patients. We conducted semi-structured interviews with urologists (n = 11), radiation oncologists (n = 12) and primary care physicians (n = 10) about their methods of educating low-risk PCa patients regarding the treatment decision, their concerns about recommending DAs, and the essential content and format considerations that need to be addressed. Physicians stressed the need for providing comprehensive patient education before the treatment decision is made and expressed concern about the current unevaluated information available on the Internet. They made recommendations for a DA that is brief, applicable to diverse populations, and that fully discloses all treatment options (including active surveillance) and their potential side effects. Echoing previous studies showing that low-risk PCa patients are making rapid and potentially uninformed treatment decisions, these results highlight the importance of providing patient education early in the decision-making process. This need may be fulfilled by a treatment DA, should physicians systematically recommend DAs to their patients. Physicians' recommendations for the inclusion of particular content and presentation methods will be important for designing a high quality DA that will be used in clinical practice.


Potentiation of tumor necrosis factor-alpha-mediated cytotoxicity of mast cells by their production of nitric oxide.
Nitric oxide (NO or endothelium-derived relaxing factor) has many of biologic actions, including the maintenance of blood pressure, inhibition of platelet aggregation, and cytotoxicity by phagocytic cells. Several cell types produce NO from L-arginine. Given recent emphasis on mast cell (MC)-dependent TNF-alpha-mediated cytotoxicity, we investigated the role of NO in rat peritoneal MC (PMC)-and intestinal mucosal mast cell-mediated cytotoxicity. MC cytotoxicity against the TNF alpha-sensitive target, WEHI-164, was potentiated by L-arginine. The NO competitive inhibitors, N omega-nitro-L-arginine and NG-methyl-L-arginine, diminished the cytotoxicity of rat PMC by 27 and 17%, respectively. However, hemoglobin, which binds to NO, inhibited the cytotoxic activity of PMC by 49% in the presence of 1 mM L-arginine and by 24% in L-arginine-free medium. The latter suggests that PMC use intracellular stores of L-arginine to produce NO. Neither hemoglobin nor NO metabolites affected human rTNF-alpha cytotoxicity. Furthermore, sodium nitroprusside, with its free radical NO group, restored PMC cytotoxicity in L-arginine-free medium to the level observed in 1 mM L-arginine medium. Studies with a platelet aggregation bioassay and various NO inhibitors confirmed that PMC produce NO. In addition, increased levels of NO2- were observed in medium of A23187, TNF-alpha, or WEHI-164-stimulated PMC.


Management of recurrent pelvic tumors.
The management of regional tumor recurrence in the pelvis traditionally has been a difficult problem for surgeons and oncologists. The only meaningful therapy for these patients is a potentially curative re-resection. The records and operative reports of 29 patients with regional pelvic tumor recurrence treated between 1981 and 1986 were reviewed. The operative procedures performed included three bowel resections, six abdominoperineal resections, eight pelvic exenterations, eight resections of tumor recurrence, and four conservative procedures. There was one operative death in this group. Significant morbidity was noted in the group but was clustered in a small number of patients operated on early in the series. The median follow-up in this series was 13 months (range, two to 51 months). Nineteen (65%) of the patients are surviving at a median follow-up of ten months (range, two to 51 months). The median survival (following resection) in the ten patients (35%) who died was 18 months. In 15 (52%) of the patients, a complete resection was performed. In this group, the survival is 80% with a median follow-up of 11 months. Seven (37%) are surviving with no evidence of disease. Palliation of symptoms occurred in 23 (79%) of the 29 patients. Radical resection of tumor recurrence in the pelvis can be performed with acceptable mortality and complication rates. This therapy should be considered for further clinical trials combining surgical and adjuvant therapy in patients with regional pelvic tumor recurrence.


Asthma and suicidal ideation and behavior among Puerto Rican older children and adolescents.
There is growing evidence of a positive association between asthma and suicidal ideation and behavior in the general community, although information on this potential association is scarce among older children and adolescents and Puerto Ricans, groups at risk for both conditions. Data came from wave 3 of the Boricua Youth Study, a longitudinal study of youth in the Bronx and San Juan conducted from 2000 to 2004. Logistic regressions for correlated data (Generalized Estimating Equation) were conducted, with asthma predicting suicidal ideation and behavior among participants 11 years or older. After adjustment for survey design; age; sex; poverty; Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, mental disorders; cigarette smoking; and stressful life events, asthma was positively associated with suicidal ideation and behavior among the Puerto Rican older children and adolescents. Public health interventions targeting Puerto Rican older children and adolescents with asthma and future studies investigating potential biological and psychological mechanisms of association are warranted.


Thyroid-stimulating immunoglobulins and the control of thyroid function.
Triiodothyronine (T3) suppression and thyrotropin-releasing hormone (TRH) tests were used to study thyroid function in 50 patients with thyroid disease. The results of the thyroid function tests were compared with the levels of serum thyroid-stimulating immunoglobulins (TSI) measured by a radio-receptor assay. In euthyroid and hyperthyroid patients, the presence of TSI corresponded with the absence of TSH control of thyroid function. However, in two hypothyroid patients with serum TSI levels readily detectable in the receptor assay, T3 suppression and TRH tests indicated that thyroid function was under TSH control.


Telemedicine during Covid-19 pandemic: Advantage or critical issue?
Telemedicine offers a support to traditional medicine, delivering clinical services when distance is a critical factor. Although this tool does not replace a medical examination, during Covid-19 pandemic, it reduces the spread of infection and avoids the need for a patient's visit. It is useful in the management of chronic disorders or for patients undergoing palliative treatment. The University Hospital of Palermo has applied this in cases of chronic illness caring for patients who cannot stop their treatment, such as Department of Onco-Haematology, Internal Medicine, Dermatology, etc. The Department of Legal Medicine of Palermo, in particular, is also using telemedicine to manage medico-legal sudden natural death investigations and dealing with the Public Prosecutor's office of Palermo. Even after the Covid-19 emergency, telemedicine will be essential to streamline outpatient visits, while at the same time limiting costs, with significant benefits for the Italian National Public Health Service budget. In conclusion, telemedicine can offer a valuable support to the doctor's activity by streamlining and facilitating their work. In this sense, the Covid-19 pandemic represents a positive input for the acceleration and enhancement of these tools.


The Diagnosis of Periprosthetic Joint Infection.
Periprosthetic joint infection remains one of the most common failure modes following total hip and total knee arthroplasty. As such, a systematic and cost effective approach to the evaluation and work-up of a patient with a suspected periprosthetic joint infection should be undertaken in every patient with a painful total joint. Although we have many diagnostic tools, a history and physical remain the most important. Many of the current laboratory tests are indirect measure of infection, lack specificity for diagnosis of infection, but serve as sensitive and cost effective screening tools. In addition, a new definition of periprosthetic infection helps to standardize the diagnosis. Biomarkers hold the promise of improved specificity and are becoming increasingly popular as a diagnostic tool.


Rheological properties and failure of alginate hydrogels with ionic and covalent crosslinks.
Polysaccharide-based hydrogels are being used in a wide variety of applications ranging from tissue engineering to food products due to their biocompatibility and the ease of gel formation. In real-life applications, hydrogels can undergo large strain deformation, which may result in structural damage leading to failure. Here, we report the nonlinear rheological properties and failure behavior of alginate hydrogels, a class of polysaccharide hydrogels, synthesized via ionic and covalent crosslinking. Gels with ionic crosslinks or ionic alginate hydrogels are prepared by addition of Ca2+ ions in the aqueous solution of sodium alginate, and the covalently crosslinked alginate gels or chemical alginate hydrogels are obtained via amidation reactions. Because of their structural differences, ionic and chemical alginate hydrogels display different scattering profiles captured by using small angle X-ray scattering (SAXS) technique. Both ionic and chemical alginate hydrogels exhibit strain stiffening behavior when subjected to large amplitude oscillatory shear (LAOS) and the strain-stiffening behavior is accompanied by negative normal stress. A custom-built cavitation rheometer has been utilized to probe the local failure behavior of these gels. The cavitation rheometry captures different defect growth or fracture mechanism in ionic versus chemical alginate hydrogels, even if these two types of gels have a similar linear elastic modulus. Based on the critical pressure for gel fracture, we have provided an estimate of the critical energy release rate.


Association between metabolic syndrome components and cardiac autonomic modulation in southern Indian adults with pre-metabolic syndrome: hyperglycemia is the major contributing factor.
Metabolic syndrome (MetS) involves multi-factorial conditions linked to an elevated risk of type 2 diabetes mellitus and cardiovascular disease. Pre-metabolic syndrome (pre-MetS) possesses two MetS components but does not meet the MetS diagnostic criteria. Although cardiac autonomic derangements are evident in MetS, there is little information on their status in pre-MetS subjects. In this study, we sought to examine cardiac autonomic functions in pre-MetS and to determine which MetS component is more responsible for impaired cardiac autonomic functions. A total of 182 subjects were recruited and divided into healthy controls (n=89) and pre-MetS subjects (n=93) based on inclusion and exclusion criteria. We performed biochemical profiles on fasting blood samples to detect pre-MetS. Using standardized protocols, we evaluated anthropometric data, body composition, baroreflex sensitivity (BRS), heart rate variability (HRV), and autonomic function tests (AFTs). We further examined these parameters in pre-MetS subjects for each MetS component. Compared to healthy controls, we observed a significant cardiac autonomic dysfunction (CAD) through reduced BRS, lower overall HRV, and altered AFT parameters in pre-MetS subjects, accompanied by markedly varied anthropometric, clinical and biochemical parameters. Furthermore, all examined BRS, HRV, and AFT parameters exhibited an abnormal trend and significant correlation toward hyperglycemia. This study demonstrates CAD in pre-MetS subjects with reduced BRS, lower overall HRV, and altered AFT parameters. Hyperglycemia was considered an independent determinant of alterations in all the examined BRS, HRV, and AFT parameters. Thus, hyperglycemia may contribute to CAD in pre-MetS subjects before progressing to MetS.


Blockade of TGF-β signaling by the TGFβR-I kinase inhibitor LY2109761 enhances radiation response and prolongs survival in glioblastoma.
Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor that tends to be resistant to the ionizing radiotherapy used to treat it. Because TGF-β is a modifier of radiation responses, we conducted a preclinical study of the antitumor effects of the TGF-β receptor (TGFβR) I kinase inhibitor LY2109761 in combination with radiotherapy. LY2109761 reduced clonogenicity and increased radiosensitivity in GBM cell lines and cancer stem-like cells, augmenting the tumor growth delay produced by fractionated radiotherapy in a supra-additive manner in vivo. In an orthotopic intracranial model, LY2109761 significantly reduced tumor growth, prolonged survival, and extended the prolongation of survival induced by radiation treatment. Histologic analyses showed that LY2109761 inhibited tumor invasion promoted by radiation, reduced tumor microvessel density, and attenuated mesenchymal transition. Microarray-based gene expression analysis revealed signaling effects of the combinatorial treatments that supported an interpretation of their basis. Together, these results show that a selective inhibitor of the TGFβR-I kinase can potentiate radiation responses in glioblastoma by coordinately increasing apoptosis and cancer stem-like cells targeting while blocking DNA damage repair, invasion, mesenchymal transition, and angiogenesis. Our findings offer a sound rationale for positioning TGFβR kinase inhibitors as radiosensitizers to improve the treatment of glioblastoma.


Long-term functional outcomes after treatment for localized prostate cancer.
The purpose of this analysis was to compare long-term urinary, bowel, and sexual function after radical prostatectomy or external-beam radiation therapy. The Prostate Cancer Outcomes Study (PCOS) enrolled 3533 men in whom prostate cancer had been diagnosed in 1994 or 1995. The current cohort comprised 1655 men in whom localized prostate cancer had been diagnosed between the ages of 55 and 74 years and who had undergone either surgery (1164 men) or radiotherapy (491 men). Functional status was assessed at baseline and at 2, 5, and 15 years after diagnosis. We used multivariable propensity scoring to compare functional outcomes according to treatment. Patients undergoing prostatectomy were more likely to have urinary incontinence than were those undergoing radiotherapy at 2 years (odds ratio, 6.22; 95% confidence interval [CI], 1.92 to 20.29) and 5 years (odds ratio, 5.10; 95% CI, 2.29 to 11.36). However, no significant between-group difference in the odds of urinary incontinence was noted at 15 years. Similarly, although patients undergoing prostatectomy were more likely to have erectile dysfunction at 2 years (odds ratio, 3.46; 95% CI, 1.93 to 6.17) and 5 years (odds ratio, 1.96; 95% CI, 1.05 to 3.63), no significant between-group difference was noted at 15 years. Patients undergoing prostatectomy were less likely to have bowel urgency at 2 years (odds ratio, 0.39; 95% CI, 0.22 to 0.68) and 5 years (odds ratio, 0.47; 95% CI, 0.26 to 0.84), again with no significant between-group difference in the odds of bowel urgency at 15 years. At 15 years, no significant relative differences in disease-specific functional outcomes were observed among men undergoing prostatectomy or radiotherapy. Nonetheless, men treated for localized prostate cancer commonly had declines in all functional domains during 15 years of follow-up. (Funded by the National Cancer Institute.).


Belowground advantages in construction cost facilitate a cryptic plant invasion.
The energetic cost of plant organ construction is a functional trait that is useful for understanding carbon investment during growth (e.g. the resource acquisition vs. tissue longevity tradeoff), as well as in response to global change factors like elevated CO2 and N. Despite the enormous importance of roots and rhizomes in acquiring soil resources and responding to global change, construction costs have been studied almost exclusively in leaves. We sought to determine how construction costs of aboveground and belowground organs differed between native and introduced lineages of a geographically widely dispersed wetland plant species (Phragmites australis) under varying levels of CO2 and N. We grew plants under ambient and elevated atmospheric CO2, as well as under two levels of soil nitrogen. We determined construction costs for leaves, stems, rhizomes and roots, as well as for whole plants. Across all treatment conditions, the introduced lineage of Phragmites had a 4.3 % lower mean rhizome construction cost than the native. Whole-plant construction costs were also smaller for the introduced lineage, with the largest difference in sample means (3.3 %) occurring under ambient conditions. In having lower rhizome and plant-scale construction costs, the introduced lineage can recoup its investment in tissue construction more quickly, enabling it to generate additional biomass with the same energetic investment. Our results suggest that introduced Phragmites has had an advantageous tissue investment strategy under historic CO2 and N levels, which has facilitated key rhizome processes, such as clonal spread. We recommend that construction costs for multiple organ types be included in future studies of plant carbon economy, especially those investigating global change.


Round, round we go - strategies for enzymatic cofactor regeneration.
Covering: up to the beginning of 2020Enzymes depending on cofactors are essential in many biosynthetic pathways of natural products. They are often involved in key steps: catalytic conversions that are difficult to achieve purely with synthetic organic chemistry. Hence, cofactor-dependent enzymes have great potential for biocatalysis, on the condition that a corresponding cofactor regeneration system is available. For some cofactors, these regeneration systems require multiple steps; such complex enzyme cascades/multi-enzyme systems are (still) challenging for in vitro biocatalysis. Further, artificial cofactor analogues have been synthesised that are more stable, show an altered reaction range, or act as inhibitors. The development of bio-orthogonal systems that can be used for the production of modified natural products in vivo is an ongoing challenge. In light of the recent progress in this field, this review aims to provide an overview of general strategies involving enzyme cofactors, cofactor analogues, and regeneration systems; highlighting the current possibilities for application of enzymes using some of the most common cofactors.


Molecular computing: paths to chemical Turing machines.
To comply with the rapidly increasing demand of information storage and processing, new strategies for computing are needed. The idea of molecular computing, where basic computations occur through molecular, supramolecular, or biomolecular approaches, rather than electronically, has long captivated researchers. The prospects of using molecules and (bio)macromolecules for computing is not without precedent. Nature is replete with examples where the handling and storing of data occurs with high efficiencies, low energy costs, and high-density information encoding. The design and assembly of computers that function according to the universal approaches of computing, such as those in a Turing machine, might be realized in a chemical way in the future; this is both fascinating and extremely challenging. In this perspective, we highlight molecular and (bio)macromolecular systems that have been designed and synthesized so far with the objective of using them for computing purposes. We also present a blueprint of a molecular Turing machine, which is based on a catalytic device that glides along a polymer tape and, while moving, prints binary information on this tape in the form of oxygen atoms.


Impact of NRTIs on lipid levels among a large HIV-infected cohort initiating antiretroviral therapy in clinical care.
to assess the associations between nucleoside reverse transcriptase inhibitors (NRTIs) and change in lipid levels among a large cohort of HIV-infected patients in routine clinical care initiating their first potent antiretroviral regimen. longitudinal observational cohort study from the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort. we used generalized estimating equations to examine the association between NRTIs and lipids accounting for within-patient correlations between repeated measures and key clinical and demographic characteristics including other antiretroviral medications. among 2267 individuals who started their first antiretroviral regimen, tenofovir with emtricitabine or lamivudine was associated with lower levels for total cholesterol, low-density lipoprotein (LDL), triglycerides, non-high-density lipoprotein (HDL), and HDL, compared with other NRTI pairs in adjusted analyses. LDL levels were highest among patients receiving didanosine/lamivudine. Triglyceride levels were highest in stavudine/lamivudine users. HDL levels were highest among patients receiving didanosine/stavudine. Hepatitis C infection and younger age were also associated with lower lipid levels. we found clinically important heterogeneity within the NRTI class of antiretroviral medications regarding their effect on lipid levels over time. Although the lipid profile of tenofovir with emtricitabine or lamivudine appeared to be less pro-atherogenic in this large longitudinal study of HIV-infected patients in routine clinical care, there was no association with beneficial HDL levels. In general, the change in lipid levels associated with most antiretroviral agents, particularly those NRTI combinations currently in common use, are relatively modest. Additional studies are needed to understand the long-term implications of these findings on cardiovascular disease risk.


Extra-Pulmonary Neuroendocrine Carcinomas: A Population-Based Study in the Netherlands.
Extra-pulmonary neuroendocrine carcinomas (EP-NEC) are rare tumours that require expertise for correct and timely diagnosis, which is essential for clinical decision making. The number of patients affected, treatment given, and the proportion surviving the disease is based on limited evidence. The aim of this study is to retrospectively analyse the incidence, treatment, and relative survival (RS) of EP-NEC patients in the Netherlands. Patients diagnosed between 2008-2012 with EP-NEC or NEC with unknown primary site (UP-NEC) were selected from the Netherlands Cancer Registry based on combinations of tumour localisation and morphology code. Incidence was studied using the European standardised (ESR) and world standardised rates, and RS was calculated using the Ederer II method. In total, 1,544 cases were analysed, 1,045 EP-NEC and 499 UP-NEC. For EP-NEC, the incidence was 1.0 per 100,000 person-years (ESR), the mean age was 68 years, and the male to female ratio was 1: 0.6. Most frequent EP-NEC localisations were the bladder and the gastrointestinal tract, and the treatment most frequently given was surgery in combination with chemotherapy. The overall 5-year RS was 38% for patients with local/regional disease (n = 447), and 7% for patients with extensive disease (n = 582). For UP-NEC patients (n = 499), the 5-year RS was 6%. This study is the first nationwide study presenting an increase in the incidence of EP-NEC patients from 196 to 260 cases annually in the Netherlands. The best 5-year RS was found for EP-NEC patients with local disease located in the bladder, where the worst 5-year RS was found for patients with disease located in the oesophagus.


Cytoplasmic Lipases-A Novel Class of Fungal Defense Proteins Against Nematodes.
Fungi are an attractive food source for predators such as fungivorous nematodes. Several fungal defense proteins and their protective mechanisms against nematodes have been described. Many of these proteins are lectins which are stored in the cytoplasm of the fungal cells and bind to specific glycan epitopes in the digestive tract of the nematode upon ingestion. Here, we studied two novel nematotoxic proteins with lipase domains from the model mushroom Coprinopsis cinerea. These cytoplasmically localized proteins were found to be induced in the vegetative mycelium of C. cinerea upon challenge with fungivorous nematode Aphelenchus avenae. The proteins showed nematotoxicity when heterologously expressed in E. coli and fed to several bacterivorous nematodes. Site-specific mutagenesis of predicted catalytic residues eliminated the in-vitro lipase activity of the proteins and significantly reduced their nematotoxicity, indicating the importance of the lipase activity for the nematotoxicity of these proteins. Our results suggest that cytoplasmic lipases constitute a novel class of fungal defense proteins against predatory nematodes. These findings improve our understanding of fungal defense mechanisms against predators and may find applications in the control of parasitic nematodes in agriculture and medicine.


Per- and Polyfluoroalkyl Substances (PFAS): Significance and Considerations within the Regulatory Framework of the USA.
Per- and polyfluoroalkyl substances (PFAS) are an emerging environmental crisis. Deemed forever chemicals, many congeners bioaccumulate and are incredibly persistent in the environment due to the presence of the strong carbon-fluorine covalent bonds. Notable PFAS compounds include perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and GenX. Robust toxicological knowledge exists for these substances, but regulatory decisions based on this knowledge has fallen behind. The United States Environmental Protection Agency (EPA) has addressed this issue with the PFAS Action Plan and EPA Council on PFAS, but the regulatory framework is severely lacking. Currently, no federal regulations or standards exist. Many occupational and non-occupational human cohorts exist that can lend knowledge on the environmental implications of PFAS and associated health effects. Occupationally, firefighters face significant exposure risks due to use of PFAS containing aqueous film-forming foams (AFFFs) and personal protective equipment contamination. Non-occupationally, wastewater discharge in North Carolina led to chronic and widespread residential exposure to GenX via drinking water contamination. This public health review seeks to convey the current and future significance of PFAS as an environmental contaminate, to lend considerations on regulatory frameworks within the USA, and to help guide and promote the need for future epidemiological studies in order to tackle this environmental emergency. While the PFAS Action Plan creates a scientific and regulatory foundation, it is important to take these lessons and apply them to future environmental health issues.


Myeloid lncRNA LOUP mediates opposing regulatory effects of RUNX1 and RUNX1-ETO in t(8;21) AML.
The mechanism underlying cell type-specific gene induction conferred by ubiquitous transcription factors as well as disruptions caused by their chimeric derivatives in leukemia is not well understood. Here, we investigate whether RNAs coordinate with transcription factors to drive myeloid gene transcription. In an integrated genome-wide approach surveying for gene loci exhibiting concurrent RNA and DNA interactions with the broadly expressed Runt-related transcription factor 1 (RUNX1), we identified the long noncoding RNA (lncRNA) originating from the upstream regulatory element of PU.1 (LOUP). This myeloid-specific and polyadenylated lncRNA induces myeloid differentiation and inhibits cell growth, acting as a transcriptional inducer of the myeloid master regulator PU.1. Mechanistically, LOUP recruits RUNX1 to both the PU.1 enhancer and the promoter, leading to the formation of an active chromatin loop. In t(8;21) acute myeloid leukemia (AML), wherein RUNX1 is fused to ETO, the resulting oncogenic fusion protein, RUNX1-ETO, limits chromatin accessibility at the LOUP locus, causing inhibition of LOUP and PU.1 expression. These findings highlight the important role of the interplay between cell-type-specific RNAs and transcription factors, as well as their oncogenic derivatives in modulating lineage-gene activation and raise the possibility that RNA regulators of transcription factors represent alternative targets for therapeutic development.


The collagen diseases.
The collagen diseases have in common certain relatively specific alterations in the tissues that are derived from the mesenchyme.In reviewing the development of this concept, the nature and the pathogenesis of these changes and the blocking effect of cortisone and ACTH are discussed. The term "diseases of the collagen system" includes a number of clinical states within a broad spectrum of variation in the basic alterations of collagenous and vascular tissues. In rheumatoid arthritis the modifications are chiefly in the somatic connective tissue; in periarteritis nodosa the blood vessel involvement is preeminent; dermatomyositis and disseminated lupus erythematosus present more intermediate mixtures of these changes.


Parietal double-cone coil stimulation in tinnitus.
Non-pulsatile tinnitus is considered to be an auditory phantom percept. The extremely emotional context of disabling tinnitus often leads to a higher level of selective attention directed toward the tinnitus. As such, tinnitus is a continuously distracting auditory event. Auditory attention is associated with the activation of the intraparietal sulcus (IPS), and modulating the IPS with 10 Hz transcranial magnetic stimulation (TMS) creates the ability to ignore salient distractors. Thus, it can be expected that modulating the parietal area might interfere with the perception of tinnitus. The effect of TMS on tinnitus is evaluated using a double-cone coil tilted to the left parietal area in 24 individuals (study 1) and in 40 individuals with the double-cone coil symmetrically overlying both parietal areas (study 2). When transient tinnitus suppression is noted, the patient is asked to estimate the decrease in tinnitus in percentage using the numeric rating scale. The procedure is repeated with stimulations at sham, 1 and 10 Hz, each stimulation session consisting of 200 pulses for study 1 and for study 2 stimulations at sham, 1, 5, and 10 Hz, each stimulation session consisting of 200 pulses. For both studies, the order of the different stimulation frequencies was randomized over the participants. For study 1, patients report a significant transient reduction of the tinnitus percept for 10 Hz stimulation in comparison with, respectively, pre-treatment, sham, and 1 Hz stimulation, with a suppression effect of 11.36 %. No significant effect was obtained for 1 Hz stimulation with the coil tilted toward the left parietal area. For study, 2 patients revealed a significant suppression effect on 1, 5, and 10 Hz in comparison with pre-treatment. However, only stimulation at 5 and 10 Hz had a significant difference in comparison with sham with a suppression effect of, respectively, 8.78 and 9.50 %. Our data suggest that the parietal area is involved in tinnitus perception and that 10 Hz TMS using the double-cone coil overlying the parietal area can modulate tinnitus.


Fetal origins of obesity.
The worldwide epidemic of obesity continues unabated. Obesity is notoriously difficult to treat, and, thus, prevention is critical. A new paradigm for prevention, which evolved from the notion that environmental factors in utero may influence lifelong health, has emerged in recent years. A large number of epidemiological studies have demonstrated a direct relationship between birth weight and BMI attained in later life. Although the data are limited by lack of information on potential confounders, these associations seem robust. Possible mechanisms include lasting changes in proportions of fat and lean body mass, central nervous system appetite control, and pancreatic structure and function. Additionally, lower birth weight seems to be associated with later risk for central obesity, which also confers increased cardiovascular risk. This association may be mediated through changes in the hypothalamic pituitary axis, insulin secretion and sensing, and vascular responsiveness. The combination of lower birth weight and higher attained BMI is most strongly associated with later disease risk. We are faced with the seeming paradox of increased adiposity at both ends of the birth weight spectrum-higher BMI with higher birth weight and increased central obesity with lower birth weight. Future research on molecular genetics, intrauterine growth, growth trajectories after birth, and relationships of fat and lean mass will elucidate relationships between early life experiences and later body proportions. Prevention of obesity starting in childhood is critical and can have lifelong, perhaps multigenerational, impact.


Vertebral body split fracture after a single-level cervical total disc replacement.
Cervical total disc replacement (TDR) is a viable option for the surgical treatment of degenerative disc disease. This 67-year-old nonsmoking male patient underwent single-level ProDisc-C cervical TDR at C5-6 without any intraoperative problem. His radicular pain improved and he had no neck pain immediately after the operation. However, on postoperative Day 3, a radiograph demonstrated a vertical split fracture of the C-5 vertebra. This fracture was managed conservatively, and 2 years postoperatively a follow-up CT scan demonstrated stable device position and fusion of the fracture. Although the linear fracture caused no neurological symptoms or device migration, the authors advocate prudence in selection and installation of keel-design prostheses, even in a single-level cervical TDR scenario.


Mechanistic studies of mouse polyamine oxidase with N1,N12-bisethylspermine as a substrate.
In mammalian cells, the flavoprotein polyamine oxidase catalyzes a key step in the catabolism of polyamines, the oxidation of N1-acetylspermine and N1-acetylspermidine to spermidine and putrescine, respectively. The mechanism of the mouse enzyme has been studied with N1,N12-bisethylspermine (BESPM) as a substrate. At pH 10, the pH optimum, the limiting rate of reduction of the flavin in the absence of oxygen is comparable to the k(cat) value for turnover, establishing reduction as rate-limiting. Oxidation of the reduced enzyme is a simple second-order reaction. No intermediates are seen in the reductive or oxidative half-reactions. The k(cat) value decreases below a pK(a) of 9.0. The k(cat)/K(m) value for BESPM exhibits a bell-shaped pH profile, with pK(a) values of 9.8 and 10.8. These pK(a) values are assigned to the substrate nitrogens. The rate constant for the reaction of the reduced enzyme with oxygen is not affected by a pH between 7.5 and 10. Active site residue Tyr430 is conserved in the homologous protein monoamine oxidase. Mutation of this residue to phenylalanine results in a 6-fold decrease in the k(cat) value and the k(cat)/K(m) value for oxygen due to a comparable decrease in the rate constant for flavin reduction. This moderate change is not consistent with this residue forming a tyrosyl radical during catalysis.


Aptamer-based multiplexed proteomic technology for biomarker discovery.
The interrogation of proteomes ("proteomics") in a highly multiplexed and efficient manner remains a coveted and challenging goal in biology and medicine. We present a new aptamer-based proteomic technology for biomarker discovery capable of simultaneously measuring thousands of proteins from small sample volumes (15 µL of serum or plasma). Our current assay measures 813 proteins with low limits of detection (1 pM median), 7 logs of overall dynamic range (~100 fM-1 µM), and 5% median coefficient of variation. This technology is enabled by a new generation of aptamers that contain chemically modified nucleotides, which greatly expand the physicochemical diversity of the large randomized nucleic acid libraries from which the aptamers are selected. Proteins in complex matrices such as plasma are measured with a process that transforms a signature of protein concentrations into a corresponding signature of DNA aptamer concentrations, which is quantified on a DNA microarray. Our assay takes advantage of the dual nature of aptamers as both folded protein-binding entities with defined shapes and unique nucleotide sequences recognizable by specific hybridization probes. To demonstrate the utility of our proteomics biomarker discovery technology, we applied it to a clinical study of chronic kidney disease (CKD). We identified two well known CKD biomarkers as well as an additional 58 potential CKD biomarkers. These results demonstrate the potential utility of our technology to rapidly discover unique protein signatures characteristic of various disease states. We describe a versatile and powerful tool that allows large-scale comparison of proteome profiles among discrete populations. This unbiased and highly multiplexed search engine will enable the discovery of novel biomarkers in a manner that is unencumbered by our incomplete knowledge of biology, thereby helping to advance the next generation of evidence-based medicine.


Nerve growth factor-induced differentiation of PC12 cells: evaluation of changes in RNA and DNA metabolism.
The relationship between both DNA and RNA metabolism and the nerve growth factor (betaNGF)-induced differentiation of PC12 cells was investigated. Cells remained in log phase growth for 4 days after exposure to betaNGF. DNA synthesis was similarly unaffected by betaNGF during this time. Thereafter, a gradual decrease in DNA synthesis was observed. In contrast, as many as 40% of the cells display neurites after 4 days exposure to betaNGF. The implication, that cells which have begun to differentiate morphologically may still synthesize DNA, was confirmed using autoradiography. The cellular RNA concentration was elevated significantly within 1 day of exposure to betaNGF and continued to increase for up to 6 days. Dose-response analysis revealed that this increase in cellular RNA, both rRNA and tRNA, closely correlates with the size and number of neurites per cell rather than with the cell's capacity to grow a neurite per se. A parallel rise in the cellular protein concentration was observed also. It was concluded, therefore, that (1) cessation of cell division is not a prerequisite for the initiation of the morphological differentiation of these cells and (2) the elevation of the cellular RNA content influences some quantitative aspects of neurite outgrowth.


Gene regulation by low level UV-B radiation: identification by DNA array analysis.
UV-B radiation alters transcript levels of various defence genes and photosynthetic genes in plants. Utilising a DNA array with 5000 ESTs and cDNAs from Arabidopsis thaliana, 70 genes were found to show a greater than two-fold induction or repression of transcript levels. Six genes (MEB5.2, PyroA, Ubq3, Lhcb6, F5D21.10 and the gene for an RNA polymerase II subunit) were tested for stress specific gene regulation on northern blots with RNA from plants exposed to low dose UV-B radiation, ozone or wounding. Transcript levels for PyroA, Uhq3 and the gene for a RNA polymerase II subunit were all specifically increased by UV-B. MEB5.2 mRNA levels also rose, whereas Lhcb6 and FSD21.10 transcript levels decreased under all stresses. The PyroA gene product in fungi is needed for biosynthesis of pyridoxine, and might have a role in protection against singlet oxygen. The Ubq3 gene encodes the ubiquitin protein that is attached to proteins destined for degradation. MEB5.2 and F5D21.10 represent novel gene products whose function have not yet been identified. Pairwise comparisons between the UV-B inducible promoters have identified a series of elements present in the MEB5.2 and PyroA promoters, absent from promoters of genes for early phenylpropanoid metabolism and that may be responsible for modulating their UV-B responses.


Treating systemic lupus erythematosus in the 21st century: new drugs and new perspectives on old drugs.
Besides treating acute flares, the management of SLE should aim at preventing organ damage accrual and drug-associated harms, improving health-related quality of life and prolonging survival. At present, therapy is based on combinations of antimalarials (mainly HCQ), considered the backbone of SLE treatment, glucocorticoids and immunosuppressive drugs. However, these regimens are not universally effective and a substantial degree of damage can be caused by exposure to glucocorticoids. In this review we provide a critical appraisal of the efficacy and safety of available treatments as well as a brief discussion of potentially novel compounds in patients with SLE. We emphasize the use of methylprednisolone pulses for moderate-severe flares, followed by low-moderate doses of oral prednisone with quick tapering to maintenance doses of ≤5 mg/day, as well as the prompt institution of immunosuppressive drugs in the setting of severe disease but also as steroid-sparing agents. Indications for the use of biologic agents, namely belimumab and rituximab, in refractory or organ-threatening disease are also presented. We conclude by proposing evidence- and experience-based treatment strategies tailored to the clinical scenario and prevailing organ involvement that can aid clinicians in managing this complex disease.


Temporary mechanical circulatory support & enhancing recovery after cardiac surgery.
This review highlights the integration of enhanced recovery principles with temporary mechanical circulatory support associated with adult cardiac surgery. Enhanced recovery elements and efforts have been associated with improvements in quality and value. Temporary mechanical circulatory support technologies have been successfully employed, improved, and the value of their proactive use to maintain hemodynamic goals and preserve long-term myocardial function is accruing. Temporary mechanical circulatory support devices promise to enhance recovery by mitigating the risk of complications, such as postcardiotomy cardiogenic shock, organ dysfunction, and death, associated with adult cardiac surgery.


A phase II study of the orally administered negative enantiomer of gossypol (AT-101), a BH3 mimetic, in patients with advanced adrenal cortical carcinoma.
Background Adrenal cortical carcinoma (ACC) is a rare cancer with treatment options of limited efficacy, and poor prognosis if metastatic. AT-101 is a more potent inhibitor of B cell lymphoma 2 family apoptosis-related proteins than its racemic form, gossypol, which showed preliminary clinical activity in ACC. We thus evaluated the efficacy of AT-101 in patients with advanced ACC. Methods Patients with histologically confirmed metastatic, recurrent, or primarily unresectable ACC were treated with AT-101 (20 mg/day orally, 21 days out of 28-day cycles) until disease progression and/or prohibitive toxicity. The primary endpoint was objective response rate, wherein a Response Evaluation Criteria In Solid Tumors (RECIST) partial response rate of 25% would be considered promising and 10% not, with a Type I error of 10% and 90% power. In a 2-stage design, 2 responses were required of the first 21 assessable subjects to warrant complete accrual of 44 patients. Secondary endpoints included safety, progression-free survival and overall survival. Results This study accrued 29 patients between 2009 and 2011; median number of cycles was 2. Seven percent experienced grade 4 toxicity including cardiac troponin elevations and hypokalemia. None of the first 21 patients attained RECIST partial response; accordingly, study therapy was deemed ineffective and the trial was permanently closed. Conclusions AT-101 had no meaningful clinical activity in this study in patients with advanced ACC, but demonstrated feasibility of prospective therapeutic clinical trials in this rare cancer.