Limitations on the uptake of mercury vapour by human erythrocytes in a closed exposure system.
Previous in vitro studies using the exposure of suspensions of normal human erythrocytes to mercury vapour (Hg0) in Warburg vessels revealed a broad variation of the cellular Hg uptake in the presence of hydrogen peroxide and furnished evidence for an oxidation of Hg0 by the catalase-H2O2 pathway. This report describes the uptake of Hg0 in the same exposure system as it depends on haematocrit, H2O2 supplementation and exposure time. The results indicate that the uptake of vapour by the whole suspensions was virtually independent of haematocrit and of the H2O2 supplementation at high rates of H2O2 infusion, whereas at low rates it was directly proportional to the amount of peroxide added. Since the retention of mercury by the medium is negligible, the haemoglobin-related (specific) uptake is inversely proportional to the haematocrit at high rates of H2O2 infusion. These results are consistent with the conclusion that the incorporation of Hg0 by erythrocytes is controlled by two processes: transfer of vapour to the cells and enzymic oxidation. The net rate of uptake is limited by the oxidizing capacity at low, and by the vapour transfer at high H2O2 supplementation. As a practical consequence of these findings the spread of the specific uptakes reported in the literature is considerably reduced if the values observed when transfer becomes rate limiting are related to the haematocrit.


Mechanism of coronary vasodilation produced by bradykinin.
Bradykinin has been demonstrated to be an endothelium-dependent vasodilator in the cerebral circulation of the mouse, but the actions of bradykinin on regional tissue perfusion in the canine coronary circulation have not been studied. The mechanism of coronary vasodilation by bradykinin was studied in open-chest, anesthetized dogs. The role of cyclooxygenase stimulation, bradykinin B2 receptor activation, and endothelium-derived relaxing factor in bradykinin-mediated vasodilation was studied in separate groups of dogs. Bradykinin was infused intracoronarily so as to avoid changes in systemic hemodynamics capable of altering the regional distribution of coronary blood flow (radioactive microspheres). Bradykinin produced a preferential increase in subendocardial blood flow. Pretreatment with indomethacin had no effect on bradykinin-mediated increases in total left ventricular flow or the transmural distribution of coronary blood flow. Blockade of bradykinin B2 receptors with the competitive antagonist [Thi5,8, D-Phe7]-bradykinin attenuated both the increase in total flow and redistribution of perfusion to the subendocardium produced by bradykinin. Inhibition of endothelium-derived relaxing factor with quinacrine, occlusion/reperfusion, or NG-monomethyl L-arginine attenuated the total increase in left ventricular flow and blocked the redistribution of flow to the subendocardium produced by bradykinin. The present results demonstrate that intracoronary infusion of bradykinin produces a preferential increase in blood flow to the subendocardium via stimulation of B2 receptors and the release of an endothelium-dependent relaxing factor that may be nitric oxide.


Electrical stimulation for fracture healing: current evidence.
This article provides an overview of the biology behind the use of electrical stimulation in fracture healing and discusses the current methods of electrical bone growth stimulation. In addition, we review the best available clinical evidence for the use of electrical stimulation in the treatment of delayed and nonunions of fractures. Our search identified 4 meta-analyses on the use of electrical stimulation on fracture healing. The most methodologically rigorous and recent meta-analysis suggests that the current evidence is insufficient to conclude a benefit of electromagnetic stimulation in improving the rate of union in patients with a fresh fracture, osteotomy, delayed union, or nonunion. The other 3 meta-analyses that we identified suggested a more significant treatment effect from electrical stimulation. Although the evidence supporting electrical stimulation does trend in favor of its use to help achieve bony union, further large, multicenter, randomized, controlled trials are required to resolve the current uncertainty surrounding the use of electrical stimulation and fracture healing.


Control of segmental expression of the cardiac-restricted ankyrin repeat protein gene by distinct regulatory pathways in murine cardiogenesis.
Although accumulating evidence suggests that the heart develops in a segmental fashion, the molecular mechanisms that control regional specification of cardiomyocytes in the developing heart remain largely unknown. In this study, we have used the mouse cardiac-restricted ankyrin repeat protein (CARP) gene as a model system to study these mechanisms. The CARP gene encodes a nuclear co-regulator for cardiac gene expression, which lies downstream of the cardiac homeobox gene, Nkx 2.5, and is an early marker of the cardiac muscle cell lineage. We have demonstrated that the expression of the gene is developmentally down regulated and dramatically induced as part of the embryonic gene program during cardiac hypertrophy. Using a lacZ/knock-in mouse and three lines of transgenic mouse harboring various CARP promoter/lacZ reporters, we have identified distinct 5' cis regulatory elements of the gene that can direct heart segment-specific transgene expression, such as atrial versus ventricular and left versus right. Most interestingly, a 213 base pair sequence element of the gene was found to confer conotruncal segment-specific transgene expression. Using the transgene as a conotruncal segment-specific marker, we were able to document the developmental fate of a subset of cardiomyocytes in the conotruncus during cardiogenesis. In addition, we have identified an essential GATA-4 binding site in the proximal upstream regulatory region of the gene and cooperative transcriptional regulation mediated by Nkx2.5 and GATA-4. We have shown that this cooperative regulation is dependent on binding of GATA-4 to its cognate DNA sequence in the promoter, which suggests that Nkx2.5 controls CARP expression, at least in part, through GATA-4.


EGFR, HER-2 and KRAS in canine gastric epithelial tumors: a potential human model?
Epidermal growth factor receptor (EGFR or HER-1) and its analog c-erbB-2 (HER-2) are protein tyrosine kinases correlated with prognosis and response to therapy in a variety of human cancers. KRAS mediates the transduction of signals between EGFR and the nucleus, and its mutation has been identified as a predictor of resistance to anti-EGFR drugs. In human oncology, the importance of the EGFR/HER-2/KRAS signalling pathway in gastric cancer is well established, and HER-2 testing is required before initiating therapy. Conversely, this pathway has never been investigated in canine gastric tumours. A total of 19 canine gastric epithelial neoplasms (5 adenomas and 14 carcinomas) were retrospectively evaluated for EGFR/HER-2 immunohistochemical expression and KRAS mutational status. Five (35.7%) carcinomas were classified as intestinal-type and 9 (64.3%) as diffuse-type. EGFR was overexpressed (≥ 1+) in 8 (42.1%) cases and HER-2 (3+) in 11 (57.9%) cases, regardless of tumour location or biological behaviour. The percentage of EGFR-positive tumours was significantly higher in the intestinal-type (80%) than in the diffuse-type (11.1%, p = 0.023). KRAS gene was wild type in 18 cases, whereas one mucinous carcinoma harboured a point mutation at codon 12 (G12R). EGFR and HER-2 may be promising prognostic and therapeutic targets in canine gastric epithelial neoplasms. The potential presence of KRAS mutation should be taken into account as a possible mechanism of drug resistance. Further studies are necessary to evaluate the role of dog as a model for human gastric cancer.


Delayed presentation of congenital diaphragmatic hernia.
Patients with congenital diaphragmatic hernias (CDH) usually present soon after birth with respiratory distress. Occasionally presentation is delayed. Twelve patients with delayed presentation (outside the neonatal period) of a total of 91 with CHD were seen over 17 years (1977-1994). Case records were reviewed to identify reasons for late presentation, evidence of morbidity, treatment and outcome. Age at presentation ranged from 6 weeks to 30 months (mean 8 months). Ten patients were aged 6 months or younger and there was an equal number of boys and girls. Seven cases were left-sided, 4 right-sided and 1 was anteriorly placed and bilateral. Ten patients presented acutely, 5 with small-bowel obstruction and 5 with respiratory distress, but all of the latter had a history of previous recurrent chest infection. Diagnosis was confirmed by radiographic examination of the chest in 10, barium meal in 1 and a 5-month-old patient had an inappropriate laparotomy and gastrojejunostomy for duodenal obstruction at an outlying hospital. Two had documented normal chest radiographs 3 and 6 months prior to diagnosis. Patients who presented with gastro-intestinal symptoms were older (mean age 1 year) compared with those with predominantly respiratory symptoms (mean age 19 weeks). None had any evidence of bowel strangulation. All were repaired via an abdominal approach. A hernial sac was found in half the cases (4/7 left and 2/5 right). Five had non-rotation of bowel. Primary repair without patch was carried out in all. One child with lung hypoplasia and multiple cardiac abnormalities died; the others recovered well. Delay in presentation of CDH is not uncommon (14% in this series). Most patients will have respiratory symptoms. A normal previous chest radiograph does not exclude the diagnosis. All patients with recurrent chest infection should have a contrast meal investigation early on. Long-term prognosis is favourable and postoperative morbidity is minimal, despite late presentation.


In-Hospital Outcomes of Acute Kidney Injury After Pediatric Cardiac Surgery: A Meta-Analysis.
Background: Cardiac surgery-associated acute kidney injury (CS-AKI) is associated with increased morbidity and mortality in both adults and children. This study aimed to investigate the in-hospital outcomes of CS-AKI in the pediatric population. Methods: PubMed/MEDLINE, Embase, Scopus, and reference lists of relevant articles were searched for studies published by August 2020. Random-effects meta-analysis was performed, comparing in-hospital outcomes between patients who developed CS-AKI and those who did not. Results: Fifty-eight publications between 2008 and 2020 consisting of 18,334 participants (AKI: 5,780; no AKI: 12,554) were included. Higher rates of in-hospital mortality (odds ratio [OR] 7.22, 95% confidence interval [CI] 5.27-9.88), need for renal replacement therapy (RRT) (OR 18.8, 95% CI 11.7-30.5), and cardiac arrhythmias (OR 2.67, 95% 1.86-4.80) were observed in patients with CS-AKI. Furthermore, patients with AKI had longer ventilation times (mean difference [MD] 1.76 days, 95% CI 1.05-2.47), pediatric intensive care unit (PICU) length of stay (MD 3.31, 95% CI 2.52-4.10), and hospital length of stay (MD 5.00, 95% CI 3.34-6.67). Conclusions: CS-AKI in the pediatric population is associated with a higher risk of mortality, cardiac arrhythmias and need for RRT, as well as greater mechanical ventilation time, PICU and hospital length of stay. These results might help improve the clinical care protocols prior to cardiac surgery to minimize the disease burden of CS-AKI in children. Furthermore, etiology-specific approaches to AKI are warranted, as outcomes are likely impacted by the underlying cause.


Near-field nanoprobing using Si tip-Au nanoparticle photoinduced force microscopy with 120:1 signal-to-noise ratio, sub-6-nm resolution.
We propose using a Si tip-Au nanoparticle (NP) combination system in photoinduced force microscopy (PiFM) to fundamentally improve its accuracy in the nanoscale characterization of light-matter interaction. Compared to conventional PiFM with Au-coated tips, such Si tip and Au NP combination enables superior photo-induced force detection while overcoming the tip-induced anisotropy by Au-coating. We map the near-field distribution of Au NPs in different arrangements achieving 120 signal-to-noise ratio and sub-6-nm resolution, even surpassing the tip-curvature limitation; we also map the azimuthally polarized beam profile showing an excellent symmetry. The proposed approach is essential to the promising single molecule spectroscopy.


Efficacy of Inhaled Treprostinil on Multiple Disease Progression Events in Patients with Pulmonary Hypertension due to Parenchymal Lung Disease in the INCREASE Trial.
Rationale: The INCREASE study of inhaled treprostinil met its primary endpoint of change in 6-minute-walk distance at Week 16. In addition, there were significantly fewer clinical worsening events in patients receiving inhaled treprostinil. However, the incidence of multiple events in the same patient is unknown. Objectives: This post hoc analysis evaluated the effect of continued treatment with inhaled treprostinil on the frequency and impact of multiple disease progression events. Methods: Patients enrolled in INCREASE were analyzed for disease progression events, defined as at least 15% decline in 6-minute-walk distance, exacerbation of underlying lung disease, cardiopulmonary hospitalization, lung transplantation, at least 10% decline in forced vital capacity, or death during the duration of the 16-week study. Measurements and Main Results: In total, 147 disease progression events occurred in the inhaled treprostinil group (89/163 patients, 55%) compared with 215 events (109/163 patients, 67%) in the placebo group (P = 0.018). There was a lower incidence of each disease progression component in the inhaled treprostinil group: 6-minute-walk distance decline (45 vs. 64 events), lung disease exacerbation (48 vs. 72 events), FVC decline (19 vs. 33), cardiopulmonary hospitalization (23 vs. 33 events), and death (10 vs. 12). Fewer patients receiving inhaled treprostinil had multiple progression events compared with those receiving the placebo (35 vs. 58, 22% vs. 36%; P = 0.005). Conclusions: Patients who received inhaled treprostinil were significantly less likely to experience further disease progression events after an initial event compared with patients receiving placebo. These results support the continuation of inhaled treprostinil despite the occurrence of disease progression in clinical practice.


Sideways adiabaticity: beyond ray optics for slowly varying metasurfaces.
Optical metasurfaces (subwavelength-patterned surfaces typically described by variable effective surface impedances) are typically modeled by an approximation akin to ray optics: the reflection or transmission of an incident wave at each point of the surface is computed as if the surface were "locally uniform," and then the total field is obtained by summing all of these local scattered fields via a Huygens principle. (Similar approximations are found in scalar diffraction theory and in ray optics for curved surfaces.) In this paper, we develop a precise theory of such approximations for variable-impedance surfaces. Not only do we obtain a type of adiabatic theorem showing that the "zeroth-order" locally uniform approximation converges in the limit as the surface varies more and more slowly, including a way to quantify the rate of convergence, but we also obtain an infinite series of higher-order corrections. These corrections, which can be computed to any desired order by performing integral operations on the surface fields, allow rapidly varying surfaces to be modeled with arbitrary accuracy, and also allow one to validate designs based on the zeroth-order approximation (which is often surprisingly accurate) without resorting to expensive brute-force Maxwell solvers. We show that our formulation works arbitrarily close to the surface, and can even compute coupling to guided modes, whereas in the far-field limit our zeroth-order result simplifies to an expression similar to what has been used by other authors.


Role of personality self-organization in development of mental order and disorder.
Normal and abnormal personality development can be quantified in terms of 15 specific steps in the self-organization of character as a complex adaptive system. Character is measured as three dimensions of Self-directedness, Cooperativeness, and Self-transcendence, each with five components corresponding to steps in personality development. Each of these steps is differentially influenced by heritable temperament dimensions, antecedent steps in character development, and life experiences. Predictions about the nonlinear dynamics of personality development, such as equifinality and multifinality, are confirmed in longitudinal data about individuals representative of the general population. The stepwise development of character determines large differences between individuals in their risk of psychopathology, as well as varying degrees of maturity and health.


Muscle RING finger-1 attenuates IGF-I-dependent cardiomyocyte hypertrophy by inhibiting JNK signaling.
Recent studies implicate the muscle-specific ubiquitin ligase muscle RING finger-1 (MuRF1) in inhibiting pathological cardiomyocyte growth in vivo by inhibiting the transcription factor SRF. These studies led us to hypothesize that MuRF1 similarly inhibits insulin-like growth factor-I (IGF-I)-mediated physiological cardiomyocyte growth. We identified two lines of evidence to support this hypothesis: IGF-I stimulation of cardiac-derived cells with MuRF1 knockdown 1) exhibited an exaggerated hypertrophy and, 2) conversely, increased MuRF1 expression-abolished IGF-I-dependent cardiomyocyte growth. Enhanced hypertrophy with MuRF1 knockdown was accompanied by increases in Akt-regulated gene expression. Unexpectedly, MuRF1 inhibition of this gene expression profile was not a result of differences in p-Akt. Instead, we found that MuRF1 inhibits total protein levels of Akt, GSK-3β (downstream of Akt), and mTOR while limiting c-Jun protein expression, a mechanism recently shown to govern Akt, GSK-3β, and mTOR activities and expression. These findings establish that MuRF1 inhibits IGF-I signaling by restricting c-Jun activity, a novel mechanism recently identified in the context of ischemia-reperfusion injury. Since IGF-I regulates exercise-mediated physiological cardiac growth, we challenged MuRF1(-/-) and MuRF1-Tg+ mice and their wild-type sibling controls to 5 wk of voluntary wheel running. MuRF1(-/-) cardiac growth was increased significantly over wild-type control; conversely, the enhanced exercise-induced cardiac growth was lost in MuRF1-Tg+ animals. These studies demonstrate that MuRF1-dependent attenuation of IGF-I signaling via c-Jun is applicable in vivo and establish that further understanding of this novel mechanism may be crucial in the development of therapies targeting IGF-I signaling.


Does anodyne light therapy improve peripheral neuropathy in diabetes? A double-blind, sham-controlled, randomized trial to evaluate monochromatic infrared photoenergy.
The purpose of this study was to determine the efficacy of anodyne monochromatic infrared photo energy (MIRE) in-home treatments over a 90-day period to improve peripheral sensation and self-reported quality of life in individuals with diabetes. This was a double-blind, randomized, sham-controlled clinical trail. We randomly assigned 69 individuals with diabetes and a vibration perception threshold (VPT) between 20 and 45 V to two treatment groups: active or sham treatment. Sixty patients (120 limbs) completed the study. Anodyne units were used at home every day for 40 min for 90 days. We evaluated nerve conduction velocities, VPT, Semmes-Weinstein monofilaments (SWM) (4-, 10-, 26-, and 60-g monofilaments), the Michigan Neuropathy Screening Instrument (MNSI), a 10-cm visual analog pain scale, and a neuropathy-specific quality of life instrument. We used a nested repeated-measures multiple ANOVA design. Two sites (great toe and fifth metatarsal) were tested on both the left and right feet of each patient, so two feet were nested within each patient and two sites were nested within each foot. To analyze the ordinal SWM scores, we used a nonparametric factorial analysis for longitudinal data. There were no significant differences in measures for quality of life, MNSI, VPT, SWM, or nerve conduction velocities in active or sham treatment groups (P > 0.05). Anodyne MIRE therapy was no more effective than sham therapy in the treatment of sensory neuropathy in individuals with diabetes.


Multicenter validation of FIB-6 as a novel machine learning non-invasive score to rule out liver cirrhosis in biopsy-proven MAFLD.
We previously developed and validated a non-invasive diagnostic index based on routine laboratory parameters for predicting the stage of hepatic fibrosis in patients with chronic hepatitis C (CHC) called FIB-6 through machine learning with random forests algorithm using retrospective data of 7238 biopsy-proven CHC patients. Our aim is to validate this novel score in patients with metabolic dysfunction-associated fatty liver disease (MAFLD). Performance of the new score was externally validated in cohorts from one site in Egypt (n = 674) and in 5 different countries (n = 1798) in Iran, KSA, Greece, Turkey and Oman. Experienced pathologists using METAVIR scoring system scored the biopsy samples. Results were compared with FIB-4, APRI, and AAR. A total of 2472 and their liver biopsy results were included, using the optimal cutoffs of FIB-6 indicated a reliable performance in diagnosing cirrhosis, severe fibrosis, and significant fibrosis with sensitivity = 70.5%, specificity = 62.9%. PPV = 15.0% and NPV = 95.8% for diagnosis of cirrhosis. For diagnosis of severe fibrosis (F3 and F4), the results were 86.5%, 24.0%, 15.1% and 91.9% respectively, while for diagnosis of significant fibrosis (F2, F3 and F4), the results were 87.0%, 16.4%, 24.8% and 80.0%). Comparing the results of FIB-6 rule-out cutoffs with those of FIB-4, APRI, and AAR, FIB-6 had the highest sensitivity and NPV (97.0% and 94.7%), as compared to FIB-4 (71.6% and 94.7%), APRI (36.4% and 90.7%), and AAR (61.2% and 90.9%). FIB-6 score is an accurate, simple, NIT for ruling out advanced fibrosis and liver cirrhosis in patients with MAFLD.


'He is now like a brother, I can even give him some blood'--relational ethics and material exchanges in a malaria vaccine 'trial community' in The Gambia.
This paper explores social relations within the 'trial community' (staff and volunteers) of a Malaria Vaccine Trial (MVT), implemented by the Medical Research Council (MRC) in The Gambia between 2001 and 2004. It situates ethical concerns with medical research within the everyday life of scientific fieldwork. Based upon discussions with volunteers and staff, we explore processes of mediation between scientific project and study population, and between formal ethics, local ethical debates and everyday practice. We observe that material contact and substantial transactions, notably of blood and medicine, are central to the construction of the MVT. These transactions are guided by a concrete and relational form of ethics, which contrasts with the abstract and vertical formal ethical principles underwriting the scientific study protocol. The success of the MVT owed much to these kinship-like ethics. One possible conclusion from these observations is that research ethics should be understood, not just as a quasi-legal frame but also as an open, searching movement, much in the same way that kinship is not merely a juridical institution and a prescriptive frame of rules, but a network made through relational work. However, this conclusion raises new problems: by contrasting formal, abstract principles to intimate, immediate relations, and economic justice to personal morality, we accept that the order of medical research is moved further out of the public and political, and into the domains of either quasi-legal claims or of private morality. Irrespective of the undeniable importance of clear-cut rules and of good face-to-face relations, a third essential foundation of medical research ethics is the democratically constituted public sphere, including equitable health services, and transparent institutions to facilitate open debate and regulate particular interests. Ultimately, the ethics of global science can rely neither on principles nor trust but requires citizenship and democratic government.


Owner experiences and complications with home use of a replacement low profile gastrostomy device for long-term enteral feeding in dogs.
The purpose of this study was to evaluate complications and owner impressions of a low profile gastrostomy device (LPGD) for enteral feeding in dogs. Medical records of dogs that had placement of a percutaneous endoscopic gastrostomy tube followed by a LPGD between 1995 and 2003 were reviewed. Fifteen dogs had 29 devices placed for a variety of disease states in which enteral nutritional support was indicated. The individual tubes were placed for a median duration of 212 d. Most complications occurred more than 15 d after placement and were of no health risk to the animals. The most common reason for LPGD replacement was leakage through the 1-way antireflux valve. Fourteen of 15 owners that were contacted were supportive of the device. Based on its durability, ease of placement, minor complications, and positive owner impressions, we conclude that the LPGD is a valuable device for long-term enteral nutritional support of dogs.


Integrating mental health services into primary care for HIV-infected pregnant and non-pregnant women: Whole Life--a theoretically derived model for clinical care and outcomes assessment.
Poor women of color who are disproportionately both infected and affected by HIV/AIDS also face multiple lifestyle and psychosocial burdens that complicate effective delivery of health care, thereby contributing to their poorer prognosis. Addressing these factors within the context of HIV/AIDS primary care for women is the aim of Whole Life, a program to integrate mental health services into primary care for HIV-infected pregnant and non-pregnant women. Whole Life utilizes a theoretically derived clinical services model that provides data for both clinical care and patient outcomes research within the constraints of a clinical setting. During a woman's first two clinic visits, data are gathered in structured interviews with standardized instruments-adapted for relevance to the population-that meet clinical and service needs, as well as measure components of the Whole Life model. Interviews are conducted by existing front-line staff who have been trained in using these instruments to gather information typically recorded in clinical notes. The implementation of Whole Life to date clearly demonstrates the feasibility of mental health-primary care services integration in a publicly funded HIV primary care clinic serving poor women of color.


A rapid survey technique for detection of leprosy.
Comparison of prevalence rates of leprosy as assessed by a rapid survey technique, in which only the exposed parts of the body were examined, with that assessed by a routine total body examination in a population of about 700, showed that most cases of leprosy were detected by the former.


Correlation between surgical manipulations and the variation of surgeon's heart rate in brain surgery: technical note.
For improvement of surgical performance and safety, we record surgeries by video cameras. However, analysis of the video records is time consuming. To help this task, we are developing methods to automatically mark up significant time points in the surgery. As a possible mean for the marking, we focused on the surgeon's heart rate. During a craniotomy of an intracranial glioma, we recorded the surgeon's electrocardiogram using a telemeter and measured the R-to-R interval (RRI). We detected the stable state of heart rate as a peak-to-peak RRI of less than 5% of the mean of RRI data from 15 consecutive heartbeats. We also quantified the frequency of brain touches by the surgeon under the surgical microscope. We examined the association between the stability of surgeon's heart rate and the brain touches using a chi-square test. As the result, the stable state of surgeon's heart rate was associated with the brain touches (p < 0.05, odds ratio 5.1). We edited a one-minute digest video of the surgery based on only the heart rate data, and it was sufficient to understand how the surgery was preceded.


The suffering stranger: medical anthropology and international morality.
Addressing global inequities has come to define a domain of activist medical anthropology called social justice studies. In a recent flagship volume, Dying for Growth: Global Inequality and the Health of the Poor, contributors describe the effect of global economic trends and neoliberal policies on the destitute and disadvantaged. In their advocacy, they use the voices and stories of the poor to explain the impact of structural adjustments. This paper uses Dying for Growth as an example through which to comment on the wider scholarly trend of using the local to validate global claims. The term "suffering stranger" describes those iconic figures whose experiences are presented in truncated first-hand accounts of suffering in order to validate broader theoretical aims. I argue that the suffering stranger masks the real absence of the voices of the poor and their suffering on the world stage. There is no international public sphere within which these voices might be heard; rather, there is a set of claims about justice and human rights. These claims, however, are themselves rooted in cultural values and are inextricably woven into global capital. I argue that, in using the voices of suffering to further a theoretical agenda, social justice activists assume the existence of a public, international domain within which those voices might be heard and that, in so doing, they further integrate the poor into destructive economic systems. Alongside the work of documenting health inequities, a truly effective activism may require assessing and critiquing existing claims of international morality.


Circulating Lipids and Acute Pain Sensitization: An Exploratory Analysis.
In individuals with low back pain, higher lipid levels have been documented and were associated with increased risk for chronic low back pain. The purpose of this research was to identify plasma lipids that discriminate participants with acute low back pain with or without pain sensitization as measured by quantitative sensory testing. This exploratory study was conducted as part of a larger parent randomized controlled trial. A cluster analysis of 30 participants with acute low back pain revealed two clusters: one with signs of peripheral and central sensitivity to mechanical and thermal stimuli and the other with an absence of peripheral and central sensitivity. Lipid levels were extracted from plasma and measured using mass spectroscopy. Triacylglycerol 50:2 was significantly higher in participants with peripheral and central sensitization compared to the nonsensitized cluster. The nonsensitized cluster had significantly higher levels of phosphoglyceride 34:2, plasmenyl phosphocholine 38:1, and phosphatidic acid 28:1 compared to participants with peripheral and central sensitization. Linear discriminant function analysis was conducted using the four statistically significant lipids to test their predictive power to classify those in the sensitization and no-sensitization clusters; the four lipids accurately predicted cluster classification 58% of the time (R = .58, -2 log likelihood = 14.59). The results of this exploratory study suggest a unique lipidomic signature in plasma of patients with acute low back pain based on the presence or absence of pain sensitization. Future work to replicate these preliminary findings is underway.


A critique of Bernstein's beyond objectivism and relativism: science, hermeneutics, and praxis.
This analysis comments on Bernstein's lack of clear understanding of subjectivity, based on his book, Beyond Objectivism and Relativism: Science, Hermeneutics, and Praxis. Bernstein limits his interpretation of subjectivity to thinkers such as Gadamer and Habermas. The authors analyze the ideas of classic scholars such as Edmund Husserl and Friedrich Nietzsche. Husserl put forward his notion of transcendental subjectivity and phenomenological ramifications of the relationship between subjectivity and objectivity. Nietzsche referred to subjectivity as "perspectivism," the inescapable fact that any and all consciousnesses exist in space and time. Consciousness is fundamentally constituted of cultural, linguistic, and historical dimensions.


Metachronous testicular tumor developing eight years after retroperitoneal extragonadal germ cell tumor.
A 30 year-old man was admitted to our hospital with a chief complaint of left flank pain. Computed tomography revealed a retroperitoneal tumor. Levels of lactic dehydrogenase, human beta-chorionic gonadotropin, alpha-fetoprotein, DUPAN-2 and carbohydrate antigen 19-9 were elevated. No abnormal findings were present according to palpation and ultrasonography of the testes. The patient was diagnosed as having a retroperitoneal extragonadal germ cell tumor (EGCT) considering the elevated markers. Resection of the tumor, two cycles of neoadjuvant and one cycle of adjuvant chemotherapy (cisplatin and etoposide) were performed. The surgical specimen showed total necrotic tissue. Eight years later, the patient noticed an enlargement of his left testicle. The tumor felt elastic and firm on his left testis. Neither distant metastasis nor lymph node metastasis was present according to computed tomography. Left high orchiectomy was performed and histology revealed seminoma. Twenty-three cases have been reported previously about metachronous testicular tumor developing after retroperitoneal EGCT. We report the 24th case.


Human anticardiolipin monoclonal autoantibodies cause placental necrosis and fetal loss in BALB/c mice.
To analyze the structure, specificity, and in vivo pathogenetic potential of 2 human anticardiolipin (aCL) monoclonal antibodies (MAb). Human aCL IgG MAb were generated from hybridized Epstein-Barr virus-induced B cell lines from a healthy subject (MAb 519) and from a patient with primary antiphospholipid syndrome (MAb 516). Studies of antigen-binding specificity and analysis of Ig V-gene mutations were carried out. The MAb were independently injected into mated female BALB/c mice, and their effect on pregnancy outcome was compared with that of MAb 57, a highly mutated and antigen-selected human IgG1lambda rabies virus antibody. Both MAb 519 and MAb 516 utilized minimally mutated V(H)DJ(H) and VkappaJkappa gene segments and bound cardiolipin and other anionic phospholipids in the absence of beta2-glycoprotein I (beta2-GPI). The mice injected with aCL MAb displayed a significantly higher rate of fetal resorption and a significant reduction in fetal and placental weight as compared with those injected with MAb 57. These findings were accompanied by a finding of placental human IgG deposition and necrosis in the aCL MAb-treated animals. The results of this study indicate that human aCL IgG that are beta2-GPI independent can induce pathology.


Hypoxia Induces Alterations in the Circadian Rhythm in Patients with Chronic Respiratory Diseases.
The function of the circadian cycle is to determine the natural 24 h biological rhythm, which includes physiological, metabolic, and hormonal changes that occur daily in the body. This cycle is controlled by an internal biological clock that is present in the body's tissues and helps regulate various processes such as sleeping, eating, and others. Interestingly, animal models have provided enough evidence to assume that the alteration in the circadian system leads to the appearance of numerous diseases. Alterations in breathing patterns in lung diseases can modify oxygenation and the circadian cycles; however, the response mechanisms to hypoxia and their relationship with the clock genes are not fully understood. Hypoxia is a condition in which the lack of adequate oxygenation promotes adaptation mechanisms and is related to several genes that regulate the circadian cycles, the latter because hypoxia alters the production of melatonin and brain physiology. Additionally, the lack of oxygen alters the expression of clock genes, leading to an alteration in the regularity and precision of the circadian cycle. In this sense, hypoxia is a hallmark of a wide variety of lung diseases. In the present work, we intended to review the functional repercussions of hypoxia in the presence of asthma, chronic obstructive sleep apnea, lung cancer, idiopathic pulmonary fibrosis, obstructive sleep apnea, influenza, and COVID-19 and its repercussions on the circadian cycles.


Chemokine receptor expression on resident and inflammatory cells in the brain of macaques with simian immunodeficiency virus encephalitis.
Although the mechanisms of human immunodeficiency virus (HIV) neuroinvasion, neuronal injury, and subsequent development of HIV-1-associated AIDS dementia complex are not fully understood, a correlation between monocyte/macrophage infiltrates in the brain and neurological disease exists. In light of the many potential roles that chemokines and chemokine receptors may play in HIV neuropathogenesis, we sought to describe their pattern of expression in the SIV-infected rhesus macaque model of HIV encephalitis. We previously demonstrated elevated expression of the chemokines macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, RANTES, and interferon-inducible protein (IP)-10 in brain of macaque monkeys with SIV encephalitis. In this study, we demonstrate that the corresponding chemokine receptors CCR3, CCR5, CXCR3, and CXCR4 are expressed in perivascular infiltrates in these same tissues. In addition, we detected CCR3, CCR5, and CXCR4 on subpopulations of large hippocampal and neocortical pyramidal neurons and on glial cells in both normal and encephalitic brain. These findings suggest that multiple chemokines and their receptors contribute to monocyte and lymphocyte recruitment to the brain in SIV encephalitis. Furthermore, the expression of known HIV/SIV co-receptors on neurons suggests a possible mechanism whereby HIV or SIV can directly interact with these cells, disrupting their normal physiological function and contributing to the pathogenesis of AIDS dementia complex.


Numerical modeling of stress in stenotic arteries with microcalcifications: a micromechanical approximation.
Most finite element models of atherosclerotic arteries do not account for the heterogeneity of the plaque constituents at the microscale. Failure of plaque lesions has been shown to be a local event, linked to stress concentrations caused by cap thinning, inflammation, macroscopic heterogeneity, and recently, the presence of microcalcifications. There is growing evidence that microcalcifications exist in the fibrous cap of plaque lesions. However, their role is not yet fully understood. The goal of the present work is to investigate the effects of localized regions of microcalcifications on the stress field of atherosclerotic plaque caps in a section of carotid artery. This is achieved by performing finite element simulations of three-dimensional fluid-structure interaction models. The material response in the region of microcalcification is modeled using a combination of finite elements, homogenization theory, and a stress concentration function that approximates the average local stresses in the fibrous tissue and microcalcification phases. The results indicate that the circumferential stress in the fibrous tissue phase increases as the volume fraction of microcalcifications is increased, and that the stress exceeds a critical threshold when the fibrous cap thickness is decreased. Furthermore, the presence of the microcalcifications significantly influences the distribution of stress by shifting the maximum circumferential stress away from the cap shoulders, where failure is most common when the effective region of microcalcification is located at the center of the cap. This is a possible explanation of why 40% of plaque ruptures occur away from the shoulder region of the cap.


MicroRNA-144-3p inhibits cell proliferation and promotes apoptosis in castration-resistant prostate cancer by targeting CEP55.
MicroRNA-144-3p (miR-144-3p) has been implicated in the tumorigenesis of multiple types of cancer. However, its role in castration-resistant prostate cancer (CRPC) remains largely unknown. This study aimed to explore the biological role of miR-144-3p in the development of CRPC. RT-qPCR was performed to measure the expression levels of miR-144-3p in CRPC tissues. CRPC cells were transfected with miR-144-3p or NC. MTT and colony formation assays were used to determine cell growth; flow cytometry was used to measure apoptosis; a luciferase reporter assay was used to predict the target genes regulated by miR-144-3p. Finally, siCEP55 or siNC was transfected into DU145 cells, and the rates of cell proliferation and apoptosis were measured. Protein expression levels were confirmed by Western blot analysis. MiR-144-3p expression was significantly decreased in both CRPC tissues and cell lines compared with that from androgen-dependent prostate cancer (ADPC) tumors. Overexpression of miR-144-3p in CRPC cells effectively inhibited proliferation and colony formation and promoted apoptosis in these CRPC cells. Additionally, miR-144-3p directly targeted centrosomal protein 55 (CEP55) and suppressed CEP55 expression. Finally, CEP55 silencing remarkably suppressed proliferation and induced apoptosis of CRPC cells, indicating that miR-144-3p affects CRPC cell survival and proliferation by downregulating CEP55. MiR-144-3p serves as a tumor suppressor in CRPC cells by directly targeting CEP55, which appears to be a novel therapeutic target for CRPC.


Corticosteroid Therapy in Combination with Antibiotics for Erysipelas.
Erysipelas, an acute infection of the dermal and subcutaneous tissue, is normally treated with antibiotics. Previous data indicated that treatment with prednisone in combination with antibiotics results in significant acceleration of the healing phase. To investigate the effectiveness of corticosteroids combined with antibiotics for the treatment of erysipelas. A retrospective study was conducted on hospitalized patients diagnosed with erysipelas between 2004 and 2011 at the Department of Dermatology at Sheba Medical Center, Israel. Data included epidemiology, medical background, and course of the disease as documented at admission and during hospitalization. Data were collected on 173 patients (66% males) who were divided into two groups: a control group treated with antibiotics only (97 patients) and a study group treated with antibiotics and prednisone (76 patients). The study group presented with a more severe form of erysipelas (bullous) and those patients were hospitalized for a longer period (8.5 vs. 7 days). Nevertheless, the study group exhibited a 71% clinical improvement shortly after being treated with prednisone, without significant side effects. Short-term follow-up revealed more edema in the study group; however, long-term follow-up revealed a higher incidence of erythema and recurrence of erysipelas in the control group. The return to full function was faster in the study group than in the control group. Combining prednisone with antibiotics for the treatment of erysipelas should be considered, especially in severe cases. In addition, a prospective double-blind study should be conducted to verify these conclusions.


A flat Universe from high-resolution maps of the cosmic microwave background radiation
The blackbody radiation left over from the Big Bang has been transformed by the expansion of the Universe into the nearly isotropic 2.73 K cosmic microwave background. Tiny inhomogeneities in the early Universe left their imprint on the microwave background in the form of small anisotropies in its temperature. These anisotropies contain information about basic cosmological parameters, particularly the total energy density and curvature of the Universe. Here we report the first images of resolved structure in the microwave background anisotropies over a significant part of the sky. Maps at four frequencies clearly distinguish the microwave background from foreground emission. We compute the angular power spectrum of the microwave background, and find a peak at Legendre multipole Ipeak = (197 +/- 6), with an amplitude delta T200 = (69 +/- 8) microK. This is consistent with that expected for cold dark matter models in a flat (euclidean) Universe, as favoured by standard inflationary models.


Endoscopic treatment of chronic radiation proctopathy.
Chronic radiation proctopathy is a complication of pelvic radiation therapy. The acute phase of radiation injury to the rectum occurs during or up to 3 months following radiation. Acute radiation injury can continue into a chronic phase or chronic radiation proctopathy may develop after a latent period of several months or years. Symptoms associated with the condition include diarrhea, rectal pain, bleeding, tenesmus, and stricture formation. Of the various symptoms, only bleeding from radiation-induced telangiectasias is amenable to endoscopic therapy. This paper summarizes the findings of experts in the field on endoscopic treatment of bleeding from chronic radiation proctopathy. Medical management is generally ineffective in controlling bleeding from chronic radiation proctopathy. Surgical intervention has a high incidence of morbidity. Promising advances have been made in endoscopic therapy, including formalin, neodymium/yttrium aluminum garnet, argon and potassium titanyl phosphate laser treatments, as well as argon plasma coagulation. Argon plasma coagulation presents an effective, efficient, inexpensive and reasonably safe noncontact method for destruction of radiation telangiectasias. Based on currently available data and trends, argon plasma coagulation is the favored treatment for bleeding from chronic radiation proctopathy.


Immunopathological studies on guinea pigs experimentally infected with Egyptian strain of Leishmania d. infantum.
Forty Guinea pigs were experimentally infected with Egyptian strain of Leishmania d. infantum. At necropsy, materials for histopathological studies were taken from spleen, liver & lymph nodes and for smears from the same organs and bone marrow as well. Also, serum samples were examined for the elevation of immunoglobulins (IgG., IgM. & IgA.). Amastigotes of Leishmania parasites were demonstrated in the kupffer cells in the liver and in the macrophages in the spleen and lymph nodes as well as the smears of the bone marrow. The immunoglobulins showed varying levels. The IgG increased with the decrease in number of tissue amastigotes. The splenic materials were positive in all the experimentally infected Guinea pigs which means that splenic puncture is the best method of diagnosing VL. However, it may be dangerous in soft spleen. The results were photographed and discussed.


The quaternary geological history of the Santa Catarina Southeastern Region (Brazil).
This paper supply subsidies for Quaternary geological reconstruction of the southeastern State of Santa Catarina coast in Brazil, being based on detailed geological mapping supported by a series of drilling data, which allowed to establish a stratigraphical hierarchy of the sedimentary deposits. Among the mapped geological units stand out the extensive Pleistocene shallow marine sandy sediments, which are commonly referred as a barrier island - lagoonal depositional system. A drilling campaign done in the domain permitted the sampling of material for 14C datings, and the obtained data confirmed some previously assumed ages. The sequence of events, that originated the Holocene deposits, has been also reconstructed through drilling and 14C dating of the collected peat and shell samples. Finally, the main characteristics of the most promising mineral prospect of the area, represented by voluminous calcareous shell deposits associated with Holocene sediments, are also presented.


The acetyltransferase activity of CBP is required for wingless activation and H4 acetylation in Drosophila melanogaster.
CBP is a critical coactivator of transcription, but little is understood about the importance of its intrinsic acetyltransferase (AT) activity in gene activation in vivo. We show that the intrinsic AT function of CBP in Drosophila melanogaster (dCBP) is necessary to maintain a dCBP overexpression phenotype in the eye, for the in vivo activation of a specific target gene, wingless, and for the global acetylation of histone H4. These findings indicate that a point mutation which alters the intrinsic AT activity of CBP (only one of many CBP functions) has profound effects on CBP-induced gene activation in a physiologically intact transcription system. Furthermore, the effects of CBP AT activity are not limited to a few specific promoters, but rather CBT AT activity may play a role in regulating global histone acetylation throughout the developing organism.


Core formation and the acquisition of fusion competence are linked during secretory granule maturation in Tetrahymena.
The formation of dense core secretory granules is a multistage process beginning in the trans Golgi network and continuing during a period of granule maturation. Direct interactions between proteins in the membrane and those in the forming dense core may be important for sorting during this process, as well as for organizing membrane proteins in mature granules. We have isolated two mutants in dense core granule formation in the ciliate Tetrahymena thermophila, an organism in which this pathway is genetically accessible. The mutants lie in two distinct genes but have similar phenotypes, marked by accumulation of a set of granule cargo markers in intracellular vesicles resembling immature secretory granules. Sorting to these vesicles appears specific, since they do not contain detectable levels of an extraneous secretory marker. The mutants were initially identified on the basis of aberrant proprotein processing, but also showed defects in the docking of the immature granules. These defects, in core assembly and docking, were similarly conditional with respect to growth conditions, and therefore are likely to be tightly linked. In starved cells, the processing defect was less severe, and the immature granules could dock but still did not undergo stimulated exocytosis. We identified a lumenal protein that localizes to the docking-competent end of wildtype granules, but which is delocalized in the mutants. Our results suggest that dense cores have functionally distinct domains that may be important for organizing membrane proteins involved in docking and fusion.


Polymyalgia rheumatica without significantly increased erythrocyte sedimentation rate. A more benign syndrome.
An erythrocyte sedimentation rate (ESR) of at least 40 mm/h is considered an important requisite for the diagnosis of polymyalgia rheumatica (PMR). However, the relative frequency and clinical features of PMR in patients without a significantly increased ESR are unclear. We performed a retrospective study of patients diagnosed as having PMR at the rheumatology divisions of 3 teaching hospitals. The diagnosis of PMR was established, regardless of the ESR, in 201 consecutive patients fulfilling the following criteria: (1) age 50 years or older, (2) severe proximal pain for more than 1 month in at least 2 of 3 areas: neck, shoulder, and/or pelvic girdles, and (3) rapid resolution of the syndrome while taking low-dose prednisone. Patients with giant cell arteritis were previously excluded from the study. The frequency and clinical features of patients with PMR and an ESR lower than 40 mm/h were analyzed. A comparative study between these patients and those with high ESRs was performed. An ESR lower than 40 mm/h was found in 41 patients (20.4%). These patients were younger (P = .02), were more frequently men (P = .006), and experienced a lower frequency of fever (P = .003) and weight loss (P = .07). Furthermore, these patients were characterized by an absence of anemia (P = .002) and a lower frequency of abnormal protein electrophoresis results (P < .001). Otherwise, their clinical syndrome, response to therapy, and frequency of relapses were similar to those of patients with classic PMR. In the entire population of 201 patients, the ESR was related to the length of treatment, number of areas involved, presence of fever, weight loss, and laboratory test result abnormalities, but it was unrelated to the duration of the illness prior to diagnosis. It is not uncommon to find a patient with PMR with an ESR lower than 40 mm/h. This syndrome is more frequent in men and it is clinically less severe than the classic form of PMR. Its recognition will allow these patients to benefit from an effective treatment with low-dose corticosteroids.


DNA adducts produced by oils, oil fractions and polycyclic aromatic hydrocarbons in relation to repair processes and skin carcinogenesis.
Ten polycyclic aromatic hydrocarbons (PAHs) mainly with three or four aromatic rings were tested for their ability to induce DNA adduct formation in mouse skin. Four of these were selected to investigate adduct formation and loss over a period of 8 days. Three mineral oils were also examined for their adduct forming ability and one was selected for adduct formation and loss over a period of 8 days. In addition, fractions derived from the same oil containing 2-3- and 4-6-ring aromatic compounds were applied to mouse skin in a non-carcinogenic oil vehicle and adduct levels were observed over an 8-day period. It was found that PAHs that had no mutagenic, initiating or carcinogenic activity and those that had mutagenic activity in bacteria but no initiating activity in mouse skin failed to produce DNA adducts in mouse skin. Two of the three PAHs with initiating activity and both complete carcinogens produced clear evidence of adduct formation, the adduct levels produced by complete carcinogens being 100-1000 times greater than those produced by initiators. Examination of adduct formation and loss with the carcinogenic PAHs benzo[a]pyrene and 5-methylchrysene over an 8-day period showed a peak at 24 h and an apparent two-phase process of adduct loss. It is suggested that the first steep loss was due to DNA repair and that the more gradual subsequent loss was probably due to epidermal hyperplasia and desquamation. With the initiator 1, 4-dimethylphenanthrene (three rings) a peak of adduct formation was seen at 2 days and adduct levels were not reduced much by 8 days. This suggested that, with initiators, adduct formation and repair may be spread over a longer period than with complete carcinogens. With the whole oils, clear evidence of adduct formation was seen with both a carcinogenic non-solvent-refined oil and with a non-carcinogenic residual oil. The level of adduct formation with the residual oil, however, was much lower than with the carcinogenic oil. When adduct formation by the carcinogenic oil was examined over 8 days, the pattern of adduct formation and loss was similar to that of a tumour initiator rather than a complete carcinogen. Peak adduct levels on the diagonal of the thin-layer chromatography (TLC) plates seemed to occur at 1 and 4 days after treatment, with no clear reduction after 8 days. From examination of adducts formed by the 2-3-ring and 4-6-ring aromatic fractions, it appeared that the main adduct spots produced by the carcinogenic oil were due to the 2-3-ring aromatic components of the oil. Adduct spots near the vertical axis of the TLC plates were also seen with the 2-3-ring and 4-6-ring fractions. The relevance of these spots is uncertain, but if they truly represent adducts, the findings suggest that they are due mainly to 4-ring PAHs. The studies suggest that the activity of carcinogenic oils is largely due to substituted 3- and 4-ring polycyclic aromatic compounds and that more attention should be paid to substituted 3-ring compounds in predicting the carcinogenic potential of oils from analytical data.


Acceleration of Magnetic Resonance Fingerprinting Reconstruction Using Denoising and Self-Attention Pyramidal Convolutional Neural Network.
Magnetic resonance fingerprinting (MRF) based on echo-planar imaging (EPI) enables whole-brain imaging to rapidly obtain T1 and T2* relaxation time maps. Reconstructing parametric maps from the MRF scanned baselines by the inner-product method is computationally expensive. We aimed to accelerate the reconstruction of parametric maps for MRF-EPI by using a deep learning model. The proposed approach uses a two-stage model that first eliminates noise and then regresses the parametric maps. Parametric maps obtained by dictionary matching were used as a reference and compared with the prediction results of the two-stage model. MRF-EPI scans were collected from 32 subjects. The signal-to-noise ratio increased significantly after the noise removal by the denoising model. For prediction with scans in the testing dataset, the mean absolute percentage errors between the standard and the final two-stage model were 3.1%, 3.2%, and 1.9% for T1, and 2.6%, 2.3%, and 2.8% for T2* in gray matter, white matter, and lesion locations, respectively. Our proposed two-stage deep learning model can effectively remove noise and accurately reconstruct MRF-EPI parametric maps, increasing the speed of reconstruction and reducing the storage space required by dictionaries.


Immunogenicity of novel consensus-based DNA vaccines against Chikungunya virus.
Chikungunya virus (CHIKV) is an emerging arbovirus and is an important human pathogen. Infection of humans by CHIKV can cause a syndrome characterized by fever, headache, rash, nausea, vomiting, myalgia, arthralgia and occasionally neurological manifestations such as acute limb weakness. It is also associated with a fatal haemorrhagic condition. CHIKV is geographically distributed from Africa through Southeast Asia and South America, and its transmission to humans is mainly through the Aedes aegypti species mosquitoes. The frequency of recent epidemics in the Indian Ocean and La Reunion islands suggests that a new vector perhaps is carrying the virus, as A. aegypti are not found there. In fact, a relative the Asian tiger mosquito, Aedes albopictus, may be the culprit which has raised concerns in the world health community regarding the potential for a CHIK virus pandemic. Accordingly steps should be taken to develop methods for the control of CHIKV. Unfortunately, currently there is no specific treatment for Chikungunya virus and there is no vaccine currently available. Here we present data of a novel consensus-based approach to vaccine design for CHIKV, employing a DNA vaccine strategy. The vaccine cassette was designed based on CHIKV capsid- and envelope-specific consensus sequences with several modifications, including codon optimization, RNA optimization, the addition of a Kozak sequence, and a substituted immunoglobulin E leader sequence. The expression of capsid, envelope E1 and E1 was evaluated using T7-coupled transcription/translation and immunoblot analysis. A recently developed, adaptive constant-current electroporation technique was used to immunize C57BL/6 mice with an intramuscular injection of plasmid coding for the CHIK-Capsid, E1 and E2. Analysis of cellular immune responses, including epitope mapping, demonstrates that electroporation of these constructs induces both potent and broad cellular immunity. In addition, antibody ELISAs demonstrate that these synthetic immunogens are capable of inducing high titer antibodies capable of recognizing native antigen. Taken together, these data support further study of the use of consensus CHIK antigens in a potential vaccine cocktail.


One-step preservation of phosphoproteins and tissue morphology at room temperature for diagnostic and research specimens.
There is an urgent need to measure phosphorylated cell signaling proteins in cancer tissue for the individualization of molecular targeted kinase inhibitor therapy. However, phosphoproteins fluctuate rapidly following tissue procurement. Snap-freezing preserves phosphoproteins, but is unavailable in most clinics and compromises diagnostic morphology. Formalin fixation preserves tissue histomorphology, but penetrates tissue slowly, and is unsuitable for stabilizing phosphoproteins. We originated and evaluated a novel one-step biomarker and histology preservative (BHP) chemistry that stabilizes signaling protein phosphorylation and retains formalin-like tissue histomorphology with equivalent immunohistochemistry in a single paraffin block. Total protein yield extracted from BHP-fixed, routine paraffin-embedded mouse liver was 100% compared to snap-frozen tissue. The abundance of 14 phosphorylated proteins was found to be stable over extended fixation times in BHP fixed paraffin embedded human colon mucosa. Compared to matched snap-frozen tissue, 8 phosphoproteins were equally preserved in mouse liver, while AMPKβ1 Ser108 was slightly elevated after BHP fixation. More than 25 tissues from mouse, cat and human specimens were evaluated for preservation of histomorphology. Selected tissues were evaluated in a multi-site, independent pathology review. Tissue fixed with BHP showed equivalent preservation of cytoplasmic and membrane cytomorphology, with significantly better nuclear chromatin preservation by BHP compared to formalin. Immunohistochemical staining of 13 non-phosphorylated proteins, including estrogen receptor alpha, progesterone receptor, Ki-67 and Her2, was equal to or stronger in BHP compared to formalin. BHP demonstrated significantly improved immunohistochemical detection of phosphorylated proteins ERK Thr202/Tyr204, GSK3-α/β Ser21/Ser9, p38-MAPK Thr180/Tyr182, eIF4G Ser1108 and Acetyl-CoA Carboxylase Ser79. In a single paraffin block BHP preserved the phosphorylation state of several signaling proteins at a level comparable to snap-freezing, while maintaining the full diagnostic immunohistochemical and histomorphologic detail of formalin fixation. This new tissue fixative has the potential to greatly facilitate personalized medicine, biobanking, and phospho-proteomic research.


Limitations of outsourcing on-the-ground biodiversity conservation.
To counteract global species decline, modern biodiversity conservation engages in large projects, spends billions of dollars, and includes many organizations working simultaneously within regions. To add to this complexity, the conservation sector has hierarchical structure, where conservation actions are often outsourced by funders (foundations, government, etc.) to local organizations that work on-the-ground. In contrast, conservation science usually assumes that a single organization makes resource allocation decisions. This discrepancy calls for theory to understand how the expected biodiversity outcomes change when interactions between organizations are accounted for. Here, we used a game theoretic model to explore how biodiversity outcomes are affected by vertical and horizontal interactions between 3 conservation organizations: a funder that outsourced its actions and 2 local conservation organizations that work on-the-ground. Interactions between the organizations changed the spending decisions made by individual organizations, and thereby the magnitude and direction of the conservation benefits. We showed that funders would struggle to incentivize recipient organizations with set priorities to perform desired actions, even when they control substantial amounts of the funding and employ common contracting approaches to enhance outcomes. Instead, biodiversity outcomes depended on priority alignment across the organizations. Conservation outcomes for the funder were improved by strategic interactions when organizational priorities were well aligned, but decreased when priorities were misaligned. Meanwhile, local organizations had improved outcomes regardless of alignment due to additional funding in the system. Given that conservation often involves the aggregate actions of multiple organizations with different objectives, strategic interactions between organizations need to be considered if we are to predict possible outcomes of conservation programs or costs of achieving conservation targets.


Modeling the population level effects of an HIV-1 vaccine in an era of highly active antiretroviral therapy.
First generation HIV vaccines may have limited ability to prevent infection. Instead, they may delay the onset of AIDS or reduce the infectiousness of vaccinated individuals who become infected. To assess the population level effects of such a vaccine, we formulate a deterministic model for the spread of HIV in a homosexual population in which the use of highly active antiretroviral therapy (HAART) to treat HIV infection is incorporated. The basic reproduction number R(0) is obtained under this model. We then expand the model to include the potential effects of a prophylactic HIV vaccine. The reproduction number R(f) is derived for a population in which a fraction f of susceptible individuals is vaccinated and continues to benefit from vaccination. We define f(*) as the minimum vaccination fraction for which R(f )< or =1 and describe situations in which it equals the critical vaccination fraction necessary to eliminate disease. When R(0) is large or an HIV vaccine is only partially effective, the critical vaccination fraction may exceed one. HIV vaccination, however, may still reduce the prevalence of disease if the reduction in infectiousness is at least as great as the reduction in the rate of disease progression. In particular, a vaccine that reduces infectiousness during acute infection may have an important public health impact especially if coupled with counseling to reduce risky behavior.


Caregiver burden of patients with Huntington's disease in South Korea.
This is the first prospective cohort study of Huntington's disease (HD) in Korea. This study aimed to investigate caregiver burden in relation to the characteristics of patients and caregivers. From August 2020 to February 2022, we enrolled patients with HD from 13 university hospitals in Korea. We collected the 12-item Zarit Burden Interview (ZBI-12) to evaluate the caregiver burden. We evaluated the clinical associates of the ZBI-12 scores by the linear regression analysis and investigated the difference between the low and high burden groups. Sixty-five patients with HD and 45 caregivers have been enrolled in this cohort study so far. The average onset of motor symptoms was 49.3±12.3 years with the average (CAG)n of 42.9±4.0 (38-65). The ZBI-12 score in our caregivers were 17.6±14.2. The higher caregiver burden was associated with the more severe Shoulson and Fahn stages (p-value=0.038) of the patients. The higher ZBI-12 score was also associated with the lower independence scale (B=-0.154, p-value=0.006) and the functional capacity (B=-1.082, p-value=0.002) of patients. The caregiving duration was longer in the high than the low burden groups. Caregivers' demographic, blood-relation, and marital and social status did not affect the burden significantly. HD patient's neurological status exerts huge impact on the caregiver burden regardless of the demographic or social status of the caregiver. This study emphasizes the need of establishing optimal support system to HD family in Korea. A future longitudinal analysis could help us understand how disease progression aggravate the caregiver burden throughout the entire disease course.


A meta-analytic review of gender variations in adults' language use: talkativeness, affiliative speech, and assertive speech.
Three separate sets of meta-analyses were conducted of studies testing for gender differences in adults' talkativeness, affiliative speech, and assertive speech. Across independent samples, statistically significant but negligible average effects sizes were obtained with all three language constructs: Contrary to the prediction, men were more talkative (d = -.14) than were women. As expected, men used more assertive speech (d = .09), whereas women used more affiliative speech (d = .12). In addition, 17 moderator variables were tested that included aspects of the interactive context (e.g., familiarity, gender composition, activity), measurement qualities (e.g., operational definition, observation length), and publication characteristics (e.g., author gender, publication source). Depending on particular moderators, more meaningful effect sizes (d > .2) occurred for each language construct. In addition, the direction of some gender differences was significantly reversed under particular conditions. The results are interpreted in relation to social-constructionist, socialization, and biological interpretations of gender-related variations in social behavior.


5-aminoimidazole-4-carboxamide-1-beta-ribofuranoside (AICAR) prevents nuclear translocation of constitutive androstane receptor by AMP-activated protein kinase (AMPK) independent manner.
The nuclear receptor superfamily consists of ligand-dependent transcription factors. Among them, constitutive androstane receptor (CAR) plays a key role in the detoxification of xenobiotics, inducing various drug-metabolizing enzymes including human CYP2B6 and its homologues of other species. AMP-activated protein kinase (AMPK) acts as an important energy sensor, being activated by an increased AMP/ATP ratio. CAR is activated by phenobarbital (PB) treatment. It has been recently reported that AMPK is involved in PB-mediated CYP2B induction both in vitro and in vivo. We investigated the relationship between the functions of AMPK and CAR in rat primary hepatocyte. The AMPK-activator 5-aminoimidazole-4-Carboxamide-1-beta-Ribofuranoside (AICAR) unexpectedly repressed PB-induced CYP2B mRNA expression as well as AMPK-inhibitor compound C. In contrast, both the AMPK-activator metformin and the constitutive active form of AMPK enhanced PB-induced PB-responsive enhancer module-driven reporter gene expression. We demonstrated that AICAR prevented nuclear translocation of CAR in an AMPK-independent manner in rat primary hepatocytes. AICAR might be a convenient probe for studying the mechanisms of PB-induced activation, especially nuclear translocation, of CAR in rat primary hepatocytes.


Increased accumulation of methotrexate by murine tumor cells in vitro in the presence of probenecid which is mediated by a preferential inhibition of efflux.
Carrier-mediated influx and efflux of [3H]methotrexate by L1210 leukemia cells was inhibited by probenecid. The concentration of probenecid required for inhibition of influx was markedly greater than that required to inhibit efflux. The concentration determined for 50% inhibition of influx was 1.35 +/- 0.15 (S.D.) mM. Inhibition of this flux was competitive (Ki = 1.23 +/- 0.2 mM) and was reversed after removal of probenecid. In contrast, the concentration determined for 50% inhibition of efflux was only 0.12 +/- 0.016 mM, and inhibition was also reversed after removal of probenecid. As a consequence of the different extent of inhibition of each flux by probenecid, the level of intracellular [3H]methotrexate at steady state was markedly increased. At 0.1 and 1 mM probenecid, the steady state level was increased 2- and 2.6-fold, respectively. These observed increases are in close agreement with that expected from the effect on each flux at these concentrations. From other data on the inhibition of each flux at higher concentrations of probenecid, a maximum effect (3- to 4-fold increase) in steady-state level would be expected at a probenecid concentration between 2 and 3 mM. A similar relationship between the inhibition by probenecid of influx and efflux of [3H]methotrexate was also shown for Sarcoma 180 and Ehrlich carcinoma cells. These results have pharmacological implications with respect to the adjuvant use of probenecid or related organic ions during folate analog therapy of human cancer.


[Patterns of mechanical stress at the successive stages of early development of frog].
The immediate relaxation deformations have been studied in the embryonic frog tissues from the late blastula stage till the early tail bud stage. As a result, the maps of mechanical stresses were constructed which were characterized by the existence of distinct tension-lines dissecting the embryonic tissues (cross-lines). A few discrete moments of development were established when new cross-lines formed or the previous ones disappeared; they are separated by the topologically invariant periods of development. The cross-lines play an important role in morphogenesis in that they determine the ways of active cell migration and trace the boundaries between different anlages. The orientation of the cross-lines coincides, as a rule, with the direction of predominant tension of tissues during the preceding topologically invariant period of development.


One-year outcomes of less frequent bevacizumab in age-related macular degeneration.
To evaluate whether a less frequent bevacizumab dosing schedule after repeated doses in short intervals would be effective in patients with subfoveal choroidal neovascularization secondary to age-related macular degeneration. Twenty-seven treatment-naive eyes of patients with subfoveal choroidal neovascularization secondary to age-related macular degeneration participated in this prospective, noncomparative, and interventional study at the Ulucanlar Eye Training and Research Hospital retina clinic. All lesion types were included. Intravitreal injections (1.25 mg/0.05 mL) of bevacizumab were given with a 6-week interval (Day 0, 6 weeks, and 12 weeks) for 3 months and then given at every 12-week interval up to 48 weeks. Main outcome measures of treatment were mean change in visual acuity and foveal center point retinal thickness from baseline documented by optical coherence tomography at 6, 12, 24, 36, and 48 weeks. The effects of patient age, baseline visual acuity, lesion composition, and lesion size on final visual acuity and loss of <15 letters of logarithm of the minimum angle of resolution (logMAR) at 48 weeks were also assessed. Of the 27 eyes, 24 eyes of 24 patients (14 men and 10 women) completed the 48-week follow-up and study protocol. Compared with baseline (0.95 ± 0.27 on Early Treatment Diabetic Retinopathy Study charts), mean best-corrected visual acuity improved to 0.77 ± 0.21 logMAR (P < 0.001) at Week 6, to 0.74 ± 0.2 logMAR (P < 0.001) at Week 12, to 0.79 ± 0.257 logMAR (P = 0.03) at Week 24, to 0.85 ± 0.26 logMAR (P = 0.54) at Week 36, and to 0.87 ± 0.27 logMAR (P = 1) at Week 48. The baseline mean center point retinal thickness that was 343 ± 64 μm decreased to 236 ± 40 μm (P < 0.001) at Week 6, to 222 ± 39 μm (P < 0.001) at Week 12, to 237 ± 37 (P < 0.001) at Week 24, to 253 ± 44 μm (P < 0.001) at Week 36, and to 268 ± 58 μm (P = 0.002) at Week 48. The maximal visual benefit obtained during the frequent dosing schedule significantly decreased by doses every 12 weeks at 48 weeks (P < 0.001). This decline in the best-corrected visual acuity gain was associated with an increase in the mean center point retinal thickness on optical coherence tomography. Patients aged <70 years and those having a baseline vision of 20/200 or worse were more likely to gain vision at 48 weeks (P = 0.001 and P = 0.02, respectively). In addition, a lesion ≤ 4 disk areas at baseline was less likely to lose <15 letters from baseline at 48 weeks (P = 0.03). No serious ocular and nonocular adverse events were noted. Although intravitreal bevacizumab administration on a schedule of a 6-week injection interval for 3 months followed by every 12-week interval for neovascular age-related macular degeneration provided an improvement or stabilization in best-corrected visual acuity with anatomical improvement. This dosing strategy is unable to maintain the visual acuity and optical coherence tomography benefits seen with more frequent dosing.


Racial disparities in surveillance mammography among older breast cancer survivors.
Despite lower incidence rates among black women and a national decline in breast cancer (BC) deaths, there is a widening gap in BC mortality rates between black and white women in the United States. A previous study evaluating data from 1992 to 1999 found a racial disparity in the receipt of surveillance mammography. We sought to evaluate whether this disparity persists between black and white women diagnosed with BC between 2000 and 2011. Using the SEER-Medicare registry, we conducted an analysis of women ≥ 66 years diagnosed with early-stage (0-III) BC between 2000 and 2011 who underwent BC surgery. The primary outcome was receipt of surveillance mammography within 12 months of surgery. Chi square analyses were used to compare characteristics between black and white women. Multivariate logistic regression was used to assess receipt of surveillance mammography after controlling for potential confounders. There were 3353 black and 40,564 white women in the final cohort. After adjusting for confounders, black women were still 24% less likely than white women to receive surveillance mammography (Odds ratio 0.76, 95% CI 0.70-0.0.82). Those who were married, younger, in the highest income quartile, diagnosed at earlier stages, had a lower comorbidity score, or who resided in metropolitan areas were more likely to receive surveillance mammography (p < 0.05). We found that older black BC survivors continue to experience lower rates of surveillance mammography, even after adjusting for multiple potential confounders. There remains a need to investigate which individual and systemic factors affect disparities in breast cancer care.


Ectopic expression of activated notch or SOX2 reveals similar and unique roles in the development of the sensory cell progenitors in the mammalian inner ear.
Hearing impairment or vestibular dysfunction in humans often results from a permanent loss of critical cell types in the sensory regions of the inner ear, including hair cells, supporting cells, or cochleovestibular neurons. These important cell types arise from a common sensory or neurosensory progenitor, although little is known about how these progenitors are specified. Studies have shown that Notch signaling and the transcription factor Sox2 are required for the development of these lineages. Previously we and others demonstrated that ectopic activation of Notch can direct nonsensory cells to adopt a sensory fate, indicating a role for Notch in early specification events. Here, we explore the relationship between Notch and SOX2 by ectopically activating these factors in nonsensory regions of the mouse cochlea, and demonstrate that, similar to Notch, SOX2 can specify sensory progenitors, consistent with a role downstream of Notch signaling. However, we also show that Notch has a unique role in promoting the proliferation of the sensory progenitors. We further demonstrate that Notch can only induce ectopic sensory regions within a certain time window of development, and that the ectopic hair cells display specialized stereocilia bundles similar to endogenous hair cells. These results demonstrate that Notch and SOX2 can both drive the sensory program in nonsensory cells, indicating these factors may be useful in cell replacement strategies in the inner ear.


Biospheric primary production during an ENSO transition.
The Sea-viewing Wide Field-of-view Sensor (SeaWiFS) provides global monthly measurements of both oceanic phytoplankton chlorophyll biomass and light harvesting by land plants. These measurements allowed the comparison of simultaneous ocean and land net primary production (NPP) responses to a major El Niño to La Niña transition. Between September 1997 and August 2000, biospheric NPP varied by 6 petagrams of carbon per year (from 111 to 117 petagrams of carbon per year). Increases in ocean NPP were pronounced in tropical regions where El Niño-Southern Oscillation (ENSO) impacts on upwelling and nutrient availability were greatest. Globally, land NPP did not exhibit a clear ENSO response, although regional changes were substantial.


Conjugation- and Aggregation-Directed Design of Covalent Organic Frameworks as White-Light-Emitting Diodes.
2D covalent organic frameworks (COFs) have emerged as a promising class of organic luminescent materials due to their structural diversity, which allows the systematic tuning of organic building blocks to optimize emitting properties. However, a significant knowledge gap exists between the design strategy and the fundamental understanding of the key structural parameters that determine their photophysical properties. In this work, we report two highly emissive sp2-C-COFs and the direct correlation of the structure (conjugation and aggregation) with their light absorption/emission, charge transfer (CT), and exciton dynamics, the key properties that determine their function as luminescent materials. We show that white light can be obtained by simply coating COFs on an LED strip or mixing the two COFs. Using the combination of time-resolved absorption and emission spectroscopy as well as computational prediction, we show that the planarity, conjugation, orientation of the dipole moment, and interlayer aggregation not only determine the light-harvesting ability of COFs but also control the exciton relaxation pathway and photoluminescent quantum yield.


[Familial proximal tubular azotemia. Elevated urea plasma levels in normal kidney function].
A family showed a renal disturbance, characterized by an elevated urea plasma concentration while glomerular filtration was found to be normal. A detailed study of renal clearance was performed on two members of this family in order to define the nature and site of the disorder. Evidence points to an isolated impairment of urea elimination, giving rise to a reduced urea concentrating ability and thus to a decrease in maximum urine concentration and water conservation. The most probable site of this impairment seems to be the proximal tubule.


Chemotherapy sensitization of glioblastoma by focused ultrasound-mediated delivery of therapeutic liposomes.
In glioblastoma, the benefit from temozolomide chemotherapy is largely limited to a subgroup of patients (30-35%) with tumors exhibiting methylation of the promoter region of the O6-methylguanine-DNA methyltransferase (MGMT) gene. In order to allow more patients to benefit from this treatment, we explored magnetic resonance image-guided microbubble-enhanced low-intensity pulsed focused ultrasound (LIFU) to transiently open the blood-brain barrier and deliver a first-in-class liposome-loaded small molecule MGMT inactivator in mice bearing temozolomide-resistant gliomas. We demonstrate that a liposomal O6-(4-bromothenyl)guanine (O6BTG) derivative can efficiently target MGMT, thereby sensitizing murine and human glioma cells to temozolomide in vitro. Furthermore, we report that image-guided LIFU mediates the delivery of the stable liposomal MGMT inactivator in the tumor region resulting in potent MGMT depletion in vivo. Treatment with this new liposomal MGMT inactivator facilitated by LIFU-mediated blood-brain barrier opening reduced tumor growth and significantly prolonged survival of glioma-bearing mice, when combined with temozolomide chemotherapy. Exploring this novel combined approach in the clinic to treat glioblastoma patients with MGMT promoter-unmethylated tumors is warranted.


Extended phase matching of high harmonics driven by mid-infrared light.
We demonstrate that phase-matched frequency upconversion of ultrafast laser light can be extended to shorter wavelengths by using longer driving laser wavelengths. Experimentally, we show that the phase-matching cutoff for harmonic generation in argon increases from 45 to 100 eV when the driving laser wavelength is increased from 0.8 to 1.3 microm. Phase matching is also obtained at higher pressures using a longer-wavelength driving laser, mitigating the unfavorable scaling of the single-atom response. Theoretical calculations suggest that phase-matched high harmonic frequency upconversion driven by mid-infrared pulses could be extended to extremely high photon energies.


Glucose metabolites, glutamate and glycerol in malignant glioma tumours during radiotherapy.
The metabolism of malignant glioma was studied in 13 patients. The main objective was to perform a study of the metabolic pattern of glucose, lactate, pyruvate, glutamate and glycerol in tumour tissue during base-line conditions and to detect any changes in the metabolism during radiotherapy. During a stereotactic biopsy, two microdialysis catheters were implanted: one in tumour and one in peri-tumoural tissue. Fasting samples were analysed daily, before and during 5 days of radiotherapy given with 2 Gy fractions. Base-line levels of glucose and pyruvate were significantly lower in tumour compared to peri-tumoural tissue (P = 0.04 and 0.023, respectively). The lactate/pyruvate ratio was significantly higher in tumour tissue (P = 0.022). In general, the levels of lactate, glutamate and glycerol were higher in tumour tissue, although not statistically significant. Further, we could not detect any significant changes during the 5 days of radiotherapy in any of the metabolites analysed. Radiotherapy up to 10 Gy given in five fractions does not influence the glucose metabolism nor does it induce any acute cytotoxic effect detected with glutamate or glycerol in malignant glioma, as assessed by microdialysis. The study confirms the glycolytic properties of glucose metabolism in malignant glioma.


Detection of T4 Polynucleotide Kinase via Allosteric Aptamer Probe Platform.
As a vital enzyme in DNA phosphorylation and restoration, T4 polynucleotide kinase (T4 PNK) has aroused great interest in recent years. Therefore, numerous strategies have been established for highly sensitive detection of T4 PNK based on diverse signal amplification techniques. However, they often need sophisticated design, a variety of auxiliary reagents and enzymes, or cumbersome manipulations. We have designed a new kind of allosteric aptamer probe (AAP) consisting of streptavidin (SA) aptamer and the complementary DNA (cDNA) for simple detection of T4 PNK without signal amplification and with minimized interference in complex biological samples. When the 5'-terminus of the cDNA is phosphorylated by T4 PNK, the cDNA is degraded by lambda exonuclease to release the fluorescein amidite (FAM)-labeled SA aptamer, which subsequently binds to streptavidin beads. The enhancement of the fluorescence signal on SA beads can be detected precisely and easily by a microscope or flow cytometer. Our method performs well in complex biological samples as a result of the enrichment of the signaling molecules on beads, as well as simple manipulations to discard the background interference and nonbinding molecules. Without signal amplification techniques, our AAP method not only avoids complicated manipulations but also decreases the time required. With the advantages of ease of operation, reliability, and robustness for T4 PNK detection in buffer as well as real biological samples, the AAP has great potential for clinical diagnostics, inhibitor screening, and drug discovery.


A comparative study on the efficacies of gonadotropin-releasing hormone (GnRH) agonist and GnRH antagonist in neoadjuvant androgen deprivation therapy combined with transperineal prostate brachytherapy for localized prostate cancer.
Neoadjuvant androgen deprivation therapy (ADT) has been suggested to confer several clinical benefits in patients with prostate cancer (PCa) undergoing transperineal prostate brachytherapy (TPPB). Unlike gonadotropin-releasing hormone (GnRH) receptor agonists, a GnRH antagonist such as degarelix can achieve castrate levels of testosterone without testosterone flare. However, normalization of serum testosterone levels following completion of neoadjuvant ADT in either form of treatment has never been compared in clinical trials. This is a single-center, open-label, randomized controlled study that will compare the efficacy and safety of degarelix with those of existing GnRH agonists combined with (125)I-TPPB. A total of 56 patients with low/intermediate-risk clinically localized PCa will be enrolled and randomized to one of two treatment groups: the GnRH agonist group and the degarelix group. Patients in the GnRH agonist group will receive leuprorelin acetate or goserelin acetate, and those in the degarelix group will receive the initial dose of 240 mg as 2 subcutaneous injections of 120 mg each, and then 80 mg of maintenance doses every 4 weeks for 12 weeks. Those randomly assigned to the 12-week intervention period will subsequently undergo 48-weeks of follow-up after (125)I-TPPB. The primary endpoint is defined as normalization of serum testosterone levels (>50 ng/dL) following completion of neoadjuvant ADT. All patients will be assessed every 4 weeks for the first 24 weeks, then every 12 weeks for the next 36 weeks after administrations of these drugs. Secondary endpoints are the proportion of normalized serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH), the percent reduction in prostate specific antigen (PSA) compared with pretreatment levels, the percent reduction in total prostate volume (TPV) during neoadjuvant ADT, the percent increase in TPV after (125)I-TPPB, the percent reduction in hemoglobin, serum alkaline phosphatase (ALP), changes in free testosterone and bone mineral content measurement, the proportion of patients who have serum testosterone levels over 50 ng/dL at 12 weeks following completion of neoadjuvant ADT, and the improvement of quality of life (QOL). The present study will provide additional insight regarding the benefit and potency of degarelix and will examine its potential as a new option for administration in neoadjuvant ADT. Identification number: UMIN000015519 . Registration date: October 24, 2014.


Flavoenzyme-catalyzed atropo-selective N,C-bipyrrole homocoupling in marinopyrrole biosynthesis.
Axially chiral biaryl compounds are frequently encountered in nature where they exhibit diverse biological properties. Many are biphenols that have C-C or C-O linkages installed by cytochrome P450 oxygenases that control the regio- and stereoselectivity of the intermolecular coupling reaction. In contrast, bipyrrole-coupling enzymology has not been observed. Marinopyrroles, produced by a marine-derived streptomycete, are the first 1,3'-bipyrrole natural products. On the basis of marinopyrrole's unusual bipyrrole structure, we explored its atropo-selective biosynthesis in Streptomyces sp. CNQ-418 in order to elucidate the N,C-bipyrrole homocoupling enzymology. Through a series of genetic experiments involving the discovery and heterologous expression of marinopyrrole biosynthesis genes, we report that two flavin-dependent halogenases catalyze the unprecedented homocoupling reaction.


Molecular analysis of genetic changes in the origin and development of renal cell carcinoma.
Renal cell carcinoma has been characterized by an abnormality on the short arm of chromosome 3 which suggests the presence of a tumor suppressor gene at this location. In order to more precisely define the location of the renal cell carcinoma gene and to differentiate molecular changes occurring in early stages of renal neoplasia versus those occurring later in malignant progression, DNA from normal and tumor tissue from 60 patients with various stages of renal cell carcinoma was analyzed for loss of alleles at different chromosomal loci. In tumor tissue from 51 of 58 evaluable patients (88%) there was loss of heterozygosity at one or more of 10 loci tested on chromosome 3 independently of tumor stage. Analysis of the genotypes identified the distal portion of 3p bounded by D3S2 and D3S22 (3p21-26) as the region of the disease gene. In tumor tissue from patients with advanced renal cell carcinoma, we found loss of heterozygosity on chromosome 11p in 5 of 21 (24%), on chromosome 13 in 3 of 9 (33%), and on chromosome 17 in 2 of 19 (11%). We found no loss of heterozygosity at the loci on chromosomes 11, 13, or 17 in tumor tissue from patients with localized renal cell carcinoma (N = 5). These data suggest the existence of a tumor suppressor gene on chromosome 3p which may be essential to the genesis of sporadic renal cell carcinoma and that other tumor suppressor genes are associated with progression of this malignancy.


A business case for tele-intensive care units.
A tele-intensive care unit (tele-ICU) uses telemedicine in an intensive care unit (ICU) setting, applying technology to provide care to critically ill patients by off-site clinical resources. The purpose of this review was to examine the implementation, adoption, and utilization of tele-ICU systems by hospitals to determine their efficiency and efficacy as identified by cost savings and patient outcomes. This literature review examined a large number of studies of implementation of tele-ICU systems in hospitals. The evidence supporting cost savings was mixed. Implementation of a tele-ICU system was associated with cost savings, shorter lengths of stay, and decreased mortality. However, two studies suggested increased hospital cost after implementation of tele-ICUs is initially expensive but eventually results in cost savings and better clinical outcomes. Intensivists working these systems are able to more effectively treat ICU patients, providing better clinical outcomes for patients at lower costs compared with hospitals without a tele-ICU.


Parkinson's disease as a system-level disorder.
Traditionally, the basal ganglia have been considered the main brain region implicated in Parkinson's disease. This single area perspective gives a restricted clinical picture and limits therapeutic approaches because it ignores the influence of altered interactions between the basal ganglia and other cerebral components on Parkinsonian symptoms. In particular, the basal ganglia work closely in concert with cortex and cerebellum to support motor and cognitive functions. This article proposes a theoretical framework for understanding Parkinson's disease as caused by the dysfunction of the entire basal ganglia-cortex-cerebellum system rather than by the basal ganglia in isolation. In particular, building on recent evidence, we propose that the three key symptoms of tremor, freezing, and impairments in action sequencing may be explained by considering partially overlapping neural circuits including basal ganglia, cortical and cerebellar areas. Studying the involvement of this system in Parkinson's disease is a crucial step for devising innovative therapeutic approaches targeting it rather than only the basal ganglia. Possible future therapies based on this different view of the disease are discussed.


Regional variations in contractile responses to prostaglandins and prostanoid receptor messenger ribonucleic acid in pregnant baboon uterus.
The aims of this study were to compare (1) the contractile responses of the lower uterine segment and fundus to prostaglandins, (2) expression of genes encoding prostanoid receptors in myo-metrium from different regions of the uterus, and (3) the distribution of expression of genes encoding prostanoid receptors (P receptors) in key intrauterine tissues. Cesarean hysterectomy was performed in 8 pregnant baboons, not in labor, in the last third of pregnancy. Contractile responses of fresh tissue were quantified in a superfusion system. Polyadenylated ribonucleic acid was extracted from frozen tissue and gene expression was quantified by Northern blot analysis with complementary deoxyribonucleic acid probes. Prostaglandin E2 contracted strips of myometrium from the fundus but had no significant effect on strips from lower uterine segment. Prostaglandin F2 alpha contracted myometrium from both regions equally. Compared with fundus tissue, lower uterine segment tissue had greater expression of EP2 receptor messenger ribonucleic acid, less expression of EP3 receptor messenger ribonucleic acid, but similar levels of EP4 receptor and FP receptor messenger ribonucleic acid. EP2 receptor, EP3 receptor, and EP4 receptor messenger ribonucleic acids were also detected in cervix, decidua, and chorion. EP2 receptor messenger ribonucleic acid was most abundant in the cervix, EP3 receptor messenger ribonucleic acid was most abundant in the myometrium, and EP4 receptor messenger ribonucleic acid was most abundant in the decidua. The reduced contractile response of lower uterine segment tissue to prostaglandin E2 is paralleled by greater inhibitory EP2 receptor expression and less contractile EP3 receptor expression, a pattern similar to that seen in the cervix. Drugs with selective activity at prostanoid receptor types and subtypes are likely to allow safer and more effective control of the uterus and cervix than native prostaglandins.