Specific binding-induced modulation of the XCL1 metamorphic equilibrium.
The metamorphic protein XCL1 switches between two distinct native structures with different functions in the human immune system. This structural interconversion requires complete rearrangement of all hydrogen bonding networks, yet fold-switching occurs spontaneously and reversibly in solution. One structure occupies the canonical α-β chemokine fold and binds XCL1's cognate G-protein coupled receptor, while the other structure occupies a dimeric, all-β fold that binds glycosaminoglycans and has antimicrobial activity. Both of these functions are important for the biologic role of XCL1 in the immune system, and each structure is approximately equally populated under near-physiologic conditions. Recent work has begun to illuminate XCL1's role in combatting infection and cancer. However, without a way to control XCL1's dynamic structural interconversion, it is difficult to study the role of XCL1 fold-switching in human health and disease. Thus, a molecular tool that can regulate the fractional population of the two XCL1 structures is needed. Here, we find by heparin affinity chromatography and NMR that an engineered XCL1 variant called CC5 can trigger a dose-dependent shift in XCL1's metamorphic equilibrium such that the receptor binding structure is depleted, and the antimicrobial structure is more heavily populated. This shift likely occurs due to formation of XCL1-CC5 heterodimers in which both protomers occupy the β-sheet structure. These findings lay the groundwork for future studies seeking to understand the functional role of XCL1 metamorphosis, as well as studies screening for a drug-like molecule that can therapeutically target XCL1 by tuning its metamorphic equilibrium. Moreover, the proof of concept presented here suggests that protein metamorphosis is druggable, opening numerous avenues for controlling biological function of metamorphic proteins by altering the population of their multiple native states.


Novel embalming solution for neurosurgical simulation in cadavers.
Surgical simulation using postmortem human heads is one of the most valid strategies for neurosurgical research and training. The authors customized an embalming formula that provides an optimal retraction profile and lifelike physical properties while preventing microorganism growth and brain decay for neurosurgical simulations in cadavers. They studied the properties of the customized formula and compared its use with the standard postmortem processing techniques: cryopreservation and formaldehyde-based embalming. Eighteen specimens were prepared for neurosurgical simulation: 6 formaldehyde embalmed, 6 cryopreserved, and 6 custom embalmed. The customized formula is a mixture of ethanol 62.4%, glycerol 17%, phenol 10.2%, formaldehyde 2.3%, and water 8.1%. After a standard pterional craniotomy, retraction profiles and brain stiffness were studied using an intracranial pressure transducer and monitor. Preservation time-that is, time that tissue remained in optimal condition-between specimen groups was also compared through periodical reports during a 48-hour simulation. The mean (± standard deviation) retraction pressures were highest in the formaldehyde group and lowest in the cryopreserved group. The customized formula provided a mean retraction pressure almost 3 times lower than formaldehyde (36 ± 3 vs 103 ± 14 mm Hg, p < 0.01) and very similar to cryopreservation (24 ± 6 mm Hg, p < 0.01). For research purposes, preservation time in the cryopreserved group was limited to 4 hours and was unlimited for the customized and formaldehyde groups for the duration of the experiment. The customized embalming solution described herein is optimal for allowing retraction and surgical maneuverability while preventing decay. The authors were able to significantly lower the formaldehyde content as compared with that in standard formulas. The custom embalming solution has the benefits from both cryopreservation (for example, biological brain tissue properties) and formaldehyde embalming (for example, preservation time and microorganism growth prevention) and minimizes their drawbacks, that is, rapid decay in the former and stiffness in the latter. The presented embalming formula provides an important advance for neurosurgical simulations in research and teaching.


Efficacy of Silodosin Dose in Medical Expulsive Therapy for Distal Ureteral Stones: A Retrospective Study.
We aimed to investigate the efficacy of silodosin 4 mg/day and 8 mg/day for medical expulsive therapy(MET) of lower ureteral stones. We retrospectively analyzed the medical records of 161 patients admitted to urologyclinics of Ahi Evran University Medical Faculty and Ankara Training and Research Hospital with distal ureteralstones and treated with MET with different doses of silodosin between January 2013 and August 2015. 81 patientswere treated with silodosin 4mg/day in group-1 and 80 patients with silodosin 8mg/day in group-2. Age, gender,complaints on admission, stone size, the distance between the stone and ureterovesical junction, stone passage rate,duration of stone passage after starting MET, and adverse effects were noted from the charts of the patients, andthe groups were compared. There were 81 patients in group-1, and 80 patients in group-2. Two groups were similar for age (P =.38)and gender (P =.92). Spontaneous stone passage was seen in 41 (50.9%) patients in group-1, and in 59 (73.8%)patients in group 2. The groups were different for spontaneous stone passage rate (P =.002). In group-1, 10 (25%)patients that could not pass their stones spontaneously and were treated with extracorporeal shockwave lithotripsy(SWL), and 30 (75%) of them were treated with ureterolithotripsy. Eight (38%) patients that could not undergoureterolithotripsy and/or anesthesia and were not able to pass their stones were treated with SWL, and 13 (62%)patients were treated with ureterolithotripsy in group-2. All of the patients were stone free at the end of the treatment. A dose of 8 mg/day should be preferred if silodosin is to be preferred for MET in lower ureteral stones.


Rod photoreceptors express GPR55 in the adult vervet monkey retina.
Cannabinoids exert their actions mainly through two receptors, the cannabinoid CB1 receptor (CB1R) and cannabinoid CB2 receptor (CB2R). In recent years, the G-protein coupled receptor 55 (GPR55) was suggested as a cannabinoid receptor based on its activation by anandamide and tetrahydrocannabinol. Yet, its formal classification is still a matter of debate. CB1R and CB2R expression patterns are well described for rodent and monkey retinas. In the monkey retina, CB1R has been localized in its neural (cone photoreceptor, horizontal, bipolar, amacrine and ganglion cells) and CB2R in glial components (Müller cells). The aim of this study was to determine the expression pattern of GPR55 in the monkey retina by using confocal microscopy. Our results show that GPR55 is strictly localized in the photoreceptor layer of the extrafoveal portion of the retina. Co-immunolabeling of GPR55 with rhodopsin, the photosensitive pigment in rods, revealed a clear overlap of expression throughout the rod structure with most prominent staining in the inner segments. Additionally, double-label of GPR55 with calbindin, a specific marker for cone photoreceptors in the primate retina, allowed us to exclude expression of GPR55 in cones. The labeling of GPR55 in rods was further assessed with a 3D visualization in the XZ and YZ planes thus confirming its exclusive expression in rods. These results provide data on the distribution of GPR55 in the monkey retina, different than CB1R and CB2R. The presence of GPR55 in rods suggests a function of this receptor in scotopic vision that needs to be demonstrated.


The Maryland Psychiatric Research Center scale and the characterization of involuntary movements.
The Maryland Psychiatric Research Center involuntary movement scale (MPRC scale) has been used in the evaluation of 1107 patients referred for drug-induced movement disorders. The scale has increased discrimination of body area and severity compared to other scales. Validity was examined using principal component analyses, pharmacologic response studies and associations with AIMS, global judgement and motor diagnosis. Reliability was examined using Cronbach's alpha, intraclass correlation coefficient (ICC) between raters and test-retest measurements. The prevalence of dyskinetic and parkinsonian signs at several levels of severity are reported. Total dyskinesia was strongly correlated with AIMS score, r = 0.97. Inter-rater reliability was 0.81-0.90 for total dyskinesia score. Receiver Operating Characteristic (ROC) analysis shows a total dyskinesia score of 4 or above to predict tardive dyskinesia, consistent with RDC-TD criteria. Hand dyskinesia showed a high prevalence comparable to that of oral dyskinesias. The MPRC scale is a valid, sensitive and reliable instrument for the rating of neuroleptic-induced dyskinetic and parkinsonian syndromes and may offer advantages over other scales in neurophysiologic research and brain imaging with its ease of use, uniform structure and greater discrimination of anatomic place and severity in the rating of involuntary movements.


Surgical management of multiple metatarsal fractures in a chinchilla (Chinchilla lanigera).
CASE DESCRIPTION A 3-month-old sexually intact female chinchilla (Chinchilla lanigera) was examined for sudden onset of non-weight-bearing lameness of the right hind limb. CLINICAL FINDINGS On physical examination, the right pes was swollen. An open wound on the medial aspect of the metatarsal region exposed the second metatarsal bone, and the pes was displaced laterally. Radiographs of the right pes revealed oblique displaced fractures of the 4 metatarsal bones. TREATMENT AND OUTCOME Surgical treatment was elected, and enrofloxacin was administered prior to surgery. The protruding fragment of the second metatarsal bone was excised, and the third and fourth metatarsal bones were repaired with intramedullary pins and external skeletal fixation. The chinchilla was bearing weight on the affected limb 9 days after surgery with only mild lameness. The implants were removed 35 days after surgery when radiographs showed bony union of the third and fourth metatarsal bones and continued reduction of the fractures of the second and fifth metatarsal bones. Fifty-six days after surgery, the chinchilla was bearing full weight on the limb, and radiographs showed bony union of the third, fourth, and fifth metatarsal bones. CLINICAL RELEVANCE Findings suggested that intramedullary pinning combined with an epoxy resin external fixator may be an effective technique for metatarsal fracture repair in chinchillas. This method allowed physiologic positioning of the limb and functional hind limb use during fracture healing. Prospective studies of fracture healing in exotic small mammals are indicated.


Gene Flow Increases Phylogenetic Structure and Inflates Cryptic Species Estimations: A Case Study on Widespread Philippine Puddle Frogs (Occidozyga laevis).
In cryptic amphibian complexes, there is a growing trend to equate high levels of genetic structure with hidden cryptic species diversity. Typically, phylogenetic structure and distance-based approaches are used to demonstrate the distinctness of clades and justify the recognition of new cryptic species. However, this approach does not account for gene flow, spatial, and environmental processes that can obfuscate phylogenetic inference and bias species delimitation. As a case study, we sequenced genome-wide exons and introns to evince the processes that underlie the diversification of Philippine Puddle Frogs-a group that is widespread, phenotypically conserved, and exhibits high levels of geographically based genetic structure. We showed that widely adopted tree- and distance-based approaches inferred up to 20 species, compared to genomic analyses that inferred an optimal number of five distinct genetic groups. Using a suite of clustering, admixture, and phylogenetic network analyses, we demonstrate extensive admixture among the five groups and elucidate two specific ways in which gene flow can cause overestimations of species diversity: 1) admixed populations can be inferred as distinct lineages characterized by long branches in phylograms; and 2) admixed lineages can appear to be genetically divergent, even from their parental populations when simple measures of genetic distance are used. We demonstrate that the relationship between mitochondrial and genome-wide nuclear $p$-distances is decoupled in admixed clades, leading to erroneous estimates of genetic distances and, consequently, species diversity. Additionally, genetic distance was also biased by spatial and environmental processes. Overall, we showed that high levels of genetic diversity in Philippine Puddle Frogs predominantly comprise metapopulation lineages that arose through complex patterns of admixture, isolation-by-distance, and isolation-by-environment as opposed to species divergence. Our findings suggest that speciation may not be the major process underlying the high levels of hidden diversity observed in many taxonomic groups and that widely adopted tree- and distance-based methods overestimate species diversity in the presence of gene flow. [Cryptic species; gene flow; introgression; isolation-by-distance; isolation-by-environment; phylogenetic network; species delimitation.].


PIM protein kinases regulate the level of the long noncoding RNA H19 to control stem cell gene transcription and modulate tumor growth.
The proviral integration site for Moloney murine leukemia virus (PIM) serine/threonine kinases have an oncogenic and prosurvival role in hematological and solid cancers. However, the mechanism by which these kinases drive tumor growth has not been completely elucidated. To determine the genes controlled by these protein kinases, we carried out a microarray analysis in T-cell acute lymphoblastic leukemia (T-ALL) comparing early progenitor (ETP-ALL) cell lines whose growth is driven by PIM kinases to more mature T-ALL cells that have low PIM levels. This analysis demonstrated that the long noncoding RNA (lncRNA) H19 was associated with increased PIM levels in ETP-ALL. Overexpression or knockdown of PIM in these T-ALL cell lines controlled the level of H19 and regulated the methylation of the H19 promoter, suggesting a mechanism by which PIM controls H19 transcription. In these T-ALL cells, the expression of PIM1 induced stem cell gene expression (SOX2, OCT-4, and NANOG) through H19. Identical results were found in prostate cancer (PCa) cell lines where PIM kinases drive cancer growth, and both H19 and stem cell gene levels. Small molecule pan-PIM inhibitors (PIM-i) currently in clinical trials reduced H19 expression in both of these tumor types. Importantly, the knockdown of H19 blocked the ability of PIM to induce stem cell genes in T-ALL cells, suggesting a novel signal transduction cascade. In PCa, increases in SOX2 levels have been shown to cause both resistance to the androgen deprivation therapy (ADT) and the induction of neuroendocrine PCa, a highly metastatic form of this disease. Treatment of PCa cells with a small molecule pan-PIM-i reduced stem cell gene transcription and enhanced ADT, while overexpression of H19 suppressed the ability of pan-PIM-i to regulate hormone blockade. Together, these results demonstrate that the PIM kinases control the level of lncRNA H19, which in turn modifies stem cell gene transcription regulating tumor growth.


[Design of transcription inhibitors on the basis of n-arylamides of 9-methyl- and 9-methoxyphenazine-1-carboxylic acids].
A convenient method of synthesis was developed and two series of N-arylamides of 9-methyl- and 9-methoxyphenazine-1-carboxylic acids were obtained. By the molecular docking method the mode of the synthesized compounds interaction with catalytic pocket of the RNA polymerase T7 transcription complex was simulated. Key ligand-receptor intermolecular contacts were identified. They are realized by various types of non-covalent interactions with line of conservative amino acid residues involved in recognition of incoming nucleotide, catalytic act of RNA synthesis as well as in stabilizing the RNA-DNA hybrid at early steps of transcription. In silico data indicate sufficient affinity of ligands for the receptor and allow to predict their ability to inhibit the functioning of RNA polymerase T7 transcription complex that is consistent with preliminary experimental results. Initial testing in a model RNA polymerase T7 transcription system demonstrates significant inhibition of in vitro RNA synthesis by investigated compounds at a concentration of 25 microg/ml (approximately 80 microM).


Effective treatment with clozapine and valproate for refractory schizophrenia-like psychosis after cerebellar hemorrhage.
The cerebellum has traditionally been regarded as an organ of motor coordination. However, the importance of the cerebellum in psychiatric disorders, behavior, and cognition is increasingly being recognized. There is no consensus concerning treatment of schizophrenia-like psychosis after cerebellar pathology. Reports describe the use of several antipsychotics, either alone or in combination with antidepressants or lithium. Clozapine is used for the treatment of refractory schizophrenia, but there are no reports of its use in the above-mentioned situation. We report the case of a 20-year-old woman who developed a schizophrenia-like psychosis after rupture of arteriovenous malformation at 13 years of age. The psychotic symptoms proved to be resistant to treatment, and several psychopharmacological schemas were tried. The clinical picture only showed consistent improvement with the combined use of clozapine and valproate. The relationship between chronic psychosis and cerebellar pathology remains poorly understood. Cases like the present one suggest that clozapine and valproate may be used safely and effectively in refractory schizophrenia-like psychosis associated with cerebellar pathology.


A case series of premenstrual disorders presenting to the UK's National Female Hormone Clinic.
We aimed to describe the clinical characteristics of female patients presenting with premenstrual disorders to a tertiary service in the UK. We conducted a retrospective case-note review of referrals to the National Female Hormone Clinic from April 2014 to August 2020. Based on clinical assessment, we determined whether the patient met criteria for premenstrual dysphoric disorder or premenstrual exacerbation of an underlying psychiatric disorder. Of 146 patients seen in clinic for premenstrual disorders, an ICD-10 psychiatric diagnosis was made in 130 (89.0%); a minority 16 (11.0%) did not have a psychiatric diagnosis. Following assessment, 94 patients (64.4%) met criteria for premenstrual dysphoric disorder and 67 (45.6%) had exacerbation of a psychiatric disorder. Patients presenting to this specialist service had complex psychiatric comorbidity; almost half presented with exacerbation of a psychiatric disorder.


High serum CA19-9 levels are associated with an increased risk of cholangiocarcinoma in patients with intrahepatic duct stones: a case-control study.
Hepatolithiasis is a known risk factor for cholangiocarcinoma (CC). Due to the high risk of complications that accompany endoscopic and surgical stone removal, it is often difficult to decide whether it is beneficial to remove intrahepatic ductal stones. We conducted a case-control study to determine the risk of developing CC and the benefit of stone removal in patients with hepatolithiasis. Twenty-three patients with CC group between 2002 and 2012 were included in this study. For each patient with CC, four control patients with hepatolithiasis were enrolled based on age and sex matching. Finally, 115 patients with hepatolithiasis were enrolled. The mean length of time that intrahepatic stones were present was 116.57 (± 98.77) months in the CC group and 80.56 (± 101.10) months in the control group. History of gastrectomy [OR 5.756 (1.329-24.930), p = 0.019], history of choledochoenterostomy (OR 4.938 [1.129-21.595], p = 0.034), serum CA19-9 level [OR 1.001 (1.000-1.001), p = 0.022], and complete removal of stones [OR 0.167 (0.052-0.539), p = 0.003] were independent predictive factors of CC. In patients who had undergone incomplete removal of stones, the occurrence of CC was significantly reduced overall as well as in a subgroup of patients with elevated CA19-9 (p = 0.015 and p = 0.006, respectively) compared to patients with a CA19-9 of <22 U/mL (p = 0.477). History of gastrectomy or choledochoenterostomy, high levels of serum CA19-9, and incomplete removal of stones were potential predictive factors of CC in patients with hepatolithiasis. Additionally, complete removal of stones may reduce the risk of CC in patients with high serum CA19-9 levels (>22 U/mL).


Resilience in the time of pandemic: The experience of community pharmacists during COVID-19.
As a result of the COVID-19 pandemic, there has been a significant disruption of the practice of pharmacy. Importantly, in many parts of the world, this disruption occurred literally overnight, requiring pharmacists to demonstrate significant adaptability and resiliency in order to manage continuing and in some cases expanding needs of patients. The objective of this research was to characterize how community pharmacy in Ontario (Canada) responded to the COVID-19 pandemic of winter/spring 2020, in particular in understanding what factors may influence or predict resiliency of individual practitioners and their workplaces. One-on-one interviews mediated through technology (Microsoft Teams) were used, following a semi-structured interview protocol. Verbatim transcripts were produced and analyzed by two independent researchers, using an inductive coding process to identify and characterize themes. A total of 21 pharmacists participated in this study. Six themes were identified: a) use of and comfort with technology; b) early adoption of corporate and professional guidance; c) workplaces that emphasized task-focus rather than multi-tasking were more resilient; d) scheduling methods and practices in the workplace are important for personal resilience; e) dedicated specialty staff allowed pharmacists to focus on their work; and f) provision of personal protective equipment was essential. Traditionally, resilience in professional practice has been characterized as a personal, not a workplace, issue. This study suggests that personal resiliency for pharmacists requires substantial workplace support; further work in this area is required to better understand how pharmacists adapt to complex and difficult situations such as pandemics.


[The effect of affinity on the type of action of ammonium compounds on skeletal muscle cholinoreceptors].
The dependence of the mode of action (agonist or antagonist) of ammonium compounds on the acetylcholine receptors (AcR) of frog skeletal muscles on their affinity for AcR was studied in experiments on musculus rectus abdominis of Rana temporaria frogs. The mode of action of the compounds proved to be dependent on the degree of the affinity and on the character of their intermolecular interactions with the receptors. The affinity of compounds of the polymethylene-bis-trimethylammonium series is determined by electrostatic and hydrophobic interaction with the AcR. In this case compounds with a low affinity constant (Ka) are poor antagonists, compounds with high Ka are strong antagonists, and compounds with intermediate Ka are partly agonists. Compounds whose affinity is determined not only by the electrostatic and hydrophobic but also by the dipole-dipole interaction (series D compounds) are pure and strong agonists.


Lifestyle Behaviors and Suicide-Related Behaviors in Adolescents: Cross-Sectional Study Using the 2019 YRBS Data.
Objective: The purpose of this research was to investigate the prevalence of lifestyle behaviors and suicide-related behaviors and the association between them using a nationally representative sample of adolescents from the USA. Methods: 13,677 high school students aged 14-18 years were included in this cross-sectional study. The research data were retrieved from the Youth Risk Behavior Surveillance System Survey in 2019. All data on age, sex, grade, race, physical activity, television time, fruit intake, and suicide-related behavior were self-reported by students. Logistic regression models were adopted to examine the association between lifestyle behaviors and the suicide-related behaviors. Results: Students who played video/computer games for ≥2 h had higher risk of suicide attempt (OR = 1.55, 95%CI: 1.30-1.85). Daily sleep duration of ≤8 h was positively associated with considering a suicide attempt (OR = 1.99, 95%CI: 1.62-2.43). In addition, participants who did not engage in any sport team were more likely to report considering a suicide attempt (OR = 1.50, 95%CI: 1.24-1.81). Conclusion: This research suggests that some lifestyle behaviors (e.g., time for video or computer use, sleep duration, sports team participation, regular breakfast intake, and substance use) are associated with increased risk of suicidal behavior and ideation in high school students. To identify the specific effect of multiple lifestyle factors in influencing the risk of suicide-related behaviors in high school students, longitudinal studies are warranted in future.


Total intravenous anaesthesia in endoscopic sinus-nasal surgery.
Aim of this randomized study (64 patients) was to improve the control of bleeding during functional endoscopic sinusal surgery by means of controlled hypotension achieved through either total intravenous anaesthesia using remifentanyl and propofol (27 patients), or inhaled using isoflurane and fentanyl (37 patients). The following parameters were monitored before administration of anaesthesia (T0), then after 15 (T1), and 30 minutes (T2): systolic, diastolic, and mean arterial pressure; heart rate; concentration of tele-exhaled carbon dioxide (PetCO2) and percentage of peripheral saturation of haemoglobin (SPO2); bleeding according to the Fromme-Boezaart scale at T2. Mean arterial pressure values were maintained between 60-70 mmHg throughout surgery. At T0, systolic arterial pressure, diastolic arterial pressure and mean arterial pressure values were seen to overlap in the two groups. Both types of anaesthesia were effective in reducing the pressure values of T0-T1 and T1-T2 trends (p<0.0001). Systolic arterial pressure at T1 is lower with total intravenous anaesthesia compared to isoflurane and fentanyl (p=0.02). PetCO2 and heart rate show a decreasing trend independently of the type of anaesthesia employed. In conclusion, the hypotensive effect of total intravenous anaesthesia and of isoflurane and fentanyl is equivalent, but only total intravenous anaesthesia is effective in reducing bleeding during functional endoscopic sinusal surgery.


Form, function and strength in the restored dentition.
The masticatory system is a biomechanical engine for the reduction of food before final absorption by the alimentary canal. These demands may lead to biological changes dominated by wear, fracture, or plastic deformation. This in turn lead to the loss of hard tissue, which is detrimental to the primary function of the oral cavity. The primary roles of restorative dentistry are to restore what is lost and to preserve remaining hard tissue, which is served by conservative techniques and the development of materials that recover the function of lost tissue. The criteria for new restorative materials should be based on the structure-property-function relationships of the hard tissues. An understanding of these relationships may lead to better methods of assessment and provide clues for the development of better synthetic analogues for enamel and dentine.


"What about me?" Perceptions of exclusion and whites' reactions to multiculturalism.
A 5-study investigation of reactions of dominant group members (i.e., White Americans) to diversity (relative to racial minority reactions) provides evidence of implicit and explicit associations between multiculturalism and exclusion and of a relationship between perceived exclusion and reactions to diversity. In Study 1, Whites but not racial minorities were faster in an implicit association task at pairing multiculturalism with exclusion than with inclusion. This association diminished in Study 2 through a subtle framing of diversity efforts as targeted toward all groups, including European Americans. In Study 3, in a "Me/Not Me" task, Whites were less likely than minorities to pair multiculturalism concepts with the self and were slower in responding to multiculturalism concepts. Furthermore, associating multiculturalism with the self (Study 3) or feeling included in organizational diversity (Study 4) predicted Whites' endorsement of diversity and also accounted for the oft-cited group status difference in support for diversity initiatives. Study 5 showed that individual differences in need to belong moderated Whites' interest in working for organizations that espouse a multicultural versus a color-blind approach to diversity, with individuals higher in need to belong less attracted to organizations with a multicultural approach. Overall, results show that the purportedly "inclusive" ideology of multiculturalism is not perceived as such by Whites. This may, in part, account for their lower support for diversity efforts in education and work settings.


Incremental prognostic value of myocardial perfusion single photon emission computed tomography for the prediction of cardiac death: differential stratification for risk of cardiac death and myocardial infarction.
The incremental prognostic value of stress single photon emission computed tomography (SPECT) for the prediction of cardiac death as an individual end point and the implications for risk stratification are undefined. We identified 5183 consecutive patients who underwent stress/rest SPECT and were followed up for the occurrence of cardiac death or myocardial infarction. Over a mean follow up of 642+/-226 days, 119 cardiac deaths and 158 myocardial infarctions occurred (3.0% cardiac death rate, 2.3% myocardial infarction rate). Patients with normal scans were at low risk (< or =0.5%/y), and rates of both outcomes increased significantly with worsening scan abnormalities. Patients who underwent exercise stress and had mildly abnormal scans had low rates of cardiac death but higher rates of myocardial infarction (0.7%/y versus 2.6%/y; P<.05). After adjustment for prescan information, scan results provided incremental prognostic value toward the prediction of cardiac death. The identification of patients at intermediate risk of nonfatal myocardial infarction and low risk for cardiac death by SPECT may result in significant cost savings when applied to a clinical testing strategy. Myocardial perfusion SPECT yields incremental prognostic information toward the identification of cardiac death. Patients with mildly abnormal scans after exercise stress are at low risk for cardiac death but intermediate risk for nonfatal myocardial infarction and thus may benefit from a noninvasive strategy and may not require invasive management.


Structural, Photophysical, and Electronic Properties of CH3NH3PbCl3 Single Crystals.
Methylammonium lead chloride (CH3NH3PbCl3 or MAPbCl3) single crystals were fabricated using the inverse temperature crystallization method, and their structural, photophysical, and electronic characteristics were studied using temperature dependent optical spectroscopy, X-ray diffraction (XRD), current-voltage, and Hall measurements. The changes in absorption and photoluminescence properties accompanied with structural changes in crystal lattice were studied within a broad temperature range of 300-20 K. XRD investigations reveal that phase changes took placed around 180 K and 175 K. At a temperature below 170 K, two different crystallographic phases were found to co-exist in the photoluminescence spectra. An asymmetric line shape with broad and weak shoulders near the absorption edges was observed in all of the major PL peaks. The weak shoulders are attributed to the missing chloride atoms on the crystal surface. The photoluminescence intensity of the crystals was strongly influenced by the environment, thereby indicating that the carrier recombination is affected by the physical desorption/absorption of gas molecules at the crystal surface. Moreover, vibronic replicas in the photoluminescence spectra at low temperature were observed for the first time. The origins of these replicas are attributed to the coupling between the vibrational/librational motions of the organic cations and the photoexcited electrons. Finally, the Hall and current-voltage measurements confirm that the crystal is an n-type semiconductor with a carrier concentration of ~2.63 × 1011 cm-3, a mobility of 4.14 cm2/V•s, and a conductivity of 1.8 × 10-8 Ω-1 cm-1 under dark and room temperature conditions.


Metabolomic Profile and Antioxidant/Anti-Inflammatory Effects of Industrial Hemp Water Extract in Fibroblasts, Keratinocytes and Isolated Mouse Skin Specimens.
Industrial hemp is a multiuse crop whose phytocomplex includes terpenophenolics and flavonoids. In the present study, the phenolic and terpenophenolic compounds were assayed in the water extract of the hemp variety Futura 75. Protective effects were also investigated in human fibroblast and keratinocytes and isolate mouse skin specimens, which were exposed to hydrogen peroxide and/or to the extract (1-500 µg/mL). The results of phytochemical analysis suggested the cannabidiol, cannabidiolic acid and rutin as the prominent phytocompounds. In the in vitro system represented by human keratinocytes and fibroblasts, the hemp extract was found to be able to protect cells from cytotoxicity and apoptosis induced by oxidative stress. Moreover, modulatory effects on IL-6, a key mediator in skin proliferation, were found. In isolated rat skin, the extract reduced hydrogen peroxide-induced l-dopa turnover, prostaglandin-E2 production and the ratio kynurenine/tryptpophan, thus corroborating anti-inflammatory/antioxidant effects. The in silico docking studies also highlighted the putative interactions between cannabidiol, cannabidiolic acid and rutin with tyrosinase and indoleamine-2,3-dioxygenase, involved in l-dopa turnover and tryptophan conversion in kynurenine, respectively. In conclusion, the present findings showed the efficacy of hemp water extract as a skin protective agent. This could be partly related to the extract content in cannabidiol, cannabidiolic acid and rutin.


Volumizing viaducts of the midface: defining the Beut techniques.
In nonsurgical facial rejuvenation, autologous fat and dermal fillers have become an effective method to achieve symmetry and balance of the midface. Nonsurgical techniques that target the dynamic anatomical relationships existing in the midface can improve rejuvenation outcomes in this commonly augmented region. The authors described techniques for fat compartment and potential space volumization of the midface via a standardized and reproducible technique. They placed emphasis on access to anatomical spaces and compartments within the midface. In 11 hemifacial cadavers, hyaluronic acid filler homogenized with red dye was injected via 3 midfacial ports that were anatomically designed to access the superficial fat compartments, deep fat compartments, or traverse the prezygomatic space. Specimens were dissected in a layered fashion to analyze relationships between the injected filler and midfacial anatomy. We have described 4 site-specific procedural techniques and created a video containing anatomical renderings of each targeted viaduct accompanied by technique demonstrations. We found that Beut techniques 1 through 4 can be performed through 3 midfacial viaducts. Port placement 1.5 cm inferolateral to the alar base in the nasolabial crease created a medial midface viaduct, suitable for access to the deep medial cheek fat, medial superficial fat compartment, premaxillary space, and adjacent superior nasolabial cheek compartment. Port placement within the nasojugal groove provided a middle midface viaduct to access the middle superficial fat compartment and medial suborbicularis oculi fat (SOOF). Port placement 1.5 cm inferolateral to the lateral canthus created a lateral midface viaduct to approach the pre-periosteal fat, prezygomatic space, lateral SOOF, and infraorbital fat compartment. Our findings indicate that anterior and lateral cheek projection, V-deformity correction, rhytid softening, and tear trough effacement can be achieved through the midfacial viaducts. Systematic assessment and site-specific nonsurgical rejuvenation of the midface may lead to increased safety, accuracy, and technique reproducibility in this commonly injected region.


A Review of the Pharmacological Action of Astragalus Polysaccharide.
Astragalus membranaceus (A. membranaceus) is a type of traditional Chinese medicine with a long history of clinical application. It is used in the improvement and treatment of various diseases as medicine and food to invigorate the spleen and replenish qi. The main components of A. membranaceus are Astragalus polysaccharide (APS), flavonoids compounds, saponins compounds, alkaloids, etc. APS is the most important natural active component in A. membranaceus, and possesses multiple pharmacological properties. At present, APS possess the huge potential to develop a drug improving or treating different diseases. In this review, we reveal the potential approaches of pre-treating and preparation on APS as much as possible and the study on content of APS and its chemical composition including different monosaccharides. More importantly, this paper summarize pharmacological actions on immune regulation, such as enhancing the immune organ index, promoting the proliferation of immune cells, stimulating the release of cytokines, and affecting the secretion of immunoglobulin and conduction of immune signals; anti-aging; anti-tumor by enhancing immunity, inducing apoptosis of tumor cells and inhibiting the proliferation and transfer of tumor cells; antiviral effects; regulation of blood glucose such as type I diabetes mellitus, type II diabetes mellitus and diabetic complications; lipid-lowering; anti-fibrosis; antimicrobial activities and anti-radiation. It provided theoretical basis for the further research such as its structure and mechanism of action, and clinical application of APS.


Dipeptidyl peptidase IV in the immune system. Effects of specific enzyme inhibitors on activity of dipeptidyl peptidase IV and proliferation of human lymphocytes.
Dipeptidyl peptidase IV (DP IV) is a membrane peptidase playing a significant role in the process of activation and proliferation of human thymus-derived lymphocytes. This conclusion is drawn from (1) the induction of this enzyme on mitogen-activated T lymphocytes (cf. Schön, E. & Ansorge, S. (1990) Biol. Chem. Hoppe-Seyler 371, 699-705) and (2) the impairment of different functions of activated T cells in the presence of specific inhibitors and antibodies against DP IV (Schön, E. & al. (1987) Eur. J. Immunol 17, 1821-1826). This paper is aimed at testing new active site-specific peptide inhibitors for their efficiency as inhibitors of lymphocyte DP IV and DNA synthesis of mitogen-stimulated lymphocytes. These inhibitors comprise (i) diacylhydroxylamine derivatives of Xaa-Pro or Xaa-Ala peptides, (ii) different oligopeptides with N-terminal Xaa-Pro-sequences, and (iii) amino-acid amides of the pyrrolidide and the thiazolidide type. The thiazolidides of epsilon-(4-nitrobenzyloxycarbonyl)-L-lysine and of L-isoleucine as well as Ala-Pro-nitrobenzoylhydroxylamine are the most effective inhibitors in both test systems, yielding half-maximal inhibitory concentrations in the micromolar range. Cell viability was not impaired in this effective concentration range. Other inhibitors of DP IV are one to two orders of magnitude less efficient in the suppression of lymphocyte proliferation.


[Complications of splenectomy].
The authors describe the problematic of postsplenectomy complications. The main group of complications came in the group of haematological indication to splenectomy. The high risk of complications present the haematological malignancy. The most serious illness complications came only in this group.


Identification and characterization of circadian clock genes in the pea aphid Acyrthosiphon pisum.
The molecular basis of circadian clocks is highly evolutionarily conserved and has been best characterized in Drosophila and mouse. Analysis of the Acyrthosiphon pisum genome revealed the presence of orthologs of the following genes constituting the core of the circadian clock in Drosophila: period (per), timeless (tim), Clock, cycle, vrille, and Pdp1. However, the presence in A. pisum of orthologs of a mammal-type in addition to a Drosophila-type cryptochrome places the putative aphid clockwork closer to the ancestral insect system than to the Drosophila one. Most notably, five of these putative aphid core clock genes are highly divergent and exhibit accelerated rates of change (especially per and tim orthologs) suggesting that the aphid circadian clock has evolved to adapt to (unknown) aphid-specific needs. Additionally, with the exception of jetlag (absent in the aphid) other genes included in the Drosophila circadian clock repertoire were found to be conserved in A. pisum. Expression analysis revealed circadian rhythmicity for some core genes as well as a significant effect of photoperiod in the amplitude of oscillations.


Image-Based Evaluation of In Vivo Degradation for Shape-Memory Polymer Polyurethane Foam.
Shape-memory polymer (SMP) polyurethane foams have been applied as embolic devices and implanted in multiple animal models. These materials are oxidatively degradable and it is critical to quantify and characterize the degradation for biocompatibility assessments. An image-based method using high-resolution and magnification scans of histology sections was used to estimate the mass loss of the peripheral and neurovascular embolization devices (PED, NED). Detailed analysis of foam microarchitecture (i.e., struts and membranes) was used to estimate total relative mass loss over time. PED foams implanted in porcine arteries showed a degradation rate of ~0.11% per day as evaluated at 30-, 60-, and 90-day explant timepoints. NED foams implanted in rabbit carotid elastase aneurysms showed a markedly faster rate of degradation at ~1.01% per day, with a clear difference in overall degradation between 30- and 90-day explants. Overall, membranes degraded faster than the struts. NEDs use more hydrophobic foam with a smaller pore size (~150-400 μm) compared to PED foams (~800-1200 μm). Previous in vitro studies indicated differences in the degradation of the two polymer systems, but not to the magnitude seen in vivo. Implant location, animal species, and local tissue health are among the hypothesized reasons for different degradation rates.


Performance of the FMF First-Trimester Preeclampsia-Screening Algorithm in a High-Risk Population in The Netherlands.
The aim of the study was to evaluate the performance of the first-trimester Fetal Medicine Foundation (FMF) screening algorithm, including maternal characteristics and medical history, blood pressure, pregnancy-associated plasma protein A and placenta growth factor, crown rump length, and uterine artery pulsatility index, for the prediction of preeclampsia in a high-risk population in the Netherlands. This is a prospective cohort including nulliparous women and women with preeclampsia or intrauterine growth restriction in previous pregnancy. We screened patients at 11-14 weeks of gestation to calculate the risk for preeclampsia. The primary outcome was preeclampsia and gestational age at delivery. Performance of the model was evaluated by area under the receiver operating characteristic (ROC) curves (AUCs) and calibration graphs; based on the ROC curves, optimal predicted risk cutoff values for our study population were defined. We analyzed 362 women, of whom 22 (6%) developed preeclampsia. The algorithm showed fair discriminative performance for preeclampsia <34 weeks (AUC 0.81; 95% CI 0.65-0.96) and moderate discriminative performance for both preeclampsia <37 weeks (AUC 0.71; 95% CI 0.51-0.90) and <42 weeks (AUC 0.71; 95% CI 0.61-0.81). Optimal cutoffs based on our study population for preeclampsia <34, <37, and <42 weeks were 1:250, 1:64, and 1:22, respectively. Calibration was poor. Performance of the FMF preeclampsia algorithm was satisfactory to predict early and preterm preeclampsia and less satisfactory for term preeclampsia in a high-risk population. However, by addressing some of the limitations of the present study, the performance can potentially improve. This is essential before implementation is considered.


Acute attenuation of glycocalyx barrier properties increases coronary blood volume independently of coronary flow reserve.
Vascular endothelium is covered with an extensive mesh of glycocalyx constituents, which acts like an effective barrier up to several micrometers thick that shields the luminal surface of the vasculature from direct exposure to flowing blood. Many studies report that various enzymatic and pharmaceutical challenges are able to increase glycocalyx porosity, resulting in farther permeation of plasma macromolecules and greater access of red blood cells into glycocalyx domain. Attenuation of glycocalyx barrier properties therefore potentially increases the amount of blood that effectively occupies available microvascular volume. We tested in the present study whether attenuation of coronary glycocalyx barrier properties actually increases coronary blood volume and whether such changes would be noticeable during measurements of coronary flow reserve using adenosine. In anesthetized goats (n = 6) with cannulated left main coronary artery that were perfused under controlled pressure, coronary blood volume was measured via the indicator-dilution technique using high-molecular-weight (2,000 kDa) dextrans as plasma tracer and labeled red blood cells as red blood cell tracer. Coronary blood volume was determined at baseline and during intracoronary infusion of adenosine causing maximal vasodilation (0.2-0.6 mg.kg(-1).h(-1)) before and after intracoronary hyaluronidase treatment (170,000 units) of the glycocalyx. With an intact glycocalyx, coronary blood volume was 18.9 +/- 1.1 ml/100 g heart tissue at baseline, which increased to 26.3 +/- 2.7 ml/100 g after hyaluronidase treatment of the coronary glycocalyx. Maximal vasodilation by administration of adenosine further increased coronary blood volume to 33.9 +/- 6.8 ml/100 g, a value not different from the maximal coronary blood volume of 33.2 +/- 5.3 ml/100 g obtained by administration of adenosine in the absence of hyaluronidase treatment. Adenosine-induced increases in coronary conductance were not affected by hyaluronidase treatment. We conclude that acute attenuation of glycocalyx barrier properties increases coronary blood volume by approximately 40%, which is of similar magnitude as additional changes in coronary blood volume during subsequent maximal vasodilation with adenosine. Furthermore, maximal coronary blood volume following administration of adenosine was similar with and without prior hyaluronidase degradation of the glycocalyx, suggesting that adenosine and hyaluronidase potentially increase glycocalyx porosity to a similar extent. Hyaluronidase-mediated changes in coronary blood volume did not affect baseline and adenosine-induced increases in coronary conductance, demonstrating that measurements of coronary flow reserve are insufficient to detect impairment of coronary blood volume recruitment in conditions of damaged glycocalyx.


Treatment decision-making in elderly women with ovarian cancer: an age-based comparison.
To investigate treatment choices and outcomes in women with ovarian cancer, comparing elderly (≥75 years) and younger patients (<75 years). A single-center retrospective analysis of patients diagnosed with ovarian cancer between 2010 and 2015. The initial treatment plan and course of treatment were extracted from medical files. Of 128 included patients, 34% were aged ≥75 years. The initial treatment plan consisted of the combination of cytoreductive surgery and platinum-based doublet chemotherapy (ie, standard treatment) in only 10% of the elderly patients with an indication for this treatment. 5% of these patients completed this treatment without adaptations (compared with 85% and 48%, respectively, in younger patients). 38% of the elderly patients with an indication for cytoreductive surgery and chemotherapy received best supportive care only. Patient preference was an important reason to withhold standard treatment. Surgery- and chemotherapy-related complications and hospital admissions did not differ between groups. Median survival was lower in the elderly (p=0.002) and in patients receiving best supportive care (p<0.001). Elderly patients were less frequently treated in accordance with the treatment guideline. To select those older patients who may benefit from (adapted) treatment is challenging. Future studies should evaluate determinants associated with treatment completion to improve outcomes in this vulnerable population.


[Silicone oil in epiretinal membranes 3-4 months following implantation: microscopic findings in 2 cases].
After vitrectomy and silicone oil instillation, several oil inclusions were found on histologic examination of recurrent epiretinal membranes 3-4 months after oil instillation. The authors discuss how far an early emulsification of silicone oil stimulates macrophages as well as other proliferating cells and thus leads to impregnation and reproliferation of epiretinal membranes. If highly refined oil is used, impregnation and its complications will perhaps become less significant.


A bacteriophage of bacillus subtilis which forms plaques only at temperatures above 50 C. 3. Inhibition of TSP-1-specific deoxyribonucleic acid synthesis at 37 C and 45 C.
The effect of temperature on phage-specific deoxyribonucleic acid (DNA) synthesis was studied in TSP-1-infected Bacillus subtilis. This was facilitated by selectively inhibiting host DNA synthesis with 6-(p-hydroxyphenylazo)-uracil. The results indicated that TSP-1 DNA synthesis did not continue at 37 C and was immediately shut down after transfer to this temperature. Incubation at 45 C greatly reduced TSP-1 DNA synthesis. Phage-specific DNA synthesis could resume at 53 C, however, when the infected culture was returned to 53 C after a 2-min incubation period at 37 C. The results suggest that the inhibition of phage DNA synthesis at 37 C is reversible. Since infected cultures returned to 53 C after 2 min at 37 C could not complete the replicative cycle, the irreversible inhibition of yet another intermediate step was suggested.


Cephalometric evaluation of Class II malocclusion treatment with cervical headgear and mandibular fixed appliances.
The present study aimed to evaluate the cephalometric changes in Class II patients treated exclusively with cervical headgear (CHG) in the maxillary arch and fixed appliances in the mandibular arch as compared with a control group. The sample comprised 82 lateral cephalograms obtained pre- (T1) and post- (T2) treatment/observation of 41 subjects, divided into two groups: group 1-25 Class II division 1 patients (20 females and five males), with a mean pre-treatment age of 10.4 years, treated for a mean period of 2.5 years and group 2-16 Class II untreated subjects (12 females and four males), with a mean initial age of 9.9 years, followed for a mean period of 2.2 years. Treatment changes between the groups were compared by means of t-tests. The results showed restriction of maxillary forward displacement and also a restriction in maxillary length growth, improvement in the maxillomandibular relationship, restriction of mandibular incisor vertical development, reduction in overjet and overbite, and improvement in molar relationship. It was concluded that this treatment protocol corrected the Class II malocclusion characteristics primarily through maxillary forward growth restriction.


Should I Change or Should I Go? Phenotypic Plasticity and Matching Habitat Choice in the Adaptation to Environmental Heterogeneity.
It can be challenging for organisms to achieve a good match between their phenotypic characteristics and environmental requirements that vary in space and time. The evolution of adaptive phenotypes can result from genetic differentiation at the population level. Individuals, however, could also change their phenotype (adaptive plasticity) or select an environment because it matches with their phenotype (matching habitat choice). It is poorly known under which conditions these different solutions to environmental heterogeneity evolve and whether they operate together. Using an individual-based simulation model, we assessed which solutions evolved depending on degree of temporal variation, costs of multiple underlying traits, and order of dispersal and development. Population genetic divergence was superseded by plasticity or matching habitat choice as temporal variation increased. Plasticity and matching habitat choice were limited by their trait costs, even when this involved only a part of the underlying traits. Independent of the order of dispersal and development, plasticity evolved more commonly than matching habitat choice, in part because the match a phenotype can achieve by matching habitat choice is limited by the types of environments available. Our results explain the apparent relative rarity of matching habitat choice in nature. At the same time, our results can be used to look for matching habitat choice in those biological systems where the conditions for other solutions seem unfavorable.


A randomized double-blind clinical trial to evaluate the efficacy of chlorhexidine, antioxidant, and hyaluronic acid mouthwashes in the management of biofilm-induced gingivitis.
To investigate the antiplaque and antigingivitis efficacy in addition to evaluating side effects and subjects' perceptions of three commercially available mouthwashes. This study was a double-blind, parallel, and short-term trial. A total of 75 dental students with biofilm-induced gingivitis were included in the final analysis of the current study. Clinical parameters (plaque index and bleeding on probing) and the staining effect were measured at baseline and after 7 days. In addition, a VAS-based assessment questionnaire was completed by the participants. All interventions significantly reduced plaque scores, but chlorhexidine (CHX) had a significantly higher effect than the hyaluronic acid (HA) and antioxidant mouthwashes. However, all mouthwashes significantly reduced the total bleeding scores to <10% in 53% of the patients, compared to the baseline record. Additionally, teeth underwent shade changes in association with all interventions by the end of the study. Analysis of feedback about the mouthwashes showed that the participants seemed to prefer the HA mouthwash over the other mouthwashes. CHX remains the most effective antiplaque mouthwash although HA and antioxidants are as effective as CHX in reducing bleeding. In addition, based on its better acceptance by the participants, HA is potentially a good alternative to CHX.


Variant serum beta-hexosaminidase as a biochemical marker of malignancy.
Previous studies have demonstrated a variant form of beta-hexosaminidase in metastatic tumor tissue of human liver and in sera from cancer patients with liver metastases. The current investigation examined sera for the presence of the variant form of beta-hexosaminidase from a large and heterogeneous group of cancer patients (with different primary sites and differing degrees of metastatic involvement), from normal controls and pathological controls with nonmalignant diseases. Comparison of the total serum beta-hexosaminidase activity levels and the percentage of the total activity comprised of beta-hexosaminidase B (Hex B) revealed no significant differences (P greater than 0.01) between the three groups. Analytical isoelectric focusing indicated that the variant beta-hexosaminidase was present in 80% of 108 cancer patients, 37% of 27 pathological controls and 11% of 18 normal controls. Examination of subgroups of the cancer patients based on the extent of metastasis revealed that there was a significant increase in total serum beta-hexosaminidase activity and the presence of variant beta-hexosaminidase in the sera as the disease progressed. These results suggest that serum beta-hexosaminidase may be a useful marker for monitoring the progression of malignant disease.


Importation, Antibiotics, and Clostridium difficile Infection in Veteran Long-Term Care: A Multilevel Case-Control Study.
Although clinical factors affecting a person's susceptibility to Clostridium difficile infection are well-understood, little is known about what drives differences in incidence across long-term care settings. To obtain a comprehensive picture of individual and regional factors that affect C difficile incidence. Multilevel longitudinal nested case-control study. Veterans Health Administration health care regions, from 2006 through 2012. Long-term care residents. Individual-level risk factors included age, number of comorbid conditions, and antibiotic exposure. Regional risk factors included importation of cases of acute care C difficile infection per 10 000 resident-days and antibiotic use per 1000 resident-days. The outcome was defined as a positive result on a long-term care C difficile test without a positive result in the prior 8 weeks. 6012 cases (incidence, 3.7 cases per 10 000 resident-days) were identified in 86 regions. Long-term care C difficile incidence (minimum, 0.6 case per 10 000 resident-days; maximum, 31.0 cases per 10 000 resident-days), antibiotic use (minimum, 61.0 days with therapy per 1000 resident-days; maximum, 370.2 days with therapy per 1000 resident-days), and importation (minimum, 2.9 cases per 10 000 resident-days; maximum, 341.3 cases per 10 000 resident-days) varied substantially across regions. Together, antibiotic use and importation accounted for 75% of the regional variation in C difficile incidence (R2 = 0.75). Multilevel analyses showed that regional factors affected risk together with individual-level exposures (relative risk of regional antibiotic use, 1.36 per doubling [95% CI, 1.15 to 1.60]; relative risk of importation, 1.23 per doubling [CI, 1.14 to 1.33]). Case identification was based on laboratory criteria. Admission of residents with recent C difficile infection from non-Veterans Health Administration acute care sources was not considered. Only 25% of the variation in regional C difficile incidence in long-term care remained unexplained after importation from acute care facilities and antibiotic use were accounted for, which suggests that improved infection control and antimicrobial stewardship may help reduce the incidence of C difficile in long-term care settings. U.S. Department of Veterans Affairs and Centers for Disease Control and Prevention.


Continuous exposure to bright light upregulates bFGF and CNTF expression in the rat retina.
To examine mRNA expression of neurotrophic factors in the retina after exposure to bright light. Male adult Sprague-Dawley rats were exposed to light of 115-130 ft-c. Retinas were collected after 1, 2, 4 or 7 days of exposure. Northern blot analysis was performed to determine mRNA levels for the following factors and their receptors: basic fibroblast growth factor (bFGF), ciliary neurotrophic factor (CNTF), acidic fibroblast growth factor (aFGF), brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1) and glial fibrillary acidic protein (GFAP). Expression of bFGF, CNTF and GFAP was localized by in situ hybridization. Exposure to light of 115-130 ft-c resulted in a substantial increase in bFGF and CNTF expression that persisted during the entire 7-day period of exposure. The peak expression of bFGF was almost 9-fold at day 2. The increase in CNTF mRNA reached a maximum of 6-fold at day 4. A small increase (50%) in IGF-1 mRNA was also seen at day 4. Among the receptors, an elevation of 3-fold in FGF receptor 1 (FGFR-1) was observed at day 2. There was also a small increase (70%) in IGF-1 receptor (IGF-1R) at day 2. In addition, the expression of GFAP showed a rapid elevation of about 8-fold by day 1 and 9-fold by day 2, and 18-fold by day 4. There was, however, no significant alteration in the expression of aFGF and BDNF. In situ hybridizations showed that the elevation of bFGF, CNTF and GFAP occurred across the entire retina with especially prominent increases over specific layers for each gene. Continuous exposure to bright light upregulates bFGF, CNTF, FGFR-1 and GFAP expression in the rat retina. The pattern of induced expression closely resembles that induced by mechanical injury, implying a common underlying mechanism.


Animal models of ischemic stroke. Part one: modeling risk factors.
Ischemic stroke is one of the leading causes of long-term disability and death in developed and developing countries. As emerging disease, stroke related mortality and morbidity is going to step up in the next decades. This is both due to the poor identification of risk factors and persistence of unhealthy habits, as well as to the aging of the population. To counteract the estimated increase in stroke incidence, it is of primary importance to identify risk factors, study their effects, to promote primary and secondary prevention, and to extend the therapeutic repertoire that is currently limited to the very first hours after stroke. While epidemiologic studies in the human population are essential to identify emerging risk factors, adequate animal models represent a fundamental tool to dissect stroke risk factors to their molecular mechanism and to find efficacious therapeutic strategies for this complex multi- factorial disorder. The present review is organized into two parts: the first part deals with the animal models that have been developed to study stroke and its related risk factors and the second part analyzes the specific stroke models. These models represent an indispensable tool to investigate the mechanisms of cerebral injury and to develop novel therapies.


Donepezil for dementia due to Alzheimer's disease.
Alzheimer's disease is the most common cause of dementia in older people. One of the aims of therapy is to inhibit the breakdown of a chemical neurotransmitter, acetylcholine, by blocking the relevant enzyme. This can be done by a group of chemicals known as cholinesterase inhibitors. However, some (like tacrine) are associated with adverse effects such as hepatotoxicity, but donepezil (E2020, Aricept) is safer. The objective of this review is to assess whether donepezil improves the well-being of patients with dementia due to Alzheimer's disease. The Cochrane Dementia and Cognitive Improvement Group's Specialized Register was searched using the terms 'donepezil', 'E2020' and 'Aricept' on 9 October 2002. This Register contains up-to-date records of all major health care databases and many ongoing trial databases. Members of the Donepezil Study Group and Eisai Inc were contacted. All unconfounded, double-blind, randomized controlled trials in which treatment with donepezil was compared with placebo for patients with mild, moderate or severe dementia due to Alzheimer's disease. Data were extracted by one reviewer (JSB ), pooled where appropriate and possible, and the weighted mean differences or Peto odds ratios (95%CI) estimated. Sixteen trials are included, involving 4365 participants. The trials were of 12, 24 or 52 weeks duration in selected patients. Available outcome data cover domains including cognitive function and global clinical state, but data on several important dimensions of outcome are unavailable. For cognition there is a statistically significant improvement for both 5 and 10 mg/day of donepezil at 24 weeks compared with placebo (-2.02 points on the ADAS-Cog scale WMD, 95%CI -2.77 to -1.26, p<0.00001; -2.92 points on the ADAS-Cog scale WMD 95% CI -3.74 to -2.10, p<0.00001)and for 10 mg/day donepezil compared with placebo at 52 weeks (1.84MMSE points, 95% CI, 0.53 to3.15, p=0.006). The results show some improvement in global clinical state (assessed by an independent clinician) in people treated with 5 and 10 mg/day of donepezil compared with placebo at 12 and 24 weeks. Benefits of treatment were also seen on measures of activities of daily living and behaviour. There were significantly more withdrawals before the end of treatment from the 10 mg/day (but not the 5 mg/day) donepezil group compared with placebo which may have resulted in some overestimation of beneficial changes at 10 mg/day.A variety of adverse effects were recorded, with more incidents of nausea, vomiting, diarrhoea and anorexia in the 10 mg/day group compared with placebo and the 5 mg/day group, but very few patients left a trial as a direct result of the intervention. People with mild, moderate or severe dementia due to Alzheimer's disease treated for periods of 12, 24 or 52 weeks with donepezil experienced benefits in cognitive function, activities of daily living and behaviour. Study clinicians rated global clinical state more positively in treated patients, and measured less decline in measures of global disease severity. Although no significant changes were measured on a patient-rated quality of life scales, the instrument used was crude and possibly unsuited to the task. The additional data now available confirm the findings of the previous issue of this review and extend the evidence for the effectiveness of treatment to at least 52 weeks and to those with severe dementia. More evidence is still needed for the economic efficacy of donepezil, but clinical efficacy is confirmed.


Effect of compatible herbs on the pharmacokinetics of effective components of Panax notoginseng in Fufang Xueshuantong Capsule.
Fufang Xueshuantong (FXT) is a well-known Chinese herbal formula which has been used to treat cardiovascular and ophthalmic diseases, especially diabetic retinopathy. Panax notoginseng (Burkill) F.H. Chen (PN) is the main herb of FXT, whose major bioactive constituents are ginsenosides. However, the scientific basis of the compatibility of FXT is still ambiguous. The present study investigated the scientific basis of the compatibility of FXT by comparing the pharmacokinetics of marker compounds after oral administrations of PN and FXT. A high performance liquid chromatography-electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) method was developed for simultaneous detection of notoginsenoside R1 (NR1), ginsenoside Rg1 (GRg1), and ginsenoside Rb1 (GRb1) in rat plasma. The pharmacokinetic studies of FXT and PN were performed using the established method with the pharmacokinetic parameters being determined by non-compartmental analysis. The results showed that the pharmacokinetic parameters (maximum concentration, area under the curve (AUC0-t), clearance, and mean residence time) of NR1, GRg1, and GRb1 were significantly different after oral administration of FXT (P<0.05) compared with PN. The AUC0-t values of GRg1 and GRb1 were 1.7- and 3.4-fold greater, respectively, in FXT than in PN. The compatible herbs of FXT could prolong the retention time and increase the systemic exposure of NR1, GRg1, and GRb1 compared with PN in vivo, providing some scientific basis for the compatibility and clinical use of FXT.


The impact of exercise on suicide risk: examining pathways through depression, PTSD, and sleep in an inpatient sample of veterans.
Suicide has a large public health impact. Although effective interventions exist, the many people at risk for suicide cannot access these interventions. Exercise interventions hold promise in terms of reducing suicide because of their ease of implementation. While exercise reduces depression, and reductions in depressive symptoms are linked to reduced suicidal ideation, no studies have directly linked exercise and suicide risk. The current study examined this association, including potential mediators (i.e., sleep disturbance, posttraumatic stress symptoms, and depression), in a sample of Veterans. SEM analyses revealed that exercise was directly and indirectly associated with suicide risk. Additionally, exercise was associated with fewer depressive symptoms and better sleep patterns, each of which was, in turn, related to lower suicide risk.


Modified Gath-Geva fuzzy clustering for identification of Takagi-Sugeno fuzzy models.
The construction of interpretable Takagi-Sugeno (TS) fuzzy models by means of clustering is addressed. First, it is shown how the antecedent fuzzy sets and the corresponding consequent parameters of the TS model can be derived from clusters obtained by the Gath-Geva (GG) algorithm. To preserve the partitioning of the antecedent space, linearly transformed input variables can be used in the model. This may, however, complicate the interpretation of the rules. To form an easily interpretable model that does not use the transformed input variables, a new clustering algorithm is proposed, based on the expectation-maximization (EM) identification of Gaussian mixture models. This new technique is applied to two well-known benchmark problems: the MPG (miles per gallon) prediction and a simulated second-order nonlinear process. The obtained results are compared with results from the literature.


Prevalence of subungual melanoma in patients with cutaneous malignant melanoma: A systematic review and meta-analysis.
Subungual melanoma (SUM) is a rare type of cutaneous malignant melanoma (CMM) associated with poor prognosis, while data regarding its prevalence are scarce. We sought to provide a comprehensive systematic review and meta-analysis of the prevalence rates of SUM among all types of CMM, considering certain demographic and clinical characteristics. The MEDLINE electronic database was searched systematically to identify eligible studies providing prevalence rate estimates of SUM in patients with CMM. Included studies were further analysed to estimate the relative prevalences of SUM according to study design, study years, geographical region and sex distribution. Twenty-eight studies met the inclusion criteria. The overall SUM prevalence was 1.9% (95% CI [1.5%-2.3%]). The prevalence of SUM did not differ significantly between population- and hospital-based studies and remained stable over time. However, it was found to be significantly higher in Asians compared to patients of other geographical regions as well as in studies with more men than women compared to those with female preponderance (p < 0.001). In all, the overall SUM prevalence among all subtypes of CMM was estimated at 1.9%, without significant changes over time, and was found to exhibit significant variability between subgroups of different geographical regions.


Serrated polyps of the colon and rectum (hyperplastic polyps, sessile serrated adenomas, traditional serrated adenomas, and mixed polyps)-proposal for diagnostic criteria.
Until recently, two major types of colorectal epithelial polyps were distinguished: the adenoma and the hyperplastic polyp. While adenomas-because of their cytological atypia-were recognized as the precursor lesions for colorectal carcinoma, hyperplastic polyps were perceived as harmless lesions without any potential for malignant progression mainly because hyperplastic polyps are missing cytological atypia. Meanwhile, it is recognized that the lesions, formerly classified as hyperplastic, represent a heterogeneous group of polyps with characteristic serrated morphology some of which exhibit a significant risk of neoplastic progression. These serrated lesions show characteristic epigenetic alterations not commonly seen in colorectal adenomas and progress to colorectal carcinoma via the so-called serrated pathway (CpG-island-methylation-phenotype pathway). This group of polyps is comprised not only of hyperplastic polyps, but also of sessile serrated adenomas, traditional serrated adenomas and mixed polyps, showing serrated and "classical" adenomatous features. Diagnostic criteria and nomenclature for these lesions are not uniform and, therefore, somewhat confusing. In a consensus conference of the Working Group of Gastroenterological Pathology of the German Society of Pathology, standardization of nomenclature and diagnostic criteria as well as recommendations for clinical management of these serrated polyps were formulated and are presented herein.


Myosin II activation promotes neurite retraction during the action of Rho and Rho-kinase.
The Rho small GTPase regulates myosin II activity through the phosphorylation of the myosin light chain (MLC) by activating Rho-kinase, which is a target of Rho. Several lines of evidence point to an important role of Rho in the action of lysophosphatidic acid (LPA) and thrombin in provoking neurite retraction in N1E-115 neuroblastoma cells. Here we examined whether Rho-kinase and myosin II are involved in neurite retraction in N1E-115 cells. We showed that the expression of constitutively active forms of Rho-kinase induced neurite retraction in NIE-115 cells and MLC phosphorylation in NIH 3T3 cells, whereas the expression of dominant negative forms of Rho-kinase inhibited the LPA-induced neurite retraction in N1E-115 cells and the serum-induced MLC phosphorylation in NIH 3T3 cells. The expression of mutant MLCT18D,S19D (substitution of Thr and Ser by Asp), which is known to lead to the activation of myosin ATPase and a conformational change of myosin II when reconstituted with myosin heavy chains in vitro, also promoted neurite retraction. These results indicate that Rho-kinase is involved in the LPA-induced neurite retraction downstream of Rho, and that myosin II activation promotes neurite retraction downstream of Rho and Rho-kinase.


"Enteroatmospheric fistulae"--gastrointestinal openings in the open abdomen: a review and recent proposal of a surgical technique.
The occurrence of an enteric fistula in the middle of an open abdomen is called an enteroatmospheric fistula, which is the most challenging and feared complication for a surgeon to deal with. It is in fact not a true fistula because it neither has a fistula tract nor is covered by a well-vascularized tissue. The mortality of enteroatmospheric fistulae was as high as 70% in past decades but is currently approximately 40% due to advanced modern intensive care and improved surgical techniques. Management of patients with an open abdomen and an enteroatmospheric fistula is very challenging. Intensive care support of organs and systems is vital in order to manage the severely septic patient and the associated multiple organ failure syndrome. Many of the principles applied to classic enterocutaneous fistulae are used as well. Control of enteric spillage, attempts to seal the fistula, and techniques of peritoneal access for excision of the involved loop are reviewed in this report. Additionally, we describe our recent proposal of a lateral surgical approach via the circumference of the open abdomen in order to avoid the hostile and granulated surface of the abdominal trauma, which is adhered to the intraperitoneal organs.


Genotype-based association models of complex diseases to detect gene-gene and gene-environment interactions.
A central problem in genetic epidemiology is to identify and rank genetic markers involved in a disease. Complex diseases, such as cancer, hypertension, diabetes, are thought to be caused by an interaction of a panel of genetic factors, that can be identified by markers, which modulate environmental factors. Moreover, the effect of each genetic marker may be small. Hence, the association signal may be missed unless a large sample is considered, or a priori biomedical data are used. Recent advances generated a vast variety of a priori information, including linkage maps and information about gene regulatory dependence assembled into curated pathway databases. We propose a genotype-based approach that takes into account linkage disequilibrium (LD) information between genetic markers that are in moderate LD while modeling gene-gene and gene-environment interactions. A major advantage of our method is that the observed genetic information enters a model directly thus eliminating the need to estimate haplotype-phase. Our approach results in an algorithm that is inexpensive computationally and does not suffer from bias induced by haplotype-phase ambiguity. We investigated our model in a series of simulation experiments and demonstrated that the proposed approach results in estimates that are nearly unbiased and have small variability. We applied our method to the analysis of data from a melanoma case-control study and investigated interaction between a set of pigmentation genes and environmental factors defined by age and gender. Furthermore, an application of our method is demonstrated using a study of Alcohol Dependence.


Surveillance for health behaviors of American Indians and Alaska Natives-findings from the behavioral risk factor surveillance system, 2000-2006.
The authors compared estimates for cancer risk factors, use of cancer screening tests, health status indicators, and access to care for American Indians and Alaska Natives (AI/ANs) and non-Hispanic whites (NHWs) in the US and for AI/ANs in 6 Indian Health Service regions. Behavioral Risk Factor Surveillance System data were aggregated from the years 2000 through 2006 and were used to calculate weighted prevalence estimates by gender for key variables except demographic variables. Compared with NHWs, AI/ANs had lower prevalence estimates for income, educational attainment, insurance coverage, and access to personal healthcare providers. AI/ANs in Alaska and NHWs had similar estimates for diabetes (approximately 6%); however, the prevalence was nearly twice as high among AI/ANs in the other regions. The prevalence of obesity was higher for AI/ANs (29.6%) than for NHWs (20.9%). The prevalence of binge drinking was higher among AI/AN males (24.9%) than among AI/AN females (8.5%). Heavy drinking was more prevalent among NHW females (5.3%) than among AI/AN females (3.5%). AI/ANs were more likely to be current smokers (31.1%) than NHWs (22.8%). The prevalence of AI/ANs who never smoked ranged from 31.5% in Alaska to 56.9% in the Southwest. In 5 of the 6 regions, AI/AN females had lower prevalence estimates of both Papanicolaou and mammography testing than NHW females. The use of colorectal cancer screening tests was more common among NHWs (53.8%) than among AI/ANs (44%). Although cancer health disparities persist among AI/ANs, the current analysis indicated that variation in the prevalence of their chronic disease risk factors may be obscured when national data are not examined by smaller geographic areas such as regions.


Irritable bowel syndrome: the problem and the problem of treating it - is there a role for probiotics?
The aim of this review is to highlight the impact of irritable bowel syndrome (IBS) in those patients who consult the medical profession and examine the therapeutic potential of probiotics in this condition, where there is a strong need for new treatment options. Traditionally, IBS is frequently regarded as a trivial condition which is certainly not life threatening and mainly psychological in origin. However, these preconceptions are misplaced, as in some patients the condition can be devastating with the pain being as severe as that of childbirth coupled with incapacitating bowel dysfunction. In addition, patients suffer from a variety of non-colonic symptoms such as low backache, constant lethargy, nausea and genito-urinary problems, all of which lead to these patients having extremely poor quality of life. Unfortunately, the treatment of IBS is very unsatisfactory with only one new medication being developed for this condition in the last 25 years. It is now recognised that IBS is a multifactorial condition with symptoms being triggered by a variety of factors, some of which appear to be influenced by probiotics, resulting in speculation that they may have therapeutic potential in this condition. There have been over thirty controlled clinical trials of probiotics in IBS with approximately two-thirds of these studies showing evidence of an improvement in symptoms. However, not all probiotics appear to be effective with different symptoms being improved by different strains and some improving symptoms more than others. Consequently, the ideal probiotic for the treatment of IBS has yet to be defined, but the evidence is good enough to encourage further research with the aim of identifying an optimal strain or strains.


Advancing Community-Engaged Research through Partnership Development: Overcoming Challenges Voiced by Community-Academic Partners.
Community-engaged research (CEnR) is a promising approach to translate research into practice. The Meharry-Vanderbilt Community Engaged Research Core (CERC) was established to support academic-community partnerships with the goal of improving community health. A successful mini-grant program has been used to foster academic community partnerships. We describe the process of developing, implementing, and sustaining a grant program and discuss how the program has informed our CEnR activities. Grant applications are solicited twice per year. Submission guidelines align with typical procedures. However, considerable guidance and support for applicants are provided. If necessary. Grant funds are awarded directly to the community partner. The CERC has awarded nearly $250,000 to support academic-community research partnerships. Both community and academic partners reported that the opportunity was beneficial and enriched their work. Resources provided by our mini-grant program enhance the development and sustainability of CEnR partnerships.


Data-driven modeling and forecasting of COVID-19 outbreak for public policy making.
This paper presents a data-driven approach for COVID-19 modeling and forecasting, which can be used by public policy and decision makers to control the outbreak through Non-Pharmaceutical Interventions (NPI). First, we apply an extended Kalman filter (EKF) to a discrete-time stochastic augmented compartmental model to estimate the time-varying effective reproduction number (Rt). We use daily confirmed cases, active cases, recovered cases, deceased cases, Case-Fatality-Rate (CFR), and infectious time as inputs for the model. Furthermore, we define a Transmission Index (TI) as a ratio between the instantaneous and the maximum value of the effective reproduction number. The value of TI indicates the "effectiveness" of the disease transmission from a contact between a susceptible and an infectious individual in the presence of current measures, such as physical distancing and lock-down, relative to a normal condition. Based on the value of TI, we forecast different scenarios to see the effect of relaxing and tightening public measures. Case studies in three countries are provided to show the practicability of our approach.


[Gene Mutation Types of Thalassemia in Chongzuo Childbearing-age Population of Guangxi Zhuang Autonomous Region of China].
To investigate the gene mutation and genotype distribution of thalassemia in the population of childbearing age in Chongzuo area of Guangxi. Six α-thalassemia and 17 β-thalassemia gene mutations common in Chinese were detected by gap-polymerase chain reaction (gap-PCR) combined with agarose gel eletrophoresis and reserve dot bolt hybridization in 29 266 cases of child-bearing age suspected of thalassemia. A total of 19 128 (65.36%) cases were identified with thalassemia. The detection rate of α-thalassemia, β-thalassemia and α-combining β-thalassemia was 45.25% (13 242/29 266), 15.47% (4 526/29 266) and 4.65% (1 360/29 266), respectively. A total carrying rate of 8 kinds of α-thalassemia gene mutations was 26.74% (15 649/58 532), including 12.51% for --SEA, followed by 5.70% for -α3.7, and 0.24% for --Thai. Among 32 α-thalassemia genotypes, the most common five were --SEA/αα, -α3.7/αα, αCSα/αα, -α4.2/αα and αWSα/αα, accounting for 47.27%, 18.31%, 8.56%, 8.52% and 7.91%, respectively, as well as 0.97% for --Thai/αα. A total carrying rate of 13 kinds of β-thalassemia gene mutations was 10.07% (5 897/58 532), including 3.63% for CD41-42, followed by 2.55% for CD17, and 0.003% for -50 (G>A). Among 17 β-thalassemia genotypes, the most common six were CD41-42/N, CD17/N, CD71-72/N, CD26/N, 28/N and IVSI-1/N, accounting for 36.15%, 25.81%, 9.43%, 8.18%, 8.09% and 7.75%. The homozygous genotype CD26/CD26 [hemoglobin (Hb): 121 g/L] and -28/-28 (Hb: 56 g/L) were respectively detected in one case, and double heterozygous genotype were detected in 5 cases, including 3 cases of CD41-42/CD26 (Hb: 41 g/L, 51 g/L, 63 g/L, respectively), 1 case of -28/IVSI-1 (Hb: 53 g/L), and 1 case of CD71-72/CD26 (Hb: 89 g/L), in which patients with moderate or severe anemia had a history of blood transfusion. Among 104 α-combining β-thalassemia genotypes, the most common were --SEA/αα, -α3.7/αα combining CD41-42/N and --SEA/αα combining CD17/N, accounting for 12.13%, 9.63% and 9.26%, respectively. In addition, 1 case of --SEA/-α3.7 combining -28/IVSI-1 (Hb: 83 g/L) and 1 case of -α3.7/αα combining CD41-42/ CD41-42 (Hb: 110 g/L) were detected without history of blood transfusion, while 1 case of αWSα/αα combining CD41-42/CD17 (Hb: 79 g/L) and 1 case of --SEA/αα combining CD17/-28 (Hb: 46 g/L) were detected with history. The detection rate of thalassemia genes is high and the mutations are diverse in the population of childbearing age in Chongzuo area of Guangxi. The common deletion genotype is --SEA/αα in α-thalassemia and CD41-42/N in β-thalassemia, and deletion genotype --Thai is not rare. There is a certain incidence of intermediate and severe β-thalassemia, and most patients require transfusion therapy. The results are beneficial for genetic consultation and intervention of thalassemia.


Wavelength-diverse polarization modulators for Stokes polarimetry.
Information about the three-dimensional structure of solar magnetic fields is encoded in the polarized spectra of solar radiation by a host of physical processes. To extract this information, solar spectra must be obtained in a variety of magnetically sensitive spectral lines at high spatial, spectral, and temporal resolution with high precision. The need to observe many different spectral lines drives the development of Stokes polarimeters with a high degree of wavelength diversity. We present a new paradigm for the design of polarization modulators that operate over a wide wavelength range with near-optimal polarimetric efficiency and are directly applicable to the next generation of multiline Stokes polarimeters. These modulators are not achromatic in the usual sense because their polarimetric properties vary with wavelength, but they do so in an optimal way. Thus, we refer to these modulators as polychromatic. We present here the theory behind polychromatic modulators, illustrate the concept with design examples, and present the performance properties of a prototype polychromatic modulator.


Introduction and establishment of the exotic mosquito species Aedes japonicus japonicus (Diptera: Culicidae) in Belgium.
The establishment of the potential vector species Aedes (Finlaya) japonicusjaponicus (Theobald) (Diptera: Culicidae) in southern Belgium is reported. The species was most likely introduced through the international trade in used tires. It was first collected in 2002 on the premises of a second-hand tire company and was sampled using different sampling methods in the two consecutive years (2003-2004). It was only in 2007 and 2008, during a national mosquito survey (MODIRISK), that its presence as adults and larvae at the above-mentioned site and at another tire company in the area was confirmed based on morphological and molecular identification. This discovery is the first record for Belgium of an exotic mosquito species that established successfully and raises the question on the need for monitoring and control. Considering the accompanying species found during the surveys, we also report here the first observation of Culex (Maillotia) hortensis hortensis (Ficalbi) in Belgium.


Ketamine and pharmacological imaging: use of functional magnetic resonance imaging to evaluate mechanisms of action.
Ketamine has been used as a pharmacological model for schizophrenia as subanesthetic infusions have been shown to produce temporary schizophrenia-like symptoms in healthy humans. More recently, ketamine has emerged as a potential treatment for multiple psychiatric disorders, including treatment-resistant depression and suicidal ideation. However, the mechanisms underlying both the psychotomimetic and the therapeutic effects of ketamine remain poorly understood. This review provides an overview of what is known of the neural mechanisms underlying the effects of ketamine and details what functional MRI studies have yielded at a systems level focused on brain circuitry. Multiple analytic approaches show that ketamine exerts robust and consistent effects at the whole-brain level. These effects are highly conserved across human and nonhuman primates, validating the use of nonhuman primate models for further investigations with ketamine. Regional analysis of brain functional connectivity suggests that the therapeutic potential of ketamine may be derived from a strengthening of executive control circuitry, making it an intriguing candidate for the treatment of drug abuse. There are still important questions about the mechanism of action and the therapeutic potential of ketamine that can be addressed using appropriate functional neuroimaging techniques.


Comparison of rejection rate and functional outcome of small bowel transplantation alone or in conjunction with the ileocecal valve versus combined small and large bowel transplantation.
Preservation of the ileocecal valve improves absorptive function and decreases the amount of small bowel needed for survival in patients with short gut syndrome. We compared the results of small and large bowel transplant (SLBTx), small bowel transplant only (SBTx), and SBTx with the ileocecal valve (ICVTx) in a porcine model. Total enterectomy was performed on 18 Yorkshire-Landrace pigs followed by orthotopic SBLTx (n = 6), SBTx (n = 6), and ICVTx (n = 6). A jejunostomy and an ileostomy were constructed for biopsies. Overall mean survival was 17 d with no statistically significant difference between groups. Rejection was seen in 6/6 SLBTx, 4/6 SBTx, and 4/6 ICVTx recipients. Acute rejection was seen in 84.3% of SLBTx, 52.3% of SBTx, and 42.5% of the ICVTx mucosal biopsy samples. Two cases of intra-abdominal infection were in the ICVTx group only. Weight loss was 147 g/d in the SLBTx group, 643 g/d in the SBTx group, and 393 g/d in the ICVTx group. While the functional outcome after SLBTx and ICVTx was noticeably better than the SBTx group, the increased rejection and intra-abdominal infection rates make transplanting the large bowel or the ileocecal valve a less attractive clinical option.


Development of a semiquantitative PCR assay using internal standard and colorimetric detection on microwell plate for pseudorabies virus.
We have developed a semiquantitative PCR assay on microtitre plates for quantitation of pseudorabies virus (PRV). The test is based on co-amplification with an internal control (IC) of the target viral DNA, followed by hybridization of the biotin-amplified products on a capture probe covalently immobilized to a Covalink-NH MicroWells plate and then visualization with colorimetric enzymatic reactions. PCR was performed in the presence of uracil-N-glycolsylase (UNG) with dUTP instead of dTTP to prevent false positive results due to carry-over contamination. Our colorimetric test had a 3.5 log dynamic range with a detection level of 30 DNA copies per PCR reaction. A standard curve for quantitation of pseudorabies virus was established from co-amplification of 10 to 10(5) PRV molecules with 1000 IC molecules. Ratios of viral optical density/IC optical density were plotted against the number of PRV DNA target molecules in the PCR amplification. Integration of 96-well formats and automation using robots at different steps of the test ensured a good repeatability. Calibration of the quantitative test using samples from experimentally-infected pigs is in progress.


Containing abjection in nursing: the end of shift handover as a site of containment.
This theoretical paper has arisen out of a national study of the end of shift nursing handover. It draws upon and offers a postmodern reformulation of the psychodynamic concepts of anxiety and defence as articulated by Menzies Lyth in her study of nursing work in the 1950s. It outlines Kristeva's concept of abjection and draws upon Bion's formulation of the concept of containing to offer an account of how, in the current context of hospital nursing, the handover can function to contain abjection.


A facile preparation of immobilized naringinase on polyethyleneimine-modified Fe3O4 magnetic nanomaterials with high activity.
Polyethyleneimine-modified Fe3O4 nanoparticles (Fe3O4-PEI) were synthesized by the one-step co-precipitation method, and the resulting material was used to immobilize naringinase from the fermentation broth of Aspergillus niger FFCC uv-11. The immobilized naringinase activity could reach up to 690.74 U per g-support at the conditions of initial naringinase activity of 406.25 U mL-1, immobilization time of 4 h, glutaraldehyde concentration of 40% (w/v), immobilization temperature of 35 °C, and pH value of 5.5, with naringinase-carrying rate and naringinase activity recovery of 92.93% and 20.89%, respectively. In addition, the immobilized naringinase exhibited good pH and temperature stability in a pH range of 3.5-6.0 and temperature range of 40-70 °C, and the optimal reaction pH and reaction temperature were optimized as 5.5 and 60 °C, respectively. Besides, the immobilized naringinase could maintain 60.58% of the original activity after 10 reuse cycles, indicating that the immobilized naringinase had good reusability. Furthermore, the immobilized naringinase also performed excellent storage stability, 87.52% of enzyme activity still remained as stored at 4 °C for one month. In conclusion, the Fe3O4-PEI could be considered as a promising support for naringinase immobilization, with the advantages of high enzyme activity loading, good reusability, storage stability and rapid recovery.


Elimination of Hunner's Ulcers by Fulguration in Patients With Interstitial Cystitis: Is It Effective and Long Lasting?
To evaluate the outcome of fulguration of Hunner's ulcers (HUs) in painful bladder syndrome/interstitial cystitis (PBS/IC) that is refractory to conservative treatment. Patients diagnosed with refractory PBS/IC and treated with fulguration between 2011 and 2013 were identified through screening of medical records. To evaluate treatment outcomes, voiding diaries, the visual analogue scale (VAS) for pain, and two IC symptom questionnaires (pelvic pain and urgency/frequency scale [PUF] and O'Leary-Sant IC symptom index and IC problem index [OS]) were used. Fulguration was deemed to be successful if the VAS score was <2 or less than half of the preoperative VAS score. In total, 27 patients with PBS/IC in whom conservative treatments had failed were enrolled. Two months after fulguration, decreases were observed in the mean 24-hour urinary frequency (from 16.0 to 10.2), 24-hour urgency episodes (8.0 to 1.8), and the VAS (5.8 to 1.2), PUF symptom (15.1 to 7.0), PUF bother (8.4 to 2.7), OS symptom (15.1 to 7.2), and OS problem (13.8 to 6.0) scores. At 5 and 10 months, all variables had worsened. At 2, 5, and 10 months, the success rates were 94.1%, 70.0%, and 33.3%, respectively. Four patients underwent one repeat fulguration on average 11.3 months after the first fulguration. Repeat fulguration was not significantly associated with any clinical characteristics. In PBS/IC that was refractory to medication or other conservative treatments, HU elimination by fulguration effectively improved symptoms. However, this effect decreased gradually over time.


Torsion of testis in Nigerians.
Torsion in a black population is presented. The clinical features are the same as the white counterpart, but the mean age is, however, much higher. There is no bias against any side of testis. Physicians are to blame for the poor salvage rate. Gangrenous testes should not be conserved and early diagnosis and treatment remain the only means of saving torted testis. Prophylactic fixation of contralateral testis is mandatory and must not be postponed. External manual detorsion is not a substitute for surgery and should not remove the sense of emergency. Relevant pathology, the mechanism of torsion and differential diagnosis are discussed.


Addressing narcissistic personality features in the context of medical care: integrating diverse perspectives to inform clinical practice.
Narcissistic personality disorder (NPD) is characterized by an unrealistic need for admiration, lack of empathy toward others, and feelings of superiority. NPD presents a unique and significant challenge in clinical practice, particularly in medical settings with limited provider contact time, as health professionals treat individuals who often require excessive admiration and have competing treatment needs. This practice review highlights real case examples across three distinct medically oriented clinical settings (inpatient and outpatient behavioral medicine and a Level I trauma center) to demonstrate the difficult and compromising situations that providers face when treating patients with general medical conditions and comorbid narcissistic personality features. The main goal of this article is to discuss the various challenges and obstacles associated with these cases in medical settings and discuss some strategies that may prove successful. A second goal is to bridge diverse conceptualizations of narcissism/NPD through the discussion of theoretical and empirical perspectives that can inform understanding of the clinical examples. Despite differing perspectives regarding the underlying motivation of narcissistic behavior, this practice review highlights that these paradigms can be integrated when sharing the same ultimate goal: to improve delivery of care across medically oriented clinical settings for patients with narcissistic features.