Transcripts involved in hemostasis: Exploring salivary complexes from Haementeria vizottoi leeches through transcriptomics, phylogenetic studies and structural features.
Throughout evolution, parasites have adapted in order to successfully intervene in the host defense, producing specific peptides and proteins. Interestingly, these peptides and proteins have been exploited as potential drug candidates against several diseases. Furthermore, biotechnology studies and cDNA libraries have remarkably contributed to identify potentially bioactive molecules. In this regard, herein, a cDNA library of salivary complexes from Haementeria vizottoi leeches was constructed, the transcriptome was characterized and a phylogenetic analysis was performed considering antistasin-like and antiplatelet-like proteins. Hundred twenty three transcripts were identified coding for putative proteins involved in animal feeding (representing about 10% of the expression level). These sequences showed similarities with myohemerythrins, carbonic anhydrases, anticoagulants, antimicrobials, proteases and protease inhibitors. The phylogenetic analysis, regarding antistasin-like and antiplatetlet-like proteins, revealed two main clades in the Rhynchobdellida leeches. As expected, the sequences from H. vizottoi have presented high similarities with those types of proteins. Thus, our findings could be helpful not only to identify new coagulation inhibitors, but also to better understand the biological composition of the salivary complexes.


Is use of CBCT without proper training justified in paediatric dental traumatology? An exploratory study.
Proper skills in radiographic diagnosis are essential for optimal management of dental trauma. To assess diagnostic accuracy obtained by paediatric dentists using Cone Beam Computed Tomography (CBCT) without specific training and to compare this with their performance using intraoral radiographs. Intraoral and CBCT images of 89 teeth, spread over twenty dental trauma cases were presented in random order to nine paediatric dentists. Diagnostic findings were compared with those of a benchmark reference. Sensitivity and specificity were calculated and compared using paired t-tests. Overall, observers' diagnostic performance was rather poor with significantly higher sensitivity when using 2D images (P = 0.017). Performance differed considerably according to the type of pathology. Using either imaging modality, sensitivity for diagnosing apical pathology and root fractures was high while the opposite was seen for inflammatory root resorption, root cracks and subluxations. Statistically significant differences between imaging modalities were seen for root fractures (P = 0.013) and apical pathology (P = 0.001), in favor of 3D, and for crown fractures (P = 0.009) in favor of 2D. Overall poor performance of paediatric dentists indicates that additional training in radiographic diagnosis is required. In order to justify the use of CBCT to increase diagnostic performance, proper training of the paediatric dentist is mandatory.


Choledochal cyst and systemic lupus erythematosus.
A 16-year-old female with systemic lupus erythematosus was diagnosed with choledochal cyst. As high-dose steroids had been prescribed for CNS lupus, surgery was performed under steroid cover. Despite postoperative pneumonia and wound infection, she is well 2 years later. There is no similar report in the literature.


Nursing students practice primary fire prevention.
The purpose of this project was to evaluate a standardized, interactive, home fire safety program for elementary school students. Senior baccalaureate nursing students in their pediatric clinical rotation taught burn prevention techniques using Hazard House, a model house filled with common household fire hazards (Hazard House, 2006, Ref. 1). Elementary school students were encouraged to identify the hazards and discuss ways in which the house could be made safer. Local firemen then briefly presented what to do if a fire occurred, how firemen may look during a rescue, and the importance of working smoke alarms in the home. A pretest-posttest design was used to examine the effectiveness of an educational intervention. The three groups of participants included 128 kindergarten students, 311 students in grades 1-2, and 61 students in grades 3-4. The tests and interventions were tailored appropriately for each age group. There was no difference in pre- and post-test scores for the students in kindergarten and grades 3-4 (p>0.05). However, there was a significant difference for students in grades 1-2 (p<0.001). It is important for nurses to assess for and teach about fire injury prevention to prevent potentially devastating irreversible injuries. The results suggest that the educational intervention was effective in improving the understanding of fire safety for students in grades 1-2. Future studies may need to include a larger sample of students for the other grades.


COVID-19 pandemic digitization lessons for sustainable development of micro-and small- enterprises.
The coronavirus (COVID-19) pandemic has undeniably influenced the global economy and environment. Major victims of the COVID-19 outbreak are Micro and Small Enterprises (MSEs), especially in developing countries, mainly because of limited use of digital technologies. This paper employs a literature review and personal insights to provide COVID-19 pandemic digitization lessons for sustainable development of MSEs from a technology for social good perspective. We develop a framework to support post COVID-19 digital transformation for sustainable development of MSEs. We find that digital payments, especially mobile money, should be a critical digital transformation priority for MSEs. Also, institutions must support MSE resources and capabilities to adopt digital transformation for business continuity, and sustainable production and consumption. Our study suggests that MSE managers and other stakeholders rethink their business strategies, incorporating crisis scenarios and business continuity plans to sustain customers virtually to enhance sustainable development. We also propose further research areas to improve the successful digital transformation of MSEs post COVID-19.


Cardio- Renal Outcomes With Long- Term Agalsidase Alfa Enzyme Replacement Therapy: A 10- Year Fabry Outcome Survey (FOS) Analysis.
Following the publication of 5-year agalsidase alfa enzyme replacement therapy (ERT) outcomes data from the Fabry Outcome Survey (FOS), 10-year data were analyzed. FOS (ClinicalTrials.gov identifier: NCT03289065) data (April 2001 to August 2018) were retrospectively analyzed. Estimated glomerular filtration rate (eGFR) and left ventricular mass indexed to height (LVMI) were analyzed after treatment start (baseline) for patients with ≥3 measurements, including baseline and year 10. Median (range) age (years) of the evaluable treated renal cohort at treatment start was 48.8 (17.9-67.3) for females (n=62), 34.4 (18.0-66.8) for males (n=90). With eGFR ≥60 mL/min/1.73 m2 at baseline, mean (95% CI) rate of eGFR change (eGFR/year) over 10 years was relatively stable in females (n=52; -0.55 [-1.12, +0.01]) and slightly declined in males (n=79; -1.99 [-2.45, -1.54]). With impaired kidney function (eGFR <60 mL/min/1.73 m2) at baseline, mean (95% CI) eGFR/year was stable in females (n=10; -0.14 [-1.43, +1.15]) and slightly declined in males (n=11; -2.79 [-4.01, -1.56]) over 10 years. Median (range) age (years) of the evaluable treated cardiac cohort at treatment start was 46.7 (3.7-67.3) for females (n=34), 28.2 (4.0-54.2) for males (n=35). With left ventricular hypertrophy (LVH; LVMI >48 g/m2.7 in females, >50 g/m2.7 in males) at baseline, mean (95% CI) LVMI/year slightly increased over 10 years in females (n=18; +1.51 [+0.91, +2.12]) and males (n=14; +0.87 (+0.19, +1.55). Without LVH at baseline, mean (95% CI) LVMI/year was stable in females (n=16; +0.52 [-0.13, +1.17]) and males (n=21; +0.57 [+0.02, +1.13]) over 10 years. Agalsidase alfa-treated patients with 10-year FOS data and preserved kidney function and/or normal LVMI at baseline remained largely stable; those with decreased kidney function or LVH at baseline experienced modest declines in renal function and/or increases in LVMI.


Prostatic atrophy: evidence for a possible role of local ischemia in its pathogenesis.
Prostatic atrophy may be histologically and at ultrasound similar to adenocarcinoma causing diagnostic confusion, its frequency increases with age but the etiopathogenesis is unknown. Based on a systematic study in autopsies previously done by one of us, ischemia due to local intense arteriosclerosis seems to be a potential factor for its pathogenesis. Absent blood flow in areas of prostatic atrophy might be a further evidence for a possible role of ischemia. From a total of 298 patients biopsied and studied by gray-scale and color Doppler transrectal ultrasound in the period 1998 to 2001, 33 patients had suspicious lesions (37 hypoechoic nodules and 3 heterogeneous lesions) showing prostatic atrophy as the only diagnosis on all these biopsied lesions. Adenocarcinoma, high-grade intraepithelial neoplasia or other atypical lesions were absent in all patients. On color Doppler the suspicious areas showed absent flow in 24/40 (60%), present flow in 12/40 (30%), and increased flow in 4/40 (10%) of the lesions. Absent flow in the majority of the lesions studied may be a further evidence for a possible role of local ischemia in the etiopathogenesis of prostatic atrophy.


Interaction of Xiphophorus and murine Fyn with focal adhesion kinase.
The Src family kinase/Focal Adhesion Kinase (FAK) complex is a signaling platform playing a crucial role in transformation downstream of oncogenic growth factor receptors. In the case of melanoma in Xiphophorus fish, the oncogenic EGF receptor orthologue Xiphophorus melanoma receptor kinase (Xmrk) effects continuous activation of the Src family kinase Fyn, but not of the other family members Src or Yes. Here, Fyn is strongly involved in promoting many tumorigenic events. Although Fyn is expressed in most mammalian tissues, there are only few reports of its involvement in the development of solid tumors. To find out whether the prominent role of Xiphophorus Fyn is based on an altered binding to its important binding partner FAK when compared to its mammalian Fyn counterparts, we performed yeast-two-hybrid analyses. We compared Xiphophorus and murine Fyn with respect to their binding to full-length and truncated FAK constructs. We found that interaction with FAK occurs similarly for Xiphophorus and mouse Fyn. Both phosphorylated FAK residue Y397 and FAK proline-rich domain are involved in Fyn binding. We also found interaction of FAK and Fyn in human melanoma cell lines. These data suggest a possible, yet unrecognized role of Fyn in the tumorigenesis of human melanoma, too.


Adrenal cortical carcinoma. A study of 32 patients.
Fifteen males and 17 females with adrenal cortical carcinoma were reviewed. Their average age at diagnosis was 50.33 years plus or minus 12.26 SD for males and 39.76 years plus or minus 12.02 SD for females. The 5-year survival rate in this series was 31.25%. Abdominal pain, weakness, and weight loss were the primary presenting symptoms, whereas abdominal mass, distant lymphadenopathy, hepatomegaly, and edema of the lower extremities were the main presenting signs. The major sites of distant metastatic involvement were the lungs, liver, lymph nodes, and bones. The best available mode of therapy was surgery. The use of ortho para 'DDD (o,p'DDD), either in addition to surgery or as the only mode of therapy, was not associated with any significant advantage to the patient. Female patients had a longer survival than males, probably because of their younger age at diagnosis.


Liver macrophages in tissue homeostasis and disease.
Macrophages represent a key cellular component of the liver, and are essential for maintaining tissue homeostasis and ensuring rapid responses to hepatic injury. Our understanding of liver macrophages has been revolutionized by the delineation of heterogeneous subsets of these cells. Kupffer cells are a self-sustaining, liver-resident population of macrophages and can be distinguished from the monocyte-derived macrophages that rapidly accumulate in the injured liver. Specific environmental signals further determine the polarization and function of hepatic macrophages. These cells promote the restoration of tissue integrity following liver injury or infection, but they can also contribute to the progression of liver diseases, including hepatitis, fibrosis and cancer. In this Review, we highlight novel findings regarding the origin, classification and function of hepatic macrophages, and we discuss their divergent roles in the healthy and diseased liver.


Determining heavy metals in spent compact fluorescent lamps (CFLs) and their waste management challenges: some strategies for improving current conditions.
From environmental viewpoint, the most important advantage of compact fluorescent lamps (CFLs) is reduction of green house gas emissions. But their significant disadvantage is disposal of spent lamps because of containing a few milligrams of toxic metals, especially mercury and lead. For a successful implementation of any waste management plan, availability of sufficient and accurate information on quantities and compositions of the generated waste and current management conditions is a fundamental prerequisite. In this study, CFLs were selected among 20 different brands in Iran. Content of heavy metals including mercury, lead, nickel, arsenic and chromium was determined by inductive coupled plasma (ICP). Two cities, Tehran and Tabriz, were selected for assessing the current waste management condition of CFLs. The study found that waste generation amount of CFLs in the country was about 159.80, 183.82 and 153.75 million per year in 2010, 2011 and 2012, respectively. Waste generation rate of CFLs in Iran was determined to be 2.05 per person in 2012. The average amount of mercury, lead, nickel, arsenic and chromium was 0.417, 2.33, 0.064, 0.056 and 0.012 mg per lamp, respectively. Currently, waste of CFLs is disposed by municipal waste stream in waste landfills. For improving the current conditions, we propose by considering the successful experience of extended producer responsibility (EPR) in other electronic waste management. The EPR program with advanced recycling fee (ARF) is implemented for collecting and then recycling CFLs. For encouraging consumers to take the spent CFLs back at the end of the products' useful life, a proportion of ARF (for example, 50%) can be refunded. On the other hand, the government and Environmental Protection Agency should support and encourage recycling companies of CFLs both technically and financially in the first place.


Changes in the morphology and protein expression of germ cells and Sertoli cells in plateau pikas testes during non-breeding season.
Plateau pikas are seasonally breeding small herbivores that inhabit the meadow ecosystem of the Qinghai-Tibetan Plateau. Testis regression in plateau pikas begins in early June, and the male pikas are completely infertile, with a dramatically reduced testis size, in late July. In this study, a decreased germ cell number in the testes was first noted in early June. By late June, only Sertoli cells and a small number of spermatogonia remained. Interestingly, large gonocyte-like germ cells were observed in early July. In late July, the number of gonocyte-like cells per tubule increased significantly, and most of the Sertoli cell nuclei moved to and clustered in the center of the seminiferous tubules. The gonocyte-like germ cells and Sertoli cells began to express AP-2γ and anti-Mullerian hormone (AMH) proteins, which were detected in the germ cells and Sertoli cells of juvenile pikas but not in adult testes. Simultaneously, LC3 puncta dramatically increased in the seminiferous tubules of the pikas' testes during the non-breeding season. Our study found that spermatogonia and Sertoli cells in non-breeding adult pikas morphologically resembled those in juvenile pikas and expressed specific markers, indicating that de-differentiation-like transitions may occur during this process.


[Trial of a hyperimmune serum against para-influenza 3, bovine adenovirus 1, infectious rhinotracheitis and mucosal disease].
A four-valent serum was obtained by parallel hyperimmunization of cattle with live viral suspensions of parainfluenza-3, bovine adenovirus I, the virus of infectious rhinotracheitis and the mucous disease virus. The serum's neutralizing titres are between 1:1280 and 1:2560. The lasting exploitation of serum producing cattle indicates that no competition exists between the four antigens used in the process of hyperimmunization. Experimental testing of the serum on calves and its application in practical work proved its prophylactic and medicative effect. These results confirm the thesis that the use of passive immunoprophylaxis is needed in respiratory diseases of calves under conditions existing in intensive cattle-breeding.


Abscess drainage with the aid of pelvic real-time sonography.
A case is described in which digital pelvic real-time ultrasound evaluation was used in order to determine the proper placement of a catheter for abscess drainage. This is the first description of utilizing this new technique as an adjunct to a surgical procedure.


Adapting global evidence-based practice guidelines to the Egyptian healthcare context: the Egyptian Pediatric Clinical Practice Guidelines Committee (EPG) initiative.
In Egypt, academic organizations, professional societies, and research groups develop clinical practice guidelines (CPGs) in order to improve patient quality care and safety. Although important improvements have been made over the past years, many of these consensus-based guideline documents still lack the transparency and methodological rigor of international standards and methodologies recommended by reference evidence-based healthcare and guideline organizations like the Guidelines International Network. In the Egyptian Pediatric Clinical Practice Guidelines Committee (EPG), we have adopted one of the CPG formal adaptation methodological frameworks named the 'Adapted ADAPTE', relevant CPG resources (e.g., the Appraisal of Guidelines for Research and Evaluation or AGREE II Instrument), and involved key stakeholders including clinical and healthcare topic experts and guideline methodologists in producing 32 trustworthy national evidence-based CPGs and one protocol customized to the healthcare context and services provided for Egyptian children. An EPG online website was launched to make these CPGs available and accessible as CPG summaries for pediatricians and relevant healthcare providers. The lessons learned, enablers, challenges, and solutions relevant to Egyptian National Pediatric CPGs identified in this paper could be used to address and enrich the debate on pediatric high-quality CPGs, especially for countries of similar contexts and systems. The online version contains supplementary material available at 10.1186/s42269-023-01059-0.


Bacteremia in connection with transurethral resection of the prostate.
A bacteriological survey of 50 consecutive patients undergoing transurethral resection of the prostate was performed. Preoperatively, 28% of the patients had asymptomatic bacteriuria. In the postoperative period, 46% of all the patients developed transient bacteremia. A significantly higher rate of bacteremia was found in patients with hypertrophy of the prostate than in those with cancer of the prostate and in patients undergoing long-lasting surgical intervention. Patients who developed bacteremia due to pathogenic bacteria were hospitalized for a significantly longer period of time.


Spaghetti Technique Versus Wide Local Excision for Lentigo Maligna Affecting the Head and Neck Regions: Surgical Outcome and Descriptive Analysis of 79 Cases from a Single Practice Cohort.
Lentigo maligna is a subtype of melanoma in situ that typically affects the head and neck region with an increasing incidence. Margin-controlled techniques, such as spaghetti technique (ST), have gained popularity over wide local excision (WLE) with a margin of 5 mm. To evaluate the outcomes of lentigo maligna cases in the head and neck area treated by either WLE or ST in a tertiary referral hospital. The secondary goal was to describe the demographic and clinical characteristics of our series. Cohort study of patients diagnosed with lentigo maligna on the head and neck region between January 2014 and February 2022 in a tertiary hospital. In total, 79 lentigo maligna were studied, corresponding to 77 patients. Fifty-three lesions (67%) were treated with WLE and 26 (33%) with ST. The mean age of the patients was 73 years and 58% were men. Most of the tumors were located on the cheek (50%) and mean lesion diameter was 2.2 cm for the ST group and 1.2 cm for the WLE group. Mean duration follow-up was 44 months. There were two local recurrences in the WLE group (2/53; 3.7%) and none in the ST group. Both WLE and ST are appropriate surgical approaches for lentigo maligna. ST offers an efficient alternative to Mohs surgery for treating lentigo maligna in the head and neck area, especially when guided by reflectance confocal microscopy.


Technical Outcomes of Porto-Mesenteric Venous Reconstruction in Pancreatic Resection Using Autologous Left Renal Vein Graft as Conduit.
Portal or superior mesenteric vein (PV-SMV) resection and reconstruction is sometimes required during pancreatic tumor resection. In patients requiring segmental venous resection with interposition grafting, the left renal vein (LRV) is an accessible autologous solution. However, long-term patency outcomes of the LRV as an interposition conduit in this setting have not been analyzed. We conducted a retrospective analysis of patients undergoing pancreatic resection with PV-SMV reconstruction using LRV between 2002 and 2022. The primary outcome was PV-SMV patency at last follow-up, assessed with postoperative CT scans and analyzed using Kaplan-Meier survival methods that account for variation in follow-up duration. Development of any postoperative acute kidney injury within 7 days of surgery and morbidity were secondary outcomes. The study cohort includes 65 patients who underwent LRV harvest; 60 (92%) ultimately underwent successful reconstruction with harvested LRV graft. Kaplan-Meier 2-year estimated patency rate of the LRV graft was 88%, with no cases of complete occlusion. Six (10%) patients experienced graft stenosis. Nine of 61 (15%) patients experienced grade II or III acute kidney injury, 6 of 9 returning to normal renal function before discharge. No difference in median serum creatinine was observed at baseline, 6 and 12 months from surgery. LRV remnant thrombosis was seen in 7 of 65 (11%) patients. Only 3 of 61 (5%) patients had persistent acute kidney injury caused by complications unrelated to LRV harvesting. Autologous LRV graft was a reliable conduit for segmental PV-SMV reconstruction, resulting in a high patency rate and marginal impact on renal function. LRV harvest is a safe and potentially ideal surgical option for PV-SMV reconstruction in pancreatic surgery.


Erratum: Predictive Models of Fever, ICU Transfer, and Mortality in Hospitalized Patients With Neutropenia: Erratum.
[This corrects the article DOI: 10.1097/CCE.0000000000000289.].


Are short femoral nails superior to the sliding hip screw? A meta-analysis of 24 studies involving 3,279 fractures.
The purpose of this meta-analysis was to compare the fixation outcome between the sliding hip screw (SHS) and intramedullary nails (IMN) in stable and unstable extracapsular proximal femoral fractures. All randomised controlled studies comparing IMNs with a SHS were considered for inclusion. Data was independently extracted and trial methodology assessed. Twenty-four randomised trials involving 3,202 patients with 3,279 fractures were included. Pooled results gave no statistically significant difference in the cut-out rate between the IMN and SHS (41/1,556 vs 37/1,626; relative risk 1.19; 95% confidence interval 0.78-1.82). Total failure rate (1,03/1,495 and 58/1,565, relative risk 1.83; 95% confidence interval 1.35-2.50) and re-operation rate (57/1,357 and 35/1,415, relative risk 1.63; 95% confidence interval 1.11-2.40) were greater with the IMN compared with the SHS. There was no evidence for a reduced failure rate with IMN in unstable trochanteric fractures.


Novel fluorescent pH sensor based on coumarin with piperazine and imidazole substituents.
A new coumarin derivative containing piperazine and imidazole moieties is reported as a fluorophore for hydrogen ions sensing. The fluorescence enhancement of the studied sensor with an increase in hydrogen ions concentration is based on the hindering of photoinduced electron transfer from the piperazinyl amine and the imidazolyl amine to the coumarin fluorophore by protonation. The presented sensor has a novel design of fluorophore-spacer-receptor(1)-receptor(2) format, which is proposed to sense two ranges of pH (from 2.5 to 5.5) and (from 10 to 12) instead of sensing one pH range. A model compound, in which the piperazinyl ring is absent, was synthesized as well to confirm the novel pH sensing of the proposed sensor.


Dose any enzyme follow the Michaelis-Menten equation?
A literature search has been conducted to see to what extent steady-state kinetics studies in the period 1965-1976 have revealed deviations from Michaelis-Menten kinetics. It was found that over 800 enzymes have been reported as giving complex curves for a variety of reasons and a group by group classification of all these enzymes has been carried out listing all the types of variations reported and the authors' explanations. In addition, for highly complex curves, we have determined the minimum degree of the rate equation. There were very few determined attempts to demonstrate adherence to the Michaelis-Menten equation over a wide variety of experimental conditions and substrate concentration and almost invariably detailed experimental work revealed unsuspected complexities. For these reasons, it is concluded that the assumption that most enzymes follow the Michaelis-Menten equation can not be supported by an appeal to the literature.


Macro kinetic studies for photocatalytic degradation of benzoic acid in immobilized systems.
Semiconductor photocatalytic process has been studied extensively in recent years due to its intriguing advantages in environmental remediation. In this study, a two-phase swirl-flow monolithic-type reactor is used to study the kinetics of photocatalytic degradation of benzoic acid in immobilized systems. Transport contributions into the observed degradation rates were determined when catalyst is immobilized. Intrinsic kinetic rate constants and its dependence on light intensity and catalyst layer thickness, values of adsorption equilibrium constant, internal as well as external mass transfer parameters were determined. The simultaneous effect of catalyst loading and light intensity and optimum catalyst layer thickness were also determined experimentally. Reaction rate constants and overall observed degradation rates were compared with slurry systems.


Dynamics and dimension of an amyloidogenic disordered state of human β(2)-microglobulin.
Human β2-microglobulin (β2m) aggregation is implicated in dialysis-related amyloidosis. Previously, it has been shown that β2m adopts an ensemble of partially unfolded states at low pH. Here we provide detailed structural and dynamical insights into the acid unfolded and yet compact state of β2m at pH 2.5 using a host of fluorescence spectroscopic tools. These tools allowed us to investigate protein conformational dynamics at low micromolar protein concentrations in an amyloid-forming condition. Our equilibrium fluorescence data in combination with circular dichroism data provide support in favor of progressive structural dissolution of β2m with lowering pH. The acid unfolded intermediate at pH 2.5 has high 8-anilinonaphthalene, 1-sulfonic acid (ANS)-binding affinity and is devoid of significant secondary structural elements. Using fluorescence lifetime measurements, we have been able to monitor the conformational transition during the pH transition from the native to the compact disordered state. Additionally, using time-resolved fluorescence anisotropy measurements, we have been able to distinguish this compact disordered state from the canonical denatured state of the protein by identifying unique dynamic signatures pertaining to the segmental chain mobility. Taken together, our results demonstrate that β2m at pH 2.5 adopts a compact noncanonical unfolded state resembling a collapsed premolten globule state. Additionally, our stopped-flow fluorescence kinetics results provide mechanistic insights into the formation of a compact disordered state from the native form.


Effects of an aorticopulmonary shunt on lung fluid balance in the young lamb.
We studied the effects of increased pulmonary blood flow on lung fluid balance in seven chronically instrumented lambs (18 +/- 1 d) with surgically created aorticopulmonary shunts. We measured mean pulmonary arterial and left atrial pressure (LAP), pulmonary blood flow, lung lymph flow, and lymph (CL) and plasma (CP) protein concentration with the shunt closed and opened. With the shunt partially open, a 35% increase in pulmonary blood flow resulted in an increase in pulmonary arterial pressure (15.5 +/- 1 to 19.5 +/- 1 torr) and LAP (2.0 +/- 0.5 to 3.5 +/- 0.5 torr). Lung lymph flow nearly doubled (1.53 +/- 0.28 to 2.83 +/- 0.52 mL/h) whereas the CL decreased (4.1 +/- 0.1 to 3.4 +/- 0.1 g/dL) resulting in a decrease in the CL/CP ratio (0.67 +/- 0.01 to 0.58 +/- 0.01). With the shunt fully open, pulmonary blood flow increased 65% over baseline, pulmonary arterial pressure increased from 16.5 +/- 2.0 to 26.5 +/- 5 torr, and LAP increased from 1.5 +/- 0.5 to 6.5 +/- 2.0 torr. Lung lymph flow increased (1.1 +/- 0.2 to 3.1 +/- 0.2 mL/h) whereas CL (4.1 +/- 0.1 to 3.1 +/- 0.3 g/dL) and CL/CP (0.66 +/- 0.02 to 0.51 +/- 0.05) decreased. All changes were statistically significant (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)


2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) alters the mRNA expression of critical genes associated with cholesterol metabolism, bile acid biosynthesis, and bile transport in rat liver: a microarray study.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a potent hepatotoxin that exerts its toxicity through binding to the aryl hydrocarbon receptor (AhR) and the subsequent induction or repression of gene transcription. In order to further identify novel genes and pathways that may be associated with TCDD-induced hepatotoxicity, we investigated gene changes in rat liver following exposure to single oral doses of TCDD. Male Sprague-Dawley rats were administered single doses of 0.4 microg/kg bw or 40 microg/kg bw TCDD and killed at 6 h, 24 h, or 7 days, for global analyses of gene expression. In general, low-dose TCDD exposure resulted in greater than 2-fold induction of genes coding for a battery of phase I and phase II metabolizing enzymes including CYP1A1, CYP1A2, NADPH quinone oxidoreductase, UGT1A6/7, and metallothionein 1. However, 0.4 microg/kg bw TCDD also altered the expression of Gadd45a and Cyclin D1, suggesting that even low-dose TCDD exposure can alter the expression of genes indicative of cellular stress or DNA damage and associated with cell cycle control. At the high-dose, widespread changes were observed for genes encoding cellular signaling proteins, cellular adhesion, cytoskeletal and membrane transport proteins as well as transcripts coding for lipid, carbohydrate and nitrogen metabolism. In addition, decreased expression of cytochrome P450 7A1, short heterodimer partner (SHP; gene designation nr0b2), farnesyl X receptor (FXR), Ntcp, and Slc21a5 (oatp2) were observed and confirmed by RT-PCR analyses in independent rat liver samples. Altered expression of these genes implies major deregulation of cholesterol metabolism and bile acid synthesis and transport. We suggest that these early and novel changes have the potential to contribute significantly to TCDD induced hepatotoxicity and hypercholesterolemia.


Arcobacter species isolated from various seafood and water sources; virulence genes, antibiotic resistance genes and molecular characterization.
Arcobacter spp. has gained clinical significance as an emerging diarrheagenic pathogen associated with water reservoirs in recent years. The complete clinical significance of Arcobacter remains rather speculative due to the virulence and antibiotic susceptibility of individual strains. This study aimed to assess the prevalence of Arcobacter spp. in fish, water, and shellfish. A total of 150 samples were collected from the Adana, Kayseri and Kahramanmaras provinces in Turkey. Arcobacter spp. was isolated from 32 (21%) of the 150 samples. The most prevalent species was A. cryaerophilus, 17 (56%), A. butzleri 13 (37%) and A. lacus 2 (6%). As a result, the ratios of the mviN, irgA, pldA, tlyA and hecA target genes were found as 17 (51%), 1 (3%), 7 (23%), 7 (23%), 1 (3%), respectively. While bla OXA-61, tetO and tetW were positive in all isolates, were found as mcr1/2/6, mcr3/7, and mcr5, genes %37.5, %25, and %34.3, respectively. Although in A. butzleri was found 10 (58%), 1 (3%), 3 (43%), 2 (28%) (mviN, irgA, pldA, and tlyA, respectively) virulence genes 7 (42%), 4 (57%), 5 (72%), 1 (3%) was found (mviN, irgA, tlyA, and hecA, respectively) virulence genes in A. cryoaerophilus. Moreover, was found for the mcr 1/2/6 7 (58%) genes, for the mcr 3/7 genes 3 (38%) in A. butzleri. In A. cryoaerophilus was found for the mcr 1/2/6 genes 5 (42%), for the mcr 3/7 genes 5 (62%), and for the mcr 5 gene 10 (100%). Thus, the current study indicated that the existence of Arcobacter spp. isolated from fish and mussel samples may pose a potential risk to public health.


Nefiracetam attenuates post-ischemic nonconvulsive seizures in rats and protects neuronal cell death induced by veratridine and glutamate.
Stroke patients are at a high risk of developing post-ischemic seizures and cognitive impairment. Nefiracetam (NEF), a pyrrolidone derivative, has been shown to possess both anti-epileptic and cognitive-enhancing properties. In this study the anti-seizure effects of NEF were evaluated in a rat model of post-ischemic nonconvulsive seizures (NCSs). Its potential mechanisms were investigated in neuronal cell culture assays of neurotoxicity associated with ischemic brain injury and epileptogenesis. In the in vivo study, rats received 24h permanent middle cerebral artery occlusion. NEF was administered intravenously either at 15 min post-injury but prior to the first NCS event (30 mg/kg, pre-NCS treatment) or immediately after the first NCS occurred (30 or 60 mg/kg, post-NCS treatment). In the in vitro study, neuronal cell cultures were exposed to veratridine or glutamate and treated with NEF (1-500 nM). The NEF pre-NCS treatment significantly reduced the NCS frequency and duration, whereas the higher NEF dose (60 mg/kg) was required to achieve similar effects when given after NCS occurred. The NEF treatment also dose-dependently (5-500 nM) protected against neuronal cell death induced by veratridine as measured by MTT cell viability assay, but higher doses (250-500 nM) were required against glutamate toxicity. The anti-seizure property of NEF was demonstrated in a clinically relevant rat model of post-ischemic NCS. The preferential effects of NEF against in vitro veratridine toxicity suggest the involvement of its modulation of sodium channel malfunction. Future studies are warranted to study the mechanisms of NEF against ischemic brain injury and post-ischemic seizures.


Cosmid clones from microdissected human chromosomal region 15q11-q13.
A human chromosomal region, 15q11-q13, was microdissected, its DNA was amplified with the primer-linker PCR method, and the PCR products were cloned into a plasmid vector to construct a microclone library. Of 193 microclones analyzed with Southern blot hybridization on hybrid cell panels, 26 (13.5%) were either single-copy (unique) or low-repetitive fragments. By screening of a cosmid library of human genomic DNA using the 26 microclones as probes, 47 positive cosmids were obtained and underwent regional mapping with chromosome fluorescence in situ hybridization (FISH). Sixteen cosmids gave FISH signals at 15p-cen, 5 at 15q11-q13, 6 at 15q22-q26, 3 at other chromosomes, and 17 no signal. These 27 cosmids mapped to chromosome 15 are useful additions to the inventory of DNA markers of this chromosome including the much interested Prader-Willi/Angelman syndrome region.


Role of somatosensory and/or vestibular sensory information in subjective postural vertical in healthy adults.
The body's subjective postural vertical (SPV) has been thought to be affected by somatosensory information. How the SPV is perceived based on what types of somatosensory information has not been determined experimentally by manipulating somatosensory conditions. We investigated the effects of disturbing the somatosensory information from a seat pad and/or vestibular sensory information on the SPV in 15 healthy adults. Their SPV values were measured under four conditions (control, somatosensory, vestibular, and somatosensory + vestibular) in random order. The average and absolute SPV values were measured. In the somatosensory condition, a foam rubber pad was placed on the seating surface and the subject's SPV was measured. In the vestibular condition, the SPV was measured during galvanic vestibular stimulation (GVS). The somatosensory + vestibular condition was used to measure the SPV during combined somatosensory and vestibular stimulation. The mean SPV value was significantly increased in the somatosensory + vestibular condition compared to the other three conditions. The absolute value of SPV was significantly increased in the somatosensory and somatosensory + vestibular conditions compared to the control and vestibular conditions. There was no significant difference in the average or absolute SPV values in the vestibular condition compared to the other conditions. There was no significant difference between SPV errors when somatosensory information was disturbed or when somatosensory + vestibular information was disturbed. When the somatosensory information from the seat was disturbed, the SPV error increased, and it also shifted under the influence of the vestibular sensory information modulation. These results indicate that somatosensory information from the seat plays an important role in SPV in healthy adults.


Identification of the molecular sex-differentiation period in the Siberian sturgeon.
Sexual development prior to gonadal sex differentiation is regulated by various molecular mechanisms. In fish, a "molecular sex-differentiation period" has been identified in species for which sex can be ascertained prior to gonadal sex differentiation. The present study was designed to identify such a period in a species for which no genetic sex markers or monosex populations are available. Siberian sturgeons undergo a slow sex-differentiation process over several months, so gonad morphology and gene expression was tracked in fish from ages 3-27 months to identify the sex-differentiation period. The genes amh, sox9, and dmrt1 were selected as male gonad markers; cyp19a1a and foxl2a as female gonad markers; and cyp17a1 and ar as markers of steroid synthesis and steroid receptivity. Sex differentiation occurred at 8 months, and was preceded by a molecular sex-differentiation period at 3-4 months, at which time all of the genes except ar showed clear expression peaks. amh and sox9 expression seemed to be involved in male sexual development whereas dmrt1, a gene involved in testis development in metazoans, unexpectedly showed a pattern similar to those of the genes known to be involved in female gonadal sex differentiation (cyp19a1 and foxl2a). In conclusion, the timing of and gene candidates involved with molecular sex differentiation in the Siberian sturgeon were identified.


Inhibition of neutrophil apoptosis after coronary bypass operation with cardiopulmonary bypass.
Granulocyte apoptosis is a key control process in the clearance of neutrophils from inflammatory sites, and its rate is modulated both in vitro and in vivo by a number of inflammatory mediators. In this study, we investigated the influence of cardiopulmonary bypass (CPB) on neutrophil apoptosis. Twenty patients undergoing coronary operation with CPB were studied. Patients undergoing off-pump (OP) coronary bypass and healthy subjects served respectively as stressed and normal groups. Interleukin-6 (IL-6), IL-8, and tumor necrosis factor-alpha were assessed on plasma collected preoperatively, at the end of CPB, and after intervals of 4, 8, 12, and 24 hours. Neutrophil apoptosis was detected by light microscopy as well as by the annexin-V assay on postoperative samples. The polymorphonuclear leukocyte (PMN) apoptotic receptors, Fas and FasL, were studied together with the activity of caspase 3 in postoperative neutrophils. Spontaneous apoptosis was significantly delayed in PMNs from CPB patients when compared with either the stressed or control patients. Neutrophils were activated, as indicated by increased surface expression of CD11b. Western blot analysis showed a normal expression of the apoptotic receptors Fas and FasL. Caspase 3 activity was found to be significantly reduced in neutrophils from CPB patients after 18 and 24 hours of culture. When control neutrophils were cultured in the presence of postoperative plasma from OP and CPB patients, apoptosis was significantly delayed. Depleting surgical plasma of IL-6 and IL-8 completely abolished this antiapoptotic effect. Inflammatory mediators during CPB prolong the functional lifespan of neutrophils through modulation of apoptosis, and potentiate the inflammatory response observed after coronary bypass operation.


Landau-Kleffner syndrome: long-term follow-up.
Landau-Kleffner syndrome (LKS) is a rare entity characterized by epilepsy and aphasia. It occurs in previously normal children, usually between three and seven years of age. The long-term outcome of LKS is not completely clear. The aim of this study is to verify the long-term follow-up of a group of patients with LKS, focusing on clinical and electroencephalographic (EEG) aspects, and quality of life. This was a transversal study. Between November 2006 and April 2007 seven patients with previous diagnosis of LKS were interviewed. They had had a follow-up of three to 16 years after their disease onset. They were all males between the ages of eight and 27 years old. All patients had normal MRI. Parents and/or patients were interviewed by one of the authors using a structured questionnaire. The Vineland Adaptive Behavior Scales, the Conner's Rating Scales-Revised, and Short-Form Health Survey (SF 36) were used. Each patient had a prolonged interictal EEG recording. All patients had normal MRI. The present investigation revealed that two patients still have seizures several years after epilepsy onset. One patient had total and three others had partial remission of language disturbance, while three patients still have aphasia and verbal auditory agnosia. With respect to quality of life, only one of our patients has a normal life at present. The remaining six patients with some sort of limitation consider the aphasia/agnosia to be the main difficulty in their lives. Five patients have normal EEGs. The long-term follow-up of patients with LKS shows that epilepsy and EEG abnormalities do not always disappear. Language disturbances tend to persist in most patients. The age of onset of language dysfunction does not seem to correlate with the prognosis for recovery of language function. Patients with LKS have an overall poor quality of life, mostly due to language difficulties.


Inhibitory effects of 2-[(diethylamino)acetyl]-1,2,3,4-tetrahydro-6, 7-dimethoxyl-1-[1'-(6"-methoxy-2"-naphthalenyl)ethyl]-isoquinoline on isolated guinea pig papillary muscle and heart atrium.
To investigate the cardiac actions of 2-[(diethylamino)acetyl]-1,2,3,4-tetrahydro-6, 7-dimethoxyl-1-[1'-(6"-methoxy-2"-naphthalenyl) ethyl]-isoquinoline (CPU57) by comparison with nifedipine and focus on its mechanism of actions. The following were measured and recorded: 1) the rate and contraction of spontaneous beating of the guinea pigs right heart atrium, 2) the isometric tension of the electrically stimulated left heart atrium and the right papillary muscles. CPU57 had negative inotropic and negative chronotropic actions in isolated heart of guinea pigs as the typical calcium antagonist, nifedipine. However, CPU57 0.01-100 mumol.L(-1) produced less cardiac inhibitory potency than nifedipine and had much stronger negative inotropic action than negative chronotropic action. The decrease in external CaCl2 concentration from 1.5 to 0.3 mmol.L(-1) or increase to 7.5 mmol.L(-1), potentiated or reduced respectively, the inhibitory action of CPU57 on the contraction in paced left heart atrium in normal CaCl2 solution. CPU57 1-10 mumol.L(-1) also inhibited contractile response to CaCl2 in paced left heart atrium with pD2' value of 4.77. CPU57 has calcium antagonism on the heart of guinea pigs.


Better assessment of neonatal jaundice at home (BEAT Jaundice @home): protocol for a prospective, multicentre diagnostic study.
Severe neonatal hyperbilirubinaemia can place a neonate at risk for acute bilirubin encephalopathy and kernicterus spectrum disorder. Early diagnosis is essential to prevent these deleterious sequelae. Currently, screening by visual inspection followed by laboratory-based bilirubin (LBB) quantification is used to identify hyperbilirubinaemia in neonates cared for at home in the Netherlands. However, the reliability of visual inspection is limited. We aim to evaluate the effectiveness of universal transcutaneous bilirubin (TcB) screening as compared with visual inspection to: (1) increase the detection of hyperbilirubinaemia necessitating treatment, and (2) reduce the need for heel pricks to quantify bilirubin levels. In parallel, we will evaluate a smartphone app (Picterus), and a point-of-care device for quantifying total bilirubin (Bilistick) as compared with LBB. We will undertake a multicentre prospective cohort study in nine midwifery practices across the Netherlands. Neonates born at a gestational age of 35 weeks or more are eligible if they: (1) are at home at any time between days 2 and 8 of life; (2) have their first midwife visit prior to postnatal day 6 and (3) did not previously receive phototherapy. TcB and the Picterus app will be used after visual inspection. When LBB is deemed necessary based on visual inspection and/or TcB reading, Bilistick will be used in parallel. The coprimary endpoints of the study are: (1) hyperbilirubinaemia necessitating treatment; (2) the number of heel pricks performed to quantify LBB. We aim to include 2310 neonates in a 2-year period. Using a decision tree model, a cost-effectiveness analysis will be performed. This study has been approved by the Medical Research Ethical Committee of the Erasmus MC Rotterdam, Netherlands (MEC-2020-0618). Parents will provide written informed consent. The results of this study will be published in peer-reviewed journals. Dutch Trial Register (NL9545).


Time-specific and cumulative effects of exposure to parental externalizing behavior on risk for young adult alcohol use disorder.
Previous studies indicate that parental externalizing behavior (EB) is a robust risk factor for alcohol use disorder (AUD) in their children, and that this is due to both inherited genetic liability and environmental exposure. However, it remains unclear whether the effects of exposure to parental EB vary as a function of timing and/or chronicity. We identified biological parents with an alcohol use disorder, drug abuse, or criminal behavior, during different periods of their child's upbringing, using Swedish national registries. Logistic regression was used to determine whether the effect of parental EB exposure during different developmental periods differentially impacted children's risk for young adult AUD (ages 19-24). In addition, we tested how multiply affected parents and/or sustained exposure to affected parents impacted risk. While parental EB increased risk for young adult AUD, timing of exposure did not differentially impact risk. Having a second affected parent increased the risk of AUD additionally, and sustained exposure to parental EB across multiple periods resulted in a higher risk of young adult AUD than exposure in only one period. In this well-powered population study, there was no evidence of "sensitive periods" of exposure to national registry-ascertained parental EB with respect to impact on young adult AUD, but sustained exposure was more pathogenic than limited exposure. These findings suggest developmental timing does not meaningfully vary the impact, but rather there is a pervasive risk for development of young adult AUD for children and adolescents exposed to parental EB.


Regional Disparities in Prevalence and Causes of Visual Impairment and Blindness, Cataract Surgical Coverage and Ocular Findings in Adults 50 Years and Older in Brazil: A Comparative Analysis between Two Population-Based Cross-Sectional Surveys Performed Within a 10-Year Interval.
To investigate disparities in the prevalence and causes of visual impairment and blindness, cataract surgical coverage, and ocular findings in older adults from two Brazilian geo-socio-demographic areas, São Paulo and Parintins cities. Data from two population-based studies including participants 50 years and older from the cities of São Paulo (São Paulo Eye Study - SPES, 2004) and Parintins (Brazilian Amazon Region Eye Survey - BARES, 2014) were aggregated. A total of 5318 participants (3677 from SPES;1641 from BARES) were included. The prevalence of severe visual impairment (SVI) and blindness were, respectively, 0.74% (0.46-1.02) and 0.77% (0.48-1.05) in SPES and 1.72% (1.09-2.35) and 3.44% (2.55-4.33) in BARES. SVI and blindness were associated with BARES study [OR = 2.27 (1.30-3.95); p = .004 - SVI] [OR:4.07 (2.51-6.60); p < .001- blindness]; and older age [OR = 10.93 (4.20-28.45); p < .001 - SPES; OR = 17.96 (8.75-36.83); p < .001 - BARES] while higher education level was a protective factor [OR = 0.21 (0.05-0.95) - SPES; p = .042; OR = 0.21 (0.05-0.91); p = .037 - BARES]. Cataract was the main cause of bilateral severe visual impairment (25.93% in SPES and 64.29% in BARES) and bilateral blindness (21.43% in SPES and 35.71% in BARES). Cataract surgical coverage was significantly lower in BARES (36.32%) compared to SPES (57.75%). The prevalence of SVI and blindness was three times higher in older adults from the Brazilian Amazon compared to those living in São Paulo city, despite a 10-year interval between the two studies. These disparities should be mitigated by initiatives to promote access to eye care services targeting underprivileged and remote Brazilian areas.


Independent association of joint space narrowing and osteophyte formation at the knee with health-related quality of life in Japan: a cross-sectional study.
To clarify the individual associations of joint space narrowing (JSN) and osteophytosis at the knee with quality of life (QOL) in Japanese men and women using a large-scale population-based cohort from the Research on Osteoarthritis Against Disability (ROAD) study. The associations of minimum joint space width (JSW) and osteophyte area in the medial compartment of the knee with QOL parameters, such as the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), were examined. Minimum JSW and osteophyte area in the medial compartment of the knee were measured using a computer-aided system for the diagnosis of knee osteoarthritis. Of the 3,040 participants in the ROAD study, the present study included 2,039 participants age 40 years or older who completed the questionnaires (741 men and 1,298 women with a mean ± SD age of 68.6 ± 10.9 years). Multiple regression analysis after adjustment for age and body mass index showed that minimum JSW was significantly associated with scores on the pain domains of the WOMAC in men and women, while osteophyte area was significantly associated with scores on the physical function domains of the WOMAC in men and women. The findings of this cross-sectional study using a large-scale population from the ROAD study indicate that JSN and osteophytosis are independently associated with QOL.


Pivotal role of microRNAs in cardiac physiology and heart failure.
Cardiac hypertrophy is a hallmark of heart failure (HF), a highly prevalent, debilitating and deadly condition in Western countries. Pronounced changes in molecular pathways governing cardiac physiology underlie hypertrophy and progression to HF. MicroRNAs, small nucleotide sequences that coordinate gene expression, may have a central role in orchestrating these changes since the hypertrophic and HF myocardium clearly shows disturbed microRNA profiles. Experimental interventions targeting miR disturbances have been shown beneficial in animal models of cardiac hypertrophy and HF. This short review discusses exciting potential diagnostic and therapeutic applications of microRNAs to cardiac hypertrophy and HF, highlighting the underlying molecular pathways.


Doxorubicin-loaded magnetic nanoparticle clusters for chemo-photothermal treatment of the prostate cancer cell line PC3.
In addition to the conventional cancer treatment such as radiotherapy, chemotherapy and surgical management, nanomedicine-based approaches have attracted widespread attention in recent years. In this paper, a promising nanocarrier, magnetic nanoparticle clusters (MNCs) as porous materials which provided enough room on the surface, was developed for loading chemotherapeutic agent of doxorubicin (DOX). Moreover, MNCs are a good near-infrared (NIR) photothermal mediator. Thus, MNCs have great potential both in photothermal therapy (PTT) and drug delivery for chemo-photothermal therapy of cancer. We firstly explored the destruction of prostate cancer in vitro by the combination of PTT and chemotherapy using DOX@MNCs. Upon NIR irradiation at 808 nm, more cancer cells were killed when PC3 cells incubated with DOX@MNCs, owing to both MNCs-mediated photothermal ablation and cytotoxicity of light-triggered DOX release. Compared with PTT or chemotherapy alone, the chemo-photothermal therapy by DOX@MNCs showed a synergistically higher therapeutic efficacy.


Change in capnogram waveform is associated with bronchodilator response and asthma control in children.
Airway hyper-reactivity, inflammation and remodeling contribute to inhomogeneity of ventilation-perfusion ratio VA·/Q· in asthma. Short-term variations in V.A/Q· can cause changes in expired capnographic indices. To measure acute changes in the phase 3 slope of the volumetric capnogram after β2-agonist inhalation (ΔSIII), for comparison with airway response based on FEV1 (ΔFEV1), and asthma control. After ethical approval and informed consent, 72 children aged 6-18 y, followed up for asthma underwent spirometry and capnography before and after β-agonist inhalation through a spacer, using a side-stream rapid infrared analyzer. Asthma control was assessed using the GINA questionnaire. Children with positive reversibility tests (defined as ΔFEV1>12%) had a significantly higher ΔSIII (m ± SE: 87.4 ± 41.4) versus those with negative tests (31.3 ± 14.0%, P = 0.001). Uncontrolled asthma was associated with a significantly larger ΔSIII (103.4 ± 64.0%, n = 7) compared to partly controlled (52.0 ± 26.1, n = 24; P = 0.009) and controlled asthma (30.8 ± 16.3, n = 41; P = 0.003). Neither Bohr dead space nor ΔFEV1 were different between asthma control groups. ΔSIII was significantly larger in children with positive response to β2-agonist, and in uncontrolled asthmatics. To our knowledge these are the first data on exhaled CO2 phase III volumetric slope change and asthma control. The observed ΔSIII could be due to an increased ventilation of inhomogeneous peripheral lung units, and merits further evaluation as a potential phenotypic biomarker in asthma.


Social factors in conditioned place preference with morphine in mice.
Using a conditioned place preference (CPP) protocol, I previously demonstrated that social interactions enhance the reinforcing properties of methamphetamine in mice. Here, I examined the influence of social interactions on morphine-induced CPP. Paired and control-paired groups both received CPP training with a cage mate. In the paired group, both mice received the same CPP training and the same type of injections (either morphine (0.1-3.0mg/kg) or saline, depending on the day). In the control-paired group, both mice received the same CPP training, but the injections were reversed. When one mouse was injected with morphine, the other was injected with saline. CPP training in the absence of a cage mate resulted in a conditioned preference when subjects were injected with 1.0 or 3.0mg/kg of morphine (but not with 0.1mg/kg). A cage mate that was not administered morphine enhanced the reinforcing effects of the 3.0mg/kg dose. In contrast, a cage mate that received morphine reduced the reinforcing property of the 1.0mg/kg dose. Results from these experiments differ from previous results concerning methamphetamine, in which a drug-free partner did not enhance the drug's effect.


Site-selective hole burning in Eu3+:Y2SiO5.
We found that the Eu3+ ion occupies several distinct sites in Y2SiO5. We were also able to perform hole-burning studies in more than 40 different transitions.


Hand impairment and activity limitations in four chronic diseases.
Retrospective cohort. Hand involvement in osteoarthritis (OA) and rheumatoid arthritis (RA) are well known to occupational and physical therapists; however, it is not known whether the impairments and activity limitations with diabetes (DMII) and systemic sclerosis (SSc) are as severe as those observed with OA and RA. To compare the hand impairments and activity limitations in the 4 diseases. A convenience sample of 156 participants received evaluations of hand impairments: strength, joint motion, and dexterity and completed a hand activity limitations questionnaire. The SSc and RA participants had weaker pinch, decreased joint motion and more activity limitations than the DMII and OA groups. There were no significant differences between the groups for right hand grip strength and pegboard dexterity, and applied dexterity. OA and DMII groups had significantly less impairments and activity limitations than the SSc and RA groups. 2C.


Optimization of a laboratory-developed test utilizing roche analyte-specific reagents for detection of Staphylococcus aureus, methicillin-resistant S. aureus, and vancomycin-resistant Enterococcus species.
Nasal and perianal swab specimens were tested for detection of Staphylococcus aureus and vancomycin-resistant Enterococcus species (VRE) using a laboratory-developed real-time PCR test and microbiological cultures. The real-time PCR and culture results for S. aureus were similar. PCR had adequate sensitivity, but culture was more specific for the detection of VRE.


The molecular dissociation of ferrihemoglobin derivatives.
Measurement of the dissociation constants of ferrihemoglobin by light scattering indicates that the quaternary structure is altered by the type of heme ligand. Fluoromethemoglobin and aquomethemoglobin, high spin derivatives with weak ligands, have tetramer-dimer dissociation constants of 80 and 50 muM, respectively. For low spin cyanmethemoglobin the dissociation constants were 1 muM (pH 6.0) and 3 muM (pH 9.0) under the general conditions of 0.1 ionic strength and 25 degrees. Of the ferrihemoglobins studied, alkaline methemoglobin (pH 9.0) has the lowest dissociation constant (0.2 muM). Dissociation constants of mixtures of alkaline and fluoromethemoglobin were significantly higher than that of the alkaline form alone. At pH 9.0 the 55 and 78% fluoride-bound derivatives had tetramer-dimer dissociation constants of 0.7 and 2 muM, respectively. The cyanmethemoglobin quaternary conformation was found to be less affected by pH than the fluoromethemoglobin and aquomethemoglobin conformations. Measurement of the dissociation constant (0.2 muM) for aquomethemoglobin-inositol hexaphosphate indicates stabilization of the tetramer by this organic phosphate. The extent of stabilization by inositol hexaphosphate does not appear to be that found for deoxyhemoglobin as suggested by Perutz (Perutz, M. F. (1972) Nature 237, 495-499) even though inducement of higher spin and iron-heme plane displacement may occur.


THE RELATION BETWEEN THE DIET AND THE DIVERTICULITIS PATHOPHYSIOLOGY: AN INTEGRATIVE REVIEW.
Diverticulitis is an acute inflammatory process that affects individuals with diverticular disease. Given the sharp increase in the diagnostic rate of such a pathological process, there was also an increased interest in elucidating the possible causes related to the development of this clinical condition. Among the main factors investigated, diet excels, the object of study of this integrative literature review. After searching the virtual health library and PubMed databases, five prospective cohort studies were selected that best answered the guiding question: "Is there a relationship between diet and the incidence of diverticulitis?". It was observed that the high intake of red meat and the low intake of dietary fiber were the most strongly associated dietary factors with the incidence of this inflammatory process. Therefore, it is evident that choosing healthy eating habits can considerably reduce the incidence of diverticulitis and, consequently, potentially more serious complications directly related to it.


FtsK Is a DNA motor protein that activates chromosome dimer resolution by switching the catalytic state of the XerC and XerD recombinases.
FtsK acts at the bacterial division septum to couple chromosome segregation with cell division. We demonstrate that a truncated FtsK derivative, FtsK(50C), uses ATP hydrolysis to translocate along duplex DNA as a multimer in vitro, consistent with FtsK having an in vivo role in pumping DNA through the closing division septum. FtsK(50C) also promotes a complete Xer recombination reaction between dif sites by switching the state of activity of the XerCD recombinases so that XerD makes the first pair of strand exchanges to form Holliday junctions that are then resolved by XerC. The reaction between directly repeated dif sites in circular DNA leads to the formation of uncatenated circles and is equivalent to the formation of chromosome monomers from dimers.


State dependent changes in error monitoring in schizophrenia.
The aim of this study was to determine if error negativity/error-related negativity (N(e)/ERN), error positivity (P(e)), correct response negativity (CRN) or correct response positivity (P(c)) amplitude are influenced by state changes in schizophrenia. Event-related potentials (ERPs) were recorded from nine schizophrenic patients while they performed a simple go/no-go task during the early stages of an acute episode and again following 6 weeks of treatment with antipsychotics. ERPs were also recorded from nine healthy participants while they performed the same task. Response-locked potentials were computed for errors of commission and for correct responses. Scores for reality distortion syndrome, psychomotor poverty syndrome and disorganization syndrome were determined for the schizophrenic participants before and after treatment using the Signs and Symptoms of Psychotic Illness (SSPI) Scale. N(e)/ERN amplitude was significantly reduced, compared with that in healthy participants, in the schizophrenic patients when acutely ill, and increased significantly following treatment. N(e)/ERN amplitude remained significantly larger in the healthy group than in the patients with schizophrenia after treatment. This study suggests that N(e)/ERN and CRN amplitude are modulated by clinical state in schizophrenia and provides further support to findings that decreased N(e)/ERN amplitude is a potentially useful trait marker for schizophrenia, while P(c) and P(e) amplitude are not abnormal.


Prevalences of autoimmune diseases in schizophrenia, bipolar I and II disorder, and controls.
Previous studies on the relationship between autoimmune diseases, schizophrenia, and bipolar disorder are mainly based on hospital discharge registers with insufficient coverage of outpatient data. Furthermore, data is scant on the prevalence of autoimmune diseases in bipolar subgroups. Here we estimate the self-reported prevalences of autoimmune diseases in schizophrenia, bipolar disorder type I and II, and controls. Lifetime prevalence of autoimmune diseases was assessed through a structured interview in a sample of 9076 patients (schizophrenia N = 5278, bipolar disorder type I N = 1952, type II N = 1846) and 6485 controls. Comparative analyses were performed using logistic regressions. The prevalence of diabetes type 1 did not differ between groups. Hyperthyroidism, hypothyroidism regardless of lithium effects, rheumatoid arthritis, and polymyalgia rheumatica were most common in bipolar disorder. Systemic lupus erythematosus was less common in bipolar disorder than in the other groups. The rate of autoimmune diseases did not differ significantly between bipolar subgroups. We conclude that prevalences of autoimmune diseases show clear differences between schizophrenia and bipolar disorder, but not between the bipolar subgroups.


Ascorbate reduces morphine-induced extracellular DOPAC level in the nucleus accumbens: A microdialysis study in rats.
Most drugs of abuse increase dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) release in the shell of the nucleus accumbens. The effects of ascorbate, which is known to modulate dopamine neurotransmission, on the extracellular level of DOPAC in the nucleus accumbens of naive rats and of rats treated acutely with morphine were studied by using in vivo microdialysis and high performance liquid chromatography with electrochemical detection (HPLC-ECD). Acute morphine (20 mg/kg ip) treatment increased the level of DOPAC in the nucleus accumbens to approximately 170% of basal level. Acute treatment with ascorbate (500 mg/kg ip) alone did not alter nucleus accumbens' DOPAC level, but pretreatment with ascorbate (500 mg/kg ip) 30 min before morphine administration attenuated the effects of acute morphine on the level of DOPAC. These results suggest that ascorbate modulates the mesolimbic dopaminergic pathway.


RhoBTB3 interacts with the 5-HT7a receptor and inhibits its proteasomal degradation.
The 5-hydroxytryptamine (5-HT)7 receptor is the most recently identified serotonin receptor and is involved in a wide variety of central nervous system (CNS) functions, namely circadian rhythm, REM sleep, depression, thermoregulation, obsessive-compulsive disorder (OCD), anxiety, schizophrenia, epilepsy, nociception, migraine, sensation-seeking behavior, impulsivity, learning and memory. These numerous (patho)physiological processes of the CNS, in which the 5-HT7 receptor is involved, most likely reflect a diverse set of signaling pathways arising from this receptor. In order to reveal new interaction partners and possibly new signaling and/or trafficking pathways, we performed a yeast two-hybrid screening, using the C-terminal tail of the 5-HT7a receptor as bait and an adult-human brain cDNA library as prey. In this way we identified RhoBTB3 as a new interaction partner of the 5-HT7a receptor. By means of co-immunoprecipitation we were able to confirm the interaction between full length 5-HT7a receptor and RhoBTB3 in HEK293T cells. Subsequent domain mapping of this interaction revealed that not only the C-terminal tail, but also the third intracellular loop of the 5-HT7a receptor is involved. In addition, immunofluorescence microscopy showed clear co-localization between the 5-HT7a receptor and RhoBTB3 at the plasma membrane and in the endoplasmic reticulum. Despite the fact that RhoBTB3 has been shown to interact with Cul3, which in turn interacts with the E3 ubiquitin ligase, Roc1, we show here that RhoBTB3 neither recruits Cul3/Roc1 to the 5-HT7a receptor nor does it mediate ubiquitination of this receptor. Instead, we demonstrate that RhoBTB3 strongly inhibits proteasomal degradation of the 5-HT7a receptor.


Nox4 as a novel therapeutic target for diabetic vascular complications.
Diabetic vascular complications can affect both microvascular and macrovascular. Diabetic microvascular complications, such as diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, and diabetic cardiomyopathy, are believed to be caused by oxidative stress. The Nox family of NADPH oxidases is a significant source of reactive oxygen species and plays a crucial role in regulating redox signaling, particularly in response to high glucose and diabetes mellitus. This review aims to provide an overview of the current knowledge about the role of Nox4 and its regulatory mechanisms in diabetic microangiopathies. Especially, the latest novel advances in the upregulation of Nox4 that aggravate various cell types within diabetic kidney disease will be highlighted. Interestingly, this review also presents the mechanisms by which Nox4 regulates diabetic microangiopathy from novel perspectives such as epigenetics. Besides, we emphasize Nox4 as a therapeutic target for treating microvascular complications of diabetes and summarize drugs, inhibitors, and dietary components targeting Nox4 as important therapeutic measures in preventing and treating diabetic microangiopathy. Additionally, this review also sums up the evidence related to Nox4 and diabetic macroangiopathy.


Maternal deaths in Australia from ruptured splenic artery aneurysms.
The rupture of a splenic artery aneurysm (SAA) in pregnancy is a highly lethal condition, but so rare that most obstetricians would not encounter it during their career. In the seven official 'Maternal Deaths in Australia' reports, that covered 21 years from 1997 to 2017, among a total of 449 direct and indirect deaths, there were nine deaths (2%) from a ruptured SAA. These cases, and other cases from the literature and the Cochrane Library, are reviewed. The aim of the review is to raise awareness among clinicians of this potentially fatal condition.


Crystallographic refinement by knowledge-based exploration of complex energy landscapes.
Although X-ray crystallography remains the most versatile method to determine the three-dimensional atomic structure of proteins and much progress has been made in model building and refinement techniques, it remains a challenge to elucidate accurately the structure of proteins in medium-resolution crystals. This is largely due to the difficulty of exploring an immense conformational space to identify the set of conformers that collectively best fits the experimental diffraction pattern. We show here that combining knowledge-based conformational sampling in RAPPER with molecular dynamics/simulated annealing (MD/SA) vastly improves the quality and power of refinement compared to MD/SA alone. The utility of this approach is highlighted by the automated determination of a lysozyme mutant from a molecular replacement solution that is in congruence with a model prepared independently by crystallographers. Finally, we discuss the implications of this work on structure determination in particular and conformational sampling and energy minimization in general.


The effectiveness of a preoperative multi-component non-pharmacologic preparation on post-tonsillectomy pain: A randomized controlled clinical trial.
Tonsillectomy is a painful operation and some studies have suggested that preoperative non-pharmacologic preparations may decrease postoperative pain. In this randomized clinical trial study, we decided to determine which is more effective in the post-tonsillectomy pain; an informative booklet or a costly, time consuming, sophisticated, and multi-component preparation program. Patients were randomly assigned into two groups. In the booklet group, children and their parents only received an informative booklet as routine information preparation. On the other hand, in the multi-component group; in addition to receiving the same booklet, children and their parents received our multi-component pre-operative preparation program. The following items were included in the package: preoperative tour in the ward, an educational DVD, and therapeutic play intervention. All patients were observed at least for 8 h as a day case or ambulatory tonsillectomy. The pain score was recorded according to the visual analog scale for seven days. Finally, the post-tonsillectomy pain scores were compared in the two groups. The multi-component group included 121 children and booklet group 120. Minimum and maximum age was 9 and 12 years. Regarding post-tonsillectomy pain, we found no significant difference between the multi-component group and the booklet group. Our data revealed that a new concept which is more cost-effective and concise booklet is as effective as costly and sophisticated methods in post-tonsillectomy pain among 9-12 years old children.


Lipoprotein(a) interactions with lipid and non-lipid risk factors in patients with early onset coronary artery disease: results from the NHLBI Family Heart Study.
A positive interaction between high plasma lipoprotein(a) [Lp(a)] and unfavorable plasma lipid levels has been reported to result in very high risk for premature coronary artery disease (CAD). We further examined this issue for men and women with early onset CAD. We also examined potential interactions between Lp(a) and non-lipid risk factors. In 338 men and women with early onset CAD (most with a positive family history of early CAD) and 480 general population controls, we measured Lp(a), lipids and other risk factors. In univariate analysis, relative odds for CAD was 1.7 (P = 0.002) for plasma Lp(a) >50 mg/dl. Elevated Lp(a) level was found to interact with adjusted plasma total/high density lipoprotein (HDL) cholesterol such that when Lp(a) was over 50 mg/dl and adjusted plasma total/HDL cholesterol >5.8, relative odds for CAD were 8.0-9.6 (P<0.0001) in multiple logistic regression. Non-lipid risk factors were generally found to multiply the risk associated with Lp(a) (as predicted by logistic regression) without evidence for interaction. We find evidence that Lp(a) does interact positively with adjusted plasma total/HDL cholesterol ratio. Aggressive risk factor intervention, especially for lipids, in those with elevated Lp(a) therefore appears indicated.


Reversible inhibition of the glycine transporter GlyT2 circumvents acute toxicity while preserving efficacy in the treatment of pain.
Available medications for chronic pain provide only partial relief and often cause unacceptable side effects. There is therefore a need for novel molecular targets to develop new therapeutics with improved efficacy and tolerability. Despite encouraging efficacy data in rodents with inhibitors of the neuronal glycine transporter-2 (GlyT2), there are also some reports of toxicity and their development was discontinued. In order to clarify the possibility of targeting GlyT2 for the treatment of pain, we have used an integrated approach comprising in vitro pharmacology, selectivity, bioavailability, in vivo efficacy and safety assessment to analyse the properties and efficacy of ALX-1393 and Org-25543, the two published GlyT2 inhibitors from which in vivo data are available. We report that these compounds have a different set of undesirable properties that limit their usefulness as pharmacological tools. Importantly, we discover that inhibitors of GlyT2 can exert an apparent reversible or irreversible inhibition of the transporter and describe a new class of reversible GlyT2 inhibitors that preserves efficacy while avoiding acute toxicity. Our pharmacological comparison of two closely related GlyT2 inhibitors with different modes of inhibition provides important insights into their safety and efficacy profiles, uncovering that in the presence of a GlyT2 mechanism-based toxicity, reversible inhibitors might allow a tolerable balance between efficacy and toxicity. These findings shed light into the drawbacks associated with the early GlyT2 inhibitors and describe a new mechanism that might serve as the starting point for new drug development.


Lung cancer incidence attributable to residential radon exposure in Finland.
This study aimed to estimate (1) the number of avoidable lung cancer cases attributable to residential radon in Finland in 2017, separately by age, sex, dwelling type and smoking status, (2) the impact of residential radon alone and the joint effect of residential radon and smoking on the number of lung cancers and (3) the potential decrease in the number of radon-attributable lung cancers if radon concentrations exceeding specified action levels (100, 200 and 300 Bq m-3) would have been mitigated to those levels. Population-based surveys of radon concentrations and smoking patterns were used. Observed radon levels were contrasted with 25 Bq m-3 representing a realistic minimum level of exposure. Lung cancer risk estimates for radon and smoking were derived from literature. Lastly, the uncertainty due to the estimation of exposure and risk was quantified using a computationally derived uncertainty interval. At least 3% and at most 8% of all lung cancers were estimated as being attributable to residential radon. For small cell carcinoma, the proportion of cases attributable to radon was 8-13%. Among smokers, the majority of the radon-related cases were attributable to the joint effect of radon and smoking. Reduction of radon exposure to 100 Bq m-3 action level would eliminate approximately 30% of radon-attributable cases. Estimates were low compared with the literature, given the (relatively high) radon levels in Finland. This was mainly due to the lower radon levels and higher smoking prevalence in flats than in houses and a more realistic point of comparison, factors which have been ignored in previous studies. The results can guide actions in radon protection and in prevention of lung cancers.


Study on the color-changing mechanism and law of visual formaldehyde sensing system based on hyperbranched polyamines.
This study focuses on addressing the limitations associated with most chemical derivatization methods commonly used for formaldehyde detection. These methods often suffer from prolonged derivative times (≥30 min) and complex procedures, which hinder their ability to meet the requirements of real-time and accurate sensing. In this research, a novel formaldehyde indicator system based on hyperbranched polyamine molecule was developed, and its mechanism and principles of color change were investigated. The findings revealed that hyperbranched polyamine molecule effectively reacts with formaldehyde, leading to a reduction in electron cloud density in the amine group N and subsequently causing a decrease in pH value. This reaction enables the visualization of formaldehyde detection through changes in the indicator spectrum. Moreover, the spectral variation pattern exhibits a strong linear correlation with the formaldehyde concentration when the PAMAM concentration is optimized. The detection limit of this method was determined to be 1.8 ppm. Notably, the reaction between PAMAM and formaldehyde is almost instantaneous, the color change is insensitive to temperature, and the method demonstrates high selectivity. Overall, this research contributes to the advancement of real-time formaldehyde monitoring technology and provides insights for future developments in this field.


Inhibition of proliferation of gastric epithelial cells by a cyclooxygenase 2 inhibitor, JTE522, is also mediated by a PGE2-independent pathway.
Cyclooxygenase-2 (COX-2) is one of the rate-limiting enzymes for prostaglandin synthesis from arachidonic acid. Although it is known that inhibition of cyclooxygenase activity delays ulcer healing, the regulatory relationship between COX-2 and its metabolites in gastric epithelial cell proliferation is not well known. To investigate whether COX-2 has an effect on gastric mucosal cell proliferation and further studied whether such effect is mediated only by prostaglandin E2 (PGE2), a representative metabolite of arachidonates in the gastric mucosa. Artificial wounds of defined area size were created on complete monolayer cell sheets of isolated rat gastric epithelial cells and rat gastric cell line RGM1 under the addition of arachidonic acid or a COX-2 selective inhibitor, JTE522. Repair of wounds was assessed by monitoring wound size, with cell proliferation detected using 5-bromodeoxyuridine staining. Quantity of secreted PGE2 was measured by enzyme immunoassay. Stimulation of foetal calf serum increased the expression of COX-2 protein and inhibition of COX-2 retarded wound healing with reduction of cell proliferation. Arachidonic acid increased PGE2 production and accelerated restoration. Combination of JTE522 and arachidonic acid resulted in a marked retardation of wound healing compared to the control, but JTE522 did not completely suppress the increase in cellular PGE2 content following the addition of arachidonate. The difference in the effects of JTE522 on PGE2 production and on wound healing suggest that the involvement of COX-2 in gastric epithelial cell proliferation is not mediated solely by PGE2.


Case Commentary: Unlocking the Potential of Bacteriophage to Prevent Recurrent Urinary Tract Infections after Kidney Transplantation.
Recurrent urinary tract infections (UTIs) are common in kidney transplant recipients, and novel prevention approaches are needed. The case presented by Le et al. (Antimicrob Agents Chemother, in press) describes a patient with recurrent UTIs due to extended-spectrum β-lactamase-producing Klebsiella pneumoniae who was successfully treated with bacteriophage therapy. This commentary highlights the potential for bacteriophage therapy to prevent recurrent UTIs, as well as outstanding questions that require further investigation.


Statistical considerations for calculation of immunogenicity screening assay cut points.
Most therapeutic proteins induce an unwanted immune response. Antibodies elicited by these therapeutic proteins may significantly alter drug safety and efficacy, highlighting the need for the strategic assessment of immunogenicity at various stages of clinical development. Immunogenicity testing is generally conducted by a multi-tiered approach whereby patient samples are initially screened for the presence of anti-drug antibodies in a screening assay. The screening assay cut point is statistically determined by evaluation of drug-naïve samples and is typically chosen to correspond to a false positive rate of 5%. While various statistical approaches for determination of this screening cut point have been commonly adopted and described in the immunogenicity literature, the performance of these approaches has not been fully evaluated. This paper reviews various statistical approaches for cut point calculation, evaluates the impact of sampling design and variability on the performance of each statistical approach, and highlights the difference between an 'average' or 'confidence-level' cut point in order to develop more specific recommendations regarding the statistical calculation of immunogenicity screening cut points.


Laser Doppler assessment of dermal circulatory changes in people with coronary artery disease.
Dermal microcirculation provides an easily accessible vasculature bed which can be used to assess endothelial mediated vasodilatation. We studied and compared microcirculatory changes in response to acetylcholine iontophoresis (ACh), local heating of the skin and reactive hyperaemia in patients with coronary artery disease (CAD). Forty eight patients with CAD were studied and compared with 25 age and sex matched control subjects. Vasodilatory changes in the dermal microcirculation were assessed in response to ACh iontophoresis, local heating of the skin and reactive hyperaemia using a laser Doppler flowmeter (LDF). Body mass index (BMI) and systolic BP were higher in people with CAD, (p=0.001, 0.043). The perfusion change (measured as absolute in agreement with our previous publish results) in response to ACh iontophoresis, local heating of the skin and reactive hyperaemia, in healthy controls was 234 (190-286), 90 (69-118), 139(106-172) arbitrary perfusion units (APU) compared to 161 (121-214), 50 (39-63), 116(77-143) APU in patients with CAD; p<0.03. The time to peak perfusion in response to reactive hyperaemia was significantly higher in patients with CAD, 14.1±4.0 vs 10.9±1.7s; p=0.001. There was a small but significant positive correlation between the perfusion change in response to ACh iontophoresis and local heating (r=0.31, p=0.035). On ROC curve analysis, perfusion changes with heating had higher sensitivity and specificity in discriminating patients with CAD from the healthy controls with an area under the curve (AUC) of 0.86, with a specificity of 92% and sensitivity of 77% compared to a perfusion changes by reactive hyperaemia, AUC of 0.68 (41% sensitivity and 91% specificity) and ACh iontophoresis, AUC of 0.76 (88% sensitivity and 60% specificity). Vasodilatation in the dermal microcirculation measured by the three techniques is attenuated in patients with coronary artery disease. Local heating of the skin is a better discriminator of patients with CAD than ACh iontophoresis and reactive hyperaemia.


A facile one-pot synthesis of 4,5-diaryl-2,2-dimethyl-3(2H)-furanones.
An efficient and practical one-pot synthesis of 4,5-diaryl-2,2-dimethyl-3(2H)-furanones has been achieved from 1,2-diarylethanones and 2-bromoisobutyryl cyanide in the presence of excess base, by employing the 'hard soft acid base' principle. The reaction scope of 2-bromoisobutyryl cyanide could be expanded to prepare a variety of 2,2-dimethyl-3(2H)-furanone derivatives other than 4,5-diaryl-2,2-dimethyl-3(2H)-furanones.


Fusobacterium chorioamnionitis: report of two cases in preterm labor with intact amniotic membranes.
Preterm labor (PTL) in women with intact membranes may be caused by developing chorioamnionitis. Fusobacterium displays the ability to cause chorioamnionitis in the presence of intact amniotic membrane. We report 2 patients with severe Fusobacterium chorioamnionitis which resulted in premature termination of pregnancy. Both patients presented with PTL and intact membranes. Neither initially appeared acutely ill. Despite the benign appearance, one woman rapidly deteriorated, requiring ventilation, pressor support, and surgical evacuation of the uterus. We feel that a Gram's Stain and proper collection of anaerobic cultures at the time of amniocentesis should be part of the evaluation of every patient with suspected chorioamnionitis.


Externalizing problems mediate the relationship between motor proficiency and internalizing problems in children: An extension of the Environmental Stress Hypothesis.
The Environmental Stress Hypothesis (ESH) is a causal theoretical framework that provides a flexible context for understanding factors that mediate the relationship between low motor proficiency and internalizing problems in children. The purpose of the present study was to use the ESH framework to determine whether body mass index (BMI), physical activity levels, psychosocial health and physical health, self-efficacy, perceived social status, prosocial behavior and externalizing problems were potential mediators between motor proficiency and internalizing factors in a population of Brazilian children. 431 children aged 7- to 10 years (240 females, 191 males) participated in the study. The variables were measured with the Movement Assessment Battery for Children, 2nd ed. (MABC-2), the Pediatric Quality of Life Inventory (PedsQL), the Strengths and Difficulties Questionnaire (SDQ), the MacArthur Subjective Social Status Scale (MacArthur SSS), the Self-efficacy Sense Assessment Roadmap (RASAE), and the Physical Activity Questionnaire (PAQ). The results indicated a direct relationship between motor proficiency and internalizing problems in a population of Brazilian children, with externalizing problems being the only variable mediating that relationship. To the best of our knowledge, this is the first time that externalizing problems were tested in the context of the ESH. Understanding and evaluating potential mediators in the relationship between motor proficiency and internalizing problems using the ESH framework is essential to promote prevention policies and interventions for school-age children.


New aspect of photodynamic diagnosis of bladder tumors: fluorescence cytology.
To establish a new diagnostic method for the detection and follow-up of bladder cancer that combines the principles of photodynamic diagnosis and urinary cytology. We investigated 46 patients scheduled for transurethral resection of a bladder tumor immediately before the resection was carried out. After intravesical instillation of either 5-aminolevulinic acid (ALA) or hypericin, urinary cytology specimens were obtained. Induced fluorescence of urothelial cells was detected by fluorescence microscopy. The results were compared with the conventional cytologic and histologic findings. In the 46 patients, 42 cases of urothelial carcinoma and 4 cases of nonspecific inflammation were diagnosed. Of the 42 patients with cancer, 19 had Stage Ta, 9 had T1, 3 had carcinoma in situ, and 11 had invasive bladder cancer. The grading was G1 in 17 patients, G2 in 6 patients, and G3 in 19 patients. In 38 cases we instilled ALA and in 8 hypericin. All 4 patients diagnosed with nonspecific inflammation had received ALA. We detected ALA-induced fluorescence in 34 of 38 cases. One of the four histologically negative cases had a false-positive finding and 1 case of urothelial carcinoma did not show fluorescence. After instillation of hypericin we could detect induced fluorescence in all cases. Our first results suggest that fluorescence cytology is more sensitive than other noninvasive tests. After additional investigation, it may become a valuable diagnostic method and may reduce the number of cystoscopies in the follow-up of bladder tumors.


Hormonal effects of an antiestrogen, tamoxifen, in normal and oligospermic men.
The administration of tamoxifen, 20 mg/day for 10 days, to normal males produced a moderate increase in luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, and estradiol levels, comparable to the effect of 150 mg of clomiphene citrate (Clomid). However, whereas Clomid produced a decrease in the LH response to LH-releasing hormone (LHRH), no such effect was seen after the administration of tamoxifen. In fact, prolonged treatment (6 weeks) with tamoxifen significantly increased the LH response to LHRL. Treatment of patients with "idiopathic" oligospermia for 6 to 9 months resulted in a significant increase in gonadotropin, testosterone, and estradiol levels. A significant increase in sperm density was observed only in subjects with oligospermia below 20 X 10(6)/ml and normal basal FSH levels. When basal FSH levels were increased or oligospermia was moderate (greater than 20 X 10(6)/ml); no effect on sperm density was seen. As sperm density increased, FSH levels decreased, suggesting an inhibin effect. Sperm motility was not improved by tamoxifen treatment. In five boys with delayed puberty, tamoxifen treatment appeared to activate the pituitary-gonadal axis and pubertal development.


Co-inoculation of Mycorrhiza and methyl jasmonate regulates morpho-physiological and antioxidant responses of Crocus sativus (Saffron) under salinity stress conditions.
Salinity stress is the second most devastating abiotic factor limiting plant growth and yields. Climate changes have significantly increased salinity levels of soil. Besides improving the physiological responses under stress conditions, jasmonates modulate Mycorrhiza-Plant relationships. The present study aimed to evaluate the effects of methyl jasmonate (MeJ) and Funneliformis mosseae (Arbuscular mycorrhizal (AM) on morphology and improving antioxidant mechanisms in Crocus sativus L. under salinity stress. After inoculation with AM, pre-treated C. sativus corms with MeJ were grown under low, moderate, and severe salinity stress. Intense salinity levels damaged the corm, root, total leaf dry weight, and area. Salinities up to 50 mM increased Proline content and Polyphenol oxidase (PPO) activity, but MeJ increased this trend in proline. Generally, MeJ increased anthocyanins, total soluble sugars, and PPO. Total chlorophyll and superoxide dismutase (SOD) activity increased by salinity. The maximum catalase and SOD activities in + MeJ + AM were 50 and 125 mM, respectively, and the maximum total chlorophyll in -MeJ + AM treatment was 75 mM. Although 20 and 50 mM increased plant growth, using mycorrhiza and jasmonate enhanced this trend. Moreover, these treatments reduced the damage of 75 and 100 mM salinity stress. Using MeJ and AM can improve the growth of saffron under various ranges of salinity stress levels; however, in severe levels like 120 mM, this phytohormone and F. mosseae effects on saffron could be adverse.


Deep-learning magnetic resonance imaging-based automatic segmentation for organs-at-risk in the brain: Accuracy and impact on dose distribution.
Normal tissue sparing in radiotherapy relies on proper delineation. While manual contouring is time consuming and subject to inter-observer variability, auto-contouring could optimize workflows and harmonize practice. We assessed the accuracy of a commercial, deep-learning, MRI-based tool for brain organs-at-risk delineation. Thirty adult brain tumor patients were retrospectively manually recontoured. Two additional structure sets were obtained: AI (artificial intelligence) and AIedit (manually corrected auto-contours). For 15 selected cases, identical plans were optimized for each structure set. We used Dice Similarity Coefficient (DSC) and mean surface-distance (MSD) for geometric comparison and gamma analysis and dose-volume-histogram comparison for dose metrics evaluation. Wilcoxon signed-ranks test was used for paired data, Spearman coefficient(ρ) for correlations and Bland-Altman plots to assess level of agreement. Auto-contouring was significantly faster than manual (1.1/20 min, p < 0.01). Median DSC and MSD were 0.7/0.9 mm for AI and 0.8/0.5 mm for AIedit. DSC was significantly correlated with structure size (ρ = 0.76, p < 0.01), with higher DSC for large structures. Median gamma pass rate was 74% (71-81%) for Plan_AI and 82% (75-86%) for Plan_AIedit, with no correlation with DSC or MSD. Differences between Dmean_AI and Dmean_Ref were ≤ 0.2 Gy (p < 0.05). The dose difference was moderately correlated with DSC. Bland Altman plot showed minimal discrepancy (0.1/0) between AI and reference Dmean/Dmax. The AI-model showed good accuracy for large structures, but developments are required for smaller ones. Auto-segmentation was significantly faster, with minor differences in dose distribution caused by geometric variations.


Diversity and species distribution of ectomycorrhizal fungi along productivity gradients of a southern boreal forest.
Coniferous forests with diverse ectomycorrhizal fungus (EMF) communities are associated with nutrient-poor, acidic soils but there is some debate whether EMF can be equally adapted to more productive, nitrogen-rich sites. We compared EMF species distribution and diversity along a replicated productivity gradient in a southern boreal forest of British Columbia (Canada). Roots from subalpine fir (Abies lasiocarpa) saplings of the understory were sampled and EMF species were identified by morphotypes supplemented with ITS rDNA analysis. There were significant changes in the distribution and abundance of 74 EMF species along the productivity gradient, with as little as 24% community similarity among contrasting sites. Species richness per plot increased asymptotically with foliar nitrogen concentrations of subalpine fir, demonstrating that many EMF species were well suited to soils with high rates of nitrogen mineralization. EMF species abundance in relation to site productivity included parabolic, negative linear, and positive exponential curves. Both multi-site and more narrowly distributed EMF were documented, and a diverse mix of mantle exploration types was present across the entire productivity gradient. The results demonstrate strong associations of EMF fungal species with edaphic characteristics, especially nitrogen availability, and a specialization in EMF communities that may contribute to the successful exploitation of such contrasting extremes in soil fertility by a single tree host.


Circulating CD34-positive cells, glomerular filtration rate and triglycerides in relation to hypertension.
Serum triglycerides have been reported to be independently associated with the development of chronic kidney disease (CKD), which is known to play a role in vascular disturbance. On the other hand, circulating CD34-positve cells, including endothelial progenitor cells, are reported to contribute to vascular repair. However, no studies have reported on the correlation between triglycerides and the number of CD34-positive cells. Since hypertension is well known factor for vascular impairment, the degree of correlation between serum triglycerides and circulating CD34-positve cells should account for hypertension status. We conducted a cross-sectional study of 274 elderly Japanese men aged ≥ 60 years (range 60-79 years) undergoing general health checkups. Multiple linear regression analysis of non-hypertensive subjects adjusting for classical cardiovascular risk factors showed that although triglyceride levels (1SD increments; 64 mg/dL) did not significantly correlate with glomerular filtration rate (GFR) (β = -2.06, p = 0.163), a significant positive correlation was seen between triglycerides and the number of circulating CD34-positive cells (β = 0.50, p = 0.004). In hypertensive subjects, a significant inverse correlation between triglycerides and GFR was observed (β = -2.66, p = 0.035), whereas no significant correlation between triglycerides and the number of circulating CD34-positive cells was noted (β = -0.004, p = 0.974). Since endothelial progenitor cells (CD34-positive cells) have been reported to contribute to vascular repair, our results indicate that in non-hypertensive subjects, triglycerides may stimulate an increase in circulating CD34-positive cells (vascular repair) by inducing vascular disturbance.