Role of Cdc42-Cla4 interaction in the pheromone response of Saccharomyces cerevisiae.
In Saccharomyces cerevisiae, the highly conserved Rho-type GTPase Cdc42 is essential for cell division and controls cellular development during mating and invasive growth. The role of Cdc42 in mating has been controversial, but a number of previous studies suggest that the GTPase controls the mitogen-activated protein (MAP) kinase cascade by activating the p21-activated protein kinase (PAK) Ste20. To further explore the role of Cdc42 in pheromone-stimulated signaling, we isolated novel alleles of CDC42 that confer resistance to pheromone. We find that in CDC42(V36A) and CDC42(V36A, I182T) mutant strains, the inability to undergo pheromone-induced cell cycle arrest correlates with reduced phosphorylation of the mating MAP kinases Fus3 and Kss1 and with a decrease in mating efficiency. Furthermore, Cdc42(V36A) and Cdc42(V36A, I182T) proteins show reduced interaction with the PAK Cla4 but not with Ste20. We also show that deletion of CLA4 in a CDC42(V36A, I182T) mutant strain suppresses pheromone resistance and that overexpression of CLA4 interferes with pheromone-induced cell cycle arrest and MAP kinase phosphorylation in CDC42 wild-type strains. Our data indicate that Cla4 has the potential to act as a negative regulator of the mating pathway and that this function of the PAK might be under control of Cdc42. In conclusion, our study suggests that control of pheromone signaling by Cdc42 not only depends on Ste20 but also involves interaction of the GTPase with Cla4.


JAK/STAT signaling pathway and its regulation on insect immunity.
JAK/STAT signaling pathway is involved in important biological processes, such as cell growth, differentiation, apoptosis and immune regulation, and is one of the most important signal transduction pathways mediated by cytokines. JAK/STAT is a relatively conserved signaling pathway in insects, which is the main immune pathway together with Toll signaling pathway and Imd signaling pathway to resist the invasion of pathogens. It plays a vital role in insect immunity, hormone regulation and other physiological regulation processes. In this review, we summarize the cytokine receptor superfamily, JAKs family, STATs family, JAK/STAT signaling pathway and its mechanism of negative feedback regulation. We analyze the important functions and the latest research progress of JAK/STAT signaling pathway in insect infected by parasites, viruses and fungi. Finally, we propose the remaining problems in the study of JAK/STAT signaling pathway, so as to provide direction and reference for further research in this field.


GIS based analysis of Intercity Fatal Road Traffic Accidents in Iran.
Road traffic accidents including intercity car traffic accidents (ICTAs) are among the most important causes of morbidity and mortality due to the growing number of vehicles, risky behaviors, and changes in lifestyle of the general population. A sound knowledge of the geographical distribution of car traffic accidents can be considered as an approach towards the accident causation and it can be used as an administrative tool in allocating the sources for traffic accidents prevention. This study was conducted to investigate the geographical distribution and the time trend of fatal intercity car traffic accidents in Iran. To conduct this descriptive study, all Iranian intercity road traffic mortality data were obtained from the Police reports in the Statistical Yearbook of the Governor's Budget and Planning. The obtained data were for 17 complete Iranian calendar years from March 1997 to March 2012. The incidence rate (IR) of fatal ICTAs for each year was calculated as the total number of fatal ICTAs in every 100000 population in specified time intervals. Figures and maps indicating the trends and geographical distribution of fatal ICTAs were prepared while using Microsoft Excel and ArcGis9.2 software. The number of fatal car accidents showed a general increasing trend from 3000 in 1996 to 13500 in 2012. The incidence of fatal intercity car accidents has changed from six in 100000 population in 1996 to 18 in 100000 population in 2012. GIS based data showed that the incidence rate of ICTAs in different provinces of Iran was very divergent. The highest incidence of fatal ICTAs was in Semnan province (IR= 35.2), followed by North Khorasan (IR=22.7), and South Khorasan (IR=22). The least incidence of fatal ICTAs was in Tehran province (IR=2.4) followed by Khozestan (IR=6.5), and Eastern Azarbayejan (IR=6.6). The compensation cost of fatal ICTAs also showed an increasing trend during the studied period. Since an increasing amount of money was being paid yearly for the car accidents, which were in their nature preventable, the key players in road safety including governments, car manufacturers, and road developers were recommended to use GIS based accident data for a more efficient planning and budgeting towards the intercity car accidents reduction.


Reduction of 2,2,2-trichloro-1-arylethanones by RMgX: mechanistic investigation and the synthesis of substituted α,α-dichloroketones.
2,2,2-Trichloro-1-arylethanones undergo high yielding reductions to the corresponding 2,2-dichloro-1-arylethanones in the presence of RMgX. A single electron transfer mechanism for the reaction is proposed based on trapping experiments. Reaction of the intermediate enolates with a range of electrophiles is described, providing a convenient route to substituted α,α-dichloro-β-hydroxyketones and related molecules.


Peripheral blood findings associated with asymptomatic lead exposure.
This study was done to determine whether erythroid alterations can be found on a peripheral blood smear from an asymptomatic person exposure to excess atmospheric lead. Thirty healthy, asymptomatic adults who lived within five miles of a major Los Angeles, California freeway for five consecutive years were studied. Erythroid cytologic alterations-including-anisocytosis, poikilocytosis, polychromasia and basophilic stippling were statistically associated with increased free erythrocyte protoporphyrin levels. These findings indicate that erythroid alterations may be found on a peripheral blood smear prior to the development of clinical symptoms of lead intoxication.


A basic analysis toolkit for biological sequences.
This paper presents a software library, nicknamed BATS, for some basic sequence analysis tasks. Namely, local alignments, via approximate string matching, and global alignments, via longest common subsequence and alignments with affine and concave gap cost functions. Moreover, it also supports filtering operations to select strings from a set and establish their statistical significance, via z-score computation. None of the algorithms is new, but although they are generally regarded as fundamental for sequence analysis, they have not been implemented in a single and consistent software package, as we do here. Therefore, our main contribution is to fill this gap between algorithmic theory and practice by providing an extensible and easy to use software library that includes algorithms for the mentioned string matching and alignment problems. The library consists of C/C++ library functions as well as Perl library functions. It can be interfaced with Bioperl and can also be used as a stand-alone system with a GUI. The software is available at http://www.math.unipa.it/~raffaele/BATS/ under the GNU GPL.


Ethical aspects of capsule endoscopy.
Capsule endoscopy is the most recent innovation in gastrointestinal endoscopy. The capsule contains a video camera that photographs the bowel for 8 h after the capsule has been orally ingested and transmits the images for interpretation to a computerized workstation. Ethical considerations of the use of capsule endoscopy should cover the following main issues: justification of the procedure, its potential benefits and harm, and patient autonomy. Capsule endoscopy has several advantages over traditional endoscopy. The procedure is painless, does not require sedation, is easy to perform and for the first time enables exploration of the entire small bowel at high magnification. However, the clinician cannot control its passive advance along the bowel. In addition, the examination may be incomplete, as the capsule reaches the cecum in only 80% of cases. This paper discusses the problems related to the new endoscopic procedure, the diagnostic yield in comparison with other procedures, proper indications for the procedure, outcome and complications.


Treatment of ovarian endometrial cysts in the context of recurrence and fertility.
An approach to ovarian endometrial cysts has changed considerably during recent years, especially in regard to treatment of recurrent endometriosis, fertility sparing and infertility management. Surgical treatment is the primary therapeutic option. The most efficient types of treatment are radical procedures involving adhesiolysis, removal of the cyst along with its capsule and any remaining endometriotic foci. However, small asymptomatic cysts should not be treated surgically, especially in patients older than 35 years. Surgical treatment can be considered in infertile women and those who failed to get pregnant despite 1-1.5 years of trials, as well as in cases in which in vitro fertilization is not an option. Also large cysts, with more than 4 cm in diameter, should be treated surgically due to the risk of their rupture or torsion. The most efficient preventive measure for recurrent ovarian endometriosis is unilateral oophorectomy with sparing the contralateral ovary. Such a procedure should be considered in women who are no longer interested in childbearing or present with another endometriotic cyst in the same ovary. The role of pharmacotherapy is fairly limited; it should be considered in patients in whom diffuse endometriosis is associated with pain. Therapeutic agents from the following groups can be used: estrogen-progestin preparation, gestagens, including progesteronereleasing intrauterine systems and gonadotropin-releasing hormone agonists. Women with infertility should get pregnant as soon as possible, and in patients who failed to get pregnant and/or are older than 35 years, in vitro fertilization should be the treatment of choice.


Showing Up: A Theoretical Model of Anti-Racist Identity and Action for Latinx Youth.
Historical and contemporary political events underscore that Latinx people do not necessarily view race and racism in the United States through a shared lens with other Latinx people and other communities of color. Thus, it is critical to understand how Latinx youth develop attitudes, beliefs, and behaviors that challenge white supremacy-or anti-racist identities and behaviors-that actively disrupt racial oppression communities of color face as well as their own communities. In this paper, we review theoretical mechanisms by which Latinx youth may develop anti-racist identities and actions on behalf of their own ethnic/racial communities and other communities oppressed by white supremacy. We conclude by offering suggestions for how institutions may support Latinx youth's anti-racist identities and actions.


NEMESIS: Noninferiority, Individual-Patient Metaanalysis of Selective Internal Radiation Therapy with 90Y Resin Microspheres Versus Sorafenib in Advanced Hepatocellular Carcinoma.
In randomized clinical trials, no survival benefit has been observed for selective internal radiation therapy (SIRT) over sorafenib in patients with advanced hepatocellular carcinoma (HCC). This study aimed to assess, through a metaanalysis, whether overall survival (OS) with SIRT, as monotherapy or followed by sorafenib, is noninferior to sorafenib and to compare safety profiles for patients with advanced HCC. Methods: We searched MEDLINE, EMBASE, and the Cochrane Library up to February 2019 to identify randomized clinical trials comparing SIRT, as monotherapy or followed by sorafenib, with sorafenib monotherapy among patients with advanced HCC. The main outcomes were OS and frequency of treatment-related severe adverse events (≥grade 3). The per-protocol population was the primary analysis population. A noninferiority margin of 1.08 in terms of hazard ratio was prespecified for the upper boundary of 95% confidence interval for OS. Prespecified subgroup analyses were performed. Results: Three randomized clinical trials, involving 1,243 patients, comparing sorafenib with SIRT (SIRveNIB and SARAH) or SIRT followed by sorafenib (SORAMIC), were included. After randomization, 411 of 635 (64.7%) patients allocated to SIRT and 522 of 608 (85.8%) allocated to sorafenib completed the studies without major protocol deviations. Median OS with SIRT, whether or not followed by sorafenib, was noninferior to sorafenib (10.2 and 9.2 mo [hazard ratio, 0.91; 95% confidence interval, 0.78-1.05]). Treatment-related severe adverse events were reported in 149 of 515 patients (28.9%) who received SIRT and 249 of 575 (43.3%) who received sorafenib only (P < 0.01). Conclusion: SIRT as initial therapy for advanced HCC is noninferior to sorafenib in terms of OS and offers a better safety profile.


Various forms of linear dipyridyls in discrete rectangles, dinuclear rods, and one-dimensional networks containing (eta5-pentamethylcyclopentadienyl)rhodium(III).
[Cp*Rh(eta1-NO3)(eta2-NO3)] (1) reacted with pyrazine (pyz) to give a dinuclear complex [Cp*Rh(eta1-NO3)(mu-pyz)(0.5)]2.CH2Cl2(3.CH2Cl2). Tetranuclear rectangles of the type [Cp*Rh(eta1,mu-X)(mu-L)(0.5)]4(OTf)4(4a: X = N3, L = bpy; 4b: X = N3, L = bpe; 4c: X = NCO, L = bpy) were prepared from [Cp*Rh(H2O)3](OTf)2 (2), a pseudo-halide (Me3SiN3 or Me3SiNCO), and a linear dipyridyl [4,4'-bipyridine (bpy) or trans-1,2-bis(4-pyridyl)ethylene (bpe)] by self-assembly through one-pot synthesis at room temperature. Treating complex with NH4SCN and dipyridyl led to the formation of dinuclear rods, [Cp*Rh(eta1-SCN)3]2(LH2) (5a: L = bpy; 5b: L = bpe), in which two Cp*Rh(eta1-SCN)3 units are connected by the diprotonated dipyridyl (LH2(2+)) through N(+)-H...N hydrogen bonds. Reactions of complex 2 with 1-(trimethylsilyl)imidazole (TMSIm) and dipyridyl (bpy or bpe) also produced another family of dinuclear rods [Cp*Rh(ImH)3]2.L (6a: L = bpy; 6b: L = bpe). Treating 1 and 2 with TMSIm and NH4SCN (in the absence of dipyridyl) generated a 1-D chain [Cp*Rh(ImH)3](NO3)2 (7) and a 1-D helix [Cp*Rh(eta1-SCN)2(eta1-SHCN)].H2O (8.H2O), respectively. The structures of complexes 3.CH2Cl2, 4a.H2O, 4c.2H2O, 5b, 6a, 7 and 8.H2O were determined by X-ray diffraction.


Bone Mineral Density is Unaltered in Women with Polycystic Ovary Syndrome.
The effects of endocrine aberrations associated with polycystic ovary syndrome (PCOS) on bone mineral density (BMD) in young women is a matter of debate. To compare BMD in young women with PCOS to age and body mass index (BMI) matched controls and to elucidate its correlation to BMI, insulin resistance and serum testosterone. We recruited 60 women with PCOS aged 14-24 years, diagnosed based on Rotterdam 2003 criteria, and 58 age matched controls. BMD was measured by dual energy X-ray absorptiometry. In addition, these subjects underwent biochemical and hormonal analysis including oral glucose tolerance test, calculation of Homeostatic Model Assessment-Insulin Resistance Index, measurement of serum thyroxine, thyrotropin, prolactin, total testosterone, dehydroepiandrosterone sulfate, follicular phase luteinizing hormone and follicle stimulating hormone. There was no difference of BMD between women with PCOS and control women (1.103±0.08 vs 1.126±0.083 g/cm2; p=0.122). In subgroup analysis based on BMI, BMD in obese women with PCOS was significantly higher than their overweight and lean counterparts at lumbar spine (p<0.001), neck of femur (p=0.005) and total hip (p<0.001). BMD was not different at any site between oligomenorrheic and non-oligomenorrheic women with PCOS. It positively correlated with BMI, waist and hip circumference in women with PCOS. No correlation was found with HOMA-IR or Testosterone. BMI is the most important determinant of BMD in women with PCOS. BMD is not different between healthy young women and those with PCOS.


An 18.3 MJ charging and discharging pulsed power supply system for the Space Plasma Environment Research Facility (SPERF): The subsystem for the magnetopause shape control coils.
The Space Plasma Environment Research Facility currently under construction at the Harbin Institute of Technology in China uses four magnetosheath coils (flux cores) and a dipole coil to generate the magnetic field required for the study on the magnetopause magnetic reconnection. Two groups of magnetopause shape control coils (labeled CK coils) are used to slightly adjust the magnetic field distribution on the magnetopause. A capacitive pulsed power supply (PPS) system with a modular design is developed to excite CK coils. The PPS system consists of six sets of PPS with the same principle and structure, which are used to excite six sub-coils of the CK coils, respectively. Each set of PPS consists of ten modules and one local controller, and each module consists of a charger and discharge unit. Each set of PPS can provide a pulsed current of no less than 400 kA for the corresponding sub-coil at 0.11 ms when the charging voltage is 20 kV, and the duration of the pulsed current from the peak to 10% of the peak is no more than 0.6 ms. The detailed design of the PPS is discussed in this paper, and the discharge test of the PPS is carried out to verify the design of the PPS. Because there are acquisition and control devices in the discharge unit, the electromagnetic interference immunity design is also discussed to ensure the normal operation of the PPS.


Reinfection with Lyme borreliosis: a retrospective follow-up study in southern Sweden.
In a 5-y retrospective follow-up study in southern Sweden that initially included > 1000 individuals with previously diagnosed erythema migrans, factors that influenced the risk of reinfection with Lyme borreliosis were elucidated. The total frequency of reinfection was 4% and the number of tick bites influenced the risk of reinfection: those bitten > 10 times during the observation period had a 4-8-fold increased risk compared with those bitten <5 times. Women manifested to a greater extent than men although both genders were bitten equally by ticks, thus indicating that women may be more susceptible to reinfection. All reinfected women were > 44 y old. The county of Kalmar including Oland was found to be highly endemic for reinfection with Lyme borreliosis. Thus the number of tick bites, gender, age and study area influenced the risk of reinfection.


Group B streptococcal bacteremia in a major teaching hospital in Malaysia: a case series of eighteen patients.
Group B Streptococcus (GBS) is a leading cause of infections such as meningitis and septicemia in neonates and pregnant women; however the significance of invasive GBS disease has not been clearly defined in non-pregnant adults. We reviewed the hospital records of 18 cases with GBS bacteremia who attended the Universiti Kebangsaan Malaysia Medical Centre from June 2010 to October 2011. We analyzed the clinical findings of both bacteremic adults and neonates and compared them to previous studies of GBS bacteremia. Serotyping was done by latex agglutination test using 10 distinct antisera (Ia, Ib, and II-IX). During the period of 1 year and 4 months, there were 18 patients with GBS bacteremia. Five cases occurred in neonates, one in a parturient woman, and 12 in other adults. All neonates with bacteremia were males and two of them were premature. Septicemia was the most common clinical presentation in neonates. They were treated with intravenous (IV) penicillin G and gentamicin. The adults included nine men (69%) and four women (31%). Their mean age was 60 years and all patients had more than two underlying conditions. The most common clinical syndrome was pneumonia (n=6, 46.5%). The others were peritonitis (n=3, 23.1%), primary bacteremia (n=2, 15.5%), septic arthritis (n=2, 15.5%), skin and soft tissue infection (n=1, 7.7%), meningitis (n=1, 8%), urinary tract infection (n=1, 8%), and intravascular device infection (n=1, 7.7%). Cardiovascular diseases (n=7, 53.8%) were the most common underlying conditions, and diabetes mellitus (n=5, 38.5%) was second. The other co-morbid conditions were hyperlipidemia (n=3, 23.1%), renal disease (n=3, 23.1%), liver disease and/or alcohol abuse (n=3, 23.1%), autoimmune disease or immunosuppressive condition (n=2, 15.5%), malignancy (n=2, 15.5%), respiratory disease (n=1, 8%), and postpartum condition (n=1, 8%), as well as miscellaneous conditions including intravenous drug abuse, HIV infection, and trauma (n=2, 15.5%). Polymicrobial bacteremia was found in five (45.4%) cases and Staphylococcus aureus was the most common concurrent bacterial isolate. Of the 18 GBS isolates in both adults and neonates, serotype Ia was predominant (38.9%), followed by VI (27.8%), V (11.1%), and III (5.5%); the remaining 16.7% were non-typeable. GBS bacteremia is a significant problem and is associated with serious underlying disease, which may result in a high rate of mortality, not only in neonates and pregnant women, but also in non-pregnant adults.


Male specific genes from dioecious white campion identified by fluorescent differential display.
Fluorescent differential display (FDD) has been used to screen for cDNAs that are differentially up-regulated in male flowers of the dioecious plant Silene latifolia in which an X/Y chromosome system of sex determination operates. To adapt FDD to the cloning of large numbers of differential cDNAs, a novel method of confirming the differential expression of these has been devised. FDD gels were Southern electro-blotted and probed with mixtures of individual cDNA clones derived from different FDD product ligation reactions. These Southern blots were then stripped and re-probed with further mixtures of individual cloned FDD products to identify the maximum number of recombinant clones carrying the true differential amplification products. Of 135 differential bands identified by FDD, 56 differential amplification products were confirmed; these represent 23 unique differentially expressed genes as determined by virtual Northern analysis and two genes expressed at or below the level of detection by virtual Northern analysis. These two low expressed genes show bands of hybridization on genomic Southern blots that are specific to male plants, indicating that they are derived from, or closely related to, Y chromosome genes.


Empyema of the gall bladder: reappraisal in the laparoscopy era.
In evaluations of laparoscopic cholecystectomy for acute cholecystitis, the role of this technique specifically for empyema of the gall bladder has not been separately addressed. Therefore, we describe the demographic characteristics, clinical and laboratory findings, management and outcome of patients presenting with empyema of the gall bladder who were treated with open cholecystectomy or laparoscopic cholecystectomy. Our retrospective evaluation included 1449 patients who underwent cholecystectomy over 88 months, including a 30-month period when open cholecystectomy was the standard operation and a 58-month period when laparoscopic cholecystectomy became the standard operation for acute and chronic cholecystitis. Of the 1449 cholecystectomies, 29 cases proved to have empyema, an incidence of 2%. Males constituted 48.3% of the patients (vs. 22% for the whole cholecystectomy group, P < or = 0.005) and the average age was 54.6 years (vs. 43 years for the whole cholecystectomy group, P < or = 0.005). The clinical picture was indistinguishable from other forms of acute cholecystitis. Laparoscopic cholecystectomy was attempted for all the patients in the laparoscopy era with a conversion rate of 42%, significantly higher than other forms of gall bladder diseases (P=0.002). Empyema of the gall bladder is more often encountered in males and the elderly. The clinical picture is indistinguishable from other forms of acute cholecystitis and a preoperative diagnosis is difficult. Early laparoscopic cholecystectomy is advisable for all patients with acute cholecystitis. A higher conversion rate is expected for patients with empyema.


Ultrafast dynamics and ultrasensitive single particle spectroscopy of optically robust core/alloy shell semiconductor quantum dots.
A "one-pot one-step" synthesis method of Core/Alloy Shell (CAS) quantum dots (QDs) offers the scope of large scale synthesis in a less time consuming, more economical, highly reproducible and high-throughput manner in comparison to "multi-pot multi-step" synthesis for Core/Shell (CS) QDs. Rapid initial nucleation, and smooth & uniform shell growth lead to the formation of a compositionally-gradient alloyed hetero-structure with very significantly reduced interfacial trap density in CAS QDs. Thus, interfacial strain gets reduced in a much smoother manner leading to enhanced confinement for the photo-generated charge carriers in CAS QDs. Convincing proof of alloy-shelling for a CAS QD has been provided from HRTEM images at the single particle level. The band gap could be tuned as a function of composition, temperature, reactivity difference of precursors, etc. and a high PLQY and improved photochemical stability could be achieved for a small sized CAS QD. From the ultrafast exciton dynamics in CdSe and InP CAS QDs, it has been shown that (a) the hot exciton thermalization/relaxation happens in <500 fs, (b) hot electron trapping dynamics occurs within a ∼1 ps time scale, (c) band edge exciton trapping occurs within a 10-25 ps timescale and (d) for CdSe CAS QDs the hot hole gets trapped in about 35 ps. From fast PL decay dynamics, it has been shown that the amplitude of the intermediate time constant can be correlated with the PLQY. A model has been provided to understand these ultrafast to fast exciton dynamical processes. At the ultrasensitive single particle level, unlike CS QDs, CdSe CAS QDs have been shown to exhibit (a) constancy of PLmax (i.e. no bluing) and (b) constancy of PL intensity (i.e. no bleaching) of the single CAS QDs for continuous irradiation for one hour under an air atmosphere. Thus, CAS QDs hold the promise of being a superior optical probe in comparison to CS QDs both at the ensemble and at the single particle level, leading to enhanced flexibility of the CAS QDs towards designing and developing next generation application devices.


Morphometry of the heart of budgerigars (Melopsittacus undulatus), Alisterus parrots (Alisterus s scapularis) and common buzzards (Buteo buteo).
In order to establish data and reference values for the thickness of the myocardium and the length of the left and the right ventricle of the avian heart, the hearts of 14 budgerigars (Melopsittacus undulatus), five Alisterus parrots (Alisterus s scapularis) (also known as Australian king parrot) and 10 common buzzards (Buteo buteo) of both sexes were examined according to a standard protocol. In order to compare the results of birds of different sizes all data were related to the size of the bird's body (length of the sternum) and the results of the measurements of the myocardial thickness in relation to the length of the heart. Results of different zones were compared by means of statistical methods within one species. Besides that a comparison between the different species was performed. Only minor significant differences were noted.


Reconciling Patient Safety and Epistemic Humility: An Ethical Use of Opioid Treatment Plans.
In this issue of the Hastings Center Report, Joshua Rager and Peter Schwartz suggest using opioid treatment agreements as public health monitoring tools to inform patients about "the requirements entailed by undergoing opioid therapy," rather than as contractual agreements to alter patients' individual behavior or to benefit them directly. Because Rager and Schwartz's argument presents suspected OTA violations as a justification to stop providing opioids yet does not highlight the broader epistemic and systemic context within which clinicians prescribe these medications, their proposal may perpetuate a climate of distrust and stigmatization without correcting systemic factors that may have placed patients and others at risk in the first place. Given the context of epistemic uncertainty regarding opioid safety and efficacy, insufficient training for opioid prescribers, and inadequate patient education, I propose replacing OTAs, which have a narrow focus on patient behaviors, with opioid treatment plans, which would promote mutual, collaborative, and shared decision-making on the most appropriate pain management program. An OTP can be ethically justified as a tool to prevent and treat iatrogenic addiction under a specific paradigm-one that adopts a default position of professional epistemic humility and holds all collaborative parties accountable in chronic pain management.


N-glycosylation of MDA-7/IL-24 is dispensable for tumor cell-specific apoptosis and "bystander" antitumor activity.
Biochemical and genetic mutation-based analyses confirm that the MDA-7/IL-24 protein can induce transformed cell-specific apoptosis through a mechanism involving endoplasmic reticulum (ER) stress-associated pathways. Covalent modifications by N-linked glycans in the ER contribute to the conformational maturation and biological functions of many proteins. Because MDA-7/IL-24 is a glycosylated protein, we investigated the role of glycosylation in mediating the specific biological and "bystander" antitumor activities of this cytokine. An adenovirus vector expressing a nonsecreted and nonglycosylated version of MDA-7/IL-24 protein was generated via deletion of its signal peptide and point mutations of its three N-glycosylated sites. In this study, we showed that this intracellular nonglycosylated protein was as effective as wild-type MDA-7/IL-24 protein in inducing apoptosis in multiple tumor cell lines. Both constructs (a) displayed transformed cell specificity and localization to the ER compartment, (b) mediated apoptosis through JAK/STAT-independent and p38(MAPK)-dependent pathways, (c) induced sustained ER stress as evidenced by expression of ER stress markers (BiP/GRP78, GRP94, XBP-1, and eIF2alpha), and (d) generated proteins that physically interacted with BiP/GRP78. Additionally, an expression construct containing the mda-7/IL-24 signal peptide linked to the mutated nonglycosylated mda-7/IL-24 gene retained the ability to induce bystander antitumor activity. These studies reveal that MDA-7/IL-24 glycosylation is not mandatory for inducing cell death or bystander activities in different cancer cells, providing new insights into the mechanism by which MDA-7/IL-24 induces apoptosis and ER stress.


Origin of the dorsal surface of the neural tube by progressive delamination of epidermal ectoderm and neuroepithelium: implications for neurulation and neural tube defects.
Knowledge of the morphogenetic events involved in the development of the dorsal portion of the neural tube is important for understanding neural tube closure, neural crest cell formation and emigration, and the origin of neural tube defects. Here, I characterize the progressive development of the tips of the neural folds during fold elevation in the trunk of mouse and chick embryos and the events leading to formation of the dorsal portion of the neural tube as the epidermal ectoderm (EE) and neuroepithelium (NE) separate from each other. The nature and timing of appearance of collagen IV, laminin and fibronectin were analysed by immunofluorescent and immunogold labelling, and ruthenium red and tannic acid were used to enhance staining for proteoglycans and glycosaminoglycans. As the neural folds elevate, the NE and EE delaminate progressively beginning at the basal surface of the lateral extremes of the neural plate. Nevertheless, the two epithelia remain connected across the zone of delamination by their previously existing basal laminae. In each fold, proteoglycan granules appear at the interface between the NE and EE before delamination begins, and then an (interepithelial) space begins to open and propagate dorsally. Other extracellular matrix (ECM) molecules appear within the space a short distance behind its tip and basal lamina deposition begins shortly thereafter. As fusion occurs, the interepithelial spaces of the two folds coalesce and the final separation of the EE from the NE is accomplished. These observations suggest that the previously recognized delay in deposition of ECM and basal lamina on the dorsal portion of the neural tube and on the overlying EE is a direct consequence of the delamination of the two epithelia and the establishment of two new basal surfaces. The observation that the surface of the dorsal third of the neural tube forms by delamination rather than by juxtaposition of previously existing basal surfaces of the two epithelial is discussed in terms of possible implications for models of neurulation and the origin of neural tube defects.


Emergent percutaneous coronary intervention for acute myocardial infarction in patients with mirror dextrocardia: case reports and brief review.
Mirror-image dextrocardia is a rare congenital abnormality with a life expectancy and risk of myocardial infarction similar to the normal population. Although there have been few case reports of emergent percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI) in mirror-image dextrocardia, physicians, especially general and interventional cardiologists encounter problems in the diagnosis and treatment of AMI in these patients. In this paper, we report our experience with two cases of emergent transradial PCI for AMI in patients with the mirror-image dextrocardia. Subsequently, we summarize clinical features, electrocardiograph characteristic, approach to emergent PCI based on a review of the literature.


Why the confusion in Hashimoto's encephalopathy?
A 13-year-old girl presented with an afebrile seizure followed by prolonged confusion and visual hallucinations. Initial investigations in the form of blood tests, cerebrospinal fluid analysis and head imaging by CT, were normal. She represented with two further episodes within a period of 3 weeks. Further investigations considering infective, metabolic and some autoimmune causes of encephalopathy were negative. An MRI head scan was normal. Thyroid function testing disclosed primary hypothyroidism and elevated antithyroid antibodies. She responded well to glucocorticoid therapy for presumed Hashimoto's encephalopathy (HE). HE describes patients with various neurological manifestations with elevated titres of antithyroid antibodies. There are no clear criteria for diagnosis, with many cases labelled as HE. Responses to corticosteroid therapy are favourable. In patients with unexplained encephalopathy, HE should be considered given the favourable response to glucocorticoid therapy.


Exogenous application of methyl jasmonate lowers the effect of cadmium-induced oxidative injury in rice seedlings.
Rice seedlings grown under 50 μM cadmium alone or in combination with 5 μM methyl jasmonate were investigated for Cd-induced oxidative injury at 3, 7 and 10 days of treatment. MeJA treatments alone did not have any significant change in antioxidant enzyme activities or levels of H2O2 and O2(·-) in roots/shoots, as compared to controls during 3-10 days. The Cd-stressed plants When supplemented with exogenous MeJA revealed significant and consistent changes in activities of antioxidant enzymes CAT, SOD, POD and GR paralleled with an increased GSH-pools than that in plants subjected to Cd-stress alone. Synthesis of GSH driven by increasing demand for GSH in response to Cd-induced oxidative stress in rice was evident. Increased activity of LOX under Cd-stress was noted. Results suggest enhanced Cd-tolerance, lowered Cd(2+) uptake, an improved membrane integrity and 'switching on' of the JA-biosynthesis by LOX in the Cd-stressed rice roots/shoots exposed to MeJA. Exposure to MeJA improved antioxidant response and accumulation of antioxidants which perhaps lowered the Cd-induced oxidative stress in rice. It is this switching on/off of the JA-biosynthesis and ROS mediated signal transduction pathway involving glutathione homeostasis via GR which helps MeJA to mitigate Cd-induced oxidative injury in rice.


Ultradian metabolic rhythm in the diazotrophic cyanobacterium Cyanothece sp. ATCC 51142.
The unicellular cyanobacterium Cyanothece sp. American Type Culture Collection (ATCC) 51142 is capable of performing oxygenic photosynthesis during the day and microoxic nitrogen fixation at night. These mutually exclusive processes are possible only by temporal separation by circadian clock or another cellular program. We report identification of a temperature-dependent ultradian metabolic rhythm that controls the alternating oxygenic and microoxic processes of Cyanothece sp. ATCC 51142 under continuous high irradiance and in high CO2 concentration. During the oxygenic photosynthesis phase, nitrate deficiency limited protein synthesis and CO2 assimilation was directed toward glycogen synthesis. The carbohydrate accumulation reduced overexcitation of the photosynthetic reactions until a respiration burst initiated a transition to microoxic N2 fixation. In contrast to the circadian clock, this ultradian period is strongly temperature-dependent: 17 h at 27 °C, which continuously decreased to 10 h at 39 °C. The cycle was expressed by an oscillatory modulation of net O2 evolution, CO2 uptake, pH, fluorescence emission, glycogen content, cell division, and culture optical density. The corresponding ultradian modulation was also observed in the transcription of nitrogenase-related nifB and nifH genes and in nitrogenase activities. We propose that the control by the newly identified metabolic cycle adds another rhythmic component to the circadian clock that reflects the true metabolic state depending on the actual temperature, irradiance, and CO2 availability.


[Treatment of epidermoid head and neck cancer with cisplatinum/bleomycin vs methotrexate/vindesine].
Treatment of patients with advanced squamous head and neck tumors demonstrates even with best surgical and x-ray techniques only five year survival rats between 10 and 30%. Chemotherapy in addition seems to improve these results. From July 79 to January 80 21 patients with advanced squamous-cell carcinoma at the head and neck region were treated in a controlled pilot study with Cisplatinum/Bleomycin or Methotrexate/vindesine. 6 patients were primarily treated with chemotherapy, all other secondary progressive disease after surgical and x-ray procedure. Without respect to the generally cell tolerated therapy modality on overall remission induction rate of 50 and 70% was observed. In a subsequent randomized controlled multicentric study both regimes will be compared concerning remission, survival and toxicity.


Effects of Reinstitution of Prolonged Mechanical Ventilation on the Outcomes of 370 Patients in a Long-Term Acute Care Hospital.
To investigate the effects of the reinstitution of continuous mechanical ventilator support of >21 days in 370 prolonged mechanical ventilation (PMV) patients, all free from ventilator support for ≥5 days. Four groups were formed based on the time and number of PMV reinstitutions and compared (group A: reinstitutions within 28 days, n = 51; group B: a single reinstitution after 28 days, n = 53; group C: multiple reinstitutions after 28 days, n = 52; and group D: no known reinstitutions, n = 214). Of the 370 patients, 156 (42%) required PMV reinstitutions. Most reinstitutions occurred within 7 months: 51 (33%) of the 156 patients within 28 days and 49 (31%) within the next 6 months. Group comparisons revealed a progression of outcomes from group A, the worst, to group D, the best, with groups B and C having intermediate but significantly different values. Decannulation was associated with an 88% decreased risk of PMV reinstitution and a 43% lower risk of death (all P < .001). Prolonged mechanical ventilation reinstitution rates were high, with most occurring within 7 months of freedom from MV. In general, the longer the period of ventilator freedom, the less the likelihood of a PMV reinstitution. The identification of 4 distinct PMV groups of patients by time and number of reinstitutions added useful prognostic information. Since PMV reinstitutions within 28 days lead to permanent MV support, >28 days of ventilator freedom provided an optimal cut point for assessing the likelihood of again requiring PMV.


Evaluating training of screening, brief intervention, and referral to treatment (SBIRT) for substance use: Reliability of the MD3 SBIRT Coding Scale.
Screening, brief intervention, and referral to treatment (SBIRT) has become an empirically supported and widely implemented approach in primary and specialty care for addressing substance misuse. Accordingly, training of providers in SBIRT has increased exponentially in recent years. However, the quality and fidelity of training programs and subsequent interventions are largely unknown because of the lack of SBIRT-specific evaluation tools. The purpose of this study was to create a coding scale to assess quality and fidelity of SBIRT interactions addressing alcohol, tobacco, illicit drugs, and prescription medication misuse. The scale was developed to evaluate performance in an SBIRT residency training program. Scale development was based on training protocol and competencies with consultation from Motivational Interviewing coding experts. Trained medical residents practiced SBIRT with standardized patients during 10- to 15-min videotaped interactions. This study included 25 tapes from the Family Medicine program coded by 3 unique coder pairs with varying levels of coding experience. Interrater reliability was assessed for overall scale components and individual items via intraclass correlation coefficients. Coder pair-specific reliability was also assessed. Interrater reliability was excellent overall for the scale components (>.85) and nearly all items. Reliability was higher for more experienced coders, though still adequate for the trained coder pair. Descriptive data demonstrated a broad range of adherence and skills. Subscale correlations supported concurrent and discriminant validity. Data provide evidence that the MD3 SBIRT Coding Scale is a psychometrically reliable coding system for evaluating SBIRT interactions and can be used to evaluate implementation skills for fidelity, training, assessment, and research. Recommendations for refinement and further testing of the measure are discussed. (PsycINFO Database Record


The effect of metformin treatment on endoplasmic reticulum (ER) stress induced by status epilepticus (SE) via the PERK-eIF2α-CHOP pathway.
Status epilepticus (SE) is defined as continuous seizure activity lasting more than 5 minutes. It results in neuronal cell death, mediated by endoplasmic reticulum (ER) stress response. Previously, metformin demonstrated neuroprotective effects in primary cortical neurons. In this study, we analyzed the effect of metformin on ER stress via the pro-apoptotic protein kinase RNA-like endoplasmic reticulum kinase (PERK)-eukaryotic initiation factor 2α (eIF2α)-C/EBP homologous protein (CHOP) pathway. SE was induced in rats by pentylenetetrazole. Following SE, the rats were treated with salubrinal, GSK2656157, or metformin. In a control group (normal saline) SE was not induced. CHOP, eIF2α, and PERK expression was determined by Western blot; apoptosis was analyzed by TUNEL assay. CHOP expression was significantly increased at 6 and 24 hours following SE. At both time points, eIF2α and PERK levels were also increased. At 6 hours, CHOP expression was significantly reduced in salubrinal, GSK2656157 and metformin groups versus SE group. eIF2α and PERK levels were decreased in metformin compared to SE group. eIF2α expression was markedly decreased in salubrinal versus SE group, while PERK expression was markedly reduced in GSK2656157 versus SE group. At 6 and 24 hours, the apoptosis rate was significantly increased in SE versus control group, while it was significantly reduced in salubrinal, GSK2656157, and metformin groups compared to SE group. The apoptosis rate also decreased in salubrinal group at 24 hours, although not to the extent observed in metformin group. Overall, CHOP expression and apoptosis induced by SE in rats were reduced with metformin. Further studies are required to evaluate the clinical relevance of metformin for patients with SE.


Disparities in outpatient antidepressant prescribing patterns and determinants of resource utilization at a tertiary care cancer center.
Our objective was to assess the prevalence of use of different classes of antidepressants, prescribing patterns, and determinants of exposure to specific types of antidepressants and resource utilization at a comprehensive cancer center from 2001 to 2006. Data were collected from the institution's outpatient pharmacy database and cross-referenced with the institution's electronic medical record system. Data collected included demographic characteristics, cancer diagnosis, comorbidities, prescribing physician and service, type and number of antidepressant prescriptions, and resource utilization. Significant differences in the usage and prescribing patterns of the type of antidepressants were found in the analysis by gender and ethnicity, with women seeing a psychiatrist more often than men (P = 0.001) and Caucasians receiving more selective serotonin reuptake inhibitors (SSRIs) than other ethnic groups (P = 0.002). In terms of resource utilization, men had significantly more hospital admissions (P < 0.0001) and emergency room visits (P = 0.004) than women, whereas non-Caucasian ethnic groups had more emergency room visits (P < 0.0001) and clinic visits (P = 0.001) than Caucasians. Further investigation of men and non-Caucasians in the screening, evaluation, and treatment of depression is necessary to confirm disparities and evaluate their possible causes.


The spiritual framework of coping through the voices of cancer survivor narratives.
Gall et al. (2005) developed a framework for spirituality by adapting and applying the transactional model of stress and coping, which is an interactive and fluid process spurred by a stressor involving spiritual appraisal, person factors, spiritual connections, spiritual coping behavior, and meaning-making impacting well-being. The components of the framework are examined through five cancer survivor narratives. The results showed that the components of the framework were experienced by the survivors, for example, various spiritual problem-solving styles were used, indication of spiritual connections to nature, others, and the transcendent. Meaning-making was common as they faced the life-threatening disease which often altered their worldview. The spirituality of the participants is reflected in the spiritual framework and the framework embraces these survivor experiences. This study has limitations due to its qualitative nature and small sample size.


The Adult Reading History Questionnaire (ARHQ) in Icelandic: Psychometric Properties and Factor Structure.
This article describes psychometric testing of an Icelandic adaptation of the Adult Reading History Questionnaire (ARHQ), designed to detect a history of reading difficulties indicative of dyslexia. Tested in a large and diverse sample of 2,187 adults, the Icelandic adaptation demonstrated internal consistency reliability (Cronbach's alpha = .92) and test-retest reliability (r = .93). Validity was established by comparing scores of adults who as children received ICD-10 diagnoses of specific reading disorder (F81.0; n = 419) to those of adults defined as nondyslexics (n = 679). ROC curve analysis resulted in an area under the curve of .92 (95% CI = .90, .93, p < .001) and a cutoff score of .43 with sensitivity of 84.5% and specificity of 83.7%. An exploratory factor analysis (n = 2,187) suggested three subscales, Dyslexia Symptoms, Current Reading, and Memory, the mean scores of which differed significantly among diagnosed dyslexics, relatives of dyslexics, and population controls. Our results support the applicability of the ARHQ in Icelandic as a self-report screening tool for adult dyslexia in Iceland.


Interhemispheric transfer of spatial and semantic information: electrophysiological evidence.
The goal of this study was to cast light on the existence of functional callosal channels for the interhemispheric transfer (IHT) of spatial and semantic information. To do so, we recorded event-related potentials in healthy humans while performing a primed odd-even discrimination task. Targets were visually presented numbers preceded by single-letter primes signaling the probable presentation of an odd or an even number. Primes and targets could appear either in the same or in different visual fields, thus requiring an IHT in the latter case. The P1 and N2 components were influenced by IHT of spatial information only, whereas the later N400 was influenced by IHT of both spatial and semantic information. This was not the case for the P3b, which was modulated by semantic validity only. These results provide novel evidence of the existence of a temporally separated interhemispheric exchange of spatial and semantic information.


Pediculosis humanus capitis in 6-7 years old schoolchildren in Valencia, Spain.
Pediculosis humanus capitis is a worldwide public health concern that affects mostly school-aged children. The aim of this study is to determine the rate of pediculosis and to determine possible risk factors in a group of primary school children in Valencia, Spain; 227 children, 6-7 years old, were selected from 7 schools. A self-reported questionnaire completed by the parents/guardians about the presence of pediculosis in their children and their knowledge about pediculosis. The results recorded in the questionnaire were analysed by SPSS® software. 30.4% of the children had pediculosis. The results showed significant variation (p < 0.05) in prevalence depending on the following factors: sex, hair length, level of parental education, family size, presence of affected family member in the home, and frequency of hair washing. Less than half of parents/guardians showed an appropriate level of knowledge on pediculosis. Pediculosis remains a health problem in Valencian schoolchildren. The family size and existence of another member with pediculosis were shown to be the main potentiating factors. Parents are not sufficiently informed about pediculosis and adopt inappropriate practices. There is a need to promote studies with the objective of determining risk factors for pediculosis as well as the need for actions to increase the knowledge of parents and healthcare professionals on this parasitosis to prevent outbreaks in the community, assure correct treatment and maintain effective epidemiological surveillance.


[Clinico-immunological parallels in patients with focal scleroderma].
Combined immunological examination of patients with focal scleroderma included studies of the humoral and cellular immunity parameters. The findings evidence that mainly immunological disorders underlie the pathogenesis of this disease, whose various combinations form this of that immunopathological pattern. An immunological classification of focal scleroderma is suggested. Clinical and immunological parallels in patients with different immunological variants of focal scleroderma are analyzed. The results permit a conclusion on the two basic mechanisms in the pathogenesis of focal scleroderma: (1) immunodeficiency involving the effector B component and (2) an isolated hyperfunction of natural killer cells.


Caution regarding potential changes in AVR practices during the COVID-19 pandemic.
To improve resource allocation in face of the COVID-19 pandemic, hospitals around the country are restricting the performance of elective surgery to preserve ventilators, operating rooms, ICU beds and protect anesthesiologists. For patients with severe aortic stenosis, efforts to bring treatment to symptomatic patients amid this pandemic might lead to favored use of catheter based management using minimalist techniques that do not require these elements. In this context, some patients with well tested surgical indications for valve replacement may be treated by catheter-based methods. It is important that outcomes for these cases are followed closely both at respective sites and in national registries. As we recover from this pandemic, surgical cases should once again be driven by multi-disciplinary discussion and clinical trial data, and not a mentality of crisis management.


Probing spatial inhomogeneity of cholinergic changes in cortical state in rat.
Acetylcholine (ACh) plays an essential role in cortical information processing. Cholinergic changes in cortical state can fundamentally change how the neurons encode sensory input and motor output. Traditionally, ACh distribution in cortex and associated changes in cortical state have been assumed to be spatially diffuse. However, recent studies demonstrate a more spatially inhomogeneous structure of cholinergic projections to cortex. Moreover, many experimental manipulations of ACh have been done at a single spatial location, which inevitably results in spatially non-uniform ACh distribution. Such non-uniform application of ACh across the spatial extent of a cortical microcircuit could have important impacts on how the firing of groups of neurons is coordinated, but this remains largely unknown. Here we describe a method for applying ACh at different spatial locations within a single cortical circuit and measuring the resulting differences in population neural activity. We use two microdialysis probes implanted at opposite ends of a microelectrode array in barrel cortex of anesthetized rats. As a demonstration of the method, we applied ACh or neostigmine in different spatial locations via the microdialysis probes while we concomitantly recorded neural activity at 32 locations with the microelectrode array. First, we show that cholinergic changes in cortical state can vary dramatically depending on where the ACh was applied. Second, we show that cholinergic changes in cortical state can vary dramatically depending on where the state-change is measured. These results suggests that previous work with single-site recordings or single-site ACh application should be interpreted with some caution, since the results could change for different spatial locations.


Ex-Situ Kinetic Investigations of the Formation of the Poly-Oxo Cluster U38.
The ex-situ qualitative study of the kinetic formation of the poly-oxo cluster U38 , has been investigated after the solvothermal reaction. The resulting products have been characterized by means of powder XRD and scanning electron microscopy (SEM) for the solid phase and UV/Vis, X-ray absorption near edge structure (XANES), extended X-ray absorption fine structure (EXAFS), and NMR spectroscopies for the supernatant liquid phase. The analysis of the different synthesis batches, stopped at different reaction times, revealed the formation of spherical crystallites of UO2 from t=3 h, after the formation of unknown solid phases at an early stage. The crystallization of U38 occurred from t=4 h at the expense of UO2 , and is completed after t=8 h. Starting from pure uranium(IV) species in solution (t=0-1 h), oxidation reactions are observed with a U(IV) /U(VI) ratio of 70:30 for t=1-3 h. Then, the ratio is inversed with a U(IV) /U(VI) ratio of 25/75, when the precipitation of UO2 occurs. Thorough SEM observations of the U38 crystallites showed that the UO2 aggregates are embedded within. This may indicate that UO2 acts as reservoir of uranium(IV), for the formation of U38 , stabilized by benzoate and THF ligands. During the early stages of the U38 crystallization, a transient crystallized phase appeared at t=4 h. Its crystal structure revealed a new dodecanuclear moiety (U12 ), based on the inner hexanuclear core of {U6 O8 } type, decorated by three additional pairs of dinuclear U2 units. The U12 motif is stabilized by benzoate, oxalates, and glycolate ligands.


Melanosome complexes and melanin macroglobules in normal human skin.
The presence of melanin macroglobules, and sometimes that of melanosome complexes also, in epidermal melanocytes has been considered a feature of various skin diseases. Opinions differ as to whether these structures can occur in normal skin. We have studied these melanin inclusions in normal Caucasian skin in the entire soma of 116 melanocytes and the occurrence of melanosomes in phagosomes of 77 Langerhans' cells obtained in different seasons. During winter the melanocytes contained few melanosomes but many melanosome complexes and melanin macroglobules. These melanosome inclusions were in 86%, localized in the most basal part of the melanocytes, particularly in the dermal protrusions. It is suggested that these structures can be transferred from epidermal melanocytes to dermal cells and that melanin macroglobules derive from melanosome complexes. Irrespective of the season, most of the Langerhans' cells contained melanosomes in their phagosomes, which suggests a phagocytic capacity of these cells and a role in the elimination of the melanin.


[Usefulness and positioning of MAB therapy for prostate cancer].
Prostate cancer is a relatively slow-growing disease compared to other cancers, and the patients tend to be older. Taking into consideration therefore life expectancy of the patients and risks of recurrence and progression, conservative treatments (mainly hormonal therapy) are often applied for early cases, as well as radical treatments (total prostatectomy and radiotherapy). Particularly in Japan, many patients start treatment with hormonal therapy alone, in both early and advanced cases. Hence, Maximal Androgen Blockade (MAB) therapy, in which surgical or medical castration (such as LH-RH agonist treatment) and anti-androgen treatment are combined, is widely exercised with the hope to enhance treatment effects. The usefulness of MAB therapy has been assessed in a number of randomized comparative studies, covering mainly metastatic cases. The efficacy of the therapy with the use of flutamide as non-steroidal anti-androgen has been confirmed in some of the studies, although the magnitude of the efficacy cannot be said major. In Phase III clinical studies of MAB therapy with bicalutamide being conducted in Japan for patients in Stages C and D, however, the patient group treated with MAB therapy demonstrated more favorable results compared to the group treated with LH-RH agonist alone, particularly in terms of time to progression (TTP) of the patients in Stage C. These are relatively new findings on the usefulness and adaptability of MAB therapy. In this Panel Discussion, views and experiences are exchanged on a wide variety of topics covering the real usefulness of MAB therapy, its adaptability, possible outcomes of hormonal therapy in early cases, and the future of MAB therapy, taking into account the prevailing opinions and current practices on prostate cancer in both the United States and Japan.


Determining pore size distribution in wet cellulose by measuring solute exclusion using a differential refractometer.
Solute exclusion was used to determine the pore volume and micropore size distribution of wet cellulosic materials. Glucose, cellobiose, and polyethylene glycol (PEG) (8 to 130 A in diameter) were used as molecular probes. Four replicates of cellulosic samples, with each sample being analyzed 4 to 8 times, gave the concentrations of each molecular probe before and after contact with cellulose. Sugar concentrations were determined by the DNS method and PEG concentrations by a differential refractometer. Deviations arising from sample-to-sample variability result in variations of solute uptake from which the pore size distribution was determined. The need for replicate samples and a statistical approach to data analysis is indicated. Consequently, the data were fitted to an empirical logistic model function based on the minimum of the residual sum of squares using the finite-difference, Levenberg-Marquardt algorithm. A smooth increasing function resulted. We report experimental methodology employing a differential refractometer, common in many laboratories having a liquid chromato-graph instrument, combined with statistical treatment of the data. This method may also find application in determining pore size distribution in wet, hydrophilic polymers used in some types of membranes, chromatographic supports, and gel-type resins.


Crystallization of amorphous Fe90Zr10 under ball milling.
The present study deals with structural transformations induced by high-energy ball-milling of an amorphous Fe90Zr10 alloy prepared by melt-spinning. The amorphous melt-spun ribbons were found to undergo crystallization into BCC alpha-Fe(Zr) nanocrystallites under high-energy ball milling. The decomposition degree of the amorphous phase increased with increasing milling time and intensity. Our results suggest that the observed crystallization is a deformation-induced process rather than a thermally induced one.


Positive and negative regulation of angiogenesis: from cell biology to the clinic.
Virtually every subspecialty in medicine in one way or another deals with angiogenesis-associated physiological or pathological processes and, without exception, every organ system in the body has many diseases in which angiogenesis is an important component. This in itself makes the study of angiogenesis mandatory, in both basic science and clinical settings. Yet the study of angiogenesis does not require this justification. As a biological process it is extraordinarily rich, touching on virtually every aspect of modern cell biology, making it almost impossible for molecular biologists, biochemists and morphologists to ignore. Considerable therapeutic benefit can now be obtained through positive or negative manipulation of the angiogenic process, and this is due in large part to the rapid transfer to the clinical setting of knowledge acquired through a cell biological approach.


Novel association of MEN1 gene mutations with parathyroid carcinoma.
Inactivating mutations of the multiple endocrine neoplasia 1 (MEN1) gene cause MEN1 syndrome, characterized by primary hyperparathyroidism (pHPT), and parathyroid and gastro-entero-pancreatic pituitary tumors. At present, only 14 cases of malignant parathyroid tumor have been associated with the syndrome, with 6 cases carrying an inactivating mutation of the MEN1 gene. The present study presents the case of a 48-year-old female who presented with multigland pHPT and multiple pancreatic lesions. The patient underwent surgery several times for the excision of parathyroid hyperplasia, carcinoma and adenoma. The MEN1 gene was screened, revealing three variants (in cis) at the intron/exon 3 boundary (IVS2-3G>C, c.497A>T and c.499G>T) detected on the DNA of the proband, not shared by her relatives. RNA sequencing revealed that the IVS2-3C>G variant caused the skipping of the exon 3. Therefore, the present study reports on a novel rare association of MEN1 syndrome and parathyroid carcinoma. The reported splicing mutation was previously identified in subjects who always developed malignant lesions; thus, a possible genotype-phenotype association may be considered.


Profiling of inflammatory cytokines produced by gingival fibroblasts after human cytomegalovirus infection.
The purpose of this study was to determine the profile of inflammatory cytokines that are produced after in vitro infection of gingival fibroblasts with human cytomegalovirus (HCMV). Gingival fibroblasts were infected with the Towne strain of HCMV and the cytokine profile in the supernatant was studied using a human inflammation antibody array. Expression of messenger RNA (mRNA) using reverse transcription-polymerase chain reaction for interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) was also analyzed in infected gingival fibroblasts and gingival specimens from subjects with and without periodontitis according to HCMV detection. HCMV was determined in subgingival samples by nested polymerase chain reaction. Gingival fibroblasts produced mainly IL-1alpha, IL-12p40, IL-12p70, IL-6, TNF-alpha, and IL-1beta after HCMV infection. Expression of mRNA for IL-1beta and TNF-alpha was increased after HCMV infection. Production of IL-1beta and TNF-alpha was increased in HCMV-positive periodontitis specimens. In addition, infected gingival fibroblasts produced more IL-8, monocyte chemoattractant protein 1, macrophage inflammatory proteins 1alpha, and 1beta over time postinfection in comparison to baseline. The lowest production of all cytokines studied corresponded to IL-2, IL-4, IL-13, and interferon-gamma. A decreasing production pattern was observed for granulocyte-macrophage colony-stimulating factor, IL-7, and IL-17 while IL-11 and macrophage colony-stimulating factor were increased at 72 h postinfection. HCMV infection in gingival fibroblasts upregulated the production of proinflammatory-related cytokines and chemokines. The expression of IL-1beta and TNF-alpha was increased both in vitro and in specimens from HCMV-positive subjects with periodontitis. The overproduction of proinflammatory cytokines and chemokines as a result of viral infection should be considered an important pathogenic mechanism linking HCMV to periodontitis in vivo.


April 2018 Flores Settlement Suit Challenges Unlawful Administration of Psychotropic Medication to Immigrant Children.
A lawsuit filed in April 2018 alleges unlawful administration of psychotropic medications to detained immigrant children in US custody. The suit, under jurisdiction of the Flores Settlement Agreement of 1997, alleges misuse of psychotropic medication to chemically restrain and control immigrant children and prolong their detention. This article describes the legal scope of the suit and considers significant ethically and clinically relevant questions it poses.


Antidepressant treatment effects on hippocampal protein turnover: Molecular and spatial insights from mass spectrometry.
A major challenge in managing depression is that antidepressant drugs take a long time to exert their therapeutic effects. For the development of faster-acting treatments, it is crucial to get an improved understanding of the molecular mechanisms underlying antidepressant mode of action. Here, we used a novel mass spectrometry-based workflow to investigate how antidepressant treatment affects brain protein turnover at single-cell and subcellular resolution. We combined stable isotope metabolic labeling, quantitative Tandem Mass Spectrometry (qTMS) and Multi-isotope Imaging Mass Spectrometry (MIMS) to simultaneously quantify and image protein synthesis and turnover in hippocampi of mice treated with the antidepressant paroxetine. We identified changes in turnover of individual hippocampal proteins that reveal altered metabolism-mitochondrial processes and report on subregion-specific turnover patterns upon paroxetine treatment. This workflow can be used to investigate brain protein turnover changes in vivo upon pharmacological interventions at a resolution and precision that has not been possible with other methods to date. Our results reveal acute paroxetine effects on brain protein turnover and shed light on antidepressant mode of action.


Human Oncoviruses and Thoracic Tumors: Understanding the Imaging Findings.
Approximately 1.4 million virus-induced cancers occur annually, representing roughly 10% of the cancer burden worldwide. Seven oncogenic DNA and RNA viruses (ie, oncoviruses) are implicated in approximately 12%-25% of all human cancers owing to a variety of mechanisms as uncommon consequences of the normal viral life cycle. These seven well-recognized human oncoviruses are Epstein-Barr virus (EBV), human T-lymphotropic virus 1, hepatitis B virus, hepatitis C virus, HIV, human papilloma virus (HPV), and human herpesvirus 8 (HHV-8). Several viruses-namely, EBV, HPV, and Kaposi sarcoma herpesvirus or HHV-8-are increasingly being recognized as being related to HIV and/or AIDS, the growing number of transplant cases, and the use of immunosuppressive therapies. Infectious and inflammatory processes, and the accompanying lymphadenopathy, are great mimickers of human oncovirus-related tumors. Although it is often difficult to differentiate these entities, the associated clinical setting and radiologic findings may provide clues for an accurate diagnosis and appropriate management. Malignant lymphoid lesions are best evaluated with multidetector chest CT. The radiologic findings of these lesions are often nonspecific and are best interpreted in correlation with clinical data and histopathologic findings. ©RSNA, 2022.


Anticlastogenic effect in human lymphocytes by the sodium salt of 3,4-secoisopimar-4(18),7,15-trien-3-oic acid.
The ability of the sodium salt of 3,4-secoisopimar-4(18),7,15-trien-3-oic acid (1), a diterpenoid obtained from Salvia cinnabarina, to inhibit the genotoxic effect of ethyl methanesulfonate (a clastogenic agent) and colcemid (an aneugenic agent), was studied using a micronucleus assay on cultured human lymphocytes. Cells were treated with 1 before (pretreatment), during (co-treatment), and after (post-treatment) treatment with the mutagens, in order to investigate the type of antimutagenic activity (desmutagenic or bioantimutagenic) manifested. In the range of concentrations tested (0.3-330 μM) 1 reduced significantly the frequency of micronuclei induced by ethyl methanesulfonate, in both pre- and co-treatment protocols (up to 74% and 70% of reduction, respectively), showing an anticlastogenic activity. Conversely, 1 did not inhibit the effect of colcemid in all treatments. The nuclear division index value of lymphocytes was not affected by treatment with 1, thus demonstrating that the anticlastogenic effect of 1 was not due to a cytotoxic effect. On the basis of the results obtained, it can be hypothesized that 1 exerts its anticlastogenic activity against ethyl methanesulfonate by a desmutagenic mechanism, possibly by chemical inactivation of the mutagen.


Association between the GIPR gene and the insulin level after glucose loading in schizophrenia patients treated with olanzapine.
Several studies have shown increased rates of hyperglycemia and diabetes in schizophrenic patients treated with olanzapine. However, the underlying mechanism is poorly understood. Glucose-dependent insulinotropic polypeptide (GIP) is known to affect insulin secretion by pancreatic β cells. Recently, a meta-analysis study reported an association between a GIP receptor (GIPR) gene polymorphism (rs10423928) and insulin secretion measured by an oral glucose tolerance test (OGTT). We assessed the influence of this GIPR gene polymorphism on glucose metabolism in 60 schizophrenic patients treated with olanzapine and 103 healthy controls. The GIPR gene polymorphism was determined using TaqMan methods. We performed repeated-measures analysis of variance (ANOVA) and one-way ANOVA for the glucose and insulin levels during OGTTs in four groups divided by the GIPR gene polymorphism and cohort (schizophrenia or control). We found significant effects of the GIPR gene and cohort on the insulin levels at 30 min. Our findings suggest that schizophrenic patients with the A allele of GIPR rs10423928 are at risk of developing hyperinsulinemia when treated with antipsychotics.


ACC.20: Impact of social media at the virtual scientific sessions during the COVID-19 pandemic.
The COVID-19 pandemic led to the American College of Cardiology (ACC) Annual Scientific Session 2020 (ACC.20) being held as a virtual event. Social media activity around a virtual event might be quite different to that of a physical meeting. The goal of this study was to assess impact of ACC.20 through Twitter and compare it to ACC.19. Data were extracted using NodeXL, with analysis in Excel. ACC.20-related tweeting was demonstrated globally. However tweeting and participants fell substantially for ACC.20. Tweeting, participation and tweet views were overestimated by the most widely used social media analysis tool used at medical conferences (Symplur). Comparing the 2019 and 2020 Scientific Sessions, the global cardiology community continued to communicate despite COVID-19, but with reduced social media activity potentially due to the briefer format, no physical interaction and private virtual chatroom during live sessions, reducing visibility of new cardiology research findings.


Toward ab initio molecular dynamics modeling for sum-frequency generation spectra; an efficient algorithm based on surface-specific velocity-velocity correlation function.
Interfacial water structures have been studied intensively by probing the O-H stretch mode of water molecules using sum-frequency generation (SFG) spectroscopy. This surface-specific technique is finding increasingly widespread use, and accordingly, computational approaches to calculate SFG spectra using molecular dynamics (MD) trajectories of interfacial water molecules have been developed and employed to correlate specific spectral signatures with distinct interfacial water structures. Such simulations typically require relatively long (several nanoseconds) MD trajectories to allow reliable calculation of the SFG response functions through the dipole moment-polarizability time correlation function. These long trajectories limit the use of computationally expensive MD techniques such as ab initio MD and centroid MD simulations. Here, we present an efficient algorithm determining the SFG response from the surface-specific velocity-velocity correlation function (ssVVCF). This ssVVCF formalism allows us to calculate SFG spectra using a MD trajectory of only ∼100 ps, resulting in the substantial reduction of the computational costs, by almost an order of magnitude. We demonstrate that the O-H stretch SFG spectra at the water-air interface calculated by using the ssVVCF formalism well reproduce those calculated by using the dipole moment-polarizability time correlation function. Furthermore, we applied this ssVVCF technique for computing the SFG spectra from the ab initio MD trajectories with various density functionals. We report that the SFG responses computed from both ab initio MD simulations and MD simulations with an ab initio based force field model do not show a positive feature in its imaginary component at 3100 cm(-1).


Conserved and nonconserved functions of the yeast and human TATA-binding proteins.
Although the TATA-binding protein (TBP) is highly conserved throughout the eukaryotic kingdom, human TBP cannot functionally replace yeast TBP for cell viability. To investigate the basis of this species specificity, we examine the in vivo transcriptional activity of human TBP at different classes of yeast promoters. Consistent with previous results, analysis of yeast/human hybrid TBPs indicates that growth defects are not correlated with the ability to promote TATA-dependent polymerase II (Pol II) transcription or to respond to acidic activator proteins. Human TBP partially complements the growth defects of a yeast TBP mutant with altered TATA element-binding specificity, suggesting that it carries out sufficient Pol II function to support viability. However, human TBP does not complement the defects of yeast TBP mutants that are specifically defective in transcription by RNA polymerase III. Three independently isolated derivatives of human TBP that permit yeast cell growth replace arginine 231 with lysine; the corresponding amino acid in yeast TBP (lysine 133) has been implicated in RNA polymerase III transcription. Transcriptional analysis indicates that human TBP functions poorly at promoters recognized by RNA polymerases I and III and at RNA Pol II promoters lacking a conventional TATA element. These observations suggest that species specificity of TBP primarily reflects evolutionarily diverged interactions with TBP-associated factors (TAFs) that are necessary for recruitment to promoters lacking TATA elements.


Stereomutations of atropisomers of sterically hindered salophen ligands.
[structure: see text] The stereomutations in nonsymmetrical salophen ligands 1-4 were studied by means of dynamic NMR and HPLC methods. DNMR experiments showed that in DMSO-d(6) hindered ligands 2-4 exist in two chiral conformations, depending on whether the imine carbon atoms are in a cis or trans disposition with respect to the plane of the central o-phenylenediamine ring, the latter being more stable by 1.0 kcal mol(-1). Owing to its higher dipole moment, in the apolar solvent C(6)D(6) the cis conformer is destabilized with respect to the trans one, in agreement with the results of ab initio calculations. In DMSO-d(6) solution the two conformers are in equilibrium through the less hindered rotation about the C6-N7 bond aligned to the a(6,7) axis, and the interconversion barriers range from 18.4 to 19.3 kcal mol(-1). The enantiomerization process is a two step-process that implies sequential rotations around the C6-N7 and the C1-N8 bonds, so that the rate determining step is the slower rotation around the more hindered C1-N8 bond aligned to the a(1,8) axis, and the energy barriers range from 21.4 to 21.9 kcal mol(-1). These values compare well with those determined by chromatography on an enantioselective HPLC column at low temperature, thus confirming that DNMR and DHPLC can be conveniently employed as complementary techniques.


Co-culture of spermatogonial stem cells with sertoli cells in the presence of testosterone and FSH improved differentiation via up-regulation of post meiotic genes.
Spermatogonial stem cells (SSCs) maintain spermatogenesis throughout life in the male. Maintenance of SSCs and induction of spermiogenesis in vitro may provide a therapeutic strategy to treat male infertility. This study investigated in vitro differentiation of mouse SSCs in presence or absence of Sertoli cells, hormones and vitamins. Spermatogonial populations were enriched from testes of 4-6 week old males by magnetic activated cell sorting and anti-Thy-1 antibody. Sertoli cells isolated from 6-8 week old testes were enriched using lectin-DSA-coated plates. Isolated SSCs were cultured in the presence of Leukemia inhibitory factor (LIF) for 7 days in gelatin-coated dishes, then dissociated and cultured for 7 days in media lacking LIF in the presence or absence of Sertoli cells, with or without FSH, testosterone and vitamins. After one week, the effects of Sertoli cells ± supplementary media on SSC differentiation was evaluated by microscopy and expression of meiotic and postmeiotic transcripts using RT-PCR. SSC colonies had limited development after LIF removal alone, exhibiting low expression of meiotic (Scp3, Th2b) but not postmeiotic transcript, and loss of Stra8 and Dazl expression. SSCs co-cultured with Sertoli cells, hormones and vitamins developed spermatid-like cells expressing postmeiotic markers (TP1, TP2, Prm1) at levels over 2-fold higher than Sertoli cells or hormone/vitamins alone. Our present SSC-Sertoli co-culture provides conditions that may allow efficient in vitro differentiation of SSCs for the treatment of male infertility.


Protective Effects of White Kidney Bean (Phaseolus vulgaris L.) against Diet-Induced Hepatic Steatosis in Mice Are Linked to Modification of Gut Microbiota and Its Metabolites.
Disturbances in the gut microbiota and its derived metabolites are closely related to the occurrence and development of hepatic steatosis. The white kidney bean (WKB), as an excellent source of protein, dietary fiber, and phytochemicals, has recently received widespread attention and might exhibit beneficial effects on a high-fat diet (HFD)-induced hepatic steatosis via targeting gut microbiota and its metabolites. The results indicated that HFD, when supplemented with WKB for 12 weeks, could potently reduce obesity symptoms, serum lipid profiles, and glucose, as well as improve the insulin resistance and liver function markers in mice, thereby alleviating hepatic steatosis. An integrated fecal microbiome and metabolomics analysis further demonstrated that WKB was able to normalize HFD-induced gut dysbiosis in mice, thereby mediating the alterations of a wide range of metabolites. Particularly, WKB remarkably increased the relative abundance of probiotics (Akkermansiaceae, Bifidobacteriaceae, and norank_f_Muribaculaceae) and inhibited the growth of hazardous bacteria (Mucispirillum, Enterorhabdus, and Dubosiella) in diet-induced hepatic steatosis mice. Moreover, the significant differential metabolites altered by WKB were annotated in lipid metabolism, which could ameliorate hepatic steatosis via regulating glycerophospholipid metabolism. This study elucidated the role of WKB from the perspective of microbiome and metabolomics in preventing nonalcoholic fatty liver disease, which provides new insights for its application in functional foods.


ARHGAP9 knockdown promotes lung adenocarcinoma metastasis by activating Wnt/β-catenin signaling pathway via suppressing DKK2.
This study aims to elucidate the effect of ARHGAP9 on lung adenocarcinoma (LUAD) metastasis, and preliminarily explore its molecular mechanism. As a result, we found that ARHGAP9 was downregulated and correlated with poor prognosis of LUAD. ARHGAP9 knockdown promoted LUAD cell proliferation, migration and invasion, inhibited cell apoptosis and reduced G0G1 cell cycle arrest, in contrast to the results of ARHGAP9 overexpression. Further RNA sequencing analysis demonstrated that ARHGAP9 knockdown in H1299 cells significantly reduced DKK2 (dickkopf related protein 2) expression. Silencing ARHGAP9 in H1299 cells while overexpressing DKK2, DKK2 reversed the promoted effects of ARHGAP9 knockdown on LUAD cell proliferation, migration and invasion. Meanwhile, the activity of Wnt/β-catenin signaling pathway was also reduced. Taken together, these data indicated that ARHGAP9 knockdown promoted LUAD metastasis by activating Wnt/β-catenin signaling pathway via suppressing DKK2. This may provide a new strategy for LUAD treatment.


(68)Ga-labeled phage-display selected peptides as tracers for positron emission tomography imaging of Staphylococcus aureus biofilm-associated infections: Selection, radiolabelling and preliminary biological evaluation.
Staphylococcus aureus is a major cause of skin and deep-sited infections, often associated with the formation of biofilms. Early diagnosis and initiated therapy is essential to prevent disease progression and to reduce complications that can be serious. Imaging techniques are helpful combining anatomical with functional data in order to describe and characterize site, extent and activity of the disease. The purpose of the study was to identify and (68)Ga-label peptides with affinity for S. aureus biofilm and evaluate their potential as bacteria-specific positron emission tomography (PET) imaging agents. Phage-displayed dodecapeptides were selected using an in vitro grown S. aureus biofilm as target. One cyclic (A8) and two linear (A9, A11) dodecapeptides were custom synthesized with 1,4,7,10-tetraazacyclododecane-N,N',N″,N‴-tetraacetic acid (DOTA) conjugated via a lysine linker (K), and for A11 also a glycine-serine-glycine spacer (GSG). The (68)Ga-labeling of A8-K-DOTA, A9-K-DOTA, and A11-GSGK-DOTA were optimized and in vitro bacterial binding was evaluated for (68)Ga-A9-K-DOTA and (68)Ga-A11-GSGK-DOTA. Stability of (68)Ga-A9-K-DOTA was studied in vitro in human serum, while the in vivo plasma stability was analyzed in mice and pigs. Additionally, the whole-body distribution kinetics of (68)Ga-A9-K-DOTA was measured in vivo by PET imaging of pigs and ex vivo in excised mice tissues. The (68)Ga-A9-K-DOTA and (68)Ga-A11-GSGK-DOTA remained stable in product formulation, whereas (68)Ga-A8-K-DOTA was unstable. The S. aureus binding of (68)Ga-A11-GSGK-DOTA and (68)Ga-A9-K-DOTA was observed in vitro, though blocking of the binding was not possible by excess of cold peptide. The (68)Ga-A9-K-DOTA was degraded slowly in vitro, while the combined in vivo evaluation in pigs and mice showed a rapid blood clearance and renal excretion of the (68)Ga-A9-K-DOTA. The preliminary in vitro and in vivo studies of the phage-display S. aureus biofilm-selected (68)Ga-A9-K-DOTA showed desirable features for a novel bacteria-specific imaging agent, despite of relative fast blood degradation in vivo.


[The effect of electroconvulsive shock on protein synthesis in Japanese quail].
Trials were conducted to study the effect of electroconvulsive shock in the susceptible period of post-natal development upon the proteosynthesis of the Japanese quail. Proteosynthesis was determined by the incorporation of labelled amino acid and nucleoside in the proteins and DNA of liver and oviduct. The tested birds showed an earlier sexual maturity, higher incorporation of labelled amino acid in protein and labelled nucleoside in DNA in liver and oviduct, and a higher egg yield at a lower feed consumption during the studied period. The results demonstrate a stimulative effect of electroconvulsive shock on proteosynthesis in liver and oviduct in the Japanese quail.


What is the effectiveness of the negative pressure wound therapy (NPWT) in patients treated with open abdomen technique? A systematic review and meta-analysis.
The open abdomen technique may be used in critically ill patients to manage abdominal injury, reduce the septic complications, and prevent the abdominal compartment syndrome. Many different techniques have been proposed and multiple studies have been conducted, but the best method of temporary abdominal closure has not been determined yet. Recently, new randomized and nonrandomized controlled trials have been published on this topic. We aimed to perform an up-to-date systematic review on the management of open abdomen, including the most recent published randomized and nonrandomized controlled trials, to compare negative pressure wound therapy (NPWT) with no NPWT and define if one technique has better outcomes than the other with regard to primary fascial closure, postoperative 30-day mortality and morbidity, enteroatmospheric fistulae, abdominal abscess, bleeding, and length of stay. According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement and the Cochrane Handbook for Systematic Reviews of Interventions, an online literature research (until July 1, 2015) was performed on MEDLINE, PubMed, Cochrane Central Register of Controlled Trials, and Cochrane Library databases. The MeSH terms and free words used "vacuum assisted closure" "vac;", "open abdomen", "damage control surgery", and "temporary abdominal closure". No language restriction was made. The initial systematic literature search yielded 452 studies. After a careful assessment of the titles and of the full text was obtained, eight articles fulfilled inclusion criteria. We analyzed 1,225 patients, of whom 723 (59%) underwent NPWT and 502 (41%) did not undergo NPWT, and performed four subgroups: VAC versus Bogota bag technique (two studies, 106 participants), VAC versus mesh-foil laparostomy (two studies, 159 participants), VAC versus laparostomy (adhesive impermeable with midline zip) (one study, 106 participants), and NPWT versus no NPWT techniques (three studies, 854 participants) in which it is not possible to perform an analysis of the different types of treatment. Comparing the NPWT group and the group without NPWT, there was no statistically significant difference in fascial closure (63.5% vs 69.5%; odds ratio [OR], 0.74; 95% confidence interval [CI], 0.27-2.06; p = 0.57), postoperative 30-day overall morbidity (p = 0.19), postoperative enteroatmospheric fistulae rate (2.1% vs 5.8%; OR, 0.63; 95% CIs, 0.12-3.15; p = 0.57), in the postoperative bleeding rate (5.7% vs 14.9%; OR, 0.58; 95% CIs, 0.05-6.84; p = 0.87), and postoperative abdominal abscess rate (2.4% vs 5.6%; OR, 0.42; 95% CI, 0.13-1.34; p = 0.14). On the other hand, statistical significance was found between the NPWT group and the group without NPWT in the postoperative mortality rate (28.5% vs 41.4%; OR, 0.46; 95% CI, 0.23-0.91; p = 0.03) and in the length of stay in the intensive care unit (mean difference, -4.53; 95% CI, -5.46 to 3.60; p < 0.00001). The limitations of the present analysis might be related to the lack of randomized controlled trials, so there is a risk of selection bias favoring NPWT. For several outcomes, there were few studies, confidence intervals were wide, and inconsistency was high, suggesting that although there were no statistically significant differences between the groups, there was insufficient evidence to show that the outcomes were similar. We can conclude from the current available data that NPWT seems to be associated with a trend toward better outcomes compared to the use of no NPWT. It does reflect the evidence presented in the current systematic review; however, the data should be interpreted with substantial caution given a number of weaknesses (in particular, the lack of statistical significance and heterogeneity between studies, i.e., small sample size of the included studies, high variability between studies). We highlight the need for randomized controlled trials having homogeneous inclusion criteria to assess the use of NPWT for the management of open abdomen. Systemic review/meta-analysis, level III.


Improved assays for DNA-polymerizing enzymes by the use of enzymatically synthesized 5-[125I]iodo-2'-deoxyuridine triphosphate, illustrated by direct quantitation of anti-HIV reverse transcriptase antibody and by serum DNA polymerase analyses.
A one-step procedure which uses enzymes in a crude extract of herpes simplex virus (HSV) type 1-infected cells to synthesize 5-[125I]iodo-2'-deoxyuridine triphosphate [( 125I]dUTP) from [125I]dU is described. The design of a one-step procedure for the purification of the product is also presented. The recovery of [125I]dUTP from [125I]dU varied between 50 and 75%, the radiochemical purity of the product was greater than 90%, and both synthesis and purification were completed within 8 h. The sensitivity and specificity of [125I]dUTP as a substrate for both DNA-dependent DNA polymerase (DNAp) and RNA-dependent DNA polymerase (reverse transcriptase, RT) were evaluated and compared to those of [3H]dTTP for the following specimens: purified cloned Klenow fragment, crude extracts of HeLa-, BHK-, and HSV-2-infected BHK cells, purified avian myeloblastosis virus RT, and purified cloned human immunodeficiency virus (HIV) RT. The [125I]dUTP was accepted as a substrate equally as well [3H]dTTP by all of the specimens at all of the concentrations tested. When the same amount of radiolabel was used, [125I]dUTP gave a sensitivity 10- to 25-fold higher than that of [3H]dTTP. The gain in sensitivity was due to the higher specific activity and a higher counting efficiency of the 125I-label compound. The use of [125I]dUTP also offered technical advantages over alternative substrates available, such as product separation without acid precipitation and exclusion of the need for scintillation cocktails. The half-life of the nucleic also gives a reasonable shelf-life for use in routine assays. Activity of less than 0.3 pg of HIV RT could be detected when the new substrate was used, and this made it possible to quantitate HIV RT antibodies (abs) in diluted serum samples without purifying the immunoglobulin. Analysis of 31 HIV-infected individuals showed that all of them had anti-HIV RT ab and that the amount of serum needed for 50% inhibition of the HIV RT activity corresponded to an amount of immunoglobulin 100-fold smaller (i.e., 0.02-31.4 micrograms) than has been previously reported. With the substrate it was also possible to detect DNAp activity in serum from healthy individuals, although a long-duration assay was required. In a long-duration assay the DNAp activity found in sera from healthy individuals was linear with respect to time, whereas the DNAp activity found in many sera from tumor patients was not. [125I]dUTP is judged to be an excellent substrate for detecting and quantifying the activity of various DNA-synthesizing enzymes and their blocking abs.


Unbiased analysis of obesity related, fat depot specific changes of adipocyte volumes and numbers using light sheet fluorescence microscopy.
In translational obesity research, objective assessment of adipocyte sizes and numbers is essential to characterize histomorphological alterations linked to obesity, and to evaluate the efficacies of experimental medicinal or dietetic interventions. Design-based quantitative stereological techniques based on the analysis of 2D-histological sections provide unbiased estimates of relevant 3D-parameters of adipocyte morphology, but often involve complex and time-consuming tissue processing and analysis steps. Here we report the application of direct 3D light sheet fluorescence microscopy (LSFM) for effective and accurate analysis of adipocyte volumes and numbers in optically cleared adipose tissue samples from a porcine model of diet-induced obesity (DIO). Subcutaneous and visceral adipose tissue samples from DIO-minipigs and lean controls were systematically randomly sampled, optically cleared with 3DISCO (3-dimensional imaging of solvent cleared organs), stained with eosin, and subjected to LSFM for detection of adipocyte cell membrane autofluorescence. Individual adipocytes were unbiasedly sampled in digital 3D reconstructions of the adipose tissue samples, and their individual cell volumes were directly measured by automated digital image analysis. Adipocyte numbers and mean volumes obtained by LSFM analysis did not significantly differ from the corresponding values obtained by unbiased quantitative stereological analysis techniques performed on the same samples, thus proving the applicability of LSFM for efficient analysis of relevant morphological adipocyte parameters. The results of the present study demonstrate an adipose tissue depot specific plasticity of adipocyte growth responses to nutrient oversupply. This was characterized by an exclusively hypertrophic growth of visceral adipocytes, whereas adipocytes in subcutaneous fat tissue depots also displayed a marked (hyperplastic) increase in cell number. LSFM allows for accurate and efficient determination of relevant quantitative morphological adipocyte parameters. The applied stereological methods and LSFM protocols are described in detail and can serve as a guideline for unbiased quantitative morphological analyses of adipocytes in other studies and species.


Bifurcations of emergent bursting in a neuronal network.
Complex neuronal networks are an important tool to help explain paradoxical phenomena observed in biological recordings. Here we present a general approach to mathematically tackle a complex neuronal network so that we can fully understand the underlying mechanisms. Using a previously developed network model of the milk-ejection reflex in oxytocin cells, we show how we can reduce a complex model with many variables and complex network topologies to a tractable model with two variables, while retaining all key qualitative features of the original model. The approach enables us to uncover how emergent synchronous bursting can arise from a neuronal network which embodies known biological features. Surprisingly, the bursting mechanisms are similar to those found in other systems reported in the literature, and illustrate a generic way to exhibit emergent and multiple time scale oscillations at the membrane potential level and the firing rate level.


Valley symmetry breaking in bilayer graphene: a test of the minimal model.
Physical properties reflecting the valley asymmetry of Landau levels in a biased bilayer graphene under a magnetic field are discussed. Within the 4-band continuum model with a Hartree-corrected self-consistent gap and finite damping factor we predict the appearance of anomalous steps in quantized Hall conductivity due to the degeneracy lifting of Landau levels. Moreover, the valley symmetry breaking effect appears as a nonsemiclassical de Haas-van Alphen effect where the reduction of the oscillation period to half cannot be accounted for through quasiclassical quantization of the orbits in reciprocal space.


Prosthesis type has minimal impact on survival after valve surgery in patients with moderate to end-stage renal failure.
Few previous studies have reported on the outcome of patients with renal failure (RF) undergoing valvular surgery, particularly with regard to choice of valve prosthesis. We retrospectively analyzed prospectively collected data from 155 patients with RF (mean age 62 +/- 14, 42% female) who underwent left-sided valve surgery from January 1998 to December 2006. Patients were divided into two groups: Group 1 (non-dialysis-dependent renal failure (NDRF); creatinine >2.5 mg/dl; n = 47, 40%) and Group 2 (renal failure dialysis (DRF); n = 108, 60%). Mechanical valves were implanted in 50 (32%) patients and bioprostheses in 63 (41%). Isolated mitral valve reconstruction was performed in 27% (n = 42) of patients. Outcome measures included hospital mortality, major postoperative complications, length of hospital stay, discharge planning and late survival. The overall hospital mortality was 19.3% (n = 30) and was not different between Groups 1 (23%) and 2 (18%). Ejection fraction, peripheral vascular disease, aortic valve replacement and reoperation were independent predictors of hospital mortality. One- and five-year survival rates were 74.4 +/- 7.8% and 53.1 +/- 10.1% in Group 1 and 75.8 +/- 4.6% and 49.1 +/- 7.1% in Group 2 (P = ns), respectively. According to the type of prostheses, hospital mortality and freedom from reoperation were similar in patients with mechanical and biological valves. Five-year survival rate was 51 +/- 10.7 for biological valves versus 55 +/- 8.4 for mechanical valves (P = ns). Hospital mortality and morbidity remain high in patients with RF undergoing valvular surgery and it is not different in NDRF and DRF patients. This study suggests that the type of valve prosthesis does not appear to have an impact on early and late survival but is limited by sample size. It may be that bioprostheses should be more widely used in patients with RF requiring valve replacement.