Outcome of peripheral venous reconstructions during tumor resection.
Peripheral venous reconstruction surgery may be necessary for appropriate oncologic resection; however, the operative approach and surgical outcomes are not well described. We report our experience with these complex reconstructions to identify best practice. We retrospectively reviewed all adult patients who underwent peripheral vein reconstruction for tumor resection at Mayo Clinic, Rochester (2000-2015). Patients were classified into three subgroups by the location: iliac (IL), lower extremity (LE), and upper extremity (UE). Location, type of reconstruction, operative morbidity, as well as long-term patency, limb salvage, recurrence-free survival, and overall survival were recorded. We identified 27 patients (11 women and 16 men), with a mean age of 55 ± 15 years, who underwent 28 operations involving vein reconstruction during tumor resection. One patient underwent two vascular reconstructions for recurrent malignant fibrous histiocytoma. Concomitant artery reconstruction was required in 16 (57%). The most commonly treated tumors were rectal cancer (n = 4) and liposarcoma (n = 3). Reconstructions were IL in 19 (68%), LE in 6 (21%), and UE in 3 (11%). Venous reconstructions consisted of 7 vein grafts (25%), 17 polytetrafluoroethylene prosthetic grafts (61%), 1 cryograft (4%), and 3 isolated patch angioplasties (11%). Two additional patch angioplasty procedures were performed in conjunction with vein grafts (1 polytetrafluoroethylene, 1 vein graft). There were no 30-day deaths. The mean hospital length of stay was 13.5 ± 10.5 days. Medications prescribed at discharge were aspirin in 15 patients (54%) and warfarin in 16 (57%). Surgical complications included renal failure (n = 5), respiratory complication (n = 3), surgical site infection (n = 5), graft infection (n = 3), and lymph leak (n = 5). The median follow-up was 4.4 years (range, 17 days-14.1 years). At 2 and 5 years, overall primary patency was 61% (95% confidence interval [CI], 41%-87%) and 61% (95% CI, 36%-87%), respectively, and overall freedom from graft thrombosis was 87% (95% CI, 69%-100%) and 87% (95% CI, 64%-100%), respectively. Graft thrombosis occurred in five patients (18%; 4 IL, 1 LE), of which four were prosthetic and one was a patch site. These were managed by thrombolysis (n = 1), thrombectomy (n = 1), and medical management (n = 3). Two patients (7.1%) underwent ipsilateral amputation at 3 and 314 days for compartment syndrome and metastatic pain. The overall survival rate was 74% (95% CI, 50%-87%) at 2 years and 56% (95% CI, 32%-75%) at 5 years. Death was predominantly from cancer-associated morbidities. Overall recurrence-free survival was 75% (95% CI, 57%-97%) at 2 years and 56% (95% CI, 31%-92%) at 5 years. In selected patients fit for advanced tumor resection, reconstruction of IL and extremity veins is a safe and durable, with excellent limb salvage. Vein and prosthetic reconstructions both appear effective; however, infectious complications and graft thrombosis remain important complications when selecting a prosthetic conduit.


Magnetic Quantum Dots Steer and Detach Microtubules From Kinesin-Coated Surfaces.
The microtubule (MT)-kinesin system has been extensively studied because of its role in cellular processes, as well as its potential use for controllably transporting objects at the nanoscale. Thus, there is substantial interest in methods to evaluate MT properties, including bending radius and the binding energy of kinesin motor proteins to MT tracks. Current methods to identify these properties include optical tweezers, microfluidic devices, and magnetic fields. Here, the use of magnetic quantum dots (i.e., MagDots) is evaluated as a method to study MT-kinesin interactions via applied magnetic forces. Magnetic fields are generated using a magnetic needle whose field gradient is quantified by finite element modeling (FEM). Magnetic force is applied to MagDot-labeled MTs and demonstrated sufficient to steer and detach MTs from kinesin-coated surfaces. Taking advantage of the dual-functionality of MagDots, the magnetic force experienced by a single MagDot and the number of MagDots on MTs are determined. The total force exerted on MTs by MagDots is estimated to be ≈0.94-2.47 pN. This approach could potentially be used to interrogate MT properties and MT-kinesin interactions, enhancing our biological understanding of this system and enabling further development of MT shuttles for nanotransport.


The risk of revision after total hip arthroplasty in young patients depends on surgical approach, femoral head size and bearing type; an analysis of 19,682 operations in the Dutch arthroplasty register.
Total hip arthroplasty (THA) is used increasingly in younger patients. There is little knowledge about the effect of THA characteristics on risk of revision, especially in young patients. Therefore, we studied the influence of both patient-related and surgical factors on the risk of revision using data from the Dutch Arthroplasty Registry (LROI). All patients younger than 55 years with a primary THA implanted in the Netherlands between 2007 and 2017 were selected (n = 19,682). The covariates age, sex, primary diagnosis, ASA-classification, surgical approach, fixation method, bearing type, head size and year of surgery were entered into Cox proportional hazards models to calculate hazard ratios for the risk of revision. The overall 5-year survival of primary THA was 95.3% (95% CI, 94.9-95.6). Use of the anterior approach resulted in a lower risk of revision than the use of the posterolateral approach (HR: 0.66, 95% CI: 0.47-0.92). THAs with a head diameter ≥ 38 mm had a higher risk of revision (HR: 1.90, 95% CI: 1.33-2.72) than THAs with 32 mm heads. Use of MoM bearings resulted in an increased risk when compared to C-PE (HR: 1.76, 95% CI: 1.27-2.43). The risk of revision in patients younger than 55 years depends on surgical approach, head size and bearing type. The anterior approach resulted in a decreased risk of revision, whereas use of ≥38 mm heads and MoM bearings resulted in an increased risk of revision for any reason.


Neuromechanics and Energetics of Walking With an Ankle Exoskeleton Using Neuromuscular-Model Based Control: A Parameter Study.
Powered ankle exoskeletons that apply assistive torques with optimized timing and magnitude can reduce metabolic cost by ∼10% compared to normal walking. However, finding individualized optimal control parameters is time consuming and must be done independently for different walking modes (e.g., speeds, slopes). Thus, there is a need for exoskeleton controllers that are capable of continuously adapting torque assistance in concert with changing locomotor demands. One option is to use a biologically inspired, model-based control scheme that can capture the adaptive behavior of the human plantarflexors during natural gait. Here, based on previously demonstrated success in a powered ankle-foot prosthesis, we developed an ankle exoskeleton controller that uses a neuromuscular model (NMM) comprised of a Hill type musculotendon driven by a simple positive force feedback reflex loop. To examine the effects of NMM reflex parameter settings on (i) ankle exoskeleton mechanical performance and (ii) users' physiological response, we recruited nine healthy, young adults to walk on a treadmill at a fixed speed of 1.25 m/s while donning bilateral tethered robotic ankle exoskeletons. To quantify exoskeleton mechanics, we measured exoskeleton torque and power output across a range of NMM controller Gain (0.8-2.0) and Delay (10-40 ms) settings, as well as a High Gain/High Delay (2.0/40 ms) combination. To quantify users' physiological response, we compared joint kinematics and kinetics, ankle muscle electromyography and metabolic rate between powered and unpowered/zero-torque conditions. Increasing NMM controller reflex Gain caused increases in average ankle exoskeleton torque and net power output, while increasing NMM controller reflex Delay caused a decrease in net ankle exoskeleton power output. Despite systematic reduction in users' average biological ankle moment with exoskeleton mechanical assistance, we found no NMM controller Gain or Delay settings that yielded changes in metabolic rate. Post hoc analyses revealed weak association at best between exoskeleton and biological mechanics and changes in users' metabolic rate. Instead, changes in users' summed ankle joint muscle activity with powered assistance correlated with changes in their metabolic energy use, highlighting the potential to utilize muscle electromyography as a target for on-line optimization in next generation adaptive exoskeleton controllers.


Being Overweight or Obese and the Development of Asthma.
Adult obesity is linked to asthma cases and is estimated to lead to 250 000 new cases yearly. Similar incidence and attributable risk (AR) estimates have not been developed for children. We sought to describe the relationship between overweight and obesity and incident asthma in childhood and quantify AR statistics in the United States for overweight and obesity on pediatric asthma. The PEDSnet clinical data research network was used to conduct a retrospective cohort study (January 2009-December 2015) to compare asthma incidence among overweight and/or obese versus healthy weight 2- to 17-year-old children. Asthma incidence was defined as ≥2 encounters with a diagnosis of asthma and ≥1 asthma controller prescription. Stricter diagnostic criteria involved confirmation by spirometry. We used multivariable Poisson regression analyses to estimate incident asthma rates and risk ratios and accepted formulas for ARs. Data from 507 496 children and 19 581 972 encounters were included. The mean participant observation period was 4 years. The adjusted risk for incident asthma was increased among children who were overweight (relative risk [RR]: 1.17; 95% confidence interval [CI]: 1.10-1.25) and obese (RR: 1.26; 95% CI: 1.18-1.34). The adjusted risk for spirometry-confirmed asthma was increased among children with obesity (RR: 1.29; 95% CI: 1.16-1.42). An estimated 23% to 27% of new asthma cases in children with obesity is directly attributable to obesity. In the absence of overweight and obesity, 10% of all cases of asthma would be avoided. Obesity is a major preventable risk factor for pediatric asthma.


Melatonin inhibits hypothalamic gonadotropin-releasing hormone release and reduces biliary hyperplasia and fibrosis in cholestatic rats.
Melatonin is a hormone produced by the pineal gland with increased circulating levels shown to inhibit biliary hyperplasia and fibrosis during cholestatic liver injury. Melatonin also has the capability to suppress the release of hypothalamic gonadotropin-releasing hormone (GnRH), a hormone that promotes cholangiocyte proliferation when serum levels are elevated. However, the interplay and contribution of neural melatonin and GnRH to cholangiocyte proliferation and fibrosis in bile duct-ligated (BDL) rats have not been investigated. To test this, cranial levels of melatonin were increased by implanting osmotic minipumps that performed an intracerebroventricular (ICV) infusion of melatonin or saline for 7 days starting at the time of BDL. Hypothalamic GnRH mRNA and cholangiocyte secretion of GnRH and melatonin were assessed. Cholangiocyte proliferation and fibrosis were measured. Primary human hepatic stellate cells (HSCs) were treated with cholangiocyte supernatants, GnRH, or the GnRH receptor antagonist cetrorelix acetate, and cell proliferation and fibrosis gene expression were assessed. Melatonin infusion reduced hypothalamic GnRH mRNA expression and led to decreased GnRH and increased melatonin secretion from cholangiocytes. Infusion of melatonin was found to reduce hepatic injury, cholangiocyte proliferation, and fibrosis during BDL-induced liver injury. HSCs supplemented with BDL cholangiocyte supernatant had increased proliferation, and this increase was reversed when HSCs were supplemented with supernatants from melatonin-infused rats. GnRH stimulated fibrosis gene expression in HSCs, and this was reversed by cetrorelix acetate cotreatment. Increasing bioavailability of melatonin in the brain may improve outcomes during cholestatic liver disease.NEW & NOTEWORTHY We have previously demonstrated that GnRH is expressed in cholangiocytes and promotes their proliferation during cholestasis. In addition, dark therapy, which increases melatonin, reduced cholangiocyte proliferation and fibrosis during cholestasis. This study expands these findings by investigating neural GnRH regulation by melatonin during BDL-induced cholestasis by infusing melatonin into the brain. Melatonin infusion reduced cholangiocyte proliferation and fibrosis, and these effects are due to GNRH receptor 1-dependent paracrine signaling between cholangiocytes and hepatic stellate cells.


Orbital dermoid and epidermoid cysts: case study.
Dermoid and epidermoid cysts of the orbit belong to choristomas, tumours that originate from the aberrant primordial tissue. Clinically, they manifest as cystic movable formations mostly localized in the upper temporal quadrant of the orbit. They are described as both superficial and deep formations with most frequently slow intermittent growth. Apart from aesthetic effects, during their growth, dermoid and epidermoid cysts can cause disturbances in the eye motility, and in rare cases, also an optical nerve compression syndrome. In this paper, we described a child with a congenital orbital dermoid cyst localized in the upper-nasal quadrant that was showing signs of a gradual enlargement and progression. The computerized tomography revealed a cyst of 1.5-2.0 cm in size. At the Maxillofacial Surgery Hospital in Nis, the dermoid cyst was extirpated in toto after orbitotomy performed by superciliary approach. Postoperative course was uneventful, without inflammation signs, and after two weeks excellent functional and aesthetic effects were achieved. Before the decision to treat the dermoid and epidermoid cysts operatively, a detailed diagnostic procedure was necessary to be done in order to locate the cyst precisely and determine its size and possible propagation into the surrounding periorbital structures. Apart from cosmetic indications, operative procedures are recommended in the case of cysts with constant progressions, which cause the pressure to the eye lobe, lead to motility disturbances and indirectly compress the optical nerve and branches of the cranial nerves III, IV and VI.


Chronic exposure to 12-O-tetradecanoylphorbol-13-acetate represses sod2 induction in vivo: the negative role of p50.
It is well documented that the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) can activate manganese superoxide dismutase (MnSOD) expression. However, it is unclear how repeated exposure to TPA following a single application of tumor initiator 7,12-dimethylbenz-(a)-anthracene causes tumor development. We generated transgenic mice expressing human MnSOD promoter- and enhancer-driven luciferase reporter gene and used a non-invasive imaging system to investigate the effects of TPA on MnSOD expression in vivo. Our data indicate that TPA initially activates MnSOD expression, but this positive effect declines after repeated applications. Changes in MnSOD expression in vivo were verified by measuring MnSOD mRNA and protein levels. Using chromatin immunoprecipitation coupled to Western analysis of the transcription factors known to be essential for the constitutive and TPA-induced transcription of MnSOD, we found that TPA treatment leads to both activation and inactivation of MnSOD gene transcription. During the activation phase, the levels of p50, p65, specificity protein 1 (Sp1) and nucleophosmin (NPM) increase after TPA treatments. Sustained treatments with TPA lead to further increase of p50 but not p65, Sp1 or NPM, suggesting that excess p50 may have inhibitory effects leading to the suppression of MnSOD. Alteration of p50 levels by expressing p50 cDNA or p50 small interfering RNA in mouse epithelial (JB6) cells confirms that p50 is inhibitory to MnSOD transcription. These findings identify p50 as having a negative effect on MnSOD induction upon repeated applications of TPA and provide an insight into a cause for the reduction of MnSOD expression during early stages of skin carcinogenesis.


Decompression of an experimental compartment syndrome in dogs with hyaluronidase.
The treatment of compartment syndromes in which elevation of intracompartmental pressure occurs is by surgical fasciotomy. This is a relatively simple procedure but may be associated with complications. This study aimed at developing an alternative method to decompress a compartment by use of the enzyme hyaluronidase. Autologous plasma was infused into the anterolateral leg compartments of six dogs to simulate compartment syndromes of 80 mmHg. Pressure decay after pressurization was recorded. The compartment pressures were then again raised to 80 mmHg by subfascial injections of 1500 units hyaluronidase in 2 ml saline injected into one compartment and 2 ml saline only into the control side. Pressure decay was again recorded. On the experimental side, a significantly faster decay rate occurred after hyaluronidase injection than after initial pressurization; 8.0 +/- 1.3 (S.E.M.) versus 3.4 +/- 0.4 (S.E.M.) mmHg/min (p less than .01). Pressure decay after hyaluronidase injection was significantly faster than after the same volume injection on the control side, over both a four-minute period (8.0 +/- 1.3 [S.E.M.] versus 4.1 +/- 0.6 [S.E.M.] mmHg/min [p less than .03]) and a 25-minute period (2.1 +/- 0.3 [S.E.M.] versus 1.3 +/- 0.1 [S.E.M.] mmHg/min [p less than .03]). Hyaluronidase removes hyaluronic acid molecules from the leg compartment fascia and, by facilitating fluid flow from the compartment, causes decompression. Hyaluronidase may then have a place in the prophylaxis and treatment of compartment syndrome, thus avoiding anesthesia and surgery.


Natural killer cells as participants in pathogenesis of rat experimental autoimmune encephalomyelitis (EAE): lessons from research on rats with distinct age and strain.
Natural killer (NK) cells, influencing dendritic cell (DC)-mediated CD4+ lymphocyte priming in draining lymph nodes (dLNs) and controlling spinal cord (SC) infiltration with encephalitogenic CD4+T lymphocytes, modulate EAE (multiple sclerosis model). This study examined their putative contribution to age-related differences in EAE development in Dark Agouti (DA) (exhibiting age-related decrease in EAE susceptibility) and Albino Oxford (AO) (becoming susceptible to EAE with aging) rats. Aging increased NK cell number in dLNs from rats of both strains. In AO rats, but not in DA ones, it also increased the numbers of IFN-γ-producing NK cells (important for DC activation) and activated/matured DCs, thereby increasing activated/matured DC/conventional Foxp3-CD4+ cell ratio and activated CD25+Foxp3-CD4+ cell number. Aging in DA rats diminished activated/matured DC/conventional Foxp3-CD4+ cell ratio and activated Foxp3-CD4+ cell number. However, MBP-stimulated CD4+ cell proliferation did not differ in dLN cell cultures from young and aged AO rats (as more favorable activated/matured DC/Foxp3-CD4+ cell ratio was abrogated by lower intrinsic CD4+ cell proliferative capacity and a greater regulatory CD25+Foxp3+CD4+ lymphocyte frequency), but was lower in those from aged compared with young DA rats. At SC level, aging shifted Foxp3-CD4+/cytotoxic CX3CR1+ NK cell ratio towards the former in AO rats, so it was less favorable in aged AO rats exhibiting prolonged neurological deficit compared with their DA counterparts. The study showed strain and age differences in number of IFN-γ-producing NK cells in EAE rat dLNs, and suggested that their pathogenetic relevance depends on frequency and/or activity of other cells involved in CD4+ T cell (auto)immune response.


Antimicrobial and Cytotoxic Secondary Metabolites from a Marine-Derived Fungus Penicillium Citrinum VM6.
Investigation of an antimicrobial and cytotoxic ethyl acetate extract prepared from solid fermentation of the marine-derived fungus Penicillium citrinum VM6 led to the isolation of eight metabolites (1-8), including one citrinin dimer dicitrinone F (1). Of these, compound 7 was isolated for the first time from the Penicillium genus and compound 1 with carbon-bridged C-7/C-7' linkage is rarely reported. All compounds (1-8) exhibited selective antimicrobial activity against the tested Gram-positive bacteria and Candida albicans with MICs of 32-256 µg/mL. Compounds 1 and 8 exhibited cytotoxicity against all tested cell lines A549, MCF7, MDA-MB-231, Hela, and AGS with IC50 values of 6.7 ± 0.2 to 29.6 ± 2.2 µg/mL, whereas compound 5 had selective cytotoxicity against the MCF7 cell lines with IC50 of 98.1 ± 7.8 µg/mL.


Hospitalising preterm infants in single family rooms versus open bay units: a systematic review and meta-analysis.
The effect of the hospital environment on health and specifically neurodevelopment in preterm infants remains under debate. We assessed outcomes of preterm infants hospitalised in single family rooms compared with common open bay units. For this systematic review and meta-analysis, we searched MEDLINE, Embase, PsycInfo, CENTRAL (the Cochrane Central Register of Controlled Trials), Web of Science, and ClinicalTrials.gov from inception to Aug 13, 2018, using controlled terms (ie, MeSH terms) and text words related to prematurity and neonatal intensive care unit design. We included randomised and non-randomised studies investigating clinical outcomes of preterm infants. We assessed methodological quality using the Cochrane Collaboration's Risk of Bias Tool for randomised controlled trials and the Cochrane Risk of Bias Tool for Non-randomised Studies of Interventions. We calculated summary estimates for meta-analysis using random effects models. The primary outcome was age appropriate long-term neurodevelopment. Secondary outcomes were length of hospital stay, sepsis, breastfeeding, growth, bronchopulmonary dysplasia, intraventricular haemorrhage, retinopathy of prematurity, and mortality. This systematic review is registered with PROSPERO, number CRD42016050643. We identified 487 records. 13 study populations (n=4793) were included. No difference in cognitive neurodevelopment was found on the Bayley Scales of Infant and Toddler Development-III at 18-24 months of corrected age (680 infants analysed; mean difference 1·04 [95% CI -3·45 to 5·52], p=0·65; I2=42%). The incidence of sepsis was lower (4165 infants analysed; 108 035 days in hospital [hospitalisation days]; risk ratio 0·63 [95% CI 0·50 to 0·78], p<0·0001; I2=0%) and exclusive breastfeeding at discharge was higher (484 infants analysed; 1·31 [1·07 to 1·61], p=0·01; I2=0%) in single family rooms than in open bay units. We found no differences in length of hospital stay, growth, bronchopulmonary dysplasia, intraventricular haemorrhage, retinopathy of prematurity, and mortality. Single family rooms should be considered to hospitalise preterm infants because incidence of sepsis is reduced and exclusive breastfeeding is higher. No difference in long-term neurodevelopment was detected. None.


Tissue specific promoters in targeting systemically delivered gene therapy.
Melanin biosynthesis is restricted to melanocytes partly as a consequence of transcriptional regulation of the mRNA coding for those enzymes involved in this biochemical pathway. Promoter sequences of these genes may be used to regulate expression of complementary DNA coding for therapeutic genes so as to provide transcriptional targeting. As a model system we have used the 5'-flanking sequences of the murine tyrosinase or tyrosinase-related protein 1 (TRP-1) genes to show that such transcriptional targeting can be accomplished both in vitro and in vivo. Using interleukin-2 (IL-2) as an example of an immunostimulatory gene and herpes simplex virus thymidine kinase (HSVTK), as an example of a prodrug-activating gene we have shown, in murine model systems, that marked antitumour effects can be achieved by targeted gene therapy approaches. Because other tumor types produce particular proteins as a consequence of specific transcription it is possible that this approach may provide a way of targeting therapeutic genes to various cancers.


Proximal tibial osteochondromas in patients with fibrodysplasia ossificans progressiva.
Fibrodysplasia ossificans progressiva is a rare autosomal dominant disorder characterized by congenital malformation of the great toes and by progressive heterotopic ossification of skeletal muscle and soft connective tissues. The disorder is caused by a recurrent missense mutation in the glycine-serine activation domain of activin A receptor type I, a bone morphogenetic protein (BMP) type-I receptor, in all classically affected individuals. Osteochondromas of the proximal part of the tibia are benign osteochondral neoplasms or orthotopic lesions of skeletal remodeling associated with dysregulated BMP signaling and have been considered an atypical feature of fibrodysplasia ossificans progressiva, but they may be underdiagnosed because of their often asymptomatic nature. The purpose of the present study was to determine the prevalence and characteristics of proximal tibial osteochondromas in individuals who have fibrodysplasia ossificans progressiva. Over a period of thirty months, we evaluated all patients with new and established fibrodysplasia ossificans progressiva for the presence of proximal tibial osteochondromas on the basis of medical history, physical examination, and radiographic studies. We quantified the prevalence of osteochondromas and characterized the types of osteochondromas to identify relevant trends. Ninety-six patients (including fifty-two female patients and forty-four male patients) with fibrodysplasia ossificans progressiva were evaluated on the basis of a history and physical examination. Plain radiographs were available for sixty-seven patients. Ninety percent of all patients had osteochondroma of the proximal part of the tibia. These lesions usually were asymptomatic, most commonly were bilateral, and typically were located at the pes anserinus. Seventy-five percent of the lesions were pedunculated, and 25% were sessile. Proximal tibial osteochondromas are a common phenotypic feature of fibrodysplasia ossificans progressiva, a finding that expands the recognized consequences of recurrent activating mutations in activin A receptor type I to include not only congenital skeletal malformations and heterotopic skeletogenesis but also benign osteochondral neoplasms or orthotopic lesions of skeletal modeling. The present study provides insight into the genetic basis of osteochondroma formation in patients with fibrodysplasia ossificans progressiva and possibly into that of more common conditions in which these lesions occur.


Comparison of LMA® Gastro™ airway and gastrolaryngeal tube in endoscopic retrograde cholangiopancreatography: a prospective randomized observational trial.
New generation airway devices with different designs have been developed as an alternative to endotracheal intubation in order to avoid adverse events associated with sedation in endoscopic procedures and to provide patent airway. We aimed to compare two supraglottic airway devices (SGADs), the LMA® Gastro™ airway and gastrolaryngeal tube (GLT), in terms of airway efficiency, performance during procedure and adverse events in endoscopic retrograde cholangiopancreatography (ERCP). A hundred-three ERCP patients without high risk of aspiration were included. Patients were randomly allocated to the LMA Gastro and GLT groups. The primary study outcomes were the comparison of the two SGADs in terms of oropharyngeal leak pressure (OLP). Secondary study outcome was SGADs-related adverse events. Procedures were completed with SGADs in fifty patients in each group. The rate of successful insertion at first attempt was 72% in GLT and 96% in LMA Gastro (P=0.004). The mean OLP of LMA Gastro Group (31.8 cmH<inf>2</inf>O) was significantly higher than that of the GLT Group (26.5 cmH<inf>2</inf>O), (P=0.0001). However, endoscopists' satisfaction was higher in GLT (P=0.0001). Mucosal damage and sore throat were lower in LMA Gastro Group. LMA® Gastro™ had a higher OLP than GLT. However, GLT was better for endoscopist satisfaction, as it provides more satisfying maneuverability. As to secondary outcome advers events were lower in LMA® Gastro™. The lower complication rates associated with the device and providing a more patent airway also highlighted the apparent clinical efficacy of LMA® Gastro™ than GLT, in ERCP.


Cloning and transposon insertion mutagenesis of virulence genes of the 100-kilobase plasmid of Salmonella typhimurium.
We have cloned regions of the 100-kilobase (kb) plasmid, pStSR100, of Salmonella typhimurium SR-11 that confer virulence to plasmid-cured S. typhimurium. Cells carrying recombinant plasmids that conferred virulence were selected by inoculating mice orally with recombinant libraries in virulence plasmid-cured S. typhimurium and harvesting isolates that infected spleens. Three plasmids, pYA401, pYA402, and pYA403, constructed with the cosmid vector pCVD305 conferred wild-type levels of virulence to plasmid-cured S. typhimurium and had a common 14-kb DNA insert sequence. Another recombinant plasmid, pYA422, constructed with the vector pACYC184, conferred to plasmid-cured S. typhimurium a wild-type 50% lethal dose (LD50) level, but mice died more slowly than when infected with wild-type S. typhimurium. Furthermore, pYA422 conferred the ability to cause a higher, but not a wild-type, level of splenic infection on plasmid-cured S. typhimurium. pYA422 had a 3.2-kb insert sequence which mapped to the center of the 14-kb common sequence of the cosmid clones. Transposon Tn5 insertion mutations in pYA403 inhibited virulence to various degrees, and when transduced into the native virulence plasmid of S. typhimurium, these Tn5 insertions decreased virulence to degrees similar to those observed when the Tn5 insertions were present in pYA403. vir-22::Tn5 in pStSR100 greatly lowered infection of spleens relative to unmutagenized virulence plasmid, while vir-26::Tn5 and vir-27::Tn5 lowered splenic infection to lesser degrees. At least three proteins were encoded by pYA403 containing 23 kb of insert sequence and subclone pYA420, containing the 14-kb common insert sequence present in all of the cosmid clones. One of these proteins, with an apparent molecular weight of 28,000, was also encoded by pYA422. The Tn5 insertion that most attenuated virulence, vir-22::Tn5, inhibited synthesis of the 28,000-molecular-weight protein. The vir-22::Tn5 insertion was complemented by recombinant plasmids encoding only the 28,000-molecular-weight protein, suggesting a role of this protein in virulence. However, recombinant plasmids, exemplified by pYA422, that encoded only the 28,000-molecular-weight protein did not confer full virulence.


Stable solution-processed molecular n-channel organic field-effect transistors.
A new solution-processable small-molecule containing electron-poor naphthalene diimide and tetrazine moieties has been synthesized. The optimized spin-coated n-channel OFETs on glass substrate shows electron mobility value up to 0.15 cm(2) V(-1) s(-1) . Inkjet-printed OFETs are fabricated in ambient atmosphere on flexible plastic substrates, which exhibits an electron mobility value up to 0.17 cm(2) V(-1) s(-1) and also shows excellent environmental and operational stability.


The role of appraisal in dysphoric affect reactivity to positive laboratory films and daily life events in depression.
Hedonic deficits are linked to protracted dysphoric affect (DA) in depression, a disorder characterised by emotion context insensitivity (ECI). Recent findings from daily life studies contradict the ECI view. This study longitudinally investigated DA across laboratory and daily life contexts and the conditions associated with discrepancies in DA reactivity. Thirty-three healthy controls and 41 adults with major depressive disorder (MDD) provided responses to neutral and positive (a) films viewed in the laboratory and (b) daily events recorded over the course of three days using ecological momentary assessment (EMA) methodology. The current study reports on participants' appraisals of films and events and their subsequent DA, both rated individually after each task and daily event. Despite large group similarities in appraisals of the positive film and life events, MDDs appraised the neutral film and neutral life events as less important (film: d = .58; event: η2 = .07) and less pleasant (film: d = .56; event: η2 = .18) relative to controls. While MDDs reported higher DA both in the laboratory and in daily life, they experienced larger decreases in DA during positive life events (B = -.77, SE = .28, t(73) = -2.70, p = .009), but not in response to the positive film relative to controls. Results indicate that higher pleasantness appraisals in daily life predicted larger decreases in DA among MDDs than controls (B = -.24, SE = .06, t(73) = -4.10, p < .001). Finally, lower pleasantness appraisals of a standardised neutral film predicted larger DA decreases among MDDs during positive life events (B = 1.28, SE = .46, t(73) = 2.77, p = .006). The implications of valence and relevance of context for DA reactivity and mood repair are discussed.


How well do diagnosis-related groups for appendectomy explain variations in resource use? An analysis of patient-level data from 10 European countries.
Appendectomy is a common and relatively simple procedure to remove an inflamed appendix, but the rate of appendectomy varies widely across Europe. This paper investigates factors that explain differences in resource use for appendectomy. We analysed 106,929 appendectomy patients treated in 939 hospitals in 10 European countries. In stage 1, we tested the performance of three models in explaining variation in the (log of) cost of the inpatient stay (seven countries) or length of stay (three countries). The first model used only the diagnosis-related groups (DRGs) to which patients were coded, the second model used a core set of general patient-level and appendectomy-specific variables, and the third model combined both sets of variables. In stage two, we investigated hospital-level variation. In classifying appendectomy patients, most DRG systems take account of complex diagnoses and comorbidities but use different numbers of DRGs (range: 2 to 8). The capacity of DRGs and patient-level variables to explain patient-level cost variation ranges from 34% in Spain to over 60% in England and France. All DRG systems can make better use of administrative data such as the patient's age, diagnoses and procedures, and all countries have outlying hospitals that could improve their management of resources for appendectomy.


Antioxidant, Anti-Inflammatory and Pro-Differentiative Effects of Chlorogenic Acid on M03-13 Human Oligodendrocyte-like Cells.
Chlorogenic acid (CGA), a polyphenol found mainly in coffee and tea, exerts antioxidant, anti-inflammatory and anti-apoptotic effects at the gastrointestinal level. However, although CGA is known to cross the blood-brain barrier (BBB), its effects on the CNS are still unknown. Oligodendrocytes (OLs), the myelin-forming cells in the CNS, are the main target in demyelinating neuroinflammatory diseases such as multiple sclerosis (MS). We evaluated the antioxidant, anti-inflammatory and anti-apoptotic roles of CGA in M03-13, an immortalized human OL cell line. We found that CGA reduces intracellular superoxide ions, mitochondrial reactive oxygen species (ROS) and NADPH oxidases (NOXs) /dual oxidase 2 (DUOX2) protein levels. The stimulation of M03-13 cells with TNFα activates the nuclear factor kappa-light-chain-enhancer of activated B cell (NF-kB) pathway, leading to an increase in superoxide ion, NOXs/DUOX2 and phosphorylated extracellular regulated protein kinase (pERK) levels. In addition, tumor necrosis factor alpha (TNF-α) stimulation induces caspase 8 activation and the cleavage of poly-ADP-ribose polymerase (PARP). All these TNFα-induced effects are reversed by CGA. Furthermore, CGA induces a blockade of proliferation, driving cells to differentiation, resulting in increased mRNA levels of myelin basic protein (MBP) and proteolipid protein (PLP), which are major markers of mature OLs. Overall, these data suggest that dietary supplementation with this polyphenol could play an important beneficial role in autoimmune neuroinflammatory diseases such as MS.


Crystallization, melting, and structure of water nanoparticles at atmospherically relevant temperatures.
Water nanoparticles play an important role in atmospheric processes, yet their equilibrium and nonequilibrium liquid-ice phase transitions and the structures they form on freezing are not yet fully elucidated. Here we use molecular dynamics simulations with the mW water model to investigate the nonequilibrium freezing and equilibrium melting of water nanoparticles with radii R between 1 and 4.7 nm and the structure of the ice formed by crystallization at temperatures between 150 and 200 K. The ice crystallized in the particles is a hybrid form of ice I with stacked layers of the cubic and hexagonal ice polymorphs in a ratio approximately 2:1. The ratio of cubic ice to hexagonal ice is insensitive to the radius of the water particle and is comparable to that found in simulations of bulk water around the same temperature. Heating frozen particles that contain multiple crystallites leads to Ostwald ripening and annealing of the ice structures, accompanied by an increase in the amount of ice at the expense of the liquid water, before the particles finally melt from the hybrid ice I to liquid, without a transition to hexagonal ice. The melting temperatures T(m) of the nanoparticles are not affected by the ratio of cubic to hexagonal layers in the crystal. T(m) of the ice particles decreases from 255 to 170 K with the particle size and is well described by the Gibbs-Thomson equation, T(m)(R) = T(m)(bulk) - K(GT)/(R - d), with constant K(GT) = 82 ± 5 K·nm and a premelted liquid of width d = 0.26 ± 0.05 nm, about one monolayer. The freezing temperatures also decrease with the particles' radii. These results are important for understanding the composition, freezing, and melting properties of ice and liquid water particles under atmospheric conditions.


[Patent foramen ovale in the adult: state of the art in 2010].
A patent foramen ovale (PFO) can be found in 25% of the normal population. Several pathologies have been related to PFO as paradoxical embolism, migraine with aura and decompression illness in divers. Finding a PFO in a young patient suffering a stroke and/or TIA is the most common situation in daily practice and where the therapeutic attitude is most controversial. Should we treat the patient with aspirin, with coumadin or should we proceed to a percutaneous closure? We think that only an open discussion with the patient explaining the pros and contras of each strategy is reasonable, because the only randomised study, CLOSURE I, comparing medical treatment with percutaneous closure has shown no difference between these two strategies in terms of clinical events at two years.


PANGEA: pipeline for analysis of next generation amplicons.
High-throughput DNA sequencing can identify organisms and describe population structures in many environmental and clinical samples. Current technologies generate millions of reads in a single run, requiring extensive computational strategies to organize, analyze and interpret those sequences. A series of bioinformatics tools for high-throughput sequencing analysis, including pre-processing, clustering, database matching and classification, have been compiled into a pipeline called PANGEA. The PANGEA pipeline was written in Perl and can be run on Mac OSX, Windows or Linux. With PANGEA, sequences obtained directly from the sequencer can be processed quickly to provide the files needed for sequence identification by BLAST and for comparison of microbial communities. Two different sets of bacterial 16S rRNA sequences were used to show the efficiency of this workflow. The first set of 16S rRNA sequences is derived from various soils from Hawaii Volcanoes National Park. The second set is derived from stool samples collected from diabetes-resistant and diabetes-prone rats. The workflow described here allows the investigator to quickly assess libraries of sequences on personal computers with customized databases. PANGEA is provided for users as individual scripts for each step in the process or as a single script where all processes, except the chi(2) step, are joined into one program called the 'backbone'.


Does imageless computer-assisted TKA lead to improved rotational alignment or fewer outliers? A systematic review.
Computer-assisted surgery (CAS) has been developed to enhance prosthetic alignment during primary TKAs. Imageless CAS improves coronal and sagittal alignment compared with conventional TKA. However, the effect of imageless CAS on rotational alignment remains unclear. We conducted a systematic and qualitative review of the current literature regarding the effectiveness of imageless CAS during TKA on (1) rotational alignment of the femoral and tibial components and tibiofemoral mismatch in terms of deviation from neutral rotation, and (2) the number of femoral and tibial rotational outliers. Data sources included PubMed, MEDLINE, and EMBASE. Study selection, data extraction, and methodologic quality assessment were conducted independently by two reviewers. Standardized mean difference with 95% CI was calculated for continuous variables (rotational alignment of the femoral or tibial component and tibiofemoral mismatch). To compare the number of outliers for femoral and tibial component rotation, the odds ratio and 95% CI were calculated. The literature search produced 657 potentially relevant studies, 17 of which met the inclusion criteria. One study was considered as having high methodologic quality, 15 studies had medium, and one study had low quality. Conflicting evidence was found for all outcome measures except for tibiofemoral mismatch. Moderate evidence was found that imageless CAS had no influence on postoperative tibiofemoral mismatch. The measurement protocol for measuring tibial rotation varied among the studies and in only one of the studies was the sample size calculation based on one of the outcome measures used in our systematic review. More studies of high methodologic quality and with a sample size calculation based on the outcome measures will be helpful to assess whether an imageless CAS TKA improves femoral and tibial rotational alignment and tibiofemoral mismatch or decreases the number of femoral and tibial rotational outliers. To statistically analyze the results of different studies, the same measurement protocol should be used among the studies.


Biochemical and pharmacological characterization of three opioid-nociceptin hybrid peptide ligands reveals substantially differing modes of their actions.
In an attempt to design opioid-nociceptin hybrid peptides, three novel bivalent ligands, H-YGGFGGGRYYRIK-NH2, H-YGGFRYYRIK-NH2 and Ac-RYYRIKGGGYGGFL-OH were synthesized and studied by biochemical, pharmacological, biophysical and molecular modelling tools. These chimeric molecules consist of YGGF sequence, a crucial motif in the N-terminus of natural opioid peptides, and Ac-RYYRIK-NH2, which was isolated from a combinatorial peptide library as an antagonist or partial agonist that inhibits the biological activity of the endogenously occurring heptadecapeptide nociceptin. Solution structures for the peptides were studied by analysing their circular dichroism spectra. Receptor binding affinities were measured by equilibrium competition experiments using four highly selective radioligands. G-protein activating properties of the multitarget peptides were estimated in [35S]GTPγS binding tests. The three compounds were also measured in electrically stimulated mouse vas deferens (MVD) bioassay. H-YGGFGGGRYYRIK-NH2 (BA55), carrying N-terminal opioid and C-terminal nociceptin-like sequences interconnected with GGG tripeptide spacer displayed a tendency of having either unordered or β-sheet structures, was moderately potent in MVD and possessed a NOP/KOP receptor preference. A similar peptide without spacer H-YGGFRYYRIK-NH2 (BA62) exhibited the weakest effect in MVD, more α-helical periodicity was present in its structure and it exhibited the most efficacious agonist actions in the G-protein stimulation assays. The third hybrid peptide Ac-RYYRIKGGGYGGFL-OH (BA61) unexpectedly displayed opioid receptor affinities, because the opioid message motif is hidden within the C-terminus. The designed chimeric peptide ligands presented in this study accommodate well into a group of multitarget opioid compounds that include opioid-non-opioid peptide dimer analogues, dual non-peptide dimers and mixed peptide- non-peptide bifunctional ligands.


Coexpression of CD40 and CD40 ligand in cutaneous T-cell lymphoma (mycosis fungoides).
Microarray analysis is a promising new approach for creating specific expression profiles of multiple genes simultaneously. We quantitatively analyzed differential gene expression patterns in mycosis fungoides-derived clonal T cells and autologous, identically cultured CD4+ lymphocytes using microarrays containing 588 cDNA segments from genes relevant to cell signaling, carcinogenesis, and apoptosis. Among other dissimilarities, neoplastic T cells showed coexpression of CD40 (Bp50) and CD40 ligand (gp39, CD154). These results could be corroborated by reverse transcription-PCR, immunohistochemistry, and two-color immunofluorescence staining. Our data suggest that in cutaneous T-cell lymphoma, CD40/CD40 ligand interactions might represent a paracrine loop that is crucial not only in preventing apoptosis or positively regulating growth but also in homing of neoplastic cells to the skin.


Prospective evaluation of hematocrit in gender-affirming hormone treatment: results from European Network for the Investigation of Gender Incongruence.
In trans persons on gender-affirming hormonal treatment, a decrease (in trans women) or increase (in trans men) in hematocrit is often observed. Reference ranges for evaluation of hematocrit levels in trans persons have not been established. This prospective cohort study is part of the European Network for the Investigation of Gender Incongruence (ENIGI). At the Ghent and Amsterdam sites, we included 625 hormone-naïve trans persons. Gender-affirming hormonal treatment was initiated at the first visit. In trans men, serum hematocrit (Hct) levels increased during the first year (+4.9 Hct %, 95% CI 3.82-5.25), with the most pronounced increase during the first 3 months (+2.7 Hct %, 95% CI 1.94-3.29). Trans men receiving testosterone esters had a larger increase in serum hematocrit levels compared to trans men receiving testosterone undecanoate (Δ 0.8 Hct %). Of 192 trans men, 22 (11.5%) developed serum hematocrit levels ≥50.0%. Trans men on testosterone undecanoate were less likely to develop hematocrit levels ≥50% or ≥52%, compared to trans men on testosterone esters, and were less likely to develop hematocrit levels ≥50%, compared to trans men on testosterone gel. In trans women, serum hematocrit had dropped by 4.1 Hct % (95% CI 3.50-4.37) after 3 months, after which only small decreases were observed. In conclusion, serum hematocrit levels can be found in the reference range of the perceived gender as from 3 months after the initiation of gender-affirming hormonal treatment.


A Cu-Based Metal-Organic Framework Cu-Cip with Cuproptosis for Cancer Therapy and Inhibition of Cancer Cell Migration.
Microflora within cancer cells plays a pivotal role in promoting metastasis of cancer. However, contemporary anticancer research often overlooks the potential benefits of combining anticancer and antibacterial agents. Consequently, a metal-organic framework Cu-Cip with cuproptosis and antibacterial properties was synthesized for cancer therapy. To enhance the anticancer effect of the material, Mn2+ was loaded into Cu-Cip, yielding Mn@Cu-Cip. The fabricated material was characterized using single-crystal X-ray diffraction, PXRD, and FT-IR. By interacting with overexpressed H2O2 to produce ROS and accumulating Cu ions in cancer cells, MOFs exhibited excellent anticancer performance. Moreover, the material displayed the function of damaging Staphylococcus aureus and Escherichia coli, revealing the admirable antibacterial properties of the material. In addition, the antibacterial ability could inhibit tumor cell migration. The Cu-based MOF revealed promising applications in the field of tumor treatment.


Subcellular localization of nucleolar protein 14 and its proliferative function mediated by miR-17-5p and E2F4 in pancreatic cancer.
Pancreatic cancer is one of the most lethal malignancies worldwide. Acquiring infinite proliferation ability is a key hallmark and basis of tumorigenesis. NOP14 is an identified ribosome biogenesis protein that plays potential roles in cell proliferation. However, the function and molecular mechanism of NOP14 remain ambiguous in most human cancers. In this study, we first investigated the subcellular localization and expression of NOP14 by multiple quantitative assays in pancreatic cancer. We confirmed that NOP14 was mainly localized in nucleolus in human pancreatic cancer cells. Then we studied the regulatory effects of this nucleolus protein on tumor cell proliferation in vitro. NOP14 was demonstrated to play a dominant pro-proliferation role in pancreatic cancer. Furthermore, we identified miR17-5p as a downstream target of NOP14. Transfection of miR17-5p mimics or inhibitors rescued the down- or upregulated effect of NOP14 on cell proliferation by regulating expression of P130. In addition, NOP14 induced expression of transcription factor E2F4 independent of miR17-5p/P130 signaling, which simultaneously activated a set of targeted genes, such as CCNE1, PIM1, AKT1 etc., to promote tumor proliferation. These findings might provide novel insights for better understanding the diverse function of NOP14 in human malignancies to develop new strategies for targeted therapy.


Diagnosis, misdiagnosis, lucky guess, hearsay, and more: an ontological analysis.
Disease and diagnosis have been the subject of much ontological inquiry. However, the insights gained therein have not yet been well enough applied to the study, management, and improvement of data quality in electronic health records (EHR) and administrative systems. Data in these systems suffer from workarounds clinicians are forced to apply due to limitations in the current state-of-the art in system design which ignore the various types of entities that diagnoses as information content entities can be and are about. This leads to difficulties in distinguishing amongst diagnostic assertions misdiagnosis from correct diagnosis, and the former from coincidentally correct statements about disease. We applied recent advances in the ontological understanding of the aboutness relation to the problem of diagnosis and disease as defined by the Ontology for General Medical Science. We created six scenarios that we analyzed using the method of Referent Tracking to identify all the entities and their relationships which must be present for each scenario to hold true. We discovered deficiencies in existing ontological definitions and proposed revisions of them to account for the improved understanding that resulted from our analysis. Our key result is that a diagnosis is an information content entity (ICE) whose concretization(s) are typically about a configuration in which there exists a disease that inheres in an organism and instantiates a certain type (e.g., hypertension). Misdiagnoses are ICEs whose concretizations succeed in aboutness on the level of reference for individual entities and types (the organism and the disease), but fail in aboutness on the level of compound expression (i.e., there is no configuration that corresponds in total with what is asserted). Provenance of diagnoses as concretizations is critical to distinguishing them from lucky guesses, hearsay, and justified layperson belief. Recent improvements in our understanding of aboutness significantly improved our understanding of the ontology of diagnosis and related information content entities, which in turn opens new perspectives for the implementation of data capture methods in EHR and other systems to allow diagnostic assertions to be captured with less ambiguity.


Differential regulation of microRNAs in end-stage failing hearts is associated with left ventricular assist device unloading.
Mechanical unloading by left ventricular assist devices (LVADs) in advanced heart failure (HF), in addition to improving symptoms and end-organ perfusion, is supposed to stimulate cellular and molecular responses which can reverse maladaptive cardiac remodeling. As microRNAs (miRNAs) are key regulators in remodeling processes, a comparative miRNA profiling in transplanted hearts of HF patients with/without LVAD assistance could aid to comprehend underlying molecular mechanisms. Next generation sequencing (NGS) was used to analyze miRNA differential expression in left ventricles of HF patients who underwent heart transplantation directly (n = 9) or following a period of LVAD support (n = 8). After data validation by quantitative real-time PCR, association with functional clinical parameters was investigated. Bioinformatics' tools were then used for prediction of putative targets of modulated miRNAs and relative pathway enrichment. The analysis revealed 13 upregulated and 10 downregulated miRNAs in failing hearts subjected to LVAD assistance. In particular, the expression level of some of them (miR-338-3p, miR-142-5p and -3p, miR-216a-5p, miR-223-3p, miR-27a-5p, and miR-378g) showed correlation with off-pump cardiac index values. Predicted targets of these miRNAs were involved in focal adhesion/integrin pathway and in actin cytoskeleton regulation. The identified miRNAs might contribute to molecular regulation of reverse remodeling and heart recovery mechanisms.


Accuracy and Precision of Alchemical Relative Free Energy Predictions with and without Replica-Exchange.
A systematic and statistically robust protocol is applied for the evaluation of free energy calculations with and without replica-exchange. The protocol is based on ensemble averaging to generate accurate assessments of the uncertainties in the predictions. Comparison is made between FEP+ and TIES-free energy perturbation and thermodynamic integration with enhanced sampling-the latter with and without the so-called "enhanced sampling" based on replica-exchange protocols. Standard TIES performs best for a reference set of targets and compounds; no benefits accrue from replica-exchange methods. Evaluation of FEP+ and TIES with REST-replica-exchange with solute tempering-reveals a systematic and significant underestimation of free energy differences in FEP+, which becomes increasingly large for long duration simulations, is confirmed by extensive analysis of previous publications, and raises a number of questions pertaining to the accuracy of the predictions with the REST technique not hitherto discussed.


Civil disobedience in scientific authorship: Resistance and insubordination in science.
The distribution of credit, resources and opportunities in science is heavily skewed due to unjust practices and incentives, hardwired into science's rules, guidelines and conventions. A form of resistance widely available is to break those rules. We review instances of rule-breaking in scientific authorship to allow for a redefinition of the concept of civil disobedience in the context of academic research, as well as the conditions on which the label applies. We show that, in contrast to whistleblowing or conscientious objection, civil disobedience targets science's injustice on a more systemic level. Its further development will ease critical evaluation of deviant actions as well as helping us evaluate deviance, defiance and discontent in science beyond issues of authorship. However, empirically, civil disobedience in science engenders uncertainties and disagreements on the local status of both act and label.


[Induced and spontaneous mutagenesis in phage T4 in Escherichia coli strains with mutant RNA polymerase].
Study was made of the frequency of induced and spontaneous mutations in phage T4 in RNA polymerase Escherichia coli strains. It has been shown that the rate of induced mutagenesis by base analogues increases in two rUV-mutants of phage T4 carrying mutations of the transition type, unlike the frameshift mutant which does not revert under these conditions. An increase in the level of spontaneous mutations in the phage is also found when RNA polymerase mutations are introduced into the system. The influence of mutant RNA polymerase on the mutation process is specific as no alteration of the recombination process in phage T4 has been found in E. coli strains with mutant RNA polymerase.


[Botulin toxin for spasticity in spinal cord damage by treating the motor endplate].
Therapeutic injection of botulin toxin is well-recognized for reducing tonus in local dystonia. However, its efficacy in reducing spasticity in spinal cord injuries is still unproven. 4 men and 1 woman (mean age 39 years, range 20-56) with spinal cord injury and debilitating spasticity, and no response to standard treatment for spasticity received injections of botulin, 200-300 U, into 4-8 points in their legs to block muscle-nerve synapses. In all 5 tonus was reduced in the area of the block, while in some it was also reduced in more distal muscles. In 1 there was reduced tonus in both the injected and contralateral leg. The therapeutic effect on tonus persisted for 3 months. In spite of objective improvement in tonus in all 5, only 3 felt subjective improvement, but in none was there improvement on standard functional scaling. We found injection of botulin toxin effective in reducing tonus in the spinal cord-injured, and to some extent in improving subjective feeling of well-being in some of them. Objective measurement might show functional improvement after larger doses of toxin injected into more muscles. This might be necessary because the muscle mass of the legs is large and the intensity of involuntary contraction is especially high in these patients.


Cardiovascular radiology. Possible factors in intravascular contrast media toxicity.
(I.) Toxicity of ionic coronary arteriography contrast media has been shown to depend on their cationic and anionic composition and their osmolality. Using a right coronary injection technique in the dog, the authors have shown a relationship between toxicity as manifested by occurrence of ventricular fibrillation and the presence of calcium binders in the contrast media. Sodium citrate and EDTA have been identified as the specific agents in certain contrast media that significantly increase the incidence of fibrillation in laboratory experiments. (II.) A deleterious synergism between water-soluble angiographic and urographic media and digitalis compounds has now been demonstrated, based on mortality studies (LD50) using bolus intravenous injections in white mice. The testing of a number of other classes of drugs for a similar effect has shown thus far that only the digitalis class exhibits this synergism. Surprisingly, the nonionic contrast medium, metrizamide, has been shown to have a greater synergistic effect with digitalis drugs than diatrizoate ionic media. (III.) In dog experiments under Nembutal anesthesia in which aortic flow, pulmonary artery and vein pressures, systemic arterial pressure, and EKG were monitored, left atrial pressure increases as soon as or before pulmonary artery pressure rises, even at low doses of ionic contrast media administered intravenously. This may indicate 1) flow to the left heart increases dramatically, or 2) there is a very early myocardial depression. The significance of the above findings and application to clinical practice will be discussed.


[Management of acute renal failure in hospital practice].
The incidence of ARF in pediatric population varies according to the definition of the syndrome. If the diagnosis is based on a decrease of glomerular filtration rate (GFR), possibly accompanied by a decrease of urinary output and the sudden change of renal function indexes, then the number of patients which can be considered affected by ARF in hospital practice is high, as it comprises all the cases with functional impairment of renal function. The availability of tables with normal values of serum creatinine for different gender and age and the knowledge of the minimal urine output compatible with the normality allows a precise diagnosis of ARF. The differential diagnosis of ARF must take into account prerenal, renal and postrenal causes. Prerenal and renal ARF may be sometimes difficult to differentiate. Indexes such as sodium fractional excretion, utilizing urinary to plasma ratios of sodium and creatinine, can be helpful: values less than 1 indicate prerenal ARF, more than 2 renal ARF. The management of ARF is dependent on the causes of ARF. Prerenal ARF is normally treated by measures of volume expansion and/or removal of the underlying cause. Renal ARF requires an accurate control of water and electrolyte balance and of nutritional status and the prevention or treatment of numerous complications, which may worsen the course of the syndrome. Indications to dialysis must be evaluated every day and an assessment of nutritional status performed. All the factors which may cause hypercatabolism, such as infections, hemorrhage, low calorie intake, must be recognized and treated. This approach allows a better control of serum urea, potassium, phosphate and acidosis. Nutrition must be implemented and an adequate protein and calorie intake must be obtained, through spontaneous oral route and, whenever required, enteral and parenteral nutrition. In conclusion, patients with mild-degree, mostly of prerenal origin, ARF represent a common finding in hospital practice. Identification and prompt treatment of the underlying cause is the best prevention of acute tubular necrosis. Patients with ARF of renal origin require, in particular, daily nutritional assessment and dietary treatment to delay the onset of dialysis.


Visual and quantitative evaluation of [18F]FES and [18F]FDHT PET in patients with metastatic breast cancer: an interobserver variability study.
Correct identification of tumour receptor status is important for treatment decisions in breast cancer. [18F]FES PET and [18F]FDHT PET allow non-invasive assessment of the oestrogen (ER) and androgen receptor (AR) status of individual lesions within a patient. Despite standardised analysis techniques, interobserver variability can significantly affect the interpretation of PET results and thus clinical applicability. The purpose of this study was to determine visual and quantitative interobserver variability of [18F]FES PET and [18F]FDHT PET interpretation in patients with metastatic breast cancer. In this prospective, two-centre study, patients with ER-positive metastatic breast cancer underwent both [18F]FES and [18F]FDHT PET/CT. In total, 120 lesions were identified in 10 patients with either conventional imaging (bone scan or lesions > 1 cm on high-resolution CT, n = 69) or only with [18F]FES and [18F]FDHT PET (n = 51). All lesions were scored visually and quantitatively by two independent observers. A visually PET-positive lesion was defined as uptake above background. For quantification, we used standardised uptake values (SUV): SUVmax, SUVpeak and SUVmean. Visual analysis showed an absolute positive and negative interobserver agreement for [18F]FES PET of 84% and 83%, respectively (kappa = 0.67, 95% CI 0.48-0.87), and 49% and 74% for [18F]FDHT PET, respectively (kappa = 0.23, 95% CI - 0.04-0.49). Intraclass correlation coefficients (ICC) for quantification of SUVmax, SUVpeak and SUVmean were 0.98 (95% CI 0.96-0.98), 0.97 (95% CI 0.96-0.98) and 0.89 (95% CI 0.83-0.92) for [18F]FES, and 0.78 (95% CI 0.66-0.85), 0.76 (95% CI 0.63-0.84) and 0.75 (95% CI 0.62-0.84) for [18F]FDHT, respectively. Visual and quantitative evaluation of [18F]FES PET showed high interobserver agreement. These results support the use of [18F]FES PET in clinical practice. In contrast, visual agreement for [18F]FDHT PET was relatively low due to low tumour-background ratios, but quantitative agreement was good. This underscores the relevance of quantitative analysis of [18F]FDHT PET in breast cancer. ClinicalTrials.gov, NCT01988324. Registered 20 November 2013, https://clinicaltrials.gov/ct2/show/NCT01988324?term=FDHT+PET&draw=1&rank=2.


Tick-borne encephalitis virus, Kyrgyzstan.
Tick-borne encephalitis virus (TBEV) is an emerging pathogen in Europe and Asia. We investigated TBEV in Kyrgyzstan by collecting small mammals and ticks from diverse localities and analyzing them for evidence of TBEV infection. We found TBEV circulating in Kyrgyzstan much farther south and at higher altitudes than previously reported.


Clear evidence for element partitioning effects in a Ti-6Al-4V alloy by the first-principles phase field method.
Ti-6 wt% Al-4 wt% V (Ti64) is an α + β titanium alloy, in which the alloying components strongly affect the mechanical properties. In this report, element partitioning effects in Ti64 are investigated by using the first-principles phase field (FPPF) method, which has recently been proposed by our group. In the FPPF method, the local free energy is calculated using a cluster expansion method in combination with density functional theory and the temperature effect is incorporated using potential renormalization theory. We have succeeded in identifying enrichment of Al (V) in the α (β) phase, i.e., the clear evidence for the element partitioning effects of Al and V, without using any thermodynamical parameter. The transformation of the β phase and the α phase in microstructure is investigated by varying the V and Al concentrations by a small amount. Our results are in excellent agreement with the recent experimental results, showing the validity of the FPPF method for ternary alloys.


CoCAS: a ChIP-on-chip analysis suite.
High-density tiling microarrays are increasingly used in combination with ChIP assays to study transcriptional regulation. To ease the analysis of the large amounts of data generated by this approach, we have developed ChIP-on-chip Analysis Suite (CoCAS), a standalone software suite which implements optimized ChIP-on-chip data normalization, improved peak detection, as well as quality control reports. Our software allows dye swap, replicate correlation and connects easily with genome browsers and other peak detection algorithms. CoCAS can readily be used on the latest generation of Agilent high-density arrays. Also, the implemented peak detection methods are suitable for other datasets, including ChIP-Seq output. The software is available for download along with a sample dataset at http://www.ciml.univ-mrs.fr/software/ferrier.htm. Supplementary data are available at Bioinformatics online.


Improving the bowel habits of elderly residents in a nursing home using probiotic fermented milk.
Our aim was to determine whether a fermented milk drink containing probiotics could improve the bowel habits of frail elderly individuals living in a nursing home. A total of 135 participants were enrolled in this pilot study. The bowel habits (stool quality and bowel movements) were recorded by nursing staff during a baseline period of 3 weeks. After this period participants received daily a fermented milk drink containing minimally 6.5×10(9) colony forming units of Lactobacillus casei Shirota (LcS) for 6 weeks. During this period, bowel habits were recorded and compared to baseline period. Forty-four participants (74-99 years old) were compliant and used for analysis. Consumption of fermented milk containing LcS significantly increased the percentage of ideal stool types per week (P<0.01), lowered the percentage of constipation stool types per week (P<0.01) and significantly lowered the percentage of diarrhoea stool types per week (P=0.016) as compared to the baseline period. The study product had no significant effect on bowel movements. During the study, no changes in laxative usage or adverse events associated with the study product were reported. Our results suggest that a fermented milk containing LcS significantly improves the bowel habits of frail elderly residents in a nursing home. These promising results should be further substantiated by a confirmatory study.


Multiple activation mechanisms of p38alpha mitogen-activated protein kinase.
The p38alpha MAPK participates in a variety of biological processes. Activation of p38alpha is mediated by phosphorylation on specific regulatory tyrosine and threonine sites, and the three dual kinases, MAPK kinase 3 (MKK3), MKK4, and MKK6, are known to be the upstream activators of p38alpha. In addition to activation by upstream kinases, p38alpha can autoactivate when interacting with transforming growth factor-beta-activated protein kinase 1-binding protein 1 (TAB1). Here we used MKK3 and MKK6 double knock-out (MKK3/6 DKO) and MKK4/7 DKO mouse embryonic fibroblast (MEF) cells to examine activation mechanisms of p38alpha. We confirmed that the MKK3/6 pathway is a primary mechanism for p38alpha phosphorylation in MEF cells, and we also showed the presence of other p38alpha activation pathways. We show that TAB1-mediated p38alpha phosphorylation in MEF cells did not need MKK3/4/6, and it accounted for a small portion of the total p38alpha phosphorylation that was induced by hyperosmolarity and anisomycin. We observed that a portion of peroxynitrite-induced phospho-p38alpha is associated with an approximately 85-kDa disulfide complex in wild-type MEF cells. Peroxynitrite-induced phosphorylation of p38alpha in the approximately 85-kDa complex is independent from MKK3/6 because only phospho-p38alpha not associated with the disulfide complex was diminished in MKK3/6 DKO cells. In addition, our data suggest interference among different pathways because TAB1 had an inhibitory effect on p38alpha phosphorylation in the peroxynitrite-induced approximately 85-kDa complex. Mutagenesis analysis of the cysteines in p38alpha revealed that no disulfide bond forms between p38alpha and other proteins in the approximately 85-kDa complex, suggesting it is a p38alpha binding partner(s) that forms disulfide bonds, which enable it to bind to p38alpha. Therefore, multiple mechanisms of p38alpha activation exist that can influence each other, be simultaneously activated by a given stimulus, and/or be selectively used by different stimuli in a cell type-specific manner.


The first archaic Homo from Taiwan.
Recent studies of an increasing number of hominin fossils highlight regional and chronological diversities of archaic Homo in the Pleistocene of eastern Asia. However, such a realization is still based on limited geographical occurrences mainly from Indonesia, China and Russian Altai. Here we describe a newly discovered archaic Homo mandible from Taiwan (Penghu 1), which further increases the diversity of Pleistocene Asian hominins. Penghu 1 revealed an unexpectedly late survival (younger than 450 but most likely 190-10 thousand years ago) of robust, apparently primitive dentognathic morphology in the periphery of the continent, which is unknown among the penecontemporaneous fossil records from other regions of Asia except for the mid-Middle Pleistocene Homo from Hexian, Eastern China. Such patterns of geographic trait distribution cannot be simply explained by clinal geographic variation of Homo erectus between northern China and Java, and suggests survival of multiple evolutionary lineages among archaic hominins before the arrival of modern humans in the region.


Negative interpretations of ambiguous 'psychosis-like' and 'anxiety-like' experiences in recovery from psychosis or anxiety.
Fear of relapse (FOR) after experiencing psychosis has been found to predict actual relapse; however, potential mechanisms underlying this relationship have not been investigated. Negative appraisals of 'prodromal symptoms' are believed to play an important role in both psychosis and mental health anxiety (MHA). This study aimed to explore whether people in recovery from psychosis or anxiety disorders show an enduring tendency to negatively interpret ambiguous experiences both related and less related to their previous mental health difficulty relative to controls. Cross-sectional between-groups questionnaire design. Participants self-reported as in recovery from psychosis (n = 33) or anxiety (n = 77) or without previous experience of mental health problems (n = 61) were recruited online or via NHS services. Interpretations of psychosis-like, anxiety-like, and external-control experiences were measured using the newly developed Experiences Interpretation Questionnaire (EIQ). MHA and FOR were measured using self-report questionnaires. People in recovery from psychosis interpreted psychosis-like experiences significantly more negatively than the other groups. Negative interpretations of anxiety-like experiences were greater than controls but comparable between mental health groups. Contrary to predictions, FOR was not significantly different between the mental health groups. MHA and FOR did not significantly predict negative interpretations of psychosis-like items in the psychosis group, however, MHA predicted negative interpretations of anxiety-like items in the anxiety group. The EIQ subscales demonstrated good test-retest reliability. People in self-defined recovery from psychosis or anxiety are more likely to negatively interpret ambiguous experiences relating to their previous mental health difficulties. Clinical and future research implications are outlined. People in recovery from psychosis or anxiety appraise possible symptoms of their previous difficulties negatively/catastrophically (as indicating relapse) relative to those without prior MH problems. Clinicians should consider attending to how people in recovery appraise possible symptoms when encouraging early signs monitoring as part of relapse prevention. This may be important to ensure that self-monitoring leads to helpful responses rather than being counterproductive, with catastrophic interpretations leading to anxiety and thus increasing the risk of relapse. Interventions drawing on CBT principles to address catastrophic interpretations of possible symptoms may potentially be a useful addition to relapse prevention work; in psychosis this may also include symptoms of anxiety.


Modeling life satisfaction in spinal cord injury: the role of psychological resources.
The aims of the study were (1) to examine the associations between the psychological resources general self-efficacy (GSE) and purpose in life (PIL), appraisals, coping and life satisfaction, and (2) to examine whether the effects of the psychological resources on life satisfaction are mediated by appraisals and coping, as proposed by the spinal cord injury adjustment model (SCIAM). Cross-sectional multicenter study conducted with persons with spinal cord injury (SCI) living in the community in Switzerland (N = 516). Pearson's correlations were calculated for aim 1, and structural equation modeling was conducted to address aim 2. GSE (r = .48) and PIL (r = .58) were positively related to life satisfaction. The initial model corresponding to the SCIAM yielded a poor model fit. The final model had a good model fit [χ (2) = 66.0, df = 21, p < .01, RMSEA = .065 (90 % confidence interval .048-.082), CFI = .97] explaining 57 % of variance of life satisfaction. PIL had a direct large effect on life satisfaction (β = .54). The influence of GSE on life satisfaction was mediated by loss appraisals. Avoidance, active and humor coping had small effects on life satisfaction. Psychological resources have a substantial effect on life satisfaction in persons with SCI. Our results correspond with the SCIAM and its conceptualization of adjustment as a multifactorial process, but did not fully support the hypothesized mediation. PIL was strongly related to higher life satisfaction and may be a suitable intervention target to support persons with SCI.


Analysis of Purified Pancreatic Islet Beta and Alpha Cell Transcriptomes Reveals 11β-Hydroxysteroid Dehydrogenase (Hsd11b1) as a Novel Disallowed Gene.
We and others have previously identified a group of genes, dubbed "disallowed," whose expression is markedly lower in pancreatic islets than in other mammalian cell types. Forced mis-expression of several members of this family leads to defective insulin secretion, demonstrating the likely importance of disallowance for normal beta cell function. Up to now, transcriptomic comparisons have been based solely on data from whole islets. This raises the possibilities that (a) there may be important differences in the degree of disallowance of family members between beta and other either neuroendocrine cells; (b) beta (or alpha) cell disallowed genes may have gone undetected. To address this issue, we survey here recent massive parallel sequencing (RNA-Seq) datasets from purified mouse and human islet cells. Our analysis reveals that the most strongly disallowed genes are similar in beta and alpha cells, with 11β-hydroxysteroid dehydrogenase (Hsd11b1) mRNA being essentially undetectable in both cell types. The analysis also reveals that several genes involved in cellular proliferation, including Yap1 and Igfbp4, and previously assumed to be disallowed in both beta and alpha cells, are selectively repressed only in the beta cell. The latter finding supports the view that beta cell growth is selectively restricted in adults, providing a mechanism to avoid excessive insulin production and the risk of hypoglycaemia. Approaches which increase the expression or activity of selected disallowed genes in the beta cell may provide the basis for novel regenerative therapies in type 2 diabetes.


[Possibility of correcting interhemispheric EEG asymmetry in the process of prevention of recurrences of alcoholism by reflexotherapy].
Patients suffering from chronic alcoholism were examined for the dynamics of the spectral characteristics of the EEG and the psychoemotional status in order to delineate the sings that may precede ++ the disease relapses or exacerbation of the syndromes related to alcohol addiction. Possibilities of functional correction by reflexotherapy of brain bioelectric activity according to the interhemispheric+ asymmetry of the EEG are reviewed. Methods of preventive treatment and prophylaxis of the development of alcohol addiction are offered.


[Structural and functional peculiarity of brain activity to performance and imaginary motor tasks in healthy persons (EEG and fMRI study)].
Bioelectrical (EEG) and hemodynamic (fMRI-response) cerebral reactions to performance and imaginary motor tasks by right or left hand were analyzed in 15 right-handed healthy persons (21-39 years old). During actual movement the main fMRI-response was registered in the area of central gyrus of the hemisphere contralateral to the working hand. Areas of activation were also revealed in the supplemental motor area and the ipsilateral hemisphere of the cerebellum. EEG data showed coherence increase in high frequency alpha- and beta-bands in the activated hemisphere. In imaginary motor tasks the intensity and topography of fMRI-response became the more variable; response was decreased in the motor area and in cerebellum, they increased in the subcortical structures and in the parietal association zones. EEG changes were very variable in this situation also; it was observe an increase of EEG coherence in the right hemisphere for higher frequency of alpha and beta spectral bands. Changes of power spectrum parameters were similar to performance and imaginary motor tasks. Spectrum power and middle frequency of beta band were increased. Topographically these changes did not correspond to activated hemisphere and it was more in the left hemisphere. These changes were reflected nonspecific component of reaction.


Nuclear magnetic resonance spectroscopy in patients with anion-gap acidosis.
Proton nuclear magnetic resonance spectroscopy was performed on blood or urine from five patients with an anion-gap metabolic acidosis. In all of these cases, this methodology allowed the rapid and specific diagnosis of the nature of the metabolic acidosis. In several of these patients, spectroscopic evidence for intoxication with toxic alcohols was obtained. On the basis of these preliminary data, proton nuclear magnetic resonance spectroscopy may be a useful technique in the evaluation of patients with anion-gap acidosis.


Bayesian analysis reveals the influence of maternal effect on pre-weaning body weights in Landlly piglets.
The present study was undertaken to estimate the (co)variance components and genetic parameters of body weights recorded in Landlly piglets from birth to weaning at weekly intervals (w0 to w6). The data pertained to body weights of 2462 piglets, born to 91 sires and 159 dams across different generations during a 7-year period from 2014 to 2020. Five animal models (I-V), differentiated by inclusion or exclusion of maternal effects with or without covariance between maternal and direct genetic effects, were fitted on the data using the Bayesian algorithm. The analyses were implemented by Gibbs sampling in the BLUPF90 program and Markov chain Monte Carlo (MCMC) methodology was used to draw samples of posterior distribution pertaining to (co)variance components. Based on deviance information criteria (DIC), model V with inclusion of direct additive genetic, direct maternal genetic and permanent environmental effect of dam as random factors along with covariance between direct additive and maternal effects best fitted the data on pre-weaning traits (w0 to w5). Whereas, model I incorporating only the direct additive genetic effect best fitted the weaning weight (w6) data in Landlly piglets. The posterior mean estimates of direct heritability under the best models for W0 to W6 were 0.13, 0.19, 0.29, 0.13, 0.26, 0.32 and 0.46, respectively. Inclusion of the maternal component helped in better partitioning of variance for different body weights in Landlly piglets. The maternal heritability ranged from 0.06 to 0.14, while the litter heritability ranged from 0.11 to 0.15 for pre-weaning weights (W0 to W5) under the best-fit models. The influence of maternal environment was greater than maternal genetic effect from birth to 4th week of age. The results implied that variations in body weight of Landlly pigs were genetically controlled to moderate levels (especially w2 and w4) with contributions from direct additive and maternal genotype that can be exploited by designing efficient breeding programmes.


Timing and clinical characteristics of topiramate-induced psychosis in a patient with epilepsy and tuberous sclerosis.
Several lines of scientific evidence showed that topiramate may induce psychotic symptoms when used as monotherapy. It has been postulated that this topiramate effect may be caused by the inhibition of frontal and prefrontal areas induced by topiramate. The clinical history of the patient described shows that topiramate may also induce psychosis when used in polytherapy. A 34-year-old man, with epilepsy associated to tuberous sclerosis complex and without a previous history of mental disorders, presented an acute onset of florid psychotic symptoms, including visual and auditory hallucinations, derealization, and depersonalization. These symptoms appeared 1 month after the introduction of topiramate, added to levetiracetam and carbamazepine, when topiramate reached the dose of 200 mg daily. Once topiramate was discontinued, the psychotic symptoms disappeared, with no recurrence in a 4-month follow-up. Psychotic symptoms were associated with topiramate administration. We hypothesized that psychotic symptoms appeared a month after the topiramate introduction because of the slow topiramate titration and protective effect of carbamazepine.


Low glucose blood levels are associated with abnormal cardiac sympatho-vagal balance in type 2 diabetic patients with coronary artery disease.
Glycemic control has been suggested to improve prognosis in diabetic patients, but recent trials failed to show benefits from intensive glycemic control. Hypoglycaemic episodes or large variability in glucose blood levels causing a sympatho-vagal imbalance of cardiac autonomic function (CAF) might play a role in this result. In our study we assessed whether blood glucose fluctuation may be related to variations in CAF during daily life in diabetic patients with coronary artery disease (CAD). Twelve patients with type 2 diabetes mellitus with CAD (65+/-4 years, 2 women) underwent simultaneous 48-hour ECG Holter monitoring and continuous interstitial glucose measurements. The highest and lowest glucose levels for each 3-hour segments of the day were identified and heart rate variability (HRV) parameters were measured on Holter recordings on 5-minute intervals centred on these times. Overall, 294 glucose levels were available for analysis. In the whole population several HRV indices were significantly lower in correspondence of the lowest glucose blood levels and this difference was much more evident in patients who were not taking beta-blockers, than in patients who were taking beta-blockers. A significant, although mild, correlation was found between glucose blood levels and several time-and frequency domain HRV variables in patients not taking beta-blockers, but not in these on beta-blockers therapy. Our data suggest that, in type 2 diabetic patients with CAD, hypoglycaemic episodes are associated with depressed HRV and that beta-blocking agents are able to contrast this relation. These interesting results merit to be investigated in a larger population of patients.


Characterizing the longitudinal relations between depressive and menstrual symptoms in adolescent girls.
This study examined the association between depressive and menstrual symptoms in adolescent girls in a 3-year longitudinal study. It was hypothesized that menstrual symptoms would increase in early adolescence and decrease in later adolescence, that girls with greater depressive symptoms would report greater menstrual symptoms, and that effects would persist after adjusting for general somatic complaints. A community sample of girls (n = 262) enrolled in an observational study by age cohort (11, 13, 15, 17 years) completed three annual visits. At each time point, girls completed the Menstrual Symptom Questionnaire, Children's Depression Inventory, and the Youth Self Report to assess general somatic complaints. Menstrual symptoms increased significantly across adolescence (p = .006) and began to plateau in later adolescence (p = .020). Depressive symptoms at study entry were significantly associated with menstrual symptoms (p < .001). When general somatic complaints were included in the models, the effect of depressive symptoms on menstrual symptoms remained significant for the sum score (p = .015) and the menstrual somatic symptoms subscale (p = .001). After adjusting for somatic complaints, initial report of depressive symptoms predicted change in menstrual symptoms only for girls with the lowest menstrual symptoms sum score (p = .025). Initial report of somatic complaints predicted change in menstrual symptoms (p = .020). Girls with higher depressive symptoms and higher somatic complaints are at greater risk for experiencing menstrual symptoms and increasing symptoms across adolescence, with a heightened vulnerability for girls with lower baseline menstrual symptoms.


Development of the Healthy Purchase Index (HPI): a scoring system to assess the nutritional quality of household food purchases.
To develop an index to assess the nutritional quality of household food purchases based on food expenditures only. A database of monthly food purchases of a convenience sample of low-income households was used to develop the Healthy Purchase Index (HPI). The HPI is the sum of two sub-scores based on expenditure shares of food categories in total household food expenditure: the purchase diversity sub-score and the purchase quality sub-score. The first was adapted from an existing diversity score. The second integrated those food categories identified as the best predictors of the nutritional quality of purchases based on associations between expenditure shares of food categories and two nutritional quality indicators: the mean adequacy ratio (MAR) and the mean excess ratio (MER). Correlation between the HPI and a score assessing adherence to French dietary guidelines (PNNS-GSmod) was performed as a first validation.Setting/ParticpantsFood purchases of 112 households from deprived neighbourhoods of Marseille (France), participating in the Opticourses and Jassur projects (2012-2015). The purchase diversity sub-score reflects the presence in food purchases of five food categories: fruits, vegetables, starches, dairy products, and meat, fish & eggs. The purchase quality sub-score is based on expenditure shares for fruit & vegetables, added fats & seasonings, sweet snacks, cheese, sugary drinks, refined grains and fish, as these were identified as predictors of the nutritional quality of purchases. The HPI was positively associated with the PNNS-GSmod (r s=0·378; P<0·001). The HPI helps assess the healthiness of household food purchases.


Single crystal diamond detector measurements of deuterium-deuterium and deuterium-tritium neutrons in Joint European Torus fusion plasmas.
First simultaneous measurements of deuterium-deuterium (DD) and deuterium-tritium neutrons from deuterium plasmas using a Single crystal Diamond Detector are presented in this paper. The measurements were performed at JET with a dedicated electronic chain that combined high count rate capabilities and high energy resolution. The deposited energy spectrum from DD neutrons was successfully reproduced by means of Monte Carlo calculations of the detector response function and simulations of neutron emission from the plasma, including background contributions. The reported results are of relevance for the development of compact neutron detectors with spectroscopy capabilities for installation in camera systems of present and future high power fusion experiments.


A transcriptomics assessment of oxygen-temperature interactions reveals novel candidate genes underlying variation in thermal tolerance and survival.
While single stress responses are fairly well researched, multiple, interactive stress responses are not-despite the obvious importance thereof. Here, using D. melanogaster, we investigated the effects of simultaneous exposures to low O2 (hypoxia) and varying thermal conditions on mortality rates, estimates of thermal tolerance and the transcriptome. We used combinations of 21 (normoxia), 10 or 5kPa O2 with control (23°C), cold (4°C) or hot (31°C) temperature exposures before assaying chill coma recovery time (CCRT) and heat knock down time (HKDT) as measures of cold and heat tolerance respectively. We found that mortality was significantly affected by temperature, oxygen partial pressure (PO2) and the interaction between the two. Cold treatments resulted in low mortality (<5%), regardless of PO2 treatment; while hot treatments resulted in higher mortality (∼20%), especially at 5kPa O2 which was lethal for most flies (∼80%). Both CCRT and HKDT were significantly affected by temperature, but not PO2, of the treatments, and the interaction of temperature and PO2 was non-significant. Hot treatments led to significantly longer CCRT, and shorter HKDT in comparison to cold treatments. Global gene expression profiling provided the first transcriptome level response to the combined stress of PO2 and temperature, showing that stressful treatments resulted in higher mortality and induced transcripts that were associated with protein kinases, catabolic processes (proteases, hydrolases, peptidases) and membrane function. Several genes and pathways that may be responsible for the protective effects of combined PO2 and cold treatments were identified. We found that urate oxidase was upregulated in all three cold treatments, regardless of the PO2. Small heat shock proteins Hsp22 and Hsp23 were upregulated after both 10 and 21kPa O2-hot treatments. Collectively, the data from PO2-hot treatments suggests that hypoxia does exacerbate heat stress, through an as yet unidentified mechanism. Hsp70B and an unannotated transcript (CG6733) were significantly differentially expressed after 5kPa O2-cold and 10kPa O2-hot treatments relative to their controls. Downregulation of these transcripts was correlated with reduced thermal tolerance (longer CCRT and shorter HKDT), suggesting that these genes may be important candidates for future research.


Rheb1 promotes tumor progression through mTORC1 in MLL-AF9-initiated murine acute myeloid leukemia.
The constitutive hyper-activation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathways has frequently been associated with acute myeloid leukemia (AML). While many inhibitors targeting these pathways have been developed, the anti-leukemic effect was not as robust as expected. As part of the molecular link between PI3K/Akt and mTOR kinase, the role of Rheb1 in AML remains unexplored. Our study aims to explore the role of Rheb1 in AML and estimate whether Rheb1 could be a potential target of AML treatment. The expressions of Rheb1 and other indicated genes were analyzed using real-time PCR. AML mouse model was established by retrovirus transduction. Leukemia cell properties and related signaling pathways were dissected by in vitro and in vivo studies. The transcriptional changes were analyzed via gene chip analysis. Molecular reagents including mTOR inhibitor and mTOR activator were used to evaluate the function of related signaling pathway in the mouse model. We observed that Rheb1 is overexpressed in AML patients and the change of Rheb1 level in AML patients is associated with their median survival. Using a Rheb1-deficient MLL-AF9 murine AML model, we revealed that Rheb1 deletion prolonged the survival of AML mice by weakening LSC function. In addition, Rheb1 deletion arrested cell cycle progression and enhanced apoptosis of AML cells. Furthermore, while Rheb1 deletion reduced mTORC1 activity in AML cells, additional rapamycin treatment further decreased mTORC1 activity and increased the apoptosis of Rheb1 (Δ/Δ) AML cells. The mTOR activator 3BDO partially rescued mTORC1 signaling and inhibited apoptosis in Rheb1 (Δ/Δ) AML cells. Our data suggest that Rheb1 promotes AML progression through mTORC1 signaling pathway and combinational drug treatments targeting Rheb1 and mTOR might have a better therapeutic effect on leukemia.


(-)-Epigallocatechin-3-gallate promotes pro-matrix metalloproteinase-7 production via activation of the JNK1/2 pathway in HT-29 human colorectal cancer cells.
Matrix metalloproteinase (MMP)-7 (matrilysin-1) plays significant roles in the growth, invasion, and metastasis of colorectal tumors, while (-)-epigallocatechin-3-gallate (EGCG), a green tea polyphenol with chemopreventive properties, has been shown to be an inhibitor of MMP-2 and MMP-9. In the present study, HT-29 human colorectal cancer cells were treated with EGCG to examine its effects on pro-MMP-7 induction and production using RT-PCR and western blot analyses. Surprisingly, EGCG (10-100 microM) treatment increased both intracellular and extracellular pro-MMP-7 protein levels (2.6-8.4-fold and 1.9-6.4-fold, respectively) in dose- and time-dependent manner, with a significant upregulation of its mRNA expression. EGCG also activated extracellular signal-regulated protein kinase (ERK)1/2, c-JUN NH2-terminal kinase (JNK)1/2 and p38 mitogen-activated protein kinase (MAPK), as previously reported. In addition, the polyphenol triggered the phosphorylation of c-JUN (Ser63 and Ser73) and induced c-JUN/c-FOS, thereby increasing the DNA binding activity of activator protein-1 (AP-1), as shown by an AP-1 luciferase reporter assay. Pharmacological blockade of MAPK activities suggested that pro-MMP-7 expression was induced via JNK1/2 activation, but not in the case of ERK1/2 or p38 MAPK. N-Acetyl-L-cysteine, superoxide (O2-) dismutase and catalase attenuated the EGCG-induced pro-MMP-7 production, suggesting an involvement of oxidative stress in these events. Conversely, EGCG spontaneously generated O2- in a cell-free system that utilized a cytochrome C reduction method. Further, (-)-epicatechin-3-gallate (25 and 100 microM) and green tea polyphenols (33 and 132 microg/ml) induced pro-MMP-7 expression, whereas (-)-epicatechin and (-)-epigallocatechin (100 microM each) did not. Induction of pro-MMP-7 expression by EGCG was also shown in another human colorectal adenocarcinoma cell line, Caco-2. Our results suggest that some green tea catechins induce pro-MMP-7 production via O2- production and the activation of JNK1/2, c-JUN, c-FOS and AP-1 in HT-29 cells.


Recent changes in the incidence in all types of drug dependence in Great Britain.
Dr T H Bewley discusses recent increases in the incidence of all types of drug dependence in Great Britain.Dr P H Connell considers the problem of amphetamine dependence historically and in different age groups and draws attention to the sociocultural patterns of behaviour which have sprung up amongst the adolescent and young adult population. Treatment is discussed.Dr R H V Ollendorff outlines a theory of drug addiction based upon seven aetiological factors, and stresses the importance of the general practitioner in treating the addict.


Short article: Impact of genetic variation in the vasopressin 1a receptor on the development of organ failure in patients admitted for acute decompensation of liver cirrhosis.
Vasopressin receptor-mediated vasoconstriction is considered to be involved in the pathogenesis of organ failure in acute-on-chronic liver failure (ACLF). We studied the association between six single nucleotide polymorphisms (SNPs) of the vasopressin 1a receptor gene and the development of organ failure in 826 patients admitted for acute decompensation of liver cirrhosis (n=641) or ACLF (n=185). No associations were found for SNPs with the presence of circulatory or renal failure. A C>T mutation in SNP rs7308855 and a T>A mutation in SNP rs7298346 showed an association with the presence of coagulation failure in the entire population (n=61, P=0.024 and 0.060, respectively) and in the subgroup of patients with ACLF (n=44, P=0.081 and 0.056, respectively). Genetic variation in the vasopressin 1a receptor was found not to be associated with circulatory or renal failure, but with the presence of coagulation failure in patients with acute decompensation of liver cirrhosis and ACLF.