Machine learning of pair-contact process with diffusion.
The pair-contact process with diffusion (PCPD), a generalized model of the ordinary pair-contact process (PCP) without diffusion, exhibits a continuous absorbing phase transition. Unlike the PCP, whose nature of phase transition is clearly classified into the directed percolation (DP) universality class, the model of PCPD has been controversially discussed since its infancy. To our best knowledge, there is so far no consensus on whether the phase transition of the PCPD falls into the unknown university classes or else conveys a new kind of non-equilibrium phase transition. In this paper, both unsupervised and supervised learning are employed to study the PCPD with scrutiny. Firstly, two unsupervised learning methods, principal component analysis (PCA) and autoencoder, are taken. Our results show that both methods can cluster the original configurations of the model and provide reasonable estimates of thresholds. Therefore, no matter whether the non-equilibrium lattice model is a random process of unitary (for instance the DP) or binary (for instance the PCP), or whether it contains the diffusion motion of particles, unsupervised learning can capture the essential, hidden information. Beyond that, supervised learning is also applied to learning the PCPD at different diffusion rates. We proposed a more accurate numerical method to determine the spatial correlation exponent [Formula: see text], which, to a large degree, avoids the uncertainty of data collapses through naked eyes.


8β-OH-THC and 8β,11-diOH-THC-minor metabolites with major informative value?
The ∆9-tetrahydrocannabinol (THC) metabolites 8β-hydroxy-THC and 8β,11-dihydroxy-THC are mentioned in the literature as potential blood markers of recent cannabis use. However, the formation of these metabolites in in vivo detectable concentrations has been described controversially. Therefore, the aim of this study was to verify the in vivo metabolism of 8β-hydroxy-THC and 8β,11-dihydroxy-THC in order to evaluate their potential as blood markers of recent cannabis use. First, we developed and validated a solid-phase-extraction method coupled with gas chromatography-mass spectrometry in order to enable the selective and very sensitive determination of 8β-hydroxy-THC and 8β,11-dihydroxy-THC. The application of this method in the analysis of 70 authentic plasma samples of cannabis users revealed positive results for both analytes. We detected 8β-hydroxy-THC in three and 8β,11-dihydroxy-THC in 37 out of the 70 analyzed samples. For 8β-hydroxy-THC, all of the three positive results were below the limit of quantification (LOQ; 0.3 ng/mL) but above the limit of detection (LOD; 0.2 ng/mL). For 8β,11-dihydroxy-THC, only two positive results were below the LOQ (0.4 ng/mL) but above the LOD (0.3 ng/mL); the remaining 35 were quantified. Hence, we were able to prove the in vivo metabolism from THC to both 8β-hydroxy-THC and 8β,11-dihydroxy-THC in detectable concentrations. The quantitative comparison of 8β-hydroxy-THC and 8β,11-dihydroxy-THC with the main cannabinoids THC, 11-hydroxy-THC, and 11-nor-9-carboxy-THC revealed no further informative value for 8β-hydroxy-THC regarding the last time of cannabis consumption. However, the detectability from 8β,11-dihydroxy-THC compared to 11-hydroxy-THC suggests a shorter detection time for 8β,11-dihydroxy-THC and thereby a promising application of this metabolite as a blood marker of recent cannabis use.


Production of citrinin by Penicillium citrinum in different liquid media.
Citrinin production by Penicillium citrinum NRRL 5907 and NRRL 1842 on liquid media was investigated. Maximum yields of pure citrinin (1.7 g./1.) were produced by P. citrinum NRRL 5907 growing on 2% yeast extract and 5% sucrose.


Efficacy and safety of abiraterone and enzalutamide for castration-resistant prostate cancer: A systematic review and meta-analysis of randomized controlled trials.
Previous evidence directly evaluating the efficacy and safety of abiraterone and enzalutamide treatment for castration-resistant prostate cancer (CRPC) is limited. We aim to include more randomized controlled trials (RCTs) to comprehensively assess the efficacy and safety of abiraterone and enzalutamide treatment. PubMed, Embase, and ClinicalTrial.gov were systematically searched. Pooled hazard ratios (HRs) were calculated using Stata 12.0 software. The comparison of the prostate-specific antigen (PSA) response rate and adverse events (AEs) between the treatment and control groups were performed using RevMan 5.3 software. Eight eligible RCTs with 6,490 patients were selected. Pooled HRs were 0.72 for overall survival, 0.45 for radiographic progression-free survival (rPFS), and 0.36 for PSA PFS. abiraterone and enzalutamide could significantly increase the PSA response rate OR = 8.67, 95%CI 4.42-17.04) and any AE occurrence (OR = 1.98, 95%CI 1.46-2.68). The treatment group had more occurrence of fatigue (OR = 1.34, 95%CI 1.20-1.49), back pain (OR = 1.15, 95%CI 1.01-1.15), hot flush (OR = 1.76, 95%CI 1.50-2.06), diarrhea (OR=1.22, 95%CI 1.07-2.40) and arthralgia (OR = 1.34, 95%CI 1.16-1.54). Particularly, AEs of special interest including any grade hypertension (OR = 2.06, 95%CI 1.71-2.47), hypokalemia (OR = 1.80, 95%CI 1.42-2.30) and fluid retention or edema (OR = 1.38, 95%CI 1.17-1.63) also occurred less in the control group. Moreover, a higher incidence of high-grade hypertension (OR = 2.60, 95%CI 1.79-3.79) and extremity pain (OR = 4.46, 95%CI 2.81-7.07) was observed in the treatment group. The survival benefits of abiraterone and enzalutamide for CRPC were evident and promising, while the risk of AE occurrence was also acceptably higher in the treatment group than in the placebo group.


Where the eyes wander: The relationship between mind wandering and fixation allocation to visually salient and semantically informative static scene content.
Vision is crucial for many everyday activities, but the mind is not always focused on what the eyes see. Mind wandering occurs frequently and is associated with attenuated visual and cognitive processing of external information. Corresponding changes in gaze behavior-namely, fewer, longer, and more dispersed fixations-suggest a shift in how the visual system samples external information. Using three computational models of visual salience and two innovative approaches for measuring semantic informativeness, the current work assessed whether these changes reflect how the visual system prioritizes visually salient and semantically informative scene content, two major determinants in most theoretical frameworks and computational models of gaze control. Findings showed that, in a static scene viewing task, fixations were allocated to scene content that was more visually salient 10 seconds prior to probe-caught, self-reported mind wandering compared to self-reported attentive viewing. The relationship between mind wandering and semantic content was more equivocal, with weaker evidence that fixations are more likely to fall on locally informative scene regions. This indicates that the visual system is still able to discriminate visually salient and semantically informative scene content during mind wandering and may fixate on such information more frequently than during attentive viewing. Theoretical implications are discussed in light of these findings.


Rapid effects of melatonin on hormonal and behavioral stressful responses in ewes.
Sheep are gregarious mammals with complex social interactions. As such, they are very sensitive to social isolation and constitute a relevant animal model to study specifically the biological consequences of social stress. We examined previously the behavioral and endocrine responses in ewes isolated socially in the familiar conspecific withdrawal model (FCW) and showed that stressful responses increased and maintenance behaviors decreased, confirming that social isolation is a strong stressor in sheep. Melatonin synchronizes seasonal and circadian rhythms; and several studies reported its implication in cognitive processes as emotion. Here we investigated its role in the modulation of social stressful responses. Firstly, we studied ewes in the FCW model during the day (characterized by low melatonin levels) and the night (characterized by high melatonin levels). We found lower stressful responses (significant lower levels of cortisol plasma, number of foot pawings, of circling attempts) during the night as compared to the day. To investigate whether these effects were due to melatonin or to darkness, we submitted ewes to FCW during the night with lights on, a condition that suppresses melatonin secretion. Ewes infused with melatonin under these conditions showed decreased stressful responses (significant lower levels cortisol plasma, number of vocalizations, time spent with the head out of the cage) as compared to ewes infused with saline. These findings demonstrate that melatonin diminishes the endocrine and behavioral impact of social isolation in ewes and support the idea that melatonin has a calming effect in socially stressful situations.


Bio-Conductive Polymers for Treating Myocardial Conductive Defects: Long-Term Efficacy Study.
Following myocardial infarction (MI), the resulting fibrotic scar is nonconductive and leads to ventricular dysfunction via electrical uncoupling of the remaining viable cardiomyocytes. The uneven conductive properties between normal myocardium and scar tissue result in arrhythmia, yielding sudden cardiac death/heart failure. A conductive biopolymer, poly-3-amino-4-methoxybenzoic acid-gelatin (PAMB-G), is able to resynchronize myocardial contractions in vivo. Intravenous PAMB-G injections into mice show that it does not cause any acute toxicity, up to the maximum tolerated dose (1.6 mL kg-1 ), which includes the determined therapeutic dose (0.4 mL kg-1 ). There is also no short- or long-term toxicity when PAMB-G is injected into the myocardium of MI rats, with no significant changes in body weight, organ-brain ratio, hematologic, and histological parameters for up to 12 months post-injection. At the therapeutic dose, PAMB-G restores electrical conduction in infarcted rat hearts, resulting in lowered arrhythmia susceptibility and improved cardiac function. PAMB-G is also durable, as mass spectrometry detected the biopolymer for up to 12 months post-injection. PAMB-G did not impact reproductive organ function or offspring characteristics when given intravenously into healthy adult rats. Thus, PAMB-G is a nontoxic, durable, and conductive biomaterial that is able to improve cardiac function for up to 1 year post-implantation.


The anticoagulant, antithrombotic and haemorrhagic effect of long-term warfarin on experimental venous and arterial thrombosis in the rat.
The amount of thrombus formed in one hour, on standard platinum wire in aorta and vena cava of 48 control and 96 warfarin treated rats of both sexes, was measured. Warfarin was given in varying doses (0.1-0.18 mg/kg) for ten consecutive days before operation to enable the coagulation factors to stabilize. Factors II, VII and X levels as well as prothrombin time (PT) values were obtained for each animal. Factor levels and PT ratio were related to reduction in arterial and venous thrombus weight. The relation between reduction in thrombus weight and depletion in coagulation factor levels was best for factor II and fairly good for factor X at all levels of anticoagulation. All animals which were haemorrhagic had factor II levels of below 15%, with a mean of 8%. At low warfarin dosage a significant reduction of thrombus (> 30%) went undetected by any test, but was least frequently undetected by factor II and most frequently undetected by PT. All rats with diminished thrombus had at least one factor depleted. Haemorrhagic animals were found with any PT ratio in excess of unity. Factor II reflected antithrombotic and haemorrhagic effects of warfarin much better than factors X, VII, or PT.


Robot-assisted-radical-cystectomy with total intracorporeal Y neobladder: Analysis of postoperative complications and functional outcomes with urodynamics findings.
To describe our robotic Y intracorporeal neobladder (ICNB) technique and to report its post-operative complications and urodynamics (UD) findings. and Methods: In this prospective study we enrolled patients affected by MIBC (T1-T4N0-N1M0) from 01/2017 to 06/2021 at our Centers. All the patients underwent robotic radical cystectomy (RARC) with Y-ICNB reconfiguration. Early and late complications were collected and classified according to Clavien-Dindo. Continence and potency at 1, 3, 6 and 12 months were evaluated. At the 3rd month of follow-up patients underwent UD. Finally, in a retrospective match paired analysis the functional outcomes of Y RARC patients were compared with a cohort of open Y radical cystectomy. 45 patients were enrolled. Overall 30-day complications were observed in 25 (55,5%) patients and 30 to 90-days complications in 4 (8,9%). 9 patients (20%) had Clavien ≥3 complications. UDs revealed median neobladder capacity of 268 cc, with a median compliance of 13 ml/cm H20; the voiding phase showed a voiding volume and a post void residual (PVR) of 154 cc and 105 cc respectively. At 12 months of follow-up 4.4%, 15.5% and 4.4% of the patients experienced urge, stress and mix urinary incontinence respectively. The comparison between Y RARC and Y open RC revealed a higher neobladder capacity with open approach (p = 0.049) with subsequent better findings during the voiding phase in terms of maximum flow (p = 0.002), voiding volume (p = 0.001) and PVR (p = 0.01). Focusing on continence recovery, a slight trend in favor of RARC was shown without reaching the statistical significance. Robotic Y-ICNB is feasible and safe as shown by the low rate of postoperative complications. Satisfying UD functional outcomes are achievable, both during filling and voiding phase.


Decahydroisoquinolines: novel competitive AMPA/kainate antagonists with neuroprotective effects in global cerebral ischaemia.
In the present studies, we have evaluated the activity of a series of glutamate receptor antagonists from the decahydroisoquinoline group of compounds both in vitro and in vivo. Compound activity at alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainate receptors was assessed using ligand binding to cloned iGluR2 and iGluR5 receptors and on responses evoked by AMPA and N-methyl-D-aspartate (NMDA) in the cortical wedge preparation. In vivo, compounds were examined for antagonist activity electrophysiologically in the rat spinal cord preparation and in the gerbil model of global cerebral ischaemia. Compounds tested were LY293558, which has been shown to protect in models of focal cerebral ischaemia, LY202157 (an NMDA antagonist), LY246492 (an NMDA and AMPA receptor antagonist), LY302679, LY292025, LY307190, LY280263, LY289178, LY289525, LY294486 (AMPA/kainate antagonists) and LY382884 (an iGluR5 selective antagonist). Results obtained support a role for AMPA receptors in cerebral ischemia. LY377770 (a mixed AMPA/iGluR5 antagonist and active isomer of LY294486) demonstrated good neuroprotection with a 2-h time window and may therefore be useful in the treatment of ischaemic conditions.


[Epithelial childhood liver tumors : An overview of the new WHO classification for pediatric tumors].
Pediatric liver tumors are very rare tumors and account for less than 1% of all childhood malignancies. By far the most common tumors are hepatoblastomas. This review discusses epithelial malignant childhood liver tumors, with particular attention to the morphology of the different hepatoblastoma subtypes. In addition, other malignant liver tumors such as the so-called hepatocellular tumor NOS and the second-most common childhood liver tumor, the hepatocellular carcinoma, are discussed. In addition to the typical morphological characteristics, the immunohistochemical and molecular aspects are also be presented, which can help to distinguish these entities with often overlapping morphology.


Trauma burden, patient demographics and care-process in major hospitals in Tanzania: A needs assessment for improving healthcare resource management.
Appropriate referrals of injured patients could improve clinical outcomes and management of healthcare resources. To gain insights for system development, we interrogated the current situation by assessing burden, patient demography, causes of injury, trauma mortality and the care-process. We used an observational, cross-sectional study design and convenience sampling to review patient charts from 3 major hospitals and the death registry in Tanzania. Injury constitutes 9-13% of the Emergency Centre census. Inpatient trauma-deaths were 8%; however, the trauma death registry figures exceeded the 'inpatient deaths' and recorded up to 16%. Most patients arrive through a hospital referral system (82%) and use a hospital transport network (76%). Only 8% of the trauma admissions possessed National Health Insurance. Road traffic collision (RTC) (69%), assault (20%) and falls (9%) were the leading causes of injury. The care process revealed a normal primary-survey rate of 73-90%. Deficiencies in recording were in the assessment of: Airway and breathing (67%), circulation (40%) and disability (80%). Most patients had non-operative management (42-57%) or surgery for wound care or skeletal injuries (43%). Laparotomies were performed in 26%, while craniotomy and chest drain-insertion were each performed in 10%. The burden of trauma is high, and the leading causes are: RTC, assault, and falls. Deaths recorded in the death registries outweigh in-hospital deaths for up to twofold. There are challenges in the care process, funding and recording. We found a functional hospital referral-network, transport system, and death registry.


Earmarking and the political support of fat taxes.
An unhealthy good causes health issues in the long run. It creates a misperceived utility loss and increases health care costs. Conversely, a healthy good provides misperceived utility gains and reduces health care costs. Individuals differ in income and in their degree of misperception; they vote over a fat tax according to their misperceived utility. A fraction of the tax proceeds is "earmarked" to reduce health insurance premiums; the remainder finances a subsidy on the healthy good. This earmarking rule is determined to maximize welfare, anticipating the induced political equilibrium. The equilibrium fat tax is always lower than the utilitarian level. This is not necessarily true with a Rawlsian objective. The determination of the earmarking rule is complex. Even in the utilitarian case, it is not just used to boost political support for the fat tax. Instead, it may involve a tradeoff between fat tax and healthy good subsidy.


Comparison of two immunoassay methods for the determination of alpha-fetoprotein in amniotic fluid.
We compared two immunoassay methods for determination of alpha-fetoprotein in amniotic fluid. The two methods showed a very good correlation and this is further confirmed by the clinical study. The electroimmunoassay (rocket immunoelectrophoresis) seems suitable for a small laboratory, whereas radioimmunoassay may be a better choice for a large laboratory.


Posterior fossa measurements. II. Size of the posterior fossa in myelomeningocele.
In seven myelomeningocele patients, six were operated upon while in one severe case no surgery was performed. The posterior fossa areas were measured and expressed by the posterior fossa ratio method. In two shunted patients both ratios were primarily below the lowest normal limit, but following shunt operation the ratios become normal. In five patients who were not shunted one only showed a normal ratio, two showed borderline values and in a fourth instance the ratio normalized but before two years had passed. The fifth case remained unoperated and therefore the natural course could be followed. In this case the decrease in the posterior fossa ratio explained the progress of hydrocephalus.


Safe Thinking and Affect Regulation (STAR): human immunodeficiency virus prevention in alternative/therapeutic schools.
To evaluate the effectiveness of Safe Thinking and Affect Regulation (STAR), a 14-session HIV-prevention program for adolescents at alternative/therapeutic schools. Because these youth frequently have difficulties with emotions and cognitions, it was designed to improve sexuality-specific affect management and cognitive monitoring, as well as HIV-related knowledge and attitudes. It was hypothesized that STAR would lead to a decrease in sexual risk and improved HIV knowledge and attitudes. Fourteen schools were randomly assigned by year either to the STAR intervention or a brief educational program. Schools received the alternate intervention the following year. A total of 185 adolescents in 29 cohorts (groups) participated in the interventions. Assessment of sexual behavior, knowledge and attitudes with audio computer-assisted self-interviews occurred at 3, 6, and 9 months post intervention. Hierarchical linear model (HLM) analyses found that adolescents in the STAR intervention reported a significantly greater decrease (p < .05) in the Sexual Risk Index than youth in the control group over the 6 months post intervention and similar improvements in the HIV Knowledge Scale and the Condom Use Self Efficacy Scale. There were no group differences between 6 and 9 months post intervention. This STAR intervention for youth in alternative schools was associated with decreased sexual risk for 6 months after the intervention. These data suggest that intervention strategies that target cognitions and affect within a sexual context might be usefully applied to improving sexual behavior but may need to be reinforced over time. Clinical trial registration information--HIV, Abuse, and Psychiatric Disorders Among Youth; http://clinicaltrials.gov; NCT00603369.


Topical versus retrobulbar anesthesia for combined phacotrabeculectomy: prospective randomized study.
To compare the safety and efficacy of topical and retrobulbar anesthesia for combined phacotrabeculectomy. Tertiary-care university hospital ambulatory surgical center. In this prospective study, 40 consecutive patients having combined phacotrabeculectomy were randomized to receive topical (n = 20) or retrobulbar (n = 20) anesthesia. Operating conditions, patient comfort, and surgical outcome were evaluated. There was no significant between-group difference in operating conditions (P =.56), pain during (P =.41) or after (P =.23) surgery, or supplemental anesthesia required (P =.49). Few patients in either group were bothered by tissue manipulation or the microscope light, although more patients in the topical group were slightly bothered by touch sensation (P =.05). Chemosis, subconjunctival hemorrhage, and eyelid hematoma were seen almost exclusively in the retrobulbar group (P <.05). Inadvertent eye movement was present more frequently in the topical group (P =.04), although this did not pose a problem to the surgeon. Topical anesthesia is a safe and effective alternative to retrobulbar anesthesia for combined phacotrabeculectomy.


Synthesis of a polymer-supported anthracene and its application as a dienophile scavenger.
A polymer-supported anthracene has been prepared and employed as a dienophile scavenger in Diels-Alder cycloadditions. [structure: see text]


Lesions of the preoptic area facilitate lordosis behavior in male and female guinea pigs.
Male and female guinea pigs received radiofrequency lesions in the medial preoptic area (MPOA). Animals were gonadectomized, treated with estrogen and progesterone, and tested for the occurrence of the lordosis response to manual stimulation. Females with MPOA lesions exhibited enhanced lordosis behavior, shorter latencies to heat, longer duration of heat and longer maximum lordosis duration than sham control females. In males with MPOA lesions, the lordosis response could be elicited by manual stimulation, in contrast to no response in the sham control males. Furthermore, MPOA-lesioned males were insensitive to the inhibitory effects of progesterone on lordosis behavior, while MPOA-lesioned females were as sensitive as sham controls to the inhibitory effects of progesterone. The results suggest that a neural mechanism resides within the MPOA which inhibits the occurrence of lordosis behavior in both male and female guinea pigs and which is not involved in a sexual dimorphism in responsiveness to progesterone.


Factors influencing physiotherapists implementation of high value care in the management of nonspecific low back pain in Indian healthcare settings: A qualitative study.
Non-specific low back pain is a common musculoskeletal condition that often requires the involvement of physiotherapists for effective management. However, there is limited understanding of the factors influencing physiotherapists' implementation of high-value care in the management of non-specific low back pain (NSLBP), particularly in Indian healthcare settings. The aim of this study was to explore the barriers and facilitators of implementation of high-value care in managing NSLBP from the perspective of physiotherapists practicing in Indian healthcare settings. Descriptive qualitative design. We adopted a descriptive phenomenological approach and purposefully selected physiotherapists (N = 15) from diverse healthcare settings, encompassing varying years of clinical experience, to capture a broad range of perspectives. Semi-structured face-to-face interviews were conducted via the Zoom video conferencing platform. Each interview lasted on average for 30-45 min, and no follow-up interviews were conducted. Data were analyzed using thematic analysis with an inductive approach. Our analysis revealed three major themes and seven sub-themes uncovering barriers and facilitators of implementation of high-value care. These themes include misconceptions about low back pain and its management among physiotherapists, their perceived lack of autonomy in clinical decision-making due to external influences, and the significance of aligning treatment plans with patient goals while considering evidence-based care. The study results provide insights into the unique challenges associated with implementation of high-value care for non-specific low back pain in Indian healthcare settings.


Tumourigenic phenotypes of human melanoma cell lines in nude mice determined by an active antitumour mechanism.
Ten human melanoma cell lines (HMCL) were tested for their ability to grow subcutaneously in nude mice. Using a standard inoculum, the HMCL could be characterized by their highly, fairly or poorly xenografting phenotype. These phenotypes were stable and the phenotype of one HMCL was recovered within cell clones derived from it. The role of nude mice natural defences in the expression of HMCL xenografting phenotypes was studied. Sublethal whole body irradiation and silica pretreatment of recipients enabled poorly tumourigenic HMCL to grow in most animals without affecting their splenic NK activity. Admixture of BCG or MDP encapsulated in liposomes with highly tumourigenic HMCL resulted in the abrogation of tumour growth in naive nude mice. The long lasting abrogating of NK activity in vivo by treatment with anti-asialo-GM1 anti-serum did not enhance the growth of a poorly tumourigenic HMCL. The HMCL were found to be resistant to in vitro murine NK activity. These results showed that the expression of the HMCL xenografting phenotypes could be controlled by the nude mice natural defences. NK cells did not seem to be largely involved whereas macrophages might be good candidates as anti-xenograft effectors.


Effects of prostaglandins on spontaneous apoptosis in gastric mucosal cells.
Prostaglandins have cytoprotective effects on gastric mucosa via the influence of various mechanisms. The purpose of this study is to examine the effects of prostaglandins on maturation-dependent spontaneous apoptosis in gastric mucosal cells in vitro, which mimics the apoptosis of gastric mucosal cells related with a rapid cell turnover rate in vivo. Both prostaglandin E1 and E2 inhibited spontaneous apoptosis in a dose-dependent manner and increased the viability of gastric mucosal cells in culture. A number of antiulcer drugs presently in clinical use were shown to increase the concentrations of prostaglandins in cells. All of the drugs tested clearly inhibited the spontaneous apoptosis in a dose-dependent manner. Based on these results, we propose that the cytoprotective effects of prostaglandins on gastric mucosa in vivo can be partially explained by an increase in the number of gastric mucosal cells present as a result of the inhibition of maturation-dependent spontaneous apoptosis.


Do patients with fibromyalgia have body image and tactile acuity distortion?
The aims of this study were twofold: (1) to compare the body image and tactile acuity of patients with fibromyalgia and asymptomatic participants, and (2) to investigate the effects of an 8-week exercise-based intervention (aerobic or Pilates exercises) on the body image, tactile acuity, and pain intensity in patients with fibromyalgia. A cross-sectional study and a secondary analysis of a randomized controlled trial were carried out, which assessed the following outcomes in 24 patients with fibromyalgia and 24 asymptomatic participants: subjective body image (Drawing Test), tactile acuity (Two-Point Discrimination Test), limb circumference (Cirtometry), and pain (Pain Numerical Rating Scale). After the assessment, the 24 patients with fibromyalgia were randomly allocated to one of the intervention groups: aerobic or Pilates. There was no significant difference in the tactile acuity of the cervical, lumbar, hands, and feet regions between the participants with fibromyalgia and the asymptomatic participants (p > 0.05). However, patients with fibromyalgia showed changes in subjective body image when the drawings were compared to the cirtometry measurements. After the intervention, there was no significant difference between aerobic exercise and Pilates for pain and tactile acuity in the cervical, lumbar, hands, and feet regions of patients with fibromyalgia (p > 0.05). Patients with fibromyalgia presented altered perception in subjective body image but not on tactile acuity, when compared to asymptomatic participants. In addition, there was no difference between aerobic exercise and Pilates for pain and tactile acuity in these patients.


Reversal of aluminum-related bone disease after substituting calcium carbonate for aluminum hydroxide.
Aluminum-related osteodystrophy, a crippling disease in patients with renal failure, can develop from the long-term ingestion of aluminum hydroxide gels. We present a diabetic patient treated with continuous ambulatory peritoneal dialysis (CAPD) who developed markedly elevated plasma aluminum levels but no musculoskeletal symptoms. Bone biopsy revealed features of the aplastic form of aluminum-related disease with significant aluminum staining, decreased osteoblastic osteoid, and decreased bone formation by double tetracycline labeling, but no excess accumulation of unmineralized osteoid. Aluminum hydroxide gels were discontinued and the patient received calcium carbonate to control hyperphosphatemia; 9 months later, a bone biopsy showed marked improvement of the aluminum-related bone disease, and at 2 to 10 months, plasma aluminum had decreased from 208.7 +/- 10.3 (SE) to 55.7 +/- 3.9 micrograms/L.


Autism spectrum disorders.
Autism spectrum disorders are being diagnosed with increasing frequency. The likelihood that a primary care provider will see a patient with autism spectrum disorder in their clinic is high. In this article, current diagnostic criteria and expected changes in DSM criteria, as well as prevalence rates and epidemiologic studies are reviewed. Recommendations for screening, including early warning signs, and best practices for diagnosis are discussed. Comprehensive evidence based intervention for ASD as well as the findings of the National Standards Project are reviewed. Medication management is also described, as are the roles of other treating professionals.


Recombinant factor VIII SQ--stability of VIII: C in homogenates from porcine, monkey and human subcutaneous tissue.
The aim of this paper was to investigate whether a formulation-based approach to understanding and addressing stability could generate a subcutaneous factor VIII preparation for patients as an alternative to the existing intravenous products. The low bioavailability of subcutaneously administered factor VIII could have several causes: proteolytic degradation of the protein in the interstitium; adsorption to tissue, in particular to acidic phospholipids such as L-alpha phosphatidyl-L-serine (phosphatidylserine); the absence of free von Willebrand factor in the interstitium; phagocytosis by macrophages in the interstitium or in the lymph nodes; and coagulation could be initiated upon injection. This study was undertaken to investigate the first three factors in-vitro (i.e., proteolytic degradation, adsorption to tissue and the protective effect of von Willebrand factor). The influence of some other macromolecular stabilisers and protease inhibitors was also investigated. The stability of factor VIII activity (VIII: C) was investigated in homogenates from porcine, monkey and human subcutaneous tissue. Possible coagulation was prevented in these studies by the presence of both citrate and antithrombin. An exploratory in-vivo study was performed in the pig; plasma samples were assayed with a factor VIII:Ag (90kDa) ELISA. The decrease in VIII:C appeared to be more pronounced in homogenates from monkey and human tissues than in porcine homogenate. The results from human tissue homogenate resembled the degradation profile seen in monkey homogenate. Both the von Willebrand factor and phosphatidylserine/phosphatidylcholine (PS/PC) liposomes showed a significant stabilising effect on VIII:C in the tissue homogenates. The qualitative pattern was similar in porcine, monkey and human tissue. A combination of several protease inhibitors seemed to have a protective effect on the stability of VIII: C albeit at high concentrations of inhibitors and the effect was less than that of PS/PC. An exploratory in-vivo study was performed in the pig with phosphatidylserine in two formulations; either in the form of PS/PC liposomes or together with Polysorbate 80 in the form of mixed micelles (phosphatidylserine/P80). Including phosphatidylserine in the formulations appeared to increase the availability, of subcutaneously administered r-VIII SQ in the pig. However, further studies are necessary, preferably in the monkey where in-vitro studies indicate a closer resemblance to the human. In conclusion, a proposed inactivation mechanism for r-VIII SQ in subcutaneous tissue could be adsorption to phospholipid surfaces followed by proteolytic degradation. However, additional studies are required due to the multitude of factors influencing the subcutaneous absorption route. A combination of protease inhibitor(s) together with phosphatidylserine-containing liposomes are suggested for further investigation, preferably in a monkey animal model.


Laminin and other basal lamina proteins with neurite promoting activity in medium conditioned by C6 glioma cells.
Neurite promoting activities (NPFs) are essential factors in neuronal differentiation. Some of them are associated with proteins of the extracellular matrix (ECM). C6 cells, a rat glioma cell line, release NPF activities into the cell culture medium. We used antibodies against ECM-proteins for enrichment and partial characterization of these activities. Results show that, (1) C6 cells express and release laminin; (2) the C6-laminin consists of 260 kD chains only and is therefore different from typical basal lamina laminin (220 and 440 kD chains), but comparable to other laminins of glial origin (chains in the 200 kD range only); (3) C6-laminin partially purified by affinity chromatography shows NPF-activity; (4) laminin concentration in C6 cell-conditioned medium is not sufficient to account for the total neurite promoting activity of the medium, and (5) in addition to laminin C6 cells express and release fibronectin and possibly type IV collagen.


Association between the gut microbiota and diet: Fetal life, early childhood, and further life.
Gut microbiota establishment and further microbiota shifts are very important for maintaining host health throughout life. There are some factors, including genetics, the mother's health and diet, delivery mode, breast or formula feeding, that may influence the gut microbiota. By the end of approximately the first 3 y of life, the gut microbiota becomes an adult-like stable system. Once established, 60 to 70% of the microbiota composition remains stable throughout life, but 30 to 40% can be altered by changes in the diet and other factors such as physical activity, lifestyle, bacterial infections, and antibiotic or surgical treatment. Diet-related factors that influence the gut microbiota in people of all ages are of great interest. Nutrition may have therapeutic success in gut microbiota correction. This review describes current evidence concerning the links between gut microbiota composition and dietary patterns throughout life.


The isolation of human lung mast cells by affinity chromatography.
A method of isolation has been developed to purify mast cells from human lung tissue. The purification steps are: (1) dispersion of human lung tissue in single-cell suspensions by enzymatic digestion, (2) partial purification by counterflow centrifugal elutriation, (3) Percoll gradient centrifugation, and (4) enrichment of the mast cells by affinity chromatography using anti-human IgE-Sepharose. Enzymatic dispersion yielded 0.6 +/- 0.2 x 10(6) mast cells per gram wet tissue with purities of 3.3 +/- 1.0% (mean +/- SEM n = 3). Elutriation and gradient centrifugation yielded 0.36 +/- 0.05 x 10(6) mast cells per gram lung tissue in fractions with purities of 30.8 +/- 10.7%. Enriched mast cell fractions were combined, and disposed of contaminating cells by affinity chromatography, thereby yielding 0.25 +/- 0.03 x 10(6) mast cells per gram lung tissue, and improving the purity to 75.3 +/- 8.3%. The purified mast cells were intact and vitality exceeded 95%. In this way from 1 g wet lung tissue 0.25 +/- 0.03 x 10(6) mast cells may be isolated with a mean recovery of 41.7 +/- 2.4% and a mean purity of 75.3 +/- 8.3%.


Mechanical model of cytoskeleton structuration during cell adhesion and spreading.
The biomechanical behavior of an adherent cell is intimately dependent on its cytoskeleton structure. Several models have been proposed to study this structure taking into account its existing internal forces. However, the structural and geometrical complexities of the cytoskeleton's filamentous networks lead to difficulties for determining a biologically realistic architecture. The objective of this paper is to present a mechanical model, combined with a numerical method, devoted to the form-finding of the cytoskeleton structure (shape and internal forces) when a cell adheres on a substrate. The cell is modeled as a granular medium, using rigid spheres (grains) corresponding to intracellular cross-linking proteins and distant mechanical interactions to reproduce the cytoskeleton filament internal forces. At the initial state (i.e., before adhesion), these interactions are tacit. The adhesion phenomenon is then simulated by considering microtubules growing from the centrosome towards transmembrane integrin-like receptors. The simulated cell shape changes in this process and results in a mechanically equilibrated structure with traction and compression forces, in interaction with the substrate reactions. This leads to a compressive microtubule network and a corresponding tensile actin-filament network. The results provide coherent shape and forces information for developing a mechanical model of the cytoskeleton structure, which can be exploitable in future biomechanical studies of adherent cells.


Comparative analysis of the genome sequences and replication profiles of chikungunya virus isolates within the East, Central and South African (ECSA) lineage.
A comparative analysis of the genomic and replication profiles of different geographical chikungunya virus (CHIKV) isolates of the East, Central and South African (ECSA) lineage was performed. Analysis of the data revealed the different growth kinetics for the different isolates. Deep genome sequencing analysis further revealed specific amino acid mutations in the viral nsP1, nsP3, nsP4, E1 and E2 proteins in the different isolates. Despite the difference in viral genomic profiles, the virus-induced ultrastructural changes within infected cells remained highly conserved among the different chikungunya virus isolates. These findings provide insights into the genomic and replication profiles of the re-emerging chikungunya virus isolates of the ECSA lineage.


Endoluminal Management of Infra-renal Aortic and Aorto-iliac Aneurysms.
This paper reviews the development of endovascular aneurysm repair (EVAR) of infra-renal aortic and iliac artery aneurysms and considers the current status and best treatment options. The vast majority of devices are bifurcated and exclude the aneurysm utilizing the same techniques for fixation and seal. The modern EVAR procedure is usually performed in a hybrid operating theatre, utilizing image fusion and other radiation-reducing techniques and using optimized procedural techniques, including percutaneous access. The best outcomes are achieved in patients whose anatomy is within device "instructions for use", but these are most commonly breached due to "hostile" neck anatomy. Endovascular options for these cases include the use of fenestrated endografts, chimney grafts and endoanchors. Concomitant iliac artery aneurysms often occur with abdominal aortic aneurysms, and endovascular options include limb extensions with internal iliac embolization as well as iliac branch devices. The durability of EVAR has recently been called into question by long-term results from early EVAR randomized trial. Findings such as infra-renal neck dilatation and aneurysm sac expansion are relatively common and associated with adverse outcomes. This durability concern mandates regular and long-term imaging and clinical surveillance. It also indicates that EVAR technology is not fully evolved with a need for further development to improve patient applicability and long-term durability.


Responses of assemblages of Orthoptera to management and use of ski slopes on upper sub-alpine meadows in the Austrian Alps.
The Orthoptera assemblages occurring on sub-alpine ski slopes were compared with those found on neighbouring unskied meadows by making frequent transect counts at two pairs of sites in the Gastein valley in the Austrian Central Alps. On one of the ski slopes no Orthoptera were present, although two species were abundant on the control meadow a few meters away. On the second ski slope, the Orthoptera assemblage exhibited reduced species richness, lower densities of individuals and a generally accelerated rate of nymphal development compared to the control meadow populations. These results may be explained in terms of the changed habitat conditions on the ski slopes and the known biologies of the species concerned. The implications of the findings for winter tourism management in high altitude ecosystems are briefly discussed.


Results of a Prospective Dose Escalation Study of Linear Accelerator-Based Virtual Brachytherapy (BOOSTER) for Prostate Cancer; Virtual HDR Brachytherapy for Prostate Cancer.
To demonstrate feasibility and toxicity of linear accelerator-based stereotactic radiation therapy boost (SBRT) for prostate cancer, mimicking a high-dose-rate brachytherapy boost. A phase 1 sequential dose escalation study of SBRT compared 20 Gy, 22 Gy, and 24 Gy to the prostate and 25 Gy, 27.5 Gy, and 30 Gy to the gross tumor volume in 2 fractions, combined with 46 Gy in 23 fractions of external beam radiation. Feasibility of dose escalation (volume receiving 125% and 150% of the dose) while meeting organ-at-risk dose constraints, grade 2 acute and late gastrointestinal and genitourinary toxicity, and freedom from biochemical failure were secondary endpoints. Thirty-six men with intermediate- and high-risk prostate cancer were enrolled with a median follow-up of 24 months. Sixty-four percent of patients had high-risk features. Nine men were enrolled to dose level 1, 6 to level 2, and 6 to level 3. Another 15 patients were treated at dose level 3 on the continuation study. Dose level 3 achieved superior 125% (23.75 Gy) and 150% (28.5 Gy) dose compared to dose levels 1 and 2, with minimal differences in organ-at-risk doses. Kaplan-Meier estimate of freedom from biochemical failure at 3 years was 93.3%. There were no late grade 2 or 3 gastrointestinal events. The late grade 2 genitourinary toxicity at 2 years was 19.3%. Prostate-specific membrane antigen positron emission tomography was performed at 2 years with no local recurrences. We have shown that a linear accelerator-based SBRT boost for prostate cancer is feasible and can achieve doses comparable to high-dose-rate boost up to the 150% isodose volumes. Rectal, bladder, and urethral doses remained low, and long-term toxicity was the same as or better than previous reports from high-dose-rate or low-dose-rate boost protocols.


Versatile human in vitro triple coculture model coincubated with adhered gut microbes reproducibly mimics pro-inflammatory host-microbe interactions in the colon.
The colonic epithelial barrier is vital to preserve gut and host health by maintaining the immune homeostasis between host and microbes. The mechanisms underlying beneficial or harmful host-microbe interactions are poorly understood and impossible to study in vivo given the limited accessibility and ethical constraints. Moreover, existing in vitro models lack the required cellular complexity for the routine, yet profound, analysis of the intricate interplay between different types of host and microbial cells. We developed and characterized a broadly applicable, easy-to-handle in vitro triple coculture model that combines chemically-induced macrophage-like, goblet and epithelial cells covered by a mucus layer, which can be coincubated with complex human-derived gut microbiota samples for 16 h. Comparison with a standard epithelial monolayer model revealed that triple cocultures produce thicker mucus layers, morphologically organize in a network and upon exposure to human-derived gut microbiota samples, respond via pro-inflammatory cytokine production. Both model systems, however, were not suffering from cytotoxic stress or different microbial loads, indicating that the obtained endpoints were caused by the imposed conditions. Addition of the probiotic Lactobacillus rhamnosus GG to assess its immunomodulating capacity in the triple coculture slightly suppressed pro-inflammatory cytokine responses, based on transcriptomic microarray analyses. TNF conditioning of the models prior to microbial exposure did not cause shifts in cytokines, suggesting a strong epithelial barrier in which TNF did not reach the basolateral side. To conclude, the triple coculture model is tolerable towards manipulations and allows to address mechanistic host-microbe research questions in a stable in vitro environment.


Aldehyde Dehydrogenase: An Off-Label Marker of Endothelial Activation in Oral Squamous Cell Carcinoma.
The vascular endothelial (VE) expression of aldehyde dehydrogenase (ALDH) 1/2 family in oral leukoplakia (OL) and oral squamous cell carcinoma (OSCC) cases has not been studied so far. The aim of this study was to illustrate the "off-label" endothelial expression of cancer stem cell (CSC) biomarker, ALDH1/2, adjacent to oral potentially malignant and malignant lesions in order to shed some light on the mechanisms leading to oral carcinogenesis. Materials and methods: The expression of CSC protein-biomarker ALDH1/2 was detected through immunohistochemistry (IHC) in 30 paraffin-embedded samples of OL and 21 samples of OSCC compared to five samples of normal oral mucosa. Statistical analysis was done using SPSS, Pearson Chi-square, and Fischer's exact test. The significance level was set at 0.05 (p≤ 0.05). Results: In oral mucosal vessels, ALDH1/2 was not expressed. It was expressed significantly more in the vessels of OSCCs compared to the OLs (Fisher's exact test, p-value= 0,001). However, when endothelial expression of ALDH1/2 in the vasculature of OLs was compared with that of the normal oral mucosa, no significant change was noticed (Fisher's exact test, p-value=1.000). Discussion: The IHC VE expression of ALDH1/2 in OSCC vasculature but not in OL indicates a possible significantly stronger activation of endothelial cells during carcinogenesis, which could be an indicator of the role of inflammation in the development of field cancerization and of prognostic value for (vascular/lymphatic) metastasis.


[The "paired cards" system. A practical and generally applicable procedure for the clinical trial of drugs (author's transl)].
A system is described which is suitable for the simulataneous double-blind study of several drugs effective in the same field of indication (e.g. analgesics). The procedure uses sequential analysis and therefore requires only limited materials, costs and personnel. It produces significant results with a minimum of patients.


MicroScale Thermophoresis: A Rapid and Precise Method to Quantify Protein-Nucleic Acid Interactions in Solution.
Interactions between nucleic acids and proteins are driving gene expression programs and regulating the development of organisms. The binding affinities of transcription factors to their target sites are essential parameters to reveal their binding site occupancy and function in vivo. Microscale Thermophoresis (MST) is a rapid and precise method allowing for quantitative analysis of molecular interactions in solution on a microliter scale. The technique is based on the movement of molecules in temperature gradients, which is referred to as thermophoresis, and depends on molecule size, charge, and hydration shell. Since at least one of these parameters is typically affected upon binding of a ligand, the method can be used to analyze any kind of biomolecular interaction. This section provides a detailed protocol describing the analysis of DNA-protein interactions, using the transcription factor TTF-I as a model protein that recognizes a 10 bp long sequence motif.


2-[2-(pyrrolidin-2-yl)propan-2-yl]-1H-pyrrole and its amide derivative 1-{2-[2-(1H-pyrrol-2-yl)propan-2-yl]pyrrolidin-1-yl}ethanone.
In the title compounds, C(11)H(18)N(2), (II), and C(13)H(20)N(2)O, (III), the pyrrolidine rings have twist conformations. Compound (II) crystallizes with two independent molecules (A and B) in the asymmetric unit. The mean planes of the pyrrole and pyrrolidine rings are inclined to one another by 89.99 (11) and 89.35 (10)° in molecules A and B, respectively. In (III), the amide derivative of (II), the same dihedral angle is much smaller, at only 13.42 (10)°. In the crystal structure of (II), the individual molecules are linked via N-H...N hydrogen bonds to form inversion dimers, each with an R(2)(2)(12) graph-set motif. In the crystal structure of (III), the molecules are linked via N-H...O hydrogen bonds to form inversion dimers with an R(2)(2)(16) graph-set motif.


Oxygen concentration affects upper thermal tolerance in a terrestrial vertebrate.
We tested the oxygen limitation hypothesis, which states that animals decline in performance and reach the upper limits of their thermal tolerance when the metabolic demand for oxygen at high temperatures exceeds the circulatory system's ability to supply adequate oxygen, in air-breathing lizards exposed to air with different oxygen concentrations. Lizards exposed to hypoxic air (6% O2) gaped, panted, and lost their righting response at significantly lower temperatures than lizards exposed to normoxic (21% O2) or hyperoxic (35% O2) air. A greater proportion of lizards in the hyperoxic treatment were able to withstand body temperatures above 44°C than in the normoxic treatment. We also found that female lizards had a higher panting threshold than male lizards, while sex had no effect on gaping threshold and loss of righting response. Body size affected the temperature at which lizards lost the righting response, with larger lizards losing the response at lower temperatures than smaller lizards when exposed to hypoxic conditions. These data suggest that oxygen limitation plays a mechanistic role in the thermal tolerance of lizards.


Antisepsis of the skin before spinal surgery with povidone iodine-alcohol followed by chlorhexidine gluconate-alcohol versus povidone iodine-alcohol applied twice for the prevention of contamination of the wound by bacteria: a randomised controlled trial.
The aim of this study was to determine whether the sequential application of povidone iodine-alcohol (PVI) followed by chlorhexidine gluconate-alcohol (CHG) would reduce surgical wound contamination to a greater extent than PVI applied twice in patients undergoing spinal surgery. A single-centre, interventional, two arm, parallel group randomised controlled trial was undertaken, involving 407 patients who underwent elective spinal surgery. For 203 patients, the skin was disinfected before surgery using PVI (10% [w/w (1% w/w available iodine)] in 95% industrial denatured alcohol, povidone iodine; Videne Alcoholic Tincture) twice, and for 204 patients using PVI once followed by CHG (2% [w/v] chlorhexidine gluconate in 70% [v/v] isopropyl alcohol; Chloraprep with tint). The primary outcome measure was contamination of the wound determined by aerobic and anaerobic bacterial growth from samples taken after disinfection. The detection of viable bacteria in any one of the samples taken after disinfection (culture-positive) was significantly lower in the group treated with both PVI and CHG than in the group treated with PVI alone (59 (29.1%) versus 85 (41.7%), p = 0.009; odds ratio 0.574; 95% confidence interval, 0.380 to 0.866). Antisepsis of the skin with the sequential application of PVI and CHG more effectively reduces the contamination of a surgical wound than PVI alone. Cite this article: Bone Joint J 2017;99-B:1354-65.


Impact of anesthesia, sex, and circadian cycle on renal afferent nerve sensitivity.
Elevated renal afferent nerve (ARNA) activity or dysfunctional reno-renal reflexes via altered ARNA sensitivity contribute to hypertension and chronic kidney disease. These nerves contain mechano- and chemosensitive fibers that respond to ischemia, changes in intrarenal pressures, and chemokines. Most studies have utilized various anesthetized preparations and exclusively male animals to characterize ARNA responses. Therefore, this study assessed the impact of anesthesia, sex, and circadian period on ARNA responses and sensitivity. Multifiber ARNA recordings were performed in male and female Sprague-Dawley rats (250-400 g) and compared across decerebrate versus Inactin, isoflurane, and urethane anesthesia groups. Intrarenal artery infusion of capsaicin (0.1-50.0 μM, 0.05 mL) produced concentration-dependent increases in ARNA; however, the ARNA sensitivity was significantly greater in decerebrate versus Inactin, isoflurane, and urethane groups. Increases in renal pelvic pressure (0-30 mmHg, 30 s) produced pressure-dependent increases in ARNA; however, ARNA sensitivity was again greater in decerebrate and Inactin groups versus isoflurane and urethane. Acute renal artery occlusion (30 s) increased ARNA, but responses did not differ across groups. Analysis of ARNA responses to increased pelvic pressure between male and female rats revealed significant sex differences only in isoflurane and urethane groups. ARNA responses to intrarenal capsaicin infusion were significantly blunted at nighttime versus daytime; however, ARNA responses to increased pelvic pressure or renal artery occlusion were not different between daytime and nighttime. These results demonstrate that ARNA sensitivity is greatest in decerebrate and Inactin-anesthetized groups but was not consistently influenced by sex.NEW & NOTEWORTHY We determined the impact of anesthesia, sex, and circadian cycle on renal afferent nerve (ARNA) sensitivity to chemical and mechanical stimuli. ARNA sensitivity to renal capsaicin infusion was greatest in decerebrate > Inactin > urethane or isoflurane groups. Elevated renal pelvic pressure significantly increased ARNA; decerebrate and Inactin groups exhibited the greatest ARNA sensitivity. Sex differences in renal afferent responses were not consistently observed. Circadian cycle altered chemosensory but not mechanosensory responses.


Response to Platinum-based Chemotherapy Rechallenge for Patients With Pembrolizumab-refractory Urothelial Carcinoma.
This study aimed to investigate the response to platinum-based chemotherapy rechallenge in patients with pembrolizumab-refractory urothelial carcinoma. We retrospectively reviewed 14 patients with pembrolizumab-refractory urothelial carcinoma. Each patient received a regimen that they had not previously received (paclitaxel plus carboplatin in 10, gemcitabine plus docetaxel and carboplatin in four). Tumor response and adverse events were assessed. We evaluated overall survival from the chemotherapy rechallenge start date until death. The median overall survival was 11.2 months. The disease-control rate was 85.7%. Partial responses occurred in the metastases in lymph nodes in three (37.5%) patients, lung in one (25%), peritoneal in three (75%), and liver in three (100%). Neutropenia of grade ≥3 occurred in 13 (92.9%) patients. The activity of platinum-based chemotherapy rechallenge after pembrolizumab was maintained. Neutropenia was observed in most patients.


Reversing breast cancer bone metastasis by metal organic framework-capped nanotherapeutics via suppressing osteoclastogenesis.
Bone metastasis is the major cause of cancer-related morbidity and mortality. To avoid further osteolysis, current treatment ideas focus on tumor cell and the inhibition of osteoclast. Herein, zeolitic imidazolate framework-8-capped Cu2-XSe composite nanoplatform (ICG@Cu2-XSe-ZIF-8) is developed for chemodynamic therapy (CDT) and photothermal therapy (PTT) treatment of malignant breast cancer bone tumors. The rational design of ZIF-8 encapsulation greatly reduces the accumulation of Cu2-XSe to damage the normal cells. Under acidic microenvironment in tumor, ZIF-8 is cleaved to release Cu2-XSe, which can subsequently degrade into Cu (+) and Cu (2+) ions to initiate a Fenton-like reaction inducing CDT. Meanwhile, Cu2-XSe is used to be an effective photothermal transduction agent for exerting the PTT effect. What's more, the selenium element in Cu2-XSe can regulates selenoprotein to inhibit tumor cells and osteoclasts. Of note, the hyperthermia induced by PTT can further enhance the CDT effect in tumor, achieving a synergistic PTT/CDT effect. Based on these advantages, ICG@Cu2-XSe-ZIF-8 effectively suppresses the tumor cells in bone tissue, and reduces the erosion of bone tissue via suppressing osteoclastogenesis. In conclusion, this study demonstrates the potential action mechanism of ZIF-8-capped nanomedicine against osteolysis in bone metastasis.


Design, synthesis, and biological evaluation of amide imidazole derivatives as novel metabolic enzyme CYP26A1 inhibitors.
All-trans-retinoic acid (ATRA) as a physiological metabolite of vitamin A is widely applied in the treatment of cancer, skin, neurodegenerative and autoimmune diseases. CYP26A1 enzyme, induced by ATRA in liver and target tissues, metabolizes ATRA into 4-hydroxyl-RA. Inhibition of CYP26A1 metabolic enzyme represents a promising strategy for discovery of new specific anticancer agents. Herein, we describe the design, synthesis and biological evaluation of a series of new amide imidazole derivatives as retinoic acid metabolism blocking agents (RAMBAs) toward CYP26A1 enzyme. First, based on the recent theoretical models (Sun et al., J. Mol. Graph. Model., 2015, 56, 10-19) a series of RAMBAs with novel scaffolds were designed using fragment-based drug discovery approach. Subsequently, the new RAMBAs were synthesized and evaluated for their biological activities. All the compounds demonstrated appropriate enzyme activities and cell activities. The promising inhibitors 20 and 23 with IC50 value of 0.22 μM and 0.46 μM toward CYP26A1, respectively, were further evaluated for CYP selectivity and the metabolic profile of ATRA. Both compounds 20 and 23 showed higher selectivity for CYP26A1 over other CYPs (CYP2D6, CYP3A4) when compared to liarozole. They also showed better inhibitory activities for the metabolism of ATRA when also compared to liarozole. These studies further validated the pharmacophore and structure-activity relationship models obtained about CYP26A1 inhibitors and highlighted the promising activities of the new series of CYP26A1 inhibitors designed from such models. They also paved the way for future development of those candidates as potential drugs.


Ultrasound mediated gold nanoclusters-capped gas vesicles for enhanced fluorescence imaging.
The intercellular tight junction inhibits tumor imaging efficiency of nanomaterials, and enhanced cellular drug delivery with efficient detection is an important tool for tumor diagnosis. Herein, we fabricate fluorescence gold nanoclusters (Au NCs) decorated gas vesicles (GV-Au) for ultrasound (US)-mediated enhanced cellular delivery and imaging, in which GVs are living cell derived protein bubbles. GV-Au is rod-shaped sack-like structure around 230 nm, and displays improved stability and fluorescence ability compared with free Au NCs. Flow cytometry assay confirms the intracellular localization of Au NCs and GV-Au with a respective 2.20-fold enhanced cellular uptake post US treatment. Confocal images reveal the efficient cellular uptake of GV-Au under US impact, indicating that GV-Au is suitable for cellular and in vivo fluorescence imaging. Our strategy provides a new idea for efficient fluorescence imaging by penetrating cell membranes at the presence of US treatment.


The long non-coding RNA HOXA11-AS activates ITGB3 expression to promote the migration and invasion of gastric cancer by sponging miR-124-3p.
miR-124-3p can inhibit integrin β3 (ITGB3) expression to suppress the migration and invasion of gastric cancer (GC), and in the process lncRNA HOXA11-AS may act as a molecular sponge. Luciferase reporter assay was conducted to verify the binding of miR-124-3p and HOXA11-AS. RT-PCR and western blot were performed to detect the expression of HOXA11-AS, miR-124-3p and ITGB3 in GC tissues and cells. Gene silence and overexpression experiments as well as cell migration and invasion assays on GC cell lines were performed to determine the regulation of molecular pathways, HOXA11-AS/miR-124-3p/ITGB3. Furthermore, the role of HOXA11-AS in GC was confirmed in mice models. We found HOXA11-AS is up-regulated in GC tissues and can bind with miR-124-3p. Through overexpression/knockdown experiments and function tests in vitro, we demonstrated HOXA11-AS can promote ITGB3 expression by sponging miR-124-3p, consequently enhance the proliferation, migration, and invasion of GC cells. Meanwhile, we validated that HOXA11-AS promotes migration and invasion of GC cells via down-regulating miR-124-3p and up-regulating ITGB3 in vivo. We demonstrated that lncRNA HOXA11-AS can increase ITGB3 expression to promote the migration and invasion of gastric cancer by sponging miR-124-3p. Our results suggested that HOXA11-AS may reasonably serve as a promising diagnostic biomarker and a potential therapeutic target of GC.


DELE1 tracks perturbed protein import and processing in human mitochondria.
Protein homeostatic control of mitochondria is key to age-related diseases and organismal decline. However, it is unknown how the diverse types of stress experienced by mitochondria can be integrated and appropriately responded to in human cells. Here we identify perturbations in the ancient conserved processes of mitochondrial protein import and processing as sources of DELE1 activation: DELE1 is continuously sorted across both mitochondrial membranes into the matrix and detects different types of perturbations along the way. DELE1 molecules in transit can become licensed for mitochondrial release and stress signaling through proteolytic removal of N-terminal sorting signals. Import defects that occur at the mitochondrial surface allow DELE1 precursors to bind and activate downstream factor HRI without the need for cleavage. Genome-wide genetics reveal that DELE1 additionally responds to compromised presequence processing by the matrix proteases PITRM1 and MPP, which are mutated in neurodegenerative diseases. These mechanisms rationalize DELE1-dependent mitochondrial stress integration in the human system and may inform future therapies of neuropathies.


Lymphocyte-mediated macrophage apoptosis during IL-12 stimulation.
In contrast to the well known immunostimulatory roles of IL-12, little has been known about its immunosuppressive roles. In the present study, IL-12-activated lymphocyte-mediated macrophage apoptosis was investigated by employing murine lymphocyte/macrophage cocultures. IL-12-activated lymphocytes and their culture supernatants induced an inducible nitric oxide synthase (iNOS)-mediated nitric oxide (NO) synthesis in macrophages. The NO synthesis was markedly inhibited by blocking antibodies to IFN-γ and TNF-α, suggesting the key role of these lymphocyte cytokines in mediating the NO synthesis. The endogenously produced NO inhibited macrophage proliferation, and induced apoptosis in concordance with the accumulation of p53, phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and DR5, and the activation of caspase-3, processes that were inhibited by N(G)-monomethyl-l-arginine, aminoguanidine (NO synthase inhibitors) and 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (an NO scavenger). These results were further supported by the findings obtained from the experiments employing IFN-γ-knockout and iNOS-knockout mice. Our study demonstrated a novel, non-contact-dependent mechanism of macrophage suppression by IL-12-activated lymphocytes: induction of growth inhibition and apoptosis of macrophages due to endogenous NO synthesis induced by cytokines secreted from IL-12-activated lymphocytes.


Tooth replacement options for partially dentate older adults: a survival analysis.
To compare the success of two different tooth replacement strategies for partially dentate older adults; namely resin bonded bridgework (RBB) provided to restore patients according to the principles of the shortened dental arch concept (SDA) and conventional full-arch rehabilitation with removable dental prostheses (RDPs). A randomised controlled clinical trial (RCT) was conducted with partially dentate adults aged 65 years or older. Each patient from the RDP group had all missing natural teeth replaced with cobalt-chromium framework RDPs. Each patient from the SDA group was restored to 10 occluding pairs of natural and replacement teeth using RBB. Patients were followed-up at 6, 12, 24, 36 months. Success rates were generated according to defined success criteria. Log-rank tests and Cox's proportional hazard models were used to compare the success of the two treatment strategies. After 36 months, 89 patients completed the RCT; n = 45 in the RDP group and n = 44 in the SDA group. The overall success rate of the SDA treatment was 90.4% compared to 73.0% for RDPs (p = 0.005). In the upper arch SDA treatment was 100% successful compared to 86.4% for RDPs (p = 0.019). In the lower arch, lower success rates were reported for both the SDA treatment (80.0%) and RDPs (60.0%) (p = 0.054). Further analyses with cox's proportional hazard models demonstrated that SDA treatment was significantly more successful than RDPs (Hazard Ratio: 2.47, p = 0.04). After 36 months SDA treatment using RBB was significantly more successful than RDPs used for conventional full-arch rehabilitation in partially dentate older adults. Functionally orientated treatment according to the principles of the SDA is a feasible alternative to RDPs for partially dentate older patients. SDA treatment using RBB can achieve higher success rates compared to RDPs in this patient group.


Diversity of the Cryptococcus neoformans-Cryptococcus gattii species complex.
More than 110 years of study of the Cryptococcus neoformans and Cryptococcus gattii species complex has resulted in an enormous accumulation of fundamental and applied biological and clinical knowledge. Recent developments in our understanding of the diversity within the species complex are presented, emphasizing the intraspecific complexity, which includes species, microspecies, hybrids, serotypes and genotypes. Each of these may have different roles in disease. An overview of obsolete and current names is presented.


Collision brain tumor with atypical meningioma and glioblastoma: Case report.
Intracranial collision tumors are rare diseases in which two distinct neoplasms are found at the same location. We present an unusual case of an intracranial collision tumor composed of atypical meningioma (WHO grade II) and glioblastoma. The case was a 56-year-old woman hospitalized due to generalized weakness and dizziness. Imaging survey revealed a right frontal lobe extra-axial mass with significant perilesional edema. The patient underwent a one-stage craniotomy for tumor removal. The pathology revealed collision brain tumors of clear cell atypical meningioma (WHO grade II) and glioblastoma. The patient had an uneventful postoperative recovery. The mechanism behind collision brain tumors remains unclear, and some experts consider these tumors sporadic events. Further research is needed to optimize preoperative diagnosis and surgical strategy for collision brain tumor patients. Surgeon should consider intracranial collision tumors when brain image indicated unusual perilesional edema of meningioma. Though there is no standard treatment for these patients, it seems one-staged surgical treatment is feasible. To our knowledge this is the first case of collision tumors with clear cell atypical meningioma (WHO grade II) and glioblastoma.


Google street view image availability in the Bronx and San Diego, 2007-2020: Understanding potential biases in virtual audits of urban built environments.
Google Street View's 'Time Machine' feature holds promise for longitudinal street audits of built and natural environments for urban health research. As images are only available when Google collected data, differential image availability over time and place could bias audit data quality. We assessed image availability at 2000 randomly selected locations within the Bronx and San Diego from which Hispanic Community Health Study/Study of Latinos (HCHS/SOL) participants were recruited. In the Bronx, a mean of 7.4 images (95% CI: 7.2,7.5) were available at each location, and 63% of those locations had imagery in 2007 and 2019. In San Diego, fewer images were available (mean 5.4, 95% CI: 5.2,5.6) especially on minor streets (mean 4.4, 95% CI: 4.1,4.6). Image availability was more spatially clustered in San Diego (Moran's I 0.14) than the Bronx (Moran's I 0.04). Differential image availability may affect precision of neighborhood change estimates assessed by longitudinal virtual audit.


Real-Life Active Surveillance of a Naphazoline/ Hypromellose Fixed Combination's Safety Profile in Peruvian Population.
Identifying the adverse reactions and the possible risks associated with the use of naphazoline 0.1% + hypromellose 0.5% (NAPH), thereby evaluating its tolerability and safety profile. A total of 236 Peruvian patients were included in an active pharmacovigilance study drug event monitoring consisting in 2 phone calls conducted in order to register adverse drug reactions (ADRs), the product's tolerability and to assess the risk concerning specific clinical and demographic characteristics using a binary logistic regression model. A total of 54 ADRs (one per patient) were reported after the use of NAPH; classified (according to the Medical Dictionary for Regulatory Activities) into two groups of System Organ Class (SOC): eye disorders and nervous system disorders; and four groups of preferred term (PT): eye irritation, vision blurred, eye pruritus and headache. All ADRs were expected, mild and not serious. No risk factors related to the clinical and demographic characteristics of the patients were identified. The low incidence of ADRs, their short recovery time, and their categorization as "mild" and "not serious" demonstrates the high tolerability in the studied population; therefore, according to the study, the safety profile for NAPH seems to be adequate, with a suitable tolerability.


Epidemiological Characteristics and Role of Connexin-43 in Patients of Syndactyly Attending a Tertiary Care Center in Odisha, India.
Syndactyly is one of the most common hereditary limb malformations. Yet, epidemiological data in our state is not reported. The current study aims to understand the Connexin-43 expression in such patients. A retrospective cohort study was done in the Department of Plastic surgery and Anatomy of All India Institute of Medical Sciences (AIIMS), Bhubaneswar. The study duration was three years, between 2019 and 2022. The total number of cases was 49 and included patients diagnosed with Syndactyly seeking surgical intervention. The demographic details and the personal and disease history were collected, analyzed, and interpreted. Immunohistochemistry study using Connexin-43. Out of the 49 patients, 26 (53.1%) were male, and 23 (46.9%) were female. Thirty nine (79.6%) had syndactyly, and 10 (20.4%) were diagnosed with syndactyly associated with another syndrome. Both complete and incomplete syndactyly was found. Strong membranous positivity of Connexin-43 was found in the keratinocytes of the stratum spinosum layer of the epidermis, while the stratum granulosum and stratum basale layer revealed negative staining. Syndactyly is mostly non-familial, sporadic with male preponderance affecting unilaterally and in incomplete form in our geographical location. We found an overt expression of Connexin-43 in these patients' stratum basale.


The political, legal, and financial issues that plastic surgery is facing and how to develop a plan to cope.
Our specialty has been a creative wonder and an outright blessing to mankind. We have honed the arts of soft-tissue reconstruction to a level never thought possible just 100 years ago. We have found solutions to wound problems long after others have given up. We have restored the destroyed features of people ravaged by disease, life circumstances, and the acts of war. We have treated the deformed child, the patient with cancer, and reversed the signs of age. But as Thomas Sowell states in his article in 1994 in Forbes Magazine on the 100th anniversary of the birth of Fredrich Hayek, the author of The Road to Serfdom, the rule of law, which Hayek saw as crucial to the economy and to the survival of freedom, is nowhere in greater danger than in the supreme court of the United States. Sowell warned of the process going on that would bring socialism to our health care delivery system. He goes on to assert that it will be paid for by "loss of freedom to make our own decisions about medical care that are literally questions of life and death. The key to the future of medicine is now in our hands. This key will open the door to every doctor's dream of having the technologies that will allow physicians to diagnose and treat all the physical ills of the human race. Or the key, on the other hand, could open the exit door through which the best and brightest will leave medicine, feeling that they no longer can take on the legal and the financial risks to themselves and their families. The road to freedom from the controlling factors noted will require a change in culture. Knowing these facts will allow the plastic surgeon in practice to accept these factors and work with them to provide better care for their patients.


Immunosuppressive treatment of focal segmental glomerulosclerosis: lessons from a randomized controlled trial.
Patients with steroid-resistant focal segmental glomerulosclerosis (FSGS) may benefit from treatment with calcineurin inhibitors. A National Institutes of Health-funded FSGS multicenter study has suggested that a combination of mycophenolate mofetil and oral dexamethasone pulses was equivalent to cyclosporine. However, since the study was underpowered, one cannot draw firm conclusions from this study. The FSGS trial underscores that FSGS is not one disease and that better predictors of outcome and response to therapy are needed.


Placental pathology in early onset pre-eclampsia and intra-uterine growth restriction in women with and without thrombophilia.
The incidence of placental thrombotic lesions in early onset preeclampsia (PE) and/or intrauterine growth restriction (IUGR) were compared between women with and without thrombophilia or hyperhomocysteinemia. Matched case-control study. 183 women with a history of early onset PE and/or IUGR were tested for thrombophilia and hyperhomocysteinemia. From the 66 women with a thrombophilic factor the placental histological slides were available in 47 women. These were matched for maternal condition (PE and/or IUGR), gestational age at delivery, parity and maternal age, to 47 women with no thrombophilic factor. All slides were revised for lymphohistiocytic villitis, fetal thrombosis and fibrin depositions. There were no significant differences between the placentas of the matched groups with and without a thrombophilic factor. Placental thrombotic and inflammatory lesions associated with early onset PE and/or IUGR do not occur more often in women with compared to women without thrombophilia or hyperhomocysteinemia.


The segmental organization of the developing shark brain based on neurochemical markers, with special attention to the prosencephalon.
Brain regionalization has been extensively studied in tetrapods, teleosts and cyclostomes. In contrast, it has not been investigated in elasmobranchs, despite their key phylogenetic position to understand brain evolution in jawed vertebrates. In this study we provide a schematic view of the segmental pattern of the developing shark brain based on mapping of the expression of Pax6 and neurochemical markers such as calretinin, tyrosine hydroxylase, serotonin, and glutamic acid decarboxylase. By correlating the cytoarchitectonic limits with the specific location of these markers, we identify transverse and longitudinal boundaries and domains, which suggest a segmental pattern, reminiscent of the one described in other vertebrates. Taken together, these data provide an initial scheme, which will be further tested and refined using a broader range of genetic markers involved in patterning and differentiation.


Bcl-2 expression promotes B- but not T-lymphoid development in scid mice.
Expression of antigen receptors is vital for the development of B and T lymphocytes. In mice with the scid mutation, which are unable to make productive rearrangements of their immunoglobulin and T-cell receptor (TCR) genes, lymphopoiesis aborts at an early stage. The death of the immature lymphocytes by apoptosis is postulated to result from a failure to receive a survival signal induced by receptor engagement. Consistent with this hypothesis, introduction of immunoglobulin or TCR transgenes into scid mice promoted an increase in B- or T-lymphoid cells, respectively. As the protein encoded by the bcl-2 gene can inhibit cell death, we tested whether lymphopoiesis could be rescued in scid mice by crossing in a bcl-2 transgene. Strikingly, the bcl-2/scid mice accumulated almost normal numbers of B-lymphoid cells which lacked surface immunoglobulin but expressed markers of maturity. T-cell development remained blocked. Introducing a TCR transgene enabled bcl-2/scid mice to develop normal numbers of CD4+8+ thymocytes even in the absence of immunological selection, suggesting that T cells become competent to respond to bcl-2 protein only after the TCR complex is displayed at the cell surface.


Detection of 4He in stratospheric particles gives evidence of extraterrestrial origin.
Whipple predicted the existence of micrometeorites, small interplanetary particles which enter the Earth's atmosphere without being melted by frictional heating. During the past 2 yr, large numbers of micrometre sized stratospheric particles have been collected which are believed to be extraterrestrial, because their elemental compositions closely match those of primitive meteorites. We report here the detection of large concentrations of 4He in some of the particles. This not only suggests an exposure to solar wind, but also indicates that these particles are true micrometeorites in the sense that they were not strongly heated by entry into the atmosphere. Strong heating would have caused much of the helium to escape.


Occam's razor and Hickam's dictum: a dermatologic perspective.
Diagnostic heuristics help ease the cognitive load in our day-to-day work. Occam's razor or the rule of diagnostic parsimony is a diagnostic heuristic often applied in dermatology. Occam's razor dictates that all things being equal, one diagnosis (as opposed to several diagnoses) should be sought to explain a patient's presentation. While this can often be helpful, it can also obscure the full picture. Hickam's dictum is an aphorism expressing the opposite opinion: "patients can have as many diseases as they damn (or darn) well please." This acknowledges that multiple simultaneous processes can be at play. This article delves into the implications of use of these approaches and offers tips through cases illustrating the limitations of Occam's razor and when Hickam's Dictum should be invoked.


A major Calanus finmarchicus overwintering population inside a deep fjord in northern Norway: implications for cod larvae recruitment success.
High Calanus finmarchicus abundances were recorded in wintertime in Vestfjorden, close to the main cod breeding grounds off Lofoten and Vesterålen, northern Norway. The mean abundance for locations with water depth >500 m was ∼37000 ind. m-2 (range: 26700-49000 ind. m-2). To our knowledge, this is the first report of massive overwintering of C. finmarchicus on the Norwegian shelf. Because of the observed size and location of this population, we argue that local overwintering on the northern Norwegian shelf can contribute significantly to sustain a C. finmarchicus population on the shelf during the period of first feeding for cod larvae. This is supported by a particle tracking model.


Surgical Management of Ear Diseases in Rabbits.
Otitis externa and media are frequently diagnosed disorders in rabbits and are particularly common in lop-eared breeds because of the specific anatomy of the ear canal. Medical management for otitis externa and media often provides only a temporary improvement in clinical signs. Surgery by means of partial or total ear canal ablation (PECA or TECA) combined with lateral bulla osteotomy (LBO) represents a feasible approach that is well tolerated and provides a good clinical outcome. Short-term complications associated with PECA/TECA-LBO include facial nerve paralysis and vestibular disease.


Cardiac magnetic resonance assessment of takotsubo cardiomyopathy.
Takotsubo cardiomyopathy is an important condition that can be difficult to differentiate from acute coronary syndrome on the basis of clinical, electrocardiogram, and cardiac enzyme assessment alone. Although coronary angiography remains important in the acute assessment of patients with suspected takotsubo cardiomyopathy, cardiac magnetic resonance (CMR) has emerged over the last decade as an important non-invasive imaging tool in the diagnosis and follow-up of this condition. We present a review highlighting the CMR features of takotsubo cardiomyopathy and its complications with particular focus on differentiating this condition from acute myocardial infarction and myocarditis.


Synergistic effect of vascular endothelial growth factor and angiopoietin-2 on progression free survival in multiple myeloma.
Bone marrow neoangiogenesis plays an important role in multiple myeloma (MM) and depends on the interplay of angiogenic cytokines. We investigated the levels of angiogenic cytokines such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiopoietin (Ang)-1, Ang-2 and hypoxia inducible factor-1 alpha (HiF-1α) in MM patients and their association with treatment outcome. Serum levels and mRNA expression of VEGF, Ang-2, Ang-1, bFGF and HiF-1α were evaluated in 71 MM patients using enzyme-linked immunosorbent assay and reverse transcriptase polymerase chain reaction. In multivariate Cox regression analysis, serum levels of VEGF≥756 pg/ml (HR 2.2, 95% CI 1.02-4.91; p=0.045) and relative mRNA expression levels of Ang-2≥0.93 (HR 21.0, 95% CI 6.27-70.45; p<0.001) were predictive of inferior progression free survival (PFS) and patients with concomitant increase in VEGF and Ang-2 had poor outcome compared to the rest of the patients (HR 32.6, 95% CI 7.20-148.36; p<0.001). These results suggest that VEGF and Ang-2 act in synergy and their expression levels at presentation are predictive of PFS in MM.


Bottle gourd rootstock-grafting promotes photosynthesis by regulating the stomata and non-stomata performances in leaves of watermelon seedlings under NaCl stress.
Previously, we found that the amelioration of photosynthetic capacity by bottle gourd (Lagenaria siceraria Standl.) rootstock in watermelon seedlings (Citrullus lanatus [Thunb.] Mansf.) with salt treatment might be closely related to the enzymes in Calvin cycle such as ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) (Yang et al., 2012). We confirmed this and showed more details in this study that improved photosynthesis of watermelon plants by bottle gourd rootstock was associated with the decreased stomata resistance and the increased photochemical activity and photosynthetic metabolism with or without 100mM NaCl stress for 3 days. The analysis of gas exchange parameters showed that self-grafted plants suffered serious non-stomatal limitation to photosynthesis under salt stress while rootstock-grafted plants were mainly affected by stomata limitation in stress conditions. Further, results showed that NaCl stress markedly reduced the chlorophyll content, damaged the structure of photosynthetic apparatus, and inhibited photochemical activity and CO2 assimilation in self-grafted plants. In contrast, rootstock-grafting increased the chlorophyll content, especially chlorophyll b, and minimized the harmful effects on photosystem II (PSII) reaction center and the thylakoids structure induced by NaCl stress. Furthermore, rootstock-grafting enhanced the content and activity of Rubisco and thus elevated carbon fixation in the leaves of watermelon scions under salt stress. The gene expressions of enzymes related to ribulose-1,5-bisphosphate (RuBP) regeneration were also up-regulated by rootstock and this probably guaranteed the sufficient supply of RuBP for the operation of Calvin cycle in watermelon scions under salt stress. Thus, bottle gourd rootstock promoted photosynthesis by the activation of stomatal and non-stomatal abilities, especially the regulation of a variety of photosynthetic enzymes, including Rubisco in grafted watermelon plants under NaCl stress.


Ab initio calculation of the Gilbert damping parameter via the linear response formalism.
A Kubo-Greenwood-like equation for the Gilbert damping parameter α is presented that is based on the linear response formalism. Its implementation using the fully relativistic Korringa-Kohn-Rostoker band structure method in combination with coherent potential approximation alloy theory allows it to be applied to a wide range of situations. This is demonstrated with results obtained for the bcc alloy system Fe(1-x)Co(x) as well as for a series of alloys of Permalloy with 5d transition metals. To account for the thermal displacements of atoms as a scattering mechanism, an alloy-analogy model is introduced. The corresponding calculations for Ni correctly describe the rapid change of α when small amounts of substitutional Cu are introduced.


Spatial topography of the excurrent duct system in the bovine testis.
The rete testis of the bull is situated within an axial mediastinum and consists of approximately 30 longitudinally arranged, anastomosing rete channels. At the cranial testicular pole all rete channels empty into a common space, the area confluens retis, which is subdivided by small septa and narrow chordae retis. The area confluens always contains numerous spermatozoa and is connected with the bulbous initial portions of the efferent ductules by short, often tortuous rete tubules. Since the connection between rete and efferent ductules is situated within the tunica albuginea, the bovine excurrent duct system is not provided with an extratesticular rete as in many other mammals. Straight testicular tubules merge from all directions to connect with superficial rete channels, but the inlets are not evenly distributed. In the periphery each straight tubule begins with a cup-like structure followed by a narrow stalk region and a heavily folded portion opening either immediately into a rete channel or into a tube-like lateral rete extension. In close contiguity to the rete testis lie extremely coiled arterial portions connecting the centripetal and the centrifugal branches of the testicular artery. Since intrinsic musculature is scarcely developed in the mediastinum, and transport of rete content relies primarily on massage due to external pressure changes, the pulsatile blood flow through these coiled arteries may influence conveyance processes within the rete testis. An intimate spatial association between area confluens retis and adjacent large, thin-walled lymph vessels may facilitate a transfer of androgens into the fluid of the rete testis.


Hypothermia in conjunction with hyperbaric oxygenation in the treatment of massive air embolism during cardiopulmonary bypass.
Massive gas embolism during cardiopulmonary bypass is a rare but ever-present danger. Following this catastrophic event, the immediate institution of core cooling on bypass may be advantageous. The remarkable complete recovery of our patient is attributed to this technique, which was used in conjunction with standard therapy.


Study of the interaction between germ cells and Sertoli cells in vitro.
The nature of membrane components involved in the binding between Sertoli cells and pachytene spermatocytes in culture and the metabolic requirements for the binding to occur have been studied. Mild proteolytic digestion of germ cells by trypsin completely inhibited adhesion of germ cells to somatic monolayer. Protein synthesis and glycosylation were required to restore the adhesive properties of trypsin-treated germ cells, showing that surface molecules involved in the binding are glycoproteins. Trypsinization of germ cells after labelling causes a great reduction of several bands which become detectable again after 12 h of recovery from trypsin digestion. Among these, two bands with apparent molecular weight (MW) of 78 000 and 51 000 could be candidate components in cell adhesion.


Articaine interaction with DSPC bilayer: a 13C and 31P solid-state NMR study.
Articaine hydrochloride, 4-methyl-3-(2-[propylamino]propionamido)-2-thiophenecarboxylic acid, methyl ester hydrochloride, is a local anaesthetic commonly used in dentistry, and is classified as an amide local anaesthetic. Solid-state (13)C and (31)P NMR were used to investigate the uncharged articaine species (sample pH 10.0) when interacting with distearoylphosphatidylcholine (DSPC) model membranes. The DSPC phospholipid bilayer was studied at four different molar ratios of articaine, 10, 25, 40, and 55 mol%, respectively. The articaine concentration-dependent decrease in the DSPC bilayer gel-to-liquid-crystalline phase-transition temperature demonstrates substantial articaine interaction with this bilayer. A DSPC bilayer contains a large hydrophobic core and the (13)C and (31)P NMR spectra of the 40 mol% articaine-containing sample demonstrate a disturbance in the molecular packing of the polar bilayer region that extends into the hydrophobic region, evidenced by carbon 2 and 3 of the stearoyl acyl chains. Observed (31)P and (13)C NMR spectral changes when articaine is increased from 40 to 55 mol%, suggest formation of articaine aggregates and decrease in DSPC bilayer perturbation at the latter articaine level.


Exposure of the cryptic Arg-Gly-Asp sequence in thrombospondin-1 by protein disulfide isomerase.
Thrombospondin-1 is a matrix protein that inhibits proliferation, motility and sprouting of endothelial cells in vitro and angiogenesis in vivo. One mechanism by which thrombospondin-1 may influence endothelial cell biology is through interaction with the endothelial cell alphav beta3 integrin receptor. This interaction is mediated via a cryptic Arg-Gly-Asp sequence in the C-terminal Ca2+-binding region of thrombospondin-1. Exposure of the Arg-Gly-Asp sequence is controlled by disulfide interchange events in the Ca2+-binding loops and C-globular domain. Limited reduction of thrombospondin-1 by dithiothreitol exposes the Arg-Gly-Asp sequence which can bind to the alphav beta3 integrin receptor and support endothelial cell spreading (X. Sun, K. Skorstengaard, D.F. Mosher, J. Cell Biol. 118 (1992) 693-701). Our aim was to identify possible physiological reductants that can mediate Arg-Gly-Asp exposure. We now report that protein disulfide isomerase, which is known to catalyze disulfide interchange in thrombospondin-1 and change its enzyme inhibitory properties and its binding to monoclonal antibodies, was secreted by bovine aortic endothelial cells and deposited on the cell surface. There was an average of approximately 2.2 fg of protein disulfide isomerase on the surface of a bovine aortic endothelial cell. Treatment of thrombospondin-1 with purified protein disulfide isomerase enhanced adhesion of endothelial cells to thrombospondin-1 in an Arg-Gly-Asp-dependent manner through the alphav beta3 integrin receptor and supported cell spreading. Both Ca2+-depleted and Ca2+-replete thrombospondin-1 were substrates for protein disulfide isomerase. These results suggest that endothelial cell derived protein disulfide isomerase may regulate Arg-Gly-Asp-dependent binding of thrombospondin-1.


Transient receptor potential vanilloid 1 inhibitors block laparotomy- and opioid-induced infarct size reduction in rats.
In light of the opioid epidemic, physicians are increasingly prescribing non-opioid analgesics to surgical patients. Transient receptor potential vanilloid 1 (TRPV1) inhibitors are potentially alternative pain therapeutics for surgery. Here, we examined in rodents whether the cardioprotection conferred by two common procedures during surgery, a laparotomy or morphine delivery, is mediated by the TRPV1 channel. We further tested whether an experimental analgesic peptide (known as P5) targeted against the TRPV1 C-terminus region interferes with laparotomy- or morphine-induced cardioprotection. Male Sprague-Dawley rats were subjected to 30 min coronary occlusion followed by 120 min reperfusion. Before ischaemia, a laparotomy with or without capsaicin application (0.1% cream, a TRPV1 activator) was performed. Additional rats were given morphine (0.3 mg·kg-1 ) with or without capsaicin. In addition, capsazepine (3 mg·kg-1 , a classical TRPV1 inhibitor), or P5 (3 mg·kg-1 , a peptide analgesic and TRPV1 inhibitor), was given either alone or prior to a laparotomy or morphine administration. Myocardial infarct size was determined. A laparotomy, in addition to combining a laparotomy with capsaicin cream, reduced infarct size versus control. Morphine, in addition to combining morphine administration with capsaicin cream, also reduced infarct size versus control. When TRPV1 inhibitors capsazepine or P5 were given, either TRPV1 inhibitor abolished the infarct size reduction mediated by a laparotomy or morphine. Inhibiting the TRPV1 channel blocks laparotomy- or morphine-induced cardioprotection. Impaired organ protection may be a potential pitfall of using TRPV1 inhibitors for pain control.


Iodine-Functionalized Titanium Carbide MXene with Ultra-Stable Pseudocapacitor Performance.
MXene has attracted a wide spread attention as promising supercapacitor electrode materials owing to excellent electronic conductivity and reversible surface redox capability. In fact, the supercapacitor performance strongly relies onsurface terminations of MXene. However, regulating the types of surface terminations for enhancing the electrochemical performance of MXene is still one of major challenge. Herein, we successfully prepared a MXene containing iodine terminations (I-Ti3C2 MXene) by facile Lewis-acidic-melt etching method and comprehensively investigated its supercapacitor performance. Benefiting from the presence of iodine terminations, the I-Ti3C2 MXene with pseudocapacitor property exhibits significantly higher specific capacitance than that of hydrofluoric acid etching MXene (HF-Ti3C2Tx MXene). Impressively, the I-Ti3C2 MXene shows extraordinary long-term cyclic performance, even when cycled at high current density of 50 A/g, that the specific capacitance retention of 91% can be obtained over 100,000 cycles, corresponding to an average specific capacitance loss of only 0.00009% per cycle. Furthermore, the mechanisms involved were clarfied by systematical characterizations. This work will provide new insights for enhancing the supercapacitor performance of MXene-based materials by surface chemistry modification.