SCD in the world, Europe, Bosnia and Herzegovina and Mostar.
Sudden cardiac death (SCD) is "a natural death due to cardiac causes, heralded by abrupt loss of consciousness within 1 hour of the onset of acute symptoms". Annual incidence is 0.36-1.28/1000 inhabitants. More than 1000 sudden deaths occur each day is in USA, and 100,000 people annually dead in the United Kingdom. Epidemiology differs greatly in 100-fold between young and old, and between developing and developed worlds. SCD is one of the leading causes of death and accounts for over 50% of the cardiac deaths. New data show that SCD is not nearly as sudden in most cases as the term may suggest. Warning symptoms that precede the sudden cardiac death are present for a surprisingly long time in many patients. Coronary artery disease (CAD) is the most common cause of death in the developed world. The major causes are inherited arrythmogenic right ventricular cardiomyopathy (ARVC), hypertrophic cardiomyopathy (HCM), anomalous coronary arteries and hereditary channelopathies (e.g., Long QT syndrome, LQTS). Prevalence is 3-4 fold higher in men, reflecting that of CAD. In adults, the incidence of CAD-related SCD varies with geography and age. The incidence of SCD increases with congestive heart failure (CHF), stroke, cancer and metabolic syndrome, particularly in the developed world. Coronary thrombi and plaque rupture or erosion are found in two thirds of SCD. In women over 50, rupture accounted for 80% of coronary thrombi. In Europe SCD accounts for 200,000 dead in 1 year. In FBiH rate of SCD fluctuates around 0.62/1000 inhabitants, in HNK it is 0.78/1000 and in Mostar 0.54/1000. A wide range of cardiac etiology and development of various management procedures in the primary and secondary preventive pharmacotherapy, device therapy, lifestyle changes and genetic profiling have had a major impact on the prediction and prevention of SCD. Improved resuscitation and defibrillation techniques together with advances in implantable pacemaker and defibrillator technology (AED) have all improved treatment outcome. Education of the Red Cross, Police, Army, Civic Protection members, public, patients and relatives to recognize and respond to symptoms of heart disease holds promise for reducing mortality attributed to sudden death. Developing a better understanding of the circumstances of sudden cardiac death and preventive measures and proper reactions to the impending events. Training in cardio-pulmonary resuscitation with public access defibrillation programs is necessary in fighting sudden death. Systematic screening of young athletes and implantation of implantable cardioverter defibrillators should prevent SCD. SCD remains one of the major public health problems in the world and is most commonly caused by CAD. Risk stratification is effective for groups, but difficult in case of individuals. There is a need for major improvements in prevention, risk protection, resuscitation and therapy.


Components of reproductive isolation between Orchis mascula and Orchis pauciflora.
Studies of the strength and nature of reproductive isolation (RI) between species can greatly contribute to our understanding of speciation. Although the role of RI in speciation is well recognized, there is a dearth of information on the contributions of different barriers between related plant species. Here, we estimated multiple components of RI between two Mediterranean orchid sister species (Orchis mascula and Orchis pauciflora), disentangling the strength and absolute contributions of seven different isolating mechanisms. Our survey includes one prepollination, two postpollination prezygotic (pollen-stigma incompatibility, conspecific pollen precedence), two intrinsic postzygotic (embryo mortality and hybrid sterility) and two extrinsic postzygotic (hybrid habitat differentiation and hybrid pollination) isolating mechanisms. We found strong RI between the investigated species, although none of the barriers were able to completely impede gene flow. Five isolating mechanisms contributed positively to the maintenance of species boundaries. Contrary to most surveys of isolating mechanisms, our data speak against a clear predominance of prepollination or of prezygotic barriers but confirm the emerging pattern of multiple barriers contributing to the maintenance of species integrity. These findings suggest an allopatric condition during early phases of species divergence. We discuss our data in the wider context of previous studies carried out in this orchid group by using a comparative approach.


Impact of the pneumococcal vaccine on long-term morbidity and mortality of adults at high risk for pneumonia.
There is debate surrounding the effectiveness of the 23-valent pneumococcal polysaccharide vaccine (PPV). We determined whether PPV was associated with reduced mortality or additional hospitalization for vaccine-preventable infections in patients previously hospitalized for community-acquired pneumonia (CAP). From 2000 through 2002, adults with CAP admitted to the hospital in Edmonton, Alberta, Canada, were enrolled in a population-based cohort. Postdischarge outcomes during 5 years were ascertained using administrative databases. The primary outcome was the composite of all-cause mortality or additional hospitalization for vaccine-preventable infections. Proportional hazards analysis was used to determine the association between PPV use and outcomes. A total of 2950 patients were followed up for a median of 3.8 years. The mean patient age was 68 years; 52% were male. One-third (n = 956) received PPV: 667 (70%) before and 289 (30%) during hospitalization. After discharge, 1404 patients (48%) died, 504 (17%) were admitted with vaccine-preventable infections, and 1626 (55%) reached the composite outcome of death or infection. PPV was not associated with reduced risk of the composite outcome (589 [62%] vs 1037 [52%] for those unvaccinated; adjusted hazard ratio [HR], 0.91; 95% confidence interval [CI], 0.79-1.04). Results were not altered in sensitivity analyses using propensity scores (adjusted HR, 0.91; 95% CI, 0.79-1.04), restricting the sample to patients 65 years or older (adjusted HR, 0.90; 95% CI, 0.77-1.04), or considering only those who received PPV at discharge (adjusted HR, 0.84; 95% CI, 0.71-1.00). One-half of patients discharged from the hospital after pneumonia die or are subsequently hospitalized with a vaccine-preventable infection within 5 years. PPV was not associated with a reduced risk of death or hospitalization. Better pneumococcal vaccination strategies are urgently needed.


The proteome of Populus nigra woody root: response to bending.
Morphological and biomechanical alterations occurring in woody roots of many plant species in response to mechanical stresses are well documented; however, little is known about the molecular mechanisms regulating these important alterations. The first forest tree genome to be decoded is that of Populus, thereby providing a tool with which to investigate the mechanisms controlling adaptation of woody roots to changing environments. The aim of this study was to use a proteomic approach to investigate the response of Populus nigra woody taproot to mechanical stress. To simulate mechanical perturbations, the taproots of 30 one-year-old seedlings were bent to an angle of 90 ° using a steel net. A spatial and temporal two-dimensional proteome map of the taproot axis was obtained. We compared the events occurring in the above-bending, central bending and below-bending sectors of the taproot. The first poplar woody taproot proteome map is reported here; a total of 207 proteins were identified. Spatial and temporal proteomic analysis revealed that factors involved in plant defence, metabolism, reaction wood formation and lateral root development were differentially expressed in the various sectors of bent vs. control roots, seemingly in relation to the distribution of mechanical forces along the stressed woody taproots. A complex interplay among different signal transduction pathways involving reactive oxygen species appears to modulate these responses. Poplar woody root uses different temporal and spatial mechanisms to respond to mechanical stress. Long-term bending treatment seem to reinforce the defence machinery, thereby enabling the taproot to better overcome winter and to be ready to resume growth earlier than controls.


Circumferential, not longitudinal, colonic stretch increases synaptic input to mouse prevertebral ganglion neurons.
The relationship between longitudinal and circular muscle tension in the mouse colon and mechanosensory excitatory synaptic input to neurons in the superior mesenteric ganglion (SMG) was investigated in vitro. Electrical activity was recorded intracellularly from SMG neurons, and muscle tension was simultaneously monitored in the longitudinal, circumferential, or both axes. Colonic intraluminal pressure and volume changes were also monitored simultaneously with muscle tension changes. The results showed that the frequency of fast excitatory postsynaptic potentials (fEPSPs) in SMG neurons increased when colonic muscle tension decreased, when the colon relaxed and refilled with fluid after contraction, and during receptive relaxation preceding spontaneous colonic contractions. In contrast, fEPSP frequency decreased when colonic muscle tension increased during spontaneous colonic contraction and emptying. Manual stretch of the colon wall to 10-15% beyond resting length in the circumferential axis of flat sheet preparations increased fEPSP frequency in SMG neurons, but stretch in the longitudinal axis to 15% beyond resting length in the same preparations did not. There was no increase in synaptic input when tubular colon segments were stretched in their long axes up to 20% beyond their resting length. The circumferential stretch-sensitive increase in the frequency of synaptic input to SMG neurons persisted when the colonic muscles were relaxed pharmacologically by nifedipine (2 microM) or nicardipine (3 microM). These results suggest that colonic mechanosensory afferent nerves projecting to the SMG function as length or stretch detectors in parallel to the circular muscle layer.


Growth suppression by an E2F-binding-defective retinoblastoma protein (RB): contribution from the RB C pocket.
Growth suppression by the retinoblastoma protein (RB) is dependent on its ability to form complexes with transcription regulators. At least three distinct protein-binding activities have been identified in RB: the large A/B pocket binds E2F, the A/B pocket binds the LXCXE peptide motif, and the C pocket binds the nuclear c-Abl tyrosine kinase. Substitution of Trp for Arg 661 in the B region of RB (mutant 661) inactivates both E2F and LXCXE binding. The tumor suppression function of mutant 661 is not abolished, because this allele predisposes its carriers to retinoblastoma development with a low penetrance. In cell-based assays, 661 is shown to inhibit G1/S progression. This low-penetrance mutant also induces terminal growth arrest with reduced but detectable activity. We have constructed mutations that disrupt C pocket activity. When overproduced, the RB C-terminal fragment did not induce terminal growth arrest but could inhibit G1/S progression, and this activity was abolished by the C-pocket mutations. In full-length RB, the C-pocket mutations reduced but did not abolish RB function. Interestingly, combination of the C-pocket and 661 mutations completely abolished RB's ability to cause an increase in the percentage of cells in G1 and to induce terminal growth arrest. These results suggest that the A/B or C region can induce a prolongation of G1 through mechanisms that are independent of each other. In contrast, long-term growth arrest requires combined activities from both regions of RB. In addition, E2F and LXCXE binding are not the only mechanisms through which RB inhibits cell growth. The C pocket also contributes to RB-mediated growth suppression.


Conjugated bilirubin affects cytokine profiles in hepatitis A virus infection by modulating function of signal transducer and activator of transcription factors.
Hepatitis A virus (HAV) infection is the major cause of acute liver failure in paediatric patients. The clinical spectrum of infection is variable, and liver injury is determined by altered hepatic enzyme function and bilirubin concentration. We recently reported differences in cytokine profiles between distinct HAV-induced clinical courses, and bilirubin has been recognized as a potential immune-modulator. However, how bilirubin may affect cytokine profiles underlying the variability in the course of infection has not been determined. Herein, we used a transcription factor (TF) binding site identification approach to retrospectively analyse cytokine expression in HAV-infected children and to predict the entire set of TFs associated with the expression of specific cytokine profiles. The results suggested that modulation of the activity of signal transducers and activators of transcription proteins (STATs) may play a central role during HAV infection. This led us to compare the degree of STAT phosphorylation in peripheral blood lymphoid cells (PBLCs) from paediatric patients with distinct levels of conjugated bilirubin (CB). Low CB levels in sera were associated with increased STAT-1 and STAT-5 phosphorylation. A positive correlation was observed between the serum interleukin-6 (IL-6) content and CB values, whereas higher levels of CB correlated with reduced serum IL-8 values and with a reduction in the proportion of PBLCs positive for STAT-5 phosphorylation. When CB was used to stimulate patients' PBLCs in vitro, the levels of IL-6 and tumour necrosis factor-α were increased. The data showed that bilirubin plays a role in STAT function and affects cytokine profile expression during HAV infection.


Efficacy and Safety of the Heat Shock Protein 90 Inhibitor RGRN-305 in Hidradenitis Suppurativa: A Parallel-Design Double-Blind Trial.
Hidradenitis suppurativa is a painful immune-mediated disorder with limited treatment options; hence, a need exists for new treatments. To evaluate the feasibility of heat shock protein 90 inhibition by RGRN-305 as a novel mechanism of action in treating moderate to severe hidradenitis suppurativa. This was a parallel-design, double-blind, proof-of-concept, placebo-controlled randomized clinical trial conducted between September 22, 2021, and August 29, 2022, at the Department of Dermatology, Aarhus University Hospital in Denmark. The study included a 1- to 30-day screening period, a 16-week treatment period, and a 4-week follow-up period. Eligibility criteria included age 18 years or older and moderate to severe hidradenitis suppurativa with 6 or more inflammatory nodules or abscesses in at least 2 distinct anatomic regions. Of 19 patients screened, 15 patients were enrolled in the study. Intention-to-treat analysis was performed. Patients were randomly assigned (2:1) to receive oral RGRN-305, 250-mg tablet, or matching placebo once daily for 16 weeks. The primary efficacy end point was the percentage of patients achieving Hidradenitis Suppurativa Clinical Response 50 (HiSCR-50) at week 16. Secondary efficacy end points included HiSCR-75 or HiSCR-90, Hidradenitis Suppurativa Physician's Global Assessment, Dermatology Life Quality Index scores, and a pain numeric rating scale. Safety was assessed by adverse events, physical examinations, clinical laboratory measurements, and electrocardiograms. A total of 15 patients were enrolled, completed the study, and were included in all analyses (10 [67%] female; median age, 29 [IQR, 23-41] years). The primary end point HiSCR-50 at week 16 was achieved by a higher percentage in the RGRN-305 group (60% [6 of 10]) than in the placebo group (20% [1 of 5]). Improvements were also observed across all secondary end points at week 16, including higher rates of the harder-to-reach HiSCR levels; 50% (5 of 10) achieved HiSCR-75 and 30% (3 of 10) achieved HiSCR-90, whereas none of the placebo-treated patients achieved HiSCR-75 or HiSCR-90. RGRN-305 was well tolerated, with no deaths or serious adverse events, and treatment-emergent adverse events were similarly frequent between the RGRN-305 and placebo groups. The findings of this trial suggest that heat shock protein 90 inhibition by RGRN-305 offers a novel mechanism of action in treating hidradenitis suppurativa, warranting further evaluation in larger trials. ClinicalTrials.gov Identifier: NCT05286567.


Connection domain mutations N348I and A360V in HIV-1 reverse transcriptase enhance resistance to 3'-azido-3'-deoxythymidine through both RNase H-dependent and -independent mechanisms.
Thymidine analogue-associated mutations (TAMs) in reverse transcriptase (RT) of the human immunodeficiency virus type 1 (HIV-1) cause resistance to 3'-azido-3'-deoxythymidine (AZT) through excision of the incorporated monophosphate. Mutations in the connection domain of HIV-1 RT can augment AZT resistance. It has been suggested that these mutations compromise RNase H cleavage, providing more time for AZT excision to occur. However, the underlying mechanism remains elusive. Here, we focused on connection mutations N348I and A360V that are frequently observed in clinical samples of treatment-experienced patients. We show that both N348I and A360V, in combination with TAMs, decrease the efficiency of RNase H cleavage and increase excision of AZT in the presence of the pyrophosphate donor ATP. The TAMs/N348I/A360V mutant accumulates transiently formed, shorter hybrids that can rebind to RT before the template is irreversibly degraded. These hybrids dissociate selectively from the RNase H-competent complex, whereas binding in the polymerase-competent mode is either not affected with N348I or modestly improved with A360V. Both connection domain mutations can compensate for TAM-mediated deficits in processive DNA synthesis, and experiments with RNase H negative mutant enzymes confirm an RNase H-independent contribution to increased levels of resistance to AZT. Moreover, the combination of diminished RNase H cleavage and increased processivity renders the use of both PP(i) and ATP advantageous, whereas classic TAMs solely enhance the ATP-dependent reaction. Taken together, our findings demonstrate that distinct, complementary mechanisms can contribute to higher levels of excision of AZT, which in turn can amplify resistance to this drug.


Preexposure prophylaxis-selected drug resistance decays rapidly after drug cessation.
Resistance to emtricitabine plus tenofovir disoproxil fumarate (FTC/TDF) or TDF alone used as preexposure prophylaxis (PrEP) has been detected in individuals who initiated PrEP during unrecognized acute HIV infection and, rarely, in PrEP breakthrough infections. PrEP-selected resistance could alter future treatment options, and therefore we sought to determine how long resistance persisted after PrEP cessation. The Partners PrEP Study was a randomized placebo-controlled trial of FTC/TDF or TDF as PrEP for HIV prevention. We previously reported that PrEP-related mutations (K65R, K70E or M184IV) were detected by 454 sequencing following seroconversion in nine individuals who acquired HIV during the Partners PrEP Study. In the current study, we used 454 sequencing to detect and quantify PrEP-related mutations in HIV RNA-positive plasma samples prior to seroconversion, as well as in plasma from 6, 12, and 24 months after PrEP cessation from these nine individuals. HIV RNA-positive, antibody-negative samples were available prior to seroconversion for four of nine individuals with resistance detected at seroconversion. In all four cases, K65R, K70E and M184IV were not detected prior to seroconversion, suggesting PrEP-related resistance was selected and not transmitted. All PrEP-selected mutations were no longer detectable by 6 months after PrEP cessation and remained undetectable at 12 and 24 months in the absence of antiretroviral therapy. Using highly sensitive assays, PrEP-selected resistance in plasma decays below detection by 6 months following drug cessation and remains undetectable for at least 24 months. Even high levels of resistance mutations during acute infection decay rapidly in the absence of ongoing PrEP exposure.


The Par3/aPKC interaction is essential for end bud remodeling and progenitor differentiation during mammary gland morphogenesis.
Mammalian polarity proteins have been studied predominantly in cell culture systems, and little is known about their functions in vivo. To address this issue, we used a shRNA lentiviral system to manipulate gene expression in mouse mammary stem/progenitor cells. Transplantation of Par3-depleted stem/progenitor cells into the mammary fat pad severely disrupted mammary development, and glands were characterized by ductal hyperplasia, luminal filling, and highly disorganized end bud structures that were unable to remodel into normal ductal structures. Unexpectedly, Par3-depleted mammary glands also had an expanded progenitor population. We identified a novel function for the atypical protein kinase C (aPKC)-binding domain of Par3 in restricting Par3 and aPKC to the apical region in mammary epithelia in vivo, and found that mammary morphogenesis is dependent on the ability of Par3 to directly bind aPKC. These results reveal a new function for Par3 in the regulation of progenitor differentiation and epithelial morphogenesis in vivo and demonstrate for the first time an essential requirement for the Par3-aPKC interaction.


Olaparib plus Durvalumab, with or without Bevacizumab, as Treatment in PARP Inhibitor-Naïve Platinum-Sensitive Relapsed Ovarian Cancer: A Phase II Multi-Cohort Study.
Early results from the phase II MEDIOLA study (NCT02734004) in germline BRCA1- and/or BRCA2-mutated (gBRCAm) platinum-sensitive relapsed ovarian cancer (PSROC) showed promising efficacy and safety with olaparib plus durvalumab. We report efficacy and safety of olaparib plus durvalumab in an expansion cohort of women with gBRCAm PSROC (gBRCAm expansion doublet cohort) and two cohorts with non-gBRCAm PSROC, one of which also received bevacizumab (non-gBRCAm doublet and triplet cohorts). In this open-label, multicenter study, PARP inhibitor-naïve patients received olaparib plus durvalumab treatment until disease progression; the non-gBRCAm triplet cohort also received bevacizumab. Primary endpoints were objective response rate (ORR; gBRCAm expansion doublet cohort), disease control rate (DCR) at 24 weeks (non-gBRCAm cohorts), and safety (all cohorts). The full analysis and safety analysis sets comprised 51, 32, and 31 patients in the gBRCAm expansion doublet, non-gBRCAm doublet, and non-gBRCAm triplet cohorts, respectively. ORR was 92.2% (95% CI, 81.1-97.8) in the gBRCAm expansion doublet cohort (primary endpoint); DCR at 24 weeks was 28.1% (90% CI, 15.5-43.9) in the non-gBRCAm doublet cohort (primary endpoint) and 74.2% (90% CI, 58.2-86.5) in the non-gBRCAm triplet cohort (primary endpoint). Grade ≥3 adverse events were reported in 47.1%, 65.6%, and 61.3% of patients in the gBRCAm expansion doublet, non-gBRCAm doublet, and non-gBRCAm triplet cohorts, respectively, most commonly anemia. Olaparib plus durvalumab continued to show notable clinical activity in women with gBRCAm PSROC. Olaparib plus durvalumab with bevacizumab demonstrated encouraging clinical activity in women with non-gBRCAm PSROC. No new safety signals were identified.


Wnt Signaling Promotes Breast Cancer by Blocking ITCH-Mediated Degradation of YAP/TAZ Transcriptional Coactivator WBP2.
Cross-talk between the Hippo and Wnt pathways has been implicated recently in breast cancer development, but key intersections have yet to be fully defined. Here we report that WBP2, a transcription coactivator that binds the Hippo pathway transcription factor YAP/TAZ, contributes to Wnt signaling and breast cancer pathogenesis. Clinically, overexpression of WBP2 in breast cancer specimens correlated with malignant progression and poor patient survival. In breast cancer cells, nuclear entry and interaction of WBP2 with β-catenin was stimulated by Wnt3A, thereby activating TCF-mediated transcription and driving malignant invasive character. Mechanistic investigations showed WBP2 levels were controlled by the E3 ligase ITCH, which bound and target WBP2 for ubiquitin-dependent proteasomal degradation. Accordingly, ITCH silencing could elevate WBP2 levels. Wnt signaling upregulated WBP2 by disrupting ITCH-WBP2 interactions via EGFR-mediated tyrosine phosphorylation of WBP2 and TAZ/YAP competitive binding. Conversely, ITCH-mediated downregulation of WBP2 inhibited TCF/β-catenin transcription, in vitro transformation, and in vivo tumorigenesis. We identified somatic mutations in ITCH, which impaired its ability to degrade WBP2 and to block its function in cancer, even while retaining binding capacity to WBP2. Thus, the Wnt pathway appeared to engage WBP2 primarily by affecting its protein stability. Our findings show how WBP2/ITCH signaling functions to link the intricate Wnt and Hippo signaling networks in breast cancer. Cancer Res; 76(21); 6278-89. ©2016 AACR.


The neuro-glial coagulonome: the thrombin receptor and coagulation pathways as major players in neurological diseases.
The neuro-glial interface extends far beyond mechanical support alone and includes interactions throu-gh coagulation cascade proteins. Here, we systematically review the evidence indicating that synaptic and node of Ranvier glia cell components modulate synaptic transmission and axonal conduction by a coagulation cascade protein system, leading us to propose the concept of the neuro-glial coagulonome. In the peripheral nervous system, the main thrombin receptor protease activated receptor 1 (PAR1) is located on the Schwann microvilli at the node of Ranvier and at the neuromuscular junction. PAR1 activation effects can be both neuroprotective or harmful, depending on thrombin activity levels. Low physiological levels of thrombin induce neuroprotective effects in the Schwann cells which are mediated by the endothelial protein C receptor. High levels of thrombin induce conduction deficits, as found in experimental autoimmune neuritis, the animal model for Guillaine-Barre syndrome. In the central nervous system, PAR1 is located on the peri-synaptic astrocyte end-feet. Its activation by high thrombin levels is involved in the pathology of primary inflammatory brain diseases such as multiple sclerosis, as well as in other central nervous system insults, including trauma, neoplasms, epilepsy and vascular injury. Following activation of PAR1 by high thrombin levels the seizure threshold is lowered. On the other hand, PAR1 activation by lower levels of thrombin in the central nervous system protects against a future ischemic insult. This review presents the known structure and function of the neuro-glial coagulonome, focusing on coagulation, thrombin and PAR1 in a pathway which may be either physiological (neuroprotective) or detrimental in peripheral nervous system and central nervous system diseases. Understanding the neuro-glial coagulonome may open opportunities for novel pharmacological interventions in neurological diseases.


Temporal Regulation of Somatic Embryogenesis by Adjusting Cellular Polyamine Content in Eggplant
Four critical stages of embryogenesis, including callus induction, cellular acquisition of morphogenetic competence, expression of embryogenic program, and development and maturation of somatic embryos during somatic embryogenesis from leaf discs of eggplant (Solanum melongena L.), were identified by scanning electron microscopy. Temporal changes in arginine decarboxylase (ADC) activity and polyamines (PAs) during critical stages of embryogenesis revealed that high levels of PAs (especially putrescine [PUT]), due to higher ADC activity in discs from the apical region (with high embryogenic capacity) than from the basal region of the leaf (with poor embryogenic capacity), were correlated with differential embryogenesis response. Kinetic studies of the up- and down-regulation of embryogenesis revealed that PUT and difluoromethylarginine pretreatments were most effective before the onset of embryogenesis. Basal discs pretreated with PUT for 4 to 7 d showed improved embryogenesis that was comparable to apical discs. PA content at various critical steps in embryogenesis from basal discs were found to be comparable to that of apical discs following adjustments of cellular PA content by PUT. In contrast, pretreatment of apical discs with difluoromethylarginine for 3 d significantly reduced ADC activity, cellular PA content, and embryogenesis to levels that were comparable to basal discs. Discs from the basal region of leaves treated with PUT for 3 d during the identified stages of embryogenesis improved their embryogenic potential.


The mechanics of multi-joint posture and movement control.
The dependence of muscle force on muscle length gives rise to a "spring-like" behavior which has been shown to play a role in the execution of single-joint posture and movement. This paper extends this concept and considers the influence of the apparent mechanical behavior of the neural, muscular and skeletal system on the control and coordination of multiple degree of freedom posture and movement. A rigorous definition of "spring-like" behavior is presented. From it a numerically quantifiable, experimental test of spring-like behavior is formulated. It is shown that if the steady-state force-displacement behavior of a limb is not spring-like, this can only be due to the action of inter-muscular feedback, and can not be due to intrinsic muscle properties. The directional character of the spring-like behavior of a multiple degree of freedom system is described. The unique way in which synergistic coactivation of polyarticular muscles may modulate the directional properties of the spring-like behavior of a multiple degree of freedom system is explained. Dynamic aspects of postural behavior are also considered. The concept of mechanical impedance is presented as a rigorous dynamic generalisation of the postural stiffness of the limb. The inertial behavior of the system is characterised by its mobility. As with the stiffness or impedance, in the multiple degree of freedom case it has a directional property. The way in which the apparent kinematic redundancy of the musculo-skeletal system may be used to modify its dynamic behavior is explained. Whereas the inertial behavior of a single limb segment is not modifiable, it is shown that the apparent inertial behavior of a multiple degree of freedom system may be modulated by repositioning the joints. A unified description of the posture and movement of a multi-joint system is presented by defining a "virtual trajectory" of equilibrium positions for the limb which may be specified by the neuro-muscular system. The way in which this approach may lead to a simplification of some the apparent computational difficulties associated with the control of multi-joint motion is discussed.


The Cell Culture Environment Regulates the Transcription Factor MafB in BV-2 Microglia.
Microglia experience dramatic molecular and functional changes when transferred from the central nervous system (CNS) to a cell culture environment. Investigators largely attribute these findings to the loss of CNS-specific microenvironmental cues that dictate the gene-regulatory networks specified by master regulator transcription factors such as V-maf musculoaponeurotic fibrosarcoma oncogene homolog B (MafB). MafB regulates macrophage differentiation and activation by activating or repressing target genes critical to these processes. Here, we show that basal MafB levels in the BV-2 microglial cell line depend on the availability of lipids in the cell culture environment. Depletion of lipids, either by serum deprivation or the use of lipid-depleted serum, reduced MafB protein levels in BV-2 cells. Using live imaging, we also observed the engulfment of apoptotic BV-2 cell debris by neighboring BV-2 cells, highlighting an additional potential source of lipids in the cell culture environment. This observation was supported by experiments showing reduced MafB protein levels in BV-2 cells cultured with various phagocytosis inhibitors (cytochalasin D, annexin V) and reduced BV-2 cell phagocytic activity with serum deprivation. In aggregate, our data suggest that serum exposure regulates the transcription factor MafB in BV-2 cells through direct and indirect mechanisms.


Light-Weight Localization and Scale-Independent Multi-gate UNET Segmentation of Left and Right Ventricles in MRI Images.
Heart segmentation in cardiac magnetic resonance images is heavily used during the assessment of left ventricle global function. Automation of the segmentation is crucial to standardize the analysis. This study aims at developing a CNN-based framework to aid the clinical measurements of the left ventricle and right ventricle in cardiac magnetic resonance images. We propose a fully automated framework for localization and segmentation of the left ventricle and right ventricle in both short- and long-axis views from cardiac magnetic resonance images. The localization module utilizes a light-weight model that detects the region of interest and feeds it to the segmentation model. Also, we propose the Multi-Gate block as an extension to the UNet to boost the segmentation performance by aggregating multi-scale features. Comparison between our proposed method and the baseline UNet was performed to show the gain in the overall performance. The reliability of the model was assessed by testing the method against cardiac magnetic resonance images with different levels of noise and deformations. Heart localization accuracy was 0.59 and 1.75 pixels in both short- and long-axis views respectively. Left and right ventricle blood-pool segmentation Dice was (0.93, 0.90) in end-systole and (0.97, 0.95) in end-diastole. The left ventricle myocardium was segmented accurately with Dice of 0.91 and 0.90 in end-systole and end-diastole respectively. Left ventricle ejection fraction was found to be highly correlated with the gold standard with r = 0.987. Moreover, the proposed pipeline is fast, achieving 0.002 sec per image on average. Adding the Multi-Gate Dilated Inception Block has boosted the performance of UNet architecture and has shown generalization ability when tested on noisy and deformed cardiac magnetic resonance images. The proposed method has proven its wide applicability and reliability for heart detection when tested on different datasets.


Consideration of future consequences as a moderator of the willingness-behavior relationship for young adult marijuana use and consequences.
The Prototype Willingness Model is a dual-processing (i.e., intentional and socially reactive) health-risk behavior model. The socially reactive path includes behavioral willingness, descriptive normative perceptions, and favorable images of individuals who engage in health-risk behavior (prototype favorability) as important predictors of health behaviors. Individual differences (such as consideration of future consequences) may potentiate the effects of behavioral willingness on health-risk outcomes, such as marijuana use. Given limited research investigating marijuana use and the Prototype Willingness Model, the goals of the current study were: 1) examine consideration of future consequences and Prototype Willingness Model social reaction pathway variables in relation to behavioral willingness to use marijuana longitudinally; and 2) determine if consideration of future consequences moderated the behavioral willingness-marijuana use relation prospectively. Young adults (N = 769) from a larger longitudinal study completed baseline and 3 follow-up assessments (Months 3, 4, 5). Behavioral willingness was positively related to a higher likelihood of use, more days having used marijuana, and more consequences prospectively, over and above baseline use. Consideration of future consequences moderated the association between behavioral willingness and hours high in a typical week. These findings support the willingness-behavior association of the Prototype Willingness Model and preliminarily demonstrate consideration of future consequences' differential impact on behavioral willingness-future marijuana use relation. Intervention and prevention implications are discussed.


Multifunctional NaYF4:Yb,Er@PE3@Fe3O4 nanocomposites for magnetic-field-assisted upconversion imaging guided photothermal therapy of cancer cells.
Even though various theranostic agents have been exploited for effective cancer therapy over the years, appropriate design and fabrication of theranostic agents with simple composition, convenient preparation, high theranostic efficiency and minimal side effects on non-cancer cells are still urgently needed. Herein, multifunctional NaYF4:Yb,Er@polyelectrolyte (PE3)@Fe3O4 nanocomposites, with upconversion luminescence, superparamagnetism and photothermal performance, are prepared by a layer-by-layer self-assembly technique. Compared with Fe3O4 nanoparticles (NPs), the nanocomposites exhibited nearly 2-fold strong absorption at 808 nm, and thus resulted in an enhanced near-infrared photothermal effect. With the assistance of an external magnetic field, a high sensitivity of upconversion fluorescence imaging and a low cancer cell viability of 13.9% were achieved under 808 nm laser irradiation. It is expected that multifunctional NaYF4:Yb,Er@PE3@Fe3O4 nanocomposites would pave the way toward promoting the clinical applications of theranostic nanomaterials.


Effect of NF-kappa B inhibition on TNF-alpha-induced apoptosis in human RPE cells.
In many cell types, tumor necrosis factor (TNF)-alpha-induced apoptosis is prevented by production of TNF-alpha-induced antiapoptotic protein, a process mediated by nuclear transcription factor (NF)-kappa B. TNF-alpha is widely expressed in proliferative vitreoretinopathy (PVR) membranes and is present in the vitreous of eyes with PVR. To understand mechanisms responsible for RPE cell survival and death in this disease, this study was conducted to determine whether specific NF-kappa B blockade by mutant inhibitory (I)-kappa B (I kappa B) affects TNF-alpha-induced cell death. Cultured human RPE cells and T-98G cells were infected with adenovirus encoding either beta-galactosidase or mutant I kappa B and then treated with TNF-alpha or interleukin (IL)-1 beta. I kappa B, inhibitor of apoptosis protein (IAP)-1, and cellular Fas-associated death domain-like interleukin-1 beta-converting enzyme-like inhibitory protein (c-FLIP) expression was determined by Western blot. Functional NF-kappa B activation was examined by luciferase reporter assay. Cell viability was evaluated by trypan blue exclusion assay. Caspase-3 activity and DNA fragmentation was measured with an enzyme-linked immunosorbent assay. Mutant I kappa B expression blocked cytokine-induced I kappa B degradation and NF-kappa B transcriptional activity in RPE cells and T-98G cells. RPE cells were resistant to TNF-alpha-induced apoptosis, even after NF-kappa B activation was specifically blocked. In contrast, TNF-alpha dramatically induced apoptosis in T-98G cells after NF-kappa B inhibition. c-IAP1 expression was not affected by TNF-alpha or mutant I kappa B, and mutant I kappa B abolished TNF-alpha-induced c-FLIP induction in RPE cells. RPE cells are resistant to TNF-alpha-induced cell death, even after NF-kappa B activation is specifically blocked. RPE cell resistance to apoptotic signals present in eyes with PVR, mediated by survival factors such as c-FLIP and c-IAP1, may help to explain unwanted and unchecked cell proliferation in this disease.


The effect of different enamel surface treatments on microleakage of fissure sealants.
The aim of this study was to evaluate the effects of different techniques of surface treatment on the microleakage of fissure sealants in permanent molar teeth in vitro. 96 extracted impacted human third molars were randomly divided into 8 surface treatment groups (n=12/group) as 1. Er: YAG laser ; (Fidelis II, Fotona, Ljubljana, Slovenia) (125 mj, 20Hz) ; 2. Er: YAG laser + 37% H3PO4 (15s) ; 3. ER: AG laser + 37% H3PO4+Prime&Bond NT ; 4. Er: YAG laser + G Bond ; 5. Er: YAG laser + Prime&Bond NT ; 6. 37% H3PO4 ; 7. 37% H3PO4 + Prime&Bond NT ; 8. G Bond. Sealant material (Clinpro, 3M ESPE, Seefeld, Germany), was applied into the fissures and light-cured for 20s with LED (Bluephase C5, Ivoclar-Vivadent, Schaan, Liechtenstein). Specimens were subjected to thermocycling (1000×, 5-55°C, dwell time: 15s) and immersed in 0.5% basic fuchsin solution for 24h at 37°C. The samples were sectioned and scored on a 3 point rating scale using a light microscope with a magnification of ×20. One-way analysis of variance was used to analyze data. Multiple comparisons were analyzed using Bonferroni test (p=0.05). Er:YAG laser showed the highest microleakage scores whereas Er YAG laser + 37% H3PO4 showed the lowest. Although 37% H3PO4 group showed higher scores than Er:YAG laser + 37% H3PO4, the difference was not statistically significant. Etching fissures with phosphoric acid is sufficient prior to fissure sealant application.


Sit-to-walk Task in Hemiplegic Stroke Patients: Relationship between Movement Fluidity and the Motor Strategy in Initial Contact.
Generally, stroke patients can walk and stand up fluidly but fulfill the sit-to-walk (STW) task with difficulty. The purpose of this study was to investigate the relationship between movement fluidity and motor strategy in the initial contact of the STW task. Thirty stroke patients and ten healthy subjects performed the STW task from a sitting position, and their movement was measured by a motion analysis system. The differences in data between patients and healthy subjects were analyzed using the Mann-Whitney U test. The relationship between fluidity index (FI) and other indices (kinetic and kinematic data in STW, functional independence measure [FIM], and Fugl-Meyer Assessment [FMA]) were analyzed using Spearman's rank correlation coefficient. The stroke patients had lower FI values than the healthy subjects and exhibited shortened step length and prolonged duration from onset to the first stance leg off. FI values correlated with trunk flexure angle at initial contact, first step length, and maximum vertical floor reaction force. The independent level of the FIM of stair climbing and walking ability and the FMA of balance also correlated with FI. There is a possibility that poor balance is one of the reasons why stroke patients are unable to start walking fluently from the sitting position. To perform the STW fluidly, patients must start walking before the trunk extension is fully completed. The relationship between FI and indices of physical ability, namely stair climbing and balance, may have therapeutic benefits for coaching the STW task to stroke patients.


Diagnostic utility of renal fine-needle aspirate cytology and ultrasound in the cat.
Objectives The primary objective of this study was to retrospectively assess the diagnostic utility of feline renal fine-needle aspiration cytology by assessing diagnostic yield, cytologic characteristics and diagnostic accuracy. The secondary objective was to characterize ultrasonographic features of sampled kidneys to determine if they influenced diagnostic yield. Methods Slides, images and patient data were collected from the University of Minnesota Veterinary Medical Center database. Slides were designated as diagnostic or non-diagnostic. Non-diagnostic slides were used in calculating diagnostic yield and excluded from other analysis. Slides were evaluated for cytologic characteristics and assigned a single primary diagnosis. Ultrasound still images were evaluated for descriptive characteristics and characteristics of specific lesions were described. Cases with confirmatory testing were used to determine diagnostic sensitivity, specificity and positive and negative predictive values for detecting neoplasia. Results Of 96 cytologic submissions available for review, diagnostic yield was 68%; 48% of samples were at least moderately cellular. Of 87 cases with ultrasound data, kidneys showing subcapsular renal infiltrate, diffuse renal enlargement without pelvic dilation and infiltrative/nodular change were more likely to yield diagnostic samples. Of 12 confirmed cases, cytology was 100% sensitive and specific for the detection of neoplasia (four round-cell tumors and two carcinomas). Three cases with non-neoplastic histologic diagnoses were considered cytologically normal, two incorrectly diagnosed the pathology present, and one correctly diagnosed the pathology. While some imaging characteristics were more commonly seen in neoplastic vs non-neoplastic lesions, the sample size was insufficient for definitive correlation. Conclusions and relevance This is the first major analysis of feline ultrasound-guided renal fine-needle aspiration cytology. This technique generates adequate samples for interpretation at rates comparable to other soft tissues and is most useful in the diagnosis of neoplasia. Some imaging characteristics are indicative of the likelihood of obtaining an adequate sample for cytologic interpretation.


Replicating dissemination and identifying mechanisms of implementation of an empirically supported treatment.
Implementation research is needed in cancer control. Replication of the dissemination of empirically supported treatments (ESTs) is important as is the identification of mechanisms by which dissemination leads to implementation. Addressing these gaps, Study 1 (Cohorts 3-6, N = 104) tests for replication of a successful dissemination to community providers (Brothers et al., 2015; Cohorts 1-2; N = 62) and Study 2 (Cohorts 1-6) tests providers' changes on dissemination outcomes as mechanisms of EST usage. The Biobehavioral Intervention (BBI), a psychological EST in cancer control, was disseminated to oncology mental health providers using manual provision, didactics, roleplays, and other strategies. Study 1 tested for pre/post changes in dissemination outcomes (BBI knowledge/skills and attitudes toward and self-efficacy to deliver ESTs/BBI) between cohorts (1-2 vs. 3-6) with repeated measures ANOVAs. In Study 2, the implementation outcome was providers' (N = 166) BBI usage with patients (percent treated). Structural equation models tested dissemination outcome changes as predictors of usage at 2- and 4-months. Study 1 replicated high dissemination outcomes and significant gains in BBI knowledge (p < .001) in Cohorts 3-6. Unlike Cohorts 1-2, significant gains were observed in self-efficacy (ps < .001) but not attitudes toward ESTs (p = .523) in Cohorts 3-6. In Study 2, gains in providers' self-efficacy (ps < .05) and EST attitudes (p = .008) predicted greater 2-month (58.4% ± 35.5%) and 4-month (66.2% ± 35.0%) usage of the BBI with patients, respectively. This is the only replication of a dissemination for a psychological EST in cancer control. Results reliably show disseminations enhancing providers' self-efficacy to use and positive attitudes toward ESTs as mechanisms for EST implementation. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Why COVID-19 modelling of progression and prevention fails to translate to the real-world.
Mathematical models were used widely to inform policy during the COVID pandemic. However, there is a poor understanding of their limitations and how they influence decision-making. We used systematic review search methods to find early modelling studies that determined the reproduction number and analysed its use and application to interventions and policy in the UK. Up to March 2020, we found 42 reproduction number estimates (39 based on Chinese data: R0 range 2.1-6.47). Several biases affect the quality of modelling studies that are infrequently discussed, and many factors contribute to significant differences in the results of individual studies that go beyond chance. The sources of effect estimates incorporated into mathematical models are unclear. There is often a lack of a relationship between transmission estimates and the timing of imposed restrictions, which is further affected by the lag in reporting. Modelling studies lack basic evidence-based methods that aid their quality assessment, reporting and critical appraisal. If used judiciously, models may be helpful, especially if they openly present the uncertainties and use sensitivity analyses extensively, which need to consider and explicitly discuss the limitations of the evidence. However, until the methodological and ethical issues are resolved, predictive models should be used cautiously.


The effects of rivastigmine on processing speed and brain activation in patients with multiple sclerosis and subjective cognitive fatigue.
Cognitive decline and fatigue are typical in multiple sclerosis (MS). However, there is no official medication for either of these symptoms. The purpose of this study was to estimate the effects of a single dose of rivastigmine on processing speed and associated brain activity in patients with MS and subjective cognitive fatigue. Fifteen patients with MS and subjective cognitive fatigue and 13 healthy controls (HCs) matched for age, gender and education performed a neuropsychological assessment and functional (f)MRI. A modified version of the Paced Visual Serial Addition Test (mPVSAT) was used as the behavioural task during fMRIs. After the first scanning session, both groups were randomly divided into two subgroups receiving either rivastigmine or placebo. A single dose of rivastigmine or placebo was administrated double-blindly and 2.5 hours later the scanning was repeated. At baseline, the patients with MS showed slower processing speed in mPVSAT compared with the HCs. They also demonstrated stronger bilateral frontal activation after sustained cognitive effort than the HCs. Performance improvement and a further activation increase in the left anterior frontal cortex and additional activation in the right cerebellum were observed in patients who received rivastigmine but not in patients on placebo, or in HCs with placebo or rivastigmine. These preliminary findings suggest that rivastigmine may improve cognitive processing speed by enhancing compensatory brain activation in patients with MS.


Protection from experimental ocular herpetic keratitis by a heat-killed virus vaccine.
New Zealand white rabbits were given limbal inoculations of a heat-killed suspension of herpes simplex virus (HSV) in a lysate of human embryonic kidney cells. At intervals of four to 14 days, the animals were challenged by intrastromal inoculation with 10,000 plaque-forming units of viable HSV. Epithelial keratitis, disciform edema, and necrotizing keratitis with neovascularization of the cornea developed in control animals. Epithelial keratitis and corneal edema also developed in the immunized animals during the first week after virus challenge, but these symptoms rapidly resolved during the following weeks. The absence of iritis, neovascularization, and necrotizing keratitis in the corneas of the immunized animals was particularly striking.


The comparison of motor performance between part and whole tasks in elderly persons.
When teaching clients a multistep functional task, therapists tend to break down the task into part tasks with discrete movements. The purpose of this study was to compare the kinematic performance between part and whole tasks in elderly persons. A counterbalanced repeated-measures design was used. Twenty elderly persons without motor problems (7 men, 13 women) performed a signature task in two conditions. For the part-task condition, the participants did the task in a step-by-step manner: (a) reach for a pen, (b) bring the pen to the paper, and (c) sign the name. For the whole-task condition, the participants performed the task in an integrated continuous flow. Kinematic performances for two movement segments (i.e., reaching for the pen, bringing the pen to the paper) were compared between conditions. Generally, the whole-task condition elicited a more efficient, more forceful, and smoother movement than the part-task condition. The results suggest the importance of keeping a multistep functional task whole.


The economic and social burden of Alzheimer disease on families in the Lombardy region of Italy.
The purpose of this study was to measure resource consumption associated with the provision of nonmedical care to noninstitutionalized patients with Alzheimer disease (AD) residing in the Lombardy Region of Italy. A questionnaire was mailed to 1,501 caregivers who sought advice from the "Federation Alzheimer Italia" in 1995. On the basis of 616 returned questionnaires, the authors estimated that a patient with AD requires 18 hours per week of paid nonmedical services and 45 hours per week of personal care provided by a primary caregiver. Primary caregivers are more likely to be women, spouses, and retired. Almost 7 of 10 patients are supported by at least a second caregiver. Annual expenditure for nonmedical cost per patient with AD is estimated to be L 13,388,000 (U.S. $8,218). Using the replacement cost approach, the authors estimated the economic cost of informal (unpaid) care to be L 72,877,000 (U.S. $44,736). Despite some limitations in the design of the survey, this first Italian study on primary data highlights the impressive economic burden of AD on families. It also shows that AD puts many Italian families at great financial risk. Adequate and timely funding arrangements should be urgently found to make resources available to future generations of patients.


Disability prevalence-context matters: A descriptive community-based survey.
There is increasing interest in the collection of globally comparable disability data. Context may influence not only the rates but also the nature of disability, thus locally collected data may be of greater use in service delivery planning than national surveys. The objective of this article was to explore the extent to which two areas, both under-resourced but geographically and socially distinct, differed in terms of the prevalence and patterns of disability. A cross-sectional descriptive survey design was utilised, using stratified cluster sampling in two under-resourced communities in the Western Cape, South Africa. Nyanga is an informal urban settlement in Cape Town and Oudtshoorn is a semi-rural town. The Washington Group Short Set of questions was used to identify persons with disabilities (PWD), and a self-developed questionnaire obtained socio-demographic information. The overall prevalence of disability was 9.7% (confidence intervals [CIs] 9.7-9.8) and the proportion of PWD was significantly different between the two sites (Chi-Sq = 129.5, p < 0.001). In the urban area, the prevalence rate of any disability was 13.1% (CIs 12.0-14.3) with 0.3% (CIs 0.1-0.6) reporting inability to perform any function at all. In contrast, the semi-rural community had a lower overall prevalence rate of 6.8% (CIs 6.0% - 7.8%) but a higher rate of those unable to perform any function: 1% (CIs 0.07-1.4). Disability was associated with gender, age, unemployment and lower income status in both areas. Deprived areas tend to show higher disability prevalence rates than the National Census estimates. However, the discrepancy in prevalence and patterns of disability between the two under-resourced areas indicates the need for locally specific data when planning health interventions.


[DNA-ase I activity in the DNA-ase I-inhibitor system].
An increase in the DNase I activity was revealed in the serum of mice after intraperitoneal injection of different antigens. This reaction is related to the antigen nature and is dissimilar in mice of different strains. The increased activity of the inhibitor in the spleen of DBA/2 and BALB/c mice was discovered after intravenous injection of bovine DNase I. A potential role of serum DNase I in the system DNase I-inhibitor is discussed.


The chromatin structure of well-spread demembranated human sperm nuclei revealed by atomic force microscopy.
The fundamental structure formed when genomic DNA is packaged by protamine in the human sperm nucleus still remains essentially unresolved. It is known that the binding of protamine, a small arginine-rich protein, to DNA generates a large dense, hydrophobic complex making the sperm chromatin structure difficult to study microscopically. To visualize the internal nuclear structures, isolated human sperm nuclei were swollen extensively in saline buffer using only a reducing agent. The nuclei were swollen during deposition onto coverglass and then imaged in the atomic force microscope (AFM). The two main results obtained from imaging individual well-spread nuclei indicate that native human sperm chromatin is: (1) particulate, consisting primarily of large nodular structures averaging 98 nm in diameter, and (2) also composed of smaller, nucleosome-like particles observed to form linear chains near the nuclear periphery. These two types of chromatin particles imaged by AFM are remarkably similar to other AFM measurements made on native and reconstituted sperm and somatic chromatin.


Development and validation of an international preoperative risk assessment model for postoperative delirium.
Postoperative delirium (POD) is a frequent complication in older adults, characterised by disturbances in attention, awareness and cognition, and associated with prolonged hospitalisation, poor functional recovery, cognitive decline, long-term dementia and increased mortality. Early identification of patients at risk of POD can considerably aid prevention. We have developed a preoperative POD risk prediction algorithm using data from eight studies identified during a systematic review and providing individual-level data. Ten-fold cross-validation was used for predictor selection and internal validation of the final penalised logistic regression model. The external validation used data from university hospitals in Switzerland and Germany. Development included 2,250 surgical (excluding cardiac and intracranial) patients 60 years of age or older, 444 of whom developed POD. The final model included age, body mass index, American Society of Anaesthesiologists (ASA) score, history of delirium, cognitive impairment, medications, optional C-reactive protein (CRP), surgical risk and whether the operation is a laparotomy/thoracotomy. At internal validation, the algorithm had an AUC of 0.80 (95% CI: 0.77-0.82) with CRP and 0.79 (95% CI: 0.77-0.82) without CRP. The external validation consisted of 359 patients, 87 of whom developed POD. The external validation yielded an AUC of 0.74 (95% CI: 0.68-0.80). The algorithm is named PIPRA (Pre-Interventional Preventive Risk Assessment), has European conformity (ce) certification, is available at http://pipra.ch/ and is accepted for clinical use. It can be used to optimise patient care and prioritise interventions for vulnerable patients and presents an effective way to implement POD prevention strategies in clinical practice.


Preexisting mental illness and risk for developing a new disorder after hurricane Katrina.
To investigate predisaster mental illness as a risk factor of poor postdisaster mental health outcomes, veterans with (n = 249) and without (n = 250) preexisting mental illness residing in the Gulf Coast during Hurricane Katrina were surveyed after Katrina and screened for posttraumatic stress disorder (PTSD), depression, generalized anxiety disorder, and panic. Logistic regression examined the association between preexisting mental disorders and positive screens after the hurricane, adjusting for demographics and exposure to hurricane-related stressors. The odds of screening positive for any new mental disorder were 6.8 times greater for those with preexisting mental illness compared with those without preexisting mental illness. Among those with preexisting PTSD, the odds of screening positive for any new mental illness were 11.9 times greater; among those with schizophrenia, 9.1 times greater; and among those with affective disorders, 4.4 times greater. Persons with preexisting mental illnesses, particularly PTSD, should be considered a high-risk group for poor outcomes after a disaster.


The tyrosine phosphatase SHP2 controls TGFβ-induced STAT3 signaling to regulate fibroblast activation and fibrosis.
Uncontrolled activation of TGFβ signaling is a common denominator of fibrotic tissue remodeling. Here we characterize the tyrosine phosphatase SHP2 as a molecular checkpoint for TGFβ-induced JAK2/STAT3 signaling and as a potential target for the treatment of fibrosis. TGFβ stimulates the phosphatase activity of SHP2, although this effect is in part counterbalanced by inhibitory effects on SHP2 expression. Stimulation with TGFβ promotes recruitment of SHP2 to JAK2 in fibroblasts with subsequent dephosphorylation of JAK2 at Y570 and activation of STAT3. The effects of SHP2 on STAT3 activation translate into major regulatory effects of SHP2 on fibroblast activation and tissue fibrosis. Genetic or pharmacologic inactivation of SHP2 promotes accumulation of JAK2 phosphorylated at Y570, reduces JAK2/STAT3 signaling, inhibits TGFβ-induced fibroblast activation and ameliorates dermal and pulmonary fibrosis. Given the availability of potent SHP2 inhibitors, SHP2 might thus be a potential target for the treatment of fibrosis.


Unsaturated N-acetyl- D-glucosaminuronic acid glycosides as inhibitors of influenza virus sialidase.
The threat of pandemic influenza is a significant concern of governments worldwide. There is a very limited and relatively expensive armament to tackle such a pandemic should it occur. This fact provides much impetus to the scientific community for the discovery of new and less expensive anti-influenza drugs. Our longstanding interest in the inhibition of influenza virus sialidase, coupled with the development of simple carbohydrates that mimic an unsaturated derivative of the enzyme's naturally-occurring ligand, N-acetylneuraminic acid, has led us to investigate the development of influenza virus sialidase inhibitors based on these mimetics. We have successfully prepared a range of these compounds, in good yield, from the relatively inexpensive carbohydrate N-acetylglucosamine utilising a short synthetic procedure. We have employed a sialidase inhibition assay for biological evaluation of the target compounds and to our delight these mimetics have displayed significant inhibition of influenza virus sialidase.


Automatic method to monitor floating macroalgae blooms based on multilayer perceptron: case study of Yellow Sea using GOCI images.
Timely and accurate information about floating macroalgae blooms (MAB), including their distribution, movement, and duration, is crucial in order for local government and residents to grasp the whole picture, and then plan effectively to restrain economic damage. Plenty of threshold-based index methods have been developed to detect surface algae pixels in various ocean color data with different manners; however, these methods cannot be used for every satellite sensor because of the spectral band configuration. Also, these traditional methods generally require other reliable indicators, and even visual inspection, in order to achieve an acceptable mapping of MAB that appears under diverse environmental conditions (cloud, aerosol, and sun glint). To overcome these drawbacks, a machine learning algorithm named Multi-Layer Perceptron (MLP) was used in this paper to establish a novel automatic method to monitor MAB continuously in the Yellow Sea, using Geostationary Ocean Color Imager (GOCI) imagery. The method consists of two MLP models, which consider both spectral and spatial features of Rayleigh-corrected reflectance (Rrc) maps. Accuracy assessment and performance comparison showed that the proposed method has the capability to provide prediction maps of MAB with high accuracy (F1-score approaching 90% or more), and with more robustness than the traditional methods. Most importantly, the model is practically adaptable for other ocean color instruments. This allows customized models to be built and used for monitoring MAB in any regional areas. With the development of machine learning models, long-term mapping of MAB in global ocean is conducive to promoting the associated studies.


[Genetic and molecular diagnostics in retinoblastoma].
Retinoblastoma is a childhood malignancy of the eye. Almost all patients with familial or bilateral disease suffer from the hereditary form of the disease that is caused by germline mutations in one allele of the RB1 gene. Tumor development is initiated by the loss of the second RB allele in a retinal progenitor cell. Most patients with isolated unilateral disease have nonhereditary retinoblastoma and thus do not carry a mutant allele in their germline. In no patient, the presence of a germline mutation can be excluded clinically. Consequently, relatives are at an increased risk for retinoblastoma. Molecular testing, however, enables accurate risk prediction provided that samples are available. In some relatives an increased risk can be excluded by segregation analysis. Most often, however, identification of the disease causing mutation is necessary for accurate risk prediction. Mutation analysis, which is impeded by the size and complexity of the RB gene, is facilitated by use of efficient screening methods. Using these methods, the oncogenic mutation can be identified in most patients. Therefore, predictive testing has become an integral part of contemporary management of retinoblastoma.


Social workers' perceptions of barriers to interpersonal therapy implementation for treating postpartum depression in a primary care setting in Israel.
Research on evidence-based practice (EBP) implementation in social work often neglects to include evaluation of application barriers. This qualitative study examined social workers' perspectives of provider- and organisational-related barriers to implementing a brief eight-session interpersonal therapy (IPT) intervention, a time-limited EBP that addresses reducing depressive symptoms and improving interpersonal functioning. Implementation took place in a primary care setting in Israel and was aimed at treating women who have postpartum depression (PPD) symptoms. Using purposeful sampling, 25 primary care licensed social workers were interviewed between IPT training and implementation regarding their perceived barriers to implementing IPT in practice. Data analysis was facilitated using a phenomenological approach, which entails identifying the shared themes and shared experiences of research participants regarding barriers to implementing IPT. Three themes emerged from the analysis of interviews: Perceived lack of flexibility of IPT intervention in comparison with more familiar methods social workers previously applied, specifically regarding the number of sessions and therapeutic topics included in the IPT protocol; insecurity and hesitance to gain experience with a new method of intervention; and organisational barriers, including difficulties with referrals, the perception of HMOs as health facilities not suitable for therapy, and time constraints. Addressing perceived barriers of social workers toward implementing EBPs, such as IPT for postpartum depression, during the training phase is crucial for enabling appropriate implementation. Future training should include examining practitioners' attitudes toward implementation of EBPs, as part of standardised training protocols.


A four-year survey of African swine fever in Malawi.
A serological survey of free-ranging domestic pigs in the Central and Southern Regions of Malawi, together with laboratory data on confirmed cases of African swine fever (ASF) and data from interviews with pig owners, undertaken over a four-year period from 1981-4, has enabled the ASF enzootic area of Malawi to be identified. The area covers much of the western part of the Central Region and includes Mchinji district and parts of Kasungu, Ntchisi, Dowa and Lilongwe districts. Mortality is substantially less than 100% in outbreaks within the enzootic area but approaches 100% in outbreaks outside this area, as shown by both the serological investigation and the interview data.


Hormonal control of tick development and reproduction.
Ecdysteroids (moulting hormones), juvenoids and neuropeptides in ticks are reviewed but, by far, the emphasis is on the former since this class of hormones has been the subject of most investigations. In immature stages of ticks, ecdysteroids have been shown to regulate moulting and to terminate larval diapause. Although there is a paucity of information on the molecular action of ecdysteroids in ticks, their action appears to be via a heterodimeric ecdysone/ultraspiracle receptor, as in insects. The role of ecdysteroids in sperm maturation in adult males is considered. In females, ecdysteroids function in the regulation of salivary glands, of production of sex pheromones and of oogenesis and oviposition. There is evidence for ecdysteroid production in the integument and pathways of hormone inactivation are similar to those in insects. Ecdysteroids also function in embryogenesis. Although evidence for the occurrence and functioning of juvenile hormones in ticks has been contradictory, in recent thorough work it has not been possible to detect known juvenile hormones in ticks, nor to demonstrate effects of extracts on insects. Factors (neuropeptides) from the synganglion affect physiological processes and limited immunocytochemical studies are reviewed. Sigificantly, a G-protein-coupled receptor has been cloned, expressed, and specifically responds to myokinins.


1,2-Trans-selective synthesis of glycosyl boranophosphates and their utility as building blocks for the synthesis of phosphodiester-linked disaccharides.
A highly 1,2-trans-selective synthesis of glycosyl boranophosphate derivatives by glycosylation of dimethyl boranophosphate with glycosyl iodides was developed. A study on the reaction mechanism indicated that the stereoselectivity of the reactions is controlled by neighboring group participation. The resultant glycosyl boranophosphate triesters were converted into the corresponding boranophosphate diesters and condensed with appropriately protected monosaccharides to give disaccharides linked with an anomeric boranophosphate linkage. Furthermore, the disaccharides worked as precursors of the corresponding phosphodiester-linked disaccharides. The whole synthesis of boranophosphate-linked disaccharides and their conversion to the phosphodiester-linked disaccharides were accomplished in good yields without loss of stereopurity at the anomeric position, indicating that the method is useful to synthesize diastereopure glycosyl phosphate-containing biomolecules.


Molecular mechanisms of tumor necrosis factor alpha-stimulated leukocyte recruitment into the murine hepatic circulation.
To date, much of the adhesion work in the liver has been restricted to sinusoids and postsinusoidal venules. However, selectins have been localized on the portal (presinusoidal) venules and these vessels have been shown to be important in metastasis of tumors. The purpose of this study was to characterize the leukocyte-endothelial interactions within the 3 compartments of the hepatic microvasculature under baseline conditions and in response to tumor necrosis factor alpha (TNF-alpha). Mice deficient in P-selectin or both E- and P-selectin were compared with wild-type (C57Bl/6, wild type) mice. Animals were injected with murine TNF-alpha (15 microg/kg intraperitoneally [IP]) and the liver was examined by fluorescence intravital microscopy 4 hours later. Under baseline conditions, leukocyte flux in the portal venules was 1.42 +/- 0.42 cells/min. Leukocyte flux in the portal venules of wild-type mice increased 8-fold in response to 4 hours of TNF-alpha stimulation. This was reduced by 50% in the P-selectin-deficient mice but was not reduced further by either the addition of an E-selectin antibody (9A9, 100 microg intravenously [IV]) to these mice or in mice deficient in both E- and P-selectin. In P-selectin-deficient mice, the addition of an antibody against alpha(4)-integrin (R1-2, 75 microg IP) reduced rolling to baseline. But in the E- and P-double-selectin-deficient mice the addition of an antibody against L-selectin (Mel 14, 3 microg/kg IV) had no effect on TNF-alpha-induced recruitment. Similar responses were seen in the central venules, however, in the sinusoids the increased number of stationary leukocytes seen in response to 4 hours of TNF-alpha stimulation in the wild-type mice was not reduced in P-selectin-deficient mice with or without the alpha(4)-integrin antibody. These data suggest that leukocytes can use alpha(4)-integrin independent of the selectins in the venules. Within the sinusoids, however, inhibition of E-selectin, P-selectin, and alpha(4)-integrin was insufficient to reduce leukocyte recruitment.


Beta-cell markers and autoantigen expression by a human insulinoma cell line: similarities to native beta cells.
In the present study we have evaluated the expression of different beta-cell markers, islet molecules and auto-antigens relevant in diabetes autoimmunity by a human insulinoma cell line (CM) in order to define its similarities with native beta cells and to discover whether it could be considered as a model for studies on immunological aspects of Type 1 diabetes. First, the positivity of the CM cell line for known markers of neuroendocrine derivation was determined by means of immunocytochemical analysis using different anti-islet monoclonal antibodies including A2B5 and 3G5 reacting with islet gangliosides, and HISL19 binding to an islet glycoprotein. Secondly, the expression and characteristics of glutamic acid decarboxylase (GAD) and of GM2-1 ganglioside, both known to be islet autoantigens in diabetes autoimmunity and expressed by human native beta cells, were investigated in the CM cell line. The pattern of ganglioside expression in comparison to that of native beta cells was also evaluated. Thirdly, the binding of diabetic sera to CM cells reacting with islet cytoplasmic antigens (ICA) was studied by immunohistochemistry. The results of this study showed that beta cell markers identified by anti-islet monoclonal antibodies A2B5, 3G5 and HISL-19 are expressed by CM cells; similarly, islet molecules such as GAD and GM2-1 ganglioside are present and possess similar characteristics to those found in native beta cells; the pattern of expression of other gangliosides by CM cells is also identical to human pancreatic islets; beta cell autoantigen(s) reacting with antibodies present in islet cell antibodies (ICA) positive diabetic sera identified by ICA binding are also detectable in this insulinoma cell line. We conclude that CM cells show close similarities to native beta cells with respect to the expression of neuro-endocrine markers, relevant beta cell autoantigens in Type 1 diabetes (GAD, GM2-1, ICA antigen), and other gangliosides. Therefore, this insulinoma cell line may be considered as an ideal model for studies aimed at investigating autoimmune phenomena occurring in Type 1 diabetes.


Matrix metalloproteinase expression in normal skin associated with basal cell carcinoma and in distal skin from the same patients.
To obviate the difficulty of ruling out confounding variables (eg, age, individual variability) as the source of differences seen when comparing tumor tissue and control tissue from unrelated individuals, we examined the expression of matrix metalloproteinase (MMP)-1 (interstitial collagenase) and MMP-9 (92-kDa gelatinase B) in histologically normal skin immediately adjacent to basal cell carcinomas (peritumoral tissue) after Mohs micrographic surgery and postauricular skin from the same patients. Peritumoral and postauricular skin samples were obtained from 17 patients undergoing Mohs surgery. Expression of MMP-1 and MMP-9 was examined in these specimens using a combination of approaches including zymography, collagen-degradation assays, and immunohistology. The expression levels of MMP-1 and MMP-9 were consistently elevated in the peritumoral tissue compared with skin from the distal site. This finding indicates that even when potentially important variables such as age and individual variability are controlled for, tumor-specific effects on the expression of MMP-9 and MMP-1 remain.


Polyisoprenylated cysteinyl amide inhibitors induce caspase 3/7- and 8-mediated apoptosis and inhibit migration and invasion of metastatic prostate cancer cells.
Metastatic castration-resistant prostate cancer (mCRPC) is the most aggressive and deadly form of prostate cancer. It is characterized by the overexpression of epidermal growth factor receptors whose signals are mediated by small monomeric G proteins of the Ras superfamily. These require polyisoprenylation for functional activity. Polyisoprenylated cysteinyl amide inhibitors (PCAIs) of polyisoprenylated methylated protein methyl esterase (PMPMEase) were developed as potential targeted therapies to mitigate excessive growth signaling in mCRPC either by inhibiting PMPMEase and/or perturbing the polyisoprenylation-dependent functional interactions. We investigated the effects of PCAIs on the viability of prostate cancer PC 3, DU 145, MDA PCa 2b, LNCaP and 22Rv1 cells, determined the effect of the PCAIs on PC 3 cell proliferation, survival and caspase-mediated apoptotic cell death. Metastatic PC 3 and DU 145 cell migration and invasion in the presence of NSL-BA-040 were determined using the scratch and matrigel invasion assays. We further investigated the effect of NSL-BA-040 on F-actin organization in TagRFP F-actin marker-transfected metastatic PC 3 cells. The PCAIs suppress mCRPC cell viability with EC50 values ranging from 1.3 to 4.0 µM for the most potent of the PCAIs against PC 3, DU 145, MDA PCa 2b, LNCaP and 22Rv cells. PCAIs induced apoptotic cell death in PC 3 and DU 145 cells as determined by annexin V/propidium iodide flow cytometry analysis through the activation of caspases 3 and 8 while also inhibiting migration and invasion through the disruption of F-actin organization. Taken together, our studies show the anti-cancer effects on mCRPC cells through induction of caspase-mediated apoptosis and F-actin-mediated inhibition of cell motility and invasion thereby indicating the anti-tumor and anti-metastatic potential of the PCAIs.


A Randomized Controlled Trial of Cash Incentives or Peer Support to Increase HCV Treatment for Persons With HIV Who Use Drugs: The CHAMPS Study.
Despite access to direct-acting antivirals, barriers to a hepatitis C virus (HCV) cure persist, especially among persons living with human immunodeficiency virus (HIV) (PLWH) who use drugs. Interventions such as peer mentors or cash incentives may improve the care continuum. The CHAMPS (Chronic HepAtitis C Management to ImProve OutcomeS) study randomized 144 PLWH, recruited from an outpatient clinic, with substance use disorders into three treatment groups: usual care (UC) (n = 36), UC plus cash incentives (n = 54), and UC plus peer mentors (n = 54) to evaluate HCV treatment uptake and cure. All participants received 12-weeks of ledipasvir/sofosbuvir (LDV/SOF). Trained peer mentors had well-controlled HIV and HCV. Cash incentives were contingent on visit attendance (maximum $220). The primary endpoint was HCV treatment initiation; secondary endpoints included sustained virologic response (SVR) and HCV reinfection. The majority of participants were male (61%), Black (93%), and unemployed (85%). Depression and active drug and alcohol use were common. Overall, 110 of 144 (76%) participants initiated LDV/SOF. Although treatment initiation rates were higher in PLWH randomized to peers (83%, 45 of 54) or cash (76%, 41 of 54) compared to UC (67%, 24 of 36), these differences were not statistically significant (P = .11). Most PLWH who initiated treatment achieved SVR (100 of 110, 91%). LDV/SOF was well tolerated; peers and cash had no effect on drug and alcohol use during therapy. One individual from the cash cohort experienced HCV reinfection. After removal of system barriers, one-third of PLWH in UC did not initiate HCV treatment. Among those who initiated, SVR rates were high. Research involving PLWH who use drugs should focus on overcoming barriers to treatment initiation. The registration data for the trial are in the ClinicalTrials.gov database, number NCT02402218.


Mitochondrial DNA phylogeography of the polytypic North American rat snake (Elaphe obsoleta): a critique of the subspecies concept.
Subspecies have been considered artificial subdivisions of species, pattern classes, or incipient species. However, with more data and modern phylogenetic techniques, some subspecies may be found to represent true species. Mitochondrial DNA analysis of the polytypic snake, Elaphe obsoleta, yields well-supported clades that do not conform to any of the currently accepted subspecies. Complete nucleotide sequences of the cytochrome b gene and the mitochondrial control region produced robust maximum-parsimony and maximum-likelihood trees that do not differ statistically. Both trees were significantly shorter than a most parsimonious tree in which each subspecies was constrained to be monophyletic. Thus, the subspecies of E. obsoleta do not represent distinct genetic lineages. Instead, the evidence points to three well-supported mitochondrial DNA clades confined to particular geographic areas in the eastern United States. This research underscores the potential problems of recognizing subspecies based on one or a few characters.


Characterization of Physiological Noise in Complex Cardiovascular Variability Series.
The cardiovascular system can be analyzed using spectral, nonlinear, and complexity metrics. Nevertheless, dynamical noise may significantly impact these quantifiers. To our knowledge, there has been no attempt to quantify the intrinsic cardiovascular system noise driving heartbeat dynamics. To this end, this study presents a novel, model-free framework to define and quantify physiological noise using nonlinear Approximate Entropy profile. The framework was tested using analytical noisy series and then applied to real Heart Rate Variability (HRV) series gathered from a publicly-available dataset of recordings from 19 young and 19 elderly subjects watching the movie "Fantasia". Results suggest that physiological noise may account for over 15% of cardiovascular dynamics and is influenced by aging, with decreased cardiac noise in the elderly compared to the young subjects. Our findings indicate that physiological noise is a crucial factor in characterizing cardiovascular dynamics, and current spectral, nonlinear, and complexity assessments should take into account underlying dynamical noise estimates.


Carotid-Falciform Optic Neuropathy: Microsurgical Treatment.
Several recent reports have implicated vascular ectasia and vessel contact in dysfunction of the visual apparatus. A subset of patients with prechiasmatic visual deterioration have an ectatic internal carotid artery (ICA) that displaces and flattens the optic nerve (ON) rostrally as the ON exits the skull base. We describe a proposed pathophysiologic mechanism and a straightforward surgical technique for dealing with this problem. Via an ipsilateral pterional craniotomy, the bony roof of the optic canal is removed. The falciform ligament is opened in parallel to the ON. Adhesions between the ICA and ON are then dissected, and a Teflon pledget is placed between the ICA and ON to complete the decompression. Patients both in the literature and in this series experienced an improvement in their vision postoperatively. We propose that 3 mechanisms contribute to this caroticofalciform optic neuropathy: 1) mass effect from ICA ectasia, 2) ON irritation from vessel pulsatility, and 3) indirect compression by the falciform ligament from above. This disease process can be treated safely using standard microsurgical techniques with excellent outcomes.


Beneficial Health Effects of Glucosinolates-Derived Isothiocyanates on Cardiovascular and Neurodegenerative Diseases.
Neurodegenerative diseases (NDDs) and cardiovascular diseases (CVDs) are illnesses that affect the nervous system and heart, all of which are vital to the human body. To maintain health of the human body, vegetable diets serve as a preventive approach and particularly Brassica vegetables have been associated with lower risks of chronic diseases, especially NDDs and CVDs. Interestingly, glucosinolates (GLs) and isothiocyanates (ITCs) are phytochemicals that are mostly found in the Cruciferae family and they have been largely documented as antioxidants contributing to both cardio- and neuroprotective effects. The hydrolytic breakdown of GLs into ITCs such as sulforaphane (SFN), phenylethyl ITC (PEITC), moringin (MG), erucin (ER), and allyl ITC (AITC) has been recognized to exert significant effects with regards to cardio- and neuroprotection. From past in vivo and/or in vitro studies, those phytochemicals have displayed the ability to mitigate the adverse effects of reactive oxidation species (ROS), inflammation, and apoptosis, which are the primary causes of CVDs and NDDs. This review focuses on the protective effects of those GL-derived ITCs, featuring their beneficial effects and the mechanisms behind those effects in CVDs and NDDs.


Extremely wide and asymmetric anterior decompression causes postoperative C5 palsy: an analysis of 32 patients with postoperative C5 palsy after anterior cervical decompression and fusion.
Single-center retrospective study. We examined whether extremely wide and asymmetric anterior decompression causes postoperative C5 palsy. Postoperative C5 palsy is a complication of cervical decompression surgery. We hypothesized that C5 palsy may be caused by nerve root impairment through extremely wide and asymmetric dural expansion due to unilateral predominant wide anterior decompression with concomitant C4-C5 foraminal stenosis. The study included 32 patients with postoperative C5 palsy from a cohort of 459 patients who underwent anterior cervical decompression and fusion at the C4-C5 disc level for cervical myelopathy. The 64 upper extremities were divided into 2 groups according to palsy side (n = 35) or nonpalsy side (n = 29). Also, to correlate radiological findings, 66 consecutive patients who underwent anterior cervical decompression and fusion without postoperative C5 palsy were selected as control. In patients with C5 palsy, the unilateral decompression width on the palsy side was significantly larger than that on the nonpalsy side (8.63 vs. 6.92 mm, P = 0.0003). In addition, the decompression width was significantly larger (15.69 vs. 14.38 mm, P = 0.02), the diameter of the C4-C5 foramen was significantly smaller (2.73 vs. 3.24 mm, P = 0.0008), the anterior spinal cord shift was significantly smaller (0.14 vs. 0.73 mm, P< 0.0001), and significant decompression asymmetry (0.74 vs. 0.89, P = 0.0003) was present in the patients with C5 palsy compared with controls. Extremely wide and asymmetric decompression concomitant with pre-existing C4-C5 foraminal stenosis may cause postoperative C5 palsy. Our findings should be valuable for surgeons considering anterior cervical decompression and fusion that includes the C4-C5 level. Surgeons should consider restriction of the decompression width to less than 15 mm and avoiding asymmetric decompression to reduce the incidence of C5 palsy.


Modelling Informal Carers' Health-Related Quality of Life: Challenges for Economic Evaluation.
There has been increasing interest in including carers' health-related qualify of life (HRQoL) in decision models, but currently there is no best practice guidance as to how to do so. Models thus far have typically assumed that carers' HRQoL can be predicted from patient health states, as we illustrate with three examples of disease-modifying treatments. However, this approach limits the mechanisms that influence carers' HRQoL solely to patient health and may not accurately reflect carers' outcomes. In this article, we identify and discuss challenges associated with modelling intervention effects on carers' HRQoL: attaching carer utilities to patient disease states, the size of the caring network, aggregation of carer and patient HRQoL, patient death, and modelling longer-term carer HRQoL. We review and critique potential alternatives to modelling carers' HRQoL in decision models: trial-based analyses, qualitative consideration, cost-consequence analysis, and multicriteria decision analysis, noting that each of these also has its own challenges. We provide a framework of issues to consider when modelling carers' HRQoL and suggest how these can be addressed in current practice and future research.


Facile light-initiated radical generation from 4-substituted pyridine under ambient conditions.
Photochemical reactions that generate stable radical species under ambient conditions find unique applications in materials science. Here we present a facile photogeneration of a stable radical species from a 4-substituted pyridine derivative in the presence of water and air at room temperature. The radical generation reaction accompanies a visible colour change to green and is repeatable multiple times.


Tick repellent properties of three Libyan plants.
Specimens of Salvadora persica Wallich (Salvadoraceae), Pistacia atlantica Desfontaines (Anacardiaceae), and Juniperus phoenicea L. (Cupressaceae) were collected at The Green Mountain in northeastern Libya. The tick-repellent effects of the essential oils from the plants were evaluated using host-seeking nymphs of Ixodes ricinus L. (Acari: Ixodidae) in the laboratory. Significant tick repellent effects were observed for the oils of all three species, but the duration of action was short. The oils were obtained by steam distillation. Volatile compounds of the essential oils were collected by solid phase microextraction and the constituents were identified by gas chromatographymass spectrometry.


Video-assisted thoracoscopic right lower lobectomy for lung cancer using the Harmonic scalpel.
A 68-year-old lady felt chest pain with tenderness of three years duration, who was a diagnosis of adenocarcinoma cell lung cancer. The accesses employed were based on the use of three ports through thoracoscope. With Harmonic scalpel all the hilar structures were isolated and separately sectioned, and systemic lymph node dissection was performed. Postoperative pathologic diagnosis was T2bN0M0 adenocarcinoma. Harmonic scalpel technique with video-assisted thoracoscopy surgery (VATS) has many advantages over traditional open thoracotomy and use of electrocautery for lobectomy in lung cancer surgery. Chief among these is greater patient safety. With Harmonic scalpel dissection, blood loss is minimal and this speeds patient recovery. It allows better visualization of key anatomic structures and permits better lymph node dissection, which is essential to reducing metastatic spread of the cancer.


CHF5074, a novel gamma-secretase modulator, restores hippocampal neurogenesis potential and reverses contextual memory deficit in a transgenic mouse model of Alzheimer's disease.
The effects of compounds interfering with gamma-secretase, the enzymatic complex responsible of the formation of the amyloid-beta (Abeta) peptide from amyloid-beta protein precursor (AbetaPP), on plaque deposition in transgenic mouse models of Alzheimer's disease are known but scanty data are available on the effects of these drugs on brain plasticity. We evaluated the effects of long-term treatment with CHF5074, a new gamma-secretase modulator, on hippocampal neurogenesis, cortical synaptophysin levels, and contextual memory in transgenic mice carrying the double Swedish mutation of AbetaPP (Tg2576). Six-month old Tg2576 mice were treated with CHF5074 (375 ppm in the diet) up to 15 months of age. Age-matched control transgenic and wild-type mice received standard diet. Compared to wild-type animals, transgenic controls showed a significant decrease in the number of doublecortin-positive neuroblasts in dentate gyrus, synaptophysin intensity in the cortex, freezing to context in the contextual fear conditioning test. Compared to transgenic controls, CHF5074 treatment of Tg2576 mice resulted in a significant attenuation of the neurogenesis impairment in hippocampus (p=0.036), normalization of synaptophysin levels in cortex (p< 0.001), attenuation of plaque burden in the cortex (p=0.033), increases astroglial reaction around plaques (p=0.001), and attenuation of activated microglia (p=0.040). These effects were associated to a complete reversal of contextual memory deficit (p=0.006). Contextual memory significantly correlated with synaptophysin immunoreactivity in the cortex (r=0.548, p=0.0038).


Approaches to interpreting and choosing the best treatments in network meta-analyses.
When randomized trials have addressed multiple interventions for the same health problem, network meta-analyses (NMAs) permit researchers to statistically pool data from individual studies including evidence from both direct and indirect comparisons. Grasping the significance of the results of NMAs may be very challenging. Authors may present the findings from such analyses in several numerical and graphical ways. In this paper, we discuss ranking strategies and visual depictions of rank, including the surface under the cumulative ranking (SUCRA) curve method. We present ranking approaches' merits and limitations and provide an example of how to apply the results of a NMA to clinical practice.


Independent actions on cyclin-dependent kinases and aryl hydrocarbon receptor mediate the antiproliferative effects of indirubins.
Indirubin, a bis-indole obtained from various natural sources, is responsible for the reported antileukemia activity of a Chinese Medicinal recipe, Danggui Longhui Wan. However, its molecular mechanism of action is still not well understood. In addition to inhibition of cyclin-dependent kinases and glycogen synthase kinase-3, indirubins have been reported to activate the aryl hydrocarbon receptor (AhR), a cotranscriptional factor. Here, we confirm the interaction of AhR and indirubin using a series of indirubin derivatives and show that their binding modes to AhR and to protein kinases are unrelated. As reported for other AhR ligands, binding of indirubins to AhR leads to its nuclear translocation. Furthermore, the apparent survival of AhR-/- and +/+ cells, as measured by the MTT assay, is equally sensitive to the kinase-inhibiting indirubins. Thus, the cytotoxic effects of indirubins are AhR-independent and more likely to be linked to protein kinase inhibition. In contrast, a dramatic cytostatic effect, as measured by actual cell counts and associated with a sharp G1 phase arrest, is induced by 1-methyl-indirubins, a subfamily of AhR-active but kinase-inactive indirubins. As shown for TCDD (dioxin), this effect appears to be mediated through the AhR-dependent expression of p27(KIP1). Altogether these results suggest that AhR activation, rather than kinase inhibition, is responsible for the cytostatic effects of some indirubins. In contrast, kinase inhibition, rather than AhR activation, represents the main mechanism underlying the cytotoxic properties of this class of promising antitumor molecules.


Nicotine withdrawal sensitivity, linkage to chr6q26, and association of OPRM1 SNPs in the SMOking in FAMilies (SMOFAM) sample.
Nicotine withdrawal symptoms are related to smoking cessation. A Rasch model has been used to develop a unidimensional sensitivity score representing multiple correlated measures of nicotine withdrawal. A previous autosome-wide screen identified a nonparametric linkage (NPL) log-likelihood ratio (LOD) score of 2.7 on chromosome 6q26 for the sum of nine withdrawal symptoms. The objectives of these analyses were to (a) assess the influence of nicotine withdrawal sensitivity on relapse, (b) conduct autosome-wide NPL analysis of nicotine withdrawal sensitivity among 158 pedigrees with 432 individuals with microsatellite genotypes and nicotine withdrawal scores, and (c) explore family-based association of single nucleotide polymorphism (SNP) at the mu opioid receptor candidate gene (OPRM1) with nicotine withdrawal sensitivity in 172 nuclear pedigrees with 419 individuals with both SNP genotypes and nicotine withdrawal scores. An increased risk for relapse was associated with nicotine withdrawal sensitivity score (odds ratio, 1.25; 95% confidence interval, 1.10-1.42). A maximal NPL LOD score of 3.15, suggestive of significant linkage, was identified at chr6q26 for nicotine withdrawal sensitivity. Evaluation of 18 OPRM1 SNPs via the family-based association test with the nicotine withdrawal sensitivity score identified eight tagging SNPs with global P values <0.05 and false discovery rate Q values <0.06. An increased risk of relapse, suggestive linkage at chr6q26, and nominally significant association with multiple OPRM1 SNPs were found with Rasch-modeled nicotine withdrawal sensitivity scores in a multiplex smoking pedigree sample. Future studies should attempt to replicate these findings and investigate the relationship between nicotine withdrawal symptoms and variation at OPRM1.


An effective method of anastomosis of the nasolacrimal canal.
An effective method of anastomosis of the nasolacrimal canal is summed up in data derived from 150 cases seen over 20 years at the People's Hospital of Jiangsu Province. This paper describes briefly this experience and analyses the success of this procedure.