Development and implementation of a community-wide infusion therapy program by hospitals and nursing homes in Syracuse, New York.
The development and implementation of an infusion therapy program in the metropolitan area of Syracuse, New York is described. The program was implemented in a number of nursing homes with training and financial support from area hospitals. It resulted in a reduced number of hospital patient days and related savings for the healthcare system.


Anger and the heart: perspectives on cardiac risk, mechanisms and interventions.
In the popular imagination, anger has long been linked to cardiovascular diseases (CVD), but empirical validation from case-control and prospective studies emerged only in the 1970's. After describing the multidimensional nature of anger and its assessment (via self-report or observed in structured interviews), this paper selectively reviews evidence in (a) behavioral epidemiology, (b) stress and biological processes with implications for cardiopathogenesis, and (c) behavioral/pharmacological interventions for anger/hostility reduction. Although evidence is inconsistent, chronic feelings of anger, cynical distrust and antagonistic behavior are at least modestly associated with risk of both initiation and progression of CVD. Anger/hostility also is linked to stress exposure and reactivity, exaggerated autonomic function, reduced heart rate variability, platelet aggregation and inflammation. Clinical and pharmacologic treatment of anger/hostility has the potential to reduce anger and its health-damaging effects. Limitations, including third-variable explanations and overlap among the negative emotions, and implications for cardiology and behavioral medicine research and practice are discussed.


Which factors affect reported headache incidences after lumbar myelography? A statistical analysis of publications in the literature.
Nineteen publications were reviewed and subjected to a combined statistical analysis (meta-analysis) regarding the influence of study design factors upon reported headache and total symptom incidences after lumbar iohexol myelography. A significant association was found between reported side effects on one hand and needle diameter, follow up time and the method of questioning respectively on the other. The combination of long follow-up time and specific questioning and the combination between larger diameter (20G) needles and long follow-up time, both seemed to be strong predictors for reporting high side effect incidences. Nine studies were similarly analyzed regarding the influence of early ambulation and contrast type upon reported headache incidences. Early ambulation significantly increased headache after iohexol or iopamidol lumbar myelography as opposed to metrizamide myelography.


Development of a novel C1q immunoadsorbent for removal of circulating immunecomplexes: quantitative isolation of hepatitis B virus surface antigen and immunecomplexes.
A technique for large scale production of human C1q from plasma by affinity chromatography on an anti-C1q column is described. Affinity purified C1q was covalently coupled to a newly developed agarose polyacrolein microsphere beads immunoadsorbent. This immunoadsorbent was utilized for quantitative removal of artificially formed bovine serum albumin (BSA)-anti-BSA immune complexes (IC). The C1q affinity column was then used for the isolation of immunecomplexes containing hepatitis B virus (HBV) surface antigen (HBsAg) from serum of an HBsAg carrier. Identical columns may be utilized for quantitative removal of a variety of IC from blood of patients with infectious and autoimmune diseases, as well as neoplastic diseases. Furthermore, dissociated immunecomplexes will provide an additional source for purification of specific antigens.


Cancer patient T cells genetically targeted to prostate-specific membrane antigen specifically lyse prostate cancer cells and release cytokines in response to prostate-specific membrane antigen.
The expression of immunoglobulin-based artificial receptors in normal T lymphocytes provides a means to target lymphocytes to cell surface antigens independently of major histocompatibility complex restriction. Such artificial receptors have been previously shown to confer antigen-specific tumoricidal properties in murine T cells. We constructed a novel zeta chain fusion receptor specific for prostate-specific membrane antigen (PSMA) termed Pz-1. PSMA is a cell-surface glycoprotein expressed on prostate cancer cells and the neovascular endothelium of multiple carcinomas. We show that primary T cells harvested from five of five patients with different stages of prostate cancer and transduced with the Pz-1 receptor readily lyse prostate cancer cells. Having established a culture system using fibroblasts that express PSMA, we next show that T cells expressing the Pz-1 receptor release cytokines in response to cell-bound PSMA. Furthermore, we show that the cytokine release is greatly augmented by B7.1-mediated costimulation. Thus, our findings support the feasibility of adoptive cell therapy by using genetically engineered T cells in prostate cancer patients and suggest that both CD4+ and CD8+ T lymphocyte functions can be synergistically targeted against tumor cells.


Cancer predisposition genes: molecular mechanisms and clinical impact on personalized cancer care: examples of Lynch and HBOC syndromes.
Up to 10% of cancers occur through the inherited mutation of a group of genes called cancer predisposition genes. Individuals who carry a mutant allele of these genes have an increased susceptibility to cancer. A growing number of cancer susceptibility genes are being identified, and the physiopathology of germline mutation-based cancer development is also being elucidated with accumulating clinical and molecular data. More importantly, the identification of familial mutations has become routine practice, which is a perfect example of bench-to-bed translational medicine. Recently, other clinical applications of predisposition genes have been exploited, especially as efficient biomarkers predicting prognosis or response to treatment. Thus, it appears interesting to give an overview of the advances and impacts of predisposition genes in personalized cancer care by taking representative and common cancer syndromes as examples: Lynch syndrome for the first example, which is related to cancer susceptibility, and breast and ovary cancer syndrome for the second example, which involves BRCA deficiency-related targeted therapy.


A novel method for the quality control of saffron through the simultaneous analysis of authenticity and adulteration markers by liquid chromatography-(quadrupole-time of flight)-mass spectrometry.
A liquid chromatography-(quadrupole-time of flight)-mass spectrometry methodology was developed to assess the authenticity of saffron through the analysis of a group of kaempferol derivatives recently proposed as novel authenticity markers as a result of a metabolomic study of saffron (kaempferol 3-O-glucoside, kaempferol 3-O-sophoroside, kaempferol 3,7-O-diglucoside, kaempferol 3,7,4'-O-triglucoside, kaempferol 3-O-sophoroside-7-O-glucoside). Geniposide was also studied as an adulteration marker of saffron with gardenia. The optimized chromatographic conditions enabling the simultaneous separation of glycosylated kaempferols and geniposide consisted of the use of a C18 column and an elution gradient with acetonitrile and water as mobile phases (both with formic acid at 0.1%). A strategy was proposed to evaluate the minimum quantifiable adulteration percentage which was established at a 0.2% regardless of the adulterant employed. The analysis of nineteen commercial samples showed the method to be specific and suitable for saffron quality control.


Applications of ultrasonography in ENT: airway assessment and nerve blockade.
This article presents a comprehensive narrative review of the published literature relating to ultrasound imaging relevant to anesthesia for ear, nose, and throat (ENT) surgery. The review comprises 2 main subject areas: the use of ultrasonography related to assessment and management of the airway, and the use of ultrasonography related to nerve blockade for ENT surgery. The relevant sonoanatomy and suitable probe placement are illustrated in relation to applicable regional anatomy (they are not discussed). The possible value of the use of ultrasonography to improve existing clinical practice in these areas is explored.


Effects of medium calcium, and agents affecting cytoskeletal function, on cellular volume and morphology in liver tissue in vitro.
The possible role of an exocytotic, vesicular mechanism in cellular volume regulation under iso-osmotic conditions has been studied in slices of rat liver. The effects of incubation conditions and agents affecting the actin cytoskeleton were examined for changes of water, ionic composition, and ultrastructure. Slices were pre-incubated at 1°C in an iso-osmotic buffered medium to induce swelling. Upon restoration to 37°C in the same medium, tissue lost water. The Na+-K+ adenosine triphosphatase (ATPase) inhibitor ouabain inhibited water extrusion of about 50%, an effect that was accompanied by the formation of characteristic vesicles in the cytoplasmic region between the Golgi apparatus and the bile canaliculi. Water extrusion in the presence of ouabain was partially inhibited by trifluoroperazine and completely inhibited when the medium was free of Ca2+. In the presence of ouabain, brefeldin A caused a small reduction of water extrusion, whereas phalloidin and cytochalasins A, D, or E caused a marked inhibition. In these conditions there was a marked increase in size and number of cytoplasmic vesicles and a more widespread distribution of them within the cells, lacking the more specific orientation to the Golgi and canalicular regions that was seen in the presence of ouabain alone. Water extrusion was inhibited by phalloidin and cytochalasins in the absence of ouabain. In conclusion, our results are consistent with the hypothesis that iso-osmotic expulsion of water from hepatocytes can proceed partly through an accumulation of water in cytoplasmic vesicles, followed by exocytosis. This mechanism does not depend on Na+-K+ ATPase activity.


Diagnostic Performance of Three-Dimensional Endothelium/Descemet Membrane Complex Thickness Maps in Active Corneal Graft Rejection.
To evaluate the performance of 3-dimensional (3D) endothelium/Descemet membrane complex thickness (En/DMT) maps vs total corneal thickness (TCT) maps in the diagnosis of active corneal graft rejection. Cross-sectional study. Eighty-one eyes (32 clear grafts and 17 with active rejection, along with 32 age-matched control eyes) were imaged using high-definition optical coherence tomography (HD-OCT), and a custom-built segmentation algorithm was used to generate 3D color-coded maps of TCT and En/DMT of the central 6-mm cornea. Regional En/DMT and TCT were analyzed and compared between the studied groups. Receiver operating characteristic curves were used to determine the accuracy of En/DMT and TCT maps in differentiating between studied groups. Main outcome measures were regional En/DMT and TCT. Both regional TCT and En/DMT were significantly greater in actively rejecting grafts compared to both healthy corneas and clear grafts (P < .001). Using 3D thickness maps, central, paracentral, and peripheral En/DMT achieved 100% sensitivity and 100% specificity in diagnosing actively rejecting grafts (optimal cut-off value [OCV] of 19 μm, 24 μm, and 26 μm, respectively), vs only 82% sensitivity and 96% specificity for central TCT, OCV of 587 μm. Moreover, central, paracentral, and peripheral En/DMT correlated significantly with graft rejection severity (r = 0.972, r = 0.729, and r = 0.823, respectively; P < .001). 3D En/DMT maps can diagnose active corneal graft rejection with excellent accuracy, sensitivity, and specificity. Future longitudinal studies are required to evaluate the predictive and prognostic role of 3D En/DMT maps in corneal graft rejection.


Association of Th1 and Th2 cytokines with transient inflammatory reaction during lenalidomide plus dexamethasone therapy in multiple myeloma.
Transient inflammatory reactions have been reported in a subpopulation of patients with multiple myeloma (MM) during lenalidomide (Len) plus dexamethasone (DEX) therapy. Here, we examined serum levels of Th1 (IL-2 and IFN-γ) and Th2 cytokines (IL-6 and TNF-α) in nine refractory or relapsed MM patients treated with Len plus low-dose DEX. Six patients showed elevation of C-reactive protein (CRP) after the initiation of therapy. In these patients, IFN-γ and IL-6 were also elevated in two and three patients, respectively. The remaining three patients showed no appreciable changes in CRP or these cytokines. Furthermore, Len enhanced the production of both Th1 and Th2 cytokines in normal peripheral blood mononuclear cells and in patient bone marrow mononuclear cells containing primary myeloma cells and lymphocytes. These results suggest that the modulation of the Th1 and Th2 cytokine production by Len may contribute to transient inflammatory reaction in MM patients.


Sorption of perfluorooctanoic acid, perfluorooctane sulfonate and perfluoroheptanoic acid on granular activated carbon.
The sorption of perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), and perfluoroheptanoic acid (PFHpA) on granular activated carbon (GAC) was characterized and compared to explore the underlying mechanisms. Sorption of the three perfluoroalkyl acids (PFAAs) on GAC appeared to be a rapid intra-particle diffusion process, which were well represented by the pseudo-second-order rate model with the sorption rate following the order PFOS > PFOA > PFHpA. Sorption isotherm data were well fitted by the Freundlich model with the sorption capacity (Kf) of PFOS, PFOA and PFHpA being 4.45, 2.42 and 1.66 respectively. This suggests that the hydrophilic head group on PFAAs, i.e. sulfonate vs carboxylic, has a strong influence on their sorption. Comparison between PFOA and PFHpA revealed that hydrophobicity could also play a role in the sorption of PFAAs on GAC when the fluorocarbon chain length is different. Analyses using Attenuated Total Reflection (ATR)-Fourier Transform Infrared (FTIR) spectroscopy suggested possible formation of a negative charge-assisted H-bond between PFAAs and the functionalities on GAC surfaces, including non-aromatic ketones, sulfides, and halogenated hydrocarbons.


Relations between infant sleep quality, physiological reactivity, and emotional reactivity to stress at 3 and 6 months.
The study examines the association between infant sleep, physiological, and emotional reactivity at 3 and 6 months of age in 89 African American infants and their caregivers. Infant sleep was objectively measured at 3 and 6months using actigraphy for 7 days and nights. At 6 months of age, dyads participated in the Still-Face Paradigm (SFP) (Tronick et al., 1978) to assess infants' physiological reactivity (via respiratory sinus arrhythmia (RSA)) and emotional reactivity. Findings revealed that infant night wakings at 3 months was positively correlated with baseline RSA at 6 months (β = .35, p < .001). Night wakings at 3 months marginally predicted negative affect during the recovery episode of SFP (β = -.26, p = .057). Further, night wakings at 6-months-old predicted more positive affect during the recovery episode of SFP (β = .34, p = .007). We discuss potential explanations for these findings such as an exuberant temperament style, parenting behavior, and lack of sleep consolidation at this early age to be the focus of future studies in this area. The current study adds to the limited research examining the relationship between sleep and reactivity in the earliest months of development. Findings reveal that it is critical to take developmental timing into account as all results were unexpected in relation to the childhood literature. Moreover, this is the first study of its kind to focus on an African American sample.


Osteopontin secreted from obese adipocytes enhances angiogenesis and promotes progression of pancreatic ductal adenocarcinoma in obesity.
Obesity is a risk factor and poor prognostic factor for pancreatic ductal adenocarcinoma (PDAC), but the underlying mechanisms remain unclear. PDAC cells and obese visceral adipocytes (O-Ad) derived from mice and humans were used to analyze interactions between the two cell types, and human microvascular endothelial cells were used for angiogenesis assay. A xenograft mouse model with subcutaneously injected PDAC cells was used for animal studies. The relationship between visceral fat and prognosis was analyzed using resected tissues from PDAC patients with and without obesity. Conditioned media (CM) from O-Ad significantly increased PDAC cell growth and migration and angiogenic capacity in both human and mice cells, and blocking osteopontin (OPN) in O-Ad canceled O-Ad-induced effects in both mouse and human cells. In addition, O-Ad directly increased the migratory and tube-forming capacities of endothelial cells, while blocking OPN canceled these effects. O-Ad increased AKT phosphorylation and VEGFA expression in both PDAC and endothelial cells, and OPN inhibition in O-Ad canceled those O-Ad-induced effects. In the xenograft model, PDAC tumor volume was significantly increased in obese mice compared with lean mice, whereas blocking OPN significantly inhibited obesity-accelerated tumor growth. OPN expression in adipose tissues adjacent to human PDAC tumor was significantly higher in obese patients than in non-obese patients. In PDAC patients with obesity, high OPN expression in adipose tissues was significantly associated with poor prognosis. Obese adipocytes trigger aggressive transformation in PDAC cells to induce PDAC progression and accelerate angiogenesis via OPN secretion.


Europeans have a higher proportion of high‑frequency deleterious variants than Africans.
Recent studies have shown that a high proportion of rare variants in European and African populations are deleterious in nature. However, the deleterious fraction of high-frequency variants is unclear. Using more than 6500 exomes we show a much higher fraction (11 %) of relatively high-frequency nonsynonymous (amino acid altering) variants (DAF 0.1–10 %) in European Americans (EA) compared to those from African Americans (AA). In contrast, this difference was only marginal (<2 %) for low-frequency nonsynonymous variants (DAF <0.1 %). Our results also revealed that the proportion of high-frequency deleterious nonsynonymous variants in EA was much higher (24 %) than that in AA and this difference was very small (4 %) for the low-frequency deleterious amino acid altering variants. We also show that EA have significantly more number of high-frequency deleterious nonsynonymous variants per genome than AA. The high proportion of high-frequency deleterious variants in EA could be the result of the well-known bottleneck experienced by European populations in which harmful mutations may have drifted to high frequencies. The estimated ages of deleterious variants support this prediction. Our results suggest that high-frequency variants could be relatively more likely to be associated with diseases in Europeans than in Africans and hence emphasize the need for population-specific strategies in genomic medicine studies.


Histone acetylation by HBO1 (KAT7) activates Wnt/β-catenin signaling to promote leukemogenesis in B-cell acute lymphoblastic leukemia.
B-cell acute lymphoblastic leukemia (B-ALL) is an aggressive hematological disorder with a dismal prognosis. The dysregulation of histone acetylation is of great significance in the pathogenesis and progression of B-ALL. Regarded as a fundamental acetyltransferase gene, the role of HBO1 (lysine acetyltransferase 7/KAT7) in B-ALL has not been investigated. Herein, we found that HBO1 expression was elevated in human B-ALL cells and associated with poor disease-free survival. Strikingly, HBO1 knockdown inhibited viability, proliferation, and G1-S cycle progression in B-ALL cells, while provoking apoptosis. In contrast, ectopic overexpression of HBO1 enhanced cell viability and proliferation but inhibited apoptotic activation. The results of in vivo experiments also certificated the inhibitory effect of HBO1 knockdown on tumor growth. Mechanistically, HBO1 acetylated histone H3K14, H4K8, and H4K12, followed by upregulating CTNNB1 expression, resulting in activation of the Wnt/β-catenin signaling pathway. Moreover, a novel small molecule inhibitor of HBO1, WM-3835, potently inhibited the progression of B-ALL. Our data identified HBO1 as an efficacious regulator of CTNNB1 with therapeutic potential in B-ALL.


Evidence that AMP-activated protein kinase can negatively modulate ornithine decarboxylase activity in cardiac myoblasts.
The responses of AMP-activated protein kinase (AMPK) and Ornithine decarboxylase (ODC) to isoproterenol have been examined in H9c2 cardiomyoblasts, AMPK represents the link between cell growth and energy availability whereas ODC, the key enzyme in polyamine biosynthesis, is essential for all growth processes and it is thought to have a role in the development of cardiac hypertrophy. Isoproterenol rapidly induced ODC activity in H9c2 cardiomyoblasts by promoting the synthesis of the enzyme protein and this effect was counteracted by inhibitors of the PI3K/Akt pathway. The increase in enzyme activity became significant between 15 and 30min after the treatment. At the same time, isoproterenol stimulated the phosphorylation of AMPKα catalytic subunits (Thr172), that was associated to an increase in acetyl coenzyme A carboxylase (Ser72) phosphorylation. Downregulation of both α1 and α2 isoforms of the AMPK catalytic subunit by siRNA to knockdown AMPK enzymatic activity, led to superinduction of ODC in isoproterenol-treated cardiomyoblasts. Downregulation of AMPKα increased ODC activity even in cells treated with other adrenergic agonists and in control cells. Analogue results were obtained in SH-SY5Y neuroblastoma cells transfected with a shRNA construct against AMPKα. In conclusion, isoproterenol quickly activates in H9c2 cardiomyoblasts two events that seem to contrast one another. The first one, an increase in ODC activity, is linked to cell growth, whereas the second, AMPK activation, is a homeostatic mechanism that negatively modulates the first. The modulation of ODC activity by AMPK represents a mechanism that may contribute to control cell growth processes.


Young cryptogenic ischemic stroke: A descriptive analysis of clinical and laboratory characteristics, outcomes and stroke recurrence.
Ischemic strokes (IS) occur also in young adults and despite an extensive work-up the cause of IS remains very often cryptogenic. Thus, effectiveness of secondary prevention may be unclear. We aimed to analyze a relationship among vascular risk factors (VRF), clinical and laboratory parameters, outcomes and recurrent IS (RIS) in young cryptogenic IS (CIS) patients. The study set consisted of young acute IS patients < 50 years enrolled in the prospective HISTORY (Heart and Ischemic STrOke Relationship studY) study registered on ClinicalTrials.gov (NCT01541163). All analyzed patients underwent transesophageal echocardiography, 24-h and 3-week ECG-Holter to assess cause of IS according to the ASCOD classification. Recurrent IS (RIS) was recorded during a follow-up (FUP). Out of 294 young enrolled patients, 208 (70.7%, 113 males, mean age 41.6 ± 7.2 years) were identified as cryptogenic. Hyperlipidemia (43.3%), smoking (40.6%) and arterial hypertension (37.0%) were the most frequent VRF. RIS occurred in 7 (3.4%) patients during a mean time of FUP 19 ± 23 months. One-year risk of RIS was 3.4% (95%CI: 1.4-6.8%). Patients with RIS were older (47.4 vs. 41.1 years, p = 0.007) and more often obese (71.4 vs. 19.7%, p = 0.006), and did not differ in any of other analyzed parameters and VRF. Multivariate logistic regression analysis showed obesity (OR: 9.527; 95%CI: 1.777-51.1) and the previous use of antiplatelets (OR: 15.68; 95%CI: 2.430-101.2) as predictors of recurrent IS. Despite a higher presence of VRF in young CIS patients, the risk of RIS was very low. Obesity and previous use of antiplatelet therapy were found the only predictors of RIS.


Cis-acting elements (E-box and NBE) in the promoter region of three maternal genes (Histone H1oo, Nucleoplasmin 2, and Zygote Arrest 1) are required for oocyte-specific gene expression in the mouse.
We examined the promoter activities of three mouse maternal genes (H1oo, Npm2, and Zar1) in oocytes and pre-implantation embryos, and examined the promoters for cis-acting elements of 5'-flanking region to obtain the best promoter for inducing oocyte-specific gene expression. For the assay, we injected firefly luciferase gene constructs under the control of the promoters into the oocytes and embryos. Each promoter region showed transcriptional activity in oocytes, but not in fertilized embryos. Deletion analysis showed that a putative E-box region at position -72 of the H1oo promoter and at the -180 of the Npm2 promoter were required for basal transcriptional activity in oocytes. Moreover, a putative NBE motif (NOBOX DNA binding elements) (-1796) was shown to enhance basal transcriptional activity of the Npm2 promoter. Thus, the E-box and/or NBE may be key regulatory regions for the expression of the examined maternal genes (H1oo and Npm2) in growing mouse oocytes.


Supply-level measures to increase uptake of family planning services in Niger: the effectiveness of improving responsiveness.
To show that low-cost attitudinal, structural and procedural changes aimed at improving responsiveness to patients have the potential to increase uptake of family planning (FP) even among populations considered reluctant to do so by health personnel. Intervention study with before-after comparison of contraceptive acceptance, couple-years of protection (CYP) and an 'index of contraceptive uptake' (IUC) in rural health centres in Niger. The intervention consists of a package of instructions to actively propose family planning, integrated within curative and under-fives consultations, coupled with measures to increase the health centres' responsiveness to their clients. Implementation of the intervention package was followed by marked increases in family planning uptake. Health services in Niger present an untapped potential for improving family planning through low-cost supply-side measures.


Chronic Ventricular Assist Device Support in Adult Congenital Heart Disease Patients: A Children's Hospital Perspective.
With improvement in early surgical outcomes in patients with complex congenital heart disease, most patients are now expected to survive to adulthood. As adult congenital heart disease (ACHD) patients age, they are at risk of heart failure, which has become the leading cause of mortality in ACHD. Some who develop advanced heart failure may not be candidates for transplant, and chronic ventricular assist device (VAD) therapy may be the only means of survival. There is limited experience with chronic VAD therapy in ACHD patients, and the outcomes are not well delineated. We describe our center's experience with chronic VAD therapy in ACHD patients receiving care exclusively within our children's hospital.


Enhanced emotional response to both negative and positive images in post-traumatic stress disorder: Evidence from pupillometry.
Post-traumatic stress disorder (PTSD) is characterised by alterations in the function of the autonomic nervous system. However, it is unclear if this dysfunction is threat-related or related to arousing stimuli in general. Pupillometry offers a simple non-invasive measure of ANS activity that can separate parasympathetic and sympathetic arousal. Participants viewed images with emotional or neutral content: 20 met diagnostic criteria for PTSD, 28 were trauma-exposed (but with no PTSD), and 17 were controls. Initial pupil constriction (a marker of parasympathetic function) was reduced for the PTSD group, while dilation due to the emotional content of the image (a marker of sympathetic activity) was greater in the PTSD group. Individuals with PTSD demonstrated enhanced physiological arousal to both threat-related and positive images. The results suggest reduced parasympathetic arousal and increased sympathetic arousal in the autonomic nervous system, which has been linked to a range of adverse health outcomes in PTSD.


Noggin recruits mesoderm progenitors from the dorsal aorta to a skeletal myogenic fate.
Embryonic mesoangioblasts are the in vitro counterpart of vessel-associated progenitors, able to differentiate into different mesoderm cell types. To investigate signals recruiting these progenitors to a skeletal myogenic fate, we developed an in vitro assay, based upon co-culture of E11.5 dorsal aorta (from MLC3F-nLacZ transgenic embryos, expressing nuclear beta galactosidase only in striated muscle) with differentiating C2C12 or primary myoblasts. Under these conditions muscle differentiation from cells originating from the vessel can be quantified by counting the number of beta gal+nuclei. Results indicated that Noggin (but not Follistatin, Chordin or Gremlin) stimulates while BMP2/4 inhibits myogenesis from dorsal aorta progenitors; neutralizing antibodies and shRNA greatly reduce these effects. In contrast, TGF-β1, VEGF, Wnt7A, Wnt3A, bFGF, PDGF-BB and IGF1 have no effect. Sorting experiments indicated that the majority of these myogenic progenitors express the pericyte marker NG2. Moreover they are abundant in the thoracic segment at E10.5 and in the iliac bifurcation at E11.5 suggesting the occurrence of a cranio-caudal wave of competent cells along the aorta. BMP2 is expressed in the dorsal aorta and Noggin in newly formed muscle fibers suggesting that these two tissues compete to recruit mesoderm cells to a myogenic or to a perithelial fate in the developing fetal muscle.


Long-term outcomes of pelvic organ prolapse repair using a mesh-capturing device when comparing single- versus multicenter use.
The aim of this study was to compare long-term effects of high-volume surgery at a single-center to multicenter use when using a mesh-capturing device for pelvic organ prolapse (POP) repair. Five years after surgery 101 (88%) at the single center were compared with 164 (81.2%) in the multicenter trial. Outcome measurements included clinical examination, prolapse-specific symptom questionnaires [Pelvic Floor Distress Inventory 20 (PFDI-20), Pelvic Floor Impact Questionnaire-short form (PFIQ-7), Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-12)] and pain estimation by VAS (0-10). Optimal apical segment outcome was 95% in the single- compared to 83.3% in the multicenter study (p < 0.001). POP recurrence in the anterior and posterior walls (POP-Q, Ba and Bp ≥ 0) was more common at the multicenter as compared to the single center [(19.8% vs 5.4%) and (26% vs 2.7%), (p < 0.001)]. Reoperations for POP and mesh-related complications were more frequent in the multicenter study [31/202 (15.3%) vs 7/116 (6.1%), p < 0.001]. Total PFDI-20, PFIQ-7 and PISQ-12 scores were comparable between the cohorts. There were no significant differences in overall pain scores in-between the cohorts during follow-up. At the single center, 1/81 patients (1.2%) had VAS 7/10, i.e. severe pain, as compared to 3/131 (2.3%) in the multicenter study (p = 0.277). Despite the high objective and subjective long-term effectiveness of the procedure in both regular use, and at a high-volume center, centralizing the use of a standardized capturing-device guided transvaginal mesh for POP repair reduced secondary interventions by more than half.


Reconsideration of interferon treatment for viral diseases: Lessons from SARS, MERS, and COVID-19.
Periodic pandemics of coronavirus (CoV)-related pneumonia have been a major challenging issue since the outbreak of severe acute respiratory syndrome (SARS) in 2002 and Middle East respiratory syndrome (MERS) in 2012. The ongoing pandemic of CoV disease (COVID-19) poses a substantial threat to public health. As for the treatment options, only limited antiviral agents have been approved hitherto, and clinicians mainly focus on currently available drugs including the conventional antiviral interferons (IFNs). In clinical practice, IFNs, when used either alone or in combination with ribavirin and/or lopinavir/ritonavir, have shown promising outcomes, to some extent, in SARS-CoV or MERS-CoV treatment. Although the efficacy and safety of IFNs in COVID-19 treatment remain unclear, their possible use merits further evaluation. We present a review that summarizes current evidence of IFN treatment for COVID-19 and elaborates on other challenges in terms of the timing of IFN treatment initiation, treatment duration, and IFN type to be used. The review findings suggested that IFN acts by directly inhibiting viral replication and activating immune cell subsets. However, there is a lack of well-designed and controlled clinical trials providing firm evidence for the efficacy or safety of IFN therapy for CoVs. Additionally, critically ill patients with multiple immunosuppression-associated comorbidities may not benefit from IFN therapy, necessitating screening of those patients who would most benefit from IFN treatment.


Cathepsin K inhibitor causes changes in crystallinity and crystal structure of newly-formed mandibular bone in rats.
Cathepsin K inhibitors are new drugs with the potential for the treatment of osteoporosis because they sustain bony remodelling better than bone resorption inhibitors such as bisphosphonates. The treatment of osteoporosis with inhibitors of bony resorption is associated with osteonecrosis of the jaw, as the deterioration in bony quality that they induce is thought to be one of its causes. The quality of bone is delineated by structural and material characteristics (which include the degree and quality of mineralisation, and depends on the content of proteoglycan and the structural integrity of the bony collagen).1,2 Animal and clinical studies have shown that cathepsin K inhibitors improve the mineral density and structural characteristics of bone, but their effect on the rest remains unknown. We therefore hypothesised that these inhibitors will affect the material characteristics of newly-formed mandibular bone. To verify our hypothesis, we used Raman microspectroscopy to examine such bone in rats that were given a cathepsin K inhibitor, and found unusual crystallinity and an increased substitution of carbonate (CO32-) in its crystal structure.


Establishment of evaluation system for biological remediation on organic pollution in groundwater using slow-release agents.
In situ bioremediation through slow-release agents can continuously degrade organic pollutants for a long time and have high application potential in solving problems such as tailing and rebound. However, the existing evaluation system is difficult to reflect the performance of bioremediation through slow-release agents, which is not conducive to the promotion of technology. It is urgent to establish a targeted evaluation system. Therefore, based on the multi-criteria decision-making method (MCDA), a comprehensive evaluation model was established. The evaluation index system was constructed for bioremediation through slow-release agents consisting of 16 indicators including pollutant degradation rate, agent preparation cost, engineering operation and maintenance cost, secondary pollution, long-term degradation stability, slow release time, slow release stability, increase in functional microbial flora, increase in total DNA content, agent particle size, solid agent morphology, liquid agent viscosity, dispersibility in aqueous phase, zeta potential, operability of agent preparation, and engineering operation management difficulty. Then, the weight of the indicators was determined by using the best-worst method (BWM), and evaluation criteria was established based on relevant norms and literature. Both and the indicators aggregation simple additive weighting (SAW) method constitute a quantitative evaluation model. The above content together constitutes a new evaluation system for biological remediation on organic pollution in groundwater using slow-release agents, which was defined as AOBS evaluation system. In order to verify the rationality and scientificity of the evaluation system, a typical bioremediation slow-release agent was evaluated using the established AOBS evaluation system. The results showed that the evaluation system could reasonably and comprehensively evaluate bioremediation through slow-release agents and provide suggestions for agent improvement.


New developmental data for Cynomya mortuorum (L., 1761) in Belgium (Diptera: Calliphoridae).
The calliphorid Cynomya mortuorum (L., 1761) is a forensically important species mainly found in the Palearctic region. Knowledge about its biology and ecology is scarce. Thermal constants as well as developmental time were studied at constant and variable regimes of 5 average temperatures: 14, 16, 18, 20 and 22°C, respectively. Total developmental time varied between 15.82±0.40 days at 22°C and 28.67±2.38 days at 14°C, for the constant regime, and between 16.05±0.67 days at 22°C and 32.79±1.77 days at 14°C, for the variable regime. No significant differences were observed between ADD, and threshold at the constant (ADD: 277.39±14.78 DD; lower threshold: 4.72°C) and variable regimes (275.99±14.16 DD; lower threshold: 5.05°C).


[Changes and significance of endogenous tissue plasminogen activators in cerebral hypoxia-ischemia in neonatal rats].
The mechanism of neonatal hypoxic-ischemic brain damage (HIBD) remains unclear and effective treatment approach is limited for this disorder. Many studies have shown that tissue-type plasminogen activator (tPA) plays an important role in nervous system. This study investigated the effect of tPA in HIBD in neonatal rats. Seven-day-old Wistar rat pups were used for the Rice-Vannucci model of neonatal hypoxia-ischemia (HI). Brain samples were collected 1, 4, and 24 hrs after HI. FITC-Dextran was injected into the left ventricle of pups after HI to observe reperfusion defects of the neonatal brain. RT-PCR and tPA zymogram were used to detect the expression and activity of tPA. Double immunostaining, terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) and DAPI staining were used to detect the expression of integrin GPIIb and fibrin and neuronal apoptosis. FITC-Dextran perfusion analysis indicated there was obvious infarct area in the neonatal brain and the expression of integrin GPIIb and fibrin increased significantly 1 hr after HI compared with the contralateral side. The infarct area decreased and the expression of integrin GPIIb and fibrin were reduced 4 hrs after HI. The expression and activity of tPA increased significantly in neonatal rats after HI, and peaked at 4 hrs after HI. The number of apoptotic neural cells increased progressively with the prolonged reperfusion time following HI. The increase of tPA in the acute phase after HIBD may be helpful to clot dissolving, but it induces neuronal apoptosis and aggravates brain injury.


Autotumour reactive T-cell clones among tumour-infiltrating T lymphocytes in B-cell non-Hodgkin's lymphomas.
Seventy-three T-cell clones (TCC) were established from tumour-infiltrating lymphocytes-T (TIL-T) derived from lymph nodes involved by B-cell non-Hodgkin's lymphomas (B-NHL) in nine patients with different histological subtypes and clinical stages. 40 TCC (55%) expressed the CD25 Ag and were also able to proliferate in the presence of irradiated autologous B-NHL cells. Among them, 23 autotumour (AuTu) proliferative TCC were found not to proliferate to autologous EBV-transformed B-cell lines, indicating that the proliferative reactivity of these TCC was preferentially directed at autologous B-NHL cells. Tested against autologous B-NHL cells, only three AuTu proliferative TCC (CD8+) showed a significant level of cytotoxicity (specific lysis > 15%). In blocking experiments, the AuTu proliferative reactivity of three TCC from one patient was strongly inhibited by anti-DR and anti-DQ mAbs, whereas that of three TCC from another patient was not affected by either anti-MHC class I or class II (DR, DP, DQ) mAbs. These findings suggest that the recognition of autologous B-NHL cells by AuTu proliferative TCC may occur through MHC-restricted as well as MHC-unrestricted mechanisms.


Characteristics of an optimized patient information material for elderly patients with obstructive pulmonary diseases based on patients' and experts' assessment.
Life-long regular use of drugs is necessary in chronic diseases like asthma and COPD. There are several methods to improve adherence including patient information and education; however, their effectiveness on the basis of practical experience is often lower than originally planned and expected. Our objective is to develop a patient information material based on the recommendations of patients and their treating healthcare professionals to fulfill their needs. A survey was conducted among pulmonologists (N = 262), asthma nurses (N = 102), general practitioners (N = 321) and patients with obstructive pulmonary disease (N = 978) using on line questionnaires. All surveyed population would prefer to use 1 to 5 pages long, A5 format patient information material based on topics considered important by patients that is appropriately segmented with pictures as well as supplementary information cards adapted to the life situation of patients and the severity of their disease. Questioned population (whose mean age was 57.2) preferred highly informative printed material. For more effective information and improvement of adherence we recommend newly structured patient information sheets and information cards with content discussed with the targeted patients and their healthcare professionals. Customized, patient-centered information materials could improve the efficiency of patient education and make the follow-up of the various therapeutic plans easier for patients.


The treatment of fistulae and ureteral stenosis after kidney transplantation.
The incidence of urological complications after kidney transplantation varies from 3% to 14%, with a probable loss of the graft in 10% to 15% of cases and a mortality rate of up to 15%, despite improvements in prevention, diagnosis, and treatment as well as the use of new immunosuppressive therapies. Urinous fistulae, which are considered early complications of transplantation, are due to ischemic damage or necrosis generally occurring in the distal third of the ureter. Preservation of accessory arteries to the lower portion of the kidney is important, as they may constitute the blood supply of this segment of the collecting system or ureter. Their ligation may lead to necrosis and urinary fistulae. Ureteral stenosis, as late complication, is related to a pathology of the ureter itself, to infections, to abscesses, to fibrosis, and to ischemia. An early endoscopic approach permits resolution in 70% of cases. The aim of this retrospective study was to determine incidence and treatment of these complications. From 1991 to 2004 we performed 453 kidney transplantations both from cadaveric and living donors. In 199 patients we performed a transvesical ureteroneocystostomy (UNCS), and in 260, an extravesical UNCS. The nine patients who showed fistulae (1.9%) underwent surgical treatment. In eight we used a direct ureteral reimplantation, and in one, a Boari flap technique. Nephrectomy was necessary in four patients, including two who died of septic complications. In all 26 cases of ureteral stenosis (5.6%), we used an endourological approach (anterograde or retrograde), with surgical treatment afterward in 11 patients (42%) nine direct reimplants, one anastomosis to the native ureter (transplantation from a living donor), and in one case a Boari flap technique four patients who underwent surgical treatment showed progressive damage to graft function. In all patients who showed fistulae we suggest surgical review: for patients with ureteral stenosis, we suggest first an endourological approach and only when it is not successful do we consider surgical treatment.


Devising a Consensus Framework for Validation of Novel Human Coding Loci.
A report on the Wellcome Trust retreat on devising a consensus framework for the validation of novel human protein coding loci, held in Hinxton, U.K., May 11-13, 2015.


Basal metabolic rate and the intrinsic rate of increase: An empirical and theoretical reexamination.
A reanalysis of data presented by Henneman (1983) to examine the relationship between intrinsic rate of increase and basal metabolism suggests there is no statistically significant correlation between the two variables when both are treated with comparable statistical techniques. In addition, I suggest there is no theoretical reason to expect a high correlation between basal metabolic rate and a population's maximum rate of increase.


PPARA/RXRA signalling regulates the fate of hepatic non-esterified fatty acids in a sheep model of maternal undernutrition.
Maternal undernutrition during late gestation accelerates body fat mobilization to provide more energy for foetal growth and development, which unbalances metabolic homeostasis and results in serious lipid metabolism disorder. However, detailed regulatory mechanisms are poorly understood. Here, a sheep model was used to explore the regulatory role of PPARA/RXRA signalling in hepatic lipid metabolism in undernutrition based on RNA sequencing and cell experiments. KOG function classification showed that lipid transport and metabolism was markedly altered in an undernourished model. In detail, when compared with the controls, fatty acid transport and oxidation and triglyceride metabolism were up-regulated in an undernourished model, while fatty acid synthesis, steroid synthesis, and phospholipid metabolism were down-regulated. Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway analysis demonstrated that PPARA/RXRA signalling pathway was altered. Moreover, PPARA signalling associated genes were positively correlated with hepatic non-esterified fatty acid (NEFA) levels, while retinol metabolism associated genes were negatively correlated with blood beta-hydroxybutyric acid (BHBA) levels. Results of primary hepatocytes showed that NEFAs could activate PPARA signalling and facilitate fatty acid oxidation (FAO) and ketogenesis, while BHBA could inhibit RXRA signalling and repress FAO and ketogenesis. Excessively accumulated NEFAs in hepatocytes promoted triglyceride synthesis. Furthermore, activation of PPARA/RXRA signalling by WY14643 and 9-cis-retinoic acid could enhance FAO and ketogenesis and reduce NEFAs accumulation and esterification. Our findings elucidate the regulatory mechanisms of NEFAs and BHBA on lipid metabolism as well as the potential role of the PPARA/RXRA signalling pathway in hepatic lipid metabolism, which may contribute to exploring new strategies to maintain lipid metabolic homeostasis in human beings.


Can local anesthesia with ropivacaine provide postoperative analgesia in extraction of impacted mandibular third molars? A randomized clinical trial.
The aim of this study was to compare the local anesthesia efficacy of ropivacaine 0.75% compared to lidocaine 2% with 1:100,000 epinephrine for postoperative analgesia following extraction of impacted mandibular third molars. In this randomized, double-blind crossover clinical trial, 30 participants underwent surgical removal of bilateral impacted mandibular third molars under local anesthesia using ropivacaine 0.75% or lidocaine 2% with 1:100,000 epinephrine. The pain was recorded on a visual analog scale at 4, 8, 12, 24, and 48 h postoperatively. The use of analgesics and the presence of adverse effects were recorded. The duration of soft tissue anesthesia in the ropivacaine group was significantly longer than that in the lidocaine group. The lidocaine group recorded significantly higher visual analog scale scores at all postoperative time intervals, except in the final 48-h period. Analgesic use was higher in the lidocaine group. Rescue medication was used by 2 patients in each group (6.7%). Significantly more postoperative bleeding was seen in the ropivacaine group. Ropivacaine 0.75% injection before the surgical procedure may be associated with preventive analgesia for extraction of impacted mandibular third molars.


Linking traditional medicine to modern phytotherapy: Chemical characterization and assessment of antioxidant and anticholinesterase effects in vitro of a natural Persian remedy for dementia.
Several natural remedies are used in the Traditional Persian Medicine (TPM) to prevent dementia, but their efficacy is debated. In this work, an improved "Safoof-e-Nesyān" formulation described in the "Qarābādin-e-Azam" pharmacopoeia was developed, and its chemical composition and antioxidant and anti-cholinesterase properties were assessed. The formulation contains a mixture (FM) of Cinnamomum cassia (CC), C. verum (CV), Pistacia lentiscus (PL), Rheum palmatum (RP), Syzygium aromaticum (SA), and Zingiber officinalis (ZO) powdered plants. Its total phenolic content is 110.45 mg GAE/g, while the total flavonoid content is 6.28 mg RE/g. 66 secondary metabolites (mainly tannins, flavonoids, anthraquinones, and gingerols) were identified by UPLC-QToF-MS analysis. FM exerts antioxidant effects by scavenging radicals, and by reducing and chelating metals such as Mb, Cu and Fe. The anticholinesterase activity of one gram of the FM equals that of 3.60 mg of the reference drug galantamine, on both acetyl- and butyryl-cholinesterase. Correlations between specific compounds and bioactivities were highlighted by multivariate analysis of data: lyoniresinol 9'-glucoside strongly correlates with antiradical activities on DPPH and ABTS and reducing activity on Cu, and with anti-AChE effects. Most of the identified flavonoids and the ellagic acid derivatives positively correlate with the reducing activity on Fe and Mb, and with anti-BChE effects. Finally, a tablet formulation of the FM was developed, and its physical properties were preliminarily assessed. Overall, our results indicate that the FM may be a useful natural remedy for dementia, although further safety and efficacy assessments in vivo are required.


Possible significance of Ph, zinc and BCR-ABL chimaerism in the pathogenesis of chronic myeloid leukaemia.
Available evidence suggests a double-pathway two-staged genetic alteration in the pathogenesis of Chronic Myeloid Leukaemia (CML). The regular Ph' defect results in BCR-ABL gene chimaerism on the one hand and suppressed synthesis of the protein responsible for Zn absorption on the other. The resulting Zn deficiency leads, through its metalloenzymes, to a low NAP activity and depressed DNA & RNA polymerase activities: the latter necessitates an adaptive mechanism to sustain cell division despite low zinc. This adaptation is in the form of another gene alteration; a point mutation in the BCR-ABL chimaeric gene, now an oncogene, whose onco-proteins are zinc-independent and stimulate cell division more efficiently (though abnormally also) than the polymerases while defying the usual mechanisms regulating DNA synthesis and cell division. Thus it seems possible that assisted transcellular zinc transport could prevent development of CML in Ph'-positive individuals and the enhanced (abnormal) cellular proliferation might be specifically inhibited.


[The role of hemodialysis and hemosorption in the complex therapy of acute poisoning].
The method of henosorption and hemodialysis was used in 50 patients with acute intoxication. A total of 44 hemosorption and 40 hemodialysis procedures were carried out in the toxicogenous and somatogenous stage of acute intoxication. Results indicate high efficacy of using extracorporal detoxication in the toxicogenous stage of acute poisoning. The method of treatment of acute chemical intoxications is described.


Pulmonary shunt is independent of decrease in cardiac output during unsupported spontaneous breathing in the pig.
During mechanical ventilation (MV), pulmonary shunt is cardiac output (CO) dependent; however, whether this relationship is valid during unsupported spontaneous breathing (SB) is unknown. The CO dependency of the calculated venous admixture was investigated, with both minor and major shunt, during unsupported SB, MV, and SB with continuous positive airway pressure (CPAP). In seven anesthetized supine piglets breathing 100% oxygen, unsupported SB, MV (with tidal volume and respiratory rate corresponding to SB), and 8 cm H2O CPAP (airway pressure corresponding to MV) were applied at random. Venous return and CO were reduced by partial balloon occlusion of the inferior vena cava. Measurements were repeated with the left main bronchus blocked, creating a nonrecruitable pulmonary shunt. CO decreased from 4.2 l/min (95% CI, 3.9-4.5) to 2.5 l/min (95% CI, 2.2-2.7) with partially occluded venous return. Irrespective of whether shunt was minor or major, during unsupported SB, venous admixture was independent of CO (slope: minor shunt, 0.5; major shunt, 1.1% · min(-1) · l(-1)) and mixed venous oxygen tension. During both MV and CPAP, venous admixture was dependent on CO (slope MV: minor shunt, 1.9; major shunt, 3.5; CPAP: minor shunt, 1.3; major shunt, 2.9% · min(-1) · l(-1)) and mixed-venous oxygen tension (coefficient of determination 0.61-0.86 for all regressions). In contrast to MV and CPAP, venous admixture was independent of CO during unsupported SB, and was unaffected by mixed-venous oxygen tension, casting doubt on the role of hypoxic pulmonary vasoconstriction in pulmonary blood flow redistribution during unsupported SB.


Familial hemiplegic migraine in pediatric patients: A genetic, clinical, and follow-up study.
The aim of this study was to describe a cohort of pediatric patients with genetically confirmed familial hemiplegic migraine (FHM). The knowledge of genotype-phenotype correlations may suggest prognostic factors associated with severe phenotypes. Hemiplegic migraine is a rare disease and data concerning the pediatric population are even more rare as they are often extrapolated from mixed cohorts. We selected patients who met International Classification of Headache Disorders, third edition criteria for FHM, who had a molecular diagnosis, and whose first attack occurred under the age of 18 years. We enrolled nine patients (seven males and two females) first referred to our three centers. Three of the nine (33%) patients had calcium voltage-gated channel subunit alpha1 A (CACNA1A) mutations, five (55%) had ATPase Na+/K+ transporting subunit alpha 2 (ATP1A2) mutations, and one had both genetic mutations. The patients experienced at least one aura feature other than hemiplegia during the first attack. The mean (SD) duration of HM attacks in the sample was 11.3 (17.1) h; 3.8 (6.1) h in the ATP1A2 group, and 24.3 (23.5) h in the CACNA1A group. The mean (SD, range) duration of follow-up was 7.4 (2.2, 3-10) years. During the first year from the disorder's onset, only four patients had additional attacks. Over the course of follow-up, the attack frequency overall was 0.4 attacks/year without a difference between the two groups (CACNA1A and ATP1A2). The study data show that most of our patients with early-onset FHM experienced infrequent and non-severe attacks, which improved over time. Furthermore, the clinical course revealed neither the appearance of novel neurological disorders or a deterioration of basic neurological or cognitive functioning.


Rehabilitation is the Critical Ingredient to Optimize Return to Sport in Athletes.
Medical providers, rehabilitation specialists, and researchers must incessantly refine and adjust specific protocols, understanding that rehabilitation is the critical ingredient for return to sport in athletes. This month introduces a Special Issue in Arthroscopy, Sports Medicine, and Rehabilitation entitled "Rehabilitation and Return to Sport in Athletes." The articles have been authored by invited experts and rehabilitation specialists deemed thought leaders. The goal of the issue is to provide readers, researchers, and clinicians high-yield and high-impact articles that will optimize return to sport in athletes. For athletes, and non-athletes alike, there lies an essential quartet for recovery: 1) correct diagnosis, 2) restoration of anatomy, 3) biological healing, and 4) functional rehabilitation. Most importantly, a coordinated rehabilitation program must be chosen with appropriate specialization to synchronize the return to play. This Special Issue explores specific rehabilitation paradigms regarding return to sport using evidence-based medicine with support from literature to optimize the functional return of athletes.


Phosphorylation of HOX11/TLX1 on Threonine-247 during mitosis modulates expression of cyclin B1.
The HOX11/TLX1 (hereafter referred to as HOX11) homeobox gene was originally identified at a t(10;14)(q24;q11) translocation breakpoint, a chromosomal abnormality observed in 5-7% of T cell acute lymphoblastic leukemias (T-ALLs). We previously reported a predisposition to aberrant spindle assembly checkpoint arrest and heightened incidences of chromosome missegregation in HOX11-overexpressing B lymphocytes following exposure to spindle poisons. The purpose of the current study was to evaluate cell cycle specific expression of HOX11. Cell cycle specific expression studies revealed a phosphorylated form of HOX11 detectable only in the mitotic fraction of cells after treatment with inhibitors to arrest cells at different stages of the cell cycle. Mutational analyses revealed phosphorylation on threonine-247 (Thr247), a conserved amino acid that defines the HOX11 gene family and is integral for the association with DNA binding elements. The effect of HOX11 phosphorylation on its ability to modulate expression of the downstream target, cyclin B1, was tested. A HOX11 mutant in which Thr247 was substituted with glutamic acid (HOX11 T247E), thereby mimicking a constitutively phosphorylated HOX11 isoform, was unable to bind the cyclin B1 promoter or enhance levels of the cyclin B1 protein. Expression of the wildtype HOX11 was associated with accelerated progression through the G2/M phase of the cell cycle, impaired synchronization in prometaphase and reduced apoptosis whereas expression of the HOX11 T247E mutant restored cell cycle kinetics, the spindle checkpoint and apoptosis. Our results demonstrate that the transcriptional activity of HOX11 is regulated by phosphorylation of Thr247 in a cell cycle-specific manner and that this phosphorylation modulates the expression of the target gene, cyclin B1. Since it is likely that Thr247 phosphorylation regulates DNA binding activity to multiple HOX11 target sequences, it is conceivable that phosphorylation functions to regulate the expression of HOX11 target genes involved in the control of the mitotic spindle checkpoint.


Prevalence of apical periodontitis and frequency of root canal treatments in liver transplant candidates.
The purpose of this study was to investigate the prevalence of apical periodontitis (AP) and endodontic treatment in liver transplant candidates and control healthy subjects. A descriptive cross-sectional study. Forty two liver transplant candidates (LTC) (study group) and 42 control subjects. Digital panoramic radiographs where used. Periapical status was scored according to the periapical index (PAI). Results were analysed statistically using the Chi-squared test and logistic regression. Radiographic signs of AP in one or more teeth was found in 79% of patients in the study group and in 50% of control subjects (p = 0.008; OR = 3.7; C. I. 95% = 1.4 - 9.5). One or more root-filled teeth (RFT) were found in 19% and 62% of study and control subjects, respectively (p = 0.0001; OR = 0.14; 95% C. I. = 0.05 - 0.38). Among LTC patients 14.7% of the teeth had AP, whereas in the control subjects 4.2% of teeth were affected (p= 0.0002). The percentage of RFT in the study and control groups was 1.5% and 6.8%, respectively (p = 0.0002). Liver transplant candidates have significantly higher prevalence of radiographic periapical lesions and lower frequency of RFT than controls healthy subjects.


Snowmelt timing, phenology, and growing season length in conifer forests of Crater Lake National Park, USA.
Anthropogenic climate change is having significant impacts on montane and high-elevation areas globally. Warmer winter temperatures are driving reduced snowpack in the western USA with broad potential impacts on ecosystem dynamics of particular concern for protected areas. Vegetation phenology is a sensitive indicator of ecological response to climate change and is associated with snowmelt timing. Human monitoring of climate impacts can be resource prohibitive for land management agencies, whereas remotely sensed phenology observations are freely available at a range of spatiotemporal scales. Little work has been done in regions dominated by evergreen conifer cover, which represents many mountain regions at temperate latitudes. We used moderate resolution imaging spectroradiometer (MODIS) data to assess the influence of snowmelt timing and elevation on five phenology metrics (green up, maximum greenness, senescence, dormancy, and growing season length) within Crater Lake National Park, Oregon, USA from 2001 to 2012. Earlier annual mean snowmelt timing was significantly correlated with earlier onset of green up at the landscape scale. Snowmelt timing and elevation have significant explanatory power for phenology, though with high variability. Elevation has a moderate control on early season indicators such as snowmelt timing and green up and less on late-season variables such as senescence and growing season length. PCA results show that early season indicators and late season indicators vary independently. These results have important implications for ecosystem dynamics, management, and conservation, particularly of species such as whitebark pine (Pinus albicaulis) in alpine and subalpine areas.


Oxidative stress and proinflammatory cytokine levels are increased in premature neonates of preeclamptic mothers with HELLP syndrome.
Respiratory distress syndrome (RDS) incidence is increased in infants of preeclamptic mothers with hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome. RDS and HELLP syndrome have been associated with oxidative stress and inflammatory processes. We hypothesize that end-tidal carbon monoxide corrected for inhaled CO (ETCOc), malondialdehyde (MDA) (markers of oxidative stress) and proinflammatory cytokine (IL-6, IL-8) production are higher in infants of preeclamptic mothers with HELLP syndrome than in those of preeclamptic mothers without HELLP syndrome. Prospective study of 36 infants of preeclamptic mothers (GA <32 weeks) admitted to the Neonatal Intensive Care Unit. ETCOc was measured at 0-12, 48-72 and 168 h postnatally using the CO-Stattrade mark End-Tidal Breath Analyzer. Simultaneously, blood was sampled for MDA, IL-8 and IL-6. At 0-12 h, ETCOc, MDA and IL-8 values (median[range]) were significantly higher in HELLP infants than in infants from preeclamptic mothers without HELLP (ETCOc 2.2 [1.5-3.9] vs. 1.8 [0.5-2.9] ppm; MDA 2.3 [1.3-4.1] vs. 1.5 [0.4-3.1] mumol/l; IL-8 145 [24-606] vs. 62 [26-397] pg/ml; all p <0.05). MDA remained significantly higher during the first 168 h of life (2.3 [0.8-5.8] vs. 1.1 [0.8-3.7] mumol/l, p = 0.02). Oxidative stress and proinflammatory cytokine levels are increased in infants of preeclamptic mothers with HELLP syndrome. These processes may cause inactivation of surfactant explaining the increased RDS incidence in these infants.


A retrospective clinicopathological study on oral lichen planus and malignant transformation: analysis of 518 cases.
To investigate the epidemiological and clinical characteristics of a relatively large cohort of patients with oral lichen planus (OLP) from eastern China. A total of 518 patients with histologically confirmed OLP in a long-term follow-up period (6 months-21.5 years) were retrospectively reviewed in our clinic. Of the 518 patients, 353 females and 165 males were identified. The average age at diagnosis was 46.3 years (range 9-81 years) with the buccal mucosa being the most common site (87.8%). At initial presentation, white lichen and red lichen was seen in 52.3% and 47.7% patients, respectively. Of these, 5 (0.96%) patients previously diagnosed clinically and histopathologically as OLP developed oral cancer. All of them were the females with no a history of smoking or alcohol use. Clinical features of eastern Chinese OLP patients were elucidated. Notably, approximately 1% of OLP developed into cancer, which provides further evidence of potentially malignant nature of OLP.


Mobile phone-assisted basic life support augmented with a metronome.
Basic life support (BLS) performed by lay rescuers is poor. We developed software for mobile phones augmented with a metronome to improve BLS. To assess BLS in lay rescuers with or without software assistance. Medically untrained volunteers were randomized to run through a cardiac arrest scenario with ("assisted BLS") or without ("non-assisted BLS") the aid of a BLS software program installed on a mobile phone. Sixty-four lay rescuers were enrolled in the "assisted BLS" and 77 in the "non-assisted BLS" group. The "assisted BLS" when compared to the "non-assisted BLS" group, achieved a higher overall score (19.2 ± 7.5 vs. 12.9 ± 5.7 credits; p < 0.001). Moreover, the "assisted BLS" when compared to the "non-assisted" group checked (64% vs. 27%) and protected themselves more often from environmental risks (70% vs. 39%); this group also called more often for help (56% vs. 27%), opened the upper airway (78% vs. 16%), and had more correct chest compressions rates (44% ± 38% vs. 14% ± 28%; all p < 0.001). However, the "assisted BLS" when compared to the "non-assisted BLS" group, was slower in calling the dispatch center (113.6 ± 86.4 vs. 54.1 ± 45.1 s; p < 0.001) and starting chest compressions (165.3 ± 93.3 vs. 87.1 ± 53.2 s; p < 0.001). "Assisted BLS" augmented by a metronome resulted in a higher overall score and a better chest compression rate when compared to "non-assisted BLS." However, in the "assisted BLS" group, time to call the dispatch center and to start chest compressions was longer. In both groups, lay persons did not ventilate satisfactorily during this cardiac arrest scenario.


Cross-species replication of a serum osteocalcin quantitative trait locus on human chromosome 16q in pedigreed baboons.
Osteocalcin (OC), a serum marker of bone formation, in its intact form reflects osteoblast activity. It is of interest to clinicians and bone biologists due to easy measurability and potential utility as an identifier of those at risk for fracture and other complications associated with bone metabolism disorders. The only published linkage study in humans shows significant evidence for a quantitative trait locus (QTL) affecting OC levels on 16q. We used the baboon, a primate model for skeletal maintenance and turnover, to detect and quantify the effects of genes on serum OC levels and to localize chromosomal regions harboring the responsible loci. We assayed OC levels in 591 pedigreed animals, assessed OC heritability, and conducted a genomewide linkage scan for evidence of QTLs affecting this phenotype. Heritability in these baboons is 0.24. Suggestive linkage is evident with markers in a region homologous to human chromosome 16q. This first genomewide linkage scan in a nonhuman primate for QTLs affecting bone formation as reflected by OC levels provides cross-species replication of the QTL on chromosome 16q previously localized in humans. Given the concordance of results of the only two genome scans for this trait in two primate species, further studies of this region are warranted.


Vascularized Bone Grafting Versus the 2-Stage Masquelet Technique for Upper-Extremity Bone Reconstruction: A Meta-Analysis.
Vascularized bone grafting (VBG) has been described as the technique of choice for larger bone defects in bone reconstruction, yielding excellent results at the traditional threshold of 6 cm as described in the literature. However, we hypothesize that the 2-stage Masquelet technique provides equivalent union rates for upper-extremity bone defects regardless of size, while having no increase in the rate of patient complications. A systematic literature review was conducted using PubMed and Scopus for outcomes after VBG and the Masquelet technique for upper-extremity bone defects of the humerus, radius, ulna, metacarpal, or phalanx (carpal defects were excluded). A meta-analysis was performed to compare outcomes following VBG and the Masquelet technique at varying defect sizes. There were 77 VBG (295 patients) and 25 Masquelet (119 patients) studies that met inclusion criteria. Patients undergoing the Masquelet technique had defect sizes ranging from 0-15 cm (average 4.5 cm), while patients undergoing VBG had defect sizes ranging from 0-24 cm (average 5.9 cm). The union rate for Masquelet patients was 94.1% with an average time to union of 5.8 months, compared to 94.9% and 4.4 months, respectively, for VBG patients. We did not identify a defect size threshold at which VBG demonstrated a significantly higher union rate. No statistically significant difference was found in union rates between techniques when using multivariable logistic regression analysis. There was no statistically significant difference in union rates between VBG and the Masquelet technique in upper-extremity bone defects regardless of defect size. Surgeons may consider the Masquelet technique as an alternative to VBG in large bone defects of the upper extremity. Therapeutic IV.


Effect of tibolone compared with sequential hormone replacement therapy on carbohydrate metabolism in postmenopausal women.
To investigate the effects of tibolone on carbohydrate metabolism, and to compare these effects with those of a sequential regimen of conjugated equine estrogens and medrogestone. This was an open-label, multicentre, comparative study. Seventy-two postmenopausal women were randomized to receive either tibolone 2.5 mg/day or conjugated equine estrogens 0.6 mg plus sequential medrogestone 5 mg (CEE/M) for six 28-day cycles. Carbohydrate metabolism was evaluated at baseline and after three and six cycles of treatment by an oral glucose tolerance test (OGTT). A blood sample was taken at 30, 60, 90 and 120 mm after glucose 75 mg dosing for determination of plasma glucose, insulin and connecting peptide (C-peptide) levels. The changes from baseline of glucose, insulin and C-peptide area-under-the-curve (AUC) values were not statistically significant after 3 and 6 months of tibolone or CEE/M treatment. There was a small transitory decrease in HbA(1C) after three cycles of treatment with tibolone. The effects of tibolone and CEE/M on carbohydrate metabolism were considered to have no clinical significance.


Intestinal transport of gentamicin with a novel, glycosteroid drug transport agent.
The objective was to investigate the ability of a glycosteroid (TC002) to increase the oral bioavailability of gentamicin. Admixtures of gentamicin and TC002 were administered to the rat ileum by injection and to dogs by ileal or jejunal externalized ports, or PO. Bioavailability of gentamicin was determined by HPLC. 3H-TC002 was injected via externalized cannulas into rat ileum or jejunum, or PO and its distribution and elimination was determined. The metabolism of TC002 in rats was evaluated by solid phase extraction and HPLC analysis of plasma, urine and feces following oral or intestinal administration. The bioavailability of gentamicin was substantially increased in the presence of TC002 in both rats and dogs. The level of absorption was dependent on the concentration of TC002 and site of administration. Greatest absorption occurred following ileal orjejunal administration. TC002 was significantly more efficacious than sodium taurocholate, but similar in cytotoxicity. TC002 remained primarily in the GI tract following oral or intestinal administration and cleared rapidly from the body. It was only partly metabolized in the GI tract, but was rapidly and completely converted to its metabolite in plasma and urine. TC002 shows promise as a new drug transport agent for promoting intestinal absorption of polar molecules such as gentamicin.


Comparison of clinical outcomes and automated performance metrics in robot-assisted radical prostatectomy with and without trainee involvement.
In this study, we investigate the effect of trainee involvement on surgical performance, as measured by automated performance metrics (APMs), and outcomes after robot-assisted radical prostatectomy (RARP). We compared APMs (instrument tracking, EndoWrist® articulation, and system events data) and clinical outcomes for cases with varying resident involvement. Four of 12 standardized RARP steps were designated critical ("cardinal") steps. Comparison 1: cases where the attending surgeon performed all four cardinal steps (Group A) and cases where a trainee was involved in at least one cardinal step (Group B). Comparison 2, where Group A is split into Groups C and D: cases where attending performs the whole case (Group C) vs. cases where a trainee performed at least one non-cardinal step (Group D). Mann-Whitney U and Chi-squared tests were used for comparisons. Comparison 1 showed significant differences in APM profiles including camera movement time, third instrument usage, dominant instrument moving time, velocity, articulation, as well as non-dominant instrument moving time and articulation (all favoring Group A p < 0.05). There was a significant difference in re-admission rates (10.9% in Group A vs 0% in Group B, p < 0.02), but not for post-operative outcomes. Comparison 2 demonstrated a significant difference in dominant instrument articulation (p < 0.05) but not in post-operative outcomes. Trainee involvement in RARP is safe. The degree of trainee involvement does not significantly affect major clinical outcomes. APM profiles are less efficient when trainees perform at least one cardinal step but not during non-cardinal steps.


1H-detected double-J-modulated INEPT-INADEQUATE for simultaneous determination of one-bond and long-range carbon-carbon connectivities and the measurement of all carbon-carbon coupling constants.
We describe a new NMR experiment, (1)H-detected double-J-modulated (DJM)-INEPT-INADEQUATE, for tracing out the carbon skeleton of molecules. This experiment allows simultaneous correlation of directly bonded carbon atoms and those separated by multiple bonds, while at the same time also providing the values of all J(CC) coupling constants. This is achieved by replacing both fixed carbon-carbon coupling evolution intervals of the INEPT-INADEQUATE experiment by variable time intervals, which are incremented in concert with the DQ evolution period (t(1)). We show that the analysis of the fine structure of cross-peaks in DJM-INEPT-INADEQUATE spectra leads to accurate values of coupling constants and give guidelines for the proper usage of the method. The proposed experiment is two times less sensitive that the original INEPT-INADEQUATE experiment. We show that, using a 600-MHz cryoprobe and 20 mg of a monosaccharide, spectra that are suitable for the analysis of coupling constants as small as 2 Hz can be obtained within 24 h. Instead of performing multiple experiments, a single DJM-INEPT-INADEQUATE experiment can thus provide a wealth of information for the structural analysis of small molecules.


Papillary eccrine adenoma. Immunohistochemical and ultrastructural analyses.
A case of papillary eccrine adenoma was analysed with immunohistochemical and ultrastructural methods regarding their direction of differentiation. It was found that the majority of the structures show either eccrine ductal or glandular differentiation. There were some segments, particularly in those exhibiting papillary growth, where cells similar to eccrine secretory (clear) cells or cells with characteristics of both ductal basal cells and glandular myoepithelial cells were present.


Hip dysplasia in Charcot-Marie-Tooth disease: report of a family.
Charcot-Marie-Tooth disease is classified into hereditary motor and sensory neuropathy (HMSN) types I and II, and affected patients present with progressive peripheral neuropathy. Some previous orthopedic studies have revealed the association of hip dysplasia with HMSN, in addition to pes cavovarus, scoliosis, and recurrent dislocation of the patella. We describe three patients from the same family who were each diagnosed as having HMSN type I with associated bilateral severe hip dysplasia, borderline abnormalities of both acetabula, and dysplastic osteoarthritis. Based on our experience with these patients and a review of previous reports, we concluded that routine screening of hip joints, especially for those with a family history of HMSN, is necessary for early diagnosis.


Nanoliposome encapsulated anesthetics for local anesthesia application.
The systemic administration of opioids leads to potentially severe and undesirable and side effects like sedation and drowsiness, vomiting and nausea, allergies, respiratory depression, and neutrophil dysfunction. The application of nanotechnology in medical field has drawn a great attention in recent times. Several treatments available are tedious and expensive. Application of nanotechnology brings about faster cure and cost effectiveness. Nanoliposomes are one of the widely used names for nanoparticles used in medicine. Recently, nanoliposomes are used as a crucial novel drug delivery systems. The use of nanoliposomal formulation brings about a good results to pain control, rapid patient recovery, increased patient comfort, treatment costs reduction, and shortens length of hospitalization. This review presents a brief description about the achievements in the field of nanoscience and nanotechnology related to the application of nanoliposomes in anesthesia.


Variegation of autism related traits across seven neurogenetic disorders.
Gene dosage disorders (GDDs) constitute a major class of genetic risks for psychopathology, but there is considerable debate regarding the extent to which different GDDs induce different psychopathology profiles. The current research speaks to this debate by compiling and analyzing dimensional measures of several autism-related traits (ARTs) across seven diverse GDDs. The sample included 350 individuals with one of 7 GDDs, as well as reference idiopathic autism spectrum disorder (ASD; n = 74) and typically developing control (TD; n = 171) groups. The GDDs were: Down, Williams-Beuren, and Smith-Magenis (DS, WS, SMS) syndromes, and varying sex chromosome aneuploidies ("plusX", "plusXX", "plusY", "plusXY"). The Social Responsiveness Scale (SRS-2) was used to measure ARTs at different levels of granularity-item, subscale, and total. General linear models were used to examine ART profiles in GDDs, and machine learning was used to predict genotype from SRS-2 subscales and items. These analyses were completed with and without covariation for cognitive impairment. Twelve of all possible 21 pairwise GDD group contrasts showed significantly different ART profiles (7/21 when co-varying for IQ, all Bonferroni-corrected). Prominent GDD-ART associations in post hoc analyses included relatively preserved social motivation in WS and relatively low levels of repetitive behaviors in plusX. Machine learning revealed that GDD group could be predicted with plausible accuracy (~60-80%) even after controlling for IQ. GDD effects on ARTs are influenced by GDD subtype and ART dimension. This observation has consequences for mechanistic, clinical, and translational aspects of psychiatric neurogenetics.


Unusual Necrotizing Encephalitis in Raccoons and Skunks Concurrently Infected With Canine Distemper Virus and Sarcocystis sp.
Canine distemper virus commonly infects free-ranging, terrestrial mesopredators throughout the United States. Due to the immunosuppressive effects of the virus, concurrent opportunistic infections are also common. Among these, secondary systemic protozoal infections have been described in a number of species. We report an unusual presentation of necrotizing encephalitis associated withSarcocystissp in four raccoons and one skunk concurrently infected with canine distemper virus. Lesions were characterized by variably sized necrotizing cavitations composed of abundant mineral admixed with inflammatory cells and protozoa.Sarcocystissp was confirmed via immunohistochemistry using a monoclonal antibody toSarcocystis neurona The pathologic changes are similar to lesions in human AIDS patients infected withToxoplasma gondii.


Morphine-induced supersensitivity to acetylcholine in skeletal muscle and its mechanism of action.
The effect of in vitro morphine pretreatment (250 micron) on the sensitivity of skeletal muscle to acetylcholine (ACh) was investigated using the isolated rectus abdominis muscle of frog. Morphine (15 to 120 min) significantly increased the sensitivity of the tissue to ACh. This increase in the sensitivity was found to be greatest after 120 min. Morphine significantly increased the sensitivity of the tissue to carbachol only after 120 min. In the presence of physostigmine, morphine did not cause further augmentation of responses to ACh. Potassium chloride-induced contractile responses were not influenced by morphine. In the presence of morphine, maximum contractile responses to ACh were significantly decreased. Highly calcium (1.62 mM) in the medium decreased the magnitude of the morphine-induced supersentivity to ACh at 120 min and antagonised the decrease in maximum contractile responses to ACh. These results suggest that morphine is causing supersensitivity by both its anticholinesterase activity and its inhibitory action on presynaptic nerve terminals.


Wnt signaling controls the stem cell-like asymmetric division of the epithelial seam cells during C. elegans larval development.
Metazoan stem cells repopulate tissues during adult life by dividing asymmetrically to generate another stem cell and a cell that terminally differentiates. Wnt signaling regulates the division pattern of stem cells in flies and vertebrates. While the short-lived nematode C. elegans has no adult somatic stem cells, the lateral epithelial seam cells divide in a stem cell-like manner in each larval stage, usually generating a posterior daughter that retains the seam cell fate and an anterior daughter that terminally differentiates. We show that while wild-type adult animals have 16 seam cells per side, animals with reduced function of the TCF homolog POP-1 have as many as 67 seam cells, and animals with reduced function of the β-catenins SYS-1 and WRM-1 have as few as three. Analysis of seam cell division patterns showed alterations in their stem cell-like divisions in the L2-L4 stages: reduced Wnt signaling caused both daughters to adopt non-seam fates, while activated Wnt signaling caused both daughters to adopt the seam fate. Therefore, our results indicate that Wnt signaling globally regulates the asymmetric, stem cell-like division of most or all somatic seam cells during C. elegans larval development, and that Wnt pathway regulation of stem cell-like behavior is conserved in nematodes.


PGE2 gel for enhancement of priming and induction of labour at term in patients with unfavorable cervix.
Fifty women (25 nulliparae and 25 multiparae) with unfavorable cervix at term were enrolled in a clinical experiment to evaluate the safety and efficacy of the intracervical application of 0.5 mg PGE2 gel for cervical softening and eventual induction of labour; duration of pregnancy (38-42 wk) was confirmed by ultrasonic records. Global analysis revealed 48 (96%) vaginal deliveries, 43 (86%) being spontaneous labour and 5 (10%) instrumentally assisted deliveries (forceps). Caesarean section was required in 2 cases (4%). Three patients, having registered no Bishop score (above 5) progress after the first treatment, went into labour upon the second application of PGE2 gel. Mean induction-delivery time was 11 h 50 min for nulliparae and 7 h 50 min for multiparae. Mean ROM/amniotomy-delivery time was 5 h 59 min for nulliparae and 3 h 11 min for multiparae. Four neonates with initial Apgar scores below 7 registered immediately higher values after adequate reanimation manouvres.


Kinase activity and specificity assay using synthetic peptides.
Phosphorylation of substrate proteins by protein kinases can lead to activation or inactivation of signaling pathways or metabolic processes. Precise understanding of activity and specificity of protein kinases are important questions in characterization of kinase functions. Here, we describe a procedure to study kinase activity and specificity using kinase-GFP complexes purified from plant material and synthetic peptides as substrates. Magnetic GFP beads allow purifying receptor-like kinase-GFP complexes from microsomal fractions. Kinase-GFP complexes are then incubated with ATP and the synthetic peptides for kinase reaction. Phosphorylation of substrate peptides is then identified and quantified by mass spectrometry.


A TD-DFT study on the cyanide-chemosensing mechanism of 8-formyl-7-hydroxycoumarin.
Proton transfer (PT) and excited-state PT process are proposed to account for the fluorescent sensing mechanism of a cyanide chemosensor, 8-formyl-7-hydroxycoumarin. The time-dependent density functional theory method has been applied to investigate the ground and the first singlet excited electronic states of this chemosensor as well as its nucleophilic addition product with cyanide, with a view to monitoring their geometries and spectrophotometrical properties. The present theoretical study indicates that phenol proton of the chemosensor transfers to the formyl group along the intramolecular hydrogen bond in the first singlet excited state. Correspondingly, the nucleophilic addition product undergoes a PT process in the ground state, and shows a similar structure in the first singlet excited state. This could explain the observed strong fluorescence upon the addition of the cyanide anion in the relevant fluorescent sensing mechanism.


Correlates of patient satisfaction and provider trust after breast-conserving surgery.
Although breast-conserving therapy (BCS) is considered the standard of care for early-stage breast cancer, up to 20% of patients are dissatisfied. The effect of treatment-related factors on patient satisfaction with their healthcare experiences is unclear. All BCS patients at the University of Michigan Medical Center who were treated between January 2002 and May 2006 were surveyed (n=714; response rate, 79.5%). Patients were queried regarding 4 aspects of their decision for surgery: satisfaction with the decision, decision regret, decisional conflict, and trust in surgeons. Independent variables included the number of re-excisions, the occurrence of postoperative complications, and postoperative breast appearance, which was assessed by using the Breast Cancer Treatment and Outcomes scale. Multiple logistic regression was used to assess the effect of the independent variables on each outcome controlling for demographic and clinical characteristics. Breast asymmetry after BCS was correlated significantly with patient satisfaction with their treatment experiences and patient distrust in surgeons. Women who reported pronounced asymmetry were significantly less likely to be satisfied with the decision for surgery compared with women who reported minimal asymmetry (odds ratio [OR], 0.43; 95% confidence interval [95% CI], 0.21-0.89). Women with pronounced asymmetry were less likely to be certain about their surgical decision (OR, 0.36; 95% CI, 0.21-0.60) and to believe that they were prepared to make the decision for surgery (OR, 0.25; 95% CI, 0.14-0.43). Increasing breast asymmetry was associated with higher surgeon distrust scores (2.14 vs 2.30 vs 2.35; P= .04) and with the occurrence of postoperative complications (distrust score: 2.23 vs 2.35; P= .03). Reoperation after BCS was not associated with patient satisfaction or trust in providers. Esthetic result after BCS was associated more profoundly with aspects of satisfaction than either surgical therapy or the occurrence of postoperative complications. The current findings indicated that surgeons who care for patients with breast cancer should identify the women at an increased risk for breast asymmetry preoperatively to effectively address their expectations of treatment outcomes.


Direct growth of vertically-oriented graphene for field-effect transistor biosensor.
A sensitive and selective field-effect transistor (FET) biosensor is demonstrated using vertically-oriented graphene (VG) sheets labeled with gold nanoparticle (NP)-antibody conjugates. VG sheets are directly grown on the sensor electrode using a plasma-enhanced chemical vapor deposition (PECVD) method and function as the sensing channel. The protein detection is accomplished through measuring changes in the electrical signal from the FET sensor upon the antibody-antigen binding. The novel biosensor with unique graphene morphology shows high sensitivity (down to ~2 ng/ml or 13 pM) and selectivity towards specific proteins. The PECVD growth of VG presents a one-step and reliable approach to prepare graphene-based electronic biosensors.


An amino acid transporter subunit as an antibody-drug conjugate target in colorectal cancer.
Advanced colorectal cancer (CRC) is difficult to treat. For that reason, the development of novel therapeutics is necessary. Here we describe a potentially actionable plasma membrane target, the amino acid transporter protein subunit CD98hc. Western blot and immunohistochemical analyses of CD98hc protein expression were carried out on paired normal and tumoral tissues from patients with CRC. Immunofluorescence and western studies were used to characterize the action of a DM1-based CD98hc-directed antibody-drug conjugate (ADC). MTT and Annexin V studies were performed to evaluate the effect of the anti-CD98hc-ADC on cell proliferation and apoptosis. CRISPR/Cas9 and shRNA were used to explore the specificity of the ADC. In vitro analyses of the antitumoral activity of the anti-CD98hc-ADC on 3D patient-derived normal as well as tumoral organoids were also carried out. Xenografted CRC cells and a PDX were used to analyze the antitumoral properties of the anti-CD98hc-ADC. Genomic as well proteomic analyses of paired normal and tumoral samples showed that CD98hc expression was significantly higher in tumoral tissues as compared to levels of CD98hc present in the normal colonic tissue. In human CRC cell lines, an ADC that recognized the CD98hc ectodomain, reached the lysosomes and exerted potent antitumoral activity. The specificity of the CD98hc-directed ADC was demonstrated using CRC cells in which CD98hc was decreased by shRNA or deleted using CRISPR/Cas9. Studies in patient-derived organoids verified the antitumoral action of the anti-CD98hc-ADC, which largely spared normal tissue-derived colon organoids. In vivo studies using xenografted CRC cells or patient-derived xenografts confirmed the antitumoral activity of the anti-CD98hc-ADC. The studies herewith reported indicate that CD98hc may represent a novel ADC target that, upon well-designed clinical trials, could be used to increase the therapeutic armamentarium against CRC.


De novo and comparative transcriptome analysis of cultivated and wild spinach.
Spinach (Spinacia oleracea L.) is an economically important green leafy vegetable crop. In this study, we performed deep transcriptome sequencing for nine spinach accessions: three from cultivated S. oleracea, three from wild S. turkestanica and three from wild S. tetrandra. A total of approximately 100 million high-quality reads were generated, which were de novo assembled into 72,151 unigenes with a total length of 46.5 Mb. By comparing sequences of these unigenes against different protein databases, nearly 60% of them were annotated and 50% could be assigned with Gene Ontology terms. A total of 387 metabolic pathways were predicted from the assembled spinach unigenes. From the transcriptome sequencing data, we were able to identify a total of ~320,000 high-quality single nucleotide polymorphisms (SNPs). Phylogenetic analyses using SNPs as well as gene expression profiles indicated that S. turkestanica was more closely related to the cultivated S. oleracea than S. tetrandra. A large number of genes involved in responses to biotic and abiotic stresses were found to be differentially expressed between the cultivated and wild spinach. Finally, an interactive online database (http://www.spinachbase.org) was developed to allow the research community to efficiently retrieve, query, mine and analyze our transcriptome dataset.


Activating Ly-49D and inhibitory Ly-49A natural killer cell receptors demonstrate distinct requirements for interaction with H2-D(d).
The activating Ly-49D receptor and the inhibitory Ly-49A receptor mediate opposing effects on natural killer (NK) cell cytotoxicity after interaction with the same major histocompatibility complex ligand, H2-D(d). To compare Ly-49D and Ly-49A interactions with H2-D(d), we created mutations in H2-D(d) and examined the functional ability of these mutants to activate lysis through Ly-49D or to inhibit lysis through Ly-49A. Specific single amino acid changes in either the H2-D(d) alpha(1) helix or the alpha(2) helix abrogated Ly-49D-mediated cytotoxicity, but these changes had no significant effect on Ly-49A-dependent inhibition. Each of three alpha(2) domain mutations in the floor of the peptide binding groove reduced functional recognition by either Ly-49D or Ly-49A, but all three were required to fully abrogate inhibition by Ly-49A. Our studies indicate that Ly-49D/H2-D(d) interactions require distinct determinants compared with Ly-49A/H2-D(d) interactions. These differences have important implications for the integration of activating and inhibitory signals in NK cells.


Sentinel Lymph Node Removal After Neoadjuvant Chemotherapy in Clinically Node-Negative Patients: When to Stop?
The maximum number of sentinel lymph nodes (SLN) to be resected to accurately stage the axilla in patients undergoing neoadjuvant chemotherapy (NAC) for the treatment of clinically node-negative (cN0) breast cancer has not been determined. We sought to determine the sequence of removal of the positive SLNs in this patient population. All patients aged ≥ 18 years diagnosed with cN0 invasive breast cancer who received NAC and underwent SLN surgery at Mayo Clinic Rochester between September 2008 and September 2018 were identified. Univariate analysis was performed to compare factors associated with positive nodes and where the first positive node was in the sequence of removal of the SLNs. We identified 446 cancers among 440 patients with a median age of 51 (IQR: 43, 61) years. At surgery, 381 (85.4%) cancers were pathologically node (ypN) negative and 65 (14.6%) were pN + . The number of nodes removed was similar for both patients with ypN0 and ypN + disease, with a median number of SLNs removed of 2.0 (IQR: 2.0, 3.0). Of all patients with a positive node, the first positive node was most commonly the 1st node removed (75.4%), and was identified by the 3rd SLN removed in all cases. Among cN0 patients treated with NAC, if a positive SLN is present, it is most commonly identified as the 1st sentinel node removed by the surgeon, and was identified by the 3rd sentinel node in our series. This suggests that once 3 SLNs have been resected, removal of additional sentinel lymph nodes does not add diagnostic value.


Dataset on statistical reduction of highly water-soluble Cr (VI) into Cr (III) using RSM.
With the excellent solubility, mobility, bioaccumulation and carcinogenesis, hexavalent chromium Cr (VI), widely exists in various industrial effluents such as chrome plating, metal finishing, pigments, and tanning. Cr (VI) is one of the toxic metal pollutants among all the heavy metals. Therefore, the purpose of this work was to convert highly water-soluble Cr (VI) into Cr (III) species using electrocoagulation (EC) process. The Box-Behnken design (BBD) as was applied to investigate the effects of major operating variables and optimization conditions. The predicted values of responses obtained using the model is agreed well with the experimental data. This work demonstrated that the Cr (VI) is entirely converted into Cr (III) in solid-phases in electrocoagulation process. It was also found that reduction increased with current density that suggesting that the reduction efficiency is closely related to the generation of floc.


Tumor-Cell-Specific Targeting of Ibrutinib: Introducing Electrostatic Antibody-Inhibitor Conjugates (AiCs).
Ibrutinib is an inhibitor of Bruton's tyrosine kinase that has been approved for the treatment of patients with chronic lymphocytic leukemia, mantle cell lymphoma and Waldenstrom's macroglobulinemia and is connected with toxicities. To minimize its toxicities, we linked ibrutinib to a cell-targeted, internalizing antibody. To this end, we synthesized a poly-anionic derivate, ibrutinib-Cy3.5, that retains full functionality. This anionic inhibitor is complexed by our anti-CD20-protamine targeting conjugate and free protamine, and thereby spontaneously assembles into an electrostatically stabilized vesicular nanocarrier. The complexation led to an accumulation of the drug driven by the CD20 antigen internalization to the intended cells and an amplification of its pharmacological effectivity. In vivo, we observed a significant enrichment of the drug in xenograft lymphoma tumors in immune-compromised mice and a significantly better response to lower doses compared to the original drug.


Social media as a recruitment method to reach a diverse sample of bereaved parents.
Recruiting a diverse group of parents who are grieving the loss of a child into research is challenging. Social media users represent all demographic groups in the United States. Online platforms, such as Facebook and Twitter, may be one potential method to reach and recruit a diverse group of bereaved parents. To our knowledge, this is the first known article to describe social media as a recruitment mechanism for bereaved parents. The purpose of this paper is to describe 1) how the social media platforms of Facebook and Twitter were used to recruit bereaved parents into a cross-sectional, online survey, and 2) the effectiveness of social media as a recruitment tool for this population. Social media has the potential to be an effective recruitment tool to reach a diverse group of users. More research is needed, however, to determine the best methods to reach fathers as well as racial and ethnic minorities.