Imaging findings in Mazabraud's syndrome: seven new cases.
To present seven new cases of Mazabraud's syndrome with particular observations on the magnetic resonance imaging findings and a review of the literature. A multi-institutional retrospective review was performed on seven patients with confirmed Mazabraud's syndrome. The patient group was composed of six women and one man, ranging in age from 39 to 65 years, with a mean age of 53 years. Fibrous dysplasia was more often polyostotic ( n=6) and right-sided ( n=4). Fibrous dysplasia involved the femur in five cases. The soft tissue myxomas were multiple in four cases and were intramuscular in origin. The most commonly affected location was the thigh ( n=4). On computed tomography, myxomas were well-circumscribed, low-attenuation masses. On magnetic resonance images, the lesions were significantly low in signal intensity on T1-weighted images and high in signal intensity on T2-weighted images relative to adjacent skeletal muscle. Enhancement of the myxomas was heterogeneous with irregular, peripheral rim enhancement, and a variable degree of central enhancement depending on the abundance of solid myxoid tissue and bridging fibrous septa. Knowledge of Mazabraud's syndrome and the imaging appearance of intramuscular myxoma is important in order to avoid unnecessary biopsies of the osseous and soft tissue lesions. The unique features of this disorder allow discrimination from soft tissue malignancies such as sarcoma.


Correlating crash severity with injury risk, injury severity, and long-term symptoms in low velocity motor vehicle collisions.
Auto insurers use a variety of techniques to control their losses, and one that has been widely employed since the mid-1990's is the Minor Impact Soft Tissue (MIST) segmentation strategy. MIST protocol dictates that all injury claims resulting from collisions producing US dollars 1000 or less in damage be "segmented", or adjusted for minimal compensation. Multiple databases were searched for studies comparing any of three dependent variables (injury risk, injury severity, or duration of symptoms) with structural damage in motor vehicle crashes of under 40 km/h (25 mph). A limited correlation between crash severity and injury claims was found. We could not determine, however, whether this relationship held across all crash severities. Other studies provided conflicting results with regard to acute injury risk, but both found no statistically significant correlation between crash severity and long-term outcome. A substantial number of injuries are reported in crashes of little or no property damage. Property damage is an unreliable predictor of injury risk or outcome in low velocity crashes. The MIST protocol for prediction of injury does not appear to be valid.


Gb3-cSrc complex in glycosphingolipid-enriched microdomains contributes to the expression of p53 mutant protein and cancer drug resistance via β-catenin-activated RNA methylation.
Glucosylceramide synthase (GCS) is a key enzyme catalyzing ceramide glycosylation to generate glucosylceramide (GlcCer), which in turn serves as the precursor for cells to produce glycosphingolipids (GSLs). In cell membranes, GSLs serve as essential components of GSL-enriched microdomains (GEMs) and mediate membrane functions and cell behaviors. Previous studies showed that ceramide glycosylation correlates with upregulated expression of p53 hotspot mutant R273H and cancer drug resistance. Yet, the underlying mechanisms remain elusive. We report herewith that globotriaosylceramide (Gb3) is associated with cSrc kinase in GEMs and plays a crucial role in modulating expression of p53 R273H mutant and drug resistance. Colon cancer cell lines, either WiDr homozygous for missense-mutated TP53 (R273H+/+) or SW48/TP53-Dox bearing heterozygous TP53 mutant (R273H/+), display drug resistance with increased ceramide glycosylation. Inhibition of GCS with Genz-161 (GENZ 667161) resensitized cells to apoptosis in these p53 mutant-carrying cancer cells. Genz-161 effectively inhibited GCS activity, and substantially suppressed the elevated Gb3 levels seen in GEMs of p53-mutant cells exposed to doxorubicin. Complex formation between Gb3 and cSrc in GEMs to activate β-catenin was detected in both cultured cells and xenograft tumors. Suppression of ceramide glycosylation significantly decreased Gb3-cSrc in GEMs, β-catenin, and methyltransferase-like 3 for m6A RNA methylation, thus altering pre-mRNA splicing, resulting in upregulated expression of wild-type p53 protein, but not mutants, in cells carrying p53 R273H. Altogether, increased Gb3-cSrc complex in GEMs of membranes in response to anticancer drug induced cell stress promotes expression of p53 mutant proteins and accordant cancer drug resistance.


Case Report: Early Resection of Pheochromocytoma in a Patient With Cardiogenic Shock Due to Pheochromocytoma-Induced Cardiomyopathy With Extracorporeal Life Support.
Pheochromocytoma-induced cardiomyopathy is a rare but potentially life-threatening complication of pheochromocytoma. It mimics the patterns of stress-induced cardiomyopathy. In severe cases, patients can develop refractory cardiogenic shock, which might require mechanical circulatory support. We presented a case of 54-year-old female who developed refractory cardiogenic shock, following an elective orthopaedic surgery complicated by cardiac arrest, requiring veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support. After urgent coronary catheterisation revealed normal coronary arteries, further evaluation of the aetiology of cardiogenic shock revealed pheochromocytoma. With a diagnosis of pheochromocytoma-induced cardiomyopathy, the patient had accelerated preoperative alpha adrenergic blockade preparation for a total of 6 days and subsequently had the tumour removed under VA-ECMO support. Postoperatively, the patient recovered well and was off ECMO support and extubated a few days later.The optimal management of pheochromocytoma-induced cardiomyopathy, especially for severe cases, is still unclear. Indeed, some cases will require mechanical circulatory support to allow left ventricular function recovery. But our case also showed that it was possible to introduce alpha blockade safely whilst the patient is on VA-ECMO and has the pheochromocytoma removed with VA-ECMO support after accelerated preoperative preparation.


What blood and organ donation can tell us about cooperation?
High-cost cooperation directed towards strangers is difficult to explain from an evolutionary perspective. Here, it is argued that by studying the behaviours, motivations, and preferences of real-world high-cost cooperators - blood and organ donors - insights can be uncovered into the mechanisms supporting cooperation. In this respect, this article details two novel mechanisms to enhance cooperation in the face of free-riding, (1) 'reactive reluctant altruism' whereby people help because they do not trust others to help and (2) the 'Good Shepherd' effect whereby cooperation is enhanced when people observed others cooperate although the social norm is to free-ride. Finally, it is argued that repeated acts of high-cost cooperation are sustained by a self-selection process based on the reinforcing effect of warm-glow.


Unraveling Size-Dependent Ion-Migration for Stable Mixed-Halide Perovskite Light-Emitting Diodes.
Mixed-halide perovskites show tunable emission wavelength across the visible-light range, with optimum control of the light color. However, color stability remains limited due to the notorious halide segregation under illumination or an electric field. Here, a versatile path toward high-quality mixed-halide perovskites with high emission properties and resistance to halide segregation is presented. Through systematic in and ex situ characterizations, key features for this advancement are proposed: a slowed and controllable crystallization process can promote achievement of halide homogeneity, which in turn ensures thermodynamic stability; meanwhile, downsizing perovskite nanoparticle to nanometer-scale dimensions can enhance their resistance to external stimuli, strengthening the phase stability. Leveraging this strategy, devices are developed based on CsPbCl1.5 Br1.5 perovskite that achieves a champion external quantum efficiency (EQE) of 9.8% at 464 nm, making it one of the most efficient deep-blue mixed-halide perovskite light-emitting diodes (PeLEDs) to date. Particularly, the device demonstrates excellent spectral stability, maintaining a constant emission profile and position for over 60 min of continuous operation. The versatility of this approach with CsPbBr1.5 I1.5 PeLEDs is further showcased, achieving an impressive EQE of 12.7% at 576 nm.


Evaluation of immunogenicity and protective efficacy of a novel Senecavirus A strain-based inactivated vaccine in mice.
Senecavirus A (SVA) is an emerging picornavirus associated with porcine idiopathic vesicular disease (PIVD), which is clinically indistinguishable from foot-and-mouth disease and other vesicular diseases in pigs. In recent years, the wide spread of SVA has caused huge economic losses to the world's pig industry. However, there are no vaccines currently available to prevent and control the infection of SVA due to the extensive diversity of SVA isolates and high cost of the pig model for vaccine evaluation. In the present study, a novel SVA CH-HNCY-2019 strain with unique amino-acid mutations in VP1, VP3 and 3C was isolated from the central part of China. A mouse model was proposed to for evaluation of the immunogenicity and protective efficacy of the inactivated CH-HNCY-2019 vaccine. The results indicated that one dose immunization of 107TCID50 inactivated CH-HNCY-2019 vaccine in mice induced a high titer of neutralizing antibody and complete protection. After challenging with the homologous virus, no viral RNA or histopathological damages were detected in the heart, liver, spleen, lung, kidney, intestine and brain tissues of the immunized mice. However, viral RNA and different degrees of histopathological damages were observed in all corresponding tissues of the unimmunized mice. In summary, the present study proved that mouse is a candidate animal model for the primary evaluation of the immunogenicity and protection efficacy of SVA vaccines for the first time. In addition, the inactivated SVA CH-HNCY-2019 vaccine was immunogenic and could protect mice against homologous viral challenges.


Multivalent biomaterial platform to control the distinct arterial venous differentiation of pluripotent stem cells.
Vascular endothelial cells (ECs) differentiated from pluripotent stem cells have enormous potential to be used in a variety of therapeutic areas such as tissue engineering of vascular grafts and re-vascularization of ischemic tissues. To date, various protocols have been developed to differentiate stem cells toward vascular ECs. However, current methods are still not sufficient to drive the distinct arterial venous differentiation. Therefore, developing refined method of arterial-venous differentiation is critically needed to address this gap. Here, we developed a biomaterial platform to mimic multivalent ephrin-B2/EphB4 signaling and investigated its role in the early arterial and venous specification of pluripotent stem cells. Our results show immobilized ephrinB2 or EphB4 on hydrogel substrates have a distinct effect on arterial venous differentiation by regulating several arterial venous markers. When in combination with Wnt pathway agonist or BMP4 signaling, the ephrin-B2/EphB4 biomaterial platform can create diverging EC progenitor populations, demonstrating differential gene expression pattern across a wide range of arterial and venous markers, as well as phenotypic markers such as anti-thrombotic, pro-atherogenic and osteogenic genes, that are consistent with the in vivo expression patterns of arterial and venous ECs. Importantly, this distinct EC progenitor population cannot be achieved by current methods of applying soluble factors or hemodynamic stimuli alone, illustrating that fine-tuning of developmental signals using the biomaterial platform offers a new approach to better control the arterial venous differentiation of stem cells.


Ubiquitylation and endocytosis of the human LAT1/SLC7A5 amino acid transporter.
The human L-type amino acid transporter 1 (LAT1), also known as SLC7A5, catalyzes the transport of large neutral amino acids across the plasma membrane. As the main transporter of several essential amino acids, notably leucine, LAT1 plays an important role in mTORC1 activation. Furthermore, it is overexpressed in various types of cancer cells, where it contributes importantly to sustained growth. Despite the importance of LAT1 in normal and tumor cells, little is known about the mechanisms that might control its activity, for example by promoting its downregulation via endocytosis. Here we report that in HeLa cells, activation of protein kinase C by phorbol 12-myristate 13-acetate (PMA) triggers efficient endocytosis and degradation of LAT1. Under these conditions we found LAT1 downregulation to correlate with increased LAT1 ubiquitylation. This modification was considerably reduced in cells depleted of the Nedd4-2 ubiquitin ligase. By systematically mutagenizing the residues of the LAT1 cytosolic tails, we identified a group of three close lysines (K19, K25, K30) in the N-terminal tail that are important for PMA-induced ubiquitylation and downregulation. Our study thus unravels a mechanism of induced endocytosis of LAT1 elicited by Nedd4-2-mediated ubiquitylation of the transporter's N-terminal tail.


A morphometric analysis of the immature human infraorbital canal.
The importance of the infraorbital canal in the growth of the maxilla and associated mid-facial region has significance for innervation of this region as well as the associated dentition, yet little is known about the development of the canal. An analysis of its dimensions and morphology during the late prenatal and early postnatal periods was thus undertaken. The aim of this study was to describe changes in the morphology, size and branching pattern of the infraorbital canal during the late prenatal and early postnatal stages of human growth. Fifty human fetal and neonatal maxillae were analyzed. The sample included 27 late prenatal individuals (30 gestational weeks and birth) and 23 early postnatal individuals (birth and 1 year). Maxillae were scanned using a Nikon XTH 225 L micro-CT unit and analyzed using VG studiomax v3.2. Measurements included the maximum width, height and surface area of each foramen associated with the infraorbital canal and the total length of the canal, bilaterally. All the measurements of the canal were greater in the early postnatal group than in the late prenatal group, while the walls and branching pattern of the canal were better developed in the postnatal group. Bone development occurred within the walls as development proceeded. Variations in the branching pattern of the canal were found. The morphology of the infraorbital canal reflected the developmental stage of associated structures such as the dentition, maxillary sinus and orbit.


Towards multimodal HPLC separations on humic acid-bonded aminopropyl silica: RPLC and LEC behavior.
In the present study, metal binding property of humic acid (HA) was successfully adapted to the ligand-exchange concept, and metal-loaded immobilized humic acid was used as a ligand exchanger stationary phase for separation of some nucleosides. Humic-acid bonded aminopropyl silica (EC-HA-APS) was turned into ligand exchanger forms by loading aqueous solutions of Cu(2+), and Co(2+) to the column (4.6 × 150; as mm) packed with EC-HA-APS. Metal ion solutions were loaded to the column in a stepwise manner where the concentration of metal ion solution being loaded to the column was increased gradually between 5 and 100mM. The progress of metal loading process was monitored via the breakthrough curves propagated stepwise. Ligand-exchange chromatography (LEC) studies were performed on an HPLC system, and chromatographic behaviors of the studied nucleosides (i.e. uridine, Urd; thymidine, Tyd; cytidine, Cyd; adenosine, Ado; and guanosine, Guo) were investigated on Cu(2+) and Co(2+) loaded forms of the EC-HA-APS (Cu-EC-HA-APS and Co-EC-HA-APS). Effect of mobile phase composition, temperature, and the type of metal ion loaded to the column on the retentive behaviors of the compounds was studied, in detail. The studied solutes exhibited mixed-mode RPLC/LEC behavior on the stationary phase. Metal-loaded column (M-EC-HA-APS) was easily regenerated into its original form, EC-HA-APS, with 98 ± 2% metal recoveries, by using aqueous mixture of EDTA+NH(3) at pH=7.5. Thus, the stationary phase exhibited a high flexibility between RPLC and LEC modes. This property, also, made it possible to convert the stationary phase into various ligand exchanger forms by loading different metal ions. Hence, capacity and selectivity of the stationary phase towards the studied species was manipulated easily by loading different metal ions to the stationary phase. Baseline separation for the studied species was achieved on Cu-EC-HA-APS and Co-EC-HA-APS and some differentiations were observed in capacity and selectivity, depending on the type of metal loaded. Thus, being as the first endeavor on usability of immobilized HA as a ligand exchanger stationary phase, the present study is believed to be useful to understand multifunctional character of HA-based solid/stationary phases.


NOD and NOR mice exhibit comparable development of lacrimal gland secretory dysfunction but NOD mice have more severe autoimmune dacryoadenitis.
The male Non-Obese Diabetic (NOD) mouse is an established model of autoimmune dacryoadenitis characteristic of Sjögren's Syndrome (SS), but development of diabetes may complicate studies. The Non-Obese Diabetes Resistant (NOR) mouse is a MHC-II matched diabetes-resistant alternative, but development of autoimmune dacryoadenitis is not well-characterized. We compare features of SS in male NOD and NOR mice at 12 and 20 weeks. Stimulated tear secretion was decreased in 12 week NOD relative to BALB/c mice (p < 0.05), while by 20 weeks both NOD and NOR showed decreased stimulated tear secretion relative to BALB/c mice (p < 0.001). Tear CTSS activity was elevated in NOD and NOR relative to BALB/c mice (p < 0.05) at 12 and 20 weeks. While NOD and NOR lacrimal glands (LG) showed increased LG lymphocytic infiltration at 12 and 20 weeks relative to BALB/c mouse LG (p < 0.05), the percentage in NOD was higher relative to NOR at each age (p < 0.05). Gene expression of CTSS, MHC II and IFN-γ in LG were significantly increased in NOD but not NOR relative to BALB/c at 12 and 20 weeks. Redistribution of the secretory effector, Rab3D in acinar cells was observed at both time points in NOD and NOR, but thinning of myoepithelial cells at 12 weeks in NOD and NOR mice was restored by 20 weeks in NOR mice. NOD and NOR mice share features of SS-like autoimmune dacryoadenitis, suggesting common disease etiology. Other findings suggest more pronounced lymphocytic infiltration in NOD mouse LG including increased pro-inflammatory factors that may be unique to this model.


Uretero-pelvic stenosis.
In a prospective series of 66 patients with uretero-pelvic stenosis ("genuine hydronephrosis") the clinical data and the results of treatment were registered. We found an estimated incidence per year of 5:100,000 inhabitants. In the age group under 10 years there was a striking majority of boys. Routine antimicrobial prophylaxis was not given; only one patient had clinical urinary tract infection postoperatively, but bacteriuria in the nephrostomy catheter was frequent. Follow-up 12 months after dismembered pyeloplasty with postoperative nephrostomy showed 85% of the patients to be cured, i.e. with no symptoms and with normal drainage from the renal pelvis. In 5% of the cases (3 patients) the result was unsatisfactory. The technique can be recommended in the treatment of ureteropelvic stenosis.


Effects of pyrrolizidine alkaloids and sesquiterpenes on snail feeding.
We determined in the laboratory the feeding response of two populations of the generalist herbivorous snail Arianta arbustorum (Helicidae) towards the composite Adenostyles alliariae and towards various allelochemicals. These were: a pyrrolizidine alkaloid (PA) extract of Adenostyles leaves; senecionine (a PA present in Adenostyles); retrorsine (a PA not present in Adenostyles) and two sesquiterpene (ST) fractions from Adenostyles: a mixture of the STs adenostylone and neoadenostylone, and deacyladenostylone. Tertiary PAs and PA N-oxides were tested separately. For each allelochemical, we tested whether it was deterrent or whether it induced changes of feeding behaviour (i.e. whether it had pre- or postingestive effects), and whether the effects were more pronounced with younger (smaller) snails. The tertiary PA extract from Adenostyles was deterrent, especially for young snails, but did not induce changes of feeding behaviour. Tertiary PA senecionine was deterrent for young snails only and induced changes of feeding behaviour. Also, consumption of untreated Petasites was higher after this treatment. Tertiary PA retrorsine was not deterrent, but induced changes of feeding behaviour. The PA N-oxides showed no activity against the snails. The mixture of adenostylone and neoadenostylone was deterrent and induced feeding aversions. Deacyladenostylone was highly deterrent, but did not induce changes of feeding behaviour. At the Jura site, PA content of Adenostyles was lower than at the Black Forest site. The snails from Jura consumed much less Adenostyles than the snails from Black Forest, and also ate a little less of the treated leaf discs. The PAs which are encountered by the snails in their natural food plants (PA extract and senecionine) were more deterrent than retrorsine (a novel compound). This suggests that the snails have mechanisms for the rejection of allelochemicals which they encounter in their natural food plants, but not for novel allelochemicals. The results suggest two hypotheses regarding the function of the allelochemicals in Adenostyles: (1) The allelochemicals act mainly on very young snails. (2) PAs render Adenostyles toxic, while STs act as feeding deterrents.


An orally administered multitarget tyrosine kinase inhibitor, SU11248, is a novel potent inhibitor of thyroid oncogenic RET/papillary thyroid cancer kinases.
The oncogenic RET/PTC tyrosine kinase causes papillary thyroid cancer (PTC). The use of inhibitors specific for RET/PTC may be useful for targeted therapy of PTC. The objective of the study was to evaluate the efficacies of the recently developed kinase inhibitors SU11248, SU5416, and SU6668 in inhibition of RET/PTC. SU11248, SU5416, and SU6668 were synthesized, and their inhibitory potencies were evaluated using an in vitro RET/PTC kinase assay. The inhibitory effects of the compounds on RET/PTC were evaluated by quantifying the autophosphorylation of RET/PTC, signal transducer and activator of transcription (STAT)-3 activation, and the morphological reversal of RET/PTC-transformed cells. An in vitro kinase assay revealed that SU5416, SU6668, and SU11248 inhibited phosphorylation of the synthetic tyrosine kinase substrate peptide E4Y by RET/PTC3 in a dose-dependent manner with IC(50) of approximately 944 nm for SU5416, 562 nm for SU6668, and 224 nm for SU11248. Thus, SU11248 effectively inhibits the kinase activity of RET/PTC3. RET/PTC-mediated Y705 phosphorylation of STAT3 was inhibited by addition of SU11248, and the inhibitory effects of SU11248 on the tyrosine phosphorylation and transcriptional activation of STAT3 were very closely correlated with decreased autophosphorylation of RET/PTC. SU11248 caused a complete morphological reversion of transformed NIH-RET/PTC3 cells and inhibited the growth of TPC-1 cells that have an endogenous RET/PTC1. SU11248 is a highly effective tyrosine kinase inhibitor of the RET/PTC oncogenic kinase.


Adenylyl cyclase 3 deficiency results in dysfunction of blood-testis barrier during mouse spermiogenesis.
Human infertility has become a global medical and social health problem. Mice deficient in type 3 adenylyl cyclase (AC3), a key enzyme that synthesizes cyclic adenosine monophosphate (cAMP), develop male infertility, although the underlying molecular mechanisms remain unknown. We performed a label-free quantitative (LFQ) proteomics analyses to identify testicular differentially expressed proteins (DEPs) and their respective biological processes. Furthermore, histological examination demonstrated that AC3 deficiency in mice led to mild impairment of spermatogenesis, including the thinning of seminiferous epithelium and local lesions in the testis. We further identified that the integrity of the blood-testis barrier (BTB) was impaired in AC3 knockout (AC3-/-) mice accompanied with the reduction in the expression of tight junctions (TJs) and ectoplasmic specialization (ESs)-related proteins. In addition, the deletion of AC3 in mice also reduced the germ cell proliferation, increased apoptosis, and decreased lipid deposition in the seminiferous tubules. Collectively, our results revealed a role of AC3 in regulating the BTB integrity during spermatogenesis. Thus, our findings provide new perspectives for future research in male infertility.


Phase I trial of murine monoclonal antibody 14G2a administered by prolonged intravenous infusion in patients with neuroectodermal tumors.
The purpose of this phase I trial was to determine the toxicity and maximum-tolerated dose (MTD) of murine monoclonal antibody (Mab) 14G2a (anti-GD2) in cancer patients. Following tracer doses of iodine-131-labeled 14G2a to determine tumor uptake, 18 patients with refractory melanoma, neuroblastoma, or osteosarcoma received unlabeled 14G2a at total concentrations of 50, 100, and 200 mg/m2 administered as daily 24-hour infusions for 5 days. The overall sensitivity of external immunoscintigraphy was 64 of 74 known metastases (86%). Toxicity from prolonged infusion of 14G2a consisted of severe generalized pain, hyponatremia, fever, rash, paresthesias, weakness, and chronic refractory postural hypotension (two patients). Toxicity was less severe in pediatric patients. The MTD of Mab was 100 mg/m2. Sixteen of 18 patients developed human antimouse antibodies (HAMA) to 14G2a. Terminal-phase half-life (T1/2) of unlabeled Mab was 6.6 +/- 1.8 hours for patients receiving 50 mg/m2 and 39.5 +/- 13.3 hours at the 100-mg/m2 level. Tumor biopsies from six melanoma patients were positive for GD2 antigen, but only two of six had trace amounts of 14G2a present. Three mixed responses (two melanoma, one osteosarcoma) and two partial responses (PRs; neuroblastoma) were observed. Mab 14G2a has modest antitumor activity at the expense of significant toxicity. Dose-limiting neurologic sequelae may significantly limit phase II studies other than in pediatric patients with neuroblastoma.


Depression and survival of breast cancer patients: A protocol for systematic review and meta-analysis.
Breast cancer is the most common malignancy in women worldwide. Compared with other malignant tumors, breast cancer patients have a higher incidence of depression and other psychiatric symptoms. The purpose of this meta-analysis was to determine the association between long-term survival and depression in patients with breast cancer. This review will include cohort studies only. Multiple databases will be searched by 2 independent reviewers, including PubMed, EMBASE, the Cochrane Library, and PsycINFO. The language of studies should be English and Chinese, published from inception to the September 2020. Two independent reviewers will carry out literature screening, research selection and data extraction. Revman5.3 software will be used to generate funnel map, assess heterogeneity, make the subgroup analysis and complete sensitivity analysis. This review will summarize the available evidence to determine the association between depression and survival in breast cancer patients. The results of this study will provide reference for the development of comprehensive treatment for breast cancer, and will promote further research. CRD42020202200.


STAT3 inhibition reduces toxicity of oncolytic VSV and provides a potentially synergistic combination therapy for hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is a refractory malignancy with a high mortality and increasing worldwide incidence rates, including the United States and central Europe. In this study, we demonstrate that a specific inhibitor of signal transducer and activator of transcription 3 (STAT3), NSC74859, efficiently reduces HCC cell proliferation and can be successfully combined with oncolytic virotherapy using vesicular stomatitis virus (VSV). The potential benefits of this combination treatment are strengthened by the ability of NSC74859 to protect primary hepatocytes and nervous system cells against virus-induced cytotoxicity, with an elevation of the VSV maximum tolerated dose in mice. Hereby we propose a strategy for improving the current regimen for HCC treatment and seek to further explore the molecular mechanisms underlying selective oncolytic specificity of VSV.


A novel quinazolinone chalcone derivative induces mitochondrial dependent apoptosis and inhibits PI3K/Akt/mTOR signaling pathway in human colon cancer HCT-116 cells.
We have synthesized a novel quinazolinone chalcone derivative (QC) and first time reported its in-vitro and in-vivo anticancer potential. It inhibited the cell proliferation of different cancer cell lines like PC-3, Panc-1, Mia-Paca-2, A549, MCF-7 and HCT-116. It induces apoptosis as measured by several biological endpoints such as apoptotic body formation, evident by Hoechst and scanning electron microscopy, enhanced annexinV-FITC binding of the cells, increased sub-G0 cell fraction, loss of mitochondrial membrane potential (Δψm), reduction of Bcl-2/Bax ratio, activation of caspase-9, caspase-3 and PARP-1 (poly-ADP Ribose polymerase) cleavage in HCT-116 cells. In spite of apoptosis, QC significantly hammers the downstream and upstream signaling cascade of PI3K/Akt/mTOR pathway and cell cycle regulator Skp-2, p21 and p27. Interestingly, QC induces the S and G2/M phase of HCT-116 cells at experimental doses. QC inhibits the tumor growth of Ehrlich ascites carcinoma (EAC), Ehrlich tumor (ET, solid) and sarcoma-180(solid) mice models. Furthermore, it was found to be non-toxic as no animal mortality (0/7) occurred during experimental doses. The present study provides an insight of anticancer potential of QC, which may be useful in managing and treating cancer.


Relationships between mitochondrial content of muscle fibres and patterns of glyogendepletion postmortem.
Sternomandibularis muscles were removed from slaughtered adult cattle immediately after exsanguination. On the basis of the density of diformazan granules deposited by a reaction for NAD tetrazolium reductase, approximately equal numbers of muscle fibres with high and low mitochondrial content were identified in serial frozen sections. In samples taken immediately after exanguination both types of muscle fibres exhibited glycogen phosphorylase activity and were stained equally by the periodic acid-Schiff (PAS) reaction for glycogen. In unstimulated muscle samples 1 hr postmortem, no loss of PAS staining was detected. In electrically stimulated samples 1 hr postmortem, large numbers of muscle fibres with a low mitochondrial content but only some muscle fibres with a high mitochondrial content became PAS-negative. Stimulation-induced glycogen depletion was completely prevented by the interfaicular injection of magnesium sulphate solution. In unstimulated samples between 5 and 24 hr postmortem, some muscle fibres with a high mitochondrial content but only a few muscle fibres with a low mitochondrial content became PAS-negative.


Self-assembly of lipase hybrid nanoflowers with bifunctional Ca2+ for improved activity and stability.
Lipase ZC12, a cold-adapted lipase derived from Psychrobacter sp. ZY124, can be effectively activated by Ca2+. Inspired by this significant property, we developed a novel immobilized lipase ZC12/Ca3(PO4)2 hybrid nanoflowers (LHNs). The LHNs have been characterized as a regular hierarchical flowerlike structure nanoflowers by scanning electron microscopy (SEM). Compared with free lipase ZC12, the LHNs exerted enhanced enzymatic activity of 206% and 2.31-fold in kcat/Km value, especially high specific activity at low temperature. After 7 successive cycles, the LHNs could still maintain its initial activity, demonstrating superior durability than the free lipase ZC12. Meanwhile, its stability basically kept unchanged in a wide range of temperature and pH. Finally, fructose laurate was transformed by the LHNs with 57.39% conversion rate which is twice as much as the free lipase. To sum up, these results validated that LHNs could emerge as an efficient immobilized lipase and possess the promising potential for practical applications.


From Corsica to Britain: new outdoor records of Ocnerodrilidae (Annelida: Clitellata) in western Europe.
The ocnerodrilids Eukerriasaltensis (Beddard, 1895) and Ocnerodrilusoccidentalis Eisen, 1878 are reported for the first time from outdoor localities above 42° N in Europe. The present new records comprise the first ever from England (River Thames, central London) and from France (River Golo, northern Corsica) and the northernmost occurrences in Italy (Liguria and Veneto). The new latitudinal limits and the numerosity of outdoor records suggest that the current environmental and climate changes are substantially enhancing the dispersal and survival possibilities of these worms, even though different transport vectors seem to be involved for the two species.


P-glycoprotein expression is induced in human pancreatic cancer xenografts during treatment with a cell cycle regulator, mimosine.
Application of several cell cycle checkpoint regulators seem to be promising in various experimental models including pancreatic cancer, and they are being evaluated in Phase I-II clinical trials. Among these compounds, mimosine, a plant-derived amino acid has shown an antineoplastic effect on human lung or pancreatic cancer xenografts in addition to cell cycle arrest in the late G1 phase. In the present study, immunosuppressed CBA mice bearing subcutaneously growing human ductal pancreatic adenocarcinomas were treated with 30 mg/kg L-mimosine for 34 days. The treatment resulted in retardation of tumor growth, accompanied by a significantly diminished proliferative activity (22.6%+/-1.7% Ki-67 positivity vs. 29.9%+/-1.1% in controls, mean+/-SEM, P<0.007) and an increased apoptotic rate (14.5+/-1.1 apoptotic cells/mm2 vs. 3.8+/-0.4/mm2 in the controls, P<0.0001). The immunohistochemical expression of the multidrug resistance gene (MDR1)-encoded P glycoprotein (p 170) was studied. The parental and the untreated tumors did not express p 170 protein, but in the mimosine-treated samples 30 to 60% of the carcinoma cells displayed a linear, membrane bound positivity. The results indicate that P-glycoprotein is inducible by a cell cycle regulator, creating an acquired resistant phenotype.


Fluoride content of bottled drinking waters available in Riyadh, Saudi Arabia.
This study aimed to examine the fluoride concentration of commercially available bottled water products in Riyadh, Saudi Arabia, and to assess the accuracy of the labeling of fluoride concentration on the tested brands. Fifteen randomly selected commercial brands of bottled water were obtained from supermarkets in Riyadh, Saudi Arabia. Three bottles of each brand were purchased, and fluoride content was measured using a combination fluoride-ion-selective electrode. The average reading for each brand was estimated and also compared with the fluoride content printed on the label. The mean (±SD) fluoride content of the 12 local bottled water samples was 0.79 (±0.09) mg/L with a range from 0.5 to 0.83 mg/L. The mean fluoride concentration of the three imported brands was 0.67 (±0.02) mg/L with a narrow range of fluoride content (0.65-0.69). All tested samples mention the fluoride content on the label except two imported brands. Five samples showed a significant difference between our evaluation and stated content of fluoride that ranged between +0.46 and -0.2 mg/L. Bottled drinking waters available in Riyadh, Saudi Arabia contain differing concentration of fluoride, but within a safe range for use as a source of systemic fluoride. In addition, the manufactures' labeling of fluoride content may be inaccurate.


Prophylactic effect of a peptide vaccine targeting TM4SF5 against colon cancer in a mouse model.
Expression of transmembrane 4 superfamily member 5 protein (TM4SF5) was implicated in hepatocellular carcinoma (HCC) and colon cancer. Previously, we have shown that immunization with TM4SF5 peptide-CpG-DNA-liposome complex induces production of TM4SF5-specific antibodies and protects mice from HCC progression in an allograft model. Here, we confirmed expression of TM4SF5 in the mouse colon cancer cell line CT-26 and found that anti-TM4SF5 antibody inhibits growth of CT-26 cells. We then immunized mice with TM4SF5 peptide-CpG-DNA-liposome complex and transplanted CT-26 cells to investigate the vaccination effects. Robust production of TM4SF5-specific antibodies was induced by challenge with CT-26 cells and the tumor growth was significantly suppressed in the immunized mice. The peptide vaccine targeting TM4SF5 consequently showed a prophylactic effect against colon cancer development in a mouse model. These results suggest that the peptide vaccine can be potentially applied in humans to treat colon cancer.


Grey wolves (Canis lupus) discriminate between familiar and unfamiliar human voices.
The ability to discriminate between different individuals based on identity cues, which is important to support the social behaviour of many animal species, has mostly been investigated in conspecific contexts. A rare example of individual heterospecific discrimination is found in domestic dogs, who are capable of recognising their owners' voices. Here, we test whether grey wolves, the nearest wild relative of dogs, also have the ability to distinguish familiar human voices, which would indicate that dogs' ability is not a consequence of domestication. Using the habituation-dishabituation paradigm, we presented captive wolves with playback recordings of their keepers' and strangers' voices producing either familiar or unfamiliar phrases. The duration of their response was significantly longer when presented with keepers' voices than with strangers' voices, demonstrating that wolves discriminated between familiar and unfamiliar speakers. This suggests that dogs' ability to discriminate between human voices was probably present in their common ancestor and may support the idea that this is a general ability of vertebrates to recognise heterospecific individuals. Our study also provides further evidence for familiar voice discrimination in a wild animal in captivity, indicating that this ability may be widespread across vertebrate species.


Perinatal deaths and insufficient antenatal care in Latvia.
A national audit on perinatal deaths was performed to assess the quality of antenatal care, and to suggest measures for improved antenatal care. Medical records of all the perinatal deaths in Latvia in the years 1995-1996 have been studied. Non-attenders and attenders of antenatal care were characterized by socio-economic and medical variables: maternal age, parity, history of perinatal outcome, health status and behavioral hazards during the index pregnancy, length of gestation and birth weight. The Nordic-Baltic perinatal death classification was used. In 85 of 442 cases (19%) of perinatal deaths women had not taken advantage of antenatal care provided for them. Non-attenders were more likely to be smokers (p<0.001) and alcohol abusers (p<0.005), above 35 years of age (p<0.005), and had higher parity (p<0.001). Non-attenders more often had systemic diseases and pregnancy complications. Neonatal complications, such as congenital syphilis (p<0.05) and other infections (p<0.05), were more common among non-attenders. There was no difference in rates of preterm birth and low birth weight between attenders and non-attenders. One fifth of mothers with perinatal death did not attend ANC, and in some women who attended ANC, lack of intervention was related to the perinatal death.


Rapid, Quantitative, High-Sensitive Detection of Escherichia coli O157:H7 by Gold-Shell Silica-Core Nanospheres-Based Surface-Enhanced Raman Scattering Lateral Flow Immunoassay.
Escherichia coli O157:H7 is regarded as one of the most harmful pathogenic microorganisms related to foodborne diseases. This paper proposes a rapid-detection biosensor for the sensitive and quantitative analysis of E. coli O157:H7 in biological samples by surface-enhanced Raman scattering (SERS)-based lateral flow immunoassay (LFIA). A novel gold-shell silica-core (SiO2/Au) nanosphere (NP) with monodispersity, good stability, and excellent SERS activity was utilized to prepare high-performance tags for the SERS-based LFIA system. The SiO2/Au SERS tags, which were modified with two layers of Raman reporter molecules and monoclonal antibodies, effectively bind with E. coli O157:H7 and form sandwich immune complexes on the test lines. E. coli O157:H7 was quantitatively detected easily by detecting the Raman intensity of the test lines. Under optimal conditions, the limit of detection (LOD) of the SiO2/Au-based SERS-LIFA strips for the target bacteria was 50 cells/mL in PBS solution, indicating these strips are 2,000 times more sensitive than colloidal Au-based LFIA strips. Moreover, the proposed assay demonstrated high applicability in E. coli O157:H7 detection in biological samples, including tap water, milk, human urine, lettuce extract and beef, with a low LOD of 100 cells/mL. Results indicate that the proposed SERS-based LFIA strip is applicable for the sensitive and quantitative determination of E. coli O157:H7.


[Pseudomonas aeruginosa infections in chronic obstructive pulmonary disease : Role of long-term antibiotic treatment].
Chronic Pseudomonas aeruginosa colonization in the airways of patients with chronic obstructive pulmonary disease (COPD) is probably associated with increased mortality and morbidity and a faster progress of COPD, although this has not been conclusively proven by studies. Studies demonstrating an improvement in prognosis in COPD patients by early eradication of Pseudomonas or at least a reduction of the bacterial burden by either inhaled or oral antibiotic maintenance therapy, are missing. An impact on the exacerbation rate has only been shown for macrolide maintenance treatment; however, this effect could be explained by the inclusion of patients with bronchiectasis in the studies. This is a group of patients for whom the effect of this kind of antibiotic treatment is well known. Further studies on the prevention and treatment of chronic Pseudomonas colonization in COPD patients are urgently needed. The stability of the respiratory microbiome probably plays an essential role in the course of the disease and should be established as a study endpoint.


Removal of pesticide residues from fresh vegetables by the coupled free chlorine/ultrasound process.
Pesticide residue in vegetables has been considered as a serious food safety problem across the whole world. This study investigates a novel advanced oxidation process (AOP), namely the coupled free chlorine/ultrasound (FC/US) process for the removal of three typical pesticides from lettuce. The removal efficiencies of dimethoate (DMT), trichlorfon (TCF) and carbofuran (CBF) from lettuce reached 86.7%, 79.8% and 71.3%, respectively by the FC/US process. There existed a synergistic effect in the coupled FC/US process for pesticide removal and the synergistic factors reached 22.3%, 19.0% and 36.4% for DMT, TCF and CBF, respectively. Based on the analysis of mass balance of pesticides, the synergistic effect was probably attributed to the efficient oxidation of pesticides both in vegetables and in water by the generated free radicals and FC. The surface area and surface structure of vegetables strongly affected the removal of pesticides by FC/US. The removal efficiency of DMT increased from 80.9% to 88.1% as solution pH increased from 5.0 to 8.0, and then decreased to 84.1% when solution pH further increased to 9.0. When the ultrasonic frequency changed from 20 to 40 kHz, a remarkable improvement in pesticide removal by FC/US was observed. As the FC concentration increased from 0 to 15 mg L-l, the removal efficiencies of pesticides increased firstly, and then became stagnant when the FC concentration further increased to 25 mg L-l. The pesticide degradation pathways based on the identified intermediates were proposed. The total chlorophyll content was reduced by less than 5% after the FC/US process, indicating a negligible damage to the quality of vegetables. It suggests that the FC/US process is a promising AOP for pesticides removal from vegetables.


Are patients with POEMS syndrome at increased risk of Salmonella aortitis?
We report a case of Salmonella infectious aortitis in a patient with POEMS (peripheral neuropathy, organomegaly, endocrinopathy, M-protein and skin changes) syndrome, possibly indicating that vasculopathy associated with POEMS syndrome may increase the risk of Salmonella endovascular infection.


Dorsal prevertebral lesions in Wegener granulomatosis: report on four cases.
Retroperitoneal fibrosis has been reported in several patients with Wegener granulomatosis (WG), but only three isolated cases of dorsal prevertebral lesions, closely resembling fibrosing mediastinitis, have been published so far. We describe four new WG patients (two men, two women), 49-59 years old at diagnosis, with dorsal prevertebral lesions, mainly right-sided, and with adjacent pleural thickening in two. These lesions were detected on computed-tomography scans at diagnosis in two patients, and occurred later in the two others. Only one of them had mild back pain. Two patients' lesions were biopsied, revealing granulomatous inflammation. In one patient, the lesion regressed under WG treatment. Lesion size did not change in the remainings. Intralesional calcifications appeared in two. None of the patients had local bone erosion, vascular or neurological complications. These prevertebral lesions might represent a dorsal form of retroperitoneal fibrosis in WG, but usually with a more benign presentation and course. WG should be included in the differential diagnosis of fibrosing mediastinitis (with tuberculosis, neoplastic diseases, sarcoidosis, histiocytosis and inflammatory pseudotumor), which may have a similar radiological appearance.


Effect of starvation and shock loads on the biodegradation of 4-chlorophenol in a discontinuous moving bed biofilm reactor.
The influence of starvation (defined as the period without substrate) and shock loads on the performance of a moving bed sequencing batch reactor degrading 4-chlorophenol (4CP) were investigated. The biomass was acclimated to biodegrade 100 mg/L of 4CP, and the colonization of the packing material was followed. Two starvation periods and two shock loads were studied. The degradation capacity of the suspended and the attached biomass present on the moving bed was also evaluated. The experiments showed that, after the starvation period, the specific degradation rate decreased from 30.5 to 28.5 and 20 mg 4CP/gVSS/h, when starvation periods of 24 and 48 h were applied, respectively. When two concentration peaks of 500 and 1,050 mg/L were applied, a loss of 6% and 8% on the specific degradation rate, respectively, was also observed. The moving bed thus showed great robustness against starvation periods and shock loads. Suspended biomass presented higher specific degradation rates, but attached biomass did not generate a metabolite that is inhibitory when it accumulates.


Chronic contained rupture of an abdominal aortic aneurysm presenting as a lower extremity neuropathy.
Rupture of an abdominal aortic aneurysm often presents with a pulsatile abdominal mass, abdominal pain, and hypotension. Recent clinical reports describe patients with less apparent clinical signs and symptoms who were found later in their evaluation to have a contained rupture of an abdominal aortic aneurysm. Even more unusual is a chronic contained rupture of an abdominal aortic aneurysm. Our patient had a chronic contained rupture of an abdominal aortic aneurysm that presented with erosion into the lumbar vertebral bodies and subsequent lumbar neuropathy. CT scan confirmed the contained rupture of the aortic aneurysm and the patient underwent successful repair of his aortic aneurysm. Our report discusses the significance of atypical presentations of abdominal aortic aneurysm rupture and the importance of prompt diagnosis and definitive repair.


A chance to cut is not always a chance to cure- fasciotomy in the treatment of rattlesnake envenomation: A retrospective poison center study.
Fasciotomy has been described in the treatment of rattlesnake-envenomation. We sought to compare the characteristics of patients undergoing fasciotomy with those where fasciotomy was discussed but not performed. A retrospective case-series constructed from a single-statewide-poison-system electronic database for cases of fasciotomy discussion or completion in rattlesnake-envenomation between January 2001 and May 2012. Age, gender, bite location, antivenom administered, compartment pressure measurements, Snakebite Severity Score (SSS) and length of hospitalization (LOS) were recorded. Comparisons were made between fasciotomy completed and where fasciotomy was only discussed. One-hundred-five cases of fasciotomy discussion or completion were identified. Fasciotomy was performed in 28 cases (27%). There was no statistically significant difference (p > 0.05) between groups in age, gender, bite site, SSS, and total number of vials of antivenom administered. Only 2 of 28 (7%) had compartment pressure measurements. Patients undergoing fasciotomy spent an additional 2 days in the hospital. Fasciotomies continue to take place, without compartment pressure measurements, and without repeat dosing of antivenom. In the absence of clear objective evidence that limb-threatening compartment syndrome occurs despite adequate antivenom administration, fasciotomy does not favorably impact morbidity and may be associated with increased costs for care following rattlesnake envenomation.


Lessons learned from the impact of the COVID-19 pandemic in Brazil on primary-care workplace learning groups.
The COVID-19 pandemic in Brazil had a major impact on face-to-face permanent education for health (PEH) workplace learning groups in primary care. The aim of the study was to explore how PEH groups in primary care changed during the COVID-19 pandemic. A qualitative exploratory evaluation study was conducted with six key participants, who answered semi-structured questions in on-line interviews. The PEH groups rapidly and successfully implemented an online approach using social media. The role of the coordinator changed from being a facilitator to an information broker for navigating the large volume of conflicting information and misinformation. The findings highlight the importance of being an agile organisation, with a 'bottom-up' approach to innovation, and the key role of having an information broker in rapidly changing and complex environments. An appreciation of the importance of the socio-technical system for technology implementation in an organisation was also highlighted, with the use of technologies that are familiar to members of the organisation.


Emotional and psychopathological disturbances in HIV-infection.
1. The evaluation of emotional disturbances, depression and anxiety in 25 HIV-Positive paired with 25 HIV-Negative male homosexuals and a control group of 15 HIV-Negative male heterosexual have shown the presence of emotional perturbations and especially of an emotional blunting, in absence of depressive or anxious episode in HIV-Positive subjects. 2. Emotional perturbations were the lowest in the HIV-Negative heterosexual group. 3. These results raise the question of the emotional deficit as an adaptative process or as the direct action of the virus. 4. Its relationship with the other emotional perturbations and their impact on the evolution of the disease are discussed.


Current percutaneous coronary intervention and coronary artery bypass grafting practices for three-vessel and left main coronary artery disease. Insights from the SYNTAX run-in phase.
Percutaneous coronary intervention with drug-eluting stents is challenging coronary artery bypass grafting (CABG) as the gold standard for treatment of three-vessel and left main coronary disease. We evaluated the current practice pattern in hospitals throughout Europe and USA. To qualify for participation in the SYNTAX (Synergy between PCI with TAXUS drug-eluting stent and Cardiac Surgery) study, a randomized trial comparing percutaneous coronary intervention with drug-eluting stent versus coronary artery bypass grafting for three-vessel and left main disease, 104 centers were asked to provide their case volume in 3 months in 2004. Anonymous procedural data were collected. A total of 12,072 patients were recorded. Coronary artery bypass grafting was the most frequently performed procedure (N=8895, 74%). Three-vessel disease (3VD) predominated in this population (N=8532, 71%) versus left main (N=3540, 29%). In the 3-month period, per center a mean of 8.3 patients with left main and 22.3 patients with three-vessel disease were treated by percutaneous coronary intervention, while 26.0 patients with left main and 60.3 patients with three-vessel disease were treated by coronary artery bypass grafting. In USA, percutaneous coronary intervention for left main and/or three-vessel disease was performed in 18% of the cases while this was performed in 29% of the cases in Europe. Of all CABG procedures, only 12% were done with total arterial grafting while 7% were treated with only venous grafts. In patients with multivessel or left main disease, still coronary artery bypass grafting remains the dominant revascularization strategy. Percutaneous coronary intervention is performed frequently without supporting data from the literature. Percutaneous coronary intervention for this indication is performed more often in Europe than in USA. Only a minority of the patients receives total arterial grafting in case of coronary artery bypass grafting. The SYNTAX trial with randomized and registry cohorts should provide guidance for selecting the preferred form of treatment.


Extent of mediastinal node metastasis in clinical stage I non-small-cell lung cancer: the role of systematic nodal dissection.
To determine the extent of lymph node metastasis in clinical stage I non-small-cell lung cancer (NSCLC). We performed a retrospective review of 524 patients with clinical stage I NSCLC who underwent lobectomy with systematic nodal dissection. The nodal status was N0 in 409 patients (78%), N1 in 44 (8%), N2 in 67 (13%), and N3 in four (0.8%). Thirty-six patients had single-level mediastinal nodal metastases and 35 had multi-level metastases. The incidence of N2/3 disease in patients with adenocarcinoma/squamous cell carcinoma/other histologic types according to tumor size was 0/0/0%, respectively, in tumors < or = 10 mm in diameter, 12/0/0% in tumors 11-20 mm in diameter, 14/4/23% in tumors 21-30 mm in diameter, and 26/14/20% in tumors >30 mm in diameter. Nodal metastases to the upper mediastinum from middle or lower lobe lesions were frequently observed in 51 N2 adenocarcinomas, whereas those to the lower mediastinum from upper lobe lesions were rare. Of 10 N2 squamous cell carcinomas, seven had regional and three had non-regional nodal metastases. The 5-year survival rate was 68, 43, and 30% in N0, N1, and N2, respectively (P<0.01, N0 versus N1, N0 and N2). Systematic mediastinal nodal dissection should be routinely performed for clinical stage I lung cancer to ensure the correct nodal status, but it might be dispensable in the patients with peripheral squamous cell carcinoma < or = 20 mm in diameter, with central squamous cell carcinoma < or = 30 mm, and with adenocarcinoma < or = 10 mm. When systematic nodal dissection cannot be performed, the incidence and extent of nodal metastases should be taken account with respect to histologic type, size, and location of the tumor.


Inter simple sequence repeat markers to assess genetic diversity of the desert date (Balanites aegyptiaca Del.) for Sahelian ecosystem restoration.
Drought and desertification are the major environmental constraints facing the Sahelian agro-ecosystems for decades. Assessing genetic diversity of native tree species is critical to assist ecosystems restoration efforts. Here we describe genetic diversity and structure of seven Balanites aegyptiaca L. natural populations distributed across the Sahelian-Saharan zone of Mauritania using 16 polymorphic ISSR primers. These generated 505 polymorphic bands. Polymorphism information content (PIC) varied from (0.13-0.29) with an average 0.23, marker index (MI) averaged 7.3 (range 3.3-10.3) and resolving power (RP) ranged from (4.53-14.6) with an average 9.9. The number of observed alleles (Na) ranged from (0.62-1.39), Effective number of alleles (Ne) varied from (1.26-1.37), Shannon's information index (I) ranged from (0.25-0.36). AMOVA analysis showed that 80% of the genetic variation was fined within populations, which is supported by a low level of genetic differentiation between population (GST = 0.21) and an overall estimate of gene flow among populations (Nm = 1.9). The dendrogram based on Jaccard's similarity coefficient and the structure analysis divided the seven populations into two main clusters in which two populations from the Saharan zone were grouped. Our results provide baseline data for genetic conservation programs of this Sahelian neglected crop and with an important econ-ecological role.


Virtual colonoscopy.
Computerized tomographic colonography (CT colonography) is a new, non-invasive technique that has been developed over the last few years; it looks at the large bowel in detail. In this chapter we look at how the examination is performed and we consider how the images are displayed. We describe the normal features of the colon, as seen using this technique, as well as the features of common pathological conditions. We will discuss screening for colorectal cancer and the performance of CT colonography; we compare the latter with other procedures currently employed in the screening and diagnosis of colorectal pathology. We consider the difficulties in interpreting these CT colonographic images and look at ways to overcome such difficulties. Finally we discuss future developments of this exciting, new technique.


Mandibular Canine Transmigration: Report of Three Cases and Literature Review.
Transmigration is a rare phenomenon seen almost exclusively in the mandibular canines. The aim of the present study is to review transmigration phenomenon. Appropriate guidelines for a systematic review were followed. The time period selected for the present systematic review was 2001-2016. The studies were selected from various electronic databases on the basis of their title, study, design, keywords, and abstracts. A total of 150 citations were searched initially, and after proper screening, 59 relevant articles were included. Additional data was obtained by searching journals and reference lists. The literature search shows that transmigration is more frequent in the mandible than maxilla. The etiology of the condition is obscure; however, multiple factors have been attributed to the condition. They are more readily recognized now with the advent of panoramic radiographs. Transmigration is a rare anomaly causing varied manifestations and requires an interdisciplinary approach for management. Early diagnosis of impacted canines is mandatory for timely treatment to ensure facial harmony and improved function.


Sex differences in the polysomnographic sleep of young adults: a community-based study.
In small, clinical samples, men have reduced slow wave sleep compared to women. Given the higher prevalence of sleep-related breathing disturbance in men, this study assessed sex differences in sleep in a large, non-clinical sample of adults and controlled for primary sleep disorders. Men and women, 31-40 years old, drawn from a longitudinal sample representative of southeast Michigan served as subjects. Each underwent a sleep study consisting of two consecutive 8-h nights of standard polysomnography (NPSG) and a multiple sleep latency test (MSLT) the intervening day. Of the 439 eligible participants, 292 (66.5%) agreed to spend two consecutive nights and the intervening day in the sleep laboratory. Standard polysomnograms that monitored respiration and leg movements were collected each night, and on the intervening day the MSLT was performed. Men had more sleep-related breathing disturbance than women. After adjusting for this higher prevalence of respiratory disturbance, men still had a lower mean sleep efficiency (i.e. increased wake time) and a higher percentage of stage 1 sleep. Men and women did not differ in most other sleep parameters and did not differ in level of daytime sleepiness on the MSLT. Sleep-related respiratory disturbance accounted for some of the sex differences in sleep. After correcting for respiratory disturbance, men still had lighter and less efficient sleep, but this was not associated with greater daytime sleepiness. Whether this reflects a sex difference in the functioning of the sleep homeostat will require further study.


Oxygenation of tumors by a hemoglobin solution.
Tumor oxygen tensions were measured using a computer-controlled PO2 microelectrode in two preclinical solid tumor models, the rat 9L gliosarcoma and the rat 13672 mammary carcinoma. Tumor oxygenation profiles were determined under four conditions: (a) during normal air breathing, (b) during carbogen breathing, (c) after intravenous administration of a solution of ultrapurified polymerized bovine hemoglobin with normal air breathing and (d) after intravenous administration of a solution of ultrapurified polymerized bovine hemoglobin with carbogen breathing. Both tumors had severely hypoxic regions under normal air-breathing conditions. Although carbogen breathing increased the oxygenation of the better-oxygenated portions of the tumor, it made no impact on the severely hypoxic tumor regions. Administration of the hemoglobin solution was effective in increasing the oxygenation throughout both tumors under normal air-breathing conditions. The addition of carbogen breathing to administration of the hemoglobin solution eliminated severe hypoxia in the 9L gliosarcoma and markedly reduced the severely hypoxic regions of the 13672 mammary carcinoma. At 24 h after administration of the hemoglobin solution the 13672 mammary carcinoma showed greater hypoxia than before treatment, which was partially corrected with carbogen breathing.


Clear cell hidradenocarcinoma developing in pacemaker pocket.
An octagenerian woman developed clear cell hidradenocarcinoma, a rare neoplasm of eccrine sweat gland origin, 4 years following pacemaker implantation in her right lateral chest. The tumor immunohistochemically mimicked a metastatic lobular breast carcinoma, for example, strongly positive estrogen, weakly positive progesterone, and weakly reactive mammoglobin. A complete surgical excision of the tumor was complemented with ipsilateral dissection of involved adjacent axillary lymph nodes. Recommended irradiation was refused by the patient. Retrospective 3-year mammogram review, 2-year postsurgery follow-up, and complete postmortem evaluation failed to prove a primary breast malignancy or other metastatic lesion elsewhere.


Formation of Avenacein Y byFusarium avenaceum Fries Sacc. isolates from poland and biological properties of the compound.
Eighteen isolates ofFusarium avenaceum Fries Sacc. originating from cereals, potato and carrot from Poland synthesized Avenacein Y in amounts ranging from 0.01 to 2.0 g/kg of wheat grain. The compound was produced in 1 kg of corn kernels by isolate KF-58, isolated, identified and used to test for antibiotic activity against plant pathogenic fungi of 11 genera. Application of Avenacein Y caused slight decrease of mycelium growth in four species only.


A fully coupled transient excited state model for the sodium channel. II. Implications for action potential generation, threshold, repetitive firing, and accommodation.
The axon membrane is simulated by standard Hodgkin-Huxley leakage and potassium channels plus a coupled transient excited state kinetic scheme for the sodium channel. This scheme for the sodium channel is as proposed previously by the author. Simulations are presented showing the form of the action potential, threshold behavior, accommodation, and repetitive firing. It is seen that the form of the individual action potential, its all-or-none nature, and its refractory period are well simulated by this model, as they are by the standard Hodgkin-Huxley model. However, the model differs markedly from the Hodgkin-Huxley model with respect to repetitive firing and accommodation to stimulating currents of slowly rising intensity, in ways that are shown to be related to those features of the sodium inactivation which are anomalous to the H-H model. The tendency for repetitive firing is highly dependent on that parameter which primarily determines the existence of the inactivation shift in voltage clamp experiments, in such a way that the more pronounced the inactivation shift, the less the tendency for repetitive firing. The tendency for accommodation is highly dependent on that parameter which primarily determines the 'tauc-tauh' separation, in such a way that the greater the separation the greater the tendency for the membrane to accommodate without firing action potentials to a slowly rising current.


Methacrylated gelatin shape-memorable cryogel subcutaneously delivers EPCs and aFGF for improved pressure ulcer repair in diabetic rat model.
Pressure ulcer (PU) in patients with diabetes mellitus (DM) is still a clinical intractable issue due to the complicated physiological characteristics by the prolonged high glucose level and impaired angiogenesis. The PU treatment includes surgical debridement, stem cell therapy and growth factors, leading to high cost and repeated professional involvement. Developing effective wound dressing combining the therapeutic cells and growth factors has become highly demanded. Herein, we reported the direct subcutaneous administration of endothelial progenitor cells (EPCs) and acid fibroblast growth factor (aFGF) with a shape-memorable methacrylated gelatin cryogel (EPCs/aFGF@GelMA) for the therapy of PU in rats with DM. This EPCs/aFGF@GelMA cryogel system presented microporous structure, elastic mechanical strength and enhanced cell migration property with controlled release of aFGF. Moreover, compared with EPCs/aFGF and GelMA alone, in vivo results showed that this EPCs/aFGF@GelMA system exhibited accelerated wound closure rate, enhanced granulation formation, collagen deposition as well as re-epithelization. Importantly, we found that the excellent positive performance of EPCs/aFGF@GelMA is due to its up-regulation of HIF-ɑ upon the wound site, modulating the microenvironment of wound site to initiate the impaired local angiogenesis. Collectively, this hybrid gelatin cryogels show great promise for biomedical applications, especially in tissue engineering and regenerative medicine.


Function of identified interneurons in the leech elucidated using neural networks trained by back-propagation.
Mechanical stimulation of the body surface of the leech causes a localized withdrawal from dorsal, ventral and lateral stimuli. The pathways from sensory to motor neurons in the reflex include at least one interneuron. We have identified a subset of interneurons contributing to the reflex by intracellular recording, and our analysis of interneuron input and output connections suggests a network in which most interneurons respond to more than one sensory input, most have effects on all motor neurons and in which each form of the behaviour is produced by appropriate and inappropriate effects of many interneurons. To determine whether interneurons of this type can account for the behaviour, or whether additional types are required, model networks were trained by back-propagation to reproduce the physiologically determined input-output function of the reflex. Quantitative comparisons of model and actual connection strengths show that model interneurons are similar to real ones. Consequently, the identified subset of interneurons could control local bending as part of a distributed processing network in which each form of the behaviour is produced by the appropriate and inappropriate effects of many interneurons.


Persistent pleural effusion after open heart surgery: giant hydatid cyst of the liver and its demonstrative images. A case report.
Approximately in 50% of the patients who have undergone coronary artery bypass surgery (CABG), pleural fluid collection occurs at the early postoperative period and resolves spontaneously. CABG was performed on a 54-year-old male. In the early postoperative period, the chest roentgenogram revealed right pleural collection. The preoperative and the postoperative hepatic function tests were nor-mal. MR scanning revealed a giant hydatid cyst at the apex of the liver. The cyst was excised through thoracotomy transphrenically and primary capitonage was applied. In the persistent right pleural effusion that occurs after open heart surgery hydatid cyst of the liver should be remembered, especially in the endemic regions.


Interleukin-1 receptor antagonist (IL-1ra) is unable to reverse cachexia in rats bearing an ascites hepatoma (Yoshida AH-130).
The mechanisms leading to the development of cancer cachexia are still poorly understood. Recently, cytokines such as interleukin 1 and tumour necrosis factor-alpha have been involved as mediators of the tissue wasting consequent to tumour growth. The rat ascites hepatoma Yoshida AH-130 is a highly anaplastic tumour that causes in the host an early and marked depletion of both the skeletal muscle and the adipose tissue, mainly accounted for by a hypercatabolic state. Profound hormonal alterations and the release of tumour necrosis factor-alpha and interleukin 1 by the tumour cells likely concur in forcing the metabolic balance towards the catabolic side [1]. In order to possibly achieve the correction of this wasting condition, the AH-130 bearing rats were administered a daily s.c. dose of interleukin 1 receptor antagonist (IL-1ra; 2 mg/kg). This factor, however, was completely ineffective in either inhibiting tumour proliferation or in preventing the consequent tissue depletion and protein hypercatabolism. These observations suggest that interleukin 1 is not important, at least in this model system, for either the development of cachexia or tumour growth.


Hippocampus versus entorhinal cortex decoupling by an NR2 subunit-specific block of NMDA receptors in a rat in vitro model of temporal lobe epilepsy.
The role of N-methyl-D-aspartate receptors (NMDARs) in the generation and maintenance of epileptic seizures has been widely investigated, however, little is known of possible separate roles played by NMDARs that contain different NR2 subunits. A better comprehension of how distinct NMDARs subtypes participate in seizure generation and/or diffusion may lead to the development of more targeted pharmacologic strategies to treat epilepsy. Therefore, we have performed an electrophysiologic investigation using a multielectrode array device, on slices comprising entorhinal cortex (EC) and hippocampus, continuously perfused in a Mg(2+) -free medium, with added 4-aminopiridine (4AP; 10-15 μm). Two separate rhythmic patterns of interictal-like activity were generated in EC and hippocampus, with EC seizures entrained to those in CA3, so that a significant degree of cross-correlation occurred. Perfusion with the NR2A-containing NMDAR antagonist [(R)-[(S)-1-(4-bromo-phenyl)-ethylamino]-(2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl)-methyl]-phosphonic acid (NVP-AAM077; 50 nm) or Zn(2+) (200 nm), did not affect the rate of interictal-like events in EC and hippocampus; however, it significantly reduced their cross-correlation, causing a substantial decoupling of the two rhythm generators. The same effect was observed with (αR,βS)-α-(4-hydroxyphenyl)-β-methyl-4-(phenylmethyl)-1-piperidinepropanol maleate (Ro25-6981; 1 μm), when coapplied with a subthreshold dose of NVP-AAM077. Our results suggest that NR2 subunits may be crucial in entraining cortical networks, leading to recruitment of wider range oscillations during epilepsy. Therefore, a pharmacologic strategy directed onto NR2 subunits may help to limit seizure diffusion and recruitment of potentially entrained oscillatory networks.


The co-delivery of adenovirus-based immune checkpoint vaccine elicits a potent anti-tumor effect in renal carcinoma.
Immune-based checkpoint therapy has made significant progress in cancer treatment, but its therapeutic effect is limited. A replication-defective adenovirus (Ad) vaccine encoding tumor antigen carbonic anhydrase IX (CAIX) combined with Ad-encoding immune checkpoint PD-L1 was developed to treat renal carcinoma. Three tumor models, subcutaneous, lung metastasis and orthotopic tumor were established, and Ad vaccines were used to immunize them and evaluate the vaccine's therapeutic effect. Compared to the single Ad vaccine group, the subcutaneous tumor growth was significantly reduced in Ad-CAIX/Ad-PD-L1 combination group. Co-immunization of Ad-CAIX/Ad-PD-L1 enhanced the induction and maturation of CD11c+ or CD8+CD11c+ DCs in the spleen and tumor and promoted the strong tumor-specific CD8+ T cell immune responses. In vivo CD8 T cell deletion assay showed that the anti-tumor effect of the Ad-CAIX/Ad-PD-L1 vaccine was mainly dependent on functional CD8+ T cell immune responses. Furthermore, the Ad-CAIX/Ad-PD-L1 vaccine effectively inhibited tumor growth and lung metastasis in metastatic or orthotopic models. These results indicate that the combination strategy of the immune checkpoint vaccine shows promising potential as an approach for malignant tumor therapy.


Accelerated, severe lupus nephritis benefits from treatment with honokiol by immunoregulation and differentially regulating NF-κB/NLRP3 inflammasome and sirtuin 1/autophagy axis.
Using honokiol (HNK), a major anti-inflammatory bioactive compound in Magnolia officinalis, we show a potent therapeutic outcome against an accelerated, severe form of lupus nephritis (ASLN). The latter may follow infectious insults that act as environmental triggers in the patients. In the current study, an ASLN model in NZB/W F1 mice was treated with HNK by daily gavage after onset of the disease. We show that HNK ameliorated the ASLN by improving renal function, albuminuria, and renal pathology, especially reducing cellular crescents, neutrophil influx, fibrinoid necrosis in glomeruli, and glomerulonephritis activity scores. Meanwhile, HNK differentially regulated T cell functions, reduced serum anti-dsDNA autoantibodies, and inhibited NLRP3 inflammasome activation in the mice. The latter involved: (a) suppressed production of reactive oxygen species and NF-κB activation-mediated priming signal of the inflammasome, (b) reduced mitochondrial damage, and (c) enhanced sirtuin 1 (SIRT1)/autophagy axis activation. In conclusion, HNK represents a new drug candidate for acute, severe episodes of LN capable of alleviating renal lesions in ASLN mice by negatively regulating T cell functions and by enhancing SIRT1/autophagy axis-lessened NLRP3 inflammasome activation.


Laryngeal Electromyographic findings in patients with vocal fold motion asymmetry.
Vocal fold motion asymmetry (VFMA) is often attributed to vocal fold paresis or an anatomical variant. Although laryngeal electromyography (LEMG) may be used to evaluate patients with vocal fold paresis, electrodiagnostic findings in VFMA have not been well defined. Review of a case series Twenty-five symptomatic patients with VFMA were examined by LEMG, and the findings were analyzed. Although all were thought to have unilateral recurrent laryngeal nerve paresis, LEMG showed only nine to have unilateral recurrent nerve paresis. There were nine with both ipsilateral recurrent laryngeal nerve and superior laryngeal nerve paresis, four with bilateral paresis, and three were normal. Reduced total number of units, reduced recruitment, motor units firing fast, and polyphasic units were more common, whereas fibrillation potentials, fasciculation, positive sharp waves, and complex repetitive discharges were uncommon. The LEMG findings are most consistent with old, healed neuropathy. McNemar's test for the acute versus chronic denervation potentials showed significant differences. VFMA has a high incidence of vocal fold paresis that can be better defined by LEMG. The site and side of paresis is often wrong based on laryngoscopy findings alone. The LEMG findings of VFMA appear to be consistent with old, healed neuropathy 4 Laryngoscope, 126:E273-E277, 2016.


Joint homeostasis, restoration, and remodeling in osteoarthritis.
Osteoarthritis is the major cause of joint failure. The outcome of the disease process is determined by complex interactions between cells and molecules steering homeostasis, destruction, restoration, and remodeling. The articular cartilage has a limited restoration and repair capacity. Genetic studies in humans and the development of mouse models have identified the role of signaling pathways that are important for skeletal development in the postnatal biology and pathology of articular cartilage. These include bone morphogenetic protein, transforming growth factor beta, fibroblast growth factor, wingless-type signaling, and their respective antagonists such as noggin and frizzled related protein. The synovium is prone to inflammation and emerging evidence suggests that innate and adaptive immune responses are important. Bone and cartilage form a biomechanical unit; stiffer bones might impair cartilage homeostasis. The biology of frizzled related protein provides a basis for the hypothesized inverse relationship between osteoarthritis and osteoporosis.


Unified Mouse and Human Kidney Single-Cell Expression Atlas Reveal Commonalities and Differences in Disease States.
Mouse models have been widely used to understand kidney disease pathomechanisms and play an important role in drug discovery. However, these models have not been systematically analyzed and compared. The authors characterized 18 different mouse kidney disease models at both bulk and single-cell gene expression levels and compared single-cell gene expression data from diabetic kidney disease (DKD) mice and from patients with DKD. Although single cell-level gene expression changes were mostly model-specific, different disease models showed similar changes when compared at a pathway level. The authors also found that changes in fractions of cell types are major drivers of bulk gene expression differences. Although the authors found only a small overlap of single cell-level gene expression changes between the mouse DKD model and patients, they observed consistent pathway-level changes. Mouse models have been widely used to understand kidney disease pathomechanisms and play an important role in drug discovery. However, these models have not been systematically analyzed and compared. We analyzed single-cell RNA sequencing data (36 samples) and bulk gene expression data (42 samples) from 18 commonly used mouse kidney disease models. We compared single-nucleus RNA sequencing data from a mouse diabetic kidney disease model with data from patients with diabetic kidney disease and healthy controls. We generated a uniformly processed mouse single-cell atlas containing information for nearly 300,000 cells, identifying all major kidney cell types and states. Our analysis revealed that changes in fractions of cell types are major drivers of differences in bulk gene expression. Although gene expression changes at the single-cell level were mostly model-specific, different disease models showed similar changes when compared at a pathway level. Tensor decomposition analysis highlighted the important changes in proximal tubule cells in disease states. Specifically, we identified important alterations in expression of metabolic and inflammation-associated pathways. The mouse diabetic kidney disease model and patients with diabetic kidney disease shared only a small number of conserved cell type-specific differentially expressed genes, but we observed pathway-level activation patterns conserved between mouse and human diabetic kidney disease samples. This study provides a comprehensive mouse kidney single-cell atlas and defines gene expression commonalities and differences in disease states in mice. The results highlight the key role of cell heterogeneity in driving changes in bulk gene expression and the limited overlap of single-cell gene expression changes between animal models and patients, but they also reveal consistent pathway-level changes.


Effect of dichlorvos on hepatic and pancreatic glucokinase activity and gene expression, and on insulin mRNA levels.
Several studies have shown that organophosphate pesticides affect carbohydrate metabolism and produce hyperglycemia. It has been reported that exposure to the organophosphate pesticide dichlorvos affects glucose homeostasis and decreases liver glycogen content. Glucokinase (EC 184.108.40.206) is a tissue-specific enzyme expressed in liver and in pancreatic beta cells that plays a crucial role in glycogen synthesis and glucose homeostasis. In the present study we analyzed the effect of one or three days of dichlorvos administration [20 mg/kg body weight] on the activity and mRNA levels of hepatic and pancreatic glucokinase as well as on insulin mRNA abundance in the rat. We found that the pesticide affects pancreatic and hepatic glucokinase activity and expression differently. In the liver the pesticide decreased the enzyme activity; on the contrary glucokinase mRNA levels were increased. In contrast, pancreatic glucokinase activity as well as mRNA levels were not affected by the treatment. Insulin mRNA levels were not modified by dichlorvos administration. Our results suggest that the decreased activity of hepatic glucokinase may account for the adverse effects of dichlorvos on glucose metabolism.


Oleanolic acid alters bile acid metabolism and produces cholestatic liver injury in mice.
Oleanolic acid (OA) is a triterpenoids that exists widely in plants. OA is effective in protecting against hepatotoxicants. Whereas a low dose of OA is hepatoprotective, higher doses and longer-term use of OA produce liver injury. This study characterized OA-induced liver injury in mice. Adult C57BL/6 mice were given OA at doses of 0, 22.5, 45, 90, and 135 mg/kg, s.c., daily for 5 days, and liver injury was observed at doses of 90 mg/kg and above, as evidenced by increases in serum activities of alanine aminotransferase and alkaline phosphatase, increases in serum total bilirubin, as well as by liver histopathology. OA-induced cholestatic liver injury was further evidenced by marked increases of both unconjugated and conjugated bile acids (BAs) in serum. Gene and protein expression analysis suggested that livers of OA-treated mice had adaptive responses to prevent BA accumulation by suppressing BA biosynthetic enzyme genes (Cyp7a1, 8b1, 27a1, and 7b1); lowering BA uptake transporters (Ntcp and Oatp1b2); and increasing a BA efflux transporter (Ostβ). OA increased the expression of Nrf2 and its target gene, Nqo1, but decreased the expression of AhR, CAR and PPARα along with their target genes, Cyp1a2, Cyp2b10 and Cyp4a10. OA had minimal effects on PXR and Cyp3a11. Taken together, the present study characterized OA-induced liver injury, which is associated with altered BA homeostasis, and alerts its toxicity potential.


Multifunctional organic nanomaterials with ultra-high photothermal conversion efficiency for photothermal therapy and inhibition of cancer metastasis.
Photothermal therapy (PTT) has gained extensive interest in tumor treatments due to its non-invasive and low-toxic nature. However, the currently available photothermal agents (PTAs) mostly show unsatisfactory photothermal conversion efficiency (PCE). Besides, as a local cancer treatment modality, PTT fails to inhibit metastasis of tumors. To address these issues, in this study, two aza-boron-dipyrromethene (aza-BODIPY)-based organic photothermal agents (OPTAs), Fc-aza-BODIPY and TPA-aza-BODIPY, were rationally coined by introducing two strong electron-donating ferrocene (Fc) moieties and two triphenylamine (TPA) rotors, which could boost intramolecular photo-induced electron transfer (PET) and molecular rotation respectively, thereby improving the PCE of aza-BODIPY dyes. After encapsulation of hydrophobic Fc-aza-BODIPY (or TPA-aza-BODIPY) and quercetin with biodegradable PLGA and DSPE-mPEG2000, the resulting nanoparticles (FAQ NPs and TAQ NPs) showed excellent optical properties with PCE of ∼72.0% and ∼79.7% and specific tumor accumulations through enhanced permeability and retention (EPR) effects. Consequently, these two NPs possessed prominent antitumor effects under 880 nm laser irradiation. Moreover, both FAQ NPs and TAQ NPs loaded with quercetin could inhibit tumor metastasis efficiently. These two multifunctional nanomaterials integrating OPTAs and anti-metastasis agents constructed a cooperative treatment program, which may provide a potential opportunity for future clinical cancer treatment.


The periaqueductal gray as a critical site to mediate reward seeking during predatory hunting.
Previous studies using morphine-treated dams reported a role for the rostral lateral periaqueductal gray (rlPAG) in the behavioral switching between nursing and insect hunting, likely to depend on an enhanced seeking response to the presence of an appetitive rewarding cue (i.e., the roach). To elucidate the neural mechanisms mediating such responses, in the present study, we first observed how the rlPAG influences predatory hunting in male rats. Our behavioral observations indicated that bilateral rlPAG NMDA lesions dramatically interfere with prey hunting, leaving the animal without chasing or attacking the prey, but do not seem to affect the general levels of arousal, locomotor activity and regular feeding. Next, using Phaseolus vulgaris-leucoagglutinin (PHA-L), we have reviewed the rlPAG connection pattern, and pointed out a particularly dense projection to the hypothalamic orexinergic cell group. Double labeled PHA-L and orexin sections showed an extensive overlap between PHA-L labeled fibers and orexin cells, revealing that both the medial/perifornical and lateral hypothalamic orexinergic cell groups receive a substantial innervation from the rlPAG. We have further observed that both the medial/perifornical and lateral hypothalamic orexinergic cell groups up-regulate Fos expression during prey hunting, and that rlPAG lesions blunted this Fos increase only in the lateral hypothalamic, but not in the medial/perifornical, orexinergic group, a finding supposedly associated with the lack of motivational drive to actively pursue the prey. Overall, the present results suggest that the rlPAG should exert a critical influence on reward seeking by activating the lateral hypothalamic orexinergic cell group.


Electroconvulsive shock (ECS) and H-endorphin-induced analgesia: unconventional interactions with naloxone.
Acute administration of electroconvulsive shock (ECS) has been shown previously to produce potent analgesia which is only partially reversed by naloxone but shows almost complete tolerance after both repeated ECS and chronic morphine administration. In an attempt to elucidate the underlying basis of ECS analgesia it was recently compared with the analgesic effect of a newly identified opioid, humoral (H)-endorphin. Intracerebroventricular (i.c.v.) injection of H-endorphin to rats produces a dose-related analgesic effect as measured by the tail flick method. Furthermore, 4 days of daily i.c.v. injections of 40 microgram of morphine resulted in complete tolerance to the analgesic effect of H-endorphin. However, naloxone only caused a partial reversal of H-endorphin analgesia. Surprisingly only the lower dose of 1 mg/kg exerted a significant antagonistic effect while a higher dose of 10 mg/kg of the antagonist was without effect. A similar unconventional profile of the effect of naloxone could be seen with ECS analgesia. Here, pretreatment with 1 mg/kg of naloxone significantly attenuated analgesia, whereas administration of 10 mg/kg of the antagonist was without effect. In contrast, catalepsy measured in the same animals was not affected by 1 mg/kg of naloxone but increasing the dose to 10 mg/kg produced a significant attenuation of ECS catalepsy. The opioid nature of H-endorphin analgesia on one hand and the unconventional dose relation with naloxone of both H-endorphin and ECS analgesia on the other hand, suggests the involvement of this opioid in analgesia induced by ECS. Furthermore, it is possible that other behavioral manipulations which display only partial opiate characteristics may be mediated by H-endorphin or similar endogenous substances.


Vanadate-sensitive phosphatidate phosphohydrolase activity in a purified rabbit kidney Na,K-ATPase preparation.
Reconstitution of purified rabbit kidney Na,K-ATPase in phosphatidylcholine/phosphatidic acid liposomes resulted in the absence of ATP in a time-, temperature- and protein-dependent formation of inorganic phosphate. This formation of inorganic phosphate could be attributed to a phosphatidate phosphohydrolase activity present in the Na,K-ATPase preparation. A close interaction of the enzyme with the substrate phosphatidic acid was important, since no or little Pi production was observed under any of the following conditions: without reconstitution, after reconstitution in the absence of phosphatidic acid, with low concentrations of detergent or at low lipid/protein ratios. The hydrolysis of phosphatidic acid was not influenced by the Na,K-ATPase inhibitor ouabain but was completely inhibited by the P-type ATPase inhibitor vanadate. Besides Pi diacylglycerol was also formed, confirming that a phosphatidate hydrolase activity was involved. Since the phosphatidate phosphohydrolase activity was rather heat- and N-ethylmaleimide-insensitive, we conclude that the phosphatidic acid hydrolysis was not due to Na,K-ATPase itself but to a membrane-bound phosphatidate phosphohydrolase, present as an impurity in the purified rabbit kidney Na,K-ATPase preparations.


Surgical Skills Training Using Simulation for Basic and Complex Hip and Knee Arthroplasty.
Skills training is important in an arthroplasty curriculum and can focus either on "part tasks" or on full procedures. The most commonly used simulations in orthopedics including arthroplasty are anatomic specimens, dry bone models, and virtual or other technology-enhanced systems. A course curriculum planning committee must identify the gaps to address, define what learners need to be able to do, and select the most appropriate simulation modality and assessment for delivery. Each simulation must have a clear structure with learning objectives, steps, and take-home messages. Feedback from learners and faculty must be integrated to improve processes and models for future learning.


Regression of Mucosa-Associated Lymphoid Tissue Lymphoma Arising From the Nonampullary Descending Part of the Duodenum by Treatment With Antibiotics in a Helicobacter pylori-Negative Patient.
We report a 63-year-old male, Helicobacter pylori-negative patient with mucosa-associated lymphoid tissue (MALT) lymphoma of the second part of the duodenum that regressed after antibiotic treatment. Esophagogastroduodenoscopy (EGD) showed flat elevation with shallow depression on the contralateral side of the ampulla of Vater. The lesion was limited to the duodenal second part. The patient had a history of Helicobacter pylori positivity, with successful eradication at 41 years of age. Twelve months after vonoprazan (VPZ)-based antibiotic treatment, the duodenal lesion had obviously regressed, and the pathological diagnosis was complete histological response (ChR). This case suggests that certain bacteria may promote the development of duodenal MALT lymphoma.


Innovation in surgery: the rules of evidence.
The intellectual infrastructures of evidence-based medicine (EBM) are the levels of evidence and the grades of recommendation for the following types of research articles: therapy/prevention, etiology/harm, prognosis, diagnosis, differential diagnosis/symptom prevalence study, economic analysis/decision analysis. The levels of evidence for therapy (1 to 5) progress from systematic reviews (with homogeneity) of randomized control trials (RCT) of high quality, level 1, to level 5-expert opinion without explicit critical appraisal, or based on physiology, bench research, or "first principles." The grades of recommendation (A, B, C, D) are founded on the quality of the evidence defined by its level. These grades are aimed at helping clinicians understand the source from whence came statements in, for example, guidelines. The development of surgical procedures and their introduction into practice has not depended upon the RCT but rather upon an enthusiast performing a case series, sometimes with clearly defined results. Should all operations and procedures be evaluated by an RCT? Clearly not, and the levels of evidence support this quite clearly with the "all or none" research category as level 1c. This relates to frequent clinical situations requiring a solution often immediate, eg, pus, a ruptured aneurysm, a sucking chest wound, that do not lend themselves to a trial, as the control regimen (doing nothing) would lead to death. Techniques evolve with experience usually based on an understanding of pathophysiology. At what point should an RCT enter into the resolution of surgical therapies? Can observational studies correctly designed and carried out do the job? Two new study classifications have been introduced: in level 1, category c "all or none" studies; and in level 2, category c "outcomes" research. In neither is there much definition. Are these the areas into which the evaluation of new surgical procedures and technology should be placed? The surgical community is faced with dramatic changes in technology and evolving techniques, and needs to define the rules of evidence applicable to their discipline with the same rigor that the EBM gurus have used, in order for surgeons to define evidence-based surgical practice.


Distribution of feline AB blood types: a review of frequencies and its implications in the Iberian Peninsula.
The objective of this study was to document the prevalence of feline blood types in the Iberian Peninsula and to determine the potential risk of incompatibility-related transfusion reactions in unmatched transfusions and the potential risk of neonatal isoerythrolysis (NI) in kittens born to parents of unknown blood type. Blood samples were obtained from blood donors of the Animal Blood Bank (BSA-Banco de Sangue Animal). Blood typing was performed using a card method (RapidVet-H Feline Blood Typing; MDS). The studied population comprised 1070 purebred and non-purebred cats from Portugal and Spain aged between 1 and 8 years. Overall, frequencies of blood types A and B were 96.5% and 3.5%, respectively. No AB cats were found. Based on these data, the potential risks of NI and transfusion reactions in unmatched transfusions were calculated to be 6.8% and 2.8%, respectively. Unlike previous studies, no type AB cats were found in this study. Although the calculated potential risks of transfusion reaction in unmatched transfusions and neonatal isoerythrolysis were low, blood typing prior to blood transfusion and blood typing of cats for breeding purposes are highly recommended.


[Guided home-based vestibular rehabilitation assisted by audiovisual media].
To describe the creation and validation process of a new audiovisual support model for the design of guided home-based vestibular rehabilitation programs (GHVR), we introduce a prospective experimental study. 89 patients who underwent vestibular rehabilitation (VR) were evaluated throughout 2009. For the model design, we built a video library with VR exercises that can be combined using DVD creation software to tailor VR protocols. Treatment incidents, adherence, need to convert to a posturography-based program and variations in the Dizziness Handicap Inventory (DHI) score and dynamic visual acuity (DVA) were assessed. A good response was found, not only with respect to adherence (5.6% abandonment), but also in the clinical parameters, with a mean DHI score variation of 33.14 points, and a decrease in lines lost in the DVA test from 4.24 to 1.52 lines at the end of the treatment. Our study results show the possibility of building an audiovisual aid for creating GHVR programs.


An efficient approach for extraction of polysaccharide from abalone (Haliotis Discus Hannai Ino) viscera by natural deep eutectic solvent.
In this study, a natural deep eutectic solvent (NADES) was proposed for the ultrasonic-assisted extraction of polysaccharides from abalone (Haliotis Discus Hannai Ino) viscera. Eleven NADESs were employed for abalone viscera polysaccharide (AVP) extraction. NADES, composed of choline chloride and ethylene glycol in a molar ratio 1: 3 had the highest extraction efficiency. The optimal extraction conditions were obtained using a four-factor, three-level Box-Behnken design and specific response surface methodology. The maximum predicted polysaccharide yield was 17.32 %. Fick's second law was fitted to the extraction process of AVP by ultrasonic-assisted NADES based on a high linear correlation (R2 ≥ 0.9). The extraction rate constants (k), diffusion coefficients (Du) and half-lives (t1/2) were calculated. Compared to the polysaccharides prepared by the conventional method, the polysaccharides extracted by NADES had a higher sugar content, lower molecular weight, more glucuronic acid, and stronger antioxidant capacity. Overall, the NADES extraction method established in this research can become a strategy for the preparation of high-purity and highly bioactive abalone viscera polysaccharides, which has implications for the exploitation and application of marine food byproduct resources.