Lamin A to Z in normal aging.
Almost since the discovery that mutations in the LMNA gene, encoding the nuclear structure components lamin A and C, lead to Hutchinson-Gilford progeria syndrome, people have speculated that lamins may have a role in normal aging. The most common HPGS mutation creates a splice variant of lamin A, progerin, which promotes accelerated aging pathology. While some evidence exists that progerin accumulates with normal aging, an increasing body of work indicates that prelamin A, a precursor of lamin A prior to C-terminal proteolytic processing, accumulates with age and may be a driver of normal aging. Prelamin A shares properties with progerin and is also linked to a rare progeroid disease, restrictive dermopathy. Here, we describe mechanisms underlying changes in prelamin A with aging and lay out the case that this unprocessed protein impacts normative aging. This is important since intervention strategies can be developed to modify this pathway as a means to extend healthspan and lifespan.


Extraosseous odontogenic fibroma with a clear cells component: a 5-year follow-up.
The extraosseous/peripheral odontogenic fibroma (E/POF) is a benign mesenchymal odontogenic tumour found on the gingival surface with clinical characteristics identical to those of reactive lesions. A histopathological analysis is the only method for determining the difference between reactive lesions and these neoplastic lesions, whose recurrence potential varies between 38.9% and 50%, highlighting the importance of correct diagnosis. The following report describes an E/POF case with a clear cells component, as well as a long-term follow-up treatment, which we emphasise due to its potential for recurrence.


Single-shot higher-order transport-of-intensity quantitative phase imaging based on computer-generated holography.
The imaging quality of quantitative phase imaging (QPI) based on the transport of intensity equation (TIE) can be improved using a higher-order approximation for defocused intensity distributions. However, this requires mechanically scanning an image sensor or object along the optical axis, which in turn requires a precisely aligned optical setup. To overcome this problem, a computer-generated hologram (CGH) technique is introduced to TIE-based QPI. A CGH generating defocused point spread function is inserted in the Fourier plane of an object. The CGH acts as a lens and grating with various focal lengths and orientations, allowing multiple defocused intensity distributions to be simultaneously detected on an image sensor plane. The results of a numerical simulation and optical experiment demonstrated the feasibility of the proposed method.


Hypolipidemic and Antioxidant Effects of Malus toringoides (Rehd.) Hughes Leaves in High-Fat-Diet-Induced Hyperlipidemic Rats.
Malus toringoides (Rehd.) Hughes (MT) leaves are traditionally used as a medicine for treating or preventing cardiovascular disease in Tibet. In addition to the effect of this medicinal plant on thrombosis, we tested its effect on dyslipidemia in a hypolipidemic rat model. A total of 60 healthy Sprague-Dawley rats were randomly divided into six groups, as follows: normal control, model control, simvastatin groups, and MT low-, medium-, and high-dose groups. The normal controls were fed with a normal diet, whereas all other groups were fed with a high-fat diet. After 6 weeks, the high-fat diet had induced hyperlipidemia in the rats, which were then orally administered with different doses of MT leaf extract (50, 100, and 200 mg/kg) for an additional 6 weeks. Serum levels of total cholesterol (TC), triglycerides (TG), low- and high-density lipoprotein cholesterol (LDL-c and HDL-c, respectively), as well as the antioxidant capacity of glutathione peroxidase (GSHP-x), superoxide dismutase (SOD), and malondialdehyde (MDA) were measured at the end of the study. MT significantly reduced serum TC, TG, and LDL-c and increased the HDL-c content in MT-treated rats compared with the model group. These changes were dose dependent. MT treatment also significantly elevated the activity of SOD and GSHP-x, and decreased the serum levels of MDA compared with untreated hyperlipidemic rats, thereby increasing serum antioxidant capacity. In addition, MT reduced liver steatosis in hyperlipidemic rats. Overall, MT exerts considerable hypolipidemic and antioxidant properties.


Perceived stress, severity of asthma, and quality of life in young adults with asthma.
People suffering from asthmatic symptoms have a lower quality of life than those without. The aim of this study is to clarify the association of quality of life with the severity of asthma, perceived stress, and other factors such as the comorbidity of allergic diseases among young adults with asthma. The study participants were 695 asthma patients, aged 20-44 years, from 29 medical centers in Japan. We excluded from the analysis of the result of the study 116 patients with complications of serious diseases, cough-variant asthma or aspirin-intolerant asthma. The patients completed the 8-Item Short-Form Health Survey (SF-8), the Airways Questionnaire 20 (AQ20), and the Japanese version of the Perceived Stress Scale (JPSS) and their doctors also provided clinical information including diagnosis, complications, severity of asthma, and results of pulmonary function and immunological tests. There was a weak correlation between the generic quality of life (SF-8) and the disease-specific quality of life (AQ20). The AQ 20 revealed almost no association with the results of pulmonary function and immunological tests, and only a slight association with comorbidity of allergic rhinitis and food allergy. The AQ20 showed a moderate relation with perceived stress (JPSS) but a weak association with the severity of asthma. The multiple logistic models demonstrated that there was no relationship between the severity of asthma and the AQ20 in females, and in the age group of 20-34 years. A major variable related to the disease-specific quality of life was perceived stress, followed by the severity of asthma. Stress management of patients with asthma may improve their quality of life.


Effect of nickel chloride on streptozotocin-induced diabetes in rats.
The potential of nickel chloride to prevent streptozotocin-induced hyperglycemia was tested in rats in vivo. To induce diabetes, streptozotocin (100 mg/kg body weight) was injected as a single dose. Streptozotocin treatment resulted in a significant decrease in plasma insulin and ceruloplasmin, and pancreatic Cu, protein, and Cu-Zn superoxide dismutase activity. In rats treated with nickel chloride (10 mg/kg body weight) and streptozotocin, these values were comparable with those observed in control rats. The results indicate that nickel chloride injected before streptozotocin prevented streptozotocin-induced hyperglycemia, and suggest that the protective effect was related to Cu-Zn superoxide dismutase activity, mediated by copper.


Effect of saccharide additives on response of ferrous-agarose-xylenol orange radiotherapy gel dosimeters.
Glucose, sucrose, starch, and locust bean gum have been used as additives to the ferrous-agarose-xylenol orange (FAX) gel dosimeter. The saccharide enhanced dosimeters were found to have a higher dose sensitivity over a standard FAX gel as measured by both optical density change and magnetic resonance imaging (MRI). With optical density measurement, OD-dose sensitivity increases were up to 55% for glucose, 122% for sucrose and 43% for starch, while locust bean gum did not give a consistent response. With MRI, R1-dose sensitivity increases were up to 178% with sucrose addition. The FAX gel with sucrose was studied in greatest detail. The OD-dose sensitivity dependence on cooling rate was reduced for the sucrose FAX gel over the standard FAX gel, which has significant implications for uniform dose sensitivity in large gel phantoms. The thermal oxidation rate in the sucrose FAX gel was up to 2.3 times higher than in the standard gel. The OD-dose sensitivity of oxygenated sucrose FAX gels was 4.3 times greater than standard FAX gels, while continued enhancement in OD-dose sensitivity with increased sucrose concentrations beyond 2.0 g/l was found only for the oxygenated sucrose FAX gels. Both the molar absorption coefficient of the ferric ion-xylenol orange complex at 543 nm and gel pH were not affected by the presence of sucrose, with the implication that the higher OD-dose sensitivity of gels with saccharides is due to increased chain reaction production of ferric ions.


Response to a Large Polio Outbreak in a Setting of Conflict - Middle East, 2013-2015.
As the world advances toward the eradication of polio, outbreaks of wild poliovirus (WPV) in polio-free regions pose a substantial risk to the timeline for global eradication. Countries and regions experiencing active conflict, chronic insecurity, and large-scale displacement of persons are particularly vulnerable to outbreaks because of the disruption of health care and immunization services (1). A polio outbreak occurred in the Middle East, beginning in Syria in 2013 with subsequent spread to Iraq (2). The outbreak occurred 2 years after the onset of the Syrian civil war, resulted in 38 cases, and was the first time WPV was detected in Syria in approximately a decade (3,4). The national governments of eight countries designated the outbreak a public health emergency and collaborated with partners in the Global Polio Eradication Initiative (GPEI) to develop a multiphase outbreak response plan focused on improving the quality of acute flaccid paralysis (AFP) surveillance* and administering polio vaccines to >27 million children during multiple rounds of supplementary immunization activities (SIAs).† Successful implementation of the response plan led to containment and interruption of the outbreak within 6 months of its identification. The concerted approach adopted in response to this outbreak could serve as a model for responding to polio outbreaks in settings of conflict and political instability.


Moral sensibilities and moral standing: Caplan on xenograft "donors".
[I]nterest in animals as a source of organs and tissues for human beings remains strong. New developments in immunosuppression technology promise to lower the technical barriers to a routine use of nonhumans as organ donors, and the image of colonies of animals kept at the ready for supplying the growing human need for new organs seems a much more plausible scenario now than it did when broached by transplantation specialists in the Sixties. As Arthur Caplan has powerfully argued, the prospects that other sources of organs may resolve the supply problem are grim.... In the face of these "pro-xenograft" pressures, it becomes all the more signficant to assess arguments against the practice that rest on considerations of the moral status of the nonhumans from whom the organs are taken. To be sure, xenograft faces other moral difficulties -- for example, concerns about the quality of informed consent obtained for recipients, worries about the possibility that xenografting will serve as a vector by which new and possibly virulent viruses become established in humans, and problems about whether such spending is equitable in the light of other unresolved human needs. Yet whether we morally wrong animals in taking their organs and their lives remains a decidedly central issue here, one that cannot be finessed away by developing better informed consent procedures, better anti-viral strategies, or by situating transplantation medicine in a just health care system.


The skin as a window to the blood: Cutaneous manifestations of myeloid malignancies.
Cutaneous manifestations of myeloid malignancies are common and have a broad range of presentations. These skin findings are classified as specific, due to direct infiltration by malignant hematopoietic cells, or non-specific. Early recognition and diagnosis can have significant clinical implications, as skin manifestations may be the first indication of underlying hematologic malignancy, can reflect the immune status and stage of disease, and cutaneous reactions may occur from conventional and targeted agents used to treat myeloid disease. In addition, infections with cutaneous involvement are common in immunocompromised patients with myeloid disease. Given the varying presentations, dermatologic findings associated with myeloid malignancies can pose diagnostic challenges for hematologists and dermatologists. In this clinical review intended for the practicing hematologist/oncologist, we discuss the presentation, diagnosis, treatment, and prognostic value of the most common cutaneous manifestations associated with myeloid malignancies using illustrative macro- and microscopic figures and with a special emphasis on practical considerations.


Purification and characterization of a simple ribonucleoprotein particle containing small nucleoplasmic RNAs (snRNP) as a subset of RNP containing heterogenous nuclear RNA (hnRNP) from HeLa cells.
A ribonucleoprotein complex whose RNA complement consists exclusively of small nuclear RNA species (snRNA) has been purified from particles containing heterogenous nuclear RNA (hnRNP) from HeLa cells. This was accomplished by taking advantage of their ability to band at a density of about 1.43 g/cm3 in plain cesium chloride as well as in cesium chloride gradients containing 0.5% sarkosyl without prior aldehyde fixation. After these two steps of equilibrium density centrifugation, these snRNPs were still largely contaminated by free proteins (and especially phosphoproteins). A final step of purification by velocity sedimentation in a sucrose gradient containing 0.5 M cesium chloride and 0.5% sarkosyl was efficient in completely eliminating all free proteins. U1, U2, U4, U5 and U6 species according to the nomenclature of Lerner et al. (Nature, (1980) 283, 220-224) were found in these purified snRNPs, while a significant part of U6 and a small amount of U2 were found in the bottom fraction. 5S species behaved entirely as free RNA and is presumably a contaminant of cytoplasmic origin. Electrophoresis of proteins from snRNP labeled in vivo with (35S) methionine, revealed four bands with migrations corresponding to molecular weights ranging between 10,000 and 14,000 daltons.


Visual diagnosis: pediatric airway emergency.
We present a case of a potentially difficult airway emergency in a pediatric patient. After presentation, we briefly review critical differences between pediatric and adult airways and management of the airway during these emergencies.


Contribution of the cyclic nucleotide gated channel subunit, CNG-3, to olfactory plasticity in Caenorhabditis elegans.
In Caenorhabditis elegans, the AWC neurons are thought to deploy a cGMP signaling cascade in the detection of and response to AWC sensed odors. Prolonged exposure to an AWC sensed odor in the absence of food leads to reversible decreases in the animal's attraction to that odor. This adaptation exhibits two stages referred to as short-term and long-term adaptation. Previously, the protein kinase G (PKG), EGL-4/PKG-1, was shown necessary for both stages of adaptation and phosphorylation of its target, the beta-type cyclic nucleotide gated (CNG) channel subunit, TAX-2, was implicated in the short term stage. Here we uncover a novel role for the CNG channel subunit, CNG-3, in short term adaptation. We demonstrate that CNG-3 is required in the AWC for adaptation to short (thirty minute) exposures of odor, and contains a candidate PKG phosphorylation site required to tune odor sensitivity. We also provide in vivo data suggesting that CNG-3 forms a complex with both TAX-2 and TAX-4 CNG channel subunits in AWC. Finally, we examine the physiology of different CNG channel subunit combinations.


Identification of potential drug targets for vascular dementia and carotid plaques by analyzing underlying molecular signatures shared by them.
Vascular dementia (VaD) and carotid atherosclerotic plaques are common in the elderly population, conferring a heavy burden on families and society. Accumulating evidence indicates carotid atherosclerotic plaques to be a risk factor for VaD. However, the underlying mechanisms for this association are mainly unknown. We analyzed temporal cortex gene expression data of the GSE122063 dataset and gene expression data of the GSE163154 dataset to identify commonly differentially expressed genes (DEGs). Then we performed functional enrichment analysis, immune cell infiltration and evaluation, correlation analysis between differentially expressed immune-related genes (DEIRGs) and immune cells, receiver operating characteristic (ROC) analysis, and drug-gene analysis. We identified 41 overlapped DEGs between the VaD and carotid atherosclerosis plaque datasets. Functional enrichment analyses revealed that these overlapped DEGs were mainly enriched in inflammatory and immune-related processes. Immunocyte infiltration and evaluation results showed that M0 macrophages, M2 macrophages, and T cells gamma delta had a dominant abundance in carotid atherosclerosis plaque samples, and M0 macrophages showed a significantly different infiltration percentage between the early and advanced stage plaques group. Resting CD4 memory T cells, M2 macrophages, and naive B cells were the top three highest infiltrating fractions in VaD. Furthermore, B cells and NK cells showed a different infiltration percentage between VaD and matched controls. We identified 12 DEIRGs, and the result of correlation analysis revealed that these DEIRGs were closely related to differentially expressed immune cells. We identified five key DEIRGs based on ROC analysis. The drug-gene interaction analysis showed that four drugs (avacopan, CCX354, BMS-817399, and ASK-8007) could be potential drugs for VaD and carotid atherosclerotic plaques treatment. Collectively, these findings indicated that inflammatory and immune-related processes be a crucial common pathophysiological mechanism shared by VaD and carotid plaques. This study might provide new insights into common molecular mechanisms between VaD and carotid plaques and potential targets for the treatment.


Interactions of "bora-penicilloates" with serine β-lactamases and DD-peptidases.
Specific boronic acids are generally powerful tetrahedral intermediate/transition state analogue inhibitors of serine amidohydrolases. This group of enzymes includes bacterial β-lactamases and DD-peptidases where there has been considerable development of boronic acid inhibitors. This paper describes the synthesis, determination of the inhibitory activity, and analysis of the results from two α-(2-thiazolidinyl) boronic acids that are closer analogues of particular tetrahedral intermediates involved in β-lactamase and DD-peptidase catalysis than those previously described. One of them, 2-[1-(dihydroxyboranyl)(2-phenylacetamido)methyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid, is a direct analogue of the deacylation tetrahedral intermediates of these enzymes. These compounds are micromolar inhibitors of class C β-lactamases but, very unexpectedly, not inhibitors of class A β-lactamases. We rationalize the latter result on the basis of a new mechanism of boronic acid inhibition of the class A enzymes. A stable inhibitory complex is not accessible because of the instability of an intermediate on its pathway of formation. The new boronic acids also do not inhibit bacterial DD-peptidases (penicillin-binding proteins). This result strongly supports a central feature of a previously proposed mechanism of action of β-lactam antibiotics, where deacylation of β-lactam-derived acyl-enzymes is not possible because of unfavorable steric interactions.


The policy & procedure manual: development of a computer-assisted process for review.
This article documents the successful development of a computer-assisted process for systematic review of nursing policies and procedures at The Queen Elizabeth Hospital, Toronto, Ontario. Through broad staff input, policies and procedures are research-based yet grounded in the reality of the facility's nursing practice. Client-related standards are written as measurable, realistic statements of desired client outcomes, and as such are standards for client care. Policies and procedures have been rated according to the Canadian Council on Health Facilities Accreditation criteria (client centered, high risk, high volume, problem prone, interservice, outcome-related), so that important policies are easily identified to provide focus for quality assurance activities. The review process is structured so that over the course of a year, all policies are circulated for review by all levels of nursing staff.


Preparation of asialoorosomucoid-polylysine conjugates.
Asialoorosomucoid-polylysine (ASOR-PL) conjugates have been recently developed as carriers of electrostatically bound DNA for targeted delivery to the hepatic asialoglycoprotein receptor (ASGPr) for gene therapy. Using acid-urea gel electrophoresis we have found that previously reported procedures for the fractionation of ASOR-PL conjugates do not efficiently remove noncovalently bound polylysine (PL) from ASOR-PL. DNA complexes prepared with these conjugates have low solubilities, which limits their usefulness for subsequent experimentation, particularly in vivo. For ASOR-PL made by carbodiimide-mediated crosslinking with 5-kDa PL, dialysis against 1 M guanidine hydrochloride is effective to remove the low molecular weight unbound PL. Dialysis is not feasible when using higher molecular weight PLs, but preparative elution acid-urea gel electrophoresis was used to isolate crude ASOR-PL fractions free of unbound PL. ASOR-PL freed of PL by dialysis or electrophoresis was further fractionated by cation-exchange HPLC on carboxymethyl-functionalized columns eluted with a mixed pH-salt gradient. Early-eluting ASOR-PL fractions isolated by a combination of preparative elution acid-urea gel electrophoresis and cation-exchange HPLC were found to be preferred for the formation of soluble DNA complexes.


Effect of Mn and P on the macroscopic texture of Ti-Nb stabilized interstitial free steels.
The effect of Mn and P on the macroscopic texture of Ti-Nb stabilized IF steels was investigated. In order to examine the evolution of microstructure and macroscopic texture during the hot-rolling, cold-rolling and annealing processes, microstructure characterization was conducted for hot-rolled, cold-rolled and annealed specimens. The initial grain size of hot-rolled specimens was a main parameter in determining the development of the macroscopic texture of the annealed specimens.


Conservative management of ectopic pregnancy with fetal cardiac activity by combined local (sonographically guided) and systemic injection of methotrexate.
To evaluate the efficacy of conservative management of ectopic pregnancy with fetal cardiac activity by combined local sonographically guided and systemic injection of methotrexate. The study group included 12 patients with ectopic pregnancy and fetal cardiac activity, treated by combined local and systemic injection of methotrexate in the period from January 1, 2000 to July 1, 2002. The outcome of these patients was compared with the outcome of 53 patients who had ectopic pregnancy without fetal cardiac activity and were being treated only by systemic injection of methotrexate during the same period of time. The success rate was 91.6% (11 out of 12) in the group of patients with ectopic fetal cardiac activity and 90.5% (48 out of 53) in the group of patients with ectopic pregnancy, but without fetal cardiac activity. There was also no significant difference between the two groups comparing the percentage of cases treated by an additional dose of methotrexate (8.3 and 13.2%, respectively), nor comparing the number of days to resolution of beta-human chorionic gonadotrophin (BHCG; 40 +/- 2 and 34 +/- 10 days, respectively). Conversely, there was a significant difference in the initial BHCG level comparing the group of patients treated by combined local and systemic injection of methotrexate (12,616 +/- 9,585 mIU/ml) and the group of patients treated by systemic injection of methotrexate (1,499 +/- 2,065 mIU/ml) (p < 0.00001). Seventy-five percent of patients (6 out of 8) diagnosed with ectopic fetal cardiac activity, who desired to become pregnant, succeeded to conceive within 6 months following the combined local and systemic injection of methotrexate. The combined local sonographically guided and systemic injection of methotrexate is associated with a successful outcome in asymptomatic patients presenting with ectopic pregnancy and fetal cardiac activity.


Co-sensitization promoted light harvesting with a new mixed-addenda polyoxometalate [Cu(C12H8N2)2]2[V2W4O19]·4H2O in dye-sensitized solar cells.
A di-vanadium-substituted Lindqvist-type polyoxometalate [Cu(C12H8N2)2]2[V2W4O19]·4H2O (1) was hydrothermally synthesized and characterized structurally by single crystal X-ray diffraction analysis. X-ray photoelectron spectroscopy and energy disperse spectroscopy tests further prove the existence of vanadium. Ultraviolet photoelectron spectroscopy and density functional theoretical studies indicate that the energy level of 1 matches well with the conduction band of the TiO2. Furthermore, considering the semiconductor-like nature of 1 and the introduction of transition metal element Cu synchronously extends the absorption to the visible region, which should also be beneficial to the photovoltaic device performance. 1-Doped TiO2 composites (denoted as 1@TiO2) have been successfully fabricated by a simple sol-gel method, and introduced into the dye-sensitized solar cells (DSSCs) as co-sensitizers in N719-sensitized photoanodes by mixing 1@TiO2 with P25 nanoparticles with different weight ratios to enhance the photoelectric conversion efficiency. The investigations show that the DSSC assembled with 1@TiO2/19P25 photoanode has the best performance and the overall improvement of the efficiency is 21.6% compared with pure P25. Furthermore, the electrochemical impedance spectroscopy and open-circuit voltage decay investigations show that the cosensitization of 1 and N719 can promote electron transfer and restrain charge recombinations in the DSSCs, resulting in a longer electron lifetime.


Calcium: a role for neuroprotection and sustained adaptation.
Sustained increases in intracellular calcium following prolonged seizures or other neurological insults have been thought to be responsible for neuronal cell death for well over two decades. For example, a seizure or a stroke can lead to excessive release of glutamate, an endogenous excitotoxin. Overactivation of receptors that interact with glutamate will raise calcium levels to stimulate a variety of signaling pathways that can impair neuronal respiration and eventually kill neurons. On the contrary, recent evidence shows that under numerous conditions calcium can prevent neurons from dying. Experimental epilepsy and ischemia models show that protection of neurons appears to depend upon the age of the animal, the amount and route of calcium elevation, timing of initial insults, and brain regions involved. This review will discuss novel findings on the protective signaling role of calcium under a wide range of pathological conditions.


Ultrasonographic bisection approximation method for gastrointestinal obstruction in ER.
The aim of this study was to evaluate the accuracies of using ultrasonography in determining the levels and causes of gastrointestinal obstruction in the emergency department. 229 patients who visited the emergency department with the clinical impression of gastrointestinal obstruction were studied. The gastrointestinal tract was systematically scanned from the anatomically fixed portions to movable portions in the peritoneum by "bisection approximation method". The obstructive levels and possible etiologies were investigated. The finding was correlated with final surgical or further radiological diagnosis. The sensitivity, specificity and accuracy of ultrasonography in determining the obstruction of gastrointestinal tract were 97%, 87% and 93%. In 150 patients with diagnosis of gastrointestinal obstruction by ultrasonography, the accuracies of predicting obstructive levels in the gastric outlet and duodenum, the jejunum and ileum, and the colon were 100%, 74%, and 98% respectively. 67%, 36%, and 78% of obstructive etiologies could be correctly judged in these segments respectively. Ultrasonography is a useful tool in the localization of obstructive levels and the determination of etiologies of gastrointestinal obstruction in the emergency room. It can guide physicians to choose further appropriate confirmation studies.


Garcinol exhibits anti-proliferative activities by targeting microsomal prostaglandin E synthase-1 in human colon cancer cells.
Colorectal cancer is the fourth leading cause of death. Various natural compounds are known to have antitumor properties. Garcinol, a polyisoprenylated benzophenone, has antioxidant and anti-inflammatory properties. In the current study, we investigated the anticancer activity of garcinol on human colorectal adenocarcinoma cell line (HT-29) human colon cancer cells. HT-29 cells were treated with various concentrations of garcinol for 24 h. The effect of garcinol on HT-29 cells proliferation was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay; the mRNA expression of microsomal prostaglandin E synthase-1 (mPGES-1), hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), C-X-C chemokine receptor type 4 (CXCR4), matrix metalloproteinase-2 (MMP-2), and matrix metalloproteinase-9 (MMP-9) were examined by quantitative real-time polymerase chain reaction; apoptosis was detected by proportion of sub-G1 cell; caspase 3 activity and prostaglandin E2 (PGE2) level were determined by enzyme-linked immunosorbent assay and HT-29 cells migration was assessed using scratch test. Garcinol preconditioning markedly decreased the expression of mPGES-1, HIF-1α, VEGF, CXCR4, MMP-2, and MMP-9. The proportion of cells in sub-G1 phase and caspase 3 activity were increased by garcinol treatment whereas the cell proliferation, PGE2 level, and cell migration were decreased in these cells, compared to the control group. Our findings suggest that garcinol plays a critical role in elevating apoptosis and inhibiting HT-29 cells proliferation, angiogenesis, and invasion by suppressing the mPGES-1/PGE2/HIF-1α signaling pathways.


Lymphocyte enumeration: a comparison between a modified avidin-biotin-immunoperoxidase system and flow cytometry.
The reliability and sensitivity of an indirect avidin-biotin-peroxidase (ABC) procedure for enumerating lymphocyte subpopulations was compared to flow cytometry (FC) employing direct immunofluorescence. Lymphocytes were enumerated by two different methods. For counting method I, which is the method of conventional FC, the number of immunostained lymphocytes was compared to the total number of lymphocytes present. The ABC procedure by method I detected a greater proportion of immunostained lymphocytes for all subsets tested than did FC. By counting method II, where the number of immunostained lymphocytes is compared to the total number of cells present, the ABC analysis still detected more total T cells than FC but the results for the two analyses were similar for T helper and T suppressor cells. Thus, the ABC technique appears to be a valid method for enumerating T lymphocyte subsets. Furthermore, as compared to FC, it offers the advantages of reduced cost, simplicity of understanding and performance, need for fewer cells, and a permanent record of lymphocyte staining. For these reasons, we feel that the ABC technique will enjoy widespread application for the identification of lymphocyte membrane antigens.


Microglia-driven regulation of oligodendrocyte lineage cells, myelination, and remyelination.
Microglia are the resident macrophages of the CNS and members of the innate immune system. As such, they serve important functions in surveillance for indicators of damage and subsequent initiation of an inflammatory response. Although often implicated in neural damage, recent studies have also suggested beneficial roles of activated microglia and inflammation in developmental and regenerative processes in the CNS. These include regulating events leading to the generation and regeneration of myelin, the insulation surrounding nerve fibers which is critical for nerve health and function. This critical review discusses the evidence for the supportive role of microglia in these processes and the cellular and molecular components involved.


Targeted Next-Generation Sequencing Identified Compound Heterozygous Mutations in MYO15A as the Probable Cause of Nonsyndromic Deafness in a Chinese Han Family.
Hearing loss is a highly heterogeneous disorder, with more than 60% of congenital cases caused by genetic factors. This study is aimed at identifying the genetic cause of congenital hearing loss in a Chinese Han family. Auditory evaluation before and after cochlear implantation and targeted next-generation sequencing of 140 deafness-related genes were performed for the deaf proband. Compound heterozygous mutations c.3658_3662del (p. E1221Wfs∗23) and c.6177+1G>T were identified in MYO15A as the only candidate pathogenic mutations cosegregated with the hearing loss in this family. These two variants were absent in 200 normal-hearing Chinese Hans and were classified as likely pathogenic and pathogenic, respectively, based on the ACMG guideline. Our study further expanded the mutation spectrum of MYO15A as the c.3658_3662del mutation is novel and confirmed that deaf patients with recessive MYO15A mutations have a good outcome for cochlear implantation.


Netilmicin versus tobramycin in multi-centre studies.
In two prospective, randomized studies conducted in West Germany and involving 80 patients, netilmicin-ticarcillin was compared to tobramycin-ticarcillin in the treatment of serious systemic infections. Both regimens were essentially identical with respect to the clinical and bacteriological results they produced. The netilmicin group developed significantly less nephrotoxicity than the tobramycin group (0% versus 15%, P = 0.03). Ototoxicity also occurred less frequently in the netilmicin-treated patients (3% versus 10%, P = 0.4). In a large collaborative study involving 15 centres, 254 patients were enrolled. Clinical and bacteriological responses were excellent, with netilmicin and tobramycin equally effective, but the incidences of nephrotoxicity and ototoxicity were lower in patients treated with netilmicin than those receiving tobramycin.


Job's syndrome with an atypical presentation.
Hyper Immunoglobulin E syndrome also called Job's or Buckley Syndrome is a rare primary immunodeficiency disease characterized by elevated serum IgE levels (> 2000 IU/ml), recurrent infections and eosinophilia. Other features include coarse facies and non-immunologic abnormalities of the dentition, bones, vasculature and connective tissues. We are reporting a case of a twenty four years old male with coarse facies who presented with severe pallor and upper gastrointestinal bleeding. Investigations revealed markedly elevated serum IgE levels (11,800 IU/ml), severe anaemia, esophageoduodenal erosions, Helicobacter pylori (H. pylori) gastritis and oro-esophageal candidiasis.


The role of ethmoid sinus surgery in the treatment of the twisted nose.
The correction of the twisted nose remains a challenge from both the functional and aesthetic points of view. It is well recognized that complete correction of this nasal deformity often necessitates not only reconfiguration of the external nasal framework, but also realignment of the septum. The occasional patient will, in addition, require concurrent middle turbinate resection and/or ethmoidectomy to enable one to achieve full correction of both his/her external and septal deformities. We will briefly outline the rationale for this approach w ith an illustrative case example.


Angular spectrum and localized model of Davis-type beam.
The angular spectrum of the Davis fifth-order linearly polarized, dual, and symmetrized fields of a focused Gaussian laser beam is obtained. Since the original Davis fields are not an exact solution of the vector wave equation and Maxwell's equations, a beam remodeling procedure within the angular spectrum is described that produces an exact solution. The spherical multipole beam shape coefficients of the remodeled beam are then obtained, and it is shown that in the weak focusing limit they simplify to the localized model Gaussian beam shape coefficients for both on-axis and off-axis beams. The angular spectrum method is then applied to a transversely confined electromagnetic beam with arbitrary profile in the focal plane, and to a general zero-order Bessel beam.


Optimizing therapy of seizures in patients with HIV and cysticercosis.
Worldwide, about 40 million people are living with HIV and 50 million people have neurocysticercosis (NCC). About 5% of patients with HIV and the majority of patients with NCC develop recurrent seizures. Mechanisms of seizure production in HIV include mass lesions, meningitis, encephalitis, and ischemia. Seizures in NCC may occur at all stages of cyst development, from the vesicular and colloidal to the calcified stages. Seizures in HIV present special problems with regard to choice of antiepileptic drug (AED) and the potential for drug-drug interactions with antiretroviral (ARV) treatments. Newer AEDs with simpler pharmacokinetic profiles may be the preferred agents, particularly when protease inhibitors form part of ARV regimens. Seizures in NCC are easily controlled with the older AEDs. Although there has been some debate about the value of antiparasitic drugs in NCC, accumulating data suggest that the use of these agents in active disease decreases the risk for development of chronic epilepsy.


Vitamin D in Chronic Kidney Disease and Dialysis Patients.
Vitamin D deficiency (<20 ng/mL) and insufficiency (20-29 ng/mL) are common among patients with chronic kidney disease (CKD) or undergoing dialysis. In addition to nutritional and sunlight exposure deficits, factors that affect vitamin D deficiency include race, sex, age, obesity and impaired vitamin D synthesis and metabolism. Serum 1,25(OH)₂D levels also decrease progressively because of 25(OH)D deficiency, together with impaired availability of 25(OH)D by renal proximal tubular cells, high fibroblast growth factor (FGF)-23 and decreased functional renal tissue. As in the general population, this condition is associated with increased morbidity and poor outcomes. Together with the progressive decline of serum calcitriol, vitamin D deficiency leads to secondary hyperparathyroidism (SHPT) and its complications, tertiary hyperparathyroidism and hypercalcemia, which require surgical parathyroidectomy or calcimimetics. Kidney Disease Outcomes Quality Initiative (KDOQI) and Kidney Disease Improving Global Outcomes (KDIGO) experts have recognized that vitamin D insufficiency and deficiency should be avoided in CKD and dialysis patients by using supplementation to prevent SHPT. Many vitamin D supplementation regimens using either ergocalciferol or cholecalciferol daily, weekly or monthly have been reported. The benefit of native vitamin D supplementation remains debatable because observational studies suggest that vitamin D receptor activator (VDRA) use is associated with better outcomes and it is more efficient for decreasing the serum parathormone (PTH) levels. Vitamin D has pleiotropic effects on the immune, cardiovascular and neurological systems and on antineoplastic activity. Extra-renal organs possess the enzymatic capacity to convert 25(OH)D to 1,25(OH)₂D. Despite many unanswered questions, much data support vitamin D use in renal patients. This article emphasizes the role of native vitamin D replacement during all-phases of CKD together with VDRA when SHPT persists.


Group sequential large sample T2-like chi2 tests for multivariate observations.
In many studies, a K degree of freedom large sample chi2 test is used to assess the effect of treatment on a multivariate response, such as an omnibus T2-like test of a difference between two treatment groups in any of K repeated measures. Alternately, a K df chi2 test may be used to test the equality of K+1 groups in a single outcome measure. Jennison and Turnbull (Biometrika 1991; 78: 133-141) describe group sequential chi2 and F-tests for normal errors linear models, and Proschan, Follmann and Geller (Statist. Med. 1994; 13: 1441-1452) describe group sequential tests for K+1 group comparisons. These methods apply to sequences of statistics that can be characterized as having an independent increments variance-covariance structure, thus simplifying the computation of the sequential variance-covariance matrix and the resulting sequential test boundaries. However, many commonly used statistics do not share this structure, including a Liang-Zeger (Biometrika 1986; 73: 13-22) GEE longitudinal analysis with an independence working correlation structure and a Wei-Lachin (J. Amer. Statist. Assoc. 1984; 79: 653-661) multivariate Wilcoxon rank test, among others. For such analyses, this paper describes the computation of group sequential boundaries for the interim analysis of emerging results using K df tests that are expressed as quadratic forms in a statistics vector that is distributed as multivariate normal, at least asymptotically. We derive the elements of the covariance matrix of multiple successive K df chi2 statistics based on established theorems on the distribution of quadratic forms. This covariance matrix is estimated by augmenting the data from the successive interim analyses into a single analysis from which the component sequential tests and their variance-covariance matrix can then be extracted. Boundary values for the sequential statistics can then be computed using the method of Slud and Wei (J. Amer. Statist. Assoc. 1982; 77: 862-868) or using the alpha-spending function of Lan and DeMets (Biometrika 1983; 70: 659-663) with a surrogate measure of information. An example is presented using the analysis of repeated cholesterol measurements in a clinical trial.


Leucocyte adhesion under haemodynamic flow conditions.
Vascular endothelial cells (EC) line the luminal side of all blood vessels and act as a selective barrier between blood and tissue. EC are constantly exposed to biochemical and biomechanical stimuli from the blood and underlying tissue. Fluid shear stress acts in parallel to the vessel wall, resulting from friction of blood against EC. Despite the importance of flow on normal EC function, much of the information regarding EC function and dysfunction has been derived from cells harvested, grown and studied in static culture. In order to study the effects of shear stress on EC function, a number of in vitro models have been developed. This chapter provides methodology for use of a system which enables recirculation of leucocytes and cell culture medium over the endothelium for a period of several minutes to days and enables investigation of the effects of prolonged leucocyte co-culture on both the endothelial and leucocyte populations.


Systemic administration of human leukocyte interferon to melanoma patients. I. Effects on natural killer function and cell population.
Natural killer (NK) cytotoxicity was assessed against K562 targets in 14 melanoma patients who received daily im doses of human leukocyte interferon (IFN) for 42 consecutive days. The most common pattern of NK activity was a decline from pretreatment levels 1 day after initiation of treatment, followed by increasing cytotoxicity with peak activity at day 7 and a subsequent gradual decline to pretreatment levels during the remaining weeks of treatment. This pattern was particularly apparent in patients who received 3 x 10(6) or 9 x 10(6) U IFN/day, while patients who received 1 X 10(6) U IFN/day tended to lack the decline at day 1 and maintained the elevated NK activity past day 7. Changes in NK activity could not be related to changes in absolute lymphocyte counts; to proportions of cells bearing membrane receptors for erythrocyte-antibody-complement, of cells bearing FC gamma receptor; or to clinical response to IFN.


Infectious complications in patients with newly diagnosed multiple myeloma: A complication from the past?
Infectious complications are an important risk factor for early mortality in patients with multiple myeloma. However, data about the impact and severity of infections in these patients in the era of new therapies have not been properly analyzed. This review has reviewed the incidence and severity of infections complications and infection-related mortality during induction treatment in patients with newly diagnosed myeloma receiving regimens with new drugs within randomized trials. The results show that infections are still a major cause of morbidity, especially among elderly patients receiving immunomodulatory drugs seen in up to 28% of patients in some trials vs less than 10% among transplant-eligible patients. Overall infection-related mortality ranged from 0-7% in transplant-ineligible patients, with no infection-related deaths in the majority of the trials including younger patients. Strategies directed to further reduce these complications and a better knowledge of their impact in patients treated outside clinical trials are needed.


A method for automatic forensic facial reconstruction based on dense statistics of soft tissue thickness.
In this paper, we present a method for automated estimation of a human face given a skull remain. Our proposed method is based on three statistical models. A volumetric (tetrahedral) skull model encoding the variations of different skulls, a surface head model encoding the head variations, and a dense statistic of facial soft tissue thickness (FSTT). All data are automatically derived from computed tomography (CT) head scans and optical face scans. In order to obtain a proper dense FSTT statistic, we register a skull model to each skull extracted from a CT scan and determine the FSTT value for each vertex of the skull model towards the associated extracted skin surface. The FSTT values at predefined landmarks from our statistic are well in agreement with data from the literature. To recover a face from a skull remain, we first fit our skull model to the given skull. Next, we generate spheres with radius of the respective FSTT value obtained from our statistic at each vertex of the registered skull. Finally, we fit a head model to the union of all spheres. The proposed automated method enables a probabilistic face-estimation that facilitates forensic recovery even from incomplete skull remains. The FSTT statistic allows the generation of plausible head variants, which can be adjusted intuitively using principal component analysis. We validate our face recovery process using an anonymized head CT scan. The estimation generated from the given skull visually compares well with the skin surface extracted from the CT scan itself.


The role of macrophage subsets in and around the heart in modulating cardiac homeostasis and pathophysiology.
Cardiac and pericardial macrophages contribute to both homeostatic and pathophysiological processes. Recent advances have identified a vast repertoire of these macrophage populations in and around the heart - broadly categorized into a CCR2+/CCR2- dichotomy. While these unique populations can be further distinguished by origin, localization, and other cell surface markers, further exploration into the role of cardiac and pericardial macrophage subpopulations in disease contributes an additional layer of complexity. As such, novel transgenic models and exogenous targeting techniques have been employed to evaluate these macrophages. In this review, we highlight known cardiac and pericardial macrophage populations, their functions, and the experimental tools used to bolster our knowledge of these cells in the cardiac context.


A Comprehensive Review of the Newest World Health Organization (WHO) Cytopathology Reporting Systems.
World Health Organization cytopathology reporting system systems have proposed for the pancreatobiliary tract, lung, lymph node, and soft tissue aligned with the updates in the World Health Organization classification of Tumor series. Among them, the pancreatobiliary tract and lung specimen reporting system have been published recently and are now a 7-tier and 5-tier category system, respectively, without any subcategorization. World Health Organization reporting systems also encourage the application of ancillary diagnostic tests like cell block preparation, immunocytochemistry, and rapid on-site evaluation for better categorization of specimens and further management, especially in indeterminate (atypical and suspicious for malignancy) and malignant cytology categories. In this brief review, we aim to provide a brief outline of both the systems and their clinical risk-based management strategies.


High glucose activates HIF-1-mediated signal transduction in glomerular mesangial cells through a carbohydrate response element binding protein.
High glucose evokes a variety of signals in mesangial cells that alter cellular functions responsible for the development of diabetic glomerulopathy. The hypoxia-inducible factor-1alpha (HIF-1alpha) regulates cellular homeostasis under hypoxic conditions, but it also has pleiotropic effects in response to cellular stresses at normoxia. Here we determined whether HIF-1alpha has a role in the regulation of mesangial cells in hyperglycemia. In the streptozotocin-induced diabetic mouse model, glomerular mesangial cells had a significant increase in HIF-1alpha expression in the nucleus. In cultured mesangial cells, high glucose enhanced the expression of HIF-1alpha and its target genes known to be involved in the development of diabetic glomerulopathy. A glucose-responsive carbohydrate response element binding protein (ChREBP) was found to have a critical role in the transcriptional upregulation of HIF-1alpha and downstream gene expression in mesangial cells exposed to high glucose. Knockdown of HIF-1alpha or ChREBP in mesangial cells abrogated the high glucose-mediated perturbation of gene expression. Our results show that ChREBP and HIF-1alpha mediate gene regulation in mesangial cells. Further studies will be needed to find out whether these findings are relevant to the development of the diabetic nephropathy.


Progressive hypervolemia despite hypoproteinemia and massive edema formation in rats with nephrotoxic serum nephritis.
Blood volume and whole kidney and single nephron function were evaluated 2 and 10 days after nephrotoxic serum nephritis (NSN) induction in Wistar rats. Progressive proteinuria, hypervolemia and edema were observed in NSN rats. Sodium retention was associated with a progressive depression of single nephron glomerular filtration rate and elevated fractional tubular reabsorption rates. Since hypervolemia rather than hypovolemia was observed in this study, edema formation must have been a consequence of intrarenal rather than extrarenal phenomena.


[Neurohumoral regulation of gastric secretion in postvagotomy syndromes].
The secretion of hormones stimulating and inhibiting gastric secretory activity was studied in 85 patients with postvagotomy syndromes. The somatropin level was found to increase significantly in gastrostasis. The lower values of the blood insulin and C-peptide content in patients with recurrent ulcers was evidently associated either with insufficiency of the pancreatic insular apparatus or with partial vagal denervation, increased STH level, and plausible inhibiting effect of glucagon. Increased somatostatin secretion in the dumping syndrome, gastrostasis, and peptic ulcers may be due to the encountered hypergastrinemia.


Synthetic laminin-like peptides and pseudopeptides as potential antimetastatic agents.
This paper describes our efforts to study structure-activity relationships, improve the antimetastatic potency, and limit the in vivo enzymatic degradation of YIGSR-NH2, a synthetic peptide from the B1 chain of laminin, which reportedly has potential as an antimetastatic agent. To this end we have synthesized a series of psi (CH2NH) peptide analogs (5-9) of YIGSR-NH2 and a number of peptides in which the Tyr residue was replaced with D-Tyr (1), Phe (2), Phe (p-F) (3), and Phe(p-NH2) (4). All new peptides were assayed in vitro for their ability to promote cell attachment in both B16F10 mouse melanoma cells and HT-1080 human fibrosarcoma cells. On the basis of the in vitro assay results, peptides 3-5, 8, and 9 were tested in vivo for their ability to inhibit tumor metastasis to the lungs in mice that were coinjected in the tail vein with B16F10 melanoma cells and 1 mg of peptide. In summary, of the nine new peptides only the Phe(p-NH2) peptide 4 showed consistent in vitro cell attachment activity, but only low in vivo antimetastatic activity.


A comprehensive study of natural gamma radioactivity levels and associated dose rates from surface soils in cyprus.
A survey was carried out to determine activity concentration levels and associated dose rates from the naturally occurring radionuclides 232Th, 238U and 40K, in the various geological formations of Cyprus, by means of high-resolution gamma ray spectrometry. A total of 115 representative soil samples were collected from all over the bedrock surface of the island, based on the different lithological units of the study area, sieved through a fine mesh, sealed in 1000 ml plastic Marinelli beakers and measured in the laboratory with respect to gamma radioactivity for a counting time of 18-h each. From the measured spectra, activity concentrations were determined for 232Th (range from 1.0 x 10(-2) to 39.8 Bq kg(-1)), 238U (from 1.0 x 10(-2) to 39.3 Bq kg(-1)) and (40)K (from 4.0 x 10(-2) to 565.8 Bq kg(-1)). Gamma absorbed dose rates in air outdoors were calculated to be in the range from 1.1 x 10(-2) to 51.3 nGy h(-1), depending on the geological features, with an overall mean value of 8.7 nGy h(-1) and a standard deviation of 8.4 nGy h(-1). This value is by a factor of about seven below the corresponding population-weighted world-averaged value of 60 nGy h(-1) and one of the lowest that has been reported from similar investigations worldwide. Assuming a 20% occupancy factor, the corresponding effective dose rates outdoors equivalent to the population were calculated to be between 1.3 x 10(-2) and 62.9 microSv y(-1), with an arithmetic mean value of 10.7 microSv y(-1) and a standard deviation of 10.3 microSv y(-1).


Immunological Evaluation of Recent MUC1 Glycopeptide Cancer Vaccines.
Aberrantly glycosylated mucin 1 (MUC1) is a recognized tumor-specific antigen on epithelial cell tumors. A wide variety of MUC1 glycopeptide anti-cancer vaccines have been formulated by many research groups. Some researchers have used MUC1 alone as an immunogen whereas other groups used different antigenic carrier proteins such as bovine serum albumin or keyhole limpet hemocyanin for conjugation with MUC1 glycopeptide. A variety of adjuvants have been used with MUC1 glycopeptides to improve their immunogenicity. Fully synthetic multicomponent vaccines have been synthesized by incorporating different T helper cell epitopes and Toll-like receptor agonists. Some vaccine formulations utilized liposomes or nanoparticles as vaccine delivery systems. In this review, we discuss the immunological evaluation of different conjugate or synthetic MUC1 glycopeptide vaccines in different tumor or mouse models that have been published since 2012.


[The treatment of children with difficult to control epilepsy].
A survey is conducted of the way difficult-to-control epileptic seizures are currently managed in paediatric practice. We also highlight the alternative means of therapy available, such as epilepsy surgery, a ketogenic diet, the use of hormones, steroids, gamma globulin and the stimulation of the vagal nerve, together with their indications, their efficiency in the different types of epilepsy and their contraindications. Mention is also made of the new antiepileptic drugs that have appeared since the nineties, as well as the reappearance of others that had fallen into disuse.


[Mycoplasma pneumoniae: update and new challenges].
Mycoplasma pneumoniae is a frequent cause of community acquired pneumonia, especially in children. Discovered by Eaton in the 1940s, it has long been considered as a virus, in part because of its difficult growth in cultures. M. pneumoniae can cause many complications, some of which are severe such as dermatological lesions or affections of the central nervous system. The laboratory diagnosis of M. pneumoniae is difficult, notably because of the fastidious growth conditions, the persistence of IgM antibody after acute infection and the debated existence of asymptomatic carriers. In recent years, the spread of mutants resistant to macrolides caused an additional challenge linked to this pathogen.


Five putative subclasses of swine IgG identified from the cDNA sequences of a single animal.
We report the sequences of more than 40 partial and complete swine C gamma cDNAs obtained by PCR cloning of first strand cDNA, and from a cDNA expression library, all from a single animal. These seem to represent five IgG subclasses, that can be grouped into two clusters; one contains IgG1 and IgG3 and the other, IgG2a, IgG2b and IgG4. IgG2a and IgG2b differ by only three amino acids, but single strand conformational polymorphism analyses of PCR-amplified IgG2-specific segments in animals of different breeds, argues for their putative subclass status. Major subclass differences are found in the hinge and C gamma 3, but differences in upper hinge length, associated with segmental flexibility in the IgGs of other species, are absent. All subclasses have identical middle hinge segments that can accommodate three interheavy chain disulfide bridges. The putative swine IgG subclasses have their greatest similarity with those of the human except for the near absence of hinge region variation. Swine subclasses such as ruminant IgG2a, have a lower hinge deletion which in human IgG1, contains one of the motifs believed necessary for interaction with Fc gamma Rs. IgG1 was the most frequently encountered subclass cDNA (25 of 43) and the single swine-mouse hybridoma tested had a sequence identical to IgG1. Partial sequence analyses of genomic clones identified one clone identical with the IgG1/IgG3 subclass cluster, two identical to the IgG2b/IgG4 subclass group, and two identical to each other but different from any of the expressed sequences reported here. Genomic blots suggest that up to eight C gamma genes are present in the genome.


Management of Post-Traumatic Rectovesical/Rectourethral Fistulas: Case Series of Complicated Injuries in Wounded Warriors and Review of the Literature.
Penetrating injuries to the pelvis and perineum can result in fistulas between the rectum and lower urinary tract. These injuries are often complicated, which creates challenges for successful repair. Operative strategies may include initial fecal and/or urinary diversion combined with an eventual trans-perineal, trans-anal, or posterior/transrectal approach, but the selected approach should be guided by precise anatomic localization of the injury. We aim to discuss different possible repair strategies as well as the relevant data surrounding gastrointestinal-genitourinary (GI-GU) fistula management. We present this series of three post-traumatic rectovesical and rectourethral fistulas to illustrate the surgical options for treatment of these conditions. In this series, we have retrospectively reviewed our experience at Walter Reed National Military Medical Center in caring for three Wounded Warriors who had suffered these types of injuries. The study was exempt from institutional review board approval because of the size of the series. Our three patients all were managed with initial urinary and fecal diversion before an eventual trans-perineal, trans-anal, or posterior/transrectal approach. All three patients ultimately underwent reversal of diverting ostomies with good functional results and successful resolution of their GI-GU fistulas. This series demonstrates the complexity of traumatic GI-GU fistulas. Successful management depended on early diversion of both urine and feces, localization of the fistula, and an interdisciplinary surgical approach specifically tailored to each patient. All three patients had favorable overall functional outcomes despite their devastating injuries. This review should help to illustrate some of the possible repair strategies for these difficult surgical problems.


Isodicentric Philadelphia Chromosome: A Rare Chromosomal Aberration in Imatinib-Resistant Chronic Myelogenous Leukemia Patients - Case Report with Review of the Literature.
The BCR-ABL1 fusion gene derived from the Philadelphia chromosome, resulting from a classical translocation event t(9;22)(q34.13;q11.23), is responsible for the pathogenesis of chronic myeloid leukemia (CML) in more than 90% of the patients. The isoderivative chromosome 22, ider(22), and relative amplification or duplication of the BCR-ABL1 gene have been considered as one of the major reasons associated with the resistance to chemotherapy with imatinib mesylate, but the data remain unclear. GTG-banding together with FISH were performed to identify the presence of the ider(22) chromosome. Reverse transcription-polymerase chain reaction (RT-PCR) for the detection of BCR-ABL1 fusion transcripts and BCR-ABL1 kinase domain mutation analysis were carried out in this study. Conventional and molecular cytogenetic analysis on metaphase chromosomes confirmed the presence of ider(22) chromosomes in both patients. Molecular characterization revealed the presence of a 210-kDa BCR-ABL1 type b3a2 and lack of mutations at the kinase domain region on the fusion product in both patients. The occurrence of the ider(22) chromosome could be considered as an important marker correlated with the aggressive progression of CML as well as the emergence of drug-resistant cell clones.


Cow Milk Consumption Increases Iodine Status in Women of Childbearing Age in a Randomized Controlled Trial.
Recent evidence has highlighted the prevalence of mild-to-moderate iodine deficiency in women of childbearing age and pregnant women, with important public health ramifications due to the role of iodine, which is required for thyroid hormone production, in neurodevelopment. Cow milk contributes the greatest amount to iodine intakes in several countries. The objective of this study was to investigate the effect of increased cow milk consumption on iodine status, thyroid hormone concentrations, and selenium status. A 12-wk randomized controlled trial was conducted in 78 low-moderate milk-consuming (<250 mL/d) healthy women (aged 18-45 y). The intervention group was asked to consume 3 L semiskimmed milk/wk, whereas the control group continued their usual milk consumption (baseline median: 140 mL/d; IQR: 40-240 mL/d). At baseline and weeks 6 and 12, participants provided a spot urine sample [urinary iodine concentration (UIC), creatinine] and a fasting blood sample (thyroid hormone concentrations, serum total selenium, selenoprotein P). At baseline, the median (IQR) UIC of all participants was 78.5 µg/L (39.1-126.1 µg/L). Changes in the median UIC from baseline to week 6 (35.4 compared with 0.6 µg/L; P = 0.014) and week 12 (51.6 compared with -3.8 µg/L; P = 0.045) were significantly greater in the intervention group compared with the control group. However, despite being higher within the intervention group at weeks 6 and 12, the change in the iodine:creatinine ratio from baseline was not significantly different between groups at either week 6 (P = 0.637) or week 12 (P = 0.178). There were no significant differences in thyroid hormone concentrations or selenium status between groups at any time point. The present study shows that the consumption of additional cow milk can significantly increase UIC in women of childbearing age. These results suggest that cow milk is a potentially important dietary source of iodine in this population group. This trial was registered at www.clinicaltrials.gov as NCT02767167.


ROS-Switchable Polymeric Nanoplatform with Stimuli-Responsive Release for Active Targeted Drug Delivery to Breast Cancer.
Tumor microenvironment plays a vital role in the process of tumor development, proliferation, invasion, and metastasis. It is well acknowledged that reduction in pH, reactive oxygen species (ROS), and increased level of glucose transporter 1 (GLUT1) have become featured intracellular and extracellular biochemical markers of cancer owing to oncogenic transformation and abnormal metabolism. To establish a distinctive drug delivery system directed against the tumor microenvironment features, we develop a newly engineered polymeric nanoplatform for efficient doxorubicin (DOX) delivery with reduced systemic toxicity and high antitumor efficiency. A thioketal cross-linker is used to improve the formulation's stability during circulation and to foster quick intracellular drug release in response to tumor's ROS potential. Furthermore, the low drug loading efficiency of conventional micelles is ameliorated in this polymeric nanoplatform via a drug-conjugation strategy with an acid-labile chemical bond. The optimized formulation, MPLs-sB-DOX micelles, possesses a high drug-loading efficiency (31%) within nanosize diameter (37.8 nm). In addition, this formulation shows significant improvement in the pharmacokinetics and biodistribution profiles with a 2.69-fold increase of tumor accumulation, while with largely reduced systemic toxicity in comparison with free DOX. With advantages of efficient cellular uptake, preferential tumor accumulation, and controlled release behaviors, MPLs-sB-DOX micelles demonstrate good tumor-targeting ability with reduced systemic toxicity, proving to be a promising formulation for breast cancer therapy.


Differential distributions of red-green and blue-yellow cone opponency across the visual field.
The color vision of Old World primates and humans uses two cone-opponent systems; one differences the outputs of L and M cones forming a red-green (RG) system, and the other differences S cones with a combination of L and M cones forming a blue-yellow (BY) system. In this paper, we show that in human vision these two systems have a differential distribution across the visual field. Cone contrast sensitivities for sine-wave grating stimuli (smoothly enveloped in space and time) were measured for the two color systems (RG & BY) and the achromatic (Ach) system at a range of eccentricities in the nasal field (0-25 deg). We spatially scaled our stimuli independently for each system (RG, BY, & Ach) in order to activate that system optimally at each eccentricity. This controlled for any differential variations in spatial scale with eccentricity and provided a comparison between the three systems under equivalent conditions. We find that while red-green cone opponency has a steep decline away from the fovea, the loss in blue-yellow cone opponency is more gradual, showing a similar loss to that found for achromatic vision. Thus only red-green opponency, and not blue-yellow opponency, can be considered a foveal specialization of primate vision with an overrepresentation at the fovea. In addition, statistical calculations of the level of chance cone opponency in the two systems indicate that selective S cone connections to postreceptoral neurons are essential to maintain peripheral blue-yellow sensitivity in human vision. In the red-green system, an assumption of cone selectivity is not required to account for losses in peripheral sensitivity. Overall, these results provide behavioral evidence for functionally distinct neuro-architectural origins of the two color systems in human vision, supporting recent physiological results in primates.


Prognosis of diabetic patients undergoing coronary artery bypass surgery compared with nondiabetics: a systematic review and meta-analysis.
The influence of diabetes mellitus (DM) on mortality and morbidity in patients undergoing coronary artery bypass graft (CABG) surgery has remained uncertain due to conflicting conclusions from clinical trials measuring the association between diabetes and perioperative risk. Therefore, a quantitative meta-analysis was undertaken to evaluate the available evidence from prospective and historic cohort clinical trials. The purpose of this study was to determine the significance and magnitude of impact of DM on mortality, morbidity and resource-related outcomes for patients undergoing CABG over the past few decades and in the contemporary setting. MEDILINE, EMBase, BIOSIS Preview, CBMDisc, CNKI and WanFang databases were searched, supplemented by hand search, without language limitations, for studies published from January 1981 to October 2008. Data extraction included study design, setting, inclusion/exclusion criteria, population characteristics, statistical method, length of follow-up and clinical outcomes. Eligible studies were assessed for quality. Of the 132 identified studies, 24 cohort studies with a median follow-up of 4.3 years were selected for analysis. A total of 100,217 patients (28,168 with DM and 72,049 without DM), were included in the meta-analysis. The pooled RR (95% CI) for mortality of diabetic versus non-diabetic patients was significantly increased at 30 days (RR 1.64, 95% CI 1.39, 1.93), 1 year (RR 1.83, 95% CI 1.56, 2.15), 3 years (RR 1.81, 95% CI 1.58, 2.09), 5 years (RR 1.66, 95% CI 1.53, 1.79) and 10 years (RR 1.55, 95% CI 1.43, 1.68) after CABG. Significant differences were also found for DM versus non-DM patients post-CABG for perioperative cerebrovascular accidents (RR 1.52; 95% CI 1.31, 1.77), postoperative acute renal failure (RR 1.63; 95% CI 1.48, 1.79), sternal infection (RR; 1.70, 95% CI 1.41-2.04) and blood transfusion (RR 1.15; 95% CI 1.08, 1.21). No significant differences were found for postoperative atrial fibrillation (AF), postoperative myocardial infarction (MI) and re-exploration for bleeding. Insufficient and/or heterogeneous data did not allow for pooled analysis of ventilator time, ICU stay, angina recurrence, repeat revascularization, hospital stay and hospital costs. Current evidence suggests that patients with DM who are undergoing CABG are at increased risk of mortality, stroke, renal failure, sternal infection and blood transfusion when compared to those without DM. This increased relative risk for perioperative mortality and complications has remained, despite evolving definitions of DM and practice patterns. Future randomized studies should focus on interventions targeted toward these complications to mitigate the risk for patients with DM.


Group work in a Dutch home care organization: does it improve the quality of working life?
Home care in The Netherlands is facing a trend towards increasing workloads, giving it the image of an unattractive sector to work in. To deal with increasing workloads and their effects, many solutions have been developed, including the concept of team or group work. This paper will address the possibilities, conditions and effects involved in the implementation of group work in home care as a means of improving the quality of working life (QWL) in this sector. To this end I have studied QWL in three jobs in two organizations for home care, one of which implemented group work. This comparison concludes that jobs in the team-based organization are more complete and challenging, bringing more job decision latitude, but also higher work pressure.


Pharmacokinetics of levofloxacin after single intravenous, oral and subcutaneous administration to dogs.
The pharmacokinetic properties of the fluoroquinolone levofloxacin (LFX) were investigated in six dogs after single intravenous, oral and subcutaneous administration at a dose of 2.5, 5 and 5 mg/kg, respectively. After intravenous administration, distribution was rapid (T½dist 0.127 ± 0.055 hr) and wide as reflected by the volume of distribution of 1.20 ± 0.13 L/kg. Drug elimination was relatively slow with a total body clearance of 0.11 ± 0.03 L kg-1 hr-1 and a T½ for this process of 7.85 ± 2.30 hr. After oral and subcutaneous administration, absorption half-life and Tmax were 0.35 and 0.80 hr and 1.82 and 2.82 hr, respectively. The bioavailability was significantly higher (p ˂ 0.05) after subcutaneous than oral administration (79.90 vs. 60.94%). No statistically significant differences were observed between other pharmacokinetic parameters. Considering the AUC24 hr /MIC and Cmax /MIC ratios obtained, it can be concluded that LFX administered intravenously (2.5 mg/kg), subcutaneously (5 mg/kg) or orally (5 mg/kg) is efficacious against Gram-negative bacteria with MIC values of 0.1 μg/ml. For Gram-positive bacteria with MIC values of 0.5 μg/kg, only SC and PO administration at a dosage of 5 mg/kg showed to be efficacious. MIC-based PK/PD analysis by Monte Carlo simulation indicates that the proposed dose regimens of LFX, 5 and 7.5 mg/kg/24 hr by SC route and 10 mg/kg/24 hr by oral route, in dogs may be adequate to recommend as an empirical therapy against S. aureus strains with MIC ≤ 0.5 μg/ml and E. coli strains with MIC values ≤0.125 μg/ml.


The licorice root derived isoflavan glabridin inhibits the activities of human cytochrome P450S 3A4, 2B6, and 2C9.
The potent antioxidants licorice root extract and glabridin, an isoflavan purified from licorice root extract, were tested for their ability to modulate the activities of several cytochrome P450 (P450) enzymes. P450 3A4, the major human drug metabolizing P450 enzyme, was inactivated by licorice root extract and by glabridin in a time-and concentration-dependent manner. The inactivation was NADPH-dependent and was not reversible by extensive dialysis. Further analysis showed that the loss in enzymatic activity correlated with a loss in the P450-reduced CO spectrum and with a loss of the intact heme moiety. In contrast, incubations of P450 3A4 with similar concentrations of 2,4-dimethylglabridin and NADPH did not lead to inactivation of P450 3A4. P450 2B6 was also inactivated by glabridin in a time- and concentration-dependent manner. The majority of the glabridin-inactivated P450 2B6 was able to form a reduced CO spectrum suggesting that the heme was not modified with this isoform. High-performance liquid chromatography analysis of the P450 heme confirmed that incubations with glabridin and NADPH did not result in the destruction of the heme moiety. The activity of P450 2C9 was competitively inhibited by glabridin, whereas P450 2D6 and P450 2E1 were virtually unaffected. The data show that glabridin can serve as a substrate for at least three human P450 enzymes and that depending on the isoform, metabolism of glabridin can lead to mechanism-based inactivation or inhibition of the P450. Heme and reduced CO spectral analysis also indicated that glabridin inactivated P450s 2B6 and 3A4 by different mechanisms.


Characteristics of liver fibrosis with different etiologies using a fully quantitative fibrosis assessment tool.
This study aimed to test the diagnostic performance of a fully quantitative fibrosis assessment tool for liver fibrosis in patients with chronic hepatitis B (CHB), primary biliary cirrhosis (PBC) and non-alcoholic steatohepatitis (NASH). A total of 117 patients with liver fibrosis were included in this study, including 50 patients with CHB, 49 patients with PBC and 18 patients with NASH. All patients underwent liver biopsy (LB). Fibrosis stages were assessed by two experienced pathologists. Histopathological images of LB slices were processed by second harmonic generation (SHG)/two-photon excited fluorescence (TPEF) microscopy without staining, a system called qFibrosis (quantitative fibrosis) system. Altogether 101 quantitative features of the SHG/TPEF images were acquired. The parameters of aggregated collagen in portal, septal and fibrillar areas increased significantly with stages of liver fibrosis in PBC and CHB (P<0.05), but the same was not found for parameters of distributed collagen (P>0.05). There was a significant correlation between parameters of aggregated collagen in portal, septal and fibrillar areas and stages of liver fibrosis from CHB and PBC (P<0.05), but no correlation was found between the distributed collagen parameters and the stages of liver fibrosis from those patients (P>0.05). There was no significant correlation between NASH parameters and stages of fibrosis (P>0.05). For CHB and PBC patients, the highest correlation was between septal parameters and fibrosis stages, the second highest was between portal parameters and fibrosis stages and the lowest correlation was between fibrillar parameters and fibrosis stages. The correlation between the septal parameters of the PBC and stages is significantly higher than the parameters of the other two areas (P<0.05). The qFibrosis candidate parameters based on CHB were also applicable for quantitative analysis of liver fibrosis in PBC patients. Different parameters should be selected for liver fibrosis assessment in different stages of PBC compared with CHB.


Scalp extension.
Surgery to correct extensive alopecia requires increasing the surface of hair-bearing scalp and removing bald scalp. Two commonly used methods, scalp expansion and scalp reduction, have disadvantages. To describe a new method, scalp extension, that employs a thin sheet of bioplastic (an extender) stretched and attached with hooks to the galea after scalp reduction. The surgical technique is described and the results compared with those of patients who have undergone scalp reduction and scalp expansion. A study of the first fifteen cases treated is presented. During the few weeks that the extender is implanted, the constant tension it exerts on the galea causes a progressive stretching of the scalp. Data from the first fifteen cases treated reveal eradication of more extensive bald areas than with scalp reduction, making it possible to cut the number of operations necessary in half while considerably shortening total treatment time. The absence of major side effects, along with the absence of any deformation of the scalp (unlike scalp expansion), explains the excellent acceptability of the instrument by patients. Scalp extension appears to be a useful adjunctive technique in hair replacement and reconstructive surgery, and has distinct advantages over standard scalp reduction and tissue expansion techniques.


The use of a constrained cementless acetabular component for instability in total hip replacement.
Recurrent dislocation after total hip arthroplasty is a disabling complication that can be difficult to treat. We evaluated the early clinical and radiographic outcome associated with the use of a constrained acetabular component for instability in total hip arthroplasty. Fifteen patients underwent either primary or revision total hip arthroplasty with a cementless constrained acetabular component for different indications. The mean patient age at surgery was 57.4 years and the mean clinical and radiological follow-up period was 26.4 months. Clinical assessment was performed by the Harris hip score and at the latest follow up patients reported outcome using the Oxford hip score questionnaire. All radiographs were evaluated for evidence of loosening. Only one patient experienced redislocation with the constrained prosthesis. The average Harris hip score increased from a preoperative mean of 22 (range, 16 - 36) to a postoperative mean of 85 (range, 66-94). Preoperatively, the mean Oxford Hip Score was 48.6, which decreased to 20.5 at the final examination. All but one of the 15 hips had a well-fixed, stable cup. Femoral component stability with bone ingrowth was achieved in 10 cases. A constrained acetabular component is an effective option for the treatment of hip instability in primary and revision arthroplasty in those at high risk of dislocation. The potential for aseptic loosening requires evaluation by long term studies.


Bioactive unnatural somatostatin analogues through bioorthogonal iodo- and ethynyl-disulfide intercalators.
Iodo- and ethynyl-containing bisalkylating bioconjugation agents 5 and 8 were achieved and allow the introduction of reactive unnatural substituents into proteins and peptides whilst the bioactive 3D structure is retained. Derivatives of the peptide hormone somatostatin bearing a single iodo or ethynyl group were prepared through intercalation into the disulfide bridge. For the first time, the exact reaction mechanism of the intercalation was elucidated by applying 2D NMR experiments and it was shown that, during the reaction, somatostatin diastereomers were formed. Site-directed modification of the ethynyl-modified peptide with a coumarin chromophore was achieved through a [1,3] dipolar Huisgen cycloaddition reaction; this suggests that such a derivative could serve as an attractive platform to prepare artificial somatostatin compound libraries. The biological activity and specificity of a representative modified somatostatin derivative was demonstrated and efficient receptor-mediated cell uptake occurred in a dose-dependent manner into receptor positive cells only. The iodo and ethynyl bioconjugation reagents presented herein could be applied for introducing such substituents into alternative peptides and proteins and, in principle, could facilitate the efficient design of a broad variety of artificial protein and peptide analogues with previously unknown bioactivities.


Tensile Behaviors and Mechanical Property Analyses of T-Welded Joint for Thin-Walled Parts in Consideration of Different TIG Welding Currents Using Multiple Damage Models and Fracture Criterions: Numerical Simulation and Experiment Validation.
In order to deeply investigate the tensile properties and fracture behaviors that are obtained by tensile tests of welded joints, constitutive and damage models are imperative for analyzing the tensile behaviors. In this work, the tensile tests are conducted on the T-welded joint specimens of aluminum alloy 6061-T6, which were cut from the T-welded joints of thin-walled parts under different welding currents of Tungsten Inert Gas Welding (TIGW). A modified Johnson-Cook (J-C) model based on the original J-C equation, Swift model, Voce model, and Hockett-Sherby (H-S) model, their linear combination model, and fracture failure model are constructed and applied to simulate tensile behaviors, combined with tensile test data. What is more, the finite element (FE) simulation of tension tests is executed with the VUMAT and VUSDFLD subroutines. Compared to those results simulated with different fracture criteria and tensile experiments, the tensile strength and yield strength of T-welded joint thin-walled parts under different welding currents were achieved, and their best mean errors were only about 1%. Furthermore, the accuracy of different fracture criteria is also evaluated by the correlation coefficient and mean squared error. The results show that the combination model can accurately predict the tensile properties and fracture behaviors of T-welded joints better than the single model, especially the results simulated with the Swift-H-S model and H-S-Voce model, which are in good agreement with tensile test results, which will provide an analysis foundation for enhancing the welding assembly quality and preventing fracture failure for complex thin-walled antenna structures.


Circadian rhythm disruption impairs tissue homeostasis and exacerbates chronic inflammation in the intestine.
Endogenous circadian clocks regulate 24-h rhythms of physiology and behavior. Circadian rhythm disruption (CRD) is suggested as a risk factor for inflammatory bowel disease. However, the underlying molecular mechanisms remain unknown. Intestinal biopsies from Per1/2 mutant and wild-type (WT) mice were investigated by electron microscopy, immunohistochemistry, and bromodeoxyuridine pulse-chase experiments. TNF-α was injected intraperitoneally, with or without necrostatin-1, into Per1/2 mice or rhythmic and externally desynchronized WT mice to study intestinal epithelial cell death. Experimental chronic colitis was induced by oral administration of dextran sodium sulfate. In vitro, caspase activity was assayed in Per1/2-specific small interfering RNA-transfected cells. Wee1 was overexpressed to study antiapoptosis and the cell cycle. Genetic ablation of circadian clock function or environmental CRD in mice increased susceptibility to severe intestinal inflammation and epithelial dysregulation, accompanied by excessive necroptotic cell death and a reduced number of secretory epithelial cells. Receptor-interacting serine/threonine-protein kinase (RIP)-3-mediated intestinal necroptosis was linked to increased mitotic cell cycle arrest via Per1/2-controlled Wee1, resulting in increased antiapoptosis via cellular inhibitor of apoptosis-2. Together, our data suggest that circadian rhythm stability is pivotal for the maintenance of mucosal barrier function. CRD increases intestinal necroptosis, thus rendering the gut epithelium more susceptible to inflammatory processes.-Pagel, R., Bär, F., Schröder, T., Sünderhauf, A., Künstner, A., Ibrahim, S. M., Autenrieth, S. E., Kalies, K., König, P., Tsang, A. H., Bettenworth, D., Divanovic, S., Lehnert, H., Fellermann, K., Oster, H., Derer, S., Sina, C. Circadian rhythm disruption impairs tissue homeostasis and exacerbates chronic inflammation in the intestine.


Local tissue flaps: definitive treatment for chronic blisters after chemical burns.
Chronic blistering in grafted burn wounds is an infrequently described but severely debilitating complication that can appear after alkali burns and seems to coincide with a delay in initial treatment. Histological studies have concluded that the pathogenesis of chronic subepidermal blister formation in previously grafted burn wounds is related to abnormalities in the basement membrane. Although several reports have described this problem, none have reported adequate treatment for the chronic blistering in previously grafted alkali burns. The authors describe the case of a 30-year-old man in whom caustic soda burns treated with excision and split-thickness skin grafting resulted in chronic subepidermal blistering that failed to improve over the next 2 years. The problem was resolved with full-thickness skin excision and reconstruction with bipedicled fasciocutaneous flaps.


Wrist-wearable medical devices: technologies and applications.
Standard HDP technologies such as COB can be involved early in the development stage. They help to form the development process and to meet size requirements without exhausting the development budget. Higher HDP production costs are negligible compared with the total development, field test and regulatory approval costs. Using HDP for miniaturisation, it is possible to make applications of previously lab-scale equipment for WMDs and for implants.


Morecambe Bay: From special measures to outstanding care.
Just under three years ago, the University Hospitals of Morecambe Bay NHS Foundation Trust was under significant pressure. Still reeling from a scandal involving the deaths of 11 babies and a mother at one of its hospitals, the trust had been placed into special measures by the Care Quality Commission (CQC) in June 2014. It's fair to say that its reputation was not good.


Neural Correlates of Depressive Symptoms in Smokers - A Systematic Review of Imaging Studies.
This review aims to summarize neuroimaging studies in order to better understand the neural correlates of depressive symptoms in tobacco smokers. Using the keywords "depressive OR depression" AND "tobacco OR nicotine OR smok* OR cigarette" AND "neuroimage OR magnetic resonance OR smri OR structural magnetic resonance OR fmri OR functional magnetic resonance OR pet OR positron emission tomography", literature search was conducted in PubMed, Web of Science and PsycINFO databases. The first and the last author read the abstracts of all the studies found in the search (n = 179). The inclusion and exclusion criteria were applied and 150 articles were excluded. Then, both authors assessed the remaining 29 studies for eligibility and 16 studies were included in the present review. In the phase of active/chronic smoking, depressive symptoms are characterized as comorbidity related to an enhancement of dopamine release, and smokers have decreased Monoamine oxidase A (MAO-A). Stimuli-related functional magnetic resonance imaging (Stimuli-fMRI) studies also show that there is a positive correlation between the level of depressive symptoms and a greater response to general negative stimuli in active/chronic smokers. In the withdrawal phase, depressive symptoms are related to the withdrawal syndrome and increased MAO-A. Stimuli-fMRI studies show that there is a negative correlation between level of depressive symptoms and reactivity to negative stimuli in recent abstinent smokers. Major areas of the reward system such as the striatum and areas related to impulse control are activated to a greater extent in depressive smokers compared to non-depressed smokers.


Lactobacilli inhibit cervical cancer cell migration in vitro and reduce tumor burden in vivo through upregulation of E-cadherin.
The present study was designed to investigate the antitumor effects of Lactobacillus and the potential mechanisms. Cell Counting Kit-8 (CCK-8) assays were carried out to determine suitable doses for investigating the inhibitory effect of lactobacilli on cell migration ability of HeLa and U14 cells in vitro. In addition, western blot assays were performed to investigate the possible mechanisms corresponding to its antitumor effects. Furthermore, a xenograft mouse model was established for investigating the E-cadherin expression in tumor tissues after treatment with lactobacilli. Our results showed that live lactobacilli [multiplicity of infection (MOI) of 1,000:1] significantly possessed inhibitory effects on cell migration ability of cervical cancer cells. Lactobacilli (MOI: 1,000:1) significantly upregulated E-cadherin expressions in HeLa and U14 cells (p<0.05). On the contrary, our results showed that inactivated lactobacilli could not affect the E-cadherin expression levels in HeLa and U14 cells. Similar to the western blot assay, immunohistochemistry results also indicated that lactobacilli treatment significantly upregulated E-cadherin in tumor tissues (p<0.05). In conclusion, our results above suggest that lactobacilli have the potential for inhibiting the migratory ability of cervical cancer cell lines, and the possible pharmacological mechanism may be closely related to the upregulation of E-cadherin.


Difficulties in the diagnosis of thyroid paraganglioma: a clinical case.
Thyroid Paragangliomas are exceptionally rare tumors and only 35 documented cases have been reported in the literature. We report an additional unusual male case of thyroid Paraganglioma associated to a chronic lymphocytic thyroiditis and a papillary microcarcinoma. A 45-year-old man presented with a solitary thyroid nodule. Physical examination revealed a smooth, well-circumscribed, firm, mobile, painless thyroid nodule in the right lobe measuring 3 cm. Ultrasound examination showed a 40 mm hypoechoic, non-homogeneous nodule with peri- and intra-nodular vascular flow. An ultrasound-guided fine needle aspiration biopsy was performed showing the presence of atypical cells (Thy 3). He underwent a total thyroidectomy associated to VI level lymphectomy. Histology showed a thyroid Paraganglioma associated to a chronic lymphocytic thyroiditis and a papillary microcarcinoma measuring 0.3 cm in the greatest dimension. Thyroid Paraganglioma is an elusive tumor. It is difficult to diagnose and should be included in the differential diagnosis of all neuroendocrine tumors of the thyroid, even those arising in men or behaving in a locally aggressive fashion.


Urban heat island intensity maps and local weather types description for a 45 French urban agglomerations dataset obtained from atmopsheric numerical simulations.
This article presents a dataset of spatial nocturnal Urban Heat Island (UHI) intensities for 45 French urban agglomerations, at a horizontal resolution of 250 m. The urban influence on air temperature at 2 m above ground level was obtained by coupling the mesoscale atmospheric model Meso-NH with the land surface model SURFEX-TEB. For each agglomeration, two specific local weather situations that favour the development of a strong UHI in summer are simulated and described in a specfic sheet. Simulation outputs have been postprocessed to 1) identify the time of day when the UHI is the most developed, 2) to merge information from both meteorological situations in order to obtain one synthetic UHI map and 3) a geographical analysis that allows to classify each city among five spatial UHI classes (Concentrated Very High Intensity; Concentrated High Intensity; Limited Intensity; Dispersed High Intensity; and Dispersed Cool Zones). This dataset can therefore be used for several purposes, from the analysis at the scale of a city to the comparison of the urban agglomerations among them.


Biocontrol strategies for Mediterranean-style fermented sausages.
Naturally fermented meat sausages have a long tradition in Mediterranean countries and are one of the most important groups of traditional foods consumed throughout Europe. Despite all the advances in food science and technology and increased regulatory requirements and concerns for safety and quality during the last decades, the challenge to control important foodborne pathogens in this type of meat products still persists. Simultaneously, growing consumer interest in safe, high quality and minimal processed products, with less additives/preservatives have driven the food industry and scientists in a crusade for innovative technologies to maintain the safety of these products by natural means. Biological control (biocontrol) fits well within this tendency. This review summarizes the latest achievements on biocontrol strategies applied to Mediterranean-style fermented sausages, namely: (i) bioprotective cultures; (ii) bacteriocins; and, (iii) essential oils (EOs).


Approach selection for resection of petroclival meningioma.
Petroclival meningiomas are surgically challenging tumors because of their deep location and involvement of critical neurovascular structures. A variety of approaches have been described, and selection of approach should be tailored to the location of the tumor relative to neurovascular structures and surgical experience. The authors present two patients with petroclival meningiomas with varying relationships to cranial nerves and skull base anatomy who underwent endoscopic endonasal and open petrosectomy approaches, to demonstrate the complementarity of the endonasal transpetrous and open transpetrosal corridors. Proficiency in both open and endonasal approaches is critical to appropriate approach selection and maximal safe resection. The video can be found here: https://stream.cadmore.media/r10.3171/2022.1.FOCVID21252.


EVOLUTIONARY ADAPTATION TO TEMPERATURE. V. ADAPTIVE MECHANISMS AND CORRELATED RESPONSES IN EXPERIMENTAL LINES OF ESCHERICHIA COLI.
We previously demonstrated temperature-specific genetic adaptation in experimental lines of Escherichia coli. Six initially identical populations were propagated for 2000 generations under each of five regimes: constant 20°C, 32°C, 37°C, and 42°C, and a daily switch between 32°C and 42°C. Glucose was the sole carbon source in all cases. Here, we examine the physiological bases of adaptation to determine whether the same mechanisms evolved among the replicate lines within each thermal regime and across different regimes. Specifically, we investigate whether changes in glucose transport may account for the temperature-specific adaptation. We compared each line's direct response of fitness to glucose with its correlated response to maltose; glucose and maltose enter the cell by different pathways, but their catabolism is identical. Except for lines maintained at the ancestral temperature (37°C), almost all derived lines had significantly different fitnesses (relative to their common ancestor) in glucose and maltose, supporting the hypothesis that adaptation involved changes in glucose transport. An alternative explanation, that maltose transport decayed by genetic drift, appears unlikely for reasons that are discussed. Although most lines showed evidence of temperature-specific adaptation in glucose transport, several different mechanisms may underlie these improvements, as indicated by heterogeneity in correlated responses (across temperatures and substrates) among replicate lines adapted to the same regime. This heterogeneity provides a latent pool of genetic variation for responding to environmental change.


Updating the chest pain algorithm: incorporating new evidence.
In 2003, we published our chest pain protocol for the management of acute coronary syndromes (ACSs) and acute myocardial infarction. Our algorithm was specifically designed for our institution, which was primary percutaneous coronary intervention (PCI) for all ST-elevation myocardial infarctions (STEMIs) and a preferred invasive approach for non-STEMIs. Since 2003, there have been numerous changes in the adjunctive pharmacotherapeutic armamentarium for PCI in both the STEMI and non-STEMI ACS context. We present our updated chest pain algorithm with a brief review of the rapidly evolving changes in adjunctive pharmacotherapy for PCI and provide a rationale for the changes that we have made to our institutional protocol. Clinical pathways need to be consistently updated and revises by incorporating new evidence from clinical trials in order to maintain clinical relevance.


Therapeutic strategies for localized prostate cancer.
Prostate-specific antigen determinations for prostate cancer screening have led to a dramatic increase in the number of men who are diagnosed with organ-confined and therefore potentially curable prostate cancer. Advances in predicting outcomes with artificial neural networks may help to recommend one therapy over another. Less invasive forms of treatment, such as high-intensity focused ultrasound, may ultimately give patients additional options for treatment. Furthermore, attempts to better define the role of both neoadjuvant hormonal therapy and chemotherapy may give higher-risk patients better outcomes than with current treatments. These advances as well as continued research will likely lead to a day when more and more men with organ-confined disease will be cured.