cFLIP regulates skin homeostasis and protects against TNF-induced keratinocyte apoptosis.
FADD, caspase-8, and cFLIP regulate the outcome of cell death signaling. Mice that constitutively lack these molecules die at an early embryonic age, whereas tissue-specific constitutive deletion of FADD or caspase-8 results in inflammatory skin disease caused by increased necroptosis. The function of cFLIP in the skin in vivo is unknown. In contrast to tissue-specific caspase-8 knockout, we show that mice constitutively lacking cFLIP in the epidermis die around embryonic days 10 and 11. When cFLIP expression was abrogated in adult skin of cFLIPfl/fl-K14CreERtam mice, severe inflammation of the skin with concomitant caspase activation and apoptotic, but not necroptotic, cell death developed. Apoptosis was dependent of autocrine tumor necrosis factor production triggered by loss of cFLIP. In addition, epidermal cFLIP protein was lost in patients with severe drug reactions associated with epidermal apoptosis. Our data demonstrate the importance of cFLIP for the integrity of the epidermis and for silencing of spontaneous skin inflammation.


MicroRNA-34a promotes genomic instability by a broad suppression of genome maintenance mechanisms downstream of the oncogene KSHV-vGPCR.
The Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded chemokine receptor vGPCR acts as an oncogene in Kaposi's sarcomagenesis. Until now, the molecular mechanisms by which the vGPCR contributes to tumor development remain incompletely understood. Here, we show that the KSHV-vGPCR contributes to tumor progression through microRNA (miR)-34a-mediated induction of genomic instability. Large-scale analyses on the DNA, gene and protein level of cell lines derived from a mouse model of vGPCR-driven tumorigenesis revealed that a vGPCR-induced upregulation of miR-34a resulted in a broad suppression of genome maintenance genes. A knockdown of either the vGPCR or miR-34a largely restored the expression of these genes and confirmed miR-34a as a downstream effector of the KSHV-vGPCR that compromises genome maintenance mechanisms. This novel, protumorigenic role of miR-34a questions the use of miR-34a mimetics in cancer therapy as they could impair genome stability.


Risk factors for dementia and self-harm: A linkage study.
People living with dementia experience poor mental health and high rates of self-harm. We investigated risk factors for self-harm in people aged > 40 years living with dementia and risk factors for dementia after self-harm. Using linked hospital data from New South Wales, Australia, we defined a dementia cohort (n = 154,811) and a self-harm cohort (n = 28,972). Using survival analyses, we investigated predictors of self-harm for the dementia cohort, and predictors of dementia for the self-harm cohort. We found self-harm or dementia diagnoses occurred most often within 24 months of a dementia diagnosis or initial self-harm presentation, respectively. Men living with dementia, and people with complex psychiatric profiles, had the greatest risk of self-harm. Men who had self-harmed had the greatest risk of dementia diagnoses. Men and people with complex psychiatric profiles and dementia may particularly benefit from post-diagnosis mental and behavioral support to reduce risk of self-harm.


Reserpinization: effects on parotid gland function.
Chronic reserpinization of mice and rabbits affected parotid gland function; cholinergic and beta-adrenergic-stimulated amylase release were significantly reduced, and cyclic-AMP and cyclic-GMP levels were significantly elevated above control-stimulated levels. Amylase released by dibutyryl-c-AMP was also reduced, suggesting a defect in stimulus-secretion coupling subsequent to c-AMP formation.


Effects of melatonin on the serum levels of pro-inflammatory cytokines and tissue injury after renal ischemia reperfusion in rats.
We investigated the changes in the serum levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6, the pro-inflammatory cytokines, and the possible effect of melatonin on the modulation of these inflammatory molecules after renal ischemia reperfusion (IR). The study was carried out in the laboratory of Department of Pharmacology. Forty-six male Wistar albino rats were divided into five groups as control (n=6), positive control (n=4), sham (n=12), renal IR (n=12), and renal IR melatonin (n=12). After 1 h renal pedicle occlusion, the blood samples were taken for the measurement of cytokine levels at second hour of the reperfusion. The rats were sacrificed after 24 h of reperfusion for histopathological evaluation. Melatonin or vehicle was administrated to IR rats. Lipopolysaccharide (LPS) was administered to the positive control group and the blood was taken at fourth hour. Serum TNF-α levels increased significantly in renal IR and LPS groups. Serum IL-6 levels were not different from control except the LPS group. There was no significant correlation between the serum TNF-α levels and the histopathological score after renal IR. Melatonin treatment reversed the increase of serum TNF-α levels and histopathological injury in renal tissue after renal IR. Melatonin may have a protective effect by reducing the serum level of TNF-α in renal IR.


The role of cannabidiol in aging.
Aging is usually considered a key risk factor associated with multiple diseases, such as neurodegenerative diseases, cardiovascular diseases and cancer. Furthermore, the burden of age-related diseases has become a global challenge. It is of great significance to search for drugs to extend lifespan and healthspan. Cannabidiol (CBD), a natural nontoxic phytocannabinoid, has been regarded as a potential candidate drug for antiaging. An increasing number of studies have suggested that CBD could benefit healthy longevity. Herein, we summarized the effect of CBD on aging and analyzed the possible mechanism. All these conclusions may provide a perspective for further study of CBD on aging.


Usefulness of the measurement of plasma beta-thromboglobulin (beta-TG) in cerebrovascular disease.
The plasma concentration of the platelet-specific protein beta-thromboglobulin (beta-TG) was measured in 39 normal subjects and 568 patients of neurological diseases. The beta-TG RIA commercially available KIT was also evaluated. Abnormally high plasma levels of beta-TG were demonstrated in groups of ischemic or obstructive cerebrovascular diseases as compared with that of normal subjects. The highest concentrations were found in 8 patients with Moya-Moya disease, (mean concentration of beta-TG was 204.4 ng/ml), completed stroke at an acute stage was next (mean beta-TG level was 194.8 +/- 70.8 ng/ml). On the other hand, many hemorrhagic cerebro-vascular diseases or other neurological diseases such as brain tumors, hydrocephalus, etc. do not show elevated beta-TG levels. In many patients with ischemic or obstructive cerebro-vascular diseases treated with anti-platelet drugs such as Aspirin, Dipyridamole, Bencyclane or Ticlopidine, a significant fall in plasma concentration of beta-TG was chronologically demonstrated. The measurement of plasma beta-TG concentration may be useful not only in the diagnosis of ischemic or obstructive cerebro-vascular disorders but also in judging the efficacy of anti-platelet therapies and prognosis.


Novel small molecule therapeutics for sickle cell disease: nitric oxide, carbon monoxide, nitrite, and apolipoprotein A-I.
A hemolysis-linked subphenotype of sickle cell disease (SCD), characterized by pulmonary hypertension, stroke, priapism and leg ulcers, is associated with decreased nitric oxide bioavailability and vasculopathy. Vasculopathy appears to have a multifactorial etiology, including mechanisms primarily that involve deficient nitric oxide (NO) signaling, but also involving altered function of NO synthase related to substrate availability and cooperating factors such as apolipoproteins. Improved understanding of the vascular pathophysiology of SCD has led to new vascular targets for translational research in SCD. This growing vascular therapeutics field in SCD is complementary to the ongoing efforts to reduce the morbidity of vaso-occlusive pain crisis. This presentation will review the current biology and translational clinical development of novel small molecules targeting sickle cell vasculopathy. Strategies targeting the hemeoxygenase-carbon monoxide pathway, the arginine-NO synthase-cGMP-phosphodiesterase 5 pathway, the nitrate-nitrite-NO pathway, and the apolipoprotein A-I pathways will be reviewed. In this context, current clinical trials of inhaled NO, CO, nitrite, sildenafil and apoA-I mimetics will be discussed.


[Deficiency of triosephosphate isomerase. Apropos of 2 new cases].
Two siblings, born of a no consanguineous couple, a female and a male, affected by a severe and progressive neurological disease and chronic hemolytic anemia are presented. Their clinical, hematological, biochemical and pathological studies are discussed. One of the patients showed a triosephosphate isomerase deficiency and the carrier condition of their parents was tested. Commentaries about physiopathology of this disease are made.


The crystal structure of Pichia pastoris lysyl oxidase.
Pichia pastoris lysyl oxidase (PPLO) is unique among the structurally characterized copper amine oxidases in being able to oxidize the side chain of lysine residues in polypeptides. Remarkably, the yeast PPLO is nearly as effective in oxidizing a mammalian tropoelastin substrate as is a true mammalian lysyl oxidase isolated from bovine aorta. Thus, PPLO is functionally related to the copper-containing lysyl oxidases despite the lack of any significant sequence similarity with these enzymes. The structure of PPLO has been determined at 1.65 A resolution. PPLO is a homodimer in which each subunit contains a Type II copper atom and a topaquinone cofactor (TPQ) formed by the posttranslational modification of a tyrosine residue. While PPLO has tertiary and quaternary topologies similar to those found in other quinone-containing copper amine oxidases, its active site is substantially more exposed and accessible. The structural elements that are responsible for the accessibility of the active site are identified and discussed.


Fluid therapy LiDCO controlled trial-optimization of volume resuscitation of extensively burned patients through noninvasive continuous real-time hemodynamic monitoring LiDCO.
This pilot trial aims at gaining support for the optimization of acute burn resuscitation through noninvasive continuous real-time hemodynamic monitoring using arterial pulse contour analysis. A group of 21 burned patients meeting preliminary criteria (age range 18-75 years with second- third- degree burns and TBSA ≥10-75%) was randomized during 2010. A hemodynamic monitoring through lithium dilution cardiac output was used in 10 randomized patients (LiDCO group), whereas those without LiDCO monitoring were defined as the control group. The modified Brooke/Parkland formula as a starting resuscitative formula, balanced crystalloids as the initial solutions, urine output of 0.5 ml/kg/hr as a crucial value of adequate intravascular filling were used in both groups. Additionally, the volume and vasopressor/inotropic support were based on dynamic preload parameters in the LiDCO group in the case of circulatory instability and oligouria. Statistical analysis was done using t-tests. Within the first 24 hours postburn, a significantly lower consumption of crystalloids was registered in LiDCO group (P = .04). The fluid balance under LiDCO control in combination with hourly diuresis contributed to reducing the cumulative fluid balance approximately by 10% compared with fluid management based on standard monitoring parameters. The amount of applied solutions in the LiDCO group got closer to Brooke formula whereas the urine output was at the same level in both groups (0.8 ml/kg/hr). The new finding in this study is that when a fluid resuscitation is based on the arterial waveform analysis, the initial fluid volume provided was significantly lower than that delivered on the basis of physician-directed fluid resuscitation (by urine output and mean arterial pressure).


A D-galactose-binding lectin purified from coronate moon turban, Turbo (Lunella) coreensis, with a unique amino acid sequence and the ability to recognize lacto-series glycosphingolipids.
A divalent, cation-independent d-galactose-binding lectin was purified from coronate moon turban Turbo (Lunella) coreensis. This lectin recognizes d-galactose and is a 38-kDa dimeric protein consisting disulphide-bonded 22-kDa polypeptides under non-reducing and reducing conditions of sodium dodecyl sulphate-polyacrylamide gel electrophoresis, respectively. Haemagglutination activity was inhibited by D-galactose, N-acetyl D-galactosamine, melibiose, lactose, porcine stomach mucin, asialofetuin and bovine submaxillary mucin. The lectin has tolerance for pH 5-11 and temperature until 50°C for 1h. The lectin strongly aggregated Gram-negative bacteria, such as Vibrio parahaemolyticus and Salmonella O7, but weakly Gram-positive strain as Staphylococcus aureus and Bacillus subtilis. The glycan-binding profile of this lectin was evaluated using frontal affinity chromatography technology and the lectin appeared to recognize oligosaccharides such as lacto-series glycosphingolipids contained in blood type A and H substances in addition to complex-type N-linked glycoproteins. Partial primary structures of 139 amino acid residues of this lectin were determined from N-terminus polypeptides and 8 peptides derived by cleavage with lysyl-endopeptidase. The primary structure was slightly similar to other known sequences of lectin; however, a repeating motif has been included.


Anaerobic/oxic/anoxic granular sludge process as an effective nutrient removal process utilizing denitrifying polyphosphate-accumulating organisms.
In a biological nutrient removal (BNR) process, the utilization of denitrifying polyphosphate-accumulating organisms (DNPAOs) has many advantages such as effective use of organic carbon substrates and low sludge production. As a suitable process for the utilization of DNPAOs in BNR, an anaerobic/oxic/anoxic granular sludge (AOAGS) process was proposed in this study. In spite of performing aeration for nitrifying bacteria, the AOAGS process can create anaerobic/anoxic conditions suitable for the cultivation of DNPAOs because anoxic zones exist inside the granular sludge in the oxic phase. Thus, DNPAOs can coexist with nitrifying bacteria in a single reactor. In addition, the usability of DNPAOs in the reactor can be improved by adding the anoxic phase after the oxic phase. These characteristics enable the AOAGS process to attain effective removal of both nitrogen and phosphorus. When acetate-based synthetic wastewater (COD: 600 mg/L, NH4-N: 60 mg/L, PO(4)-P: 10 mg/L) was supplied to a laboratory-scale sequencing batch reactor under the operation of anaerobic/oxic/anoxic cycles, granular sludge with a diameter of 500 microm was successfully formed within 1 month. Although the removal of both nitrogen and phosphorus was almost complete at the end of the oxic phase, a short anoxic period subsequent to the oxic phase was necessary for further removal of nitrogen and phosphorus. As a result, effluent concentrations of NH(4)-N, NO(x)-N and PO(4)-P were always lower than 1 mg/L. It was found that penetration depth of oxygen inside the granular sludge was approximately 100 microm by microsensor measurements. In addition, from the microbiological analysis by fluorescence in situ hybridization, existence depth of polyphosphate-accumulating organisms was further than the maximum oxygen penetration depth. The water quality data, oxygen profiles and microbial community structure demonstrated that DNPAOs inside the granular sludge may be responsible for denitrification in the oxic phase, which enables effective nutrient removal in the AOAGS process.


Neuropeptides mediate the ozone-induced increase in the permeability of the tracheal mucosa in guinea pigs.
We examined the effects of acute exposure to ozone on the permeability of the tracheal mucosa and the contribution of neural pathways to the effects of ozone using horseradish peroxidase (HRP; mol wt 40,000) as a marker of lumen-to-blood transfer of a macromolecule in guinea pigs in vivo. Each guinea pig was anesthetized and exposed for 30 min to either ozone [0.5 or 3 parts/million (ppm)] or air. Immediately after exposure, a tracheal segment was isolated between two polyethylene cannulas in vivo and filled with HRP solution (50 mg/ml). Blood samples were drawn before and 10, 20, 30, and 40 min after the intratracheal instillation of HRP. The plasma levels of HRP in guinea pigs exposed for 30 min to 3 ppm of ozone, but not to 0.5 ppm of ozone, were significantly greater than those in guinea pigs exposed to air. Although the increased plasma HRP levels after exposure to 3 ppm of ozone were unaffected by propranolol or atropine, they were completely inhibited by pretreatment with capsaicin (50 mg/kg sc, injected in two doses). These results suggest that endogenous neuropeptides mediate the ozone-induced increase in the permeability of the tracheal mucosa in guinea pigs in vivo, but neither an adrenergic nor a cholinergic pathway appears to be involved.


Etiological and preventive implications in alcohol carcinogenesis.
The current state of knowledge of the epidemiological association of alcohol and tobacco consumption with cancers of the head and neck in humans is reviewed. The possible involvement of alcohol-associated nutritional deficiencies in the etiology of head and neck cancer is considered. Data are presented which indicate that in vitro metabolism of the hepatocarcinogen N-nitrosopyrrolidine is increased in microsomal fractions isolated from ethanol-consuming hamsters. Relevant studies in experimental animals are discussed in the context of possible mechanisms that could account for the increased risk of cancer in heavy drinkers who smoke.


Anti-glycation effect of gold nanoparticles on collagen.
Gold nanoparticles (GNPs) have been reported to exhibit a variety of biological effects including anti-inflammatory and anti-oxidant activities. The extent of an in vitro glycation reaction mixture of collagen and glycolaldehyde was assayed to investigate the inhibition of glycolaldehye-derived advanced glycation end products (glycol-AGEs) formation with GNPs in collagen, which is a major protein component of the human dermis. GNP-treated collagen showed significantly less glycation (56.3 ± 4.2%) than an untreated glycation control. Moreover, GNP-treated glycation in a collagen lattice model significantly decreased the AGEs distribution in the model system. Taken together, these results suggest that GNPs have the potential for use in the prevention of glycation-induced skin aging.


PifC and Osa, Plasmid Weapons against Rival Conjugative Coupling Proteins.
Bacteria display a variety of mechanisms to control plasmid conjugation. Among them, fertility inhibition (FI) systems prevent conjugation of co-resident plasmids within donor cells. Analysis of the mechanisms of inhibition between conjugative plasmids could provide new alternatives to fight antibiotic resistance dissemination. In this work, inhibition of conjugation of broad host range IncW plasmids was analyzed in the presence of a set of co-resident plasmids. Strong FI systems against plasmid R388 conjugation were found in IncF/MOBF12 as well as in IncI/MOBP12 plasmids, represented by plasmids F and R64, respectively. In both cases, the responsible gene was pifC, known also to be involved in FI of IncP plasmids and Agrobacterium T-DNA transfer to plant cells. It was also discovered that the R388 gene osa, which affects T-DNA transfer, also prevented conjugation of IncP-1/MOBP11 plasmids represented by plasmids RP4 and R751. Conjugation experiments of different mobilizable plasmids, helped by either FI-susceptible or FI-resistant transfer systems, demonstrated that the conjugative component affected by both PifC and Osa was the type IV conjugative coupling protein. In addition, in silico analysis of FI proteins suggests that they represent recent acquisitions of conjugative plasmids, i.e., are not shared by members of the same plasmid species. This implies that FI are rapidly-moving accessory genes, possibly acting on evolutionary fights between plasmids for the colonization of specific hosts.


Patterns of care given migrant workers in Utah by private physicians and clinics.
This comparison of the care given migrant workers in Utah by private physicians with that provided by clinics demonstrates that clinics can provide more services and meet more of their needs. For a population group in need of an organization that can function specifically for them, the clinic offers many advantages. The clinic's role can also be expanded to become a focal point in the community for a comprehensive health care program for the disadvantaged. Although the cost of such a program may exceed the cost of traditional curative care from individual private physicians, the potential gains make it worth attempting. If long-term health is valued above short-term palliation, then the clinic would appear to be the best method of achieving this goal.


Attitude of Saudi Plastic Surgery Residents Toward Pursuing Burn Practice.
Burn injuries comprise the most common accidents worldwide. The delivery of burn care has been adversely affected by the absence of effective burn management and aesthetic services. This study attempts to address the attitude of Saudi residents of plastic surgery toward obtaining a burn fellowship and to examine the factors that might influence their decisions in this regard. An online survey was sent to 39 plastic surgery residents in Saudi Arabia including levels from PGY 1 to 6 in the academic year of 2019. The questionnaire was used to demonstrate interest, knowledge, and major factors influencing or discouraging residents from choosing Burn as a subspecialty in their future career. Residents responded to knowledge questions on a scale of 3 (below average/average/above average). The response rate was 84%. Thirty-three residents completed the questionnaire. The age group was between 30 and 34 years. Only 27% of the respondents expressing interest in burn practice. The main factors that make the plastic surgery resident avoid pursuing burn fellowship were multiple operations sessions, lifestyle, financial outcome, and emotional aspects. On the other hand, the paucity of burn surgeons and being involved in the humanitarian mission were attracting factors. Most of the residents believe that burn must be obligatory and continue to be part of all plastic surgery training programs (100%). In Saudi Arabia, the relative paucity of specialist mentors on plastic surgery programs may limit residents' exposure to subspecialties such as burn during plastic surgery rotational experiences. The findings from this survey may help plastic surgery program directors or burn surgeons, in particular, to find out strategies to attract future trainees.


[Immunochemical study of alpha and beta forms of NAD-kinase from the rabbit liver].
As shown in immunochemical experiments alpha- and beta-forms of NAD-kinase from rabbit liver tissue consisted of oligomers involving subunits with molecular mass of 33,000 and 62,000, respectively. Both oligomers of the alpha-type with Mr 180,000 and 150,000 and of the beta-type with Mr 280,000 precipitated with the antibodies produced against the alpha-enzyme of Mr 180,000. Use of immunosorbents produced after immobilization of the alpha- and beta-forms of NAD-kinase on odiphile enabled to estimate the ratio of antigenic determinants in oligomers of both NAD-kinase forms. Subunit of the enzyme beta-form carried 3-fold more determinants than the subunits of the alpha-form. The isozyme nature of the alpha- and beta-forms of NAD-kinase is discussed.


Multiple viral hepatitis in injection drug users and associated risk factors.
While infections due to hepatitis B virus (HBV) and hepatitis C virus (HCV) have been well-studied in injection drug users (IDUs), hepatitis A virus (HAV) infection and coinfection with multiple hepatitis viruses have received less attention. Hepatitis serology as well as sociodemographic and drug-related parameters were explored in patients (n = 1512) admitted for opiate detoxification. Antibodies to HAV were positive in 57.7%, to HBV in 53.0%, and to HCV in 75.0% of the sample. Lack of any hepatic marker was reported in 11.2%; one marker was positive in 24.7%; two markers were positive in 31.2%; and all markers were positive in 32.9%. In patients with one positive marker, 58.8% had had exposure to HCV, and 27% had exposure to HAV. In patients with two positive markers, 46.7% were HAV/HCV and 41.8% HBV/HCV antibody positive. Presence of HBV and HCV antibodies was associated with older age, longer duration of (i.v.) heroin use, and a higher number of rehabilitation treatment episodes (anova), current coconsumption of cocaine was associated with presence of antibodies to either HAV, HBV, and HCV. Coinfection with hepatic viruses is highly relevant in IDUs, although HAV does not necessarily share the same risk factors relevant for HBV or HCV transmission. The need for outreach vaccination programs is emphasized for HAV and HBV in the target population. Primary prevention should be implemented before initiation or at early stages of a drug career. Epidemiology and transmission of HAV in IDUs requires further research.


Prognostic microRNA/mRNA signature from the integrated analysis of patients with invasive breast cancer.
The optimal management of breast cancer (BC) presents challenges due to the heterogeneous molecular classification of the disease. We performed survival analysis on a cohort of 466 patients with primary invasive ductal carcinoma (IDC), the most frequent type of BC, by integrating mRNA, microRNA (miRNA), and DNA methylation next-generation sequencing data from The Cancer Genome Atlas (TCGA). Expression data from eight other BC cohorts were used for validation. The prognostic value of the resulting miRNA/mRNA signature was compared with that of other prognostic BC signatures. Thirty mRNAs and seven miRNAs were associated with overall survival across different clinical and molecular subclasses of a 466-patient IDC cohort from TCGA. The prognostic RNAs included PIK3CA, one of the two most frequently mutated genes in IDC, and miRNAs such as hsa-miR-328, hsa-miR-484, and hsa-miR-874. The area under the curve of the receiver-operator characteristic for the IDC risk predictor in the TCGA cohort was 0.74 at 60 mo of overall survival (P < 0.001). Most relevant for clinical application, the integrated signature had the highest prognostic value in early stage I and II tumors (receiver-operator characteristic area under the curve = 0.77, P value < 0.001). The genes in the RNA risk predictor had an independent prognostic value compared with the clinical covariates, as shown by multivariate analysis. The integrated RNA signature was successfully validated on eight BC cohorts, comprising a total of 2,399 patients, and it had superior performance for risk stratification with respect to other RNA predictors, including the mRNAs used in MammaPrint and Oncotype DX assays.


Thinking outside the silicon box: molecular and logic as an additional layer of selectivity in singlet oxygen generation for photodynamic therapy.
A simple derivative of a well-known dye bodipy appears to be a satisfactory sensitizer for singlet oxygen. Moreover, the rate of singlet oxygen generation can be modulated by two cancer-related cellular parameters, sodium ion concentration and acidity. Singlet oxygen generation rate is maximal when sodium ions and an organic acid were added. The operation of this molecular automaton follows AND logic, which introduces an additional layer of selectivity in the photodynamic action of the reagent. It should also be noted that in this system sensing, computing and actuating functions are realized within a single molecule.


Is the Effect of Anhedonia on Smoking Cessation Greater for Women Versus Men?
Anhedonia has been recognized as a major risk factor for smoking persistence. Potential gender differences in the effect of anhedonia on smoking cessation have not been studied. Using data from a completed clinical trial of maintenance nicotine patch therapy, we hypothesized that gender would moderate the effect of anhedonia on short-term abstinence, such that anhedonic women would be less likely to achieve abstinence. Participants (N = 525; 50% female, 48.2% Black/African American, average age: 46 years) received 21mg/day nicotine patch and four brief behavior counseling sessions over 8 weeks. Participants were classified at baseline using the Snaith-Hamilton Pleasure Scale as anhedonic (scores > 2) or hedonic (scores ≤ 2). Bioverified 7-day point prevalence abstinence was measured at week 8. Using logistic regression analysis, we tested the interaction of anhedonia by gender predicting abstinence, adjusting for age, race, nicotine dependence, and baseline depressive symptomatology. Seventy participants (13%) were classified as anhedonic. Men were more likely to be anhedonic than women (16.6% vs. 10.2%, p = .03). Contrary to our hypothesis, the interaction of anhedonic status (hedonic vs. anhedonic) by gender was nonsignificant (p = .18). There was a main effect of hedonic capacity, such that anhedonia predicted abstinence, odds ratio = 3.24, 95% confidence interval = 1.39-7.51, p = .006. Both male and female anhedonic smokers were more likely to be abstinent, which contrasts with prior research indicating that anhedonia is a risk factor for difficulty quitting. This unexpected finding may be explained by a possible selective benefit of nicotine patch therapy, which has been observed in some studies to have antidepressant effects. This is the first study to examine whether the association between pretreatment anhedonia and smoking cessation differs by gender. For both women and men, anhedonia was associated with a greater likelihood of abstinence after 8 weeks of treatment with 21mg/day nicotine patch and behavior counseling. Our findings indicate that the association between anhedonia and smoking cessation is not as clear as has been assumed and may depend in part on the type of treatment delivered.


Sex, disease and stigma in South Africa: historical perspectives.
This paper attempts to analyse historically why stigma and denial around HIV/AIDS is so powerful in South Africa, so powerful that ailing family members can be shunned and evicted. For many observers, the answer lies simply in its being a venereal disease, in its connotation with promiscuity and unregulated sexuality. We argue that this is not an adequate explanation. Pre-colonial African societies were relatively open about sexuality. Though pre-marital and adulterous pregnancy certainly caused social disruption, extra-marital sex per se was not stigmatised. Even the sexual shame introduced (unevenly) by Christianity and its hybridised forms is inadequate in explaining the degree of stigma associated with HIV/AIDS. We extend the discussion by exploring the stigma associated with various forms of pollution and the inevitability of death. The peculiarly interwoven mixture of sexual transgression, pollution and delayed death, we argue, makes HIV/AIDS an extraordinarily powerful generator of stigma.


Downregulation of lncRNA H19 inhibits migration and invasion of human osteosarcoma through the NF-κB pathway.
The present study aimed to investigate the role of long non-coding RNA (lncRNA) H19 in the development of osteosarcoma and to determine the underlying mechanism involved. A total of 40 patients with osteosarcoma were selected and the expression level of H19 in tumor tissue and adjacent healthy tissue was detected by reverse transcription‑quantitative polymerase chain reaction. Survival curves were plotted using the Kaplan‑Meier method to investigate the prognostic value of H19 expression level for patients with osteosarcoma. H19 knockdown osteosarcoma cell lines were constructed using small interfering (si)RNA transfection. Cell migration and invasion abilities were measured by Transwell migration and invasion assays, respectively. Western blot analysis was performed to detect the expression levels of phosphatidylinositol 3‑kinase (PI3K), phospho (p)‑PI3K, RAC‑alpha serine/threonine‑protein kinase (AKT), p‑AKT and NF‑κB inhibitor α (IκBα) in osteosarcoma cells transfected with H19 siRNA. Expression level of H19 was significantly elevated in tumor tissue compared with adjacent healthy tissue. Expression level of H19 was positively associated with distant metastasis of osteosarcoma (P<0.01), but not with gender and age. Overall survival of patients with osteosarcoma with high H19 level was significantly shorter compared with patients with low H19 expression (P<0.05). H19 knockdown significantly reduced migration and invasion ability of osteosarcoma cells. Significantly decreased levels of p‑PI3K and p‑AKT, and elevated level of IκBα were observed in H19 knockdown osteosarcoma cells compared with control osteosarcoma cells, while no significant differences in levels of PI3K and AKT were observed. Therefore, the present study demonstrated that knockdown of lncRNA H19 can inhibit migration and invasion of human osteosarcoma cells by inhibiting the nuclear factor-κB pathway.


Wolfram Syndrome 1: From Genetics to Therapy.
Wolfram syndrome 1 (WS1) is a rare neurodegenerative disease transmitted in an autosomal recessive mode. It is characterized by diabetes insipidus (DI), diabetes mellitus (DM), optic atrophy (OA), and sensorineural hearing loss (D) (DIDMOAD). The clinical picture may be complicated by other symptoms, such as urinary tract, endocrinological, psychiatric, and neurological abnormalities. WS1 is caused by mutations in the WFS1 gene located on chromosome 4p16 that encodes a transmembrane protein named wolframin. Many studies have shown that wolframin regulates some mechanisms of ER calcium homeostasis and therefore plays a role in cellular apoptosis. More than 200 mutations are responsible for WS1. However, abnormal phenotypes of WS with or without DM, inherited in an autosomal dominant mode and associated with one or more WFS1 mutations, have been found. Furthermore, recessive Wolfram-like disease without DM has been described. The prognosis of WS1 is poor, and the death occurs prematurely. Although there are no therapies that can slow or stop WS1, a careful clinical monitoring can help patients during the rapid progression of the disease, thus improving their quality of life. In this review, we describe natural history and etiology of WS1 and suggest criteria for a most pertinent approach to the diagnosis and clinical follow up. We also describe the hallmarks of new therapies for WS1.


Quality control of the physical and technical aspects of mammography in the Norwegian breast-screening programme.
The aim of this study was to establish a system for quality control of technical and physical aspects of mammography in the national Norwegian breast-screening programme, and to evaluate test results obtained during the 4-year pilot project period. Quality control (QC) procedures for the X-ray unit, film and processing, cassettes and screens, view boxes, and image quality were described in two QC manuals. Frequent and relatively simple tests were performed by radiographers on-site and results reported semi-annually to an inspection group established at the Norwegian Radiation Protection Authority (NRPA). Tests requiring special equipment were performed prior to start of screening (first status controls), then annually by the NRPA group, which also assembled and analysed the data from the first 4 years. The analyses were done mainly with reference to stated standard or guidance levels and the degree of deviation from such values. Results for tests of i.a. focal spot size, exposure time, radiation output, mean absorbed glandular dose, reference optical density, sensitometry, and AEC performance are presented. The standard of the equipment tested was in general high. Although some deviations from optimal performance were seen throughout the project, the equipment mostly performed well within the stated limiting values.


Urgent needs of caregiving in ageing populations with Alzheimer's disease and other chronic conditions: Support our loved ones.
The ageing process begins at birth. It is a life-long process, and its exact origins are still unknown. Several hypotheses attempt to describe the normal ageing process, including hormonal imbalance, formation of reactive oxygen species, DNA methylation & DNA damage accumulation, loss of proteostasis, epigenetic alterations, mitochondrial dysfunction, senescence, inflammation, and stem cell depletion. With increased lifespan in elderly individuals, the prevalence of age-related diseases including, cancer, diabetes, obesity, hypertension, Alzheimer's, Alzheimer's disease and related dementias, Parkinson's, and other mental illnesses are increased. These increased age-related illnesses, put tremendous pressure & burden on caregivers, family members, and friends who are living with patients with age-related diseases. As medical needs evolve, the caregiver is expected to experience an increase in duties and challenges, which may result in stress on themselves, and impact their own family life. In the current article, we assess the biological mechanisms of ageing and its effect on body systems, exploring lifestyle and ageing, with a specific focus on age-related disorders. We also discussed the history of caregiving and specific challenges faced by caregivers in the presence of multiple comorbidities. We also assessed innovative approaches to funding caregiving, and efforts to improve the medical system to better organize chronic care efforts, while improving the skill and efficiency of both informal and formal caregivers. We also discussed the role of caregiving in end-of-life care. Our critical analysis strongly suggests that there is an urgent need for caregiving in aged populations and support from local, state, and federal agencies.


Isotopic graphene-isolated-Au-nanocrystals with cellular Raman-silent signals for cancer cell pattern recognition.
For cancer diagnosis, technologies must be capable of molecular recognition, and they must possess a built-in pattern recognition component for efficient imaging and discrimination of targeted cancer cells. Surface enhanced Raman scattering (SERS) tags based on plasmonically active nanoparticles hold promise for accurate and efficient cancer cell recognition, owing to ultra-narrow peak and sensitive optical properties. However, a complex fingerprint spectrum increases data analysis difficulty, making it necessary to develop multicolor SERS tags with a simple fingerprint spectrum. To address this, we herein fabricated SERS-encoded nanoparticles (NPs) with stable and simple fingerprint spectrum through synthesis of isotopic cellular Raman-silent graphene-isolated-Au-nanocrystals (GIANs) and conjugation with phospholipid-polyethylene glycol-linked aptamers to target proteins overexpressed on the cancer cell surface. GIANs, which possess the properties of graphitic nanomaterials, such as super-stable optical properties and high Raman cross-section, showed enhanced SERS signals. The 2D-band Raman shift of GIAN, which located in the cellular Raman-silent region, was easily regulated through fabrication of isotopic GIANs without changing their molecular structure. Such GIAN tags demonstrated multiplexed Raman imaging capability, both in vivo and in vitro, with low background interference. Moreover, cell membrane protein (nucleolin, mucin and epithelial cell adhesion molecule)-specific, aptamer-conjugated isotopic GIANs were fabricated and feasibly applied to built-in coding for rapid imaging and pattern recognition of targeted cancer cells. Such isotopic GIAN-aptamer-encoders show high potential for efficient cancer cell identification and diagnosis.


Clinical, geographical, and temporal risk factors associated with presentation and outcome of vivax malaria imported into the United Kingdom over 27 years: observational study.
To examine temporal and geographical trends, risk factors, and seasonality of imported vivax malaria in the United Kingdom to inform clinical advice and policy. Observational study. National surveillance data from the UK Public Health England Malaria Reference Laboratory, data from the International Passenger Survey, and international climactic data. All confirmed and notified cases of malaria in the UK (n=50,187) from 1987 to 2013, focusing on 12,769 cases of vivax malaria. Mortality, sociodemographic details (age, UK region, country of birth and residence, and purpose of travel), destination, and latency (time between arrival in the UK and onset of symptoms). Of the malaria cases notified, 25.4% (n=12,769) were due to Plasmodium vivax, of which 78.6% were imported from India and Pakistan. Most affected patients (53.5%) had travelled to visit friends and relatives, and 11.1% occurred in tourists. Imported P vivax is concentrated in areas with large communities of south Asian heritage. Overall mortality was 7/12,725 (0.05%), but with no deaths in 9927 patients aged under 50 years. Restricting the analysis to those aged more than 50 years, mortality was 7/2798 (0.25%), increasing to 4/526 (0.76%) (adjusted odds ratio 32.0, 95% confidence interval 7.1 to 144.0, P<0.001) in those aged 70 years or older. Annual notifications decreased sharply over the period, while traveller numbers between the UK and South Asia increased. The risk of acquiring P vivax from South Asia was year round but was twice as high from June to September (40 per 100,000 trips) compared with the rest of the year. There was strong seasonality in the latency from arrival in the UK to presentation, significantly longer in those arriving in the UK from South Asia from October to March (median 143 days) versus those arriving from April to September (37 days, P<0.001). Travellers visiting friends and family in India and Pakistan are most at risk of acquiring P vivax, and older patients (especially those >70 years) are most at risk of dying; these groups should be targeted for advice before travelling. The risk of acquiring vivax malaria is year round but higher during summer monsoons, masked by latency. The latency of time to clinical presentation of imported vivax malaria in the UK is highly seasonal; seasonal latency has implications for pretravel advice but also for the control of malaria in India and Pakistan. A reduced incidence of vivax malaria in travellers may mean further areas of South Asia can be considered not to need malaria chemoprophylaxis.


Empagliflozin reduces podocyte lipotoxicity in experimental Alport syndrome.
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are anti-hyperglycemic agents that prevent glucose reabsorption in proximal tubular cells. SGLT2i improves renal outcomes in both diabetic and non-diabetic patients, indicating it may have beneficial effects beyond glycemic control. Here, we demonstrate that SGLT2i affects energy metabolism and podocyte lipotoxicity in experimental Alport syndrome (AS). In vitro, we found that the SGLT2 protein was expressed in human and mouse podocytes to a similar extent in tubular cells. Newly established immortalized podocytes from Col4a3 knockout mice (AS podocytes) accumulate lipid droplets along with increased apoptosis when compared to wild-type podocytes. Treatment with SGLT2i empagliflozin reduces lipid droplet accumulation and apoptosis in AS podocytes. Empagliflozin inhibits the utilization of glucose/pyruvate as a metabolic substrate in AS podocytes but not in AS tubular cells. In vivo, we demonstrate that empagliflozin reduces albuminuria and prolongs the survival of AS mice. Empagliflozin-treated AS mice show decreased serum blood urea nitrogen and creatinine levels in association with reduced triglyceride and cholesterol ester content in kidney cortices when compared to AS mice. Lipid accumulation in kidney cortices correlates with a decline in renal function. In summary, empagliflozin reduces podocyte lipotoxicity and improves kidney function in experimental AS in association with the energy substrates switch from glucose to fatty acids in podocytes.


Septic arthritis and osteomyelitis due to the chromoblastomycosis agent Fonsecaea pedrosoi.
Fonsecaea pedrosoi is the most common agent of chromoblastomycosis, a chronic localized fungal infection of the skin and subcutaneous tissues mainly involving the lower extremities. We report a rare case of septic arthritis and osteomyelitis due to the chromoblastomycosis agent F pedrosoi, which was successfully treated with arthrotomy and debridement, followed by a long course of oral antifungal therapy. To our knowledge, this is the second case of F pedrosoi osteomyelitis treated successfully to be ever reported.


Relaxant effects and durations of action of formoterol and salmeterol on the isolated human bronchus.
The objective of this study was to evaluate the potency and efficacy (intrinsic activity) of formoterol and salmeterol and their duration of action in comparison with other beta-adrenoceptor agonists in isolated human bronchi. Human bronchi were obtained at thoracotomy from patients with lung cancer. Potency (-log of the concentration of drug inducing 50% of maximal relaxation (-log EC50)) and efficacy (maximal effect (Emax), % of response to theophylline 3 x 10(-3) mol.l-1) were determined by analysis of cumulative isometric concentration-response curves to beta 2-adrenoceptor agonists in bronchial rings at resting tone or contracted maximally with acetylcholine 10(-3) mol.l-1 to induce functional antagonism. The onset and duration of action of beta-adrenoceptor agonists were measured by assessing the relaxant activity of drugs on the basal tone of isolated bronchi. In terms of potency, the rank order of the substances studied was formoterol > fenoterol > or = salmeterol > or = isoprenaline > or = salbutamol > or = adrenaline > or = terbutaline. Formoterol was 150-200 times more potent than isoprenaline. On preparations contracted with acetylcholine 10(-3) mol.l-1 the intrinsic activity (IA) of salbutamol, terbutaline and salmeterol compared with that of isoprenaline ranged 0.62-0.66. Intrinsic activity was higher with formoterol (0.84) and fenoterol (0.75). The onset of action of formoterol (2.14 +/- 0.55 min, n = 11) was not significantly different from that of salbutamol (1.90 +/- 0.24 min, n = 8) but shorter than that of salmeterol (6.40 +/- 1.40 min, n = 10).(ABSTRACT TRUNCATED AT 250 WORDS)


Physiologically based pharmacokinetic modeling for sequential metabolism: effect of CYP2C19 genetic polymorphism on clopidogrel and clopidogrel active metabolite pharmacokinetics.
Clopidogrel is a prodrug that needs to be converted to its active metabolite (clopi-H4) in two sequential cytochrome P450 (P450)-dependent steps. In the present study, a dynamic physiologically based pharmacokinetic (PBPK) model was developed in Simcyp for clopidogrel and clopi-H4 using a specific sequential metabolite module in four populations with phenotypically different CYP2C19 activity (poor, intermediate, extensive, and ultrarapid metabolizers) receiving a loading dose of 300 mg followed by a maintenance dose of 75 mg. This model was validated using several approaches. First, a comparison of predicted-to-observed area under the curve (AUC)0-24 obtained from a randomized crossover study conducted in four balanced CYP2C19-phenotype metabolizer groups was performed using a visual predictive check method. Second, the interindividual and intertrial variability (on the basis of AUC0-24 comparisons) between the predicted trials and the observed trial of individuals, for each phenotypic group, were compared. Finally, a further validation, on the basis of drug-drug-interaction prediction, was performed by comparing observed values of clopidogrel and clopi-H4 with or without dronedarone (moderate CYP3A4 inhibitor) coadministration using a previously developed and validated physiologically based PBPK dronedarone model. The PBPK model was well validated for both clopidogrel and its active metabolite clopi-H4, in each CYP2C19-phenotypic group, whatever the treatment period (300-mg loading dose and 75-mg last maintenance dose). This is the first study proposing a full dynamic PBPK model able to accurately predict simultaneously the pharmacokinetics of the parent drug and of its primary and secondary metabolites in populations with genetically different activity for a metabolizing enzyme.


Alopecia mucinosa responding to antileprosy treatment: are we missing something?
Three cases with single lesion of Alopecia mucinosa (follicular mucinosis) were treated with antileprosy treatment and showed rapid and complete resolution of the lesions with no recurrence on extended follow-up. Two children, a boy aged 14 years and a girl aged 12 years presented themselves, each, with a single hypopigmented, hypoesthetic patch on the face. Clinically leprosy was suspected, however, skin biopsy from both patients revealed follicular mucinosis as the only pathological finding, without any granulomas. Based on clinical suspicion both were started on multi drug therapy (MDT) for leprosy with complete resolution of the lesions. The third case, male, aged 22 years presented with a single erythematous, hypoesthetic plaque on the forehead. This lesion had been diagnosed as follicular mucinosis with folliculo-tropic mycosis fungoides, in the USA. He too responded completely within 3 months with rifampicin, ofloxacin, minocycline (ROM) treatment, which was given once monthly for a total of 6 months and remains free of disease since the past 1 year. Follicular mucinosis as the only pathology may be seen in facial lesions of clinically suspected leprosy in children and young adults. Based on histological findings these cannot be diagnosed as leprosy and will be considered as Alopecia mucinosa. These lesions, however, are always single and show rapid and complete response to antileprosy treatment. The authors suggest that in regions endemic for leprosy, such as India, single lesion Alopecia mucinosa on the face in children and young adults should be given antileprosy treatment.


Spectrograph based on a single diffractive element for real-time measurement of circular dichroism.
In this study, a novel and simple diffractive spectrographic method for real-time measurements of circular dichroism (CD) is considered from a theoretical and experimental approach. A demonstrator prototype of the CD spectrograph has been developed and its performance has been compared with a commercial phase-modulation CD spectrometer. The main element of the device is a polarization holographic grating, recorded in a thin photosensitive organic film, by two interfering opposite circularly polarized beams. A peculiarity of this grating is that the amplitude of the +1 (-1) order of diffraction is proportional to the right (left) circular polarization component of the incoming beam. Here we demonstrate that the CD spectrum of a specimen can be easily evaluated from the intensities of the diffracted beams. A white light beam passing through the specimen is diffracted from the grating and the intensities of the +/-1 orders of diffraction are measured. Due to the spectral selectivity of the grating, the CD at each wavelength can be evaluated at the same time using two linear array detectors.


Invasion Dynamics of Teratogenic Infections in Light of Rubella Control: Implications for Zika Virus.
The greatest burden for a subset of pathogens is associated with infection during pregnancy. Evidence for teratogenic effects of Zika Virus have highlighted the importance of understanding the epidemiology of such pathogens. Rubella is perhaps the most classic example, and there is much to be learned from the long history of modelling associated with this virus. We extended an existing framework for modeling age-specific dynamics of rubella to illustrate how the body of knowledge of rubella dynamics informs the dynamics of teratogenic infections more broadly, and particularly the impact of control on such infections in different transmission settings. During invasion, the burden in women of childbearing age is expected to peak, but then fall to low levels before eventually levelling out. Importantly, as illustrated by rubella dynamics, there is potential for a paradoxical effect, where inadequate control efforts can increase the burden. Drawing on the existing body of work on rubella dynamics highlights key knowledge gaps for understanding the risks associated with Zika Virus. The magnitude and impacts of sterilizing immunity, plus antigenic maps measuring cross-protection with other flaviviruses, and the magnitude of transmission, as well as likely impact of control efforts on transmission are likely to be key variables for robust inference into the outcome of management efforts for Zika Virus.


Computer simulation of human motion in sports biomechanics.
This chapter has covered some important aspects of the computer simulation of human motion in sports biomechanics. First the definition and the advantages and limitations of computer simulation were discussed; second, research on various sporting activities were reviewed. These activities included basic movements, aquatic sports, track and field athletics, winter sports, gymnastics, and striking sports. This list was not exhaustive and certain material has, of necessity, been omitted. However, it was felt that a sufficiently broad and interesting range of activities was chosen to illustrate both the advantages and the pitfalls of simulation. It is almost a decade since Miller [53] wrote a review chapter similar to this one. One might be tempted to say that things have changed radically since then--that computer simulation is now a widely accepted and readily applied research tool in sports biomechanics. This is simply not true, however. Biomechanics researchers still tend to emphasize the descriptive type of study, often unfortunately, when a little theoretical explanation would have been more helpful [29]. What will the next decade bring? Of one thing we can be certain: The power of computers, particularly the readily accessible and portable microcomputer, will expand beyond all recognition. The memory and storage capacities will increase dramatically on the hardware side, and on the software side the trend will be toward "user-friendliness." It is likely that a number of software simulation packages designed specifically for studying human motion [31, 96] will be extensively tested and could gain wide acceptance in the biomechanics research community. Nevertheless, a familiarity with Newtonian and Lagrangian mechanics, optimization theory, and computers in general, as well as practical biomechanical insight, will still be a prerequisite for successful simulation models of human motion. Above all, the biomechanics researcher will still have to bear in mind that his or her model is merely a simplified representation of the real-world system and, as such, has certain limitations. In conclusion, it is evident that the path we have followed has been an interesting and varied one. The way ahead looks equally interesting and diverse, and we can certainly look forward with confidence to the exciting challenges and benefits that computer simulation of human motion will bring.


The Insulin Receptor Is Colocalized With the TRPV1 Nociceptive Ion Channel and Neuropeptides in Pancreatic Spinal and Vagal Primary Sensory Neurons.
Recent observations demonstrated the expression of the insulin receptor (InsR) and its functional interaction with the transient receptor potential vanilloid type 1 receptor (TRPV1) in sensory ganglion neurons. Because sensory nerves are implicated in pancreatic inflammatory processes, we studied the colocalization of the InsR with TRPV1 and proinflammatory neuropeptides in spinal and vagal pancreatic afferent neurons. Immunohistochemistry and quantitative morphometry were used to analyze the expression of TRPV1, InsR, substance P (SP), and calcitonin gene-related peptide (CGRP) in retrogradely labeled pancreatic dorsal root ganglion (DRG) and nodose ganglion (NG) neurons. The proportions of retrogradely labeled pancreatic TRPV1-, InsR-, SP-, and CGRP-immunoreactive neurons amounted to 68%, 48%, 33%, and 54% in DRGs and 64%, 49%, 40%, and 25% in the NGs. Of the labeled DRG and NG neurons, 23% and 35% showed both TRPV1 and InsR immunoreactivity. Colocalization of the InsR with SP or CGRP was demonstrated in 14% and 28% of pancreatic DRG and 24% and 8% of pancreatic NG neurons. The present findings provide morphological basis for possible functional interactions among the nociceptive ion channel TRPV1, the InsR, and the proinflammatory neuropeptides SP and CGRP expressed by pancreatic DRG and NG neurons.


Nanoparticles meet cell membranes: probing nonspecific interactions using model membranes.
Nanotoxicity studies have shown that both carbon-based and inorganic engineered nanoparticles can be toxic to microorganisms. Although the pathways for cytotoxicity are diverse and dependent upon the nature of the engineered nanoparticle and the chemical environment, numerous studies have provided evidence that direct contact between nanoparticles and bacterial cell membranes is necessary for cell inactivation or damage, and may in fact be a primary mechanism for cytotoxicity. The propensities for nanoparticles to attach to and disrupt cell membranes are still not well understood due to the heterogeneous and dynamic nature of biological membranes. Model biological membranes can be employed for systematic investigations of nanoparticle-membrane interactions. In this article, current and emerging experimental approaches to identify the key parameters that control the attachment of ENPs on model membranes and the disruption of membranes by ENPs will be discussed. This critical information will help enable the "safe-by-design" production of engineered nanoparticles that are nontoxic or biocompatible, and also allow for the design of antimicrobial nanoparticles for environmental and biomedical applications.


Human spleen cell generation of factors stimulating human pluripotent stem cell, erythroid, and myeloid progenitor cell growth.
Mitogen-stimulated murine spleen cells produce humoral substances capable of supporting murine hematopoiesis and pluripotent stem cell proliferation in vitro. Thus, we evaluated conditioned media generated by human spleen cells (SCM) in the presence or absence of mitogens for factors stimulatory for human pluripotent (CFU-GEMM), erythroid (BFU-E), and myeloid (CFU-GM) precursors. Two and one half percent to 10% SCM stimulated proliferation of all three types of precursor cells from nonadherent buoyant human marrow target cells. Mitogen-stimulated SCM augmented CFU-GM (175% to 225%), whereas CFU-GEMM and BFU-E growth was essentially unchanged. Cell separation procedures used to determine which cells provided these microenvironmental stimuli indicated that nonadherent mononuclear spleen cells provided the bulk of the CSF-GM, whereas adherent cells (95% nonspecific esterase + monocyte-macrophages) and nonadherent cells provided similar proportions of CSF-mix and erythroid burst-promoting activity (BPA). The nonadherent cells generating high levels of CSF-mix, BPA, and CSF-GM were predominantly Leu-1-negative, ie, non-T, cells. In the presence or absence of mitogens, SCM was a more potent source (1.3- to 3.8-fold) than peripheral leukocyte CM of the growth factors for the three progenitor cell types. Specific in situ cytochemical stains for analyzing morphology of myeloid colonies demonstrated that SCM stimulated the proliferation of the same types and proportions of colonies as human placental CM, suggesting that these CMs may contain similar CSF-GMs. These data show the contribution of spleen cell subsets to the generation of hematopoietic growth factors and the responsiveness of these cells to various mitogenic stimuli.


Changes in Anthropometric Measures, Nutritional Indices and Gastrointestinal Symptoms Following One Anastomosis Gastric Bypass (OAGB) Compared with Roux-en-y Gastric Bypass (RYGB).
Bariatric surgery is an effective treatment for obesity with new procedures emerging. However, despite comparable weight loss and improvements in metabolic outcomes, research on nutritional and gastrointestinal symptoms remains limited. Here we compare clinical data on weight, nutritional disorders and gastrointestinal symptoms of patients before and following one anastomosis gastric bypass (OAGB) and Roux-en-Y gastric Bypass (RYGB). In this retrospective study, data on anthropometry, nutritional indices, dietary intake and gastrointestinal symptoms were retrieved in cohorts of patients up to 2 years following OAGB and RYGB. Seventy-three patients had either a RYGB (28) or an OAGB (45), with 71% seeking these as a revisional procedure. Significant and higher weight loss was observed in the OAGB cohort at 1 year (%TWL 33.0 ± 8.5 vs. 26.6 ± 12.4), albeit comparable at 2 years postoperatively (%TWL 29.0 ± 11.1 vs. 34.1 ± 11.2). Disorders such as vitamin D, active B12, folate, homocystein (Hcy) and hyperparathyroidism were present following both surgeries. Levels of vitamin D, ferritin and total protein significantly worsened over time. Gastrointestinal symptoms of diarrhoea, steatorrhoea and reflux were higher in the OAGB cohort while the RYGB cohort reported more dumping syndrome (DS). Significant and similar weight loss results are seen following both OAGB and RYGB. Nutritional disorders were common in both cohorts and increased over time. However, the OAGB patients reported more gastrointestinal side effects, which may contribute to poor quality of life and nutritional consequences. Prospective and longer-term studies investigating the nutritional and gastrointestinal health of patients undergoing OAGB is recommended.


Vitamin B12 inhibits α-synuclein fibrillogenesis and protects against amyloid-induced cytotoxicity.
Vitamin B12 (VB12) is a necessary micronutrient for growth and the development of the nervous system. Severe deficiencies of VB12 have been linked to damage of learning and memory ability and cognitive decline, along with several neurological diseases. Misfolding and aggregation of α-synuclein (αSN) into insoluble fibrils is associated with the onset and progression of Parkinson's disease (PD), which affects tens of millions of elderly patients all over the world. Developing novel inhibitors to obstruct the aggregation of αSN has become a topic of intense research. In this study, the inhibitory effect of VB12 against the fibrillogenesis and cytotoxicity of αSN was systematically analyzed using thioflavin T (ThT) fluorescence, atomic force microscopy (AFM), circular dichroism (CD) spectroscopy and cytotoxicity assays. Both ThT and AFM results showed that VB12 could inhibit αSN fibrillogenesis in a dose-dependent manner. CD data suggested that VB12 delays the conformational conversion of αSN to β-sheet rich structures, especially to the parallel β-sheet conformation. As a result, VB12 greatly alleviated the cytotoxicity of αSN aggregates. Moreover, VB12 was also found to disassemble preexisting mature αSN fibrils and attenuate the consequent cytotoxicity. These findings not only provide a comprehensive understanding of the inhibitory effect of VB12 on αSN fibrillogenesis, but also identify a valuable nutrient source that possesses great potential to be developed as a new functional food ingredient to help alleviate PD.


Prophylactic mesh use during primary stoma formation to prevent parastomal hernia.
Introduction Parastomal hernia (PSH) is a common problem following stoma formation. The optimal technique for stoma formation is unknown although recent studies have focused on whether placement of prophylactic mesh at stoma formation can reduce PSH rates. The aim of this study was to systematically review use of prophylactic mesh versus no mesh with regard to occurrence of PSH and peristomal complications. Methods A systematic search was performed using PubMed, Embase™ and the Cochrane Library to identify randomised controlled trials that analysed placement of prophylactic mesh versus no mesh at time of initial surgery. Meta-analysis was performed using random effects methods. Results A total of 506 studies were identified by our search strategy. Of these, 8 studies were included, involving 430 patients (217 mesh vs 213 no mesh). Prophylactic mesh placement resulted in a significantly lower rate of PSH formation (42/217 [19.4%] vs 92/213 [43.2%]) with a combined risk ratio of 0.40 (95% confidence interval [CI]: 0.21-0.75, p=0.004). Placement of prophylactic mesh did not result in increased peristomal complications (15/218 [6.9%] vs 16/227 [7.0%]) with a combined risk ratio of 1.0 (95% CI: 0.49-2.01, p=0.990). Conclusions Prophylactic placement of mesh at primary stoma formation may reduce the incidence of PSH, without an increase in peristomal complications. However, the overall quality of the randomised controlled trials included in the meta-analysis was poor, and should prompt caution regarding the applicability of the findings of the individual studies and the meta-analysis to everyday practice.


Beta 3-adrenergic receptors are responsible for the adrenergic inhibition of insulin-stimulated glucose transport in rat adipocytes.
The inhibition of insulin-stimulated glucose transport by isoprenaline, a mixed beta-adrenergic-receptor (AR) agonist, is well documented in rat adipocytes. Since it has been described that rat adipocytes possess not only beta 1- and beta 2- but also beta 3-ARs, the influence of various subtype-selective beta-AR agonists and antagonists on 2-deoxyglucose (2-DG) transport was assessed in order to characterize the beta-AR subtype involved in the adrenergic counter-regulation of the insulin effect. The stimulation of 2-DG transport by insulin was counteracted, in a dose-dependent manner, by all the beta-AR agonists tested, and the magnitude of the inhibition followed the rank order: BRL 37344 > isoprenaline = noradrenaline >> dobutamine = procaterol. The same rank order of potency was obtained for lipolysis activation. This is not in accordance with the pharmacological definition of a beta 1- or a beta 2-adrenergic effect, but agrees with the pharmacological pattern of a beta 3-adrenergic effect. The inhibitory effect of the beta 3-agonist BRL 37344 on insulin-stimulated 2-DG transport was not reversed by either the selective beta 1-antagonist ICI 89406 or the beta 2-antagonist ICI 118551. In addition, neither of these beta-antagonists was able to block the isoprenaline and noradrenaline effects, supporting major beta 3-adrenoceptor-subtype involvement in the adrenergic inhibition of insulin-stimulated 2-DG transport. Like isoprenaline, BRL 37344 inhibited (60% inhibition) insulin-stimulated glucose transport only when adenosine deaminase was present in the assay. Furthermore, the maximal inhibitory effects of isoprenaline and BRL 37344 were not additive, and were both dependent on albumin concentration in the incubation medium: they increased when the albumin concentration decreased in the medium from 3.5 to 1%. To conclude, the similarities between isoprenaline and BRL 37344 action on insulin-stimulated 2-DG transport, the poor efficacy of the beta 1-/beta 2-agonists and the lack of effect of selective beta 1- and beta 2-antagonists are compelling arguments to support the important role of beta 3-adrenoceptors in the adrenergic inhibition of glucose transport in rat adipocytes.


A negative feedback role for the ovaries of the mare on tonic LH secretion before the first ovulation of the breeding season.
Eleven anoestrous mares were assigned randomly to Group A (intact, n = 6) or Group B (ovariectomized in January, n = 5). Jugular blood samples were collected during February to April. Ovarian activity was assessed by ultrasound and ovulation was confirmed by progesterone analysis. Intact mares ovulated between 2 and 28 April. Mean diameter of the largest follicle was less than 20 mm on 17 or 18 March (Period 3), but increased to 29 mm by 31 March or 1 April (Period 4). During Periods 1 and 2 (14 or 15 February and 3 or 4 March) mean luteinizing hormone (LH) concentrations were similar in both groups. In intact mares, circulating concentrations remained low during Periods 3 and 4. In contrast, in ovariectomized mares concentrations tended to increase during Period 3, and were significantly increased by Period 4, at which time concentrations were significantly (P less than 0.05) greater in ovariectomized as opposed to intact mares. Increased concentrations of LH in ovariectomized mares during Periods 3 and 4 were associated with well defined pulsatile profiles. In contrast, pulses in intact mares remained infrequent and low in amplitude during the same time periods. The absence of LH pulses in intact mares during Periods 3 and 4 may reflect a low pulse frequency or a decrease in amplitude such that pulses escape detection. These results support the hypothesis that in intact mares, low circulating concentrations of LH during the transition into the breeding season, in part, may reflect inhibition by a factor of ovarian origin. It remains to be determined whether this apparent inhibition of LH secretion undergoes a seasonal modification in effectiveness and plays a role in regulating the annual breeding cycle of the mare.


The case for ostectomy--a time-tested therapeutic modality in selected periodontitis sites.
Although ostectomy has been proven in numerous studies to be an effective means of reducing pocket depth, some clinicians still question its merits. To determine the efficacy of ostectomy for the treatment of periodontitis, 870 pairs of presurgical and postsurgical radiographs of sites treated by ostectomy were examined. The postsurgical radiographs, taken 5 to 30 years postoperatively, revealed distinct lamina dura and demonstrated that ostectomy is an effective and predictable technique for intercepting the progressive loss of attachment in selected sites with periodontitis.


Guillain-barré syndrome during active brucellosis.
It has been reported that approximately two thirds of patients diagnosed with Guillain-Barré syndrome (GBS) have had a prodromal illness within a four-week period preceding the onset of GBS. This prodromal illness is most commonly an upper respiratory tract illness or, secondly, gastroenteritis. However, specific infectious agents, such as mycoplasma, cytomegalovirus, Ebstein-Barr virus, vaccinia, variola, campylobacter, varicella-zoster, measles, mumps, hepatitis A and B viruses, rubella, influenza A and B viruses, coxackie and echoviruses, have also been reported to be certain or probable etiologic antecedent agents of GBS. In contrast, GBS during active brucellosis has rarely been reported. This article presents the case of a 28 year-old male patient with GBS during active brucellosis who responded fully to treatment directed to brucellosis. and it is stressed that brucellosis should be considered as a probable etiologic agent in patients with GBS who live in areas where brucellosis is endemic.


Posttraumatic lymphocyte response: a comparison between peripheral blood T cells and tissue T cells.
T-cell response to trauma has been assessed primarily by sampling peripheral blood lymphocytes. We hypothesized that lymphocytes residing in tissue and traveling through lymph vessels are more likely to be activated by tissue injury and hemorrhage-induced hypoperfusion. We compared peripheral blood T-cell response with tissue or lymph T-cell response in an ovine model of multiple injury. Anesthetized adult sheep instrumented with a chronic prefemoral lymph fistula were subjected to lower-extremity fractures, fixed-volume hemorrhage, resuscitation, and fracture stabilization. Peripheral blood and tissue T-cell receptor expression was determined at baseline and after injury. At baseline, we found significant differences in the expression of CD4, CD8, and L selectin between peripheral blood T cells and tissue T cells. After trauma, the percentage of tissue T cells expressing CD8 decreased from 19 +/- 9 to 14 +/- 5 (p < 0.05) and the percentage expressing gammadelta-TcR receptors decreased from 12 +/- 4 to 7 +/- 2 (p < 0.05). T-cell phenotype composition in peripheral blood was not affected by trauma. Peripheral blood T-cell composition differs from tissue T-cell composition before and after trauma. Trauma produced changes in tissue T-cell phenotypes but not in peripheral blood T-cell phenotypes.


Calcium alendronate-coated composite scaffolds promote osteogenesis of ADSCs via integrin and FAK/ERK signalling pathways.
Bioceramic-biopolymer composites have been used extensively as bone tissue engineering scaffolds due to their bioactive properties. However, composite scaffolds are insufficient in inducing osteogenic differentiation of stem cells. In this study, a strategy for the local delivery of bioactive factors by coating calcium alendronate (ALC) on the surface of composite scaffolds was systematically evaluated for the first time. The coated ALC not only displayed excellent cytocompatibility and cell adhesion properties but also resulted in the significant upregulation of osteogenic related gene expression, osteogenic related protein levels, alkaline phosphatase (ALP) activity and calcium deposition of ADSCs. Furthermore, our results suggested that the molecular mechanism of ADSC osteogenic differentiation induced by the constructed ALC may be related to the integrin binding and the activation of FAK/ERK signalling pathways. These findings suggested that ALC-coated composite scaffolds can serve as bone tissue engineering scaffolds, providing a simple and universal method to improve the osteogenic differentiation of ADSCs by calcium phosphate-containing composite materials.


Intravoxel incoherent motion (IVIM) imaging in human achilles tendon.
Limited microcirculation has been implicated in Achilles tendinopathy and may affect healing and disease progression. Existing invasive and noninvasive approaches to evaluate tendon microcirculation lack sensitivity and spatial coverage. To develop a novel Achilles tendon intravoxel incoherent motion (IVIM) MRI protocol to overcome the limitations from low tendon T2 /T2 * value and low intratendinous blood volume and blood velocity to evaluate tendon microcirculation. Prospective. Sixteen healthy male participants (age 31.0 ± 2.1) were recruited. A stimulated echo readout-segmented echo planar imaging (ste-RS-EPI) IVIM sequence at 3.0T. The feasibility of the proposed ste-RS-EPI IVIM protocol combined with Achilles tendon magic angle effect was evaluated. The sensitivity of the protocol was assessed by an exercise-induced intratendinous hemodynamic response in healthy participants. The vascular origin of the observed IVIM signal was validated by varying the diffusion mixing time and echo time. Two-tailed t-tests were used to evaluate differences (P < 0.05 was considered significant). Consistent with known tendon hypovascularity, the midportion Achilles tendon at baseline showed significantly lower IVIM-derived perfusion fraction (fp ) (3.1 ± 0.9%) compared to the proximal and distal Achilles tendon (6.0 ± 1.8% and 6.1 ± 2.0%, respectively; P < 0.01). Similarly, the midportion Achilles tendon exhibited significantly lower baseline blood flow index (D*×fp ) (40.9 ± 19.2, 18.3 ± 5.3, and 32.0 ± 9.4 in proximal, midportion, and distal Achilles tendon, respectively; P < 0.01). Eccentric heel-raise exercise led to ∼2 times increase of Achilles tendon blood flow in healthy participants. Consistent with its vascular origin, the estimated fp demonstrated a high dependency to IVIM protocol parameters, while the T1 /T2 -corrected absolute intratendinous microvascular blood volume fraction (Vb ) did not vary. Achilles tendon ste-RS-EPI IVIM noninvasively assessed baseline values and exercise-induced changes to tendon microcirculation in healthy tendon. 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;48:1690-1699.


Molecular Investigation of Francisella-Like Endosymbiont in Ticks and Francisella tularensis in Ixodid Ticks and Mosquitoes in Turkey.
This study was carried out to investigate the molecular prevalence of Francisella-like endosymbionts (FLEs) and Francisella tularensis in ticks (Acari: Ixodidae) and mosquitoes in Turkey. Genomic DNA pools were constructed from a total of 1477 adult hard ticks of Rhipicephalus (Rh.) annulatus, Rh. turanicus, Rh. sanguineus, Rh. bursa, Haemaphysalis (Hae.) parva, Hae. sulcata, Hyalomma marginatum marginatum, H. anatolicum anatolicum, H. anatolicum excavatum, H. detritum detritum, H. dromedarii, Dermacentor marginatus, and Ixodes ricinus species, which were collected from several barns, cattle, and people. Genomic DNA was also extracted from pools consisting of 6203 adult female mosquito species belonging to Aedes vexans, Culex (Cx.) pipiens, Cx. hortensis, Cx. theileri, Culiseta annulata, and Anopheles maculipennis species. Conventional PCR and TaqMan probe-based real- time PCR targeting the 16S rRNA gene for FLEs and the lpnA gene for F. tularensis, respectively, were performed on the DNA isolates obtained. FLEs and F. tularensis were not found in any genomic DNA pools constructed from ixodid ticks and mosquitos. This study represents the first investigation of F. tularensis and FLEs in potential vector ticks and mosquitoes by molecular methods in Turkey. The present study provides useful insights into the molecular epidemiology of F. tularensis and FLEs. One of the major conclusions of the study is that tularemia outbreaks may be essentially due to direct transmission from the environment (especially from water) in Turkey and not to vector-borne transmission.


The selective value of alleles underlying polygenic traits.
To define the genetic and ecological circumstances that are conducive to evolution via genetic drift at the allelic level, the selection coefficient for a constituent allele of arbitrary effect is derived for a polygenic character exposed to stabilizing selection. Under virtually all possible conditions, alleles within the class for which the absolute value of the average effect is less than 10(-2) phenotypic standard deviations are neutral with respect to each other. In addition, when the mean phenotype is at the optimum and the genetic variance is in selection-drift-mutation equilibrium, a considerable amount of neutral evolution is expected in the class of alleles with intermediate effects on the phenotype. These results help clarify how molecular evolution via genetic drift may occur at a locus despite intense selection and provide a potential mechanistic explanation for the neutral theory of molecular evolution.


Tetrodotoxin-bupivacaine-epinephrine combinations for prolonged local anesthesia.
Currently available local anesthetics have analgesic durations in humans generally less than 12 hours. Prolonged-duration local anesthetics will be useful for postoperative analgesia. Previous studies showed that in rats, combinations of tetrodotoxin (TTX) with bupivacaine had supra-additive effects on sciatic block durations. In those studies, epinephrine combined with TTX prolonged blocks more than 10-fold, while reducing systemic toxicity. TTX, formulated as Tectin, is in phase III clinical trials as an injectable systemic analgesic for chronic cancer pain. Here, we examine dose-duration relationships and sciatic nerve histology following local nerve blocks with combinations of Tectin with bupivacaine 0.25% (2.5 mg/mL) solutions, with or without epinephrine 5 µg/mL (1:200,000) in rats. Percutaneous sciatic blockade was performed in Sprague-Dawley rats, and intensity and duration of sensory blockade was tested blindly with different Tectin-bupivacaine-epinephrine combinations. Between-group comparisons were analyzed using ANOVA and post-hoc Sidak tests. Nerves were examined blindly for signs of injury. Blocks containing bupivacaine 0.25% with Tectin 10 µM and epinephrine 5 µg/mL were prolonged by roughly 3-fold compared to blocks with bupivacaine 0.25% plain (P < 0.001) or bupivacaine 0.25% with epinephrine 5 µg/mL (P < 0.001). Nerve histology was benign for all groups. Combinations of Tectin in bupivacaine 0.25% with epinephrine 5 µg/mL appear promising for prolonged duration of local anesthesia.


Exploring the effect of Colorado's recreational marijuana policy on opioid overdose rates.
Opioid overdose death rates have continued to spike exponentially from the start of the 21st century, creating what is known to be one of the worst public health crises in the United States. Simultaneously, as more states began passing medical cannabis laws (MCLs), the idea that marijuana was the solution to the opioid crisis began to spread nationwide. As some states have maintained strict medical marijuana policies, others-such as Colorado-have expanded their statutes to allow recreational marijuana sales within their state. Researchers have been able to provide sense of the public health implications resulting from MCLs, but little is known about the effects of this marijuana policy expansion. This preliminary study will focus on exploring the statewide effects of Colorado's recreational marijuana policy on the state's opioid overdose death rates. Because Colorado has existing panel data for opioid overdose death rates, we can use statistical software to define and create an optimal control group to adequately resemble Colorado's outcome variable of interest. This process known as the synthetic control method can provide a valid counterfactual for Colorado's opioid overdose outcomes in the absence of this policy-a Colorado that did not expand marijuana policy to the point recreational dispensaries were established. Opioid overdose death rate data from the Centers for Disease Control and Prevention's Wide-ranging Online Data for Epidemiologic Research (WONDER) will be used to construct a synthetic control unit composed of a donor pool of states resembling Colorado's regulatory environment pertaining to marijuana before legalization. The synthetic control unit allows for a comparative observation of overdose rate trends in Colorado and its synthetic counterpart for the years 1999-2017, all while including a set of predictor variables for robustness checks. A difference-in-difference estimate will then help us observe the effects of the treatment given to Colorado. Inference tests will be conducted to evaluate the method's predictive power and significance of the results. The results of the synthetic control model and its outcomes showed that the estimated negative 5% drop in overdose death rates was deemed insignificant on conducting a placebo in-space analysis, meaning there is not enough evidence to prove that opening recreational dispensaries as a result of recreational marijuana legislation was instrumental in reducing Colorado's ongoing opioid crisis depicted through opioid overdose deaths. Owing to the lack of additional post-treatment data and captured lagged effects, it is too soon to dismiss this policy as inadequate in combating the opioid epidemic. Once additional post-treatment data become available, the study can be reproduced to obtain more robust results and achieve a clearer understanding of the policy implications shown.


Biodiversity as a multidimensional construct: a review, framework and case study of herbivory's impact on plant biodiversity.
Biodiversity is inherently multidimensional, encompassing taxonomic, functional, phylogenetic, genetic, landscape and many other elements of variability of life on the Earth. However, this fundamental principle of multidimensionality is rarely applied in research aimed at understanding biodiversity's value to ecosystem functions and the services they provide. This oversight means that our current understanding of the ecological and environmental consequences of biodiversity loss is limited primarily to what unidimensional studies have revealed. To address this issue, we review the literature, develop a conceptual framework for multidimensional biodiversity research based on this review and provide a case study to explore the framework. Our case study specifically examines how herbivory by whitetail deer (Odocoileus virginianus) alters the multidimensional influence of biodiversity on understory plant cover at Black Rock Forest, New York. Using three biodiversity dimensions (taxonomic, functional and phylogenetic diversity) to explore our framework, we found that herbivory alters biodiversity's multidimensional influence on plant cover; an effect not observable through a unidimensional approach. Although our review, framework and case study illustrate the advantages of multidimensional over unidimensional approaches, they also illustrate the statistical and empirical challenges such work entails. Meeting these challenges, however, where data and resources permit, will be important if we are to better understand and manage the consequences we face as biodiversity continues to decline in the foreseeable future.


An investigation and assessment of the muscle damage and inflammation at injection site of aluminum-adjuvanted vaccines in guinea pigs.
Aluminum salt adjuvants (Als) have been the most widely used adjuvants in vaccines and known to be effective in intramuscular inoculation. However, in rare cases, some Al containing vaccines caused serious adverse events such as chronic pain at the site of the injection. The Als cause mild tissue damage at the inoculation site, allowing the antigen to be locally retained at the inoculation site and thus potentiate innate immunity. This is required to elicit effectiveness of vaccination. However, there is concern that chronic muscle damage might potentially lead to serious adverse events, such as autoimmune disease and movement disorders. In this study, muscle damage caused by several Al containing vaccines were examined in guinea pigs. Mild and moderate inflammation were observed following Al containing split influenza virus vaccine, formalin-inactivated diphtheria-pertussis-tetanus and Salk polio vaccine. While massive inflammation and muscle damage were observed in Al-containing human papillomavirus vaccine-inoculated animals. However, the severities of damage were not associated with their Al contents. Masson's trichrome staining and immunostaining revealed that injured muscle at the inoculated site recovered within one month of vaccination, whereas inflammatory nodules remained. Flow cytometric analyses of the infiltrating cells revealed that the number of CD45+ lymphocytes and potential granulocytes were increased following vaccination. The number of infiltrated cells seemed to be associated with severity of muscle damages. These observations revealed that Al containing vaccine-induced muscle damage is reparable, and severity of transient muscle damages seemed to be determined by type of antigen or types of Al salts rather than Al content.


The 'wet mind': water and functional neuroimaging.
Functional neuroimaging has emerged as an important approach to study the brain and the mind. Surprisingly, although they are based on radically different physical approaches both positron emission tomography (PET) and magnetic resonance imaging (MRI) make brain activation imaging possible through measurements involving water molecules. So far, PET and MRI functional imaging have relied on the principle that neuronal activation and blood flow are coupled through metabolism. However, a new paradigm has emerged to look at brain activity through the observation with MRI of the molecular diffusion of water. In contrast with the former approaches diffusion MRI has the potential to reveal changes in the intrinsic water physical properties during brain activation, which could be more intimately linked to the neuronal activation mechanisms and lead to an improved spatial and temporal resolution. However, this link has yet to be fully confirmed and understood. To shed light on the possible relationship between water and brain activation, this introductory paper reviews the most recent data on the physical properties of water and on the status of water in biological tissues, and evaluates their relevance to brain diffusion MRI. The biophysical mechanisms of brain activation are then reassessed to reveal their intimacy with the physical properties of water, which may come to be regarded as the 'molecule of the mind'.


Energy transport in the presence of long-range interactions.
We study energy transport in the paradigmatic Hamiltonian mean-field (HMF) model and other related long-range interacting models using molecular dynamics simulations. We show that energy diffusion in the HMF model is subdiffusive in nature, which confirms a recently obtained intriguing result that, despite being globally interacting, this model is a thermal insulator in the thermodynamic limit. Surprisingly, when additional nearest-neighbor interactions are introduced to the HMF model, an energy superdiffusion is observed. We show that these results can be consistently explained by studying energy localization due to thermally generated intrinsic localized excitation modes (discrete breathers) in nonlinear discrete systems. Our analysis for the HMF model can also be readily extended to more generic long-range interacting models where the interaction strength decays algebraically with the (shortest) distance between two lattice sites. This reconciles many of the apparently counterintuitive results presented recently [C. Olivares and C. Anteneodo, Phys. Rev. E 94, 042117 (2016)2470-004510.1103/PhysRevE.94.042117; D. Bagchi, Phys. Rev. E 95, 032102 (2017)2470-004510.1103/PhysRevE.95.032102] concerning energy transport in two such long-range interacting models.


Novel cardiolipins from uncultured methane-metabolizing archaea.
Novel cardiolipins from Archaea were detected by screening the intact polar lipid (IPL) composition of microbial communities associated with methane seepage in deep-sea sediments from the Pakistan margin by high-performance liquid chromatography electrospray ionization mass spectrometry. A series of tentatively identified cardiolipin analogues (dimeric phospholipids or bisphosphatidylglycerol, BPG) represented 0.5% to 5% of total archaeal IPLs. These molecules are similar to the recently described cardiolipin analogues with four phytanyl chains from extreme halophilic archaea. It is worth noting that cardiolipin analogues from the seep archaeal communities are composed of four isoprenoidal chains, which may contain differences in chain length (20 and 25 carbon atoms) and degrees of unsaturation and the presence of a hydroxyl group. Two novel diether lipids, structurally related to the BPGs, are described and interpreted as degradation products of archaeal cardiolipin analogues. Since archaeal communities in seep sediments are dominated by anaerobic methanotrophs, our observations have implications for characterizing structural components of archaeal membranes, in which BPGs are presumed to contribute to modulation of cell permeability properties. Whether BPGs facilitate interspecies interaction in syntrophic methanotrophic consortia remains to be tested.


Preclinical toxicology and biodistribution studies of recombinant adeno-associated virus 1 human acid α-glucosidase.
A biodistribution and toxicology study was performed to test the acute toxicities of intradiaphragmatic injection of a recombinant adeno-associated virus (rAAV) 2/1-human acid alpha-Glucosidase (hGAA) driven by a cytomegalovirus (CMV) promoter (rAAV1-CMV-hGAA) in New Zealand white rabbits and in the rodent Pompe disease model by injecting at the right quadriceps. Studies performed using fluoroscopy and AAV2-GFP demonstrated spread upon intradiaphragmatic injection, and the ability of AAV to infect and express acid α-glucosidase (GAA) throughout the diaphragm. For the preclinical study, 10 rabbits (5 male, 5 female) were divided into two groups, vehicle control (Lactated Ringer's) and test article (1.5×10(12) vector genomes [vg] rAAV1-CMV-hGAA), and euthanized on day 21. After direct visualization, the left hemidiaphragm was injected at three locations. There was up to a 2,500-fold increase in circulating anti-AAV1 antibodies directed to the vector capsids. In addition, up to an 18-fold increase in antibodies against the GAA protein was generated. Injection sites maintained up to 1.0×10(5) vg/μg genomic DNA (gDNA), while uninjected sites had up to 1.0×10(4) vg/μg gDNA. Vector DNA was present in blood at 24 hr postinjection at up to 1.0×10(6) vg/μg gDNA, followed by a decrease to 1.0×10(3) vg/μg gDNA at euthanization on day 21. Nominal amounts of vector DNA were present in peripheral organs, including the brain, spinal cord, gonads, and skeletal muscle. Upon histopathological examination, fibroplasias of the serosal surface were noted at diaphragm injections sites of both groups. In addition, an increase in mononuclear cell infiltration in the diaphragm and esophagus in vector-dosed animals was found. Elevated creatine phosphokinase levels, an indicator of muscle repair, was observed in all animals postprocedure but persisted in vector-injected rabbits until euthanization. A follow-up study suggested that this was directed against the human transgene expression in a foreign species. Overall, this study demonstrates diffusion of vector throughout the diaphragm after localized injections.


Blockade of endothelial G(i) protein enhances early engraftment in intraportal cell transplant to mouse liver.
The limited availability of liver donors and recent progress in cell therapy technologies has centered interest on cell transplantation as a therapeutic alternative to orthotopic liver transplant for restoring liver function. Following transplant by intraportal perfusion, the main obstacle to cell integration in the parenchyma is the endothelial barrier. Transplanted cells form emboli in the portal branches, inducing ischemia and reperfusion injury, which cause disruption of endothelial impermeability and activate the immune system. Approximately 95% of transplanted cells fail to implant and die within hours by anoikis or are destroyed by the host immune system. Intravascular perfusion of Bordetella pertussis toxin (PTx) blocks endothelial G(i) proteins and acts as a reversible inducer of actin cytoskeleton reorganization, leading to interruption of cell confluence in vitro and increased vascular permeability in vivo. PTx treatment of the murine portal vascular tree 2 h before intraportal perfusion of embryonic stem cells facilitated rapid cell engraftment. By 2 h postperfusion, the number of implanted cells in treated mice was more than fivefold greater than in untreated controls, a difference that was maintained to at least 30 days posttransplant. We conclude that prior to cell transplant, PTx blockade of the G(i) protein pathway in liver endothelium promotes rapid, efficient cell implantation in liver parenchyma, and blocks chemokine receptor signaling, an essential step in early activation of the immune system.


Testosterone Protects Against Severe Influenza by Reducing the Pro-Inflammatory Cytokine Response in the Murine Lung.
Influenza A virus pathogenesis may differ between men and women. The 2009 H1N1 influenza pandemic resulted in more documented hospitalizations in women compared to men. In this study, we analyzed the impact of male sex hormones on pandemic 2009 H1N1 influenza A virus disease outcome. In a murine infection model, we could mimic the clinical findings with female mice undergoing severe and even fatal 2009 H1N1 influenza compared to male mice. Treatment of female mice with testosterone could rescue the majority of mice from lethal influenza. Improved disease outcome in testosterone treated female mice upon 2009 H1N1 influenza A virus infection did not affect virus titers in the lung compared to carrier-treated females. However, reduction in IL-1β cytokine expression levels strongly correlated with reduced lung damage and improved influenza disease outcome in female mice upon testosterone treatment. In contrast, influenza disease outcome was not affected between castrated male mice and non-castrated controls. Here, influenza infection resulted in reduction of testosterone expression in male mice. These findings show that testosterone has protective functions on the influenza infection course. However, 2009 H1N1 influenza viruses seem to have evolved yet unknown mechanisms to reduce testosterone expression in males. These data will support future antiviral strategies to treat influenza taking sex-dependent immunopathologies into consideration.


Laparoscopic surgery for colon cancer: a systematic review.
Colorectal cancer is the second leading cause of cancer-related death in western countries. The objective of this systematic review was to show that laparoscopic-assisted colon resection for cancer is not inferior to open colectomy with respect to cancer survival and perioperative outcomes. We performed a comprehensive literature review. Inclusion criteria were adults aged over 16 years with a colon resection for documented colon cancer and randomized controlled trials with laparoscopic- assisted or open resections. We excluded studies that did not document colon cancer recurrence in their article. We assessed data extraction and study quality and performed a quantitative data analysis. Six published and 4 unpublished studies fulfilled our inclusion criteria, with a total of 1262 patients. All primary and secondary outcomes showed good homogeneity, except for morbidity, which was described heterogeneously between the studies. There was no disadvantage to laparoscopic colon resection in any of these primary and secondary outcomes, compared with the conventional open technique. The results of this study suggest that, although there is no definitive answer, present evidence indicates that laparoscopic colon cancer resection is as safe and efficacious as the conventional open technique.