Linear and undulating periodized strength plus aerobic training promote similar benefits and lead to improvement of insulin resistance on obese adolescents

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

"TEACHING FROM A CRITICAL, ANTI-RACIST PERSPECTIVE-BASED PEDAGOGY TO PREPARE WHITE STUDENTS FOR CULTURAL DIVERSITY: RESISTANCE AND CONSEQUENCES"

How are faculty of color retained once they are recruited? More importantly, how do factors such as white student resistance and negative disposition toward faculty of color impact the retention of faculty of color?

Evaluation of the Effects of a Preoperative 2-Hour Fast With Maltodextrine and Glutamine on Insulin Resistance, Acute-Phase Response, Nitrogen Balance, and Serum Glutathione After Laparoscopic Cholecystectomy: A Controlled Randomized Trial

Background: Prolonged preoperative fasting increases insulin resistance (IR). The authors investigated whether an abbreviated preoperative fast with glutamine (GLN) plus a carbohydrate (CHO)-based beverage would improve the organic response after surgery. Methods: Forty-eight female patients (19-62 years) were randomized to either standard fasting (control group) or to fasting with 1 of 3 different beverages before video-cholecystectomy. Beverages were consumed 8 hours (400 mL; placebo group: water; GLN group: water with 50 g maltodextrine plus 40 g GLN; and CHO group: water with 50 g maltodextrine) and 2 hours (200 mL; placebo: water; GLN: water with 25 g maltodextrine plus 10 g GLN; and CHO: water with 25 g maltodextrine) before anesthesia. Blood samples were collected pre- and postoperatively. Results: The mean (SEM) postoperative homeostasis model assessment-insulin resistance was greater (P < .05) in control patients (4.3 [1.3]) than in the other groups (placebo, 1.6 [0.3]; CHO, 2.3 [0.4]; and GLN, 1.5 [0.1]). Glutathione was significantly higher (P < .01) in the GLN group than in both CHO and control groups. Interleukin-6 increased in all groups except the GLN group. The C-reactive protein/albumin ratio was higher (P < .05) in controls than in CHO and GLN groups. The nitrogen balance was less negative in GLN (-2.5 [0.8] gN) than in both placebo (-9.0 [2] gN; P = .001) and control (-6.6 [0.4] gN; P = .04) groups. Conclusions Preoperative intake of a GLN-enriched CHO beverage appears to improve IR and antioxidant defenses and decreases the inflammatory response after video-cholecystectomy. (JPEN J Parenter Enteral Nutr. 2012; 36: 43-52)

Colistin Resistance in Escherichia coli and Salmonella enterica Strains Isolated from Swine in Brazil

Reports about acquired resistance to colistin in different bacteria species are increasing, including E. coli of animal origin, but reports of resistance in wild S. enterica of different serotypes from swine are not found in the literature. Results obtained with one hundred and twenty-six E. coli strains from diseased swine and one hundred and twenty-four S. enterica strains from diseased and carrier swine showed a frequency of 6.3% and 21% of colistin-resistant strains, respectively. When comparing the disk diffusion test with the agar dilution test to evaluate the strains, it was confirmed that the disk diffusion test is not recommended to evaluate colistin resistance as described previously. The colistin MIC 90 and MIC 50 values obtained to E. coli were 0.25 mu g/mL and 0.5 mu g/mL, the MIC 90 and MIC 50 to S. enterica were 1 mu g/mL and 8 mu g/mL. Considering the importance of colistin in control of nosocomial human infections with Gram-negative multiresistant bacteria, and the large use of this drug in animal production, the colistin resistance prevalence in enterobacteriaceae of animal origin must be monitored more closely.

Long-term interdisciplinary therapy reduces endotoxin level and insulin resistance in obese adolescents

Abstract Aim The purpose of the present study was to assess the dietary fat intake, glucose, insulin, Homeostasis model assessment for insulin resistance HOMA-IR, and endotoxin levels and correlate them with adipokine serum concentrations in obese adolescents who had been admitted to long-term interdisciplinary weight-loss therapy. Design The present study was a longitudinal clinical intervention of interdisciplinary therapy. Adolescents (n = 18, aged 15–19 y) with a body mass index > 95th percentile were admitted and evaluated at baseline and again after 1 year of interdisciplinary therapy. We collected blood samples, and IL-6, adiponectin, and endotoxin concentrations were measured by ELISA. Food intake was measured using 3-day diet records. In addition, we assessed glucose and insulin levels as well as the homeostasis model assessment for insulin resistance (HOMA-IR). Results The most important finding from the present investigation was that the long-term interdisciplinary lifestyle therapy decreased dietary fat intake and endotoxin levels and improved HOMA-IR. We observed positive correlations between dietary fat intake and endotoxin levels, insulin levels, and the HOMA-IR. In addition, endotoxin levels showed positive correlations with IL-6 levels, insulin levels and the HOMA-IR. Interestingly, we observed a negative correlation between serum adiponectin and both dietary fat intake and endotoxin levels. Conclusions The present results indicate an association between dietary fat intake and endotoxin level, which was highly correlated with a decreased pro-inflammatory state and an improvement in HOMA-IR. In addition, this benefits effect may be associated with an increased adiponectin level, which suggests that the interdisciplinary therapy was effective in improving inflammatory pathways.

Mechanism of resistance to tyrosine kinase inhibitors in philadelphia-positive acute lymphblastic leukaemia (all): from genetic alterations to impaired RNA editing

The Ph chromosome is the most frequent cytogenetic aberration associated with adult ALL and it represents the single most significant adverse prognostic marker. Despite imatinib has led to significant improvements in the treatment of patients with Ph+ ALL, in the majority of cases resistance developed quickly and disease progressed. Some mechanisms of resistance have been widely described but the full knowledge of contributing factors, driving both the disease and resistance, remains to be defined. The observation of rapid development of lymphoblastic leukemia in mice expressing altered Ikaros (Ik) isoforms represented the background of this study. Ikaros is a zinc finger transcription factor required for normal hemopoietic differentiation and proliferation, particularly in the lymphoid lineages. By means of alternative splicing, Ikaros encodes several proteins that differ in their abilities to bind to a consensus DNA-binding site. Shorter, DNA nonbinding isoforms exert a dominant negative effect, inhibiting the ability of longer heterodimer partners to bind DNA. The differential expression pattern of Ik isoforms in Ph+ ALL patients was analyzed in order to determine if molecular abnormalities involving the Ik gene could associate with resistance to imatinib and dasatinib. Bone marrow and peripheral blood samples from 46 adult patients (median age 55 yrs, 18-76) with Ph+ ALL at diagnosis and during treatment with imatinib (16 pts) or dasatinib (30 pts) were collected. We set up a fast, high-throughput method based on capillary electrophoresis technology to detect and quantify splice variants. 41% Ph+ ALL patients expressed high levels of the non DNA-binding dominant negative Ik6 isoform lacking critical N-terminal zinc-fingers which display abnormal subcellular compartmentalization pattern. Nuclear extracts from patients expressed Ik6 failed to bind DNA in mobility shift assay using a DNA probe containing an Ikaros-specific DNA binding sequence. In 59% Ph+ ALL patients there was the coexistence in the same PCR sample and at the same time of many splice variants corresponded to Ik1, Ik2, Ik4, Ik4A, Ik5A, Ik6, Ik6 and Ik8 isoforms. In these patients aberrant full-length Ikaros isoforms in Ph+ ALL characterized by a 60-bp insertion immediately downstream of exon 3 and a recurring 30-bp in-frame deletion at the end of exon 7 involving most frequently the Ik2, Ik4 isoforms were also identified. Both the insertion and deletion were due to the selection of alternative splice donor and acceptor sites. The molecular monitoring of minimal residual disease showed for the first time in vivo that the Ik6 expression strongly correlated with the BCR-ABL transcript levels suggesting that this alteration could depend on the Bcr-Abl activity. Patient-derived leukaemia cells expressed dominant-negative Ik6 at diagnosis and at the time of relapse, but never during remission. In order to mechanistically demonstrated whether in vitro the overexpression of Ik6 impairs the response to tyrosine kinase inhibitors (TKIs) and contributes to resistance, an imatinib-sensitive Ik6-negative Ph+ ALL cell line (SUP-B15) was transfected with the complete Ik6 DNA coding sequence. The expression of Ik6 strongly increased proliferation and inhibited apoptosis in TKI sensitive cells establishing a previously unknown link between specific molecular defects that involve the Ikaros gene and the resistance to TKIs in Ph+ ALL patients. Amplification and genomic sequence analysis of the exon splice junction regions showed the presence of 2 single nucleotide polymorphisms (SNPs): rs10251980 [A/G] in the exon2/3 splice junction and of rs10262731 [A/G] in the exon 7/8 splice junction in 50% and 36% of patients, respectively. A variant of the rs11329346 [-/C], in 16% of patients was also found. Other two different single nucleotide substitutions not recognized as SNP were observed. Some mutations were predicted by computational analyses (RESCUE approach) to alter cis-splicing elements. In conclusion, these findings demonstrated that the post-transcriptional regulation of alternative splicing of Ikaros gene is defective in the majority of Ph+ ALL patients treated with TKIs. The overexpression of Ik6 blocking B-cell differentiation could contribute to resistance opening a time frame, during which leukaemia cells acquire secondary transforming events that confer definitive resistance to imatinib and dasatinib.

Resistance against strongylid nematodes in two high prevalence Equine Recurrent Airway Obstruction families has a genetic basis

A recent study showed increased resistance against strongylid nematodes in offspring of a stallion affected by recurrent airway obstruction (RAG) compared with unrelated pasture mates. Resistance against strongylid nematodes was associated with RAG affection. Hypothesis: Resistance against strongylid nematodes has a genetic basis. The genetic variants influencing strongylid resistance also influence RAG susceptibility. Faecal samples from the half-sibling offspring of two RAG-affected Warmblood stallions 98 offspring from the first family (family 1) and 79 from the second family (family 2) were analysed using a combined sedimentation-flotation method. The phenotype was defined as a binary trait - either positive or negative for egg shedding. The influence of non-genetic factors on egg shedding was analysed using SAS, the mode of inheritance was investigated using PAP and iBay, and the association between shedding of strongyle eggs and RAG was estimated by odds ratios. Previously established genotypes for 315 microsatellite markers were used for QTL analyses using GRID QTL. The inheritance of "strongylid egg shedding" is influenced by major genes on ECA15 and ECA20. Shedding of strongylid eggs is associated with RAG in family 1 but not in family 2. Conclusions: The status of "shedding of strongyle eggs" has a genetic background. The results were inconclusive as to whether "egg shedding" and RAG share common genetic components. Our results suggest that it may be possible to select for resistance against strongylid nematodes.

Antibiotic resistance profile of Staphylococcus rostri, a new species isolated from healthy pigs

Staphylococcus rostri is a newly described Staphylococcus species that is present in the nasal cavity of healthy pigs. Out of the 225 pigs tested at slaughterhouse, 46.7% carried the new species alone and 22% in combination with Staphylococcus aureus. An antibiotic resistance profile was determined for S. rostri and compared to that of S. aureus isolated from the same pig. Resistance to tetracycline specified by tet(M), tet(K) and tet(L), streptomycin (str(pS194)), penicillin (blaZ), trimethoprim (dfr(G)), and erythromycin and clindamycin (erm genes), were found in both species; however, with the exception of streptomycin and trimethoprim, resistance was higher in S. aureus. S. rostri isolates display very low genetic diversity as demonstrated by pulsed-field gel electrophoresis, which generated two major clusters. Several clonal complexes (CC1, CC5, CC9, CC30 and CC398) were identified in S. aureus with CC 9 and CC 398 being the most frequent. Our study gives the first overview of the distribution, genetic relatedness, and resistance profile of one coagulase-negative Staphylococcus species that is commonly present in the nares of healthy pigs in Switzerland, and shows that S. rostri may harbor resistance genes associated with transferable elements like Tn916.

Impact of antibiotic use on carbapenem resistance in Pseudomonas aeruginosa: is there a role for antibiotic diversity?

In this study, we aimed to evaluate the relationship between the rates of resistance of Pseudomonas aeruginosa to carbapenems and the levels and diversity of antibiotic consumption. Data were retrospectively collected from 20 acute care hospitals across 3 regions of Switzerland between 2006 and 2010. The main outcome of the present study was the rate of resistance to carbapenems among P. aeruginosa. Putative predictors included the total antibiotic consumption and carbapenem consumption in defined daily doses per 100 bed days, the proportion of very broad-spectrum antibiotics used, and the Peterson index. The present study confirmed a correlation between carbapenem use and carbapenem resistance rates at the hospital and regional levels. The impact of diversifying the range of antibiotics used against P. aeruginosa resistance was suggested by (i) a positive correlation in multivariate analysis between the above-mentioned resistance and the proportion of consumed antibiotics having a very broad spectrum of activity (coefficient = 1.77; 95% confidence interval, 0.58 to 2.96; P < 0.01) and (ii) a negative correlation between the resistance and diversity of antibiotic use as measured by the Peterson homogeneity index (coefficient = -0.52; P < 0.05). We conclude that promoting heterogeneity plus parsimony in the use of antibiotics appears to be a valuable strategy for minimizing the spread of carbapenem resistance in P. aeruginosa in hospitals.

Presence of new mecA and mph(C) variants conferring antibiotic resistance in Staphylococcus spp. isolated from the skin of horses before and after clinic admission

Because of the frequency of multiple antibiotic resistance, Staphylococcus species often represent a challenge in incisional infections of horses undergoing colic surgery. To investigate the evolution of antibiotic resistance patterns before and after preventative peri- and postoperative penicillin treatment, staphylococci were isolated from skin and wound samples at different times during hospitalization. Most staphylococci were normal skin commensals and belonged to the common coagulase-negative group. In some cases they turned out to be opportunistic pathogens present in wound infections. MICs were determined for 12 antibiotics, and antibiotic resistance genes were detected by microarray. At hospital admission, horses harbored staphylococci that were susceptible to antibiotics or resistant to one group of drugs, mainly due to the presence of new variants of the methicillin and macrolide resistance genes mecA and mph(C), respectively. After 3 days, the percentage of Staphylococcus isolates displaying antibiotic resistance, as well as the number of resistance genes per isolate, increased moderately in hospitalized horses without surgery or penicillin treatment but dramatically in hospitalized horses after colic surgery as well as penicillin treatment. Staphylococcus species displaying multiple resistance were found to harbor mainly genes conferring resistance to beta-lactams (mecA and blaZ), aminoglycosides [str and aac(6')-Ie-aph(2')-Ia], and trimethoprim [dfr(A) and dfr(D)]. Additional genes conferring resistance to macrolides [mph(C), erm(C), and erm(B)], tetracycline [tet(K) and tet(M)], chloramphenicol [cat(pC221) and cat(pC223)], and streptothricin (sat4) appeared in several strains. Hospitalization and preventive penicillin use were shown to act as selection agents for multidrug-resistant commensal staphylococcal flora.

Clinical and molecular features of methicillin-resistant, coagulase-negative staphylococci of pets and horses

OBJECTIVES To determine the antibiotic resistance and fingerprint profiles of methicillin-resistant coagulase-negative staphylococci (MRCoNS) from animal infections among different practices and examine the history of antibiotic treatment. METHODS Isolates were identified by mass spectrometry and tested for antimicrobial resistance by broth dilution, microarrays and sequence analysis of the topoisomerases. Diversity was assessed by PFGE, icaA PCR and staphylococcal cassette chromosome mec (SCCmec), arginine catabolic mobile element (ACME) and multilocus sequence typing. Clinical records were examined retrospectively. RESULTS MRCoNS were identified as Staphylococcus epidermidis (n=20), Staphylococcus haemolyticus (n=17), Staphylococcus hominis (n=3), Staphylococcus capitis (n=1), Staphylococcus cohnii (n=1) and Staphylococcus warneri (n=1). PFGE identified one clonal lineage in S. hominis isolates and several in S. haemolyticus and S. epidermidis. Fourteen sequence types were identified in S. epidermidis, with sequence type 2 (ST2) and ST5 being predominant. Ten isolates contained SCCmec IV, seven contained SCCmec V and the others were non-typeable. ACMEs were detected in 11 S. epidermidis isolates. One S. hominis and 10 S. epidermidis isolates were icaA positive. In addition to mecA-mediated β-lactam resistance, the most frequent resistance was to gentamicin/kanamycin [aac(6')-Ie-aph(2')-Ia, aph(3')-III] (n=34), macrolides/lincosamides [erm(C), erm(A), msr, lnu(A)] (n=31), tetracycline [tet(K)] (n=22), streptomycin [str, ant(6)-Ia] (n=20), trimethoprim [dfr(A), dfr(G)] (n=17), sulfamethoxazole (n = 34) and fluoroquinolones [amino acid substitutions in GyrA and GrlA] (n=30). Clinical data suggest selection through multiple antibiotic courses and emphasize the importance of accurate diagnosis and antibiograms. CONCLUSIONS MRCoNS from animal infection sites are genetically heterogeneous multidrug-resistant strains that represent a new challenge in the prevention and therapy of infections in veterinary clinics.

Extended-spectrum cephalosporin-resistant Gram-negative organisms in livestock: an emerging problem for human health?

Escherichia coli, Salmonella spp. and Acinetobacter spp. are important human pathogens. Serious infections due to these organisms are usually treated with extended-spectrum cephalosporins (ESCs). However, in the past two decades we have faced a rapid increasing of infections and colonization caused by ESC-resistant (ESC-R) isolates due to production of extended-spectrum-β-lactamases (ESBLs), plasmid-mediated AmpCs (pAmpCs) and/or carbapenemase enzymes. This situation limits drastically our therapeutic armamentarium and puts under peril the human health. Animals are considered as potential reservoirs of multidrug-resistant (MDR) Gram-negative organisms. The massive and indiscriminate use of antibiotics in veterinary medicine has contributed to the selection of ESC-R E. coli, ESC-R Salmonella spp. and, to less extent, MDR Acinetobacter spp. among animals, food, and environment. This complex scenario is responsible for the expansion of these MDR organisms which may have life-threatening clinical significance. Nowadays, the prevalence of food-producing animals carrying ESC-R E. coli and ESC-R Salmonella (especially those producing CTX-M-type ESBLs and the CMY-2 pAmpC) has reached worryingly high values. More recently, the appearance of carbapenem-resistant isolates (i.e., VIM-1-producing Enterobacteriaceae and NDM-1 or OXA-23-producing Acinetobacter spp.) in livestock has even drawn greater concerns. In this review, we describe the aspects related to the spread of the above MDR organisms among pigs, cattle, and poultry, focusing on epidemiology, molecular mechanisms of resistance, impact of antibiotic use, and strategies to contain the overall problem. The link and the impact of ESC-R organisms of livestock origin for the human scenario are also discussed.

Eluding antibiotic resistance: capitalizing on antimicrobial peptides interaction with the lipid bilayer

It is widely accepted that the emergence of drug-resistant pathogens is the result of the overuse and misuse of antibiotics. Infectious Disease Society of America, Center for Disease Control and World Health Organization continue to view, with concern, the lack of antibiotics in development, especially those against Gram-negative bacteria. Antimicrobial peptides (AMPs) have been proposed as an alternative to antibiotics due to their selective activity against microbes and minor ability to induce resistance. For example, the Food and Drug Administration approved Daptomycin (DAP) in 2003 for treatment of severe skin infections caused by susceptible Gram-positive organisms. Currently, there are 12 to 15 examples of modified natural and synthetic AMPs in clinical development. But most of these agents are against Gram-positive bacteria. Therefore, there is unmet medical need for antimicrobials used to treat infections caused by Gram-negative bacteria. In this study, we show that a pro-apoptotic peptide predominantly used in cancer therapy, (KLAKLAK)2, is an effective antimicrobial against Gram-negative laboratory strains and clinical isolates. Despite the therapeutic promise, AMPs development is hindered by their susceptibility to proteolysis. Here, we demonstrate that an all-D enantiomer of (KLAKLAK)2, resistant to proteolysis, retains its activity against Gram-negative pathogens. In addition, we have elucidated the specific site and mechanism of action of D(KLAKLAK)2 through a repertoire of whole-cell and membrane-model assays. Although it is considered that development of resistance does not represent an obstacle for AMPs clinical development, strains with decreased susceptibility to these compounds have been reported. Staphylococci resistance to DAP was observed soon after its approval for use and has been linked to alterations of the cell wall (CW) and cellular membrane (CM) properties. Immediately following staphylococcal resistance, Enterococci resistance to DAP was seen, yet the mechanism of resistance in enterococci remains unknown. Our findings demonstrate that, similar to S. aureus, development of DAP-resistance in a vancomycin-resistant E. faecalis isolate is associated with alterations of the CW and properties of the CM. However, the genes linked to these changes in enterococci appear to be different from those described in S. aureus.

Generalized resistance resources of informal caregivers: A study of demands for care, competing demands, perception of burden and cognitive stress

This study examines the relationship among psychological resources (generalized resistance resources), care demands (demands for care, competing demands, perception of burden) and cognitive stress in a selected population of primary family caregivers. The study utilizes Antonovsky's Salutogenic Model of Health, specifically the concept of generalized resistance resources (GRRs), to analyze the relative effect of these resources on mediating cognitive stress, controlling for other care demands. The study is based on a sample of 784 eligible caregivers who (1) were relatives, (2) had the main responsibility for care, defined as a primary caregiver, and (3) provided a scaled stress score for the amount of overall care given to the care recipient (family member). The sample was drawn from the 1982 National Long-Term Care Survey (NLTCS) of individuals who assisted a given NLTCS sample person with ADL limitations.^ The study tests the following hypotheses: (a) There will be a negative relationship between generalized resistance resources (GRRs) and cognitive stress controlling for care demands (demands for care, competing demands, and perceptions of burden); (b) of the specific GRRs (material, cognitive, social, cultural-environmental) the social domain will represent the most significant factor predicting a decrease in cognitive stress; and (c) the social domain will be more significant for the female than the male primary family caregiver in decreasing cognitive stress.^ The study found that GRRs had a statistically significant mediating effect on cognitive stress, but the GRRs were a less significant predictor of stress than perception of burden and demands for care. Thus, although the analysis supported the underlying hypothesis, the specific hypothesis regarding GRRs' greater significance in buffering cognitive stress was not supported. Second, the results did not demonstrate the statistical significance or differences among the GRR domains. The hypothesis that the social GRR domain was most significant in mediating stress of family caregivers was not supported. Finally, the results confirmed that there are differences in the importance of social support help in mediating stress based on gender. It was found that gender and social support help were related to cognitive stress and gender had a statistically significant interaction effect with social support help. Implications for clinical practice, public health policy, and research are discussed. ^

Assessing the paradox between transmitted and acquired HIV-1 drug resistance in the Swiss HIV Cohort Study from 1998 to 2012.

BACKGROUND  Transmitted HIV-1 drug-resistance mutations(TDR) are transmitted from treatment-failing or treatment-naïve patients. Although prevalence of drug-resistance in treatment-failing patients has declined in developed countries, TDR prevalence has not. Mechanisms causing this paradox are poorly explored. METHODS  We included recently-infected, treatment-naïve patients with genotypic-resistance-tests performed ≤1year post-infection and <2013. Potential risk factors for TDR were analyzed using logistic regression. Association of TDR prevalences with population viral load(PVL) from treatment-patients during 1997-2011 was estimated with Poisson regression for all TDR and individually for most frequent resistance-mutations against each drug class(M184V/L90M/K103N). RESULTS  We included 2421 recently-infected, treatment-naïve patients and 5399 treatment-failing patients. TDR prevalence fluctuated considerably over time. Two opposing developments could explain these fluctuations: generally continuous increases in TDR(Odds Ratio[OR]=1.13,p=0.010), punctuated by sharp decreases when new drug-classes were introduced. Overall, TDR prevalence increased with decreasing PVL(Rate Ratio[RR]=0.91/1000Log10-PVL,p=0.033). Additionally, we observed that the transmitted high-fitness-cost mutation M184V was positively associated with PVL of treatment-failing patients carrying M184V(RR=1.50/100Log10-PVL,p<0.001). Such association was absent and negative for K103N(RR-K103N=1.00/100Log10-PVL,p=0.99) and L90M(RR-L90M=0.75/100Log10-PVL,p=0.022), respectively. CONCLUSIONS  Transmission of antiretroviral drug-resistance is temporarily reduced by the introduction of new drug classes and driven by treatment-failing and treatment-naïve patients. These findings suggest a continuous need for new drugs, early detection/treatment of HIV-1-infection.