Effect of turbinate surgery on mucociliary clearance. A systematic review and metanalysis / Efecto de la cirugía turbinal en el aclaramiento mucociliar. Revisión sistemática y metaanálisis

Despite the fact that turbinate surgery provides satisfactory results regarding nasal obstruction, most of these procedures are destructive, to some extent, for the respiratory epithelium. There are valid hypotheses suggesting either that turbinate surgery may improve mucociliary clearance (MCC) by improving rhinitis, as well hypotheses suggesting that these surgeries may impair it by damaging the nasal ciliated epithelia. This systematic review is designed with the objective of exploring the effect of turbinate surgery on MCC. Pubmed (Medline), the Cochrane Library, EMBASE, SciELO were analyzed. Four authors members of the YO-IFOS rhinology study group independently analyzed the articles. Extracted variables encompassed: sample size, age, indication for surgery, surgical technique, method used to measure mucociliary clearance, mucociliary transport time before and after surgery, and main outcome. 15 studies with a total population of 1936 participants (1618 patients excluding healthy controls) met the inclusion criteria. 9 studies could be combined in a metanalysis, wich revealed a non-statistically significant decrease of 3.86 min in MCTT after turbinate surgery (p = 0.06). The subgroup analysis of the 5 cohorts who underwent microdebrider turbinoplasty reached statistical significance under a random effect model, revealing a 7.02 min decrease in MCTT (p < 0.001). The laser turbinoplasty subgroup, composed of 4 cohorts, also reached significance, although the difference was lower than that for microdebrider turbinoplasty, 1.01 min (p < 0.001). This systematic review and meta-analysis suggests that turbinate surgery does not compromise mucociliary clearance. The available evidence also suggests that turbinate surgery with mucosa sparing techniques improves MCC, while with aggressive techniques it increases or remains the same. ... . (AU)

A pesar de que la cirugía turbinal tiene efectos positivos en la ventilación nasal, gran parte de estos procedimientos son agresivos con el epitelio respiratorio. Existen hipótesis que sugieren que la cirugía turbinal puede mejorar el aclaramiento mucociliar (AMC) al mejorar la rinitis, así como alterarlo al lesional el epitelio nasal. Esta revisión se diseña con el objetivo de explorar el efecto de la cirugía turbinal en el AMC. Se revisó Pubmed (Medline), the Cochrane Library, EMBASE, SciELO. 4 autores miembros de YO-IFOS grupo de estudio en rinología, analizaron de manera independiente los artículos. Las variables analizadas fueron tamaño muestral, edad, indicación quirúrgica, técnica quirúrgica, método de medición de AMC, AMC antes y después de la cirugía y resultado principal. Se incluyeron 15 estudios con 1936 participantes (1618 excluyendo controles sanos). 9 estudios fueron combinados en un metanálisis que demostró una diferencia no estadísticamente significativa de -3,86 minutos en AMC tras cirugía (p = 0,06). El análisis por subgrupos de las 5 cohortes sometidas a turbinoplastia con microdebridador si fueron estadísticamente significativas con una diferencia de -7,02 minutos (p < 0,001). El grupo sometido a laser (4 cohortes) también obtuvo diferencia estadística, aunque menor, -1,01 minutos (p < 0,001). Esta revision y metaanálisis sugiere que la cirugía turbinal no afecta al aclaramiento mucociliar. La evidencia disponible también sugiere que las técnicas menos agresivas con la mucosa mejoran el AMC, mientras que las agresivas podrían aumentarlo o no modificarlo. Este efecto beneficioso se observa desde el 1º al 3º mes postquirúrgico. Sin embargo, para poder obtener adecuadas conclusiones, debe existir un método estandarizado para medir el AMC, así como un método para describir adecuadamente la extensión quirúrgica. (AU)

Effect of turbinate surgery on mucociliary clearance. A systematic review and metanalysis.

Despite the fact that turbinate surgery provides satisfactory results regarding nasal obstruction, most of these procedures are destructive, to some extent, for the respiratory epithelium. There are valid hypotheses suggesting either that turbinate surgery may improve mucociliary clearance (MCC) by improving rhinitis, as well hypotheses suggesting that these surgeries may impair it by damaging the nasal ciliated epithelia. This systematic review is designed with the objective of exploring the effect of turbinate surgery on MCC. Pubmed (Medline), the Cochrane Library, EMBASE, SciELO were analyzed. Four authors members of the YO-IFOS rhinology study group independently analyzed the articles. Extracted variables encompassed: sample size, age, indication for surgery, surgical technique, method used to measure mucociliary clearance, mucociliary transport time before and after surgery, and main outcome. 15 studies with a total population of 1936 participants (1618 patients excluding healthy controls) met the inclusion criteria. 9 studies could be combined in a metanalysis, wich revealed a non-statistically significant decrease of 3.86 min in MCTT after turbinate surgery (p = 0.06). The subgroup analysis of the 5 cohorts who underwent microdebrider turbinoplasty reached statistical significance under a random effect model, revealing a 7.02 min decrease in MCTT (p < 0.001). The laser turbinoplasty subgroup, composed of 4 cohorts, also reached significance, although the difference was lower than that for microdebrider turbinoplasty, 1.01 min (p < 0.001). This systematic review and meta-analysis suggests that turbinate surgery does not compromise mucociliary clearance. The available evidence also suggests that turbinate surgery with mucosa sparing techniques improves MCC, while with aggressive techniques it increases or remains the same. This beneficial effect is evident since the first to third month after surgery. However, for solid conclusions, a standard way to measure MCTT should be stablished, as well as a method to appropriately describe the extension of the surgery.

The Role of Corticosteroid Nasal Irrigations in the Management of Chronic Rhinosinusitis: A State-of-the-Art Systematic Review.

Chronic rhinosinusitis (CRS) is a highly prevalent condition. CRS is usually managed with intranasal corticosteroids, useful both before as well as after endoscopic sinus surgery (ESS). However, the greatest drawback of these low-volume sprays is the inadequate delivery into the paranasal sinuses, even after ESS. Recent studies have shown that high-volume steroid nasal rinse (HSNR) has a significantly better penetration of the paranasal sinuses. The purpose of this state-of-the-art review is to systematically overview the current literature about the role of nasal rinses with steroids in CRS. Four authors examined four databases (Embase, Pubmed, Scielo, Cochrane). This review identified 23 studies answering 5 research questions. It included 1182 participants, 722 cases, and 460 controls. Available evidence suggests a potential positive effect of HSNR, which seems to be higher in CRS with nasal polyps. More well-designed studies are needed in order to obtain solid conclusions. The evidence is solid regarding the safety of this treatment modality in the short and long-term. We expect that this lack of severe negative effects will facilitate the acceptance of this treatment modality and the development of future studies.

Allergic rhinitis and dental caries: A systematic review.

OBJECTIVE: Dental caries is one of the most common chronic diseases affecting millions of people globally. Some studies revealed the presence of bidirectional relationship between allergic rhinitis (AR) and oral diseases, with each disease having a potential impact on the other. In this study we aimed to systematically review the literature and analyze the available evidence regarding whether AR contributes to the development of dental caries. METHODS: Three authors, members of the YO-IFOS rhinology study group, independently analyzed the data sources (Pubmed, the Cochrane Library, EMBASE, SciELO) for papers assessing the relationship between rhinitis and caries, in adult and pediatric patients. RESULTS: Eight studies met the inclusion criteria (87612 participants). Six studies were performed in children. A total of three studies found an association between AR and dental caries. Only two studies had adjusted the measure of effect for potentially confounding variables. Regarding the quality of the selected studies according to the NICE classification, the most observed methodological limitations detected were: (1) the cross-sectional design of the included studies which could have introduced a simultaneity bias, and (2) not clearly reporting the inclusion and exclusion criteria. CONCLUSION: This systematic review can neither confirm nor deny the presence of an association between AR and caries. Despite the evidence is very scarce to conclude a relationship between AR and caries, the option for examining patients with repetitive caries by an otolaryngologist and those with AR by odontologist should be considered, as these examinations do not possess any risk for the patient.

Allergic rhinitis and dental caries: A systematic review

Objective: Dental caries is one of the most common chronic diseases affecting millions of people globally. Some studies revealed the presence of bidirectional relationship between allergic rhinitis (AR) and oral diseases, with each disease having a potential impact on the other. In this study we aimed to systematically review the literature and analyze the available evidence regarding whether AR contributes to the development of dental caries. Methods: Three authors, members of the YO-IFOS rhinology study group, independently analyzed the data sources (Pubmed, the Cochrane Library, EMBASE, SciELO) for papers assessing the relationship between rhinitis and caries, in adult and pediatric patients. Results: Eight studies met the inclusion criteria (87612 participants). Six studies were performed in children. A total of three studies found an association between AR and dental caries. Only two studies had adjusted the measure of effect for potentially confounding variables. Regarding the quality of the selected studies according to the NICE classification, the most observed methodological limitations detected were: (1) the cross-sectional design of the included studies which could have introduced a simultaneity bias, and (2) not clearly reporting the inclusion and exclusion criteria. Conclusion: This systematic review can neither confirm nor deny the presence of an association between AR and caries. Despite the evidence is very scarce to conclude a relationship between AR and caries, the option for examining patients with repetitive caries by an otolaryngologist and those with AR by odontologist should be considered, as these examinations do not possess any risk for the patient (AU)

A Trace Mineral Injection before Joining and Lambing Increases Marking Percentages and Lamb Weights on Diverse Farms in Victoria, Australia.

This study was conducted on five commercial farms across Victoria, Australia, between September 2018 and November 2019, where the TM status of ewes was within normal ranges before joining. Mix breed ewes (n = 1484) were randomly allocated to receive either nil treatment (Control) or two injections of an ITM product containing zinc (40 mg/mL), manganese (10 mg/mL), selenium (3 mg/mL), and copper (10 mg/mL); 0.2 mL per 10 kg BW (Multimin® plus Copper for Sheep, Virbac (Australia) Pty Ltd., Milperra, NSW, Australia) 30 days before the start of joining and 30 days before the start of lambing. Approximately 90 days after joining, pregnancy status and conception rate were determined by ultrasound. The marking rate was determined approximately four weeks after the end of lambing, and lamb weights were determined at weaning (12 weeks after the end of lambing). In all farms, ITM treatment did not affect the conception rate. The average conception rate was 156 ± 11.0% (p > 0.05). The marking rate of ITM ewes was 9% higher than control ewes (95% Confidence Interval 3−21%). Lambs born to ITM ewes were 2.31 kg heavier at weaning than lambs born to control ewes (p < 0.001). Although not significant, ewe mortality across farms was 1.3% lower in the ITM group than in the control group. On average, ewes treated with ITM pre-joining and pre-lambing produced more and heavier lambs that represent an extra AU$ 2338 per 100 ewes net benefit for the producer. These results help to understand strategic TM supplementation for animal health, performance and farm profitability beyond the treatment of clinical deficiencies.

Rhinomanometry with and without decongestant used to select children for adenoidectomy: a cohort study.

OBJECTIVE: Adenoid hypertrophy may coexist, and often does, with rhinitis. Therefore, in some cases, adenoidectomy alone, despite the fact that it reduces nasal resistance, may be insufficient to restore nasal breathing. Juliusson et al. suggested using rhinomanometry with and without nasal decongestant as a method for selecting patients for adenoidectomy. In this study, we aim to assess whether the decongestant test, when using normative data, is useful to select children for adenoidectomy. METHODS: Children between 4 and 15 years old undergoing adenoidectomy were selected from two tertiary referral university hospitals. Participants underwent anterior active rhinomanometry with and without nasal decongestant before and after surgery. Parents fill in the sinus and nasal quality-of-life survey (SN5). RESULTS: 47 participants were included, and mean age 6.5 ± 2.15. 2 cohorts were defined according to the result of the nasal decongestant test (> 40% improvement in nasal resistance or not). There is a statistically significant difference between groups, with a higher improvement in nasal resistance and airflow after adenoidectomy in the group with less than 40% improvement in nasal resistance. CONCLUSIONS: In conclusion, this study supports the use of the decongestant test with rhinomanometry to select children for adenoidectomy; especially as it has proven to be a simple technique, harmless, fast, and easily performed on collaborative children.

Long-term Evaluation of Residual Viremia in a Clinical Trial of Dolutegravir Plus Lamivudine as Maintenance Treatment for Participants With and Without Prior Lamivudine Resistance.

In this pilot clinical trial, we evaluated rates of residual replication in persons without lamivudine resistance-associated mutations in proviral DNA population sequencing who switched to dolutegravir plus lamivudine. After 144 weeks, there was no signal of changes in residual viremia based on qualitative detection methods, irrespective of past lamivudine resistance. Clinical Trials Registration. NCT03539224.

Assessing the Listeria monocytogenes transference during mechanical slicing of mozzarella cheese.

Listeriosis is a foodborne disease caused by Listeria monocytogenes (LM) and has been linked to the consumption of sliced mozzarella cheese. This study aimed to assess the LM transference during mechanical slicing of mozzarella cheese and its growth during refrigerated storage. Mozzarella cheese was contaminated with LM and 100 slices containing approximately 5 log CFU/slice were produced. Next, 100 slices of non-contaminated cheese were sliced using a contaminated blade (3.67log CFU/10 cm2). LM was quantified on the blade and slices right after slicing and after storage at 10 °C for 10 and 15 days. Results demonstrated that increasing counts of LM were transferred to the blade, comparing the first and the fifth slices (2.71 and 3.22log CFU/10 cm2, respectively, p ≤ 0.05), however, transference stabilized after the 50th slice (3.75 CFU/10 cm2). The blade transferred 1.69-2.66 log CFU/g of LM to different slices. At the end of the storage at 10 °C by 10 and 15 days, LM counts increased to 1.51 and 1.69 log CFU/g, respectively, indicating that LM population can increase if the cheese is stored for a long time.

Detection of archived lamivudine-associated resistance mutations in virologically suppressed, lamivudine-experienced HIV-infected adults by different genotyping techniques (GEN-PRO study).

BACKGROUND: Previously selected lamivudine resistance-associated mutations (RAMs) may remain archived within the proviral HIV-DNA. OBJECTIVES: To evaluate the ability of proviral DNA genotyping to detect lamivudine RAMs in HIV-1 virologically suppressed participants; the correlation between Sanger and next generation sequencing (NGS); and predictive factors for detection of lamivudine RAMs in proviral DNA. METHODS: Cross-sectional study of participants on stable antiretroviral therapy and suppressed for ≥1 year. Analysis of proviral DNA was performed by Sanger sequencing in whole blood and by NGS in PBMCs. RESULTS: We analysed samples from 102 subjects (52 with and 50 without lamivudine RAMs in historical plasma RNA-genotypes). Among participants with previous lamivudine resistance, Sanger sequencing detected RAMs in 26.9%. Detection rates significantly increased using NGS: 47.9%, 64.6%, 75% and 87.5% with the 20%, 10%, 5% and 1% thresholds, respectively. As for participants without historical lamivudine resistance, Sanger detected the RAMs in 1/49 (2%), and NGS (5% threshold) in 8/45 (17.8%). Multivariate models fitted to the whole population revealed that having a history of lamivudine resistance was a risk factor for detection of lamivudine RAMs by NGS. Among participants with historical lamivudine resistance, multivariate analysis showed that a longer time since HIV diagnosis was associated with persistence of archived mutations by NGS at thresholds of >10% [OR 1.10 (95% CI: 1.00-1.24)] and >5% [OR 1.16 (95% CI: 1.02-1.32)]. CONCLUSIONS: Proviral DNA Sanger sequencing does not detect the majority of historical lamivudine RAMs. NGS increases the sensitivity of detection at lower thresholds, although the relevance of these minority populations with lamivudine RAMs needs further evaluation.

A pilot study comparing the pharmacokinetics of injectable cyanocobalamin and hydroxocobalamin associated with a trace mineral injection in cattle.

Injectable vitamin B12 (cobalamin) is traditionally used to prevent or treat vitamin B12 deficiencies in ruminants. Sheep and human studies have demonstrated the superiority of a single dose of hydroxocobalamin (OHB12) over cyanocobalamin (CNB12) in maintaining high levels of cobalamin in plasma and liver. However, limited data are available for cattle. The purpose of this study was to compare the pharmacokinetics of two forms of cobalamin-OHB12 and CNB12-as a single subcutaneous injection of 28 µg/kg BW at the same time of a trace mineral injection in six non-cobalt/B12 -deficient Holstein-Friesian steers. Plasma and liver samples were obtained to determine cobalamin concentration after treatment. Cyanocobalamin had lower retention in plasma and liver than OHB12 (p < .05). Cobalamin levels peaked in plasma by 8 h after treatment in both groups. However, OHB12 reached a higher peak compared to CNB12. Levels of cobalamin in plasma dropped closer to baseline levels 24 h after CNB12 treatment while OHB12 maintained higher concentrations. Hydroxocobalamin increased significantly hepatic concentration of cobalamin 28 days after treatment, while CNB12 did not increase liver levels relative to pre-treatment (p < .05). These results confirm that a single subcutaneous OHB12 injection increases the level of cobalamin in the blood in the first 24 hours, and this increase is maintained in the liver for at least 28 days.

Long-term efficacy of dolutegravir plus lamivudine for maintenance of HIV viral suppression in adults with and without historical resistance to lamivudine: Week 96 results of ART-PRO pilot study.

BACKGROUND: In the ART-PRO pilot trial there were no virological failures through 48 weeks of treatment with dolutegravir plus lamivudine in suppressed individuals with and without archived lamivudine resistance-associated mutations (RAMs) detected through next-generation sequencing (NGS) but without evidence of lamivudine RAMs in baseline proviral DNA population sequencing. OBJECTIVES: To present 96 week results from ART-PRO. METHODS: Open-label, single-arm pilot trial. At baseline, all participants switched to dolutegravir plus lamivudine. Participants were excluded if proviral DNA population genotyping detected lamivudine RAMs. To detect resistance minority variants, proviral DNA NGS was retrospectively performed from baseline samples. For this analysis the efficacy endpoint was the proportion of participants with <50 HIV-1 RNA copies/mL at week 96. Safety and tolerability outcomes were incidence of adverse events and treatment discontinuations. RESULTS: Forty-one participants were included, 21 with lamivudine RAMs in historical plasma RNA genotypes. Baseline proviral DNA NGS detected lamivudine RAMs (M184V/I and/or K65R/E/N) above a 5% threshold in 71.4% (15/21) and 15% (3/20) of participants with and without history of lamivudine resistance, respectively. At 96 weeks, 90.2% of participants achieved the efficacy endpoint. Between week 48 and 96 there was one discontinuation due to consent withdrawal and no discontinuations related to adverse events. Two participants had a transient viral rebound, both re-suppressed on dolutegravir plus lamivudine. Through week 96, there were no virological failures. CONCLUSIONS: In this pilot trial, dolutegravir plus lamivudine maintained virological suppression at 96 weeks despite historical lamivudine resistance and persisting archived minority lamivudine RAMs.

El sentido de vida, una condición existencial / The meaning of life, an existential condition

El ser humano siempre ha estado en la constante búsqueda de sentido y preguntándose por su existencia. El hombre moderno además de encontrase en esa búsqueda, también se halla permeado por la angustia constante, está sometido a la cosificación de sí mismo, la hipeconectividad, el consumismo, la incertidumbre y la inmediatez, lo cual lo conduce de manera casi inminente al aburrimiento y el tedio, es decir, a la frustración existencial, llevándolo a enfrentarse con sus pseudosatisfactores y dejándolo de cara ante el vacío de su propia existencia y el cuestionamiento: ¿para qué estoy en el mundo?

Human beings have been in a constant search for meaning and wondering about its existence. The modern man, in addition to finding himself in this search, is also permeated by constant anguish, is subjected to the objectification of himself, hyper-connectivity, consumerism, uncertainty and immediacy, which leads him almost imminently to boredom, which is existential frustration, leading him to face his pseudo-satisfiers and leaving him face to face with the emptiness of his own existence and the question: what am I in the world for?

Dolutegravir plus lamivudine for maintenance of HIV viral suppression in adults with and without historical resistance to lamivudine: 48-week results of a non-randomized, pilot clinical trial (ART-PRO).

BACKGROUND: We investigated the efficacy of a switch to dolutegravir plus lamivudine in aviremic individuals without evidence of persistent lamivudine resistance-associated mutations in baseline proviral DNA population sequencing. METHODS: Open-label, single-arm, 48-week pilot trial. HIV-1 infected adults, naïve to integrase inhibitors, with CD4+ above 350 cell/µL and fewer than 50 HIV-1 RNA copies per mL the year prior to study entry switched to dolutegravir plus lamivudine. Participants were excluded if baseline proviral DNA population genotyping detected lamivudine resistance-associated mutations. To detect resistance minority variants, proviral DNA next-generation sequencing was retrospectively performed from baseline samples. Primary efficacy endpoint was proportion of participants with fewer than 50 HIV-1 RNA copies per mL at week 48. Safety and tolerability outcomes were incidence of adverse events and treatment discontinuations. ART-PRO is registered with ClinicalTrials.gov, NCT03539224. FINDINGS: 41 participants switched to dolutegravir plus lamivudine, 21 with lamivudine resistance mutations in historical plasma genotypes. Baseline next-generation sequencing detected lamivudine resistance mutations (M184V/I and/or K65R/E/N) over a 5% threshold in 15/21 (71·4%) and 3/20 (15%) of participants with and without history of lamivudine resistance, respectively. At week 48, 92·7% of participants (38/41) had fewer than 50 HIV-1 RNA copies per mL. There were no cases of virologic failure. Three participants with historical lamivudine resistance were prematurely discontinued from the study (2 protocol violations, one adverse event). Ten participants (4 in the group with historical lamivudine resistance) had a transient viral rebound, all resuppressed on dolutegravir plus lamivudine. There were 28 drug-related adverse events, only one leading to discontinuation. INTERPRETATION: In this pilot trial, dolutegravir plus lamivudine was effective in maintaining virologic control despite past historical lamivudine resistance and presence of archived lamivudine resistance-associated mutations detected by next generation sequencing. Further studies are needed to confirm our results. FUNDING: Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III PI16/00837-PI16/00678.

Effects of heat stress on animal physiology, metabolism, and meat quality: A review.

Heat stress is one of the most stressful events in the life of livestock with harmful consequences for animal health, productivity and product quality. Ruminants, pigs and poultry are susceptible to heat stress due to their rapid metabolic rate and growth, high level of production, and species-specific characteristics such as rumen fermentation, sweating impairment, and skin insulation. Acute heat stress immediately before slaughter stimulates muscle glycogenolysis and can result in pale, soft and exudative (PSE) meat characterized by low water holding capacity (WHC). By contrast, animals subjected to chronic heat stress, have reduced muscle glycogen stores resulting in dark, firm and dry (DFD) meat with high ultimate pH and high WHC. Furthermore, heat stress leads to oxidative stress, lipid and protein oxidation, and reduced shelf life and food safety due to bacterial growth and shedding. This review discusses the scientific evidence regarding the effects of heat stress on livestock physiology and metabolism, and their consequences for meat quality and safety.

High Levels of Resistance to Cephalosporins Associated with the Presence of Extended-Spectrum and AmpC ß-Lactamases in Escherichia coli from Broilers in Southern Brazil.

The clinical importance of extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli has increased steadily over the years. The presence of the blaTEM, blaSHV, and blaCTX-M genes in the environment has been recently recognized as an important issue in the dissemination of resistance to cephalosporins. Food animals are considered important vectors for transfer of ESBL genes from the environment to humans. The objective of this study was to characterize the ESBL genes (blaTEM, blaSHV, and blaCTX-M types) that were most prevalent among 343 ceftazidime-resistant E. coli isolates (17 batches from 12 different farms) obtained from cloacal swabs of broiler chicken in southern Brazil. The blaSHV, blaCTX-M, blaTEM, blaIMP-type, blaVIM-type, blaNDM-1, blaKPC-type, blaGES-type, blaOXA-48, and mcr-1 genes were evaluated by polymerase chain reaction. A total of 27 (7.9%) E. coli isolates were positive for ESBL genes as follows: 24 for blaCTX-M (23 blaCTX-M-2 Group and 1 blaCTX-M-8) and 3 for blaSHV (2 blaSHV-2a and 1 blaSHV-18). A random sample of 32 ceftazidime/cefotaxime-resistant isolates that were negative for ESBL genes were evaluated for the presence of blaCMY-2 and 24 (75%) tested positive. We detected the blaCMY-2 gene in isolates from all farms. All isolates positive for ESBL or blaCMY-2 are considered multidrug resistant (resistant to at least three antibiotic classes). Our results suggest that broiler chickens are an important reservoir of blaCMY-2 and ESBL genes, including blaSHV-2a, described for the first time in animals originating from Brazil in this study, and blaSHV-18, which has never been described in Brazil before. This fact highlights the importance of controlling the use of antibiotics in animal production to reduce environmental sources of resistance genes.

Conjugates of Cryptophycin and RGD or isoDGR Peptidomimetics for Targeted Drug Delivery.

RGD-cryptophycin and isoDGR-cryptophycin conjugates were synthetized by combining peptidomimetic integrin ligands and cryptophycin, a highly potent tubulin-binding antimitotic agent across lysosomally cleavable Val-Ala or uncleavable linkers. The conjugates were able to effectively inhibit binding of biotinylated vitronectin to integrin αvß3, showing a binding affinity in the same range as that of the free ligands. The antiproliferative activity of the novel conjugates was evaluated on human melanoma cells M21 and M21-L with different expression levels of integrin αvß3, showing nanomolar potency of all four compounds against both cell lines. Conjugates containing uncleavable linker show reduced activity compared to the corresponding cleavable conjugates, indicating efficient intracellular drug release in the case of cryptophycin-based SMDCs. However, no significant correlation between the in vitro biological activity of the conjugates and the integrin αvß3 expression level was observed, which is presumably due to a non-integrin-mediated uptake. This reveals the complexity of effective and selective αvß3 integrin-mediated drug delivery.