ABSTRACT
The inoculum effect, characterized by diminished antibacterial activity at high bacterial inocula, is studied in the context of beta-lactam and beta-lactamase inhibitor combinations against beta-lactamase-producing Enterobacterales. The inhibition of ESBL + OXA-48 and KPC enzymes, in combination with ceftazidime, demonstrates encouraging results. In this study, 20 Klebsiella pneumoniae isolates were tested with different inocula (1-5 × 105 and 1-5 × 107 cfu/ml) using broth microdilution methods. The inoculum effect was observed in meropenem against OXA-48 + CTX-M-15- and KPC-2-producing isolates but not with ceftazidime/avibactam. Notably, meropenem exhibited inoculum effect against carbapenemase-producing strains, whereas ceftazidime-avibactam remained effective. We conclude that ceftazidime-avibactam is recommended for high-inoculum infections.
ABSTRACT
OBJECTIVES: To conduct brainstem MRI shape analysis across neurodegenerative parkinsonisms and control subjects (CS), along with its association with clinical and cerebrospinal fluid (CSF) correlates. METHODOLOGY: We collected demographic and clinical variables, performed planimetric and shape MRI analyses, and determined CSF neurofilament-light chain (NfL) levels in 84 participants: 11 CS, 12 with Parkinson's disease (PD), 26 with multiple system atrophy (MSA), 21 with progressive supranuclear palsy (PSP), and 14 with corticobasal degeneration (CBD). RESULTS: MSA featured the most extensive and significant brainstem shape narrowing (that is, atrophy), mostly in the pons. CBD presented local atrophy in several small areas in the pons and midbrain compared to PD and CS. PSP presented local atrophy in small areas in the posterior and upper midbrain as well as the rostral pons compared to MSA. Our findings of planimetric MRI measurements and CSF NfL levels replicated those from previous literature. Brainstem shape atrophy correlated with worse motor state in all parkinsonisms and with higher NfL levels in MSA, PSP, and PD. CONCLUSION: Atypical parkinsonisms present different brainstem shape patterns which correlate with clinical severity and neuronal degeneration. In MSA, shape analysis could be further explored as a potential diagnostic biomarker. By contrast, shape analysis appears to have a rather limited discriminant value in PSP. KEY POINTS: ⢠Atypical parkinsonisms present different brainstem shape patterns. ⢠Shape patterns correlate with clinical severity and neuronal degeneration. ⢠In MSA, shape analysis could be further explored as a potential diagnostic biomarker.
Subject(s)
Multiple System Atrophy , Parkinson Disease , Parkinsonian Disorders , Humans , Pilot Projects , Retrospective Studies , Parkinsonian Disorders/diagnosis , Mesencephalon/diagnostic imaging , Parkinson Disease/diagnostic imaging , Pons/diagnostic imaging , Magnetic Resonance Imaging , Multiple System Atrophy/diagnosis , Atrophy , Biomarkers , Diagnosis, DifferentialABSTRACT
Identification of risk factors influencing the duration of carriage of multidrug-resistant Gram-negative bacilli (MDR-GNB) may be useful for infection control. The aim of this study is to estimate the impact of several factors collected for routine hospital surveillance on the duration of carriage of selected MDR-GNB. From January 2015 to July 2021, patients with at least two clinical/surveillance samples positive for MDR-GNB different from ESBL-producing E. coli or AmpC - exclusively producing Enterobacterales were assessed. Microorganisms, age, number of admissions, clinical or rectal sample, sex, and admission service were evaluated as risk factors. Multivariate analysis was performed by a Cox proportional hazard model. A total of 1981 episodes of colonization were included. Involved microorganisms were ESBL-Klebsiella pneumoniae (KP) in 1057 cases (53.4%), other ESBL-non-E. coli Enterobacterales in 91 (4.6%), OXA-48-KP in 263 (13.3%), KPC-KP in 90 (4.5%), VIM-KP in 29 (1.5%), carbapenemase-producing non-KP Enterobacterales (CP-non-KP) in 124 (6.3%), and MDR Pseudomonas aeruginosa (MDR-PAER) in 327 (16.5%). No differences in duration of colonization were observed among ESBL-KP (median colonization time 320 days), ESBL-non-E. coli Enterobacterales (226 days), OXA48-KP (305 days), and MDR-PAER (321 days). For each group, duration of colonization was significantly longer than that of KPC-KP (median colonization time 60 days), VIM-KP (138 days), and CP-non-KP (71 days). Male sex (HR = 0.88; 95% CI 0.78-0.99), detection in Hepatology-Gastroenterology (HR = 0.71; 95% CI 0.54-0.93), clinical sample (HR = 0.61; 95% CI 0.53-0.69), and > 2 admissions after first detection (HR = 0.47; 95% CI 0.42-0.52) were independent predictors of longer carriage, whereas VIM-KP (HR = 1.61; 95% CI 1.04-2.48), KPC-KP (HR = 1.85; 95% CI 1.49-2.3), and CP-non-KP (HR = 1.92; 95% CI 1.49-2.47) were associated with shorter colonization time. Duration of colonization was significantly longer for ESBL-KP, other ESBL-non-E. coli Enterobacterales, OXA-48-KP, and MDR-PAER. For these microorganisms, prolonging surveillance up to 2.5-3 years should be considered. Male sex, clinical sample, multiple readmissions, admission service, and type of microorganism are independent predictors of the duration of carriage.
Subject(s)
Gram-Negative Bacteria , beta-Lactamases , Humans , Male , Hospitalization , Risk Factors , Gastrointestinal Tract/microbiology , Klebsiella pneumoniae , Escherichia coli , Drug Resistance, Multiple, Bacterial , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic useABSTRACT
INTRODUCTION: It remains unclear whether rheumatoid arthritis might be a cause of false positive of the histology for the diagnosis of prosthetic joint infection. Our aim was to evaluate the usefulness of the histology for the diagnosis of infection during hip and knee prosthesis revision in patients with rheumatoid arthritis. MATERIALS AND METHODS: All patients with the diagnosis of rheumatoid arthritis (RA) undergoing hip or knee revision surgery (total or partial) were retrospectively reviewed. Positive histology was considered when ≥ 5 neutrophils per high-power field (400×) were found in at least five separate microscopic fields. Patients who presented ≥ 2 positive cultures for the same microorganism or the presence of fistula were considered as "true positives". RESULTS: Thirty-two hip (n = 12) and knee (n = 20) revision procedures were performed. Sensitivity, specificity, positive and negative predictive value of the histology were 50%, 78.6%, 25% and 91.7%, respectively. Six out of the eight patients presenting with positive histology had negative cultures (75.0% of false positives). CONCLUSIONS: Our results suggest that, in the context of RA, negative histological results have a very high negative predictive value. RA poses false positive histology results for the diagnosis of infection during hip and knee revision when conventional cultures are used for diagnosis of infection.
Subject(s)
Arthritis, Rheumatoid , Arthroplasty, Replacement, Hip , Hip Prosthesis , Knee Prosthesis , Prosthesis-Related Infections , Arthritis, Rheumatoid/complications , Arthritis, Rheumatoid/surgery , Humans , Prosthesis-Related Infections/surgery , Reoperation , Retrospective StudiesABSTRACT
Tetraspanins are a superfamily of transmembrane proteins that in flatworms have structural roles in the development, maturation or stability of the tegument. Several tetraspanins are considered as potential candidates for vaccines or drugs against helminths. Monopisthocotylean monogeneans are ectoparasites of fish that are health hazards for farmed fish. The aim of this study was to identify in silico putative tetraspanins in the genomic datasets of four monopisthocotylean species. The analysis predicted and classified 40 tetraspanins in Rhabdosynochus viridisi, 39 in Scutogyrus longicornis, 22 in Gyrodactylus salaris and 13 in Neobenedenia melleni, belonging to 13 orthologous groups. The high divergence of tetraspanins made it difficult to annotate their function. However, a conserved group was identified in different metazoan taxa. According to this study, metazoan tetraspanins can be divided into 17 monophyletic groups. Of the 114 monogenean tetraspanins, only seven were phylogenetically close to tetraspanins from non-platyhelminth metazoans, which suggests that this group of proteins shows rapid sequence divergence. The similarity of the monopisthocotylean tetraspanins was highest with trematodes, followed by cestodes and then free-living platyhelminths. In total, 27 monopisthocotylean-specific and 34 flatworm-specific tetraspanins were identified. Four monogenean tetraspanins were orthologous to TSP-1, which is a candidate for the development of vaccines and a potential pharmacological target in trematodes and cestodes. Although studies of tetraspanins in parasitic flatworms are scarce, this is an interesting group of proteins for the development of new methods to control monogeneans.
Subject(s)
Fish Diseases , Platyhelminths , Tetraspanins , Animals , Fish Diseases/parasitology , Fishes , Phylogeny , Platyhelminths/genetics , Platyhelminths/metabolism , Tetraspanins/chemistry , Tetraspanins/classification , Tetraspanins/geneticsABSTRACT
Vogt-Koyanagi-Harada (VKH) is an autoimmune disease characterized by inflammation in tissues that contain melanocytes. We aimed to increase the knowledge regarding immunological pathways deregulated in VKH disease. We compared the percentages of circulating natural killer (NK), NK T and T cells expressing the activatory markers: CD16, CD69, NK group 2D (NKG2D), natural cytotoxicity triggering receptor 3 (Nkp30), natural cytotoxicity triggering receptor 1 (Nkp46) and the inhibitory marker: NK group 2 member A (NKG2A) in 10 active VKH patients, 20 control subjects (CTR) and seven patients with Behçet disease (BD) by flow cytometry. Cytotoxic potential of NK cells was determined through the degranulation marker CD107a expression after contact with K562 cells by flow cytometry. Moreover, plasmatic levels of 27 cytokines were determined with a multiplex bead-based assay. VKH patients showed higher percentages of NKG2Dpos NK and NK T cells versus CTR. The cytotoxic potential of NK cells induced by K562 cells was comparable between VKH patients and CTR. Finally, higher concentrations of interleukin (IL)-4, IL-5, IL-7, IL-17 and platelet-derived growth factor-subunits B (PDGF-bb) were detected in plasma of VKH patients versus CTR. The immune profile of VKH patients was similar to that of BD patients.
Subject(s)
Killer Cells, Natural/immunology , NK Cell Lectin-Like Receptor Subfamily K/immunology , Natural Killer T-Cells/immunology , Uveomeningoencephalitic Syndrome/immunology , Adult , Becaplermin/blood , Becaplermin/immunology , Becaplermin/metabolism , Behcet Syndrome/blood , Behcet Syndrome/immunology , Behcet Syndrome/metabolism , Cells, Cultured , Cytokines/blood , Cytokines/immunology , Cytokines/metabolism , Female , Flow Cytometry , Humans , K562 Cells , Killer Cells, Natural/metabolism , Male , Middle Aged , NK Cell Lectin-Like Receptor Subfamily K/blood , NK Cell Lectin-Like Receptor Subfamily K/metabolism , Natural Killer T-Cells/metabolism , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Uveomeningoencephalitic Syndrome/metabolism , Uveomeningoencephalitic Syndrome/therapyABSTRACT
Ring dosimeters for personal dosimetry are calibrated in accredited laboratories following ISO 4037-3 guidelines. The simultaneous irradiation of multiple dosimeters would save time, but has to be carefully studied, since the scattering conditions could change and influence the absorbed dose in nearby dosimeters. Monte Carlo simulations using PENELOPE-2014 were performed to explore the need to increase the uncertainty ofHp0.07in the simultaneous irradiation of three and five DXT-RAD 707H-2 (Thermo Scientific) ring dosimeters with beam qualities: N-30, N-80 and N-300. Results show that the absorbed dose in each dosimeter is compatible with each of the others and with the reference simulation (a single dosimeter), with a coverage probability of 95% (k= 2). Comparison with experimental data yielded consistent results with the same coverage probability. Therefore, five ring dosimeters can be simultaneously irradiated with beam qualities ranging, at least, between N-30 and N-300 with a negligible impact on the uncertainty ofHp0.07.
Subject(s)
Radiation Dosimeters , Radiometry , Calibration , Computer Simulation , Monte Carlo MethodABSTRACT
INTRODUCTION: Colorectal cancer (CRC) is a worldwide problem of public health and arises mainly from polyps. In last 25 years, a strategy called chemoprevention that consists of food intake like purple corn and turmeric or chemical substances like acetyl salicylic acid (ASA) and non-steroidal anti-inflammatory drugs (NSAIDs) that prevent effectively carcinogenesis reducing the risk of polyp development. OBJECTIVE: To determine the efficacy and safety of lyophilized concentrate of purple corn (Zea mays L.) 200 mg in the prevention of colonic polyps development in private gastroenterological practice Methods: we randomly assigned 112 patients (cases) to receive this product and 112 patients (controls) to receive placebo, during 3 years. Both groups had similar demographic, clinical and medical history characteristics. RESULTS: we found that cases developed 83% less polyps than controls (p <0.001). The cases that developed polyps were smaller in number, size and histology than at the beginning of the trial. The adverse events that cases presented were 4.5% similar to controls, mainly petechiae. CONCLUSION: We conclude that the lyophilized concentrate of purple corn (Zea mays L.) 200 mg was effective and safe in preventing the developmentof colonic polyps.
Subject(s)
Colonic Polyps , Zea mays , Anti-Inflammatory Agents, Non-Steroidal , Aspirin , Chemoprevention , Colonic Polyps/prevention & control , HumansABSTRACT
BACKGROUND AND OBJECTIVE: Since the initial anecdotal reports of coronavirus disease 2019 (COVID-19) from China, a growing number of studies have reported on smell and/or taste dysfunction (STD). Objective: The aim of our study was to investigate the frequency and severity of STD in COVID-19 patients and to evaluate the association with demographic characteristics, hospital admission, symptoms, comorbidities, and blood biomarkers. METHODS: We performed a multicenter cross-sectional study on patients who were positive for SARS-CoV-2 (n=846) and controls (n=143) from 15 Spanish hospitals. Data on STD were collected prospectively using an in-person survey. The severity of STD was categorized using a visual analog scale. We analyzed time to onset, recovery rate, time to recovery, hospital admission, pneumonia, comorbidities, smoking, and symptoms. RESULTS: STD was at least 2-fold more common in COVID-19-positive patients than in controls. COVID-19-positive hospitalized patients were older, with a lower frequency of STD, and recovered earlier than outpatients. Analysis stratified by severity of STD showed that more than half of COVID-19 patients presented severe loss of smell (53.7%) or taste (52.2%); both senses were impaired in >90%. In the multivariate analysis, older age (>60 years), being hospitalized, and increased C-reactive protein were associated with a better sense of smell and/or taste. COVID-19-positive patients reported improvement in smell (45.6%) and taste (46.1%) at the time of the survey; in 90.6% this was within 2 weeks of infection. CONCLUSION: STD is a common symptom in COVID-19 and presents mainly in young and nonhospitalized patients. More studies are needed to evaluate follow-up of chemosensory impairment.
Subject(s)
Betacoronavirus , Coronavirus Infections/complications , Coronavirus Infections/epidemiology , Olfaction Disorders/epidemiology , Olfaction Disorders/etiology , Pneumonia, Viral/complications , Pneumonia, Viral/epidemiology , Taste Disorders/epidemiology , Taste Disorders/etiology , Adult , Age Factors , Aged , Aged, 80 and over , Betacoronavirus/genetics , Betacoronavirus/immunology , COVID-19 , Case-Control Studies , Coronavirus Infections/diagnosis , Coronavirus Infections/virology , Cross-Sectional Studies , Female , Hospitalization , Humans , Male , Middle Aged , Olfaction Disorders/diagnosis , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/virology , Polymerase Chain Reaction , Public Health Surveillance , SARS-CoV-2 , Severity of Illness Index , Spain/epidemiology , Symptom Assessment , Taste Disorders/diagnosis , Young AdultABSTRACT
Dalbavancin is a lipoglycopeptide with potent activity against Gram-positive microorganisms, a long half-life, a favorable safety profile, and a high concentration in bone, which makes it an interesting alternative for treatment of osteoarticular infections. We performed a multicentric retrospective study of all patients with an osteoarticular infection (septic arthritis, spondylodiscitis, osteomyelitis, or orthopedic implant-related infection) treated with at least one dose of dalbavancin between 2016 and 2017 in 30 institutions in Spain. In order to evaluate the response, patients with or without an orthopedic implant were separated. A total of 64 patients were included. Staphylococcus epidermidis and Staphylococcus aureus were the most frequent microorganisms. The reasons for switching to dalbavancin were simplification (53.1%), adverse events (25%), or failure (21.9%). There were 7 adverse events, and no patient had to discontinue dalbavancin. In 45 cases, infection was related to an orthopedic implant. The implant material was retained in 23 cases, including that in 15 (65.2%) patients that were classified as cured and 8 (34.8%) that presented improvement. In 21 cases, the implants were removed, including those in 16 (76.2%) cases that were considered successes, 4 (19%) cases were considered improved, and 1 (4.8%) case that was considered a failure. Among the 19 cases without implants, 14 (73.7%) were considered cured, 3 (15.8%) were considered improved, and 2 (10.5%) were considered failures. The results show that dalbavancin is a well-tolerated antibiotic, even when >2 doses are administered, and is associated with a high cure rate. These are preliminary data with a short follow-up; therefore, it is necessary to gain more experience and, in the future, to establish the most appropriate dose and frequency.
Subject(s)
Bone and Bones/microbiology , Joints/microbiology , Osteomyelitis/microbiology , Teicoplanin/analogs & derivatives , Aged , Female , Gram-Positive Bacteria/drug effects , Gram-Positive Bacteria/pathogenicity , Humans , Male , Microbial Sensitivity Tests , Middle Aged , Osteomyelitis/drug therapy , Staphylococcus aureus , Staphylococcus epidermidis/drug effects , Staphylococcus epidermidis/pathogenicity , Teicoplanin/therapeutic useABSTRACT
Familial mediterranean fever (FMF) is an inherited autoinflammatory disorder characterized by recurrent episodes of fever and painful inflammation involving the intra-abdominal organs, the lungs and the joints, which is highly prevalent in specific ethnic groups including the Iranians. We report a 12-year-old boy from Iran, with a clinical history of recurrent fever. Based on the suggestive clinical data, mutational analysis revealed the presence of the novel c.1945C>T heterozygous variant in exon 10, which leads to a leucine to phenylalanine change at position 649 of the protein. The mutation was inherited from the mother. This novel mutation lies in exon 10 of the MEFV gene, which encodes for a domain called B30.2-SPRY, located in the C-terminal region of the pyrin protein and contains the most frequent mutations associated with FMF. The present report expands the spectrum of MEFV gene mutations associated with FMF. The uniqueness of this study, compared with other published case reports, consists in the new mutation found in the MEFV gene. In fact, new mutations in this gene are of high interest, in order to better understand the role of this gene in autoinflammation.
Subject(s)
Familial Mediterranean Fever/genetics , Mutation , Pyrin/genetics , Child , Humans , Iran , MaleABSTRACT
The question of what monetary value should be assigned to consumed resources, that is to say the choice of the unit cost, is a major consideration in terms of impact on the cost analysis results. To date, no agreement has been reached regarding this methodological question. The choices made by methodologists and the subsequent impact on the results of the analysis are only rarely put forward. This work addresses the theoretical framework of health strategy evaluations that can be carried out either in the normative framework of the conventional economic approach of well-being, referred to as welfarist, or in that of an approach referred to as extra-welfarist. It also provides elements that help clarify the choice of the hospital unit costs used to calculate the cost of health strategies, so as to reconcile the use of such studies and improve their comparability. What is preferable, opting for specific per hospital unit costs or applying a standard unit cost to all facilities? How should a standard cost be calculated? Is it appropriate to calculate an average of the unit costs, as recommended by certain guidelines? The advantages and the limitations of the various modes of assessing hospital resources in the setting of multicentric trials are discussed.
Subject(s)
Cost-Benefit Analysis/methods , Health Care Costs , Health Resources/economics , Hospital Costs , Multicenter Studies as Topic , Cost-Benefit Analysis/standards , France/epidemiology , Health Care Costs/classification , Health Care Costs/standards , Health Care Costs/statistics & numerical data , Health Resources/organization & administration , Health Resources/standards , Hospital Costs/organization & administration , Hospital Costs/standards , Humans , Multicenter Studies as Topic/economics , Multicenter Studies as Topic/statistics & numerical dataABSTRACT
Fluoroscopy guided interventional procedures provide remarkable benefits to patients. However, medical staff working near the scattered radiation field may be exposed to high cumulative equivalent doses, thus requiring shielding devices such as lead aprons and thyroid collars. In this situation, it remains an acceptable practice to derive equivalent doses to the eye lenses or other unprotected soft tissues with a dosimeter placed above these protective devices. Nevertheless, the radiation backscattered by the lead shield differs from that generated during dosimeter calibration with a water phantom. In this study, a passive personal thermoluminescent dosimeter (TLD) was modelled by means of the Monte Carlo (MC) code Penelope. The results obtained were validated against measurements performed in reference conditions in a secondary standard dosimetry laboratory. Next, the MC model was used to evaluate the backscatter correction factor needed for the case where the dosimeter is worn over a lead shield to estimate the personal equivalent dose H p (0.07) to unprotected soft tissues. For this purpose, the TLD was irradiated over a water slab phantom with a photon beam representative of the result of a fluoroscopy beam scattered by a patient. Incident beam angles of 0° and 60°, and lead thicknesses between the TLD and phantom of 0.25 and 0.5 mm Pb were considered. A backscatter correction factor of 1.23 (independent of lead thickness) was calculated comparing the results with those faced in reference conditions (i.e., without lead shield and with an angular incidence of 0°). The corrected dose algorithm was validated in laboratory conditions with dosimeters irradiated over a thyroid collar and angular incidences of 0°, 40° and 60°, as well as with dosimeters worn by interventional radiologists and cardiologists. The corrected dose algorithm provides a better approach to estimate the equivalent dose to unprotected soft tissues such as eye lenses. Dosimeters that are not shielded from backscatter radiation might underestimate personal equivalent doses when worn over a lead apron and, therefore, should be specifically characterized for this purpose.
Subject(s)
Fluoroscopy/methods , Radiation Dosimeters/standards , Thermoluminescent Dosimetry/standards , Calibration , Equipment Design , Lead , Protective Clothing , Thermoluminescent Dosimetry/instrumentationABSTRACT
BACKGROUND: Rhabdomyosarcoma (RMS) is the most common type of soft tissue sarcoma in children. The Hedgehog (HH) pathway is known to develop an oncogenic role in RMS. However, the molecular mechanism that drives activation of the pathway in RMS is not well understood. METHODS: The expression of HH ligands was studied by qPCR, western blot and immunohistochemistry. Functional and animal model studies were carried out with cells transduced with shRNAs against HH ligands or treated with HH-specific inhibitors (Vismodegib and MEDI-5304). Finally, the molecular characterisation of an off-target effect of Vismodegib was also made. RESULTS: The results showed a prominent expression of HH ligands supporting an autocrine ligand-dependent activation of the pathway. A comparison of pharmacologic Smoothened inhibition (Vismodegib) and HH ligand blocking (MEDI-5304) is also provided. Interestingly, a first description of pernicious off-target effect of Vismodegib is also reported. CONCLUSIONS: The clarification of the HH pathway activation mechanism in RMS opens a door for targeted therapies against HH ligands as a possible alternative in the future development of better treatment protocols. Moreover, the description of a pernicious off-target effect of Vismodegib, via unfolded protein response activation, may mechanistically explain its previously reported inefficiency in several ligand-dependent cancers.
Subject(s)
Carcinogenesis/pathology , Cell Proliferation , Hedgehog Proteins/metabolism , Rhabdomyosarcoma/pathology , Transcription Factors/metabolism , Animals , Apoptosis , Carcinogenesis/genetics , Carcinogenesis/metabolism , Cell Movement , Female , Hedgehog Proteins/genetics , Humans , Ligands , Mice , Mice, SCID , Rhabdomyosarcoma/genetics , Rhabdomyosarcoma/metabolism , Signal Transduction , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
The antibiotic linezolid is a ribosomal inhibitor with excellent efficacy. Although the administration period has been reduced to 28 days, side effects, usually of hematologic or neuropathic origin, are still reported due to secondary inhibition of mitochondrial protein synthesis. Susceptibility to linezolid toxicity remains unknown. Therefore, the objective of this study was to gain an understanding of clinical heterogeneity in response to identical linezolid exposures through exhaustive examination of the molecular basis of tissue-dependent mitotoxicity, consequent cell dysfunction, and the association of mitochondrial genetics with adverse effects of linezolid administered for the recommended period. Peripheral blood mononuclear cells (PBMC) and skin nerve fibers from 19 and 6 patients, respectively, were evaluated before and after a 28-day linezolid treatment in order to assess toxic effects on mitochondria and cells. Mitochondrial DNA haplotypes and single nucleotide polymorphisms (SNPs) in ribosomal sequences where linezolid binds to mitochondrial ribosomes were also analyzed to investigate their genetic contributions. We found that linezolid reduced mitochondrial protein levels, complex IV activity, and mitochondrial mass in PBMC and was associated with a trend toward an increase in the rate of apoptosis. In skin tissue, mitochondrial mass increased within nerve fibers, accompanied by subclinical axonal swelling. Mitochondrial haplogroup U, mutations in 12S rRNA, and the m.2706AâG, m.3197TâC, and m.3010GâA polymorphisms in 16S rRNA showed a trend toward an association with increased mitochondrial and clinical adverse effects. We conclude that even when linezolid is administered for a shorter time than formerly, adverse effects are reported by 63% of patients. Linezolid exerts tissue-dependent mitotoxicity that is responsible for downstream cellular consequences (blood cell death and nerve fiber swelling), leading to adverse hematologic and peripheral nervous side effects. Multicentric studies should confirm genetic susceptibility in larger cohorts.
Subject(s)
Anti-Bacterial Agents/toxicity , Cyclooxygenase 2/metabolism , Leukocytes, Mononuclear/drug effects , Linezolid/toxicity , Mitochondria/drug effects , Nerve Fibers/drug effects , Protein Synthesis Inhibitors/toxicity , Voltage-Dependent Anion Channels/metabolism , Adult , Aged , Aged, 80 and over , Electron Transport Complex IV/metabolism , Female , Humans , Male , Middle Aged , Mitochondria/genetics , Mitochondrial Proteins/metabolism , Polymorphism, Single Nucleotide/genetics , RNA, Ribosomal/genetics , RNA, Ribosomal, 16S/genetics , Skin/cytology , Skin/innervationABSTRACT
BACKGROUND: Preoperative chemoradiotherapy followed by surgical mesorectal resection is the standard of care for locally advanced rectal carcinomas. Yet, predicting that patients will respond to treatment remains an unmet clinical challenge. EXPERIMENTAL DESIGN: Using laser-capture microdissection we isolated RNA from stroma and tumour glands from prospective pre-treatment samples (n = 15). Transcriptomic profiles were obtained hybridising PrimeView Affymetrix arrays. We modelled a carcinoma-associated fibroblast-specific genes filtering data using GSE39396. RESULTS: The analysis of differentially expressed genes of stroma/tumour glands from responder and non-responder patients shows that most changes were associated with the stromal compartment; codifying mainly for extracellular matrix and ribosomal components. We built a carcinoma-associated fibroblast (CAF) specific classifier with genes showing changes in expression according to the tumour regression grade (FN1, COL3A1, COL1A1, MMP2 and IGFBP5). We assessed these five genes at the protein level by means of immunohistochemical staining in a patient's cohort (n = 38). For predictive purposes we used a leave-one-out cross-validated model with a positive predictive value (PPV) of 83.3%. Random Forest identified FN1 and COL3A1 as the best predictors. Rebuilding the leave-one-out cross-validated regression model improved the classification performance with a PPV of 93.3%. An independent cohort was used for classifier validation (n = 36), achieving a PPV of 88.2%. In a multivariate analysis, the two-protein classifier proved to be the only independent predictor of response. CONCLUSION: We developed a two-protein immunohistochemical classifier that performs well at predicting the non-response to neoadjuvant treatment in rectal cancer.
Subject(s)
Gene Expression Profiling , Immunohistochemistry/methods , Neoadjuvant Therapy , Rectal Neoplasms/therapy , Collagen Type I/genetics , Collagen Type I, alpha 1 Chain , Collagen Type III/genetics , Combined Modality Therapy , Cytokines/genetics , Female , Fibronectins , Humans , Insulin-Like Growth Factor Binding Protein 5/genetics , Male , Matrix Metalloproteinase 2/genetics , Middle Aged , Prognosis , Rectal Neoplasms/classification , Rectal Neoplasms/genetics , Rectal Neoplasms/pathology , TranscriptomeABSTRACT
AIMS: This study was conducted to isolate and identify propionate-producing bacteria that can be used as an inoculum in improving wet brewers grains and rumen fermentation via increasing propionate concentration. METHODS AND RESULTS: A strain of Lactobacillus that exhibits high levels of propionate production was identified and characterized as Lactobacillus mucosae 521129 by 16S rRNA gene sequencing and phylogenetic analyses. Wet brewers grains were fermented through L. mucosae inoculation and resulted in an increase in propionate concentration. Fermented wet brewers grains were used in in vitro rumen fermentation and revealed that L. mucosae-fermented wet brewers grains produced more gas and had higher accumulations propionate and total volatile fatty acid (VFA) than the control. The fewest methanogen DNA copies were detected in L. mucosae-fermented wet brewers grains. CONCLUSION: Identified L. mucosae improved the fermentation of wet brewers grains and the in vitro rumen fermentation via increasing propionate and total VFA concentrations. SIGNIFICANCE AND IMPACT OF THE STUDY: The presented research provided the identification of L. mucosae 521129 as a propionate producer and was metabolically profiled. Furthermore, data present the putative application of this organism in improving the fermentation of wet brewers grains and in vitro rumen fermentation.
ABSTRACT
Staphylococcus aureus bacteremic pneumonia is an uncommon cause of hospitalization, with a high mortality rate. However, published reports are scarce and have included a small number of cases. All patients with S. aureus bacteremic pneumonia were prospectively collected in our institution from 2000 to 2014, and a retrospective revision was performed to identify risk factors associated with methicillin resistance and to update the mortality of this entity. A total of 98 patients were admitted: 57.1 % were due to methicillin-susceptible S. aureus (MSSA) and 42.8 % due to methicillin-resistant S. aureus (MRSA). In 40 patients (40.8 %), the infection was community acquired. Thirteen were ventilator-associated pneumonia episodes. The most frequent comorbidities were chronic lung disease (34.7 %), chronic renal failure (31.6 %), diabetes mellitus (29.6 %), and cardiovascular disease (31.6 %). Septic shock was present in 46 patients (46.9 %). The 30-day mortality was 46.9 %. MRSA infections occurred in older patients, more frequently with cardiovascular diseases, and they had received antibiotic treatment in the previous month more often than MSSA-infected patients. Patients with infection due to MSSA presented more frequently with septic shock, but they received more frequently appropriate empirical antibiotic therapy than patients with MRSA pneumonia (96 % vs. 38.1 %), and no differences in mortality were observed between both groups. In conclusion, S. aureus bacteremic pneumonia is a severe infection that, nowadays, affects people with comorbidities and the mortality is still high.
Subject(s)
Bacteremia , Pneumonia, Staphylococcal/epidemiology , Pneumonia, Staphylococcal/microbiology , Staphylococcus aureus , Adult , Aged , Anti-Bacterial Agents/pharmacology , Community-Acquired Infections , Comorbidity , Cross Infection , Female , Humans , Male , Methicillin-Resistant Staphylococcus aureus , Middle Aged , Mortality , Pneumonia, Staphylococcal/diagnosis , Pneumonia, Staphylococcal/drug therapy , Retrospective Studies , Spain/epidemiologyABSTRACT
OBJECTIVE: The main objective of this systematic literature review is to identify the safest and most effective sedative drugs so as to ensure successful sedation with as few complications as possible. STUDY DESIGN: A systematic literature review of the PubMed MEDLINE database was carried out using the key words "conscious sedation," "drugs," and "dentistry." A total of 1,827 scientific articles were found, and these were narrowed down to 473 articles after applying inclusion and exclusion criteria. These 473 studies were then individually assessed for their suitability for inclusion in this literature review. RESULTS: A total of 21 studies were selected due to their rigorous study design and conduciveness to further, more exhaustive analysis. The selected studies included a total of 1,0003 patients classified as ASA I or II. Midazolam was the drug most frequently used for successful sedation in dental surgical procedures. Ketamine also proved very useful when administered intranasally, although some side effects were observed when delivered via other routes of administration. Both propofol and nitrous oxide (N2O) are also effective sedative drugs. CONCLUSIONS: Midazolam is the drug most commonly used to induce moderate sedation in dental surgical procedures, and it is also very safe. Other sedative drugs like ketamine, dexmedetomidine and propofol have also been proven safe and effective; however, further comparative clinical studies are needed to better demonstrate which of these are the safest and most effective.