The competitive, dynamic and changing environment in which companies operate today, pose new challenges that allow them to grow and maintain themselves over time, aspects such as customer ...satisfaction, innovation, and social responsibility are increasingly used objectives by the companies. However, elements such as quality and productivity continue to be critical factors in business sustainability. For this, companies must use methodologies and tools to diagnose their processes, identify their critical points and invest in strategies that optimize the operations of their value chain, the use of their resources, and the quality of their products, in order to overcome always the expectations of the clients and achieve differentiation in the market.
The goal of this work is to diagnosis of the situation of the production process in the value chain of the processing and marketing of fish and Shellfish Company as a case study. Also aims to, the identification of waste or MUDA, that affect the quality and productivity of the products. Improvement proposals under Lean Manufacturing tools, for increase the performance in the value chain under study were made. As main results, we can highlight improvement proposals through the lean tools, which promote advances in the organization of the plant and process times.
Pattern Recognition Receptors (PRRs) are proteins capable of recognizing molecules frequently found in pathogens (the so-called Pathogen-Associated Molecular Patterns-PAMPs), or molecules released by ...damaged cells (the Damage-Associated Molecular Patterns-DAMPs). They emerged phylogenetically prior to the appearance of the adaptive immunity and, therefore, are considered part of the innate immune system. Signals derived from the engagement of PRRs on the immune cells activate microbicidal and pro-inflammatory responses required to eliminate or, at least, to contain infectious agents. Molecularly controlled forms of cell death are also part of a very ancestral mechanism involved in key aspects of the physiology of multicellular organism, including the elimination of unwanted, damaged or infected cells. Interestingly, each form of cell death has its particular effect on inflammation and on the development of innate and adaptive immune responses. In this review article, we discuss some aspects of the molecular interplay between the cell death machinery and signals initiated by the activation of PRRs by PAMPs and DAMPs.
Acid rain causes significant damage to rice plants, affecting the photosynthetic machinery and growth. 24-epibrassinolide (EBR) is an organic steroid, which, used at low concentrations, positively ...regulates plant growth and mitigates deleterious effects related to environmental changes. The aim of this study was to investigate whether exogenous treatment with 24-epibrassinolide can alleviate the negative effects of simulated acid rain (SAR) and the possible tolerance mechanism involved by evaluating chlorophyll fluorescence, gas exchange, the antioxidant system and leaf anatomical variables. The experiment was randomized with four treatments: two simulated acid rain treatments (0 and 0.5 M H
2
SO
4
, described as − SAR and + SAR, respectively) and two concentrations of brassinosteroids (0 and 100 nM EBR, described as − EBR and + EBR, respectively). Our results show that plants exposed to SAR suffered negative interferences; however, EBR-treated plants presented benefits related to chlorophyll fluorescence, alleviation of the photoinhibition in photosystem II and protection against damage caused by the imbalance of reactive oxygen species. Additionally, EBR promoted increases in gas exchange that were clearly linked to stomatal regulation, improving the uptake and distribution of CO
2
in intercellular spaces. This research revealed that EBR attenuated the negative effects of SAR, increasing the activities of superoxide dismutase (12%), catalase (17%), ascorbate peroxidase (17%) and peroxidase (33%), reducing thylakoid membrane damage, as confirmed by increases in chlorophyll and carotenoids. Finally, the effects of EBR observed in plants under SAR demonstrate that this substance positively modulated important anatomical structures linked to leaf protection, increasing trichome density (8%), epicuticular wax (48%) and the aerenchyma area (100%). These results provide evidence that EBR confers tolerance to rice plants exposed to SAR.
The pathology of respiratory syncytial virus (RSV) infection was evaluated 1 day after an outpatient diagnosis of RSV in a child who died in a motor vehicle accident. We then identified 11 children ...with bronchiolitis from the Vanderbilt University autopsy log between 1925 and 1959 who met criteria for possible RSV infection in the preintensivist era. Their tissue was re-embedded and evaluated by routine hematoxylin and eosin and PAS staining and immunostaining with RSV-specific antibodies. Tissue from three cases was immunostain-positive for RSV antigen and was examined in detail. Small bronchiole epithelium was circumferentially infected, but basal cells were spared. Both type 1 and 2 alveolar pneumocytes were also infected. Although, not possible for archival cases, tissue from the index case was evaluated by immunostaining with antibodies to define the cellular components of the inflammatory response. Inflammatory infiltrates were centered on bronchial and pulmonary arterioles and consisted of primarily CD69+ monocytes, CD3+ double-negative T cells, CD8+ T cells, and neutrophils. The neutrophil distribution was predominantly between arterioles and airways, while the mononuclear cell distribution was in both airways and lung parenchyma. Most inflammatory cells were concentrated submuscular to the airway, but many cells traversed the smooth muscle into the airway epithelium and lumen. Airway obstruction was a prominent feature in all cases attributed to epithelial and inflammatory cell debris mixed with fibrin, mucus, and edema, and compounded by compression from hyperplastic lymphoid follicles. These findings inform our understanding of RSV pathogenesis and may facilitate the development of new approaches for prevention and treatment.
Abstract
The assessment of measurable residual disease (MRD) in bone marrow has proven of prognostic relevance in patients with multiple myeloma (MM). Nevertheless, and unlike other hematologic ...malignancies, the use of MRD results to make clinical decisions in MM has been underexplored to date. In this retrospective study, we present the results from a multinational and multicenter series of 400 patients with MRD monitoring during front-line therapy with the aim of exploring how clinical decisions made based on those MRD results affected outcomes. As expected, achievement of MRD negativity at any point was associated with improved PFS versus persistent MRD positivity (median PFS 104 vs. 45 months,
p
< 0.0001). In addition, however, 67 out of 400 patients underwent a clinical decision (treatment discontinuation, intensification or initiation of a new therapy) based on MRD results. Those patients in whom a treatment change was made showed a prolonged PFS in comparison with those 333 patients in which MRD results were not acted upon (respectively, mPFS 104 vs. 62 months,
p
= 0.005). In patients who achieved MRD negativity during maintenance (
n
= 186) on at least one occasion, stopping therapy in 24 patients vs. continuing in 162 did not alter PFS (mPFS 120 months vs. 82 months,
p
= 0.1). Most importantly, however, in patients with a positive MRD during maintenance (
n
= 214), a clinical decision (either intensification or change of therapy) (
n
= 43) resulted in better PFS compared to patients in whom no adjustment was made (
n
= 171) (mPFS NA vs. 39 months,
p
= 0.02). Interestingly, there were no significant differences when MRD was assessed by flow cytometry or by next-generation sequencing. Herein, we find that MRD is useful in guiding clinical decisions during initial therapy and has a positive impact on PFS in MM patients. This potentially opens a new dimension for the use of MRD in MM, but this role still remains to be confirmed in prospective, randomized clinical trials.
Achievement of enteral autonomy (EA) is the ultimate treatment goal in pediatric intestinal failure (IF). We aimed to assess predictors of EA in pediatric short bowel syndrome (SBS) and explore the ...impact of residual small bowel (SB) and large bowel (LB) length on EA.
A retrospective cohort study was performed on infants aged <12 months (n = 367, six centers) with SBS referred between 2010 and 2015. The cohort was stratified based on the achievement of EA. Statistical testing was completed using t-test, chi-square, Cox proportional hazards regression model, and Kaplan-Meier analysis.
EA was achieved in 229 patients. In the multivariable analysis, the percentage of residual LB (hazard ratio HR = 1.02; 95% CI = 1.01-1.02) and SB (HR = 1.01; 95% CI = 1.01-1.02) length, presence of the ileocecal valve (HR = 2.02; 95% CI=1.41-2.88), and not coming from a high-volume transplantation center (HR = 2.42; 95% CI = 1.68-3.49) were positively associated with EA, whereas a negative association was seen with the presence of stoma at the time when shortest remnant was documented (HR = 0.72; 95% CI = 0.52-1.00). EA achievement was significantly different between the anatomical subgroups (log-rank test P < 0.001) with an EA rate of 80.4% in infants with ≥50% SB and LB (median time 209 days); 62.5% with ≥50% SB and <50% LB (397 days); 58.3% with <50% SB and ≥50% LB (1192 days), and 25.9% with <50% SB and LB. Necrotizing enterocolitis (NEC) was not associated with a better achievement of EA (NEC vs other etiologies: log-rank test P = 0.33).
Overall, 62% of infants with IF secondary to SBS achieved EA over a mean time of follow-up of 2.3 years. A colon length of >50% can compensate for the loss of small bowel (<50%) and account for similar EA rates as those in children with residual SB > 50%.
The cofactor tetrahydrobiopterin (BH
) is a critical regulator of nitric oxide synthase (NOS) function and redox signaling, with reduced BH
implicated in multiple cardiovascular disease states. In ...the myocardium, augmentation of BH
levels can impact on cardiomyocyte function, preventing hypertrophy and heart failure. However, the specific role of endothelial cell BH
biosynthesis in the coronary circulation and its role in cardiac function and the response to ischemia has yet to be elucidated. Endothelial cell-specific
knockout mice were generated by crossing
with Tie2cre mice, generating
Tie2cre mice and littermate controls. GTP cyclohydrolase protein and BH
levels were reduced in heart tissues from
Tie2cre mice, localized to endothelial cells, with normal cardiomyocyte BH
. Deficiency in coronary endothelial cell BH
led to NOS uncoupling, decreased NO bioactivity, and increased superoxide and hydrogen peroxide productions in the hearts of
Tie2cre mice. Under physiological conditions, loss of endothelial cell-specific BH
led to mild cardiac hypertrophy in
Tie2cre hearts. Endothelial cell BH
loss was also associated with increased neuronal NOS protein, loss of endothelial NOS protein, and increased phospholamban phosphorylation at serine-17 in cardiomyocytes. Loss of cardiac endothelial cell BH
led to coronary vascular dysfunction, reduced functional recovery, and increased myocardial infarct size following ischemia-reperfusion injury. Taken together, these studies reveal a specific role for endothelial cell
/BH
biosynthesis in cardiac function and the response to cardiac ischemia-reperfusion injury. Targeting endothelial cell
and BH
biosynthesis may provide a novel therapeutic target for the prevention and treatment of cardiac dysfunction and ischemia-reperfusion injury.
We demonstrate a critical role for endothelial cell
/BH
biosynthesis in coronary vascular function and cardiac function. Loss of cardiac endothelial cell BH
leads to coronary vascular dysfunction, reduced functional recovery, and increased myocardial infarct size following ischemia/reperfusion injury. Targeting endothelial cell
and BH
biosynthesis may provide a novel therapeutic target for the prevention and treatment of cardiac dysfunction, ischemia injury, and heart failure.
The Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone (MGTX) showed that thymectomy combined with prednisone was superior to prednisone alone in improving clinical ...status as measured by the Quantitative Myasthenia Gravis (QMG) score in patients with generalised non-thymomatous myasthenia gravis at 3 years. We investigated the long-term effects of thymectomy up to 5 years on clinical status, medication requirements, and adverse events.
We did a rater-blinded 2-year extension study at 36 centres in 15 countries for all patients who completed the randomised controlled MGTX and were willing to participate. MGTX patients were aged 18 to 65 years at enrolment, had generalised non-thymomatous myasthenia gravis of less than 5 years' duration, had acetylcholine receptor antibody titres of 1·00 nmol/L or higher (or concentrations of 0·50–0·99 nmol/L if diagnosis was confirmed by positive edrophonium or abnormal repetitive nerve stimulation, or abnormal single fibre electromyography), had Myasthenia Gravis Foundation of America Clinical Classification Class II–IV disease, and were on optimal anticholinesterase therapy with or without oral corticosteroids. In MGTX, patients were randomly assigned (1:1) to either thymectomy plus prednisone or prednisone alone. All patients in both groups received oral prednisone at doses titrated up to 100 mg on alternate days until they achieved minimal manifestation status. The primary endpoints of the extension phase were the time-weighted means of the QMG score and alternate-day prednisone dose from month 0 to month 60. Analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00294658. It is closed to new participants, with follow-up completed.
Of the 111 patients who completed the 3-year MGTX, 68 (61%) entered the extension study between Sept 1, 2009, and Aug 26, 2015 (33 in the prednisone alone group and 35 in the prednisone plus thymectomy group). 50 (74%) patients completed the 60-month assessment, 24 in the prednisone alone group and 26 in the prednisone plus thymectomy group. At 5 years, patients in the thymectomy plus prednisone group had significantly lower time-weighted mean QMG scores (5·47 SD 3·87 vs 9·34 5·08; p=0·0007) and mean alternate-day prednisone doses (24 mg SD 21 vs 48 mg 29; p=0·0002) than did those in the prednisone alone group. 14 (42%) of 33 patients in the prednisone group, and 12 (34%) of 35 in the thymectomy plus prednisone group, had at least one adverse event by month 60. No treatment-related deaths were reported during the extension phase.
At 5 years, thymectomy plus prednisone continues to confer benefits in patients with generalised non-thymomatous myasthenia gravis compared with prednisone alone. Although caution is appropriate when generalising our findings because of the small sample size of our study, they nevertheless provide further support for the benefits of thymectomy in patients with generalised non-thymomatous myasthenia gravis.
National Institutes of Health, National Institute of Neurological Disorders and Stroke.
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