Reduced Fluid Accumulation Research Articles

Torsemide in Edema Associated with Chronic Kidney Disease.

Torsemide is a loop diuretic used to manage edema associated with chronic kidney disease (CKD) and acute kidney injury (AKI). It acts by inhibiting sodium and chloride ions reabsorption in the ascending limb of the loop of Henle, thereby increasing urine output and reducing fluid accumulation. Compared to other diuretics, torsemide has an extended duration of action, higher bioavailability, and its elimination route is primarily through the hepatic route, making it effective in patients with CKD and AKI. Clinical studies indicate that torsemide can improve symptoms of fluid overload and potentially enhance renal function.

Advancements in the Treatment of Diabetic Macular Edema: Current Strategies and Future Directions

This narrative review examines current and emerging treatment strategies for diabetic macular edema (DME), a complication of diabetic retinopathy characterised by fluid accumulation in the macula, which can lead to vision impairment. The incidence of DME is particularly high in patients with long-standing diabetes and advanced retinopathy. The current treatment options for DME include anti-vascular endothelial growth factor (anti-VEGF) agents, corticosteroids, and laser therapies. Anti-VEGF agents, including bevacizumab, ranibizumab, aflibercept, and the more recently developed brolucizumab and faricimab, have been demonstrated to reduce macular thickness and improve visual acuity. Brolucizumab offers the advantage of fewer injections due to its longer duration of action, although it carries a higher risk of ocular inflammation compared to other anti-VEGF agents. The dual inhibition of the VEGF and angiopoietin-2 (Ang-2) pathways by faricimab may enhance vascular stability and reduce inflammation, potentially improving patient outcomes. Steroid therapies, including dexamethasone, fluocinolone acetonide, and triamcinolone acetonide, represent an alternative for patients who do not respond adequately to anti-VEGF treatment. Laser therapies, including focal, navigated, and subthreshold laser treatments, remain a crucial component in the management of DME, with the ability to seal leaking vessels and reduce fluid accumulation. In order to achieve the best outcomes for patients, it is essential to continue to advance these treatment modalities and adopt a personalised, multifaceted approach.

Ascities after Liver Cirrhosis Diagnosis and Treatment

Ascites, the accumulation of fluid in the abdominal cavity, is a common complication in patients with cirrhosis. Approximately 50% of patients with compensated cirrhosis will develop ascites over a 10-year period, marking a significant milestone in the progression of end-stage liver disease. Survival rates decrease after the onset of ascites, with only 50% of patients surviving 2 to 5 years, depending on the underlying cause of cirrhosis, The management of ascites involves salt restriction and diuretic use, which are effective in about 90% of patients in reducing fluid accumulation and symptoms. In cases where ascites does not respond to these measures, additional interventions such as large-volume paracentesis may be necessary as a temporary solution or for symptomatic relief while awaiting liver transplantation, for patients with refractory ascites, the transjugular intrahepatic portosystemic shunt (TIPS) procedure can be considered. This involves creating a shunt between the portal vein and hepatic vein to reduce portal hypertension. TIPS can serve as a bridge to liver transplantation or provide long-term palliation, but careful monitoring for bacterial peritonitis is essential. Patients at high risk for bacterial peritonitis should receive antibiotic prophylaxis to prevent this serious infection. Prompt diagnostic paracentesis is necessary when spontaneous bacterial peritonitis is suspected, involving the removal and analysis of fluid from the abdominal cavity

A pilot study to assess the effects of preventing fluid retention in the legs by wearing compression stockings on overnight airway narrowing in mild asthma.

Nocturnal asthma is a sign of asthma worsening and could be partially due to more fluid drawn into the thorax during sleep by gravitational force and/or pharyngeal collapse in those with obstructive sleep apnea. Wearing compression stockings during the day reduces fluid shift from the legs to the neck overnight. However, the potential effect of wearing compression stockings to reduce fluid accumulation in the leg and to improve nocturnal small airway narrowing in patients with asthma has not been investigated. This study investigates whether reducing leg fluid volume by wearing compression stockings during the day would attenuate small airway narrowing in patients with asthma before and after sleep. We enrolled 11 participants with asthma. All participants underwent overnight polysomnography with or without wearing compression stockings for 2weeks. Before and after sleep, leg fluid volume (LFV) was measured by bioelectrical impedance, and airway narrowing was primarily assessed by respiratory system resistance and reactance at 5Hz (R5 and X5 respectively) using oscillometry. After 2weeks of wearing compression stockings, the LFV measured in the evening was reduced (∆ = - 192.6 ± 248.3ml, p = 0.02), and R5 and X5 improved (∆ = - 0.7 ± 0.9 cmH2O/L/s, p = 0.03 and 0.2 ± 1.4 cmH2O/L/s, p = 0.05 respectively). No changes were observed in the morning. Preventing fluid retention in the legs by wearing compression stockings for 2weeks during the day, reduced LFV and airway narrowing in the evening in all participants with asthma, but not in the morning after sleep.

Comparison of toxicities between Vibrio fluvialis and Vibrio furnissii strains isolated from environmental samples

Gastrointestinal episodes associated with Vibrio species have been rising worldwide in the last few years. In this study, toxicities of two very well characterized V. fluvialis and V. furnissii strains, isolated from environmental samples, were used to investigate the comparative pathogenicity of these strains. The results showed that there is a positive relationship between toxin production as well as a high interspecies correlation. In the analysis of toxicity, both species showed positive results with close similarity in cell death on BHK-21 cell line and destruction of RBC, which were indicative of cytotoxic and hemolytic activity, respectively. Besides, molecular analysis showed the absence of ctx, tdh, trh, stx1 and stx2 genes. On the other hand, reduced fluid accumulation ratio in rabbit ileal loop assay and paralysis of hind legs of Swiss Albino mice were observed for V. furnissi strain, which indicates the differences in pathogenicity between the two species.
 Bangladesh J Microbiol, Volume 38, Number 2, December 2021, pp 73-77

EP.TH.177Safety profile of SurgiMend Acellular Dermal Matrix and Mentor implant assisted immediate breast reconstruction – Our experience at the Princess Royal University Hospital

Abstract Background ADM (Acellular Dermal Matrix) assisted implant-based immediate breast reconstruction (IBR) is a common technique worldwide. Various ADMs are available manufactured from different sources. The Surgimend ADM (fetal bovine dermis) is fenestrated and rich in type I/III collagen; it is claimed to reduce fluid accumulation and promote healing. Methods Retrospective observational analysis exploring safety profile using combination of SurgiMend MacroPorous (MP)/SurgiMend PRS and Mentor CPG/Mentor Siltex implants between January 2018 to December 2019. Patients with unilateral/bilateral IBR following Nipple sparing (NSM) or Skin sparing mastectomy (SSM) were included. The primary outcome was minor complications (seroma (>100ml on USS), hematoma, wound infection and infected seromas). Secondary outcome was major complications (flap necrosis, capsular contracture, implant explantation and Red Breast Syndrome). Results Six (16.2%) bilateral and 31 (83.8%) unilateral IBR were performed in 37 patients. Mean age was 53.78 years. No major complications were recorded. Conclusions The Surgimend ADM and Mentor implant combination demonstrate a good safety profile. Higher rates of seroma in this study could be explained by overdiagnosis and treatment at our unit, which in turn might imply as a result that no major complications were detected and no implant loss.

Diuretics decrease fluid balance in patients on invasive mechanical ventilation: the randomized-controlled single blind, IRIHS study

BackgroundFluid overload has been associated with increased morbidity and mortality in critically ill patients. The goal of this study was to assess the efficacy and safety of a diuretic strategy to overcome positive fluid balance in patients on invasive mechanical ventilation.MethodsDesign: Multicenter, single-blind, randomized-controlled study. Patients were randomized into a diuretic (furosemide) or a control group. Patients were eligible in case of fluid overload defined as in-ICU weight increase ≥ 3%, invasive mechanical ventilation (FiO2 ≤ 60% and PEEP ≤ 10 cm H2O on inclusion) and hemodynamic stabilization. The primary outcome was fluid balance, defined as weight variation from reference weight to successful extubation. The main secondary outcome was the safety of diuretic.Results171 patients were randomized. After 5 exclusions, 166 patients were included in the analysis: 77 in the diuretic and 89 in the control group. Fluid balance was 1.4 [− 2.5 to 4.5] kg in the diuretic and 6.4 [0.5–11.2] kg in the control group (p < 0.001). In the multiple imputation analysis, fluid balance was significantly decreased in the diuretic group (mean difference = − 4.8 95% CI [− 7.3 to − 2.5], p < 0.001). Eleven (14%) patients died in the diuretic group and 16 (18%) patients in the control group (p = 0.5). There was a worsening of Acute Kidney Injury in 67 (75.3%) patients of the control group versus 46 (59.7%) patients in the diuretic group (p = 0.03).ConclusionsIn this multicenter randomized-controlled study, protocolized diuretic therapy reduced fluid accumulation in patients receiving mechanical ventilation and was well tolerated with a favorable safety profile.Trial registration NCT 02345681, Registered January 26 2015, Prospectively registered, https://clinicaltrials.gov/ct2/show/NCT02345681?term=02345681&draw=2&rank=1.

Repurposing calcium-sensing receptor agonist cinacalcet for treatment of CFTR-mediated secretory diarrheas.

Diarrhea is a major cause of global mortality, and outbreaks of secretory diarrhea such as cholera remain an important problem in the developing world. Current treatment of secretory diarrhea primarily involves supportive measures, such as fluid replacement. The calcium-sensing receptor (CaSR) regulates multiple biological activities in response to changes in extracellular Ca2+. The FDA-approved drug cinacalcet is an allosteric activator of CaSR used for treatment of hyperparathyroidism. Here, we found by short-circuit current measurements in human colonic T84 cells that CaSR activation by cinacalcet reduced forskolin-induced Cl– secretion by greater than 80%. Cinacalcet also reduced Cl– secretion induced by cholera toxin, heat-stable E. coli enterotoxin, and vasoactive intestinal peptide (VIP). The cinacalcet effect primarily involved indirect inhibition of cystic fibrosis transmembrane conductance regulator–mediated (CFTR-mediated) Cl– secretion following activation of CaSR and downstream phospholipase C and phosphodiesterases. In mice, cinacalcet reduced fluid accumulation by more than 60% in intestinal closed loop models of cholera and traveler’s diarrhea. The cinacalcet effect involved both inhibition of CFTR-mediated secretion and stimulation of sodium-hydrogen exchanger 3–mediated absorption. These findings support the therapeutic utility of the safe and commonly used drug cinacalcet in CFTR-dependent secretory diarrheas, including cholera, traveler’s diarrhea, and VIPoma.

Multifunctional transcription factor CytR of Vibrio cholerae is important for pathogenesis.

Vibrio cholerae, the Gram-negative facultative pathogen, resides in the aquatic environment and infects humans and causes diarrhoeagenic cholera. Although the environment differs drastically, V. cholerae thrives in both of these conditions aptly and chitinases play a vital role in their persistence and nutrient acquisition. Chitinases also play a role in V. cholerae pathogenesis. Chitinases and its downstream chitin utilization genes are regulated by sensor histidine kinase ChiS, which also plays a significant role in pathogenesis. Recent exploration suggests that CytR, a transcription factor of the LacI family in V. cholerae, also regulates chitinase secretion in environmental conditions. Since chitinases and chitinase regulator ChiS is involved in pathogenesis, CytR might also play a significant role in pathogenicity. However, the role of CytR in pathogenesis is yet to be known. This study explores the regulation of CytR on the activation of ChiS in the presence of mucin and its role in pathogenesis. Therefore, we created a CytR isogenic mutant strain of V. cholerae (CytR¯) and found considerably less β-hexosaminidase enzyme production, which is an indicator of ChiS activity. The CytR¯ strain greatly reduced the expression of chitinases chiA1 and chiA2 in mucin-supplemented media. Electron microscopy showed that the CytR¯ strain was aflagellate. The expression of flagellar-synthesis regulatory genes flrB, flrC and class III flagellar-synthesis genes were reduced in the CytR¯ strain. The isogenic CytR mutant showed less growth compared to the wild-type in mucin-supplemented media as well as demonstrated highly retarded motility and reduced mucin-layer penetration. The CytR mutant revealed decreased adherence to the HT-29 cell line. In animal models, reduced fluid accumulation and colonization were observed during infection with the CytR¯ strain due to reduced expression of ctxB, toxT and tcpA. Collectively these data suggest that CytR plays an important role in V. cholerae pathogenesis.

Fluid overload after coronary artery bypass graft in patients on maintenance hemodialysis is associated with prolonged time on mechanical ventilation

BackgroundFluid overload is a risk factor for morbidity, mortality, and prolonged ventilation time after surgery. Patients on maintenance hemodialysis might be at higher risk. We hypothesized that fluid accumulation would be directly associated with extended ventilation time in patients on hemodialysis, as compared to patients with chronic kidney disease not on dialysis (CKD3–4) and patients with normal renal function (reference group).MethodsThis is a prospective observational study that included patients submitted to isolated and elective coronary artery bypass surgery, divided in 3 groups according to time on mechanical ventilation: < 24 h, 24-48 h and > 48 h. The same observer followed patients daily from the surgery to the hospital discharge. Cumulative fluid balance was defined as the sum of daily fluid balance over the first 5 days following surgery.ResultsPatients requiring more than 48 h of ventilation (5.3%) had a lower estimated glomerular filtration rate, were more likely to be on maintenance dialysis, had longer anesthesia time, needed higher dobutamine and noradrenaline infusion following surgery, and had longer hospitalization stay. Multivariate analysis revealed that the fluid accumulation, scores of sequential organ failure assessment in the day following surgery, and the renal function (normal, chronic kidney disease not on dialysis and maintenance hemodialysis) were independently associated with time in mechanical ventilation. Among patients on hemodialysis, the time from the surgery to the first hemodialysis session also accounted for the time on mechanical ventilation.ConclusionsFluid accumulation is an important risk factor for lengthening mechanical ventilation, particularly in patients on hemodialysis. Future studies are warranted to address the ideal timing for initiating dialysis in this scenario in an attempt to reduce fluid accumulation and avoid prolonged ventilation time and hospital stay.

Long-term effects of cardiac rehabilitation on sleep apnea severity in patients with coronary artery disease.

Sleep apnea (SA) is prevalent among patients with coronary artery disease (CAD) and increases cardiovascular risk. A previous study showed that 1 month of cardiac rehabilitation (CR) reduced severity of SA in patients with CAD by reducing fluid accumulation in the legs during the day and the amount of fluid shifting rostrally into the neck overnight. The aim of this study was to evaluate whether CR will lead to longer-term attenuation of SA in patients with CAD. Fifteen patients with CAD and SA who had participated in a 1-month randomized trial of the effects of exercise training on SA were followed up until they completed 6 months of CR (age: 65 ± 10 years; body mass index: 27.0 ± 3.9 kg/m²; apnea-hypopnea index [AHI]: 39.0 ± 16.7). The AHI was evaluated at baseline by polysomnography and then at 6 months by portable monitoring at home. Cardiorespiratory fitness (VO2peak) was evaluated via a graded cardiopulmonary exercise test at baseline and 6 months later. The 6-month CR program included once weekly, 90-minute, in-facility exercise sessions, and 4 days per week at-home exercise sessions. After 6 months of CR, there was a 54% reduction in the AHI (30.5 ± 15.2 to 14.1 ± 7.5, P < .001). Body mass index remained unchanged, but VO2peak increased by 27% (20.0 ± 6.1 to 26.0 ± 8.9 mL/kg/min, P = .04). Participation in CR is associated with a significant long-term decrease in the severity of SA. This finding suggests that attenuation of SA by exercise could be a mechanism underlying reduced mortality following participation in CR in patients with CAD and SA. This study is registered at www.controlled-trials.com with identifier number ISRCTN50108373.

Critical Adverse Impact of IL-6 in Acute Pneumovirus Infection.

Severe respiratory virus infections feature robust local host responses that contribute to disease severity. Immunomodulatory strategies that limit virus-induced inflammation may be of critical importance, notably in the absence of antiviral vaccines. In this study, we examined the role of the pleiotropic cytokine IL-6 in acute infection with pneumonia virus of mice (PVM), a natural rodent pathogen that is related to respiratory syncytial virus and that generates local inflammation as a feature of severe infection. In contrast to Influenza A, PVM is substantially less lethal in IL-6 -/- mice than it is in wild-type, a finding associated with diminished neutrophil recruitment and reduced fluid accumulation in lung tissue. Ly6Chi proinflammatory monocytes are recruited in response to PVM via a CCR2-dependent mechanism, but they are not a major source of IL-6 nor do they contribute to lethal sequelae of infection. By contrast, alveolar macrophages are readily infected with PVM in vivo; ablation of alveolar macrophages results in prolonged survival in association with a reduction in virus-induced IL-6. Finally, as shown previously, administration of immunobiotic Lactobacillus plantarum to the respiratory tracts of PVM-infected mice promoted survival in association with diminished levels of IL-6. We demonstrated in this study that IL-6 suppression is a critical feature of the protective mechanism; PVM-infected IL-6 -/- mice responded to low doses of L. plantarum, and administration of IL-6 overcame L. plantarum-mediated protection in PVM-infected wild-type mice. Taken together, these results connect the actions of IL-6 to PVM pathogenesis and suggest cytokine blockade as a potential therapeutic modality in severe infection.

Zinc oxide nanoparticles provide anti-cholera activity by disrupting the interaction of cholera toxin with the human GM1 receptor

Vibrio cholerae causes cholera and is the leading cause of diarrhea in developing countries, highlighting the need for the development of new treatment strategies to combat this disease agent. While exploring the possibility of using zinc oxide (ZnO) nanoparticles (NPs) in cholera treatment, we previously found that ZnO NPs reduce fluid accumulation in mouse ileum induced by the cholera toxin (CT) protein. To uncover the mechanism of action of ZnO NPs on CT activity, here we used classical (O395) and El Tor (C6706) V. cholerae biotypes in growth and biochemical assays. We found that a ZnO NP concentration of 10 μg/ml did not affect the growth rates of these two strains, nor did we observe that ZnO NPs reduce the expression levels of CT mRNA and protein. It was observed that ZnO NPs form a complex with CT, appear to disrupt the CT secondary structure, and block its interaction with the GM1 ganglioside receptor in the outer leaflet of the plasma membrane in intestinal (HT-29) cells and thereby reduce CT uptake into the cells. In the range of 2.5-10 μg/ml, ZnO NPs exhibited no cytotoxicity on kidney (HEK293) and HT-29 cells. We conclude that ZnO NPs prevent the first step in the translocation of cholera toxin into intestinal epithelial cells without exerting measurable toxic effects on HEK293 and HT-29 cells.

Drain Placement Does Not Increase Infectious Complications After Retromuscular Ventral Hernia Repair with Synthetic Mesh: an AHSQC Analysis

BackgroundThe use of surgical drains after ventral hernia repair (VHR) remains controversial. Some have concerns of increased infectious complications; others advocate that drains reduce fluid accumulation and surgical site occurrences (SSO). The aim of our study was to investigate the impact of retromuscular drains on SSO following retromuscular VHR with synthetic mesh. MethodsUtilizing the Americas Hernia Society Quality Collaborative, patients between January 2013 and January 2016 undergoing retromuscular VHR with synthetic mesh were assessed for the presence of a drain. Propensity score matched patients (2 drains: 1 no drain) were evaluated for 30-day rates of SSO, surgical site infections (SSI) and SSO requiring procedural intervention (SSOPI). ResultsFive hundred eighty-one patients were identified as having undergone open, retromuscular VHR with synthetic mesh. Four hundred eighty-one patients with drains and 100 without drains. After matching, 300 patients were compared, 200 with drain placement and 100 without. Retromuscular drains were less likely to develop a noninfectious SSO (OR, 0.33). Drain placement was not associated with SSI (OR, 1.30) or SSOPI (OR, 0.94). ConclusionDrain placement after retromuscular VHR with synthetic mesh is a common practice. Based on an analysis of early outcomes, surgical drains do not increase the risk of surgical infectious complications, and may be protective against some SSOs, such as seroma formation.

Structure and function of Vibrio cholerae accessory cholera enterotoxin in presence of gold nanoparticles: Dependence on morphology

BackgroundAccessory cholera enterotoxin (Ace) is a classical enterotoxin produced by Vibrio cholerae, the causative agent for cholera. Considering the crucial role of Ace in pathogenesis of cholera, we explored the modulation of structure/function of Ace using gold nanoparticles (AuNPs) of different size and shape – spherical (AuNS10 and AuNS100, the number indicating the diameter in nm) and rod (AuNR10). MethodsBiophysical techniques have been used to find out structural modulation of Ace by AuNPs. Effect of AuNP on Ace conformation was monitored by far-UV CD; urea-induced unfolding and binding of Ace to various AuNPs were studied by tryptophan fluorescence. In vivo experiments using mouse ileal loop and Ussing chamber were carried out to corroborate biophysical data. ResultsBiophysical data revealed degradation of Ace by AuNR10 and AuNS100, not by AuNS10. The feature of AuNR10 having high aspect ratio, but with the same transverse diameter as that of AuNS10 enabled us to explore the importance of morphology on modulation of protein structure/function. The equilibration time for adsorption shows dependence on the radius of curvature, being largest for AuNR10. In vivo experiments revealed the efficacy of AuNR10 and AuNS100 for reduced fluid accumulation, indicative of the loss of activity of Ace. ConclusionsWe show how biophysical studies and in vivo experiments go hand-in-hand in establishing the efficacy and role of size/shape of AuNPs on a toxin structure. General significanceThe effect of AuNP on toxin depends on its morphology. The targeted modulation of Ace could be of therapeutic benefit for gastrointestinal disorders.

Does fluid management affect the occurrence of acute kidney injury?

To describe the potential impact of different fluid management strategies on renal outcomes in critically ill and postoperative patients. Uncritical fluid administration may induce renal compartment syndrome and renal venous congestion, which contribute to kidney dysfunction. In more than 5000 randomized surgical or septic patients, goal-directed therapy did not reduce fluid accumulation, acute kidney injury (AKI) development or need for renal replacement therapy. In contrast to synthetic colloids, which increase the risk of AKI, albumin solutions and balanced crystalloids appear well tolerated from a renal standpoint in medical and surgical patients requiring intensive care. However, any clinical benefits compared with 0.9% sodium chloride have not yet been demonstrated. Although synthetic colloids should be avoided in patients with or at risk of AKI, the renal efficacy of using albumin solutions and/or balanced crystalloids as alternatives to 0.9% sodium chloride in high-risk patients is yet to be confirmed or refuted. Improved goal-directed protocols, which minimize unnecessary fluid administration and reduce potentially harmful effects of fluid overload, need to be developed and tested.

Fluid Responsiveness Assessment Using Passive Leg Raising Test to Reduce Fluid Administration and Weight Gain in Patients with Septic Shock

Background: Several observational studies have demonstrated an association between fluid accumulation and mortality in sepsis. Our aim was to determine if assessment of fluid responsiveness by a passive leg raising (PLR) algorithm could reduce fluid accumulation after 3 days in the intensive care unit (ICU) in patients with septic shock. Methods: This was an open-label single-centre randomised clinical trial performed in a surgical ICU in a tertiary centre in Stockholm, Sweden. We randomised adult (>18 years) patients with septic shock admitted to the ICU to a PLR group or a standard of care group. An increase in stroke volume index of at least 10% on the PLR test was required for the clinician to administer a fluid bolus to patients in the PLR group. Results: We randomised 34 patients. The mean (SD) weight gain after three full ICU-days was 0.6 ± 3.2 kg in the PLR group and 1.3 ± 3.9 kg in the control group (P = 0.59). The median (IQR) amount of administered resuscitation fluid during the study period was 2103 (1283-2645) ml in the PLR group and 2408 (954-5045) ml in the control group (P = 0.38). We could implement a protocol that required a positive PLR-test before administration of resuscitation fluids, but recruitment rate was low. The trial was terminated early for futility. Conclusion: The PLR protocol was not meaningful in our clinical setting, as weight gain was already low in the control group. To increase feasibility of a trial which implements a PLR-test we recommend using a non-invasive hemodynamic measurement, to include restriction of maintenance fluids in the protocol and to investigate the level of weight gain in the setting where the trial is to be performed before the start of the trial. (Funded by Stockholm County Council; ClinicalTrials.gov number, NCT02301585.) Citation: Maria Cronhjort, Magnus Bergman, Eva Joelsson-Alm, Mona-Britt Divander, Emma Jerkegren, Anca Balintescu, et al. Fluid Responsiveness Assessment Using Passive Leg Raising Test to Reduce Fluid Administration and Weight Gain in Patients with Septic Shock. J Anesth Perioper Med 2017; 4 : 169-78. doi: 10.24015/ JAPM.2017.0049 This is an open-access article, published by Evidence Based Communications (EBC). This work is licensed under the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium or format for any lawful purpose. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Role of a sensor histidine kinase ChiS of Vibrio cholerae in pathogenesis

Vibrio cholera survival in an aquatic environment depends on chitin utilization pathway that requires two factors, chitin binding protein and chitinases. The chitinases and the chitin utilization pathway are regulated by a two-component sensor histidine kinase ChiS in V. cholerae. In recent studies these two factors are also shown to be involved in V. cholerae pathogenesis. However, the role played by their upstream regulator ChiS in pathogenesis is yet to be known. In this study, we investigated the activation of ChiS in presence of mucin and its functional role in pathogenesis. We found ChiS is activated in mucin supplemented media. The isogenic chiS mutant (ChiS−) showed less growth compared to the wild type strain (ChiS+) in the presence of mucin supplemented media. The ChiS− strain also showed highly retarded motility as well as mucin layer penetration in vitro. Our result also showed that ChiS was important for adherence and survival in HT-29 cell. These observations indicate that ChiS is activated in presence of intestinal mucin and subsequently switch on the chitin utilization pathway. In animal models, our results also supported the in vitro observation. We found reduced fluid accumulation and colonization during infection with ChiS− strain. We also found ChiS− mutant with reduced expression of ctxA, toxT and tcpA. The cumulative effect of these events made V. cholerae ChiS− strain hypovirulent. Hence, we propose that ChiS plays a vital role in V. cholerae pathogenesis.

Pharmacology of the retinal pigment epithelium, the interface between retina and body system

The retinal pigment epithelium (RPE) is a close, interactive partner to the photoreceptors as well as an interface with the endothelium of the choroid and thus with the body's circulatory system. To fulfill these roles, the RPE communicates with neighboring tissue by secretion of a large variety of factors and is able to react to secreted factors via a plethora of transmembrane receptors. Clinically relevant local pharmacological effects are caused by anti-VEGF-A treatment in choroidal neovascularization or by carboanhydrase inhibitors reducing fluid accumulation in the macula. Being exposed to the bloodstream, the RPE reacts to systemic disease, such as diabetes or hypertension, but also to systemic pharmacological intervention, for example to hypotensive drugs acting on the renin-angiotensin-system. Sustained pharmacological treatments, in particular, cause side effects at the RPE with consequences for both RPE function and photoreceptor survival. Among these are systemic inhibition of angiotensin-converting enzyme, insulin treatment in diabetes and anti-VEGF-A therapy. Given the special anatomical and functional relationships of the RPE, pharmacological intervention targeting either the eye or the body systemically should take potential alteration of RPE and subsequently photoreceptor function into account.

To use or not to use hydroxyethyl starch in intraoperative care: are we ready to answer the 'Gretchen question'?

The decision of the European Medicines Agency (EMA) against the use of hydroxyethyl starch (HES)-based volume replacement solutions in critically ill patients has led to a general uncertainty when dealing with HES-based solutions, even though HES-containing solutions can still be used for the treatment of hypovolaemia caused by acute (sudden) blood loss. This review discusses current evidence of the intraoperative use of HES-based solutions. HES solutions are often criticized for possible side-effects on the kidney, the coagulation system or tissue storage. Relevant differences exist between modern 6% HES 130/0.4 and older generation of starches. Because of pathophysiological differences between elective surgery and critical illness, the evidence on renal injury and coagulation impairment with HES administration cannot be generalized. Current data suggest that there is no clinically relevant impact of 6% HES 130/0.4 administration on perioperative renal function and coagulation. Over-resuscitation is a frequent problem associated with adverse outcomes. Due to the higher volume effect, fluid overload with HES is probably more harmful than with crystalloids, whereas goal-directed use of HES may be able to reduce intraoperative fluid accumulation and overload. The use of 6% HES 130/0.4 in elective surgery patients is associated with reduced fluid accumulation and no clinically relevant difference in bleeding or the rate of acute kidney injury as compared with crystalloid use alone. Current data do not allow a conclusion on mortality. As they provide no benefit, older starch preparations should not be used.