Strengthening preparedness against global health threats: A paradigm shift based on One Health approaches.

The implementation of preparedness strategies to prevent and mitigate the impact of global health threats poses several challenges. It should promptly identify cross-cutting drivers of pandemic threats, assess context-specific risks, engage multiple stakeholders, and translate complex data from multiple sources into accessible information for action. This requires a coordinated, multidisciplinary and multisectoral effort engaging systems that, most of the time, work in isolation. The One Health (OH) approach promotes the collaboration and communication among different disciplines and sectors, and could be applied across the preparedness phases at national and international level. We discuss here gaps and needs in preparedness strategies, which can benefit from the OH approach, and a set of actionable recommendations, as shared with the G20-2021 with a dedicated Policy Brief. The discussion adds to the current debate about OH operationalization and promotes a paradigm shift towards coordinated prevention and preparedness strategies for early assessment and management of global health threats.

Determinants of weight, psychological status, food contemplation and lifestyle changes in patients with obesity during the COVID-19 lockdown: a nationwide survey using multiple correspondence analysis.

INTRODUCTION: The corona virus disease 2019 (COVID-19) pandemic forced most of the Italian population into lockdown from 11 March to 18 May 2020. A nationwide survey of Italian Clinical Nutrition and Dietetic Services (Obesity Centers or OCs) was carried out to assess the impact of lockdown restrictions on the physical and mental wellbeing of patients with obesity (PWO) who had follow-up appointments postponed due to lockdown restrictions and to compare determinants of weight gain before and after the pandemic. METHODS: We designed a structured 77-item questionnaire covering employment status, diet, physical activity and psychological aspects, that was disseminated through follow-up calls and online between 2 May and 25 June 2020. Data were analyzed by multiple correspondence analysis (MCA) and multiple linear regression. RESULTS: A total of 1,232 PWO from 26 OCs completed the questionnaires (72% female, mean age 50.2 ± 14.2 years; mean BMI 34.7 ± 7.6 kg/m2; 41% obesity class II to III). During the lockdown, 48.8% gained, 27.1% lost, while the remainder (24.1%) maintained their weight. The mean weight change was +2.3 ± 4.8 kg (in weight gainers: +4.0 ± 2.4 kg; +4.2% ± 5.4%). Approximately 37% of participants experienced increased emotional difficulties, mostly fear and dissatisfaction. Sixty-one percent reduced their physical activity (PA) and 55% experienced a change in sleep quality/quantity. The lack of online contact (37.5%) with the OC during lockdown strongly correlated with weight gain (p < 0.001). Using MCA, two main clusters were identified: those with unchanged or even improved lifestyles during lockdown (Cluster 1) and those with worse lifestyles during the same time (Cluster 2). The latter includes unemployed people experiencing depression, boredom, dissatisfaction and increased food contemplation and weight gain. Within Cluster 2, homemakers reported gaining weight and experiencing anger due to home confinement. CONCLUSIONS: Among Italian PWO, work status, emotional dysregulation, and lack of online communication with OCs were determinants of weight gain during the lockdown period.

Plasmonic Metasurfaces for Specific SERS Detection of Shiga Toxins.

The interest in the development of nanoscale plasmonic technologies has dramatically increased in recent years. The photonic properties of plasmonic nanopatterns can be controlled and tuned via their size, shape, or the arrangement of their constituents. In this work, we propose a 2D hybrid metallic polymeric nanostructure based on the octupolar framework with enhanced sensing property. We analyze its plasmonic features both numerically and experimentally, demonstrating the higher values of their relevant figures of merit: we estimated a surface-enhanced Raman spectroscopy (SERS) enhancement factor of 9 × 107 and a SPR bulk sensitivity of 430 nm/RIU. In addition, our nanostructure exhibits a dual resonance in the visible and near-infrared region, enabling our system toward multispectral plasmonic analysis. Finally, we illustrate our design engineering strategy as enabled by electron beam lithography by the outstanding performance of a SERS-based biosensor that targets the Shiga toxin 2a, a clinically relevant bacterial toxin. To the best of our knowledge, this is the first time that a SERS fingerprint of this toxin has been evidenced.

Computed tomographic and ultrasonographic findings of abdominal arterial pseudoaneurysms caused by systemic mycosis in dogs.

OBJECTIVES: To describe multidetector CT and ultrasonographic characteristics of abdominal arterial pseudoaneurysms (segmental dilatations of an artery with a ruptured tunica intima) arising secondary to systemic mycosis in dogs. MATERIALS AND METHODS: Retrospective study on dogs with confirmed histological diagnosis of a fungal pseudoaneurysm and the availability of multidetector CT or ultrasound images. RESULTS: At the time of admission, the three dogs included in this study demonstrated segmental arterial dilation, irregular arterial wall thickening, and increased echogenicity or attenuation within the local perivascular fat on ultrasound and multidetector CT images. Follow-up examinations revealed progressive increase in arterial wall thickening and saccular dilation with formation of a pseudoaneurysm in affected vessels of two dogs. CLINICAL SIGNIFICANCE: Multidetector CT and ultrasonography can be useful imaging modalities in the diagnosis and monitoring of abdominal arterial pseudoaneurysms caused by systemic mycosis.

Pathogenic Escherichia coli and enteric viruses in biosolids and related top soil improvers in Italy.

AIMS: To investigate the presence of genomic traits associated with a set of enteric viruses as well as pathogenic Escherichia coli in top soil improvers (TSI) from Italy. METHODS AND RESULTS: Twenty-four TSI samples originating from municipal sewage sludges, pig manure, green and household wastes were analysed by real time PCR for the presence of hepatitis E virus (HEV), porcine and human adenovirus (HuAdV), norovirus, rotavirus and diarrhoeagenic E. coli. None of the samples was found positive for HEV or rotavirus. Four samples were positive for the presence of nucleic acids from human norovirus, two of them being also positive for HuAdV. Real time PCR screening gave positive results for many of the virulence genes characteristic of diarrhoeagenic E. coli in 21 samples. These included the verocytotoxin-coding genes, in some cases associated with intimin-coding gene, and markers of enteroaggregative, enterotoxigenic and enteroinvasive E. coli. CONCLUSIONS: These results provide evidence that enteric viruses and pathogenic E. coli may be released into the environment through the use of sludge-derived TSI. SIGNIFICANCE AND IMPACT OF THE STUDY: The results highlight that the TSI-related environmental risk for the food chain should be more deeply assessed.

Characterization of an emergent clone of enteroinvasive Escherichia coli circulating in Europe.

Enteroinvasive Escherichia coli (EIEC) cause intestinal illness indistinguishable from that caused by Shigella, mainly in developing countries. Recently an upsurge of cases of EIEC infections has been observed in Europe, with two large outbreaks occurring in Italy and in the United Kingdom. We have characterized phenotypically and genotypically the strains responsible for these epidemics together with an additional isolate from a sporadic case isolated in Spain. The three isolates belonged to the same rare serotype O96:H19 and were of sequence type ST-99, never reported before in EIEC or Shigella. The EIEC strains investigated possessed all the virulence genes harboured on the large plasmid conferring the invasive phenotype to EIEC and Shigella while showing only some of the known chromosomal virulence genes and none of the described pathoadaptative mutations. At the same time, they displayed motility abilities and biochemical requirements resembling more closely those of the non-pathogenic E. coli rather than the EIEC and Shigella strains used as reference. Our observations suggested that the O96:H19 strains belong to an emerging EIEC clone, which could be the result of a recent event of acquisition of the invasion plasmid by commensal E. coli.

Hyper/hypoglycemia and acute kidney injury in critically ill patients.

BACKGROUND & AIMS: Abnormalities of blood glucose (BG) concentration (hyper- and hypoglycemia), now referred to with the cumulative term of dysglycemia, are frequently observed in critically ill patients, and significantly affect their clinical outcome. Acute kidney injury (AKI) may further complicate glycemic control in the same clinical setting. This narrative review was aimed at describing the pathogenesis of hyper- and hypoglycemia in the intensive care unit (ICU), with special regard to patients with AKI. Moreover, the complex relationship between AKI, glycemic control, hypoglycemic risk, and outcomes was analyzed. METHODS: An extensive literature search was performed, in order to identify the relevant studies describing the epidemiology, pathogenesis, treatment and outcome of hypo- and hyperglycemia in critically ill patients with AKI. RESULTS AND CONCLUSION: Patients with AKI are at increased risk of both hyper-and hypoglycemia. The available evidence does not support a protective effect on the kidney by glycemic control protocols employing Intensive Insulin Treatment (IIT), i.e. those aimed at maintaining normal BG concentrations (80-110 mg/dl). Recent guidelines taking into account the high risk for hypoglycemia associated with IIT protocols in critically ill patients, now suggest higher BG concentration targets (<180 mg/dl or 140-180 mg/dl) than those previously recommended (80-110 mg/dl). Notwithstanding the limited evidence available, it seems reasonable to extend these indications also to ICU patients with AKI.

Defining pathogenic verocytotoxin-producing Escherichia coli (VTEC) from cases of human infection in the European Union, 2007-2010.

During 2007-2010, 13 545 confirmed human verocytotoxin (VT)-producing Escherichia coli (VTEC) infections were reported in the European Union, including 777 haemolytic uraemic syndrome (HUS) cases. Clinical manifestations were reported for 53% of cases, 64% of which presented with diarrhoea alone and 10% with HUS. Isolates from 85% of cases were not fully serotyped and could not be classified on the basis of the Karmali seropathotype concept. There is no single or combination of phenotypic or genetic marker(s) that fully define 'pathogenic' VTEC. Isolates which contain the vtx2 (verocytotoxin 2) gene in combination with the eae (intimin-encoding) gene or aaiC (secreted protein of enteroaggregative E. coli) and aggR (plasmid-encoded regulator) genes have been associated with a higher risk of more severe illness. A molecular approach targeting genes encoding VT and other virulence determinants is thus proposed to allow an assessment of the potential severity of disease that may be associated with a given VTEC isolate.

[Disglycemia in patients with acute kidney injury in the ICU]. / Alterazioni glicemiche nel danno renale acuto in terapia intensiva.

Derangements of glucose metabolism are common among critically ill patients. Critical illness- associated hyperglycemia (CIAH) is characterized by raised blood glucose levels in association with an acute event that is reversible after resolution of the underlying disease. CIAH has many causes, such as changes in counter-regulatory hormone status, release of sepsis mediators, insulin resistance, drugs and nutritional factors. It is associated with increased mortality risk. This association appears to be strongly influenced by diabetes mellitus as a comorbidity, suggesting the need for an accurate individualization of glycemic targets according to baseline glycemic status. Hypoglycemia is also very common in this clinical context and it has a negative prognostic impact. Many studies based on intensive insulin treatment protocols targeting normal blood glucose values have in fact documented both an increased incidence of hypoglycemia and an increased mortality risk. Finally, glycemic control in the ICU is made even more complex in the presence of acute kidney injury. On one hand, there is in fact a reduction of both the renal clearance of insulin and of gluconeogenesis by the kidney. On the other hand, the frequent need for renal replacement therapy (dialysis / hemofiltration) may result in an energy intake excess, under the form of citrate, lactate and glucose in the dialysate/reinfusion fluids. With regard to the possible renal protective effects afforded by intensive glycemic control protocols, the presently available evidence does not support a reduction in the incidence of AKI and/or the need for RRT with this approach, when compared with standard glucose control. Thus, the most recent guidelines now suggest higher blood glucose targets (<180 mg/dl or 140-180 mg/dl) than in the past (80-110 mg/dl). Albeit with limited evidence, it seems reasonable to extend these indications also to patients with AKI in the intensive care unit. Further studies are needed in order to better ascertain the effects of dysglycemia on the outcome of patients with AKI.

[Nutritional support in acute kidney injury]. / Supporto nutrizionale nel danno renale acuto.

Optimal nutritional requirements and nutrient intake composition for patients with acute kidney injury is still a partially unresolved issue. Targeting nutritional support to the actual protein and energy needs improves the clinical outcome of critically ill patients. So far, very few data are currently available on this topic in acute kidney injury. In this specific clinical condition, the risk for under- and overfeeding may be increased by factors interfering on nutrient need estimation, such as rapidly changing body weight due to fluid balance variations, nutrient losses and hidden calorie sources from renal replacement therapy. Moreover, since acute kidney injury is now considered a kidney-centered inflammatory syndrome, the renoprotective role of specific pharmaconutrients with anti-inflammatory properties remains to be fully defined. This review is aimed at discussing recently published results concerning quantitative and qualitative aspects of the nutritional approach to acute kidney injury in critically ill patients.

A severe foodborne outbreak of diarrhoea linked to a canteen in Italy caused by enteroinvasive Escherichia coli, an uncommon agent.

We describe a foodborne outbreak in Italy caused by enteroinvasive Escherichia coli (EIEC), an enteric pathogen uncommon in industrialized countries. On 14 April 2012 a number of employees of the city of Milan Fire Brigade (FB) were admitted to hospital with severe diarrhoea after attending their canteen. Thirty-two patients were hospitalized and a total of 109 cases were identified. A case-control study conducted on 83 cases and 32 controls attending the canteen without having symptoms identified cooked vegetables to be significantly associated with the disease. Stool samples collected from 62 subjects were screened for enteric pathogens using PCR-based commercial kits: 17 cases and two asymptomatic kitchen-workers were positive for the Shigella marker gene ipaH; an ipaH-positive EIEC strain O96:H19 was isolated from six cases. EIEC may cause serious dysentery-like outbreaks even in Western European countries. Microbiologists should be aware of microbiological procedures to detect EIEC, to be applied especially when no common enteric pathogens are identified.

Use of virulence determinants and seropathotypes to distinguish high- and low-risk Escherichia coli O157 and non-O157 isolates from Europe.

The presence of 10 virulence genes was examined using polymerase chain reaction (PCR) in 365 European O157 and non-O157 Escherichia coli isolates associated with verotoxin production. Strain-specific PCR data were analysed using hierarchical clustering. The resulting dendrogram clearly separated O157 from non-O157 strains. The former clustered typical high-risk seropathotype (SPT) A strains from all regions, including Sweden and Spain, which were homogenous by Cramer's V statistic, and strains with less typical O157 features mostly from Hungary. The non-O157 strains divided into a high-risk SPTB harbouring O26, O111 and O103 strains, a group pathogenic to pigs, and a group with few virulence genes other than for verotoxin. The data demonstrate SPT designation and selected PCR separated verotoxigenic E. coli of high and low risk to humans; although more virulence genes or pulsed-field gel electrophoresis will need to be included to separate high-risk strains further for epidemiological tracing.

A new pathogenicity island carrying an allelic variant of the Subtilase cytotoxin is common among Shiga toxin producing Escherichia coli of human and ovine origin.

Subtilase (SubAB) is a cytotoxin elaborated by some Shiga Toxin (Stx)-producing Escherichia coli (STEC) strains usually lacking the locus of enterocyte effacement (LEE). Two variants of SubAB coding genes have been described: subAB(1) , located on the plasmid of the STEC O113 98NK2 strain, and subAB(2) , located on a pathogenicity island (PAI) together with the tia gene, encoding an invasion determinant described in enterotoxigenic E. coli. In the present study, we determined the entire nucleotide sequence of the PAI containing the subAB(2) operon, termed Subtilase-Encoding PAI (SE-PAI), and identified its integration site in the pheV tRNA locus. In addition, a PCR strategy for discriminating the two subAB allelic variants was developed and used to investigate their presence in E. coli strains belonging to different pathotypes and in a large collection of LEE-negative STEC of human and ovine origin. The results confirmed that subAB genes are carried predominantly by STEC and showed their presence in 72% and 86% of the LEE-negative strains from human cases of diarrhoea and from healthy sheep respectively. Most of the subAB-positive strains (98%) identified possessed the subAB(2) allelic variant and were also positive for tia, suggesting the presence of SE-PAI. Altogether, our observations indicate that subAB(2) is the prevalent SubAB-coding operon in LEE-negative STEC circulating in European countries, and that sheep may represent an important reservoir for human infections with these strains. Further studies are needed to assess the role of tia and/or other genes carried by SE-PAI in the colonization of the host intestinal mucosa.

Assessment of NGAL as an early biomarker of acute kidney injury in adult cardiac surgery patients.

Early and predictive acute kidney injury (AKI) markers may be decisive for the clinical outcome of heart surgery. Hence, this study set out to evaluate the biological variability of urinary neutrophil gelatinase-associated lipocalin (uNGAL) levels in adult cardiac surgery patients, to test their feasibility as a biomarker of early AKI in a routine laboratory setting. uNGAL levels were measured with an automated immunoassay in urine samples from patients undergoing cardiac surgery using cardiopulmonary bypass, at the time of admission (T0) and 4 hours (T1) and 24 hours (T2) after surgery. Patients without post-operative AKI did not show significant differences in urine NGAL levels after surgery. In contrast, patients developing AKI displayed a significant increase (P=0.011) in uNGAL levels compared to T0. This increase was detectable at an earlier time point (T1, 4 hours) with respect to serum creatinine (T2, 24 hours). Confirming its utility as a biomarker, at T1 the uNGAL levels were significantly higher in AKI patients than in non-AKI patients (P=0.021). A receiver operating characteristic curve analysis of the uNGAL assay gave a sensitivity of 55.3 (95percent confidence interval, 26.59-78.73), a specificity of 72.9 (95 percent CI, 55.88-86.21), and a cut-off value for AKI prediction of 55.2. These results support the notion that urinary NGAL is an earlier marker of AKI than serum creatinine. However, the cut-off value of the assay was too low to consider it as a positive or negative diagnostic marker in AKI patients with moderate degree of severity. Likewise, its sensitivity and specificity were not high enough for it to be considered better than the others currently in use.

Characteristics of the enteroaggregative Shiga toxin/verotoxin-producing Escherichia coli O104:H4 strain causing the outbreak of haemolytic uraemic syndrome in Germany, May to June 2011.

The Escherichia coli strain causing a large outbreak of haemolytic uraemic syndrome and bloody diarrhoea in Germany in May and June 2011 possesses an unusual combination of pathogenic features typical of enteroaggregative E. coli together with the capacity to produce Shiga toxin. Through rapid national and international exchange of information and strains the known occurrence in humans was quickly assessed.We describe simple diagnostic screening tools to detect the outbreak strain in clinical specimens and a novel real-time PCR for its detection in foods.

[Continuous renal replacement therapies (CRRT) will remain the most widely adopted dialysis modality in the critically ill]. / A favore delle CRRT: le terapie sostitutive renali continue rimarranno le metodiche prevalenti nelle unita' di terapia intensiva.

In the last 10-15 years, user-friendly continuous renal replacement therapy (CRRT) machines have played a major role in increasing the popularity of these techniques in intensive care settings. At present it is not clear which modality of renal replacement therapy (RRT) is optimal for critically ill patients with acute kidney injury (AKI). The choice between different modalities should therefore not be based on unproven ''outcome'' advantages but on evaluation of the clinical picture and logistical circumstances. In hypercatabolic patients, CRRT and sustained low-efficiency dialysis (SLED) have been shown to provide similar metabolic control, but uncontrolled studies suggested a better hemodynamic stability during CRRT, intended as a higher mean arterial pressure and/or less frequent need to increase inotropic or vasoactive drugs. The incidence of hemorrhagic complications is higher with CRRT; however, in particular conditions, such as in patients at high risk of bleeding, CRRT can be performed without anticoagulation or with the use of alternative anticoagulation protocols. Among the different modalities, regional anticoagulation with citrate appears to be the most promising, and the continuous development of simplified protocols for citrate CRRT might facilitate the more extensive use of this technique in the near future. The presence of a mismatch between prescribed and delivered dialysis dose is frequently reported as an important drawback of CRRT. However, data from a recent study designed to evaluate the prognostic impact of the intensity of renal support in critically ill patients with AKI showed that the target Kt/V was obtained in only 67-69% of intermittent hemodialysis (IHD) sessions. Data from several studies comparing the costs of different RRT modalities showed that CRRT is more expensive than IHD or SLED. However, the costs related to SLED can fluctuate within a wide range and in particular settings the higher costs of CRRT could be partially justified by logistical advantages. Further improvements in CRRT device characteristics, anticoagulation protocols, and adaptation of dialysis/replacement fluids to clinical needs will possibly contribute to maintaining, in the coming years, the key role of CRRT in the treatment of hemodynamically unstable critically ill patients requiring RRT.

[Acute renal failure following cardiac surgery]. / Insufficienza renale acuta post-cardiochirurgica.

Acute renal failure (ARF) develops in 1-30% of patients who undergo cardiac surgery and is associated with a high mortality rate (15-30%). Several risk factors (pre- and intra-operative) for ARF have been identified. Pre-operative factors are strictly related to cardiovascular disease, advanced age and baseline renal dysfunction, while intra-operative factors are linked with the type of cardiac surgery, the duration of cardiopulmonary bypass and aortic cross-clamping. These factors provide an opportunity to quantify the risk of ARF based on pre-operative data, and for this purpose a clinical score to predict post-operative ARF has recently been developed. Moreover, this score could allow the identification of those patients who may take advantage of preventive strategies. Mortality in patients who develop severe ARF requiring dialysis is particularly high (50-80%). Therefore, an early diagnosis of ARF and a timely and aggressive renal replacement therapy could improve the outcome.

[Pharmacotherapy of sepsis]. / La sepsi: terapia farmacologica.

Despite an increasingly understanding of the pathogenetic mechanisms of sepsis, its mortality remains extremely high, caused mainly by hemodynamic impairment-related alterations frequently present in severe sepsis. Currently, treatment of sepsis is based on hemodynamic support, antibiotic therapy, surgical excision of infectious foci and immunomodulatory therapy. In fact, a massive host inflammatory infection response has recently emerged to substantially contribute to the development of septic shock and multiple organ dysfunction. Many clinical trials on various pharmacological agents have been conducted: glucocorticoids, nonsteroidal anti-inflammatory drugs (NSAIDs), antithrombin III (AT III), anti-endotoxin monoclonal antibodies, nitric oxide inhibitors, interleukin-1 receptor antagonist, anti-tumor necrosis factor (TNF) antibodies. Apart from some likely favourable findings connected to low doses of glucocorticoids, most studies yielded disappointing results. Nevertheless, the use of recombinant human activated protein C (drotrecogin-alpha) has recently proven to have a mortality reduction effect particularly in patients with severe sepsis and dysfunction of at least two organs. Furthermore, the early treatment of hemodynamic instability with volume expanders and vasopressors (early goal-directed therapy), and a strict glycemic control represent important measures in order to significantly reduce mortality from severe sepsis and septic shock, and are fundamental guidelines recommended by most scientific societies (Surviving Sepsis Campaign).

[Polymyxin-B direct hemoperfusion (PMX-DHP) in gram negative sepsis]. / L'moperfusione diretta con Polimixina-B (PMX-DHP) nel trattamento della sepsi da gram negativi.

UNLABELLED: Severe sepsis and septic shock have a mortality rate that may range between 28 and 50%. It is estimated that approximately 200,000 patients die per annum in the USA as a consequence of sepsis. The reduction of plasma endotoxin levels to achieve a favourable outcome for septic patients has been previously demonstrated but the effectiveness of treatments targeting single inflammatory mediators during established sepsis has been disappointing. Furthermore,some clinical study clinically showed valuable reduction in cytokine levels by hemofiltration alone. The prompt removal of endotoxins could be an effective way to reduce the immunological activation and the amount of NO produced by endotoxin-activated inducible NO-synthase in many tissues and cells. The polymyxin B cartridge is an extracorporeal hemoperfusion device (PMX-DHP) known to remove circulating endotoxins. Open-label clinical trials testing PMX-DHP have demonstrated its safety in the septic shock treatment while the overall survival rate significantly improved in comparison with the control groups. The purpose of this study was to investigate the effects of PMX-DHP on redox status, inflammatory cytokine profile, monocytes and PMN leukocyte activation in Gram-negative sepsis. Prospective study: six patients, 2 males and 4 females 60.5+/-24.5 years old, in ICU for severe Gram-negative sepsis (emergency surgery for intra abdominal infection). Two PMX-DHP runs, at T0 and T1; 2 hours each; the first within 24 hours from sepsis diagnosis or 12 hours after emergency surgery, the first PMX-DHP at T0, the second after 24 hours.; APACHE II score at T0: 20.1+/-3.7; SOFA score 14.2+/-2.5; organ failure: 3+/-1.5; norepinephrine(Ne) in 1 patient; Ne + dopamine (DA) in 4 patients; DA in 1 patient only. Mean dosage: Ne 0.24 mcg/kg/min; DA 8.9 mcg/kg/min. Four patients in CRRT (continuous veno-venous hemofiltration, AN69 hemofilter) for the entire length of the study. QB 100+/-10 ml/min. Pre and post PMX-DHP, plasma endotoxins as well as anti-IL 1-beta, IL2, IL4, IL5, IL6, IL8, IL10, TNF-alpha, GM-CSF, IFN-gamma levels were measured. Expression of CD64 on monocytes and PMN leukocytes and I -2r CD25 on CD4+ T cells by flow cytometry. Total and reduced plasma cysteine, homocysteine, glutathione (GSH); plasma glutathione peroxidase (GSH-Px) and reductase (GSH-Rx); erythrocyte GSH (eGSH), eGSH-Px and eGSH-Rx; NADP and NADPH and their ratio assessed pre and post PMX-DHP, all compared with 15 age and gender-matched healthy subjects for complete REDOX characterization. RESULTS: We observed a significant reduction of endotoxin levels post PMX-DHP; CD64 monocytes and PMN leukocytes overexpression returned to normal; pro-inflammatory cytokines Il6, Il 10 and TNF-alpha were significantly reduced. We detected no differences in plasma levels of anti-IL 1-beta, IL2, IL4, IL5, IL8, GM-CSF, IFN-gamma pre versus post PMX-DHP. SOFA score from 14.2+/-2.5 to 8.9+/-2.1 post PMX-DHP runs. Four out of six patients survived and were discharged; mortality was 33% versus the anticipated 51%. CONCLUSION: PMX-DHP reduces circulating endotoxins, down-activates monocytes and PMN leukocytes, reduces pro-Inflammatory cytokines and corrects the redox environment imbalance preventing oxidative damage to endothelial cells and the metabolic and functional microvascular derangements that usually lead to multi-organ failure and septic shock.

[Pharmacokinetic principles and drug-dosing adjustments during continuous renal replacement therapies (CRRT)]. / Principi di farmacocinetica e aggiustamento posologico dei farmaci nell terapie sostitutive renali continue (CRRT).

In the critically ill, acute renal failure (ARF) and "Multiple Organ Dysfunction Syndrome" (MODS) can be associated with significant modifications of many pharmacokinetic parameters, such as protein binding, volume of distribution and total body clearance. The start of renal replacement therapy (RRT) represents an additional variable to take in consideration for drug-dosing adjustments. Drugs significantly eliminated by the kidney are likely to be removed during RRT and a supplemental dose or further dosing adjustments are required if extracorporeal clearance is more than 25-30% of total body clearance. The impact of RRT on plasma drug concentrations can be substantially different in relation to the type of treatment (diffusive, convective or both), membrane characteristics (low-flux or high-flux), filter surface area and prescribed dialysis dose. The molecular weight cut-offs of high-flux membrane are much higher than the molecular weight of most drugs. Therefore, molecular size will not be a limitation for the removal of the unbound fraction of the drugs most commonly used in the critically ill undergoing continuous renal replacement therapy (CRRT). However, diffusive clearance could be significantly lower than convective clearance for drugs in the middle molecular weight range. In any case, the extracorporeal clearances report-ed with the use of high-volume CRRT (>50-60 L/2 h) are often surprisingly elevated and can lead to drug underdosing in clinical conditions where adequate antibiotic treatment is essential.