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The identification of patient-derived, tumor-reactive T cell receptors (TCRs) as a basis for personalized transgenic T cell therapies remains a time- and cost-intensive endeavor. Current approaches to identify tumor-reactive TCRs analyze tumor mutations to predict T cell activating (neo)antigens and use these to either enrich tumor infiltrating lymphocyte (TIL) cultures or validate individual TCRs for transgenic autologous therapies. Here we combined high-throughput TCR cloning and reactivity validation to train predicTCR, a machine learning classifier that identifies individual tumor-reactive TILs in an antigen-agnostic manner based on single-TIL RNA sequencing. PredicTCR identifies tumor-reactive TCRs in TILs from diverse cancers better than previous gene set enrichment-based approaches, increasing specificity and sensitivity (geometric mean) from 0.38 to 0.74. By predicting tumor-reactive TCRs in a matter of days, TCR clonotypes can be prioritized to accelerate the manufacture of personalized T cell therapies., (© 2024. The Author(s).)

Background and Objectives : Postoperative non-invasive ventilation (NIV) has been proposed as an attractive strategy to reduce morbidity in obese subjects undergoing general anaesthesia. The increased body mass index (BMI) correlates with loss of perioperative functional residual capacity, expiratory reserve volume, and total lung capacity. The aim of the current study is to evaluate the efficacy of NIV in a post-anaesthesia care unit (PACU) in reducing post-extubation acute respiratory failure (ARF) after biliointestinal bypass (BIBP) in obese patients. Materials and Methods : A retrospective analysis was conducted from January 2019 to December 2020 to compare acute respiratory failure within the first 72 postoperative hours and oximetry values of obese patients who underwent BIBP after postoperative NIV adoption or conventional Venturi mask. Results : In total, 50 patients who received NIV postoperative protocol and 57 patients who received conventional Venturi mask ventilation were included in the study. After 120 min in PACU pH, pCO 2 , pO 2 , and SpO 2 were better in the NIV group vs. control group ( p < 0.001). Seventy-two hours postoperatively, one patient (2%) in the NIV group vs. seven patients (12.2%) in the control group developed acute respiratory failure. Therefore, conventional Venturi mask ventilation resulted in being significantly associated ( p < 0.05) with postoperative ARF with an RR of 0.51 (IC 0.27-0.96). Conclusions : After bariatric surgery, short-term NIV during PACU observation promotes a more rapid recovery of postoperative lung function and oxygenation in obese patients, reducing the necessity for critical care in the days following surgery. Therefore, as day-case surgery becomes more advocated even for morbid obesity, it might be considered a necessary procedure.

The polymorphism L412F in TLR3 has been associated with several infectious diseases. However, the mechanism underlying this association is still unexplored. Here, we show that the L412F polymorphism in TLR3 is a marker of severity in COVID-19. This association increases in the sub-cohort of males. Impaired macroautophagy/autophagy and reduced TNF/TNFα production was demonstrated in HEK293 cells transfected with TLR3 L412F -encoding plasmid and stimulated with specific agonist poly(I:C). A statistically significant reduced survival at 28 days was shown in L412F COVID-19 patients treated with the autophagy-inhibitor hydroxychloroquine (p = 0.038). An increased frequency of autoimmune disorders such as co-morbidity was found in L412F COVID-19 males with specific class II HLA haplotypes prone to autoantigen presentation. Our analyses indicate that L412F polymorphism makes males at risk of severe COVID-19 and provides a rationale for reinterpreting clinical trials considering autophagy pathways. Abbreviations: AP: autophagosome; AUC: area under the curve; BafA1: bafilomycin A1; COVID-19: coronavirus disease-2019; HCQ: hydroxychloroquine; RAP: rapamycin; ROC: receiver operating characteristic; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TLR: toll like receptor; TNF/TNF-α: tumor necrosis factor.

Introduction: Port-a-caths are long-stay central catheters often used for chemotherapy or parenteral nutrition. The implantation of a port-a cath, despite being involved in routine procedures, is also associated with immediate and delayed complications. Complications are rare but must be known and managed by operators., Case Report: A delayed complication related to the presence of a port-a-cath, consisting in the fragmentation of the catheter, has been reported, in a 63-years-old female patient. The port was placed via subclavian venous access and affected by pinch-off syndrome, which resulted in catheter malfunction and then in fragmentation from compression by the subclavius-costoclavicular complex. The onset symptom was device malfunction., Discussion and Conclusion: The focus in the management of this rare but possible complication was the quick removal of the device and of the catheter fragment in the endovascular lumen with collaboration between different medical specialists., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Noninvasive mechanical ventilation is the main supportive measure used in patients with pediatric ARDS (PARDS), but adjunctive pharmacological therapies (corticosteroids, inhaled nitric oxide [iNO], surfactant replacement therapy and neuromuscular blocking drugs) are also used, although limited data exists to inform of this practice., Areas Covered: The authors review the current challenges in the pharmacological management of PARDS and highlight the few certainties currently available., Expert Opinion: Children with PARDS must not be treated as young adults with ARDS, essentially because children's lungs differ substantially from those of adults and PARDS occurs in children differently than ARDS in adults. Pharmacological treatments available for PARDS are relatively few and, since there is great uncertainty about their effectiveness also because of the extreme heterogeneity of this syndrome, it is necessary to conduct large clinical trials using currently available definitions and considering recent pathobiological knowledge. The aim is to identify homogeneous subgroups or phenotypes of children with PARDS that may benefit from the specific pharmaceutical approach examined. It will be then necessary to link endotypes and outcomes to appropriately target therapies in future trials, but this will be possible only after it will be possible to identify the different PARDS endotypes.

In medulloblastomas, genetic alterations resulting in over-activation and/or deregulation of proteins involved in Hedgehog (HH) signaling lead to cellular transformation, which can be prevented by inhibition of primary ciliogenesis. Here, we investigated the role of MAPK15 in HH signaling and, in turn, in HH-mediated cellular transformation. We first demonstrated, in NIH3T3 mouse fibroblasts, the ability of this kinase of controlling primary ciliogenesis and canonical HH signaling. Next, we took advantage of transformed human medulloblastoma cells belonging to the SHH-driven subtype, i.e., DAOY and ONS-76 cells, to ascertain the role for MAPK15 in HH-mediated cellular transformation. Specifically, medullo-spheres derived from these cells, an established in vitro model for evaluating progression and malignancy of putative tumor-initiating medulloblastoma cells, were used to demonstrate that MAPK15 regulates self-renewal of these cancer stem cell-like cells. Interestingly, by using the HH-related oncogenes SMO-M2 and GLI2-DN, we provided evidences that disruption of MAPK15 signaling inhibits oncogenic HH overactivation in a specific cilia-dependent fashion. Ultimately, we show that pharmacological inhibition of MAPK15 prevents cell proliferation of SHH-driven medulloblastoma cells, overall suggesting that oncogenic HH signaling can be counteracted by targeting the ciliary gene MAPK15, which could therefore be considered a promising target for innovative "smart" therapies in medulloblastomas.

Inhibition of DDX3X expression or activity reduces proliferation in cells from various tumor tissues, in particular in breast cancer, and its expression often correlates to tumor aggressiveness. This makes DDX3X a prominent candidate for the design of drugs for novel personalized therapeutic strategies. Starting from an in silico drug discovery approach, a group of molecules has been selected by molecular docking at the RNA binding site of DDX3X. Here, the most promising among them, FHP01, was evaluated in breast cancer preclinical models. Specifically, FHP01 exhibited very effective antiproliferative and killing activity against different breast cancer cell types, among which those from triple-negative breast cancer (TNBC). Interestingly, FHP01 also inhibited WNT signaling, a key tumorigenic pathway already correlated to DDX3X functions in breast cancer model cell lines. Ultimately, FHP01 also caused a significant reduction, in vivo, in the growth of MDA MB 231-derived TNBC xenograft models. Importantly, FHP01 showed good bioavailability and no toxicity on normal peripheral blood mononuclear cells in vitro and on several mouse tissues in vivo. Overall, our data suggest that the use of FHP01 and its related compounds may represent a novel therapeutic approach with high potential against breast cancer, including the triple-negative subtype usually correlated to the most unfavorable outcomes because of the lack of available targeted therapies.

Background: Acute severe asthma is a life-threatening medical emergency. Characteristics of asthma include increased airway resistance and dynamic pulmonary hyperinflation that can manifest in dangerous levels of hypercapnia and acidosis, with significant mortality and morbidity. Severe respiratory distress can lead to endotracheal intubation followed by mechanical ventilation, which can cause increased air trapping with dynamic hyperinflation, predisposing the lungs to barotraumas., Case Presentation: The present case report describes the use of the minimally invasive ECCO 2 R ProLUNG ® (Estor) with protective low-tidal-volume ventilation, in a Caucasian patient with near-fatal asthma and with no response to conventional therapy., Conclusions: Since hypercarbia rather than hypoxemia is the primary abnormality in status asthmaticus, a rescue therapeutic strategy combining the ECCO 2 R membrane ProLUNG ® (Estor) with ultra-protective low-tidal-volume ventilation can be successfully applied to limit the risk of severe barotrauma during invasive mechanical ventilation. ECCO 2 R ProLUNG ® is a partial respiratory support technique that, based on the use of an extracorporeal circuit with a gas-exchange membrane, achieves relevant CO 2 clearance directly from the blood using double-lumen venous-venous vascular access, at blood flow in the range of 0.4-1.0 L/minute.

Oxidative stress plays a key role in the pathophysiology of retinal diseases, including age-related macular degeneration (AMD) and diabetic retinopathy, which are the major causes of irreversible blindness in developed countries. An excess of reactive oxygen species (ROS) can directly cause functional and morphological impairments in retinal pigment epithelium (RPE), endothelial cells, and retinal ganglion cells. Antioxidants may represent a preventive/therapeutic strategy and reduce the risk of progression of AMD. Among antioxidants, N-acetyl-L-cysteine (NAC) is widely studied and has been proposed to have therapeutic benefit in treating AMD by mitigating oxidative damage in RPE. Here, we demonstrate that N-acetyl-L-cysteine ethyl ester (NACET), a lipophilic cell-permeable cysteine derivative, increases the viability in oxidative stressed RPE cells more efficiently than NAC by reacting directly and more rapidly with oxidizing agents, and that NACET, but not NAC, pretreatment predisposes RPE cells to oxidative stress resistance and increases the intracellular reduced glutathione (GSH) pool available to act as natural antioxidant defense. Moreover, we demonstrate the ability of NACET to increase GSH levels in rats' eyes after oral administration. In conclusion, even if experiments in AMD animal models are still needed, our data suggest that NACET may play an important role in preventing and treating retinal diseases associated with oxidative stress, and may represent a valid and more efficient alternative to NAC in therapeutic protocols in which NAC has already shown promising results.

The ability to generate large numbers of distinct types of human dendritic cells (DCs) in vitro is critical for accelerating our understanding of DC biology and harnessing them clinically. We developed a DC differentiation method from human CD34 + precursors leading to high yields of plasmacytoid DCs (pDCs) and both types of conventional DCs (cDC1s and cDC2s). The identity of the cells generated in vitro and their strong homology to their blood counterparts were demonstrated by phenotypic, functional, and single-cell RNA-sequencing analyses. This culture system revealed a critical role of Notch signaling and GM-CSF for promoting cDC1 generation. Moreover, we discovered a pre-terminal differentiation state for each DC type, characterized by high expression of cell-cycle genes and lack of XCR1 in the case of cDC1. Our culture system will greatly facilitate the simultaneous and comprehensive study of primary, otherwise rare human DC types, including their mutual interactions., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Mature differentiated macrophages can self-maintain by local proliferation in tissues and can be extensively expanded in culture under specific conditions, but the mechanisms of this phenomenon remain only partially defined. Here, we show that SIRT1, an evolutionary conserved regulator of life span, positively affects macrophage self-renewal ability in vitro and in vivo Overexpression of SIRT1 during bone marrow-derived macrophage differentiation increased their proliferative capacity. Conversely, decrease of SIRT1 expression by shRNA inactivation, CRISPR/Cas9 mediated deletion and pharmacological inhibition restricted macrophage self-renewal in culture. Furthermore, pharmacological SIRT1 inhibition in vivo reduced steady state and cytokine-induced proliferation of alveolar and peritoneal macrophages. Mechanistically, SIRT1 inhibition negatively regulated G1/S transition, cell cycle progression and a network of self-renewal genes. This included inhibition of E2F1 and Myc and concomitant activation of FoxO1, SIRT1 targets mediating cell cycle progression and stress response, respectively. Our findings indicate that SIRT1 is a key regulator of macrophage self-renewal that integrates cell cycle and longevity pathways. This suggests that macrophage self-renewal might be a relevant parameter of ageing., (© 2017 The Authors.)

Dendritic cells (DCs) are critical for the launching of protective T cell immunity in response to viral infection. Viruses can directly infect DCs, thereby compromising their viability and suppressing their ability to activate immune responses. How DC function is maintained in light of this paradox is not understood. By analyzing the susceptibility of primary human DC subsets to viral infections, we report that CD141 + DCs have an innate resistance to infection by a broad range of enveloped viruses, including HIV and influenza virus. In contrast, CD1c + DCs are susceptible to infection, which enables viral antigen production but impairs their immune functions and survival. The ability of CD141 + DCs to resist infection is conferred by RAB15, a vesicle-trafficking protein constitutively expressed in this DC subset. We show that CD141 + DCs rely on viral antigens produced in bystander cells to launch cross-presentation-driven T cell responses. By dissociating viral infection from antigen presentation, this mechanism protects the functional capacity of DCs to launch adaptive immunity against viral infection., (Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

A role for bone-marrow-derived cells (BMDCs) in tissue repair and malignancy onset has been proposed, but their contribution is still debated. We tested the ability of BMDCs containing the inducible kras(V12) oncogene to initiate lung adenocarcinoma. For our experimental strategy, we reconstituted lethally irradiated wild type mice with BMDCs carrying inducible kras(V12) and subsequently induced oncogene expression by 4-OHT administration. Epithelial lung lesions, from adenoma to adenocarcinomas, appeared at successive time points. These results show that lung tumors were derived from donor BMDCs and indicate a direct involvement of bone marrow cells in the development of epithelial cancers.

Purpose: Zymosan-induced generalized inflammation is the only experimental model that reproduces characteristics of human multiple organ dysfunction syndrome (MODS). Toll-like receptors (TLRs) are key components in innate immune responses and their signaling pathway is known to activate target genes such as nuclear factor-κB (NF-κB) and cytokines that are involved in inflammation and immune responses. We previously reported that hyperbaric oxygen (HBO) therapy is effective in the treatment of severe zymosan-induced inflammation in MODS. The aim of this study was to investigate the effect of HBO exposure on TLR2 and TLR4 signal transduction and organ dysfunction during MODS induced by zymosan in the rat., Methods: Male Wistar rats were randomized into four groups and treated as follows: (1) saline solution (control); (2) zymosan; (3) HBO 4 and 11 h after zymosan injection; (4) HBO 4 and 11 h after saline solution injection. Zymosan-induced damage of the lungs, liver, and small intestine was evaluated using histology and biochemistry. The activation of the TLR signaling pathway was measured with Western blot, reverse transcriptase polymerase chain reaction analysis (RT-PCR), and immunohistochemistry., Results: Zymosan induced a severe inflammatory response characterized by the activation of the TLR signaling pathway and by an organ dysfunction. HBO exposure significantly reduced the development of lung, liver, and intestine injury in our experimental model. It also significantly reduced the zymosan-induced expression of TLR2 and TLR4, NF-κB activation, and cytokine production., Conclusions: Taken together, these results suggest that, by interfering with the TLR pathway, HBO treatment may exert a protective effect against tissue injury caused by zymosan-induced generalized inflammation.

Endemic, sporadic and HIV-associated Burkitt lymphoma (BL) all have a B-cell phenotype and a MYC translocation, but a variable association with the Epstein-Barr virus (EBV). However, there is still no satisfactory explanation of how EBV participates in the pathogenesis of BL. A recent investigation suggested that EBV-positive and EBV-negative BL have different cells of origin. In particular, according to immunoglobulin gene mutation analysis, EBV-negative BLs may originate from early centroblasts, whereas EBV-positive BLs seem to arise from postgerminal center B cells or memory B cells. The appearance of a germinal center phenotype in EBV-positive cells might thus derive from a block in B-cell differentiation. The exit from the germinal center involves a complex series of events, which require the activation of BLIMP-1, and the consequent downregulation of several target genes. Here, we investigated the expression of specific miRNAs predicted to be involved in B-cell differentiation and found that hsa-miR-127 is differentially expressed between EBV-positive and EBV-negative BLs. In particular, it was strongly upregulated only in EBV-positive BL samples, whereas EBV-negative cases showed levels of expression similar to normal controls, including microdissected germinal centers (GC) cells. In addition, we found evidence that hsa-miR-127 is involved in B-cell differentiation process through posttranscriptional regulation of BLIMP1 and XBP1. The overexpression of this miRNA may thus represent a key event in the lymphomagenesis of EBV positive BL, by blocking the B-cell differentiation process.

Objective: To evaluate the effects of hyperbaric oxygen (HBO) therapy on the coagulation cascade using an experimental model of multiple organ failure syndrome (MOFS)., Design: MOFS was induced by zymosan (500mg/kg i.p.) in rats. HBO therapy (2ATA) was administered in a cylindrical steel chamber 4 and 11h after zymosan administration. In a separate set of experiments animals were monitored for 72h, and systemic toxicity was scored., Intervention: Eighteen hours after zymosan administration, rats were killed and blood samples were used for analysis of hemocoagulative parameters, hemodynamics, and arterial blood gas., Main Results: Zymosan administration caused MOFS by affecting the coagulation cascade, as shown by a significant increase in plasma levels of fibrinogen, tissue plasminogen activator, inhibitor of tissue plasminogen activator of type 1, and plasma levels of fibrin degradation products vs. control rats. Zymosan-induced MOFS was also characterized by a significant increase in von Willebrand antigen plasma levels vs. controls. Moreover, zymosan administration induced a significant fall in mean arterial blood pressure and alteration in blood gas values. HBO therapy significantly reduced the derangements of coagulation cascade, the fall in mean blood pressure and alteration in blood gas induced by zymosan administration., Conclusions: The hypercoagulability induced by zymosan could be responsible for organ failure and death. Our data demonstrate that HBO therapy significantly prevents the alteration in the coagulation cascade and arterial blood gas in an experimental model of MOFS.

Objective: This study investigated the effects of hyperbaric oxygen (HBO) therapy on the cardiovascular alteration (e.g. mean arterial pressure, vascular reactivity of thoracic aorta rings changes) caused by zymosan in rats., Design: Rats., Setting: University research laboratory., Intervention and Measurements: We investigated the effects of HBO therapy (2 ATA at the fourth and eleventh hours after study onset) on the cardiovascular alteration caused by zymosan (500 mg/kg, administered i.p. as a suspension in saline) in rats. Cardiovascular alterations were assessed 18 h after administration of zymosan and/or HBO therapy., Results: Treatment of rats with HBO therapy attenuated the vasoplegic response to zymosan. In fact, the analysis of arterial pressure curves revealed no signs of vasoplegic shock. The aorta rings of animals treated with zymosan and HBO had a significantly increased contraction to norepinephrine (NE) and endothelin-1 (ET-1) and dilation to acetylcholine (ACh) compared with the zymosan group. The HBO therapy also attenuated the increase of malondialdehyde (MDA) levels caused by zymosan in the aorta. Immunohistochemical analysis for nitrotyrosine and for iNOS revealed positive staining in the aorta from zymosan-treated rats. The degree of staining for nitrotyrosine and iNOS was markedly reduced in tissue sections obtained from zymosan-rats treated with HBO therapy., Conclusion: This study provides the first evidence that HBO therapy attenuates the degree of zymosan-induced cardiovascular derangement in the rat.

Objective: Propofol has been shown to produce a predictable and easily attainable level of sedation in postcardiac, head-injured, general trauma patients. The commencement of hemodiafiltration itself has not been shown to significantly influence the requirement for propofol. We report on a patient who underwent binephrectomy complicated by sepsis-induced adult respiratory distress syndrome (ARDS)., Design: Case report., Setting: Largest nonteaching hospital in Southern Italy., Patients/subjects: An 18-year-old male underwent a surgical procedure for splenectomy and right nephrectomy for severe abdominal trauma. On the 10th postoperative day, the patient was admitted into our intensive care unit (ICU) for acute respiratory and renal failure due to ARDS and left renal infarction., Interventions: Continuous venovenous hemodiafiltration was carried out through a double-lumen cannula. Sedation was initially achieved with propofol up to standard doses into a nonfemoral venous site. Because the optimal level of sedation was not achieved, the initial propofol infusion rate was increase to 3.5 mg/kg, and then an intravenous bolus of morphine (.01 mg/kg) was administered twice daily., Results: The administration of morphine was fundamental to achieving an optimal level of sedation. ARDS resolved and, 10 days later, the patient was transferred to the surgical unit, then discharged home after 14 days., Conclusion: Hemodiafiltration was found to influence the clinical requirement for propofol. The optimal level of sedation is achieved with the addition of morphine.

The standard tracheostomy technique, described in 1909 by Jackson, has been increasingly used in intensive care units. Since 1957, several different types of percutaneous tracheostomy techniques have been described and performed with the support of bronchoscopic transillumination. The authors present the case of a respiratory failure due to obstruction of the upper airway by an exceptionally large goiter, which was successfully resolved by a standard open surgical tracheostomy. In this case, surgical tracheostomy was preceded by bronchoscopic transillumination, which facilitated identification of the appropriate tracheostomy site.

The aim of the present study was to evaluate the effects of hyperbaric oxygen (HBO) therapy on multiple organ failure induced by zymosan. Administration of zymosan (500 mg/kg) in the rat induced neutrophil infiltration in the lung, liver, and intestine as evaluated by increase in myeloperoxidase (MPO) activity. Therefore, lipid peroxidation was significantly increased in zymosan-treated rats. This inflammatory process coincided with the damage of lung, liver, and small intestine. Immunohistochemical examination demonstrated a marked increase in the immunoreactivity to nitrotyrosine in the lung, liver, and small intestine of zymosan-shocked rats. HBO (2 absolute Atmosphere) exposure attenuates the increase in the tissue levels of MPO and malondialdehyde (MDA) caused by zymosan in the lung, liver, and intestine. In addition, HBO (2 absolute Atmosphere) was effective in preventing the development of lung, liver, and intestine injury. Taken together, the present results demonstrate that HBO may also be an efficacious treatment in multiple organ failure induced by zymosan.

About 80% of nosocomial infections are caused by aerobic bacteria. Pseudomonas aeruginosa is a Gram-negative bacterium belonging to the Pseudomonadaceae family; P. aeruginosa is responsible for 6-22% of all hospital infections. The aim of this study was to evaluate the efficacy of hyperbaric oxygen (HBO2) therapy (2 atm abs x 55 min.day-1) alone for 8 days and combined with antibiotic chemotherapy (amikacin 15 mg.kg-1.day-1 for 8 days by intraperitoneal route) in rats infected subcutaneously and via the pulmonary route. In the rats infected by P. aeruginosa, HBO2 induced a reduction in mortality and morbidity with bacteria eradication in blood culture, bronchial aspirate, and skin biopsies when compared to control. These effects were increased by the use of amikacin, an antibiotic used for the treatment of sensitive Gram-negative bacteria.

Objective: To evaluate the effects of hyperbaric oxygen (HBO) therapy on zymosan-induced shock in rats. Zymosan, a cell wall component of the yeast Saccharomyces cerevisiae, induces inflammation by causing the production of various cytokines and pro-inflammatory mediators. The administration of zymosan to rats represents a new experimental shock model by inducing acute peritonitis, severe hypotension, and signs of systemic illness. However, it has been recently proposed that the zymosan-induced shock, like septic shock, may be mediated by overproduction of nitric oxide., Design: Experimental study., Setting: Institute of Pharmacology and Toxicology, 2nd University of Naples, Naples, Italy., Subjects: Male rats were treated with zymosan (500 mg/kg) by intraperitoneal route, with HBO (2 Absolute Atmosphere) or with zymosan and HBO (2 Absolute Atmosphere)., Measurements and Main Results: Peritoneal exudate, plasma, and peritoneal nitric oxide metabolites (NOx) and zymosan determined a time-dependent increase in peritoneal and plasma NOx concentrations, and peritoneal leukocytes were determined. Moreover, symptomatology was observed. The administration of zymosan caused the appearance of a severe illness in the rats characterized by ruffled fur, lethargy, conjunctivitis, diarrhea, and a significant loss of body weight. All zymosan-treated rats developed an acute peritonitis, producing turbid exudate. Zymosan determined a time-dependent increase in peritoneal, plasma NOx, and tumor necrosis factor (TNF)-alpha concentrations. Morbidity of zymosan shocked rats has been attenuated and no mortality was observed by treatment with HBO. These findings were associated with a significant reduction either of peritoneal leukocytes and exudate, or plasma and peritoneal NOx concentrations. Moreover, TNF-alpha levels were significantly reduced in animals shocked by zymosan and treated with HBO.

Objective: There are several reports of documented adverse cardiac effects during treatment with beta-agonists. Since one should be aware that this may be a problem in patients with preexisting cardiac disorders, we have conducted a randomized, single-blind, balanced, crossover, placebo-controlled study to assess the cardiac effects of two single doses of formoterol (12 microg and 24 microg) and one single dose of salmeterol (50 microg) in 12 patients suffering from COPD with preexisting cardiac arrhythmias and hypoxemia (PaO2<60 mm Hg)., Design: Each patient was evaluated at a screening visit that included spirometry, blood gas analysis, plasma potassium measurement, and 12-lead ECG. In following nonconsecutive days, all patients underwent Holter monitoring 24 h during each of the four treatments. Holter monitoring was started soon before drug administration in the morning. Plasma potassium level was measured before drug inhalation, at 2-h intervals for 6 h, and at 9, 12, and 24 h following administration. None of our patients took rescue medication during the 24-h period., Results: Holter monitoring showed a heart rate higher after formoterol, 24 microg, than after formoterol, 12 microg, and salmeterol, 50 microg, and supraventricular or ventricular premature beats more often after formoterol, 24 microg. Formoterol, 24 microg, significantly reduced plasma potassium level for 9 h when compared with placebo, whereas formoterol, 12 microg, was different after 2 h and salmeterol, 50 microg, from 4 to 6 h., Conclusions: The results of this study suggest that if a COPD patient is suffering from preexisting cardiac arrhythmias and hypoxemia, long-acting beta-agonists may have adverse effects on the myocardium, although the recommended single dose of salmeterol and formoterol, 12 microg, allows a higher safety margin than formoterol, 24 microg.

Background: We evaluated the diuretic output in patients with decompensated chronic heart failure (CHF), previously treated by i.v. infusion with dobutamine and dopamine (dob-dop) or with amrinone (amr). Our target was to identify the possible discrepancies in urinary output perhaps linked to the different type of inotropic stimulation in the two subsets., Methods: Adjunctive therapy with dob-dop or amr was chosen because the administration of diuretics only, without cardiac support, as tested in previous hospitalizations, had been demonstrated to produce unfavourable results, mainly expressed by finding of a low output syndrome in 50% of cases or more. The administration of i.v. infusion was maintained during 17 hours (1000 min approximatively), and included infusion in separate pumps of the two amines, dobutamine at dose of 5 micrograms/kg/min and dopamine at dose of 2.8 micrograms/kg/min or, alternatively, i.v. infusion of amr, administered at dose of 7 micrograms/kg/min. Infusion volumes were similar in the two subsets. The two subsets were homogeneous relatively to renal impairment, i.e. to the parameters (urinary Na, U/P creatinine, U/P urea, urinary osmolality) we fixed as markers idoneous to demonstrate the occurrence of organic renal damage (acute tubular necrosis)., Results: The diuresis was recovered in all 24 patients, and the urine volume resulted more pronounced in the subset attributed to the dob-dop at both the 8th and the 17th hour readings. We found no harmful alterations in HR and AP, whereas renal function parameters have been shown to enhance in both the dob-dop and amr arms. The diuretic effectiveness of the SIEV obtained by catecholamine implementation exercised a synergistic, favourable effect on diuresis, renal flow, glomerular filtration rate, and sodium post-proximal delivery. Amr resulted less effective then dob-dop simultaneous administration relatively to the diuretic effect. No remarkable differences were found in the two subsets as regards the heart rate, whereas a decrease in arterial pressure was found after amr. A persistent shift towards a condition of chronic renal failure, was identified in 4/24 patients, the two groups despite of the prolonged treatment at optimized doses: no remarkable side effects were reported., Conclusions: Thus, the selective effect upon renal hemodynamics, as exercised by dob-dop infusion low doses of dop, together with the enhanced renal output due to dob, has been shown to be more effective than amr influence: thus, the catecholamine therapeutical approach has been demonstrated to possess the best effectiveness in excitation of diuresis, among the CHF oliguric patients.

Background: The influence on renal function caused by acute myocardial infarction complicated by hypotension has been studied. Particularly, a possible difference in renal functional pattern related to different localization and/or extension of necrotic myocardial area was investigated., Methods: The study has been performed in 12 cases of acute myocardial infarction, involving anteroseptal (7) or inferodorsal (5) myocardial wall. The score of parietal asynergy resulted 13.28 in anterior vs 7.6 in inferior localization (p < 0.001)., Results: The decrease in systolic pressure, conversely, resulted not significantly different in the two groups. The renal function was assessed by measuring the urinary output (V) and creatinine clearance (CrCl). During the first 24 hours, both parameters resulted more preserved in inferior than in anterior AMI (V-552 vs 214 ml; p < 0.005; CrCl 70.6 vs 33.42; p < 0.001). Thus 1) the pressure decrease resulted unrelated to the size of asynergy and 2) the markers of renal function, although the decrease in brachial pressure has been identical in the two groups, have been shown to decrease more profoundly in the anterior infarction., Discussion and Conclusions: This may depends upon the reflex interruption of efferent nervous sympathetic drive toward the renal arteriolar bed, occurring in inferior infarction, despite of the systemic hypotension, and able to exercising a beneficial influence on the glomerular filtration rate (GFR). This reflex modulation has been demonstrated as effective in the inferior, but not in the anterior localization of infarction, this different haemodynamic pattern being able to explain the more pronounced decrease in GFR and diuresis in anterior than inferior AMI, as observed in our study.

The effects of prolonged (20 day) hyperbaric exposure (HBO) to oxygen on non adrenergic non cholinergic (NANC) contractile and relaxant responses of rat trachea were examined. The electrical field stimulation (EFS) of rat tracheal rings was performed at 30 Hz and contractile and relaxant responses were assessed in the absence or in the presence of pretreatment with L-nitro-arginine-methyl-ester (L-NAME), an inhibitor of NO synthase, and L-Arginine (L-ARG), a precursor of NO synthesis, plus L-NAME. Our data demonstrated that L-NAME significantly (p < 0.05) enhanced the contractile responses induced by EFS (controls 30.6 +/- 0.99%; L-NAME 76.07 +/- 2.00%) and statistically (p < 0.05) reduced the relaxant component of EFS (controls 31.10 +/- 0.46; L-NAME 15.00 +/- 0.12); these effects were reversed when tissues were pretreated with L-ARG plus L-NAME, suggesting that NO plays a modulatory role in cholinergic neurotransmission and participates in EFS relaxant responses. Moreover, prolonged HBO exposure (20 days) at 202.6 and 303.9 kPa did not modify the contractile or relaxant responses induced by EFS, nor modify the L-NAME or L-ARG effects on EFS responses.

About 80% of nosocomial infections are caused by aerobic bacteria. The Pseudomonas aeruginosa is a Gram-negative bacterium pertaining to the Pseudomonadaceae family. P. aeruginosa is responsible for 6-22% of all hospital infections. The aim of this paper is to evaluate the efficacy of both hyperbaric oxygen-therapy (HBO 2 Atm x 35 min/day) alone for 8 days and when associated to the chemoantibiotic therapy (amikacine 15 mg/kg/day for 8 days intraperitoneal), in rats infected through pulmonary and subcutaneous intake. In rats affected by P. aeruginosa, HBO induces a significant reduction in mortality and morbility with bacteria eradication in blood culture findings, bronchial aspirate and skin biopsies. These effects were increased by the use of amikacine which is an antibiotic used for the treatment of Gram-negative bacteria.

The authors report their experience, matured in 10 years, in the management of cancer of the rectum and large bowel complicated by obstruction; 425 patients out of 493 total cases of colorectal cancer presented an intestinal obstruction and underwent emergency surgery. In 386 cases it was possible to perform resection (91%). The surgical treatment of the patients with right colon obstruction usually consisted of a right hemicolectomy. The surgical treatment of left colon obstruction is still controversial; in the experience of the authors it was accomplished by Hartmann operation mainly until 1985; in recent years the authors have introduced a procedure of intraoperative anterograde irrigation of the colon and they have performed resection-anastomosis in a single stage successfully but only in selected patients. In 4 out of twelve cases of cancer of the splenic flexure a subtotal colectomy was performed with one stage ileo-sigmoid anastomosis crowned with success. The authors examine the operative and postoperative mortality of the patients with colorectal cancer and point out that 5 years survival is worse in patients with colorectal obstruction compared to elective operations (24% versus 41%).