Organ Malfunctions Research Articles

Dermatološki izazovi u pandemiji kovida 19 - značaj dermokozmetičkih preparata

Introduction. Although COVID-19 is present in a milder form nowadays, systemic disorders caused by the virus lead to multiple organ malfunctions. Skin manifestations are the consequence of the disease itself but also the result of preventative measures taken to avoid the infection. They generally do not require pharmacotherapy except in severe cases. Depending on the severity of COVID-19-related skin disorder, cosmeceuticals are often recommended in their management. In this study, we highlighted skin adverse events related to all aspects of COVID-19 pandemic aiming to provide a comprehensive overview and enlighten the role of cosmeceuticals in the treatment of those skin issues, according to published studies and guidelines. Methods. Different steps were conducted in preparation of this review-identification of all factors that affect skin in pandemics (protective measures, disease itself, post-COVID syndrome), selection and classification of reported skin symptoms which could be managed using cosmeceuticals, according to relevant papers and guidelines. Discussion. Skin challenges in COVID-19 pandemics could be divided into three main categories: 1) Cutaneous manifestations of COVID-19 disease; 2) Cutaneous symptoms as a result of wearing protective equipment and using disinfectants, and 3) Cutaneous symptoms related to the post COVID-19 syndrome. Conclusion. Cosmeceuticals, a unique category of products between cosmetics and pharmaceuticals, are highly recommended in literature for the management of the aforesaid changes except in severe skin disorders. Since the introduction of cosmeceutical concept, those topicals have become an extremely important part of dermatologist's armamentarium. COVID-19 pandemic confirms their importance.

Strategies of cerebral protection and neurologic dysfunctions after circulatory arrest: back to the future?

The introduction of deep hypothermic circulatory arrest (CA) was the factor that contributed to the diffusion of aortic arch surgery in the surgical world. The progressive quest to improve the outcome of such a complex surgery included the introduction of different tools to better protect the brain, such as retrograde or antegrade cerebral perfusion. The increased experience not only resulted in a continuous improvement of the results, but also facilitated the widespread adoption of arch surgery across most of the cardiac Centers. The trend moved towards a gradual rise in the temperature (from ≤ 20 to 30 °C), coupled with a preference for selective/unilateral antegrade cerebral perfusion for brain protection. Nevertheless, results are not perfect and neurologic dysfunctions, temporary or permanent, remain a frequent complication. The spinal cord is not completely protected by cerebral perfusion and ischemia of the lower body can cause organ malfunctions with severe consequences. After decades, the field is still open for new strategies to minimize the damages intrinsic to the procedure. This review will briefly describe the energetics of the brain, the mechanisms of neurologic dysfunctions, and the advantages and disadvantages of the strategies of cerebral protection commonly used during CA for aortic arch surgery.

Toxicological Effects of Fine Particulate Matter (PM2.5): Health Risks and Associated Systemic Injuries-Systematic Review.

Previous studies focused on investigating particulate matter with aerodynamic diameter ≤ 2.5µm (PM2.5) have shown therisk of disease development, and association with increased morbidity and mortality rates. The current review investigate epidemiological and experimental findings from 2016 to 2021, which enabled the systemic overview of PM2.5's toxic impacts on human health. The Web of Science database searchused descriptive terms to investigate theinteraction among PM2.5 exposure, systemic effects, and COVID-19 disease. Analyzed studies have indicated that cardiovascular and respiratory systems have been extensively investigated and indicated as the main air pollution targets. Nevertheless, PM2.5 reaches other organic systems and harms the renal, neurological, gastrointestinal, and reproductive systems. Pathologies onset and/or get worse due to toxicological effects associated with the exposure to this particle type, since it can trigger several reactions, such as inflammatory responses, oxidative stress generation and genotoxicity. These cellular dysfunctions lead to organ malfunctions, as shown in the current review. In addition, thecorrelation between COVID-19/Sars-CoV-2 and PM2.5 exposure was also assessed to help better understand the role ofatmospheric pollution in the pathophysiology of this disease. Despite the significant number of studies about PM2.5'seffects on organic functions, available in the literature, there are still gaps in knowledge about how this particulate matter can hinder human health. The current review aimed to approach the main findings about the effect of PM2.5 exposure on different systems, and demonstrate the likely interaction of COVID-19/Sars-CoV-2 and PM2.5.

B2M gene knockout in HEK293T cells by non-viral delivery of CRISPR-Cas9 system for the generation of universal cells

BackgroundAllogeneic stem cells are the most potent sources for replacing cell, tissue, and organ malfunctions. The clinical use of these stem cells has been limited due to the risk of immune system rejection due to the incompatibility of human leukocyte (HLA) antigens between donors and recipients. To overcome this limitation, we used the CRISPR/Cas9 system to eliminate the β2 microglobulin (B2M) gene, which plays a vital role in the expression of HLA class I.ResultsNon-viral transfer of two gRNAs targeting the first exon and intron in the B2M gene results in large deletions in the target region. In addition, the results of this study showed that 11.11% and 22.22% of cells received genomic changes as homozygous and heterozygous, respectively.ConclusionIn conclusion, we have shown that the dual guide RNA strategy is a simple and efficient method for modifying genes. As a result, these cells can be proposed as universal cells that are not detectable in the cell therapy system and transplantation by the receptor immune system.

Spike Protein of SARS‐CoV‐2 Activates Macrophages and Contributes to Induction of Acute Lung Inflammations in Mice

BackgroundCoronavirus disease 2019 (COVID‐19) patients exhibit multiple organ malfunctions with a primary manifestation of acute and diffuse lung injuries. The Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is crucial to mediate viral entry into host cells; however, whether it can be cellularly pathogenic and contribute to pulmonary hyper‐inflammations in COVID‐19 is not well known.Methods and FindingsIn this study, we developed a Spike protein‐pseudotyped (Spp) lentivirus with the proper tropism of SARS‐CoV‐2 Spike protein on the surface and tracked down the fate of Spp in wild type C57BL/6J mice receiving intravenous injection of the virus. A lentivirus with vesicular stomatitis virus glycoprotein (VSV‐G) was used as the control. Two hours post‐infection (hpi), Spp showed more than 27‐75 times more viral burden in the lungs than other organs; it also exhibited about 3‐5 times more viral burden than VSV‐G lentivirus in the lungs, liver, kidney and spleen. Acute pneumonia was evident in animals 24 hpi. Spp lentivirus was mainly found in LDLR+ macrophages and pneumocytes in the lungs, but not in MARC1+ macrophages. IL6, IL10, CD80 and PPAR‐γ were quickly upregulated in response to infection of Spp lentivirus in the lungs in vivo as well as in macrophage‐like RAW264.7 cells in vitro. We further confirmed that forced expression of the Spike protein in RAW264.7 cells could significantly increase the mRNA levels of the same panel of inflammatory factors.ConclusionsOur results demonstrate that the Spike protein of SARS‐CoV‐2 alone can induce cellular pathology, e.g. activating macrophages and contributing to induction of acute inflammatory responses.

Therapeutic evaluation of anti-trypanosoma activity of ethanol extracts of Jatropha curcas roots in comparison with diminazene aceturate in Trypanosoma brucei brucei–parasitized rats

Jatropha curcas is used as an old herbal therapy in the treatment of several vector-borne diseases in several parts of Africa. Considering the burden of trypanosoma infection and the cost of currently available drugs, the search for more drugs that are effective, affordable and accessible is warranted. To investigate the anti-trypanosoma and ameliorative effects of ethanol extracts of Jatropha curcas root (EEJCR) on organ malfunctions associated with trypanosoma infection in rats, and its phytoconstituents and acute toxicity profile. Thirty rats were divided into six groups of rats (n = 5): nonparasitized rats in group 1 served as normal control and parasitized (1.8 × 106 trypanosomes/ml of Trypanosoma brucei brucei–infected blood) rats in group 2 served as trypanosome control. Parasitized rats in group 3 were treated with reference drug (diminazene aceturate) while groups 4–6 were treated with 100, 200 and 400 mg/kg/day b.w. p.o. of EEJCR, respectively for 7 days. The acute toxicity profile of EEJCR was established in mice using the standard method. In a dose-dependent fashion, EEJCR reduced trypanosoma parasitaemia; 400 mg/kg/day b.w. of EEJCR gave 82.96% chemosuppression compared with 100% by diminazene aceturate. EEJCR also ameliorated trypanosoma-modified haematological and biochemical dysfunctions in a dose-related manner. The presence of tannins, steroids, flavonoids, terpenoids, phenols, glycosides and alkaloids was detected in EEJCR and it was tolerable up to 5000 mg/kg b.w. This study showed that EEJCR is safe, has anti-trypanosoma activity and reverses haematological and biochemical markers of organ malfunctions associated with trypanosoma infection. This observation justifies the old routine use of such herbal therapy in medicinal practices to treat trypanosomiasis.

Significance of taurine transporter (TauT) in homeostasis and its layers of regulation (Review).

Taurine (2-aminoethanesulfonic acid) contributes to homeostasis, mainly through its antioxidant and osmoregulatory properties. Taurine's influx and efflux are mainly mediated through the ubiquitous expression of the sodium/chloride-dependent taurine transporter, located on the plasma membrane. The significance of the taurine transporter has been shown in various organ malfunctions in taurine-transporter-null mice. The taurine transporter differentially responds to various cellular stimuli including ionic environment, electrochemical charge, and pH changes. The renal system has been used as a model to evaluate the factors that significantly determine the regulation of taurine transporter regulation.

Avian Mycobacteriosis in a Rescued Harpy Eagle from Darien Forest, Panama

Background: The Harpy eagle (Harpia harpyia) is the largest raptor in the Neotropical region, distributed in low densities within primary forest habitats from southern Mexico to east-central Brazil, including Central America and Panama. Although locally extinct due to habitat degradation, human poaching and reduction of tropical forests in recent decades, some remnant populations are known to be small and isolated. Thus, information on its ecology, including infectious diseases, is critical for conservation efforts and management of populations of this emblematic species in the wild. Avian Mycobacteriosis (AM) is a chronic disease affecting a wide range of birds and mammals and clinical cases have been sporadically reported, although in harpy eagles, has not been documented. In addition, scant information exists on pathologies affecting raptors, therefore, this report expands the knowledge on infectious diseases affecting wild birds. This study describes the first case of AM in an immature harpy eagle rescued from Darien gap and presents details of the clinical manifestation of the disease and its histological findings.Case: An immature harpy eagle was presented to a rescue center after being confiscated by Ministry of Environment from a local farm in a remote region of Eastern Panama, in the Darien gap. The raptor had a history of having been kept in captivity for approximately five weeks, cohabiting with backyard poultry and fed corn, raw duck and chicken provided by farm owners. Stagnant water was offered for drinking. The harpy eagle arrived to the facility very lethargic and emaciated. Physical examination revealed damaged plumage, poor body condition and dyspnea. Complete blood count revealed anemia and leukocytosis based on lymphocytosis and eosinophilia. Biochemical profile evidenced an increased level of aspartate aminotransferase (AST), phosphorus and total plasma protein. Most remarkable radiographic findings were splenomegaly, hepatomegaly and increased opacity in kidneys, intestines, and aerial sacs. None of the other diagnostic tests performed were conclusive, like tracheal, esophageal and cloacal cultures for fungal infection and fecal exam. After one week of treatment, it showed a remarkable recovery, but at the end of the second week, declined dramatically, dying in the third week of treatment. Post-mortem examination revealed the presence of diffuse granulomas in multiple organs. Histologic examination with gram and Ziehl Neelsen staining revealed the presence of gram-positive and acid-fast bacteria, compatible with Mycobacterium-like bacilli. PCR-restriction fragment length polymorphism analysis of the hsp65, digested with BstEII and HaEIII restriction enzymes confirmed the presence Mycobacterium avium complex in tissues samples.Discussion: This is the first report of AM in a harpy eagle, presenting an extreme emaciation with dyspnea, abnormalities in spleen, liver and air sacs. Biochemical and hematological parameters revealed alterations consistent with infection and organ malfunctions in liver, but Mycobacteriosis was not suspected initially and it was necessary to support the diagnosis with histopathological studies and DNA amplification for a proper identification of the disease. This allowed us to confirm that ante-mortem clinical diagnosis of Avian Mycobacteriosis can be challenging, especially in birds who usually show non-specific signs of the disease and external lesions are not commonly observed. Further studies are requiring to determine the characteristics and clinical signs of this disease in this and other raptors. Also, to determine the source of infection affecting raptors and other protected species in the Neotropical region, especially for diseases with relevance in the conservation of birds and animal health control.

Methanol extracts of Fagara zanthoxyloides leaves possess antimalarial effects and normalizes haematological and biochemical status of Plasmodium berghei-passaged mice

Context: The resistance of Plasmodium species to many available antimalarials calls for a continuous search for newer antimalarial agents. One possible source of new antimalarials is from natural sources such as Fagara zanthoxyloides Lam (Rutaceae), a medicinal plant used traditionally for treating malaria in South-Eastern Nigeria, Uganda and Asia.Objectives: To investigate the application of methanol extracts of F. zanthoxyloides in combating malaria infection and its associated disorders.Materials and methods: Methanol extracts of F. zanthoxyloides leaves (MEFZ) were evaluated for in vivo antimalarial activity. MEFZ at doses of 200, 400, and 600 mg/kg/d were administered orally for 4 consecutive days (days 0–4) to P. berghei-infected mice. The possible ameliorative effects of MEFZ on malaria-associated organ malfunctions were also assessed.Results: At 200, 400 and 600 mg/kg b.w., respectively, MEFZ produced 82.37% and 68.39%, 84.84%, and 90.75%, 95.95% and 92.67% chemosuppression and inhibition of P. berghei, respectively, comparable to 98.67% and 97.29% by combisunate, a standard antimalarial. The IC50 of MEFZ was estimated to be 235.23 mg/kg b.w. Similarly, treatment of parasitized mice with MEFZ significantly restored the malaria-modified haematological and biochemical status of the parasitized-MEFZ-treated mice compared with parasitized-untreated mice. MEFZ was tolerable up to 5000 mg/kg b.w dose; hence, the LD50 is above 5000 mg/kg b.w.Discussion and conclusions: The results of this curative assay demonstrated that MEFZ has antimalarial effects and normalized haematological and biochemical aberrations generated by malaria. The isolation of the antimalarial principles in MEFZ is warranted; they could be lead molecules for the development of new antimalarials.

Continuous glucose monitoring with a flexible biosensor and wireless data acquisition system

Glucose is a central substance in the human metabolism, and its concentration in human body fluid can reflect various diseases and organ malfunctions. We demonstrate a thin, flexible sensor and an associated wireless readout integrated circuit (IC) that can be used to continuously monitor glucose level over a very wide glucose concentration range. The sensor is fabricated on flexible and robust graphene petals deposited on thin carbon fibers with biocompatible materials. Graphene petals offer sensitivity of 5.67 μAmM−1 cm-2 with a sensing range from 2 μM to 66 mM. Mechanical properties of the graphene petals provide a sensor lifetime exceeding four weeks. The readout IC harvests magnetic energy from a nearby power source, acquires glucose information, and wirelessly transmits data to the user. Linearity of analog/digital circuit blocks are verified by amperometric glucose measurements while consuming less than 21μW. The sensor and readout system can be readily integrated with other sensors or drug-delivery actuators for diagnosis and therapies for diabetes.

Mouse positioning device for blood brain barrier FUS exposure

Gaucher’s disease is an inherited metabolic disorder that results in a deficiency of the enzyme glucocerebrosidase, which acts on the glycolipid glucocerebroside. This causes a rapid accumulation of glucocerebroside in affected persons, which manifests in organ malfunctions and disfiguration, swelling, and severe neurologic complications, among other symptoms. Enzyme replacement therapy can manage the symptoms but when the brain is affected, the treatment is not effective since the enzymes cannot cross the blood brain barrier (BBB). Imaging of enzyme replacement therapy has shown that only insignificant amounts reach the brain.[1] In this work, we intend to evaluate brain uptake of enzyme replacement after BBB opening mediated by focused ultrasound (FUS) to validate this delivery technique for the treatment of neurologic complications caused by Gaucher’s disease. Our goal is to develop a system for Blood Brain Barrier delivery that can be followed up using positron emission tomography (PET) imaging. It will then be used to create and validate the delivery after intravenous injection of radiolabelled enzymes.

Defibrillators

Defibrillators

Amyloidosis and spontaneous hepatic bleeding, transcatheter therapy for hepatic parenchymal bleeding with massive intraperitoneal hemorrhage: a case report and review of the literature

Hepatic hemorrhage can be devastating, especially in patients with underlying hepatic pathology. This is a case report of a 50-year-old man who presented to the emergency room with Stage 3 shock as evidenced by a systolic blood pressure of 90 mmHg, a heart rate of 125 beats per minute, respiration of 32, with delayed capillary refill and agitation. At this time, he was found to have a massive spontaneous intra-abdominal hemorrhage with an advanced stage of amyloidosis with multiple organ malfunctions. The initial diagnosis was based on an abdominal computed tomography scan and the patient was taken expeditiously to a hybrid angiography suite for a celiac angiogram. An intraoperative diagnosis of extravasation from amyloid related vasculopathy was made based on the angiographic appearance of hepatic circulation. Coil embolization of the feeding branch of the bleeder was achieved using the interlock coil system and a completion angiogram was done showing complete cessation of active bleeding. The postoperative phase was uneventful and the patient was discharged home on postoperative day three. His postoperative visit at five months later was unremarkable.

New mouse models for metabolic bone diseases generated by genome-wide ENU mutagenesis

Metabolic bone disorders arise as primary diseases or may be secondary due to a multitude of organ malfunctions. Animal models are required to understand the molecular mechanisms responsible for the imbalances of bone metabolism in disturbed bone mineralization diseases. Here we present the isolation of mutant mouse models for metabolic bone diseases by phenotyping blood parameters that target bone turnover within the large-scale genome-wide Munich ENU Mutagenesis Project. A screening panel of three clinical parameters, also commonly used as biochemical markers in patients with metabolic bone diseases, was chosen. Total alkaline phosphatase activity and total calcium and inorganic phosphate levels in plasma samples of F1 offspring produced from ENU-mutagenized C3HeB/FeJ male mice were measured. Screening of 9,540 mice led to the identification of 257 phenodeviants of which 190 were tested by genetic confirmation crosses. Seventy-one new dominant mutant lines showing alterations of at least one of the biochemical parameters of interest were confirmed. Fifteen mutations among three genes (Phex, Casr, and Alpl) have been identified by positional-candidate gene approaches and one mutation of the Asgr1 gene, which was identified by next-generation sequencing. All new mutant mouse lines are offered as a resource for the scientific community.

Microparticles in physiological and in pathological conditions

Chronic diseases pose a severe burden to modern National Health Systems. Individuals nowadays have a far more extended lifespan than in the past, but healthy living was only scantily extended. As much as longer life is desirable, it is saddened by chronic diseases and organ malfunctions. One contributor to these problems was recognized to be represented by microparticles (MPs). Our purpose is to better understand MPs, to contrast their ominous threat and possible clinical importance. For this intent we correlated MPs with thrombotic pathologies, hemophilia, malaria, diabetes, cardiovascular diseases, endothelial dysfunctions, pulmonary hypertension, ischemic stroke, pre-eclampsia, rheumatologic diseases-rheumatoid arthritis, polymyositis-dermatomyositis, angiogenesis and tumor progression-cancer; we listed the possibilities of using them to improve transfusion methods, as a marker for acute allograft rejection, in stem cell transplantation, as neuronal biomarkers, to understand gender-specific susceptibility for diseases and to improve vaccination methods and we presented some methods for the detection of MPs.

Lysosomal Modulatory Drugs for a Broad Strategy Against Protein Accumulation Disorders

Protein accumulation leads to CNS effects in Alzheimer's disease, frontotemporal dementia, and other age-related disorders. Common mechanisms may contribute to the progressive pathology in the different protein accumulation disorders, and synergistic toxicity between dissimilar protein structures may also be involved. Among several avenues being pursued to reduce proteins prone to oligomerization and/or aggregation, a lysosomal avenue has been described that regulates the lysosomal system's broad clearance capability. Lysosomes are the primary site for protein clearance, to remove old and misfolded proteins and maintain cellular homeostasis. Small-molecule lysosomal modulators trigger a feedback response in vitro and in vivo, resulting in marked up-regulation of cathepsins and other lysosomal enzymes without any indications of synaptic pathology, behavioral abnormalities, or major organ malfunctions. For the characterization and screening of lysosomal modulatory drugs, the hippocampal slice model of protein accumulation has proved very useful. The model exhibits experimentally-induced phosphorylated tau species, paired helical filament deposits, ubiquitinated inclusions, and protein oligomers, thus providing a valuable tool to study the associated sequelae underlying progressive cellular and synaptic compromise. In the absence of modulatory drugs, the protein accumulation events lead to microtubule destabilization, transport failure, and synaptic decline. When lysosomal modulators are administered to slices with pre-existing deposits, protein accumulations are reduced causing normalization of tau chemistry, restoration of tubulin structures and tubulin-binding proteins, and recovery of synaptic composition. Thus, positive modulators of the lysosomal system represent first-in-class drugs, providing a suitable strategy to enhance protein clearance, promote synaptic health, and slow the progression of proteinopathies.

Long-term effects of human butyrylcholinesterase pretreatment followed by acute soman challenge in cynomolgus monkeys

Human serum butyrylcholinesterase (Hu BChE) was demonstrated previously to be an effective prophylaxis that can protect animals from organophosphate nerve agents. However, in most of those studies, the maximum dose used to challenge animals was low (<2× LD 50), and the health of these animals was monitored for only up to 2 weeks. In this study, six cynomolgus monkeys received 75 mg of Hu BChE followed by sequential doses (1.5, 2.0, 2.0× LD 50) of soman 10 h later for a total challenge of 5.5× LD 50. Four surviving animals that did not show any signs of soman intoxication were transferred to WRAIR for the continuous evaluation of long-term health effects for 14 months. Each month, blood was drawn from these monkeys and analyzed for serum chemistry and hematology parameters, blood acetylcholinesterase (AChE) and BChE levels. Based on the serum chemistry and hematology parameters measured, no toxic effects or any organ malfunctions were observed up to 14 months following Hu BuChE protection against exposure to 5.5× LD 50 of soman. In conclusion, Hu BChE pretreatment not only effectively protects monkeys from soman-induced toxicity of the immediate acute phase but also for a long-term outcome.

Neuroborreliosis with extrapyramidal symptoms: a case report

The disease of Lyme is a tick-borne infection. It involves skin, the nervous system, joints and the heart. Spirochaeta Borrelia burgdorferi is the etiologic agent of the disease. In the majority of cases, clinical symptoms, like migrating erythema, occur from 3 to 30 days, sometimes to 3 months after a bite from a tick. The early disseminated infection involves multiple migrating erythema, neuroborreliosis, arthritis, myocarditis and other organ-related symptoms. The late stage of chronic infection involves chronic atrophic leg dermatitis, neurological and rheumatological symptoms, and other organ-related symptoms which persist for above 12 months. The diagnosis of the disease of Lyme is based upon specific clinical symptoms confirmed by serologic tests. The two-step diagnostic protocol including the ELISA method, confirmed by the Western-blot test, is optimal. The present article describes a case of a 59-year-old man, a computer specialist, who often spends his free time walking in woods for recreation, and who was bitten by a tick 3 years before hospitalization. The bite resulted in migrating erythema that subsided without antimicrobial treatment. In spite of this, the man had not changed his hobby exposing himself to bites from ticks. One year later, multiple migrating erythema and extrapyramidalis symptoms appeared without any other organ malfunctions. In the current year, the patient was admitted to the Infectious Diseases Hospital, and received antibiotics (ceftriaxon) with following neurological improvement. Several months later, extrapyramidal symptoms increased. On the day of admission to the hospital, the neurologic examination showed abnormalities of upper and lower limbs movements (propulsive walking and the right lower leg traction), the right hand tremor, pouts of the face, and sleepiness.

Role of Nonesterified Unsaturated Fatty Acids in the Pathophysiological Processes of Leptospiral Infection

Organ malfunctions in patients with leptospirosis have been associated with the bacterial glycolipoprotein endotoxin and with its nonesterified unsaturated fatty acid (NEUFA) components. We examined the involvement of NEUFAs in the pathophysiological processes of leptospirosis. Patients showed a moderate increase in serum concentrations of oleic and linoleic acids but an important decrease in serum concentrations of albumin. A highly significant correlation between serum concentrations of creatinine or total bilirubin and the oleic-plus-linoleic acid : albumin ratio was revealed. We used the Na(+),K(+)-ATPase inhibitory property of NEUFAs to test the capacity of serum to prevent the cytotoxic effects of NEUFAs in vitro. Albumin solutions and serum samples from healthy volunteers, but not serum samples from severely affected patients, were able to revert the Na(+),K(+)-ATPase inhibition by oleic acid. On the basis of these data, we defined a "serum protection factor" that can be helpful in predicting NEUFA toxicity. Our data support the concept that the administration of human albumin to patients may be helpful in severe leptospirosis cases.

Salvage chemotherapy for refractory or relapsed post-transplant lymphoproliferative disorder in patients after solid organ transplantation with a combination of carboplatin and etoposide.

This pilot study assessed the feasibility and efficacy of salvage chemotherapy (carboplatin and etoposide; CE) supported by granulocyte colony-stimulating factor (GCSF) in patients with refractory or relapsed post-transplant lymphoproliferative disorder (PTLD) following solid organ transplantation. Intensified salvage regimens were not feasible for these patients, due to their immunosuppressive conditions and potential organ (especially kidney and bone marrow) malfunctions. Salvage chemotherapy consisted of carboplatin [area under the curve (AUC) 4], on day 1, etoposide (120 mg/m2), on days 1-3 and GCSF (5 microg/kg) starting on day 5. This therapeutic regimen was planned to be repeated every 21 d. Nine patients (seven with refractory, two with relapsed disease) were enrolled. Five patients were heart transplant recipients, three liver transplant recipients and one patient had been a double lung transplant recipient. Five patients achieved a complete remission (CR), with follow-up at 92, 39, 55+, 17 and 9+ months. One patient showed stable disease after two cycles of CE and one patient had progressive disease. Two patients experienced early deaths, after the first and third cycles of chemotherapy respectively. One died of septic complications and one because of a perforated intestine, which had been infiltrated by lymphoma. In respect of the difficulties experienced in treating patients with refractory or relapsed PTLD after solid organ transplantation, the combination of carboplatin and etopoide with GCSF support (filgrastim) proved to be an effective regimen.