Dimerization leads to changes in APP (amyloid precursor protein) trafficking mediated by LRP1 and SorLA.

Proteolytic cleavage of the amyloid precursor protein (APP) by α-, ß- and γ-secretases is a determining factor in Alzheimer's disease (AD). Imbalances in the activity of all three enzymes can result in alterations towards pathogenic Aß production. Proteolysis of APP is strongly linked to its subcellular localization as the secretases involved are distributed in different cellular compartments. APP has been shown to dimerize in cis-orientation, affecting Aß production. This might be explained by different substrate properties defined by the APP oligomerization state or alternatively by altered APP monomer/dimer localization. We investigated the latter hypothesis using two different APP dimerization systems in HeLa cells. Dimerization caused a decreased localization of APP to the Golgi and at the plasma membrane, whereas the levels in the ER and in endosomes were increased. Furthermore, we observed via live cell imaging and biochemical analyses that APP dimerization affects its interaction with LRP1 and SorLA, suggesting that APP dimerization modulates its interplay with sorting molecules and in turn its localization and processing. Thus, pharmacological approaches targeting APP oligomerization properties might open novel strategies for treatment of AD.

Immune effector cell-associated neurotoxicity syndrome: A therapeutic approach in the critically ill.

Immunotherapy with chimeric antigen-specific receptor modified T cells, known as CAR-T, is emerging as a promising approach to hematological malignancies. In this regard, CAR-T against human cluster of differentiation (CD) 19 has demonstrated antitumor efficacy in application to B cell neoplasms resistant to conventional therapy. However, activation of the immune system induces severe and specific complications which can prove life-threatening. These include cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (known as ICANS) - the latter being the subject of the present review. Although the physiopathological mechanisms underlying ICANS are not well known, a number of clinical and biological factors increase the risk of developing neurotoxicity associated to CAR-T therapy. Treatment is based on close monitoring, measures of support, anticonvulsivants, corticosteroids, and early admission to intensive care. The present study offers a comprehensive review of the available literature from a multidisciplinary perspective, including recommendations from intensivists, neurologists and hematologists dedicated to the care of critically ill adults.

Immune effector cell-associated neurotoxicity syndrome: A therapeutic approach in the critically ill. / Síndrome de neurotoxicidad asociada a células inmunoefectoras: un enfoque terapéutico en el paciente crítico.

Immunotherapy with chimeric antigen-specific receptor modified T cells, known as CAR-T, is emerging as a promising approach to hematological malignancies. In this regard, CAR-T against human cluster of differentiation (CD) 19 has demonstrated antitumor efficacy in application to B cell neoplasms resistant to conventional therapy. However, activation of the immune system induces severe and specific complications which can prove life-threatening. These include cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (known as ICANS) - the latter being the subject of the present review. Although the physiopathological mechanisms underlying ICANS are not well known, a number of clinical and biological factors increase the risk of developing neurotoxicity associated to CAR-T therapy. Treatment is based on close monitoring, measures of support, anticonvulsivants, corticosteroids, and early admission to intensive care. The present study offers a comprehensive review of the available literature from a multidisciplinary perspective, including recommendations from intensivists, neurologists and hematologists dedicated to the care of critically ill adults.

Regulation of visceral adipose tissue-derived serine protease inhibitor by nutritional status, metformin, gender and pituitary factors in rat white adipose tissue.

Visceral adipose tissue-derived serine protease inhibitor (vaspin) is a recently discovered adipocytokine mainly secreted from visceral adipose tissue, which plays a main role in insulin sensitivity. In this study, we have investigated the regulation of vaspin gene expression in rat white adipose tissue (WAT) in different physiological (nutritional status, pregnancy, age and gender) and pathophysiological (gonadectomy, thyroid status and growth hormone deficiency) settings known to be associated with energy homeostasis and alterations in insulin sensitivity. We have determined vaspin gene expression by real-time PCR. Vaspin was decreased after fasting and its levels were partially recovered after leptin treatment. Chronic treatment with metformin increased vaspin gene expression. Vaspin mRNA expression reached the highest peak at 45 days in both sexes after birth and its expression was higher in females than males, but its levels did not change throughout pregnancy. Finally, decreased levels of growth hormone and thyroid hormones suppressed vaspin expression. These findings suggest that WAT vaspin mRNA expression is regulated by nutritional status, and leptin seems to be the nutrient signal responsible for those changes. Vaspin is influenced by age and gender, and its expression is increased after treatment with insulin sensitizers. Finally, alterations in pituitary functions modify vaspin levels. Understanding the molecular mechanisms regulating vaspin will provide new insights into the pathogenesis of the metabolic syndrome.

Treatment for recurrent hepatitis C virus infection after liver transplantation.

Cirrhosis due to hepatitis C virus (HCV) infection is the current leading indication for orthotopic liver transplantation (OLT) in the world. This series reports our program's experience with the treatment of HCV infection after the development of histological hepatitis. Between March 2002 and June 2008, patients with recurrent HCV were selected for treatment if the liver biopsy showed at least the F2 degree of Metavir score. HCV viral load was measured at 4, 12 and 24 weeks as well as at the end of treatment and at 6 months thereafter for patients who became HCV RNA negative (sustained virological response [SVR]). In this period, we performed 287 liver transplantations in 279 patients, including 117 (42%) who had HCV cirrhosis as the indication for OLT of whom 25 were eligible for antiviral treatment. Twelve patients completed treatment, 7 remain on treatment, and 6 were discontinued. The principal collateral effect was anemia. Only 1 patient had an episode of acute cellular rejection, which responded to adjustment of immunosuppression. Antiviral treatment in transplanted patients was feasible and did not seem to induce severe immunological effects. Adjuvant therapies to reduce cytopenias are frequently required, principally erythropoietin. The best results were observed with the pegylated interferon alfa (PEG) plus ribavirin (RBV) group: 38.9% of SVR. We recommend antiviral treatment of eligible patients with confirmed HCV recurrence using PEG plus RBV.

Living donor liver transplantation for acute liver failure: a single center experience.

OBJECTIVE: Orthotopic liver transplantation (OLT) is the principal therapy for acute liver failure (ALF). The mortality on the waiting list for deceased donor liver transplantation (DDLT) is high, principally in countries where donation rates are low. Living donor liver transplantation (LDLT) seems an option for the treatment of ALF, although some ethical issues need to be considered. Herein we have evaluated LDLT results among patients with ALF and discussed the ethical aspects of procedures performed in emergency situations. PATIENTS AND METHODS: From March 2002 to October 2008, we performed 301 liver transplantations, including 103 from living donors. ALF was responsible for 10.6% of all transplantations; LDLT was only considered for pediatric recipients among whom 7 children displayed ALF. RESULTS: One patient died on postoperative day 33 due to hepatic artery thrombosis. One patient died at 2 months after transplantation due to biliary sepsis, resulting in an overall survival rate of 71%. The average time for donor discharge was 5 days. No mortality or major complications were observed. CONCLUSIONS: The survival of children with ALF undergoing LDLT was comparable to published data. Furthermore, despite the fact that the available time to prepare the donors was limited, no serious complications were observed in the postoperative period. Thus, using living donors for children with ALF is an effective, safe alternative that can be extremely useful in countries with low donation rates.

Selective sensitization to clavulanic acid and penicillin V.

Allergic reactions to beta-lactam antibiotics have been reported frequently and may occur because of sensitization to unique haptens or to determinants shared with other drugs. A woman who received 1 tablet of amoxicillin-clavulanic acid developed wheals and flares although she had previously tolerated the same preparation well. Levels of specific immunoglobulin (Ig) E to penicillin V, penicillin G, amoxicillin, and ampicillin were undetectable. Skin tests to amoxicillin, penicillin major determinant and minor determinant mixture were negative. The patient tolerated oral challenge with 500 mg of amoxicillin but developed wheals and flares when challenged with amoxicillin-clavulanic acid 500/125 mg. A histamine release test was negative with amoxicillin but positive with the amoxicillin-clavulanic acid and clavulanic acid. A prick test to the combination was positive. Specific IgE to penicillin V later became positive while remaining negative to other beta-lactams. No inhibition was obtained using penicillin V against clavulanic acid and amoxicillin but was complete when penicillin V was used in the solid-phase and as the inhibitor. No cross-reactivity was proven between these sensitizations.

Value of perfusion lung scans in selection of patients for vena cava interruption.

Sixty-seven patients with pulmonary embolic disease (diagnosed clinically and with perfusion lung scans) were studied. In 48 of them, the scans were interpreted as positive for pulmonary emboli and in 19, as questionable. All 67 patients underwent pulmonary arteriography. The pulmonary arteriogram showed no evidence of pulmonary embolus in 11 of the 48 patients with positive findings on lung scan and no evidence in 12 of the 19 patients with questionable lung scan. Because of the high false-positive rate of the perfusion lung scan, we strongly recommend angiographic confirmation of pulmonary embolism when interruption of inferior vena cava is contemplated for the prevention of recurrence of pulmonary embolism.

Acute right ventricular failure is caused by inadequate right ventricular hypothermia.

The hypothesis of this study was that inadequate right ventricular hypothermia contributes to the right ventricular dysfunction occasionally observed after cardiac operations. Dogs were placed on cardiopulmonary bypass, and 60 minute periods of hypothermic myocardial ischemia were imposed. Left ventricular temperature was always maintained at 15 degrees C and right ventricular temperatures were maintained at 15 degrees C (Group I, n = 8), 25 degrees C (Group II, n = 8), and 35 degrees C (Group III, n = 8). These temperatures were produced by infusion of hypothermic crystalloid cardioplegic solution and appropriate topical cooling and heating of the left and right ventricles, respectively. Multiple indices of ventricular function were obtained 15, 30, 45, and 60 minutes after bypass and compared to prebypass control values. In all Group I animals (left ventricular temperature = 15 degrees C, right ventricular temperature = 15 degrees C), postischemic indices of right ventricular function were not different from control values (p = NS). In Group II (left ventricular temperature = 15 degrees C, right ventricular temperature = 25 degrees C), two animals died 30 and 45 minutes after bypass, respectively, of right ventricular failure. In the other six animals in Group II, all indices of right ventricular function were significantly reduced (p less than 0.05) except for right ventricular systolic pressure. In Group III (left ventricular temperature = 15 degrees C, right ventricular temperature = 35 degrees C), two animals could not be weaned from cardiopulmonary bypass because of right ventricular akinesia. Six animals were weaned from bypass, but two died 15 minutes, one died 30 minutes, and one 45 minutes after bypass. Two animals lived 60 minutes, but all indices of right ventricular function were decreased. Failure to maintain right ventricular temperatures below 25 degrees C during 1 hour of cardiac ischemia in the dog can result in fatal right ventricular failure.

The natural history of pancreatic pseudocysts: a unified concept of management.

Between 1971 and 1976, ninety-three patients with a clinical diagnosis of pseudocyst confirmed by ultrasonography were identified from a group of 923 patients admitted for pancreatic disease. Uncertainties in diagnosis and/or rapid progression of underlying pancreatitis led to urgent laparotomy and drainage in eleven of the ninety-three patients. Another twenty-eight patients underwent elective drainage of the pseudocyst. The remaining fifty-four constituted the study group and were followed with serial clinical and sonographic examinations until either spontaneous resolution occurred, complications developed, or the patients did not return. Complications arising during the period of observation in the untreated patients (rupture, abscess, jaundice, and hemorrhage) occurred more than twice as commonly as spontaneous resolution (41 per cent versus 20 per cent), and led directly to death in seven cases (14 per cent). No deaths occurred in the group of patients undergoing elective surgical drainage (p less than 0.05). The interval between presumed formation of the pseudocyst and the development of a complication averaged 13.5 +/- 6 weeks. Prolonged observation of pancreatic pseudocysts in the expectation of spontaneous resolution exposed the patient to an unwarranted risk, which, after seven weeks, greatly exceeded the mortality of elective surgery.

Counting of lymphocyte subpopulations using standard versus low-dose antiCD3 monoclonal antibody treatment.

The monoclonal anti-CD3 antibody is used as part of prophylaxis and also in treatment of rejection. In the present article we analyzed changes in different lymphocyte subpopulations after anti-CD3 treatment. T lymphocytes were decreased under anti-CD3 antibody administration, with a simultaneous increase in B lymphocytes but no changes in natural killer (NK)cells. No differences were found between patients administered anti-CD3 antibody (Ab) at 5 versus 2.5 mg/d. It is uncertain whether these changes may be implicated in the lack of response or in the prophylactic effects of anti-CD3 Ab.

Molecular characterization of the Leishmania braziliensis L6 ribosomal protein.

By screening a Leishmania braziliensis complementary DNA library with a pool of sera from leishmaniasis patients, the gene coding for L6 ribosomal protein was isolated. The sequence, genomic organization, and transcription of this gene are described in this article. The sequence analysis of the L. braziliensis L6 gene shows a single open reading frame, which codes for a protein of 192 amino acids (aa) with a hypothetical molecular mass of 20.9 kDa. The protein exhibits significant sequence similarity to L6 ribosomal proteins from higher eukaryotes and yeast. Thus, the L. braziliensis L6 protein contains 4 functional motifs, which are located at equivalent positions in other L6 ribosomal proteins described previously. Interestingly, the L6 ribosomal protein from L. braziliensis contains a specific region of 14 aa and a tyrosine kinase motif, which is absent in human and C. elegans L6 protein. The locus coding the L. braziliensis L6 ribosomal protein is formed by 2 gene copies arranged in tandem and located in a chromosome of approximately 0.9. Mb. The genes are actively transcribed as 2 polyadenylated transcripts of approximately 1.15 and 0.85 kb, which differ in their steady-state level and stability.

Cloning and molecular characterization of the cDNA encoding histone H1 from Leishmania braziliensis.

The isolation and molecular characterization of the histone H1-encoding gene from Leishmania braziliensis was carried out. The gene is present in the genome as a single copy and transcribed as a polyadenylated transcript of 830 nucleotides. The deduced amino acid sequence has in its central region the DNA binding K-[K/R]-A-A-[A/P] motif, which is repeated in tandem 9 times.

[Reticulated pigment anomaly of the skinfolds]. / Anomalía pigmentaria reticulada de los pliegues.

We report a case of reticulate pigmented anomaly of the flexures in a 54 years-old white male patient. His lesions had developed during the last 30 years, involving neck, axillae, groins, anterior chest wall, scrotum, buttocks and thighs. The abnormality is characterized by pigmented epidermal downgrowths, with similar lesions developing around dilated pilosebaceous follicles. The condition may be compared with acanthosis nigricans. For this reason it is important to recognize this new genodermatosis in order to avoid unnecessary investigations to exclude visceral malignancy.

Cellulitis and nodular skin lesions due to Fusarium spp in liver transplant: case report.

Fusariosis is one of the emerging invasive fungal infections over the last decade. However, its recent rise has been in its ability to produce disseminated infection in severely immunosuppressed patients with neutropenia. In solid organ transplantation, fusariosis remains an uncommon picture mainly with nodules, subcutaneous abscesses, ulcers, or necrotic skin lesions resembling erthyma gangrenosum. Herein, we have reported a case of cellulitis, subcutaneous nodules, and abscesses due to Fusarium spp in a liver transplantation patient who was successfully treated with polyenes and surgical resection.

Methylene blue used as a bridge to liver transplantation postoperative recovery: a case report.

Hepatopulmonary syndrome is defined as a triad of liver disease, arterial hypoxemia, and intrapulmonary vascular dilatation. The clinical hallmark of this disorder is the impairment of pulmonary gas exchange, not necessarily correlated with the severity of the underlying liver disease. Liver transplantation (OLT) is the only definitive treatment for this syndrome. However, patients with preoperative partial pressure of arterial oxygen (PaO(2)) under 50 mm Hg are exposed to an unacceptably high postoperative mortality and morbidity. Herein we have described a case of a 15-year-old female patient who underwent OLT and was treated with methylene blue in the early postoperative period to improve hypoxemia. We suggest that the use of methylene blue after liver transplantation can decrease postoperative complications and mortality rates in these patients.