Effects of Metal Exposures on Juvenile Clams,Mercenaria mercenaria

Bulletin of Environmental Contamination and Toxicology - Elevated metal concentrations occur throughout the coastal zone due to urbanization and various anthropogenic activities. The lethal...     

Rehabilitation in spinal cord injury

Caring for the new quadriplegic is an immense undertaking involving multiple health care professionals who must function as a team. The physician in charge must understand rehabilitation principles and be able to communicate with all members of the team caring for the patient. Rehabilitation principles, if considered early, can greatly decrease the length of stay of the patient and allow him to maximize his potential for recovery. A basic knowledge of physicial and occupational therapy in paraplegia and quadriplegia in the acute stage as well as functional expectations in the long term have been presented.     

Rekonstruktion nach Unterschenkelfehlheilung

Trauma und Berufskrankheit - Fehlheilungen am diaphysären Unterschenkel lassen sich im Einzelnen folgendermaßen charakterisieren: · Infekt, oberflächlich/tief, ·...     

Intracellular accumulation of the amyloidogenic L68Q variant of human cystatin C in NIH/3T3 cells.

AIM: To study the cellular transport of L68Q cystatin C, the cystatin variant causing amyloidosis and brain haemorrhage in patients suffering from hereditary cystatin C amyloid angiopathy (HCCAA). METHODS: Expression vectors for wild-type and L68Q cystatin C were constructed and used to transfect mouse NIH/3T3 cells. Stable cell clones were isolated after cotransfection with pSV2neo. Clones expressing human wild-type and L68Q cystatin C were compared with respect to secreted cystatin C by enzyme linked immunosorbent assay (ELISA), and for intracellular cystatin C by western blotting and immunofluorescence cytochemistry. Colocalisation studies in cells were performed by double staining with antibodies against human cystatin C and marker proteins for lysosomes, the Golgi apparatus, or the endoplasmic reticulum, and evaluated by confocal microscopy. RESULTS: Concentrations of human cystatin C secreted from transfected NIH/3T3 cells were similar to those secreted from human cells in culture. In general, clones expressing the gene encoding L68Q cystatin C secreted slightly lower amounts of the protein than clones expressing wild-type human cystatin C. Both immunofluorescence cytochemistry and western blotting experiments showed an increased accumulation of cystatin C in cells expressing the gene encoding L68Q cystatin C compared with cells expressing the gene for the wild-type protein. The intracellularly accumulating L68Q cystatin C was insoluble and located mainly in the endoplasmic reticulum. CONCLUSIONS: The cellular transport of human cystatin C is impeded by the pathogenic amino acid substitution Leu68-->Gln. The resulting intracellular accumulation and increased localised concentration of L68Q cystatin C might be an important event in the molecular pathophysiology of amyloid formation and brain haemorrhage in patients with HCCAA.     

Zum Stoffwechsel des Skeletmuskels

Zusammenfassung 1. Bei zwölf Hochleistungssportlern wurden in Ruhe, während Fahrradergometerarbeit und in der Erholungsphase Sauerstoffdruck, Kohlensäuredruck, pH, Standardbicarbonat und base excess im vorwiegend aus der arbeitenden Muskulatur stammenden Blut und im Arterienblut gemessen. Die erhaltenen Werte werden mit entsprechenden, bei untrainierten Personen gewonnenen Daten verglichen.2. Weder von den Trainierten noch von den Untrainierten wird bei maximaler Belastung der venöse kritische Sauerstoffdruck erreicht. Dies geht nicht nur aus den während Höchstbelastung gewonnenen Daten für den femoralvenösen O₂-Druck hervor, sondern auch aus dem Verhalten des Quotienten Lactat/Pyruvat.3. Die Dauerleistung des Trainierten wird in Meereshöhe wahrscheinlich nicht von der O₂-Versorgung des Muskelgewebes oder durch die Ansäuerung des Blutes bzw. des Gewebes begrenzt.4. Die Abnahme des venösen O₂-Druckes während Belastung ist nicht die Ursache einer vermehrten Lactatabgabe, welche bei den Untrainierten früher und ausgeprägter erfolgt als bei Trainierten. Vielmehr scheint sie die Folge einer begrenzten oxydativen Zelleistung zu sein.5. Folgende, beim Sportler gegenüber Untrainierten unterschiedlichen Befunde sprechen dafür, daß beim Trainierten während Belastung eine gegenüber dem Untrainierten erhöhte Muskeldurchblutung auftritt, welche für die Dauerleistung von Bedeutung sein dürfte: Während geringer Belastung sinkt P o _20076-0304 beim Sportler nur wenig ab. Eine Belastung von 200 W stellt für den Untrainierten eine maximale, für den Trainierten erst eine submaximale Arbeit dar. Bei beiden Gruppen beträgt hierbei der femoralvenöse O₂-Druck etwa 21 mm Hg. Ohne daß P o _20076-0304 noch wesentlich absinkt, vermag der Trainierte seine Leistung noch weiter auf 300 W zu steigern, was nicht allein mit der pH-bedingten und einer temperaturabhängigen Rechtsverschiebung der O₂-Dissoziationskurve erklärt werden kann.6. Nur im arteriellen Blut wird pH während Belastung vorwiegend durch die anfallende Milchsäure bestimmt. Dagegen ist pH_20076-0304 außerdem wesentlich vom CO₂-Druck abhängig. Sportler zeigen unter Maximalbelastung weder im arteriellen noch im femoralvenösen Blut niedrigere pH-Werte als nicht trainierte Personen. Eine stärkere Säuerung des Gewebes während maximaler Arbeit oder gar eine erhöhte Säureverträglichkeit des Gewebes als Trainingseffekt ist daher unwahrscheinlich.Mit Unterstützung durch die Deutsche Forschungsgemeinschaft und das Kuratorium für Sportmedizinische Forschung.     

Letermovir in lung transplant recipients with cytomegalovirus infection: A retrospective observational study

Letermovir is a new antiviral drug approved for the prophylaxis of CMV infection in allogeneic stem cell transplants. The aim of the study was to assess the therapeutic efficacy of letermovir in difficult to treat CMV infections in lung transplant recipients. All lung transplant recipients between March 2018 and August 2020, who have been treated with letermovir for ganciclovir-resistant or refractory CMV infection were included in the study and analysed retrospectively. In total, 28 patients were identified. CMV disease was present in 15 patients (53.6%). In 23 patients (82.1%), rapid response was noticed, and CMV-viral load could be significantly decreased (>1 log₁₀) after a median of 17 [14–27] days and cleared subsequently in all of these patients. Five patients (17.9%) were classified as non-responder. Thereof, development of a mutation of the CMV UL56 terminase (UL-56-Gen: C325Y) conferring letermovir resistance could be observed in three patients (60%). Common side effects were mild and mostly of gastrointestinal nature. Mild adjustments of the immunosuppressive drugs were mandatory upon treatment initiation with letermovir. In addition to other interventions, letermovir was effective in difficult to treat CMV infections in lung transplant recipients. However, in patients with treatment failure mutation conferring letermovir, resistance should be taken into account.     

Phase II study of pemetrexed with and without folic acid and vitamin B12 as front-line therapy in malignant pleural mesothelioma.

PURPOSE: This phase II clinical study evaluated the efficacy of pemetrexed for the treatment of malignant pleural mesothelioma (MPM). PATIENTS AND METHODS: Patients with a histologically proven diagnosis of MPM, chemotherapy-naive measurable lesions, and adequate organ function received pemetrexed (500 mg/m2) intravenously over 10 minutes every 3 weeks. After a protocol change, most patients also received folic acid and vitamin B12 supplementation to improve safety. RESULTS: A total of 64 patients were enrolled. Nine (14.1%) of the 64 patients had a partial response. The Kaplan-Meier estimate for median overall survival was 10.7 months. Forty-three patients received vitamin supplementation for all courses of therapy, and 21 patients did not. Seven of the nine responders were vitamin supplemented. The median overall survival was 13.0 months for supplemented patients and 8.0 months for nonsupplemented patients. Vitamin-supplemented patients completed more cycles of therapy than nonsupplemented patients (median, six v two cycles, respectively). Grade 3/4 neutropenia (23.4%) and grade 3/4 leukopenia (18.8%) were the most common laboratory toxicities. Fatigue and febrile neutropenia were the most commonly reported nonlaboratory events (grade 3, 6.3%; grade 4, 0.0% each). The incidence of these toxicities was generally lower in the supplemented patients. CONCLUSION: Single-agent pemetrexed for MPM resulted in a moderate response rate (14.1%) and median overall survival of 10.7 months. Patients supplemented with folic acid and vitamin B12 tolerated treatment better (less toxicity and more cycles of treatment) and had a 5-month greater median overall survival than nonsupplemented patients. These results indicate that patients with MPM could benefit from single-agent pemetrexed treatment combined with vitamin supplementation.     

ATP-dependent para-aminohippurate transport by apical multidrug resistance protein MRP2

BACKGROUND: Para-aminohippurate (PAH), a widely used model substrate for organic anion transport in proximal tubule epithelia, was investigated as a substrate for the apical multidrug resistance protein MRP2 (symbol ABCC2). This ATP-dependent export pump for anionic conjugates and additional amphiphilic anions was cloned recently and localized to the apical membrane of proximal tubules in human and rat kidney. METHODS: Membrane vesicles from HEK-MRP2 cells containing recombinant human MRP2 and from control vector-transfected HEK-Co cells were incubated with various concentrations of [3H]PAH, and the net ATP-dependent transport into inside-out vesicles was determined. Comparative studies were performed with membrane vesicles containing recombinant human MRP1. RESULTS: Transport rates at 10 micromol/L PAH were 21.9 +/- 1.9 and 1.6 +/- 0.4 pmol x mg protein-1 x min-1 (means +/- SEM, N = 10) with membrane vesicles from HEK-MRP2 and HEK-Co cells, respectively. The Km value for PAH was 880 micromol/L. The high-affinity substrate leukotriene C4 and the inhibitor of MRP-mediated transport, MK571, inhibited MRP2-mediated transport of PAH (100 nmol/L) with IC50 values of 3.3 and 4.0 micromol/L, respectively. The nephrotoxic mycotoxin ochratoxin A inhibited MRP2-mediated PAH transport with an IC50 value of 58 micromol/L. Ochratoxin A was itself a substrate for MRP2. CONCLUSIONS: PAH is a good substrate for the ATP-dependent export pump MRP2. The localization and function of MRP2 indicate that this unidirectional transport protein contributes to the secretion of PAH and other amphiphilic anions into the lumen of kidney proximal tubules.     

A dyadic genotype–phenotype approach to diagnostic criteria for Proteus syndrome

Phenotype‐based diagnostic criteria were developed for Proteus syndrome in 1999 and updated in 2006. Subsequently, the causative mosaic gene alteration was discovered, the c.49G>A p.E17K variant in AKT1. As well, a number of overlapping overgrowth disorders attributable to mosaic PIK3CA variants have now been characterized, leading to the designation of PIK3CA‐related overgrowth spectrum (PROS). Finally, ongoing work to better characterize Proteus syndrome has led to identification of additional features of that disorder that could be useful in diagnostic criteria. We have taken the opportunity of these discoveries to re‐evaluate the Proteus syndrome diagnostic criteria. Here we propose a new set of diagnostic criteria that establishes a weighted, point‐based system for the phenotypic attributes and then integrates that with the potential molecular test results to result in one of two designations: AKT1‐related Proteus syndrome or AKT1‐related overgrowth spectrum. A patient whose only manifestation is an AKT1 c.49G>A‐positive tumor would receive neither of these designations. Here we review the rational basis of diagnostic criteria and argue that a unitary diagnostic entity is a distinct gene‐phenotype dyad and that this should be the model for all mendelian disorders. The gene‐alone or phenotype‐alone approach is inadequate to rigorously delineate a unitary diagnostic entity.     

Cotransport of reduced glutathione with bile salts by MRP4 (ABCC4) localized to the basolateral hepatocyte membrane

The liver is the major source of reduced glutathione (GSH) in blood plasma. The transport protein mediating the efflux of GSH across the basolateral membrane of human hepatocytes has not been identified so far. In this study we have localized the multidrug resistance protein 4 (MRP4; ABCC4) to the basolateral membrane of human, rat, and mouse hepatocytes and human hepatoma HepG2 cells. Recombinant human MRP4, expressed in V79 hamster fibroblasts and studied in membrane vesicles, mediated ATP-dependent cotransport of GSH or S-methyl-glutathione together with cholyltaurine, cholylglycine, or cholate. Several monoanionic bile salts and the quinoline derivative MK571 were potent inhibitors of this unidirectional transport. The K(m) values were 2.7 mmol/L for GSH and 1.2 mmol/L for the nonreducing S-methyl-glutathione in the presence of 5 micromol/L cholyltaurine, and 3.8 micromol/L for cholyltaurine in the presence of 5 mmol/L S-methyl-glutathione. Transport of bile salts by MRP4 was negligible in the absence of ATP or without S-methyl-glutathione. These findings identify a novel pathway for the efflux of GSH across the basolateral hepatocyte membrane into blood where it may serve as an antioxidant and as a source of cysteine for other organs. Moreover, MRP4-mediated bile salt transport across the basolateral membrane may function as an overflow pathway during impaired bile salt secretion across the canalicular membrane into bile. In conclusion, MRP4 can mediate the efflux of GSH from hepatocytes into blood by cotransport with monoanionic bile salts.