RESUMO
Epidemiologic data indicate that overweight and obesity are on the rise worldwide. Psychiatric patients are particularly vulnerable in this respect as they have an increased prevalence of overweight and obesity, and often experience rapid, highly undesirable weight gain under psychotropic drug treatment. Current treatment strategies in psychiatry are oriented towards polypharmacy, so that the information on drug-induced weight gain from earlier monotherapy studies is of very limited validity. We have analyzed the longitudinal data of 832 inpatients with ICD-10 diagnoses of either F2 (schizophrenia; n = 282) or F3 (major depression; n = 550) with the goal of ranking treatment regimens in terms of weight gain, side effects, and response to treatment. The patient data were complemented by the data of 3180 students aged 18-22 years, with which we aimed to identify factors that enable the early detection and prevention of obesity and mental health problems. After 3 weeks of treatment, 47.7% of F2 patients and 54.9% of F3 patients showed a weight gain of 2 kg and more. Major predictive factors were "starting weight" (r = 0.115), "concurrent medications" (r = 0.176), and "increased appetite"(r = 0.275). Between 11 and 30% of the observed variance in weight gain could be explained by these factors, complemented by sex and age. The comparison between monotherapy (n = 409) and polypharmacy (n = 399) revealed significant drawbacks for polypharmacy: higher weight gain (p = 0.0005), more severe side effects (p = 0.0011), and lower response rates (F2: p = 0.0008); F3: p = 0.0101). The data of 3180 students made it clear that overweight and obesity often begin early in life among those affected, and are interconnected with personality traits, while increasing the risk of developing psychosomatic disturbances, mental health problems, or somatic illnesses. Although the available data did not readily lead to a comprehensive, clinically applicable model of unwanted weight gain, our results have nevertheless demonstrated that there are ways to successfully counteract such weight gain at early stages of treatment.
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Current treatment standards in psychiatry are oriented towards polypharmacy, that is, patients receive combinations of several antidepressants, antipsychotics, mood stabilizers, anxiolytics, hypnotics, antihistamines, and anticholinergics, along with other somatic treatments. In tandem with the beneficial effects of psychopharmacological drug treatment, patients experience significant adverse reactions which appear to have become more frequent and more severe with the rise of ubiquitous polypharmacy. In this study, we aimed to assess today's acute inpatient treatment of depressive and schizophrenic disorders with focus on therapeutic strategies, medications, adverse side effects, time course of recovery, and efficacy of treatments. Of particular interest was the weighing of the benefits and drawbacks of polypharmacy regimens. We recruited a total of 320 patients hospitalized at three residential mental health treatment centers with a diagnosis of either schizophrenic (ICD-10: "F2x.x"; n = 94; "F2 patients") or depressive disorders (ICD-10: "F3x.x"; n = 226; "F3 patients"). The study protocol included (1) assessment of previous history by means of the SADS Syndrome Check List SSCL-16 (lifetime version); (2) repeated measurements over 5 weeks assessing the time course of improvement by the Hamilton Depression Scale HAM-D and the Positive and Negative Syndrome Scale PANSS, along with medications and adverse side effects through the Medication and Side Effects Inventory MEDIS; and (3) the collection of blood samples from which DNA and serum were extracted. Polypharmacy was by far the most common treatment regimen (85%) in this study. On average, patients received 4.50 ± 2.68 medications, consisting of 3.30 ± 1.84 psychotropic drugs, plus 0.79 ± 1.13 medications that alleviate adverse side effects, plus 0.41 ± 0.89 other somatic medications. The treating psychiatrists appeared to be the main determining factor in this context, while «previous history¼ and «severity at baseline¼ played a minor role, if at all. Adverse drug reactions were found to be an inherent component of polypharmacy and tended to have a 2-3 times higher incidence compared to monotherapy. Severe adverse reactions could not be attributed to a particular drug or drug combination. Rather, the empirical data suggested that severe side effects can be triggered by virtually all combinations of drugs, provided patients have a respective vulnerability. In terms of efficacy, there were no advantages of polypharmacy over monotherapy. The results of this study underlined the fact that polypharmacy regimens are not equally suited for every patient. Specifically, such regimens appeared to have a negative impact on treatment outcome and to obfuscate the "natural" time course of recovery through a multitude of interfering factors. Evidence clearly speaks against starting just every therapeutic intervention in psychiatry with a combination of psychopharmaceuticals. We think that it is time for psychiatry to reconsider its treatment strategies, which are far too one-sidedly fixated on psychopharmacology and pay far too little attention to alternative approaches, especially in mild cases where psychotherapy without concurrent medication should still be an option. Also, regular exercises and sports can definitely be an effective therapeutic means in a considerable number of cases. General practitioners (GPs) are particularly in demand here.
Assuntos
Antipsicóticos , Psiquiatria , Esquizofrenia , Antipsicóticos/efeitos adversos , Depressão , Humanos , Estudos Longitudinais , Polimedicação , Psicotrópicos/efeitos adversos , Esquizofrenia/tratamento farmacológico , Esquizofrenia/epidemiologiaRESUMO
Somatodendritic missorting of the axonal protein TAU is a hallmark of Alzheimer's disease and related tauopathies. Rodent primary neurons and iPSC-derived neurons are used for studying mechanisms of neuronal polarity, including TAU trafficking. However, these models are expensive, time-consuming, and/or require the killing of animals. In this study, we tested four differentiation procedures to generate mature neuron cultures from human SH-SY5Y neuroblastoma cells and assessed the TAU sorting capacity. We show that SH-SY5Y-derived neurons, differentiated with sequential RA/BDNF treatment, are suitable for investigating axonal TAU sorting. These human neurons show pronounced neuronal polarity, axodendritic outgrowth, expression of the neuronal maturation markers TAU and MAP2, and, importantly, efficient axonal sorting of endogenous and transfected human wild-type TAU, similar to mouse primary neurons. We demonstrate that the N-terminal half of TAU is not sufficient for axonal targeting, as a C-terminus-lacking construct (N-term-TAUHA) is not axonally enriched in both neuronal cell models. Importantly, SH-SY5Y-derived neurons do not show the formation of a classical axon initial segment (AIS), indicated by the lack of ankyrin G (ANKG) and tripartite motif-containing protein 46 (TRIM46) at the proximal axon, which suggests that successful axonal TAU sorting is independent of classical AIS formation. Taken together, our results provide evidence that (i) SH-SY5Y-derived neurons are a valuable human neuronal cell model for studying TAU sorting readily accessible at low cost and without animal need, and that (ii) efficient axonal TAU targeting is independent of ANKG or TRIM46 enrichment at the proximal axon in these neurons.
Assuntos
Segmento Inicial do Axônio , Animais , Anquirinas , Segmento Inicial do Axônio/metabolismo , Axônios/metabolismo , Linhagem Celular Tumoral , Humanos , Camundongos , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Transporte Proteico , Proteínas tau/metabolismoRESUMO
Over the past 2 decades, polypharmacy has become the de-facto standard of acute treatment in psychiatry where patients with psychiatric disorders receive a multiple medication regimen. There is growing evidence for a potential link between major psychiatric disorders and inflammatory processes. Combining these two aspects aims at avoiding polypharmacy attempts among patients with inflammatory activation through alternative treatment strategies. In this study, we addressed the following questions: (1) to what extent can polypharmacy be explained through the factors "diagnosis", "previous history", "severity at baseline", "age", "gender", and "psychiatrist in charge"; (2) what are the differences between polypharmacy and monotherapy regarding efficacy and side effect profiles; and (3) what amount of between-patient variance is explainable by the natural antibody immunoglobulin M (IgM) within each diagnostic group. This naturalistic longitudinal study was comprised of 279 patients under therapy with a clinical diagnosis of depressive (ICD-10: "F3x.x"; n = 195) or schizophrenic disorders (ICD-10: "F2x.x"; n = 84). The study protocol included (1) assessment of previous history by the SADS Syndrome Check List SSCL-16 (lifetime version); (2) repeated measurements over 5 weeks assessing the time course of improvement by the Hamilton Depression Scale HAM-D and the Positive and Negative Syndrome Scale PANSS, along with medication and unwanted side effects through the Medication and Side Effects Inventory MEDIS; and (3) the collection of blood samples from which DNA and serum were extracted. The association between inflammatory response system and psychiatric disorders was detailed by fitting multi-layer Neural Net (NN) models to the observed data ("supervised learning"). The same approach was used to set up prediction models of side effects. Our data showed that polypharmacy was omnipresent. Yet the various polypharmacy regimens had no advantage over monotherapy: we even found slightly larger baseline score reductions under monotherapy, independent of primary diagnoses and for comparable baseline severities. Most patients experienced unwanted side effects. The close link between side effects and treatment regimen was revealed by a linear model in which the mere number of drugs explained a significant (p < 0.001) proportion of the observed variance. As to the inflammatory response system: For the F2 patients, our NN model identified a 22.5% subgroup exhibiting a significant correlation of r = 0.746 (p = 0.0004) between global schizophrenia scores and IgM levels, along with a correct prediction of response of 94.4%, thus explaining 55.7% of the observed between-patient variance. For the F3 patients, our NN model identified a 19.6% subgroup exhibiting a significant correlation of r = 0.644 (p = 0.00003) between global depression scores and IgM levels, along a correct prediction of response of 89.6%, thus explaining 41.4% of the observed between-patient variance. Polypharmacy is omnipresent in today's acute treatment of psychiatric disorders. Given the large proportion of patients with unwanted side effects and the strong correlation between side effects and the number of drugs, polypharmacy approaches are not equally suited for every patient. In terms of efficacy, there are no advantages of polypharmacy over monotherapy. Most notably, our study appears to have cleared the way for the reliable identification of a subgroup of patients for whom the inflammatory response system is a promising target of therapeutic intervention.
Assuntos
Antidepressivos/farmacologia , Antipsicóticos/farmacologia , Transtorno Depressivo Maior , Imunoglobulina M/sangue , Inflamação/imunologia , Avaliação de Resultados em Cuidados de Saúde , Polimedicação , Esquizofrenia , Adulto , Antidepressivos/administração & dosagem , Antidepressivos/efeitos adversos , Antipsicóticos/administração & dosagem , Antipsicóticos/efeitos adversos , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/imunologia , Transtorno Depressivo Maior/fisiopatologia , Feminino , Hospitais Psiquiátricos/estatística & dados numéricos , Humanos , Inflamação/sangue , Estudos Longitudinais , Aprendizado de Máquina , Masculino , Pessoa de Meia-Idade , Redes Neurais de Computação , Psiquiatria/normas , Psiquiatria/tendências , Esquizofrenia/tratamento farmacológico , Esquizofrenia/imunologia , Esquizofrenia/fisiopatologia , SuíçaRESUMO
Calcineurin dephosphorylates nuclear factor of activated T cells transcription factors, thereby facilitating T cell-mediated immune responses. Calcineurin inhibitors are instrumental for immunosuppression after organ transplantation but may cause side effects, including hypertension and electrolyte disorders. Kidneys were recently shown to display activation of the furosemide-sensitive Na-K-2Cl cotransporter (NKCC2) of the thick ascending limb and the thiazide-sensitive Na-Cl cotransporter (NCC) of the distal convoluted tubule upon calcineurin inhibition using cyclosporin A (CsA). An involvement of major hormones like angiotensin II or arginine vasopressin (AVP) has been proposed. To resolve this issue, the effects of CsA treatment in normal Wistar rats, AVP-deficient Brattleboro rats, and cultured renal epithelial cells endogenously expressing either NKCC2 or NCC were studied. Acute administration of CsA to Wistar rats rapidly augmented phosphorylation levels of NKCC2, NCC, and their activating kinases suggesting intraepithelial activating effects. Chronic CsA administration caused salt retention and hypertension, along with stimulation of renin and suppression of renal cyclooxygenase 2, pointing to a contribution of endocrine and paracrine mechanisms at long term. In Brattleboro rats, CsA induced activation of NCC, but not NKCC2, and parallel effects were obtained in cultured cells in the absence of AVP. Stimulation of cultured thick ascending limb cells with AVP agonist restored their responsiveness to CsA. Our results suggest that the direct epithelial action of calcineurin inhibition is sufficient for the activation of NCC, whereas its effect on NKCC2 is more complex and requires concomitant stimulation by AVP.
Assuntos
Inibidores de Calcineurina/toxicidade , Ciclosporina/toxicidade , Células Epiteliais/efeitos dos fármacos , Imunossupressores/toxicidade , Túbulos Renais Distais/efeitos dos fármacos , Alça do Néfron/efeitos dos fármacos , Membro 1 da Família 12 de Carreador de Soluto/agonistas , Animais , Arginina Vasopressina/farmacologia , Células Cultivadas , Ciclo-Oxigenase 2/metabolismo , Células Epiteliais/metabolismo , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Túbulos Renais Distais/metabolismo , Túbulos Renais Distais/fisiopatologia , Alça do Néfron/metabolismo , Alça do Néfron/fisiopatologia , Masculino , Ratos Brattleboro , Ratos Wistar , Renina/metabolismo , Membro 1 da Família 12 de Carreador de Soluto/genética , Membro 1 da Família 12 de Carreador de Soluto/metabolismo , Membro 3 da Família 12 de Carreador de Soluto/agonistas , Membro 3 da Família 12 de Carreador de Soluto/genética , Membro 3 da Família 12 de Carreador de Soluto/metabolismo , Fatores de Tempo , Equilíbrio Hidroeletrolítico/efeitos dos fármacosRESUMO
The human restricted pathogen Moraxella catarrhalis is an important causal agent for exacerbations in chronic obstructive lung disease in adults. In such patients, increased numbers of granulocytes are present in the airways, which correlate with bacteria-induced exacerbations and severity of the disease. Our study investigated whether the interaction of M. catarrhalis with the human granulocyte-specific carcinoembryonic antigen-related cell adhesion molecule (CEACAM)-3 is linked to NF-κB activation, resulting in chemokine production. Granulocytes from healthy donors and NB4 cells were infected with M. catarrhalis in the presence of different inhibitors, blocking antibodies and siRNA. The supernatants were analysed by enzyme-linked immunosorbent assay for chemokines. NF-κB activation was determined using a luciferase reporter gene assay and chromatin-immunoprecipitation. We found evidence that the specific engagement of CEACAM3 by M. catarrhalis ubiquitous surface protein A1 (UspA1) results in the activation of pro-inflammatory events, such as degranulation of neutrophils, ROS production and chemokine secretion. The interaction of UspA1 with CEACAM3 induced the activation of the NF-κB pathway via Syk and the CARD9 pathway and was dependent on the phosphorylation of the CEACAM3 ITAM-like motif. These findings suggest that the CEACAM3 signalling in neutrophils is able to specifically modulate airway inflammation caused by infection with M. catarrhalis.
Assuntos
Proteínas Adaptadoras de Sinalização CARD/metabolismo , Antígeno Carcinoembrionário/metabolismo , Granulócitos/fisiologia , Moraxella catarrhalis/fisiologia , Infecções por Moraxellaceae/microbiologia , Quinase Syk/metabolismo , Degranulação Celular , Quimiocinas/metabolismo , Granulócitos/microbiologia , Células HEK293 , Interações Hospedeiro-Patógeno , Humanos , Explosão Respiratória , Transdução de SinaisRESUMO
Intraarticular fractures of the distal tibia (pilon fractures) are caused by axial forces, usually in combination with torsional moments. Routine diagnostics include plain films and three dimensional (3D) imaging with computed tomography (CT). Treatment is often impaired by complex fracture configurations and thin soft tissue layers. The management of complex pilon fractures with soft tissue injuries has seen many trends, with changes toward staged protocols of temporary external fixation followed by delayed open reduction and internal fixation (ORIF), minimally invasive percutaneous plate osteosynthesis (MIPPO) techniques and special implants, the benefits of negative pressure wound sealing and early "fix and flap" efforts to reconstruct soft tissue defects. Reduction and fixation must involve respectful management and careful handling of soft tissues in order to minimize the well-known complications of this difficult fracture. The proper approach is one of the keys to success. Approach planning is based on the careful and thorough analysis of the fracture pattern in the 3D data set, which is the basis for a successful strategy for articular reconstruction.
Assuntos
Traumatismos do Tornozelo/diagnóstico por imagem , Traumatismos do Tornozelo/cirurgia , Fraturas Intra-Articulares/diagnóstico por imagem , Fraturas Intra-Articulares/cirurgia , Fraturas da Tíbia/diagnóstico por imagem , Fraturas da Tíbia/cirurgia , Traumatismos do Tornozelo/classificação , Fixadores Externos , Fixação de Fratura/métodos , Humanos , Interpretação de Imagem Assistida por Computador , Imageamento Tridimensional , Fraturas Intra-Articulares/classificação , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Osteonecrose/classificação , Osteonecrose/diagnóstico por imagem , Osteonecrose/cirurgia , Lesões dos Tecidos Moles/classificação , Lesões dos Tecidos Moles/diagnóstico por imagem , Lesões dos Tecidos Moles/cirurgia , Fraturas da Tíbia/classificação , Tomografia Computadorizada por Raios XRESUMO
Acute compartment syndrome (ACS) of the foot represents a rare complication following trauma of the lower extremity. Early diagnosis and treatment are necessary to prevent poor outcome. The study was conducted to describe etiology and treatment of foot ACS. In the current study, patients diagnosed with and treated for ACS between 1st December 2000 and 30th September 2007 were included. Mechanism of injury, additional injuries and treatment was analyzed. We included 31 patients (21 males) with a mean age of 33.8 ± 16.9 years. Most injuries were caused by a motor vehicle accident, while nearly 20 % occurred after a low-energy mechanism. Multiple injuries with a mean ISS of 19.5 ± 11.0 were present in 14 patients. Superficial infections occurred in 6 feet, while a deep infection only developed in one patient. Acute compartment syndrome of the foot has a low incidence. A thorough clinical examination in patients on risk is required to provide timely diagnosis and adequate surgical decompression.
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The diagnosis of unclear soft tissue tumors represents a common problem in everyday clinical practice. Magnetic resonance imaging often reveals some first information about soft tissue tumors; however, clarification of the dignity can only be achieved by histopathological examination. Most of the lesions are benign but should be treated as a malignant tumor until this can be excluded as unnecessary surgery or biopsies can complicate treatment and worsen the prognosis. These aspects in particular are summarized and discussed in this article.
Assuntos
Extremidades/cirurgia , Sarcoma/diagnóstico , Sarcoma/cirurgia , Neoplasias de Tecidos Moles/diagnóstico , Algoritmos , Braço/patologia , Braço/cirurgia , Biópsia por Agulha Fina/métodos , Comportamento Cooperativo , Diagnóstico Diferencial , Extremidades/patologia , Humanos , Comunicação Interdisciplinar , Leiomiossarcoma/diagnóstico , Leiomiossarcoma/patologia , Leiomiossarcoma/cirurgia , Imageamento por Ressonância Magnética , Imagem por Ressonância Magnética Intervencionista/métodos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Sarcoma/patologia , Neoplasias de Tecidos Moles/patologia , Neoplasias de Tecidos Moles/cirurgia , Procedimentos DesnecessáriosRESUMO
AIM: Von Hippel-Lindau protein (VHL) provides the degradation of hypoxia-inducible factor (HIF). Tetracycline-induced, Pax8-rtTA-based knockout of VHL (VHL-KO) affects all renal tubules and periportal hepatocytes and leads to sustained upregulation of HIF. Here, we study the phenotype of VHL-KO in both organs, the time course of changes, and long-term morpho-functional outcome. METHODS: Mice with doxycycline-induced VHL-KO and controls (CON) were followed for up to 9 months. Systemic and tissue parameters were evaluated using clinical chemistry, histology, immunohistochemistry, RT-PCR and in situ hybridisation. RESULTS: At day 3 following VHL-KO, substantial abundance of HIF-1α and -2α was detected in the nuclei of hepatocytes and renal tubular epithelia. Hypoxia, induced by bleeding anaemia, did not further augment HIF signal. Erythropoietin mRNA was detectable in hepatocytes but not in the kidney. Vascular endothelial growth factor mRNA was upregulated in kidney but not in liver. At day 7 following VHL-KO, the renal capillary density was enhanced, reaching its maximum at day 14. Blood haemoglobin increased constantly up to day 28 (23.3 vs. 15.8 g dL(-1) , VHL-KO vs. CON). Thereafter, it was kept within the normal range by weekly blood collections. Pathological changes were absent from kidney and liver 9 months after VHL-KO. CONCLUSIONS: Inducible, Pax8-rtTA-based deletion of VHL leads to organ-specific expression of epithelial HIF and erythropoietin in liver and kidney without causing pathological changes. Uniform, maximal and sustained HIF activation along the renal tubule may serve to study the potential benefits of hypoxia adaptation in experimental renal injury.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Rim/metabolismo , Fígado/metabolismo , Fatores de Transcrição Box Pareados/genética , Transativadores/genética , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo , Animais , Capilares/metabolismo , Eritropoese , Eritropoetina/genética , Eritropoetina/metabolismo , Feminino , Genótipo , Hemoglobinas/metabolismo , Imuno-Histoquímica , Hibridização In Situ , Rim/irrigação sanguínea , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Neovascularização Fisiológica , Fator de Transcrição PAX8 , Fenótipo , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Tempo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Proteína Supressora de Tumor Von Hippel-Lindau/genéticaRESUMO
PURPOSE: Prognostic impact of nodal status or lymphadenectomy in advanced ovarian cancer is still unclear. Known best prognostic impact in advanced ovarian cancer has the residual tumor mass. The aim of this retrospective study is to examine the importance of nodal status in correlation with residual tumor mass. METHODS: One hundred and fifty-seven consecutive patients with primary stage III ovarian cancer underwent surgery between 01/2000 and 06/2007 at the Department of gynecology and obstetrics, University Hospital, Tübingen, Germany. All patients got stage-related surgery and platin-based chemotherapy. Median follow-up time was 53.5 months, and all patients were included in the study. RESULTS: Resection status and nodal status are significant prognostic factors in our study (P < 0.001). In FIGO III, patients without residual tumor (R0) had significant best OS and PFS independent to node status (N0/N+; P = 0.002) compared to patients with residual tumor. In contrast, node status had significant positive impact on PFS in patients without residual tumor and node negativity. With the increase in residual tumor, the influence of lymphnode metastases on prognosis is decreasing. CONCLUSION: Main intention of primary surgery is R0 resection with best prognosis in advanced stages. A systematic lymphadenectomy in cases with R0 resection or residual tumor <1 cm seems to be reasonable with positive impact on prognosis. Node status has impact on prognosis in patients with negative node after R0 resection with best PFS in FIGO III. Further prospective studies had to show whether systematic lymphadenectomy in suboptimally tumor-reduced patients can improve prognosis.
Assuntos
Linfonodos/patologia , Linfonodos/cirurgia , Metástase Linfática/patologia , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Excisão de Linfonodo/métodos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasia Residual/patologia , Neoplasia Residual/cirurgia , Prognóstico , Estudos Retrospectivos , Análise de SobrevidaRESUMO
Hemorrhage is frequently seen during the early phases of polytrauma management and intensive care treatment of the severely injured. Traumatic coagulopathy as well as the sometimes overlooked hyperfibrinolysis may lead to further complications. Therefore, transfusion of blood products and coagulation factors is often crucial. Jehova's Witnesses reject transfusions of blood and blood products due to religious convictions. In this case report a therapeutic approach of a multiple trauma patient suffering from traumatic brain injury, blunt chest trauma and liver laceration is described, who has been treated without blood products. As one main focus, ethical as well as legal aspects are discussed. Beside therapeutic concepts, such as the administration of coagulation factors, recombinant erythropoietin and iron, ethical and legal aspects remain part of the controversial discussion.
Assuntos
Transfusão de Sangue , Lesões Encefálicas/diagnóstico , Hemorragia/terapia , Testemunhas de Jeová , Fígado/lesões , Lesão Pulmonar/diagnóstico , Traumatismo Múltiplo/terapia , Religião e Medicina , Baço/lesões , Algoritmos , Fatores de Coagulação Sanguínea/administração & dosagem , Lesões Encefálicas/cirurgia , Contraindicações , Contusões/diagnóstico , Contusões/terapia , Cuidados Críticos/métodos , Eritropoetina/administração & dosagem , Feminino , Hemorragia/diagnóstico , Técnicas Hemostáticas , Humanos , Traumatismo Múltiplo/diagnóstico , Ruptura , Tomografia Computadorizada por Raios X , Centros de Traumatologia , Ultrassonografia , Adulto JovemRESUMO
Unilateral ureteral obstruction (UUO), a model of tubulointerstitial scarring (TIS), has a propensity toward regeneration of renal parenchyma after release of obstruction (RUUO). No information exists on the contribution of stem cells to this process. We performed UUO in FVB/N mice, reversed it after 10 days, and examined kidneys 3 wk after RUUO. UUO resulted in attenuation of renal parenchyma. FACS analysis of endothelial progenitor (EPC), mesenchymal stem (MSC) and hematopoietic stem (HSC) cells obtained from UUO kidneys by collagenase-dispersed single-cell suspension showed significant increase in EPC, MSC, and HSC compared with control. After RUUO cortical parenchyma was nearly restored, and TIS score improved by 3 wk. This reversal process was associated with return of stem cells toward baseline level. When animals were chronically treated with nitric oxide synthase (NOS) inhibitor at a dose that did not induce hypertension but resulted in endothelial dysfunction, TIS scores were not different from control UUO, but EPC number in the kidney decreased significantly; however, parenchymal regeneration in these mice was similar to control. Blockade of CXCR4-mediated engraftment resulted in dramatic worsening of UUO and RUUO. Similar results were obtained in caveolin-1-deficient but not -overexpressing mice, reflecting the fact that activation of CXCR4 occurs in caveolae. The present data show increase in EPC, HSC, and MSC population during UUO and a tendency for these cells to decrease to control level during RUUO. These processes are minimally affected by chronic NOS inhibition. Blockade of CXCR4-stromal cell-derived factor-1 (SDF-1) interaction by AMD3100 or caveolin-1 deficiency significantly reduced the UUO-associated surge in stem cells and prevented parenchymal regeneration after RUUO. We conclude that the surge in stem cell accumulation during UUO is a prerequisite for regeneration of renal parenchyma.
Assuntos
Rim/patologia , Rim/fisiopatologia , Regeneração , Células-Tronco/patologia , Obstrução Ureteral/patologia , Obstrução Ureteral/fisiopatologia , Animais , Benzilaminas , Caveolina 1/metabolismo , Divisão Celular/efeitos dos fármacos , Quimiocina CXCL12/antagonistas & inibidores , Ciclamos , Progressão da Doença , Inibidores Enzimáticos/farmacologia , Fibrose , Células-Tronco Hematopoéticas/patologia , Compostos Heterocíclicos/farmacologia , Córtex Renal/patologia , Masculino , Células-Tronco Mesenquimais/patologia , Camundongos , Camundongos Endogâmicos , Óxido Nítrico Sintase/antagonistas & inibidores , Receptores CXCR4/antagonistas & inibidores , Recuperação de Função Fisiológica , ômega-N-Metilarginina/farmacologiaRESUMO
We previously reported on the differential presence of transcripts related to the human endogenous retrovirus (HERV)-W family in cerebrospinal fluid and plasma from patients with first-episode schizophrenia compared with control individuals. Whether this is a consequence of qualitative or quantitative differences in transcription of genomic regions harboring HERV-W elements is not known. The purpose of the present study was therefore to characterize the transcribed HERV-W elements in mononuclear cells obtained from 30 patients first hospitalized for schizophrenia-related psychosis and from 26 healthy control individuals. We observed elevated total levels of HERV-W gag (2.1-fold, P < 0.01) but not env transcripts in the cells of patients compared with controls. By using the melting temperatures of the amplicons as a proxy marker for sequence identity, no absolute qualitative differences was detected between the two groups. Mapping of the detected transcripts identified several intronic and intergenic HERV-W elements transcribed in the cells, including elements previously considered transcriptionally silent. Element-specific assays revealed elevated levels of intronic transcripts containing HERV-W gag sequence from the putative gene PTD015 on chromosome 11q13.5 (1.6-fold, P < 0.05) in the patients compared with the controls. Thus, studies aiming to further understanding of complex human disease such as schizophrenia may need to be extended beyond the strictly protein-coding fraction of the transcriptome.
Assuntos
Retrovirus Endógenos/genética , Transtornos Psicóticos/virologia , Esquizofrenia/virologia , Transcrição Gênica/genética , Cromossomos Humanos Par 11 , Perfilação da Expressão Gênica , Regulação Viral da Expressão Gênica/fisiologia , Produtos do Gene gag/genética , Humanos , Íntrons/genética , Linfócitos/virologia , Transtornos Psicóticos/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Esquizofrenia/genética , Análise de Sequência de DNA , Proteínas do Envelope Viral/genéticaRESUMO
In renal epithelia, vasopressin influences salt and water transport, chiefly via vasopressin V(2) receptors (V(2)Rs) linked to adenylyl cyclase. A combination of vasopressin-induced effects along several distinct portions of the nephron and collecting duct system may help balance the net effects of antidiuresis in cortex and medulla. Previous studies of the intrarenal distribution of V(2)Rs have been inconclusive with respect to segment- and cell-type-related V(2)R expression. Our study therefore aimed to present a high-resolution analysis of V(2)R mRNA expression in rat, mouse, and human kidney epithelia, supplemented with immunohistochemical data. Cell types of the renal tubule were identified histochemically using specific markers. Pronounced V(2)R signal in thick ascending limb (TAL) was corroborated functionally; phosphorylation of Na(+)-K(+)-2Cl(-) cotransporter type 2 (NKCC2) was established in cultured TAL cells from rabbit and in rats with diabetes insipidus that were treated with the V(2)R agonist desmopressin. We found solid expression of V(2)R mRNA in medullary TAL (MTAL), macula densa, connecting tubule, and cortical and medullary collecting duct and weaker expression in cortical TAL and distal convoluted tubule in all three species. Additional V(2)R immunostaining of kidneys and rabbit TAL cells confirmed our findings. In agreement with strong V(2)R expression in MTAL, kidneys from rats with diabetes insipidus and cultured TAL cells revealed sharp, selective increases in NKCC2 phosphorylation upon desmopressin treatment. Macula densa cells constitutively showed strong NKCC2 phosphorylation. Results suggest comparably significant effects of vasopressin-induced V(2)R signaling in MTAL and in connecting tubule/collecting duct principal cells across the three species. Strong V(2)R expression in macula densa may be related to tubulovascular signal transfer.
Assuntos
Células Epiteliais/metabolismo , Medula Renal/metabolismo , Alça do Néfron/metabolismo , Receptores de Vasopressinas/metabolismo , Adenilil Ciclases/metabolismo , Animais , Antidiuréticos/farmacologia , Células Cultivadas , Desamino Arginina Vasopressina/farmacologia , Humanos , Córtex Renal/citologia , Córtex Renal/metabolismo , Medula Renal/citologia , Túbulos Renais Coletores/citologia , Túbulos Renais Coletores/metabolismo , Alça do Néfron/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/metabolismo , Distribuição Aleatória , Ratos , Ratos Brattleboro , Ratos Wistar , Simportadores de Cloreto de Sódio-Potássio/metabolismo , Membro 1 da Família 12 de Carreador de SolutoRESUMO
Early kidney development is associated with the coordinated branching of the renal tubular and vascular system and hypoxia has been proposed to be a major regulatory factor in this process. Under low oxygen levels, the hypoxia-inducible transcription factor (HIF) regulates the expression of genes involved in angiogenesis, erythropoiesis and glycolysis. To investigate the role of HIF in kidney development, we analyzed the temporal and spatial expression of the oxygen regulated HIF-1alpha and -2alpha subunits at different stages of rat and human kidney development. Using double-staining procedures, localization of the HIF target geneproducts vascular endothelial growth factor (VEGF) and endoglin was studied in relation to HIFalpha. In both species, we found marked nuclear expression of HIF-1alpha in medullary and cortical collecting ducts and in glomerular cells. In contrast, HIF-2alpha was expressed in interstitial and peritubular cells podocytes of the more mature glomeruli. After completion of glomerulogenesis and nephrogenesis, HIF-1alpha and -2alpha were no longer detectable. The HIF-target gene VEGF colocalized with HIF-1alpha protein in glomeruli and medullary collecting ducts. HIF-2alpha colocalized with the endothelium-associated angiogenic factor, endoglin. Both HIFalpha isoforms are activated in the developing kidney in a cell-specific and temporally controlled manner, indicating a regulatory role of oxygen tension in nephrogenesis. HIF-1alpha seems to be primarily involved in tubulogenesis and HIF-2alpha in renal vasculogenesis. Both isoforms are found in glomerulogenesis, potentially having synergistic effects.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/análise , Subunidade alfa do Fator 1 Induzível por Hipóxia/análise , Rim/química , Rim/embriologia , Animais , Antígenos CD , Fatores de Transcrição Hélice-Alça-Hélice Básicos/fisiologia , Endoglina , Humanos , Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/análise , Masculino , Ratos , Ratos Sprague-Dawley , Receptores de Superfície Celular , Molécula 1 de Adesão de Célula Vascular/análise , Fator A de Crescimento do Endotélio Vascular/análiseRESUMO
It is generally accepted that iron homeostasis is mainly controlled in the gastrointestinal tract by absorption of dietary iron. However, recent studies have shown that the kidneys are also involved in iron metabolism. Since the iron-regulatory and antimicrobial peptide hormone hepcidin was originally isolated from human urine we have investigated the expression as well as the zonal and cellular localization of hepcidin in the mammalian kidney and developed an ELISA assay to analyze hepcidin concentrations in serum and urine. The expression of hepcidin was shown by RT-PCR and immunoblot experiments; its cellular localization was studied by immunocytochemistry in human, mouse and rat kidney, which revealed similar patterns of immunoreactivity. Hepcidin expression was absent from the proximal tubule and descending and ascending thin limbs. There was strong expression in the thick ascending limb of the cortex and in connecting tubules. Moderate expression was noted in the thick ascending limb and collecting ducts of the medulla and in collecting ducts of the papilla. Importantly, the cells of the macula densa were unstained. At the cellular level, hepcidin was localized to the apical cell pole of the renal epithelial cells. Based on its presence in urine, hepcidin may be released apically into the urine. Enhanced levels of hepcidin were determined in patients with chronic renal insuffciency (156.8 ng/ml, controls 104.2 ng/ml) indicating that the kidneys may metabolize and/or eliminate the circulating peptide. From the expression of hepcidin in the mammalian kidney, we have concluded that the iron-regulatory hormone is an intrinsic renal peptide which is not only eliminated by the kidney but is also synthesized in the kidney tubular system. Localization of hepcidin in the kidney implicates an iron-regulatory role of this peptide hormone in the renal tubular system, possibly in connection with the iron transporter divalent metal transporter-1.
Assuntos
Peptídeos Catiônicos Antimicrobianos/análise , Rim/química , Adulto , Animais , Peptídeos Catiônicos Antimicrobianos/biossíntese , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática/métodos , Células Epiteliais/química , Feminino , Hepcidinas , Homeostase , Humanos , Immunoblotting , Imuno-Histoquímica/métodos , Ferro/metabolismo , Rim/metabolismo , Falência Renal Crônica/metabolismo , Túbulos Renais/química , Túbulos Renais/metabolismo , Fígado/química , Fígado/metabolismo , Masculino , Camundongos , Ratos , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
BACKGROUND: Laparoscopic surgery for patients with cancer has been debated because of the susceptibility that laparoscopic incisions have shown for metastatic tumor growth. Structural damage of the mesothelial layer attributable to the pneumoperitoneum may facilitate intraabdominal tumor cell adhesion and growth. The influence of carbon dioxide (CO(2)) and helium pneumoperitoneum on the morphology of the peritoneum was examined. METHODS: A total of 50 rats received colon carcinoma (DHB/TRb) cells intraperitoneally and CO(2) (n = 25) or helium (n = 25) pneumoperitoneum at 15 mmHg for 15 min. After different periods (2, 12, 24, 48, and 96 h), the rats were killed, and the peritoneum was examined by scanning electron microscopy. Control animals (n = 5) were without pneumoperitoneum. RESULTS: The control animals and most of the rats with pneumoperitoneum showed no peritoneal alterations. In four animals of each group, inflammatory alterations of the peritoneum such as bulging and retraction of mesothelial cells were observed at different time points. Tumor cells adherent to the peritoneum were found in a total of six animals. Peritoneal carcinomatosis, tumor nodules, or infiltration of the peritoneum by tumor cells was not observed. CONCLUSIONS: The study demonstrated that the morphologic integrity of the rat peritoneum is not disturbed when CO(2) or helium is used for insufflation combined with the intraperitoneal injection of carcinoma cells. Pneumoperitoneum therefore probably is not the condition causing peritoneal changes that favor intraperitoneal tumor growth.
Assuntos
Dióxido de Carbono/farmacologia , Hélio/farmacologia , Laparoscopia , Peritônio/efeitos dos fármacos , Peritônio/patologia , Pneumoperitônio Artificial , Animais , Neoplasias do Colo/patologia , Masculino , Microscopia Eletrônica de Varredura , Transplante de Neoplasias/patologia , Pneumoperitônio Artificial/métodos , RatosRESUMO
The presence of distant metastases is the main prognostic factor in patients with breast cancer and has a significant influence in the choice of therapy. Therefore, chest X-ray, bone scintigraphy and ultrasound of the abdomen are performed to detect distant metastases at diagnosis and follow-up. Fluorodeoxyglucose positron emission tomography (FDG PET) has been shown to provide sensitive detection of primary tumour and metastases for many tumour entities, but little information is available about the diagnostic value for breast cancer patients. This study retrospectively compared FDG PET for detection of metastatic disease with chest X-ray, bone scintigraphy and ultrasound of the abdomen, referred to as "conventional diagnostic procedures" (CDPs), in 50 breast cancer patients. Imaging procedures were analysed in a blinded fashion with the results classified as "no evidence of metastases", "equivocal" and "evidence of metastases". Clinical follow-up and the results of other imaging modalities including computed tomography and magnetic resonance imaging were used to determine if metastases were present. FDG PET identified metastatic disease with a sensitivity and specificity of 86% and 90% as compared to 36% and 95% for CDPs, respectively. Regarding "equivocal" and "evidence of metastases" as positive, the sensitivity of CDPs increased to 57% with a corresponding specificity of 81%, whereas sensitivity and specificity of FDG PET remained unchanged. Regarding different localities of metastases the sensitivity of FDG PET was superior in the detection of pulmonary metastases and especially of lymph node metastases of the mediastinum in comparison to chest X-ray, whereas the sensitivity of FDG PET in the detection of bone and liver metastases was of the same magnitude as compared with bone scintigraphy and ultrasound of the abdomen.
Assuntos
Neoplasias da Mama/diagnóstico , Carcinoma Ductal de Mama/diagnóstico , Carcinoma Ductal de Mama/secundário , Carcinoma Lobular/diagnóstico , Carcinoma Lobular/secundário , Diagnóstico por Imagem/métodos , Tomografia Computadorizada de Emissão , Adulto , Idoso , Idoso de 80 Anos ou mais , Reações Falso-Negativas , Reações Falso-Positivas , Feminino , Fluordesoxiglucose F18 , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Compostos Radiofarmacêuticos , Estudos Retrospectivos , Sensibilidade e Especificidade , Método Simples-CegoRESUMO
OBJECTIVE: The experience of pregnancy is mainly influenced by the availability of prenatal screening procedures. Previous screening studies focus on somatic abnormalities. The psychological experience of the parents-to-be recedes into the background. The purpose of the present study was to analyze the emotional mood of pregnant women and their partners before and their psychological stress before and after different prenatal screening procedures (ultrasound, chorionic villus sampling or amniocentesis). METHODS: In the study, 140 pregnant women, and, in 108 cases, their partners, were asked to complete questionnaires before and immediately after the prenatal testing. Depending on the applied prenatal procedure, the subjects were assigned to: the invasive group (amniocentesis or chorionic villus sampling) and the noninvasive group (ultrasound group). We used the German version of the Centre for Epidemiological Studies-Depression Scale of Hautzinger and the short questionnaire of actual situative perceived stress of Müller. RESULTS: Before the prenatal examination, the mean level of depression of pregnant women was the highest in the noninvasive group compared to the invasive group, although the between-group difference was not significant. However, for their male partners, the mean level of depression was significantly different between the noninvasive and the invasive groups. Furthermore, women undergoing invasive diagnostic or noninvasive diagnostic procedures were significantly more depressed than their partners. The analysis of the actual stress ratings showed a significant reduction from the prescreening to the postscreening stress for pregnant women and their partners in both groups. CONCLUSIONS: This study reveals that the individual experience of prenatal diagnosis is not determined by the invasiveness of the procedure. Immediate visual presentation of the fetus and confirmation of a normal test result reduce stress that has previously been induced by the prenatal test itself. This contradiction should be discussed with the parents.