RESUMO
BACKGROUND: People discharged from in-patient psychiatric facilities have highly elevated rates of suicide, and there is increasing concern about natural mortality among the seriously mentally ill. METHOD: A meta-analysis of English-language, peer-reviewed longitudinal studies of mortality among patients discharged from in-patient psychiatric facilities was conducted using papers published in MEDLINE, PsycINFO or EMBASE (from 1 January 1960 to 1 April 2018) located using the terms ((suicid*).ti AND (hospital OR discharg* OR inpatient OR in-patient OR admit*)).ab and ((mortality OR outcome* OR death*) AND (psych* OR mental*)).ti AND (admit* OR admis* OR hospital* OR inpatient* OR in-patient* OR discharg*).ab. Pooled mortality rates for aggregated natural and unnatural causes, and the specific causes of suicide, accident, homicide, vascular, neoplastic, respiratory, gastrointestinal, infectious and metabolic death were calculated using a random-effects meta-analytic model. Between-study heterogeneity was investigated using subgroup analysis and metaregression. RESULTS: The pooled natural death rate of 1128 per 100 000 person-years exceeded the pooled unnatural deaths of 479 per 100 000 person-year among studies with varying periods of follow-up. Natural deaths significantly exceeded unnatural deaths among studies with a mean follow-up of longer than 2 years, and vascular deaths exceeded suicide deaths among studies with mean period of follow-up of 5 years or longer. CONCLUSION: Suicide may be the largest single cause of death in the short term after discharge from in-patient psychiatric facilities but vascular disease is the major cause of mortality in the medium- and long-term.
Assuntos
Doenças Cardiovasculares , Causas de Morte , Transtornos Mentais , Alta do Paciente , Suicídio , Doenças Cardiovasculares/mortalidade , Humanos , Transtornos Mentais/epidemiologia , Alta do Paciente/estatística & dados numéricos , Suicídio/estatística & dados numéricosRESUMO
OBJECTIVE: Toe systolic pressure is a component of the standard vascular and diabetic foot assessment. Until now,clinicians have measured only first toe pressure given a lack of evidence for measurements of the other toes. In diabetic patients, first toe measurements are often not possible because of ulceration or amputation. It was hypothesized that the adjacent second toe systolic pressure measurements would be interchangeable with those of the first toe. METHODS: A prospective study was performed on 100 participants with diabetes mellitus. Duplicate systolic toe pressures were measured in the first toe and adjacent second toe using the Systoe Automated Toe Pressure System, Systoe Photophlethysmograph Sensor Cuff, and occlusion cuffs measuring 120 x 25 mm for the first toe and 90 x 15 mm for the second toe. Correlation analysis was followed by Ordinary Least Products regression to detect and distinguish fixed and proportional bias between the two toe measurements. The acceptable limits of interchangeable results were defined as 5-10 mmHg. RESULTS: Correlation coefficient r » 0.908; p < 0.001. Eighty-two percent of the variations in the second toe measurements were accounted for by knowing the first toe measurements and vice versa. Ordinary Least Products regression showed no fixed or proportional bias between the two methods of measurement: second toe systolic pressure = (-0.579) + (1.038) * first toe systolic pressure. Repeatability analysis showed a 0.5%variation between duplicate measurements. CONCLUSIONS: This is the first study which demonstrates that second toe systolic pressures are interchangeable with those of the first toe. Second toe pressures can be used in diabetic patients whose first toe pressures cannot be assessed.
Assuntos
Determinação da Pressão Arterial/métodos , Diabetes Mellitus/fisiopatologia , Pé Diabético/diagnóstico , Doença Arterial Periférica/diagnóstico , Dedos do Pé/irrigação sanguínea , Adulto , Idoso , Idoso de 80 Anos ou mais , Determinação da Pressão Arterial/instrumentação , Angiopatias Diabéticas/diagnóstico , Angiopatias Diabéticas/fisiopatologia , Pé Diabético/fisiopatologia , Desenho de Equipamento , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/fisiopatologia , Estudos Prospectivos , Reprodutibilidade dos Testes , SístoleAssuntos
Coristoma/patologia , Doenças do Esôfago/patologia , Esofagoscopia/métodos , Glândulas Sebáceas , Adulto , Biópsia por Agulha , Doenças do Esôfago/diagnóstico , Feminino , Seguimentos , Refluxo Gastroesofágico/diagnóstico , Refluxo Gastroesofágico/tratamento farmacológico , Humanos , Imuno-Histoquímica , Doenças Raras , Medição de RiscoRESUMO
Lipoprotein lipase deficiency causes severe hypertriglyceridaemia due to chylomicronaemia, and leads to recurrent and potentially life-threatening pancreatitis. This disorder can only be managed by dietary fat restriction as drugs are ineffective. We review the experience with familial chylomicronaemia in patients who attended the lipid clinics at Groote Schuur Hospital and Red Cross Children's War Memorial Hospital in Cape Town. Criteria for inclusion were an initial plasma triglyceride concentration of >15 mmol/l and a typical type I Fredrickson hyperlipidaemia pattern on plasma lipoprotein electrophoresis. A total of 29 patients were seen over 25 years. The mean age of presentation was 10 years, but ranged from 0 to 43 years. The modes of presentation differed: pancreatitis (N=16), eruptive xanthomata (N=2), coincidental detection of hypertriglyceridaemia (N=2), screening relatives (N=7), and after death from pancreatitis (N=1). Plasma triglycerides responded rapidly and dramatically to dietary fat restriction, and some patients sustained good control of the hyperlipidaemia. The onset of pancreatitis was earlier in patients of Indian ancestry, suggesting a genotype/phenotype interaction within this disorder. Genetic work-up indicated founder effects in the Afrikaner and Indian patients. Lipaemic plasma should be taken seriously at all ages, and necessitates work-up at specialised clinics where the diagnosis of chylomicronaemia or type I hyperlipidaemia facilitates appropriate dietary management that can prevent pancreatitis.
Assuntos
Hiperlipoproteinemia Tipo I/complicações , Hiperlipoproteinemia Tipo I/epidemiologia , Hipertrigliceridemia/epidemiologia , Hipertrigliceridemia/etiologia , Adolescente , Adulto , Criança , Pré-Escolar , Dieta com Restrição de Gorduras , Feminino , Efeito Fundador , Humanos , Hipertrigliceridemia/terapia , Achados Incidentais , Lactente , Recém-Nascido , Masculino , Programas de Rastreamento , Mutação , Pancreatite/epidemiologia , Pancreatite/etiologia , Grupos Raciais , África do Sul/epidemiologia , Xantomatose/epidemiologia , Xantomatose/etiologiaRESUMO
BACKGROUND AND OBJECTIVE: Regulation of epithelial cell behavior associated with periodontitis is not well elucidated but many responses will ultimately be regulated by growth factor receptors. Using a rat experimental periodontitis model, protein and gene expression of select growth factor receptors in junctional and pocket epithelium were examined. MATERIAL AND METHODS: Periodontal disease was induced by daily topical application of lipopolysaccharide using an established protocol. Animals were killed at time 0 (control), and at 2 and 8 wk. Frozen tissue samples were collected from the right palatal gingival soft tissue, and the left periodontal tissues were decalcified and embedded in paraffin. Laser microdissection and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to quantify keratinocyte growth factor receptor (KGFR), hepatocyte growth factor receptor (HGFR), epidermal growth factor receptor (EGFR) and fibroblast growth factor receptor 1 (FGFR1) gene expression, and in situ RT-PCR localized these increases to specific epithelial cells. Receptor protein expression was examined immunohistochemically. In cell culture, induction of HGFR and KGFR protein expression by serum, lipopolysaccharide and pro-inflammatory cytokines were examined using flow cytometry. RESULTS: Eight-week tissue samples exhibited histological changes consistent with periodontitis. KGFR and HGFR gene and protein expression were significantly induced at the 8 wk time point. KGFR expression was significantly up-regulated in basal and parabasal pocket epithelial cells, but HGFR was up-regulated throughout the pocket epithelium. In cell culture serum, lipopolysaccharide and pro-inflammatory cytokines, interleukin-1beta and tumour necrosis factor-alpha significantly induced KGFR protein receptor expression, but HGFR expression was only induced by serum. CONCLUSION: KGFR and HGFR are highly up-regulated in this model of periodontal disease and may play a significant role in regulating the proliferation and migration of pocket epithelium.
Assuntos
Inserção Epitelial/metabolismo , Bolsa Periodontal/metabolismo , Receptores Proteína Tirosina Quinases/biossíntese , Animais , Inserção Epitelial/citologia , Células Epiteliais/metabolismo , Citometria de Fluxo , Regulação Enzimológica da Expressão Gênica , Imuno-Histoquímica , Interleucina-1/metabolismo , Lipopolissacarídeos/metabolismo , Masculino , Proteínas Proto-Oncogênicas c-met/biossíntese , Ratos , Ratos Wistar , Receptores Proteína Tirosina Quinases/análise , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/biossíntese , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/agonistas , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Suínos , Fator de Necrose Tumoral alfa/metabolismo , Regulação para CimaRESUMO
Maintenance of the specialised environment of the central nervous system requires barriers provided by the endothelium of brain microvessels (the blood-brain barrier (BBB)) or the epithelium lining the ventricles (CSF-brain barrier) or the choroid plexus (blood-CSF barrier). Inter-endothelial junctions are more extensive in the BBB than in other tissues, with elaborate tight junctions. However, few differences in the molecular composition of these junctions have been described. Here, we show, in both human and mouse brain, that the type II classical cadherin, cadherin-10, is expressed in BBB and retinal endothelia, but not in the leaky microvessels of brain circumventricular organs (CVO), or in those of non-CNS tissues. This expression pattern is distinct from, and reciprocal to, VE-cadherin, which is reduced or absent in tight cortical microvessels, but present in leaky CVO vessels. In CVO, the barrier function is switched from the microvasculature to the adjacent ventricular epithelium, which we also find to express cadherin-10. In the vessels of gliobastoma multiforme tumours, where BBB is lost, cadherin-10 is not detected. This demonstration of a distinctive expression pattern of cadherin-10 suggests that it has a pivotal role in the development and maintenance of brain barriers.
Assuntos
Barreira Hematoencefálica/metabolismo , Caderinas/metabolismo , Artérias Cerebrais/metabolismo , Células Endoteliais/metabolismo , Animais , Antígenos CD/metabolismo , Barreira Hematoencefálica/citologia , Neoplasias Encefálicas/metabolismo , Artérias Cerebrais/citologia , Ventrículos Cerebrais/citologia , Ventrículos Cerebrais/metabolismo , Células Endoteliais/citologia , Feminino , Glioblastoma/metabolismo , Humanos , Camundongos , Invasividade Neoplásica/fisiopatologia , Artéria Retiniana/citologia , Artéria Retiniana/metabolismo , Órgão Subfornical/citologia , Órgão Subfornical/metabolismoRESUMO
Familial hypercholesterolaemia is a clinical entity comprising high concentrations of low density lipoproteins, tendinous deposition of cholesterol in a large proportion of affected subjects, and a propensity for the development of atherosclerosis and its complications in the coronary arteries. The aim of this review is to integrate publications with clinical experience into a concise profile of the disorder and its management. In less than a century this disease has been recognised, its lipoprotein derangement identified and numerous causal mutations have been detected. Although the phenotype is most commonly due to the occurrence of mutations in the low density lipoprotein receptor, defects in the apolipoprotein B100 may result in a similar phenotype. The same phenotype has also been linked to a gene and its product, PCSK9 and NARC1, that may be involved in the regulation of cholesterol in the cell. In the past few decades statins, by inhibiting cholesterol synthesis at the rate-limiting enzyme (hydroxymethylglutaryl coenzyme A reductase) have been developed and proven safe and effective in reducing the low density lipoprotein cholesterol, promoting regression and reducing mortality and morbidity. Additionally, advances in imaging techniques are allowing non-invasive insights into the impact of the disease on atherosclerosis. For these reasons there should be a high index of suspicion for this treatable condition in which genetic therapy and further modulation of atherosclerosis can be expected in the future.
Assuntos
Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/terapia , Diagnóstico Diferencial , Humanos , Hiperlipoproteinemia Tipo II/fisiopatologiaRESUMO
We investigated the expression and activity of arginine transporters and endothelial nitric oxide synthase (eNOS) in human placental microvascular endothelial cells (HPMEC). Using RT-PCR amplification products for eNOS, CAT1, CAT2A, CAT2B, CAT4, 4F2hc (CD98), rBAT and the light chains y+LAT1, y+LAT2, and b0+T1 were detected in HPMEC, but not B0+. Immunohistochemistry and Western blotting confirmed the presence of 4F2hc and CAT1 protein in HPMEC. 4F2hc-light chain dimers were indicated by a shift in molecular mass detected under nonreducing conditions. L-Arginine transport into HPMEC was independent of Na+ or Cl- and was inhibited by the neutral amino acid glutamine, but not by cystine. The Ki for glutamine inhibition was greater in the absence of Na+. Kinetic analysis supported a two-transporter model attributed to system y+L and system y+. Expression of eNOS in HPMEC was detectable by immunohistochemistry and ELISA but not by Western blotting. Activity of eNOS in HPMEC, measured over 48 h, either as the basal production of nitric oxide (NO) or as the accumulation of intracellular cGMP was not detectable. We conclude that HPMEC transport cationic amino acids by systems y+ and y+L and that basal eNOS expression and activity in these cells is low.
Assuntos
Sistemas de Transporte de Aminoácidos Básicos/metabolismo , Arginina/metabolismo , Endotélio Vascular/metabolismo , Óxido Nítrico Sintase/metabolismo , Placenta/irrigação sanguínea , Sistemas de Transporte de Aminoácidos Básicos/genética , Transporte Biológico , Capilares/citologia , Células Cultivadas , Endotélio Vascular/enzimologia , Cadeia Pesada da Proteína-1 Reguladora de Fusão/metabolismo , Humanos , Óxido Nítrico Sintase Tipo III , RNA Mensageiro/metabolismo , Transcrição GênicaRESUMO
Anterior sacral meningoceole is a rare occurrence and presentation as a perianal abscess has not been previously reported. The case is presented and the condition discussed. The potential risks of failing to establish the diagnosis, prior to surgery, are outlined.
Assuntos
Abscesso/etiologia , Doenças do Ânus/etiologia , Meningocele/diagnóstico , Meningocele/cirurgia , Adulto , Diagnóstico Diferencial , Humanos , Região Lombossacral , Imageamento por Ressonância Magnética , Masculino , Meningocele/complicações , Tomografia Computadorizada por Raios XRESUMO
Matrilysin is a matrix metalloproteinase expressed in exocrine and mucosal epithelium in many human tissues. Immunohistochemical staining showed that matrilysin is expressed in suprabasal cells of junctional epithelium facing the teeth and in epithelial cell rests of Malassez. No matrilysin expression was seen in the periodontal pocket tissue. In a tissue culture model mimicking junctional epithelium, matrilysin expression was also observed in suprabasal epithelial cells. Of 13 anaerobic oral bacterial species tested, F. nucleatum, F. necrophorum, P. endodontalis, and P. denticola stimulated matrilysin expression in porcine periodontal ligament epithelial cells from 2.5- to 5.7-fold, compared with untreated cells. The enzyme was localized in intracytoplasmic vesicles that also reacted with antibodies against lysosomal membrane protein h-lamp-1. The results indicate that matrilysin may play an important role in the normal physiology of junctional epithelium.
Assuntos
Inserção Epitelial/enzimologia , Metaloproteinase 7 da Matriz/biossíntese , Ligamento Periodontal/enzimologia , Adolescente , Adulto , Animais , Bactérias Anaeróbias/imunologia , Northern Blotting , Células Cultivadas , Vesículas Citoplasmáticas/enzimologia , Células Epiteliais/enzimologia , Feminino , Regulação Enzimológica da Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Mucosa Bucal/enzimologia , Ligamento Periodontal/citologia , Suínos , Regulação para CimaRESUMO
Homozygous familial hypercholesterolemia is a rare disorder resulting in severe premature atherosclerosis. Drug therapy was previously viewed as inadequate for control of the dyslipidemia, so portacaval shunting, plasmapheresis, and liver transplantation were undertaken to treat this condition. Despite these drastic measures, additional cholesterol-lowering treatment may still be required. Furthermore, there is a need for pharmacologic control until additional measures can be undertaken. The statins, an evolving class of cholesterol-modifying drugs, represent a significant development in the treatment of homozygous familial hypercholesterolemia. The experience with statins in this condition is limited, but some insight into their utility has been gained from studies reviewed in this article. It is recommended that high doses of statins be used in combination with other lipid-modifying strategies for the best control of the dyslipidemia of homozygous familial hypercholesterolemia.
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Ensaios Clínicos como Assunto , Homozigoto , Humanos , Resultado do TratamentoRESUMO
Endothelial adherens junctions (AJ) and tight junctions (TJ) are important determinants of vascular permeability and cell morphology. Here, we investigate their regulation, in primary human placental microvascular endothelial cell (HPMEC) cultures, by either aFGF plus heparin (ECGS) or elevated cAMP. The proliferation of HPMEC was weakly stimulated by ECGS, while cAMP was inhibitory. ECGS had little effect on transendothelial resistance (TER), but increased macromolecular permeability, whereas cAMP induced a twofold increase in TER and reduced macromolecular permeability. Ultrastructurally, ECGS-treated HPMEC exhibited an "activated" phenotype typified by proliferating cells, with poorly organized cell-cell junctions, whereas cAMP-treated cells appeared quiescent and markedly flattened with extended paracellular junctions, resembling endothelium in situ. The expression and localization of junctional molecules, F-actin, and junctional phosphotyrosine were examined by confocal microscopy and immunoblotting. Junctional molecules in ECGS-treated cells were less organized at lateral membranes than in control cells, whereas in cAMP-treated cells, they were highly localized at continuous contacts. These differences correlated with the intensity of junctional phosphotyrosine, being lowest with cAMP treatment. In the AJ of ECGS-treated and control cells, beta-catenin predominated but in cAMP-treated cells, gamma-catenin/plakoglobin was enriched. In addition, cAMP upregulated junctional expression of VE-cadherin and PECAM-1 and increased the levels of the TJ molecules occludin and ZO-1. The expression levels of junctional components, and their tyrosine phosphorylation, play an important role in dynamic regulation of endothelial cell-cell junctions.
Assuntos
Junções Aderentes/metabolismo , AMP Cíclico/farmacologia , Endotélio Vascular/efeitos dos fármacos , Fator 1 de Crescimento de Fibroblastos/farmacologia , Junções Íntimas/metabolismo , Actinas/metabolismo , Junções Aderentes/efeitos dos fármacos , Junções Aderentes/ultraestrutura , Caderinas/metabolismo , Permeabilidade Capilar , Adesão Celular/fisiologia , Divisão Celular/efeitos dos fármacos , Divisão Celular/fisiologia , Tamanho Celular/efeitos dos fármacos , Extensões da Superfície Celular/metabolismo , Extensões da Superfície Celular/ultraestrutura , Células Cultivadas , Meios de Cultura Livres de Soro , Proteínas do Citoesqueleto/metabolismo , Impedância Elétrica , Endotélio Vascular/metabolismo , Endotélio Vascular/ultraestrutura , Feminino , Humanos , Proteínas de Membrana/metabolismo , Microcirculação , Microscopia de Fluorescência , Ocludina , Fosfoproteínas/metabolismo , Placenta/irrigação sanguínea , Placenta/citologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Gravidez , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/ultraestrutura , Proteína da Zônula de Oclusão-1RESUMO
The placental endothelium contributes to regulating transplacental exchange and maintaining the immunological maternofetal barrier. We characterized the endothelial phenotype in human normal term placentae with a panel of antibodies to endothelial antigens using a standardized immunofluorescence method. Placental endothelium strongly expressed vWF, PAL-E, H-antigen, thrombomodulin, PECAM-1, CD34, CD36, ICAM-1, CD44, thy-1, A10/33-1, VE-cadherin, caveolin-1 and HLA-G, whereas occludin, claudin-1, eNOS, angiotensin converting enzyme (ACE), ICAM-2, endoglin and integrin-alphathetabeta(3)were weakly expressed. PGI(2)synthase, tissue factor, E-selectin and VCAM-1 were not detected. Some antigens were heterogenously expressed along the vascular tree or within individual villi. Expression of ACE, eNOS, vWF, P-selectin, E-selectin, integrin alpha(v)beta(3)and endoglin was stronger in the maternal decidual vessels, while PECAM-1, CD44, thy-1 and caveolin-1 expression was stronger in fetal vessels. Some endothelial markers were present in trophoblasts and stroma. Endothelial proliferation was apparent in mature intermediate and terminal villi. There was limited inflammatory response to TNFalpha in explants, characterized by upregulation of vWF, P-selectin, PECAM-1 and CD44, downregulation of thrombomodulin, but no increase in ICAM-1 expression, nor induction of E-selectin, VCAM-1 or tissue factor. These patterns of heterogeneity, proliferative activity and inflammatory activation may underlie the specific physiological roles of the placental endothelium.
Assuntos
Endotélio Vascular/citologia , Placenta/irrigação sanguínea , Adulto , Biomarcadores/análise , Moléculas de Adesão Celular/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Técnicas de Cultura de Órgãos , Fenótipo , Gravidez , Antígeno Nuclear de Célula em Proliferação/metabolismo , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
ELOXATIN (Oxaliplatin) is a novel platinum containing anti-cancer agent with a diaminocyclohexane carrier ligand which has been approved in several major European countries. Clinical studies have demonstrated that the compound exhibits marked activity against colorectal cancers in combination with 5-fluorouracil (5-FU). The aim of this work was to develop and validate a highly sensitive inductively coupled plasma mass spectrometry assay for the determination of oxaliplatin-derived platinum in plasma ultrafiltrate, plasma and whole blood and to apply this technique to clinical pharmacokinetic studies with oxaliplatin. Ultratrace detection of platinum in plasma ultrafiltrate was achieved using ultrasonic nebulisation combined with ICP-MS. This technique allows detection of platinum at the 0.001 microg Pt/ml level in only 100 microl of matrix. Assays in blood and plasma utilised a standard Meinhardt nebuliser and spray chamber, achieving detection limits of 0.1 microg Pt/ml in 100 and 200 microl of matrix, respectively. The assays were validated (accuracy and precision within +/- 15%) over the concentration ranges: 0.001-0.250 microg Pt/ml in plasma ultrafiltrate and 0.1-10 microg Pt/ml for plasma and whole blood. The effect of sample digestion. dilution, long term frozen storage and quantitation in the presence of 5-FU were also investigated and validated. The method was used to monitor platinum exposure following oxaliplatin administration (130 mg/m2) to cancer patients. Following a 2 h i.v. infusion, peak platinum levels declined in a triphasic manner in all blood compartments. Free platinum was detected in plasma ultrafiltrate at low levels (0.001 0.010 microg Pt/ml) for up to 3 weeks. In conclusion, a highly sensitive and specific assay has been developed for the determination of platinum in biofluids. This method enabled characterisation of the long term exposure to platinum in patients following oxaliplatin treatment.
Assuntos
Antineoplásicos/farmacocinética , Compostos Organoplatínicos/farmacocinética , Platina/sangue , Humanos , Espectrometria de Massas , Oxaliplatina , Sensibilidade e EspecificidadeRESUMO
The mechanism underlying a transition of the oral cavity mucosal epithelium towards susceptibility to opportunistic infections in HIV-seropositive patients was investigated. Phenotypic markers CD1a, HLA-DR, and CD86 of oral mucosal Langerhans' cells (LCs), p17 core protein of human immunodeficiency virus (HIV), and CD45RO of memory T cells were labeled on oral hairy leukoplakia lesional biopsies and clinically normal autologous tissue of HIV-infected patients. HIV p17 protein was detected in association with mucosal LCs, mainly within the lesional epithelium. There were significant correlations between the detection of HIV p17 and the depletion of LCs, and between the depletion of LCs and the presence of hairy leukoplakia lesions. Conjugates of activated LCs and memory T cells were also evident in the submucosal area of lesional biopsies. The findings from this study support the hypothesis that oral mucosal LCs are also the target of HIV infection. Cytopathic changes of LCs caused by productive HIV infection may contribute to selective depletion of LCs, which may impair the mucosal immunologic protection against colonization by microorganisms causing HIV-associated oral mucosal lesions.
Assuntos
Infecções por HIV/patologia , HIV/fisiologia , Células de Langerhans/virologia , Mucosa Bucal/patologia , Infecções Oportunistas Relacionadas com a AIDS/patologia , Antígenos CD/análise , Antígenos CD1/análise , Antígeno B7-2 , Efeito Citopatogênico Viral , Suscetibilidade a Doenças , Células Epiteliais/imunologia , Células Epiteliais/virologia , HIV/imunologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , Soronegatividade para HIV , Soropositividade para HIV/patologia , Antígenos HLA-DR/análise , Humanos , Memória Imunológica , Células de Langerhans/imunologia , Antígenos Comuns de Leucócito/análise , Leucoplasia Pilosa/patologia , Masculino , Glicoproteínas de Membrana/análise , Mucosa Bucal/imunologia , Mucosa Bucal/virologia , Fenótipo , Estatísticas não Paramétricas , Linfócitos T/patologia , Proteínas do Core Viral/análiseRESUMO
Patients with homozygous familial hypercholesterolaemia (HoFH) have markedly elevated low density lipoprotein (LDL) cholesterol levels that are refractory to standard doses of lipid-lowering drug therapy. In the present study we evaluated the effect of atorvastatin on steady state concentrations of plasma lipids and mevalonic acid (MVA), as well as on 24-h urinary excretion of MVA in patients with well characterized HoFH. Thirty-five HoFH patients (18 males; 17 females) received 40 mg and then 80 mg atorvastatin/day. The dose of atorvastatin was increased further to 120 mg/day in 20 subjects and to 160 mg/day in 13 subjects who had not achieved LDL cholesterol goal, or in whom the dose of atorvastatin had not exceeded 2.5 mg/kg body wt per day. LDL cholesterol levels were reduced by 17% at the 40 mg/day and by 28% at the 80 mg/day dosage (P<0.01). Reduction in LDL cholesterol in the five receptor negative patients was similar to that achieved in the 30 patients with residual LDL receptor activity. Plasma MVA and 24-h urinary excretion of MVA, as markers of in vivo cholesterol synthesis, were elevated at baseline and decreased markedly with treatment. Urinary MVA excretion decreased by 57% at the 40 mg/day dose and by 63% at the 80 mg/day dosage (P<0. 01). There was a correlation between reduction in LDL cholesterol and reduction in urinary MVA excretion; those patients with the highest basal levels of MVA excretion and thus the highest rates of cholesterol synthesis having the greatest reduction in LDL cholesterol (r=0.38; P=0.02). Increasing the dose of atorvastatin to 120 and 160 mg/day did not result in any further reduction in LDL cholesterol or urinary MVA excretion suggesting a plateau effect with no further inhibition of cholesterol synthesis at doses of atorvastatin greater than 80 mg/day.
Assuntos
Anticolesterolemiantes/uso terapêutico , Colesterol/biossíntese , Ácidos Heptanoicos/uso terapêutico , Homozigoto , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Pirróis/uso terapêutico , Adolescente , Adulto , Anticolesterolemiantes/administração & dosagem , Atorvastatina , Biomarcadores/sangue , Biomarcadores/urina , Criança , Pré-Escolar , Colesterol/sangue , LDL-Colesterol/sangue , DNA/genética , Análise Mutacional de DNA , Feminino , Ácidos Heptanoicos/administração & dosagem , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/metabolismo , Masculino , Ácido Mevalônico/sangue , Ácido Mevalônico/urina , Mutação , Polimorfismo Conformacional de Fita Simples , Prognóstico , Pirróis/administração & dosagem , Receptores de LDL/sangue , Receptores de LDL/genéticaRESUMO
The last 40 years has been a period of remarkable evolution of organ transplantation from nothing to a well-established form of treatment with good short-term and tolerable long-term results. Nevertheless by ten years approximately 50% of grafts will have been lost due, mainly, to chronic rejection or the side-effects of immunosuppressive therapy. We now have a number of extremely powerful immunosuppressive drugs and antibodies with different mechanisms of action and the stage is set for a move from current continuous high dose immunosuppressive maintenance therapy to low dose or no maintenance immunosuppression. True tolerance can occur in man, examples being successful bone marrow transplantation and patients with liver grafts who have stopped immunosuppression after years of good function. The antibody Campath 1H with a unique target CH52 on T & B lymphocytes and monocytes has been used to eliminate lymphocytes from the blood for a month in patients with renal allografts who have then been maintained on half dose Cyclosporin without any other maintenance drug. The results with a mean two year follow-up have been encouraging, 29 patients having good function without receiving maintenance steroids. It is likely that this protocol could be improved since dosage timing and various minimal maintenance immunosuppressive protocols have not been fully investigated. This almost or "Prope" tolerance could be a major step forward providing a better quality of life for patients and inexpensive maintenance immunosuppression.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticorpos Antineoplásicos/uso terapêutico , Antígenos de Neoplasias , Ciclosporina/administração & dosagem , Imunossupressores/administração & dosagem , Transplante de Rim , Adulto , Idoso , Alemtuzumab , Anticorpos Monoclonais Humanizados , Antígenos CD/imunologia , Antígeno CD52 , Cadáver , Feminino , Glicoproteínas/imunologia , Humanos , Tolerância Imunológica , Masculino , Pessoa de Meia-Idade , Transplante HomólogoRESUMO
AIMS: In 1998 the British Society of Gastroenterology (BSG) published national guidelines for the management of acute pancreatitis (AP) in an attempt to improve diagnosis and reduce mortality rates. A comparative audit was undertaken of the management of AP against the BSG recommendations. METHODS: A retrospective analysis of 53 patients (median age 61 (range 24-95) years) admitted with AP during 1998 was undertaken and a comparison was made with the BSG guidelines. RESULTS: Some 70 per cent (n = 37) of the patients were admitted with mild AP and 30 per cent (n = 16) with severe AP. The BSG recommendations are shown in parentheses in the following text. The overall mortality rate was 17 per cent (less than 10 per cent), zero in mild AP and 56 per cent in patients with severe AP (less than 30 per cent). A correct diagnosis of AP was made within 48 h of admission in all patients (100 per cent). Severity stratification within 48 h using the Glasgow criteria and C-reactive protein (CRP) level, as suggested by the BSG, was done in approximately 80 per cent of patients. Table 1. CRP was measured in 51 per cent of the patients within the first 4 days (100 per cent) and at the end of the first week (100 per cent). Gallstones and alcohol counted for 72 per cent of causes of AP and the aetiology was determined in 77 per cent (75-80 per cent). All patients with severe AP were managed in a high-dependency or intensive therapy unit with central venous pressure monitoring and prophylactic intravenous antibiotics, and underwent dynamic computed tomography within 3-10 days of admission (100 per cent). Some 86 per cent of patients with suspected common bile duct (CBD) stones (jaundice, deranged liver function tests, dilated CBD) underwent endoscopic retrograde cholangiopancreatography with or without duct drainage and clearance. CONCLUSIONS: Management of AP closely mirrors the BSG guidelines, but fails to fully address severity stratification with respect to LDH, CRP and PaO2 at 48 h. A thorough analysis of patients with severe AP (i.e. extent of pancreatic necrosis, onset of infection) has been undertaken to explain the mortality rate and it is proposed to prospectively audit admissions with AP in 1999 in order to close the audit loop.
RESUMO
Pancreatic elastase-1 (EL-1) is a specific human protease synthesised by the acinar cells. It is stable, unaffected by exogenous pancreatic enzyme treatment, and correlates well with stimulated pancreatic function tests. We report our experience of EL-1 measurements in 142 patients from a large cystic fibrosis (CF) clinic. The median patient age was 7.7 years (range, 0.1-20.8 years), 93 were homozygous and 38 heterozygous for DeltaF508, and 11 had other or unidentified mutations. There were 85 non-CF control subjects. Seven were pancreatic sufficient (PS). The median (quartile 1-quartile 3) fecal EL-1 of the 135 pancreatic insufficient (PI) patients was 10 microg/g stool (2.5-33); of the 7 PS patients, 698 microg/g stool (400.5-824.5), and of the non-CF controls, 615 microg/g stool (420-773). Using the Mann-Whitney U test, there was a statistically significant difference for fecal EL-1 activity between the PS and PI patients (P = 0.0001) and the PI and control group (P < 0.0001), but not between the control and PS groups (P = 0.63). Median (quartile 1-quartile 3) fecal EL-1 in the pancreatic insufficient DeltaF508 homozygotes was 10 microg/g stool (2-33), and in the heterozygotes 12 microg/g stool (4-39) (not significant, P = 0.62). We now use fecal EL-1 as evidence of PI in screened CF infants (reliable over the age of 2 weeks); in older CF patients at diagnosis; for confirming the need for pancreatic enzymes in patients referred to the clinic already taking enzymes; for annual monitoring of PS patients to detect the onset of PI; and as supporting evidence when excluding the diagnosis of CF in patients attending the pediatric gastroenterology clinic. The low values in the first 2 weeks in some normal and premature infants, and the persisting normal values in PS infants, make the fecal EL-1 test unsuitable for neonatal CF screening.
Assuntos
Fibrose Cística/fisiopatologia , Insuficiência Pancreática Exócrina/diagnóstico , Fezes/enzimologia , Pâncreas/fisiopatologia , Elastase Pancreática/análise , Adolescente , Adulto , Fatores Etários , Criança , Pré-Escolar , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Estudos de Avaliação como Assunto , Insuficiência Pancreática Exócrina/tratamento farmacológico , Heterozigoto , Homozigoto , Humanos , Lactente , Mutação/genética , Pancreatina/uso terapêuticoRESUMO
BACKGROUND: Campath 1H is a depleting, humanized anti-CD52 monoclonal antibody that has now been used in 31 renal allograft recipients. The results have been very encouraging and are presented herein. METHODS: Campath 1H was administered, intravenously, in a dose of 20 mg, on day 0 and day 1 after renal transplant. Low-dose cyclosporine (Neoral) was then initiated at 72 hr after transplant. These patients were maintained on low-dose monotherapy with cyclosporine. RESULTS: At present, the mean follow-up is 21 months (range: 15-28 months). All but one patient are alive and 29 have intact functioning grafts. There have been six separate episodes of steroid-responsive rejection. One patient has had a recurrence of her original disease. Two patients have suffered from opportunistic infections, which responded to therapy. One patient has died secondary to ischemic cardiac failure. CONCLUSIONS: Campath 1H has resulted in acceptable outcomes in this group of renal allograft recipients. This novel therapy is of equal efficacy compared to conventional triple therapy, but allows the patient to be steroid-free and to be maintained on very-low-dose immunosuppressive monotherapy.