RESUMO
A functional microcirculation is crucial for the normal function of an organism. In many physiopathological situations, impaired microcirculation may contribute to the development or progress of diseases. Microcirculation is closely interrelated with blood and especially plasma rheology. Thus, improvement of plasma viscosity has beneficial effects on rheology, microcirculation, and the related tissue microenvironment. However, at best tools that only have a minor influence on plasma viscosity exist so far. Fibrinogen is known to be the major contributor to plasma viscosity, making it an interesting target for therapeutic intervention. An adsorber specific for fibrinogen was developed on the basis of the TheraSorb technology. The TheraSorb technology (PlasmaSelect AG, Teterow, Germany) allows the selective removal of components from human blood plasma by means of an affinity chromatography column. A ligand specific for a defined plasma component is coupled to a solid matrix (sepharose) thus binding and eliminating the target molecule from plasma. Using a fibrinogen specific pentapeptide as ligand, selective removal of fibrinogen, fibrin, and degradation products, containing the target sequence of these molecules, can be obtained. The LIFE-18, a state-of-the-art integrated plasma therapy instrument, is used to perform the treatment. The procedure improves plasma and whole blood viscosity in a dose dependent manner as shown in Phase 1 and 2 clinical trials. This article describes the first clinical experience in patients with diabetic foot syndrome and provides an outlook for further clinical and scientific investigations related to this promising new procedure.
Assuntos
Viscosidade Sanguínea , Fibrinogênio , Hemorreologia , Plasmaferese/instrumentação , Pé Diabético/fisiopatologia , Pé Diabético/terapia , Desenho de Equipamento , Humanos , MicrocirculaçãoRESUMO
Changing financial incentives have strongly influenced dosing patterns of recombinant human erythropoietin (rHuEPO) since its introduction in 1989. Although guidelines for prescribing rHuEPO exist, the extent to which they are adhered to is unknown. Using a retrospective cohort observational study design, the factors influencing the initial dosing of rHuEPO prescribed to 413 hemodialysis patients in 1994 were examined. Patient weight, the only recommended guideline, was not found to be a significant predictor of dosing of rHuEPO after controlling for selected patient demographic and clinical characteristics. The strongest predictor for initial rHuEPO dosing was hematocrit followed by White race (p < 0.05). Finally, each subsequent month was associated with a significantly larger initial rHuEPO dose, reflecting the general trend in increasing dose since 1991 (p < 0.001). In conclusion, despite the recent DOQI guidelines for treatment of anemia among persons with chronic renal failure, providers are not using patient weight as an independent criterion for determining dosing of rHuEPO.
Assuntos
Anemia/tratamento farmacológico , Eritropoetina/uso terapêutico , Guias de Prática Clínica como Assunto , Diálise Renal , Adolescente , Adulto , Peso Corporal , Estudos de Coortes , Eritropoetina/administração & dosagem , Feminino , Previsões , Hematócrito , Humanos , Falência Renal Crônica/terapia , Análise dos Mínimos Quadrados , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Padrões de Prática Médica , Proteínas Recombinantes , Análise de Regressão , Estudos Retrospectivos , Transferrina/análise , População BrancaRESUMO
Destructive spondyloarthropathy is a serious complication in patients with end-stage renal disease. We report a case of fatal cervical spondyloarthropathy in a patient on hemodialysis who presented with severe pain in the cervical area. Magnetic resonance imaging (MRI) of the cervical spine showed a soft tissue mass at the cervico-occipital hinge with spinal cord compression and destructive lesions of the cervical vertebrae. The patient became quadriplegic during the MRI procedure and died a few days later. Postmortem examination showed deposition of beta2-microglobulin in the cervico-occipital hinge. A unique feature of this case was the documented presence of systemic beta2-microglobulin amyloid deposits involving the spleen that to our knowledge has not been reported previously. Clinical suspicion and early detection of lesions caused by dialysis-related amyloidosis (DRA) may help to prevent significant morbidity and mortality in long-term dialysis patients.
Assuntos
Amiloidose/metabolismo , Vértebras Cervicais , Diálise Renal/efeitos adversos , Osteofitose Vertebral/metabolismo , Baço/metabolismo , Microglobulina beta-2/metabolismo , Amiloidose/etiologia , Evolução Fatal , Humanos , Imageamento por Ressonância Magnética , Masculino , Microscopia Eletrônica , Pessoa de Meia-Idade , Fatores de Risco , Osteofitose Vertebral/etiologiaRESUMO
Heparin and saline are commonly used to fill hemodialysis central venous catheters to prevent their thrombosis during the interdialytic period. The purpose of this prospective clinical study was to evaluate whether replacing heparin with citrate or polygeline could ensure satisfactory catheter function without exposing patients to the risk of systemic heparinization. Thirty end-stage renal disease (ESRD) patients with subclavian or jugular single lumen catheters as temporary vascular access for hemodialysis were enrolled. After the insertion of the catheters, the patients were randomly assigned to one of the following three filling groups: Group A, heparin; Group B, citrate; Group C, polygeline. Before each dialysis, the filling solution was aspirated and clot volume, if present, was measured. The catheter usage time and the clot volume were 23 +/- 24 days and 0.052 +/- 0.035 ml in Group A, 51 +/- 36 days and 0.059 +/- 0.032 ml in Group B, and 32 +/- 10 days and 0.056 +/- 0.038 ml in Group C, respectively. Our results indicate that citrate or polygeline can replace heparin effectively as a filling solution for single lumen temporary hemodialysis catheters.
Assuntos
Anticoagulantes/administração & dosagem , Cateterismo Venoso Central/métodos , Ácido Cítrico/administração & dosagem , Heparina/administração & dosagem , Substitutos do Plasma/administração & dosagem , Poligelina/administração & dosagem , Diálise Renal/métodos , Idoso , Feminino , Humanos , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Trombose/etiologia , Trombose/prevenção & controleRESUMO
Despite treatment with intensive immunosuppressive drug regimens, the prognosis of patients suffering from severe progressive autoimmune diseases like systemic lupus erythematosus (SLE), nephrotic syndrome (NS), and Behçet's disease is poor. Side effects (infections and malignant tumors) often occur. In the present trial, 35 patients suffering from autoimmune diseases (SLE, n = 21; NS, n = 10; and Behçet's disease, n = 4) were treated for 3.7 +/- 2.0 years with 2.5 +/- 0.6 mg cyclosporine/kg body weight/day in addition to corticosteroids alone or in combination with azathioprine and/or cyclophosphamide. In active stages of the diseases with extremely high concentrations of anti-ds-DNA-antibodies, antinuclear antibodies, circulating immunocomplexes, and reduced complement concentrations, therapeutic plasma exchange (TPE) has been applied. Compared with previous treatment modalities, significantly (p < 0.05) more effective and rapid reductions of the antibodies were reached. Clinical disorders improved within 1-6 weeks. All patients reported increased performance and a better quality of life. After 1-12 months, the previously required doses of immunosuppressive drugs and the frequency of TPE could be reduced by 40-100%. After 13.4 +/- 11.8 months in 17 of 35 patients (8 with SLE, 5 with NS, 4 with Behçet's disease), cyclosporine was established as the monotherapy. No severe side effects were registered. In treating active stages of severe progressive autoimmune diseases and forms with persistent high antibody levels, the addition of TPE to conventional therapy was very effective, as observed in both clinical and laboratory parameters.
Assuntos
Síndrome de Behçet/terapia , Ciclosporina/uso terapêutico , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/terapia , Síndrome Nefrótica/terapia , Troca Plasmática , Corticosteroides/uso terapêutico , Adulto , Idoso , Formação de Anticorpos , Azatioprina/uso terapêutico , Síndrome de Behçet/tratamento farmacológico , Terapia Combinada , Ciclofosfamida/uso terapêutico , Ciclosporina/administração & dosagem , Ciclosporina/efeitos adversos , Feminino , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Síndrome Nefrótica/sangue , Síndrome Nefrótica/tratamento farmacológico , Estudos Prospectivos , Proteinúria/urina , Qualidade de VidaRESUMO
Ion beam-based processes such as ion implantation (silicone rubber) and ion beam-assisted deposition (silver-based coatings) affect the outer micron layers of catheter surfaces. These processes were used on the common catheter materials of silicone and polyurethane. In 56 rats, surface (Spi-Silicone and Spi-Argent I and II) catheter segments were implanted for 1, 3, and 6 weeks. After removal, these pieces were investigated for bacterial colonization and fixed for scanning electron microscopic evaluation. As controls, untreated catheter segments were implanted in 28 rats. Bacterial colonization was found in 2.4% in the surface treated catheter pieces versus 7.1% in the control group. The scanning electron microscope investigations showed low thrombogenicity in all of the treated catheters independent of the implantation times.
Assuntos
Cateteres de Demora/efeitos adversos , Prata , Animais , Materiais Biocompatíveis , Microscopia Eletrônica , Ratos , Borracha/toxicidade , Silício/toxicidade , Infecções Estafilocócicas/etiologia , Propriedades de Superfície , Trombose/induzido quimicamenteRESUMO
Adrenoleukodystrophy (ALD) is an X-linked disorder of metabolism of very long chain fatty acids (VLCFAs) with a frequency of up to 1:20,000 in males. VLCFAs C24:0 and C26:0 accumulate in the cholesterol ester and ganglioside fraction in plasma and red cells. Symptoms of ALD are ataxia, loss of visual and auditory functions, and cerebral convulsions. Up to the present, no sure therapeutic approaches have been established. Efforts were reported by dietary regimens with VLCFA restriction and glyceroltrioleate and glyceroltrierucate intake. In the present trial, we report a 55-year-old Caucasian male suffering from progressive ALD with spastic paraparesis. He has had a positive family history since the eighteenth century. In this patient treated with maximum dietary therapy over a period of 60 months, no normalization of C24:0 and C26:0 was reached, and neurological disorders were progressive. As a result, plasmapheresis was applied during the period 1990-1994 and since then for more selective adsorption of VLCFAs, dextran sulfate adsorption (Liposorber, Kaneka, Japan). During this period (64 months), C24:0 and C26:0 levels were reduced by 54.5% and 51.8%, respectively (p = 0.0001). The patient experienced a significant improvement in performance and general well-being. There has been no further progression of neuronal disorders to document.
Assuntos
Adrenoleucodistrofia/terapia , Plasmaferese , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Thirty patients (13 males, 17 females) suffering from familial hypercholesterolemia resistant to diet and lipid-lowering drugs were treated for 48.7 +/- 19.2 months (range, 2-87 months) with low density lipoprotein (LDL) apheresis. Three different systems (dextran sulfate adsorption for 27 of 30 [Kaneka, Liposorber, Japan], immunoadsorption system for 2 of 30 [Baxter, Therasorb, Germany], immunoadsorption system with special lipoprotein a [Lp(a)] columns for 1 of 30 patients [Lipopak, Pocard, Russia]) were applied. Before LDL apheresis 24 of 30 patients suffered from coronary heart disease (CHD) with angina symptoms. With LDL apheresis, reductions of 46% for total cholesterol, 49% for LDL, 30% for Lp(a), and 38% for triglycerides were reached. Severe side effects such as shock or allergic reactions were very rare (0.5%). In the course of treatment, an improvement in general well-being and increased performance were experienced in 27 of 30 patients. A 60 to 100% reduction of nitrate medication was observed in 17 of 24 patients. Regarding the different apheresis systems used, at the end of the trial there were no significant differences with respect to the clinical outcome experienced by the patients and concerning total cholesterol, LDL, high density lipoprotein, and triglyceride concentrations. But to reduce high Lp(a) levels, the immunoadsorption method with special Lp(a) columns seems to be the most effective (-57% versus 25% [Kaneka] and 23% [Baxter]). The present data clearly demonstrate that treatment with LDL apheresis of patients suffering from familial hypercholesterolemia, resistant to maximum conservative therapy, is very effective and safe, even in long-term application.
Assuntos
Remoção de Componentes Sanguíneos , Hiperlipidemias/terapia , Lipoproteínas LDL/isolamento & purificação , Adulto , Remoção de Componentes Sanguíneos/efeitos adversos , Remoção de Componentes Sanguíneos/instrumentação , Remoção de Componentes Sanguíneos/estatística & dados numéricos , Distribuição de Qui-Quadrado , Terapia Combinada , Feminino , Humanos , Hiperlipidemias/sangue , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/terapia , Lipoproteínas LDL/sangue , Masculino , Pessoa de Meia-Idade , Estatísticas não Paramétricas , Fatores de Tempo , Resultado do TratamentoRESUMO
The prognosis of patients suffering from progressive systemic lupus erythematosus (pSLE) is poor, despite treatment with intensive drug regimens with combinations of corticosteroids, azathioprine and cyclophosphamide. Side-effects such as infections and malignomas often occur. In the present trial, 21 patients (four male, 17 female, aged 37.9 +/- 12.8) suffering from pSLE for 9.4 +/- 2.6 years, were treated for 2.3 +/- 1.8 years with drug regimens as mentioned above. Then, over a period of 6.4 +/- 2.6 (range 1-8) years, in addition to conventional therapies, cyclosporin (2.5 +/- 0.6 mg/kg body wt/d) and, in active stages of the disease with extremely high concentrations of anti-ds-DNA-, anti-nuclear antibodies and circulating immunocomplexes, plasmapheresis (therapeutic plasma exchange (TPE)) have been applied. Compared with previous treatment modalities, significantly (P < 0.05) more effective and rapid reduction of antibodies was achieved. Clinical symptoms improved within 2 to 4 weeks. Under the new therapeutic regimen all patients reported increased performance and a better quality of life. After 5 to 48 (17.5 +/- 13.8) months, cyclosporin was established as mono-therapy for 8/21 patients. In] the other cases, corticosteroids, azathioprine and cyclophosphamide were reduced by 40 to 100%. No severe side-effects were seen. In acute stages of pSLE and in forms with persistently high antibody levels, the addition of TPE to conventional therapy was very effective, with regard to improving both clinical and laboratory parameters.
Assuntos
Ciclosporina/administração & dosagem , Lúpus Eritematoso Sistêmico/terapia , Plasmaferese , Adolescente , Adulto , Ciclosporina/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
In total, 30 patients suffering from familial hypercholesterolemia, resistant to diet and lipid-lowering drugs, were treated for up to 6 years (3.6 + or - 1.6; range, 0.2-6.8 years) with low-density lipoprotein (LDL) apheresis. Three different systems were used; the dextran sulfate adsorption system (Kaneka) for 27 of 30 patients, the immunoadsorption system from Baxter for 2 of 30 patients, and the immunoadsorption system with special lipoprotein(a) (Lp[a]) columns from Lipopak for one patient. Prior to the LDL apheresis, 23 of 30 patients suffered from coronary heart disease. Twenty of 23 patients suffered intermittently from symptoms of angina, excertional dyspnea, and claudication. With LDL apheresis, reductions of 47% for total cholesterol, 49% for LDL, 26% for Lp(a), and 40% for triglycerides were reached. Severe side effects such as shock or allergic reactions were very rare (0.55%). In the course of treatment with LDL apheresis, an improvement in general well-being and increased performance were experienced in 27 of 30 patients. A reduction of nitrate medication between 60 and 100% was observed in 17 of 23 patients. The present data clearly demonstrate that treatment with LDL apheresis in patients suffering from severe familial hyperlipidemia, resistant to maximum conservative therapy, is very effective and safe even over long periods of time.
Assuntos
HDL-Colesterol/isolamento & purificação , LDL-Colesterol/isolamento & purificação , Hiperlipoproteinemia Tipo II/terapia , Plasmaferese , Adsorção , Adulto , Idoso , Apolipoproteínas B/sangue , Apolipoproteínas B/isolamento & purificação , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Doença das Coronárias/fisiopatologia , Doença das Coronárias/terapia , Sulfato de Dextrana/química , Sulfato de Dextrana/metabolismo , Feminino , Fibrinogênio/isolamento & purificação , Humanos , Hiperlipoproteinemia Tipo II/dietoterapia , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Imunoadsorventes , Lipoproteína(a)/sangue , Lipoproteína(a)/isolamento & purificação , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Plasmaferese/efeitos adversos , Triglicerídeos/sangue , Triglicerídeos/isolamento & purificaçãoRESUMO
Hyperlipidemia and elevated lipoprotein (a) (Lp[a]) levels have been linked to the development and progression of premature atherosclerosis. Our study concerned 2 white male patients (aged 36 and 42 years) with heterozygous familial hypercholesterolemia and extremely elevated Lp(a) concentrations that were resistant to diet regimens and lipid-lowering drugs. The patients were treated with low-density lipoprotein (LDL) apheresis for 59 months (Liposorber system, Kaneka, Japan) and 19 months (immunoadsorption system, special Lp(a) columns; Lipopak; Pocard, Russia), respectively. The concentration of Lp(a) decreased on average by 50%, total cholesterol by 27%, LDL cholesterol by 41%, triglycerides by 43%, and fibrinogen by 16%. High-density lipoprotein (HDL) cholesterol increased by approximately 4%. Before treatment with LDL apheresis, each patient had suffered 3 myocardial infarctions, and had had 4 and 6 coronary angiographies with 2 and 4 percutaneous transluminal angioplasties (PTCAs), respectively. Since treatment with LDL apheresis, no myocardial infarctions or cardiac complaints were observed. In the course of treatment, both patients reported an increased performance. Available data suggest that LDL apheresis may be effective in the treatment of patients, the only risk factor for premature atherosclerosis being extremely elevated Lp(a) concentrations.
Assuntos
LDL-Colesterol/isolamento & purificação , Doença das Coronárias/terapia , Hiperlipoproteinemia Tipo II/terapia , Lipoproteína(a)/isolamento & purificação , Plasmaferese , Adulto , Distribuição de Qui-Quadrado , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Doença das Coronárias/fisiopatologia , Fibrinogênio/isolamento & purificação , Humanos , Imunoadsorventes/química , Imunoadsorventes/metabolismo , Lipoproteína(a)/sangue , Estudos Longitudinais , Masculino , Triglicerídeos/sangue , Triglicerídeos/isolamento & purificação , População BrancaRESUMO
Two male caucasian patients (36 and 42 years old) with heterozygous familial hypercholesterolemia and extremely elevated lipoprotein Lp(a) concentrations, resistant to diet and lipid-lowering drugs, were treated with low-density lipoprotein (LDL)-apheresis for 55 months (liposorber system, Kaneka, Japan) and 15 months (immunoadsorption system, special Lp(a) columns, Lipopak, Pocard, Russia). Lp(a) dropped on average by 50%, total cholesterol by 27%, LDL-cholesterol by 42%, triglycerides by 43%, and the fibrinogen concentration by 16%.
Assuntos
Remoção de Componentes Sanguíneos , Lipoproteína(a)/sangue , Lipoproteínas LDL/sangue , Lipoproteínas LDL/isolamento & purificação , Adulto , Humanos , MasculinoRESUMO
Using blood-contacting catheters, infections, thromboses, and stenoses are among the most frequent complications. They are caused by surface properties of the basic material. Ion beam based processes such as ion implantation (silicone rubber) and ion beam assisted deposition (silver-based coatings) affect only the outer micron of the treated material surface; there is little effect on bulk properties. These processes were employed also in the production of large-bore catheters used for extra-corporeal detoxification. In a prospective study in 56 patients, 72 large-bore catheters were inserted into the internal jugular and subclavian veins and investigated after removal for bacterial colonization using a scanning electron microscope. In 24 patients 30 surface-treated catheters (Spi-Argent I n = 14; Spi-Silicone n = 16) were used. 42 untreated catheters used in 32 patients served as controls. Bacterial colonization was observed in 8.9% in contrast to 38.1% in untreated catheters. The scanning electron microscopic investigations showed in all catheters a low thrombogenicity. The ion beam based processes make the surface-treated catheters thrombus and infection resistant.
Assuntos
Cateterismo Venoso Central/instrumentação , Microscopia Eletrônica de Varredura , Contagem de Colônia Microbiana , Contaminação de Equipamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
In hyperlipidemia and, in particular, elevated lipoprotein (a) [Lp(a)] levels there appears to be pronounced linkage between the development and progression of atherosclerosis. Our study concerned two Caucasian male patients with heterozygous forms of familial hypercholesterolemia and extremely high Lp(a) concentrations. Maximal diet regimens and the use of lipid lowering drugs achieved a serum total-, LDL-cholesterol and triglyceride reduction of up to 30%, but no reduction of the Lp(a) level was discernible. Both patients suffered three myocardial infarctions and several coronary angiographies with percutaneous transluminal angioplasties (PTCA) were necessary. In 1989, we commenced treatment with LDL-apheresis. At present, after 78 LDL-aphereses in the case of the 41-year-old patient (48 months, dextran sulfate adsorption, KANEKA, Japan) and 38 aphereses in the case of the 35-year old patient (8 months, immunoadsorption, special Lp[a] columns, LIPOPAK, POCARD, Russia), the Lp(a) has dropped an average of 53%, total cholesterol 31%, LDL-cholesterol 40% and triglycerides 42%. During this period neither mycardial infarctions nor cardiac complaints were observed. In the course of treatment, both patients experienced an improvement in general well-being and increased performance. These results are very encouraging: LDL-apheresis may be effective in the treatment of patients, the only risk factor for premature atherosclerosis being an extremely high Lp(a) concentration.
Assuntos
Remoção de Componentes Sanguíneos , Heterozigoto , Hiperlipoproteinemia Tipo II/sangue , Lipoproteína(a)/sangue , Lipoproteínas LDL/sangue , Adulto , Humanos , Hiperlipoproteinemia Tipo II/genética , MasculinoRESUMO
This article describes new bistable valves, and introduces a new soft heart that is easy to implant. Earlier, five polyurethane (PU) valves were implanted in the mitral position in sheep. All five survived for 1 year or more, and the valves, although calcified, were intact. Since the opening resistance was somewhat high, valves that are bistable were developed, which means they may be open or closed. These valves have lower opening resistance, and regurgitation is similar to that of mechanical valves. Eight calves have been implanted with a new, soft total artificial heart (TAH). Seven had bistable leaflet valves; the eighth had mechanical (Bicer) valves in the inflow position. Four of the calves were sacrificed after 22 to 43 days. At autopsy, the number of thromboemboli found, particularly in the kidneys, was low compared with previous experiments. None of these animals received anticoagulants other than the heparin given during heart/lung bypass.
Assuntos
Próteses Valvulares Cardíacas , Coração Artificial , Poliuretanos , Animais , Velocidade do Fluxo Sanguíneo , Pressão Sanguínea , Bovinos , Modelos Cardiovasculares , Desenho de Prótese , Trombose/etiologiaRESUMO
The utilization of nitrogen from 15N-labeled Saccharomyces cerevisiae cells was studied in 6 infants by means of oral pulse labeling, comparing native and heat-treated yeast cells. The 15N dose used was 3 mg/kg. The body weight of the subjects varied between 5500 and 9400 g. The yeast cells were harvested from a culture medium which contained 15N ammonium chloride as the only source of nitrogen. The 15N-enrichment of the cells amounted to 95 atom-%. In the course of 48 h following the administration of the native yeast cells, 11% of the tracer dose were renally excreted. The corresponding value after labeling with heat-treated yeast cells was 17.9%. The cumulative renal excretion of the tracer tended to be faster as compared with pulse labeling of the native yeast cells. A paired comparison with labeled native and heated yeast cells in 3 subjects did not reveal any differences in the retention rate of 15N. When untreated 15N yeast cells were administered, 13.2% of the tracer dose were excreted in the urine and 10% respectively in the faeces. The retention was 76.8%. After single pulse labeling with 3 mg 15N/kg from heat-treated yeast cells the corresponding values were 19.4%, 4.4% and 76.2%, respectively. The kinetic of the renal 15N excretion points at the partial absorption of the yeast nitrogen from the colon.