Differences in the pressures of canal anal and rectal sensitivity in patients with fecal incontinence, chronic constipation and healthy subjects.

INTRODUCTION: There exists a great variability in the manometric findings between patients with anal incontinence (AI) and healthy subjects. The correlation between the pressures of the anal canal and the AI is not exact by the wide rank of normal values. OBJECTIVES: Prospective study to evaluate differences in the pressures of the anal canal and in rectal sensitivity in patients with AI, chronic constipation (CC) and healthy subjects. MATERIAL AND METHODS: Ninety four patients with AI, 36 patients with CC and 15 healthy subjects were included. The following data were obtained: age, sex, resting pressure, anal canal length (ACL), squeeze maximum pressure (SMP), squeeze pressure duration (SPD), first sensation, urge and maximum tolerated volume (MTV). Statistical study: test of Kruskal-Wallis, test of Mann-Whitney, and multinomial logistic regression test. RESULTS: There were significant differences in the resting pressure (p < 0.001), the ACL (p < 0.001) and the SMP (p < 0.01) in the group of AI with respect to the other two groups. The volume for the first sensation was significantly lower in the healthy subjects than that in the other two groups (p < 0.05). The urge volume and the MVT were smaller in the group with AI with respect to the other groups (p < 0.001). In multivariate analysis the age, the resting pressure and the volume for the first sensation and urge increase the relative risk for AI. CONCLUSIONS: The greater age, the decrease in anal canal resting pressure and the alteration of rectal sensation increase the risk for AI.

The pathogenesis of primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) would develop when the immune system comes across a microorganism with proteins similar to those in the piruvate dehydrogenase complex E2 (PDC-E2), or a neoantigen resulting from a xenobiotic-modified autoantigen. This would lead to an innate immune response where TLRs would play a pivotal mediating role, which would give rise to a local microenvironment favoring an adaptive immune response. Such response would be particularly strong in individuals with selected genetic characteristics. The genetic characteristics underlying this predisposition remain unknown, but they likely entail small numbers of scarcely-active regulatory T cells. The AE2 anion exchanger, which is deficient in patients with PBC, may reduce the number and activity of regulatory T cells. NK cells are also pivotal in the preparation of an adaptive response, as they release a number of cytokines and chemokines that favor and recruit antigen-presenting cells to activate B and T cells - CD4+ Th1 and CD8+. An activation of the former would increase the production of IgM and anti-mitochondrial IgG and IgA antibodies against PDC-E2. An activation of CD8+ cells, also sensitive to PDC-2 as aberrantly expressed on the surface of BECs and SECs, would result in apoptosis for these epithelial cells, and in small bile-duct destruction. Immune response is likely inadequately suppressed because of the small numbers of scarcely-active regulatory T cells, the latter resulting from low genetic expression and activity of the AE2 transporter.

[An analysis of the causes, characteristics, and consequences of reexposure to a drug or compound responsible for a hepatotoxicity event]. / Análisis de las causas, características y consecuencias de la reexposición al fármaco o compuesto responsable de un episodio de hepatotoxidad.

INTRODUCTION: reexposure to a causal agent represents a potentially serious event in hepatotoxicity. OBJECTIVES: to assess the characteristics and outcome of cases with positive reexposure. MATERIAL AND METHODS: a retrospective study of cases with evidence of positive reexposure included in Registro Español de Hepatopatías Asociadas a Medicamentos, and an analysis of their relation to demographic and clinical variables, causality, course, and consequences. RESULTS: of a total of 520 cases 31 (6%) met reexposure criteria. Fatal outcomes, needs for admission, and mean recovery time were all higher for hepatocellular-type toxic injury. The most commonly identified drug class was antibiotics. On most occasions (73%) reexposure to the causal compound escaped notice because of: absence of index case diagnosis, lack of information to patients and their physicians, and (12%) development of cross reactions between structurally similar drugs. CONCLUSIONS: accidental reexposure to a drug or a structurally-related compound after an initial hepatotoxicity event is common and may have serious consequences, particularly in hepatocellular-type toxicity. Careful history taking and reflecting diagnostic suspicion in the initial episode s record may reduce the incidence of this iatrogenic event.

Refractory hepatic hydrothorax: successful treatment with octreotide.

We report the case of a patient that developed hepatic hydrothorax as the first complication of liver cirrhosis. Due to the lack of response to diuretics, pleurodesis and TIPS, treatment with octreotide was started with resolution of hydrothorax. To the best of our knowledge, this is the third reported case of refractory hepatic hydrothorax with complete and sustained response to octreotide.

Clinical, anorectal manometry and surface electromyography in the study of patients with fecal incontinence.

OBJECTIVE: to demonstrate the role of the clinical, anorectal manometry and surface electromyography in the assessment of patients with fecal incontinence. PATIENTS AND METHODS: ninety-three patients with fecal incontinence are retrospectively reviewed and the data obtained from the directed clinical history, physical examination of the anal region, digital rectal examination, anorectal manometry and surface electromyography are analyzed. A treatment was administered in accordance with the alterations encountered and the results evaluated at 3 and 12 months. RESULTS: fecal incontinence was predominant (91.4%) in women age 59.7+/-11. A background of obstetric risks (48.2%) was frequent in women. Also, 73.1% of the patients presented diarrhea. The anorectal manometry (ARM) demonstrated some alterations in 90.3% of the patients, whereas a hypotonic sphincter was the most common finding (85.7%). Rectal sensitivity or distensibility alterations were present in the rest of the patients. In 79.2% ofthe cases, hypotonic sphincter was associated with rectal sensitivity or distensibility alterations. In 65.2% of patients with hypotonic external anal sphincter, damage of the pudendal nerve was found and therefore biofeedback was indicated in 41.9% of them. CONCLUSIONS: the clinical study of the patients, together with the anorectal manometry and surface electromyography enables the identification of the cause of FI and its treatment. These studies demonstrate that in most cases the origin of the incontinence is due to multiple etiologies, however the treatment of some of the factors involved frequently improves the symptomatology.

Collagen alpha1(I) gene contains an element responsive to tumor necrosis factor-alpha located in the 5' untranslated region of its first exon.

The aims of the present study were to identify the cis-acting element through which tumor necrosis factor-alpha (TNFalpha) inhibits collagen alpha1(I) gene transcription and the trans-acting factors involved in this effect in cultured hepatic stellate cells. Deletion analysis of the collagen alpha1(I) promoter demonstrated that TNFalpha inhibited gene expression through an element located between -59 and + 116 bp relative to the transcription start site. DNase I protection assays revealed a footprint between +68 and +86 bp of the collagen first exon, the intensity of which decreased when the DNA probe was incubated with nuclear protein from TNFalpha-treated hepatic stellate cells. This footprint contained a G+C-rich box. Transfection experiments demonstrated that mutations in this G+C-rich element abrogated the inhibitory effect of TNFalpha on the collagen alpha1(I) promoter. Gel retardation experiments using a radiolabeled oligonucleotide containing sequences of this region confirmed that TNFalpha treatment decreased the formation of two complexes between nuclear proteins and DNA. These complexes were efficiently blocked with an oligonucleotide containing an Spl-binding site and were supershifted with specific Spl and Sp3 antibodies. These results suggest that TNFalpha inhibits collagen alpha1(I) gene expression by decreasing the binding of Spl to a G+C-rich box in the 5' untranslated region of its first exon.

Sp family of transcription factors is involved in iron-induced collagen alpha1(I) gene expression.

The purpose of this study was to identify the cis-acting elements and the trans-acting factors involved in the iron-induced expression of the collagen alpha1(I) (COL1aI) gene. Rat hepatic stellate cells were cultured in the presence of 50 microM ferric chloride, 50 microM ascorbic acid, and 250 microM citric acid (Fe/AA/CA), and the effects on collagen gene expression and the binding of nuclear proteins to the COL1aI promoter were measured. The Fe/AA/CA treatment induced a time- and dose-dependent increase in the cellular levels of COL1aI mRNA that was abrogate by pretreating cells with cycloheximide, antioxidants, and inhibitors of aldehyde-protein adduct formation. Transient transfection experiments showed that Fe/AA/CA exerted its effect through regulatory elements located between -220 and -110 bp of the COL1aI promoter. Gel retardation assays showed that Fe/AA/CA increased the binding of nuclear proteins to two elements located between -161 and -110 bp of the COL1aI promoter. These bindings were blocked by unlabeled consensus Sp1 oligonucleotide and supershifted with Sp1 and Sp3 antibodies. Finally, Fe/AA/CA increased cellular levels of the Sp1 and Sp3 proteins and Sp1 mRNA. Treatment with Fe/AA/CA stimulates COL1aI gene expression by inducing the synthesis of Sp1 and Sp3 and their binding to two regulatory elements located between -161 and -110 bp of the COL1aI promoter.

Interleukin-6 increases rat metalloproteinase-13 gene expression through stimulation of activator protein 1 transcription factor in cultured fibroblasts.

The role of IL-6 in collagen production and tissue remodeling is controversial. In Rat-1 fibroblasts, we measured the effect of IL-6 on matrix metalloproteinase-13 (MMP-13), c-jun, junB, and c-fos gene expression, binding of activator protein 1 (AP1) to DNA, amount of AP1 proteins, immunoreactive MMP-13 and TIMP-1 proteins, and Jun N-terminal kinase activity. We show that IL-6 increased MMP-13-mRNA and MMP-13 protein. These effects were exerted by acting on the AP1-binding site of the MMP-13 promoter, as shown by transfecting cells with reporter plasmids containing mutations in this element. Mobility shift assays demonstrated that IL-6 induced the DNA binding activity of AP1. This effect was accompanied by a marked increase in c-Jun, JunB, and c-Fos mRNA, as well as in c-Jun protein and its phosphorylated form. The latter is not due to increased Jun N-terminal kinase activity but to a decreased serine/threonine phosphatase activity. We conclude that IL-6 increases interstitial MMP-13 gene expression at the promoter level. This effect seems to be mediated by the induction of c-jun, junB, and c-fos gene expression, by the binding of AP1 to DNA, by increasing phosphorylated c-Jun, and by the inhibition of serine/threonine phosphatase activity. These effects of IL-6 might contribute to remodeling connective tissue.

G proteins are involved in the suppression of collagen alpha 1 (I) gene expression in cultured rat hepatic stellate cells.

We analyse the role of the G proteins in regulating collagen gene expression by measuring collagen alpha 1(I) mRNA levels in cultured hepatic stellate cells in basal conditions and after stimulating or inhibiting the major intracellular signalling pathways. Stimulation of Gs protein and adenylyl cyclase or the addition of 8Br-cAMP to the cells led to a decrease in collagen alpha 1(I) mRNA levels, while blocking protein kinase A abolished this effect. Blocking Gi protein, phospholipase A2 and C, calcium channels and calmodulin resulted in a significant increase in collagen mRNA levels. PKC stimulation led to a marked decrease in these levels. These results suggest that collagen gene expression is inhibited by a number of intracellular pathways. A Gs and a pertussis toxin-sensitive G protein seem to initiate cellular response. Transcription factors, acting in these pathways, must be identified. However, it seems that they do not need to be synthesised.

[Serum aminoterminal procollagen type-III peptide in the diagnosis of chronic hepatopathies]. / Péptido aminoterminal del procolágeno tipo III sérico en el diagnóstico de las hepatopatías crónicas.

BACKGROUND: The aims of the present study were to 1) compare the serum levels of the aminoterminal peptide of procollagen type III (PIIIP) in patients with different chronic liver diseases, 2) correlate their concentrations with histologic features in liver biopsy and 3) evaluate their use in the diagnosis of liver diseases and in recognition of fibrosis. METHODS: With these aims PIIIP was determined in 57 patients with different chronic liver diseases and in 50 healthy donors. RESULTS: PIIIP was significantly elevated in patients with chronic active hepatitis (18.3 +/- 5.5 ng/ml; p less than 0.01) and with liver cirrhosis (27.8 +/- 11.7 ng/ml; p less than 0.001). The serum levels of this peptide related significantly with the severity of liver disease (p less than 0.001) in addition to the degree of morphometric liver fibrosis (Rs: 0.736; p less than 0.001) and with the degree of histologic activity (Rs: 0.78; p less than 0.001). The correlation between PIIIP and fibrosis was due to the relation between the same and inflammation. The levels of this peptide which were higher than 15 ng/ml were a sensitive test for the diagnosis of active liver disease (0.80) and cirrhosis (0.87) permitting differentiation between chronic and persistent active hepatitis. The differentiation between chronic active hepatitis and cirrhosis was only possible when 24 ng/ml were taken as a discriminative level. CONCLUSIONS: The comparison of serum levels of the aminoterminal peptide of procollagen type III (PIIIP) in patients with different chronic liver diseases can predict moderate or high degrees of inflammatory activity when PIIIP are higher than 15 ng/ml. This test is of use for evaluating chronic hepatopathies although the levels reflect the activity of inflammation better than the degree of hepatic fibrosis.

Antidiuretic hormone and renal function after water loading in patients with cirrhosis of the liver.

Renal function and plasma antidiuretic hormone (ADH) levels were studied basally and after oral water load in four groups of subjects: 15 healthy controls (group I), 15 cirrhotics without ascites (group II), 15 cirrhotics with ascites (group III), and 10 decompensated cirrhotics with hyponatremia (group IV). Renal function and ADH levels were normal in group II. In groups III and IV water diuresis and fractional proximal sodium excretion were significantly decreased, whereas fractional distal sodium resorption and fractional excretion of potassium did not differ from those of controls. Basal ADH was significantly increased only in patients of group IV. In these patients ADH remained abnormally high after water loading. ADH did not correlate with water diuresis, plasma osmolality, mean arterial pressure, and plasma renin activity. We conclude that impaired water excretion in decompensated cirrhotics without hyponatremia cannot be ascribed to high serum levels of ADH. On the contrary, it seems to be related mainly to a reduced delivery of filtrate to the diluting segment of the nephron. In cirrhotic patients with hyponatremia high levels of ADH may play an additional role.

Laparoscopic findings in polyarteritis nodosa.

We describe the laparoscopic findings of 6 patients with histologically proven P.A.N. In 5 cases a fibrous thickening of the liver capsule was observed. The capsular thickening was present only along the course of the arteries, and with a segmental distribution, presented the appearance of an "arterial coat'. Biopsy of these segments demonstrated typical inflammatory infiltrates of P.A.N. None of the 248 laparoscopic examinations used as controls had such findings. In conclusion, these laparoscopic findings may represent the segmental arterial lesions of P.A.N., although further studies are necessary to establish its diagnostic sensitivity and specificity.

[Laparoscopic findings in chronic hepatic porphyria (author's transl)]. / Laparoskopische Befunde bei der chronischen hepatischen Porphyrie: Graufleckung der Leberoberfläche.

The incidence and significance of gray patches on the hepatic surface found at laparoscopy was investigated in 50 patients with chronic hepatic porphyria. The color change was found in 38 patients; in 28 patients well defined gray dots were found. The incidence is not related to the degree of the metabolic disturbance. The gray patches contained 3-9 times more porphyrine than adjacent normally colored areas. Gray color and histological changes do coincide.

[Laparoscopy in the diagnosis of polycystic kidneys (author's transl)]. / La laparoscopie dans le diagnostic des reins polykystiques.

Nineteen cases of polycystic kidney disease were studied by laparoscopy in order to demonstrate the presence of renal cysts. The right kidney was seen in all cases and the left in 14. Cysts were not seen in 2 cases in the right kidney and 7 cases in the left. At endoscopy the cysts hve the appearance of thin-walled vesicles, highly variable in number and size. Diagnosis by intravenous pyelography was not possible in 7 cases whilst laparoscopy failed to provide the necessary evidence in only 2 patients.