Systemic and regional hemodynamics in patients with liver cirrhosis and ascites with and without functional renal failure

Systemic, femoral, and renal hemodynamics were evaluated in 7 control subjects and 20 cirrhotic patients with ascites, 14 of them without (group A) and 6 with (group B) functional renal failure. Hyperdynamic systemic circulation, increased plasma volume, and hyperreninism were present in groups A and B. These changes were more severe in group B, which showed, as compared with group A, lower total vascular resistances and mean arterial pressure together with increased cardiac index and plasma renin activity. Significant differences in regional hemodynamics were also observed between groups. In group A, femoral and renal fractions of cardiac output were respectively increased and reduced as compared with controls. By contrast, in group B, both fractions of cardiac output were reduced when compared either with controls or with group A. In the entire patient group there was a close direct correlation between femoral and renal fractions of cardiac output (r = 0.88; p less than 0.001) and both of them correlated independently with total vascular resistances (r = 0.79; p less than 0.001 in both cases). These results indicate that, in nonazotemic cirrhotics with ascites, vasodilatation in extrasplanchnic areas contributes to the genesis of the hyperdynamic circulation. The presence in group B of a reduced flow to extrasplanchnic territories, in association with an increase of the hyperdynamic circulatory status, suggests that exacerbation of splanchnic vasodilatation is involved in the development of the hepatorenal syndrome. Finally, in cirrhosis, the changes that occur in systemic hemodynamics appear to influence renal function and renal blood flow.     

Ectasia in the origin of the left subclavian artery--a case report of congenital malformation of the aortic arch

A rare congenital anomaly of the aortic arch is presented, consisting of an ectasia of the left subclavian artery associated with narrowing of the aortic arch in an asymptomatic twenty-three-year-old woman.     

Prolonged duration of gonadotropin inhibition by a third generation GnRH antagonist

The dose-response effects of a single administration of Nal-Lys-GnRHant (antagonist) on serum LH and FSH concentrations were compared to the effects of Nal-Glu-GnRHant in monkeys. Twenty ovariectomized monkeys were divided into four sc treatment groups: a) 1.0 mg/kg Nal-Glu-GnRHant; or Nal-Lys-GnRHant at b) 0.3; c) 1.0; d) 3.0 mg/kg. Each monkey received vehicle (propylene glycol/water, 1:1) on day 0, followed by an antagonist preparation on day 11. Serum LH and FSH were measured by RIA; serum LH was also measured by in vitro bioassay. The short-term effects were similar among the four treatment groups. Typically, serum LH declined (p less than 0.05) within 4 to 8 h, achieving maximal reduction by 24 h. Serum FSH levels declined more slowly, but were significantly reduced by 24 h (p less than 0.05). Recovery during the study interval to pretreatment control values occurred in only two groups: a) Nal-Glu-GnRHant (1.0 mg/kg) by day 4 post-treatment and b) Nal-Lys-GnRHant (0.3 mg/kg) by day 2 post-treatment. Monkeys receiving 1.0 or 3.0 mg/kg Nal-Lys-GnRHant had a prolonged inhibition of serum LH and FSH levels. In all animals, serum FSH and LH returned to control levels within 2 months. The duration of gonadotropin inhibition was also prolonged when the Nal-Lys-GnRHant was administered iv. In contrast, Nal-Glu-GnRHant reduced serum LH and FSH for 3 days or less in all monkeys. The serum bioassayable LH levels paralleled those of immunoassayable LH. The prolonged inhibition of gonadotropin secretion following Nal-Lys-GnRHant distinguishes its action from those of previous GnRH antagonists and make this compound of great interest for clinical investigations.     

Ligand-dependent polyubiquitination of c-kit gene product: a possible mechanism of receptor down modulation in M07e cells

Quantities of proteins in cells are balanced by protein synthesis and degradation. Protein ubiquitination is an important adenosine- triphosphate dependent proteolytic pathway for "short-lived" proteins. We show that soluble steel-factor (SLF) stimulation at 37 degrees C rapidly induced polyubiquitination of c-kit protein in growth-factor- dependent human-myeloid cell line M07e, resulting in smeared, retarded migration of c-kit protein in sodium dodecyl sulfate-polyacrylamide gel electrophoresis in the molecular weight region of 145 kD. Receptor ubiquitination was almost completely absent when cells were treated with SLF at 4 degrees C or at 37 degrees C in the presence of 0.2% sodium azide, or when the cells were pretreated with anti-c-kit monoclonal antibody or genistein, a tyrosine-kinase inhibitor. This suggested that c-kit ubiquitination was ligand dependent and appeared to require intrinsic tyrosine-kinase activation of the c-kit protein. Flow-cytometric analysis of c-kit expression on the cell surface of M07e cells showed down modulation of c-kit within 5 minutes after soluble-SLF treatment at 37 degrees C. However, rapid receptor down modulation was almost completely suppressed when cells were treated with SLF at 4 degrees C or at 37 degrees C in the presence of 0.2% sodium azide, conditions that concomitantly suppressed polyubiquitination of c-kit protein. In addition, these conditions almost completely suppressed radiolabeled SLF (125I-SLF) internalization after ligand-receptor interaction. Pulse-chase studies of 35S-methionine-labeled c-kit protein showed that SLF stimulation at 37 degrees C strikingly enhanced c-kit degradation (T1/2; approximately 20 minutes) compared with that in cells stimulated with SLF at 4 degrees C or at 37 degrees C with 0.2% sodium azide. However, in the presence of chloroquine, which blocks lysosomal degradation, this ligand-induced c-kit degradation at 37 degrees C was only suppressed in part. These data suggest that SLF-induced polyubiquitination of the c- kit receptor protein may play a role in regulation of c-kit-encoded protein-receptor expression in M07e cells.     

δ-aminolevulinate dehydratase activity in lung cancer patients and its relationship with oxidative stress

This study investigated the δ-aminolevulinate dehydratase (δ-ALA-D) activity in whole blood as well as the parameters of oxidative stress, such as reactive species (RS) levels in serum, thiobarbituric acid reactive substances (TBARS) levels, the superoxide dismutase (SOD) and catalase (CAT) activities, as well as total thiols (T-SH) and non-protein thiols (NPSH) levels in platelets. Moreover, the content of vitamin C and E in plasma and serum, respectively, in lung cancer patients was also investigated. We collected blood samples from patients (n = 28) previously treated for lung cancer with chemotherapy. Patients were classified as stage IIIb and IV according to the Union for International Cancer Control (UICC). Results showed a decrease of 37% in δ-ALA-D activity in patients with lung cancer when compared to the control group. RS and TBARS levels were 8% and 99% higher in the patient group, respectively. The activity of SOD and CAT as well as the vitamin C content were 41%, 35% and 127% lower in patients when compared with controls, respectively. However, T-SH and vitamin E levels were 27% and 44% higher in lung cancer patients, respectively. Results show that the overproduction of reactive species in patients with lung cancer may be interfering with the activity of δ-ALA-D. Likewise, the decrease in the activity of this enzyme may be contributing for the oxidative stress.     

Pathology after eculizumab in dense deposit disease and C3 GN

Eculizumab might benefit C3 glomerulopathies mediated by dysregulation of the alternative complement pathway. Here, we report renal biopsy findings before and after eculizumab therapy in three patients with dense deposit disease and two with C3 GN. All pretreatment biopsies had glomerular and tubular basement membrane deposits that stained exclusively for C3 without significant Ig. After 1 year of therapy, there was reduction in active glomerular proliferation and neutrophil infiltration in three of five patients, consistent with effective C5 blockade, which prevents production of chemotactin C5a. One individual with mild mesangial disease had no significant change in activity or chronicity. One patient exhibited persistent activity and worsening chronicity despite therapy. Immunofluorescence showed no significant reduction in C3 or C5b-9, and electron microscopy revealed persistent deposits in all cases, suggesting a long t(1/2) of C5b-9 in extracellular matrix. Normal renal biopsies stained positive for C5b-9 in glomeruli, tubular basement membranes, and vessel walls, albeit at lower intensity than in C3 glomerulopathy. This indication of physiologic levels of C5b-9 activation in normal kidney potentially explains the localization of deposits in patients with dysregulation of the alternative complement pathway. All post-treatment biopsies showed de novo monoclonal staining for IgG-κ in the same distribution as C3 and C5b-9, mimicking monoclonal Ig deposition disease (MIDD). Staining of the γ heavy chain was restricted to the IgG2 and IgG4 subclasses, suggesting the binding of monoclonal eculizumab to C5 in renal tissues. The long-term effects of this apparent drug-tissue interaction are unknown.     

Leiomyosarcoma of the deep femoral vein. A rare cause of venous obstruction in lower limbs and an alternative diagnosis to chronic venous thrombus

Primary venous leiomyosarcoma of the extremities is an uncommon, but aggressive, tumoral entity with a high rate of local recurrence and early hematogenous metastasis. In the present article, we report a case of leiomyosarcoma of the vena profunda femoris. This pathology causes deep venous thrombosis-like symptoms. No improvement in lower limb status and a significant and progressive increase in the diameter of the vein as seen using ultrasonography could indicate tumor disease. Particular care must be taken to avoid biopsies due to the possible dissemination. We must complete the medical study with imaging techniques, and the tumor must be removed as soon as possible for histopathological diagnosis. After a follow-up of 12 months, there was no evidence of local or metastatic recurrence in our patient.     

Mechanisms Involved in the Development and Healing of Diabetic Foot Ulceration

We examined the role of vascular function and inflammation in the development and failure to heal diabetic foot ulcers (DFUs). We followed 104 diabetic patients for a period of 18.4 ± 10.8 months. At the beginning of the study, we evaluated vascular reactivity and serum inflammatory cytokines and growth factors. DFUs developed in 30 (29%) patients. DFU patients had more severe neuropathy, higher white blood cell count, and lower endothelium-dependent and -independent vasodilation in the macrocirculation. Complete ulcer healing was achieved in 16 (53%) patients, whereas 13 (47%) patients did not heal. There were no differences in the above parameters between the two groups, but patients whose ulcers failed to heal had higher tumor necrosis factor-α, monocyte chemoattractant protein-1, matrix metallopeptidase 9 (MMP-9), and fibroblast growth factor 2 serum levels when compared with those who healed. Skin biopsy analysis showed that compared with control subjects, diabetic patients had increased immune cell infiltration, expression of MMP-9, and protein tyrosine phosphatase-1B (PTP1B), which negatively regulates the signaling of insulin, leptin, and growth factors. We conclude that increased inflammation, expression of MMP-9, PTP1B, and aberrant growth factor levels are the main factors associated with failure to heal DFUs. Targeting these factors may prove helpful in the management of DFUs.Diabetic foot ulcers (DFUs) are one of the most common and serious complications of diabetes and affects 15% of all diabetic patients, leading to >80,000 amputations per year in the U.S. and results in a high financial burden (1,2). Neuropathy, peripheral vascular disease, and reduced resistance to infection are recognized risk factors leading to the development of DFUs, which have all the characteristics of a chronic wound (3,4).In the current study, we have well characterized and prospectively followed-up a large number of diabetic patients, the majority of whom were at risk for developing foot ulceration. Our main hypothesis was that changes in the peripheral nerve function and the diabetes-associated proinflammatory state are related not only to the development of DFUs but also to wound-healing failure.