Time of Dropout From the Liver Transplant List in Patients With Hepatocellular Carcinoma: Clinical Behavior According to Tumor Characteristics and Severity of Liver Disease.

BACKGROUND: Prolonged time on the waiting list affects post-transplant survival of patients with hepatocellular carcinoma (HCC). However, it is not yet known which patients will be at higher risk for early dropout from the list. We investigate specific risk factors for early waiting list dropout in patients with HCC. METHODS: This was a single-center, intention-to-treat analysis of adults with HCC, within the Milan criteria, from July 2006 through September 2013. Patients were divided into groups according to waiting list time. The main end point was dropout from the list. RESULTS: The dropout rates of the study cohort at 3, 6, and 12-months were 6.4%, 12.4%, and 17.7%, respectively. Patients who dropped out from the list tended to be older, with blood types A and O, and with higher Child-Pugh and Model for End-Stage Liver Disease (MELD) scores. They also had larger nodules, responded poorly to trans-arterial chemo-embolization (TACE), and had a higher alpha-fetoprotein. Those with blood types B and AB appeared to be protected for dropout (odds ratio [OR] = 0.21, P = .02). Patients who responded to TACE were also protected (OR = 0.22, P < .001). When we looked into time to dropout, the only baseline characteristic that stood out was a higher MELD score (13 for those dropping out up to 90 days vs 10 for those dropping out after 180 days, P = .0025). CONCLUSIONS: We conclude that patients who drop out early from the list are primarily driven by the severity of liver disease. Patients who had progressive HCC had a high tumor load and poor response to loco-regional therapies, dropping out from the list after 180 days of inclusion.

A randomised controlled trial of periconal eye blockade with or without ultrasound guidance.

We randomly allocated 129 participants with normal eyes to periconal blockade with (n = 69) or without (n = 60) ultrasound guidance before cataract surgery. There was no difference in the rates of complication, 1/69 and 0/60, respectively, p = 1.0. The rate of intraconal needle placement was 1/69 with ultrasound and 12/60 without ultrasound, a relative risk (95% CI) of 0.07 (0.01-0.55), p < 0.0001.

Response to transarterial chemoembolization in candidates with hepatocellular carcinoma within Milan criteria does not predict post-transplant disease-free survival.

INTRODUCTION: Few groups have studied the impact of pretransplant transarterial chemoembolization (TACE) in the outcomes of liver transplant recipients with hepatocellular carcinoma (HCC). We verified whether response to TACE in HCC candidates impacts post-transplant disease-free survival. METHODS: This a single center retrospective study of patients who underwent liver transplantation from 2006-2013. Included were those transplanted due to HCC within the Milan criteria who were treated with TACE in the pre-transplant period. Response to TACE followed the modified RECIST (mRECIST) criteria. Disease free-survival was the main endpoint of the study. RESULTS: We included 187 patients in this study. The population had an average age of 57.5 years, predominantly formed by men (82.5%), with an average IMC of 26.7, MELD of 13, with viral hepatitis as main cause of liver disease. Average waiting time was 253 days and follow-up was 27.3 months. Based on response to TACE, 3-year disease-free survival was 84.1% for those with complete response to TACE, 84.1% for those with partial response to TACE, 85.7% for those with stable disease and 100% for patients with progressive disease. Multivariate analysis did not identify response to TACE as a predictor of disease-free post-transplant survival. CONCLUSIONS: Response to TACE in candidates with HCC within Milan criteria does not predict post-transplant disease-free survival.

Dydrogesterone does not reverse the cardiovascular benefits of percutaneous estradiol.

OBJECTIVE: To evaluate the influence of dydrogesterone on estimated cardiovascular risk of users of hormone replacement therapy (HRT) (with percutaneous 17ß-estradiol in monotherapy and in combination with dydrogesterone) and HRT non-users through the Framingham score tool for a period of 2 years. METHODS: Framingham scores were calculated from the medical records of patients treated for at least 2 years with 17ß-estradiol alone or in combination with dydrogesterone, along with HRT non-users, through the analysis of patient medical records, followed for at least 2 years at Instituto Estadual de Diabetes e Endocrinologia Luiz Capriglione. RESULTS: Improvements in lipid profile, glucose and blood pressure levels, which reduced the estimated cardiovascular risk, were observed in the 17ß-estradiol group. Similar changes were observed in the users of 17ß-estradiol + dydrogesterone, suggesting that this progestogen does not attenuate the effects caused by 17ß-estradiol. CONCLUSIONS: Both HRT groups showed a reduction in their Framingham score. In contrast to data from other HRT investigations on cardiovascular risk, these formulations proved to be safe, even in the first year of use.

Treatment of advanced hepatocellular carcinoma with very low levels of amplitude-modulated electromagnetic fields.

BACKGROUND: Therapeutic options for patients with advanced hepatocellular carcinoma (HCC) are limited. There is emerging evidence that the growth of cancer cells may be altered by very low levels of electromagnetic fields modulated at specific frequencies. METHODS: A single-group, open-label, phase I/II study was performed to assess the safety and effectiveness of the intrabuccal administration of very low levels of electromagnetic fields amplitude modulated at HCC-specific frequencies in 41 patients with advanced HCC and limited therapeutic options. Three-daily 60-min outpatient treatments were administered until disease progression or death. Imaging studies were performed every 8 weeks. The primary efficacy end point was progression-free survival 6 months. Secondary efficacy end points were progression-free survival and overall survival. RESULTS: Treatment was well tolerated and there were no NCI grade 2, 3 or 4 toxicities. In all, 14 patients (34.1%) had stable disease for more than 6 months. Median progression-free survival was 4.4 months (95% CI 2.1-5.3) and median overall survival was 6.7 months (95% CI 3.0-10.2). There were three partial and one near complete responses. CONCLUSION: Treatment with intrabuccally administered amplitude-modulated electromagnetic fields is safe, well tolerated, and shows evidence of antitumour effects in patients with advanced HCC.

The potential role of increased adrenal volume in the pathophysiology of obesity-related type 2 diabetes.

The hypothalamic-pituitary-adrenal (HPA) axis seems to play an important role in obesity and Type 2 diabetes (DM). The aim of the present study was to determine the adrenal volume in obese patients with DM in comparison to obese non-diabetic patients. Eleven diabetic obese and 19 non-diabetic obese women were sequentially invited to take part in the study. Computed tomography (CT) scan of the abdomen was performed to determine adrenal volume, visceral (VF) and sc fat (SCF). Daily urinary free cortisol (UFC) was used as a measure of integrated cortisol production. In the diabetic patients, hemoglobin A1c was measured as an index of metabolic control. Compared to nondiabetic controls, patients with diabetes had a significantly higher total adrenal volume (4.29+/-1.50 vs 2.95+/-1.64; p=0.03). A highly significant correlation was detected between VF and VF/SCF ratio and total adrenal volume in the whole group (r=0.36, p=0.04 and r=0.48, p=0.008, respectively). This study, therefore, suggests an association between abdominal obesity, enlarged adrenals and Type 2 diabetes. These findings support the hypothesis that an increased activity of the HPA axis in obese subjects may be involved in the pathogenesis of Type 2 diabetes.

Ultrastructure of the salivary glands of Rhodnius domesticus Neiva & Pinto, 1923 (Hemiptera: Reduviidae).

The fine structure of the salivary glands of the triatomine bug Rhodnius domesticus was investigated. Stereomicroscopy and scanning electron microscopy showed that each salivary gland pair contains two close and independent units: the larger is reddish and elongated (principal gland), while the smaller is round and translucent (accessory gland). The accessory gland opens at the base of the main excretion duct, which arises at the medial portion of the principal gland. An accessory duct emerges at the base of the main excretion duct, above the accessory gland opening, and runs towards the digestive tract. Transmission electron microscopy showed that both gland units are formed by a single layer of epithelial gland cells, surrounded by a thick basal lamina containing tracheolae and muscle cell fibers. Adjacent gland cells are interconnected by interdigitations of their lateral plasma membranes and by septate junctions. Microvilli are present at the apical domain of the gland cell plasma membrane, which allow faster diffusion of the saliva towards the gland lumen. Several mitochondria, abundant endoplasmic reticulum profiles and usually one elongated nucleus are observed in the gland cells. According to standard nomenclatures, the salivary gland cells can be classified as type I cells, secreting the saliva into a large gland lumen.

Lipid distribution in salivary glands of larvae and adult bees (Hymenoptera: Apidae).

Cytochemical studies were carried out to establish lipid distribution in the salivary glands of larvae and adult bees, using the imidazole buffer technique. In the duct cells of the larval salivary gland, the reaction was positive in the epicuticle and negative in the glandular lumen. The absence of smooth endoplasmic reticulum and the presence of lipids in the intercellular space suggest that lipids absorbed from the haemolymph could be used in the constitution of the epicuticle, after having been conveyed through the epithelium. In adult workers (new-emerged, nurse and forager workers), the head salivary glands presented a positive reaction in the secretion in glandular lumen, identifying its lipidic nature.

Autoimmune keratolysis in a patient with leukocytoclastic vasculitis: unusual erythema elevatum diutinum with granulomatous pattern.

PURPOSE: Leukocytoclastic vasculitis (LCCV) is an immune complex-mediated, small vessel disease that is clinically characterized by the presence of palpable purpuric lesions, most often in association with rheumatic diseases. Ocular manifestations of LCCV are rare. METHODS: We describe a patient with an unusual granulomatous pattern of erythema elevatum diutinum (EED) associated with autoimmune keratolysis. RESULTS: We studied a 64-year-old man with decreased visual acuity and nodular lesions in both hands. Ocular examination revealed bilateral superior corneal melting with perforation in the left eye and conjunctival thickening in both eyes, in association with a severe inflammatory reaction. Histopathologic examination of the conjunctiva revealed granulomatous vasculitis with neutrophilic infiltrate, giant cells, and fibroblastic proliferation. A punch biopsy taken from his skin showed similar characteristics that suggested EED; however, there were no giant cells. CONCLUSION: To our knowledge, autoimmune keratolysis secondary to cutaneous LCCV (EED) has not been described previously, and there has been no description of granulomatous reaction (in the conjunctiva) in EED.

Use of optical coherence tomography (OCT) and indirect ophthalmoscopy in the diagnosis of macular edema in diabetic patients.

OBJECTIVES: To evaluate the use of Optical Coherence Tomography (OCT) in the diagnosis of macular edema (ME) in diabetic patients in comparison to indirect ophthalmoscopy (IO) and, in addition, to study the characteristics of these patients. METHODS: 165 patients were randomly selected to join the study in 1998. Ophthalmological, clinical and laboratory examinations were performed for all these patients. RESULTS: Diabetic retinopathy was identified in 143 eyes (44.7%) and ME in 58 (18.3% of the total and 40.5% of the patients with retinopathy). 82.7% (48) of the eyes with ME could be diagnosed with OCT, against 62.0% (36) with IO. Haemoglobin A1c was the only variable that showed a significant association with ME, when compared to control (p < 0.05). Retinopathy was associated with the presence of nephropathy (p = 0.01) and neuropathy (p = 0.001), but ME was not (NS for both). 68% of patients without ME had a visual acuity of more than 50%. CONCLUSIONS: OCT is a new method that can help the evaluation of ME in diabetic patients. It can be used not only to diagnose the lesion, but also to follow up the patients during treatment. High levels of haemoglobin A1c might be associated with the presence of ME. Diabetic complications (nephropathy and neuropathy) are associated with retinopathy but not with macular edema.

Alpha-ketoisocaproate increases the in vitro 32P incorporation into intermediate filaments in cerebral cortex of rats.

In this study we investigated the effects of alpha-ketoisocaproic (KIC), alpha-ketoisovaleric (KIV) and alpha-keto-beta-methylvaleric (KMV) acids on the phosphorylation of intermediate filament (IF) proteins of cerebral cortex of rats. Tissue slices were incubated with [32P] orthophosphate in the presence or absence of the acids. The intermediate filament enriched cytoskeletal fraction was isolated and the radioactivity incorporated into neurofilament subunits, vimentin and glial fibrillary acidic protein was measured. Results demonstrated that KIC significantly increased phosphorylation of these proteins whereas the other acids had no effect. Experiments using protein kinase inhibitors indicated that the effect of KIC was mediated by Ca2+/calmodulin- and cAMP-dependent protein kinases. This study provides evidence that KIC, a key metabolite accumulating in maple syrup urine disease, increases phosphorylation of IF proteins.

Hemorrhagic ascites associated with endometriosis. A case report.

BACKGROUND: Endometriosis associated with massive, bloody ascites is an unusual occurrence. This report draws attention to this condition as a complication of endometriosis, with the description of a case and a review of 31 others. CASE: A 41-year-old, black nulligravida with massive, bloody ascites and a pelvic mass underwent laparotomy, and an intraoperative microscopic examination ruled out malignancy. The histologic report was compatible with endometriosis. The patient was treated with a GnRH analog, with progressive reduction of ascitic fluid and full remission after six months. CONCLUSION: Bloody ascites should be considered a complication of endometriosis, especially in nulliparous women of childbearing age with abdominal distention, a pelvic mass, dysmenorrhea, abdominal pain, weight loss and eventual pleural effusion, suggesting a diagnosis of ovarian malignancy.

Phenylalanine inhibition of the phosphorylation of cytoskeletal proteins from cerebral cortex of young rats is prevented by alanine.

BACKGROUND: Phenylalanine has been considered the main responsible agent for the brain damage that occurs in phenylketonuria. METHODS AND RESULTS: In this work we studied the effect of this amino acid on the in vitro phosphorylation of cytoskeletal proteins of the cerebral cortex of rats. We observed that 2 mM phenylalanine, a concentration usually found in the plasma of phenylketonuric patients, decreased the in vitro 32P incorporation into these proteins. In addition, we investigated the effect of alanine on the inhibition of 32P incorporation into cytoskeletal proteins caused by phenylalanine. We observed that 0.5 mM alanine did not alter 32P incorporation but prevented the inhibition provoked by phenylalanine. CONCLUSION: In case the inhibition of cytoskeletal protein phosphorylation by phenylalanine also occurs in human phenylketonuria, it is possible that alanine supplementation to the phenylalanine-restricted diet may be beneficial to these patients.

Methylmalonic and propionic acids increase the in vitro incorporation of 32P into cytoskeletal proteins from cerebral cortex of young rats through NMDA glutamate receptors.

In this study we investigated the effects of methylmalonic acid (MMA) and propionic acid (PA) on the phosphorylation of cytoskeletal proteins of cerebral cortex of rats. Slices of tissue were incubated with 32P-orthophosphate in the presence or absence of glutamate, MMA, PA and ionotropic or metabotropic glutamate receptor agonists. The cytoskeletal fraction was isolated and the radioactivity incorporated into the cytoskeletal proteins was measured. Results demonstrated that the acids, glutamate and NMDA increased the phosphorylation of the proteins studied. However, this effect was not observed for non-NMDA ionotropic agonists or metabotropic agonists. Experiments using glutamate receptor antagonists confirmed that MMA and PA at the same concentrations as found in tissues from propionic or methylmalonic acidemic children increase the phosphorylation of cytoskeletal proteins, possibly via NMDA glutamate receptors. Therefore, it is feasible that these findings may be related to the neurological dysfunction characteristic of these disorders.

Effects of neonatal cerebral hypoxia-ischemia on the in vitro phosphorylation of synapsin 1 in rat synaptosomes.

Synapsins are phosphoproteins related to the anchorage of synaptic vesicles to the actin skeleton. Hypoxia-ischemia causes an increased calcium influx into neurons through ionic channels gated by activation of glutamate receptors. In this work seven-day-old Wistar rats were submitted to hypoxia-ischemia and sacrificed after 21 hours, 7, 30, or 90 days. Synaptosomal fractions were obtained by Percoll gradients and incubated with 32P (10 microCi/g). Proteins were analysed by SDS-PAGE and radioactivity incorporated into synapsin 1 was counted by liquid scintillation. Twenty-one hours after hypoxia-ischemia we observed a reduction on the in vitro phosphorylation of synapsin 1, mainly due to hypoxia, rather than to ischemia; this effect was reversed at day 7 after the insult. There was another decrease in phosphorylation 30 days after the event interpreted as a late effect of hypoxia-ischemia. No changes were observed at day 90. Our results suggest that decreased phosphorylation of synapsin 1 could be related to neuronal death that follows hypoxia-ischemia.

Acute effects of ethanol and ethanol plus furosemide on pancreatic capillary blood flow in rats.

The effects of intravenous ethanol and ethanol plus furosemide on pancreatic capillary blood flow (PCBF) were investigated using a laser-Doppler flowmeter. Forty Sprague-Dawley male rats were divided into 4 groups: (1) control, (2) 80% ethanol, (3) 80% ethanol plus furosemide, and (4) furosemide. Mean arterial blood pressure and heart rate were monitored. Levels of serum amylase, calcium, electrolytes, ethanol, and furosemide (groups 3 and 4) were measured, and samples of pancreatic tissue were obtained. The ethanol and furosemide levels were statistically different (p < 0.05). PCBF significantly decreased (p < 0.05) in group 2, increased (p < 0.05) in group 3, and did not differ (p > 0.05) between groups 1 and 4. Histopathologic analysis revealed swollen acini in group 2 and sparse focal necrosis without acinar swelling in group 3. The depressant effect of ethanol on PCBF may be the result of its direct action on pancreatic cells causing edema and capillary compression rather than on primary vascular control mechanisms that adjust blood flow. Furosemide counters this effect.

Action of alpha-methyldopa on human umbilical circulation in vitro.

To determine the possible effects of alpha-methyldopa on the motility of human umbilical artery, a total of 53 arterial segments were perfused with different concentrations of the drug as follows: 38 segments with 125, 250 and 500 ng/ml of the drug, 9 segments with 500 ng/ml alpha-methyldopa in combination with 10(-7) M yohimbine, and 6 segments with 10(-7) M yohimbine alone. alpha-Methyldopa had a vasoconstrictor effect at all doses employed, with a clear dose-effect correlation (p less than 0.01). The vasoconstrictor effect of 500 ng/ml alpha-methyldopa was fully inhibited in the presence of 10(-7) M yohimbine. These results suggest that alpha 2-adrenergic receptors are present in the umbilical circulation and that alpha-methyldopa may play a role in the control of this circulation.

Estriol reduces the reactivity of the human umbilical artery to mechanical stimuli.

The effect of estriol on the reactivity of the human umbilical artery to mechanical stimulation was studied using an in vitro perfusion method. The mechanical stimuli were produced by force applied to the outer surface of the vessel through a system consisting of a lever with equal length arms which was activated by small weights of known mass placed on one of the arms. The contractions of the preparations were proportional to the weights applied. When a 0.5-gram stimulus was applied, the mean contractile response of seven preparations was 46.7 +/- 2.72 mm Hg (mean +/- SEM). The addition of 10 micrograms/ml estriol to the nutrient fluid (Tyrode) caused a (mean 6.8 +/- 1.32 mm Hg) reduction of the response to the mechanical stimuli. We suggest that estrogens, and estriol in particular, play an important role in the modulation of the reactivity of the human umbilical artery during pregnancy in the presence of the mechanical stimulation caused by intrauterine fetal movements.

Measurement of T4, T3 and reverse T3 levels, resin T3 uptake, and free thyroxin index in blood from the intervillous space of the placenta, in maternal peripheral blood, and in the umbilical artery and vein of normal parturients and their conceptuses.

T4, T3, and reverse T3 (rT3) levels and the free thyroxine index were measured in blood collected from the intervillous space (IVS) after placental expulsion and compared to the values in maternal peripheral blood and in umbilical artery and umbilical vein of 21 clinically normal parturients and their conceptuses. T4 levels in maternal peripheral blood did not differ significantly from T4 levels in the IVS, but were significantly higher than those detected in umbilical vein and artery (p less than 0.05). There was no difference in T4 levels between umbilical vein and artery. The free thyroxine index was similar for the maternal compartments (maternal peripheral blood and IVS), but differed significantly from the fetal compartments (umbilical vein and umbilical artery). T3 levels in maternal peripheral blood were significantly higher than in the IVS, both of these values being significantly higher than in the fetal compartments. There was no difference in T3 levels between umbilical vein and artery. rT3 levels of maternal peripheral blood were one third that of the IVS (p less than 0.05). rT3 levels of the umbilical vein were 1.5 times higher than those of the IVS (p less than 0.05) and 5.2 times higher than those of maternal peripheral blood (p less than 0.005). No significant difference was obtained between umbilical vein and artery. The increase in rT3 and the decrease in T3 in the IVS in relation to maternal peripheral blood support the hypothesis that the placenta may preferentially convert T4 to rT3 at the expense of T3. The present data, however, do not permit the identification of the site where this conversion takes place.