Indwelling peritoneal catheters in patients with cirrhosis and refractory ascites.

BACKGROUND: The prevalence of spontaneous bacterial peritonitis (SBP) in hospitalised cirrhotics with ascites is 10-30%. Treatment for refractory ascites includes paracenteses, transjugular intrahepatic portosystemic shunt or drain placement; the latter is discouraged due to a perceived infection risk. AIM: This study aimed to evaluate the risk of bacterial peritonitis (BP) with peritoneal drains in patients with Child-Pugh class B or C cirrhosis and determine their impact on survival. METHODS: We conducted a retrospective review of end-stage liver disease (ESLD) patients with non-malignant, refractory ascites who had peritoneal drains placed for ≥3 days at Loyola University between 1999 and 2009. Cell counts were performed at drain placement and within 72 h. BP was defined as ascitic polymorphonuclear neutrophils >250/mm(3) . Univariate analysis assessed the association between demographics, laboratory markers and development of BP. Kaplan-Meier curve estimates by infection were constructed and survival distributions were compared using log-rank statistic. RESULTS: There were 227 drain placements during the study period. Twenty-two per cent were diagnosed with BP (12% had SBP at drain placement; 10% developed BP within 72 h). There was no association between BP and baseline characteristics. Patients who developed BP within 72 h of drain placement had 50% mortality at 5 months compared with 50 months in those without infection (log-rank P ≤ 0.003). CONCLUSION: In ESLD patients who received an indwelling peritoneal catheter, there was 10% risk of developing BP and significant mortality increase. Though placing drains is not the mainstay of treatment for refractory ascites, we confirm the theoretical adverse risk of peritoneal drains on infection and survival in cirrhotics.

Impact of structural and metabolic variations on the toxicity and carcinogenicity of hydroxy- and alkoxy-substituted allyl- and propenylbenzenes.

The metabolic fate of a compound is determined by numerous factors including its chemical structure. Although the metabolic options for a variety of functional groups are well understood and can often provide a rationale for the comparison of toxicity based on structural analogy, at times quite minor structural variations may have major consequences for metabolic outcomes and toxicity. In this perspective, the effects of structural variations on metabolic outcomes is detailed for a group of related hydroxy- and alkoxy-substituted allyl- and propenylbenzenes. These classes of compounds are naturally occurring constituents of a variety of botanical-based food items. The classes vary from one another by the presence or absence of alkylation of their para-hydroxyl substituents and/or the position of the double bond in the alkyl side chain. We provide an overview of how these subtle structural variations alter the metabolism of these important food-borne compounds, ultimately influencing their toxicity, particularly their DNA reactivity and carcinogenic potential. The data reveal that detailed knowledge of the consequences of subtle structural variations for metabolism is essential for adequate comparison of structurally related chemicals. Taken together, it is concluded that predictions in toxicological risk assessment should not be performed on the basis of structural analogy only but should include an analogy of metabolic pathways across compounds and species.

Recurrent laryngopyocele: CT-guided hookwire localization for re-excision surgery.

Laryngopyocele recurrence after initial surgical resection is a very rare occurrence. We present a case of recurrent laryngopyocele in which CT fluoroscopy-guided hookwire placement was used to facilitate resection. In this article, we illustrate the imaging findings of laryngopyocele, review the approach to management, and describe the CT fluoroscopy-guided hookwire placement procedure.

The fetal larynx and pharynx: structure and development on two- and three-dimensional ultrasound.

OBJECTIVES: To present a systematic approach for evaluating the fetal pharynx and larynx based on two- and three-dimensional ultrasound (2D-US and 3D-US) modalities, describing the sonographic appearance and function of the fetal upper respiratory tract and measuring the anatomical components of the pharynx and larynx. METHODS: Gravidae presenting from the late first trimester to mid-gestation for routine booked examinations with structurally normal singleton fetuses of confirmed gestational age were enrolled. Transabdominal 2D-US was performed for anatomical and functional evaluation of the pharynx and larynx. Color Doppler was used to show fluid motion in the target area. 3D-US (Voluson® E6 with RAB-4-8-D transducer) scans of the fetal neck were acquired during fetal quiescence and in the absence of movements of the pharynx and larynx. Multiplanar reconstruction (MPR) in post-processing allowed adjustment of the volume to obtain the coronal plane. After a learning period to understand the sonographic anatomy of the target area, we measured the pharynx width and height, the upper, middle and lower larynx width and the larynx height. Render mode was applied for spatial evaluation of the target area. We developed a new methodological approach for structured evaluation of the fetal pharynx and larynx based on five spatial planes: posterior and anterior coronal planes and high, mid and low axial planes. RESULTS: We examined 582 fetuses during the second trimester of pregnancy; target anatomy was imaged successfully in 218 patients at 11-24 gestational weeks. Acquisition added approximately 1 min to examination time. Rates of successful visualization and measurements increased significantly as pregnancy progressed, being 23% (46/194) at 11-13 weeks, 29% (69/240) at 14-16 weeks, 35% (18/51) at 17-19 weeks and 88% (85/97) at 20-24 weeks (P < 0.01). Pharynx components identified were: the sphenoid bone, pterygoid processes, constrictor muscles, piriform recesses and uvula. Larynx components identified were: the epiglottis, aryepiglottic folds, corniculate cartilages, arytenoid cartilages, cricoid cartilage, thyroid cartilage and vocal cords. MPR showed the biconcave shape of the uvula, which may explain the 'equals sign' observed on 2D-US. We observed the bilateral mode of movements of the constrictor muscles, aryepiglottic folds and vocal cords, and the bidirectional fluid jet flows through the larynx. Scatterplots of measured structures vs gestational age were created. Pharynx width ranged from 0.11 to 0.93 (mean ± SD, 0.48 ± 0.17) cm; pharynx height ranged from 0.23 to 2.01 (mean ± SD, 0.94 ± 0.34) cm; upper larynx width ranged from 0.04 to 0.37 (mean ± SD, 0.15 ± 0.07) cm; middle larynx width ranged from 0.08 to 0.77 (mean ± SD, 0.34 ± 0.16) cm; lower larynx width ranged from 0.05 to 0.64 (mean ± SD, 0.24 ± 0.11) cm; and larynx height ranged from 0.20 to 1.83 (mean ± SD, 0.71 ± 0.31) cm. All measurements were positively correlated with gestational age. CONCLUSIONS: The fetal larynx and pharynx can be evaluated thoroughly using 2D- and 3D-US modalities. Knowledge of normal anatomy, function and biometry may prove useful in the evaluation of anatomical or functional pathology involving the fetal upper respiratory tract. Recognition of anatomical anomalies may enhance fetal intervention such as balloon placement in cases of diaphragmatic hernia.

Spinal matrix metalloproteinase 3 mediates inflammatory hyperalgesia via a tumor necrosis factor-dependent mechanism.

Matrix metalloproteinases (MMPs) have been implicated in the modulation of synaptic plasticity, glial activation, and long-term potentiation in the CNS. Here we demonstrate for the first time a mechanism for the regulation of nociceptive processing by spinal MMP-3 during peripheral inflammation. We first determined by western blotting that the catalytic (active) form of MMP-3 (cMMP-3) is increased in lumbar spinal cord following peripheral inflammation in rats. The peripheral inflammation-induced thermal hyperalgesia and tactile hypersensitivity was transiently (2-3 h) attenuated by intrathecal (IT) pretreatment with either an MMP-3 inhibitor (NNGH), or a broad spectrum MMP inhibitor (GM6001). In addition, IT delivery of cMMP-3 evoked hypersensitivity, whereas the pro (enzymatically inactive) form of MMP-3 did not. This suggests a pro-algesic effect of spinal MMP-3 mediated by an enzymatic mechanism. This cMMP-3-induced hypersensitivity is concurrent with increased tumor necrosis factor (TNF) in the spinal cord. The hypersensitivity behavior is prevented by intrathecal etanercept (TNF blockade). Treatment with cMMP-3 resulted in an increase in TNF release from spinal primary microglial, but not astrocyte cultures. These findings thus present direct evidence implicating MMP-3 in the coordination of spinal nociceptive processing via a spinal TNF-dependent mechanism.

Added value of the gray-scale whirlpool sign in the diagnosis of adnexal torsion.

OBJECTIVE: Adnexal torsion is a common gynecologic emergency affecting females of all ages. Expedient diagnosis and treatment are important, particularly in young fertile patients to preserve ovarian viability. Classical parameters for the clinical and sonographic diagnosis of adnexal torsion have very high false-positive rates, approaching 50%. The sonographic 'whirlpool' sign has been shown to be effective for visualizing the torsed part in the prenatal diagnosis of malrotation of the midgut with volvulus, as well as scrotal and ovarian torsion. We aimed to evaluate the efficacy of the whirlpool sign in the diagnosis of torsion, as compared to a protocol based on 'classic' sonographic signs of torsion alone. METHODS: This was a retrospective chart review. Files of all patients who underwent laparoscopy for suspected torsion at our center between January 2006 and May 2009 were extracted and reviewed. Ultrasound reports were retrieved from our computerized database. Patients were assigned to the study group if the whirlpool sign had been investigated during pre-procedural evaluation or to the control group if only the standard protocol had been applied. RESULTS: Eighty women were referred for laparoscopy for suspected adnexal torsion during the study period. In 22 women the ultrasound investigation had included the whirlpool sign (study group) while 58 had been examined by the standard protocol (control group). Twenty women in the study group had a positive whirlpool sign on ultrasound, 18 of whom (90.0%) had confirmed torsion on laparoscopy. In the control group 32 of 58 (55.2%) women had confirmed torsion on laparoscopy. CONCLUSION: The addition of the sonographic whirlpool sign to the preoperative sonographic evaluation of patients with suspected torsion appears to improve the rate of true-positive diagnoses as confirmed by laparoscopy. Copyright © 2010 ISUOG. Published by John Wiley & Sons, Ltd.

A case of myelodysplastic syndrome in a liver transplant patient.

Although the incidence of (myelodysplastic syndrome (MDS)) is higher among heart and lung transplant recipients than the general population, the same has not been shown in liver transplant (OLT) patients. We present the second known case of MDS after OLT. Case reports of MDS in OLT were identified using PubMed. Patient data were gathered from the patient and the medical record. A 54-year-old Caucasian man underwent OLT in 2003 and again in 2004 for hepatitis C-related cirrhosis. In 2007, the patient developed weakness, malaise, and shortness of breath. Laboratory studies revealed pancytopenia. Bone marrow biopsy showed MDS, with refractory anemia and excess blasts-1. The patient underwent chemotherapy and reduction in immunosuppression without a clinical response. Our experience suggested that MDS, although rare, should be considered in the differential diagnosis of pancytopenia after OLT. Once diagnosed, immunosuppression reduction, chemotherapy, and even stem cell transplantation may be the appropriate treatment in selected candidates.

Review article: the diagnosis and management of alcoholic hepatitis.

BACKGROUND: Alcoholic hepatitis is a severe, cholestatic liver disease occurring in patients with alcohol abuse. Mortality is substantial; however, therapies may improve clinical outcomes. AIM: To provide an updated review of the epidemiology, diagnosis, staging and treatment of alcoholic hepatitis. METHODS: A MEDLINE literature search was performed to identify pertinent articles. Relevant clinical abstracts were also reviewed. RESULTS: Severe alcoholic hepatitis occurs in a small fraction of patients who abuse alcohol. The 28-day mortality ranges from 30% to 50% in most series. Diagnosis is generally based on clinical features, with a limited role for liver biopsy. Beneficial treatment options include alcohol abstinence and nutritional therapy. Despite variable results in clinical trials, corticosteroids and pentoxifylline appear to provide moderate survival benefit. Anti-tumour necrosis factor agents and antioxidants have not proven beneficial, and should be limited to clinical trials. Liver transplant is not a frequent option given the active or recent alcohol use. CONCLUSIONS: Severe alcoholic hepatitis is a clinically-diagnosed condition associated with significant mortality. Alcohol abstinence and nutritional therapy have been associated with improved clinical parameters and should be considered in all patients. Corticosteroid therapy and pentoxifylline therapy appear to show moderate survival benefit and should be considered as first-line therapeutic agents.

The FEMA GRAS assessment of alpha,beta-unsaturated aldehydes and related substances used as flavor ingredients.

This publication is the 12th in a series of safety evaluations performed by the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA). In 1993, the Panel initiated a comprehensive program to re-evaluate the safety of more than 1700 GRAS flavoring substances under conditions of intended use. Since then, the number of flavoring substances has grown to more than 2200 chemically-defined substances. Elements that are fundamental to the safety evaluation of flavor ingredients include exposure, structural analogy, metabolism, toxicodynamics and toxicology. Scientific data relevant to the safety evaluation for the use of aliphatic, linear alpha,beta-unsaturated aldehydes and structurally related substances as flavoring ingredients are evaluated. The group of substances was reaffirmed as GRAS (GRASr) based, in part, on their self-limiting properties as flavoring substances in food; their low level of flavor use; the rapid absorption and metabolism of low in vivo concentrations by well-recognized biochemical pathways; adequate metabolic detoxication at much higher levels of exposure in humans and animals; the wide margins of safety between the conservative estimates of intake and the no-observed-adverse effect levels determined from subchronic and chronic studies. While some of the compounds described here have exhibited positive in vitro genotoxicity results, evidence of in vivo genotoxicity and carcinogenicity occurs only under conditions in which animals are repeatedly and directly exposed to high irritating concentrations of the aldehyde. These conditions are not relevant to humans who consume alpha,beta-unsaturated aldehydes as flavor ingredients at low concentrations distributed in a food or beverage matrix.

The FEMA GRAS assessment of aromatic substituted secondary alcohols, ketones, and related esters used as flavor ingredients.

This publication is the 11th in a series of safety evaluations performed by the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA). In 1993, the Panel initiated a comprehensive program to re-evaluate the safety of more than 1700 GRAS flavoring substances under conditions of intended use. The list of GRAS substances has now grown to more than 2100 substances. Elements that are fundamental to the safety evaluation of flavor ingredients include exposure, structural analogy, metabolism, pharmacokinetics and toxicology. Flavor ingredients are evaluated individually and in the context of the available scientific information on the group of structurally related substances. In this monograph, a detailed interpretation is presented on the renal carcinogenic potential of the aromatic secondary alcohol alpha-methylbenzyl alcohol, aromatic ketone benzophenone, and corresponding alcohol benzhydrol. The relevance of these effects to the flavor use of these substances is also discussed. The group of aromatic substituted secondary alcohols, ketones, and related esters was reaffirmed as GRAS (GRASr) based, in part, on their rapid absorption, metabolic detoxication, and excretion in humans and other animals; their low level of flavor use; the wide margins of safety between the conservative estimates of intake and the no-observed-adverse effect levels determined from subchronic and chronic studies and the lack of significant genotoxic and mutagenic potential.

Urinary tract calculi and thresholds in carcinogenesis.

Numerous chemicals administered to rodents at relatively high doses produce urinary tract calculi, resulting in erosions or ulcerations of the urothelium, consequent regenerative hyperplasia, and ultimately tumors. This is a high-dose (threshold) phenomenon, which appears to occur more readily in rodents than in primates, including humans. Several anatomic and urinary physiologic differences between rodents and humans affect the quantitative extrapolation from results in rodent bioassays to human risk assessment. For most chemicals producing tumors by this mode of action, human exposures are significantly lower than would be expected to be required for production of calculi, and therefore pose no carcinogenic hazard to humans.

Alternative models for carcinogenicity testing: weight of evidence evaluations across models.

Twenty-one chemicals were evaluated by standardized protocols in 6 mouse models that have been sugggested as alternatives to the 2-year mouse bioassay. Included were genotoxic and nongenotoxic chemicals, carcinogens and noncarcinogens, immunosuppressive and estrogenic agents, peroxisome proliferators, and chemicals producing cancer in rodents by other mechanisms. Mice were sacrificed at the end of 6 to 12 months, depending on the model. Standardized histopathology, biostatistical analyses, and criteria for overall evaluation of the results were employed. The TgAC transgenic (dermal and oral administration), the Tg-rasH2 transgenic, the heterozygous p53 gene knockout, the homozygous XPA and homozygous XPA-heterozygous p53 gene knockout, and the neonatal mouse models were evaluated. The chemicals were also evaluated in the in vitro SHE assay. Comparison of the results between the various in vivo models suggest that they might have usefulness as screening bioassays for hazard identification for potential human carcinogens. They have the benefits of being quicker, less expensive, and involve fewer animals than the traditional 2-year mouse bioassay. They do not appear to be overly sensitive. However, they do not definitively distinguish between genotoxic and nongenotoxic carcinogens, and they do not have 100% specificity for identifying human carcinogens. Like the 2-year bioassay, the results from these models need to be evaluated in conjunction with other information on a chemical in an overall weight-of-evidence, integrated analytical approach to assess risk for human exposures.

Regulation of Apterous activity in Drosophila wing development.

Apterous is a LIM-homeodomain protein that confers dorsal compartment identity in Drosophila wing development. Apterous activity requires formation of a complex with a co-factor, Chip/dLDB. Apterous activity is regulated during wing development by dLMO, which competes with Apterous for complex formation. Here, we present evidence that complex formation between Apterous, Chip and DNA stabilizes Apterous protein in vivo. We also report that a difference in the ability of Chip to bind the LIM domains of Apterous and dLMO contributes to regulation of activity levels in vivo.

Alternative models for carcinogenicity testing.

The International Conference on Harmonisation Expert Working Group on Safety suggested that under certain circumstances, data from alternative assays could be used in safety evaluation in place of a second bioassay. Several alternatives were discussed. Six of these models were evaluated in a collaborative effort under the auspices of the Health and Environmental Sciences Institute (HESI) branch of the International Life Sciences Institute (ILSI). Standard protocols, pathology review, and statistical evaluations were developed. Twenty-one chemicals were evaluated, including genotoxic, nongenotoxic, carcinogenic, and noncarcinogenic chemicals. The models that were evaluated included the p53(+/-) heterozygous knockout mouse, the rasH2 transgenic mouse, the TgAC transgenic mouse (dermal and oral administration), the homozygous XPA knockout and the XPA/p53 knockout mouse models. Also evaluated were the neonatal mouse models and the Syrian Hamster Embryo (SHE) transformation assay. The results of this comprehensive study suggest that some of these models might be useful in hazard identification if used in conjunction with information from other sources in a weight of evidence, integrated analysis approach to risk assessment.

Effects of spectator ligands on the specific recognition of intrastrand platinum-DNA cross-links by high mobility group box and TATA-binding proteins.

The results presented describe the effects of various spectator ligands, attached to a platinum 1,2-intrastand d(GpG) cross-link in duplex DNA, on the binding of high mobility group box (HMGB) domains and the TATA-binding protein (TBP). In addition to cisplatin-modified DNA, 15-base pair DNA probes modified by [Pt(1R,2R-diaminocyclohexane)](2+), cis-[Pt(NH(3))(cyclohexylamine)](2+), [Pt(ethylenediamine)](2+), cis-[Pt(NH(3))(cyclobutylamine)](2+), and cis-[Pt(NH(3))(2-picoline)](2+) were examined. Electrophoretic mobility shift assays show that both the A and B domains of HMGB1 as well as TBP discriminate between different platinum-DNA adducts. HMGB1 domain A is the most sensitive to the nature of the spectator ligands on platinum. The effect of the spectator ligands on protein binding also depends highly on the base pairs flanking the platinated d(GpG) site. Double-stranded oligonucleotides containing the AG*G*C sequence, where the asterisks denote the sites of platination, with different spectator ligands are only moderately discriminated by the HMGB proteins and TBP, but the recognition of dsTG*G*A is highly dependent on the ligands. The effects of HMGB1 overexpression in a BG-1 ovarian cancer cell line, induced by steroid hormones, on the sensitivity of cells treated with [Pt(1R,2R-diaminocyclohexane)Cl(2)] and cis-[Pt(NH(3))(cyclohexylamine)Cl(2)] were also examined. The results suggest that HMGB1 protein levels influence the cellular processing of cis-[Pt(NH(3))- (cyclohexylamine)](2+), but not [Pt((1R,2R)-diaminocyclohexane)](2+), DNA lesions. This result is consistent with the observed binding of HMGB1a to platinum-modified dsTG*G*A probes but not with the binding affinity of HMGB1a and HMGB1 to platinum-damaged dsAG*G*C oligonucleotides. These experiments reinforce the importance of sequence context in platinum-DNA lesion recognition by cellular proteins.

Cisplatin: from DNA damage to cancer chemotherapy.

Cisplatin [cis-DDP, cis-diamminedichloroplatinum(II)] is a potent anticancer drug that has been used successfully to treat tumors of the head, neck, lungs, and genitourinary tract. The biological activity of cisplatin was discovered serendipitously more than 30 years ago, and since that time research efforts have focused on elucidating its mechanism of action. The present review provides a historical perspective of our attempts to understand this complex phenomenon and the results of recent work that guides our current activities in this field. Continued efforts to understand the mechanism of genotoxicity of cisplatin are expected to lead to the discovery of new drugs and combinations for the improvement of cancer chemotherapy.

Effect of sulfosulfuron on the urine and urothelium of male rats.

Sulfosulfuron, developed as a herbicide, caused increased microcrystalluria and the formation of urinary tract calculi when fed to male and female rats in a chronic 2-year study at doses of 5,000 ppm and 20,000 ppm. Hyperplasia was also seen in urinary bladders at 5,000 ppm and 20,000 ppm, almost exclusively in the presence of observable calculi/microcalculi. Urinary bladder tumors were found in 2 females in the 5000 ppm group, both in the presence of calculi. No increased microcrystalluria, calculi, or tumors were found at doses of 500 ppm and lower. In the current study, 5 groups of male Sprague-Dawley rats were fed sulfosulfuron at doses of 50, 500, 5,000, and 20,000 ppm for 10 weeks. Ten animals were co-administered 5,000 ppm sulfosulfuron with 12,300 ppm NH4Cl to determine if inhibition of the formation of calculi would prevent any urothelial effects of treatment with sulfosulfuron. Ten animals in the control group and in the high-dose sulfosulfuron group were fed only basal diet for an additional 10 weeks to determine if the effects of sulfosulfuron on the bladder epithelium were reversible. There was an increased incidence of microcrystalluria observed at 5,000 and 20,000 ppm. There was no increase in microcrystalluria observed in the urine of rats co-administered sulfosulfuron and NH4Cl. Urinary bladder calculi were found in the bladder of 1 animal fed 20,000 ppm. Examination by light microscopy showed diffuse papillary/nodular hyperplasia of the bladder epithelium in this animal. No increased microcrystalluria was observed after withdrawal of the chemical from the diet and the bladder epithelium was normal by light microscopy. The hyperplastic effects associated with the feeding of high doses of sulfosulfuron occur only with the appearance of urinary tract calculi. Based on these results and anatomical differences between rats and humans, it may be concluded that the hyperplastic and carcinogenic effects of sulfosulfuron in rats are high-dose, threshold phenomena that are not likely to occur in humans under environmentally relevant exposures.