Azapeptide activity-based probes for the SARS-CoV-2 main protease enable visualization of inhibition in infected cells.

The COVID-19 pandemic has revealed the vulnerability of the modern, global society. With expected waves of future infections by SARS-CoV-2, treatment options for infected individuals will be crucial in order to decrease mortality and hospitalizations. The SARS-CoV-2 main protease is a validated drug target, for which the first inhibitor has been approved for use in patients. To facilitate future work on this drug target, we designed a solid-phase synthesis route towards azapeptide activity-based probes that are capped with a cysteine-reactive electrophile for covalent modification of the active site of Mpro. This design led to the most potent ABP for Mpro and one of the most potent inhibitors reported thus far. We demonstrate that this ABP can be used to visualize Mpro activity and target engagement by drugs in infected cells.

Small molecule inhibitor of Igf2bp1 represses Kras and a pro-oncogenic phenotype in cancer cells.

Igf2bp1 is an oncofetal RNA binding protein whose expression in numerous types of cancers is associated with upregulation of key pro-oncogenic RNAs, poor prognosis, and reduced survival. Importantly, Igf2bp1 synergizes with mutations in Kras to enhance signalling and oncogenic activity, suggesting that molecules inhibiting Igf2bp1 could have therapeutic potential. Here, we isolate a small molecule that interacts with a hydrophobic surface at the boundary of Igf2bp1 KH3 and KH4 domains, and inhibits binding to Kras RNA. In cells, the compound reduces the level of Kras and other Igf2bp1 mRNA targets, lowers Kras protein, and inhibits downstream signalling, wound healing, and growth in soft agar, all in the absence of any toxicity. This work presents an avenue for improving the prognosis of Igf2bp1-expressing tumours in lung, and potentially other, cancer(s).

Rapid Covalent-Probe Discovery by Electrophile-Fragment Screening.

Covalent probes can display unmatched potency, selectivity, and duration of action; however, their discovery is challenging. In principle, fragments that can irreversibly bind their target can overcome the low affinity that limits reversible fragment screening, but such electrophilic fragments were considered nonselective and were rarely screened. We hypothesized that mild electrophiles might overcome the selectivity challenge and constructed a library of 993 mildly electrophilic fragments. We characterized this library by a new high-throughput thiol-reactivity assay and screened them against 10 cysteine-containing proteins. Highly reactive and promiscuous fragments were rare and could be easily eliminated. In contrast, we found hits for most targets. Combining our approach with high-throughput crystallography allowed rapid progression to potent and selective probes for two enzymes, the deubiquitinase OTUB2 and the pyrophosphatase NUDT7. No inhibitors were previously known for either. This study highlights the potential of electrophile-fragment screening as a practical and efficient tool for covalent-ligand discovery.

A multiplexed screening method for pluripotency.

Measurement of Alkaline Phosphatase (ALP) level is a widely used procedure in clinical and basic research. We present a simple and inexpensive luminescence-based method that allows multiplexed measurement and normalization of intracellular ALP levels in one sample well. The method comprises two commercially available reagents enabling quantification of ALP levels and cell number by two sequential luminescence readouts. Using this method we were able to detect and analyze somatic reprogramming into pluripotent stem cells. The method is highly applicable for High Throughput Screening (HTS) campaigns and analysis.

A generic, cost-effective, and scalable cell lineage analysis platform.

Advances in single-cell genomics enable commensurate improvements in methods for uncovering lineage relations among individual cells. Current sequencing-based methods for cell lineage analysis depend on low-resolution bulk analysis or rely on extensive single-cell sequencing, which is not scalable and could be biased by functional dependencies. Here we show an integrated biochemical-computational platform for generic single-cell lineage analysis that is retrospective, cost-effective, and scalable. It consists of a biochemical-computational pipeline that inputs individual cells, produces targeted single-cell sequencing data, and uses it to generate a lineage tree of the input cells. We validated the platform by applying it to cells sampled from an ex vivo grown tree and analyzed its feasibility landscape by computer simulations. We conclude that the platform may serve as a generic tool for lineage analysis and thus pave the way toward large-scale human cell lineage discovery.

Identification of a promising drug candidate for the treatment of type 2 diabetes based on a P2Y(1) receptor agonist.

The activation by extracellular nucleotides of pancreatic P2Y receptors, particularly, the P2Y(1)R subtype, increases insulin secretion. Therefore, we developed analogues of the P2Y(1)R receptor agonist 2-MeS-ADP, as potential antidiabetic drugs. Analogue 3A was found to be a potent P2Y(1)R agonist (EC(50) = 0.038 µM vs 0.0025 µM for 2-MeS-ADP) showing no activity at P2Y(2/4/6)Rs. Analogue 3A was stable at pH 1.4 (t(1/2) = 7.3 h) and resistant to hydrolysis vs 2-MeS-ADP by alkaline phosphatase (t(1/2) = 6 vs 4.5 h), human e-NPP1 (4% vs 16% hydrolysis after 20 min), and human blood serum (30% vs 50% hydrolysis after 24 h). Intravenous administration of 3A in naive rats decreased blood glucose from 155 mg/dL to normal values, ca. 87 mg/dL, unlike glibenclamide, leading to subnormal values (i.e., 63 mg/dL). Similar observations were made for streptozotocin (STZ)-treated and db(+)/db(-) mouse models. Furthermore, 3A inhibits platelet aggregation in vitro and elongates bleeding time in mice (iv administration of 30 mg of 3A/kg), increasing bleeding time to 16 vs 9 min for Prasugrel. Oral administration of 30 mg/kg 3A to rats increased tail bleeding volume, similar to aspirin. These findings suggest that 3A may be an effective treatment for type 2 diabetes by reducing both blood glucose levels and platelet aggregation.

Doppler ultrasound for the assessment of conservatively treated blunt splenic injuries: a prospective study.

INTRODUCTION: The type and need for follow-up of non-operatively managed blunt splenic injuries remain controversial. The use of Doppler ultrasound to identify post-traumatic splenic pseudoaneurysms, considered to be the main cause of "delayed" splenic rupture, has not been well described. PATIENTS AND METHODS: A 5-year prospective study was performed from 2004 to 2008. All patients with blunt splenic injury diagnosed with computerized tomography, who were treated non-operatively, were included in the study. Doppler ultrasound examination was performed 24-48 h post-injury. Consecutive Doppler ultrasound examinations were done on 7, 14 and 21 days post-injury for patients diagnosed with a splenic pseudoaneurysm. Demographic and clinical data were collected. Ambulatory follow-up continued for 4 weeks after hospital discharge. RESULTS: A total of 38 patients were enrolled in the study. Grading of splenic injury demonstrated 19 (50%) patients with Grade I, 16 (42%) with Grade II and 3 (8%) with Grade III injuries. Two patients (5%) had pseudoaneurysms. All pseudoaneurysms underwent complete resolution within 2 weeks after diagnosis. No patients received blood products, or had angio-embolization or surgery during the study period. All patients were found to be asymptomatic and stable at the 4-week follow-up. CONCLUSIONS: Doppler ultrasound can be an effective and a safe noninvasive modality for evaluation and follow-up of patients with blunt splenic injury. The utility and cost-effectiveness of routine surveillance requires further study.

A novel insulin secretagogue based on a dinucleoside polyphosphate scaffold.

Dinucleoside polyphosphates exert their physiological effects via P2 receptors (P2Rs). They are attractive drug candidates, as they offer better stability and specificity compared to nucleotides, the most common P2 receptor ligands. The activation of pancreatic P2Y receptors by nucleotides increases insulin secretion. Therefore, in the current study, dinucleoside polyphosphate analogues (di-(2-MeS)-adenosine-5',5''-P(1),P(4),alpha,beta-methylene-tetraphosphate), 8, (di-(2-MeS)-adenosine-5',5''-P(1),P(4),beta,gamma-methylene-tetraphosphate), 9, and di-(2-MeS)-adenosine-5',5''-P(1),P(3),alpha,beta-methylene triphosphate, 10, were developed as potential insulin secretagogues. Analogues 8 and 9 were found to be agonists of the P2Y(1)R with EC(50) values of 0.42 and 0.46 microM, respectively, whereas analogue 10 had no activity. Analogues 8-10 were found to be completely resistant to hydrolysis by alkaline phosphatase over 3 h at 37 degrees C. Analogue 8 also was found to be 2.5-fold more stable in human blood serum than ATP, with a half-life of 12.1 h. Analogue 8 administration in rats caused a decrease in a blood glucose load from 155 mg/dL to ca. 100 mg/dL and increased blood insulin levels 4-fold as compared to basal levels. In addition, analogue 8 reduced a blood glucose load to normal values (80-110 mg/dL), unlike the commonly prescribed glibenclamide, which reduced glucose levels below normal values (60 mg/dL). These findings suggest that analogue 8 may prove to be an effective and safe treatment for type 2 diabetes.

The E3 ubiquitin-ligase Bmi1/Ring1A controls the proteasomal degradation of Top2alpha cleavage complex - a potentially new drug target.

BACKGROUND: The topoisomerases Top1, Top2alpha and Top2beta are important molecular targets for antitumor drugs, which specifically poison Top1 or Top2 isomers. While it was previously demonstrated that poisoned Top1 and Top2beta are subject to proteasomal degradation, this phenomena was not demonstrated for Top2alpha. METHODOLOGY/PRINCIPAL FINDINGS: We show here that Top2alpha is subject to drug induced proteasomal degradation as well, although at a lower rate than Top2beta. Using an siRNA screen we identified Bmi1 and Ring1A as subunits of an E3 ubiquitin ligase involved in this process. We show that silencing of Bmi1 inhibits drug-induced Top2alpha degradation, increases the persistence of Top2alpha-DNA cleavage complex, and increases Top2 drug efficacy. The Bmi1/Ring1A ligase ubiquitinates Top2alpha in-vitro and cellular overexpression of Bmi1 increases drug induced Top2alpha ubiquitination. A small-molecular weight compound, identified in a screen for inhibitors of Bmi1/Ring1A ubiquitination activity, also prevents Top2alpha ubiquitination and drug-induced Top2alpha degradation. This ubiquitination inhibitor increases the efficacy of topoisomerase 2 poisons in a synergistic manner. CONCLUSIONS/SIGNIFICANCE: The discovery that poisoned Top2alpha is undergoing proteasomal degradation combined with the involvement of Bmi1/Ring1A, allowed us to identify a small molecule that inhibits the degradation process. The Bmi1/Ring1A inhibitor sensitizes cells to Top2 drugs, suggesting that this type of drug combination will have a beneficial therapeutic outcome. As Bmi1 is also a known oncogene, elevated in numerous types of cancer, the identified Bmi1/Ring1A ubiquitin ligase inhibitors can also be potentially used to directly target the oncogenic properties of Bmi1.

C-reactive protein distribution and correlates among men and women with chronic coronary heart disease.

BACKGROUND: C-reactive protein (CRP) elevated in inflammation is associated with atherosclerotic disease. We describe the distribution of CRP and its association with coronary heart disease (CHD) risk factors in a large CHD patient group. METHODS: This analysis comprises 2,723 male and 256 female CHD patients, included in the Bezafibrate Infarction Prevention (BIP) study. High sensitive CRP levels were determined in frozen plasma samples. RESULTS: CRP distribution, was normalized upon log transformation. Levels among women were higher than in men in the entire group (4.4 vs. 3.5 mg/l) and in each age group. Co-morbidities, smoking, lower education level, and use of cardiovascular drugs, were associated with elevated CRP levels in both sexes. The correlation between CRP and body mass index (BMI), insulin and glucose was stronger among women. The explained variability in CRP level was larger in women (20%) compared to men (13%). Among women, BMI explained 10% of CRP variability, whereas the contribution of each variable among men was significantly smaller. CONCLUSIONS: Among men and women with CHD, CRP level was correlated with traditional risk factors and to a lesser degree to manifestation of CHD. BMI is the main contributor to CRP variability, explained by these factors among women.

Endoscopic sphincterotomy and temporary internal stenting for bile leaks following complex hepatic trauma.

BACKGROUND: Biliary leak secondary to blunt or penetrating hepatic trauma and damage to the intrahepatic biliary tree remains a challenging problem. The role and safety of endoscopic retrograde cholangiopancreatography (ERCP) and stenting in this setting were studied. METHODS: All trauma victims who developed a bile leak secondary to hepatic trauma were included. Bile leak was defined as the appearance of bile in a surgical wound or intra-abdominal drain after surgery, following percutaneous drainage of a perihepatic bile collection, or evidence of a leak on hepatobiliary scintigraphy. ERCP was performed within 24 h of diagnosis and included biliary sphincterotomy and internal stenting. Recovery was defined as cessation of leakage. RESULTS: Between 1996 and 2004, six patients with penetrating injuries and five with blunt abdominal injuries were treated according to the study protocol. Eight underwent surgery to control bleeding or for additional intra-abdominal injuries. All bile leaks resolved completely within 10 days of ERCP. One patient died from pulmonary sepsis; ten recovered without hepatobiliary sequelae. CONCLUSION: ERCP, biliary sphincterotomy and temporary internal stenting, together with percutaneous drainage of intra-abdominal or intrahepatic bile collections, represent a safe and effective strategy for the management of bile leaks following both blunt and penetrating hepatic trauma.

The trans-Golgi network-associated human ubiquitin-protein ligase POSH is essential for HIV type 1 production.

HIV type 1 (HIV-1) was shown to assemble either at the plasma membrane or in the membrane of late endosomes. Now, we report an essential role for human ubiquitin ligase POSH (Plenty of SH3s; hPOSH), a trans-Golgi network-associated protein, in the targeting of HIV-1 to the plasma membrane. Small inhibitory RNA-mediated silencing of hPOSH ablates virus secretion and Gag plasma membrane localization. Reintroduction of native, but not a RING finger mutant, hPOSH restores virus release and Gag plasma membrane localization in hPOSH-depleted cells. Furthermore, expression of the RING finger mutant hPOSH inhibits virus release and induces accumulation of intracellular Gag in normal cells. Together, our results identify a previously undescribed step in HIV biogenesis and suggest a direct function for hPOSH-mediated ubiquitination in protein sorting at the trans-Golgi network. Consequently, hPOSH may be a useful host target for therapeutic intervention.

The impact of a resident's seniority on operative time and length of hospital stay for laparoscopic appendectomy: outcomes used to measure the resident's laparoscopic skills.

BACKGROUND: Laparoscopic appendectomy (LA) frequently is performed by residents during calls. This study aimed at evaluating residents' surgical skills using parameters of operating time, length of hospital stay (LOS), and conversion rate in correlation with the operating team's level of seniority. In addition, this study compared the operating time for LA with that for open appendectomy performed by the same teams, and identified deterministic factors that have an impact on such parameters. METHODS: All records of patients undergoing appendectomy performed by residents alone during a 32-month period were reviewed retrospectively. Eight residents were assigned to two levels of seniority: juniors 3 years (S). Operating time and LOS were compared between the three surgical teams, namely, J/J, J/S, and S/J as operating and assistant surgeons, respectively. Operating time, conversion rates, and LOS were compared for the same team combinations. RESULTS: Residents alone performed 341 (151 laparoscopic and 190 open) appendectomies during on-call hours. Four of the residents had been 3 years or less in residency (J), and four had been in residency more than 3 years (S). The overall mean operating time was 1.33 +/- 0.48 h for LA and 1.2 +/- 0.5 h for open appendectomy (p = 0.016). The operating time correlated with the level of training for both LA (J/J, 1.6 +/- 0.38 h; J/S, 1.41 +/- 0.37 h; S/J, 1. 25 +/- 0.4 h; p = 0.03, ANOVA) and open appendectomy (J/J, 1.53 +/- 0.89 h; J/S, 1.4 +/- 0.63 h; S/J, 0.86 +/- 0.45 h; p = 0.023, ANOVA). The mean LOS was 2.9 +/- 3.1 days for open appendectomy and 2.1 +/- 2.8 days for LA (p = 0.065), and was not different after operation by any of the teams (J/J, J/S, S/J) for either the open or the laparoscopic procedure. CONCLUSIONS: There is a distinct difference in the surgical skills of residents according to level of seniority, as primarily reflected by operating time. Laparoscopic appendectomy requires longer time to perform in a teaching setting, but the most deterministic factor that dictates operating time is the composition of the surgical team rather than the laparoscopic approach.

140 consecutive cases of minimally invasive, radio-guided parathyroidectomy: lessons learned and long-term results.

BACKGROUND: The advent of highly accurate parathyroid imaging and the ever-increasing trend towards minimally invasive procedures have changed considerably the surgical approach to the patient with primary hyperparathyroidism (PHPT) caused by a single parathyroid adenoma. This study analyzes the short- and longer-term results of 140 patients who underwent minimally invasive, radio-guided parathyroidectomy. METHODS: Demographic, clinical, and pre-operative imaging data, operative findings, and short- and long-term results of 140 consecutive patients operated within a 20 months period (8/1999-4/2002), were prospectively entered into a database. Immediate pre-operative sestamibi scintigraphy with skin marking of focal adenoma uptake were followed by intraoperative hand-held gamma probe for the removal of the parathyroid adenoma by unilateral minimal access surgery. Preoperative and surgical data were analyzed and correlated to outcomes, measured by success or failure to cure PHPT, associated morbidity and mortality, predictive value of localizing studies, and postoperative laboratory results in the immediate as well as long-term period. RESULTS: 140 patients, mean age: 55.1 +/- 14.1 years (range 19-88 years), female to male ratio 94:46 with PHPT proven by concomitantly elevated serum calcium and parathormone (PTH) levels, with a single adenoma identified by sestamibi single photon emission tomography (SPECT) scintigraphy and high-resolution sonography, underwent minimally invasive, radio-guided parathyroidectomy. Mean serum levels of preoperative calcium, phosphorus, and PTH were 11.6 +/- 0.8 mg/dL (range 9.1-14), 3.0 +/- 0.3 mg/dL, and 147.1 +/- 94.3 pg/mL (range 68-784), respectively. Overall, in 3 out of 140 patients (2.1%), focused, minimally invasive surgery failed to identify and remove the adenoma. Positive predictive value when both localizing modalities concurred was 99.2%. Positive predictive value of SPECT scan alone was 97.2%. Overall success rate was 97.8% (137/140). 24 hours postoperative mean serum calcium was 9.2 +/- 0.8 mg/dL and at 6 months mean serum calcium, phosphorus, and PTH were 9.4 +/- 1.06 mg/dL, 3.2 +/- 0.8 mg/dL, and 32.1 +/- 11.9 pg/mL, respectively (p = 0.0001). There was no mortality. In 2 patients (1.4%) there was transient vocal cord paresis and there were 8 instances of clinically significant hypocalcemia. In 3 cases (2.1%), a second adenoma manifested itself 9-14 months following surgery and was removed by minimal access procedure. CONCLUSIONS: Minimally invasive, radio-guided focused parathyroidectomy for a single adenoma is safe and effective in curing hyperparathyroidism with a 97% success rate. A second adenoma occurring in less than 3% may be successfully treated with a second minimal access operation. The combined positive predictive value of concurring sestamibi SPECT scintigraphy and sonography of 99.2% may increase success rate, and thus implementing this technique in patients with concurring sonography and scintigraphy may be advocated.

Pitfalls and complications with laparoscopic intraperitoneal expanded polytetrafluoroethylene patch repair of postoperative ventral hernia.

BACKGROUND: This study reviewed our experience with laparoscopic ventral postoperative (incisional) hernia repair. METHODS: Clinical data from the first 100 cases were analyzed retrospectively. RESULTS: Between 1997 and 2000, 64 women and 36 men (mean age, 58.4 +/- 13.6 years; range, 27-87 years) underwent laparoscopic hernioplasty. Hernias (mean diameter, 6.2 +/- 3.7 cm) were in a midline (74%), subcostal (10%), or other incision location, and were recurrent in 25%, of the patients. The mean operative time was 119 +/- 77 min. Extensive adhesiolysis was necessary in 37 cases. There was no mortality. The recorded complications included inadvertent enterotomies (n = 6), seromas (n = 11), prolonged ileus (n = 4), and prolonged fever (n = 3). Seven cases were converted; to repair accidental enterotomies (n = 4) due to difficult adhesiolysis (n = 2), or to control bleeding (n = 1). Six patients underwent reoperation because of enetric leak (n = 3) or bowel obstruction (n = 3). There were two documented recurrences (2%). The mean follow-up period was 19 months (range, 12-54 months). CONCLUSIONS: Laparoscopic intraperitoneal approach to postoperative ventral (incisional) hernia repair may be associated with significant complications and morbidity, which can be prevented in part by meticulous technique and liberal conversions. The justification of this procedure is the low recurrence rate, according to preliminary results.

Fibroadenoma of the breast: analysis of associated pathological entities--a different risk marker in different age groups for concurrent breast cancer.

BACKGROUND: Fibroadenoma, one of the most common benign breast lesions, has a characteristic age-specific incidence and is associated with other pathological entities in 50% of cases. The clinical or imaging diagnosis of fibroadenoma may be erroneous, and in some cases is found to be invasive cancer. The clustering of such entities, their correlation with age, and the risk of synchronous breast malignancy are uncertain. OBJECTIVE: To explore the possibility of any significant clustering of fibroadenoma-associated benign breast diseases and to assess the possible risk of concomitant breast cancer. METHODS: We analyzed the pathological results of 147 women undergoing excisional biopsies for fibroadenoma diagnosed pre-operatively either by clinical examination and imaging (n = 17) or by radiology alone (n = 30). The inter-relationships among all entities associated with fibroadenoma were studied by hierarchical cluster analysis. The correlation of the various pathologies with the risk of invasive breast cancer in relation to the patient's age was also evaluated. RESULTS: Fibroadenoma-associated pathologies were found in 48% of the cases: sclerosing adenosis (23%), duct ectasia (17.7%), apocrine metaplasia (15.6%), florid fibrocystic disease (12.9%), duct papillomatosis (11.6%), infiltrating duct carcinoma (5.4%), duct carcinoma in situ (3.4%), and 1 case of lobular carcinoma in situ (0.6%). An orderly internal hierarchy and three significant clusters emerged: a) epithelial apocrine metaplasia, duct ectasia and sclerosing adenosis (similarity coefficients 16.0, 11.0 and 8.0 respectively); b) papillomatosis, florid fibrocystic disease and calcifications (similarity coefficients of 6.0, 4.0 and 2.0 respectively); and c) infiltrating duct carcinoma and duct carcinoma in situ (similarity coefficients of 1.8 and 1.6 respectively). Seven of the eight patients with breast cancer were older than 40 years. CONCLUSIONS: In about half of the cases fibroadenoma was associated with other pathological entities clustered in an orderly hierarchy. The rarity of synchronous breast cancer in the younger age group and its more common association with fibroadenoma in the older age groups dictate a different approach to each. The finding of fibroadenoma in women older than 40 indicates the need for surgical excision.

Critical graft size in adult-to-adult living donor liver transplantation: impact of the recipient's disease.

The aim of this study is to analyze the impact of the recipient's disease severity on graft size requirements and outcome in adult-to-adult living donor liver transplantation. A limiting factor in adult-to-adult living donor liver transplantation has been adequacy of graft size. A minimal graft-recipient weight ratio (GRWR) of 0.8% to 1% has been suggested, without taking the recipient's disease into account. Forty adults underwent liver transplantation using left (n = 10; mean weight, 481 +/- 83 g) or right lobes (n = 30; mean weight, 845 +/- 182 g). We recorded graft survival, Child-Turcotte-Pugh score, and occurrence of small-for-size syndrome (poor bile production, prolonged postoperative prothrombin time, and cholestasis without ischemia markers). Small grafts were defined as GRWR of < or =0.85%. Large grafts were defined as GRWR greater than 0.85%. Six patients died within 6 months of transplantation (early patient survival rate, 85%); two patients died late of tumor recurrence. Among transplant recipients with normal liver function or Child's class A, there was no significant difference with the use of small (n = 6) or large (n = 9) grafts (graft survival rates, 83% v 88%, respectively; P =.65). Among patients with Child's class B or C, graft survival rates were 74% in recipients of large grafts (n = 19) and 33% in recipients of small grafts (n = 6; P =.023). Five of 6 patients with Child's class B or C who received small grafts developed small-for-size syndrome; 2 patients died (1 patient after retransplantation) and 3 patients survived (2 patients after retransplantation). Graft function and survival are influenced not only by graft size, but also by pretransplantation disease severity. GRWR as low as 0.6% can be used safely in patients without cirrhosis or in patients with Child's class A. Transplant recipients with Child's class B or C require a GRWR greater than 0.85% to avoid small-for-size syndrome and related complications.

Transepithelial intestinal excretion of ciprofloxacin in humans.

The excretion of ciprofloxacin in the small bowel was studied in 40 patients undergoing bowel surgery. Ciprofloxacin (200 mg) was administered iv, and intestinal samples were collected over a 120-min period. In ileal loops ciprofloxacin concentrations reached a peak of 4.0 mg/L, whereas in caecal fluid samples, concentrations were < 0.16 mg/L. Ciprofloxacin administered directly into the ileal and caecal loops did not result in measurable blood levels for 2 h. The results confirm that ciprofloxacin is selectively excreted into the small bowel.

Comparison of surgical outcomes for hepatocellular carcinoma in patients with hepatitis B versus hepatitis C: a western experience.

BACKGROUND: We reviewed our experience in patients with hepatocellular carcinoma (HCC) and chronic hepatitis to determine if differences exist in preoperative status and postoperative survival between those with hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. METHODS: We reviewed the records of 240 consecutive patients with HCC who underwent hepatic resection or liver transplantation at Mount Sinai Hospital between February 1990 and February 1998. Patients who tested negative for hepatitis B antigen and hepatitis C antibody (74 patients) as well as those who tested positive for both (2 patients) were excluded. Age as well as preoperative platelet count, prothrombin time (PT), albumin, and total bilirubin were measured in all patients. The presence of encephalopathy or ascites also was noted. Explanted livers and resection specimens were examined for size, number, and differentiation of tumors as well as the presence of vascular invasion and cirrhosis in the surrounding parenchyma. RESULTS: One hundred twenty-one patients with HCC tested positive for HCV, and 43 tested positive for HBV. A significantly higher proportion of patients with HCV required transplant for the treatment of their HCC when compared to those with HBV. In the resection group, patients with HCV were significantly older that those with HBV. They also had significantly lower mean preoperative platelet counts and albumin levels and higher mean PT and total bilirubin levels. Resected patients with HCV had significantly less-differentiated tumors and a higher incidence of vascular invasion and cirrhosis when compared to those with HBV. There was no statistical difference in the multicentricity and size of tumors between the two groups. The 5-year disease-free survival was significantly higher for HBV patients treated with resection when compared to those with HCV (49% vs. 7%, P = .0480). Patients with HCC and HCV had significantly longer 5-year disease-free survival with transplant when compared to resection (48% vs. 7%, P = .0001). Transplanted patients with HBV and HCC had preoperative status, pathological findings, and survival similar to those of patients with HCV. CONCLUSIONS: Based on preoperative liver function and tumor location, a much higher proportion of HCC patients with HBV were candidates for resection. Significant differences in preoperative status, tumor characteristics and disease-free survival exist between HCC patients with chronic HBV and HCV infection who have not yet reached end-stage liver disease. Serious consideration should be given to transplanting resectable HCC with concomitant HCV, especially in cases with small tumors.