Navigating portal hypertension: Unlocking safe passage to healthy pregnancy in EHPVO.

BACKGROUND AND AIMS: Pregnancy is associated with hyperdynamic circulatory state and increased risk of portal hypertension related complications in patients with extra-hepatic portal vein obstruction (EHPVO). We aim to study the impact of EHPVO on pregnancy-related outcomes with focus on subset of patients with UGIB (upper GI bleed). METHODS: Retrospective analysis of obstetric, maternal and neonatal outcomes of patients with EHPVO registered between January 2006 and December 2022. Forty-five patients were included. Forty-five healthy females with low-risk pregnancies formed the control group. RESULTS: Adverse obstetric and neonatal outcomes were comparable between EHPVO and control group (22% vs. 28.6%; p > .05; low birth weight/ small for gestational age 17.8% vs. 36%, p = .0918 and 14.2% vs. 10%, p = .5698 respectively). Adverse outcomes were similar in patients with and without history of UGIB (26.3% vs. 19.4%, p = .0814; 17.8% vs. 36%, p = .0918; 14.2% vs. 10%, p = .5698). There was no maternal mortality in both the groups. A total of 7% pregnancies in EHPVO patients were complicated by ascites. CONCLUSIONS: EHPVO pregnancies have successful obstetric and neonatal outcomes with adequate management of portal hypertension.

Predictors of proximal migration of straight biliary plastic stents.

BACKGROUND/AIMS: Proximal biliary plastic stent migration (PSM) remains a challenging complication. The study aims at determining the PSM rate, retrieval outcomes and factors associated with PSM. METHODS: Endoscopy database was analyzed from January 2016 to January 2021 to identify 1137 patients, who underwent stent removal or repeat endoscopic retrograde cholangiopancreatography (ERCP). Demography, methods of stent retrieval, outcomes and complications were noted. Logistic regression was performed to determine risk factors for PSM. Propensity score matching was done in a 1:1 manner using age, sex, comorbidities and indication to assess endoscopy-related factors. Clinical trial registration done (CTRI/2022/02/040516). RESULTS: PSM was noted in 74 (6.5%) cases. Stent retrieval was successful in 94.59% (70/74) of cases. A balloon catheter (46/74) was commonly used. Technical failure was due to an impacted stent (2) and stent above the stricture (2). Complications were seen in 2.7% of cases. On multi-variate regression, sphincteroplasty at index ERCP (Odds ratio [OR] = 5.68, 95% confidence interval [CI] = 2.7-11.89), stent length < 10 cm (OR = 8.53, 95% CI = 3.2-22.47), 7-Fr stent (OR = 18.25, 95% CI = 6.5-50.64), dilated bile duct (mean diameter- 9.2 ± 3.94 mm) (OR = 0.384, 95% CI = 0.18-0.72) and delayed ERCP by > 3 months from index ERCP (OR = 15.28, 95% CI = 8.1-28.49). After performing propensity score matching for age, sex, comorbidities and indication to determine endoscopy-related factors, 7-Fr stent size (OR 3.495; 95% CI-1.23-9.93) and duration of indwelling stent for more than three months (OR-3.37; 95% CI-1.646-6.76) were significantly associated with proximal stent migration. CONCLUSION: Proximally migrated straight stents can be successfully retrieved using standard accessories. The use of 7-Fr size stent, stents indwelling for more than three months, sphincteroplasty at index ERCP, stent length < 10 cm and dilated bile duct were associated with increased risk of proximal migration of straight biliary plastic stents. After propensity score matching, the use of 7-Fr size stents and stent indwelling for over three months were endoscopy-related factors associated with proximal migration.

Determination of the class and isoform selectivity of small-molecule histone deacetylase inhibitors.

The human HDAC (histone deacetylase) family, a well-validated anticancer target, plays a key role in the control of gene expression through regulation of transcription. While HDACs can be subdivided into three main classes, the class I, class II and class III HDACs (sirtuins), it is presently unclear whether inhibiting multiple HDACs using pan-HDAC inhibitors, or targeting specific isoforms that show aberrant levels in tumours, will prove more effective as an anticancer strategy in the clinic. To address the above issues, we have tested a number of clinically relevant HDACis (HDAC inhibitors) against a panel of rhHDAC (recombinant human HDAC) isoforms. Eight rhHDACs were expressed using a baculoviral system, and a Fluor de Lystrade mark (Biomol International) HDAC assay was optimized for each purified isoform. The potency and selectivity of ten HDACs on class I isoforms (rhHDAC1, rhHDAC2, rhHDAC3 and rhHDAC8) and class II HDAC isoforms (rhHDAC4, rhHDAC6, rhHDAC7 and rhHDAC9) was determined. MS-275 was HDAC1-selective, MGCD0103 was HDAC1- and HDAC2-selective, apicidin was HDAC2- and HDAC3-selective and valproic acid was a specific inhibitor of class I HDACs. The hydroxamic acid-derived compounds (trichostatin A, NVP-LAQ824, panobinostat, ITF2357, vorinostat and belinostat) were potent pan-HDAC inhibitors. The growth-inhibitory effect of the HDACis on HeLa cells showed that both pan-HDAC and class-I-specific inhibitors inhibited cell growth. The results also showed that both pan-HDAC and class-I-specific inhibitor treatment resulted in increased acetylation of histones, but only pan-HDAC inhibitor treatment resulted in increased tubulin acetylation, which is in agreement with their activity towards the HDAC6 isoform.

New onset of multiple organ dysfunction after receiving long-term high-dose piperacillin for outpatient treatment of osteomyelitis.

Toxic side effects of piperacillin occur in many organ systems and may be cumulative dose related. We report a patient receiving long-term high-dose piperacillin to accommodate convenient outpatient intravenous therapy of osteomyelitis. He developed life-threatening multiorgan dysfunction on day 20 of piperacillin administration after 49 days of antibiotics, suggesting a likely adverse drug reaction. Piperacillin should be administered according to the manufacturer's recommendations of dosage, frequency and duration, and suggested monitoring. Unorthodox treatment regimens are discouraged.

Novel amide derivatives as inhibitors of histone deacetylase: design, synthesis and SAR.

Enzymatic inhibition of histone deacetylase (HDAC) activity is emerging as an innovative and effective approach for the treatment of cancer. A series of novel amide derivatives have been synthesized and evaluated for their ability to inhibit human HDACs. Multiple compounds were identified as potent HDAC inhibitors (HDACi), with IC(50) values in the low nanomolar (nM) range against enzyme activity in HeLa cell extracts and sub-microM for their in vitro anti-proliferative effect on cell lines. The introduction of an unsaturated linking group between the terminal aryl ring and the amide moiety was the key to obtain good potency. This approach yielded compounds such as (E)-N-[6-(hydroxyamino)-6-oxohexyl]-3-(7-quinolinyl)-2-propenamide (27) (HDAC IC(50) 8 nM) which showed potent in vivo activity in the P388 mouse leukemia syngeneic model (an increased lifespan (ILS) of 111% was obtained).