Ethnic Differences in Anorectal Manometry Findings in Patients With Fecal Incontinence:Results From a Multiethnic Cohort According to the London Classification

Background/Aims@#Clinical rates of fecal incontinence (FI) are known to vary based on race and ethnicity. It is unclear if anorectal manometry (ARM) findings in patients with FI differ based on ethnicity. @*Methods@#High-resolution ARM studies performed between 2014-2021 due to FI at 2 hospitals with multiethnic populations were retrospectively reviewed. @*Results@#Four hundred and seventy-nine subjects were included––87 (18.2%) Arab Israelis, 76 (15.9%) immigrants from the former Soviet Union, and 316 (66.0%) Jewish Israelis. Median age was 67 years old (76.0% women: 90.4% were parous). The Arab Israeli group had higher rates of smoking, diabetes, and obesity. Over 95% of ARM’s were abnormal per the London classification including 23% with “combined anal hypotension and hypocontractility,” 36% with “anal normotension with anal hypocontractility,” 67% with “dyssynergia,” and 65% with either “rectal hyposensation” or “borderline rectal hyposensation.” On univariate analyses, significant differences between the ethnic groups were noted in the rates of “anal hypotension with normal contractility,” “combined anal hypotension with anal hypocontractility,” and “dyssynergia.” In multivariate logistic regression analyses controlling for age, gender, parity, smoking, diabetes, and obesity, the Arab Israeli group remained several times more likely to have “combined anal hypotension and hypocontractibility” compared to the other groups. @*Conclusions@#Ethnicity impacts ARM findings in patients with FI. The reason for this is unclear and future studies on ethnically diverse populations evaluating the clinical relevance of these findings are warranted.

Targeting whole body metabolism and mitochondrial bioenergetics in the drug development for Alzheimer's disease

Aging is by far the most prominent risk factor for Alzheimer's disease (AD), and both aging and AD are associated with apparent metabolic alterations. As developing effective therapeutic interventions to treat AD is clearly in urgent need, the impact of modulating whole-body and intracellular metabolism in preclinical models and in human patients, on disease pathogenesis, have been explored. There is also an increasing awareness of differential risk and potential targeting strategies related to biological sex, microbiome, and circadian regulation. As a major part of intracellular metabolism, mitochondrial bioenergetics, mitochondrial quality-control mechanisms, and mitochondria-linked inflammatory responses have been considered for AD therapeutic interventions. This review summarizes and highlights these efforts.

Enhanced degradation of organic contaminants using catalytic activity of carbonaceous structures: A strategy for the reuse of exhausted sorbents.

Generation of hydroxyl radicals (⋅OH) is the basis of advanced oxidation process (AOP). This study investigates the catalytic activity of microporous carbonaceous structure for in-situ generation of ⋅OH radicals. Biochar (BC) was selected as a representative of carbon materials with a graphitic structure. The work aims at assessing the impact of BC structure on the activation of H2O2, the reinforcement of the persistent free radicals (PFRs) in BC using heavy metal complexes, and the subsequent AOP. Accordingly, three different biochars (raw, chemically- and physiochemically-activated BCs) were used for adsorption of two metal ions (nickel and lead) and the degradation of phenol (100 mg/L) through AOP. The results demonstrated four outcomes: (1) The structure of carbon material, the identity and the quantity of the metal complexes in the structure play the key roles in the AOP process. (2) the quantity of PFRs on BC significantly increased (by 200%) with structural activation and metal loading. (3) Though the Pb-loaded BC contained a larger quantity of PFRs, Ni-loaded BC exhibited a higher catalytic activity. (4) The degradation efficiency values for phenol by modified biochar in the presence of H2O2 was 80.3%, while the removal efficiency was found to be 17% and 22% in the two control tests, with H2O2 (no BC) and with BC (no H2O2), respectively. Overall, the work proposes a new approach for dual applications of carbonaceous structures; adsorption of metal ions and treatment of organic contaminants through in-situ chemical oxidation (ISCO).

Achalasia During Pregnancy: Proposed Management Algorithm Based on a Thorough Literature Review

Fewer than 40 cases of achalasia occurring in pregnant woman have been reported in the literature. Given the rarity of achalasia during pregnancy, and the numerous treatment options that are available for achalasia in general, no guidelines exist for the management of achalasia during pregnancy. Diagnosis of new cases may be difficult as symptoms and physiological changes that occur during pregnancy may obscure the clinical presentation of achalasia. The management of achalasia in pregnancy is also challenging. Treatment decisions should be individualized for each case, considering both the welfare of the mother and the fetus.Since pregnant women suffering from achalasia represent a diagnostic and therapeutic challenge with complex maternal-fetal aspects to consider, we have reviewed the available literature on the subject and summarized current diagnostic and therapeutic options.Additionally, we present a management algorithm as a means to guide treatment of future cases. We recommend that a conservative approach should be adopted with bridging therapies performed until after delivery when definitive treatment of achalasia can be more safely performed.

Urea functionalization of ultrasound-treated biochar: A feasible strategy for enhancing heavy metal adsorption capacity.

The main objective of a series of our researches is to develop a novel acoustic-based method for activation of biochar. This study investigates the capability of biochar in adsorbing Ni(II) as a hazardous contaminant and aims at enhancing its adsorption capacity by the addition of extra nitrogen and most probably phosphorous and oxygen containing sites using an ultrasono-chemical modification mechanism. To reach this objective, biochar physically modified by low-frequency ultrasound waves (USB) was chemically treated by phosphoric acid (H3PO4) and then functionalized by urea (CO(NH2)2). Cavitation induced by ultrasound waves exfoliates and breaks apart the regular shape of graphitic oxide layers of biochar, cleans smooth surfaces, and increases the porosity and permeability of biochar's carbonaceous structure. These phenomena synergistically combined with urea functionalization to attach the amine groups onto the biochar surface and remarkably increased the adsorption of Ni(II). It was found that the modified biochar could remove > 99% of 100 mg Ni(II)/L in only six hours, while the raw biochar removed only 73.5% of Ni(II) in twelve hours. It should be noted that physical treatment of biochar with ultrasound energy, which can be applied at room temperature for a very short duration, followed by chemical functionalization is an economical and efficient method of biochar modification compared with traditional methods, which are usually applied in a very severe temperature (>873 K) for a long duration. Such modified biochars can help protect human health from metal-ion corrosion of degrading piping in cities with aging infrastructure.

Recent developments in topoisomerase-targeted cancer chemotherapy

The DNA topoisomerase enzymes are essential to cell function and are found ubiquitously in all domains of life. The various topoisomerase enzymes perform a wide range of functions related to the maintenance of DNA topology during DNA replication, and transcription are the targets of a wide range of antimicrobial and cancer chemotherapeutic agents. Natural product-derived agents, such as the camptothecin, anthracycline, and podophyllotoxin drugs, have seen broad use in the treatment of many types of cancer. Selective targeting of the topoisomerase enzymes for cancer treatment continues to be a highly active area of basic and clinical research. The focus of this review will be to summarize the current state of the art with respect to clinically used topoisomerase inhibitors for targeted cancer treatment and to discuss the pharmacology and chemistry of promising new topoisomerase inhibitors in clinical and pre-clinical development.

In vitro and in vivo cytochrome P450 3A enzyme inhibition by Aframomum melegueta and Denniettia tripetala extracts

Objective To evaluate the in vitro and in vivo inhibitory effects of two commonly used herbs, Aframomum melegueta (A. melengueta) and Dennettia tripetala (D. tripetala) on CYP 3A enzymes. Methods In vitro inhibition of the enzymes were assessed with microsomes extracted from female albino rats using erythromycin-N-demethylation assay (EMND) method while their in vivo effects were measured by estimating simvastatin plasma concentrations in rats. Pharmacokinetic parameters were determined using non-compartmental analysis as implemented in WinNonlin pharmacokinetic program. Results EMND assay with intestinal microsomes indicated that aqueous extracts of D. tripetala and A. melengueta significantly (P < 0.05) inhibited intestinal CYP 3A activity at both 50 μg and 100 μg concentrations. Petroleum ether extract of D. tripetala and ethanol extracts of A. melengueta inhibited intestinal CYP3A activity at 100 μg but not at 50 μg concentrations. All the extracts showed an in vitro dose dependent CYP 3A inhibition with liver microsomes. In vivo analysis showed that pre-treatment with the extracts enhanced systemic absorption of simvastatin with reductions in metabolizing enzymes activity as indicated in significant increases in maximal concentration, area under curve, area under moment curve and mean resident time of simvastatin (P < 0.05). Conclusions Herbal preparations containing these plants' extracts should be used with caution especially in patients on CYP450 3A substrate medications.

Axillary Reconstruction for Hidradenitis Suppurativa with an Inner-Arm Transposition Flap Creating a Brachioplasty Effect

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic skin condition that can affect any area with apocrine sweat glands and has the potential to involve multiple sites concurrently. Commonly affected sites include the axilla, groin, perineum and perianal areas. In this study we performed a literature review on the surgical methods for HS and describe an innovative technique for reconstructing axilla HS using an inner-arm transposition flap. METHODS: We reviewed all cases (5 cases from 4 patients) of transposition flap reconstruction performed by the senior author at a single London tertiary hospital from 2008–2013. Patient related outcome measures were collected using the Derriford appearance scale (DAS 24) and a study specific questionnaire. RESULTS: All patients were satisfied with their final result. One out of five cases had a complication but did not result in flap failure. There is no disease recurrence to date. DAS 24 scores collected demonstrated acceptable postoperative distress that did not deviate far from the norm tables while study specific questionnaire reveal desirable outcomes. CONCLUSIONS: We have managed to achieve our aim through the use of the innovative inner-arm transposition flap. Our study hopes to provide an additional technique for axillary reconstruction. This technique offers the effective concealment of scars with the benefit of tightening of the arm tissue producing ‘brachioplasty like’ effects. All things considered it would be reasonable to conclude the innovative flap technique is a reliable, effective, and simple method that results in multiple benefits.

In vitro and in vivo cytochrome P450 3A enzyme inhibition by Aframomum melegueta and Denniettia tripetala extracts

OBJECTIVE@#To evaluate the in vitro and in vivo inhibitory effects of two commonly used herbs, Aframomum melegueta (A. melengueta) and Dennettia tripetala (D. tripetala) on CYP 3A enzymes.@*METHODS@#In vitro inhibition of the enzymes were assessed with microsomes extracted from female albino rats using erythromycin-N-demethylation assay (EMND) method while their in vivo effects were measured by estimating simvastatin plasma concentrations in rats. Pharmacokinetic parameters were determined using non-compartmental analysis as implemented in WinNonlin pharmacokinetic program.@*RESULTS@#EMND assay with intestinal microsomes indicated that aqueous extracts of D. tripetala and A. melengueta significantly (P < 0.05) inhibited intestinal CYP 3A activity at both 50 μg and 100 μg concentrations. Petroleum ether extract of D. tripetala and ethanol extracts of A. melengueta inhibited intestinal CYP3A activity at 100 μg but not at 50 μg concentrations. All the extracts showed an in vitro dose dependent CYP 3A inhibition with liver microsomes. In vivo analysis showed that pre-treatment with the extracts enhanced systemic absorption of simvastatin with reductions in metabolizing enzymes activity as indicated in significant increases in maximal concentration, area under curve, area under moment curve and mean resident time of simvastatin (P < 0.05).@*CONCLUSIONS@#Herbal preparations containing these plants' extracts should be used with caution especially in patients on CYP450 3A substrate medications.

Janus Reversal and Coulomb Blockade in Ferrocene-Perylenebisimide and N,N,N',N'-Tetramethyl-para-phenylenediamine-Perylenebisimide D-σ-A Rectifiers.

Sandwiches "EGaIn|Ga2O3|LB monolayer of 2|Au" and "EGaIn|Ga2O3|LB monolayer of 3|Au" rectify. They are formed from a Langmuir-Blodgett (LB) monolayer of 2 or 3 transferred onto thermally evaporated gold. Molecules 2 and 3 are of the donor-sigma-acceptor (D-σ-A) type and have the same perylenebisimide (PBI) acceptor as previously studied molecule 1. Molecule 1 has the weak donor pyrene, 2 has the good donor ferrocene, and 3 has the very strong donor N,N,N',N'-tetramethyl-p-phenylenediamine (TMPD). All three molecules have a long swallowtail ending in a thioacetyl group, which ensures slow chemisorption onto the Au electrode. These molecules were contacted directly by a gallium indium eutectic (EGaIn) drop, covered by a defective oxide Ga2O3 layer. As before for 1, the direction of rectification for 2 is bias-dependent. In the ±1.0 V range, the rectification is at positive V, with a rectification ratio (RR) that is initially greater than 5 and then decreases on successive scans to 2, while the currents decrease by as much as 2 orders of magnitude. In the ±2.5 V range, the rectification direction for 2 reverses, while upon repeated scanning the rectification ratio (in the negative direction) increases and the currents decrease. For molecule 3, both directions have a charge-trapped state (Coulomb blockade) leading to Voffset in both biases, but at high potentials rectification set is, with large RR (up to 2,800) at ±2.5 V.

Stereoselective synthesis, biological evaluation, and modeling of novel bile acid-derived G-protein coupled bile acid receptor 1 (GP-BAR1, TGR5) agonists.

GP-BAR1 (also known as TGR5), a novel G-protein coupled receptor regulating various non-genomic functions via bile acid signaling, has emerged as a promising target for metabolic disorders, including obesity and type II diabetes. However, given that many bile acids (BAs) are poorly tolerated for systemic therapeutic use, there is significant need to develop GP-BAR1 agonists with improved potency and specificity and there also is significant impetus to develop a stereoselective synthetic methodology for GP-BAR1 agonists. Here, we report the development of highly stereo-controlled strategies to investigate a series of naturally occurring bile acid derivatives with markedly enhanced GP-BAR1 activity. These novel GP-BAR1 agonists are evaluated in vitro using luciferase-based reporter and cAMP assays to elucidate their biological properties. In vivo studies revealed that the GP-BAR1 agonist 23(S)-m-LCA increased intestinal GLP-1 transcripts by 26-fold. Additionally, computational modeling studies of selected ligands that exhibit enhanced potency and specificity for GP-BAR1 provide information on potential binding sites for these ligands in GP-BAR1.

DNA methyltransferase DNMT3A associates with viral proteins and impacts HSV-1 infection.

Viral infections can alter the cellular epigenetic landscape, through modulation of either DNA methylation profiles or chromatin remodeling enzymes and histone modifications. These changes can act to promote viral replication or host defense. Herpes simplex virus type 1 (HSV-1) is a prominent human pathogen, which relies on interactions with host factors for efficient replication and spread. Nevertheless, the knowledge regarding its modulation of epigenetic factors remains limited. Here, we used fluorescently-labeled viruses in conjunction with immunoaffinity purification and MS to study virus-virus and virus-host protein interactions during HSV-1 infection in primary human fibroblasts. We identified interactions among viral capsid and tegument proteins, detecting phosphorylation of the capsid protein VP26 at sites within its UL37-binding domain, and an acetylation within the major capsid protein VP5. Interestingly, we found a nuclear association between viral capsid proteins and the de novo DNA methyltransferase DNA (cytosine-5)-methyltransferase 3A (DNMT3A), which we confirmed by reciprocal isolations and microscopy. We show that drug-induced inhibition of DNA methyltransferase activity, as well as siRNA- and shRNA-mediated DNMT3A knockdowns trigger reductions in virus titers. Altogether, our results highlight a functional association of viral proteins with the mammalian DNA methyltransferase machinery, pointing to DNMT3A as a host factor required for effective HSV-1 infection.

Aneurysm of the Posterior Meningeal Artery Embedded Within a Dorsal Exophytic Medullary Hemangioblastoma: Surgical Management and Review of Literature

Hemangioblastomas are World Health Organization (WHO) Grade I neoplasms of the hindbrain and spinal cord, whose management can be complicated by preoperative hemorrhage. We report on a case of a young female in extremis with posterior fossa hemorrhage following rupture of a fusiform posterior meningeal artery aneurysm embedded within a medullary hemangioblastoma. We discuss management options, including operative staging and embolization, and review similar cases of hemangioblastoma associated with aneurysm.

Discovery of host-viral protein complexes during infection.

Viruses have co-evolved with their hosts, developing effective approaches for hijacking and manipulating host cellular processes. Therefore, for their efficient replication and spread, viruses depend on dynamic and temporally regulated interactions with host proteins. The rapid identification of host proteins targeted by viral proteins during infection provides significant insights into mechanisms of viral protein function. The resulting discoveries often lead to unique and innovative hypotheses on viral protein function. Here, we describe a robust method for identifying virus-host protein interactions and protein complexes, which we have successfully utilized to characterize spatial-temporal protein interactions during infections with either DNA or RNA viruses, including human cytomegalovirus (HCMV), herpes simplex virus type 1 (HSV-1), pseudorabies virus (PRV), human immunodeficiency virus (HIV-1), Sindbis, and West Nile virus (WNV). This approach involves cryogenic cell lysis, rapid immunoaffinity purification targeting a virus or host protein, followed by identification of associated proteins using mass spectrometry. Like most proteomic approaches, this methodology has evolved over the past few years and continues to evolve. We are presenting here the updated approaches for each step, and discuss alternative strategies allowing for the protocol to be optimized for different biological systems.

An improved synthesis of 6α-ethylchenodeoxycholic acid (6ECDCA), a potent and selective agonist for the Farnesoid X Receptor (FXR).

The active, potent, and selective Farnesoid X Receptor (FXR) agonist 6α-ethylchenodeoxycholic acid (6ECDCA) has been synthesized in improved yield compared to the published methodologies. The synthesis employed selective oxidation of one of the two hydroxyls of the readily-available starting material chenodeoxycholic acid (CDCA) as a key step. After protection of the remaining hydroxyl, LDA/HMPA/EtI/PPTS provided an efficient deprotonation/ethylation/deprotection sequence. The two synthetic improvements that allow a productive yield are the use of PCC in the oxidation step, and the use of HMPA/ethyl iodide in the stereoselective alkylation step. This synthesis offers an economical and efficient strategy which provides a simple and cost-effective procedure for potential large-scale production of this promising FXR agonist, which is a research tool and potential drug substance of current interest.

Unimolecular electronic devices.

The first active electronic components used vacuum tubes with appropriately-shaped electrodes, then junctions of appropriately-doped Ge, Si, or GaAs semiconductors. Electronic components can now be made with appropriately-designed organic molecules. As the commercial drive to make ever-smaller and faster circuits approaches the 3-nm limit, these unimolecular organic devices may become more useful than doped semiconductors. Here we discuss the electrical contacts between metallic electrodes and organic molecular components, and survey representative organic wires composed of conducting groups and organic rectifiers composed of electron-donor and -acceptor groups, and the Aviram-Ratner proposal for unimolecular rectification. Molecular capacitors and amplifiers are discussed briefly. Molecular electronic devices are not only ultimately small (<3 nm in all directions) and fast, but their excited states may be able to decay by photons, avoiding the enormous heat dissipation endured by Si-based components that decay by phonons. An all-organic computer is an ultimate, but more distant, goal.

Interstaple dithiol cross-linking in Au25(SR)18 nanomolecules: a combined mass spectrometric and computational study.

A systematic study of cross-linking chemistry of the Au(25)(SR)(18) nanomolecule by dithiols of varying chain length, HS-(CH(2))(n)-SH where n = 2, 3, 4, 5, and 6, is presented here. Monothiolated Au(25) has six [RSAuSRAuSR] staple motifs on its surface, and MALDI mass spectrometry data of the ligand exchanged clusters show that propane (C3) and butane (C4) dithiols have ideal chain lengths for interstaple cross-linking and that up to six C3 or C4 dithiols can be facilely exchanged onto the cluster surface. Propanedithiol predominately exchanges with two monothiols at a time, making cross-linking bridges, while butanedithiol can exchange with either one or two monothiols at a time. The extent of cross-linking can be controlled by the Au(25)(SR)(18) to dithiol ratio, the reaction time of ligand exchange, or the addition of a hydrophobic tail to the dithiol. MALDI MS suggests that during ethane (C2) dithiol exchange, two ethanedithiols become connected by a disulfide bond; this result is supported by density functional theory (DFT) prediction of the optimal chain length for the intrastaple coupling. Both optical absorption spectroscopy and DFT computations show that the electronic structure of the Au(25) nanomolecule retains its main features after exchange of up to eight monothiol ligands.

Haemosiderin deposition in Donkey (Equus asinus) livers: Comparison of quantitative histochemistry for iron and liver iron content.

Post mortem liver samples from 12 donkeys (Equus asinus) aged 21-57 years (4 females, 1 stallion, 7 geldings), were assessed chemically for copper and iron content on a wet weight basis and histologically for stainable iron. Chemical liver copper content ranged from 2.7 to 4.8µg/g (mean 3.5±0.05µg/g). Chemical liver iron content ranged from 524 to 5010µg/g (mean 1723±1258µg/g). Histochemical iron was measured morphometrically using a computer-based image analysis system; percentage section area staining for iron ranged from 0.84% to 26.69% (mean 10.82±8.36%). There was no clear correlation, within the wide range of iron values, between histochemically demonstrable iron and chemically measured iron content. No clear age-related increase was apparent for either parameter in these aged donkeys. The accumulation of iron in the liver of donkeys may represent a physiological haemosiderosis rather than pathological haemochromatosis.

Indocyanine Green Videoangiography for Confirmation of Bypass Graft Patency

OBJECTIVE: The aim of the study is to determine the efficacy of indocyanine green (ICG) videoangiography for confirmation of vascular anastomosis patency in both extracranial-intracranial and intracranial-intracranial bypasses. METHODS: Intraoperative ICG videoangiography was used as a surgical adjunct for 56 bypasses in 47 patients to assay the patency of intracranial vascular anastomosis. These patients underwent a bypass for cerebral ischemia in 31 instances and as an adjunct to intracranial aneurysm surgery in 25. After completion of the bypass, ICG was administered to assess the patency of the graft. The findings on ICG videoangiography were then compared to intraoperative and/or postoperative imaging. RESULTS: ICG provided an excellent visualization of all cerebral arteries and grafts at the time of surgery. Four grafts were determined to be suboptimal and were revised at the time of surgery. Findings on ICG videoangiography correlated with intraoperative and/or postoperative imaging. CONCLUSION: ICG videoangiography is rapid, effective, and reliable in determining the intraoperative patency of bypass grafts. It provides intraoperative information allowing revision to reduce the incidence of technical errors that may lead to early graft thrombosis.

Surgical Management of Intracranial Aneurysms in the Endovascular Era : Review Article

The advent of endovascular therapy for intracranial aneurysms and the rapid advances in that field have supplanted microsurgical treatment for many intracranial aneurysms. Applying current outcome data and other parameters, nuances of selecting the modality of treatment for intracranial aneurysms are reviewed. Patient factors, such a age, co-morbidities, vasospasm and other medical conditions, are addressed. A custom-tailored multimodality treatment paradigm for the management of ruptured and unruptured aneurysms will maximize the favorable results seen in this difficult patient population.