Introduction
Recurrent allograft steatosis occurs in one-third of transplanted livers. Antidiabetic agents like glucagon-like peptide-1 receptor agonists (GLP1RA) and sodium-glucose cotransporter ...type-2 (SGLT2) inhibitors are effective in the management of obesity and hepatic steatosis in the general population; however, there is limited evidence supporting their use in allograft steatosis. We aimed to evaluate their effects on steatosis, body weight, and glycemic control in liver transplant recipients at our institution.
Methods
In this single-center retrospective cohort study of liver transplant recipients currently on a GLP1RA or SGLT2 inhibitor (transplanted 2015–2022), we compared clinical and radiological data before medication use and at follow-up. Differences were compared using Wilcoxon signed-rank test.
Results
Thirty-seven liver transplant recipients were taking the agents. Diabetes was the most common indication (
n
= 33) followed by obesity (
n
= 4). Median follow up was 427 days (301,798). Among those with documented steatosis (
n
= 21), steatosis improved in 5, worsened in 4, remained unchanged in 1, and change could not be evaluated in 11 due to lack of comparable pre and post imaging. Average weight loss was 3.2 kg (
p
< 0.001) and BMI decreased by 1.2 kg/m
2
(
p
< 0.001). Hemoglobin A1c decreased by 0.6 mmol/mol (
p
= 0.0014), insulin requirement reduced by 7 units/day (
p
= 0.02), and there was no change in additional antidiabetic medications.
Discussion
GLP1RA and SGLT-2 inhibitors are tolerated in transplant patients and result in weight loss and better glycemic control. They are promising agents to treat recurrent or de-novo liver allograft steatosis, but further research is needed to evaluate long-term outcomes in liver transplant recipients.
Macrolides of different ring sizes are critically important antimicrobials for human medicine and veterinary medicine, though the widely used 15-membered ring azithromycin in humans is not approved ...for use in veterinary medicine. We document here the emergence of azithromycin-resistant
among the NARMS culture collections between 2011 and 2021 in food animals and retail meats, some with co-resistance to ceftriaxone or decreased susceptibility to ciprofloxacin. We also provide insights into the underlying genetic mechanisms and genomic contexts, including the first report of a novel combination of azithromycin resistance determinants and the characterization of multidrug-resistant plasmids. Further, we highlight the emergence of a multidrug-resistant
Newport clone in food animals (mainly cattle) with both azithromycin resistance and decreased susceptibility to ciprofloxacin. These findings contribute to a better understating of azithromycin resistance mechanisms in
and warrant further investigations on the drivers behind the emergence of resistant clones.
Reactive oxygen and nitrogen species (ROS and RNS) produced by the phagocytic cells are the most common arsenals used to kill the intracellular pathogens. However, Leishmania, an intracellular ...pathogen, has evolved mechanisms to survive by counterbalancing the toxic oxygen metabolites produced during infection. Polyamines, the major contributor in this anti-oxidant machinery, are largely dependent on the availability of L-arginine in the intracellular milieu. Argininosuccinate synthase (ASS) plays an important role as the rate-limiting step required for converting L-citrulline to argininosuccinate to provide arginine for an assortment of metabolic processes. Leishmania produce an active ASS enzyme, yet it has an incomplete urea cycle as it lacks an argininosuccinate lyase (ASL). There is no evidence for endogenous synthesis of L-arginine in Leishmania, which suggests that these parasites salvage L-arginine from extracellular milieu and makes the biological function of ASS and the production of argininosuccinate in Leishmania unclear. Our previous quantitative proteomic analysis of Leishmania promastigotes treated with sub-lethal doses of ROS, RNS, or a combination of both, led to the identification of several differentially expressed proteins which included ASS. To assess the involvement of ASS in stress management, a mutant cell line with greatly reduced ASS activity was created by a double-targeted gene replacement strategy in L. donovani promastigote. Interestingly, LdASS is encoded by three copies of allele, but Western blot analysis showed the third allele did not appear to express ASS. The free thiol levels in the mutant LdASS-/-/+ cell line were decreased. Furthermore, the cell viability in L-arginine depleted medium was greatly attenuated on exposure to different stress environments and was adversely impacted in its ability to infect mice. These findings suggest that ASS is important for Leishmania donovani to counterbalance the stressed environments encountered during infection and can be targeted for chemotherapeutic purpose to treat visceral leishmaniasis.
An efficient and environmentally benign synthesis of benzopyrano4,3-
e1,2,4-triazolo3,4-
b1,3,4-thiadiazepines is described from 4-amino-5-alkyl-3-mercaptotriazole and substituted 3-arylidene ...flavonones under microwave irradiation using basic alumina as solid support.
A facile, dry media procedure has been developed for the synthesis of a series of a new class of fluorine containing 3-alkyl-7-chloro-11a,12-dihydro-11-phenyl-12-(substituted aryl)-11
H-benzopyrano4,3-
e1,2,4-triazolo3,4-
b1,3,4-thiadiazepines (
4a–
k) under microwaves using basic alumina as solid support. The reaction time has been brought down from hours (60–65
h) to minutes (3–5
min) with improved yield as compared to conventional method, demonstrating the versatility of the process. The method reported herein is devoid of the hazards of solution-phase reactions. The synthesized compounds have been screened ‘in vitro’ for anti-fungal activity against
Rhizoctonia solani,
Fusarium oxysporum and
Collectotrichum capsici. Most of the compounds have shown good activity against these pathogens.
Attributing illness to food Batz, Michael B; Doyle, Michael P; Morris, Jr, Glenn ...
Emerging infectious diseases,
07/2005, Volume:
11, Issue:
7
Journal Article
Peer reviewed
Open access
Identification and prioritization of effective food safety interventions require an understanding of the relationship between food and pathogen from farm to consumption. Critical to this cause is ...food attribution, the capacity to attribute cases of foodborne disease to the food vehicle or other source responsible for illness. A wide variety of food attribution approaches and data are used around the world, including the analysis of outbreak data, case-control studies, microbial subtyping and source tracking methods, and expert judgment, among others. The Food Safety Research Consortium sponsored the Food Attribution Data Workshop in October 2003 to discuss the virtues and limitations of these approaches and to identify future options for collecting food attribution data in the United States. We summarize workshop discussions and identify challenges that affect progress in this critical component of a risk-based approach to improving food safety.
In vector-borne diseases such as leishmaniasis, the sand fly midgut is considered to be an important site for vector-parasite interaction. Digestive enzymes including serine peptidases such as ...trypsin and chymotrypsin, which are secreted in the midgut are one of the obstacles for Leishmania in establishing a successful infection. The presence of some natural inhibitors of serine peptidases (ISPs) has recently been reported in Leishmania. In the present study, we deciphered the role of these ISPs in the survival of Leishmania donovani in the hostile sand fly midgut environment.
In silico and co-immunoprecipitation studies were performed to observe the interaction of L. donovani ISPs with trypsin and chymotrypsin. Zymography and in vitro enzyme assays were carried out to observe the inhibitory effect of purified recombinant ISPs of L. donovani (rLdISPs) on trypsin, chymotrypsin and the sand fly midgut peptidases. The expression of ISPs in the amastigote to promastigote transition stages were studied by semi-quantitative RT-PCR and Western blot. The role of LdISP on the survival of ISP overexpressed (OE) and ISP knocked down (KD) Leishmania parasites inside the sand fly gut was investigated by in vitro and in vivo cell viability assays.
We identified two ecotin-like genes in L. donovani, LdISP1 and LdISP2. In silico and co-immunoprecipitation results clearly suggest a strong interaction of LdISP molecules with trypsin and chymotrypsin. Zymography and in vitro enzyme assay confirmed the inhibitory effect of rLdISP on trypsin, chymotrypsin and the sand fly midgut peptidases. The expression of LdISP2 was found to be strongly associated with the amastigote to promastigote phase transition. The activities of the digestive enzymes were found to be significantly reduced in the infected sand flies when compared to uninfected. To our knowledge, our study is the first report showing the possible reduction of chymotrypsin activity in L. donovani infected sand flies compared to uninfected. Interestingly, during the early transition stage, substantial killing was observed in ISP2 knocked down (ISP2KD) parasites compared to wild type (WT), whereas ISP1 knocked down (ISP1KD) parasites remained viable. Therefore, our study clearly indicates that LdISP2 is a more effective inhibitor of serine peptidases than LdISP1.
Our results suggest that the lack of ISP2 is detrimental to the parasites during the early transition from amastigotes to promastigotes. Moreover, the results of the present study demonstrated for the first time that LdISP2 has an important role in the inhibition of peptidases and promoting L. donovani survival inside the Phlebotomus argentipes midgut.
There is considerable heterogeneity among the Shiga toxin type 2 (Stx2) toxins elaborated by Shiga toxin-producing Escherichia coli (STEC). One such Stx2 variant, the Stx2d mucus-activatable toxin ...(Stx2dact), is rendered more toxic by the action of elastase present in intestinal mucus, which cleaves the last two amino acids of the A2 portion of the toxin A subunit. We screened 153 STEC isolates from food, animals, and humans for the gene encoding Stx2dact by using a novel one-step PCR procedure. This method targeted the region of stx₂dact that encodes the elastase recognition site. The presence of stx₂dact was confirmed by DNA sequencing of the complete toxin genes. Seven STEC isolates from cows (four isolates), meat (two isolates), and a human (one isolate) that carried the putative stx₂dact gene were identified; all were eae negative, and none was the O157:H7 serotype. Three of the isolates (CVM9322, CVM9557, and CVM9584) also carried stx₁, two (P1332 and P1334) carried stx₁ and stx₂c, and one (CL-15) carried stx₂c. One isolate, P1130, harbored only stx₂dact. The Vero cell cytotoxicities of supernatants from P1130 and stx₁ deletion mutants of CVM9322, CVM9557, and CVM9584 were increased 13- to 30-fold after treatment with porcine elastase. Thus, Stx2dact-producing strains, as detected by our one-step PCR method, can be isolated not only from humans, as previously documented, but also from food and animals. The latter finding has important public health implications based on a recent report from Europe of a link between disease severity and infection with STEC isolates that produce Stx2dact.
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•LNC formulation of combinational drugs afforded tailored physicochemical properties.•LNCs allow high loading capacity and superior storage stability.•Drug loaded LNCs induced ...cytotoxicity in breast cancer cells and stem cells.•Combinatorial drug delivery by LNCs are effective against breast cancer stem cells.
Cancer stem cells (CSCs) comprise a diminutive population of the tumor but pose major obstacles in cancer treatment, often their presence being correlated with poor prognosis, therapeutic resistance and relapse. Nanocarriers of combined drugs regimes demonstrate improved pharmacokinetics and decreased systemic toxicity by targeting the bulk tumor cells along with CSCs, holding the key to future successful chemotherapy. Herein, we developed lipid nanocapsules (LNCs) with co-encapsulated paclitaxel (PTX) and salinomycin (SAL) to eliminate breast cancer cells (MCF-7; non-bCSCs) and cancer stem cells (bCSCs) respectively. LNCs loaded with either PTX or SAL alone or in combination were fabricated by the phase inversion temperature (PIT) method. Physicochemical properties such as nano-size (90 ± 5 nm) and spherical morphology of LNCs were confirmed by dynamic light scattering (DLS) and scanning electron microscopy (SEM) respectively. More than 98 % encapsulation efficiency of drug, alone or in combination, and their controlled drug release was obtained. Drug loaded LNCs were efficiently internalized and exhibited cytotoxicity in non-bCSCs and bCSCs, with dual drug loaded LNCs offering superior cytotoxicity and anti-bCSCs property. Drug loaded nanocapsules induced apoptosis in bCSCs, potentiated with the co-delivery of paclitaxel and salinomycin. Synergistic cytotoxic effect on both cells, non-bCSCs and bCSCs and effective reduction of the tumor mammospheres growth by co-encapsulated paclitaxel and salinomycin suggest LNCs to be promising for treatment of breast cancer.
The abilities of 34 Campylobacter jejuni and 9 Campylobacter coli isolates recovered from retail meats to adhere to and invade human intestinal epithelial T84 cells were examined and compared with ...those of a well-characterized human clinical strain, C. jejuni 81-176, to better assess the pathogenic potential of these meat isolates. The meat isolates exhibited a wide range of adherence and invasion abilities; a few of the isolates adhered to and invaded T84 cells almost as well as did C. jejuni 81-176. There was a significant correlation between the adherence ability and the invasion ability of the Campylobacter isolates. The presence of eight putative virulence genes in these Campylobacter isolates that are potentially responsible for adherence and invasion or that encode cytolethal distending toxin was determined using PCR. All Campylobacter isolates possessed flaA, cadF, pldA, cdtA, cdtB, and cdtC, and most (91%) also contained the ciaB gene. However, the virB11 gene, carried by virulence plasmid pVir, was absent in almost all the Campylobacter isolates. Our findings indicated that C. jejuni and C. coli present in retail meat were diverse in their ability to adhere to and invade human intestinal epithelial cells and that the putative virulence genes were widespread among the Campylobacter isolates. Thus, despite of the presence of the putative virulence genes, only some but not all Campylobacter strains isolated from retail meat can effectively invade human intestinal epithelial cells in vitro.
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