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We aimed to assess the extent to which people with type 2 diabetes or pre-diabetes, obesity (BMI 30-45 kg/m2) and moderate obstructive sleep apnoea (OSA) requiring continuous positive airway pressure ventilation (CPAP) were able to discontinue CPAP following EndoBarrier-related weight loss. We assessed sleep and metabolic parameters before, during and after EndoBarrier in 12 participants with moderate OSA requiring CPAP (75% female, 8/12 [66%] type 2 diabetes, 4/12 [34%] prediabetes, mean ± SD age 52.6 ± 9.7 years, BMI 37.4 ± 3.5 kg/m2, median duration of OSA while on CPAP 9.0 [7.0-15.0] months). With EndoBarrier in-situ, mean ± SD Apnoea Hypopnoea Index (AHI) fell by 9.1 ± 5.0 events/h from 18.9 ± 3.8 to 9.7 ± 3.0 events/h (p < .001) with an associated reduction in symptoms of daytime sleepiness (mean Epworth Sleepiness Score) such that all the 12 participants no longer required CPAP according to National Institute for Health and Care Excellence criteria. After EndoBarrier removal, 10/12 (83%) patients attended follow-up and at 12 months after removal, AHI remained below 15 in 5/10 (50%) patients but in other five the AHI rose above 15 such that restarting CPAP was recommended as justified by their symptoms. Rather than restart CPAP, two patients lost the regained weight and their AHI dropped below 15 again. Thus, 7/10 (70%) of patients were able to remain off CPAP 12 or more months after EndoBarrier removal. These results demonstrate major benefit of EndoBarrier in moderate OSA, allowing all patients to discontinue CPAP during treatment, and with maintenance of improvement at follow-up in 70%. They confirm previously demonstrated metabolic improvements in diabetes and obesity.

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A man in his 70s, admitted to intensive care unit following an out of hospital cardiac arrest, had a nasogastric (NG) tube inserted on admission. Correct placement of the NG tube had been confirmed using National Patient Safety Agency (NPSA) criteria and was used for feeding without incident. He remained intubated and ventilated throughout his stay. On day 9 his oxygen requirements increased with subsequent chest imaging revealing an incidental gastric perforation secondary to NG tube migration. The NG tube was removed intact and undamaged. The patient appeared to improve without sequelae from the perforation or signs of abdominal sepsis. Unfortunately his condition deteriorated due to a large right atrial thrombus and life sustaining treatments were withdrawn.

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Hypersensitivity pneumonitis (HP), also known as extrinsic allergic alveolitis, is a granulomatous, non-IgE-mediated hypersensitivity reaction of the alveoli and distal bronchioles presenting as an acute, subacute or chronic condition. It is most commonly associated with exposure to extrinsic allergens (eg, avian dust, mould and tobacco) and medications including antiarrhythmics (eg, amiodarone), cytotoxics (eg, methotrexate) and antiepileptics (eg, carbamazepine). Individuals diagnosed with this condition can present with severe hypoxia and respiratory failure. The fundamental principle of management is to remove the causative allergen. Evidence implicating selective serotonin reuptake inhibitors as a causative agent is limited, and this case report describes a rare clinical presentation of HP associated with sertraline, how it was diagnosed and subsequently treated. It is anticipated that raising awareness of this interaction will assist multidisciplinary teams, managing patients diagnosed with HP, to be more cognisant of sertraline as being an aetiological factor for this condition.

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Sirtuins catalyze NAD(+)-dependent protein deacetylation and are critical regulators of transcription, apoptosis, metabolism, and aging. There are seven human sirtuins (SIRT1-7), and SIRT1 has been implicated as a key mediator of the pathways downstream of calorie restriction that have been shown to delay the onset and reduce the incidence of age-related diseases such as type 2 diabetes. Increasing SIRT1 activity, either by transgenic overexpression of the Sirt1 gene in mice or by pharmacological activation by small molecule activators resveratrol and SRT1720, has shown beneficial effects in rodent models of type 2 diabetes, indicating that SIRT1 may represent an attractive therapeutic target. Herein, we have assessed purported SIRT1 activators by employing biochemical assays utilizing native substrates, including a p53-derived peptide substrate lacking a fluorophore as well as the purified native full-length protein substrates p53 and acetyl-CoA synthetase1. SRT1720, its structurally related compounds SRT2183 and SRT1460, and resveratrol do not lead to apparent activation of SIRT1 with native peptide or full-length protein substrates, whereas they do activate SIRT1 with peptide substrate containing a covalently attached fluorophore. Employing NMR, surface plasmon resonance, and isothermal calorimetry techniques, we provide evidence that these compounds directly interact with fluorophore-containing peptide substrates. Furthermore, we demonstrate that SRT1720 neither lowers plasma glucose nor improves mitochondrial capacity in mice fed a high fat diet. SRT1720, SRT2183, SRT1460, and resveratrol exhibit multiple off-target activities against receptors, enzymes, transporters, and ion channels. Taken together, we conclude that SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1.

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Low molecular weight peptidomimetic compounds based on O-malonyl tyrosine and O-carboxymethyl salicylic acid are potent inhibitors of PTP1B. Modifications of the N-terminal Boc-Phe moiety were undertaken in an effort to improve physical chemical properties and to achieve cellular activity. Although Phe ultimately proved to be the optimal N-terminal amino acid, several viable replacements for the Boc group were identified, two of which afforded analogues that were effective at enhancing the insulin-stimulated uptake of 2-deoxyglucose by L6 myocytes.

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Protein tyrosine phosphatases (PTPs) constitute a diverse family of enzymes that, together with protein tyrosine kinases, control the level of intracellular tyrosine phosphorylation, thus regulating many cellular functions. PTP1B negatively regulates insulin signaling, in part, by dephosphorylating key tyrosine residues within the regulatory domain of the beta-subunit of the insulin receptor, thereby attenuating receptor kinase activity. Inhibitors of PTP1B would therefore have the potential of prolonging the phosphorylated (activated) state of the insulin receptor and are anticipated to be a novel treatment of the insulin resistance characteristic of type 2 diabetes. We previously reported a series of small molecular weight peptidomimetics as competitive inhibitors of PTP1B, with the most active analogues having K(i) values in the low nanomolar range. Furthermore, we confirmed that the O-carboxymethyl salicylic acid moiety is a remarkably effective novel phosphotyrosine mimetic. Because of the low cell permeability of this compound class, it was important to investigate the possibility of replacing one or both of the remaining carboxyl groups while maintaining PTP1B inhibitory activity. The analogues described herein further support the importance of an acidic functionality at both positions of the tyrosine head moiety. An important discovery was the ortho tetrazole analogue 29 (K(i) = 2.0 microM), which was equipotent to the dicarboxylic acid analogue 2 (K(i) = 2.0 microM). Solution of the X-ray cocrystal structure of the ortho tetrazole analogue 29 bound to PTP1B revealed that the tetrazole moiety is well-accommodated in the active site and binds in a fashion similar to the ortho carboxylate analogue 2 reported previously. This novel monocarboxylic acid analogue revealed significantly higher Caco-2 cell permeability as compared to all previous compounds. Furthermore, compound 29 exhibited modest enhancement of insulin-stimulated 2-deoxyglucose uptake by L6 myocytes.

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Protein tyrosine phosphatase 1B (PTP1B) negatively regulates insulin signaling in part by dephosphorylating key tyrosine residues within the regulatory domain of the beta-subunit of the insulin receptor (IR), thereby attenuating receptor tyrosine kinase activity. Inhibition of PTP1B is therefore anticipated to improve insulin resistance and has recently become the focus of discovery efforts aimed at identifying new drugs to treat type II diabetes. We previously reported that the tripeptide Ac-Asp-Tyr(SO(3)H)-Nle-NH(2) is a surprisingly effective inhibitor of PTP1B (K(i) = 5 microM). With the goal of improving the stability and potency of this lead, as well as attenuating its peptidic character, an analogue program was undertaken. Specific elements of the initial phase of this program included replacement of the N- and C-termini with non-amino acid components, modification of the tyrosine subunit, and replacement of the tyrosine sulfate with other potential phosphate mimics. The most potent analogue arising from this effort was triacid 71, which inhibits PTP1B competitively with a K(i) = 0.22 microM without inhibiting SHP-2 or LAR at concentrations up to 100 microM. Overall, the inhibitors generated in this work showed little or no enhancement of insulin signaling in cellular assays. However, potential prodrug triester 70 did induce enhancements in 2-deoxyglucose uptake into two different cell lines with concomitant augmentation of the tyrosine phosphorylation levels of insulin-signaling molecules. Key elements of the overall SAR reported herein include confirmation of the effectiveness and remarkable PTP1B-specificity of the novel tyrosine phosphate bioisostere, O-carboxymethyl salicylic acid; demonstration that the tyrosine skeleton is optimal relative to closely related structures; replacement of the p-1 aspartic acid with phenylalanine with little effect on activity; and demonstration that inhibitory activity can be maintained in the absence of an N-terminal carboxylic acid. An X-ray cocrystal structure of an analogue bearing a neutral N-terminus (69) bound to PTP1B is reported that confirms a mode of binding similar to that of peptidic substrates.

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