IntroductionRoux-en-Y gastric bypass surgery (RYGB) reduces albuminuria and the long-term incidence of end-stage renal disease in patients with obesity and diabetes. Preclinical modeling in experimental diabetic kidney disease demonstrates that improvements in glomerular structure likely underpin these findings.Research design and methodsIn adult male Zucker diabetic fatty (ZDF) rats, we profiled the effect of RYGB on weight and metabolic control as well biochemical, structural and ultrastructural indices of diabetic renal injury. Furthermore, we sequenced the renal cortical transcriptome in these rats and used bioinformatic pathway analyses to characterize the transcriptional alterations governing the renal reparative response to RYGB.ResultsIn parallel with improvements in weight and metabolic control, RYGB reduced albuminuria, glomerulomegaly, podocyte stress and podocyte foot process effacement. Pathway analysis of RYGB-induced transcriptomic changes in the renal cortex highlighted correction of disease-associated alterations in fibrosis, inflammation and biological oxidation pathways. RYGB reversed disease-associated changes in the expression of transforming growth factor (TGF)-β superfamily genes that strongly correlated with improvements in structural measures of glomerulopathy.ConclusionsImproved glomerular structure in ZDF rats following RYGB is underpinned by pathway level changes, including interruption of the TGF-β-driven early profibrotic programme. Our data provide an important layer of experimental support for clinical evidence demonstrating that RYGB arrests renal damage in patients with obesity and type 2 diabetes.

After esophagectomy, patients demonstrate an exaggerated postprandial satiety gut hormone response, which may mediate postoperative changes in satiety, body weight, and gastrointestinal quality of life.

Individual chemical motifs are known to introduce structural distortions to the porphyrin macrocycle, be it in the core or at the periphery of the macrocycle. The interplay when introducing two or more of these known structural motifs has been scarcely explored and is not necessarily simply additive; these structural distortions have a chance to compound or negate to introduce new structural types. To this end, a series of compounds with complementary peripheral (5,15-disubstitution) and core (acidification) substitution patterns were investigated. The single-crystal X-ray structures of 18 5,15-diphenylporphyrin, 5,15-diphenylporphyrindi-ium diacid, and related compounds are reported, including the first example of a 5,15-dialkylporphyrindi-ium. Normal-coordinate structural decomposition (NSD) analysis is used for a detailed analysis of the conformation of the porphyrin subunit within the crystal structures. An elongation of porphyrin macrocycles along the C5,C15- axis (B2g symmetry) is observed in all of the free base porphyrins and porphyrin dications; distance across the core is around 0.3 Å in the free base and diacid compounds, and more than doubled in 5,15-dipentylporphyrin and 5,15-dipentylporphyrindi-ium diacid. While the free base porphyrins are largely planar, a large out-of-plane distortion can be observed in 5,15-diphenylporphyrin diacids, with the expected “projective saddle” shape characteristic for such systems. The combination of these two distortions (B2u and B2g) from regular porphyrin structure results in a macrocycle best characterized in the chiral point-group D2. A rare structural type of a cis-hydrogen bond chelate is observed for 5,15-dipentylporphyrindi-ium diacid, which adopts an achiral C2v symmetry. Crystallographic data indicate that the protonated porphyrin core forms hydrogen bonding chelates (N-H⋯X⋯H-N) to counter-anions. Weaker interactions, such as induced intramolecular C-H⋯O interactions from the porphyrin periphery are described, with distances characteristic of charge-assisted interactions. This paper offers a conceptual framework for accessing porphyrin macrocycles with designable distortion and symmetry, useful for the selective perturbation of electronic states and a design-for-application approach to solid state porphyrin materials.

Rational building strategies and appropriate synthons have been developed for the use of triptycene as a rigid presenting scaffold. Palladium catalyzed cross-coupling reactions such as, Sonogashira and Suzuki couplings were used to install a variety of different synthetic handles around the triptycene periphery in a high yielding and controlled manner. These triptycene molecular handles were investigated for their potential in the construction of molecular arrays with defined spatial orientation e.g., for host-guest interactions or drug delivery systems. Such molecular synthons afforded expansion from the triptycene core employing arm extension increasing the internal free volume characteristic of triptycene scaffolds for such applications. In addition a range of mesogenic and glycosyl triptycene derivatives were achieved as a synthetic proof of concept for future work on potential drug delivery systems.

Background Reduced appetite and weight loss are common after esophagectomy (ES), and this cohort demonstrates an exaggerated postprandial satiety gut hormone response. Satiety gut hormones modulate food reward, resulting in reduced energy intake. Objectives This study aimed to determine the effect of satiety gut hormone modulation by measuring the effect of the somatostatin analog octreotide on appetitive behavior among patients after ES. Methods In this randomized, double-blind, placebo-controlled crossover study, patients ≥1 y after ES and matched controls received either 1 mL 0.9% saline or 1 mL (100 μg) octreotide subcutaneously before completing a progressive ratio task. A measure of appetitive behavior, this task requires subjects to undertake progressively increasing amounts of work to obtain a sweet-fat reinforcer; the final completed increment (breakpoint) represents reinforcer reward value. Separate cohorts were studied in the fasted or 1-h postprandial states. Results Thirty-six subjects (ES, n = 18; matched controls, n = 18) were studied. The ES subjects were 2.5 ± 0.3 y postoperation and had a weight loss of 14.6% ± 2.6% and elevated postprandial glucagon-like peptide 1 compared with controls (49.2 ± 13.4 compared with 20.2 ± 2.3 pM; P = 0.04). Octreotide did not alter the breakpoint among ES or control subjects when tested in a fasting condition (ES: 980 ± 371 compared with 1700 ± 584 clicks; P = 0.16; controls: 1056 ± 274 compared with 1124 ± 273 clicks; P = 0.81). When tested 1 h postprandially, octreotide was associated with an increased breakpoint compared with placebo among ES subjects (322 ± 143 compared with 246 ± 149 clicks; P = 0.04) but not controls (248 ± 119 compared with 247 ± 120 clicks; P = 0.97). Conclusions Attenuation of the exaggerated postprandial satiety gut hormone response is associated with increased appetitive behavior toward a sweet-fat stimulus among patients post-ES. Suppression of satiety gut hormones may be a novel target to increase appetite, food intake, and body weight among patients after ES. This study was registered at clinicaltrials.gov as NCT02381249.

Background: Oesophagectomy is associated with reduced appetite, weight loss and postprandial hypoglycaemia, the pathophysiological basis of which remains largely unexplored. This study aimed to investigate changes in enteroendocrine function after oesophagectomy.Methods: In this prospective study, 12 consecutive patients undergoing oesophagectomy were studied before and 10 days, 6, 12 and 52 weeks after surgery. Serial plasma total fasting ghrelin, and glucagon-like peptide 1 (GLP-1), insulin and glucose release following a standard 400-kcal mixed-meal stimulus were determined. CT body composition and anthropometry were assessed, and symptom scores calculated using European Organisation for Research and Treatment of Cancer (EORTC) questionnaires. Results: At 1 year, two of the 12 patients exhibited postprandial hypoglycaemia, with reductions in bodyweight (mean(s.e.m.) 17⋅1(3⋅2) per cent, P < 0⋅001), fat mass (21.5(2.5) kg versus 25.5(2.4) kg before surgery; P = 0⋅014), lean body mass (51.5(2.2) versus 54.0(1.8) kg respectively; P = 0⋅003) and insulin resistance (HOMA-IR: 0.84(0.17) versus 1.16(0.20); P = 0⋅022). Mean(s.e.m.) fasting ghrelin levels decreased from postoperative day 10, but had recovered by 1 year (preoperative: 621⋅5(71⋅7) pg/ml; 10 days: 415⋅1(59⋅80) pg/ml; 6 weeks: 309⋅0(42⋅0) pg/ml; 12 weeks: 415⋅8(52⋅1) pg/ml; 52 weeks: 547⋅4(83⋅2) pg/ml; P < 0⋅001) and did not predict weight loss (P = 0⋅198). Postprandial insulin increased progressively at 10 days, 6, 12 and 52 weeks (mean(s.e.m.) insulin AUC 0-30 min : fold change 1⋅7(0⋅4), 2⋅0(0⋅4), 3⋅5(0⋅7) and 4⋅0(0⋅8) respectively; P = 0⋅001). Postprandial GLP-1 concentration increased from day 10 after surgery (P < 0⋅001), with a 3⋅3(1⋅8)-fold increase at 1 year (P < 0⋅001). Peak GLP-1 level was inversely associated with the postprandial glucose nadir (P = 0⋅041) and symptomatic neuroglycopenia (Sigstad score, P = 0⋅017, R 2 = 0⋅45). GLP-1 AUC predicted loss of weight (P = 0⋅008, R 2 = 0⋅52) and fat mass (P = 0⋅010, R 2 = 0⋅64) at 1 year.Conclusion: Altered enteroendocrine physiology is associated with early satiety, weight loss and postprandial hypoglycaemia after oesophagectomy.

Nitrazolam and clonazolam are 2 designer benzodiazepines available from Internet retailers. There is growing evidence suggesting that such compounds have the potential to cause severe adverse events. Information about tolerability in humans is scarce but typically, low doses can be difficult to administer for users when handling bulk material. Variability of the active ingredient in tablet formulations can also be of a concern. Customs, toxicology and forensic laboratories are increasingly encountering designer benzodiazepines, both in tablet and powdered form. The unavailability of reference standards can impact on the ability to identify these compounds. Therefore, the need arises for exploring in-house approaches to the preparation of new psychoactive substances (NPS) that can be carried out in a timely manner. The present study was triggered when samples of clonazolam were received in powdered and tablet form at a time when reference material for this drug was commercially unavailable. Therefore, microscale syntheses of clonazolam and its deschloro analog nitrazolam were developed utilizing polymer-supported reagents starting from 2-amino-2'-chloro-5-nitrobenzophenone (clonazolam) and 2-amino-5-nitrobenzophenone (nitrazolam). The final reaction step forming the 1,2,4-triazole ring moiety was performed within a gas chromatography-mass spectrometry (GC-MS) injector. A comparison with a preparative scale synthesis of both benzodiazepine derivatives showed that microscale synthesis might be an attractive option for a forensic laboratory in terms of time and cost savings when compared with traditional methods of synthesis and when qualitative identifications are needed to direct forensic casework. The reaction by-product profiles for both the micro and the preparative scale syntheses are also presented.

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