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Background: Sleeve gastrectomy is the most performed metabolic surgical procedure worldwide. However, conflicting results offer no clear evidence about its long-term clinical comparability to Roux-en-Y gastric bypass. This study aims to determine their equivalent long-term weight loss effects., Methods: This randomised open-label controlled trial was conducted from 2012 until 2017 in two Dutch bariatric hospitals with a 5-year follow-up (last follow-up July 29th, 2022). Out of 4045 patients, 628 were eligible for metabolic surgery and were randomly assigned to sleeve gastrectomy or Roux-en-Y gastric bypass (intention-to-treat). The primary endpoint was weight loss, expressed by percentage excess body mass index (BMI) loss. The predefined clinically relevant equivalence margin was -13% to 13%. Secondary endpoints included percentage total kilograms weight loss, obesity-related comorbidities, quality of life, morbidity, and mortality. This trial is registered with Dutch Trial Register NTR4741: https://onderzoekmetmensen.nl/nl/trial/25900., Findings: 628 patients were randomised between sleeve gastrectomy (n = 312) and Roux-en-Y gastric bypass (n = 316) (mean age 43 [standard deviation (SD), 11] years; mean BMI 43.5 [SD, 4.7]; 81.8% women). Excess BMI loss at 5 years was 58.8% [95% CI, 55%-63%] after sleeve gastrectomy and 67.1% [95% CI, 63%-71%] after Roux-en-Y gastric bypass (difference 8.3% [95% CI, -12.5% to -4.0%]). This was within the predefined margin ( P  < 0.001). Total weight loss at 5 years was 22.5% [95% CI, 20.7%-24.3%] after sleeve gastrectomy and 26.0% [95% CI, 24.3%-27.8%] after Roux-en-Y gastric bypass (difference 3.5% [95% CI, -5.2% to -1.7%]). In both groups, obesity-related comorbidities significantly improved after 5 years. Dyslipidaemia improved more frequently after Roux-en-Y gastric bypass (83%, 54/65) compared to sleeve gastrectomy (62%, 44/71) ( P  = 0.006). De novo gastro-oesophageal reflux disease occurred more frequently after sleeve gastrectomy (16%, 46/288) vs Roux-en-Y gastric bypass (4%, 10/280) ( P  < 0.001). Minor complications were more frequent after Roux-en-Y gastric bypass (5%, 15/316) compared to sleeve gastrectomy (2%, 5/312). No statistically significant differences in major complications and health-related quality of life were encountered., Interpretation: In people living with obesity grades 2 and 3, sleeve gastrectomy and Roux-en-Y gastric bypass had clinically comparable excess BMI loss according to the predefined definition for equivalence. However, Roux-en-Y gastric bypass showed significantly higher total weight loss and significant advantages in secondary outcomes, including dyslipidaemia and GERD, yet at a higher rate of minor complications. Major complications, other comorbidities, and overall HRQoL did not significantly differ between the groups., Funding: Not applicable., Competing Interests: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr. SN reported receiving a Medtronic Educational Grant to the Catharina Obesity centre. No other authors reported disclosures., (© 2024 The Author(s).)

Background: Anti-drug antibodies are associated with treatment failure to anti-TNF agents in patients with inflammatory bowel disease (IBD)., Aim: To assess whether immunogenicity to a patient's first anti-TNF agent would be associated with immunogenicity to the second, irrespective of drug sequence METHODS: We conducted a UK-wide, multicentre, retrospective cohort study to report rates of immunogenicity and treatment failure of second anti-TNF therapies in 1058 patients with IBD who underwent therapeutic drug monitoring for both infliximab and adalimumab. The primary outcome was immunogenicity to the second anti-TNF agent, defined at any timepoint as an anti-TNF antibody concentration ≥9 AU/ml for infliximab and ≥6 AU/ml for adalimumab., Results: In patients treated with infliximab and then adalimumab, those who developed antibodies to infliximab were more likely to develop antibodies to adalimumab, than patients who did not develop antibodies to infliximab (OR 1.99, 95%CI 1.27-3.20, p = 0.002). Similarly, in patients treated with adalimumab and then infliximab, immunogenicity to adalimumab was associated with subsequent immunogenicity to infliximab (OR 2.63, 95%CI 1.46-4.80, p < 0.001). For each 10-fold increase in anti-infliximab and anti-adalimumab antibody concentration, the odds of subsequently developing antibodies to adalimumab and infliximab increased by 1.73 (95% CI 1.38-2.17, p < 0.001) and 1.99 (95%CI 1.34-2.99, p < 0.001), respectively. Patients who developed immunogenicity with undetectable drug levels to infliximab were more likely to develop immunogenicity with undetectable drug levels to adalimumab (OR 2.37, 95% CI 1.39-4.19, p < 0.001). Commencing an immunomodulator at the time of switching to the second anti-TNF was associated with improved drug persistence in patients with immunogenic, but not pharmacodynamic failure., Conclusion: Irrespective of drug sequence, immunogenicity to the first anti-TNF agent was associated with immunogenicity to the second, which was mitigated by the introduction of an immunomodulator in patients with immunogenic, but not pharmacodynamic treatment failure., (© 2022 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Competing Interests: Competing interests: None declared.

Competing Interests: Intérêts concurrents: Neil Chanchlani est titulaire d’une bourse de recherche clinique de Crohn’s and Colitis UK. Aucun autre intérêt concurrent n’a été déclaré. Déclaration d’intérêts: Neil Chanchlani est rédacteur associé pour le CMAJ, mais n’a pas participé au processus ayant mené au choix de cet article.

Competing Interests: Competing interests: Neil Chanchlani receives funding from Crohn’s and Colitis UK through a clinical research fellowship. He is an associate editor of CMAJ, but not involved in the review or decision to accept this manuscript for publication. No other competing interests were declared.

The specific combination for conditioning regimens in hematopoietic stem cell transplantation continues to be a premier area of focus in research. Although conditioning regimens have significantly evolved over time, obstacles continue to persist, including regimen-related toxicities, graft-versus-host disease, and disease relapse. Gemcitabine (2',2'-difluoro 2'-deoxycytidine, dFdC) is a pyrimidine nucleoside analog that distinguishes itself from other agents in the class by possessing a favorable pharmacokinetic and cytotoxic profile, while maintaining acceptable toxicities. Given the desirable properties, gemcitabine has garnered much attention and been assessed in several conditioning regimens. In this article, we review the pharmacology of gemcitabine with other nucleoside analogs and report the findings of pivotal trials conducted in both autologous and allogeneic transplantation. The positive results suggest a potential future role for gemcitabine and necessitate the need to conduct studies to further define its role., (Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Despite significant advances in prevention and treatment strategies, graft-versus-host disease remains the most significant cause of morbidity and nonrelapse mortality after allogeneic hematopoietic cellular transplantation. Corticosteroids remain the standard frontline therapy for graft-versus-host disease; however, a considerable number of patients will not respond adequately and others will be significantly affected by adverse effects. Extracorporeal photopheresis is one of several secondary therapies which have shown promise in the clinical setting. While the procedure itself has been around for over 20 years, our understanding of the mechanisms from which therapeutic benefits are seen, and the population they are seen in, remains limited. In this article, we review the use of extracorporeal photopheresis for the treatment of graft-versus-host disease including details covering the procedure's mechanism of action, safety profile and clinical efficacy data.

Proteins in sieve tube exudate from Cucumis melo L., Cucumis sativus L. and Cucurbita maxima Duch. were analysed by gel electrophoresis and isoelectric focusing. Estimated molecular weights and isoelectric points for the major and minor proteins from each plant species are presented. Electrophoresis revealed striking differences between the protein complements of exudatc from the two genera investigated. Similarly, although a few exudate proteins from the two species of Cucumis possessed identical molecular weights, several major proteins were peculiar to each species. Isoelectric focusing of proteins in exudate samples from the three plants confirmed the marked differences in their protein complements. Furthermore, focusing also revealed differences between cultivars of Cucumis sativus. Both Cucumis sativus and Cucurbita maxima possessed relatively large amounts of basic proteins; these were absent in exudate from Cucumis melo. The implications of these results are discussed in relation to present concepts regarding the interrelationships and possible functional roles of P-proteins.

Extracts of large quantities of petioles and of isolated vascular tissues of Heracleum mantegazzianum have been analysed for actomyosin-like contractile proteins. Concentrated preparations, subjected to a standard isolation and purification procedure for actomyosin, failed to demonstrate either superprecipitation or viscosity changes in response to the addition of ATP and divalent cations. In addition, ATPase activities in phloem and xylem extracts have been fractionated by gel electrophoresis and characterised with regard to their substrate specificity, pH optima and ion requirements. Phloem extracts provide two phosphatases: one is non-specific in its substrate requirements; the other is a nucleoside triphosphatase but is stimulated only by monovalent cations and is also present in xylem extracts. All the enzymes are strongly inhibited by divalent cations and do not possess any of the characteristics of ATPases associated with contractile systems. The results are discussed in relation to the postulated involvement of contractile proteins in the translocation of sugars in phloem.

The growth responses of a sunflower seedling (Helianthus annuus L.), subjected to repeated inversion, were characterized by time-lapse recording in conjunction with video image analysis. The investigation revealed a characteristic response pattern and established that the directional movement of the seedling is achieved by both inhibition and stimulation of growth in the normal growing regions. The complex growth changes in contiguous regions of the hypocotyl are such as seem to be inexplicable in terms of an environmentally imposed gradient of a single growth substance.

Proteins in sieve tube exudate from Ricinus communis L., Acer pseudoplatanus L., Aesculus hippocastanum L., Cucumis melo L., and two cultivars each of Cucumis sativus L., Cucurbita pepo L. and Cucurbita maxima Duchesne were fractionated and compared using polyacrylamide gel electrophoresis. Striking differences in major exudate proteins were displayed among the genera and species examined. Even cultivars within a single species, although showing general similarities, differed in some prominent proteins. Estimated molecular weights of the major exudate proteins from each plant are presented. The effects of reducing and chaotropic agents on the aggregation and subunit composition of exudate proteins from Cucumis sativus have been investigated. The problems involved in relating structure, function and biochemistry of P-protein are discussed.

Protein subunits present in phloem exudate from 17 cultivars, 5 species and 3 genera of the Cucurbitaceae have been fractionated by SDS-gel electrophoresis. The degree of difference in the phloem protein patterns appears to reflect the taxonomic relationships of the plants: there were major differences among genera, significant differences and similarities among species, and relatively few differences among cultivars of a single species. A representative of another family (Acer pseudoplatanus; Aceraceae) provided a completely different electrophoretic pattern. Each plant displayed a consistent protein pattern, irrespective of the organ from which exudate was obtained or the age and physiological status of the plant. Neither complete etiolation nor transition to the flowering phase effected any change in phloem proteins. The differences in phloem proteins between plants and the unusual properties of major subunits from different protein complements, render improbable many of the present ideas concerning the origin and function of P-protein.

The occurrence of high haemagglutinating (lectin) activity in phloem exudate from three cucurbit species is reported. The protein responsible for this lectin activity in Cucurbita maxima Duch. has been isolated by cation exchange chromatography on Sepharose and identified by gel electrophoresis. The lectin showed agglutinating activity at concentrations as low as 0.1 μg/ml. No sugar, including those transported in the phloem of these species, interacted with agglutination. The lectin could not be extracted from cucurbit seed, but appeared in 5-day old seedlings. The possible role of a lectin in the sieve element is discussed.

Regional growth in vertical and horizontal etiolated sunflower hypocotyls from which the apical hook tissue had been either partly or wholly excised, was measured 24 h later, the regions having been demarcated with resin beads. Removal of the cotyledons (an excision which included the distal end of the shoot apex) had little effect on growth during this period but excision of the apical hook significantly reduced growth. In vertically orientated seedlings, removal of half of the hook severely reduced growth in all other growing regions and removal of the entire hook totally inhibited growth. This inhibition of growth was not a consequence of the removal of the region of growth but a consequence of the removal of a region on which growth was dependent. In horizontal seedlings, the situation was more complex inasmuch as a horizontal orientation itself induced growth in previously non-growing regions. This new growth was localised in its extent and was not as severely affected by progressive excision of the hook as was growth in vertical seedlings. The results are discussed in terms of overall growth co-ordination in the hypocotyl.

A calcium-binding macromolecule, with an estimated molecular weight greater than 100,000, was detected in phloem exudate from Cucurbita maxima and related species. The macromolecule was a component of sieve tube sap, rather than a contaminant leached from cell walls or cut parenchyma cells during exudate collection. The protein nature of this macromolecule was deduced from its size, lability, susceptibility to proteolytic digestion, and by the dependence of calcium-binding activity on thiol-protecting agents. This protein is distinct from the major proteins of exudate and does not appear to be related to calmodulin.

Photographic observations on germinating seedlings of Lepidium sativum L., Cucumis sativus L., and Helianthus annuus L. showed that the hypocotyl hook is not present in the seed but forms during the early stages of growth. Evidence that gravity plays a major role in inducing curvature of the hypocotyl, and in maintaining the hook once it has been formed, was obtained from clinostat experiments, from the use of morphactin to remove geotropic sensitivity and from inversion of seedlings to change the direction of the geostimulus. In L. sativum and H. annuus gravity perception seemed to be the only mechanism responsible for hook formation. In C. sativus hook formation was additionally aided by the mode of emergence of the cotyledons from the seed coat but gravity played an indirect role in regulating such emergence. Further evidence that hook formation is linked to a georesponse was derived from a comparison of hypocotyl development in wild-type Arabidopsis thaliana seedlings with that of an ageotropic mutant, hook formation being found to occur only in the wild type. Hook formation and maintenance is discussed in terms of contrasting geosensitivity between the apical and basal ends of the hypocotyl and it is suggested that light-induced hook opening is a reversal to a condition of uniformly negative georesponse throughout the hypocotyl.

Experiments with horizontal etiolated sunflower (Helianthus annuus L.) seedlings supported centrally such that both apical and basal ends are free to react to geostimulus, revealed that the apical end commences curvature 1 to 2 hours earlier than the basal end. The later curvature in the basal region is a consequence of the absence of growth in the initial period rather than merely slower growth. A comparison of zonal growth rates in a vertical and a horizontal seedling confirmed that geostimulus induces a renewal of growth in a region where growth had ceased. Removing the apical half of the hypocotyl showed that the curvature resulting from this growth initiation in the basal region is dependent on attachment to the apical region. Evidence that this dependence is unlikely to be due to energy deficiency is adduced. The prior response of the apical end to geostimulus and the apically dependent later initiation of new growth in the basal region are compatible with the delay inherent in message transport from apex to base and are considered as evidence for apical involvement in the totality of the seedling's georesponse.

The existence of different auxin sensitivities in epidermal and subepidermal tissues (KV Thimann, CL Schneider 1938 Plant Physiol 25: 627-641) suggests a refinement to the Cholodny-Went theory which overcomes some of the difficulties associated with it. A model is presented to account for the inverse tropic responses of shoots and roots through differences in the respective locations of the auxin-sensitive tissues.

The sulfur requirements of tobacco (Nicotiana tabacum L. var. Xanthi) XD cells grown in chemically defined liquid media can be satisfied by sulfate, thiosulfate, l-cyst(e)ine, l-methionine or glutathione, and somewhat less effectively by d-cyst (e) ine, d-methionine or dl-homocyst (e)ine. Sulfate uptake is inhibited after a 2 hr lag by l-cyst (e)ine, l-methionine, l-homocyst(e)ine or l-isoleucine, but not by any of the other protein amino acids, nor by d-cyst(e)ine. l-cyst(e)ine is neither a competitive nor a non-competitive inhibitor of sulfate uptake. Its action most closely resembles apparent uncompetitive inhibition. Inhibition of sulfate uptake by l-cyst(e)ine can be partially prevented by equimolar l-arginine, l-lysine, l-leucine, l-phenylalanine, l-tyrosine or l-tryptophan, but is little affected by any of the other protein amino acids. The effective amino acids are apparent competitive inhibitors of l-cyst(e)ine uptake after a 2 hr lag. Inhibition of sulfate uptake by l-methionine cannot be prevented, nor can uptake of l-methionine be inhibited by any single protein amino acid. The results suggest the occurrence of negative feedback control of sulfate assimilation by the end products, the sulfur amino acids, in cultured tobacco cells.

Colchicine has been demonstrated by ion-exchange and by gelfiltration assay to bind to a protein fraction derived from the higher plant Heracleum mantegazzianum. Colchicine-binding protein from a plant source was much more unstable than tubulin from animal preparations. The tissues of Heracleum vary in their content of colchicine-binding activity. No activity was obtained from non-vascular tissue. Phloem has at most, twice as much activity as xylem. The significance of these results is discussed in relation to a proposed degree of homology between P protein of phloem and microtubule protein.

The ultrastructure of P1 and P2 proteins in the sieve elements of Heracleum mantegazzianum is described. P1-protein tubules are closely associated with stacks of membranes, are often linked by short cross-bridges, and occasionally display a hexagonal packing. Incubation with the alkaloids vinblastine and colchicine had no discernible effects on the ultrastructure of the sieve elements at various stages during differentiation. Evidence for and against any similarities between P1-protein tubules and cytoplasmic microtubules is discussed.