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Background: Neglected anterior glenohumeral dislocations provide a challenging problem for physicians. For many patients with these injuries, reverse shoulder arthroplasty has been the treatment of choice, although the preservation of the patient's own humeral head might have significant advantages. Methods: We present a case of a 66-year-old male with a neglected anterior glenohumeral dislocation that he sustained 6 weeks prior when he was hit by a car as a pedestrian. Radiographic imaging revealed a large off-track Hill-Sachs deformity and a fracture of the greater tuberosity in addition to the persisting glenohumeral dislocation. We performed open reduction and to aid stability, an infraspinatus tendon remplissage and a Latarjet procedure were performed. Results: Apart from minor and self-limiting neuropraxia, recovery was without complications. At 24 month follow-up, the patient had no impairment in general activities, had no residual pain, and had a good active range of motion. Conclusions: The authors, therefore, believe that a combination of infraspinatus tendon remplissage and the Latarjet procedure seems a feasible alternative for reverse shoulder arthroplasty and can preserve the patient's own humeral head.

Background: About 20% of proximal humerus fractures (PHFs) are unstable and/or markedly displaced and therefore require surgery. Locking plate fixation after anatomical reduction has become the current treatment of choice for these fractures in the active population. However, studies have shown complication rates up to 36%, such as loss of reduction and avascular necrosis. To date, data from literature are inconclusive on outcomes following the use of an intramedullary fibula allograft in PHFs, possibly due to the case mix. It is hypothesized that the use of a fibula allograft is beneficial to prevent secondary displacement of the fracture in cases where the medial hinge is markedly displaced and unstable, resulting in better clinical and patient reported outcomes., Methods: In this multicenter matched cohort study, patients with an unstable, displaced PHF, including anatomic neck fractures and significantly displaced surgical neck fractures, were included. Patients that were treated with a locking plate augmented with a fibula allograft were matched to patients who had undergone locking plate reconstruction without the allograft. The matches were made based on fracture characteristics, age, and performance status. Functional outcomes, Patient Reported Outcome Measures, complications, and radiographic results were compared., Results: Twelve patients with fibula allograft augmented osteosyntheses were included and matched to 12 control patients. The mean age was 58 years in the fibula allograft group compared to 62 years in the control group. Minimum follow-up was 12 months. Disability of the Arm Shoulder and Hand score, Constant Shoulder score, abduction, and external rotation were significantly better in the fibula allograft group (17.4 ± 8.6 vs. 26.1 ± 19.2, P  = .048; 16.5 ± 11.5 vs. 19.8 ± 16.5 P  = .040; mean 127° ± 38° vs. mean 92° ± 49° P  = -.045; 50° ± 21° vs. mean 26° ± 23°, P  = .004). There was no statistically significant difference in the Oxford Shoulder score between groups ( P  = .105). The Visual Analog Scale was not significantly different between groups (3.1 ± 1.8 vs. 1.6 ± 1.9, P  = .439). Radiographic union was reached in 11 patients of the fibula allograft group compared to 8 in the control group ( P  = .317). The complication rate was twice as high in the control group (3 vs. 7)., Conclusion: Additional support of the medial hinge in unstable PHFs with a locking plate in combination with a fibula allograft appears to create a more stable construct without compromising the viability of the articular surface of the head. The use of a fibula allograft in selected complex cases could therefore result in better clinical outcomes with lower complication rates., (© 2023 The Author(s).)

Vaccines are a promising therapeutic alternative to monoclonal antibodies against HER-2+ breast cancer. We present the preclinical activity of an ES2B-C001, a VLP-based vaccine being developed for human breast cancer therapy. FVB mice challenged with HER-2+ mammary carcinoma cells QD developed progressive tumors, whereas all mice vaccinated with ES2B-C001+Montanide ISA 51, and 70% of mice vaccinated without adjuvant, remained tumor-free. ES2B-C001 completely inhibited lung metastases in mice challenged intravenously. HER-2 transgenic Delta16 mice developed mammary carcinomas by 4−8 months of age; two administrations of ES2B-C001+Montanide prevented tumor onset for >1 year. Young Delta16 mice challenged intravenously with QD cells developed a mean of 68 lung nodules in 13 weeks, whereas all mice vaccinated with ES2B-C001+Montanide, and 73% of mice vaccinated without adjuvant, remained metastasis-free. ES2B-C001 in adjuvant elicited strong anti-HER-2 antibody responses comprising all Ig isotypes; titers ranging from 1−10 mg/mL persisted for many months. Antibodies inhibited the 3D growth of human HER-2+ trastuzumab-sensitive and -resistant breast cancer cells. Vaccination did not induce cytokine storms; however, it increased the ELISpot frequency of IFN-γ secreting HER-2-specific splenocytes. ES2B-C001 is a promising candidate vaccine for the therapy of tumors expressing HER-2. Preclinical results warrant further development towards human clinical studies.

The continued rise of antibiotic resistance is a global concern that threatens to undermine many aspects of modern medical practice. Key to addressing this threat is the discovery and development of new antibiotics that operate by unexploited modes of action. The so-called calcium-dependent lipopeptide antibiotics (CDAs) are an important emerging class of natural products that provides a source of new antibiotic agents rich in structural and mechanistic diversity. Notable in this regard is the subset of CDAs comprising the laspartomycins and amphomycins/friulimicins that specifically target the bacterial cell wall precursor undecaprenyl phosphate (C 55 -P). In this study we describe the design and synthesis of new C 55 -P-targeting CDAs with structural features drawn from both the laspartomycin and amphomycin/friulimicin classes. Assessment of these lipopeptides revealed previously unknown and surprisingly subtle structural features that are required for antibacterial activity. High-resolution crystal structures further indicate that the amphomycin/friulimicin-like lipopeptides adopt a unique crystal packing that governs their interaction with C 55 -P and provides an explanation for their antibacterial effect. In addition, live-cell microscopy studies provide further insights into the biological activity of the C 55 -P targeting CDAs highlighting their unique mechanism of action relative to the clinically used CDA daptomycin., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

A recently discovered bisubstrate inhibitor of Nicotinamide N -methyltransferase (NNMT) was found to be highly potent in biochemical assays with a single digit nanomolar IC 50 value but lacking in cellular activity. We, here, report a prodrug strategy designed to translate the observed potent biochemical inhibitory activity of this inhibitor into strong cellular activity. This prodrug strategy relies on the temporary protection of the amine and carboxylic acid moieties of the highly polar amino acid side chain present in the bisubstrate inhibitor. The modification of the carboxylic acid into a range of esters in the absence or presence of a trimethyl-lock (TML) amine protecting group yielded a range of candidate prodrugs. Based on the stability in an aqueous buffer, and the confirmed esterase-dependent conversion to the parent compound, the isopropyl ester was selected as the preferred acid prodrug. The isopropyl ester and isopropyl ester-TML prodrugs exhibit improved cell permeability, which also translates to significantly enhanced cellular activity as established using assays designed to measure the enzymatic activity of NNMT in live cells.

Nicotinamide N -methyltransferase (NNMT) methylates nicotinamide to form 1-methylnicotinamide (MNA) using S -adenosyl-l-methionine (SAM) as the methyl donor. The complexity of the role of NNMT in healthy and disease states is slowly being elucidated and provides an indication that NNMT may be an interesting therapeutic target for a variety of diseases including cancer, diabetes, and obesity. Most inhibitors of NNMT described to date are structurally related to one or both of its substrates. In the search for structurally diverse NNMT inhibitors, an mRNA display screening technique was used to identify macrocyclic peptides which bind to NNMT. Several of the cyclic peptides identified in this manner show potent inhibition of NNMT with IC 50 values as low as 229 nM. The peptides were also found to downregulate MNA production in cellular assays. Interestingly, substrate competition experiments reveal that these cyclic peptide inhibitors are noncompetitive with either SAM or NA indicating they may be the first allosteric inhibitors reported for NNMT., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The synthesis of a new class of benzotriazole-derived α-amino acid is described using a highly efficient nucleophilic aromatic substitution of ortho -fluoronitrobenzenes with l-3-aminoalanine and a polymer-supported nitrite reagent-mediated diazotization and cyclization of the subsequent 1,2-aryldiamines as the key steps. Further functionalization of the benzotriazole unit by preparation of halogenated analogues and Suzuki-Miyaura cross-coupling with aryl boronic acids allowed the synthesis of α-amino acids with conjugated side chains. Analysis of the photophysical properties of these α-amino acids revealed that incorporation of electron-rich substituents results in charge-transfer-based, fluorescent compounds with MegaStokes shifts.

Phenylpropanoids, such as flavonoids and stilbenoids, are of great commercial interest, and their production in Saccharomyces cerevisiae is a very promising strategy. However, to achieve commercially viable production, each step of the process must be optimised. We looked at carbon loss, known to occur in the heterologous flavonoid pathway in yeast, and identified an endogenous enzyme, the enoyl reductase Tsc13, which turned out to be responsible for the accumulation of phloretic acid via reduction of p-coumaroyl-CoA. Tsc13 is an essential enzyme involved in fatty acid synthesis and cannot be deleted. Hence, two approaches were adopted in an attempt to reduce the side activity without disrupting the natural function: site saturation mutagenesis identified a number of amino acid changes which slightly increased flavonoid production but without reducing the formation of the side product. Conversely, the complementation of TSC13 by a plant gene homologue essentially eliminated the unwanted side reaction, while retaining the productivity of phenylpropanoids in a simulated fed batch fermentation., (© FEMS 2016.)

Postoperative renal failure is a common complication after open repair of an abdominal aortic aneurysm. The amino acid arginine is formed in the kidneys from its precursor citrulline, and citrulline is formed from glutamine in the intestines. Arginine enhances the function of the immune and cardiovascular systems, which is important for recovery after surgery. We hypothesized that renal arginine production is diminished after ischemia-reperfusion injury caused by clamping of the aorta during open abdominal aortic surgery and that parenteral glutamine supplementation might compensate for this impaired arginine synthesis. This open-label clinical trial randomized patients who underwent clamping of the aorta during open abdominal aortic surgery to receive a perioperative supplement of intravenous alanyl-glutamine (0.5 g·kg(-1)·day(-1); group A, n = 5) or no supplement (group B, n = 5). One day after surgery, stable isotopes and tracer methods were used to analyze the metabolism and conversion of glutamine, citrulline, and arginine. Whole body plasma flux of glutamine, citrulline, and arginine was significantly higher in group A than in group B (glutamine: 391 ± 34 vs. 258 ± 19 μmol·kg(-1)·h(-1), citrulline: 5.7 ± 0.4 vs. 2.8 ± 0.4 μmol·kg(-1)·h(-1), and arginine: 50 ± 4 vs. 26 ± 2 μmol·kg(-1)·h(-1), P < 0.01), as was the synthesis of citrulline from glutamine (4.8 ± 0.7 vs. 1.6 ± 0.3 μmol·kg(-1)·h(-1)), citrulline from arginine (2.3 ± 0.3 vs. 0.96 ± 0.1 μmol·kg(-1)·h(-1)), and arginine from glutamine (7.7 ± 0.4 vs. 2.8 ± 0.2 μmol·kg(-1)·h(-1)), respectively (P < 0.001 for all). In conclusion, the production of citrulline and arginine is severely reduced after clamping during aortic surgery. This study shows that an intravenous supplement of glutamine increases the production of citrulline and arginine and compensates for the inhibitory effect of ischemia-reperfusion injury., (Copyright © 2016 the American Physiological Society.)

Background: Jejunal feeding is preferred instead of gastric feeding in patients who are intolerant to gastric feeding or at risk of aspiration. However, the impact of gastric feeding compared with that of jejunal feeding on postprandial circulating plasma glucose and amino acid concentrations and the associated endocrine response in vivo in humans remains largely unexplored., Objective: We compared the impact of administering enteral nutrition as either gastric feeding or jejunal feeding on endocrine responses in vivo in humans., Design: In a randomized, crossover study design, 12 healthy young men (mean ± SD age: 21 ± 2 y) received continuous enteral nutrition that contained noncoagulating proteins for 12 h via a nasogastric tube or a nasojejunal tube placed 30-40 cm distal to the ligament of Treitz. Blood samples were collected during the 12-h postprandial period to assess the rise in plasma glucose, amino acid, and gastrointestinal hormone concentrations., Results: No differences were observed in the postprandial rise in circulating plasma amino acid and glucose concentrations between regimens. Jejunal feeding resulted in higher peak plasma insulin concentrations than did gastric feeding (392 ± 53 compared with 326 ± 54 pmol/L, respectively; P < 0.05). The postprandial rise in plasma cholecystokinin, peptide YY (PYY), glucagon-like peptide 1 (GLP-1), and glucagon-like peptide 2 (GLP-2) concentrations was greater after jejunal feeding than after gastric feeding, with higher peak concentrations and a greater postprandial incremental AUC for GLP-1 and cholecystokinin (all P < 0.05). Plasma ghrelin concentrations did not differ between regimens., Conclusions: Enteral nutrition with gastric or jejunal feeding in healthy young men results in similar postprandial plasma amino acid and glucose concentrations. However, the endocrine response differs substantially, with higher peak plasma cholecystokinin, PYY, GLP-1, and GLP-2 concentrations being attained after jejunal feeding. This effect may result in an improved anabolic response, greater insulin sensitivity, and an improved intestinotropic effect. Nevertheless, it may also lead to delayed gastric emptying. This trial was registered at trialregister.nl as NTR2801., (© 2016 American Society for Nutrition.)

Glutamine supplementation in specific groups of critically ill patients results in favourable clinical outcome. Enhancement of citrulline and arginine synthesis by glutamine could serve as a potential mechanism. However, while receiving optimal enteral nutrition, uptake and enteral metabolism of glutamine in critically ill patients remain unknown. Therefore we investigated the effect of a therapeutically relevant dose of L-glutamine on synthesis of L-citrulline and subsequent L-arginine in this group. Ten versus ten critically ill patients receiving full enteral nutrition, or isocaloric isonitrogenous enteral nutrition including 0.5 g/kg L-alanyl-L-glutamine, were studied using stable isotopes. A cross-over design using intravenous and enteral tracers enabled splanchnic extraction (SE) calculations. Endogenous rate of appearance and SE of glutamine citrulline and arginine was not different (SE controls versus alanyl-glutamine: glutamine 48 and 48%, citrulline 33 versus 45%, and arginine 45 versus 42%). Turnover from glutamine to citrulline and arginine was not higher in glutamine-administered patients. In critically ill nonseptic patients receiving adequate nutrition and a relevant dose of glutamine there was no extra citrulline or arginine synthesis and glutamine SE was not increased. This suggests that for arginine synthesis enhancement there is no need for an additional dose of glutamine when this population is adequately fed. This trial is registered with NTR2285.

Background: Dietary protein is required to attenuate the loss of muscle mass and to support recovery during a period of hospitalization. Jejunal feeding is preferred over gastric feeding in patients who are intolerant of gastric feeding. However, the impact of gastric vs. jejunal feeding on postprandial dietary protein digestion and absorption kinetics in vivo in humans remains largely unexplored., Objective: We compared the impact of gastric vs. jejunal feeding on subsequent dietary protein digestion and amino acid (AA) absorption in vivo in healthy young men., Methods: In a randomized crossover study design, 11 healthy young men (aged 21 ± 2 y) were administered 25 g specifically produced intrinsically l-[1-(13)C]phenylalanine-labeled intact casein via a nasogastric and a nasojejunal tube placed ~30 cm distal to the ligament of Treitz. Protein was provided in a 240-mL solution administered over a 65-min period in both feeding regimens. Blood samples were collected during the 7-h postprandial period to assess the increase in plasma AA concentrations and dietary protein-derived plasma l-[1-(13)C]phenylalanine enrichment., Results: Jejunal feeding compared with gastric feeding resulted in higher peak plasma phenylalanine, leucine, total essential AA (EAA), and total AA concentrations (all P < 0.05). This was attributed to a more rapid release of dietary protein-derived AAs into the circulation, as evidenced by a higher peak plasma l-[1-(13)C]phenylalanine enrichment concentration (2.9 ± 0.2 vs. 2.2 ± 0.2 mole percent excess; P < 0.05). The total postprandial plasma AA incremental area under the curve and time to peak did not differ after jejunal vs. gastric feeding. Plasma insulin concentrations increased to a greater extent after jejunal feeding when compared with gastric feeding (275 ± 38 vs. 178 ± 38 pmol/L; P < 0.05)., Conclusions: Jejunal feeding of intact casein is followed by more rapid protein digestion and AA absorption when compared with gastric feeding in healthy young men. The greater postprandial increase in circulating EAA concentrations may allow a more robust increase in muscle protein synthesis rate after jejunal vs. gastric casein feeding. This trial was registered at trialregister.nl as NTR2801., (© 2015 American Society for Nutrition.)

Unlabelled: Supplementation with arginine in combination with atorvastatin is more efficient in reducing the size of an atherosclerotic plaque than treatment with a statin or arginine alone in homozygous Watanabe heritable hyperlipidemic (WHHL) rabbits. We evaluated the mechanism behind this feature by exploring the role of the arginine/asymmetric dimethylarginine (ADMA) ratio, which is the substrate and inhibitor of nitric oxide synthase (NOS) and thereby nitric oxide (NO), respectively., Methods: Rabbits were fed either an arginine diet (group A, n = 9), standard rabbit chow plus atorvastatin (group S, n = 8), standard rabbit chow plus an arginine diet with atorvastatin (group SA, n = 8) or standard rabbit chow (group C, n = 9) as control. Blood was sampled and the aorta was harvested for topographic and histological analysis. Plasma levels of arginine, ADMA, cholesterol and nitric oxide were determined and the arginine/ADMA ratio was calculated., Results: The decrease in ADMA levels over time was significantly correlated to fewer aortic lesions in the distal aorta and total aorta. The arginine/ADMA ratio was correlated to cholesterol levels and decrease in cholesterol levels over time in the SA group. A lower arginine/ADMA ratio was significantly correlated to lower NO levels in the S and C group., Discussion: A balance between arginine and ADMA is an important indicator in the prevention of the development of atherosclerotic plaques.

Background: Arginine plays a role in many different pathways in multiple cell types. Consequently, a shortage of arginine, caused by pathologic conditions such as cancer or injury, has the potential to disturb many cellular and organ functions. Glutamine is the ultimate source for de novo synthesis of arginine in humans via the intestinal-renal axis. Therefore, we hypothesized that parenteral glutamine supplementation may stimulate the interorgan pathway of arginine production., Objectives: The objectives were to quantify arginine production from its precursor glutamine and to establish the contribution of the kidneys to de novo synthesis of arginine in patients receiving intravenous supplementation of glutamine dipeptide during major abdominal surgery., Design: Whole-body and renal metabolism of glutamine, citrulline, and arginine was assessed by stable isotope techniques in 7 patients receiving a perioperative supplement of intravenous alanyl-glutamine (0.5 g · kg(-1) · d(-1))., Results: Plasma glutamine, citrulline, and arginine concentrations increased significantly in patients receiving intravenous glutamine dipeptide. At whole-body level, 91% of total citrulline turnover was derived from glutamine, whereas 49% of whole-body citrulline turnover was used for de novo synthesis of arginine. The kidneys were responsible for 75% of whole-body arginine production from citrulline., Conclusions: Glutamine and citrulline are important sources for de novo arginine synthesis. The kidneys are the main production site for endogenous arginine. After comparison of these results with previous similar studies, our data suggest that an intravenous glutamine supplement doubles renal arginine production from citrulline. This trial was registered at www.trialregister.nl as NTR2914., (© 2014 American Society for Nutrition.)

Pharmaco-nutrients have beneficial effects on protective and immunological mechanisms in patients undergoing surgery, which are important for recovery after injury and in combating infectious agents. The aim of this review article was to outline the potential of the administration of nutritional substrates to surgical patients and the underlying mechanisms that make them particularly important in peri-operative care. Surgery causes a stress response, which has catabolic effects on the body's substrate stores. The amino acid glutamine is a stimulating agent for immune cells. It activates protective mechanisms through its role as a precursor for antioxidants and it improves the barrier function of the gut. Arginine also enhances the function of the immune system, since it is the substrate for T-lymphocytes. Furthermore, n-3 PUFA stabilise surgery-induced hyper-inflammation. Taurine is another substrate that may counteract the negative effects of surgical injury on acid-base balance and osmotic balance. These pharmaco-nutrients rapidly become deficient under the influence of surgical stress. Supplementation of these nutrients in surgical patients may restore their protective and immune-enhancing actions and improve clinical outcome. Moreover, pre-operative fasting is still common practice in the Western world, although fasting has a negative effect on the patient's condition and the recovery after surgery. This may be counteracted by a simple intervention such as administering a carbohydrate-rich supplement just before surgery. In conclusion, there are various nutritional substrates that may be of great value in improving the condition of the surgical patient, which may be beneficial for post-operative recovery.

Background: Plasma arginine concentrations are lower in patients with cancer, which indicates that arginine metabolism may be disturbed in these patients. Arginine supplementation has been associated with positive effects on antitumor mechanisms and has been shown to reduce tumor growth and to prolong survival. Furthermore, the prognosis of patients with head and neck cancer remains disappointing. Insufficient intake frequently leads to malnutrition, which contributes to high morbidity and mortality rates., Objective: The aim of this study was to assess the long-term effects of perioperative arginine supplementation in severely malnourished patients with head and neck cancer., Design: In this double-blind, randomized, controlled trial, we randomly assigned 32 severely malnourished patients with head and neck cancer to receive 1) standard perioperative enteral nutrition (n = 15) or 2) arginine-supplemented perioperative enteral nutrition (n = 17). The primary outcome was long-term (≥10 y) survival. Secondary outcomes included the long-term appearance of locoregional recurrence, distant metastases, and second primary tumors., Results: No significant differences in baseline characteristics were observed between groups. The group receiving arginine-enriched nutrition had a significantly better overall survival (P = 0.019) and better disease-specific survival (P = 0.022). Furthermore, the arginine-supplemented group had a significantly better locoregional recurrence-free survival (P = 0.027). No significant difference in the occurrence of distant metastases or occurrence of a second primary tumor was observed between the groups., Conclusion: Perioperative arginine-enriched enteral nutrition significantly improved the long-term overall survival and long-term disease-specific survival in malnourished patients with head and neck cancer.