Discovery of BIO-8169─A Highly Potent, Selective, and Brain-Penetrant IRAK4 Inhibitor for the Treatment of Neuroinflammation.

Interleukin receptor associated kinase 4 (IRAK4) plays an important role in innate immune signaling through Toll-like and interleukin-1 receptors and represents an attractive target for the treatment of inflammatory diseases and cancer. We previously reported the development of a potent, selective, and brain-penetrant imidazopyrimidine series of IRAK4 inhibitors. However, lead molecule BIO-7488 (1) suffered from low solubility which led to variable PK, compound accumulation, and poor in vivo tolerability. Herein, we describe the discovery of a series of pyridone analogs with improved solubility which are highly potent, selective and demonstrate desirable PK profiles including good oral bioavailability and excellent brain penetration. BIO-8169 (2) reduced the in vivo production of pro-inflammatory cytokines, was well tolerated in safety studies in rodents and dog at margins well above the predicted efficacious exposure and showed promising results in a mouse model for multiple sclerosis.

State of the art review. Complications after carpal tunnel release.

Carpal tunnel release (CTR) is the most performed surgery of the upper extremity. It is effective but not without complications. This state-of-the-art review covers most common intra- and postoperative complications after CTR. As endoscopic carpal tunnel release (ECTR) has developed over time, severe complications, such as nerve lesions, have diminished. ECTR still has a higher risk on transient nerve lesions. Open CTR on the other hand has a higher incidence of wound-related problems, including scar tenderness, irrespective of incision used. Most complications, such as pillar pain and infection, are ill-defined in the literature, leaving the exact incidence unknown and proposing challenges in treatment. The same is true for failure of treatment. Optimizing the length and location of incisions has played a vital role in reducing intra- and postoperative complications in CTR. It is expected that technical advances, such as ultrasound-guided percutaneous carpal tunnel release, will continue to play a role in the future.Level of evidence: V.

Nickel-Electrocatalytic Decarboxylative Arylation to Access Quaternary Centers.

There is a pressing need, particularly in the field of drug discovery, for general methods that will enable direct coupling of tertiary alkyl fragments to (hetero)aryl halides. Herein a uniquely powerful and simple set of conditions for achieving this transformation with unparalleled generality and chemoselectivity is disclosed. This new protocol is placed in context with other recently reported methods, applied to simplify the routes of known bioactive building blocks molecules, and scaled up in both batch and flow. The role of pyridine additive as well as the mechanism of this reaction are interrogated through Cyclic Voltammetry studies, titration experiments, control reactions with Ni(0) and Ni(II)-complexes, and ligand optimization data. Those studies indicate that the formation of a BINAPNi(0) is minimized and the formation of an active pyridine-stabilized Ni(I) species is sustained during the reaction. Our preliminary mechanistic studies ruled out the involvement of Ni(0) species in this electrochemical cross-coupling, which is mediated by Ni(I) species via a Ni(I)-Ni(II)-Ni(III)-Ni(I) catalytic cycle.

Acetylcholine and noradrenaline enhance foraging optimality in humans.

Foraging theory prescribes when optimal foragers should leave the current option for more rewarding alternatives. Actual foragers often exploit options longer than prescribed by the theory, but it is unclear how this foraging suboptimality arises. We investigated whether the upregulation of cholinergic, noradrenergic, and dopaminergic systems increases foraging optimality. In a double-blind, between-subject design, participants (N = 160) received placebo, the nicotinic acetylcholine receptor agonist nicotine, a noradrenaline reuptake inhibitor reboxetine, or a preferential dopamine reuptake inhibitor methylphenidate, and played the role of a farmer who collected milk from patches with different yield. Across all groups, participants on average overharvested. While methylphenidate had no effects on this bias, nicotine, and to some extent also reboxetine, significantly reduced deviation from foraging optimality, which resulted in better performance compared to placebo. Concurring with amplified goal-directedness and excluding heuristic explanations, nicotine independently also improved trial initiation and time perception. Our findings elucidate the neurochemical basis of behavioral flexibility and decision optimality and open unique perspectives on psychiatric disorders affecting these functions.

Protocol for Endoscopic Versus Open Cubital tunnel release (EVOCU): an open randomized controlled trial : EVOCU trial: Endoscopic Versus Open Cubital tunnel release.

BACKGROUND: Cubital tunnel syndrome is the second most common entrapment neuropathy of the upper extremity. Surgical decompression of the ulnar nerve aims to improve complaints and prevent permanent damage to the nerve. Open and endoscopic release of the cubital tunnel are both used in common practice, but none has proven to be superior. This study assesses patient reported outcome and experience measures (PROMs and PREMs respectively), in addition to objective outcomes of both techniques. METHODS: A prospective single-center open randomized non-inferiority trial will take place at the Plastic Surgery Department in the Jeroen Bosch Hospital, the Netherlands. 160 patients with cubital tunnel syndrome will be included. Patients are allocated to endoscopic or open cubital tunnel release by randomization. The surgeon and patients are not blinded for treatment allocation. The follow-up time will take 18 months. DISCUSSION: Currently, the choice for one of the methods is based on surgeon's preferences and degree of familiarity with a particular technique. It is assumed that the open technique is easier, faster and cheaper. The endoscopic release, however, has better exposure of the nerve and reduces the chance of damaging the nerve and might decrease scar discomfort. PROMs and PREMs have proven potential to improve the quality of care. Better health care experiences are associated with better clinical outcome in self-reported post-surgical questionnaires. Combining subjective measures with objective outcomes, efficacy, patient treatment experience and safety profile could help differentiating between open and endoscopic cubital tunnel release. This could aid clinicians in evidence based choices towards the best surgical approach in patients with cubital tunnel syndrome. TRIAL REGISTRATION: This study is registered prospectively with the Dutch Trial Registration under NL9556. Universal Trial Number (WHO-UTN) U1111-1267-3059. Registration date 26-06-2021. The URL: https://www.trialregister.nl/trial/9556.

Masquelet Procedure for the Treatment of Intra-articular Defects of the Wrist.

Background The purpose of this case series is to show our experiences with the Masquelet procedure in a variety of infected defects of the wrist. Case Description All consecutive patients that were treated between 2015 and 2021 were included in this case series. Five patients were included with an infected defect of the wrist, involving the radiocarpal and/or the distal radioulnar joints (DRUJ). All patients underwent thorough debridement of the defect and the created void was filled with a gentamicin/vancomycin cement spacer. Cultures were taken and appropriate antibiotic therapy was initiated. Two patients had a renewal of the cement spacer before definitive surgery. Finally, two patients received a DRUJ prosthesis, two patients had autologous bone grafting and wrist arthrodesis and one patient kept the cement spacer as distal ulna prosthesis due to minor complaints. Literature Review Current literature provides examples of the Masquelet procedure in traumatic defects or non-unions of the long bones. These cases are almost always about metaphyseal or diaphyseal defects but rarely include intra-articular joint defects therefore no comparisons could be made between the cases we reported with any existing literature. Clinical Relevance The Masquelet procedure showed to be effective in eradicating infected defects of the wrist involving the radiocarpal joint and/or DRUJ. All patients had an aseptic environment before performing definitive surgery. This technique showed to be save and no reinfections occurred.

Complete Genome Sequence of Stenotrophomonas maltophilia 1800, a New Bacterial Strain with Potential for Bioremediation of Oil-Contaminated Environments.

Stenotrophomonas maltophilia strain 1800 was isolated from the effluent of an industrial oil refinery in Algeria. Its genome was sequenced using Illumina MiSeq (2 × 150-bp read pairs) and Oxford Nanopore (long reads) technologies and assembled using Unicycler. It is composed of one chromosome of 4.83 Mb.

Systematic review and meta-analysis of surgical options for recurrent or persistent carpal tunnel syndrome: simple decompression versus coverage of the median nerve.

We performed a systematic review on the success of different surgical techniques for the management of recurrent and persistent carpal tunnel syndrome. Twenty studies met the inclusion criteria and were grouped by the type of revision carpal tunnel release, which were simple open release, open release with flap coverage or open release with implant coverage. Meta-analysis showed no difference, and pooled success proportions were 0.89, 0.89 and 0.85 for simple open carpal tunnel release, additional flap coverage and implant groups, respectively. No added value for coverage of the nerve was seen. Our review indicates that simple carpal tunnel release without additional coverage of the median nerve seems preferable as it is less invasive and without additional donor site morbidity. We found that the included studies were of low quality with moderate risk of bias and did not differentiate between persistent and recurrent carpal tunnel syndrome.

Ovarian hormones and obesity.

BACKGROUND: Obesity is caused by an imbalance between energy intake, i.e. eating and energy expenditure (EE). Severe obesity is more prevalent in women than men worldwide, and obesity pathophysiology and the resultant obesity-related disease risks differ in women and men. The underlying mechanisms are largely unknown. Pre-clinical and clinical research indicate that ovarian hormones may play a major role. OBJECTIVE AND RATIONALE: We systematically reviewed the clinical and pre-clinical literature on the effects of ovarian hormones on the physiology of adipose tissue (AT) and the regulation of AT mass by energy intake and EE. SEARCH METHODS: Articles in English indexed in PubMed through January 2016 were searched using keywords related to: (i) reproductive hormones, (ii) weight regulation and (iii) central nervous system. We sought to identify emerging research foci with clinical translational potential rather than to provide a comprehensive review. OUTCOMES: We find that estrogens play a leading role in the causes and consequences of female obesity. With respect to adiposity, estrogens synergize with AT genes to increase gluteofemoral subcutaneous AT mass and decrease central AT mass in reproductive-age women, which leads to protective cardiometabolic effects. Loss of estrogens after menopause, independent of aging, increases total AT mass and decreases lean body mass, so that there is little net effect on body weight. Menopause also partially reverses women's protective AT distribution. These effects can be counteracted by estrogen treatment. With respect to eating, increasing estrogen levels progressively decrease eating during the follicular and peri-ovulatory phases of the menstrual cycle. Progestin levels are associated with eating during the luteal phase, but there does not appear to be a causal relationship. Progestins may increase binge eating and eating stimulated by negative emotional states during the luteal phase. Pre-clinical research indicates that one mechanism for the pre-ovulatory decrease in eating is a central action of estrogens to increase the satiating potency of the gastrointestinal hormone cholecystokinin. Another mechanism involves a decrease in the preference for sweet foods during the follicular phase. Genetic defects in brain α-melanocycte-stimulating hormone-melanocortin receptor (melanocortin 4 receptor, MC4R) signaling lead to a syndrome of overeating and obesity that is particularly pronounced in women and in female animals. The syndrome appears around puberty in mice with genetic deletions of MC4R, suggesting a role of ovarian hormones. Emerging functional brain-imaging data indicates that fluctuations in ovarian hormones affect eating by influencing striatal dopaminergic processing of flavor hedonics and lateral prefrontal cortex processing of cognitive inhibitory controls of eating. There is a dearth of research on the neuroendocrine control of eating after menopause. There is also comparatively little research on the effects of ovarian hormones on EE, although changes in ovarian hormone levels during the menstrual cycle do affect resting EE. WIDER IMPLICATIONS: The markedly greater obesity burden in women makes understanding the diverse effects of ovarian hormones on eating, EE and body adiposity urgent research challenges. A variety of research modalities can be used to investigate these effects in women, and most of the mechanisms reviewed are accessible in animal models. Therefore, human and translational research on the roles of ovarian hormones in women's obesity and its causes should be intensified to gain further mechanistic insights that may ultimately be translated into novel anti-obesity therapies and thereby improve women's health.

Peri-operative care for patients undergoing lymphaticovenular anastomosis: A systematic review.

BACKGROUND: Lymphaticovenular anastomosis (LVA) is a supermicrosurgical procedure that involves the anastomosis of a functional lymphatic channel to a venule. Although peri-operative care might be an important contributor to the success of this technique, evidence about optimal peri-operative care seems limited. This review aims to summarize the peri-operative methods used by authors reporting on LVA. METHODS: A systematic search of the literature was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Peri-operative care used by authors was summarized and listed in a pre-defined form. Studies were also graded on quality of evidence by the GRADE system and a lymphedema surgery-specific system. RESULTS: In total, 22 studies were identified describing peri-operative measures. Although most authors were sparse in their description of peri-operative management, most recommended initiation of conventional compression therapy at 1-4 weeks after surgery. Prophylactic antibiotics, elevation of the affected limb, bandaging, low-molecular-weight heparin, prostaglandin E1, and manual pressure therapy were also described. The quality of evidence of the included studies was low on average. CONCLUSION: Although supermicrosurgical LVAs are gaining in popularity, there are no high-quality prospective trials evaluating these new techniques and the description of peri-operative management is scarce. Of the available studies, a peri-operative management consisting of prophylactic antibiotics, elevation of the affected limb during night and hospital stay, and compression therapy 4 weeks post-surgery for 6 months seems to be preferred. Future studies should describe a detailed peri-operative protocol to allow for a better comparison between study results and to determine optimal peri-operative recommendations.

Pancreaticoduodenectomy for adenocarcinoma of the pancreatic head is justified in elderly patients: A Retrospective Cohort Study.

BACKGROUND: The increasing elderly population is an inevitable trend worldwide in developed countries. Therefore, we aimed to assess the experience of a tertiary pancreatic center with a very homogenous population comprising only patients diagnosed with PDAC of the pancreatic head in patients older than 75 years of age compared to their younger counterparts regarding the benefit in life expectancy and tumor biological aggressiveness. METHODS: 300 patients underwent partial pancreaticoduodenectomy (PD) or pylorus preserving pancreaticoduodenectomy (PPPD) for PDAC of the pancreatic head between 2002 and 2012 and were evaluated with regard to their co-morbidities, clinicopathological and perioperative variables, postoperative morbidity, mortality and long term survival. Therefore, two groups according to the age at the procedure (A: <75 years, n = 241, B: ≥75 years, n = 59) were designed. RESULTS: There were no differences between groups with regard to gender, performed procedure (PPPD or PD), operation time, blood loss, tumor invasiveness and grade of tumor differentiation, R-status, lymph node ratio, 30-day mortality, length of stay and adjuvant chemotherapy. Extended resections including total pancreatectomy were slightly more often performed in younger patients (p = 0.071) and trended toward a higher rate of surgical complications in patients <75 years of age (p = 0.183). A higher rate of preoperative co-morbidities in elderly patients (group B), was associated with more postoperative non-surgical complications (p = 0.002) in this group of patients. However, the median overall survival (19.2 vs. 18.4 months) did not differ significantly between groups. CONCLUSIONS: Major pancreatic surgery for ductal adenocarcinoma of the pancreatic head is justified in elderly patients. With careful patients' selection and prudent perioperative management, elderly patients will have a similar long term outcome despite the higher rate of postoperative morbidity based on non-surgical complications.

Arsenite response in Coccomyxa sp. Carn explored by transcriptomic and non-targeted metabolomic approaches.

Arsenic is a toxic metalloid known to generate an important oxidative stress in cells. In the present study, we focused our attention on an alga related to the genus Coccomyxa, exhibiting an extraordinary capacity to resist high concentrations of arsenite and arsenate. The integrated analysis of high-throughput transcriptomic data and non-targeted metabolomic approaches highlighted multiple levels of protection against arsenite. Indeed, Coccomyxa sp. Carn induced a set of transporters potentially preventing the accumulation of this metalloid in the cells and presented a distinct arsenic metabolism in comparison to another species more sensitive to that compound, i.e. Euglena gracilis, especially in regard to arsenic methylation. Interestingly, Coccomyxa sp. Carn was characterized by a remarkable accumulation of the strong antioxidant glutathione (GSH). Such observation could explain the apparent low oxidative stress in the intracellular compartment, as suggested by the transcriptomic analysis. In particular, the high amount of GSH in the cell could play an important role for the tolerance to arsenate, as suggested by its partial oxidation into oxidized glutathione in presence of this metalloid. Our results therefore reveal that this alga has acquired multiple and original defence mechanisms allowing the colonization of extreme ecosystems such as acid mine drainages.

Constitutive arsenite oxidase expression detected in arsenic-hypertolerant Pseudomonas xanthomarina S11.

Pseudomonas xanthomarina S11 is an arsenite-oxidizing bacterium isolated from an arsenic-contaminated former gold mine in Salsigne, France. This bacterium showed high resistance to arsenite and was able to oxidize arsenite to arsenate at concentrations up to 42.72 mM As[III]. The genome of this strain was sequenced and revealed the presence of three ars clusters. One of them is located on a plasmid and is organized as an "arsenic island" harbouring an aio operon and genes involved in phosphorous metabolism, in addition to the ars genes. Neither the aioXRS genes nor a specific sigma-54-dependent promoter located upstream of aioBA genes, both involved in regulation of arsenite oxidase expression in other arsenite-oxidizing bacteria, could be identified in the genome. This observation is in accordance with the fact that no difference was observed in expression of arsenite oxidase in P. xanthomarina S11, whether or not the strain was grown in the presence of As[III].

Analysis of pyrrolizidine alkaloids and evaluation of some biological activities of Algerian Senecio delphinifolius (Asteraceae).

Although Senecio species are known as sources of potentially toxic pyrrolizidine alkaloids (PAs), some species of this genus are traditionally used as remedies, notably in Algeria. In this paper, the evaluation of biological activities and the analysis of PAs of Algerian specimens of Senecio delphinifolius Vahl are reported. The n-butanolic extract of the herb showed a weak antibacterial effect against Escherichia coli with a MIC of 1 mg/mL, but was inactive against Staphylococcus aureus and Pseudomonas aeruginosa. The n-butanolic extracts of the roots, stems and herb showed a modest antioxidant activity, scavenging the free radical DPPH with respective IC50 values of 55.3, 50.2 and 13.3 microg/mL. A cytotoxic effect against a series of human tumor cell lines was observed with the n-butanolic extract from stems (IC50 ranging between 34 and 88 microg/mL). The herb of the evaluated sample contains 140 ppm of PAs (senecionine, seneciphylline, integerrimine, senkirkine) and PA-related alkaloids (dehydrosenkirkine and neosenkirkine). As the major PAs belong to the toxic series (1,2-unsaturation in the pyrrolizidine cycle and macrocyclic diester), the use of S. delphinifolius should be discouraged in traditional medicine.

Bacterial metabolism of environmental arsenic--mechanisms and biotechnological applications.

Arsenic causes threats for environmental and human health in numerous places around the world mainly due to its carcinogenic potential at low doses. Removing arsenic from contaminated sites is hampered by the occurrence of several oxidation states with different physicochemical properties. The actual state of arsenic strongly depends on its environment whereby microorganisms play important roles in its geochemical cycle. Due to its toxicity, nearly all organisms possess metabolic mechanisms to resist its hazardous effects, mainly by active extrusion, but also by extracellular precipitation, chelation, and intracellular sequestration. Some microbes are even able to actively use various arsenic compounds in their metabolism, either as an electron donor or as a terminal electron acceptor for anaerobic respiration. Some microorganisms can also methylate inorganic arsenic, probably as a resistance mechanism, or demethylate organic arsenicals. Bioavailability of arsenic in water and sediments is strongly influenced by such microbial activities. Therefore, understanding microbial reactions to arsenic is of importance for the development of technologies for improved bioremediation of arsenic-contaminated waters and environments. This review gives an overview of the current knowledge on bacterial interactions with arsenic and on biotechnologies for its detoxification and removal.

Clinical outcome of IBD-associated versus sporadic colorectal cancer: a matched-pair analysis.

PURPOSE: This study assesses the perioperative course and long-term survival of inflammatory bowel disease (IBD)-associated vs. sporadic colorectal cancer (IBD-CRC vs. SCRC) after elimination of known confounders. METHODS: Between 1991 and 2007, n = 3,299 patients underwent surgery for CRC at our institution. Thirty-three IBD patients were identified and compared to 165 SCRC using a matched-pair analysis (1:5 scenario). As matching parameters were used: age, gender, Union Internationale Contre le Cancer (UICC) stage, site of primary lesion, and date of surgery. After univariate analysis of the perioperative course, a multivariate survival analysis (Cox) of all patients (n = 198) was performed. RESULTS: Significant differences were shown for preoperative symptoms (p = 0.022), transfusion rate (p = 0.01), ileostomy construction rate (p = 0.001), total complication rate (p = 0.042), and hospital stay (15 vs. 11 days, p < 0.001). Local tumor recurrence was three times higher in IBD-CRC (p = 0.004), and the 5-year survival rate was lower (49 % vs. 67 %, p = 0.03). IBD, advanced UICC stage, and synchronous liver metastasis were identified as independent prognostic factors. CONCLUSION: We demonstrate for the first time survival differences between IBD-CRC and SCRC after elimination of five known confounders. This might be caused by a difference in tumor biology resulting in a higher local recurrence rate in IBD-CRC.

Chemical composition, antioxidant properties and anti-cholinesterase activity of Cordia gilletii (Boraginaceae) leaves essential oil.

This study aimed to investigate for the first time the chemical composition, the antioxidant properties and the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity of the essential oil from the leaves of Cordia gilletii De Wild (Boraginaceae). The essential oil, characterized by 23 constituents (90.1% of the total oil), was constituted by terpene derivatives (25.6%) and non-terpene derivatives (64.5%), among which aldehydes, fatty acids and alkanes were present with the percentage of 16.5%, 18.8% and 23.1%, respectively. The antioxidant activity of C. gilletii essential oil was screened by two in vitro tests: DPPH and beta-carotene bleaching test. The essential oil revealed antioxidant activity with an IC50 value of 75.0 and 129.9 microg/mL on DPPH radical and beta-carotene decoloration tests, respectively. Moreover, C. gilletii inhibited AChE enzyme with an IC50 value of 105.6 microg/mL.