ABSTRACT
Under Rh-catalyzed conditions, secondary amines and anilines function as directing groups to facilitate regioselective C-C bond activation of nonactivated cyclopropanes. The resulting amino-stabilized rhodacycles undergo carbonylative C-N bond formation en route to challenging seven- and eight-membered lactams. The processes represent rare examples where C-C bond oxidative addition of nonactivated cyclopropanes is exploited in reaction design.
Subject(s)
Cyclopropanes , Nitrogen , Amines/chemistry , Catalysis , Cyclopropanes/chemistry , Nitrogen/chemistryABSTRACT
PURPOSE: To appraise the measurement properties of generic patient-reported outcome measures (PROMs) measuring postoperative quality of life in adults undergoing elective abdominal surgery. METHODS: We conducted a systematic review of PROMs administered after elective abdominal surgery. We systematically searched Ovid MEDLINE, Embase, the Cumulative Index to Nursing & Allied Health Literature database, and the Cochrane Library from earliest available dates to July 24, 2021, using relevant search terms. Articles were included if they reported assessment of measurement properties of a generic PROM/s measuring postoperative quality of life in adults who had undergone elective abdominal surgery. We used the Consensus-based Standards for the selection of health status Measurement Instruments (COSMIN) Risk of Bias checklist to assess methodological quality. We synthesized the data and used the COSMIN criteria for good measurement properties and the Grading of Recommendations, Assessment, Development and Evaluations criteria to rate the certainty of evidence. RESULTS: Of 12,121 identified articles, nine articles assessing five PROMs (SF-6D, EQ-5D, SF-36, SF-12, PROMIS-10) met inclusion criteria. Measurement properties assessed included internal consistency (n = 2), construct validity (n = 5), and responsiveness (n = 8). Two PROMs had high quality evidence for a single measurement property each. The SF-6D demonstrated high quality evidence for responsiveness and the EQ-5D had high quality evidence for construct validity. CONCLUSION: There is insufficient evidence to support the choice of a specific generic PROM to evaluate quality of life following elective abdominal surgery. Clinicians and researchers should be aware of the current limitations in knowledge of the measurement properties of available PROMs.
Subject(s)
Patient Reported Outcome Measures , Quality of Life , Adult , Checklist , Consensus , Health Status , Humans , Quality of Life/psychologyABSTRACT
Rash after contact with butterflies has not been previously reported in the medical literature to our knowledge. We describe potentially the first suspected case of a cutaneous reaction to the Compton tortoiseshell butterfly (Nymphalis vaualbum) in a young boy who developed urticaria after the modified hairs of the butterfly embedded within his finger. His urticaria improved through treatment with oral and topical steroids as well as systemic antihistamines. This case report expands the variety of insect species that may cause human disease and should raise awareness for this possible reaction.
Subject(s)
Butterflies , Urticaria , Animals , Histamine Antagonists , Humans , Male , Urticaria/drug therapy , Urticaria/etiologyABSTRACT
α-Galactosylceramide (α-GalCer; KRN7000) is a ligand for the glycoprotein CD1d that presents lipid antigens to natural killer T cells. Therefore, KRN7000 as well as some modified versions thereof have been widely investigated as part of novel immunotherapies. To examine the impact of structural modification, we investigated KRN7000 and C6-modified KRN7000 at the air-liquid interface using monolayer isotherms, BAM, IRRAS, GIXD, and TRXF. The amino group has no influence on the highly ordered sub-gel structures found at lateral pressures relevant for biological membranes. Neither lateral compression nor the protonation state of the amino group has a measurable effect on the lattice structure, which is defined by strong and rigid intermolecular hydrogen bonds. However, the first-order phase transition found for the C6-functionalized α-GalCer is connected with an extraordinary surface-inhibited nucleation. Our study demonstrates that KRN7000 can be functionalized at C6 without significantly changing the structural properties.
Subject(s)
Galactosylceramides/chemistry , Nitrogen/chemistry , Thermodynamics , Air , Hydrogen Bonding , Molecular Conformation , Surface PropertiesABSTRACT
Aminocyclopropanes equipped with pendant nucleophiles undergo carbonylative heterocyclization triggered by C-C bond activation to generate eight-membered N-heterocycles. In these processes, intramolecular "capture" of a rhodacyclopentanone intermediate by an aryl or N-based nucleophile is followed by C-C or C-N bond-forming "collapse" to the targets. These studies demonstrate how the combination of cyclopropane strain release and the templating effect of catalytically generated metallacycles can be harnessed to enable otherwise challenging medium ring closures.
ABSTRACT
Streptococcus pneumoniae remains a deadly disease in small children and the elderly even though conjugate and polysaccharide vaccines based on isolated capsular polysaccharides (CPS) are successful. The most common serotypes that cause infection are used in vaccines around the world, but differences in geographic and demographic serotype distribution compromises protection by leading vaccines. The medicinal chemistry approach to glycoconjugate vaccine development has helped to improve the stability and immunogenicity of synthetic vaccine candidates for several serotypes leading to the induction of higher levels of specific protective antibodies. Here, we show that marketed CPS-based glycoconjugate vaccines can be improved by adding synthetic glycoconjugates representing serotypes that are not covered by existing vaccines. Combination (coformulation) of synthetic glycoconjugates with the licensed vaccines Prevnar13 (13-valent) and Synflorix (10-valent) yields improved 15- and 13-valent conjugate vaccines, respectively, in rabbits. A pentavalent semisynthetic glycoconjugate vaccine containing five serotype antigens (sPCV5) elicits antibodies with strong in vitro opsonophagocytic activity. This study illustrates that synthetic oligosaccharides can be used in coformulation with both isolated polysaccharide glycoconjugates to expand protection from existing vaccines and each other to produce precisely defined multivalent conjugated vaccines.
Subject(s)
Bacterial Vaccines/immunology , Polysaccharides/immunology , Streptococcus pneumoniae/immunology , Animals , Antibodies, Bacterial/immunology , Glycoconjugates/immunology , Pneumococcal Infections/immunology , Polysaccharides/chemical synthesis , Rabbits , Serogroup , Vaccines, Conjugate/immunology , Vaccines, Synthetic/immunologyABSTRACT
One of the most established roles of oxytocin (OT) is in inducing uterine contractions and labor. Apart from inducing contractions, our recent studies showed that OT can also activate proinflammatory pathways in both human myometrial and amnion cells, which suggests that the proinflammatory role of OT should be taken into account when developing tocolytics targeting the OT/oxytocin receptor (OTR) system. The OTR antagonist, atosiban, is currently used therapeutically for the treatment of preterm labor. We previously showed that atosiban fails to inhibit the proinflammatory effects of OT in human amnion; atosiban alone activates nuclear factor-κB (NF-κB) and mitogen activated protein kinases, thus upregulating downstream prolabor genes. In contrast with our findings with atosiban, the presence of the orally active OTR antagonist, nolasiban, reduced the effect of OT on NF-κB and p38 kinase activation in both myometrial and amnion cells. Consistent with the activation of these inflammatory mediators, OT led to increases in the expression of cyclooxygenase-2 and phosphorylated cytosolic phospholipase A2, which was reflected in prostaglandin E2 synthesis. Inhibition of NF-κB activation by nolasiban also translated to suppression of downstream prolabor gene expression, such as cyclooxygenase-2, C-C motif chemokine ligand 2, interleukin-6, and interleukin-8. We also demonstrated that nolasiban treatment alone has no significant stimulatory effect on both the myometrium and amnion. In conclusion, our findings indicate that nolasiban possesses promising potential as a novel tocolytic agent for both acute and maintenance therapy, as it inhibits both myometrial contractions and the proinflammatory effects of OT without the biased agonist effects.
Subject(s)
Amnion/metabolism , Myometrium/metabolism , Oximes/pharmacology , Pyrrolidines/pharmacology , Receptors, Oxytocin/antagonists & inhibitors , Signal Transduction/drug effects , Vasotocin/analogs & derivatives , Amnion/drug effects , Chemokine CCL5/metabolism , Enzyme Activation/drug effects , Female , Humans , Inflammation Mediators/metabolism , Labor, Obstetric/drug effects , Labor, Obstetric/genetics , Mitogen-Activated Protein Kinases/metabolism , Models, Biological , Myometrium/drug effects , NF-kappa B/metabolism , Oximes/chemistry , Pregnancy , Prostaglandins/biosynthesis , Pyrrolidines/chemistry , Receptors, Oxytocin/metabolism , Signal Transduction/genetics , Up-Regulation/drug effects , Vasotocin/pharmacologyABSTRACT
The identification of immunogenic glycotopes that render glycoconjugate vaccines protective is key to improving vaccine efficacy. Synthetic oligosaccharides are an attractive alternative to the heterogeneous preparations of purified polysaccharides that most marketed glycoconjugate vaccines are based on. To investigate the potency of semi-synthetic glycoconjugates, we chose the least-efficient serotype in the current pneumococcal conjugate vaccine Prevnar 13, Streptococcus pneumoniae serotype 3 (ST3). Glycan arrays containing synthetic ST3 repeating unit oligosaccharides were used to screen a human reference serum for antibodies and to define the recognition site of two ST3-specific protective monoclonal antibodies. The glycan array screens identified a tetrasaccharide that was selected for in-depth immunological evaluation. The tetrasaccharide-CRM197 carrier protein conjugate elicited protective immunity as evidenced by opsonophagocytosis assays and protection against pneumonia caused by ST3 in mice. Formulation of the defined protective lead candidate glycotope has to be further evaluated to elicit optimal long-term immunity.
Subject(s)
Oligosaccharides/therapeutic use , Pneumococcal Infections/prevention & control , Pneumococcal Vaccines/therapeutic use , Streptococcus pneumoniae/immunology , Vaccines, Conjugate/therapeutic use , Animals , Cell Line , Female , Humans , Immunization , Mice , Mice, Inbred C57BL , Oligosaccharides/chemistry , Oligosaccharides/immunology , Pneumococcal Infections/immunology , Pneumococcal Vaccines/chemistry , Pneumococcal Vaccines/immunology , Vaccines, Conjugate/chemistry , Vaccines, Conjugate/immunologyABSTRACT
Mouse ovarian germ cells enter meiosis in a wave that propagates from anterior to posterior, but little is known about contribution of germ cells to initiation or propagation of meiosis. In a Ror2 mutant with diminished germ cell number and migration, we find that overall timing of meiotic initiation is delayed at the population level. We use chemotherapeutic depletion to exclude a profoundly reduced number of germ cells as a cause for meiotic delay. We rule out sex reversal or failure to specify somatic support cells as contributors to the meiotic phenotype. Instead, we find that anomalies in the distribution of germ cells as well as gonad shape in mutants contribute to aberrant initiation of meiosis. Our analysis supports a model of meiotic initiation via diffusible signal(s), excludes a role for germ cells in commencing the meiotic wave and furnishes the first phenotypic demonstration of the wave of meiotic entry. Finally, our studies underscore the importance of considering germ cell migration defects while studying meiosis to discern secondary effects resulting from positioning versus primary meiotic entry phenotypes.
Subject(s)
Germ Cells/metabolism , Gonads/pathology , Meiosis/genetics , Receptor Tyrosine Kinase-like Orphan Receptors/genetics , Animals , Cell Count , Cell Movement/genetics , Cell Shape/genetics , Female , Germ Cells/growth & development , Germ Cells/pathology , Gonads/growth & development , Mice , Mutation , Ovary/growth & development , Ovary/metabolism , Ovary/pathology , Signal Transduction/geneticsABSTRACT
BACKGROUND: The nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1) is required for pro-inflammatory effects of TNFα. Our previous studies demonstrated that PARP-1 mediates TNFα-induced NF-κB activation in glia. Here, we evaluated the mechanisms by which TNFα activates PARP-1 and PARP-1 mediates NF-κB activation. METHODS: Primary cultures of mouse cortical astrocytes and microglia were treated with TNFα and suitable signaling pathway modulators (pharmacological and molecular). Outcome measures included calcium imaging, PARP-1 activation status, NF-κB transcriptional activity, DNA damage assesment and cytokine relesease profiling. RESULTS: TNFα induces PARP-1 activation in the absence of detectable DNA strand breaks, as measured by the PANT assay. TNFα-induced transcriptional activation of NF-κB requires PARP-1 enzymatic activity. Enzymatic activation of PARP-1 by TNFα was blocked in Ca(2+)-free medium, by Ca(2+) chelation with BAPTA-AM, and by D609, an inhibitor of phoshatidyl choline-specific phospholipase C (PC-PLC), but not by thapsigargin or by U73112, an inhibitor of phosphatidyl inisitol-specific PLC (PI -PLC). A TNFR1 blocking antibody reduced Ca(2+) influx and PARP-1 activation. TNFα-induced PARP-1 activation was also blocked by siRNA downregulation of ERK2 and by PD98059, an inhibitor of the MEK / ERK protein kinase cascade. Moreover, TNFα-induced NF-κB (p65) transcriptional activation was absent in cells expressing PARP-1 that lacked ERK2 phosphorylation sites, while basal NF-κB transcriptional activation increased in cells expressing PARP-1 with a phosphomimetic substitution at an ERK2 phophorylation site. CONCLUSIONS: These results suggest that TNFα induces PARP-1 activation through a signaling pathway involving TNFR1, Ca(2+) influx, activation of PC-PLC, and activation of the MEK1 / ERK2 protein kinase cascade. TNFα-induced PARP-1 activation is not associated with DNA damage, but ERK2 mediated phosphorylation of PARP-1.
Subject(s)
Mitogen-Activated Protein Kinase 1/physiology , NF-kappa B/drug effects , Poly(ADP-ribose) Polymerases/physiology , Transcriptional Activation/drug effects , Tumor Necrosis Factor-alpha/pharmacology , Type C Phospholipases/physiology , Animals , Calcium Signaling/drug effects , Chelating Agents/pharmacology , DNA Damage , Enzyme Activation/drug effects , Female , MAP Kinase Signaling System/drug effects , Male , Mice , Poly (ADP-Ribose) Polymerase-1 , RNA, Small Interfering/genetics , Receptors, Tumor Necrosis Factor, Type I/genetics , Receptors, Tumor Necrosis Factor, Type I/metabolism , Type C Phospholipases/antagonists & inhibitorsABSTRACT
The ß-borylation reaction of α,ß-unsaturated aldehyde-derived imines, formed in situ, has been studied using a one-pot methodology, as a route to ß-boryl aldehydes. The instability of the ß-boryl aldehydes meant that derivatisation was required and routes to both acetal derivatives and homoallylic boronates were examined. ß-Boryl acetals were also found to be unstable, however, the formation of homoallylic boronate derivatives using an in situ imine hydrolysis-Wittig olefination protocol was found to be suitable, resulting in an efficient synthesis with high enantiomeric excesses.
ABSTRACT
We report efficient, catalytic, asymmetric total syntheses of both (R)-fluoxetine and (S)-duloxetine from α,ß-unsaturated aldehydes conducting five sequential one-pot steps (imine formation/copper mediated ß-borylation/transimination/reduction/oxidation) followed by the specific ether group formation which deliver the desired products (R)-fluoxetine in 45% yield (96% ee) and (S)-duloxetine in 47% yield (94% ee).
Subject(s)
Chemistry, Organic/methods , Fluoxetine/chemical synthesis , Imines/chemical synthesis , Thiophenes/chemical synthesis , Duloxetine Hydrochloride , Fluoxetine/chemistry , Imines/chemistry , Thiophenes/chemistryABSTRACT
A combination of in situ IR spectroscopy (ReactIR) and DFT calculations have been used to understand what factors govern the selectivity in the addition of primary amines to α,ß-unsaturated aldehydes and ketones, i.e., 1,2- versus 1,4-addition. It has been found that the 1,2-addition products (α,ß-unsaturated imines following addition and elimination) usually predominate for most systems. However, exceptions, such as methyl vinyl ketone, selectively give 1,4-addition products. This has been rationalized by DFT calculations that show that major conformational effects are involved, controlled mainly by steric effects of carbonyl substituents, resulting in a model that provides simple and predictable preparation of α,ß-unsaturated imines for in situ utilization in synthesis.
ABSTRACT
A one-pot synthesis of chiral amino alcohols from α,ß-unsaturated aldehydes is reported which circumvents competitive 1,2- versus 1,4-boryl addition, by means of using a sterically hindered amine-derived imine. In addition to the complete chemoselectivity, modification of the Cu(I) catalyst with readily available chiral diphosphines, such as (R)-DM-BINAP, gave the 1,4-boryl addition products with high levels of asymmetric induction.
ABSTRACT
An efficient, 4-step, one-pot, highly stereoselective route to γ-amino alcohols has been developed via an in situ α,ß-unsaturated imine formation, ß-boration, reduction (C=N) and oxidation (C-B) sequence and especially for certain water-soluble γ-amino alcohols, a further step can be added to directly access the corresponding 1,3-oxazine derivatives.
ABSTRACT
OBJECTIVES: To determine the relationship between lower limb symptoms and generic health-related quality of life (HRQL) in patients with varicose veins (VV). METHODS: 284 patients on the waiting list for VV treatment completed the Short Form-12 (SF12) and a questionnaire asking about the presence of lower limb symptoms commonly attributed to venous disease (pain or ache, itching, tingling, cramp, restless legs, a feeling of swelling, and heaviness). RESULTS: Median age was 57 years (interquartile range 45-67); 100 (35%) were male, and 182 (64%) had CEAP clinical grade 2 or 3 disease. Jonckheere-Terpstra test for trend revealed that both physical (P < .0005) and mental (P = .001) HRQL worsened as the reported number of symptoms increased. Patients reporting tingling (P = .016, Mann-Whitney U test), cramp (P = .001), restless legs (P < .0005), swelling (P < .0005), and heaviness (P < .0005) had a significantly worse physical HRQL than those who did not. Mental HRQL was also significantly worse in patients with tingling (P = .010), cramp (P = .008), restless legs (P = .040), swelling (P = .001), and heaviness (P = .035). These significant relationships remained, and pain was also correlated with worse physical HRQL (P = .011), when linear regression was performed to control for CEAP clinical grade, age and sex. CONCLUSIONS: Physical and mental HRQL is significantly worse in VV patients with lower limb symptoms irrespective of the clinical stage of disease. This observation confirms that VV are not primarily a cosmetic problem and that NHS rationing of treatment to those with CEAP C4-6 disease excludes many patients who would benefit from intervention in terms of HRQL. Generic HRQL instruments also allow comparison with interventions for other chronic conditions.
Subject(s)
Quality of Life , Surveys and Questionnaires , Varicose Veins/diagnosis , Aged , Chronic Disease , Cost of Illness , England , Female , Health Care Rationing , Humans , Linear Models , Male , Mental Health , Middle Aged , Patient Selection , Predictive Value of Tests , Prognosis , Risk Assessment , Risk Factors , Severity of Illness Index , State Medicine , Varicose Veins/complications , Varicose Veins/physiopathology , Varicose Veins/psychology , Varicose Veins/therapyABSTRACT
The area of boron conjugate addition via diboration (ß-boration) has grown rapidly since the first examples appeared in the late 1990s. This article aims to give a comprehensive review of the current advances in ß-boration (of electron deficient alkenes), providing a commentary upon the development of the asymmetric version. To date, many mechanistic models have been put forward to explain the experimental observations and this review surveys some of these key ideas. Recently, the development of organocatalytic methodologies that facilitate ß-boration have also been demonstrated and current ideas regarding the mechanisms of such processes are examined.
ABSTRACT
OBJECTIVES: To describe duplex ultrasound (DUS) outcomes 12 months following ultrasound-guided foam sclerotherapy (UGFS) of recurrent great saphenous varicose veins (GSVV). METHODS: A consecutive series of UK National Health Service patients underwent serial DUS examinations following UGFS with 3% sodium tetradecyl sulphate for symptomatic recurrent GSVV. RESULTS: 91 treated legs (CEAP C(2/3) 58, C(4) 21, C(5) 8, C(6) 4) belonging to 73 patients (24 male) of median age 58 (range 32-86) years were enrolled between November 2004 and May 2007. The median volume of foam used was 8 (range 4-14) ml. Above-knee (AK) and below-knee (BK) GSV reflux was present in 88 (97%) and 80 (88%) legs respectively prior to treatment. AK and BK-GSV reflux was completely eradicated by a single session of UGFS in 86 (98%) and 74 (93%) legs respectively; and by two sessions of UGFS in 88 (100%) and 77 (97%) legs respectively. In those legs where GSV reflux had been eradicated, recanalisation occurred in 7/78 (9%) AK and 8/68 (12%) BK-GSV segments after 12 months follow-up. Retreatment, where undertaken, with a single UGFS session effectively eradicated all GSV reflux in all cases of recanalisation. DISCUSSION: A single session of UGFS can eradicate reflux in the AK and BK-GSV in over 93% of patients with symptomatic recurrent GSVV. Re-recurrence at 12 months is superior to that reported after redo GSV surgery, similar to that observed following other minimally-invasive techniques and, when it occurs, is effectively and simply treated by a single further session of UGFS.
Subject(s)
Saphenous Vein/diagnostic imaging , Sclerosing Solutions/therapeutic use , Sclerotherapy/methods , Sodium Tetradecyl Sulfate/therapeutic use , Ultrasonography, Doppler, Duplex , Ultrasonography, Interventional , Varicose Veins/therapy , Adult , Aged , Aged, 80 and over , England , Female , Humans , Male , Middle Aged , Recurrence , Retreatment , Time Factors , Treatment Outcome , Varicose Veins/diagnostic imagingABSTRACT
OBJECTIVES: To determine healing and recurrence rates following ultrasound-guided foam sclerotherapy (UGFS) of superficial venous reflux (SVR) in patients with healed (clinical, etiologic, anatomic and pathophysiologic (CEAP) classification, C5) and open (C6) chronic venous ulceration (CVU). METHODS: Between 1 March 2005 and 31 December 2009, 130 consecutive patients (132 limbs, 49 CEAP C5, 83 C6) of median age 70 (interquartile range (IQR) 56-76) years underwent UGFS as part of their treatment for CVU. RESULTS: The median (IQR) follow-up time was 16 (12-32) months. One C6 patient moved abroad 1 week after UGFS and was lost to follow-up. Healing was observed in 67/82 (82%) remaining C6 patients at a median (IQR) of 1 (1-2) month following their first UGFS treatment. In 49 limbs originally treated for C5 disease, and in 67 limbs treated for C6 that healed following UGFS, there were five recurrent ulcers during the follow-up period, giving a 4.9% Kaplan-Meier estimate of recurrence at 2 years. In legs treated for C6 and C5 disease, the median (IQR) ulcer-free periods were 22 (IQR 9-32) and 14 (IQR 8-36) months, respectively. DISCUSSION: Healing rates following UGFS for CVU are comparable to those reported after surgery but recurrence may be lower. UGFS is a safe, clinically effective and, thus, highly attractive minimally invasive alternative to surgery in patients with C5 and C6 disease.