Unlocking the Chain-Walking Process in Gold Catalysis.

The successful realization of gold-catalyzed chain-walking reactions, facilitated by ligand-enabled Au(I)/Au(III) redox catalysis, has been reported for the first time. This breakthrough has led to the development of gold-catalyzed annulation reaction of alkenes with iodoarenes by leveraging the interplay of chain-walking and π-activation reactivity mode. The reaction mechanism has been elucidated through comprehensive experimental and computational studies.

Ligand-Enabled Gold-Catalyzed C(sp2)-S Cross-Coupling Reactions.

Herein we report C(sp2)-S cross-coupling reactions of aryl iodides and arylsulfonyl hydrazides under ligand-enabled, Au(I)/Au(III) redox catalysis. This strategy operates under mild reaction conditions, requires no prefunctionalized aryl coupling partner, and works across several aryl iodides. The utility of this protocol is highlighted through the synthesis of various medicinally relevant biaryl sulfones. The reaction mechanism is supported with control experiments, mass spectrometry, and NMR studies.

Short-Term Relocation Stress-Induced Hematological and Immunological Changes in Saimiri boliviensis boliviensis.

Nonhuman primates are frequently transported to a new location or temporarily relocated within their colony. Both transportation and relocation expose animals to new environments, causing them to undergo a stress response (before adapting). In our NHP colony, the mentioned situations are not infrequent for many reasons, including maintenance. The objective of this study was to determine whether abrupt changes consisting of relocation, housing, separation, and grouping could influence hematological and immunological parameters and thereby functional activity. The current study used squirrel monkeys as a model to investigate the stress-inducing effects of relocation within a facility, while animals acclimated to new situations (physical, housing). A detailed blood analysis revealed significant changes in lymphocytes, triglycerides, total protein, creatinine, and ALT. Flow cytometric analysis of peripheral blood showed reduction in CD3+, CD4+, and CD8+ T cells and monocytes, while B cells and natural killer (NK) cells changed with relocation. Simultaneously, changes in functional activity of immune cells altered proliferative responses and as shown by ELISpot (IFN γ). Though the parameters studied are not affected as severely as those in animals transported by road or air, stress responses induced by intrafacility relocation are significant and worth consideration. Our findings indicate that squirrel monkeys mimic the features seen in humans exposed to social stressors and may serve an important model for understanding the mechanisms of stress-induced immune dysfunction in humans.

The interplay of carbophilic activation and Au(I)/Au(III) catalysis: an emerging technique for 1,2-difunctionalization of C-C multiple bonds.

Gold complexes have emerged as the catalysts of choice for various functionalization reactions of C-C multiple bonds due to their inherent carbophilic nature. In a parallel space, efforts to realize less accessible cross-coupling reactivity have led to the development of various strategies that facilitate the arduous Au(I)/Au(III) redox cycle. The interplay of the two important reactivity modes encountered in gold catalysis, namely carbophilic activation and Au(I)/Au(III) catalysis, has allowed the development of a novel mechanistic paradigm that sponsors 1,2-difunctionalization reactions of various C-C multiple bonds. Interestingly, the reactivity as well as selectivity obtained through this interplay could be complementary to that obtained by the use of various other transition metals that mainly involved the classical oxidative addition/migratory insertion pathways. The present review shall comprehensively cover all the 1,2-difunctionalization reactions of C-C multiple bonds that have been realized by the interplay of the two important reactivity modes and categorized on the basis of the method that has been employed to foster the Au(I)/Au(III) redox cycle.

Innate immunity stimulation via CpG oligodeoxynucleotides ameliorates Alzheimer's disease pathology in aged squirrel monkeys.

Alzheimer's disease is the most common cause of dementia and the only illness among the top 10 causes of death for which there is no disease-modifying therapy. The failure rate of clinical trials is very high, in part due to the premature translation of successful results in transgenic mouse models to patients. Extensive evidence suggests that dysregulation of innate immunity and microglia/macrophages plays a key role in Alzheimer's disease pathogenesis. Activated resident microglia and peripheral macrophages can display protective or detrimental phenotypes depending on the stimulus and environment. Toll-like receptors (TLRs) are a family of innate immune regulators known to play an important role in governing the phenotypic status of microglia. We have shown in multiple transgenic Alzheimer's disease mouse models that harnessing innate immunity via TLR9 agonist CpG oligodeoxynucleotides (ODNs) modulates age-related defects associated with immune cells and safely reduces amyloid plaques, oligomeric amyloid-ß, tau pathology, and cerebral amyloid angiopathy (CAA) while promoting cognitive benefits. In the current study we have used a non-human primate model of sporadic Alzheimer's disease pathology that develops extensive CAA-elderly squirrel monkeys. The major complications in current immunotherapeutic trials for Alzheimer's disease are amyloid-related imaging abnormalities, which are linked to the presence and extent of CAA; hence, the prominence of CAA in elderly squirrel monkeys makes them a valuable model for studying the safety of the CpG ODN-based concept of immunomodulation. We demonstrate that long-term use of Class B CpG ODN 2006 induces a favourable degree of innate immunity stimulation without producing excessive or sustained inflammation, resulting in efficient amelioration of both CAA and tau Alzheimer's disease-related pathologies in association with behavioural improvements and in the absence of microhaemorrhages in aged elderly squirrel monkeys. CpG ODN 2006 has been well established in numerous human trials for a variety of diseases. The present evidence together with our earlier, extensive preclinical research, validates the beneficial therapeutic outcomes and safety of this innovative immunomodulatory approach, increasing the likelihood of CpG ODN therapeutic efficacy in future clinical trials.

Ligand-enabled gold-catalyzed 1,2-heteroarylation of alkenes.

By adopting the interplay between ligand-enabled Au(i)/Au(iii) catalysis and the unique π-activation mode of gold complexes, a highly coveted 1,2-heteroarylation of alkenes has been accomplished. The present ligand-enabled approach not only circumvents the requirement for strong sacrificial oxidants or photocatalysts but also operates under mild reaction conditions by utilizing simple and non-prefunctionalized aryl coupling partners.

Class C CpG Oligodeoxynucleotide Immunomodulatory Response in Aged Squirrel Monkey (Saimiri Boliviensis Boliviensis).

One means of stimulating the mammalian innate immune system is via Toll-like receptor 9 (TLR9) being exposed to unmethylated cytosine-phosphate-guanine (CpG) DNA, also known as pathogen-associated molecular patterns (PAMPs) of microbial origin. Synthetic CpG oligodeoxynucleotides (ODNs) with defined CpG motifs possess broad immunostimulatory properties that make CpG ODNs suitable as therapeutic interventions in a variety of human disease conditions, including Alzheimer's disease (AD). Rodent models are often used to preclinically test the effectiveness of CpG ODN therapeutic agents for AD and other disorders. However, the translatability of findings in such models is limited due to the significant difference of the expression of TLR9 between primates and rodents. The squirrel monkey (SQM), a New World non-human primate (NHP), is known to be phylogenetically proximate to humans, and develops extensive age-dependent cerebral amyloid angiopathy (CAA), a key pathological feature of AD. Hence, this model is currently being used to test AD therapeutics. In the present study, we conducted the first examination of Class C CpG ODN's immunomodulatory role in elderly SQMs. We documented the effectiveness of CpG ODN to trigger an immune response in an aged cohort whose immune system is senescent. The specific immune response patterns detected here closely resembled CpG ODN-induced immunostimulatory patterns observed in prior human studies. Overall, our findings provide critical data regarding the immunomodulatory potential of CpG ODN in this NHP model, allowing for future translational studies of innate immunity stimulation via TLR9 agonists for diverse indications, including AD therapeutics.

Gold-Catalyzed Cycloisomerization of Pyridine-Bridged 1,8-Diynes: An Expedient Access to Luminescent Cycl[3.2.2]azines.

Gold-catalyzed diyne cycloisomerizations involving carbene/alkyne metathesis have been the focal point of attention for the past few years as it offers great potential to build complex polycyclic architectures. However, the design of novel cycloisomerizations has been mostly limited to 1,5/1,6- diynes and has remained very challenging to apply for higher 1,n-diynes. Herein, we disclose an unprecedented cycloisomerization of pyridine-bridged 1,8-diynes involving carbene/alkyne metathesis to access luminescent cycl[3.2.2]azines.

Hypopharyngeal Airway Surgery for Obstructive Sleep Apnea: Morbidity in the Early Postoperative Period.

STUDY OBJECTIVE: To determine if hypopharyngeal surgery for obstructive sleep apnea is associated with significant morbidity in the early post-operative period. METHODS: Patients with a diagnosis of obstructive sleep apnea who underwent hypopharyngeal surgery at a tertiary care facility between November 2012 and September 2013 were included in this study. Surgical outcomes were assessed from medical records review and a 14 question telephone survey. Results: Twenty-two patients underwent hypopharyngeal surgery for obstructive sleep apnea (OSA). No patient experienced intra-operative complications, post-operative O2 desaturation <90%, prolonged admission for inadequate pain control, pulmonary edema, or airway compromise requiring re-intubation. Post-operative complications included one episode of nasal hemorrhage, one infection requiring hospitalization, and one episode of dehydration treated with IV fluids. 25% of patients experienced some degree of post-operative dysphonia, and 87.5% of patients experienced post-operative dysphagia. The average rating for post-operative pharyngeal pain was 3.5 of 10 by week 3 and 1.75 of 10 by week 4. Most patients described decreased snoring (93.75%), improved feeling of overall health (75%), and increased daytime energy (62.5%). All patients undergoing hypopharyngeal airway surgery were discharged within 23 hours. CONCLUSION: Hypopharyngeal surgery is a safe and well tolerated procedure for the treatment of OSA. Our findings suggest that hypopharyngeal surgery may be performed on an outpatient basis.

Differential distribution and energy status-dependent regulation of the four CART neuropeptide genes in the zebrafish brain.

The cocaine- and amphetamine-regulated transcript (CART) neuropeptide has been implicated in the neural regulation of energy homeostasis across vertebrate phyla. By using gene-specific in situ hybridization, we have mapped the distribution of the four CART mRNAs in the central nervous system of the adult zebrafish. The widespread neuronal expression pattern for CART 2 and 4 suggests a prominent role for the peptide in processing sensory information from diverse modalities including olfactory and visual inputs. In contrast, CART 1 and 3 have a much more restricted distribution, predominantly located in the nucleus of the medial longitudinal fasciculus (NMLF) and entopeduncular nucleus (EN), respectively. Enrichment of CART 2 and 4 in the preoptic and tuberal areas emphasizes the importance of CART in neuroendocrine functions. Starvation resulted in a significant decrease in CART-positive cells in the nucleus recessus lateralis (NRL) and nucleus lateralis tuberis (NLT) hypothalamic regions, suggesting a function in energy homeostasis for these neurons. Similarly, the EN emerges as a novel energy status-responsive region. Not only is there abundant and overlapping expression of CART 2, 3, and 4 in the EN, but also starvation induced a decrease in CART-expressing neurons in this region. The cellular resolution mapping of CART mRNA and the response of CART-expressing nuclei to starvation underscores the importance of CART neuropeptide in energy processing. Additionally, the regional and gene-specific responses to energy levels suggest a complex, interactive network whereby the four CART gene products may have nonredundant functions in energy homeostasis.

Stapler-assisted closure in total laryngectomy.

The total laryngectomy is a surgical procedure that requires technically sound reconstruction in order to preserve a patient's swallowing function. Traditionally, a handsewn technique has been utilized to accomplish this endeavor. Recent applications of surgical stapling devices have been noted in an attempt to circumvent the need for handsewn reconstruction. This paper documents the application of a surgical stapling device in reconstructing a total laryngectomy defect. A brief review of the literature is provided to compare the differences between handsewn techniques and stapling techniques.

Oropharyngeal reconstruction using the supraclavicular artery island flap: a new flap alternative.

UNLABELLED: Oropharyngeal reconstruction following head and neck oncologic resection has utilized local, regional, and free tissue transfer flap options. The modality utilized is often guided by the type of defect created as well as the surgeon's preference. In this article, the authors introduce the application of the supraclavicular artery island flap as a reconstructive modality following oropharyngeal oncologic ablation. Five patients underwent head and neck oncologic resection for oropharyngeal squamous cell carcinoma followed by single-stage reconstruction with an ipsilateral supraclavicular artery island flap. There were no flap failures and only one postoperative complication consisting of a postoperative oral-cutaneous fistula that resolved without surgical intervention. There were no donor-site complications. The supraclavicular artery island flap is a viable alternative for oropharyngeal reconstruction following head and neck oncologic resection. It is a regional flap that can be harvested without microsurgical expertise and yields reliable postoperative results. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Bezold's abscess: a unique complication of otitis media.

Otitis media is one of the more common pathologic entities treated by primary care physicians and otolaryngologists. With antibiotic therapy, the majority of these infections do not progress beyond the primary disease process. However, there are situations during which the primary otitis media may not resolve, and complications can form as a result of its persistence. One such complication is the formation of a Bezold's abscess. This results from an underlying coalescent mastoiditis which progresses laterally into the deep neck space. The following is a case presentation of a Bezold's abscess followed by a discussion detailing the pathophysiology, presentation, diagnosis, and treatment of this disease process.

Reconstruction of large lateral facial defects utilizing variations of the cervicopectoral rotation flap.

Large lateral facial defects as a result of trauma or head and neck oncologic surgery can present a challenging reconstructive dilemma for the operating surgeon. A number of options currently exist for reconstructing such defects, including skin grafts, myocutaneous flaps, and free vascularized flaps. The decision to utilize one approach versus another depends largely on the nature of the defect, anatomical location, and the experience of the surgeon. This article describes our experience utilizing cervicopectoral rotation flaps with and without myocutaneous flaps to reconstruct large lateral facial defects after head and neck oncologic surgery.