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Objective: Head and neck cancer is a significant contributor to global otolaryngologic disease burden, with a disproportionate impact on low- and middle-income countries. This study investigates the factors contributing to delays in head and neck cancer diagnosis at the University Teaching Hospital of Kigali (CHUK)., Methods: Cross-sectional study of all patients with a pathologic diagnosis of head and neck cancer presenting to CHUK between January 2021 and June 2022. Sociodemographic data, tumor characteristics, and reasons for delay were collected. Univariate and multivariable analyses were undertaken to evaluate risk factors for delays., Results: Eighty-one patients met criteria for inclusion. Median duration from patient first reported symptoms to initial medical consultation was 52 weeks, from initial medical consultation to referral to CHUK was 4 weeks, and from referral to final pathologic diagnosis was 6 weeks. The most common reason for delay to referral to CHUK was financial (37.04%). Patients who visited traditional healers had higher odds of delay between symptom onset and medical consultation (OR 3.51, CI 1.05-11.70). Delays in final diagnosis after referral were most commonly due to OR availability for biopsy (37.04%) and time for pathology results after biopsy (35.80%). OR availability had a significant impact on duration to final diagnosis (OR 59.48, CI 7.17-493.67). Stage 4 disease had the shortest time to final diagnosis (OR 0.05, CI 0.01-0.45)., Conclusion: Understanding the reasons for delayed diagnosis of head and neck cancer may help guide improvements in care, with the goal of reducing global head and neck burden of disease., Level of Evidence: 3; prospective non-random follow-up study Laryngoscope, 134:1663-1669, 2024., (© 2023 The American Laryngological, Rhinological and Otological Society, Inc.)

Objectives: To evaluate the impact of different techniques of microvascular venous anastomosis on the outcome of free tissue transfer to the head and neck. Methods: Retrospective case series of patients undergoing microvascular free tissue transfer (MFTT) from January 2006 to September 2021. Chi-square tests and t -tests were utilized to identify differences in flap outcomes by technique, and log-binomial regression analyses were utilized to identify differences in flap outcomes by technique. Results: A total of 1055 consecutive MFTTs were analyzed. One hundred four cases required a return to the operating room for any reason, and 19 were attributed to venous compromise (18.0%). Ultimately, there were 22 FTT failures requiring complete revision (2.1%). In total, 1055 MFTTs involved 1352 venous anastomoses, ranging from 1 to 3 anastomoses in each case. End-to-end (ETE) was used 1040 times (76.9%) and end-to-side (ETS) 204 times (15.0%). The calculated risk ratio for venous complication for ETS compared with ETE was 1.17 (0.34-3.98). A microvascular coupler was used in 355 cases (33.6%). The calculated risk ratio for coupler compared with suture anastomoses was 0.92 (0.35-2.39). Conclusions: There were no significant difference in regard to outcomes of MFTT when comparing ETE with ETS, nor when comparing coupler with suture anastomoses.

Fifty years ago, in July 1973, providing care to patients with end stage kidney disease changed dramatically with the implementation of legislation (PL 92-603) that deemed chronic renal disease to be a disability and provided coverage under Medicare for the treatment of the disease. In this article, we discuss the impact of the implementation of PL 92-603., (Copyright© by the American Nephrology Nurses Association.)

Importance: Research in facial plastic and reconstructive surgery (FPRS) in the global health setting, especially in low- and middle-income countries (LMICs), is increasing year by year. As this work progresses, it will be crucial to include voices and perspectives of individuals living in the LMICs being studied., Objective: To characterize and understand international collaborations in published literature on FPRS care in a global health setting and report patterns in whether these articles included authors from the LMICs in which the studies took place., Evidence Review: A systematic bibliometric scoping review of articles in Scopus from 1971 to 2022 was performed using a set list of search terms; studies were included using predetermined inclusion and exclusion criteria. Studies met criteria for inclusion if the abstract or text contained information regarding surgeons from a different country performing surgery or conducting research in an LMIC within the domain of FPRS. Exclusion criteria were studies that did not mention a facial plastic or reconstructive surgery and studies where both an HIC and LMIC were not mentioned., Findings: A total of 286 studies met criteria for inclusion. The highest percentage of studies (n = 72, 25.2%) were conducted across multiple countries. A total of 120 studies (41.9%) discussed cleft lip/palate. Overall, 141 studies (49.5%) included at least 1 author from the host LMIC; 89 (31.1%) had first authors from LMICs, and 72 (25.2%) had senior authors from LMICs. A total of 79 studies (27.6%) described humanitarian clinical service trips without mentioning research or education in the text. The remaining studies described research, education projects, or a combination. The published literature on humanitarian service trips had the lowest rate of inclusion of a first or senior author from the host LMICs., Conclusions and Relevance: In this systematic bibliometric scoping review, findings showed a general trend of increased international work in the field of FPRS. However, there continues to be a paucity of inclusive authorship trends, with the majority of studies not including first or senior authors from LMICs. The findings presented here encourage new collaborations worldwide, as well as the improvement of existing efforts.

Objectives: Parotidectomy defects can leave patients with considerable functional and cosmetic deformities. We aim to compare the success rates and complications associated with vascularized versus nonvascularized adipofascial grafts for reconstruction, including flap failure, return to surgery, infection, and delay to adjuvant treatment. Methods: Retrospective case series of patients undergoing either adipofascial anterolateral thigh (AFALT) free tissue transfer or free fat transfer (FFT) after parotidectomy from January 2010 to January 2020. Group comparisons and logistic regression were used to determine predictors of outcome measures. Results: Seventy-six patients underwent AFALT reconstruction, and 73 patients underwent FFT reconstruction. Patients treated with AFALT reconstruction had more aggressive tumor characteristics and underwent more complex resections, most commonly radical parotidectomy ( n  = 55, 72.4%). Postoperative complications at both the donor and recipient sites were more common in the FFT group ( N  = 20, 27.4% in FFT vs. N  = 11, 14.5% in AFALT, odds ratio = 0.45, 95% confidence interval = 0.20-1.02, p  = 0.052). Conclusions: Although used in more advanced disease and in a more heavily treated wound bed, the AFALT free flap was safe and associated with fewer infectious complications than that offered by FFT.

Objectives: Craniomaxillofacial (CMF) trauma represents a significant proportion of global surgical disease burden, disproportionally affecting low- and middle-income countries where care is often delayed. We investigated risk factors for delays to care for patients with CMF trauma presenting to the highest-volume trauma hospital in Rwanda and the impact on complication rates., Study Design: This prospective cohort study comprised all patients with CMF trauma presenting to the University Teaching Hospital of Kigali, Rwanda, between June 1 and October 1, 2020., Setting: Urban referral center in resource-limited setting., Methods: Epidemiologic data were collected, and logistic regression analysis was undertaken to explore risk factors for delays in care and complications., Results: Fifty-four patients (94.4% men) met criteria for inclusion. The mean age was 30 years. A majority of patients presented from a rural setting (n = 34, 63%); the most common cause of trauma was motor vehicle accident (n = 18, 33%); and the most common injury was mandibular fracture (n = 28, 35%). An overall 78% of patients had delayed treatment of the fracture after arrival to the hospital, and 81% of these patients experienced a complication (n = 34, P = .03). Delay in treatment was associated with 4-times greater likelihood of complication (odds ratio, 4.25 [95% CI, 1.08-16.70]; P = .038)., Conclusion: Delay in treatment of CMF traumatic injuries correlates with higher rates of complications. Delays most commonly resulted from a lack of surgeon and/or operating room availability or were related to transfers from rural districts. Expansion of the CMF trauma surgical workforce, increased operative capacity, and coordinated transfer care efforts may improve trauma care., Competing Interests: Disclosures: Competing interests: None. Sponsorships: None. Funding source: None., (© The Authors 2022.)

Objective: To better understand the impact of the otolaryngology-specific workforce on the burden of related diseases., Study Design: Retrospective analysis of existing workforce density data as compared with the incidence, mortality, and morbidity data for 4 otolaryngologic diseases., Setting: An overall 138 countries with known otolaryngology-head and neck surgery workforce and epidemiologic data., Methods: We obtained raw data on workforce estimates of ear, nose, and throat surgical specialists from the World Health Organization. Disease burdens for 4 conditions were estimated via 2 ratios, the mortality:incidence ratio (MIR) and YLD:incidence ratio (years lost to disability), as specified in the Global Burden of Disease database. These were correlated to country-specific otolaryngologist density data in univariate and multivariate analyses., Results: Increased density of the ear, nose, and throat workforce correlated with better outcomes for otolaryngologic-treated surgical diseases. A 10% increase in otolaryngology workforce density was associated with a 0.27% reduction in YLD:incidence ratio for chronic otitis media, a 0.94% reduction in MIR for lip and oral cavity cancer, a 1.46% reduction in MIR for laryngeal cancer, and a 1.34% reduction in MIR for pharyngeal cancer (all P < .001)-an effect that remained after adjustment for health systems factors for all conditions but chronic otitis media., Conclusion: The density of the surgical workforce is assumed to affect disease outcomes, but ours is the first analysis to show that increased workforce density for a specific surgical specialty correlates with improved disease outcomes. While there is a consensus to increase access to health care providers, quantifying the effect on disease outcomes is an important metric for those performing health economics modeling, particularly where resources are limited., Competing Interests: Disclosures: Competing interests: None. Sponsorships: None. Funding source: None., (© The Authors 2022.)

Objective: The prognostic significance of bone invasion in oral cavity squamous cell carcinoma (OCSCC) after accounting for tumor size, nodal spread, and surgical margins is controversial. The aim of this study is to determine whether patients with pT4aN0 oral cavity squamous cell carcinoma with bone invasion have improved overall and disease-free survival with adjuvant treatment., Methods: We conducted a retrospective review of medical records from 64 patients with stage pT4aN0 due to mandibular involvement who underwent surgery from 2000 to 2020. Kaplan-Meier analysis compared disease-free survival and overall survival between groups who underwent surgery only versus surgery and adjuvant therapy. The prognostic impact of adjuvant therapy was assessed using multivariate analysis and reported as hazard ratios., Results: There were no statistically significant differences in clinicopathologic features or mean follow-up between patients who received surgery only and patients who received surgery with RT/CCRT (radiotherapy/concurrent chemoradiation therapy). 5-year disease-free (42.5% versus 65.9%, p = 0.02) and overall survival (43.6% versus 69.0%, p = 0.014) were improved in groups who received surgery and RT/CCRT. Regression analysis controlling for clinicopathologic characteristics, including tumor size, identified radiation as an independent predictor of improved disease-free survival (HR: 0.04, p < 0.001) and overall survival (HR: 0.10, p < 0.001)., Conclusion: Adjuvant RT/CCRT in patients with pT4N0 OCSCC with mandibular bone involvement is associated with improved disease-free and overall survival. This association was significant regardless of tumor pathologic features such as size or margin status. These findings may help guide physicians in counseling patients regarding risks and benefits of adjuvant RT/CCRT and inform practice guidelines., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: For human papilloma virus-associated oropharynx squamous cell carcinoma (HPV+ OPSCC), we evaluated the distribution of neck-level lymph node (LN) metastasis, based on postsurgical histopathology, and the incidence of and risk factors for occult LN metastases, as these patterns need clarification for this newer cancer subset., Study Design: Retrospective cohort study., Setting: National Cancer Database (NCDB)., Methods: We analyzed 2358 patients in the NCDB with HPV+ OPSCC who underwent neck dissection (ND) from 2010 to 2015. Incidence and distribution of LN metastases were calculated for neck levels I to V. Variables associated with occult LN metastasis were assessed by multivariate logistic regression., Results: In therapeutic NDs (n = 1935), the following proportions of positive LNs were found: level I, 9.0% (n = 175); level II, 81.0% (n = 1568); level III, 29.6% (n = 573); level IV, 11.9% (n = 230); and level V, 4.9% (n = 95). In elective NDs (n = 423), occult-positive LNs were found in 35.8% (n = 152), with the following proportions by level: level I, 3.3% (n = 14); level II, 26.9% (n = 114); level III, 8.7% (n = 37); level IV, 4.0% (n = 17); and level V, 0.2% (n = 1). The presence of occult LNs was independently associated with a Charlson-Deyo score of 1 (odds ratio, 2.26; 95% CI, 1.18-4.31; P = .014) and lymphovascular invasion (odds ratio, 5.91; 95% CI, 3.21-11.18; P < .001). Occult LN metastases were not significantly associated with pT classification, primary site, or number of LNs resected., Conclusion: For HPV+ OPSCC, occult nodal disease is common. Therapeutic NDs should encompass at least levels II, III, and IV and possibly I, whereas elective NDs could possibly encompass levels II and III., Level of Evidence: 4.

Objectives/hypothesis: For early-stage oral tongue carcinoma and carcinoma in situ (ESOTCCIS), we evaluated patient-reported quality-of-life (QOL) outcomes following resection with primary closure (R-PC)., Study Design: Retrospective review at an academic cancer center., Methods: Thirty-nine ESOTCCIS patients (Tis, T1, T2) who underwent R-PC without radiation completed the University of Washington Quality of Life Questionnaire Version 4 (UW-QOL) at least 6 months since R-PC (mean = 2.39 years; range = 0.5-6.7 years). We compared UW-QOL scores for pain, swallowing, chewing, speech, and taste to established normative population scores. Multivariable regression analysis evaluated factors associated with QOL impairment., Results: ESOTCCIS patients who underwent R-PC in comparison to the normative population reported significantly worse mean speech (87.7 vs. 98, P < .001) and taste (85.6 vs. 95, P = .002) scores and no significant differences in mean pain (91.7 vs. 86, P = .96), swallowing (100 vs. 98, P = .98), chewing (97.4 vs. 94, P = .98) scores. For speech and taste, 59% (23/39) reported no postoperative change from baseline, whereas 41% (16/39) and 35.9% (14/39) reported mild impairment, respectively. Overall, postoperative QOL was reported as good, very good, or outstanding by 87.2% (34/39). Higher American Society of Anesthesiologists class, cT1 compared to CIS, and ventral tongue involvement were independently associated with worse speech. Age < 60 years was independently associated with worse taste., Conclusions: ESOTCCIS patients who undergo R-PC without radiation can expect long-term swallowing, chewing, and pain to be in the normative range. Although a majority of patients can expect to achieve normative speech and taste outcomes, R-PC carries the risks of mild speech and/or taste impairments., Level of Evidence: 4 Laryngoscope, 131:312-318, 2021., (© 2020 The American Laryngological, Rhinological and Otological Society, Inc.)

Objective: Survival outcomes for human papillomavirus-associated oropharynx squamous cell carcinoma (HPV + OPSCC) treated with surgery alone are unclear. To increase understanding, we assessed overall survival (OS) outcomes using the national cancer database (NCDB)., Methods: We conducted a retrospective analysis of OS of 736 NCDB HPV + OPSCC patients who underwent surgery alone from 2010 to 2014 using univariate and multivariate analyses and the Kaplan-Meir method., Results: Multivariable analysis found the following independent risk factors for death: American Joint Commission on Cancer (AJCC) 8th edition pathologic stage(p)N2 versus pN0 disease (hazard ratio [HR], 5.5; P = 0.000006), macroscopic extranodal extension (ENE) versus non-ENE (HR, 4.9; P < 0.02), a positive lymph nodes (LN) percentage of ≥10% (HR, 4.2; P = 0.0002), and five or more positive LNs (HR, 4.9; P = 0.00004). Three-year OS was significantly worse for AJCC 8th edition pN2 versus pN0 but not for 7th edition pN2 versus pN0 disease. Five-year OS was significantly worse for positive versus negative surgical margins, AJCC 8th edition stage II versus I, and either microscopic or macroscopic ENE versus non-ENE positive LNs. For 523 (71%) AJCC 8th edition stage I patients and for 283 (38%) patients who were pT1-T2, with negative margins, pN0-N1, with ≤4 pathologic LNs, without ENE, and with >20 LNs removed during neck dissection, the 3-year OS rates were 93% and 95%, respectively, and the 5-year OS rates were 91% and 95%, respectively., Conclusion: In the context of the lack of detail and possible inaccuracies found in the NCDB, surgery alone for AJCC 8th edition stage I HPV + OPSCC, particularly pT1-T2, pN0-N1 with ≤4 pathologic LNs, without ENE, and with negative surgical margins has a high OS., Level of Evidence: 4 Laryngoscope, 130:E423-E435, 2020., (© 2019 The American Laryngological, Rhinological and Otological Society, Inc.)

P2Y receptors have been reported to modulate gastrointestinal functions. The newest family member is the nucleotide-sugar receptor P2Y14. P2ry14 mRNA was detected throughout the rat gut, with the highest level being in the forestomach. We investigated the role of the receptor in stomach motility using cognate agonists and knockout (KO) mice. In rat isolated forestomach, 100 microM UDP-glucose and 100 muM UDP-galactose both increased the baseline muscle tension (BMT) by 6.2+/-0.6 and 1.6+/-0.6 mN (P<0.05, n=3-4), respectively, and the amplitude of contractions during electrical field stimulation (EFS) by 3.7+/-1.7 and 4.3+/-2.5 mN (P<0.05, n=3-4), respectively. In forestomach from wild-type (WT) mice, 100 microM UDP-glucose increased the BMT by 1.0+/-0.1 mN (P<0.05, n=6) but this effect was lost in the KO mice (change of -0.1+/-0.1 mN, n=6). The 100 microM UDP-glucose also increased the contraction amplitude during EFS in this tissue from the WT animals (0.9+/-0.4 mN, P < 0.05, n=6) but not from the KO mice (0.0+/-0.2 mN, n=6). In vivo, UDP-glucose at 2,000 mg/kg ip reduced gastric emptying in rats by 49.7% (P<0.05, n=4-6) and in WT and KO mice by 56.1 and 66.2%, respectively (P<0.05, n=7-10) vs. saline-treated control animals. There was no significant difference in gastric emptying between WT and KO animals receiving either saline or d-glucose. These results demonstrate a novel function of the P2Y14 receptor associated with contractility in the rodent stomach that does not lead to altered gastric emptying after receptor deletion and an ability of UDP-glucose to delay gastric emptying without involving the P2Y14 receptor.

Chemotherapy treatment can lead to delayed gastric emptying, early satiety, anorexia, nausea and vomiting, described collectively as the cancer-associated dyspepsia syndrome (CADS). Administration of ghrelin (GHRL), an endogenous orexigenic peptide known to stimulate gastric motility, has been shown to reduce the symptoms of CADS induced in relevant animal models with the potent chemotherapeutic agent, cisplatin. We examined the effects in the rat of cisplatin (6 mg/kg i.p.) treatment on the expression of GHRL and ghrelin receptor (GHSR) mRNAs in the hypothalamus and the stomach at a time-point (2 days) when the effects of cisplatin are pronounced. In addition, plasma levels of GHRL (acylated and total including des-acyl GHRL) were measured and the effect on these levels of treatment with the synthetic glucocorticoid dexamethasone (2 mg/kg s.c. bd.) was investigated. Cisplatin increased GHSR mRNA expression in the stomach (67%) and hypothalamus (52%) but not GHRL mRNA expression and increased the percentage of acylated GHRL (7.03+/-1.35% vs. 11.38+/-2.40%) in the plasma. Dexamethasone reduced the plasma level of acylated GHRL and the percentage of acylated GHRL to values below those in animals treated with saline alone (7.03+/-1.35% vs. 2.60+/-0.49%). Our findings support the hypothesis that an adaptive upregulation of the ghrelin receptor may occur during cancer chemotherapy-associated dyspepsia. This may have a role in defensive responses to toxic challenges to the gut. In addition, our results provide preliminary evidence for glucocorticoid modulation of plasma ghrelin levels.

Aim: Consumption of a palatable diet can induce hyperphagia, leading to weight gain (dietary obesity) and insulin resistance in rats. Thiazolidinediones (TZDs) can also induce hyperphagia in rats but conversely have an insulin-sensitizing effect. The aim of this study was to investigate whether preventing TZD-induced hyperphagia (i.e. energy restriction) in dietary obese (DIO) rats would enhance the insulin-sensitizing effects of treatment at a therapeutic dose; and, within this paradigm, to produce an original survey of candidate TZD-gene targets in the clinically relevant visceral white adipose tissue (WAT) depot., Methods: DIO rats that were either freely fed or energy restricted (i.e. pair-fed to the level of untreated controls) were treated with rosiglitazone maleate (RSG; 3 mg/kg/day) for 2 weeks, the restricted group controlling for treatment-induced hyperphagia and weight gain. The outcome measures were circulating concentrations of various biochemical markers of insulin resistance, and gene expression was measured in epididymal WAT., Results: In both freely fed and pair-fed groups, compared to untreated DIO controls, RSG reduced plasma levels of insulin (-29% and -43%; p < 0.05 and p < 0.001, respectively), free fatty acids (FFAs; -45% and -48%; p < 0.01 and p < 0.001, respectively) and triglycerides (TGs; -63% and -72%; both p < 0.001), reflected in improved insulin sensitivity, as measured by homeostasis model assessment (-29% and -43%; p < 0.01 and p < 0.0001). RSG also increased the expression of the fatty acid transport/synthesis genes, fatty acid transport protein (2.4-3.2-fold), epidermal fatty acid-binding protein (FABP; 1.7-2.0-fold), heart FABP (25-29-fold) and fatty acid synthase (2.3-2.9-fold; all p < 0.05) in both groups. Adipocyte FABP was also increased by RSG treatment, but only in combination with energy restriction (1.52-fold; p < 0.05) as was hexokinase II expression (p < 0.001). In contrast, the drug had no effect on expression of several genes associated with lipolysis. Although obesity-induced hyperleptinaemia was normalized only in the energy-restricted group, leptin messenger RNA (mRNA) expression was reduced in both treated groups (all p < 0.01). Resistin and tumour necrosis factor-alpha expression was also reduced, though in the latter case, only with energy restriction (p < 0.05). Other adipokines were unaffected by RSG treatment., Conclusion: Our results clearly show that energy restriction enhances the therapeutic efficacy of TZDs and suggest that this occurs, at least in part, through a modulatory effect on gene expression in visceral WAT. These findings improve our understanding of the underlying mechanistic basis for the clinical usefulness of dietary restriction as an adjunct to TZD therapy in type 2 diabetes.

The G protein-coupled receptors, GPR41 and GPR43, are activated by short-chain fatty acids (SCFAs), with distinct rank order potencies. This study investigated the possibility that SCFAs modulate intestinal motility via these receptors. Luminal SCFA concentrations within the rat intestine were greatest in the caecum (c. 115 mmol L(-1)) and proximal colon. Using similar concentrations (0.1-100 mmol L(-1)), SCFAs were found to inhibit electrically evoked, neuronally mediated contractions of rat distal colon, possibly via a prejunctional site of action; this activity was independent of the presence or absence of the mucosa. By contrast, SCFAs reduced the amplitude but also reduced the threshold and increased the frequency of peristaltic contractions in guinea-pig terminal ileum. In each model, the rank-order of activity was acetate (C2) approximately propionate (C3) approximately butyrate (C4) > pentanoate (C5) approximately formate (C1), consistent with activity at the GPR43 receptor. GPR43 mRNA was expressed throughout the rat gut, with highest levels in the colon. However, the ability of SCFAs to inhibit neuronally mediated contractions of the colon was similar in tissues from wild-type and GPR43 gene knockout mice, with identical rank-orders of potency. In conclusion, SCFAs can modulate intestinal motility, but these effects can be independent of the GPR43 receptor.

Many cancer patients receiving chemotherapy experience fatigue, disturbed circadian rhythms, anorexia and a variety of dyspeptic symptoms including nausea. There is no animal model for this 'chemotherapy-related malaise' so we investigated the behavioural and molecular effects of a potent chemotherapeutic agent, cisplatin (CP, 6 mg/kg, i.p.) in rats. Dark-phase horizontal locomotor activity declined post-CP reaching a nadir on day 3 (P < 0.001), before recovering after 7 days. CP's effect was most marked in the late part (05.00-07.00) of the dark-phase. Food intake reached a nadir (P > 0.001) at 2 days, coincident with an increase in gastric contents (cisplatin 9.04+/-0.8 vs. saline 2.32+/-0.3 g; P < 0.001). No changes occurred in hypothalamic mRNA expression for AGRP, NPY, HCRT, CRH, IL-1, IL-6, TNFalpha, ABCG1, SLC6A4, PPIA and HPRT mRNA but tryptophan hydroxylase (TPH) mRNA was decreased (47%, P < 0.05) at day 21 post-CP. This shows that despite marked behavioural effects of cisplatin, only a discrete change (TPH) was found in hypothalamic mRNA expression and that occurred when the animals' behaviour had recovered. Findings are discussed in relation to the neuropharmacology of chemotherapy-induced malaise.

Glycogen synthase kinase-3 (GSK-3) protein levels and activity are elevated in skeletal muscle in type 2 diabetes, and inversely correlated with both glycogen synthase activity and insulin-stimulated glucose disposal. To explore this relationship, we have produced transgenic mice that overexpress human GSK-3beta in skeletal muscle. GSK-3beta transgenic mice were heavier, by up to 20% (P < .001), than their age-matched controls due to an increase in fat mass. The male GSK-3beta transgenic mice had significantly raised plasma insulin levels and by 24 weeks of age became glucose-intolerant as determined by a 50% increase in the area under their oral glucose tolerance curve (P < .001). They were also hyperlipidemic with significantly raised serum cholesterol (+90%), nonesterified fatty acids (NEFAs) (+55%), and triglycerides (+170%). At 29 weeks of age, GSK-3beta protein levels were 5-fold higher, and glycogen synthase activation (-27%), glycogen levels (-58%) and insulin receptor substrate-1 (IRS-1) protein levels (-67%) were significantly reduced in skeletal muscle. Hepatic glycogen levels were significantly increased 4-fold. Female GSK-3beta transgenic mice did not develop glucose intolerance despite 7-fold overexpression of GSK-3beta protein and a 20% reduction in glycogen synthase activation in skeletal muscle. However, plasma NEFAs and muscle IRS-1 protein levels were unchanged in females. We conclude that overexpression of human GSK-3beta in skeletal muscle of male mice resulted in impaired glucose tolerance despite raised insulin levels, consistent with the possibility that elevated levels of GSK-3 in type 2 diabetes are partly responsible for insulin resistance.

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a critical regulator of adipocyte differentiation. Whilst 15-deoxy-delta(12,14)-prostaglandin J2 (15-d-PGJ2) has been identified as a putative endogenous ligand for this transcription factor, it is unclear whether the enzymes necessary for 15-d-PGJ2 biosynthesis are co-expressed with PPARgamma. Prostaglandin D2 synthase (PGDS) enzymes represent the terminal enzymatic components responsible for 15-d-PGJ2 production. Both glutathione (GSH)-dependent and GSH-independent PGDS isoenzymes exist. We have, therefore, examined the expression of PGDS isoenzymes in mouse 3T3-L1 adipocytes, and various human tissues. The GSH-independent PGDS was found to be expressed in 3T3-L1 cells both before and after their differentiation into adipocytes. By contrast, we were unable to detect expression of the GSH-dependent PGDS at any stage during the adipose conversion of 3T3-L1 cells. Quantitative analysis of mRNA levels for PPARgamma and each PGDS isoenzyme revealed their co-expression in a number of human tissues and cell types, including adipose tissue, placenta, prostate, and macrophages. These data reveal the potential for de novo 15-d-PGJ2 synthesis in the context of PPARgamma expression, suggesting that this prostaglandin may contribute to PPARgamma signalling in vivo.

Expression levels of mRNA are commonly measured as a ratio of test to reference gene. The assumption is that reference genes such as beta-actin or cyclophilin are unaffected by treatment and act as steady-state controls. TaqMan real-time RT-PCR was used to test these assumptions in a rat model of cerebral ischaemia (tMCAO). Following measurement of 24 genes, we show that reference genes in this animal model fail the criteria for steady-state controls. Neuronal loss, glial proliferation and an influx of leukocytes into the lesioned brain result in major disturbance to cell populations. The mRNA for reference genes, as for test genes, reflects these changes. Specific mRNA levels vary according to the choice of reference gene to which they are normalised. In the process of resolving reference gene issues, mRNA increases were discovered for leukaemia inhibitory factor, nestin and galanin in rat brain hemispheres affected by ischaemia. Results are reported for a further 21 genes and mathematical and statistical methods are described that allow in this study fraction-fold changes in mRNA to be detected.

A single dose of the orexin-1 (OX1) receptor antagonist 1-(2-methylbenzoxazol-6-yl)-3-[1,5] naphthyridin-4-yl urea hydrochloride (SB-334867-A) reduces orexin-A-induced feeding and natural feeding in Sprague Dawley rats. In this study, the anti-obesity effects of SB-334867-A were determined in genetically obese (ob/ob) mice dosed with SB-334867-A (30 mg/kg, i.p.) once daily for 7 days, and then twice daily for a further 7 days. SB-334867-A reduced cumulative food intake and body weight gain over 14 days. Total fat mass gain, determined by Dual Emission X-ray Absorptiometry, was reduced, while gain in fat-free mass was unchanged. Fasting (5 h) blood glucose was also reduced at the end of the study, with a trend to reduced plasma insulin. Interscapular brown adipose tissue (BAT) weight was reduced, the tissue was noticeably darker in colour and quantitative PCR (TaqMan) analysis of this tissue showed a trend to an increase in uncoupling protein-1 mRNA expression, suggesting that SB-334867-A might stimulate thermogenesis. This was confirmed in a separate study in which a single dose of SB-334867-A (30 mg/kg, i.p.) increased metabolic rate over 4 h in ob/ob mice. OX1 receptor mRNA was detected in BAT, and its expression was increased by 58% by treatment with SB-334867-A. This is the first demonstration that OX1 receptor antagonists have potential as both anti-obesity and anti-diabetic agents.

In the present report we clarify the role of PPARgamma in differentiation and function of human-derived monocyte/macrophages in vitro. Rosiglitazone, a selective PPARgamma activator, had no effect on the kinetics of appearance of monocyte/macrophage differentiation markers or on cell size or granularity. Depletion of PPARgamma by more than 90% using antisense oligonucleotides did not influence accumulation of oxidized LDL or prevent the upregulation of CD36 that normally accompanies oxLDL treatment. In contrast, PPARgamma depletion reduced the expression of ABCA1 and LXRalpha mRNAs. Metalloproteinase-9 expression, a marker of atherosclerotic plaque vulnerability, was suppressed by rosiglitazone. We conclude that activation of PPARgamma does not affect monocyte/macrophage differentiation. In addition, PPARgamma is not absolutely required for oxLDL-driven lipid accumulation, but is required for full expression of ABCA1 and LXRalpha. Our data support a role for rosiglitazone as a potential directly acting antiatherosclerotic agent.

GSH-dependent prostaglandin D(2) synthase (PGDS) enzymes represent the only vertebrate members of class Sigma glutathione S-transferases (GSTs) identified to date. Complementary DNA clones encoding the orthologous human and rat GSH-dependent PGDS (hPGDS and rPGDS, respectively) have been expressed in Escherichia coli, and the recombinant proteins isolated by affinity chromatography. The purified enzymes were both shown to catalyse specifically the isomerization of prostaglandin (PG) H(2) to PGD(2). Each transferase also exhibited GSH-conjugating and GSH-peroxidase activities. The ability of hPGDS to catalyse the conjugation of aryl halides and isothiocyanates with GSH was found to be less than that of the rat enzyme. Whilst there is no difference between the enzymes with respect to their K(m) values for 1-chloro-2,4-dinitrobenzene, marked differences were found to exist with respect to their K(m) for GSH (8 mM versus 0.3 mM for hPGDS and rPGDS, respectively). Using molecular modelling techniques, amino acid substitutions have been identified in the N-terminal domain of these enzymes that lie outside the proposed GSH-binding site, which may explain these catalytic differences. The tissue-specific expression of PGDS also varies significantly between human and rat; amongst the tissues examined, variation in expression between the two species was most apparent in spleen and bone marrow. Differences in catalytic properties and tissue-specific expression of hPGDS and rPGDS appears to reflect distinct physiological roles for class Sigma GST between species. The evolution of divergent functions for the hPGDS and rPGDS is discussed in the context of the orthologous enzyme from chicken.

The diverse biological actions of extracellular nucleotides in tissues and cells are mediated by two distinct classes of P2 receptor, P2X and P2Y. The G protein-coupled P2Y receptors comprise at least six mammalian subtypes (P2Y(1,2,4,6,11,12)), all of which have been cloned from human tissues, as well as other species. The P2Y receptor subtypes differ in their pharmacological selectivity for various adenosine and uridine nucleotides, which overlap in some cases. Data concerning the mRNA expression patterns of five P2Y receptors (P2Y(1,2,4,6,11)) in different human tissues and cells are currently quite limited, while P2Y mRNA distribution in the human brain has not previously been studied. In this study, we have addressed this deficiency in receptor expression data by using a quantitative reverse transcription-polymerase chain reaction approach to measure the precise mRNA expression pattern of each P2Y receptor subtype in a number of human peripheral tissues and brain regions, from multiple individuals, as well as numerous human cell lines and primary cells. All five P2Y receptors exhibited widespread yet subtype-selective mRNA expression profiles throughout the human tissues, brain regions and cells used. Our extensive expression data indicate the many potentially important roles of P2Y receptors throughout the human body, and will help in elucidating the physiological function of each receptor subtype in a wide variety of human systems.

A recent hypothesis concerning the function of uncoupling protein-3 (UCP-3) depends upon a positive relationship with mitochondrial thioesterase (MTE-1) in situations where fatty acid beta-oxidation is increased. MTE-1 mRNA levels are raised in transgenic mice overexpressing UCP-3 in skeletal muscle and we sought to extend these findings by quantifying in vivo expression of endogenous MTE-1, UCP-1, UCP-2, and UCP-3 mRNA levels in white adipose tissue, interscapular brown adipose tissue, and skeletal muscle in db/db mice. In this study we show that changes in MTE-1 mRNA levels as a result of differences between db/db vs db/+ mice or following long-term treatment of db/db mice with rosiglitazone or Wy-14,643 were more closely correlated with changes in UCP-3 than either UCP-1 or UCP-2 mRNA levels in the tissues examined. The present data contribute to the argument that UCP-3 and MTE-1 are linked within the same metabolic pathway either in response to, or as regulators of, fatty acid beta-oxidation., (Copyright 2001 Academic Press.)

The precise mechanism by which PPARgamma activation by thiazolidinediones (TZDs) improves insulin sensitivity is still unclear. Recent studies have focused on the role of adipocytokines in metabolic control and their regulation by TZDs. In this study, we compared the chronic effects of antihyperglycemic doses of the TZD rosiglitazone, the beta3-adrenoceptor agonist BRL-35135, and the PPARalpha agonist Wy-14,643 on the mRNA expression of adipocytokines in WAT of db/db mice. Rosiglitazone treatment decreased adiponectin and resistin mRNA levels by 57 and 72%, respectively (P < 0.001), with no effect on the level of TNFalpha or RELMalpha transcripts. In comparison, Wy-14,643 reduced adiponectin transcript levels by 31% (P = 0.015) while BRL-35135 increased RELMalpha mRNA expression by 245% (P < 0.001) without effect on the other transcripts. Our results indicate that although a reduction in adiponectin and resistin mRNA levels in WAT by rosiglitazone treatment of diabetic mice may contribute to the antidiabetic effects, an alteration in TNFalpha, adiponectin, resistin, or RELMalpha mRNA expression is not absolutely required for the regulation of blood glucose concentration in the db/db mouse., (Copyright 2001 Academic Press.)

Mice overexpressing human UCP-3 in skeletal muscle (UCP-3tg) are lean despite overeating, have increased metabolic rate, and their skeletal muscle mitochondria show increased proton conductance. The true function of UCP-3 however, has yet to be determined. It is assumed that UCP-3tg mice have increased fatty acid beta-oxidation to fuel their increased metabolic rate. In this study we have quantified skeletal muscle mRNA levels of a number of genes involved in fatty acid metabolism. mRNA levels of uncoupling protein-2, carnitine palmitoyl transferase-1beta and fatty acid binding proteins, and transporters were unchanged when compared to wild-type mice. Lipoprotein lipase mRNA was slightly, but significantly, increased by 50%. The most notable change in gene expression was a threefold increase in mitochondrial thioesterase (MTE-1) expression. In the face of a chronic increase in mitochondrial uncoupling these changes suggest that increased flux of fatty acids through the beta-oxidation pathway does not necessarily require marked changes in expression of genes involved in fatty acid metabolism. The large increase in MTE-1 both confirms the importance of this gene in situations where mitochondrial beta-oxidation is increased and supports the hypothesis that UCP-3 exports fatty acids generated by MTE-1 in the mitochondrion., (Copyright 2001 Academic Press.)

Uncoupling protein-3 (UCP-3) is a recently identified member of the mitochondrial transporter superfamily that is expressed predominantly in skeletal muscle. However, its close relative UCP-1 is expressed exclusively in brown adipose tissue, a tissue whose main function is fat combustion and thermogenesis. Studies on the expression of UCP-3 in animals and humans in different physiological situations support a role for UCP-3 in energy balance and lipid metabolism. However, direct evidence for these roles is lacking. Here we describe the creation of transgenic mice that overexpress human UCP-3 in skeletal muscle. These mice are hyperphagic but weigh less than their wild-type littermates. Magnetic resonance imaging shows a striking reduction in adipose tissue mass. The mice also exhibit lower fasting plasma glucose and insulin levels and an increased glucose clearance rate. This provides evidence that skeletal muscle UCP-3 has the potential to influence metabolic rate and glucose homeostasis in the whole animal.

Objectives: To determine the effects of obesity on fasting plasma leptin levels and assess the effects of feeding on plasma leptin and OB gene expression in subcutaneous adipose tissue in non-diabetic subjects., Design: Blood and subcutaneous adipose tissue needle biopsy samples were obtained after an overnight fast and 1, 2 and 3 h following a mixed meal (606 kcal)., Subjects: Eighteen female subjects: eight lean with a mean age of 40.1 yr (range 20-65) and mean body mass index of 22.24 kg/m2 (range 18.6-26.6) and ten obese subjects with a mean age of 48.6 yr (range 29-71) and body mass index of 33.53 kg/m2 (range 28.7-41.7)., Results: Apart from obesity the only significant difference between groups was a 2.6 fold higher fasting plasma leptin concentration in obese subjects compared to leans (26.9 +/- 2.9 vs 10.2 +/- 2.22 (P < 0.05) respectively). Adipose tissue OB mRNA levels were not significantly higher in the obese group. Plasma leptin correlated with BMI and visceral fat weight in lean subjects only. No significant association between plasma leptin and adiposity was evident in obese patients. In addition, there was no association between plasma leptin and the insulin: glucose ratio (an index of insulin sensitivity). Following a mixed meal, post-prandial plasma insulin levels were significantly increased, with a concomitant significant reduction in plasma NEFA levels in both groups. Despite the large increase in plasma insulin, there were no post-prandial changes in either plasma leptin concentrations or subcutaneous adipose tissue OB mRNA levels in either lean or obese subjects., Conclusions: The data indicate that plasma leptin levels are correlated with the degree of adiposity, especially in lean subjects, and confirm that circulating leptin levels are greater in obese subjects than lean subjects. The present study also failed to show a significant association between plasma leptin and insulin sensitivity in lean and obese women. Furthermore, plasma leptin and subcutaneous adipose tissue OB gene expression are not under short term regulation following feeding in fasted lean or obese female subjects.

The effects of the thiazolidinedione insulin sensitiser BRL 49653 on plasma leptin concentrations and on epididymal fat OB, PPAR-gamma and aP2 mRNA expression were examined in high-fat-fed and high-carbohydrate-fed adult Wistar rats. Diets were given for 4 weeks, with BRL 49653 (10 micromol/kg/day) administered by oral gavage for the last 4 days. Treatment with BRL 49653 reduced plasma leptin concentrations in high-fat-fed rats from 2.34 +/- 0.19 (n=9) to 1.42 +/- 0.09 (n=9) ng/ml (p<0.001). Plasma leptin was unaffected by BRL 49653 in the high-carbohydrate-fed rats. There was no difference in OB mRNA expression between high-fat-fed and high-carbohydrate-fed rats, with or without treatment. PPAR-gamma and aP2 mRNA expression were significantly increased in the high-fat-fed rats treated with BRL 49653 (p < 0.01 and p < 0.001 respectively), but not in carbohydrate-fed rats.

HMOs and other network-based health plans are harnessing the power of information--building integrated data infrastructures to meet the needs of members, caregivers, and employers.

Turnover of employees is a natural event. It is sometimes a relief when a particular employee leaves the office. On the other hand, the cost of losing any employee can be high because of the costs related to lost productivity, training, and the time required for recruiting a replacement. Because of these cost elements, it makes sense to try to delay an employee's departure. By "buying time," the manager can minimize the time required to recruit a replacement and possibly even redistribute the workload among current employees before the job-hunting employee leaves the organization. This approach allows the manager to control the situation. Sometimes it is better to let the employee leave immediately upon submitting a resignation if this will avoid disruption in work flow or the "chemistry" among the rest of the employees. Some employees become negative in their behavior patterns once they decide to leave the organization. The knowledge that an employee is looking for a new position is vitally important information to a manager. The clues provided by the job-hunting employee can go a long way toward maintaining the stability of the work force and the effectiveness of the manager in achieving the goals of the organization.

Background: Human papilloma virus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) is rising in prevalence and is associated with better survival than HPV-negative OPSCC. In surgically treated HPV-negative OPSCCs, adverse pathologic features such as positive surgical margins, extra-nodal extension (ENE) and perineural invasion are well described to portend worse clinical outcomes. These adverse pathological features, however, are not validated prognostic markers among surgically treated HPV-positive OPSCCs. To that end, we pooled all available evidence to address the prognostic significance of these histologic features., Patients and Methods: This meta-analysis was performed according to PRISMA guidelines. PubMed, Web of Science and Embase databases were systematically searched for articles evaluating 13 known adverse histopathological prognostic factors of surgically treated HPV-associated OPSCC. Data analysis was done using R v4.0.5., Results: A total of 32 studies (n = 31,535) fulfilled the inclusion criteria. ENE and advanced pT stage were associated with poorer overall survival (OS) [hazard ratio (HR):1.80, 95% confidence interval (CI) [1.59-2.03], p < 0.0001, HR: 3.28, 95% CI [2.20-4.87], p = 0.0025]; disease-specific survival (DSS) (HR: 3.14, 95% CI [1.20-8.26], p = 0.0327, HR: 3.49, 95% CI [2.45-4.96], p = 0.0043) and disease-free survival (DFS) (HR: 2.03, 95% CI [1.05-3.94], p = 0.0397, HR: 3.66, 95% CI [2.81-4.77], p = 0.0001) respectively. The presence of lymphovascular invasion (HR: 1.46, 95% CI [1.22-1.75], p = 0.0018) and positive margins (HR: 1.50, 95% CI [1.185-1.899], p = 0.0069) significantly worsen OS., Conclusion: ENE, advanced pT stage, positive margins and lymphovascular invasion were adverse histologic prognostic marker among surgically treated HPV-positive OPSCC. The presence of these factors should be carefully evaluated in order to select the optimal patients for surgical treatment., (© 2024. Society of Surgical Oncology.)

Background: Despite the important role of the Aesthetic Plastic Surgery (APS) journal in the field of aesthetic plastic surgery, there is a notable absence of literature that focuses exclusively on the bibliometric analysis of this journal. In recognition of APS's 48 years of publishing, this study aims to perform a bibliometric analysis of the articles published in the APS (1976-2023)., Methods: Articles published in the APS were extracted from the Web of Science Core Collection database. VOSviewer was employed to perform bibliometric analyses. Microsoft Excel was utilized to analyse the publication and citation trends., Results: From 1976 to 2023, 5134 articles were published in the APS. These articles were contributed by 12,963 researchers from 3354 institutions across 91 countries. The USA and China were the leading contributors. The most prolific author is Luan Jie from China. The co-citation networks highlighted the influence of the journal Plastic and Reconstructive Surgery. We categorized the articles into four groups, and the results show that articles with the highest publications and citations in the APS are related to facial cosmetic surgery. In terms of specific surgical procedures, breast augmentation surgery has garnered consistent attention from researchers over the past 48 years, ranking first in both the number of publications and citations., Conclusion: The findings of this study indicate that the APS is a significant scientific journal, is widely utilized by global researchers in the field of aesthetic plastic surgery, and spans diverse knowledge domains., Level of Evidence V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 ., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature and International Society of Aesthetic Plastic Surgery.)

Background and Objectives: Dual amylin and calcitonin receptor agonists (DACRAs) are therapeutic candidates in the treatment of obesity with beneficial effects on weight loss superior to suppression of food intake. Hence, suggesting effects on energy expenditure by possibly targeting mitochondria in metabolically active tissue., Methods: Male rats with HFD-induced obesity received a DACRA, KBP-336, every third day for 8 weeks. Upon study end, mitochondrial respiratory capacity (MRC), - enzyme activity, - transcriptional factors, and -content were measured in perirenal (pAT) and inguinal adipose tissue. A pair-fed group was included to examine food intake-independent effects of KBP-336., Results: A vehicle-corrected weight loss (23.4 ± 2.8%) was achieved with KBP-336, which was not observed to the same extent with the food-restricted weight loss (12.4 ± 2.8%) (P < 0.001). Maximal coupled respiration supported by carbohydrate and lipid-linked substrates was increased after KBP-336 treatment independent of food intake in pAT (P < 0.01). Moreover, oligomycin-induced leak respiration and the activity of citrate synthase and β-hydroxyacetyl-CoA-dehydrogenase were increased with KBP-336 treatment (P < 0.05). These effects occurred without changes in mitochondrial content in pAT., Conclusions: These findings demonstrate favorable effects of KBP-336 on MRC in adipose tissue, indicating an increased energy expenditure and capacity to utilize fatty acids. Thus, providing more mechanistic insight into the DACRA-induced weight loss., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Cisplatin is a widely used antineoplastic drug. However, cisplatin-induced dyspepsia syndromes, including delayed gastric emptying, gastric distension, early satiety, nausea, and vomiting, often force patients to take doses lower than those prescribed or even refuse treatment. D-methionine has an appetite-enhancing effect and alleviates weight loss during cisplatin treatment., Methods: This work established a model of anorexia and dyspepsia symptoms with intraperitoneal injection of cisplatin (5 mg/kg) once a week for three cycles. Presupplementation with or without D-methionine (300 mg/kg) was performed. Orexigenic and anorexigenic hormones (ghrelin, leptin, and glucagon-like peptide-1), tryptophan hydroxylase 1 (TPH1), 5-hydroxytryptamine receptors (5-HT 2C and 5-HT 3 ), and hypothalamic feeding-related peptides were measured by immunohistochemistry staining, enzyme-linked immunosorbent assay, and real-time PCR assay., Key Results: Cisplatin administration caused marked decrease in appetite and body weight, promoted adipose and fat tissue atrophy, and delayed gastric emptying and gastric distension, and D-methionine preadministration prior to cisplatin administration significantly ameliorated these side effects. Besides, cisplatin induced an evident increase in serum ghrelin level, TPH1 activity, and 5-HT 3 receptor expression in the intestine and decreased plasma leptin levels and gastric ghrelin mRNA gene expression levels. D-methionine supplementation recovered these changes. The expression of orexigenic neuropeptide Y/agouti-related peptide and anorexigenic cocaine- and amphetamine-regulated transcript proopiomelanocortin neurons were altered by D-methionine supplementation in cisplatin-induced anorexia rats., Conclusions and Inferences: D-methionine supplementation prevents cisplatin-induced anorexia and dyspepsia syndrome possibly by attenuating intestinal tryptophan hydroxylase 1 activity and increasing plasma leptin concentration. Therefore, D-methionine can be used as an adjuvant therapy for treating cisplatin-induced adverse effects., (© 2020 John Wiley & Sons Ltd.)

The action of protein kinases and protein phosphatases is essential for multiple physiological responses. Each protein kinase displays its own unique substrate specificity and a regulatory mechanism that may be modulated by association with other proteins. Protein kinases are classified as dual-specificity kinases and dual-specificity phosphatases. Dual-specificity phosphatases are important signal transduction enzymes that regulate various cellular processes in coordination with protein kinases and play an important role in obesity. Impairment of insulin signaling in obesity is largely mediated by the activation of the inhibitor of kappa B-kinase beta and the c-Jun N-terminal kinase (JNK). Oxidative stress and endoplasmic reticulum (ER) stress activate the JNK pathway which suppresses insulin biosynthesis. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) are important for proper regulation of glucose metabolism in mammals at both the hormonal and cellular levels. Additionally, obesity-activated calcium/calmodulin dependent-protein kinase II/p38 suppresses insulin-induced protein kinase B phosphorylation by activating the ER stress effector, activating transcription factor-4. To alleviate lipotoxicity and insulin resistance, promising targets are pharmacologically inhibited. Nifedipine, calcium channel blocker, stimulates lipogenesis and adipogenesis by downregulating AMPK and upregulating mTOR, which thereby enhances lipid storage. Contrary to the nifedipine, metformin activates AMPK, increases fatty acid oxidation, suppresses fatty acid synthesis and deposition, and thus alleviates lipotoxicity. Obese adults with vascular endothelial dysfunction have greater endothelial cells activation of unfolded protein response stress sensors, RNA-dependent protein kinase-like ER eukaryotic initiation factor-2 alpha kinase (PERK), and activating transcription factor-6. The transcriptional regulation of adipogenesis in obesity is influenced by AGC (protein kinase A (PKA), PKG, PKC) family signaling kinases. Obesity may induce systemic oxidative stress and increase reactive oxygen species in adipocytes. An increase in intracellular oxidative stress can promote PKC-β activation. Activated PKC-β induces growth factor adapter Shc phosphorylation. Shc-generated peroxides reduce mitochondrial oxygen consumption and enhance triglyceride accumulation and lipotoxicity. Liraglutide attenuates mitochondrial dysfunction and reactive oxygen species generation. Co-treatment of antiobesity and antidiabetic herbal compound, berberine with antipsychotic drug olanzapine decreases the accumulation of triglyceride. While low-dose rapamycin, metformin, amlexanox, thiazolidinediones, and saroglitazar protect against insulin resistance, glucagon-like peptide-1 analog liraglutide inhibits palmitate-induced inflammation by suppressing mTOR complex 1 (mTORC1) activity and protects against lipotoxicity., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Objective: To determine the cost-effectiveness of surveillance imaging with PET/CT scan among patients with human papillomavirus-positive oropharyngeal squamous cell carcinoma., Study Design: Cost-effectiveness analysis., Setting: Oncologic care centers in the United States with head and neck oncologic surgeons and physicians., Methods: We compared the cost-effectiveness of 2 posttreatment surveillance strategies: clinical surveillance with the addition of PET/CT scan versus clinical surveillance alone in human papillomavirus-positive oropharyngeal squamous cell carcinoma patients. We constructed a Markov decision model which was analyzed from a third-party payer's perspective using 1-year Markov cycles and a 30-year time horizon. Values for transition probabilities, costs, health care utilities, and their studied ranges were derived from the literature., Results: The incremental cost-effectiveness ratio for PET/CT with clinical surveillance versus clinical surveillance alone was $89,850 per quality-adjusted life year gained. Flexible fiberoptic scope exams during clinical surveillance would have to be over 51% sensitive or PET/CT scan cost would have to exceed $1678 for clinical surveillance alone to be more cost-effective. The willingness-to-pay threshold at which imaging surveillance was equally cost-effective to clinical surveillance was approximately $80,000/QALY., Conclusion: Despite lower recurrence rates of human papillomavirus-positive oropharyngeal cancer, a single PET/CT scan within 6 months after primary treatment remains a cost-effective tool for routine surveillance when its cost does not exceed $1678. The cost-effectiveness of this strategy is also dependent on the clinical surveillance sensitivity (flexible fiberoptic pharyngoscopy), and willingness-to-pay thresholds which vary by country., (© 2023 The Authors. Otolaryngology-Head and Neck Surgery published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngology-Head and Neck Surgery Foundation.)

Objective: To survey members of the otolaryngology community about their personal and observed experiences of being treated differently because of one's physical attributes, cultural norms, or preferences in the workplace., Study Design: Cross-sectional survey., Setting: International Electronic Survey., Methods: We invited members of the international otolaryngology community including 3 European or American otorhinolaryngological Societies to complete a survey about personal/observed experience of differential treatment in the workplace related to age, biological sex; disability, gender identity, language proficiency, military experience, citizenship, ethnicity/race, political belief, and sexual orientation. Results were analyzed according to participant ethnicity/race (white vs non-white) and gender (male vs female) RESULTS: Four hundred seven participants completed the evaluations: 301 white (74%) and 106 non-white (26%) participants. Non-white participants reported significantly more experiences of differential treatment (microaggressions) than white participants (p < .05). Non-white participants more frequently felt that they needed to work harder for the same opportunities as their peers and were more likely to consider leaving a position because of an unsupportive environment. In general, females reported more frequent experiences with differential treatment related to sexual orientation, biological sex, and gender identity than males., Conclusion: We recognized reports of differential treatment as a proxy for microaggressions. Non-white members of the otolaryngology community self-report experiencing or observing more microaggressions than white members in the workplace. Acknowledging the existence and impact of microaggressions in the field of Otolaryngology is the first step towards cultivating an inclusive, diverse workforce where all members feel supported, validated, and welcomed., (© 2023 American Academy of Otolaryngology-Head and Neck Surgery Foundation.)

Migraine is a debilitating disorder that afflicts over 1 billion people worldwide, involving attacks that result in a throbbing and pulsating headache. Migraine is thought to be a neurovascular event associated with vasoconstriction, vasodilation, and neuronal activation. Understanding signaling in migraine pathology is central to the development of therapeutics for migraine prophylaxis and for mitigation of migraine in the prodrome phase before pain sets in. The fact that both vasoactivity and neural sensitization are involved in migraine indicates that agonists which promote these phenomena may very well be involved in migraine pathology. One such group of agonists is the purines, in particular, adenosine phosphates and their metabolites. This manuscript explores what is known about the relationship between these metabolites and migraine pathology and explores the potential for such relationships through their known signaling pathways. Reported receptor involvement in vasoaction and nociception., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Polycystic ovary syndrome (PCOS) is a common condition in reproductive-aged women that induces reproductive and metabolic derangements. Women with PCOS seem to have disturbances in lipid metabolism in the adipose tissue. Nevertheless, gene expression in adipose tissue of PCOS women and its relation to other disturbances have been fragmentarily investigated. We utilized microarray data to identify the most important up- and down-regulated candidate genes in adipose tissue of PCOS women in contrast to healthy women using the meta-analysis technique. Microarray data produced from three independent experiments (n = 3) conducted on adipose tissue in women with PCOS were retrieved from ArrayExpress. Then, the datasets were merged using the metaSeq package in Rstudio and differentially expressed genes (DEGs) were selected in the studies. The integrative bioinformatics analyses of candidate genes were performed by gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and protein-protein interaction (PPI) network construction. Of these, 12 up-regulated genes and 12 down-regulated genes were identified and assessed as the most highly up-regulated and down-regulated genes in adipose tissue of women with PCOS. These DEGs that were annotated by KEGG analysis were mainly involved in PI3K-Akt, MAPK, Rap1, and Ras signaling pathways, and pathways in cancer such as hepatocellular carcinoma and gastric cancer, as well as metabolic pathways, and brain disorder pathways such as Alzheimer's disease and Huntington disease pathways. In the PPI networks, PRDM10, FGFR2, IGF1R, and FLT1 were the key nodes in the up-regulated networks, while the NDUFAB1 and NME2 proteins were key in the down-regulated networks. Overall, these findings provide insight into the gene expression in adipose tissue of PCOS women and its relation to other disturbances., (© 2022. The Author(s), under exclusive licence to Society for Reproductive Investigation.)

Purpose of Review: Excellent outcomes following contemporary treatment of human papillomavirus (HPV)-positive oropharyngeal carcinoma (HPV+ OPC) have prompted the exploration of deintensification approaches to minimize treatment-related toxicities. This review describes the landscape of deintensification to date (up to November 2022)., Recent Findings: Although several deintensification trials have been published, none are practice changing. Three phase III randomized-controlled trials studying cetuximab and radiation therapy vs. standard chemoradiotherapy all showed inferior outcomes. Although some phase II trials reported favourable outcomes, they are often single-arm trials without an adequate control arm, thereby limiting the ability to modify practice., Summary: Substantial effort has been expended to explore deintensification options for selected HPV+ OPC patients aiming to avoid unnecessary toxicity. Strategies have included replacing cisplatin with cetuximab, reduced chemotherapy or radiotherapy intensity, reduction of radiotherapy volumes and risk stratification after trans-oral surgery or following induction chemotherapy. Challenges remain in the current deintensification landscape, including identifying the most suitable candidates along with a choice of most appropriate deintensification strategies. Promising selection criteria included either static baseline features or kinetic characteristics of clinical-biological parameters. Practice-changing trials remain elusive, and the search continues to attempt optimization of the therapeutic ratio for these patients., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Uncoupling protein-3 (UCP3) is a mitochondrial transmembrane protein highly expressed in the muscle that has been implicated in regulating the efficiency of mitochondrial oxidative phosphorylation. Increasing UCP3 expression in skeletal muscle enhances proton leak across the inner mitochondrial membrane and increases oxygen consumption in isolated mitochondria, but its precise function in vivo has yet to be fully elucidated. To examine whether muscle-specific overexpression of UCP3 modulates muscle mitochondrial oxidation in vivo, rates of ATP synthesis were assessed by 31 P magnetic resonance spectroscopy (MRS), and rates of mitochondrial oxidative metabolism were measured by assessing the rate of [2- 13 C]acetate incorporation into muscle [4- 13 C]-, [3- 13 C]-glutamate, and [4- 13 C]-glutamine by high-resolution 13 C/ 1 H MRS. Using this approach, we found that the overexpression of UCP3 in skeletal muscle was accompanied by increased muscle mitochondrial inefficiency in vivo as reflected by a 42% reduction in the ratio of ATP synthesis to mitochondrial oxidation., (© 2022 Federation of European Biochemical Societies.)

Purpose: The effect of manipulating the fatty acid profile of the diet over generations could affect the susceptibility to develop obesity and metabolic disorders. Although some acute effects were described, the impact of transgenerational continuous supplementation with omega 3 fatty acids on metabolic homeostasis and skeletal muscle metabolic flexibility during a nutritional stress is unknown., Methods: We analyzed the effect of an obesogenic diet in mice after transgenerational supplementation with an omega-3 rich oil (mainly EPA) or a control oil. Young F3 animals received a high fat and high sucrose diet for 4 months. Whole-body biometric data were recorded and lipidomic/transcriptomic adaptations were explored in the skeletal muscle., Results: F3 mice from the lineage supplemented with EPA gained less weight, fat mass, and exhibited better metabolic parameters after the obesogenic diet compared to mice from the control lineage. Transcriptomic exploration of skeletal muscle showed differential regulation of biological processes such as fibrosis, fatty acid catabolism, and inflammation between lineages. These adaptations were associated to subtle lipid remodeling of cellular membranes with an enrichment in phospholipids with omega 3 fatty acid in mice from the EPA lineage., Conclusion: Transgenerational and continuous intake of EPA could help to reduce cardiovascular and metabolic risks related to an unbalanced diet by the modulation of insulin sensitivity, fatty acid metabolism, and fibrosis in skeletal muscle., (© 2021. Springer-Verlag GmbH, DE part of Springer Nature.)

Background: The oncologic outcomes of surgery alone for patients with American Joint Committee on Cancer 7th edition (AJCC 7th) pN2a and pN2b human papillomavirus-associated oropharynx squamous cell carcinoma (HPV+OPSCC) are not clear., Methods: The authors performed a 12-institution retrospective study of 344 consecutive patients with HPV+OPSCC (AJCC 7th pT0-3 N3 M0) treated with surgery alone with 6 months or more of follow-up using univariate and multivariate analyses., Results: The 2-year outcomes for the entire cohort were 91% (182 of 200) disease-free survival (DFS), 100% (200 of 200) disease-specific survival (DSS), and 98% (200 of 204) overall survival (OS). The 18 recurrences within 2 years were 88.9% (16 of 18) local and/or regional recurrences and 11.1% (2 of 18) distant metastases. Recurrences were not significantly associated with smoking, pT stage, or pN stage. The 16 patients with locoregional recurrences within 2 years all underwent successful salvage treatments (median follow-up after salvage: 13.1 months), 43.8% (7 of 16) of whom underwent salvage surgery alone for a 2-year overall salvage radiation need of 4.5% (9 of 200). The 2-year outcomes for the 59 evaluable patients among the 109 AJCC 7th pT0-2 N2a-N2b patients with 1 to 3 pathologic lymph nodes (LNs) were as follows: local recurrence, 3.4% (2 of 59); regional recurrence, 8.4% (5 of 59); distant metastases, 0%; DFS, 88.1% (52 of 59); DSS, 100% (59 of 59); OS, 96.7% (59 of 61); and salvage radiation, 5.1% (3 of 59)., Conclusions: With careful selection, surgery alone for AJCC 7th pT0-T2N0-N2b HPV+OPSCC with zero to 3 pathologic LNs without perineural invasion, extranodal extension, or positive margins results in high DFS, DSS, OS, and salvage treatment success. Because of the short-term follow-up, these data support further investigation of treatment de-escalation in this population., (© 2021 American Cancer Society.)

Background: Cisplatin is an antineoplastic drug known to produce intense vomiting, gastric dysmotility, and peripheral neuropathy. Monosodium glutamate (MSG) is a flavor enhancer with prokinetic properties potentially useful for cancer patients under chemotherapy. Our aim was to test whether MSG may improve gastrointestinal motor dysfunction and other adverse effects induced by repeated cisplatin in rats., Methods: Male Wistar rats were exposed or not to MSG (4 g L -1 ) in drinking water from week 0 to 1 week after treatment. On the first day of weeks 1-5, rats were treated with saline or cisplatin (2 mg kg -1  week -1 , ip). Gastrointestinal motility was measured by radiological methods after first and fifth administrations, as well as 1 week after treatment finalization. One week after treatment, the threshold for mechanical somatic sensitivity was recorded. Finally, samples of stomach, terminal ileum and kidneys were evaluated in sections using conventional histology. The myenteric plexus was immunohistochemically evaluated on distal colon whole-mount preparations., Key Results: Monosodium glutamate prevented the development of cisplatin-induced neuropathy and partially improved intestinal transit after the fifth cisplatin administration with little impact on gastric dysmotility. MSG did not improve the histological damage of gut wall, but prevented the changes induced by cisplatin in the colonic myenteric plexus., Conclusion and Inferences: Our results suggest that MSG can improve some dysfunctions caused by anticancer chemotherapy in the gut and other systems, associated, at least partially, with neuroprotectant effects. The potentially useful adjuvant role of this food additive to reduce chemotherapy-induced sequelae warrants further evaluation., (© 2020 John Wiley & Sons Ltd.)

The synaptic event called the inhibitory junction potential (IJP) was arguably one of the more important discoveries made by Burnstock and arguably one of his finer legacies. The discovery of the IJP fundamentally changed how electromechanical coupling was visualised in gastrointestinal smooth muscle. Its discovery also set in motion the search for novel inhibitory neurotransmitters in the enteric nervous system, eventually leading to proposal that ATP or a related nucleotide was a major inhibitory transmitter. The subsequent development of purinergic signalling gave impetus to expanding the classification of surface receptors for extracellular ATP, not only in the GI tract but beyond, and then led to successive phases of medicinal chemistry as the P2 receptor field developed. Ultimately, the discovery of the IJP led to the successful cloning of the first P2Y receptor (chick P2Y1) and expansion of mammalian ATP receptors into two classes: metabotropic P2Y receptors (encompassing P2Y1, P2Y2, P2Y4, P2Y6, P2Y11-14 receptors) and ionotropic P2X receptors (encompassing homomeric P2X1-P2X7 receptors). Here, the causal relationship between the IJP and P2Y1 is explored, setting out the milestones reached and achievements made by Burnstock and his colleagues.

Background: The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has increased substantially in recent decades, particularly p16-positive human papillomavirus (HPV)-related OPSCC, which has risen by 50% in western countries. HPV-positivity is the most favourable non-anatomic predictor of oropharyngeal cancer outcomes, which underscores the importance of incorporating this variable into the cancer staging system., Methods: In the present article, we review the differences between the 7th and 8th editions of the AJCC staging system, with particular focus on the role of HPV-positivity in patients with head and neck cancer., Results: In the previous edition (7th edition) of the AJCC/UICC manual, HPV status and its correlation with nodal metastasis were not considered, thereby leading to incorrect lymph node (N) staging and, potentially, inadequate treatment and worse outcomes. The 8th edition of the AJCC manual addresses these issues, providing more accurate discrimination between groups and better risk stratification in patients with HPV-positive OPSCC. In the future, additional adjustments are likely to be needed, such as unification of the pathological and clinical staging models., Conclusions: The new staging system is substantially more accurate than the previous system and should be widely adopted in routine clinical practice.