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Background. The authors conducted a prospective cohort study to determine whether poor glycemic control is a contraindication to implant therapy in patients with type 2 diabetes. Methods. The study sample consisted of 117 edentulous patients, each of whom received two mandibular implants, for a total of 234 implants. Implant-retained mandibular overdentures were loaded after a four-month healing period and followed up for an additional one year. The authors assessed implant survival and stability (by means of resonance frequency analysis) relative to glycated hemoglobin A1c (HbA1c) levels, with baseline levels up to 11.1 percent and levels as high as 13.3 percent over one year. Results. Implant survival rates for 110 of 117 patients who were followed up for one year after loading were 99.0 percent, 98.9 percent and 100 percent, respectively, for patients who did not have diabetes (n = 47), those with well-controlled diabetes (n = 44) and those with poorly controlled diabetes (n = 19). The authors considered the seven patients lost to follow-up as having had failed implants; consequently, their conservative estimates of survival rates in the three groups were 93.0 percent, 92.6 percent and 95.0 percent (P = .6510). Two implants failed at four weeks, one in the nondiabetes group and the other in the well-controlled diabetes group. Delays in implant stabilization were related directly to poor glycemic control. Conclusions. The results of this study indicate that elevated HbA1c levels in patients with type 2 diabetes were not associated with altered implant survival one year after loading. However, alterations in early bone healing and implant stability were associated with hyperglycemia. Practical Implications. Within the clinical parameters of this study, the findings indicate likely implant success among patients with type 2 diabetes who lacked good glycemic control. Further investigation, including longer-term evaluation, is needed. [ABSTRACT FROM AUTHOR]

Background. Type 2 diabetes mellitus (T2DM) is a growing health problem worldwide. People with T2DM are at risk of experiencing periodontitis and likely require treatment. Using data from the national multicenter Diabetes and Periodontal Therapy Trial (DPTT), the authors assessed patient-based characteristics associated with the clinical response to nonsurgical therapy. Methods. The DPTT investigators randomly assigned adults with T2DM (hemoglobin A1c [HbA1c] ≥ 7 percent and < 9 percent) and moderate to advanced periodontitis to receive immediate or delayed therapy (scaling and root planing, oral hygiene instruction, chlorhexidine rinse). The investigators assessed probing depth (PD), clinical attachment level (CAL), bleeding on probing (BOP), and medical conditions at baseline, three months and six months. Six-month changes in mean PD, CAL and BOP defined the treatment response. Complete data were available for 473 of 514 DPTT participants. The authors used multiple regression models to evaluate participant-level factors associated with the response. Results. More severe baseline PD, CAL and BOP were associated with greater improvements in these same measurements (P < .0001). Hispanic participants experienced greater improvements in PD and CAL than did non-Hispanic participants (P < .0001). Obese participants (those with a body mass index > 30 kilograms per square meter) experienced greater reductions in PD and BOP than did participants who were not obese (P < .001). Age, sex, HbA1c values, diabetes duration, and smoking were not associated with change in any outcome (P > .1). Conclusions. In patients with T2DM, baseline disease severity was associated with the clinical response to nonsurgical periodontal therapy Body mass index and Hispanic ethnicity--but not glycemic control, diabetes duration or smoking--also may be useful in predicting clinical changes in this population. Practical Implications. These findings could help clinicians identify patients with T2DM who may or may not respond well to initial periodontal treatment. [ABSTRACT FROM AUTHOR]

Background: Intracellular signaling pathways mediate specific responses to growth factors. The manipulation of these pathways ultimately may be used to control the clinical outcomes of periodontal regenerative therapy. The purpose of this study was to examine the role of the p38 signal transduction pathway in the responses of periodontal cells to platelet-derived growth factor-BB (PDGF).Methods: Primary cultures of human periodontal ligament cells (PDLs) and gingival fibroblasts (GFs) were used for all experiments. Cell numbers, 3H-thymidine incorporation, and Boyden chamber assays were used to characterize the effects of SB 203580 (SB), a specific inhibitor of the p38 signaling pathway, on cell proliferation and migration. An in vitro wound model also was used to assess the effects of SB. For the in vitro wound assay, triplicate wells were incubated for 1, 3, 5, and 7 days using 0.1% fetal bovine serum (FBS), 10% FBS +/- 10 microM SB, or 20 ng/ml PDGF +/- 10 microM SB. Digital histomorphometric analysis assessed cellular fill within the wound area.Results: SB specifically inhibited PDGF-induced migration in the Boyden chamber assays without affecting cell proliferation. The wound model data showed similar levels of wound fill for PDLs and GFs in 10% FBS. Relative to 10% FBS, PDLs stimulated with PDGF showed significantly (P < 0.01, analysis of variance) greater wound fill (74%) than GFs (12%). SB inhibited the PDGF-induced wound fill of PDLs and GFs by 64% and 57%, respectively. This inhibition was significant (P < 0.01, ANOVA) only for PDLs. The addition of SB to 10% FBS did not significantly affect the wound fill response of either cell type compared to 10% FBS alone.Conclusions: These results demonstrate that periodontal cells possess distinct responses to PDGF that may be altered at the signal transduction level. The manipulation of these responses through the use of inhibitors to specific signaling pathways may enhance our control of periodontal regeneration in the future. [ABSTRACT FROM AUTHOR]

Background: The association between periodontal disease and coronary artery disease (CAD) has been investigated in numerous studies with inconsistent results. Resolving these differences is complicated by the use of varying definitions of CAD. The aim of this study was to investigate the association between angiographically-defined CAD and periodontal disease. Methods: Non-smoking, non-diabetic patients, over 40 years of age, with no history of a myocardial infarction in the previous 6 months and who had undergone cardiac catheterization within the previous 12 months were enrolled in this study. Subjects were classified as having CAD (CAD+) if they had 50% stenosis in at least one major epicardial artery and classified as CAD negative (CAD-) if they had <50% stenosis in all identified arteries. Periodontal disease severity was measured through bleeding on probing, probing depth, clinical attachment level (CAL), gingival recession, number of missing teeth, and radiographic bone loss. Results: One hundred (53 = CAD+; 47 = CAD-) patients were examined. CAD+ patients were more likely to be male (CAD+ 83.0% male; CAD- 40.4% male; P= 0.001), and were older (CAD+ 65.3 years; CAD- 60.8 years; P= 0.0138). Although all patients reported they were currently non-smokers and had not smoked for at least 5 years, the fraction who were former smokers was greater for CAD+ patients (66% versus 24.4%; P = 0.0001) and mean pack/year history of smoking was higher for CAD+ patients (15.8 versus 4.5; P = 0.0003). Mean CAL (3.13 mm versus 2.78 mm; P 0.0227), number of sites with CAL > or = 6 mm (6.85 versus 3.32; P = 0.0242), radiographic bone loss (3.60 mm versus 3.18 mm; P = 0.0142) were greater for CAD+ patients than for CAD- patients. However, after adjustment for age and previous smoking history, factors common to both diseases, the associations of CAD and periodontal disease were reduced and were not statistically significant (odds ratio [OR]: mean CAL OR = 1.06; number of sites with CAL > or = 6 mm OR = 1.03; mean radiographic bone loss OR = 1.31; P > or = 0.2055). Conclusions: After accounting for factors common to both periodontal disease and CAD, there was no significant association between periodontal disease and chronic CAD as assessed angiographically. Further investigations into the relationship between periodontal disease and CAD should clearly separate chronic CAD and acute coronary events. [ABSTRACT FROM AUTHOR]

A report is presented on an Arkansas survey of microwave ovens and radiation leakage. The findings are described and apparently indicate that maintenance is the important factor in keeping radiation emissions to a minimum. [ABSTRACT FROM AUTHOR]

Presents the reaction of the author to the theme of "American Documentation"'s convention, which is Levels of Interaction Between Man and Information. Reasons why the author finds the theme compelling; Developments and problems in information technology; Types of informational requirements of organizations; Internal information systems; Information and the external environment; Emerging problems; Invasion of privacy; Need for safeguards; Man versus machine; Need for a new understanding; Conclusion.

Influenza virus-induced respiratory pneumonia remains a major public health concern. Obesity, metabolic diseases, and female sex are viewed as independent risk factors for worsened influenza virus-induced lung disease severity. However, lack of experimental models of severe obesity in female mice limits discovery-based studies. Here, via utility of thermoneutral housing (30 °C) and high-fat diet (HFD) feeding, we induced severe obesity and metabolic disease in female C57BL/6 mice and compared their responses to severely obese male C57BL/6 counterparts during influenza virus infection. We show that lean male and female mice have similar lung edema, inflammation, and immune cell infiltration during influenza virus infection. At standard housing conditions, HFD-fed male, but not female, mice exhibit severe obesity, metabolic disease, and exacerbated influenza disease severity. However, combining thermoneutral housing and HFD feeding in female mice induces severe obesity and metabolic disease, which is sufficient to amplify influenza virus-driven disease severity to a level comparable to severely obese male counterparts. Lastly, increased total body weights of male and female mice at time of infection correlated with worsened influenza virus-driven disease severity metrics. Together, our findings confirm the impact of obesity and metabolic disease as key risk factors to influenza disease severity and present a novel mouse experimental model suitable for future mechanistic interrogation of sex, obesity, and metabolic disease traits in influenza virus-driven disease severity., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Vertical transmission of obesity is a critical contributor to the unabated obesity pandemic and the associated surge in metabolic diseases. Existing experimental models insufficiently recapitulate "human-like" obesity phenotypes, limiting the discovery of how severe obesity in pregnancy instructs vertical transmission of obesity. Here, via utility of thermoneutral housing and obesogenic diet feeding coupled to syngeneic mating of WT obese female and lean male mice on a C57BL/6 background, we present a tractable, more "human-like" approach to specifically investigate how maternal obesity contributes to offspring health. Using this model, we found that maternal obesity decreased neonatal survival, increased offspring adiposity, and accelerated offspring predisposition to obesity and metabolic disease. We also show that severe maternal obesity was sufficient to skew offspring microbiome and create a proinflammatory gestational environment that correlated with inflammatory changes in the offspring in utero and adulthood. Analysis of a human birth cohort study of mothers with and without obesity and their infants was consistent with mouse study findings of maternal inflammation and offspring weight gain propensity. Together, our results show that dietary induction of obesity in female mice coupled to thermoneutral housing can be used for future mechanistic interrogations of obesity and metabolic disease in pregnancy and vertical transmission of pathogenic traits.

Introduction: Inflammation is a common unifying factor in experimental models of non-alcoholic fatty liver disease (NAFLD) progression. Recent evidence suggests that housing temperature-driven alterations in hepatic inflammation correlate with exacerbated hepatic steatosis, development of hepatic fibrosis, and hepatocellular damage in a model of high fat diet-driven NAFLD. However, the congruency of these findings across other, frequently employed, experimental mouse models of NAFLD has not been studied., Methods: Here, we examine the impact of housing temperature on steatosis, hepatocellular damage, hepatic inflammation, and fibrosis in NASH diet, methionine and choline deficient diet, and western diet + carbon tetrachloride experimental models of NAFLD in C57BL/6 mice., Results: We show that differences relevant to NAFLD pathology uncovered by thermoneutral housing include: (i) augmented NASH diet-driven hepatic immune cell accrual, exacerbated serum alanine transaminase levels and increased liver tissue damage as determined by NAFLD activity score; (ii) augmented methionine choline deficient diet-driven hepatic immune cell accrual and increased liver tissue damage as indicated by amplified hepatocellular ballooning, lobular inflammation, fibrosis and overall NAFLD activity score; and (iii) dampened western diet + carbon tetrachloride driven hepatic immune cell accrual and serum alanine aminotransferase levels but similar NAFLD activity score., Discussion: Collectively, our findings demonstrate that thermoneutral housing has broad but divergent effects on hepatic immune cell inflammation and hepatocellular damage across existing experimental NAFLD models in mice. These insights may serve as a foundation for future mechanistic interrogations focused on immune cell function in shaping NAFLD progression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Oates, Sawada, Giles, Alarcon, Damen, Szabo, Stankiewicz, Moreno-Fernandez and Divanovic.)

Background: Understanding gender-associated bias in aging and obesity-driven metabolic derangements has been hindered by the inability to model severe obesity in female mice., Methods: Here, using chow- or high fat diet (HFD)-feeding regimens at standard (T S ) and thermoneutral (T N ) housing temperatures, the latter to model obesity in female mice, we examined the impact of gender and aging on obesity-associated metabolic derangements and immune responsiveness. Analysis included quantification of: (i) weight gain and adiposity; (ii) the development and severity of glucose dysmetabolism and non-alcoholic fatty liver disease (NAFLD); and (iii) induction of inflammatory pathways related to metabolic dysfunction., Results: We show that under chow diet feeding regimen, aging was accompanied by increased body weight and white adipose tissue (WAT) expansion in a gender independent manner. HFD feeding regimen in aged, compared to young, male mice at T S , resulted in attenuated glucose dysmetabolism and hepatic steatosis. However, under T S housing conditions only aged, but not young, HFD fed female mice developed obesity. At T N however, both young and aged HFD fed female mice developed severe obesity. Independent of gender or housing conditions, aging attenuated the severity of metabolic derangements in HFD-fed obese mice. Tempered severity of metabolic derangements in aged mice was associated with increased splenic frequency of regulatory T (T reg ) cells, Type I regulatory (Tr1)-like cells and circulating IL-10 levels and decreased vigor of HFD-driven induction of inflammatory pathways in adipose and liver tissues., Conclusion: Our findings suggest that aging-associated altered immunological profile and inflammatory vigor may play a dominant role in the attenuation of obesogenic diet-driven metabolic dysfunction.

Emerging evidence suggests a key contribution to non-alcoholic fatty liver disease (NAFLD) pathogenesis by Th17 cells. The pathogenic characteristics and mechanisms of hepatic Th17 cells, however, remain unknown. Here, we uncover and characterize a distinct population of inflammatory hepatic CXCR3 + Th17 (ihTh17) cells sufficient to exacerbate NAFLD pathogenesis. Hepatic ihTh17 cell accrual was dependent on the liver microenvironment and CXCR3 axis activation. Mechanistically, the pathogenic potential of ihTh17 cells correlated with increased chromatin accessibility, glycolytic output, and concomitant production of IL-17A, IFNγ, and TNFα. Modulation of glycolysis using 2-DG or cell-specific PKM2 deletion was sufficient to reverse ihTh17-centric inflammatory vigor and NAFLD severity. Importantly, ihTh17 cell characteristics, CXCR3 axis activation, and hepatic expression of glycolytic genes were conserved in human NAFLD. Together, our data show that the steatotic liver microenvironment regulates Th17 cell accrual, metabolism, and competence toward an ihTh17 fate. Modulation of these pathways holds potential for development of novel therapeutic strategies for NAFLD., Competing Interests: Declaration of interests S.D. is a consultant for Janssen Research & Development., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The impact of immune mediators on weight homeostasis remains underdefined. Interrogation of resistance to diet-induced obesity in mice lacking a negative regulator of Toll-like receptor signaling serendipitously uncovered a role for B cell activating factor (BAFF). Here we show that overexpression of BAFF in multiple mouse models associates with protection from weight gain, approximating a log-linear dose response relation to BAFF concentrations. Gene expression analysis of BAFF-stimulated subcutaneous white adipocytes unveils upregulation of lipid metabolism pathways, with BAFF inducing white adipose tissue (WAT) lipolysis. Brown adipose tissue (BAT) from BAFF-overexpressing mice exhibits increased Ucp1 expression and BAFF promotes brown adipocyte respiration and in vivo energy expenditure. A proliferation-inducing ligand (APRIL), a BAFF homolog, similarly modulates WAT and BAT lipid handling. Genetic deletion of both BAFF and APRIL augments diet-induced obesity. Lastly, BAFF/APRIL effects are conserved in human adipocytes and higher BAFF/APRIL levels correlate with greater BMI decrease after bariatric surgery. Together, the BAFF/APRIL axis is a multifaceted immune regulator of weight gain and adipose tissue function.

White adipose tissue inflammation, in part via myeloid cell contribution, is central to obesity pathogenesis. Mechanisms regulating adipocyte inflammatory potential and consequent impact of such inflammation in disease pathogenesis remain poorly defined. We show that activation of the type I interferon (IFN)/IFNα receptor (IFNAR) axis amplifies adipocyte inflammatory vigor and uncovers dormant gene expression patterns resembling inflammatory myeloid cells. IFNβ-sensing promotes adipocyte glycolysis, while glycolysis inhibition impeded IFNβ-driven intra-adipocyte inflammation. Obesity-driven induction of the type I IFN axis and activation of adipocyte IFNAR signaling contributes to obesity-associated pathogenesis in mice. Notably, IFNβ effects are conserved in human adipocytes and detection of the type I IFN/IFNAR axis-associated signatures positively correlates with obesity-driven metabolic derangements in humans. Collectively, our findings reveal a capacity for the type I IFN/IFNAR axis to regulate unifying inflammatory features in both myeloid cells and adipocytes and hint at an underappreciated contribution of adipocyte inflammation in disease pathogenesis.

Obesity is a prevalent predisposing factor to non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease in the developed world. NAFLD spectrum of disease involves progression from steatosis (NAFL), to steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). Despite clinical and public health significance, current FDA approved therapies for NAFLD are lacking in part due to insufficient understanding of pathogenic mechanisms driving disease progression. The etiology of NAFLD is multifactorial. The induction of both systemic and tissue inflammation consequential of skewed immune cell metabolic state, polarization, tissue recruitment, and activation are central to NAFLD progression. Here, we review the current understanding of the above stated cellular and molecular processes that govern macrophage contribution to NAFLD pathogenesis and how adipose tissue and liver crosstalk modulates macrophage function. Notably, the manipulation of such events may lead to the development of new therapies for NAFLD., (Copyright © 2019 Oates, McKell, Moreno-Fernandez, Damen, Deepe, Qualls and Divanovic.)

Background: The authors conducted a prospective cohort study to determine whether poor glycemic control is a contraindication to implant therapy in patients with type 2 diabetes., Methods: The study sample consisted of 117 edentulous patients, each of whom received two mandibular implants, for a total of 234 implants. Implant-retained mandibular overdentures were loaded after a four-month healing period and followed up for an additional one year. The authors assessed implant survival and stability (by means of resonance frequency analysis) relative to glycated hemoglobin A1c (HbA1c) levels, with baseline levels up to 11.1 percent and levels as high as 13.3 percent over one year., Results: Implant survival rates for 110 of 117 patients who were followed up for one year after loading were 99.0 percent, 98.9 percent and 100 percent, respectively, for patients who did not have diabetes (n = 47), those with well-controlled diabetes (n = 44) and those with poorly controlled diabetes (n = 19). The authors considered the seven patients lost to follow-up as having had failed implants; consequently, their conservative estimates of survival rates in the three groups were 93.0 percent, 92.6 percent and 95.0 percent (P = .6510). Two implants failed at four weeks, one in the nondiabetes group and the other in the well-controlled diabetes group. Delays in implant stabilization were related directly to poor glycemic control., Conclusions: The results of this study indicate that elevated HbA1c levels in patients with type 2 diabetes were not associated with altered implant survival one year after loading. However, alterations in early bone healing and implant stability were associated with hyperglycemia.

Purpose: For dental implants to be successful, osseointegration must occur, but it is unknown how much time must pass for osseointegration to be established. Preclinical studies suggested that titanium implants with a sandblasted and acid-etched (SLA) surface were more osteoconductive and allowed more rapid osseointegration than machined or turned implant surfaces. The hypothesis of this study was that implants with an SLA surface could be loaded in half the conventional healing time of machined-surface implants and that, after loading, the implants would be successful for 5 years., Materials and Methods: A prospective multicenter clinical study was conducted with 439 implants placed in native bone in 135 edentulous and partially edentulous patients. Abutments were attached to the implant with 35 Ncm of torque without countertorque after 6 weeks in type I to III bone and after 12 weeks in type IV bone. The patients were carefully evaluated for 5 years., Results: Most implants were placed in nonsmoking, nondiabetic patients with a mean age of 55 years (range, 21 to 82 years). Eighty percent of the implants were 10 or 12 mm long, 96% had a diameter of 4.1 mm, and 78% were placed in type II or III bone. Patients maintained good oral hygiene and were satisfied with the restorations. Four implants failed, and one implant was deemed unsuccessful between surgery and the 1-year postloading visit. No implants failed or were unsuccessful in subsequent years. The cumulative survival and success rates for 385 implants in 120 patients after 5 years were 99.1% and 98.8%, respectively., Conclusion: Implants with an SLA surface can be restored in 6 weeks for type I to III bone and 12 weeks for type IV bone. Furthermore, they can be maintained after loading for 5 years with very high success and survival rates.

Background: Patients with poor-risk rectal cancer defined by MRI can be at high risk of disease recurrence despite standard chemoradiotherapy and optimum surgery. We aimed to assess the safety and long-term efficacy of neoadjuvant chemotherapy with capecitabine and oxaliplatin before chemoradiotherapy and total mesorectal excision, a treatment strategy developed to enhance the outcome of this population., Methods: Between November, 2001, and August, 2005, we enrolled eligible patients with poor-risk rectal cancer defined by high-resolution MRI and without metastatic disease. The protocol was amended in January, 2004, following clinically significant cardiotoxic events (nine events in eight of 77 patients), to exclude patients with a recent history of clinically significant cardiac problems. Patients received 12 weeks of neoadjuvant capecitabine and oxaliplatin (oxaliplatin 130 mg/m2 on day 1 with capecitabine 1000 mg/m2 twice daily for 14 days every 3 weeks) followed by chemoradiotherapy (54 Gy over 6 weeks) with capecitabine (825 mg/m2 twice daily), total mesorectal excision, and 12 weeks of postoperative adjuvant capecitabine (1250 mg/m2 twice daily for 14 days every 3 weeks). The primary endpoint was pathological complete response rate. We followed up patients for a median of 55 months (IQR 47-67). Efficacy analyses were undertaken for the intention-to-treat population, unless otherwise specified. This study is registered with ClinicalTrials.gov, number NCT00220051., Findings: 105 eligible patients were enrolled. Radiological response rates after neoadjuvant chemotherapy and chemoradiotherapy were 74% (78/105) and 89% (93/105), respectively. 97 patients underwent surgery, of whom 95 underwent total mesorectal excision, of whom 93 had microscopically clear resection margins and 21 had pathological complete response (21/105 [20%]). 3-year progression-free and overall survival were 68% (95% CI 59-77) and 83% (76-91), respectively. 3-year relapse-free survival for patients who had complete resection was 74% (65-83). Following the protocol amendment for cardiovascular safety, only one further thromboembolic event was reported (fatal pulmonary embolism)., Interpretation: Intensification of systemic therapy with neoadjuvant combination chemotherapy before standard treatment is feasible in poor-risk potentially operable rectal cancer, with acceptable safety and promising long-term outcomes. Future development of this multidisciplinary treatment strategy in randomised trials is warranted., Funding: UK National Health Service, Sanofi-Aventis., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Longitudinal quality of life (QOL) assessment is infrequently made in adjuvant therapy for colorectal cancer (CRC). This analysis aims to assess QOL and quality adjusted survival (QAS) in patients receiving adjuvant 5-FU for stage II and III CRC. We performed a multicentre study in which 801 patients were randomised to 6 months of bolus 5-FU/leucovorin (LV n = 404) or 12 weeks of protracted venous infusion (PVI) 5-FU (n = 397). There were significant differences in the deterioration of QOL scores at week 2 with bolus 5-FU/LV compared to PVI 5-FU (P < 0.001), coinciding with toxicity peak during the first cycle. Following week 12, global QOL recovered to baseline when PVI 5-FU was stopped but this was delayed with bolus 5-FU/LV until completion at week 24. QOL scores significantly improved in both arms during follow-up (P < 0.001) and reached a plateau by year 1 without incremental improvement between years 2 and 5. There was a trend towards better QAS with PVI 5-FU. Twelve weeks of adjuvant PVI 5-FU was associated with significantly better QOL during treatment and faster time to recovery compared to 6 months of bolus 5-FU/LV.