Porphyromonas gingivalis HmuY‐Induced Production of Interleukin‐6 and IL‐6 Polymorphism in Chronic Periodontitis

Background: In chronic periodontitis (CP), the gene polymorphism of interleukin‐6 (IL‐6) to 174C/G has been associated with the altered production of this cytokine. The aim of this pilot study is to compare the allelic and genotypic frequencies in patients with CP with control individuals without periodontitis (NP) and to measure the production of IL‐6 by whole blood cells stimulated with Porphyromonas gingivalis HmuY protein. Methods: DNA was isolated from peripheral blood cells of 49 patients with CP and 60 control individuals classified as NP, and genotyping was performed by polymerase chain reaction using sequence‐specific primers. Whole blood cells from 29 patients with CP and 30 control individuals were stimulated for 48 hours with HmuY, and IL‐6 levels were measured using enzyme‐linked immunosorbent assay. Results: The proportion of individuals carrying the G allele at position –174 of the IL‐6 gene was higher in the group with CP (85.7%) than in the normal control group (73.3%; P <0.03). P. gingivalis HmuY‐induced production of IL‐6 was higher in the group with CP (P <0.05). Conclusions: Our findings suggest that P. gingivalis HmuY may be associated with increased IL‐6 production during CP. Furthermore, patients with periodontitis and individuals with higher HmuY‐induced production of IL‐6 show a high frequency of the G allele at position –174.     

Long‐Term Stability of Contour Augmentation With Early Implant Placement Following Single Tooth Extraction in the Esthetic Zone: A Prospective,Cross‐Sectional Study in 41 Patients With a 5‐ to 9‐Year Follow‐Up

Background: Early implant placement with simultaneous contour augmentation is documented with short‐ and medium‐term studies. The long‐term stability of contour augmentation is uncertain. Methods: In this prospective, cross‐sectional study, 41 patients with an implant‐borne single crown were examined twice, in 2006 and 2010. Clinical, radiologic, and esthetic parameters were assessed at both examinations. In addition, a cone beam computed tomographic (CBCT) image was obtained during the second examination to assess the dimensions of the facial bone wall. Results: All 41 implants demonstrated ankylotic stability without signs of peri‐implant infection at both examinations. The clinical parameters remained stable over time. Satisfactory esthetic outcomes were noted, as assessed by the pink and white esthetic score (PES/WES) indices. Overall, the PES scores were slightly higher than the WES scores. None of the implants developed mucosal recession over time, as confirmed by values of the distance between implant shoulder and mucosal margin and cast measurements. The periapical radiographs yielded stable peri‐implant bone levels, with a mean distance between implant shoulder and first visible bone‐implant contact value of 2.18 mm. The CBCT analysis demonstrated a mean thickness of the facial bone wall ≈2.2 mm. In two implants (4.9%) no facial bone wall was detectable radiographically. Conclusions: This prospective cross‐sectional study demonstrates stable peri‐implant hard and soft tissues for all 41 implants examined and satisfactory esthetic outcomes overall. The follow‐up of 5 to 9 years confirmed again that the risk for mucosal recession is low with early implant placement. In addition, contour augmentation with guided bone regeneration was able to establish and maintain a facial bone wall in 95% of patients.     

Randomized Controlled Trial to Compare Two Bone Substitutes in the Treatment of Bony Dehiscences

Aim: This in vivo split‐mouth randomized controlled trial compared a synthetic bone substitute with a bovine bone mineral to cover bone dehiscences after implant insertion. Materials and Methods: Fourteen patients received four to six implants to support an overdenture. Two comparable dehiscences within the same patient were first covered with a layer of autogenous bone, followed by a layer of either Bio‐Oss® (group 1; Geistlich Pharma AG, Wolhusen, Switzerland) or Straumann BoneCeramic® (group 2; Institut Straumann AG, Basel, Switzerland) and sealed by a resorbable membrane. The change in vertical dimension of the defect was measured at implant placement and at abutment connection (6.5 months). Clinical and radiological parameters were evaluated up to 1 year of loading. Results: The vertical size of the defect at surgery was 6.4 ± 1.6 mm for group 1 and 6.4 ± 2.2 mm for group 2 sites, measured from the implant shoulder. After 6.5 months, the depth of the defect was reduced to 1.5 ± 1.2 mm and 1.9 ± 1.2 mm for group 1 and group 2 sites, respectively (p > 0.05). No implants failed during follow‐up. Mean marginal bone loss over the SLActive surface was 0.94 mm (group 1), 0.81 mm (group 2), and 0.93 mm (group 3, no dehiscence) after 1 year of loading. Conclusion: Both bone substitutes behaved equally effectively.     

Ulnar Nerve Innervation of the Triceps Muscle: Real or Apparent? An Anatomic Study

Background

Since the 18th century, the existence of ulnar nerve innervation of the medial head of the triceps brachii muscle has been controversial. The evidence for or against such innervation has been based on macroscopic dissection, an unsuitable method for studying intraneural topography or intramuscular branching. The study of smaller specimens (embryos or fetuses) by means of serial histologic sections may resolve the controversy.

Questions/Purposes

Using fetal specimens and histology we determined the contributions of the ulnar and radial nerves to innervation of the triceps brachii muscle.

Methods

We histologically examined 15 embryonic and fetal arms. Radial nerve branches obtained from six adult arms were analyzed immunohistochemically to determine motor fiber content.

Results

The medial head of the triceps brachii muscle was always innervated by the radial nerve (ulnar collateral branch). The branches seeming to leave the ulnar nerve at elbow level were the continuation of the radial nerve that had joined the ulnar nerve sheath via a connection in the axillary region. Immunohistochemistry revealed motor and nonmotor fibers in this radial nerve branch.

Conclusions

A connection between the radial and ulnar nerves sometimes may exist, resulting in an apparent ulnar nerve origin of muscular branches to the medial head of the triceps, even though in all our specimens the fibers could be traced back to the radial nerve.

Clinical Relevance

Before performing or suggesting new muscle and nerve transpositions using this apparent ulnar innervation, the real origin should be confirmed to avoid failure.     

Developmental outcomes of children with congenital diaphragmatic hernia: A multicenter prospective study

Purpose

To determine developmental outcomes and associated factors in patients with congenital diaphragmatic hernia (CDH) at 2 years of age.

Methods

This is a multicenter prospective study of a CDH birth cohort. Clinical and socioeconomic data were collected. Bayley Scales of Infant Development (BSID-III) and Vineland Adaptive Behavior Scales (VABS-II) were performed at 2 years of age.

Results

BSID-III and VABS-II assessments were completed on 48 and 49 children, respectively. The BSID-III mean cognitive, language, and motor scores were significantly below the norm mean with average scores of 93 ± 15, 95 ± 16, and 95 ± 11. Ten percent (5/47) scored more than 2 standard deviations below the norm on one or more domains. VABS-II scores were similar to BSID-III scores with mean communication, daily living skills, social, motor, adaptive behavior scores of 97 ± 14, 94 ± 16, 93 ± 13, 97 ± 10, and 94 ± 14. For the BSID-III, supplemental oxygen at 28 days, a prenatal diagnosis, need for extracorporeal membrane oxygenation (ECMO) and exclusive tube feeds at time of discharge were associated with lower scores. At 2 years of age, history of hospital readmission and need for tube feeds were associated with lower scores. Lower socioeconomic status correlated with lower developmental scores when adjusted for significant health factors.

Conclusion

CDH patients on average have lower developmental scores at 2 years of age compared to the norm. A need for ECMO, oxygen at 28 days of life, ongoing health issues and lower socioeconomic status are factors associated with developmental delays.     

PD-1, but Not PD-L1, Expressed by Islet-Reactive CD4+ T Cells Suppresses Infiltration of the Pancreas During Type 1 Diabetes

The inhibitory receptor programmed death-1 (PD-1) constrains type 1 diabetes (T1D) in the nonobese diabetic (NOD) mouse. However, how PD-1 influences diabetogenic CD4⁺ T cells during natural diabetes is not fully understood. To address this question, we developed a novel model to investigate antigen-specific CD4⁺ T cells under physiological conditions in vivo. We transferred a low number of naïve CD4⁺ T cells from the BDC2.5 mouse into prediabetic NOD mice to mimic a physiological precursor frequency and allowed the cells to become primed by endogenous autoantigen. Transferred BDC2.5 T cells became activated, differentiated into T-bet⁺ IFN-γ–producing cells, and infiltrated the pancreas. In this model, loss of PD-1, but not programmed death ligand-1 (PD-L1), on the antigen-specific CD4⁺ T cell resulted in increased cell numbers in the spleen, pancreas-draining lymph node, and pancreas. PD-1 deficiency also increased expression of the chemokine receptor CXCR3. Lastly, histological data showed that a loss of PD-1 caused BDC2.5 cells to penetrate deep into the islet core, resulting in conversion from peri-insulitis to destructive insulitis. These data support a model by which PD-1 regulates islet-reactive CD4⁺ T cells in a cell intrinsic manner by suppressing proliferation, inhibiting infiltration of the pancreas, and limiting diabetes.Type 1 diabetes (T1D) is an autoimmune disease mediated by T-cell destruction of the insulin-producing β-cells in the pancreatic islets of Langerhans (1). The nonobese diabetic (NOD) mouse is a classic model for studying T1D because it shares many similarities with human T1D, including the requirement of CD4⁺ T cells for disease (2–4). However, knowledge of how diabetogenic CD4⁺ T cells are regulated and how this regulation fails, causing T1D, is limited owing to a lack of tools to monitor endogenous diabetogetic CD4⁺ T cells.Common models used to study diabetogenic CD4⁺ T cells in NOD mice include adoptive transfer of high numbers of naïve or in vitro activated T-cell receptor (TCR) transgenic cells into wild-type (WT) or lymphopenic NOD recipients (5–10). While informative, these approaches fail to recapitulate the natural inflammatory environment present in NOD mice and the timing associated with T1D progression. Previous work in other systems showed that transferring lower numbers of naïve T cells allowed greater clonal expansion on a per cell basis and more efficient effector cell differentiation (11–14). Since we speculate that endogenous autoantigen in the NOD mouse is low, we predicted that limiting the diabetogenic precursor frequency would be essential for autoantigen encounter and activation. Therefore, in this study we developed a new model by transferring a small number of islet-specific BDC2.5 transgenic CD4⁺ T cells (15,16) into prediabetic NOD mice to mimic an endogenous preimmune repertoire.The inhibitory receptor programmed death-1 (PD-1) interacting with programmed death ligand-1 (PD-L1) is critical for suppressing diabetes, since disrupting PD-1/PD-L1 interactions accelerates T1D in NOD mice (7,17–19) and polymorphisms in PD-1 have been associated with human T1D (20). Previous studies demonstrated roles for the PD-1 pathway by inhibiting CD4⁺ T-cell survival, proliferation, and cytokine production using in vitro and in vivo systems (5,7,21–24). However, since many of the in vivo studies relied on adoptive transfer of nonphysiologically high numbers of TCR transgenic T cells, the cellular mechanisms by which PD-1 constrains diabetogenic CD4⁺ T cells in hosts with a normal T-cell repertoire remain unclear. We therefore reexamined the role of PD-1 in regulating CD4⁺ T cells in vivo using a new adoptive transfer model that more closely mimics the normal naïve preimmune repertoire. Our results show that PD-1 expressed by the BDC2.5 T cell is required to regulate proliferation, chemokine receptor CXCR3 expression, infiltration of the pancreas, and diabetes pathogenesis.     

Pioglitazone Acutely Reduces Energy Metabolism and Insulin Secretion in Rats

Our objective was to determine if the insulin-sensitizing drug pioglitazone acutely reduces insulin secretion and causes metabolic deceleration in vivo independently of change in insulin sensitivity. We assessed glucose homeostasis by hyperinsulinemic-euglycemic and hyperglycemic clamp studies and energy expenditure by indirect calorimetry and biotelemetry in male Wistar and obese hyperinsulinemic Zucker diabetic fatty (ZDF) rats 45 min after a single oral dose of pioglitazone (30 mg/kg). In vivo insulin secretion during clamped hyperglycemia was reduced in both Wistar and ZDF rats after pioglitazone administration. Insulin clearance was slightly increased in Wistar but not in ZDF rats. Insulin sensitivity in Wistar rats assessed by the hyperinsulinemic-euglycemic clamp was minimally affected by pioglitazone at this early time point. Pioglitazone also reduced energy expenditure in Wistar rats without altering respiratory exchange ratio or core body temperature. Glucose-induced insulin secretion (GIIS) and oxygen consumption were reduced by pioglitazone in isolated islets and INS832/13 cells. In conclusion, pioglitazone acutely induces whole-body metabolic slowing down and reduces GIIS, the latter being largely independent of the insulin-sensitizing action of the drug. The results suggest that pioglitazone has direct metabolic deceleration effects on the β-cell that may contribute to its capacity to lower insulinemia and antidiabetic action.Major drugs developed to treat type 2 diabetes aim at either increasing insulin secretion or reducing insulin resistance (1–4). Two classes of insulin-sensitizing agents are currently used, the biguanides (metformin) and the thiazolidinediones (TZDs), of which the only one still recommended for use in some countries is pioglitazone (5). TZDs are peroxisome proliferator–activated receptor-γ (PPARγ) agonists. They stimulate adipocyte differentiation, relieving other tissues from fat excess, thereby reducing their resistance to insulin (6,7). The beneficial effects of TZDs are not limited to increased insulin sensitivity and also include preservation of β-cell function (8). It is thought that the beneficial effect of TZDs on β-cell function in vivo is indirect and occurs via a relief of the need for insulin hypersecretion because of their insulin sensitizing action. We should, however, consider the possibility that the classical antidiabetic insulin sensitizers, pioglitazone and metformin, might also have beneficial effects on glucose homeostasis via direct reduction of insulin hypersecretion independently of insulin resistance.We previously demonstrated in vitro that pioglitazone acutely slows down glucose and lipid metabolism in the β cell and inhibits glucose-induced insulin secretion (GIIS) primarily at submaximal and much less at maximal glucose concentrations (right shift in the glucose dose response) via a PPARγ-independent mechanism (9). These acute effects of pioglitazone are likely attributable to complex I inhibition of the electron transport chain (10) and involve reduced glucose oxidation, decreased ATP levels, and increased AMPK activation (9). Interestingly, metformin causes similar effects (J.L. and M.P., unpublished data). Hence, we proposed the novel concept of “metabolic deceleration” as a mode of action of some antidiabetic drugs and suggested that the action of pioglitazone to reduce glucose metabolism and insulin secretion in the β-cell may partly explain its beneficial effects (9). The concept that metabolic deceleration protects the β-cell from both oxidative and endoplasmic reticulum stress has recently been reviewed (11,12).In the current study we performed in vivo experiments in normal Wistar and obese Zucker diabetic fatty (ZDF) rats to better understand how acute treatment with pioglitazone alters glucose homeostasis, with particular focus on how it reduces hyperinsulinemia. The following questions were asked: 1) Can we confirm in vivo our previous in vitro findings in isolated rat islet and β-cell line that pioglitazone acutely reduces insulin secretion? 2) Is this acute effect of pioglitazone on insulin secretion independent of its effects on insulin sensitivity? and 3) Does pioglitazone acutely slow down whole-body energy metabolism?