Cross-talk between the complement system and endothelial cells in physiologic conditions and in vascular diseases

The endothelial layer represents a continuous physical barrier that controls coagulation and allows selective passage of soluble molecules and circulating cells across the vessel wall into the tissue. The functional activity of the endothelial cells may be influenced by their interaction with components of the complement system. In this review we shall discuss the complex interplay that can be established between the endothelium and complement proteins or activation products. Endothelial cells may also secrete several complement components which contribute to the circulating pool. This process can be regulated by cytokines and other pro-inflammatory stimuli. In addition, complement activation products stimulate endothelial cells to acquire a pro-inflammatory and pro-coagulant status. Expression of regulatory molecules on the cell surface provides protection against an undesired attack by complement activation products. Unrestricted complement activation under pathological conditions may lead to structural and functional changes of the endothelium resulting in vascular disease.     

Relationship of stress, distress and inadequate coping behaviors to periodontal disease.

BACKGROUND: The association of stress, distress, and coping behaviors with periodontal disease was assessed. METHODS: A cross-sectional study of 1,426 subjects between the ages of 25 and 74 years in Erie County, New York, was carried out to assess these relationships. Subjects were asked to complete a set of 5 psychosocial questionnaires which measure psychological traits and attitudes including discrete life events and their impact; chronic stress or daily strains; distress; coping styles and strategies; and hassles and uplifts. Clinical assessment of supragingival plaque, gingival bleeding, subgingival calculus, probing depth, clinical attachment level (CAL) and radiographic alveolar crestal height (ACH) was performed, and 8 putative bacterial pathogens from the subgingival flora measured. RESULTS: Reliability of subjects' responses and internal consistencies of all the subscales on the instruments used were high, with Cronbach's alpha ranging from 0.88 for financial strain to 0.99 for job strain, uplifts, and hassles. Logistic regression analysis indicated that, of all the daily strains investigated, only financial strain was significantly associated with greater attachment and alveolar bone loss (odds ratio, OR = 1.70, 95% CI = 1.09 to 2.65 and OR = 1.68, 95% CI = 1.20 to 2.37, respectively) after adjusting for age, gender, and cigarette smoking. When coping behaviors were evaluated, it was found that those with more financial strain who were high emotion-focused copers (a form of inadequate coping) had a higher risk of having more severe attachment loss (OR = 2.24, 95% CI = 1.15 to 4.38) and alveolar bone loss (OR = 1.91, 95% CI = 1.15 to 3.17) than those with low levels of financial strain within the same coping group, after adjustment for age, gender, and cigarette smoking. Similar results were found among the low problem-focused copers for AL (OR = 2.21, 95% CI = 1.11 to 4.38) and ACH (OR = 2.12, 95% CI = 1.28 to 3.51). However, subjects with high levels of financial strain who reported high levels of problem-based coping (considered adequate or good coping) had no more periodontal disease than those with low levels of financial strain, suggesting that the effects of stress on periodontal disease can be moderated by adequate coping behaviors. CONCLUSIONS: We find that psychosocial measures of stress associated with financial strain and distress manifest as depression, are significant risk indicators for more severe periodontal disease in adults in an age-adjusted model in which gender (male), smoking, diabetes mellitus, B. forsythus, and P. gingivalis are also significant risk indicators. Of considerable interest is the fact that adequate coping behaviors as evidenced by high levels of problem-based coping, may reduce the stress-associated risk. Further studies also are needed to help establish the time course of stress, distress, and inadequate coping with respect to the onset and progression of periodontal disease, and the mechanisms that explain this association.     

Bioabsorbable Calcaneo-Stop Implant for the Treatment of Flexible Flatfoot: A Retrospective Cohort Study at a Minimum Follow-Up of 4 Years

Arthroereisis of the subtalar joint is a common surgical technique in Europe for the management of flexible flatfoot in the pediatric population. In most cases, it is performed using a calcaneo-stop metallic screw. Despite the good clinical results, screw removal is always advised after 2 to 3 years. The use of a bioabsorbable screw might overcome the need for a second operation to remove a nonabsorbable device. We report the results of a biodegradable calcaneo-stop screw at a minimum of 4 years of follow-up. Eighty-eight procedures were performed on 44 children. All patients were clinically and radiologically evaluated preoperatively and at a minimum 4-year follow-up period. Patient satisfaction and plantar collapse using Viladot's classification were recorded. Meary's talus–first metatarsal angle and talocalcaneal angle were measured on radiographs preoperatively and at the last follow-up visit. The presence of the device at the last follow-up examination was assessed by magnetic resonance imaging. The mean follow-up duration was 56 months. Of the 44 patients, 33 (75%) reported excellent clinical outcomes, 9 (20.5%) good outcomes, and 2 (4.5%) poor. Foot print improvement was registered for all patients. The mean Meary's talus–first metatarsal angle had improved from 160.6° ± 7.7° preoperatively to 170.6° ± 6.5° at the last follow-up visit (p < .001). The talocalcaneal angle had decreased from 39.9° ± 5.2° preoperatively to 29.4° ± 4° at the last follow-up examination (p < .001). At the 4-year follow-up point, the implant could be seen to have almost completely biodegraded on magnetic resonance imaging. Two screw breakages occurred. The bioabsorbable calcaneo-stop screw seems to be an effective solution for flexible flatfoot in pediatric patients. Also, owing to its biodegradable composition, the need of a second operation for implant removal will not always be necessary.     

Randomized Phase 2b Trial of Tofacitinib (CP‐690,550) in De Novo Kidney Transplant Patients: Efficacy,Renal Function and Safety at 1 Year

In this Phase 2b study, 331 low‐to‐moderate risk de novo kidney transplant patients (approximately 60% deceased donors) were randomized to a more intensive (MI) or less intensive (LI) regimen of tofacitinib (CP‐690, 550), an oral Janus kinase inhibitor or cyclosporine (CsA). All patients received basiliximab induction, mycophenolic acid and corticosteroids. Primary endpoints were: incidence of biopsy‐proven acute rejection (BPAR) with a serum creatinine increase of ≥0.3 mg/dL and ≥20% (clinical BPAR) at Month 6 and measured GFR at Month 12. Similar 6‐month incidences of clinical BPAR (11%, 7% and 9%) were observed for MI, LI and CsA. Measured GFRs were higher (p < 0.01) at Month 12 for MI and LI versus CsA (65 mL/min, 65 mL/min vs. 54 mL/min). Fewer (p < 0.05) patients in MI or LI developed chronic allograft nephropathy at Month 12 compared with CsA (25%, 24% vs. 48%). Serious infections developed in 45%, 37% and 25% of patients in MI, LI and CsA, respectively. Anemia, neutropenia and posttransplant lymphoproliferative disorder occurred more frequently in MI and LI compared with CsA. Tofacitinib was equivalent to CsA in preventing acute rejection, was associated with improved renal function and less chronic allograft histological injury, but had side‐effects at the doses evaluated.     

Silymarin,a Possible Hepatoprotector in Dairy Cows: Biochemical and Histological Observations

Silymarin, a standardized extract from Silybum marianum seed, is a natural hepatoprotector used for the treatment of liver diseases in man. The aim of this study was to investigate its safety and efficacy in periparturient dairy cows. Ten treated and 10 control pregnant dairy cows were paired by parity, body condition score (BCS), health condition and previous milk production. Treatment consisted of daily 10 g per animal of silymarin extract administered as oral drenches, from 10 days prior to the calving date to 15 days after calving. Blood samples and liver biopsies were taken from each animal at 7 and 30 days after calving. Hepatic functions were evaluated by assay of plasma β‐hydroxybutyrate (BHBA), total cholesterol, high‐density lipoproteins, low‐density lipoproteins, triglyceride and total bilirubin. The histological aspect of the liver was assessed in biopsies. Clinical chemistry values were similar for both groups and effects at different times (day 7 versus day 30; P < 0.05) were attributed to physiological variations in periparturient cows. Histology showed fat accumulation in the liver of both groups, as it is expected in periparturient dairy cows. In treated cows, fat‐rich hepatocytes were observed near the central vein. These observations suggest that, at the used dosage, S. marianum extract has no adverse effect on the liver of lactating cows, and presents no objective evidence for a hepatoprotective effect in this species.     

Expression of fully functional tetrameric human hemoglobin in Escherichia coli.

Synthetic genes encoding the human alpha- and beta-globin polypeptides have been expressed from a single operon in Escherichia coli. The alpha- and beta-globin polypeptides associate into soluble tetramers, incorporate heme, and accumulate to greater than 5% of the total cellular protein. Purified recombinant hemoglobin has the correct stoichiometry of alpha- and beta-globin chains and contains a full complement of heme. Each globin chain also contains an additional methionine as an extension to the amino terminus. The recombinant hemoglobin has a C4 reversed-phase HPLC profile essentially identical to that of human hemoglobin A0 and comigrates with hemoglobin A0 on SDS/PAGE. The visible spectrum and oxygen affinity are similar to that of native human hemoglobin A0. The recombinant protein shows a reduction in Bohr and phosphate effects, which may be attributed to the presence of methionine at the amino termini of the alpha and beta chains. We have also expressed the alpha- and beta-globin genes separately and found that the expression of the alpha-globin gene alone results in a marked decrease in the accumulation of alpha-globin in the cell. Separate expression of the beta-globin gene results in high levels of insoluble beta-globin. These observations suggest that the presence of alpha- and beta-globin in the same cell stabilizes alpha-globin and aids the correct folding of beta-globin. This system provides a simple method for expressing large quantities of recombinant hemoglobin and allows facile manipulation of the genes encoding hemoglobin to produce functionally altered forms of this protein.