Evidence for low-grade systemic proinflammatory activity in patients with posttraumatic stress disorder

Posttraumatic stress disorder (PTSD) may increase cardiovascular risk but the psychophysiological mechanisms involved are elusive. We hypothesized that proinflammatory activity is elevated in patients with PTSD as diagnosed by the Clinician Administered PTSD Scale (CAPS) interview. Plasma levels of proinflammatory C-reactive protein (CRP), interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha, and of anti-inflammatory IL-4 and IL-10 were measured in 14 otherwise healthy PTSD patients and in 14 age- and gender-matched healthy non-PTSD controls. Levels of TNF-alpha (p=0.038; effect size Cohen's d=0.58) and of IL-1beta (p=0.075, d=0.68) were higher in patients than in controls. CRP (d=0.10), IL-6 (d=0.18), IL-4 (d=0.42), and IL-10 (d=0.37) were not significantly different between groups. Controlling for traditional cardiovascular risk factors, mood, and time since trauma revealed lower IL-4 in patients than in controls (p=0.029) and rendered group differences in TNF-alpha and IL-1beta insignificant. In all subjects, TNF-alpha correlated with total (frequency and intensity) PTSD symptom cluster of re-experiencing (r=0.49, p=0.008), avoidance (r=0.37, p=0.050), and hyperarousal (r=0.42, p=0.026), and with PTSD total symptom score (r=0.37, p=0.054). Controlling for time since trauma attenuated these associations. The correlation between IL-1beta and total avoidance symptoms (r=0.42, p=0.028) became insignificant when controlling for anxiety and depression. IL-4 correlated with total hyperarousal symptoms (r=-0.38, p=0.047), and after controlling for systolic blood pressure and smoking status, with PTSD total symptom score (r=-0.41, p=0.035). PTSD patients showed a low-grade systemic proinflammatory state, which, moreover, was related to PTSD symptom levels suggesting one mechanism by which PTSD could contribute to atherosclerotic disease.

What has ageing to do with periodontal health and disease?

Periodontitis is a multi-factorial disease and in most cases also a disease with a chronic progression. Exposure to factors which contribute to periodontitis occurs over a long period, so that at the time of diagnosis it may be difficult to identify and evaluate what co-factors have contributed to its development. These include exposure to bacteria and viruses, inflammation, genetic factors, health behaviours and a variety of social factors, socio-economic status, behavioural and nutritional habits, the ability to cope with stress and the ability of the immune system to fight infections. Many patients in their 50s also experience other conditions such as heart disease, diabetes mellitus, or rheumatoid arthritis and recent reports on the associations and potential biological mechanisms by which periodontitis can be linked to other systemic diseases suggest that the patient with periodontitis is a challenged individual. Neither individuals nor their oral health care providers are currently prepared for the challenges in oral health care as the expectation of successful ageing with remaining and aesthetically functional teeth is increasing. The scientific evidence is, however, growing, and while the opportunities to prepare for successful ageing exist they must be included in the educational process of both current and future oral health care providers and their patients.

177Lu-AMBA: Synthesis and characterization of a selective 177Lu-labeled GRP-R agonist for systemic radiotherapy of prostate cancer

Gastrin-releasing peptide receptors (GRP-R) are upregulated in many cancers, including prostate, breast, and lung. We describe a new radiolabeled bombesin (BBN) analog for imaging and systemic radiotherapy that has improved pharmacokinetics (PK) and better retention of radioactivity in the tumor. METHODS: DO3A-CH2CO-G-4-aminobenzoyl-Q-W-A-V-G-H-L-M-NH2 (AMBA) was synthesized and radiolabeled. The human prostate cancer cell line PC-3 was used to determine the binding (Kd), retention, and efflux of 177Lu-AMBA. Receptor specificity was determined by in vitro autoradiography in human tissues. PK and radiotherapy studies were performed in PC-3 tumor-bearing male nude mice. RESULTS: 177Lu-AMBA has a high affinity for the GRP-R (Kd, 1.02 nmol/L), with a maximum binding capacity (Bmax) of 414 fmol/10(6) cells (2.5 x 10(5) GRP-R/cell). Internalization was similar for 177Lu-AMBA (76.8%), 177Lu-BBN8 (72.9%), and 125I-[Tyr4]-BBN (74.9%). Efflux was markedly lower for 177Lu-AMBA (2.9%) compared with 177Lu-BBN8 (15.9%) and 125I-[Tyr4]-BBN (46.1%). By receptor autoradiography, Lu-AMBA binds specifically to GRP-R (0.8 nmol/L) and to the neuromedin B receptor (NMB-R) (0.9 nmol/L), with no affinity for the bb3 receptor (>1,000 nmol/L). 177Lu-AMBA was renally excreted (55 %ID 1 h [percentage injected dose at 1 h]); tumor uptake at 1 and 24 h was 6.35 %ID/g and 3.39 %ID/g, respectively. One or 2 doses of 177Lu-AMBA (27.75 MBq/dose) significantly prolonged the life span of PC-3 tumor-bearing mice (P < 0.001 and P < 0.0001, respectively) and decreased PC-3 tumor growth rate over controls. When compared using World Health Organization criteria, mice receiving 2 doses versus 1 dose of 177Lu-AMBA demonstrated a shift away from stable/progressive disease toward complete/partial response; by RECIST (Response Evaluation Criteria in Solid Tumors), median survival increased by 36% and time to progression/progression-free survival increased by 65%. CONCLUSION: 177Lu-AMBA binds with nanomolar affinity to GRP-R and NMB-R, has low retention of radioactivity in kidney, demonstrates a very favorable risk-benefit profile, and is in phase I clinical trials.

Uveitic glaucoma and Rosai-Dorfman disease (sinus histiocytosis)

PURPOSE: To report a novel association of uveitic glaucoma with Rosai-Dorfman disease. METHODS: Case report. RESULTS: A 67-year-old Caucasian woman presented with a chronic bilateral granulomatous uveitis which did not respond to conventional topical steroid therapy. She also had raised intraocular pressures, glaucomatous optic disc changes and diffuse nodular fibrous skin lesions. Subsequent skin biopsy immuno-cytochemistry showed S-100 staining, consistent with Rosai-Dorfman disease. The uveitis and glaucoma were highly resistant to standard medical treatments, but completely resolved together with the systemic features of the disease after six months. CONCLUSIONS: Rosai-Dorfman disease has not previously been reported to cause uveitic glaucoma and should be considered in non-responsive cases presenting with a rash. The disease is entirely self-limiting and early diagnosis may therefore avoid unnecessary trabeculectomy and/or systemic immune suppression.

Neoadjuvant interstitial high-dose-rate (HDR) brachytherapy combined with systemic chemotherapy in patients with breast cancer

BACKGROUND AND PURPOSE: This is the first study investigating neoadjuvant interstitial high-dose-rate (HDR) brachytherapy combined with chemotherapy in patients with breast cancer. The goal was to evaluate the type of surgical treatment, histopathologic response, side effects, local control, and survival. PATIENTS AND METHODS: 53 patients, who could not be treated with breast-conserving surgery due to initial tumor size (36/53) or due to an unfavorable breast-tumor ratio (17/53), were analyzed retrospectively. All but one were in an intermediate/high-risk group (St. Gallen criteria). The patients received a neoadjuvant protocol consisting of systemic chemotherapy combined with fractionated HDR brachytherapy (2 x 5 Gy/day, total dose 30 Gy). In cases, where breast-conserving surgery was performed, patients received additional external-beam radiotherapy (EBRT, 1.8 Gy/day, total dose 50.4 Gy). In patients, who underwent mastectomy but showed an initial tumor size of T3/T4 and/or more than three infiltrated lymph nodes, EBRT was also performed. RESULTS: In 30/53 patients (56.6%) breast-conserving surgery could be performed. The overall histopathologic response rate was 96.2% with a complete remission in 28.3% of patients. 49/53 patients were evaluable for follow-up. After a median of 58 months (45-72 months), one patient showed a mild fibrosis of the breast tissue, three patients had mild to moderate lymphatic edema of the arm. 6/49 (12.2%) patients died of distant metastases, 4/49 (8.2%) were alive with disease, and 39/49 (79.6%) were free from disease. Local recurrence was observed in only one case (2%) 40 months after primary therapy. After mastectomy, this patient is currently free from disease. CONCLUSION: The combination of interstitial HDR brachytherapy and chemotherapy is a well-tolerated and effective neoadjuvant treatment in patients with breast cancer. Compared to EBRT, treatment time is short. Postoperative EBRT of the whole breast -- if necessary -- is still possible after neoadjuvant brachytherapy. Even though the number of patients does not permit definite conclusions, the results are promising regarding survival and the very low rate of local recurrences.

Association of lipopolysaccharide-binding protein and coronary artery disease in men

OBJECTIVES: In this study we tested the hypothesis that lipopolysaccharide-binding protein (LBP) might be able to be used as a biomarker for coronary artery disease (CAD). BACKGROUND: The mechanisms by which the innate immune recognition of pathogens could lead to atherosclerosis remain unclear. Lipopolysaccharide-binding protein is the first protein to encounter lipopolysaccharide and to deliver it to its cellular targets, toll-like receptors; therefore, its presence might be a reliable biomarker that indicates activation of innate immune responses. METHODS: A total of 247 men undergoing elective coronary angiography were studied, and the extent of coronary atherosclerosis was assessed by 2 established scores: "extent score" and "severity score." Levels of LBP, markers of inflammation, and traditional risk factors for CAD were assessed. RESULTS: Serum LBP concentration was significantly increased in 172 patients with angiographically confirmed CAD compared with 75 individuals without coronary atherosclerosis (20.6 +/- 8.7 pg/ml vs. 17.1 +/- 6.0 pg/ml, respectively; p = 0.002). Moreover in multivariable logistic regression analyses, adjusted for established cardiovascular risk factors and markers of systemic inflammation, LBP was a significant and independent predictor of prevalent CAD (p < 0.05 in all models). CONCLUSIONS: Lipopolysaccharide-binding protein might serve as a novel marker for CAD in men. The present results underlie the potential importance of innate immune mechanisms for CAD. Further studies are warranted to bolster the data and to identify pathogenetic links between innate immune system activation and atherosclerosis.

Orbital manifestation of whipple's disease: an atypical case

BACKGROUND: Whipple's disease is a systemic disorder caused by an infection with a gram-positive bacillus, Tropheryma whipplei. Almost every organ system can be affected in Whipple's disease, resulting in varying clinical symptoms. CASE REPORT: As far as we are aware, this report of a 61-year-old male is the first presenting with a periorbital manifestation of the disease, with severe exophthalmos and optic nerve involvement, leading to rapid visual loss. This emergency case was successfully treated by a surgical orbital decompression combined with systemic use of antibiotics and steroids. CONCLUSION: Whipple's disease can affect the periorbital tissues and the optic nerve, causing massive exophthalmos and serious transient visual loss. In such a case surgical decompression of the affected orbit combined with antibiotics and steroids is a recommended valid treatment option.

Recurrent ischemic colitis in a patient with leiden factor V mutation and systemic lupus erythematous with antiphospholipid syndrome

Ischemic colitis results from insufficient blood supply to the large intestine and is often associated with hypercoagulable states. The condition comprises a wide range presenting with mild to fulminant forms. Diagnosis remains difficult because these patients may present with non-specific abdominal symptoms. We report a 51- year-old female patient with known Leiden factor V mutation as well as systemic lupus erythematous along with antiphospholipid syndrome suffering from recurrent ischemic colitis. At admission, the patient complained about abdominal pain, diarrhea and rectal bleeding lasting for 24 hours. Laboratory tests showed an increased C-reactive protein (29.5 mg/dl), while the performed abdominal CT-scan revealed only a dilatation of the descending colon along with a thickening of the bowel wall. Laparotomy was performed showing an ischemic colon and massive peritonitis. Histological examination proved the suspected ischemic colitis. Consecutively, an anti-coagulation therapy with coumarin and aspirin 100 was initiated. Up to the time point of a follow up examination no further ischemic events had occurred. This case illustrates well the non-specific clinical presentation of ischemic colitis. A high index of suspicion, recognition of risk factors and a history of non-specific abdominal symptoms should alert the clinicians to the possibility of ischemic disease. Early diagnosis and initiation of anticoagulation therapy or surgical intervention in case of peritonitis are the major goals of therapy.

[Effects of tobacco use on systemic health: relevant information for dentistry (II)--part 2: cardiovascular diseases and public health issues]

This is the sixth and concluding part of a series of publications from the Swiss task force named "Smoking - Intervention in the private dental office" on the topic "tobacco use and dental medicine". The focus of this review is the effects of smoking for the development of atherosclerosis as pathohistological correlate for acute coronary syndrome (ACS), arterial occlusive disease, and cerebrovascular diseases (stroke). Additionally, a causal relationship between tobacco use and an increased rate for complications during pregnancy and child birth will be discussed. Next to causal therapy of local and systemic diseases in general, an emphasis must be given to tobacco use prevention and cessation. Finally, important public health issues concerning smoking and tobacco use will be demonstrated, and options to improve the current situation will be presented.

Cardiovascular disease and periodontitis: an update on the associations and risk

BACKGROUND: Associations between periodontitis and cardiovascular diseases have been recognized. MATERIAL AND METHODS: New literature since the last European Workshop on Periodontology has been reviewed. RESULTS: The lack of reliable epidemiological data on disease prevalence makes an assessment of the associations and risks between periodontitis and cardiovascular diseases difficult. Two recent meta-analysis reports have identified associations between periodontitis and cardiovascular diseases (odds ratios: 1.1-2.2). Different surrogate markers for both disease entities, including serum biomarkers, have been investigated. Brachial artery flow-mediated dilatation, and carotid intima media thickness have in some studies been linked to periodontitis. Studies are needed to confirm early results of improvements of such surrogate markers following periodontal therapy. While intensive periodontal therapy may enhance inflammatory responses and impair vascular functions, studies are needed to assess the outcome of periodontal therapies in subjects with confirmed cardiovascular conditions. Tooth eradication may also reduce the systemic inflammatory burden of individuals with severe periodontitis. The role of confounders remain unclear. CONCLUSIONS: Periodontitis may contribute to cardiovascular disease and stroke in susceptible subjects. Properly powered longitudinal case-control and intervention trials are needed to identify how periodontitis and periodontal interventions may have an impact on cardiovascular diseases.

Successful lower extremity angioplasty improves brachial artery flow-mediated dilation in patients with peripheral arterial disease

INTRODUCTION: Peripheral arterial disease (PAD) is associated with systemic impaired flow-mediated dilation (FMD) and increased risk for cardiovascular events. Decreased FMD may be caused by a decrease in arterial shear stress due to claudication and inflammation due to muscle ischemia and reperfusion. We assumed that endovascular revascularization of lower limb arterial obstructions ameliorates FMD and lowers inflammation through improvement of peripheral perfusion. METHODS: The study was a prospective, open, randomized, controlled, single-center follow-up evaluation assessing the effect of endovascular revascularization on brachial artery reactivity (FMD) measured by ultrasound, white blood cell (WBC) count, high-sensitive C-reactive protein (hs-CRP), and fibrinogen. We investigated 33 patients (23 men) with chronic and stable PAD (Rutherford 2 to 3) due to femoropopliteal obstruction. Variables were assessed at baseline and after 4 weeks in 17 patients (group A) who underwent endovascular revascularization and best medical treatment, and in 16 patients (group B) who received best medical treatment only. RESULTS: FMD did not differ between group A and B (4.96% +/- 1.86% vs 4.60% +/- 2.95%; P = .87) at baseline. It significantly improved after revascularization in group A (6.44% +/- 2.88%; P = .02) compared with group B at 4 weeks of follow-up (4.53% +/- 3.17%; P = .92), where it remained unchanged. The baseline ankle-brachial index (ABI) was similar for group A and B (0.63 +/- 0.15 vs 0.66 +/- 0.10; P = .36). At 4 weeks of follow-up, ABI was significantly increased in group A (1.05 +/- 0.15; P = .0004) but remained unchanged in group B (0.62 +/- 0.1). WBC counts of the two groups were comparable at baseline (group A: 7.6 +/- 2.26 x 10(6)/mL and group B: 7.8 +/- 2.02 x 10(6)/mL, P = .81). In group A, the leukocyte count significantly decreased after angioplasty from 7.6 +/- 2.26 to 6.89 +/- 1.35 x 10(6)/mL (P = .03). For group B, WBC count did not differ significantly compared with baseline (7.76 +/- 2.64 x 10(6)/mL; P = .94). No effects were observed on hs-CRP or fibrinogen from endovascular therapy. CONCLUSION: Endovascular revascularization with reestablishment of peripheral arterial perfusion improves FMD and reduces WBC count in patients with claudication. Revascularization may therefore have clinical implications beyond relief of symptoms, for example, reducing oxidative stress caused by repeated muscle ischemia or increased shear stress due to improved ambulatory activity.

Gene and stem cell therapy in peripheral arterial occlusive disease

Peripheral arterial occlusive disease (PAOD) is a manifestation of systemic atherosclerosis strongly associated with a high risk of cardiovascular morbidity and mortality. In a considerable proportion of patients with PAOD, revascularization either by endovascular means or by open surgery combined with best possible risk factor modification does not achieve limb salvage or relief of ischaemic rest pain. As a consequence, novel therapeutic strategies have been developed over the last two decades aiming to promote neovascularization and remodelling of collaterals. Gene and stem cell therapy are the main directions for clinical investigation concepts. For both, preclinical studies have shown promising results using a wide variety of genes encoding for growth factors and populations of adult stem cells, respectively. As a consequence, clinical trials have been performed applying gene and stem cell-based concepts. However, it has become apparent that a straightforward translation into humans is not possible. While several trials reported relief of symptoms and functional improvement, other trials did not confirm this early promise of efficacy. Ongoing clinical trials with an improved study design are needed to confirm the potential that gene and cell therapy may have and to prevent the gaps in our scientific knowledge that will jeopardize the establishment of angiogenic therapy as an additional medical treatment of PAOD. This review summarizes the experimental background and presents the current status of clinical applications and future perspectives of the therapeutic use of gene and cell therapy strategies for PAOD.

Combined approach to hepatocellular carcinoma: a new treatment concept for nonresectable disease

Depending on tumor burden, hepatic function and patients' performance status, hepatocellular carcinoma is treated by surgery, local procedures, systemic therapy or palliation. The majority of patients are diagnosed at a stage where local therapy is the treatment of choice. Recently, the multikinase inhibitor sorafenib was found to improve the survival of patients with advanced hepatocellular carcinoma and conserved liver function. In this manuscript, we summarize the experimental evidence supporting the combination of a systemic targeted therapy with a local therapy. We also discuss the pros and cons of different schedules of combining such treatments. We conclude that there is enough of a theoretical argument to design clinical trials testing this strategy.

[Systemic ANCA-associated vasculitis--diagnosis and therapy]

ANCA-associated vasculitis represents a group of small-vessel vasculitides, including Wegener's granulomatosis, microscopic polyangiitis and the Churg-Strauss-syndrome. These diseases affect mainly small arteries, venules and capillaries, showing a lack of immunocomplex formation on immunohistology, the so-called "pauci-immune" vasculitis. Nevertheless, Anti-Neutrophil Cytoplasmatic Autoantibodies (ANCA's) are pathogenic for this type of disease. In spite of important advances in technical diagnostic tools, careful medical history and clinical examinations often give the clues for the correct diagnosis. Recent collaborative therapeutic studies have lead to therapeutic schemas that are much more adapted to the individual disease state. Besides the acute and sometimes life-threatening form of ANCA-vasculitis, chronic disease and relapses become more important in clinical practice. Thus, therapeutic efficacy must be outweighed against long-term toxicity to make the right choice for therapeutic intervention in ANCA-associated vasculitis.

Relation of morning serum cortisol to prothrombotic activity in women with stable coronary artery disease

BACKGROUND: Increased circulating cortisol levels have been associated with severity of atherosclerosis. Low-grade systemic thrombogenicity plays a major role in the initiation and progression of coronary disease. We hypothesized a direct relationship between cortisol and hemostasis factors related to a prothrombotic state in coronary artery disease. METHODS: We measured morning serum cortisol and activated clotting factor VII, fibrinogen, von Willebrand factor antigen, and plasminogen activator inhibitor-1 activity in 285 women (56 +/- 7 years) between 3 and 6 months after an acute coronary event. To test whether the relationship between cortisol and hemostasis factors would be independent, statistical adjustment was made for demographic, biomedical, life style, and psychosocial variables. RESULTS: Higher serum cortisol levels predicted higher fibrinogen (beta = .17, P = .001) and higher von Willebrand factor (beta = .16, P = .008), all independently of covariates, including C-reactive protein, which was also an independent predictor of fibrinogen (beta = .20, P = .001) and von Willebrand factor (beta = .16, P = .004). Higher levels of vital exhaustion were associated with higher levels of activated clotting factor VII independently of covariates and depression (beta = .18, P = .045). Cortisol showed crude correlations with vital exhaustion (r = .14, P = .022) and with depression (r = .13, P = .043) but did not mediate the relationship between psychosocial variables and hemostatic factors. CONCLUSIONS: Morning serum cortisol showed a modest but independent association with prothrombotic activity in women with coronary artery disease suggesting that increased cortisol levels might contribute to atherosclerosis via eliciting a hypercoagulable state.