Arterial stiffness indexes and serum cytokine levels in seronegative spondyloarthritis: relationships between stiffness markers and metabolic and immunoinflammatory variables.

OBJECTIVE: The aim of this study was to investigate the relationship between immunoinflammatory markers and indexes of arterial stiffness in patients with seronegative spondyloarthritis (SpA). METHOD: We enrolled consecutive patients with inflammatory seronegative SpA referred to a rheumatology outpatient clinic. Control subjects were patients admitted in the same period for any cause other than chronic inflammatory disease or acute cardiovascular and cerebrovascular events. Carotid-femoral pulse wave velocity (PWV) was measured and the aortic pressure waveform was used to calculate the augmentation index (Aix). We also evaluated plasma levels of C-reactive protein (CRP), interleukin (IL)-1ß, tumour necrosis factor (TNF)-α, and interleukin (IL)-6 as markers of immunoinflammatory activation. RESULTS: This study enrolled 53 patients with SpA and 55 control subjects. After adjustment for blood glucose, cholesterol, and triglyceride levels, and systolic (SBP) and diastolic blood pressure (DBP), patients with seronegative SpA showed higher mean PWV and Aix compared to controls. Moreover, in patients with seronegative SpA, we observed higher mean plasma levels of IL-6, IL-1ß, and TNF-α in subjects with mean PWV > 8 m/s in comparison with those with PWV < 8 m/s. Multivariate analysis revealed a significant association between PWV > 8 m/s and male gender, age, diabetes, hypertension, low density lipoprotein cholesterol (LDL-C) > 120 mg/dL, total cholesterol (TC) > 200 mg/dL, coronary artery disease (CAD), microalbuminuria, carotid plaque, and plasma levels of IL-6, IL-1ß, and TNF-α. CONCLUSIONS: These findings emphasize the role of inflammatory variables and metabolic factors in indexes of high arterial stiffness. Thus, an inflammatory-metabolic background may influence the pathogenesis of increased arterial stiffness in seronegative inflammatory arthritis.

Humanitarian mission improves health conditions of schoolchildren in Ethiopia. the case of Adwa.

OBJECTIVE: The objective of this study is to compare health conditions of schoolchildren receiving aids from the mission Kidane Mehret Integrated Project (KMIP) in the city of Adwa, Ethiopia, with the ones of the general population. METHODS: From September, 2008, to November, 2008, 400 children were randomly selected in the school inside KMIP and in the one of Adi Abetu. In phase 1, a questionnaire was distributed to children's families. In phase 2, children underwent physical examination. RESULTS: Girls from KMIP started weaning on average at 7.3+/-3.9 vs 8.3+/-4.7 months of the control group (p>0.05); boys from KMIP started weaning on average at 6.7+/-4.1 vs 8.7+/-5.1 months of the control group (p<0.01). Centiles for height for age, weight for age and BMI for age were significantly higher in girls attending KMIP compared to the control group. CONCLUSIONS: Merged data suggests the significant impact of KMIP on the schoolchildren of Adwa. Moreover, women and youngest children, usually the most discriminates, were the band of the society that benefited most from the aids coming from the mission.

Met-Ile-Phe-Leu derivatives: full and partial agonists of human neutrophil formylpeptide receptors.

The biological action of a series of Met-Ile-Phe-Leu analogues was analyzed on human neutrophils, to evaluate their ability to interact with formylpeptide receptors and to induce the related neutrophil responses. Three in vitro assays were carried out: receptor binding, chemotaxis and superoxide anion release. Our results demonstrate that formyl-Met-Ile-Phe-Leu derivatives act as more potent full agonists than formyl-Met-Leu-Phe, the tripeptide normally used as a model chemoattractant for the study of cell functions. On the other hand, the presence of N-ureidoisopropyl substituent in tetrapeptides imparts weak partial agonist properties. It has furthermore been demonstrated that the C-terminal methyl esterification or amination weakly influences the properties of tetrapeptide homologues. Finally, t-Boc-Met-Ile-Phe-Leu derivatives do not appear able to interact with formylpeptide receptors.

Binding thermodynamics and intrinsic activity of adenosine A1 receptor ligands.

A thermodynamic analysis of the binding to rat cortex adenosine A1 receptors of 5'-deoxyribose-N6-cyclopentyladenosine (full agonist) and several 8-alkylamino homologues of N6-cyclopentyladenosine (partial agonists) was performed. The intrinsic activity of the compounds was also evaluated by measuring the inhibition of forskolin-stimulated 3'-5'-cyclic adenosine monophosphate (c-AMP) levels in isolated epididymal rat adipocytes. Standard free energy (deltaG), enthalpy (deltaH ) and entropy (deltaS ) of the binding equilibrium were determined by affinity measurements carried out at different temperatures (0, 10, 20, 25, 30 degrees C). Affinity constants of drug-receptor interactions were obtained by displacement experiments in the presence of 1nM [3H]N6-cyclohexyladenosine. Levels of c-AMP were evaluated by performing competitive binding assays. As the affinity of the ligands was found to increase with temperature enhancement, the binding of full and partial agonists is therefore totally entropy-driven. Standard entropy values of a wide series of adenosine derivatives, including the compounds under examination, are strictly correlated to those of intrinsic activity. Similarly, deltaS values appear correlated to the in vivo ability of the adenosine derivatives to inhibit rat heart rate. Thermodymanic data of adenosine A1 receptor ligands are proposed as an indicator of their pharmacodynamics.

Conformational aspects of human formylpeptide receptor antagonists.

The conformation of several Phe-D-Leu-Phe-D-Leu-Phe analogues was analyzed using infrared absorption and circular dichroism. Their effect on human neutrophils was verified by receptor binding and chemotaxis assays. The results demonstrate that the compounds examined prefer an ordered conformation (beta-turn) in amphipatic environment, and that they are able to antagonize the neutrophil functions evoked by CHO-Met-Leu-Phe.

Phe-D-Leu-Phe-D-Leu-Phe derivatives as formylpeptide receptor antagonists in human neutrophils: cellular and conformational aspects.

We synthesized several Phe-d-Leu-Phe-d-Leu-Phe analogues in which tert-butyloxycarbonyl and four different ureido substituents were included at the N-terminal of the peptides, obtained as free acid and methyl-ester derivatives. Their biological action was analysed on human neutrophil responses induced by N-formyl-Met-Leu-Phe (fMLF). Several in vitro assays were carried out: receptor binding, measurement of Ca2+ intracellular concentration, chemotaxis, superoxide anion production and enzyme release. A conformational investigation, using infrared absorption and circular dichroism, was also performed. Our results demonstrate that the compounds examined prefer an ordered conformation (beta-turn) in amphipathic environment, and are able to antagonize the neutrophil functions evoked by fMLF. Moreover, the extent of inhibition of Ca2+ intracellular enhancement, as well as of superoxide anion production and granule enzyme release, appears related to their affinity toward the formylpeptide receptor. The free acid peptide derivatives appear to be more active antagonists than the methyl-ester ones.

Synthesis, biological activity and conformational studies of geometrically restricted tripeptide analogues of the chemoattractant HCO-Met-Leu-Phe-OMe.

The formyl tripeptides containing 2-azetidinecarboxylic acid 2, 2-piperidinecarboxylic acid 3 and norvaline 4 in position 2 were synthesized and their biological activity was evaluated. The conformation of peptides was studied by CD and FT-IR techniques. While 2 and 3 do not show either chemotactic activity or superoxide production, 4 retains both activities.

Predictors of transcutaneous oxygen tension in the lower limbs of diabetic subjects.

We examined neuropathy, ankle pressure index (API), and other factors as predictors of transcutaneous oxygen (TcPO2) in the lower limbs of 657 diabetic subjects. Eligible subjects underwent a clinical assessment that included three standard measures of autonomic neuropathy. TcPO2 measurements were performed at 37 degrees C and 44 degrees C at four lower limb locations. Associations between potential predictors and TcPO2 were tested using univariate and multivariate statistics. Mean TcPO2 at any site did not differ by presence of autonomic neuropathy at either temperature, except for a significantly lower value at 44 degrees C below the knee (56.5 versus 59.2 mmHg, p = 0.021). In multivariate analysis, autonomic neuropathy was significantly and independently related to leg 44 degrees C TcPO2 only (coefficient = -2.6734, p = 0.0182). Much stronger associations were seen between TcPO2 and age, ankle blood pressure, and relative body weight on the plantar foot; and between API, glycosylated haemoglobin, ankle blood pressure, and pedal oedema on the dorsal foot and leg. We conclude that factors related to lower limb TcPO2 vary depending on measurement site. Autonomic neuropathy is not an important determinant of TcPO2 in the feet of diabetic subjects. Although several predictors of TcPO2 were identified, most of the variance of this measurement remains unexplained.

Paradoxical transcutaneous oxygen response to cutaneous warming on the plantar foot surface: a caution for interpretation of plantar foot TcPO2 measurements.

We examined the effect of cutaneous warming on the transcutaneous oxygen measurement (TcPO2) at standard locations below the knee, on the dorsal foot, on the plantar right great toe, and on the plantar surface under the second metatarsal head of 656 diabetic and 16 nondiabetic subjects. All subjects underwent a directed medical history, physical examination, and neurovascular lower extremity evaluation and assessment of autonomic neuropathy. Associations between autonomic neuropathy and TcPO2 were tested using two-way analysis of variance and multiple linear regression. An unexpected, statistically significant fall in TcPO2 occurred with cutaneous warming from 37 degrees C to 44 degrees C on the plantar great toe surface that did not differ by presence of autonomic neuropathy, or the presence of diabetes (mean change: -8.82 mmHG, 95% confidence interval [CI]: -7.70 to -9.93). The TcPO2 measured at the plantar metatarsal head site also fell with cutaneous warming from 37 degrees C to 44 degrees C (mean change: -9.67 mmHG, 95% CI: -7.75 to -11.59). As expected, the TcPO2 increased with cutaneous warming from 37 degrees C to 44 degrees C on the dorsal foot site (mean rise:= 35.61 mmHg, 95% CI: 34.18 to 37.04). The mean TcPO2 at any site did not differ by presence of autonomic neuropathy at either 37 degrees C or 44 degrees C. We conclude that cutaneous warming leads to a paradoxical fall in TcPO2 on the plantar foot surface that does not depend on the presence of autonomic neuropathy or diabetes. Caution in interpretation of ambient versus warmed plantar TcPO2 values is recommended.

The independent contributions of diabetic neuropathy and vasculopathy in foot ulceration. How great are the risks?

OBJECTIVE: To describe the relative contributions of neurological and vascular abnormalities to the overall risk of diabetic foot ulceration. RESEARCH DESIGN AND METHODS: A case-control study of diabetic veterans from the Seattle Veterans Affairs Medical Center was conducted using data collected from 46 patients with diabetic foot ulcers and 322 control subjects. Neuropathy was determined by vibratory, monofilament, and tendon reflex testing. Macrovascular disease was measured by ankle-arm blood pressure index, and cutaneous perfusion was measured by transcutaneous oxygen tension (TcPO2) on the dorsal foot. A multivariate logistic regression model was used to adjust for confounding variables and to calculate the odds ratios (ORs) for each independent risk factor. RESULTS: Three variables were significant independent predictors of foot ulceration: absence of Achilles tendon reflexes (adjusted OR 6.48, 95% confidence interval [CI] 2.37-18.06), insensate to the 5.07 monofilament (adjusted OR 18.42, 95% CI 3.83-88.47), and TcPO2 < 30 mmHg (adjusted OR 57.87, 95% CI 5.08-658.96). Absent vibratory sensation and low ankle-arm blood pressure index were not significant independent risk factors. CONCLUSIONS: Both neuropathy and vasculopathy are strong independent risk factors for the development of diabetic foot ulcers. In our model, the strongest risk factor is impaired cutaneous oxygenation. However, in the clinical setting, sensory examination with a 5.07 monofilament probably remains the single most practical measure of risk assessment.

The health and functional status of veterans with diabetes.

OBJECTIVE: To determine the extent of functional impairment among veterans with diabetes and investigate whether such functional impairment is associated with measures of glycemic control, sensory neuropathy, lower extremity macrovascular disease, or other comorbid conditions. RESEARCH DESIGN AND METHODS: A 20-item general health survey (SF-20) developed by the Medical Outcomes Study (MOS) Group, was administered to 577 subjects participating in a prospective study of risk factors for diabetic foot ulceration. Measures of glycemic control and neurovascular disease included GHb, sensory lower extremity neuropathy assessed by aesthesiometry, and segmental lower extremity doppler blood pressures. RESULTS: Veterans with diabetes have major decreases in all domains of functional status; 87% were in poor health in terms of physical functioning and 86% in terms of health perceptions. Those with advancing age, symptoms of neuropathy and claudication, and a medical history of complications associated with diabetes had significantly more impairment of health status than those without. GHb values did not correlate with functional status measures. Subjects with neuropathy had statistically significant functional impairment. Subjects with vasculopathy had only two significantly low health status measures. CONCLUSIONS: In summary, the findings from this survey reveal that veterans with diabetes have low functional status scores. The presence of symptoms and complications accounts for only part of the impairments experienced by this group.

Definitions and guidelines for assessment of wounds and evaluation of healing.

BACKGROUND: Chronic wounds represent a worldwide problem. For laboratory and clinical research to adequately address this problem, a common language needs to exist. OBSERVATION: This language should include a system of wound classification, a lexicon of wound descriptors, and a description of the processes that are likely to affect wound healing and wound healing end points. CONCLUSIONS: The report that follows defines wound, acute wound, chronic wound, healing and forms of healing, wound assessment, wound extent, wound burden, and wound severity. The utility of these definitions is demonstrated as they relate to the healing of a skin wound, but these definitions are broadly applicable to all wounds.

Underreporting of diabetes on death certificates, King County, Washington.

We estimated the reporting of diabetes on death certificates for persons known to have diabetes. Surveillance of 19 hospitals and two paramedic emergency medical services during 12 months in Seattle and King County, Washington, ascertained acute ischemic heart disease events for persons with diabetes and yielded 1235 persons with suspected ischemic heart disease. Mortality was 23.6%, and 41% of death certificates listed diabetes. The reporting of diabetes on the death certificate was not random, and it varied by patient and physician characteristics. Diabetes is strongly linked to fatal ischemic heart disease, but its importance is underrepresented by death certificates for some subgroups.

Risk factors for amputation in patients with diabetes mellitus. A case-control study.

OBJECTIVE: To identify and quantify risk factors for lower extremity amputation in persons with diabetes mellitus. DESIGN: Case-control study. SETTING: A Veterans Affairs medical center. PATIENTS: Eighty patients having amputation associated with diabetes and 236 diabetic controls without limb lesions were enrolled before surgery from the 21,167 inpatient care and outpatient surgical patients seen at the Seattle Veterans Affairs Medical Center during a 30-month period. MEASUREMENTS: Selected vascular, neuropathic, environmental, health care, self care, nutritional, metabolic, lifestyle, and psychosocial risk factors were measured in all patients before surgery. RESULTS: Statistically significant risk factors identified from analysis included insufficient mean below-knee and foot cutaneous circulation (odds ratio, 161; 95% CI, 55.1 to 469); ankle-arm blood pressure index less than 0.45 (odds ratio, 55.8; CI, 14.9 to 209); absence of lower leg vibratory perception (odds ratio, 15.5; CI, 8.3 to 28.7); low levels of high-density lipoprotein (HDL) subfraction 3 less than or equal to 0.7 mumol/L (odds ratio, 4.9; CI, 2.9 to 8.3); and no previous outpatient diabetes education (odds ratio, 3.2; CI, 1.6 to 6.6). A logistic regression analysis done to control for the potentially confounding effects of age; race; socioeconomic status; diabetes duration, type, and severity confirmed these findings and added a statistically significant interaction between foot transcutaneous oxygen tension and peripheral vascular disease history. Clinical interventions to alter these risk factors were identified, including aggressive treatment of infection, diabetes education, protective footwear, and preventive footcare. CONCLUSIONS: Multiple risk factors exist along the continuum of conditions and events leading to lower extremity amputation in diabetes. Modification of certain risk factors by patients and health professionals may reduce the risk for amputation and thus decrease the human and dollar costs that accompany limb loss in this prevalent chronic disease.

Evolutionary pattern of the H 3 haemagglutinin of equine influenza viruses: multiple evolutionary lineages and frozen replication.

The nucleotide and deduced amino acid sequences of the haemagglutinin genes coding for the HA 1 domain of H3N8 equine influenza viruses isolated over wide regions of the world were analyzed in detail to determine their evolutionary relationships. We have constructed a phylogenetic model tree by the neighbour-joining method using nucleotide sequences of 15 haemagglutinin genes, including those of five viruses determined in the present study. This gene tree revealed the existence of two major evolutionary pathways during a twenty five-year period between 1963 to 1988, and each pathway appeared to consist of two distinct lineages of haemagglutinin genes. Furthermore, our analysis of nucleotide sequences showed that two distinct lineages of equine H3N8 viruses were involved in an equine influenza outbreak during the period of December 1971-January 1972 in Japan. The number of nucleotide changes between strains was proportional to the length of time (in years) between their isolation except for three of the HA genes. However, there are three exceptional strains isolated in 1971, 1987, and 1988, respectively. The haemagglutinin gene in these strains showed a small number of nucleotide substitutions after they branched off around 1963, suggesting an example of frozen replication. Although the estimated rate (0.0094/site/year) of synonymous (silent) substitutions of the haemagglutinin gene of equine H3N8 viruses was nearly the same as that of human H 1 and H 3 haemagglutinin genes, the rate of nonsynonymous (amino-acid changing) substitutions of the former equine virus gene was estimated to be 0.00041/site/year--that is about 5 times lower than that estimated for the human H 3 haemagglutinin gene. The present study is the first demonstration that multiple evolutionary lineages of equine H3N8 influenza virus circulated since 1963.

Immediate and long-term efficacy of systemic antibiotics for eradicating nasal colonization with Staphylococcus aureus.

The efficacy of nine antibiotics used in different nonrandomized regimens for eradicating nasal colonization with Staphylococcus aureus was investigated in 72 patients. Dicloxacillin, erythromycin and three cephalosporins had eradicated colonization in about 75% of cases at early follow-up (less than or equal to 20 days) and in less than or equal to 50% at late follow-up (greater than or equal to 20 days). Clindamycin had eradicated colonization in all 13 patients at both follow-up times. One of two patients was successfully treated with fleroxacin, as were three of five with enoxacin. Among 21 patients treated with ofloxacin, colonization was eradicated in 20 (95%) at early follow-up and in all six of those from whom late follow-up cultures were obtained. Thus, clindamycin and ofloxacin appear to be useful systemic antibiotics for eradicating nasal colonization with Staphylococcus aureus.

Chronology and determinants of tissue repair in diabetic lower-extremity ulcers.

The natural history of tissue repair and the critical determinants of faulty healing of diabetic ulcers remain obscure despite recent advances in our knowledge of the cellular physiology of normal cutaneous healing. To characterize the chronology and identify important factors affecting healing, we applied an objective method to quantify the rate of wound healing of full-thickness lower-extremity ulcers in 46 diabetic outpatients who received local wound care under a standardized clinical protocol. The initial ulcer healing rate, eventual status of tissue repair, and definitive clinical outcome were not significantly associated with age; diabetes type, duration, or treatment; level or change in glycosylated hemoglobin; current smoking; presence of sensory neuropathy; ulcer location or class; initial infection; or frequency of recurrent infections. However, direct measures of local cutaneous perfusion, estimated by periwound measurements of transcutaneous O2 tension (TcPo2) and transcutaneous CO2 tension (TcPco2), were significantly associated with the initial rate of tissue repair (P = 0.003 and 0.005, respectively). The strong prediction of early healing by these parameters of local skin perfusion was independent from the effects of segmental Doppler arterial blood pressure at the dorsalis pedis, although eventual ulcer reepithelialization was significantly related to foot blood pressure and periwound TcPo2 and TcPco2. We conclude that periwound cutaneous perfusion is the critical physiological determinant of diabetic ulcer healing, indicating a 39-fold increased risk of early healing failure when the average periwound TcPo2 is less than 20 mmHg.

Diagnosis of osteomyelitis in the presence of soft-tissue infection and radiologic evidence of osseous abnormalities: value of leukocyte scintigraphy.

To evaluate the usefulness of 111In-leukocyte scintigraphy for identifying osteomyelitis in the presence of soft-tissue infection, we prospectively studied 45 bone sites adjacent to soft-tissue infection in patients with abnormal findings on radiographs and 99mTc bone scans that were suggestive of osteomyelitis. 111In-leukocyte scans were analyzed in terms of the intensity of abnormal uptake and its location relative to bone. The diagnosis of osteomyelitis was established from results of percutaneous bone biopsy culture (n = 35), histologic examination of surgical specimens (n = 8), and clinical follow-up (n = 2). Osteomyelitis was present at 22 sites, including 16 of 18 sites with increased leukocyte uptake in bone, resulting in a sensitivity of 73%, specificity of 91%, and positive predictive value of 89% for this finding. Osteomyelitis was present at four of 17 sites with predominantly soft-tissue localization of leukocyte activity in the region of bone, none of seven sites with normal leukocyte scans, and two of three sites with diminished leukocyte uptake in bone. Although not helpful in distinguishing infectious from noninfectious bone abnormalities, 3- and especially 24-hr bone scans viewed in conjunction with leukocyte studies provided important correlation to aid in estimating the location of focal abnormal leukocyte uptake. The finding of soft-tissue infection with increased uptake of labeled leukocytes that extends to involve adjacent bone strongly suggests concurrent osteomyelitis. When the presence of abnormal leukocyte uptake in bone is uncertain, additional imaging and possibly biopsy may be required to establish or exclude the diagnosis of osteomyelitis.