A modified calculation of ankle-brachial pressure index is far more sensitive in the detection of peripheral arterial disease

BACKGROUND: Ankle-brachial pressure index (ABI) is a simple, inexpensive, and useful tool in the detection of peripheral arterial occlusive disease (PAD). The current guidelines published by the American Heart Association define ABI as the quotient of the higher of the systolic blood pressures (SBPs) of the two ankle arteries of that limb (either the anterior tibial artery or the posterior tibial artery) and the higher of the two brachial SBPs of the upper limbs. We hypothesized that considering the lower of the two ankle arterial SBPs of a side as the numerator and the higher of the brachial SBPs as the denominator would increase its diagnostic yield. METHODS: The former method of eliciting ABI was termed as high ankle pressure (HAP) and the latter low ankle pressure (LAP). ABI was assessed in 216 subjects and calculated according to the HAP and the LAP method. ABI findings were confirmed by arterial duplex ultrasonography. A significant arterial stenosis was assumed if ABI was <0.9. RESULTS: LAP had a sensitivity of 0.89 and a specificity of 0.93. The HAP method had a sensitivity of 0.68 and a specificity of 0.99. McNemar's test to compare the results of both methods demonstrated a two-tailed P < .0001, indicating a highly significant difference between both measurement methods. CONCLUSIONS: LAP is the superior method of calculating ABI to identify PAD. This result is of great interest for epidemiologic studies applying ABI measurements to detect PAD and assessing patients' cardiovascular risk.

Testing strategies and follow-up for coeliac disease in a general internal medicine outpatient department from 2000 to 2005

PRINCIPLES: Coeliac disease (gluten sensitive enteropathy) is a genetically determined disorder with an incidence in the general population that is comparable to type 2 diabetes mellitus. Awareness of this fact and of the often atypical and oligosymptomatic manifestations is only now gaining ground in the medical profession. A high index of suspicion is important in order to minimise diagnostic and therapeutic delay. METHODS: Testing patterns and follow-up for coeliac disease in our institution have been analysed retrospectively for the past five years. The current literature was reviewed with respect to recommendations for clinical practice. RESULTS: A total of 271 patients were tested for coeliac disease over a period of five years. Only in 24 patients were positive results found; after further work-up, the final number of cases with certain or presumed coeliac disease was four. Followup was often difficult, many patients being lost after a single visit. CONCLUSIONS: This study showed that the number of tests ordered in our institution, more often for abdominal than atypical symptoms, has started to increase in the past two years. It also showed that screening tests have found their place in general clinical practice, while the final choice of tests needs to be determined in accordance with available guidelines and local resources. Upper endoscopy with small bowel biopsy remains the gold standard for diagnosis, but its place in follow-up is less certain. Coeliac disease is a disorder for which there is a definite treatment (gluten free diet); if it is left untreated diminished quality of life and potentially serious complications may ensue. Further education of the medical profession regarding coeliac disease, its incidence, presentation and treatment, is clearly indicated..

A degradation-sensitive anionic trypsinogen (PRSS2) variant protects against chronic pancreatitis

Chronic pancreatitis is a common inflammatory disease of the pancreas. Mutations in the genes encoding cationic trypsinogen (PRSS1) and the pancreatic secretory trypsin inhibitor (SPINK1) are associated with chronic pancreatitis. Because increased proteolytic activity owing to mutated PRSS1 enhances the risk for chronic pancreatitis, mutations in the gene encoding anionic trypsinogen (PRSS2) may also predispose to disease. Here we analyzed PRSS2 in individuals with chronic pancreatitis and controls and found, to our surprise, that a variant of codon 191 (G191R) is overrepresented in control subjects: G191R was present in 220/6,459 (3.4%) controls but in only 32/2,466 (1.3%) affected individuals (odds ratio 0.37; P = 1.1 x 10(-8)). Upon activation by enterokinase or trypsin, purified recombinant G191R protein showed a complete loss of trypsin activity owing to the introduction of a new tryptic cleavage site that renders the enzyme hypersensitive to autocatalytic proteolysis. In conclusion, the G191R variant of PRSS2 mitigates intrapancreatic trypsin activity and thereby protects against chronic pancreatitis.

Development of a highly sensitive and specific assay to detect Staphylococcus aureus in bovine mastitic milk

Diagnosis of udder infections with Staphylococcus aureus by bacteriological milk testing of quarter milk samples is often not satisfactory. To get reliable results, repeated sampling is necessary, which is normally too expensive. Therefore, we developed a test that allows the highly specific detection of Staph. aureus in bovine milk samples at very low concentrations. It is based on a fast procedure to prepare bacteria from milk, followed by DNA extraction and quantitative PCR. The whole analysis is done within 5 h. For clinical milk samples, the analytical sensitivity of the assay was 50.7 times and 507 times higher than conventional bacteriology with 100 and 10 microL, respectively. The diagnostic specificity was 100%. The test is further characterized by a low intra- and interassay variability as well as by a good recovery of Staph. aureus from raw milk. Furthermore, a high correlation (R = 0.925) between the agar plate counts and the quantitative PCR methodology over the whole range of measurement was found. In addition, our test revealed considerably more positive results than bacteriology. Due to its favorable properties, the assay might become an important diagnostic tool in the context of bovine mastitis caused by Staph. aureus.

Myeloid-related protein 8/14 complex is released by monocytes and granulocytes at the site of coronary occlusion: a novel, early, and sensitive marker of acute coronary syndromes

AIMS: We investigated whether myeloid-related protein 8/14 complex (MRP8/14) expressed by infiltrating monocytes and granulocytes may represent a mediator and early biomarker of acute coronary syndromes (ACS). METHODS AND RESULTS: Immunohistochemistry of coronary thrombi was done in 41 ACS patients. Subsequently, levels of MRP8/14 were assessed systemically in 75 patients with ACS and culprit lesions, with stable coronary artery disease (CAD), or with normal coronary arteries. In a subset of patients, MRP8/14 was measured systemically and at the site of coronary occlusion. Macrophages and granulocytes, but not platelets stained positive for MRP8/14 in 76% of 41 thrombi patients. In ACS, local MRP8/14 levels [22.0 (16.2-41.5) mg/L] were increased when compared with systemic levels [13.4 (8.1-14.7) mg/L, P = 0.03]. Systemic levels of MRP8/14 were markedly elevated [15.1 (12.1-21.8) mg/L, P = 0.001] in ACS when compared with stable CAD [4.6 (3.5-7.1) mg/L] or normals [4.8 (4.0-6.3) mg/L]. Using a cut-off level of 8 mg/L, MRP8/14 but not myoglobin or troponin, identified ACS presenting within 3 h from symptom onset. CONCLUSION: In ACS, MRP8/14 is markedly expressed at the site of coronary occlusion by invading phagocytes. The occurrence of elevated MRP8/14 in the systemic circulation prior to markers of myocardial necrosis makes it a prime candidate for the detection of unstable plaques and management of ACS.

GH mutant (R77C) in a pedigree presenting with the delay of growth and pubertal development: structural analysis of the mutant and evaluation of the biological activity

A heterozygous missense mutation in the GH-1 gene converting codon 77 from arginine (R) to cysteine (C), which was previously reported to have some GH antagonistic effect, was identified in a Syrian family. The index patient, a boy, was referred for assessment of his short stature (-2.5 SDS) at the age of 6 years. His mother and grandfather were also carrying the same mutation, but did not differ in adult height from the other unaffected family members. Hormonal examination in all affected subjects revealed increased basal GH, low IGF-I concentrations, and subnormal IGF-I response in generation test leading to the diagnosis of partial GH insensitivity. However, GH receptor gene (GHR) sequencing demonstrated no abnormalities. As other family members carrying the GH-R77C form showed similar alterations at the hormonal level, but presented with normal final height, no GH therapy was given to the boy, but he was followed through his pubertal development which was delayed. At the age of 20 years he reached his final height, which was normal within his parental target height. Functional characterization of the GH-R77C, assessed through activation of Jak2/Stat5 pathway, revealed no differences in the bioactivity between wild-type-GH (wt-GH) and GH-R77C. Detailed structural analysis indicated that the structure of GH-R77C, in terms of disulfide bond formation, is almost identical to that of the wt-GH despite the introduced mutation (Cys77). Previous studies from our group demonstrated a reduced capability of GH-R77C to induce GHR/GH-binding protein (GHBP) gene transcription rate when compared with wt-GH. Therefore, reduced GHR/GHBP expression might well be the possible cause for the partial GH insensitivity found in our patients. In addition, this group of patients deserve further attention because they could represent a distinct clinical entity underlining that an altered GH peptide may also have a direct impact on GHR/GHBP gene expression causing partial GH insensitivity. This might be responsible for the delay of growth and pubertal development. Finally, we clearly demonstrate that GH-R77C is not invariably associated with short stature, but that great care needs to be taken in ascribing growth failure to various heterozygous mutations affecting the GH-IGF axis and that careful functional studies are mandatory.

Oxygen-sensitive 3He-MRI in bronchiolitis obliterans after lung transplantation

Oxygen-sensitive 3He-MRI was studied for the detection of differences in intrapulmonary oxygen partial pressure (pO2) between patients with normal lung transplants and those with bronchiolitis obliterans syndrome (BOS). Using software developed in-house, oxygen-sensitive 3He-MRI datasets from patients with normal lung grafts (n = 8) and with BOS (n = 6) were evaluated quantitatively. Datasets were acqiured on a 1.5-T system using a spoiled gradient echo pulse sequence. Underlying diseases were pulmonary emphysema (n = 10 datasets) and fibrosis (n = 4). BOS status was verified by pulmonary function tests. Additionally, 3He-MRI was assessed blindedly for ventilation defects. Median intrapulmonary pO2 in patients with normal lung grafts was 146 mbar compared with 108 mbar in patients with BOS. Homogeneity of pO2 distribution was greater in normal grafts (standard deviation pO2 34 versus 43 mbar). Median oxygen decrease rate during breath hold was higher in unaffected patients (-1.75 mbar/s versus -0.38 mbar/s). Normal grafts showed fewer ventilation defects (5% versus 28%, medians). Oxygen-sensitive 3He-MRI appears capable of demonstrating differences of intrapulmonary pO2 between normal lung grafts and grafts affected by BOS. Oxygen-sensitive 3He-MRI may add helpful regional information to other diagnostic techniques for the assessment and follow-up of lung transplant recipients.

Variation in habitat choice and delayed reproduction: Adaptive queuing strategies or individual quality differences?

In most species, some individuals delay reproduction or occupy inferior breeding positions. The queue hypothesis tries to explain both patterns by proposing that individuals strategically delay breeding (queue) to acquire better breeding or social positions. In 1995, Ens, Weissing, and Drent addressed evolutionarily stable queuing strategies in situations with habitat heterogeneity. However, their model did not consider the non - mutually exclusive individual quality hypothesis, which suggests that some individuals delay breeding or occupy inferior breeding positions because they are poor competitors. Here we extend their model with individual differences in competitive abilities, which are probably plentiful in nature. We show that including even the smallest competitive asymmetries will result in individuals using queuing strategies completely different from those in models that assume equal competitors. Subsequently, we investigate how well our models can explain settlement patterns in the wild, using a long-term study on oystercatchers. This long-lived shorebird exhibits strong variation in age of first reproduction and territory quality. We show that only models that include competitive asymmetries can explain why oystercatchers' settlement patterns depend on natal origin. We conclude that predictions from queuing models are very sensitive to assumptions about competitive asymmetries, while detecting such differences in the wild is often problematic.

Activities of ertapenem, a new long-acting carbapenem, against penicillin-sensitive or -resistant pneumococci in experimental meningitis

The penetration of ertapenem, a new carbapenem with a long half-life, reached 7.1 and 2.4% into inflamed and noninflamed meninges, respectively. Ertapenem had excellent antibacterial activity in the treatment of experimental meningitis due to penicillin-sensitive and -resistant pneumococci, leading to a decrease of 0.69 +/- 0.17 and 0.59 +/- 0.22 log(10) CFU/ml x h, respectively, in the viable cell counts in the cerebrospinal fluid. The efficacy of ertapenem was comparable to that of standard regimens (ceftriaxone monotherapy against the penicillin-sensitive strain and ceftriaxone combined with vancomycin against the penicillin-resistant strain). In vitro, ertapenem in concentrations above the MIC was highly bactericidal against both strains. Even against a penicillin- and quinolone-resistant mutant, ertapenem had similar bactericidal activity in vitro.

Efficacies of BMS 284756 against penicillin-sensitive, penicillin-resistant, and quinolone-resistant pneumococci in experimental meningitis

BMS 284756 penetrated well into inflamed meninges (44% +/- 11%) and produced good bactericidal activity (-0.82 +/- 0.22 Delta log(10) CFU/ml. h) in the treatment of experimental meningitis in rabbits due to a penicillin-sensitive strain. BMS 284756 monotherapy had a greater potency than the standard regimen of ceftriaxone and vancomycin (-0.49 +/- 0.08 Delta log(10) CFU/ml. h) against a penicillin-resistant strain (MIC, 4 mg/liter). Even against a penicillin- and quinolone-resistant strain, BMS 284756 showed good bactericidal activity (-0.52 +/- 0.12 Delta log(10) CFU/ml. h). The antibacterial activity of BMS 284756 was confirmed by time-killing assays over 8 h in vitro.

Linezolid against penicillin-sensitive and -resistant pneumococci in the rabbit meningitis model

Linezolid, a new oxazolidinone antibiotic, showed good penetration (38+/-4%) into the meninges of rabbits with levels in the CSF ranging from 9.5 to 1.8 mg/L after two i.v. injections (20 mg/kg). Linezolid was clearly less effective than ceftriaxone against a penicillin-sensitive pneumococcal strain. Against a penicillin-resistant strain, linezolid had slightly inferior killing rates compared with the standard regimen (ceftriaxone combined with vancomycin). In vitro, linezolid was marginally bactericidal at concentrations above the MIC (5 x and 10 x MIC).

Comparative efficacy of trovafloxacin in experimental endocarditis caused by ciprofloxacin-sensitive, methicillin-resistant Staphylococcus aureus

The new fluoroquinolone trovafloxacin was tested against a ciprofloxacin-sensitive, methicillin-resistant Staphylococcus aureus strain in the rabbit model of endocarditis. Trovafloxacin was more effective than vancomycin (CFU/g of vegetation, 2.65 +/- 1.87 versus 4.54 +/- 2.80 [mean +/- standard deviation]; P < 0.05) or ampicillin-sulbactam plus rifampin (4.9 +/- 1.1 CFU/g). The addition of ampicillin-sulbactam to trovafloxacin tended to reduce titers further.