High levels of serum sclerostin and DKK1 in a case of Klippel-Trénaunay syndrome.

Klippel-Trénaunay syndrome (KTS) is described as a complex syndrome characterized by various combinations of capillary, venous, and lymphatic malformations associated with bone and soft tissue hypertrophy. We report a case of a 67-year-old postmenopausal Caucasian women with KTS that shows elevated levels of sclerostin and Dickkopf-related protein 1 (DKK1). Dual-energy X-ray absorptiometry (DXA) BMD T-scores at lumbar spine and femur were normal. Serum calcium and phosphorus levels were consistently normal, 25-hydroxyvitamin D (25OHD) < 30 ng/mL, and normal parathyroid hormone (PTH). Turnover markers (serum osteocalcin [OCN], and carboxy-terminal cross-linking telopeptide of type 1 collagen [CTx]) were in the reference limits. It is interesting to note that the serum levels of sclerostin and DKK-1 were significantly higher in our patient with KTS than in a healthy volunteer (control), without impact on bone mineral density and bone formation markers. In fact, in our patient, the BMD at lumbar spine and femur was normal, and osteocalcin was not suppressed. Based on what is known, we would have expected to find low levels of the inhibitors of the Wnt system, perhaps we can explain the data as a response to the compensation for ß-catenin hyper-transformation.

Subcutaneous administration of tocilizumab is effective in myointimal hyperplasia remodelling in refractory Takayasu arteritis.

Takayasu arteritis (TA) is a chronic inflammatory disease of unknown origin that involves large and mediumsized arteries, primarily the aorta and its major branches. TA is a therapeutic challenge because corticosteroids and conventional immunosuppressive agents are not always effective or safe. Interleukin 6 (IL-6) has emerged as a key cytokine in the pathogenesis of TA and its serum levels have been shown to well correlate with disease activity. We report a 19 years old female patient with TA refractory to conventional immunosuppressive agents, successfully treated with subcutaneous tocilizumab, a humanized monoclonal antibody against IL-6 receptor, in which ultrasonography (US) was used as imaging tool to follow up the patient. Currently, clinical indices of disease activity, inflammatory markers, carotid intima media thickness (cIMT) as well as carotid pulse wave velocity (cPWV) normalised, while the prednisone dosage has been tapered. Tocilizumab appears to be a good option in refractory TA, with a remarkable steroid-sparing effect. In addition, it seems to have a favourable effect on endothelial function, as it improved cIMT and PWV.

Circulating progenitor cells in rheumatoid arthritis: association with inflammation and oxidative stress.

OBJECTIVES: To evaluate the association between inflammation, oxidative stress, and circulating progenitor cell (CPC) number and redox equilibrium, vascular lesions and accelerated atherosclerosis in rheumatoid arthritis (RA). METHOD: Circulating CD34+ cells were isolated from 33 RA patients and 33 controls. Reactive oxygen species (ROS) levels and mRNA expression of manganese superoxide dismutase (MnSOD), catalase (CAT), glutathione peroxidase type 1 (GPx-1) antioxidant enzymes, and the gp91phox-containing nicotinamide adenine dinucleotide phosphate (NADPH) oxidase NOX2 were measured in CD34+ cells. C-reactive protein (CRP), fibrinogen, erythrocyte sedimentation rate (ESR), carotid intima-media thickness (cIMT), and arterial stiffness (AS) were also evaluated. We investigated the relationships between inflammatory markers, vascular parameters, cell number, and antioxidant enzymes. RESULTS: CD34+ cell number was lower in RA patients than in controls. In CD34+ cells from RA patients, ROS levels, MnSOD mRNA, and NOX2 mRNA were higher, while mRNA expression of GPx-1 and CAT was significantly lower. The AS, pulse wave velocity (PWV), and augmentation index (AIx) were higher, as was cIMT. CD34+ cell number was inversely correlated with CRP, ROS, PWV, and AIx, and with the CAT/MnSOD and GPx-1/MnSOD ratios. CRP was correlated with MnSOD mRNA, PWV, and AIx but not with CAT and GPx-1 mRNA. CONCLUSIONS: Our data show a link between inflammation, oxidative stress, and the impairment of the antioxidant system of CPCs and their number, and with arterial stiffness in RA subjects. This could suggest a perspective on the accelerated development of vascular damage and atherosclerosis in RA.

Prevalence of virulence-associated genotypes of Helicobacter pylori and correlation with severity of gastric pathology in patients from western Sicily, Italy.

In a bacterium like Helicobacter pylori, which is characterized by a recombinant population structure, the associated presence of genes encoding virulence factors might be considered an expression of a selective advantage conferred to strains with certain genotypes and, therefore, a potentially useful tool for predicting the clinical outcome of infections. However, differences in the geographical and ethnic prevalence of the H. pylori virulence-associated genotypes can affect their clinical predictive value and need to be considered in advance. In this study we carried out such an evaluation in a group of patients living in Sicily, the largest and most populous island in the Mediterranean Sea. cagA, vacA, babA2, hopQ, oipA, sabA, and hopZ were the H. pylori virulence-associated genes assayed; their presence, expression status or allelic homologs were detected in H. pylori DNA samples and/or isolated strains, obtained by gastric biopsy from 90 Sicilian patients with chronic gastritis, inactive (n = 37), active (n = 26), or active with peptic ulcer (n = 27). Genotypes cagA (+), vacAs1, vacAm1, babA2 (+), and hopQ I, I/II were identified in 51.8, 80.4, 35.2, 47.3, and 67.7% of the different samples respectively. Only these genotypes were associated with each other and with the active form of chronic gastritis, irrespective of the presence of a peptic ulcer. In our isolates their prevalence was more similar to values observed in the north of Italy and France than to those observed in Spain or other Mediterranean countries that are closer and climatically more similar to western Sicily.

Pamidronate Treatment of Osteonecrosis of the Hip in Young Male.

BACKGROUND: Aseptic osteonecrosis of the hip is a clinical entity in which the necrotic process of the bone leads to pain and progressive disability. OBJECTIVE: Pamidronate seems to reduce drastically the activation of the osteoclasts so that it can be useful only in the early stage of the disease, delaying the time of bone collapsing. METHOD: A 27-years-old male was treated with pamidronate for three consecutive days every four weeks. RESULTS: After three months the patient came back at control showing a marked improvement in clinical condition, referred full recover from pain and dysmotility with improvement of the quality of life, which was confirmed by the result of MRI he had for control. CONCLUSION: We reported a case of aseptic osteonecrosis of the hip which was successfully treated pamidronate at dosage of 45 mg.

Selective decontamination of the digestive tract reduces bacterial bloodstream infection and mortality in critically ill patients. Systematic review of randomized, controlled trials.

A systematic review and meta-analysis of randomized controlled trials (RCTs) of selective decontamination of the digestive tract (SDD) was undertaken to evaluate the impact of this procedure on bacterial bloodstream infection and mortality. Data sources were Medline, Embase, Cochrane Register of Controlled Trials, previous meta-analyses, and conference proceedings, without restriction of language or publication status. RCTs were retrieved that compared oropharyngeal and/or intestinal administration of antibiotics as part of the SDD protocol, with or without a parenteral component, with no treatment or placebo in the controls. The three outcome measures were patients with bloodstream infection, causative micro-organisms, and total mortality. Fifty-one RCTs conducted between 1987 and 2005, comprising 8065 critically ill patients were included in the review; 4079 patients received SDD and 3986 were controls. SDD significantly reduced overall bloodstream infections [odds ratio (OR), 0.73; 95% confidence interval (CI), 0.59-0.90; P=0.0036], gram-negative bloodstream infections (OR, 0.39; 95% CI, 0.24-0.63; P<0.001) and overall mortality (OR, 0.80; 95% CI, 0.69-0.94; P=0.0064), without affecting gram-positive bloodstream infections (OR, 1.06; 95% CI, 0.77-1.47). The subgroup analysis showed an even larger impact of SDD using parenteral and enteral antimicrobials on overall bloodstream infections, bloodstream infections due to gram-negative bacteria and overall mortality with ORs of 0.63 (95% CI, 0.46-0.87; P=0.005), 0.30 (95% CI, 0.16-0.56; P<0.001), and 0.74 (95% CI, 0.61-0.91; P=0.0034), respectively. Twenty patients need to be treated with SDD to prevent one gram-negative bloodstream infection and 22 patients to prevent one death.

Pharmacological induction of heme oxygenase-1 inhibits iNOS and oxidative stress in renal ischemia-reperfusion injury.

Nitric oxide (NO), produced by nitric oxide synthase, is implicated in the pathophysiology of renal ischemia/reperfusion (I/R) injury. This study sought to elucidate the impact of pharmacological induction of heme oxygenase-1 (HO-1) on renal I/R injury. Rats were subjected to 45 minutes of renal ischemia followed by various times of reperfusion (30 minutes, 1 hour, or 3 hours). Plasma from sacrificed rats was obtained, and the kidneys processed for the expression of iNOS, cleaved caspase-3, p38MAPK and for immunohistochemical analysis. Furthermore, we determined renal and plasma levels of lipid hydroperoxides, total thiol groups, and plasmatic NO2-/NO3- formation. Our results showed a time-dependent increase in iNOS expression, which was also confirmed by increased plasma formation of NO2-/NO3-. Interestingly, this effect was reversed by pretreatment (12 hours) with SnCl2, a potent and specific inducer of renal HO-1 expression and activity, or by intraperitoneal injection of biliverdin (10 mg/kg). Furthermore, we observed a concomitant reduction in plasma and renal LOOH formation, a normalization of renal total thiol content, a reduction of caspase-3-mediated apoptosis, and a significant increase in p38MAPK phosphoration. Taken together, these results suggested that HO-1 and its byproduct biliverdin play major roles in the pathophysiological cascade leading to renal I/R injury.

Evaluation of the threshold value for the modified early warning score (MEWS) in medical septic patients: a secondary analysis of an Italian multicentric prospective cohort (SNOOPII study).

BACKGROUND: Due to aging and resources limitation, septic patients are often admitted to medical wards (MWs). Early warning deterioration is a relevant issue in this setting. Unfortunately, a suitable prognostic score has not been identified, yet. AIM: To explore the ability of Modified Early Warning Score (MEWS) to predict the in-hospital mortality in septic patients admitted to MWs. DESIGN: Secondary analysis of a multicentric prospective study. METHODS: Consecutive septic patients with positive blood culture admitted to 31 Italian MWs were included. Baseline characteristics, clinics, isolates, rate of transfer to ICU, MEWS was collected on admission according to the study protocol. The accuracy of MEWS in predicting the in-hospital mortality was assessed with the area under the receiver-operating characteristic curves. Sensitivity, specificity, positive and negative predictive value (PPV and NPV), likelihood ratio (LR) were calculated for different MEWS cut-offs and age/comorbidities subgroups. RESULTS: In total 526 patients were included in this analysis. Median MEWS was (range 0-11). In-hospital mortality was 14.8% and transfer to ICU 1.3%. Mortality progressively increased according to MEWS (3% in MEWS 0 vs. 27% in MEWS >5; Chi square for trend P < 0.05). The AUC of MEWS in predicting in-hospital mortality was 0.596 (95% CI, 0.524, 0.669). MEWS did not appear to have an adequate sensitivity, sensibility, PPV, NPV and LR both in the whole population and in the pre-specified subgroups. CONCLUSIONS: Our findings do not seem to support the use of MEWS to predict the in-hospital mortality risk of sepsis in MWs.

Detection and quantification of mammaglobin in the blood of breast cancer patients: can it be useful as a potential clinical marker? Preliminary results of a GOIM (Gruppo Oncologico dell'Italia Meridionale) prospective study.

BACKGROUND: Mammaglobin is expressed mainly in mammary tissue, overexpressed in breast cancer (BC) and rarely in other tissue. The aim of this study was to assess the sensitivity and specificity of transcript MGB1 detection and to evaluate the role of MGB1 as potential clinical marker for the detection of disseminated cancer cells in the blood of BC patients. PATIENTS AND METHODS: A consecutive series of 23 BC tissues, 36 peripheral blood BC samples and 35 healthy peripheral blood samples was prospectively recruited to investigate MGB1 expression by means of a quantitative Real Time RT-PCR assay. RESULTS: MGB1 overexpression in tissue samples of BC patients is significantly associated only with high level of Ki67 (P <0.05). None of the samples from peripheral blood of 35 healthy female individuals were positive for MGB1 transcript. In contrast MGB1 mRNA expression was detected in three of 36 (8%) peripheral blood of BC patients. CONCLUSIONS: Our preliminary results demonstrate that the detection of MGB1 transcript in peripheral blood of BC patients was specific but with low sensitivity. MGB1 overexpression by itself or in combination with Ki67 might be considered an index of BC progression.

Mechanical loads modulate tidal volume and lung washout during high-frequency percussive ventilation.

High-frequency percussive ventilation (HFPV) has been proved useful in patients with acute respiratory distress syndrome. However, its physiological mechanisms are still poorly understood. The aim of this work is to evaluate the effects of mechanical loading on the tidal volume and lung washout during HFPV. For this purpose a single-compartment mechanical lung simulator, which allows the combination of three elastic and four resistive loads (E and R, respectively), underwent HFPV with constant ventilator settings. With increasing E and decreasing R the tidal volume/cumulative oscillated gas volume ratio fell, while the duration of end-inspiratory plateau/inspiratory time increased. Indeed, an inverse linear relationship was found between these two ratios. Peak and mean pressure in the model decreased linearly with increasing pulsatile volume, the latter to a lesser extent. In conclusion, elastic or resistive loading modulates the mechanical characteristics of the HFPV device but in such a way that washout volume and time allowed for diffusive ventilation vary agonistically.

Contribution of the ubiquitin-proteasome pathway to overall muscle proteolysis in hypercatabolic patients.

The influence of the gene expression of critical components of the cytoplasmic and lysosomal proteolytic pathways on the rate of protein degradation was evaluated in the leg skeletal muscle of 8 severely traumatized patients. Muscle proteolysis was determined as the intramuscular phenylalanine rate of appearance by L-[ring-2H5]phenylalanine infusion and the leg arteriovenous catheterization technique combined with muscle biopsy. Muscle mRNA levels of UbB polyubiquitin and cathepsin B were determined by reverse transcriptase-competitive polymerase chain reaction and expressed as a percent of the mRNA level of the housekeeping gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH). In the patients, individual values for UbB polyubiquitin mRNA levels directly correlated with the rate of muscle proteolysis (r = .76, P < .05), whereas no correlation (r = .10) was found between cathepsin B mRNA levels and proteolysis. Thus, after trauma, the rate of muscle proteolysis appears to be largely regulated by the ubiquitin-proteasome system at the level of gene transcription.

Plasmapheresis in the critically ill patient.

Despite the wide number of diseases currently or previously treated with plasma exchange and plasmapheresis, the clinical effectiveness of these treatments has been established by large, controlled clinical trials only in few clinical conditions. The firmly accepted and the possible indications for these techniques in critically ill patients are reviewed and discussed, as well as their complications and possible side effects.

Are most ICU infections really nosocomial? A prospective observational cohort study in mechanically ventilated patients.

A prospective cohort study was undertaken with two end points: (i) to compare the 48 h time cut-off with the carrier state criterion for classifying infections, and (ii) to determine a time cut-off more in line with the carrier state concept. All patients admitted to the intensive care unit and expected to require mechanical ventilation for a period > or = 3 days were enrolled. Surveillance cultures of throat and rectum were obtained on admission and thereafter twice weekly to distinguish micro-organisms that were imported into the intensive care unit from those acquired during the stay in the unit. A total of 117 patients with median age of 61 years and median Simplified Acute Physiology Score II of 42, were included in the study. Of these patients, 48 (41%) developed a total of 74 infection episodes. Using the 48 h cut-off point, 80% of all infections were classified as ICU-acquired. According to the carrier state criterion, 44 infections (60%) were of primary endogenous development caused by micro-organisms imported into the intensive care unit. Seventeen secondary endogenous (23%) and 13 exogenous (17%) infections were caused by bacteria acquired in the unit. The carrier state classification allowed the transfer of 49% of infections from the ICU-acquired group into the import group. A time cut-off of nine days was found to identify ICU-acquired infections better than two days. These data suggest that monitoring of carriage of micro-organisms may be a more realistic approach to classify infections developing in the intensive care unit.

Effects of growth hormone administration on skeletal muscle glutamine metabolism in severely traumatized patients: preliminary report.

We have investigated the effects of 24 h human recombinant growth hormone (hGH) administration on leg muscle glutamine exchange and protein kinetics in severely traumatized patients. Muscle amino acid exchange and protein balance were evaluated using the leg arteriovenous balance technique, whereas changes in skeletal muscle free amino acid concentrations were evaluated in biopsy specimens. hGH infusion decreased phenylalanine release from protein degradation by 56 +/- 14%, and the rate of branched chain amino acid catabolism by 51 +/- 10%. Glutamine release from leg muscle was suppressed by 58 +/- 12%. This latter effect was completely accounted for by a hGH-mediated suppression of glutamine synthesis in skeletal muscle. In conclusion, growth hormone administration in trauma patients may restrain protein and amino acid catabolism in skeletal muscle. However, the growth hormone-mediated suppression of glutamine production we have observed in this study could decrease the systemic availability of this amino acid. During growth hormone treatment, this potential side-effect could be prevented by an exogenous glutamine administration.

Effects of mechanical load on flow, volume and pressure delivered by high-frequency percussive ventilation.

High-frequency percussive ventilation (HFPV) has proved its unique efficacy in the treatment of acute respiratory distress, when conventional mechanical ventilation (CMV) has demonstrated a limited response. We analysed flow (V(dot)), volume (V) and airway pressure (Paw) during ventilation of a single-compartment mechanical lung simulator, in which resistance (R) and elastance (E) values were modified, while maintaining the selected ventilatory settings of the HFPV device. These signals reveal the physical effect of the imposed loads on the output of the ventilatory device, secondary to constant (millisecond by millisecond) alterations in pulmonary dynamics. V(dot), V and Paw values depended fundamentally on the value of R, but their shapes were modified by R and E. Although peak Paw increased 70.3% in relation to control value, mean Paw augmented solely 36.5% under the same circumstances (maximum of 9.4 cm H2O). Finally, a mechanism for washing gas out of the lung was suggested.

Metabolic response to injury and sepsis: changes in protein metabolism.

The metabolic response to trauma and sepsis involves an increased loss of body proteins. Specific sites of changes of protein and amino acid metabolism have been identified. In skeletal muscle, the rate of proteolysis is accelerated greatly. The rate of protein synthesis also may be increased but not enough to match the increase in degradation. Intramuscular glutamine concentration is decreased because of increased efflux and possibly decreased de novo synthesis. In the liver, the rate of synthesis of selected proteins (i.e., albumin, transferrin, prealbumin, retinol-binding protein, and fibronectin) is decreased, whereas acute phase protein synthesis is accelerated. Tissues characterized by rapidly replicating cells, such as enterocytes, immune cells, granulation tissue, and keratinocytes, exhibit early alterations in the case of decreased protein synthesis capacity. In these tissues, glutamine use is accelerated. Increased stress hormone (cortisol and glucagon) and cytokine secretion, as well as intracellular glutamine depletion, are potential mediators of altered protein metabolism in trauma and sepsis. However, the relative importance of these factors has not been clarified. Therapy of acute protein catabolism may include the use of biosynthetic human growth hormone, possibly in combination with insulin-like growth factor-1, and the administration of metabolites at pharmacologic doses. We recently studied the effects of carnitine and alanyl-glutamine administration in severely traumatized patients. We found that both carnitine and the glutamine dipeptide restrained whole-body nitrogen loss without affecting selected indices of protein metabolism in the skeletal muscle.

Drug-induced hyperthermia in a patient with persistent vegetative state. Case report and review of the literature.

The case of posttraumatic patient with persistent vegetative state and severe and prolonged hyperthermia (T = 39-40 degrees C for more than 20 days), in absence of infection, is described. Diffuse muscular rigidity, treated with L-dopa, slightly preceded the onset of hyperthermia, which was treated with several antipyretics, including phenotiazines. The withdrawal of these drugs and the administration of dantrolene and bromocriptine was followed by the restoration of the normal body temperature.

Traumatic blunt carotid injury: clinical experience and review of the literature.

To evaluate the symptoms, the associated lesions, the treatment and the outcome of patients with blunt carotid injury (BCI), we reviewed the records of all patients admitted to our intensive care unit with head trauma between May 1991 and May 1995. A patient's assessment included the commonly used severity scores and cranial computed tomography (CT). Other diagnostic investigations were performed according to the clinical setting. Four patients (2 males, 2 females, age 29 +/- 13 years) out of 145 were diagnosed to have BCI. At admission, the Glasgow Coma Scale (GCS) was > or = 12 in all patients, and was associated with hemiparesis in three of them; the fourth became paretic 48 hours later. No pathological elements were demonstrated at the initial CT scan, whilst subsequent examinations showed signs of ischaemia after a variable interval from admission. In every patient the radiologic investigations demonstrated a thrombotic obstruction of the internal carotid artery (ICA), associated with an intimal dissection in two cases. Three patients were discharged with only minor neurologic symptoms. The fourth patient was referred to our ICU after the development of a massive hemispheric infarction, and died 3 days after admission.