Umbilical cord blood serum procalcitonin by Time-Resolved Amplified Cryptate Emission (TRACE) technology: reference values of a potential marker of vertically transmitted neonatal sepsis.

BACKGROUND: Neonatal infection remains a major diagnostic problem because of non-specific clinical signs and symptoms, as well as low sensitivity and specificity of routine laboratory tests. C-reactive protein (CRP), white blood cell count, absolute neutrophil count and immature/total neutrophil ratio are the most widely used tests in the diagnosis of sepsis and provide useful information, but none of these has demonstrated to be reliable in detecting all septic infants. Procalcitonin (PCT) has been suggested as a potentially useful laboratory test performed in umbilical cord blood when perinatal bacterial sepsis is under investigation. METHODS: In this study, the reference interval for umbilical cord blood serum PCT was established for the first time by Time-Resolved Amplified Cryptate Emission (TRACE) technology. RESULTS: The reference interval for PCT in umbilical cord blood serum ranged from 0.04 to 0.43 microg/L in 168 non-infected newborn infants (95% CI 0.02-0.06 and 0.35-0.60 microg/L, respectively). Cord blood serum PCT correctly classified one infected patient out of 90 newborn infants at risk of vertically transmitted sepsis and identified another neonate as a potentially infected patient despite having negative blood cultures. However, cord blood CRP misclassified 21 out of the 90 patients as infected neonates. CONCLUSIONS: Cord blood PCT measured by TRACE is a potentially more useful early marker of neonatal sepsis than cord blood CRP.     

Serial quantification of procalcitonin (PCT) predicts clinical outcome and prognosis in patients with community-acquired pneumonia (CAP)

Procalcitonin (PCT), a calcitonin precursor, is commonly measured in the setting of community-acquired pneumonia (CAP). However, the clinical significance of serial PCT changes has not been established. We conducted a prospective observational study of 122 patients with CAP. Thirty-day mortality was the primary endpoint. Secondary endpoints included: (1) initial treatment failure, (2) 30-day mortality and/or initial treatment failure, and (3) intensive care unit (ICU) admission. In subgroup analysis, we classified patients into pneumococcal pneumonia and non-pneumococcal pneumonia groups. The baseline frequency of 30-day mortality was 10.7%. Increases in serum PCT levels from admission to Day 3 were observed with statistically higher frequency in patients with 30-day mortality (P = 0.002). For secondary endpoints, only the 30-day mortality and/or initial treatment failure group was statistically significant (P = 0.007). Subgroup analysis revealed statistically significant changes in the non-pneumococcal pneumonia group (N = 85) across several endpoints, including 30-day mortality (P = 0.001), initial treatment failure (P = 0.013), and 30-day mortality and/or initial treatment failure (P < 0.001). No significant changes in endpoint measurements were found in the pneumococcal pneumonia group (N = 28). Interestingly, serum PCT levels at the time of diagnosis were higher in patients with pneumococcal pneumonia than those with non-pneumococcal pneumonia (P = 0.006), and this positively correlated with disease severity scores for all patients (PCT vs. PSI: R = 0.380, P < 0.001; PCT vs. A-DROP: R = 0.422, P < 0.001) and for non-pneumococcal pneumonia (PCT vs. PSI: R = 0.468, P < 0.001; PCT vs. A-DROP: R = 0.448, P < 0.001), but not for pneumococcal pneumonia. In conclusion, serial quantification of PCT can predict clinical outcomes for patients with CAP.     

A Cerebral Recovery Index (CRI) for early prognosis in patients after cardiac arrest

Introduction

Electroencephalogram (EEG) monitoring in patients treated with therapeutic hypothermia after cardiac arrest may assist in early outcome prediction. Quantitative EEG (qEEG) analysis can reduce the time needed to review long-term EEG and makes the analysis more objective. In this study, we evaluated the predictive value of qEEG analysis for neurologic outcome in postanoxic patients.

Methods

In total, 109 patients admitted to the ICU for therapeutic hypothermia after cardiac arrest were included, divided over a training and a test set. Continuous EEG was recorded during the first 5 days or until ICU discharge. Neurologic outcomes were based on the best achieved Cerebral Performance Category (CPC) score within 6 months. Of the training set, 27 of 56 patients (48%) and 26 of 53 patients (49%) of the test set achieved good outcome (CPC 1 to 2). In all patients, a 5 minute epoch was selected each hour, and five qEEG features were extracted. We introduced the Cerebral Recovery Index (CRI), which combines these features into a single number.

Results

At 24 hours after cardiac arrest, a CRI <0.29 was always associated with poor neurologic outcome, with a sensitivity of 0.55 (95% confidence interval (CI): 0.32 to 0.76) at a specificity of 1.00 (CI, 0.86 to 1.00) in the test set. This results in a positive predictive value (PPV) of 1.00 (CI, 0.73 to 1.00) and a negative predictive value (NPV) of 0.71 (CI, 0.53 to 0.85). At the same time, a CRI >0.69 predicted good outcome, with a sensitivity of 0.25 (CI, 0.10 to 0.14) at a specificity of 1.00 (CI, 0.85 to 1.00) in the test set, and a corresponding NPV of 1.00 (CI, 0.54 to 1.00) and a PPV of 0.55 (CI, 0.38 to 0.70).

Conclusions

We introduced a combination of qEEG measures expressed in a single number, the CRI, which can assist in prediction of both poor and good outcomes in postanoxic patients, within 24 hours after cardiac arrest.     

Cerebral responses to pain in patients suffering acute post-dental extraction pain measured by positron emission tomography (PET)

Previous studies with normal volunteers have demonstrated distributed cortical responses to experimental heat pain within a network of structures. The network includes the insula, anterior cingulate, prefrontal, inferior parietal and somatosensory cortices. Patients suffering from chronic nociceptive pain following rheumatoid arthritis (RA) have shown damped central responses to experimental heat pain applied to the back of the right hand. In this study of patients with acute, left-sided, post-molar-extraction (surgical) pain, we assessed the cortical responses to experimental heat pain, applied to the back of the right hand, using positron emission tomography (PET), and compared the responses with a previously reported control group and the RA group. In response to the experimental heat pain, the surgical group indicated significantly increased regional cerebral blood flow in the prefrontal cortex [Brodman's area (BA) 44] ipsilateral to the heat stimulus. Contralateral increases were detected in the putamen and transverse temporal gyrus (BA 40/41/42) with bilateral increases in the insular cortex. Compared to the control and RA group, there were significantly reduced responses in the anterior cingulate (BA 24), pre-frontal medial, and orbito-frontal (BA 9/10/32/47) cortices. These results suggest that relatively discrete regions of the cerebral cortex are responsible for acute nociceptive processing during an acute inflammatory episode. The reduced frontal and anterior cingulate responses to the experimental heat pain (applied to the right hand) during acute inflammatory pain (left jaw) illustrates cortical modulation of nociceptive processing that may be related to non-somatotopic, bilateral, nociceptive inputs to these areas.     

A positron-emitting internal marker for identification of normal tissue by positron emission tomography: phantom studies and validation in patients.

PURPOSE: This study evaluated in a phantom model and verified in patients with lung cancer whether the use of an internal positron-emitting labeled marker could localize a critical structure by positron emission tomography (PET) imaging and verify multimodality image registration. MATERIALS AND METHODS: An initial device and method were developed to demonstrate by dedicated PET the location of the normal esophagus in a phantom and in three patients using a column of 2-deoxy-2-[18F]fluoro-D-glucose (FDG) solution between proximal and distal gas phases in polyurethane tubing. The device was assessed for possible loss of radioactivity. PET, CT and PET-CT fusion imaging followed. RESULTS: X-rays of the marker device showed a continuous fluid column. No leakage of contents was detected. The internal marker in the phantom and in patients allowed visualization by PET of the esophagus, and verified an image registration algorithm. CONCLUSIONS: A positron-emitting internal marker was constructed, demonstrated to retain tracer, and shown to be capable of verifying an image registration algorithm and identifying a critical structure, the esophagus, by PET in a phantom and in patients.     

A new predictive and prognostic marker (ATP bioluminescence and positron emission tomography) in vivo and in vitro for delivering adjuvant treatment plan to invasive breast tumor patients.

The cell proliferation rate has been used to assess the biological aggressiveness and the metastatic potential of breast carcinoma. Different methods (flow cytometric S phase and proliferation associated antigens) have been used to assess the rate of proliferation previously. In this preliminary study, the cell proliferation rate of normal (N=45), benign (N=29) and invasive breast tumor tissue (N=70) has been quantified in vitro by ATP bioluminescence assay. Next, individual prognostic factor (tumor grades, lymph node involvement, estrogen and progesterone receptor and HER-2 status) has been correlated with the level of metabolic rate (ATP). The results showed that invasive tumor had the highest level of ATP bioluminescence compared with that of benign tumor (mean difference=1.97) and the normal breast tissue (mean difference=2.75). In addition, ATP level positively correlated with the number of axillary lymph node involvement (r(spearman)=0.433, P=0.021). These findings suggested that the measurement of ATP level may serve as a mean for the detection of cell proliferation and hence a surrogate marker for disease prognosis.     

Normal values of liver elasticity measured by real-time tissue elastography (RTE) in healthy infants and children

Purpose

To define normal values of liver elasticity measured by real-time tissue elastography (RTE) in healthy infants and children.

Methods

RTE was performed on 91 children and adolescents by two experienced observers (female, n = 43; male, n = 48) and in two age groups (0–10 years, n = 45; 11–20 years, n = 46). Hepatopathies were excluded clinically by extensive laboratory testing and by ultrasound. RTE provides a histogram from a region of interest (ROI) in the liver representing the degree of stiffness of the liver. The distribution of the colors in the histogram corresponds to organ elasticity. By calculating the mean of stiffness values, a numerical value is expressed in arbitrary units (a.u.) representing the mean elasticity of the liver (MEAN). Additionally, the percentage values of relatively stiffer areas (color coded in blue) in the ROI can be calculated (%AREA). A Mann–Whitney U test was performed for these two parameters according to gender. The reproducibility of these values was determined with an intraclass correlation coefficient (ICC) test on another group of 18 healthy volunteers.

Results

The median elasticity was 106 a.u. Gender did not have an influence on the parameters (MEAN: p = 0.052; %AREA: p = 0.051). Age-specific analyses did not yield any significant difference between the two age groups for either of the two analyzed parameters (MEAN: p = 0.059; %AREA: p = 0.058). The ICC test demonstrated a moderate agreement for MEAN (ICC = 0.582) and %AREA (ICC = 0.659).

Conclusion

Real-time elastography is a new sonography-based method and may be used as a supportive analysis to assess liver parenchyma elasticity in children, especially when fibrosis is suspected. We measured RTE normal values in children as reference data.     

Detection of cytomegalovirus (CMV) antigens in kidney biopsies and transplant nephrectomies as a marker for renal graft dysfunction.

Chronic rejection accounts for the greatest loss of renal allografts. HLA mismatching has been minimised by organ allocation and new immunosuppressive drugs have been employed, but the average cadaveric graft survival still does not exceed 12 years. Though the aetiology is multifactorial, one contributory factor for this condition is cytomegalovirus (CMV). Detection of CMV in kidney biopsies and sera can diagnose and monitor this inflammatory event and define its role in chronic nephropathy. Twenty five biopsies taken at the time of transplantation, 10 biopsies for graft dysfunction and tissue blocks from 20 explanted kidney grafts were collected and investigated for CMV antigens by immunohistochemistry. Tissue samples were snap frozen and cryostat sections were incubated with monoclonal antibodies for CMV antigens followed by immunoperoxidase staining. In 12 out of 20 transplant nephrectomies CMV antigens were found. Only two of these patients had clinical CMV disease. Time 0 biopsies from CMV seronegative donors (n = 11) and CMV seropositive donors (n = 14) were negative for CMV antigens. The prevalence of CMV antigens in grafts lost due to chronic rejection was 60%. These antigens were not found within the time 0 biopsies, but were detected in 30% of biopsies taken at the time of clinical graft dysfunction. CMV appears to contribute to chronic rejection even without clinical disease.     

Differentiated therapy with prostaglandin E1 (alprostadil) after orthotopic liver transplantation: the usefulness of procalcitonin (PCT) and hepatic artery resistive index (RI) for the evaluation of early graft function and clinical course.

Increasing demand for donor organs has led to new pharmacological concepts for reducing ischemia-reperfusion injury (I/R) of the graft after liver transplantation to prevent primary non-functioning of the organ. Prostaglandins have proved to be cytoprotective in several experimental models of ischemia and transplantation. The prophylactic administration after orthotopic liver transplantation is still a subject of controversial discussion. The aim of our study was the evaluation of the post-transplant hepatic artery resistive index (RI) measured by color Doppler imaging, in combination with postoperative elevation of transaminases, as parameters indicating the need for a differentiated systemic therapy with prostaglandin E1 (PGE1) (alprostadil). In addition, the value of serum procalcitonin (PCT) as a postoperative parameter for the extent of I/R is investigated. In the case of post-transplant elevated hepatic artery RI (RI > 0.75), the administration of PGE1 led to a significant reduction of transaminases (p < 0.05) and a decline of the RI. In addition, postoperative PCT levels could be reduced significantly by PGE1 application. These results suggest that determination of RI is feasible for indicating a need for therapy with PGE1. Its targeted application reduces hepatocellular damage due to I/R after liver transplantation.     

Plasma cytomegalovirus (CMV) DNA load predicts CMV disease and survival in AIDS patients.

In this study, baseline plasma from 619 persons with acquired immunodeficiency syndrome (AIDS) (median CD4+ lymphocyte count -21/microl) who participated in a trial to determine the efficacy of oral ganciclovir for cytomegalovirus (CMV) disease prevention were evaluated for CMV DNA load by qualitative and quantitative polymerase chain reaction (PCR), and correlated with the development of CMV disease and survival. For participants without detectable plasma CMV DNA, the 12-mo Kaplan-Meier CMV disease event rate was 14% and 1% for the placebo and ganciclovir groups, respectively (P < 0.001). For PCR positive participants, CMV disease developed in 43% of placebo and 26% ganciclovir recipients (P < 0.017). Among placebo recipients, CMV PCR positivity was associated with a 3.4-fold increased risk of developing CMV disease (P < 0.001) whereas CD4+ lymphocyte count was not a useful predictor (P = 0.47). A positive plasma CMV DNA PCR was also associated with a 2.5-fold increased risk of death. Each log10 increase in baseline CMV DNA load was associated with a 3.1-fold increase in CMV disease (P < 0.001) and a 2.2-fold increase in mortality (P < 0.001). These data indicate that the risk of developing CMV disease and death in persons with advanced AIDS is directly related to the quantity of CMV DNA in plasma, and is a better predictor than CD4+ lymphocyte count in this population.     

Plasma 1,25(OH)2 vitamin d measured by radioimmunoassay and cytosol radioreceptor assay in normal subjects and patients with primary hyperparathyroidism and renal failure

Antibodies to 1α,25-dihydroxy vitamin D₃ 25-hemisuccinate linked to albumin were produced and an immunoassay for 1,25-dihydroxy vitamin D developed. Plasma 1,25-dihydroxy vitamin D concentrations were compared using an immunoassay and cytosol radioreceptor assay. Both assays gave comparable results but the immunoassay was more reproducible, slightly more sensitive and had a lower detection limit.Using the immunoassay the plasma 1,25-dihydroxy vitamin D was 110.5 pmol/l (S.D. 29.4) in normal subjects; there was no difference between males and premenopausal females. It was negatively related to plasma phosphate. In renal failure and primary hyperparathyroidism plasma 1,25(OH)₂D was positively related to radiocalcium absorption. Following 1 and 2 μg of 1,25-dihydroxy vitamin D₃ given orally the peak plasma concentration occurs within 12 h.     

The effect of Clexane (low-molecular-weight heparin) on the hemostatic system and on the incidence of postoperative thrombotic complications in gynecological cancer patients

Clexane in a dose of 40 mg before and after surgery notably decreased the intensity of chronic intravascular blood coagulation during surgical treatment of oncogynecological patients. Only 3% patients developed thrombosis of deep veins of the lower limbs after Clexane, while in the group administered no Clexane, 20% developed this complication. Preventive administration of Clexane did not cause an increase of the operative blood loss. The incidence of wound hematomas in patients administered Clexane and nonfractionated heparin was negligible and virtually the same.     

The character and structure of infectious complications in patients with chronic renal failure, who received or did not receive replacement therapy (hemodialysis)

The subjects of the study were 176 patients with chronic renal failure (CRF) (101 men; 75 women) aged 17 to 81. Stage I CRF was found in 46 patients, stage II CRF--in 69 patients, and stage III CRF--in 61 patients. Thirty-one patients with stage III CRF received program hemodialysis. Chronic glomerulonephritis was the main cause of CRF. With the progress of CRF, the frequency of infectious complications grew up to 2.2% in stage I, 7.2% in stage II, and 36.1% in stage III. The rate of infectious complications was higher in patients on program dialysis vs. patients without it: 51.6 and 20%, respectively. Pneumonia was the most frequent complication regardless CRF stage.     

C-reactive protein, leukocyte count and D-dimer monitoring after orthopedic surgery: early diagnosis of infectious or thromboembolic complications. Part one: C-reactive protein and leukocyte count as an aid in diagnosing postoperative infection]

OBJECTIVES: To evaluate the usefulness of monitoring C-reactive protein (CRP) level and leukocyte count for early diagnosis of infection following orthopedic surgery. METHOD: A cohort of 179 patients was followed: group 1 comprised 128 patients undergoing lower limb arthroplasty, group 2 comprised 29 patients undergoing lower limb surgery without implant, and group 3 comprised 22 patients undergoing spinal or upper limb surgery. CRP level and leukocyte count were systematically measured on admission and then once a week for 4 weeks. Wound infections, other infections, wound disconnection without infection and hematoma were noted. CRP level and leukocyte count were monitored postoperatively in patients with and without complications. RESULTS: CRP level was 4- to 8-fold above the normal range at the first postoperative measurement but normalized within the next 3 weeks (reaching normal levels by the 30th postoperative day, on average). In the 7 cases of wound infection (WI), the CRP level rose to 28-fold above normal and was significantly different from that in without infection or with intercurrent infection (P<0.01). A receiver operating characteristic (ROC) curve was established for CRP level, and for a value of 60 (12-fold above the normal range) the sensitivity was 100%, the specificity 83.6% and the negative predictive value 100%. The variation in leukocyte count was minor, with a significant difference noted between only patients not infected or those with WI (P<0.05). DISCUSSION AND CONCLUSIONS: Measurement of CRP level can be used for early diagnosis of wound infection. In the case of strong clinical suspicion or in the presence of high risk factors, when the level is at 12-fold or more above the normal range, the diagnosis of infection is highly probable.     

Effect of age on functional P-glycoprotein in the blood-brain barrier measured by use of (R)-[(11)C]verapamil and positron emission tomography

INTRODUCTION: P-glycoprotein (P-gp) is an efflux transporter responsible for the transport of various drugs across the blood-brain barrier (BBB). Loss of P-gp function with age may be one factor in the development and progression of neurodegenerative diseases. The aim of this study was to assess the effect of aging on BBB P-gp function. Furthermore, the relationship between BBB P-gp activity and peripheral P-gp activity in CD3-positive leukocytes was investigated. Finally, plasma pharmacokinetics of carbon 11-labeled (R)-verapamil was evaluated. METHODS: (R)-[(11)C]verapamil and positron emission tomography were used to assess gray matter P-gp function. Because (R)-[(11)C]verapamil is a substrate for P-gp, the volume of distribution of (R)-[(11)C]verapamil in the brain inversely reflects P-gp function in the BBB. RESULTS: Mean volume of distribution values for 5 young healthy volunteers (age range, 21-27 years) and 5 elderly healthy volunteers (age range, 59-68 years) were 0.62+/-0.10 and 0.73+/-0.07, respectively (P=.03). The activity index of P-gp activity in CD3-positive leukocytes was 2.88+/-0.77 in young volunteers and 1.76+/-0.58 in elderly volunteers (P=.02). CONCLUSION: This study showed decreased P-gp activity during aging. Consequently, the brain may be exposed to higher drug and toxin levels in elderly subjects.     

Study of combined anticoagulant (fluindione)-aspirin therapy in patients with atrial fibrillation at high risk for thromboembolic complications. A randomized trial (FFAACS)

BACKGROUND: A combination of low-dose aspirin (A) and anticoagulation (AC) may provide better protection against thromboembolic events compared with AC alone in high-risk patients with atrial fibrillation (AF). METHODS: We performed a multicentric placebo-controlled double blind-trial to test the preventive efficacy against thromboembolic events of the addition of aspirin (A) (100 mg) or placebo (P) to anticoagulant treatment in patients with high-risk atrial fibrillation. A total of 157 patients were included, with atrial fibrillation and previous thromboembolic event or older than 65 years with either a history of hypertension, a recent episode of heart failure or a left ventricular dysfunction. All patients received fluindione (F) and P or F and A, with an INR target between 2 and 2.6. The primary endpoint was a combined endpoint of stroke (ischaemic or haemorrhagic), myocardial infarction, systemic arterial emboli or vascular death. RESULTS: The study had to be stopped prematurely owing to a too low recruitment rate. During follow-up (0.84 years) 3 non-fatal thromboembolic events were recorded (1P, 2A) and 6 patients died (3P, 3A), none of them from a thromboembolic complication. However, 3 deaths were secondary to severe haemorrhagic complications (1P, 2A). Non-fatal haemorrhagic complications occurred more often in group A (n = 10, 13.1 pour cent) compared with group P (n = 1, 1.2 pour cent), p = 0.003. CONCLUSION: The FFAACS study was not able to show any therapeutic benefit from the addition of aspirin to anticoagulant in patients with high-risk AF. Such a combination increased the incidence rate of bleeding complications, which therefore greatly reduces its potential overall benefit.     

Drug and excipient diffusion and solubility in acrylate adhesives measured by infrared-attenuated total reflectance (IR-ATR) spectroscopy.

Infrared-attenuated total reflectance (IR-ATR) was used to measure drug and excipient diffusion in acrylate pressure-sensitive adhesives. The first part describes diffusion of drug and excipient from one adhesive layer to another. The IR-ATR spectrometer is used to continuously monitor the rate at which drug and excipient diffuse into the 'receptor' adhesive layer. In this way, the ability of the drug and/or excipient to leave an adhesive can be determined without any influence of receptor fluids or skin membranes. Data is reported here for terpineol and testosterone diffusion in isooctyl acrylate (IOA) and IOA-acrylic acid (AA) adhesives. It is shown that the diffusion rate is much higher in IOA adhesive than in IOA-AA adhesive. The second part describes the use of IR-ATR to measure the solubility of liquids in adhesives. In this method, a liquid excipient is placed in direct contact with an adhesive layer containing no excipient. The IR-ATR spectrometer is used to continuously monitor the rate at which excipient diffuses into the 'receptor' adhesive layer. At equilibrium, the IR spectrum can be compared to both the pure adhesive spectrum and the pure excipient spectrum to determine the solubility of the excipient in the adhesive. Data are reported here for terpineol in an IOA adhesive and for several liquids in an IOA-vinyl acetate adhesive.