Using Single-Photon Emission Computerized Tomography on Patients With Positive Quantitative Electroencephalogram to Evaluate Chronic Mild Traumatic Brain Injury With Persistent Symptoms.

Background: Following mild traumatic brain injury (mTBI), also known as concussion, many patients with chronic symptoms (>3 months post injury) receive conventional imaging such as computed tomography (CT) or magnetic resonance imaging (MRI). However, these modalities often do not show changes after mTBI. We studied the benefit of triaging patients with ongoing symptoms >3 months post injury by quantitative electroencephalography (qEEG) and then completing a brain single positron emission computed tomography (SPECT) to aid in diagnosis and early detection of brain changes. Methods: We conducted a retrospective case review of 30 outpatients with mTBI. The patients were assessed by a neurologist, consented, and received a qEEG, and if the qEEG was positive, they consented and received a brain SPECT scan. The cases and diagnostic tools were collectively reviewed by a multidisciplinary group of physicians in biweekly team meetings including neurology, nuclear medicine, psychiatry, neuropsychiatry, general practice psychotherapy, neuro-ophthalmology, and chiropractic providers. The team noted the cause of injury, post injury symptoms, relevant past medical history, physical examination findings, and diagnoses, and commented on patients' SPECT scans. We then analyzed the SPECT scans quantitatively using the 3D-SSP software. Results: All the patients had cerebral perfusion abnormalities demonstrated by SPECT that were mostly undetectable by conventional imaging (CT/MRI). Perfusion changes were localized primarily in the cerebral cortex, basal ganglia, and cingulate cortex, and correlated with the patients' symptoms and examination findings. Qualitative and quantitative analyses yielded similar results. Most commonly, the patients experienced persistent headache, memory loss, concentration difficulties, depression, and cognitive impairment post mTBI. Because of their symptoms, most of the patients were unable to return to their previous employment and activity level. Conclusion: Our findings outline the physical basis of neurological and psychiatric symptoms experienced by patients with mTBI. Increased detection of mTBI can lead to development of improved targeted treatments for mTBI and its various sequelae.

Dopamine receptor D2 (DRD2), dopamine transporter solute carrier family C6, member 4 (SLC6A3), and catechol-O-methyltransferase (COMT) genes as moderators of the relation between maternal history of maltreatment and infant emotion regulation.

Although infants less than 18 months old are capable of engaging in self-regulatory behavior (e.g., avoidance, withdrawal, and orienting to other aspects of their environment), the use of self-regulatory strategies at this age (as opposed to relying on caregivers) is associated with elevated behavioral and physiological distress. This study investigated infant dopamine-related genotypes (dopamine receptor D2 [DRD2], dopamine transporter solute carrier family C6, member 4 [SLC6A3], and catechol-O-methyltransferase [COMT]) as they interact with maternal self-reported history of maltreatment to predict observed infant independent emotion regulation behavior. A community sample (N = 193) of mother-infant dyads participated in a toy frustration challenge at infant age 15 months, and infant emotion regulation behavior was coded. Buccal cells were collected for genotyping. Maternal maltreatment history significantly interacted with infant SLC6A3 and COMT genotypes, such that infants with more 10-repeat and valine alleles of SLC6A3 and COMT, respectively, relative to infants with fewer or no 10-repeat and valine alleles, utilized more independent (i.e., maladaptive) regulatory behavior if mother reported a more extensive maltreatment history, as opposed to less. The findings indicate that child genetic factors moderate the intergenerational impact of maternal maltreatment history. The results are discussed in terms of potential mechanism of Gene × Environment interaction.

Exercise Training Increases Parietal Lobe Cerebral Blood Flow in Chronic Stroke: An Observational Study.

Exercise is increasingly recommended as an essential component of stroke rehabilitation, yet uncertainty remains with respect to its direct effect on the cerebral vasculature. The current study first demonstrated the repeatability of pseudo-continuous arterial spin labeling (ASL) magnetic resonance imaging (MRI) in older adults with stroke, and then investigated the change in cerebrovascular function following a 6-month cardiovascular rehabilitation program. In the repeatability study, 12 participants at least 3 months post-stroke underwent two ASL imaging scans 1 month apart. In the prospective observational study, eight individuals underwent ASL imaging and aerobic fitness testing before and after a 6-month cardiovascular rehabilitation program. Cerebral blood flow (CBF) and the spatial coefficient of variation of CBF (sCoV) were quantified to characterize tissue-level perfusion and large cerebral artery transit time properties, respectively. In repeat scanning, intraclass correlation (ICC) indicated moderate test-retest reliability for global gray matter CBF (ICC = 0.73) and excellent reliability for sCoV (ICC = 0.94). In the observational study, gray matter CBF increased after training (baseline: 40 ± 13 vs. 6-month: 46 ± 12 ml·100 g-1·min-1, P = 0.036). The greatest change occurred in the parietal lobe (+18 ± 12%). Gray matter sCoV, however, did not change following training (P = 0.31). This study provides preliminary evidence that exercise-based rehabilitation in chronic stroke enhances tissue-level perfusion, without changing the relative hemodynamic properties of the large cerebral arteries.

Maternal DRD2, SLC6A3, and OXTR genotypes as potential moderators of the relation between maternal history of care and maternal cortisol secretion in the context of mother-infant separation.

A mother's cortisol secretion is importantly associated with her own mental health and her infant's cortisol secretion. This study investigated the influences of maternal history of care and maternal DRD2, SLC6A3, and OXTR genotypes on maternal cortisol in the context of infant stress. A community sample of 296 mother-infant dyads completed a maternal separation at infant age 17 months. Maternal salivary cortisol, buccal cells, and self-reported history of care were collected. Multilevel models revealed that history of care had a greater influence on maternal baseline cortisol (but not cortisol trajectory) for mothers with more plasticity alleles of SLC6A3 (10R) and OXTR (G), relative to mothers with fewer or no plasticity alleles. Findings indicate that a mother's history of care is related to her cortisol secretion in anticipation of infant stress, but that this relation depends on her genetic characteristics. Findings are discussed in relation to the maternal protective system and anticipatory cortisol secretion.

Unattended Hospital and Home Sleep Apnea Testing Following Cerebrovascular Events.

BACKGROUND: Home sleep apnea testing (HSAT) is an alternative to polysomnography for the detection of obstructive sleep apnea (OSA). We assessed the feasibility of HSAT as an unattended screening tool for patients with a stroke or transient ischemic attack (TIA). AIMS: The primary outcome was the feasibility of unattended HSAT, as defined by analyzability of the data. Secondary outcomes included determining (1) predictors of obtaining nonanalyzable sleep data and (2) time to OSA detection and continuous positive airway pressure (CPAP) initiation. METHODS: In this single-center prospective observational study, inpatients or outpatients who had sustained a stroke or TIA were screened for OSA using the ApneaLink Plus ambulatory sleep monitor in their home or hospital room. RESULTS: There were 102 patients who completed unattended sleep monitoring. Mean age was 68.7 ± 13.7 years, 55.9% were male, 57.8% were outpatients, and 77.5% had a stroke (22.5% with TIA). Eighty-two (80.4%) patients obtained four or more hours of analyzable sleep data. Functional dependence (defined as a modified Rankin Scale of >2) and elevated body mass index were independently associated with obtaining nonanalyzable data. OSA was detected in 63.4% (52 of 82) of patients and, of those, 34 of 52 (65.4%) initiated CPAP therapy. The mean time from study recruitment to HSAT was 1.7 days (median: 1, interquartile range [IQR]: 2) and CPAP was initiated on average within 62.7 days of recruitment (median: 53, IQR: 30). CONCLUSIONS: Unattended HSAT can be feasibly implemented after stroke or TIA. This method facilitates rapid diagnosis and management of OSA in both the outpatient and inpatient settings.

Identifying obstructive sleep apnea after stroke/TIA: evaluating four simple screening tools.

OBJECTIVE: Despite its high prevalence and unfavorable clinical consequences, obstructive sleep apnea (OSA) often remains underappreciated after cerebrovascular events. The purpose of our study was to evaluate the clinical utility of four simple paper-based screening tools for excluding OSA after stroke or transient ischemic attack (TIA). PATIENTS/METHODS: Sixty-nine inpatients and outpatients with stroke or TIA during the past 180 days completed the 4-Variable screening tool (4V), STOP-BAG questionnaire (ie, STOP-BANG questionnaire without the neck circumference measurement), Berlin questionnaire, and the Sleep Obstructive apnea score optimized for Stroke (SOS). They subsequently underwent objective testing using a portable sleep monitoring device. Cutoffs were selected to maximize sensitivity and exclude OSA (AHI ≥ 10) in ≥10% of the cohort. RESULTS: The mean age was 68.3 ± 14.2 years and 47.8% were male. Thirty-two patients (46.4%) were found to have OSA. Male sex, body mass index (BMI), and atrial fibrillation were independent predictors of OSA. Among the screening tools, the 4V had the greatest area under the curve (AUC) of 0.688 (p = 0.007); the sensitivity was 96.9% for a cutoff of <6. The STOP-BAG also significantly detected OSA with an AUC of 0.677 (p = 0.012); the sensitivity was 93.8% for a cutoff of <2. Scores on the 4V and STOP-BAG were significantly correlated with the AHI. CONCLUSIONS: The 4V and STOP-BAG questionnaire may aid clinicians with ruling out OSA within 180 days of stroke/TIA. Due to the atypical presentation of poststroke/TIA OSA, these tools are only moderately predictive; objective testing should still be used for OSA diagnosis in this population.

MATERNAL SELF-REPORTED DEPRESSIVE SYMPTOMS AND MATERNAL CORTISOL LEVELS INTERACT TO PREDICT INFANT CORTISOL LEVELS.

Three basic findings have emerged from research on maternal depressive symptoms and offspring hypothalamic-pituitary-adrenal functioning: (a) Mothers' depressive symptoms are positively associated with their offsprings' cortisol stress response, (b) numerous individual and interpersonal maternal characteristics moderate this association, and (c) maternal and infant cortisol levels are highly correlated. In combination, these findings have suggested that maternal cortisol levels may moderate the relation between maternal depressive symptoms and infant cortisol responsivity; the current study assessed this hypothesis. Participants were 297 mother-infant dyads who were recruited from the community. Maternal depressive symptoms were assessed via self-report. Dyads participated in two differentially stressful infant challenges when infants were 16 and 17 months old. Mother and infant salivary cortisol was collected before and after challenges. Results indicate that maternal cortisol levels moderated associations between maternal depressive symptoms and infant cortisol levels across both challenges. Infants showed higher cortisol levels if their mothers had both higher depressive symptoms and higher cortisol levels, as compared to infants of mothers with higher depressive symptoms and lower cortisol, and to infants of mothers with lower depressive symptoms and either higher or lower cortisol levels. We discuss findings in relation to environmental and biological factors that may contribute to the intergenerational transmission of depressive symptoms.

DRD2 and SLC6A3 moderate impact of maternal depressive symptoms on infant cortisol.

Both maternal depressive symptoms and infants' dopamine-related genetic characteristics have been linked to infants' hypothalamic-pituitary-adrenal (HPA) functioning. This study investigated the interactive influence of maternal depressive symptoms and infant DRD2 and SLC6A3 genotypes on infant cortisol reactivity; whether this interaction reflects diathesis-stress or differential susceptibility; and whether this interaction influences the flexibility of the infant cortisol response across challenges known to exert differential effects on infant cortisol reactivity. A community sample of 314 mother-infant dyads participated in toy frustration (age 16 months) and maternal separation (age 17 months) challenges, and salivary cortisol was collected at baseline, +20, and +40min. Maternal depressive symptoms were assessed with the Beck Depression Inventory-II at infant age 16 months. Infant buccal cells were collected at both time points for genotyping. DRD2 and SLC6A3 genotypes moderated the relation between maternal depressive symptomatology and infant cortisol reactivity in a diathesis-stress manner in the context of toy frustration, and in a differential susceptibility manner in the context of maternal separation. Higher levels of maternal depressive symptoms predicted reduced cortisol flexibility across challenges for infants with at least one A1 allele of DRD2 and infants with the 10/10 genotype of SLC6A3. Results suggest that maternal depressive symptomatology is related to infants' cortisol reactivity and to the flexibility of that reactivity across psychosocial challenges, but this relation is dependent on the infant's genetic characteristics.

Lung ultrasound: a useful tool in diagnosis and management of bronchiolitis.

BACKGROUND: Clinical assessment is the gold standard for diagnosis of bronchiolitis. To date, only one study found LUS (Lung Ultrasound) to be a valuable tool in the diagnosis of bronchiolitis. Aim of this study is to evaluate the accuracy of lung ultrasonography in the diagnosis and management of bronchiolitis in infants. METHODS: This was an observational cohort study of infants admitted to our Pediatric Unit with suspected bronchiolitis. A physical examination and lung ultrasound scans were performed on each patient. Diagnosis and grading of bronchiolitis was assessed according to a clinical and a ultrasound score. An exploratory analysis was used to assess correspondence between the lung ultrasound findings and the clinical evaluation and to evaluate the inter-observer concordance between the two different sonographs. RESULTS: One hundred six infants were studied (average age 71 days). According to our clinical score, 74 infants had mild bronchiolitis, 30 had moderate bronchiolitis and two had severe bronchiolitis. 25 infants composed the control group. Agreement between the clinical and sonographic diagnosis was good (90.6%) with a statistically significant inter-observer ultrasound diagnosis concordance (89.6%). Lung ultrasound permits the identification of infants who are in need of supplementary oxygen with a specificity of 98.7%, a sensitivity of 96.6%, a positive predictive value of 96.6% and a negative predictive value of 98.7%. An aberrant ultrasound lung pattern in posterior chest area was collected in 86% of infants with bronchiolitis. In all patients clinical improvement at discharge was associated with disappearance of the previous LUS findings. Subpleural lung consolidation of 1 cm or more in the posterior area scan and a quantitative classification of interstitial syndrome based on intercostal spaces involved bilaterally, good correlate with bronchiolitis severity and oxygen use. CONCLUSIONS: The lung ultrasound findings strictly correlate with the clinical evaluations in infants with bronchiolitis and permit the identification of infants who are in need of supplementary oxygen with high specificity. Scans of the posterior area are more indicative in ascertaining the severity of bronchiolitis. TRIAL REGISTRATION: Clinical Trial Registration NCT01993797.

Summary cortisol reactivity indicators: Interrelations and meaning.

Research on the hypothalamic pituitary adrenal (HPA) axis has involved a proliferation of cortisol indices. We surveyed recently published HPA-related articles and identified 15 such indices. We sought to clarify their biometric properties, specifically, how they interrelate and what they mean, because such information is rarely offered in the articles themselves. In the present article, the primary samples consist of community mothers and their infants (N = 297), who participated in two challenges, the Toy Frustration Paradigm and the Strange Situation Procedure. We sought to cross-validate findings from each of these samples against the other, and also against a clinically depressed sample (N = 48) and a sample of healthy older adults (N = 51) who participated in the Trier Social Stress Test. Cortisol was collected from all participants once before and twice after the challenges. These heterogenous samples were chosen to obtain the greatest possible range in cortisol levels and stress response regulation. Using these data, we computed the 15 summary cortisol indices identified in our literature survey. We assessed inter-relations amongst indices and determined their underlying dimensions via principal component analysis (PCA). The PCAs consistently extracted two components, accounting for 79%-93% of the variance. These components represent "total cortisol production" and "change in cortisol levels." The components were highly congruent across challenge, time, and sample. High variable loadings and explained factor variance suggest that all indices represent their underlying dimensions very well. Thus the abundance of summary cortisol indices currently represented in the literature appears superfluous.

Maternal sensitivity and infant and mother adrenocortical function across challenges.

Findings regarding associations between maternal sensitivity and infant and mother adrenocortical function have been inconsistent. Nor have studies addressed the issue of intra-individual, between-challenge cortisol variability in the context of maternal sensitivity. In this study, we combine several design features aimed at sensitizing analyses to these issues. Cortisol secretion of 297 infants and their mothers was assessed in response to different challenges at 16 and 17 months. Extensive, structured observations of maternal sensitivity were conducted at infant age 16 months. Data were analyzed with multilevel modeling using an actor-partner interdependence model. We found that maternal sensitivity was related to infant, but not maternal, cortisol levels and also to infant-mother cortisol attunement. Infants of more sensitive mothers, as compared to infants of less sensitive mothers, showed greater cortisol variability across challenges, with relatively steep cortisol decreases and increases, depending on challenge. Mother and infant cortisol levels were highly correlated and this attunement was higher among dyads with more sensitive mothers than among dyads with less sensitive mothers. The results show nuanced attunement in a low-risk sample, with the infants of higher sensitivity mothers showing greater intra-individual variability across challenges. High cortisol response variability across challenges may simultaneously permit adaptation to threat and protect the infant from overexposure to corticosteroids.

Evalutation of mycophenolic acid systemic exposure by limited sampling strategy in kidney transplant recipients receiving enteric-coated mycophenolate sodium (EC-MPS) and cyclosporine.

BACKGROUND: Enteric-coated mycophenolate sodium (EC-MPS) and mycophenolate mofetil (MMF) are prodrugs of mycophenolic acid (MPA). Although many patients still receive MMF as an inosine monophosphate dehydrogenase inhibitor, EC-MPS could be considered a reliable alternative to MMF in the immunosuppressive protocols of kidney transplant recipients. MPA shows high pharmacokinetic variability and consequently a 12-h area under the curve (AUC(0-12)) should be used to guide the therapeutic dosage. However, patient compliance and economic costs make MPA AUC(0-12) an unpractical approach. Limited sampling strategies or predictive systemic drug exposure equation models based on limited sampling times are available only for MMF but lack for EC-MPS. METHODS: The present study enrolled 26 kidney transplant recipients receiving EC-MPS as part of their immunosuppressive therapy. Twenty-six full MPA AUC(0-12) were performed. By using multiple stepwise regression analysis, we obtained several predictive equations of MPA systemic exposure in this group of patients. The value of the selected equations was tested in a subsequently enrolled group of 26 kidney transplant recipients. RESULTS: The best equations obtained in the first group of patients were the following: 22.906 + 3.880·C(0) + 1.117·C(1) + 7.527·C(8) (r = 0.901) and 35.064 +3.784·C(0) + 1.002·C(1) + 1.192·C(2) (r = 0.846). These equation models showed an optimal agreement between the full AUCs and estimated AUCs by using the validation group of patients. CONCLUSIONS: Limited sampling strategies are useful for MPA AUC(0-12) estimation in patients receiving EC-MPS and cyclosporine. The choice of one or the other equation model depends on the pharmacokinetic characteristics of the patients, in particular the potential presence of enterohepatic recirculation.

Ethical and Policy Considerations in the Application of Pharmacogenomic Testing for Tardive Dyskinesia: Case Study of the Dopamine D3 Receptor.

Tardive dyskinesia (TD) is a serious adverse effect often associated with the first generation antipsychotic medications used in the management of mental health disorders such as schizophrenia. Pharmacogenomics is the study of human genomic variation in relation to individual and population variability in medication response and side effects. Neuropsychiatry is one of the clinical domains in which pharmacogenomic approaches have been extensively studied. In the late 1990s, the Glycine9 (Gly9) allele of the Serine-9-Glycine (Ser9Gly) polymorphism in dopamine D3 receptor gene (DRD3) was found to be associated with both a liability to, and worsened severity of, TD in schizophrenic patients treated with typical antipsychotics. This initial discovery has been subsequently replicated and testing for the Ser9Gly polymorphism has now become commercially available. The question that currently presents itself is whether its use should be encouraged for patients who may be prescribed a typical or atypical antipsychotic medication. However, the translation of this new technology to clinical practice presents multiple social, ethical and policy challenges. Though pharmacogenomic testing holds much promise in this scenario, many important questions remain to be answered before its widespread use can be medically and ethically justified. This article highlights the key advances in our understanding of the role of human genetic variation in the D3 receptor in relation to TD. Then, issues of uncertainty, consent, confidentiality, and access are considered with respect to the use of DRD3 polymorphism testing in risk stratification for susceptibility to tardive dyskinesia. We propose three recommendations that may help bring this technology into the clinic: 1) prospective pharmacogenomic studies of DRD3 polymorphism and TD risk should be conducted; 2) the design of such studies should be influenced by scientists, ethicists and policy makers to protect potentially vulnerable patients; and 3) appropriate knowledge transfer to front-line health care workers must take place.

Absence of pharmacokinetic interference of moxifloxacin on cyclosporine and tacrolimus in kidney transplant recipients.

This study investigates the potential pharmacokinetic interactions between an antimicrobial agent, moxifloxacin, and 2 immunosuppressant drugs, cyclosporine and tacrolimus, in kidney transplant recipients. Twenty-two kidney transplant patients needing antibiotic therapy for urinary tract infections are enrolled. Eleven patients are under cyclosporine treatment and the other 11 patients are under tacrolimus treatment. Because the urinary tract infections are caused by gram-negative aerobes sensitive to moxifloxacin, this antibiotic is administered by oral route at a dose of 400 mg/d for 1 week; in each patient pharmacokinetic studies are carried out before and at the seventh day of therapy. For both immunosuppressors, none of the pharmacokinetic parameters investigated show statistically significant differences between values obtained before and during treatment with moxifloxacin. In fact, the concentration-time profiles of monoclonal cyclosporine, polyclonal cyclosporine, and tacrolimus are not significantly different before and during the antimicrobial therapy. The results of the present study rule out interference of moxifloxacin with both cyclosporine and tacrolimus kinetics and indicate that the concomitant administration of the fluoroquinolone and cyclosporine or tacrolimus does not require modifications of the dosages of 2 immunosuppressant drugs.

Oxidative stress in tardive dyskinesia: genetic association study and meta-analysis of NADPH quinine oxidoreductase 1 (NQO1) and Superoxide dismutase 2 (SOD2, MnSOD) genes.

INTRODUCTION: Tardive dyskinesia (TD) is a potentially irreversible side effect of antipsychotic medication treatment that occurs in approximately 25% of chronically treated schizophrenia patients. Oxidative stress has been one of the proposed mechanisms influencing TD risk. Pae et al. (2004) originally reported a significant association between TD and the NADPH quinine oxidoreductase 1 (NQO1) gene Pro187Ser (C609T, rs1800566) polymorphism in Korean schizophrenia patients; however, subsequent studies have not consistently replicated these findings. Similarly, Hori et al. (2000) reported an association between TD and the Manganese superoxide dismutase SOD2 (MnSOD) gene Ala9Val (rs4880) polymorphism in a Japanese sample, but most research groups failed to replicate their positive findings. AIMS: We investigated the role of the NQO1 polymorphism Pro187Ser and SOD2 (Ala9Val) in a group of well-characterized schizophrenia patients (N=223) assessed for TD. We also performed a meta-analysis of all the previously published TD studies, including data from our sample, on these polymorphisms, Pro187Ser (N=5 studies) and Ala9Val (N=9 studies). RESULTS: We did not observe a significant association of the Pro187Ser or Ala9Val polymorphism with TD occurrence or AIMS scores in our Caucasian and African American samples when analyzed independently. Meta-analysis did not reveal a significant association of the Pro187Ser/Ala9Val alleles or genotypes with TD occurrence. CONCLUSIONS: Neither the NQO1 Pro187Ser nor the SOD2 Ala9Val appear to play a major role in TD risk, although additional polymorphisms should be tested before the role of NQO1 and SOD2 in TD can be completely excluded.

Movements in brain death: a systematic review.

Brain death is the irreversible lost of function of the brain including the brainstem. The presence of spontaneous or reflex movements constitutes a challenge for the neurological determination of death. We reviewed historical aspects and practical implications of the presence of spontaneous or reflex movements in individuals with brain death and postulated pathophysiological mechanisms. We identified and reviewed 131 articles on movements in individuals with confirmed diagnosis of brain death using Medline from January 1960 until December 2007, using 'brain death' or 'cerebral death' and 'movements' or 'spinal reflex' as search terms. There was no previous systematic review of the literature on this topic. Plantar withdrawal responses, muscle stretch reflexes, abdominal contractions, Lazarus's sign, respiratory-like movements, among others were described. For the most part, these movements have been considered to be spinal reflexes. These movements are present in as many as 40-50% of heart-beating cadavers. Although limited information is available on the determinants and pathophysiological mechanisms of spinal reflexes, clinicians and health care providers should be aware of them and that they do not preclude the diagnosis of brain death or organ transplantation.

Does protracted antiviral therapy impact on HCV-related liver cirrhosis progression?

AIM: To study the outcomes of patients with compensated hepatitis C virus-related cirrhosis. METHODS: Twenty-four grade A5 and 11 grade A6 of Child-Pugh classification cirrhotic patients with active virus replication, treated for a mean period of 31.3 +/- 5.1 mo with moderate doses of interferon-alpha and ribavirin, were compared to a cohort of 36 patients with similar characteristics, without antiviral treatment. Salivary caffeine concentration, a liver test of microsomal function, was determined at the starting and thrice in course of therapy after a mean period of 11 +/- 1.6 mo, meanwhile the resistive index of splenic artery at ultra sound Doppler, an indirect index of portal hypertension, was only measured at the beginning and the end of study. RESULTS: Eight out of the 24 A5- (33.3%) and 5 out of the 11 A6- (45.45%) treated-cirrhotic patients showed a significant improvement in the total overnight salivary caffeine assessment. A reduction up to 20% of the resistive index of splenic artery was obtained in 3 out of the 8 A5- (37.5%) and in 2 out of the 5 A6- (40%) cirrhotic patients with an improved liver function, which showed a clear tendency to decrease at the end of therapy. The hepatitis C virus clearance was achieved in 3 out of the 24 (12.5%) A5- and 1 out of the 11 (0.091%) A6-patients after a median period of 8.5 mo combined therapy. In the cohort of non-treated cirrhotic patients, not only the considered parameters remained unchanged, but 3 patients (8.3%) had a worsening of the Child-Pugh score (P = 0.001). CONCLUSION: A prolonged antiviral therapy with moderate dosages of interferon-alpha and ribavirin shows a trend to stable liver function or to ameliorate the residual liver function, the entity of portal hypertension and the compensation status at acceptable costs.

Immunoassay determination of rapamycin: reliability of the method with respect to liquid chromatography mass spectrometric quantification.

Immunochemical assays represent a promising tool for quantification of immunosuppressants in organ transplanted patients, because they require small sample volumes and minimum sample pre-treatment; nevertheless considerations about method specificity, sensitivity and reproducibility cannot be overlooked. The present paper investigates the reliability of using the immunoparticle enzyme immunoassay (MEIA) for the quantification of blood rapamycin (RAPA) levels in therapeutic drug monitoring of renal transplanted patients with respect to a validated liquid chromatography tandem mass spectrometric (LC/ESI-MSMS) method, used as reference. Linearity of MEIA was tested over the range 0.0-30.0 ng/mL, with accuracy and precision within acceptable limits. Fifty-two blood samples were collected from 42 renal transplanted patients and analyzed simultaneously by both methods. The Pearson's regression analysis gave the following parameters: correlation equation [RAPA](MEIA) = 1.330 + 0.776 [RAPA](LC/ESI-MSMS), r = 0.8526, SD = 1.778, p < 0.0001. The obtained average rapamycin concentration was 8.8 +/- 3.4 ng/mL using MEIA and 9.6 +/- 3.7 ng/mL for LC/ESI-MSMS, with an overall underestimation of about 6% of the immunoenzymatic test. Accuracy of MEIA ranged from -33% to 36% with respect to the reference mass spectrometric method. Although immunoenzymatic test represents a fast and sufficiently accurate method for its use in clinical practice, specificity of the assay is still not sufficiently investigated and reference methods and/or Proficiency Testing Scheme should be used as external control.

A prospective study of acute drug-induced liver injury in patients suffering from non-alcoholic fatty liver disease.

AIM: Liver damage due to facultative hepatotoxins is scarcely foreseeable. We evaluated the prevalence of acute drug-induced liver injury (DILI) in a specific setting, assessing eventual interactions with pre-existing hepatic illnesses. METHODS: The research was carried out in an Italian tertiary care hospital, by analyzing 248 patients with non-advanced liver disease, divided into two well-matched groups: 174 patients (median age 53, 94 females) with hepatitis C virus-related chronic hepatitis; and 74 (median age 55, 39 females) with non-alcoholic fatty liver disease (NAFLD). RESULTS: Six patients (2.4% of the whole population) belonging to the NAFLD group (chi(2)-test, P = 0.004) suffered from acute hepatoxicity related to the following drugs, that is antihypertensive, acting on platelet aggregation, antimicrobial, non-steroidal anti-inflammatory and proton pump inhibitor. The NAFLD presence was an independent risk factor in determining drug-related acute hepatitis, with an odds ratio of 3.95 (95% confidence intervals: 11.48-1.35). Central obesity was relevant in every patient with acute toxicity. Alcohol consumption and drug association did not influence the acute drug-induced liver damage. CONCLUSION: NAFLD conveys a nearly fourfold increase of DILI risk in obese middle-aged patients. NAFLD, characterized by mitochondrial dysfunction, could predispose to drug-induced hepatotoxicity that probably shares the same pathophysiological mechanism.