Adrenomedullin as a potential biomarker involved in patients with hereditary hemorrhagic telangiectasia.

BACKGROUND: Adrenomedullin (AM) is a vasoactive peptide mostly secreted by endothelial cells with an important role in preserving endothelial integrity.  The relationship between AM and hereditary hemorrhagic telangiectasia (HHT) is unknown. We aimed to compare the serum levels and tissue expression of AM between HHT patients and controls. METHODS: Serum AM levels were measured by radioimmunoassay and compared between control and HHT groups. AM levels were also compared among HHT subgroups according to clinical characteristics. The single nucleotide polymorphism (SNP) rs4910118 was assessed by restriction analysis and sequencing. AM immunohistochemistry was performed on biopsies of cutaneous telangiectasia from eight HHT patients and on the healthy skin from five patients in the control group. RESULTS: Forty-five HHT patients and 50 healthy controls were included, mean age (SD) was 50.7 (14.9) years and 46.4 (9.9) years (p = 0.102), respectively. HHT patients were mostly female (60% vs 38%, p = 0.032). Median [Q1-Q3] serum AM levels were 68.3 [58.1-80.6] pg/mL in the HHT group and 47.7 [43.2-53.8] pg/mL in controls (p<0.001), with an optimal AM cut-off according to Youden's J statistic of 55.32 pg/mL (J:0.729). Serum AM levels were similar in the HHT subgroups. No patient with HHT had the SNP rs4910118. AM immunoreactivity was found with high intensity in the abnormal blood vessels of HHT biopsies. CONCLUSIONS: We detected higher AM serum levels and tissue expression in patients with HHT than in healthy controls. The role of AM in HHT, and whether AM may constitute a novel biomarker and therapeutic target, needs further investigation.

Gender differences in hereditary hemorrhagic telangiectasia severity.

BACKGROUND: Gender differences in organ involvement and clinical severity have been poorly described in hereditary hemorrhagic telangiectasia (HHT). The aim of this study was to describe differences in the severity of HHT manifestations according to gender. METHODS: Severity was measured according to Epistaxis Severity Score (ESS), Simple Clinical Scoring Index for hepatic involvement, a general HHT-score, needing for invasive treatment (pulmonary or brain arteriovenous malformations -AVMs- embolization, liver transplantation or Young's surgery) or the presence of adverse outcomes (severe anemia, emergency department -ED- or hospital admissions and mortality). RESULTS: One hundred forty-two (58.7%) women and 100 (41.3%) men were included with a mean age of 48.9 ± 16.6 and 49 ± 16.5 years, respectively. Women presented hepatic manifestations (7.1% vs 0%) and hepatic involvement (59.8% vs 47%), hepatic AVMs (28.2% vs 13%) and bile duct dilatation (4.9% vs 0%) at abdominal CT, and pulmonary AVMs at thoracic CT (35.2% vs 23%) more often than men. The Simple Clinical Scoring Index was higher in women (3.38 ± 1.2 vs 2.03 ± 1.2), and more men were considered at low risk of harboring clinically significant liver disease than women (61% vs 25.3%). These differences were mantained when considering HHT1 and HHT2 patients separetely. Duodenal telangiectasia were more frequent in men than women (21% vs 9.8%). Invasive treatments were more frequently needed in women (28.2% vs 16%) but men needed attention at the ED more often than women (48% vs 28.2%), with no differences in ESS, HHT-score, anemia hospital admissions or mortality. CONCLUSIONS: HHT women showed more severe hepatic involvement than men, also among HHT1 and HHT2 patients. Women had higher prevalence of pulmonary AVMs and needed invasive procedures more frequently, while men needed attention at the ED more often. These data might help physicians to individualize HHT patients follow-up.

Temporal relationship between perceptual and physiological events triggered by nociceptive heat stimuli.

A combined assessment tool for the perceptual-motor aspects of pain processing will be valuable to clinicians. Fifteen healthy subjects were exposed to contact-heat stimulation (Pathway, Medoc, Israel) to assess perception through a simple task (motor response or conscious appraisal of the time the stimulus was felt) or with a dual task (both responses). The outcome measure was the temporal relationship between contact heat evoked potentials (CHEPS), reaction time (RT) and conscious awareness (AW). There were different temporal profiles for CHEPs, RT and AW to changes in stimulus intensity, AW being the least affected. Performing the dual task led to a significantly more pronounced effect on RT than on AW, while CHEPS were not influenced by task performance. Our results support the dissociation between physiological, behavioral and cognitive events elicited by nociceptive stimuli. The time of conscious appraisal of stimulus occurrence is a complementary information to other responses such as evoked potentials or behavioral tasks. The combined assessment of physiological and behavioral aspects of pain processing may provide clinicians with information on the different paths followed by nociceptive afferent inputs in the central nervous system.

Liver Transplant Patient Carriers of Polymorphism Cyp3a5*1 Donors May Need More Doses of Tacrolimus From the First Month After Transplantation.

BACKGROUND: The aim of this work was to evaluate the CYP3A5:CYP3A5*1/CYP3A5*3 (6986A>G) polymorphism related to the pharmacokinetic characteristics of tacrolimus during the first 3 months after transplantation, analyzing both donor and recipient genotype, in liver transplant patients. METHODS: This retrospective, single-center, cohort study included patients who had been treated with tacrolimus monotherapy with or without corticoids (n = 67). Donors and recipients were genotyped for the CYP3A5*3 allele polymorphism (6986A>G) by use of a TaqMan polymerase chain reaction technique. The presence or absence of the *1 allele ("minor-allele") was analyzed for correlation with the tacrolimus dose-normalized ratio during the 3 months after transplantation. RESULTS: The following observations were obtained in the population studied: (1) Frequency of the minor allele*1 was much lower both in recipients (11.9% versus 88.1%) and donors (19.4% versus 80.6%), with no statistically significant differences between both distributions. (2) Recipient genotype for CYP3A5*1/*3-polymorphism had no influence in tacrolimus pharmacokinetics, with no differences between carriers and non-carriers of the minor-allele*1. (3) However, from the first month after transplantation, patients with grafts from donor carriers of minor allele*1 had lower concentration-dose ratios compared with patients with grafts from donor non-carriers of that allele (71.1 versus 119.3 and 90.5 versus 126.3, for 30 and 90 days after transplantation, respectively; P < .05). CONCLUSIONS: The presence of the CYP3A5-6986A>G-polymorphism in the donor affects tacrolimus pharmacokinetics in the recipient, although the difference was statistically significant only for the first month after transplantation. This means that in liver transplant patients receiving grafts from donors carrying the CYP3A5*1-polymorphism, a larger dose of tacrolimus from the first month after transplantation would be needed. The evidence provided in this study showed no effect of the recipient genotype.

The StartReact effect in tasks requiring end-point accuracy.

OBJECTIVE: Fast and accurate movements are often performed in response to a sensory signal. In reaction time tasks, execution of open loop movements is speeded up when a startling auditory stimulus (SAS) is applied together with the imperative signal (IS). In this study, we examined the effects of a SAS on the performance of a task that demands accuracy. METHODS: Nine subjects were asked to move a monitored pen to a target point located in a table at a fixed angular distance of 30 degrees from a start point. The target was a spot of three possible diameters: 5, 10, and 20mm. Finger force for pen holding, pen tip pressure against the table and kinematic variables of the forearm movement were measured for three conditions: control, SAS delivered at IS (SAS-IS trials) and SAS delivered during movement execution (SAS-MOV trials). RESULTS: Two movement phases could be identified in the movement trajectory and force profile. The first phase, ballistic, was significantly shortened in SAS-MOV trials, with earlier and larger peak velocity and peak force with respect to control trials. The second phase, slow approach to target, was longer in SAS-IS trials but not in SAS-MOV trials. Accuracy was maintained throughout all conditions and stimulation modes. CONCLUSIONS: A SAS speeds up only the first (ballistic) part of the movement in an accuracy task. Slower target approach compensates for the accelerated initial movement. No changes in the last part of the movement are seen when a SAS is delivered after movement onset. SIGNIFICANCE: The StartReact effect is restricted to the onset of a complex movement, when muscles are activated in a ballistic mode, without feedback.

Prior history of FDI muscle contraction: different effect on MEP amplitude and muscle activity.

Motor evoked potentials (MEPs) in the right first dorsal interosseous (FDI) muscle elicited by transcranial magnetic stimulation of left motor cortex were assessed in ten healthy subjects during maintenance of a fixed FDI contraction level. Subjects maintained an integrated EMG (IEMG) level with visual feedback and reproduced this level by memory afterwards in the following tasks: stationary FDI muscle contraction at the level of 40 ± 5 % of its maximum voluntary contraction (MVC; 40 % task), at the level of 20 ± 5 % MVC (20 % task), and also when 20 % MVC was preceded by either no contraction (0-20 task), by stronger muscle contraction (40-20 task) or by no contraction with a previous strong contraction (40-0-20 task). The results show that the IEMG level was within the prescribed limits when 20 and 40 % stationary tasks were executed with and without visual feedback. In 0-20, 40-20, and 40-0-20 tasks, 20 % IEMG level was precisely controlled in the presence of visual feedback, but without visual feedback the IEMG and force during 20 % IEMG maintenance were significantly higher in the 40-0-20 task than those in 0-20 and 40-20 tasks. That is, without visual feedback, there were significant variations in muscle activity due to different prehistory of contraction. In stationary tasks, MEP amplitudes in 40 % task were higher than in 20 % task. MEPs did not differ significantly during maintenance of the 20 % level in tasks with different prehistory of muscle contraction with and without visual feedback. Thus, in spite of variations in muscle background activity due to different prehistory of contraction MEPs did not vary significantly. This dissociation suggests that the voluntary maintenance of IEMG level is determined not only by cortical mechanisms, as reflected by corticospinal excitability, but also by lower levels of CNS, where afferent signals and influences from other brain structures and spinal cord are convergent.

The StartReact effect on self-initiated movements.

Preparation of the motor system for movement execution involves an increase in excitability of motor pathways. In a reaction time task paradigm, a startling auditory stimulus (SAS) delivered together with the imperative signal (IS) shortens reaction time significantly. In self-generated tasks we considered that an appropriately timed SAS would have similar effects. Eight subjects performed a ballistic wrist extension in two blocks: reaction, in which they responded to a visual IS, and action, in which they moved when they wished within a predetermined time window. In 20-25% of the trials, a SAS was applied. We recorded electromyographic activity of wrist extension and wrist movement kinematic variables. No effects of SAS were observed in action trials when movement was performed before or long after SAS application. However, a cluster of action trials was observed within 200 ms after SAS. These trials showed larger EMG bursts, shorter movement time, shorter time to peak velocity, and higher peak velocity than other action trials (P < 0.001 for all), with no difference from Reaction trials containing SAS. The results show that SAS influences the execution of self-generated human actions as it does with preprogrammed reaction time tasks during the assumed building up of preparatory activity before execution of the willed motor action.

[Control of different electromyogram levels of M. abductor pollicis brevis by means of visual feedback in healthy subjects].

We studied voluntary control of integrated electromyogram (IEMG) in the range of 20 +/- 5% and 40 +/- 5% of the IEMG of m. abductor pollicis brevis during its maximum voluntary contraction with and without visual feedback. Healthy subjects performed IEMG control with visual feedback in 5 trials; IEMG control with visual feedback in 5 trials for 5 days, and the reproduction of memorized IEMG value without visual feedback after 5 trials of IEMG under the visual control. The accuracy of IEMG control was estimated by the following parameters: time of IEMG being out of the required 10% range (ERROR); IEMG variability (VARIABILITY), and the bias of IEMG mean level (BIAS) during 30-sec trials. The IEMG control in the range of 20 +/- 5% with visual feedback improved in all subjects over the course of 5 trials. Within 5-day training, ERROR and VARIABILITY reduced on the first day only; during the last 4 days there was no accuracy increase. ERROR increased more than twice when the 20% IEMG level was reproduced without vision. The IEMG control in the range of 40 +/- 5% improved neither during 5 trials, nor during 5 days of training with visual feedback. ERROR increased for about 1.5 times when the 40% IEMG level was reproduced without vision. It was concluded that the motor system, particularly the motor cortex, could control the given level of muscle activity using the visual feedback.

Load detection and discrimination in a catching task: role of haptic and auditory information.

The aim of this study was to verify the contribution of haptic and auditory cues in the quick discrimination of an object mass. Ten subjects had to brake with the right hand the movement of a cup due to the falling impact of an object that could be of two different masses. They were asked to perform a quick left hand movement if the object was of the prescribed mass according to the proprioceptive and auditory cues they received from object contact with the cup and did not react to the other object. Three conditions were established: with both proprioceptive and auditory cues, only with proprioceptive cue or only with an auditory cue. When proprioceptive information was available subjects advanced responses time to the impact of the heavy object as compared with that of the light object. The addition of an auditory cue did not improve the advancement for the heavy object. We conclude that when a motor response has to be chosen according to different combinations of auditory and proprioceptive load-related information, subjects used mainly haptic information to fast respond and that auditory cues do not add relevant information that could ameliorate the quickness of a correct response.

Trends on schizophrenia admissions during the deinstitutionalisation process in Spain (1980-2004).

BACKGROUND: The deinstitutionalisation reform in Spain started after 1980 with the aim of reducing the need for hospitalisation, length of stay and the number of psychiatric hospital beds, as well as fostering psychiatric patient's involvement in the community. The aim of this study was to review how this reform process has affected the management of schizophrenic patients from 1980 to 2004. METHODS: Longitudinal (1980-2004) study describing variables related to hospital morbidity in schizophrenia patients. RESULTS: Hospital admission rate has gradually increased from 1980 to 2004 from 3.71 admissions per 10,000 inhabitants to 5.89, respectively. Considering the type of admission, emergency or elective, whilst the latter has slightly decreased from 2.24 in 1980 to 1.72 in 2004, the first has almost tripled from 1.47 to 4.17. The point-prevalence of schizophrenic patients receiving inpatient treatment each year has decreased 78% in this period. Length of stay, in days per admission episode, has also decreased from 148 days in 1980 to 35 days in 2004. CONCLUSION: One of the main impacts of the psychiatric health care reform in Spain has been the considerable reduction in hospital capacity devoted to schizophrenic patients, based on the significant decrease in point-prevalence. Thus, it seems relevant to design new studies to quantify the resource reallocation to other areas of care, such as pharmacological treatment and community services.

Voluntary ankle flexor activity and adaptive coactivation gain is decreased by spasticity during subacute spinal cord injury.

Although spasticity has been defined as an increase in velocity-dependent stretch reflexes and muscle hypertonia during passive movement, the measurement of flexor muscle paresis may better characterize the negative impact of this syndrome on residual motor function following incomplete spinal cord injury (iSCI). In this longitudinal study Tibialis Anterior (TA) muscle paresis produced by a loss in maximal voluntary contraction during dorsiflexion and ankle flexor muscle coactivation during ramp-and-hold controlled plantarflexion was measured in ten patients during subacute iSCI. Tibialis Anterior activity was measured at approximately two-week intervals between 3-5 months following iSCI in subjects with or without spasticity, characterized by lower-limb muscle hypertonia and/or involuntary spasms. Following iSCI, maximal voluntary contraction ankle flexor activity was lower than that recorded from healthy subjects, and was further attenuated by the presence of spasticity. Furthermore the initially high percentage value of TA coactivation increased at 75% but not at 25% maximal voluntary torque (MVT), reflected by an increase in TA coactivation gain (75%/25% MVT) from 2.5+/-0.4 to 7.5+/-1.9, well above the control level of 2.9+/-0.2. In contrast contraction-dependent TA coactivation gain decreased from 2.4+/-0.3 to 1.4+/-0.1 during spasticity. In conclusion the adaptive increase in TA coactivation gain observed in this pilot study during subacute iSCI was also sensitive to the presence of spasticity. The successful early diagnosis and treatment of spasticity would be expected to further preserve and promote adaptive motor function during subacute iSCI neurorehabilitation.

Incidence of spinal cord injury worldwide: a systematic review.

BACKGROUND: Incidence studies of spinal cord injury (SCI) are important for health-care planning and epidemiological research. This review gives a quantitative update on SCI epidemiology worldwide through a statistical evaluation of incidence rates. METHODS: A systematic review was conducted. For each study, the crude rate ratio was calculated and, when possible, age- and gender-adjusted incidence rate ratios with 95% CI were determined by direct adjustment or using Poisson regression. RESULTS: Thirteen studies were included. Annual crude incidence rates in traumatic SCI varied from 12.1 per million in The Netherlands to 57.8 per million in Portugal. Compared to the Portuguese reference study, incidence rates showed a 3-fold variation, with the highest rates in Canada and Portugal. Most traumatic SCI studies showed a bimodal age distribution. The first peak was found in young adults between 15 and 29 years and a second peak in older adults (mostly > or = 65 years). Motor vehicle accidents and falls were the most prevalent causes of injury accounting for nearly equal percentages. In contrast, another age pattern in non-traumatic SCI reflected steadily increasing incidence with advancing age. CONCLUSIONS: The results show significant variation in SCI incidence with changing epidemiological patterns. A trend towards increased incidence in the elderly was observed, likely due to falls and non-traumatic injury.

Usefulness of reagent strips for checking cure in spontaneous bacterial peritonitis after short-course treatment.

BACKGROUND: The usefulness of reagent strips to check cure of spontaneous bacterial peritonitis have not been evaluated to date. AIM: To assess the usefulness of ascitic fluid analysis by means of reagent strips to check cure after a 5-day antibiotic course. METHODS: We prospectively included all cirrhotic patients diagnosed with spontaneous bacterial peritonitis. On day 5, conventional and reagent strip ascitic fluid analyses were performed. RESULTS: Fifty-three episodes of spontaneous bacterial peritonitis in 51 cirrhotic patients were included. Five patients died before the fifth day and in two patients, the control paracentesis yielded no ascitic fluid. In nine out of 46 cases (19.6%), spontaneous bacterial peritonitis had not resolved by day 5. In 32 out of 33 cases in which the ascitic fluid polymorphonuclear count was <250/microL at day five, the reagent strips was negative. The negative predictive value of the reagent strip at fifth day was 97% and the LR- 0.13. CONCLUSIONS: Almost 20% of episodes of spontaneous bacterial peritonitis do not resolve with a short-course of antibiotic treatment. In view of the high negative predictive value and low likelihood ratio for a negative test, reagent strips analysis may be an alternative to conventional cytology if a 5-day antibiotic therapy is planned.

Antral mass due to cytomegalovirus infection requiring gastrectomy in a liver transplant recipient.

The incidence of cytomegalovirus (CMV) infection after liver transplantation (LT) has decreased in recent years. Advances in immunosuppression and CMV prophylaxis have improved the management of CMV disease. Organ involvement is infrequent and gastrointestinal CMV disease is quite rare. Few cases of an antral mass due to CMV infection have been described; those reported to date have mostly been in patients with acquired immunodeficiency syndrome. We describe a case of a CMV-seronegative liver transplant patient who received a seropositive liver graft. Owing to gastrointestinal complaints, CMV prophylaxis was stopped one month after LT. The patient developed an antral mass due to CMV infection and an anastomotic biliary stricture. Antigenemia became negative with ganciclovir, but this treatment did not eliminate the mass. Ganciclovir resistance was ruled out as well as other causes of antral mass, especially malignancy. The patient finally required gastrectomy and hepaticojejunostomy. We conclude that CMV disease is less common today but should be included in the diagnosis of gastrointestinal mass after transplantation.

Preliminary results of treatment with pegylated interferon alpha 2A for chronic hepatitis C virus in kidney transplant candidates on hemodialysis.

INTRODUCTION: At present, there is little published information on the outcome of treatment with pegylated interferon (Peg-IF alpha 2a) in hepatitis C virus (HCV)-infected hemodialysis patients awaiting renal transplantation. The objective of this study was to assess the efficacy and tolerance of Peg-IF alpha 2a in this population. PATIENTS AND METHODS: Twelve noncirrhotic HCV-infected patients (10 men, 50 +/- 8 years of age, genotype 1b 84%), were prescribed Peg-IF alpha 2a, at 135 microg/wk for 48 weeks. Liver biopsy was performed in 11 of 12 cases. RESULTS: Six patients completed 48 weeks of treatment, with one end of treatment response (ETR), two sustained viral responses (SVRs), and three HCV relapses. Treatment was shorter in the six remaining patients: two cases 24 weeks (one due to medical reasons with relapse, one due to nonresponse), one patient chose to discontinue at 14 weeks (with relapse), one patient died of stroke at 10 weeks, and in two additional patients interferon was withdrawn at 18 weeks because of severe anemia (SVR) and at 26 weeks due to prolonged fever (relapse). Other secondary treatment-related events included anemia (requiring transfusion in two patients and major erythropoietin administration in six), and fever in four patients. CONCLUSIONS: Peg-IF had limited efficacy in this group, with ETR in 83%, SVR in only 25%, and recurrence in 50%. Tolerance was moderate, with 4/12 (33%) discontinuing treatment due to adverse events, personal decision, or death. Large randomized controlled studies are needed to determine the role of Peg-IF treatment in this population.

Risk of acute liver injury associated with the use of drugs: a multicentre population survey.

BACKGROUND: Acute liver injury of uncertain aetiology is often drug related and quantitative information about the associated risk is scarce. AIM: To estimate the risk of acute liver injury associated with the use of drugs. METHODS: In a population survey study, 126 cases of acute liver injury were prospectively assembled from January 1993 to December 1999, in patients over 15 years of age, in 12 hospitals in Barcelona (Spain). We estimated the relative risk for each drug as the ratio between the incidence of acute liver injury among the exposed population to the drug and the incidence of acute liver injury among those not exposed to it. Drug consumption data were used to estimate the exposed population. RESULTS: Isoniazid, pyrazinamide, rifampicin, amoxicillin with clavulanic acid, erythromicin, chlorpromazine, nimesulide, and ticlopidine presented the highest risk (point relative risk > 25). Amoxicillin, metoclopramide, captopril and enalapril, furosemide, hydrochlorothiazide, fluoxetine, paroxetine, diazepam, alprazolam, lorazepam, metamizole, low-dose acetylsalicylic acid and salbutamol showed the lowest risk (point relative risk < 5). CONCLUSIONS: This study provides a risk estimation of serious liver disease for various drugs that will be useful in its diagnosis and management, and when comparing with the drug therapeutic benefit in each indication. Some observed associations would be worth specific studies.

Clinical features and outcome of spontaneous bacterial peritonitis in HIV-infected cirrhotic patients: a case-control study.

The aim of this study was to evaluate the clinical characteristics and outcome of spontaneous bacterial peritonitis, a serious complication in patients with cirrhosis and ascites, in an HIV-infected cirrhotic population. Thirty-five HIV-infected cirrhotic patients who developed spontaneous bacterial peritonitis during a 12-year period were compared with 70 non-HIV-infected cirrhotic subjects. Patients were matched according to the date of the first episode of spontaneous bacterial peritonitis. A bacteriological diagnosis was made in 37 of 47 (79%) and in 50 of 97 (52%) episodes in the HIV group and in the non-HIV group, respectively (p=0.003), and Streptococcus pneumoniae was isolated more frequently in the HIV group (22 vs. 8%, p=0.02). Median survival after the initial diagnosis of spontaneous bacterial peritonitis was 2.9 and 14.0 months in the HIV group and non-HIV group, respectively. Age (hazard ratio [HR] 1.04; 95%CI 1.01-1.07), male sex (HR 2.55; 95%CI 1.34-4.83), Child-Pugh score at first spontaneous bacterial peritonitis episode (HR 1.29; 95%CI 1.10-1.54), renal impairment at first spontaneous bacterial peritonitis episode (HR 2.61; 95%CI 1.49-4.62), and HIV infection (HR 9.81; 95%CI 4.03-23.84) were independently associated with higher long-term mortality after the first diagnosis of spontaneous bacterial peritonitis. In conclusion, HIV-infected cirrhotic patients with spontaneous bacterial peritonitis have a higher rate of bacteriological diagnosis and a more frequent pneumococcal etiology than non-HIV-infected subjects. Life expectancy in these patients, once spontaneous bacterial peritonitis has developed, is poor. These data are particularly relevant for determining the optimal time for liver transplantation in this population.