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Volume XIII, Number 1, 2009 - Therapeutics Pharmacology and Clinical Toxicology

Review



State-of-Art - Long-lasting effects of antipsychotics treatment

V. A. Voicu, F. Radulescu
Abstract: The authors make a short presentation of antipsychotics mechanisms consecutive to the interaction with receptors of the neurotransmission systems, respectively the meso-cortico-limbic dopaminergic system, the serotoninergic, glutamatergic, cholinergic systems and so on. Hence, a brief review is performed by means of the pharmacological proofs of schizophrenia pathogenic theories. Another of the regarded domains addresses the etio-pathogenic aspects of schizophrenia as background for potential pharmacologic targets - the genetic component and the impact of factors which disrupt the neurodevelopment and / or initiated neurodegeneration processes in favorable contexts. The authors analyze the eff ects of antipsychotics correlated on various receptor levels with the complex therapeutic eff ects on schizophrenia. Existing data show that these eff ects can either be: 1) the direct consequence of action on receptor or the indirect outcome of counter-regulations determined in other neuromediation systems, or 2) these eff ects can be relatively immediate (a matter of hours - days) or slowly instated (weeks) or, these eff ects can not appear at all (resistance to treatment, non-responders etc.). In this regard, two concepts are brought into discussion: the therapeutic eff ects with immediate onset and defi nition after 2-3 weeks and the slow eff ects, sharpened up after around one month and either defi ned or not after a few months. Another type of reasonings are also brought into discussion: the slow and late eff ects of antidepressants, the onset of the addiction phenomenon as a complex neuroadaptive process, and also the experimental and clinical proof that antipsychotics induce complex phenomena on cerebral structures. In fact, in the context of chronic antipsychotic treatment, the brain behave according to the acknowledged rules: it launches short latency, rapid processes with homeostatic destiny, thus initiating a series of other, slower reactions, implying protein and receptor synthesis, synaptic plasticity, neuroplasticity, neurogenesis etc. These processes, which entail changes in the expression of certain genes, are approached as epigenetic phenomena which confer to the organism, on one hand, fl exibility and adaptability and, on the other hand, genomic stability. Given this context, the authors deem that there are convincing arguments (either direct or indirect) towards admitting that throughout the interaction antipsychotic - pathogenic psychotic processes, two successive interdependent and correlated phases are envisaged: 1) the pharmacodynamic phase where the active compound determines the known eff ects consecutive to antagonizing or activating the receptors for which it has affi nity and 2) the pharmacotherapeutic phase implying slower, more complex processes. The rapid counter-regulations of the interconnected neurotransmission systems are part of the phenomena which probably initiate slower and more complex reactions entailing compensatory phenomena in a positive or negative sense (up or downregulation) at receptor level, neuromediator synthesis, synaptic connections or even the emergence of new neurons in certain cerebral regions. This second phase will outline the fi nal therapeutic response which will install in weeks, months. In connection with the rearrangement, modulation and resetting between diff erent neurotransmission systems (aff ected in the schizophrenia context), on the basis of the presented epigenetic processes, we might either report or not an individual therapeutic eff ect as hinted end-point.

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State-of-Art - Clinical Pharmacology and Clinical Pharmacy: Competition or Collaboration?

Svetlana Golocorbin-Kon, Mladena Lalic, A. Raskovic, Sasa Vukmirovic, Z. Tomic, M. Mikov
Abstract: Clinical pharmacology and clinical pharmacy bring together professionals who have firm grounding in the principles of drug therapy and who aim to improve the safety and effi cacy of treatments for the benefi ts of patients. However, there are clear differences, typically in the undergraduate and less prominent in postgraduate education. Clinical pharmacologists and clinical pharmacists are accountable for the same target groups. Clinical pharmacology and clinical pharmacy share similar and parallel development, history, the same goal and the same fi nancial resources (they compete for the same financial sources). As an academic discipline, Clinical Pharmacology has been developed over the past 40 years, but its impact on health care services has been less conspicuous. Clinical pharmacy has had a quicker and more coordinated development in health care services dominated and synchronized by the American College of Clinical Pharmacy, but a less notable advance as academic discipline. Collaboration between clinical pharmacology and clinical pharmacy should be possible. In practice, competition and domination of one group can always be discerned depending on the country or the area of the country. Clinical pharmacology - clinical pharmacy collaboration is important for the benefit of patients, education, authorities and clinical pharmacology and clinical pharmacy associations and development.

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The involvement of HLA Antigens in HIV Infection

L. Negrutiu, O. Rosca
Abstract: The link between HLA types and HIV disease progression has been known for over a decade. Now from, among others, the researches have reanalyzed many data from the Multi-Center AIDS Cohort (MACS). McMichael and colleagues have also documented CTL escape through the mutation of viral peptides which are to be -presented- by HLA class I (A, B, C) to the immune system (CD8 cells). More recently it has been shown that HLA class I alleles B27 and B57 are associated with better disease prognosis, while others (such as B35) are associated with worse outcome. The mechanism by which HLA influences disease progression is not yet understood. Some researchers have suggested that particular HLA molecules may be directly involved in restricting HIV replication, although more research is needed to understand this process.

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Original Papers


The role of risk factors and infective endocarditis classification in the assessment of appropriate empirical therapy

Adriana Slavcovici, A. Streinu-Cercel, Doina Tatulescu, Amanda Radulescu, Simona Mera, C. Marcu, D. Vesbianu, Adriana Topan
Abstract: Invasive medical procedures, increasing life span, immunosenescence and antibiotic use have changed the epidemiological and bacteriological profi le of infective endocarditis (IE) with direct consequences in the assessment of appropriate empirical therapy. Objective: The aim of the study was to classify IE according to predictive factors for drug resistant or multidrug resistant microorganisms in order to establish the appropriate therapeutic options. The study represents an attempt to apply Carmelis risk stratification (used for the management of severe infections) in IE. Materials and methods: We performed a retrospective study comprising of 270 consecutive episodes of IE admitted in the University Hospital of Infectious Diseases Cluj-Napoca during 1998-2008. The diagnosis of IE was established upon modified Duke criteria. Risk factors were ranked with 1, 2 or 3 points according to Carmelis risk stratification including: the degree of contact between the patient and the health care system (invasive procedures - present or absent), prior antibiotic treatments and patient characteristics (age, comorbidities, immune status). The highest final score allowed us to classify IE in three strata: IE with score 1, 2 or 3. For each risk category we evaluated the etiology and resistance patterns. Results: Using Carmeli scoring system we found 111 (41%) IE score 1 (community acquired IE), 87 (32%) IE with score 2 (IE associated to health care assistance or community acquired but with increased prediction of multidrug resistance), 72 (27%) IE stratified with `Carmeli score` 3 (usually nosocomial IE). Blood cultures were positive in 50.5% of score 1 IE and the identified strains were: 41% oral streptococci, 30.4% staphylococci (9% MRSA), 7% enterococci. Among score 2 we found 63% IE with positive blood culture: 23.6% staphylococci (16.4% meti-R), 29% oral streptococci, 9% other streptococcal strains, 21.8% Enterococcus spp and 18% Gram negative rods. Among score 3 IE we found 80.5% positive blood cultures. The identified strains were: 46.50% staphylococci (13.8% MRSA), 19% Enterococcus spp., 7% Streptococcus spp. (other oral streptococci), 10.3% Gram negative rods mostly resistant to the classical antibiotics. Multidrug resistant strains had a significantly higher prevalence in score 2 and 3 IE (21.8% and 25.8% respectively, p=0.007). We found significant correlations between the IE with score 2 and 3 and prosthetic valves, enterococcal or staphylococcal etiology and MDR. Conclusions: We found significant differences in the etiology and resistance patterns in risk stratified IE classified with `Carmeli score` 1, 2 or 3 that are essentially valuable in the assessment of the appropriate empirical therapy.

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Controversies in late neuroborreliosis and multiple sclerosis - case series

Amanda Radulescu, Doina Tatulescu, Lacrimioara Perju-Dumbrava, Mirela Flonta, Augusta Astilean, Melinda Horvat
Abstract: The etiology of MS remains uncertain, bacterial infection with B. burgdorferi is most frequently incriminated. Neuroimaging criteria considered in the diagnosis of MS can also be fulfi lled in NB, the joint feature being demyelinating lesions. We present the diagnosis and treatment diffi culties in NB versus MS and other clinical considerations. Methods We retrospectively studied all consecutive cases of neuroborreliosis hospitalized in the University Hospital of Infectious Diseases during 2006-2008. The diagnosis was established through clinical criteria (using a probability score for Lyme disease), serological criteria (enzyme immunoassay for IgM and IgG antibodies followed by confi rmatory Western blot) and MS diagnosis was stratifi ed as confirmed or possible according to MacDonalds criteria. Results There were 36 cases of probable or highly probable neuroborreliosis (score =6), out of which ten cases were also diagnosed as possible (5) or confirmed MS (5). The age range was 19 to 43 years, with female predominance (7/10). The clinical picture was marked by poor stamina and fatigue, paresthesia mainly in the lower extremities, palsies (facial or in the limbs), diffi cult walking and vertigo. In all cases the screening enzyme immunoassay was positive for IgM antibodies, confi rmatory Western blots were positive in four out of seven tests performed. Tick exposure was identified in 5 cases without erythema migrans. In all patients cerebral imaging examination revealed demyelinating lesions that were interpreted as late NB and/or MS (possible or confirmed). Treatment with neurotropic drugs and antibiotics was done and the fi ve patients with confirmed MS received beta interferon or corticosteroids. All cases demonstrated improvement after 6 weeks of sequential treatment (ceftriaxone and doxycycline). In one case, the diagnosis of cerebral lymphoma was considered suggesting the association between NB and MS or neuroborreliosis mimicking primary eff usion lymphoma. Conclusions. The diagnosis of MS and NB are diffi cult showing remarkable clinical and neuroimaging similarities. The infectious etiology of MS remains probable and in patients with possible MS it is reasonable to evaluate B. burgdorferi infection in order to ensure etiologic treatment.

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Local versus systemic Endomorphin 2 in a Carrageenan model of inflammatory hyperalgesia

Magdalena Leon, Irina M. Jaba, B. Tamba, O. C. Mungiu
Abstract: Inflammation effectively increases the activation of opioid receptors on peripheral terminals of sensory neurons. The resulting infl ammatory hyperalgesia responds to local treatment with opioid analgesics by decreasing its intensity. Comparatively, much less is known about the effi ciency of opioid peptides administered peripherally at the infl ammation site. The study examined the antihyperalgesia elicited by endomorphin 2, a miu agonist, when administered peripherally in a model of acute infl ammation with carrageenan. The effects of locally administered endomorphin 2 in three diff erent doses were investigated with behavioral assays. The local paw injection of endomorphin at the site of infl ammation induced an antihyperalgesic effect. For confirmation of the peripheral mechanism of analgesia, the peptide was systemically administered (i.p.) and at the dosage we used, endomorphin 2 was not signifi cantly antihyperalgesic. Endomorphin 2 was antihyperalgesic without signifi cantly affecting edema. In conclusion, the antihyperalgesic effect of the endomorphin 2 is not secondary to a reduction of edema, since reduction of edema does not occur. These observations plead for an action at the level of opioid receptors on nerve terminals rather than on immune cells.

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Eicosanoids in opiate-induced physical dependence in rats

D. Chelarescu, M. Nechifor
Abstract: Prostaglandins and leukotrienes are important autacoids of the central nervous system that intervene in normal and pathologic processes. Th ese eicosanoids could play important roles in morphineinduced withdrawal syndrome, as proven in diff erent experimental setups. In our studies, synthetic analogues of PGF2alfa (cloprostenol) and PGE1 (misoprostol) and a leukotriene LT1 receptor antagonist (montelukast) have influenced some of the symptoms of morphine (M) withdrawal (without interfering with other symptoms) in rats. Cloprostenol has signifi cantly influenced certain symptoms: grooming, aggressive postures, teeth chattering, compulsive mastication, and explorations (e.g. grooming 17±2.5 in M+ClPG group vs 37±4.5 in M group) but not the others. Misoprostol (Mis) also has a diff erentiated effect, reducing: compulsive mastication, jumpings, aggressive positions and penile erection [e.g jumpings from 8.7±0.45 in morphine (M) group to 1.3±0.066 in M +Mis 100 (p<0.01); 4±0.2 in M+Mis 50 (p<0.01) and 7.6±0.4 in M+Mis 5 (NS)]. Our data plead for a selective and diff erentiated influence of PGE1, PGF2a and peptidoleukotrienes in opiate-induced physical dependence.

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Systemically administered Cobalt - pharmacological data regarding an antinociceptive action

B. I. Tamba, Irina M. Jaba, Dunarea, G. Ionescu, O. C. Mungiu
Abstract: Aim of investigation. Cobalt (Co) is an essential divalent trace element. Because Zinc and Magnesium (also divalent trace elements) are well known for their infl uence on the nociceptive processes, we looked upon the possible modulator eff ect in nociception after systemically administered Co. Methods. Groups of 7 mice were treated with Cobalt Chloride (3.75 mg/kg body weight), administered intraperitoneal. Diff erent tests were used for evaluating the antinociceptive eff ect or the infl uence on behavior of the tested substances: thermal nociception (hot plate test, tail fl ick test), chemical nociception (writhing test) and spontaneous behavior (activity cage assay). Results. Our preliminary data for response latencies for hot-plate and tail-fl ick tests suggest that systemically administered Co produces a signifi cant analgesic eff ect under thermal nociceptive stimulation. The spontaneous behavior assay also shows a signifi cant decrease of activity in the tested animals. Discussion. Pain inhibition is even more signifi cant in conditions of chemical nociceptive stimulation, in a model of visceral pain. Conclusion. Th e mechanism through which Co exerts its analgesic eff ect is still unclear, and will require more investigations, including dose-eff ect analysis, though it may be related to the infl uence of haeme oxygenase-1 on the infl ammatory pain pathways.

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Research on the incidence of side and adverse effects of Linezolid and Vancomycin in adult patients

M. Nechifor, Diana Ciubotariu, Magdalena Cuciureanu, D. I. Chelarescu, Cristina Mihaela Ghiciuc, V. Luca
Abstract: We have searched for the incidence of side eff ects of linezolid and vancomycin therapy in adult patients with sepsis, hospitalised during 2000 - 2007 in the Infectious Diseases Hospital Iasi. In the study, we admitted patients treated with vancomycin (n=255, median dose 1g bid i.v., mean therapy duration 8.41±2.46 days) and linezolid (n=197, median dose 0.6g bid, 64.97% p.o. and 35.02% i.v., mean therapy duration 10.82±3.58 days. We have only considered patients with at least 4 days of treatment with studied antibiotics and cases with identifi ed etiologic bacteria. Main adverse reactions noticed for vancomycin were: coetaneous rash (31 cases, 12.15%), abdominal pain (18 cases, 7.05%), vomiting (10 cases, 3.92%). Phlebitis was noticed in 84 cases (32.94%). Only 1 case manifested convulsions (0.39%). Serum billirubine levels increased in 29 cases (11.37%). Main adverse reactions noticed for linezolid were: diarrhoea (12 cases, 6.09%), vomiting (8 cases, 4.06%), coetaneous rash (5 cases, 2.53%). Also, psychomotor agitation was noticed in 7 cases (3.55%). 2 patients (1.01%) presented intense cough, and this symptom was associated with prescribed antibacterial therapy. None of the cases taken into study imposed replacement of the antibacterial drug due to adverse reactions. The incidence of adverse reactions was significantly lower in the case of linezolid vs. vancomycin, in the conditions of comparable efficacy.

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Serum profile of IL-6, TNF-alpha, IL-12 and IFN-gamma in early sepsis

Simona Mera, Doina Tatulescu, Cristina Cismaru, Adriana Slavcovici, Virginia Zanc, Mirela Flonta, D. Carstina
Abstract: Priming and modulation of the immune response in severe infections are driven by bacterial products and endogenous mediators, such as cytokines. We analyzed several proinflammatory cytokines in the early sepsis and studied their correlation with aetiology and severity. Methods. In 24 septic patients we analyzed serum levels of IL-6, TNF-alpha, IL-12 and IFN-gamma in the early sepsis. 14 healthy volunteers served as controls. Results. IL-12 and IFN-gamma were undetectable both in controls and patients. Septic patients had a median TNF-alpha concentration of 6 pg/ml at admission that decreased at the following time-points. In controls, TNF-alpha was undetectable. In patients, IL-6 reached a median of 78 pg/ml at admission and diminished subsequently. Patients with severe sepsis had the highest IL-6 levels. TNF-alpha showed similar levels and kinetics for urinary and respiratory sepsis, yet in respiratory sepsis IL-6 increased more prominently. Gram positive sepsis led to higher amounts of TNF-alpha and IL-6 than Gram negative sepsis. Two out of fi ve non-survivors had very high IL-6 at admission that did not follow the later descendent trend. Conclusions. Since we did not detect circulating levels of IL-12 and IFN-gamma, it appears that sepsis does not to elicit an adaptive immune response in its early phases. The low levels of TNF-alpha may be due to the short half-life of the molecule. IL-6 release might be infl uenced by the site of infection and aetiology, and it could serve as a potential parameter in monitoring septic patients.

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Abdominal echography on HIV infected patientss

M. Arbune, V. sūtefanescu, L. Butunoiu
Abstract: The study asseses abdominal echographic fi ndings (AEF) in 204 HIV-positive patients. The most frequent AEF were found on the liver (46% hepatomegaly, 43,6% hyperechogenity, 26% steatosis), spleen (49,9% hypertrophy, 26% hyperechogenity, 18,7% calcifi cations) and kidney (24% hypotrophy, 15,2% lithiasis, 13,7% loss of corticomedular diff erentiation, 11,7% caliceal enlargement). Pelvic echography was available in 70/103 women for diagnosis of pregnant uterus (19), ovarian cyst (4), polycystic ovary (15), uterine fi broma (2). Statistical correlations were found: hepatomegaly - male sex (p=0,03), hepatomegaly - immunity (p=0,004), steatosis - female sex (p=0,002), steatosis -lipodystrophy (p<0,001), liver hyperechogenity - HBV (p=0,02); the span of antiretroviral experience infl uenced kidney hypotrophy (p=0,011) and kidney structural fi ndings (KSF) (p<0,001); TB was related to splenic calcifi cations (p<0,001) and KSF (p=0,035); Indinavir experience showed kidney hypotrophy (p<0,001) and KSF (p<0,001). HIV related AEF were found in 89% patients. Echography is an eff ective method for the management of HIV infection evolution and antiretroviral therapy.

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Predictive factors and diagnostic scores applying in tuberculous meningitis

Adriana Slavcovici, C. Marcu, Doina Tatulescu, Amanda Radulescu, Simona Clichici, Adriana Filip, Cristina Cismaru, D. Vesbianu, Ioana sūosa
Abstract: Tuberculous meningitis represents a severe manifestation of the systemic infection. Clinical and laboratory diagnosis based on classical methods is diffi cult and delayed. The current rapid diagnostic tests are costly and sometimes inaccessible. Objectives. We aimed to optimize the diagnostic strategy by establishing the features that are quickly available and have the best predictive value for TBM diagnosis by using two variants of scoring. Methods: We retrospectively studied 58 non-HIV cases of possible TBM hospitalized in the Cluj-Napoca Clinic of Infectious Diseases during 2000-2007. The inclusion criteria were: meningitis syndrome, nonpurulent cerebrospinal fluid with lymphocytes predominance, decreased glucose and increased protein levels. We established the signifi cant clinical, laboratory and imagistic features through univariate analysis. These variables were used in a modifi ed Th waites and Kumars diagnostic scoring (score-1 and-2, respectively). We calculated likelihood ratios for TBM prediction accuracy. Results. The diagnosis was microbiologically confi rmed in 33.3% of all patients after 3 weeks in average. Statistical analysis revealed nine variables signifi cantly predictive for TBM diagnosis: prodrome duration=7 days or =14 days, age<23 years, WBC<9000/mm3, cerebrospinal fluid white-cell count <300/ mm3, CSF neutrophils proportion <50% or <22%, paralysis, extrapyramidal signs / ataxia/ myoclonus / tremor. Using the adapted scoring 1, the posttest probability reached 92%. By using score 2 (based on three variables) we found a signifi cant increase of the TBM prognosis (pLR = 5.2, nLR = 0.2, posttest probability =94%). Conclusions. The confirmatory diagnosis of TBM is delayed and occurs in a small proportion of cases. Early TBM diagnosis may be improved by using Thwaites and Kumars diagnostic scoring adapted to our available variables that were signifi cantly found in the study population.

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Therapeutical Practice


The usefulness of B Natriuretic Peptide in the anesthetic perioperative evaluation

A. Muresan, R. Macovei
Abstract: Cardiac failure is a frequently associated pathology in surgical diseases, both as emergency or as programmed surgery, which requires a particular approach to anesthesia, from the commencement of the anamnesis and the clinical examination. Assessment of the brain natriuretic peptide can be useful as diagnosis marker but also as prognostic element of cardiac failure, in particular of left ventricular distress; it also conveys a signifi cant input in the diff erential diagnosis with acute pulmonary dyspneic pathology. An early detection of perioperative myocardial ischemia is essential to the syndromes therapeutic approach.

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Severe neurodegenerative disease in a patient with primary humoral immunodeficiency

N. Iagaru, Eliza Cinteza
Abstract: Acquired neurodegenerative diseases represent a large group of pathologic conditions. Th ere are reports suggesting that there is a linkage between these neurodegenerative diseases and the plasma products administration. The authors describe a case of primary immunodefi ciency with severe neurodegenerative disease. The patient is a 17-year-old male who was diagnosed initially with Bruton-type agammaglobulinemia when 4 years old. The diagnosis was changed to probable Wiskott - Aldrich syndrome (thrombocytopenia - many episodes of purpura described, eczema, recurrent bacterial infections), although the genetic study did not confi rm WASP mutation. For 13 years he received intravenous immunoglobulin (IVIG) replacement initially monthly and then at 4 months intervals. At 16 years of age, he presented with symptoms of mental deterioration, pyramidal and extrapyramidal signs, and gait disturbance. The MRI confi rmed nervous structures abnormalities. He had no history of infection of the central nervous system and the tests for Enteroviruses were negative. Such events can appear in the clinical course of the patients receiving IVIG treatment and should be monitored for neurodegenerative disease.

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Renal risk evaluation in contrast media-induced nephropathy

B. Popa, Monica Popiel, L. Gulie
Abstract: Contrast media-induced nephropathy (CIN) in patients receiving intraarterial iodinated contrast media is a chemotoxic adverse reaction that is often under-recognized in clinical practice due to the very low incidence of this morbidity. Th e renal impairment is usually temporary, but in a small number of patients acute renal failure can develop and dialysis may be necessary. Patients with both diabetes and pre-existing renal impairment are at the highest risk. Practices for identifying patients at risk vary: it may be possible to identify patients who may be at risk using screening questionnaires. Th e prevalence of CIN correlates with contrast media dose: therefore the amount of CM has to be minimized in all patients, especially in those with higher risk. Non-ionic monomers (low osmolar CM) are benefi cial in comparison with ionic monomers (high osmolar CM) in patients with pre-existing renal impairment. Various drugs that have been used in attempts to prevent CIN have provided contradictory results in clinical trials and therefore their eff ectiveness remains to be proven. Still, adequate hydration pre - and postangiography remains the most effi cient preventive therapy.

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Exanthema associated with the West Nile virus infection

Victoria Birlutiu, Cornelia Ceianu, Claudia Bucur
Abstract: The West Nile virus infection (WN) was identifi ed in Romania through the acute meningitis and encephalitis epidemic in 1996 associated with an unusually high rate of mortality and sequel rate. The forms of WN infection without connected brain damage remain unidentifi ed in the absence of the acute phase serology (IgM WNV) given the fact that 80% of the WN infections progress asymptomatically, 20 % as feverish syndromes and less than 1 % may present CNS disease. An aspect novel to the fi eld literature is the association of the WN infection with a maculopapular exanthema in non-feverish conditions, aspect which we would like to present as follows. The studied case may testify to WN virus circulation within the Romanian boundaries up to date, 2008, having a display of clinical forms which have as main characteristics not the neurological signs but rather hypothermia and inter-infectious exanthema. Although uncommon, the maculopapular eruption accompanied or not by pruritus and cutaneous hyperesthesia, may suggest, under certain environmental conditions (hot season with mosquito readership in the area) serological investigation for the WN infection.

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