Chronic dietary exposure to aristolochic acid and kidney function in native farmers from a Croatian endemic area and Bosnian immigrants.

BACKGROUND AND OBJECTIVES: Improvements in agricultural practices in Croatia have reduced exposure to consumption of aristolochic acid-contaminated flour and development of endemic (Balkan) nephropathy. Therefore, it was hypothesized that Bosnian immigrants who settled in an endemic area in Croatia 15-30 years ago would be at lower risk of developing endemic nephropathy because of reduced exposure to aristolochic acid. To test this hypothesis, past and present exposure to aristolochic acid, proximal tubule damage as a hallmark of endemic nephropathy, and prevalence of CKD in Bosnian immigrants were analyzed. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this cross-sectional observational study from 2005 to 2010, 2161 farmers were divided into groups: indigenous inhabitants from endemic nephropathy and nonendemic nephropathy villages and Bosnian immigrants; α-1 microglobulin-to-creatinine ratio >31.5 mg/g and eGFR<60 ml/min per 1.73 m(2) were considered to be abnormal. RESULTS: CKD and proximal tubule damage prevalence was significantly lower in Bosnian immigrants than inhabitants of endemic nephropathy villages (6.9% versus 16.6%; P<0.001; 1.3% versus 7.3%; P=0.003, respectively); 20 years ago, Bosnian immigrants observed fewer Aristolochia clematitis in cultivated fields (41.9% versus 67.8%) and fewer seeds among wheat seeds (6.1% versus 35.6%) and ate more purchased than homemade bread compared with Croatian farmers from endemic nephropathy villages (38.5% versus 14.8%, P<0.001). Both Croatian farmers and Bosnian immigrants observe significantly fewer Aristolochia plants growing in their fields compared with 15-30 years ago. Prior aristolochic acid exposure was associated with proximal tubule damage (odds ratio, 1.64; 95% confidence interval, 1.04 to 2.58; P=0.02), whereas present exposure was not (odds ratio, 1.31; 95% confidence interval, 0.75 to 2.30; P=0.33). Furthermore, immigrant status was an independent negative predictor of proximal tubule damage (odds ratio, 0.40; 95% confidence interval, 0.19 to 0.86; P=0.02). CONCLUSIONS: Bosnian immigrants and autochthonous Croats residing in endemic areas are exposed significantly less to ingestion of aristolochic acid than in the past. The prevalence of endemic nephropathy and its associated urothelial cancers is predicted to decrease over time.

Prevalence of genetic polymorphisms of CYP2C9 and VKORC1 - implications for warfarin management and outcome in Croatian patients with acute stroke.

BACKGROUND: Data on the prevalence of CYP2C9 and VKORC1 genes and their influence on anticoagulant effect and warfarin dose in stroke patients are scarce. The aim of this study was to determine the occurrence and significance of these gene polymorphisms and to establish pharmacogenetic algorithm to estimate the dose of introduction. Also, the goal was to determine tailored safety and intensity of anticoagulation response depending on the allelic variants and their impact on the clinical outcome in acute stroke patients in Croatia. METHODS: A total of 106 consented acute stroke patients were tested for CYP2C9 2, 3 and VKORC1 1173C>T gene polymorphisms. We estimated the dose of introduction and monitored anticoagulant effect obtained by INR values, time to reach stable dose, stable maintenance dose, time spent within the therapeutic/supratherapeutic INR range, occurrence of dosage side effects and clinical outcome depending on genotypes. RESULTS: We found that 83% of stroke patients in our study were carriers of multiple allelic variants. The predicted initial dose correlated with the stable warfarin maintenance dose (p=0.0311) and we correctly estimated the dose for 81.5% of 61.3% of study patients who required higher/lower doses than average. Warfarin dosage complications were slightly more frequent among the carriers of CYP2C9 2, 3 compared to the carriers of VKORC1 1173T alleles (68. 9% versus 62.5%), but their occurrence did not affect the final clinical outcome. CONCLUSION: Our data indicated rapid and safe anticoagulation achieved by using pharmacogenetically-predicted warfarin dose in high-risk acute stroke patients without increasing the risk of warfarin dosage complications in an elderly population.

Variation in presentation and presence of DNA adducts and p53 mutations in patients with endemic nephropathy--an environmental form of the aristolochic acid nephropathy.

BACKGROUND: Endemic nephropathy (EN) and associated urothelial cell cancers (UUC) are an environmental form of aristolochic acid nephropathy where the most probable rout of ingestion of aristolochic acid (AA) was made by bread contaminated with AA, leading to chronic dietary intoxication. Clinical courses of three members of the same family, similarly exposed to toxin, who exhibited different clinical courses of the disease are presented. METHODS: Questionnaires on AA exposure were taken. Tissue samples were obtained during therapeutic nephrouretectomies. Histopathology, immunohistochemical detection of p53, p53 mutation screening in tumor DNA and analysis on the presence of aristolactam (AL)-DNA adducts were performed. RESULTS: Case 1 had UUC with typical EN histopathological signs, whereas Case 2 had bilateral UUCs with typical EN histopathological signs. In contrast, the patient in Case 3 initially showed renal insufficiency, complicated afterwards by right UUC, and later on by left UUC with histopathological end-stage chronic changes but without typical EN changes. AA-DNA adducts and specific p53 mutational spectra (A:T→ T:A transversion) were found in tissues of cases 1 and 2. CONCLUSION: Diverse clinical courses seem to be related not to differences in exposure but to differences in metabolic activation or detoxification of AA and/or DNA repair resulting from different genetic polymorphisms.

An infrequent type of stroke with an unusual cause and successful therapy: basilar artery occlusion caused by a cardiac papillary fibroelastoma recanalized 12 hours after onset.

We herein report the case of a 32-year-old woman with sudden onset ataxia, limb dysmetria and somnolence. Emergency radiological findings showed bilateral cerebellar and thalamic infarctions as a result of a basilar artery occlusion. The patient was treated with intra-arterial (IA) and mechanical thrombolysis 12 hours after symptom onset and showed an excellent recovery. A diagnostic workup revealed a tumor mass on the mitral valve that was surgically removed, while a histological analysis confirmed a diagnosis of cardiac papillary fibroelastoma.

Beware of "old" Horner syndrome.

PURPOSE: Chronic Horner syndrome is a rare clinical condition, the etiology of which often remains undiscovered. A patient is presented with an 8-year history of Horner syndrome who was diagnosed with multiple cervical artery dissections. CASE REPORT: A 42-year-old woman presented to our emergency department with a severe occipital headache that woke her up from sleep 3 days earlier. She had a history of headaches and recalled one in particular dating back to 2003. At that time, she sought medical attention at general practitioner's office because of the terrible headache and a noticeable disparity of her pupils. She was told that she had miosis of the right pupil. The examination conducted in 2011 revealed Horner syndrome with right miosis and ptosis. A four-vessel cerebral angiography revealed an occlusion of the right internal carotid artery. The morphology of stenosis and pseudoaneurysm of C1 segment of left internal carotid artery, as well as a pseudoaneurysm of V3/V4 junction of left vertebral artery indicated a probable dissective etiology. CONCLUSIONS: This case illustrates that Horner syndrome with a chronic presentation can be as potentially dangerous as its acute counterpart and should be judiciously investigated.

Systemic thrombolytic therapy in acute ischemic stroke--new experiences in spreading network of stroke units in Croatia.

BACKGROUND: The aims of this paper are: 1) to present the data of systemic thrombolysis for ischemic stroke in five Croatian centers from July 2008 till January 2010; 2) to compare the results between centers and; 3) to compare data with previously published results from 2006 to 2008 period from our center, and with the data from SITS (Safe Implementation of Treatments in Stroke). METHODS: We retrospectively reviewed the medical data of thrombolysed patients in following hospitals: University Hospital Center Zagreb (91 patients), University Hospital Split (25 patients), University Hospital Osijek (22 patients), General Hospital Varazdin (21 patient), and General Hospital Zadar (7 patients). RESULTS: The "time to door" for all centers was 79.71±38.63 min, the "door to needle" period was 64.39±24.18 min. Systolic and diastolic blood pressures at admission were 158.65±27.72 and 90.18±15.03 mm Hg, respectively. Systolic and diastolic blood pressures measured immediately prior to administering rt-PA were 152.19±23.17 and 85.40±15.27 mm Hg, respectively. Initial median NIHSS score was 12, median NIHSS 2h post thrombolysis was 8, and 7th day after rt-PA treatment 4. Intracerebral hemorrhages or secondary hemorrhagic transformations occurred in 21 (12.65%) patients, among which nine were symptomatic. In a 4.5h time window total of 17 patients were thrombolysed. We did not find any differences in outcome between this group and group of patients thrombolysed in the 3h time-window. The group of patients older than 80 years had a worse outcome. CONCLUSIONS: According to our data, treatment with rt-PA is safe, feasible and effective for stroke patients in both university as well as regional hospitals having stroke units established. Organization of stroke units in regional hospitals, as well as systematic education of public health workers and neurologists, leads to the possibility for each patient to reach the nearest stroke unit and gets the thrombolytic therapy in the therapeutic time window.

Cardiac papillary fibroelastoma: source of cerebral embolism treated with intravenous thrombolysis.

We present the case of a 41-year-old man with sudden development of left hemiparesis due to infarction of the right middle cerebral artery that was successfully treated with intravenous (IV) thrombolysis with alteplase. Transthoracic echocardiography showed a small mass in the left ventricle. The patient underwent surgical resection, and histological examination of the mass confirmed the diagnosis of papillary fibroelastoma. It remains to be investigated whether heart ultrasound evaluation should be performed before IV thrombolysis in selected patients with stroke, given the apparently increased risk of bleeding. However, IV thrombolysis should not be postponed due to a lengthy investigation, because of its potential for reducing morbidity in patients with stroke.

Systemic thrombolysis with recombinant tissue plasminogen activator in acute ischemic stroke: first Croatian experiences.

In September 2003, recombinant tissue plasminogen activator (rt-PA) for acute treatment of ischemic stroke was finally approved by the Croatian Ministry of Health. For the next 5 years, only three stroke units in the country implemented this therapy in their routine practice until summer 2008, when neurological wards in most Croatian hospitals started to treat acute stroke patients with systemic thrombolysis. We present a 2-year experience of thrombolytic therapy (2006-2008) in the stroke unit of the University Hospital in Zagreb, Croatian largest hospital, serving nearly one-fifth of the citizens of Croatia. Obtained data (vitals at admission and before administration of rt-PA; NIHSS and MRS scores at admission, 2 h and 7th day after rt-PA treatment, "time to door" and "door to needle" intervals, duration of hospital treatment as well as outcomes and complications of our 66 thrombolysed patients) are presented and discussed. We also present our results regarding benefits of this therapy as well as possible reasons for complications noticed.

Isolated nontraumatic abducens nerve palsy.

INTRODUCTION: Abducens nerve palsy (ANP) is the most common isolated palsy. The injury of the abducens nerve can occur anywhere along its long course, so differential diagnosis of ANP occasionally demands thorough investigation to find the proper cause. PATIENTS: Ten patients with isolated ANP are presented. The causes included nasopharyngeal carcinoma, diabetes, cholesteatoma of the inner ear, carotid-cavernous fistula, subarachnoid bleeding, hydrocephalus, toxic ANP, multiple sclerosis, clinically isolated syndrome suggestive of multiple sclerosis, and Tolosa-Hunt syndrome. DISCUSSION: Based on the cases presented and review of the literature, we argue that every patient with isolated nontraumatic ANP requires brain MRI as an initial diagnostic tool. If this finding remains inconclusive, additional tests including angiography and CSF examination should be performed.

[Classical type of Fabry disease without angiokeratomas--a case report]. / Klasicni oblik Fabryjeve bolesti bez angiokeratoma--prikaz bolesnika.

A patient with classical type of Fabry disease is described. The appearance and character of neuropathic pain during hemodyalisis is described. Characteristic changes in head shape and changes of hands and fingers are the additional phenotypic characteristics of Fabry disease. Enzyme replacement therapy administered in the early phase of the disease could prevent disease complications and early patient's death.

Series of seizures as a sign of development of recurrent malignant neuroleptic syndrome - a case report.

Neuroleptic malignant syndrome (NMS) is an uncommon but sometimes fatal complication of neuroleptics and other medications that involve the central dopaminergic system. Many diagnostic criteria have been proposed for NMS but because of its variable presentation, universal criteria have not been established yet. Hyperthermia, disturbances of consciousness, extrapyramidal and autonomic symptoms are common features of NMS. We report the case of a 36 years old woman suffering from chronic schizophrenia and treated with flufenazine and olanzapine, who presented with series of generalised tonic-clonic seizures as the acute onset of recurrent malignant neuroleptic syndrome. Although atypical neuroleptics were previously thought to have less risk for MNS, combination of conventional and atypical neuroleptics in therapy increases the risk of NMS development and olanzapine might be responsible for the epileptic manifestations at the onset of fulminant NMS.