Brain Protease Activated Receptor 1 Pathway: A Therapeutic Target in the Superoxide Dismutase 1 (SOD1) Mouse Model of Amyotrophic Lateral Sclerosis.

Glia cells are involved in upper motor neuron degeneration in amyotrophic lateral sclerosis (ALS). Protease activated receptor 1 (PAR1) pathway is related to brain pathologies. Brain PAR1 is located on peri-synaptic astrocytes, adjacent to pyramidal motor neurons, suggesting possible involvement in ALS. Brain thrombin activity in superoxide dismutase 1 (SOD1) mice was measured using a fluorometric assay, and PAR1 levels by western blot. PAR1 was localized using immunohistochemistry staining. Treatment targeted PAR1 pathway on three levels; thrombin inhibitor TLCK (N-Tosyl-Lys-chloromethylketone), PAR1 antagonist SCH-79797 and the Ras intracellular inhibitor FTS (S-trans-trans-farnesylthiosalicylic acid). Mice were weighed and assessed for motor function and survival. SOD1 brain thrombin activity was increased (p < 0.001) particularly in the posterior frontal lobe (p = 0.027) and hindbrain (p < 0.01). PAR1 levels were decreased (p < 0.001, brain, spinal cord, p < 0.05). PAR1 and glial fibrillary acidic protein (GFAP) staining decreased in the cerebellum and cortex. SOD1 mice lost weight (≥17 weeks, p = 0.047), and showed shorter rotarod time (≥14 weeks, p < 0.01). FTS 40mg/kg significantly improved rotarod scores (p < 0.001). Survival improved with all treatments (p < 0.01 for all treatments). PAR1 antagonism was the most efficient, with a median survival improvement of 10 days (p < 0.0001). Our results support PAR1 pathway involvement in ALS.

The laboratory profile in idiopathic intracranial hypertension.

While overweight and female gender play an undisputable role in the pathogenesis of idiopathic intracranial hypertension (IIH), the contribution of other factors is still unclear. We have evaluated the laboratory findings of patients with IIH in an attempt to find the influence of abnormalities on the disease course. Included were 82 females after menarche and males older than 18 years who were followed up for at least 1 year. A wide range of laboratory parameters were examined at the time of presentation. The most frequent abnormal laboratory findings were elevated C reactive protein (CRP) (51 %), thrombophilia (31 %), increased plasma cortisol levels (29 %) and elevated lactate dehydrogenase (LDH) (20 %). Patients with elevated CRP and patients with thrombophilia had an unfavorable visual outcome. Increased cortisol levels and abnormal calcium correlated with a higher rate of recurrence. The visual outcome of patients with elevated LDH was better than those with normal LDH. It seems that certain metabolic, inflammatory and coagulation abnormalities may influence the course of IIH. If confirmed in further studies, these findings could contribute to elucidation of the etiology and prognosis of IIH.

Fatigue during an episode of benign paroxysmal positional vertigo.

Fatigue is characterized by weariness unrelated to exertion levels. It has been reported in chronic neurological diseases such as multiple sclerosis, Parkinson disease and stroke. Patients with benign paroxysmal positional vertigo (BPPV) often complain about fatigue during a vertigo attack. No attention has been paid to this symptom in the literature so far. We were interested to evaluate the frequency and factors influencing fatigue in BPPV. Patients treated for idiopathic BPPV during the years 2011-2012 were prospectively evaluated for the presence of fatigue. During the first visit, patients were asked to complete two questionnaires based on their experience during the last week: the Fatigue severity scale and the Hospital anxiety and depression scale. Patients' demographic data and BPPV characteristics were registered. Among 172 patients treated for BPPV, 40 (23.2 %) reported fatigue. The mean fatigue score was 4.73 ± 1.98 indicating moderate fatigue. No correlation was found between fatigue and anxiety or fatigue and depression. Fatigue scores were inversely related to age (r = -0.36, p = 0.020) and were not dependent on the type of BPPV, its recurrence, background diseases, gender, duration of vertigo or the presence of autonomic symptoms. Moderate fatigue is quite common during an attack of BPPV. It seems to be a genuine symptom of the entity that might worsen patients' distress. For severe or persistent fatigue treatment with fatigue relieving drugs such as amantadine, methylphenidate or modafinil could be tried in the future.

Contrast-Enhanced Computed Tomography as a Necessary Scan in Acute Stroke: A Case Series.

BACKGROUND: We present a number of exemplary cases where the diagnostic value of the contrast-enhanced computed tomography (CT) after CT angiography in our acute stroke imaging protocol was of fundamental clinical significance. METHODS: We retrospectively reviewed 7 cases presented to the emergency room, between 2012 and 2014, suspected of acute stroke, with findings diagnosed by the contrast-enhanced CT. RESULTS: Seven exemplary cases: acute midbrain infarct versus posterior-fossa artefact differentiation in contrast-enhanced CT; differentiation between an M1 occlusion and an internal carotid artery dissection in contrast-enhanced CT; diagnosis of veno-occlusive disease rather than arterial occlusion; bleeding arterial aneurysm revealed by contrast-enhanced CT; previously unsuspected sinus vein thrombosis; sinus vein thrombosis suspected in CT angiography, ruled out by contrast-enhanced CT; and space occupying lesion clearly diagnosed by contrast-enhanced CT. CONCLUSIONS: Adding contrast-enhanced CT as a part of the acute stroke imaging protocol presents additional diagnoses and avoids pitfalls. Therefore, we consider the contrast-enhanced CT to be essential to the acute stroke setting imaging protocol.

IgG accumulates in inhibitory hippocampal neurons of experimental antiphospholipid syndrome.

Mice immunized with ß2-glycoprotein I (ß2GPI) are an experimental model of the antiphospholipid syndrome (eAPS) displaying elevated titers of antiphospholipid antibodies (aPL). We presently studied whether the behavioral hyperactivity in eAPS mice is associated with in vivo binding and accumulation of IgG in the brain. At 6 weeks post immunization eAPS mice had significantly higher levels of aPL (1.32 ± 0.28 and 0.02 ± 0.01 AU, p < 0.001 by t-test) compared to adjuvant immunized controls, as measured by ELISA. Significant hyperactivity in a staircase test in the eAPS mice compared to controls was found in stair-climbing (18.4 ± 0.9 and 12.0 ± 1.7, respectively) and rearing measures (23.5 ± 2.1 and 12.5 ± 1.9, p < 0.01 by t-test). Immunofluorescence staining in eAPS mice revealed significant in vivo accumulation of IgG in cortical and hippocampal neurons which was not seen in controls. Staining for IgG was markedly intense in inhibitory interneurons co-stained for GAD67 in the hippocampus of eAPS mice. The integrity of the blood brain barrier (BBB) evaluated by injection of Evans blue (EB) was impaired in eAPS and adjuvant immunized mice compared to naïve mice. Electrophysiological recordings in hippocampal brain slices showed altered response to paired pulse stimulation as well as dysregulation of carbachol-induced γ- oscillations in eAPS mice compared to control. Penetration into the brain and direct interaction of aPL with inhibitory interneurons in the hippocampus may explain the hyperactive behavior of the eAPS mice. A direct role of aPL in causing CNS dysfunction points to these antibodies as an important therapeutic target in APS.

Headache during a cluster of benign paroxysmal positional vertigo attacks.

OBJECTIVE: In view of patients' recurrent complaints, we were interested in investigating the frequency and headache characteristics in patients during a benign paroxysmal positional vertigo (BPPV) cluster. METHODS: Patients with BPPV treated at an outpatient dizziness clinic were interviewed about the presence of headache; its quality, localization, severity, time course, and aggravating and alleviating factors; and headache-related disability during their present vertigo cluster. RESULTS: Among 152 patients with BPPV, 53 (34.8%) reported headache associated with vertigo. According to The International Classification of Headache Disorders, 8 (15%) patients could be classified as migraine without aura (1.1), 14 (26%) were classified as infrequent episodic tension-type headache associated with pericranial tenderness (2.1.1), 23 (43%) were classified as infrequent episodic tension-type headache without pericranial tenderness (2.1.2), 6 (11%) had cervicogenic headache (11.2.1), and in 2 (4%) patients, the headache could not be specified (14.2). Fifty-two age-matched BPPV patients without headache did not differ in history of headaches, BPPV history, or background diseases. The distribution of canal involvement and number of treatment maneuvers was also similar in both groups. CONCLUSION: Headache is frequent in BPPV. The most common is tension-type headache, followed by migraine and cervicogenic headache. Head pain seems to be an independently associated epiphenomenon of BPPV that can worsen patients' distress.

Croatian Action on Salt and Health (CRASH): On the Road to Success-Less Salt, More Health.

The World Health Organization recommends adjusting salt intake as a part of the nine global targets to reduce premature mortality from non-communicable chronic diseases as a priority and the most cost-effective intervention. In 2006, the main aim of the Croatian Action on Salt and Health was to decrease salt intake by 16% because of its critical intake and consequences on human health. We have organized educative activities to increase awareness on salt harmfulness, define food categories of prime interest, collaborate with industries and determine salt intake (24 h urine sodium excretion). It was determined that the proportion of salt in ready-to-eat baked bread should not exceed 1.4%. In the period 2014-2022, salt in semi-white bread was reduced by 14%, 22% in bakery and 25% in the largest meat industry. Awareness of the harmfulness of salt on health increased from 65.3% in 2008 to 96.9% in 2023 and salt intake was reduced by 15.9-1.8 g/day (22.8% men, 11.7% women). In the last 18 years, a significant decrease in salt intake was achieved in Croatia, awareness of its harmfulness increased, collaboration with the food industry was established and regulatory documents were launched. However, salt intake is still very high, underlying the need for continuation of efforts and even stronger activities.

Otolith dysfunction as a possible cause for the development of idiopathic scoliosis.

BACKGROUND: To investigate whether otolith system, as a major contributor to muscles for postural control, might play a role in the pathogenesis of idiopathic scoliosis (IS). METHODS: Cervical vestibular-evoked myogenic potentials (VEMP) testing was applied to investigate the otolith function in patients with IS. Twenty-nine healthy patients (mean age 13.5±2.5 y, 4 males) were included. In all but 2 patients, the major curve deviation was to the right and the mean angle deviation was 49.7±21.6 degrees. Nineteen age-matched individuals (10 males) served as controls. RESULTS: The P13 (first positive wave) latencies were comparable in both groups. Patients with IS had significantly longer N23 (first negative wave) latencies than controls. A high correlation between the age and N23 latencies on the right was found in IS patients. A link between the scoliosis angle and VEMP latencies could not be demonstrated.The VEMP amplitudes were higher in patients than in controls, whereas the amplitude asymmetry ratio was similar in both groups. CONCLUSIONS: This work brings further evidence for vestibular abnormalities in patients with IS. Prospective studies are needed to elucidate a possible causative relationship between otolith dysfunction and the development of scoliosis. LEVEL OF EVIDENCE: III.

Effects of magnesium, chromium, iron and zinc from food supplements on selected aquatic organisms.

The aim of this study was to determine the effect of uncontrolled environmental disposal of food supplements containing magnesium (Mg), chromium (Cr), iron (Fe) and zinc (Zn) on selected aquatic organisms including freshwater algae Scenedesmus subspicatus and Raphidocelis subcapitata, water flea Daphnia magna and duckweed Lemna minor. Thirty different food supplements containing Mg, Cr, Fe and Zn were analyzed. Results were expressed as effective concentration 50 (EC50), i.e. growth inhibiting Mg, Cr, Fe and Zn (mg/L) concentration immobilizing 50% of treated organisms. Particular metal EC50 differed significantly (p < 0.001) among study organisms, as follows (in ascending order): Scenedesmus subspicatus EC50 Fe (median 46.9 mg/L) < Zn (59.8 mg/L) < Mg (73.0 mg/L) < Cr (88.1 mg/L) (KW-H(3;120) = 36.856; p < 0.001); Raphidocelis subcapitata EC50 Fe (median 44.9 mg/L) < Zn (52.6 mg/L) < Mg (62.2 mg/L) < Cr (76.8 mg/L) (KW-H(3;120) = 44.0936; p < 0.001); Daphnia magna EC50 Zn (median 59.4 mg/L) < Cr (79.2 mg/L) < Fe (80.8 mg/L) Mg (82.0 mg/L) (KW-H(3;120) = 39.2637; p < 0.001); and Lemna minor EC50 Zn (median 131.0 mg/L) < Fe (186.8 mg/L) < Mg (192.5 mg/L) < Cr (240.4 mg/L) (KW-H(3;120) = 58.6567; p < 0.001). Uncontrolled environmental disposal of food supplements containing Mg, Cr, Fe and Zn exerts adverse effects on aquatic organisms. Therefore, legal provisions should regulate both the utilization and disposal of food supplements into the environment.

[The variety of symptoms in patients with benign paroxysmal positional vertigo--revision].

Despite its frequent occurrence and effective treatment options, benign paroxysmal positional vertigo (BPPV) still remains underestimated in the community. Acquaintance of the physician with the various presentation symptoms assists in recognition of the entity. We report the complaints and subjective outcome in our cohort of BPPV patients and discuss the possible origin of the atypical, but common, symptoms.

Beliefs and emotional reactions in patients with benign paroxysmal positional vertigo: a longitudinal study.

OBJECTIVE: Psychologic studies in patients with benign paroxysmal positional vertigo (BPPV) are scarce, considering the high frequency of the disorder. We performed a repeated-measures design questionnaire study in a cohort of patients with BPPV before and after treatment to investigate the dynamics of the psychologic findings and possible treatment consequences. METHODS: Thirty-seven consecutive patients with idiopathic BPPV participated in the study. During the first visit and 2 to 3 months after therapy, the patients completed 4 questionnaires: the Dizziness Handicap Inventory, the Illness Perception Questionnaire-Revised, the Intolerance of Uncertainty Scale, and the State-Trait Anxiety Inventory. RESULTS: The scores for all questioned items did not change before and after treatment except for the physical handicap scores. Correlation was found between the grade of functional and emotional impact of the disease and belief in consequences as well as anxiety levels of the patients. Moreover, uncertainty scores were in correlation with emotional impact, anxiety levels, and perceived consequences of the disease. The belief in personal control of the condition was correlated with the belief in treatment control and understanding of the disease. CONCLUSION: The main finding in this study is the lack of a significant change in beliefs and emotional reactions in patients with BPPV after treatment of their condition. Physicians dealing with BPPV should be aware that the disease is not solely a somatic condition but has a serious impact on the patient's mental state. Selected patients might benefit from anxiolytic medication.

Unilateral mimicking bilateral BPPV- a forgotten entity? Characteristics of a large cohort of patients, comparison with posterior canal BPPV and clinical implications.

OBJECTIVE: Unilateral mimicking bilateral benign paroxysmal positional vertigo (umb-BPPV) was attributed to inappropriate head positioning during testing of the posterior canal. Despite its inclusion in the Diagnostic criteria for the classification of vestibular disorders of the Bárány Society, the clinical characteristics and treatment responsiveness of this BPPV subtype have not been intensively studied. METHODS: Records of patients with BPPV seen at a single outpatient dizziness clinic during the years 2000-2020 were reviewed. Eighty seven patients with umb-BPPV and 86 random patients with posterior canal BPPV (p-BPPV) were retrieved. Their demographics and BPPV characteristics were analyzed. RESULTS: Patients' and BPPV characteristics were similar in umb- and p-BPPV except for the prevalence of males in the umb-BPPV group. No differences were found between treatment responsiveness and recurrences in both groups. The recurrence rate of umb-BPPV was not influenced by age, gender, BPPV side, duration of symptoms or treatment responsiveness during the first attack. CONCLUSIONS: In accordance with our hypothesis about mixed canalo- and cupulolithiasis as the underlying mechanism of umb-BPPV, patients did not differ in characteristics and treatment responsiveness from p-BPPV patients. Recognition of umb-BPPV is important since inappropriate treatment can cause an unnecessary delay in therapy success.

Awareness of benign paroxysmal positional vertigo in central Israel.

BACKGROUND: Despite its frequent occurrence and effective treatment options, benign paroxysmal positional vertigo (BPPV) still remains under-estimated in the community. METHODS: We reviewed referral letters and medical records of 120 patients who were treated for BPPV at our Dizziness Clinic during the years 2006-2008 and searched for factors that possibly contribute to missing this entity. RESULTS: The referral diagnosis could be clustered into four groups: BPPV (25.6%), further unspecified vertigo (36.6%), dizziness (27.5%) and other (10%). BPPV was recognized more frequently by ENT doctors than by other specialists.Patients referred with the correct diagnosis of BPPV were significantly younger and the duration of their symptoms shorter than in other referral groups. Patients in the distinct referral groups did not differ in the presence of autonomic symptoms or a history of another serious disease. A history typical of BPPV could be obtained in all but 11 patients, but position dependence was noted by the referring physician only in 55 patients, 31 of them correctly assigned as possible BPPV. Only in two patients was the Dix-Hallpike test performed. Thirty two patients were diagnosed with BPPV in the past, but this did not influence the recognition of the recurrence of this clinical entity. About 40% of patients had an audiogram and/or brainstem auditory evoked potentials. Electronystagmography was performed in 7.5% and brain imaging in 14% of patients before referral. CONCLUSION: Our results show that BPPV is still an under-recognized entity.Education and the demand on specialists to learn how to treat BPPV, could improve the situation.

Bilateral Posterior Canal Benign Paroxysmal Positional Vertigo Tends to Reoccur.

OBJECTIVE: We analyzed the clinical characteristics of quite a large cohort of patients with bilateral posterior canal benign paroxysmal positional vertigo (bil-BPPV) with respect to the rate and types of recurrence. STUDY DESIGN: Retrospective case review. SETTING: Outpatient dizziness clinic. PATIENTS: About 2,050 patients diagnosed with BPPV during the years 2003 to 2018 were reviewed. RESULTS: Sixty (2.9%) were diagnosed with bil-BPPV. Fifty three (88%) were idiopathic and seven (12%) posttraumatic. Multiple BPPV episodes were encountered in 28 (47%) patients. Patients with bil-BPPV and multiple BPPV episodes were comparable with patients with a single attack of bil-BPPV except for older age and longer follow up. The most frequent type of recurrence following a bil-BPPV episode was posterior canal canalolithiasis (37.5%) and bil-BPPV (31.3%). Combined (posterior and horizontal) BPPV was encountered in 12.5% while horizontal canal involvement was found in only 7% of recurrences. CONCLUSIONS: The prevalence of bil-BPPV amongst all BPPV patients was lower than previously reported possibly due to stricter selection criteria. Older age and longer follow up of patients with multiple BPPV episodes than those with a single episode of bil-BPPV is in accordance with the theory of degenerative otoconia loosening. In contrast to the general consensus regarding random recurrences of BPPV side and subtypes, bil-BPPV recurred more frequently than expected. This might be the consequence of individual vulnerability to head movements, increased bone metabolism or an underlying vestibular pathology.

Cognitive dysfunction evaluation in multiple sclerosis patients treated with interferon beta-1b: an open-label prospective 1 year study.

BACKGROUND: The cognitive impairment (frontal, parietal) in many patients with multiple sclerosis does not correlate with the degree of neurological disability and disease duration. Frontal/prefrontal cognitive impairment requires neuropsychological diagnostic tools. OBJECTIVES: To evaluate the clinical effect of IFNbeta-1b (Betaferon) treatment on cognitive function and event-related potential as compared to the clinical course (EDSS) in MS patients during 1 year of follow-up. METHODS: This prospective open-label design study included 16 consecutive patients with relapsing forms of MS attending the MS outpatient clinic. Mean EDSS score was calculated prior to starting treatment. Parietal lobe event-related potential P300 was elicited using an auditory physical stimulus to an alert subject. Mean P300 amplitude and latency were calculated for the group before treatment. The Wisconsin Card Sorting Test, which measures frontal lobe functions, was performed before the treatment. After 1 year of treatment a second P300 and Wisconsin test were performed and the mean change between visit 1 and baseline was calculated for each parameter. Correlation between the change in P300 and the Wisconsin test score at baseline was measured using the paired t-test. RESULTS: There was a significant reduction in P300 amplitude and latency after 1 year of treatment with IFNbeta-1b: from 20.3 +/- 8.3 microv to 13.1 +/- 10.6 microv (P = 0.026) for amplitude, and from 312.9 +/- 15.6 msec to 302.0 +/- 17.0 msec (P = 0.002) for latency. The Perseverative Response (raw score) and the Perseverative Response U.S. Census age-matched standard score showed a significant improvement--from 20.7 +/- 30.7 to 13.1 +/- 10.6 (P = 0.001) and 96.7 +/- 15.7 to 100.1 +/- 11.1 (P = 0.0025) respectively--after 1 year of treatment. A mild but not significant improvement was observed on the EDSS after 1 year of treatment: 2.9 +/- 0.5 to 2.8 +/- 1.1. CONCLUSIONS: A cognitive decline in MS patients may have a negative impact on the quality of life, affecting all active daily living domains. IFNbeta-1b, a disease-modifying therapy, has demonstrated a positive therapeutic effect on cognitive dysfunction, unrelated to its effect on the EDSS score and course of the disease.

Palpitations: could they be neurogenic? A case report.

BACKGROUND: Palpitations usually occur in patients with arrhythmias of cardiac origion, in conditions associated with increased catecholamine levels, and in psychiatric disorders. A rare etiology of palpitations is seizures with autonomic features. REVIEW SUMMARY: We report a 24-year-old man with a several-week history of episodic palpitations, weakness, dizziness, and presyncopal phenomena. Subsequent events included loss of consciousness, with postevent confusion and tonic movements. A low-grade astrocytoma was diagnosed in the right frontal lobe. CONCLUSION: This case emphasizes the importance of detailed history in the diagnosis of epilepsy.