Getaw Worku Hassen

A novel calpain inhibitor for the treatment of acute experimental autoimmune encephalomyelitis

Aberrant activation of calpain plays a key role in the pathophysiology of several neurodegenerative disorders. Calpain is increasingly expressed in inflammatory cells in EAE and is significantly elevated in the white matter of patients with multiple sclerosis, thus calpain inhibition could be a target for therapeutic intervention. The experiments reported here employed a myelin oligodendrocyte glycoprotein-induced disease model in C57Bl/6 mice (EAE) and a novel calpain inhibitor, targeted to nervous tissue. CYLA was found to reduce clinical signs of EAE and prevent demyelination and inflammatory infiltration in a dose- and time-dependent manner. Oral administration of the diacetal prodrug was equally effective.

Prevention of Axonal Injury using Calpain Inhibitor in Chronic Progressive Experimental Autoimmune Encephalomyelitis

Axonal injury is the major correlate of permanent disability in neurodegenerative diseases such as multiple sclerosis (MS), especially in secondary-progressive MS which follows relapsing-remitting disease course. Proteolytic enzyme, calpain, is a potential candidate for causing axonal injury. Most current treatment options only target the inflammatory component of MS. Previous work using calpain inhibitor CYLA in our laboratory showed significant reduction in clinical sign, demyelination and tissue calpain content in acute experimental autoimmune encephalomyelitis (EAE). Here we evaluated markers of axonal injury (amyloid precursor protein, Na(v)1.6 channels), neuronal calpain content and the effect of CYLA on axonal protection using histological methods in chronic EAE [myelin oligodendrocyte glycoprotein (MOG)-induced disease model of MS]. Intraperitoneal application of CYLA (2 mg/mouse/day) significantly reduced the clinical signs, tissue calpain content, demyelination and inflammatory infiltration of EAE. Similarly, markers for axonal injury were barely detectable in the treated mice. Thus, this novel drug, which markedly suppresses the disease course, axonal injury and its progression, is a candidate for the treatment of a neurodegenerative disease such as multiple sclerosis.

Lactate induced excitotoxicity in hippocampal slice cultures

During the initial minutes of cerebral ischemia, lactic acid accumulates and acidifies brain pH to 6.0-6.7. Glutamate is also released during ischemia that activates glutamate receptors and induces excitotoxicity. While glutamate excitotoxicity is well established to induce ischemic injury, a role of lactic acidosis in ischemic brain damage is poorly understood. This study analyzes acidosis neurotoxicity in hippocampal slice cultures in the presence or absence of lactate. At pH 6.7, neuronal loss was similar whether or not lactate was present. At pH 6.4, neuronal loss was significantly greater in the presence of lactate suggesting that lactate potentiates the acidosis toxicity. At pH 6.4 in the presence of lactate, NMDA or non-NMDA receptor antagonists reduced neuronal loss, while in the absence of lactate, NMDA or non-NMDA receptor antagonists had little effect. [3H]-Glutamate uptake was inhibited by acidic pH, and the amount of inhibition was significantly greater in the presence of lactate. These findings suggest that lactate plays a role in acidosis neurotoxicity by inducing excitotoxicity. Lactic acidosis and excitotoxicity have been previously thought to be independent events during ischemia. This study suggests that during ischemia, lactic acidosis contributes to excitotoxic neuronal loss.

Hyperthermia and severe rhabdomyolysis from synthetic cannabinoids

Synthetic cannabinoids (SC) have exploded on to the scene. With this rise in SC use, the number of complications and potential adverse effects are also well documented in the literature and is on the rise. The most frequently cited side effects are behavioral in nature and range for severe agitation to psychosis and delirium. We report a case of hyperthermia with severe rhabdomyolysis from SC use.

A novel calpain inhibitor for treatment of transient retinal ischemia in the rat.

After an acute ischemia/reperfusion of the rat retina, the activation of cytotoxic proteases, including calpain, results in necrosis and apoptosis of retinal ganglion cells resulting in their degeneration. Using a systemically administered calpain inhibitor that crosses the blood–retinal barrier would provide for novel systemic intervention that protects the retina from acute injury and loss of function. Herein, we study a novel calpain peptide inhibitor, cysteic–leucyl–argininal (CYLA), in an in-vivo rat model of retinal ischemia to determine functional protection using electroretinography. The CYLA prodrug was administered intraperitoneally before and/or after ischemia–reperfusion at concentrations of 20–40 mg/kg. We found that administering 20 mg/kg of CYLA only after ischemia provides significant preservation of retinal function.

Anterior chamber depth measurement using ultrasound to assess elevated intraocular pressure

Increased anterior chamber pressure also known as intraocular pressure can result from conditions such as glaucoma and trauma. The pressure in the anterior chamber is measured using tonometer. Measurement of the intraocular pressure is essential, as it requires immediate medical attention to alleviate pain and to avoid temporary or permanent damage to intraocular structures. Bedside ocular ultrasound (US) has gained popularity in recent years. It has been used to assess intracranial pressure via optic nerve sheath diameter (ONSD) and evaluate retinal detachment, vitreous hemorrhage, or pupillary reflex in a trauma patient. We report 2 cases of patients with glaucoma and a case of a patient with trauma to the eye with swelling. Anterior chamber depth measurement was conducted and compared with measurements of intraocular pressure (IOP) using a tonometer.

Isolated T Wave Inversion in Lead aVL: An ECG Survey and a Case Report

Background. Computerized electrocardiogram (ECG) analysis has been of tremendous help for noncardiologists, but can we rely on it? The importance of ST depression and T wave inversions in lead aVL has not been emphasized and not well recognized across all specialties. Objective. This studys goal was to analyze if there is a discrepancy of interpretation by physicians from different specialties and a computer-generated ECG reading in regard to a TWI in lead aVL. Methods. In this multidisciplinary prospective study, a single ECG with isolated TWI in lead aVL that was interpreted by the computer as normal was given to all participants to interpret in writing. The readings by all physicians were compared by level of education and by specialty to one another and to the computer interpretation. Results. A total of 191 physicians participated in the study. Of the 191 physicians 48 (25.1%) identified and 143 (74.9%) did not identify the isolated TWI in lead aVL. Conclusion. Our study demonstrated that 74.9% did not recognize the abnormality. New and subtle ECG findings should be emphasized in their training so as not to miss significant findings that could cause morbidity and mortality.

CorrespondenceAnterior chamber depth measurement using ultrasound to assess elevated intraocular pressure

The rise in recreational drug abuse and corresponding increases in the production of newer and more potent synthetic drugs are alarming [1]. Our institution has experienced periodic increases in emergency department (ED) visits from synthetic drug use at music festivals [2,3]. However more recently, daily visits have increased significantly due to synthetic cannabinoid (SC) abuse. The Substance Abuse and Mental Health Services Administration reported 11 406 SC ED visits in 2010 increasing to 28 531 in 2012 [4]. Presenting symptoms include agitation, altered mental status, seizures, vomiting, delusions, and hallucinations. Manypatients require sedation and continuous cardiac andpulse oximetry monitoring, leading to increased length of stay in the ED and ED crowding. A study by Pines [5] recently reported that ED crowding contributed to a 5% higher chance of death, 1% longer hospital stay, and 1% higher costs per admission. In 2012, the White House reported that the use of SC contributed to 11.3% of the illicit drug use by 12th graders [6]. Their relatively low cost and ease of availability made them increasingly popular [2]. Sold as K2, Spice or Fake weed, they compromise a variety of herbal mixtures that are intentionally adulterated with SC compounds in order to produce marijuana-like effects [7,8]. Clearly labeledas “not forhumanconsumption” and marketed as incense, the packaging specifically indicates that they do not contain tetrahydrocannabinol (THC)-like compounds such as JWH018, HU-210, or CP-47. The first severe toxic effects of SCs were reported in 2010 in Iowa when an 18 year old male committed suicide after smoking K2, leading to efforts to categorized SC as class I controlled substances in 2012 [9]. Despite these legislative efforts, the distribution of SCs is difficult to control as continuous minimal alterations of the chemical structure enable them to be legally marketed as aromatic products and incense [3]. Castaneto et al [10] reported symptoms such as suicidal ideations and thought disorder that required inpatient psychiatric admission from SC use in young healthy men. Their pronounced central inhibition of γ-amino butyric acid as compared with tetrahydrocannabinol (THC) is thought to lower seizure threshold [2]. Currently, there is no specific antidote to reverse the toxic effects of SCs. The concomitant use of other substances such as phencyclidine, cocaine, and alcohol further complicates the clinical picture. These substances can produce anxiety, tremors, hypertension, tachycardia, and tachydysrhythmia [11]. Chest pain is a common complaint, and a case of myocardial infarction and death has been reported [12]. Synthetic cannabinoids increase psychomotor activity and dystonia, leading to an increased risk of rhabdomyolysis and renal failure [13]. It remains vitally important for ED physicians to recognize symptoms of SC intoxication in order to prevent life-threatening events. Surveillance of SC use is of utmost public health importance in order to assess prevalence of abuse and adverse outcomes. Information about the type of SC used and the corresponding symptoms, as well as the demographics of SC users, may help assess risks of adverse outcomes associated with specific products and initiate community outreach and education to prevent their increased use.

Controlled Cortical Impact-induced Neurodegeneration Decreases after Administration of the Novel Calpain-inhibitor Gabadur

One aspect of secondary injury in traumatic brain injury is the marked increase in intracellular calcium and resultant over-activation of the calcium-dependent neutral cysteine protease calpain. Gabadur is a novel protease inhibitor with calpain-inhibition properties formulated from the classic protease inhibitor leupeptin linked to a pregabalin carrier. This construction allows the entire compound to cross the blood-brain barrier after peripheral administration to better target the site of injury. In this study, a single intraperitoneal dose of Gabadur was administered immediately following controlled cortical impact injury in rats. Neocortical slices were examined at 48 h post-injury via Fluoro-Jade B staining, revealing an improvement in cortical neurodegeneration in Gabadur treated rats. Levels of detrimental active calpain-2 measured via western blot were also decreased in rats receiving Gabadur. This data supports the benefit of targeted protease inhibition in the treatment of traumatic brain injury.

Intrafissural fat mimicking pulmonary embolism

A 48-year old man was admitted to our psychiatric department. Our medical team was consulted for preoperative evaluation prior to external fixation of a fractured fibula. Physical examination was unremarkable except for truncal obesity (BMI: 32). Admitting chest X-ray (CXR) showed a wedge density in left lower lobe obscuring the left hemi diaphragm on the frontal view (Figure 1(A)) and a triangular area of increased opacity with the fissure extending upward from it on the lateral view (Figure 1(B)). Based on his recent history of a leg fracture and wedge density on CXR, a chest CT scan with contrast to rule out pulmonary emboli was performed. Coronal views of the chest CT revealed a homogenous mass with the density of fat that abutted the anterior diaphragmatic surface at its base and tapered into the major fissure at the apex (Figure 1(C)). Axial CT views showed the fat pad being drawn into the fissure and covered with parietal pleura (Figure 1(D)). Homogenous fat attenuation with encases anatomic structures helped to differentiate this mass from a focal tumour. In simple obesity, excessive fat is generally stored at various body sites, notably in the subcutaneous tissue, perirenal tissue, omentum, and mesentery. Although more fatty tissue may be present within the mediastinum in obese persons, an amount of fat sufficient to produce significant finding on the chest roentgenogram is not common. Because thoracic fat is mobile and plastic, it can assume a variety of distributions and shapes. A small collection of supra-diaphragmatic fat is occasionally invaginates into the inferior aspect of the major interlobar fissure. Fat collections can be confusing, and even mimic tumours. Fatty tissue is radiolucent but, its lucency is lost to a certain degree because of adjacent, more lucent pulmonary tissue. Fat that is drawn into fissures looks as if it is in the pleural space, but it is actually extrapleural, as it is covered by parietal pleura. This essay highlights the variable and potentially confusing manifestations of normal thoracic fat on plain radiographs and CT scans. Extra-pleural fat collections is a benign condition and may be related to general obesity. Although rare, it should be considered in the differential diagnosis of mediastinal masses, particularly in obese individuals.