Role of induced pluripotent stem cells in diagnostic cardiology.

Ethical concerns about stem cell-based research have delayed important advances in many areas of medicine, including cardiology. The introduction of induced pluripotent stem cells (iPSCs) has supplanted the need to use human stem cells for most purposes, thus eliminating all ethical controversies. Since then, many new avenues have been opened in cardiology research, not only in approaches to tissue replacement but also in the design and testing of antiarrhythmic drugs. This methodology has advanced to the point where induced human cardiomyocyte cell lines can now also be obtained from commercial sources or tissue banks. Initial studies with readily available iPSCs have generally confirmed that their behavioral characteristics accurately predict the behavior of beating cardiomyocytes in vivo. As a result, iPSCs can provide new ways to study arrhythmias and heart disease in general, accelerating the development of new, more effective antiarrhythmic drugs, clinical diagnoses, and personalized medical care. The focus on producing cardiomyocytes that can be used to replace damaged heart tissue has somewhat diverted interest in a host of other applications. This manuscript is intended to provide non-specialists with a brief introduction and overview of the research carried out in the field of heart rhythm disorders.

Professor Henry Urich 1916-2015: A London neuropathologist and his Polish heritage.

This is the story of a tumultuous life, lived with enthusiasm and considerable academic success, despite destruction of his cultural heritage in Poland, and loss of his family, by the cruelty of the invading Soviet and Nazi armies in 1939. As a newly qualified doctor from the Polish Medical School at the University of Edinburgh, he was parachuted into Arnhem with the Polish airborne forces, survived, educated himself in British ways and habits, and rapidly succeeded in the medical hierarchy to become an esteemed neuropathologist not only at The London Hospital, but internationally. His central European background provided him with the linguistic and multicultural skills to excel in this highly specialised area of medical science. He was one of the last of the classically trained neuropathologists.

Applied Force During Prone Restraint: Is Officer Weight a Factor?

INTRODUCTION: It has been suggested that law enforcement officer (LEO) weight on the backs of prone subjects may cause asphyxia. METHODS: Law enforcement officers used their agency-trained "local" single- and double-knee techniques, the "Wisconsin" 3-Point Ground Stabilization, and the Human Factor Research Group Inc single-knee tactical handcuffing techniques, and the weight force was measured. RESULTS: Forty-one LEOs (36 men, 5 women) participated, aged 38.4 ± 8.3 years, and weighing 96.2 ± 19.4 kg. The double-knee technique transmitted more weight than single knee (P < 0.0001). Wisconsin technique force was lower than other single-knee techniques (P < 0.0001). Double-knee weight was 23.3 kg plus 24% of LEO's body weight. Mean values for local and Human Factor Research Group Inc single-knee were 30.9 and 32.9 kg, respectively. The Wisconsin single knee weight force was given by 15.4 kg plus 9.5 kg for a male. CONCLUSIONS: A double-knee technique applies more weight force than single-knee techniques. The Wisconsin single-knee technique provides the least weight force of single-knee techniques. Law enforcement officer body weight is irrelevant to prone-force weight with single-knee techniques. With double-knee restraint, it has a modest influence. Our data do not support the hypothesis of restraint asphyxia.

A possible biomarker for methadone related deaths.

Methadone (MTH) concentrations in those dying of MTH toxicity totally overlap concentrations where the presence of MTH is only an incidental finding, making it very difficult to make distinctions in actual cases. A biomarker, be it anatomical or biochemical for MTH toxicity is badly needed, particularly if that markers were known to disrupt effective ventilation. Because the brainstem houses the regulatory centers for cardiorespiratory-control enters, it would seem to be the most likely anatomical site to seek abnormalities in cardiorespiratory control. OBJECTIVE: To locate and describe the cells of nucleus of the solitary tract (TS)(NTS) in human brainstem and determine if neuronal cell death, either necrotic or apoptotic, within the TS of humans is more common in deaths due directly to MTH toxicity than with in the solitary tract itself. DESIGN, SETTING, PARTICIPANTS: This was a single cohort study of MTH related decedents autopsied at a large university hospital. Each decedent had a recent history of non medical/illicit MTH use and had been pronounced dead in the field, prior to ever reaching the hospital. Complete autopsy and complete toxicology testing were performed on the formalin fixed brains of each individual. Multiple blocks were prepared of the area of interest, namely the tissue lying immediately between the inferior and the super colliculi. This volume, by definition, would have included the area of the Rostral Ventrolateral Medulla (RVLM), the location of the TS. Immunohistochemistry studies utilizing caspase-9 reaction (a protease enzyme involved in the process of preprogrammed death) were performed in order to estimate the degree and proportion of neuronal apoptosis, and also access the degree of classical necrosis within the NTS. MAIN OUTCOMES AND MEASURES: The primary outcome measure was the presence or absence of neuronal apoptosis and/or necrosis within the NTS. RESULTS: Cells displaying evidence of early apoptosis and advanced apoptosis, consisting primarily of nuclear fragmentation, admixed with other neurons displaying the features of classic necrosis were found. Evidence of classic necrosis was identifiable in most of the controls, though minor degrees of apoptosis were identifiable with Caspase staining and quantitative image analysis of immunohistochemical stains. CONCLUSIONS: and Relevance: Our study shows that neurons, primarily along the TS, but occasionally in other cell nuclei (even controls) are vulnerable, both to direct MTH toxicity (via apoptosis) and indirectly (via hypoxia leading to classical cell necrosis). When MTH is found to be present in significant concentrations, but apoptotic lesions are absent, it would be reasonable to assume that MTH was not primarily the cause of cardiorespiratory arrest.

The problem of police-related cardiac arrest.

The term "positional asphyxia" was originally used to describe the situation in which the upper airways becomes compromised by sharp angulation of the head or neck, or where the chest wall is splinted and the diaphragm is prevented from moving because of an unusual position of the body. The term was redefined in the early 1980s to describe sudden death during physical restraint of an individual who is in a prone position. A large percent of reported victims were overweight males. Most were in early middle age and manifesting psychotic behavior at the time of death. Most were reported to have unremarkable autopsies, save for the finding, in many cases, of cocaine or methamphetamine (more recently synthetic cannabinoids and cathinones as well). As no cause of death was apparent (other than non-specific signs such as pulmonary edema), it became common practice to attribute death to force exerted on the decedent's back. When experimental studies with human volunteers disproved this notion, the term "restraint asphyxia" was substituted for positional asphyxia, but with nearly the exact same meaning. No experimental study has ever determined the actual amount of force necessary to cause asphyxia by force applied to the back (although the range of required static force is known), nor the duration for which it must be applied. This review discusses the epidemiology and the evidence for and against the theory of "restraint/positional" asphyxia. It also considers alternative theories of causation, including the findings of studies suggesting that cardiac channelopathies/cardiomyopathies may explain many cases of ARD.

Levamisole adulterated cocaine and pulmonary vasculitis: Presentation of two lethal cases and brief literature review.

The first case reports of levamisole-related disease in cocaine users were published in 2010, although levamisole adulteration of cocaine was first recognized several years earlier. Currently, more than 70% of street cocaine seizures, in the US and the EU, contain levamisole, which could potentially be converted to aminorex, though the reasons for this practice still remain obscure. Here we report two fatal cases of isolated pulmonary vasculitis in abusers of levamisole-adulterated cocaine, where a complete autopsy, full toxicological analysis by gas chromatography-mass spectrometry (GC-MS) using a previously published method of Karch et al. and histological examination were performed. A control group composed of 11 cases of cocaine related deaths, where the presence of levamisole was excluded in blood, urine and hair, was used. Recent literature on the human pharmacokinetics of levamisole and aminorex is also reviewed. The toxicological analysis revealed positive qualitative and quantitative results for cocaine, benzoylecgonine and levamisole in both cases. In case 1 levamisole was found at the concentration of 13.5 and 61.3mg/L in blood and urine respectively, whereas in case 2 at 17.9 and 70.2mg/L. The histological examination highlighted in case 1 in heart samples microscopic evidence of the typical remodeling changes associated with chronic stimulant abuse, whereas lungs showed numerous lymphocytes surrounding and infiltrating the wall of small pulmonary vessels and a perivascular fibrosis with transforming fibroblasts. In case 2, the myocardial samples showed wide fields of myocardial necrosis characterized by hypercontraction of the myocytes with thickened Z-lines and short sarcomeres, whereas lung samples showed a significant intimal thickening of arteriole walls and lymphocytic infiltration of the wall and edema. Moreover, there were also numerous perivascular lymphocytic infiltrates. Although the pathological cardiac findings have allowed us to establish the cause of death in both cases, the presence of pulmonary vasculitis in the lungs represent a further complication. If the disease had progressed to hemorrhage, it certainly would have been a contributory cause of death. The two cases here reported allow us to advance a hypothesis about the possible correlation between the consumption of levamisole adulterated cocaine and pulmonary vasculitis and the comparison of these findings with the control group support this hypothesis. However, this hypothesis is still weak, taking into consideration the fact that pulmonary vasculitis was detected in 2 cases only, making it impossible to exclude a different etiology of this finding. Only through careful histological lung examinations of further cases of fatalities, related to levamisole adulterated cocaine, can this hypothesis be confirmed or refuted.

Cathinone neurotoxicity ("The "3Ms").

Synthetic cathinones are designer drugs of the phenethylamine class, structurally and pharmacologically similar to amphetamine, 3,4-methylenedioxymethamphetamine (MDMA), cathinone and other related substances. New analogues, legal at least, until formally banned (a time consuming process), are introduced almost daily The United Nations estimates nearly 250 new drug analogues are produced per year. Various combinations of these drugs are sold under the name of "bath salts". They can be ingested by any route and some appear capable of causing great harm, mostly behavioral. One drug in particular, MDVP, appears to frequently cause symptoms indistinguishable from the classic findings in Excited Delirium Syndrome (ExDS). Little is known about the pathology or clinical toxicology of these drugs but their molecular mechanism of action seems to be identical with that of cocaine. This mini-review examines what little is known on the subject and explains the suspected mechanisms of excited delirium syndrome.

Epidemiological and clinical data of amniotic fluid embolism in forensic settings.

Amniotic fluid embolism (AFE) is a serious obstetric emergency, burdened with a high rate of mortality and morbidity and possible permanent neurological sequelae for those women who survive. The clinical presentation commonly includes: acute hypotension or cardiac arrest, acute hypoxia (dyspnea, cyanosis or respiratory arrest) and coagulopathy (intravascular coagulation or severe haemorrhage), which usually occur during labour, caesarean section or within 30 minutes of delivery. Some cases for the rapidity of clinical presentation, which can result in fatal outcome, run the risk of not being recognized, therefore a proper post mortem examination and histological investigation is fundamental in case of maternal death in order to make the diagnosis and should not be underestimated the incidence of this serious pathological condition. In this paper, firstly the Authors investigated the fatality rates in AFE patients and its incidence in pregnancy related deaths, extrapolating epidemiological data regarding the role of this pathology among the leading causes of maternal mortality. Secondly the contribution of autopsy has been evaluated and further investigation performed on post mortem in order to confirm or make the diagnosis of AFE to better understand this clinical entity that still remains unclear under numerous aspects.

Aminorex associated with possible idiopathic pulmonary hypertension in a cocaine user.

The conversion of levamisole to aminorex in horses was first described in 2009 and, for the first time, confirmed in humans two years later by our laboratory. Aminorex and levamisole interfere with serotonin metabolism and both are proven cause of potentially fatal idiopathic pulmonary hypertension (IPH). Because most of the world's seizures of illicit cocaine is now contaminated with levamisole, this raises the possibility that users of levamisole adulterated cocaine users may be at risk for IPH. Here we describe the first case of IPH in a user of levamisole-contaminated cocaine. Levamisole and aminorex were both identified and quantified in hair and other biological specimens by means gas chromatography/mass spectrometry system (levamisole: urine, 75.05ng/mL; blood, 15.05ng/mL; brain, >0.15ng/g; liver, >0.15ng/g; hair, 12.15ngmg; aminorex: urine, 38.62ng/mL; blood, 8.92ng/mL, brain >0.15ng/g; liver, 0.15ng/g; hair 7.35ng/mg; cocaine, benzoylecgonine, morphine, 6-acetylmorphine, methadone, 2-ethylidine-1, 5-dimetil-3, 3 diphenylpyrrolidine were also detected). Moreover histological changes associated with IPH were observed in the lung. As IPH produces relatively non-specific symptoms in its early stages, this index case may serve as a harbinger of many more cases to come. It should also alert clinicians to the possibility that their patient may be suffering from this relatively rare disorder.

Aminorex poisoning in cocaine abusers.

Levamisole is found in more than 80% of illicit cocaine seized within United States borders. Percentages are somewhat lower in Europe. In 2009, controlled in vivo studies demonstrated that horses metabolize levamisole to aminorex. Earlier this year our laboratory demonstrated that the same conversion occurs in man. Levamisole itself causes aplastic anemia and numerous reports have begun to appear in the literature, but the conversion of levamisole to aminorex is of much more concern. Aminorex ingestion was responsible for a five-year epidemic (1967-1972) of idiopathic pulmonary hypertension (IPH) confined to Switzerland, Austria, and Germany, the only countries where aminorex had been marketed as an anorectic. The incidence of IPH reverted to normal levels as soon as aminorex was withdrawn. In most cases onset of symptoms in IPH began after six to nine months of aminorex use, with average dosage ranges of 10 to 40 mg per day. The outcome was almost uniformly fatal. The conversion rate of levamisole to aminorex has not been established, but given the high daily intake of cocaine by many abusers, it seems likely that many of them will have ingested enough contaminated cocaine to ultimately cause IPH. Until the disease is well established, the symptoms of IHP are vague, and existing drug registries specifically exclude drug abusers, making it difficult to track these cases. This review is intended to draw attention to what may be a slowly emerging new epidemic.

Excited delirium syndrome (ExDS): redefining an old diagnosis.

Recently, the National Institute of Justice (NIJ) of the United States of America convened a meeting of experts in the area of Excited Delirium Syndrome (ExDS). The history of ExDS, the clinical presentation, the pathophysiology, differential diagnoses and management options were discussed. Though the specific pathophysiological pathways of ExDS have yet to be formally defined, considerable research has been undertaken on this topic. It is important for law enforcement, medical and other healthcare professionals to be familiar with current knowledge about the syndrome. This paper summarizes the current state and knowledge of ExDS.

The unique histology of methamphetamine cardiomyopathy: a case report.

This report describes the histological changes observed in the heart a young methamphetamine abuser who died of heart failure. Most of the microscopic changes in the heart have previously been described in experimental animals, but never clearly illustrated in man. Gross examination of the heart revealed concentric myocardial hypertrophy (heart weight 470 g versus median predicted weight of 312 g). Areas of old myocardial infarction were also evident, along with enzymatic evidence indicating that a new infarct had occurred. Myocardial remodeling was extensive with perivascular and interstitial fibrosis, cellular vacuolization, and ongoing myocyte destruction with proliferation of fibromyocytes in the intestitum. Of note were the widespread, bizarre looking, distorted, cell nuclei. They were reminiscent of those seen in viral-induced dilated congestive cardiomyopathy. Clinical chemical measurements also showed unequivocal evidence of both evolving infarction and profound heart failure, with a BNP > 5000. This pattern has not previously been reported in humans, probably because forensic pathologists rarely examine the hearts of methamphetamine abusers microscopically. If the pattern observed here is typical for methamphetamine-induced cardiotoxicity, it could well explain increasing reports of heart failure in methamphetamine abusers. It might also be diagnostic for the disorder.

Determination of aminorex in human urine samples by GC-MS after use of levamisole.

The Drug Enforcement Administration (DEA) reports that as of October 2010, 79% of all cocaine seized in the United States contained levamisole. The equine conversion of levamisole to aminorex has been demonstrated. However, the metabolic fate of levamisole in humans is unknown. Nevertheless, as aminorex is amphetamine-like and hallucinogenic, it may be used as an adulterant to increase the effects of cocaine. We report here the results of in vivo studies demonstrating for the first time that not only equine, but also canine and human metabolism all result in aminorex formation. Levamisole and aminorex were extracted from real urine samples by liquid-liquid extraction and identified and quantified by GC-MS (identification by 3 ions per substance, LLOQ at 0.15ng/ml for both).

A multidisciplinary approach to the investigation of a collapsed building.

Investigating the collapse of a building poses multiple and complex forensic challenges. Large numbers of specialized personnel and equipment are required, as are the combined technical skills of many different kinds of forensic investigators. Forensic pathology teams are integral to these efforts. This report describes the investigation that occurred after a building collapsed in southern Italian location. Several families were still living in small, and abandoned building built in the early 20th century. The buildings were located over cellars 3 meters underground, known locally as "the caves." Eight people were found dead under the debris of one of the collapsed houses and 6 were brought out alive. A team of forensic pathologists and engineers was appointed to investigate the causes of death and of the collapse, respectively. A complete autopsy was performed in every case, along with radiologic assessment and toxicological analysis. Autopsy findings were coded using the Abbreviated Injury Scale and the New Injury Severity Score. Systems for victim identification, arrangements for human remains, management of dead bodies, evaluation of the different patterns of injuries and, finally, detailed identification of the cause of death all played an important role.