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In 1820, Frederick Accum published a book, best known by its biblical subtitle ‘Death in the Pot', showing the widespread fraudulent and dangerous adulteration of common foods and drinks bought in London. Despite its brief popularity, there was no effective legislation in Britain until 1875 after more extensive analytical surveys by Hassall and Letheby in 1855 and a parliamentary enquiry had confirmed the frauds and risks to public health. There were similar surveys and legal action against food adulteration in France and Germany towards the end of the 19th century. In the USA, campaigning by Harvey Wiley and others revealed the same risks and frauds and led to the Pure Foods and Drugs Act in 1906 and formation of the FDA. We should have celebrated Accum’s bicentennial in 2020 to recognise his achievement and to remind us of the continuing dangers of food adulteration today.

Methoxyflurane is an inhaled analgesic administered via a disposable inhaler which has been used in Australia for over 40 years for the management of pain associated with trauma and for medical procedures in children and adults. Now available in 16 countries worldwide, it is licensed in Europe for moderate to severe pain associated with trauma in conscious adults, although additional applications are being made to widen the range of approved indications. Considering these ongoing developments, we reviewed the available evidence on clinical usage and safety of inhaled analgesic methoxyflurane in trauma pain and in medical procedures in both adults and children. Published data on methoxyflurane in trauma and procedural pain show it to be effective, well tolerated, and highly rated by patients, providing rapid onset of analgesia. Methoxyflurane has a well-established safety profile; adverse events are usually brief and self-limiting, and no clinically significant effects on vital signs or consciousness levels have been reported. Nephrotoxicity previously associated with methoxyflurane at high anesthetic doses is not reported with low analgesic doses. Although two large retrospective comparative studies in the prehospital setting showed inhaled analgesic methoxyflurane to be less effective than intravenous morphine and intranasal fentanyl, this should be balanced against the administration, supervision times, and safety profile of these agents. Given the limitations of currently available analgesic agents in the prehospital and emergency department settings, the ease of use and portability of methoxyflurane combined with its rapid onset of effective pain relief and favorable safety profile make it a useful nonopioid option for pain management. Except for the STOP! study, which formed the basis for approval in trauma pain in Europe, and a few smaller randomized controlled trials (RCTs), much of the available data are observational or retrospective, and further RCTs are currently underway to provide more robust data.

Mitochondrial encephalopathies are a heterogeneous group of disorders that, usually carry grave prognosis. Recently a homozygous mutation, Gly372Ser, in the TIMM50 gene, was reported in an abstract form, in three sibs who suffered from intractable epilepsy and developmental delay accompanied by 3-methylglutaconic aciduria. We now report on four patients from two unrelated families who presented with severe intellectual disability and seizure disorder, accompanied by slightly elevated lactate level, 3-methylglutaconic aciduria and variable deficiency of mitochondrial complex V. Using exome analysis we identified two homozygous missense mutations, Arg217Trp and Thr252Met, in the TIMM50 gene. The TIMM50 protein is a subunit of TIM23 complex, the mitochondrial import machinery. It serves as the major receptor in the intermembrane space, binding to proteins which cross the mitochondrial inner membrane on their way to the matrix. The mutations, which affected evolutionary conserved residues and segregated with the disease in the families, were neither present in large cohorts of control exome analyses nor in our ethnic specific exome cohort. Given the phenotypic similarity, we conclude that missense mutations in TIMM50 are likely manifesting by severe intellectual disability and epilepsy accompanied by 3-methylglutaconic aciduria and variable mitochondrial complex V deficiency. 3-methylglutaconic aciduria is emerging as an important biomarker for mitochondrial dysfunction, in particular for mitochondrial membrane defects.

Mitochondrial encephalopathies are a heterogeneous group of disorders that, usually carry grave prognosis. Recently a homozygous mutation, Gly372Ser, in the TIMM50 gene, was reported in an abstract form, in three sibs who suffered from intractable epilepsy and developmental delay accompanied by 3-methylglutaconic aciduria. We now report on four patients from two unrelated families who presented with severe intellectual disability and seizure disorder, accompanied by slightly elevated lactate level, 3-methylglutaconic aciduria and variable deficiency of mitochondrial complex V. Using exome analysis we identified two homozygous missense mutations, Arg217Trp and Thr252Met, in the TIMM50 gene. The TIMM50 protein is a subunit of TIM23 complex, the mitochondrial import machinery. It serves as the major receptor in the intermembrane space, binding to proteins which cross the mitochondrial inner membrane on their way to the matrix. The mutations, which affected evolutionary conserved residues and segregated with the disease in the families, were neither present in large cohorts of control exome analyses nor in our ethnic specific exome cohort. Given the phenotypic similarity, we conclude that missense mutations in TIMM50 are likely manifesting by severe intellectual disability and epilepsy accompanied by 3-methylglutaconic aciduria and variable mitochondrial complex V deficiency. 3-methylglutaconic aciduria is emerging as an important biomarker for mitochondrial dysfunction, in particular for mitochondrial membrane defects.

The Mirasol PRT System (Gambro BCT, Lakewood, CO) for platelets and plasma uses riboflavin and UV light to reduce pathogens and inactivate white blood cells in donated blood products. An extensive toxicology program, developed in accordance with International Organisation for Standardisation (ISO) 10993 guidelines, was performed for the Mirasol PRT system. Test and control articles for most of the reported studies were treated (test) or untreated (control) blood products. For some studies, pure lumichrome (the major photoproduct of riboflavin) or photolyzed riboflavin solution was used. Systemic toxicity was evaluated with in vivo animal studies in the acute and subchronic settings. Developmental toxicity was evaluated with an in vivo animal study. Genotoxicity and neoantigenicity were evaluated with in vitro and in vivo tests. Hemocompatibility and cytotoxicity were assessed with standard, in vitro assays. The pharmacokinteics, excretion, and tissue distribution of (14)C-riboflavin and its photoproducts was evaluated with an in vivo animal study. The possible presence of leachable or extractable compounds (from the disposable set) was evaluated with novel assays for measuring these compounds in blood. No treatment-related toxicity was observed in any of the studies.

Developmental immunotoxicity is new both as an area of scientific study and as a potential source of concern in the protection of the public health. It is a combination of three nascent sciences and one older established area of study–immunology, `Development’, toxicological science and the practical application of experimental findings to indicate risks to man and means to control them. This hardworking and very successful meeting, organized by the Immunotoxicology Technical Committee (ITC) of the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) with input from the U.S. Environmental Protection Agency (EPA), provided an appropriate setting in which scientists from industrial, academic and regulatory backgrounds were able to debate how the development of the immune system might be affected by toxicity, and ways in which transient and permanent harmful effects might occur. There was considerable interest in how the basic processes and structures of immunity and development might be affected by model substances, which could afford examples to demonstrate the value of laboratory methods to detect developmental immunotoxicity. There were vigorous discussions about testing strategies, about techniques, about how to `validate’ laboratory methods when there was relatively little consistent information from man to identify suitable positive control substances and cardinal disorders, and about how best to employ the sparse information to support the effective prediction of risk.

During a conference sponsored by the National Institute of Environmental Health Sciences (NIEHS) and Laboratories and Clinics Group (LCG) Biosciences, held on April 5–6, 2001, in Cambridge, United Kingdom, newly emergent and characterized animal models and technologies enhancing the understanding of prostatic cancer were presented and compared with aspects of the disease in man. The participants provided an overview of human prostatic cancer and identiŽ ed data gaps and research needs for focused strategies for therapeutic intervention and prevention. The speakers deŽ ned the characteristics of currently available animal models and identiŽ edways in which these models can be used to address research questions relevant to prostatic biology and disease.

The goal of this chapter is to discuss the general principles of risk assessment and risk communication as they relate to the use of excipients in drug products. A vital need of the user of any pro...

Head and neck squamous cell carcinoma (HNSCC), the eighth most common cancer worldwide, accounts for approximately 600,000 new cases per year. The mobile tongue is the most common site for oral cancer and is associated with a poorer survival than other HNSCC sites. Standard therapeutic strategies have failed to significantly improve survival rates that have remained around 50% over the past four decades. In the last decade intense investigations on oral cancer highlighted the mandatory role of the tumor microenvironment (TME), in addition to the genetic aberrations and molecular biology changes within the cancer cells. Furthermore, the molecular crosstalk between cancer cells and TME components (i.e., cancer-associated fibroblasts, inflammatory pro-tumorigenic cells, etc.) has a crucial role in growth, invasion, spread and metastases of the cancer cells and consequently leads to poor prognosis. Recent studies suggest that plant-derived dietary agents nutraceuticals, especially curcumin and green tea, have the advantage to combat both malignant cells and TME components, unlike standard anti-cancer protocols that target only cancer cells. However, due to a very low bioavailability, nutraceuticals do not currently constitute an integral part of these protocols. Ongoing developments in nanotechnology for improved delivery are expected to overcome their challenging pharmacokinetics.

The pathogen inactivation process developed by Cerus and Baxter Healthcare Corporations uses the psoralen, S-59 (amotosalen) in an ex vivo photochemical treatment (PCT) process to inactivate viruses, bacteria, protozoans, and leukocytes in platelet concentrates and plasma. Studies were performed by intravenous infusion of S-59 PCT formulations-compound adsorption device (CAD) treatment and with non-UVA illuminated S-59, using doses that were multiples of potential clinical exposures. The studies comprised full pharmacokinetic, single and repeated-dose (up to 13 weeks duration) toxicity, safety pharmacology (CNS, renal, and cardiovascular), reproductive toxicity, genotoxicity, carcinogenicity testing in the p53- mouse, vein irritation, and phototoxicity. No specific target organ toxicity (clinical or histopathological), reproductive toxicity, or carcinogenicity was observed. S-59 and/or PCT formulations demonstrated CNS, ECG, and phototoxicity only at supraclinical doses. Based on the extremely large safety margins (>30,000 fold expected clinical exposures), the CNS and ECG observations are not considered to have any toxicological relevance. Additionally, after a complete assessment, mutagenicity and phototoxicity results are not considered relevant for the proposed use of INTERCEPT platelets. Thus, the results of an extensive series of in vitro and in vivo studies have not demonstrated any toxicologically relevant effects of platelet concentrates prepared by the INTERCEPT system.

The STM (Scanning Tunneling Microscope) has been used for characterizing the microstructure of various steel samples by utilizing its surface imaging properties. The subgrain sizes of 15 different samples of steel (in the range 20 nm to 250 nm) were studied by the STM and compared with the results obtained using X-ray diffraction (XRD) by employing line profile analysis of the Bragg peaks. Good agreement was observed between the two sets of data of subgrain sizes. This work establishes STM as a useful characterization tool for studies in metallurgy and metal physics.

This report is the outcome of a workshop organized by the International Life Sciences Institute-European Branch (ILSI Europe), on the "Risks of Risk Assessment in Foods" held on 18 February 1998 in Brussels, Belgium. The meeting discussed Risk Assessment as the principal means by which the European Union evaluates the potential harm arising from the use of existing and new products. The experiences of the parties involved have often shown that the concepts underlying risk assessment are complex and not always fully understood. There is an urgent need to familiarize industry, policy makers and the scientific community with developments in the basic principles and terminology of risk assessment. Therefore, the workshop aimed to review key areas in risk assessment and to provide an open forum for learning and discussion between all interested parties.

The transport of large particles across the intestinal mucosa and the mechanisms of transfer of the particles into the body are still little understood. Fluorescent polystyrene latex particles (2 μm diam.) were administered orally to young male Sprague-Dawley rats in doses of 2.33 times 103, 2.33 times 106 and 2.33 times 109 particles. After 60 min, Peyer’s patches and Peyer’s patch-free tissues were collected from the small intestine and colon. A novel technique was used to exclude non-translocated particles adherent to the mucosal surface; the intestinal epithelium was stripped from the intestine by immersion in Hanks’ balanced salt solution containing 1.5 mM EDTA. Particles in solubilized samples of intact and epithelium-stripped Peyer’s patches and Peyer’s patch-free intestinal tissue and colon were quantified by fluorescence microscopy. The location of particles within the intact and epithelium-stripped gut samples was revealed by confocal microscopy. Particles were shown to have been taken up along the entire length of the small and large intestines via both Peyer’s patches and the normal intestinal epithelium. The number of particles detected in the distal region was greater than in the proximal part of the small intestine, although the difference was not statistically significant. This study has revealed that large numbers of non-translocated particles adhered to the mucosal surface resulting in a high background count. The assay system was considerably improved by the epithelium-stripping technique. The process of transepithelial uptake is a potentially important route of uptake of toxic, immunologically active and radioactive substances. These particles are much larger than the conventionally accepted upper limit for absorbed materials.

Taking advantage of the feasibility to obtain well-prepared surfaces, an extensive work has been done in studying X-ray diffraction line broadening effects from flat polycrystalline samples of uranium and uranium alloys. The broadening analysis has been used as a semiquantitative method for measuring inhomogeneity of alloying, hardness, and residual thermal stresses. Good correlation between the microstrain and the hardness was found after heat treatments and cold work. A comparable correlation was found between the microstrain in the supersaturated α-uranium phase quenched from the γ region, and the concentration of the alloying elements. The measured microstrain in the supersaturated α-uranium phase was used as a quantitative value for determination of the solubility limit of Ta and W in γ-uranium. As a result of this study it was found that the limit of solubility is approximately 2.6 and 2.0 at. % for Ta and W, respectively.

2H Double quantum-filtered (DQF) NMR spectroscopy of deuterated water is sensitive to the presence of order in biological systems. This is because the only nuclei that are detected are those with residual quadrupolar interactions due to their anisotropic motion. In the present study, samples of aorta, coronary and carotid arteries, and vena cava were studied in parallel by 2H DQF NMR and by light microscopy. The average quadrupolar splitting, calculated from the NMR data, varies considerably among the different blood vessels, with high reproducibility for each type of vessel. Polarization microscopy examinations using collagen-specific staining with picrosirius red, have shown a variety of color profiles for the different blood vessels. These reflect different physical modes of aggregation (packing and thickness) of collagen fibers. A correlation was found between the NMR parameters and the color profiles of the picrosirius red-stained sections. Treating the blood vessels with 90% formic acid resulted in the elimination of the 2H DQF NMR signal. Histological analysis demonstrated a complete degradation of collagen and muscle, whereas the elastin filaments were preserved. Evidence is given that the 2H DQF NMR signal is dominated by the contribution of water molecules interacting with the collagen fibers.

The retention at room temperature of the γ-U and β-U structures containing 0.43 and 1.0 at % W respectively is achieved by rapid cooling from high temperature. The metastable β-U structure subsequently undergoes an isothermal shear-like transformation into a strained variant of the α-U structure

Eight of the known chemical substances associated with neoplasia in man are known to target the urinary bladder urothelium. Preneoplastic changes have been identified following exposure to each of these chemicals, and they have also been seen to occur in many species of lab animals. The most important such change is preneoplastic hyperplasia. Adaptive hyperplasia is the first form of hyperplasia to appear. It can be seen both in untreated controls and dosed animals. The distinguishing features are that in treated groups it does not progress with dose or time, and the process is reversible. Reparative hyperplasia involves disruption of homeostasis. Its severity increases with dose and time. It is not seen in controls but it is still reversible during the recovery segment after exposure to a toxic substance. When reparative hyperplasia continues beyond a certain threshold of time and dose, it progresses to preneoplastic hyperplasia, which further progresses with continued stimulation to frank neoplasia. The synthetic beta-lactam penem antibiotic FCE 22891 and its metabolite FCE 22101 caused adaptive urothelial hyperplasia of the urinary bladder only in rats and in no other species. Based on the pharmacokinetic profile of FCE 22891 and FCE 22101, it can be deduced that the morphologic finding of adaptive urothelial hyperplasia is caused by reduction of intravesicular urine pH. This effect has no relevance to therapeutic use in humans. Further, it is important to distinguish adaptive and reparative hyperplasia in preclinical toxicity studies.

Mixtures of Np, Pu and Am were administered to primates (C. jacchus) by gastric intubation to measure their fractional gastrointestinal absorption (f1 values). The values obtained were about 2 x 10(-3) and 1 x 10(-3), respectively, for Np and Pu administered as the citrate, and 2 x 10(-3) and 6 x 10(-4), respectively, for Pu and Am in potato. The significance of these values in terms of absorption in humans is discussed.

Complete evaluation of the toxicity of a new chemical entity requires critical analysis of the pattern of positive and negative findings in all types of toxicity tests, pharmacokinetics and metabolism in the species examined, and correlation of the effects with information about its pharmacodynamic and pharmacological properties. The goal is to obtain sufficient understanding of the mechanisms underlying the therapeutic and toxic effects of the compound to permit a well-supported extrapolation from the test to the target species. The Expert Report system in the European Community is based on comprehensive 25-page reviews of information about a compound arranged under 3 headings: Chemistry and Pharmacy, Pharmacology and Toxicology, and Clinical Studies. Each section requires a searching review of the experimental work and the relevant literature, integration of the findings, and then careful correlation among these 3 main areas of knowledge to indicate the circumstances of safe and effective use of the drug.

The death of Socrates in 399 BCE, as reported by Plato in the Phaedo, is usually attributed to poisoning with common hemlock. His progressive centripetal paralysis is characteristic of that poison. Socrates is said to have had a prominent loss of sensation extending centrally from his legs, which is not a feature of hemlock poisoning, and he seems not to have had the unpleasant taste or common gastrointestinal effects of that poison. It is suggested that Plato gave a modified account of the death of Socrates for political and other reasons by describing a more “noble” death.

Reactive rf-magnetron sputtering has been employed for the growth of thin films of InN on the (001) face of mica at a variety of substrate temperatures from 50 to 550 °C. These films have been characterized by x-ray scattering, stylus profilometry, and electrical transport measurements, and their topography has been studied by SEM and STM. At low deposition temperatures, the InN films exhibit texture [(00.1)InN‖ (001)mica], while at higher deposition temperatures a large fraction of the grains are heteroepitaxial [(00.1)InN‖(001)mica, (2.0)InN · (060)mica]. The utility of the x-ray precession method in the determination of this heteroepitaxial relationship is highlighted. The films exhibit a local mobility maximum near a substrate temperature of 350 °C, beyond which a sharp increase in resistivity associated with voids and cracks owing to the onset of secondary grain growth leads to a dramatic decrease in electrical mobility. At the highest growth temperatures, however, the interconnection between grains improves and lower resistivity and higher mobility are re-established.

Nonclinical studies in animals and in in vitro systems are essential steps in the development of a new chemical entity, both to demonstrate actions indicative of efficacy and to examine toxicity as a guide to safety. The scientific basis of prediction and extrapolation are examined, with special references to factors that lead to uncertainty in suggesting potential hazards in man.

Respiration induces fluctuations in heart rate and arterial blood pressure, originating from either mechanical effect of respiration or from changes in autonomic nervous system activity. In order to study the relationship between cardiovascular hemodynamics and the two phases of respiration, inspiration and expiration, we used the photoplethysmographic (PPG) signal, which reflects the cardiac-induced changes in the tissue blood volume. The time of inspiration and expiration was determined by a novel depth-of-breath sensor. The PPG and the depth-of-breath signals were simultaneously recorded during long breathing period of 12 s duration per breath. In most examinations the finger blood volume increased during inspiration, probably due to higher sympathetic activity during expiration. In a minority of examinations tissue blood volume decreased during inspiration probably due to the mechanical effect of low pressure in the thoracic cavity during inspiration.

The terrifying dog in the Hound of the Baskervilles is described as having 'blazing eyes' and a 'luminous muzzle', appearances attributed by Watson and Holmes to the application of phosphorus. Review of the toxicity and flammability of white phosphorus make this improbable. It is suggested that Conan Doyle's description was probably influenced by knowledge of the recent and much publicized discovery of luminescence due to the radioactivity of uranium salts.

Quantitative optical microscopy, ultrasonic sound velocity measurements, and transmission electron microscopy (TEM) have been used to follow the kinetics of the isothermal martensitic transformation in an uranium 1.6 at. pct gallium alloy. The results indicate that the apparent relatively slow growth of the α′ martensite plates within the β-uranium matrix actually consists of the nucleation of numerous new martensitic platelets on the martensitic plate-matrix interface and their subsequent growth at a rate similar to that in athermal martensites.

The phenomenological double-shear theory of martensite crystallography has been applied to the β → α′ martensitic transformation in the U-1.6 at. pct Ga alloy. A correspondence matrix for the β → α′ transformation was derived from the experimentally determined β/α′ orientation relationship, and the double lattice invariant shear was considered as a combination of the principal slip (010) [100]a with one of the minor slips in the α-uranium structure. The theoretical predictions of the habit plane are in good agreement with the experimental observations.

Oral and perioral herpes simplex virus infections are commonly seen and managed by the dental practitioner. Many topical and oral antiviral agents are available in Israel. However, only a few regimens are based on solid evidence. The purpose of this study was to review the mode of action of antiviral agents and to present therapeutic regimens supported by randomized control trials.

Oro-facial manifestations of herpes simplex virus (HSV) infections are very common, and include primary herpetic gingivo-stomatitis, recurrent herpes labialis and recurrent intra-oral herpes. Recent research in molecular biology has advanced our knowledge of the HSV pathogenesis and behavior. Understanding the exact mechanism of HSV latency and reactivation enables improvement of drug therapy and prevention strategies of HSV infections. The aim of this review is to update the recent development in the biological and clinical research related to HSV infection, focusing on oral and perioral lesions.

Oral cancer continues to afflict the general population in growing numbers with a relatively low survival rate. Today, through histology, the potential danger of a pre-cancerous lesion can be detected, yet it does not reflect with certainty its biologic behavior. Recent studies have shown that some pre-cancerous lesions with mild dysplasia may undergo malignant transformation and lesions with severe dysplasia may remain quiet. Our goal is to locate the relatively small population of patients that are at high risk for malignant transformation at an early stage of carcinogenesis so they can be treated effectively. Methods that can identify the molecular and DNA changes may provide the data needed to predict the true malignant potential of a pre-cancerous lesion and its potential for transformation with a higher degree of certainty. The purpose of this article was to review some of the diagnostic options that are being studied and their link to carcinogenesis.

Oral mucositis (OM), an inevitable side effect of almost all anti-cancer treatments, affects the patient's physiological functions and their psychological well being. In spite of numerous treatment modalities for this condition, there is still a lack of evidence-based clinical trials that can provide a single efficient pharmacologic agent or intervention for either prevention or treatment of OM. This study analyses and summarizes some of the more "accepted" modalities for treatment of OM. It is recommended that these modalities rely on simple, convenient and innocuous interventions, which should be adjusted for each individual complaint. Well-designed, controlled and standardized studies are necessary to validate effectiveness of available, as well as newly developed interventions for OM.

The delay, stage at diagnosis and referral pattern of 543 oro/oropharyngeal cancer patients in Israel were investigated. About two-thirds of the malignancies were diagnosed at early stages. In more than two-thirds there was a delay of at least 2 months from the onset of signs and symptoms up to diagnosis, with a non-significant relationship between stage and delay. A significant correlation ( P = 0.002) was found between delay and malignancy site. A delay of more than 4 months was observed in 71% of the patients with lip cancer. Cancers of the lip, palate and buccal mucosa were more frequently diagnosed at early stages. A significant correlation ( P = 0.001) was found between stage at diagnosis and referral source. Although 86% of the cancers were diagnosed by physicians, nearly half were already at an advanced stage; when the cancers were diagnosed by dentists, 81% of the remainder were at early stages. No significant relationship was found between the referral medical profession and site of diagnosis. No nasopharyngeal, oropharyngeal or laryngeal cancers were diagnosed by dentists.