Cholemic Nephrosis: An Autopsy Study of a Forgotten Entity.

OBJECTIVE: The aim of the study is to do a clinicopathologic study of post mortem kidney biopsies with significant deposition of bilirubin pigment within tubular epithelial cells and in the lumen of distal tubules as a bile cast. MATERIAL AND METHOD: All post mortem specimens with acute tubular necrosis, with the presence of bile casts in tubules or bile pigment deposition in the tubular epithelium during the period 2015-2018 were examined for gross and histopathology along with biochemical parameters and viral markers. RESULTS: Bile casts with sloughed renal tubular epithelial cells and occasional macrophages were present in the distal convoluted tubule in 78.6% of biopsies (11/14). The plugging of distal convoluted tubule with casts was similar to that seen in myeloma and myoglobin cast nephropathies. Bilirubin pigment deposition was present in 35.7% (5/14) of cases. The frequency of bile casts in each biopsy was variable and it did not have any association with serum bilirubin levels or etiology of liver dysfunction. A striking difference from earlier studies is the high number of toxin-induced liver damage including six cases of paraquat and 2 cases of yellow phosphorus poisoning. CONCLUSION: This study proves importance of the bile cast nephropathy as a reason for kidney injury, especially with varied hepatotoxic etiologies, especially paraquat and yellow phosphorus.

Induction of Autophagy by Vasicinone Protects Neural Cells from Mitochondrial Dysfunction and Attenuates Paraquat-Mediated Parkinson's Disease Associated α-Synuclein Levels.

Mitochondrial dysfunction and disturbed mitochondrial dynamics were found to be common phenomena in the pathogenesis of Parkinson's disease (PD). Vasicinone is a quinazoline alkaloid from Adhatoda vasica. Here, we investigated the autophagy/mitophagy-enhancing effect of vasicinone and explored its neuroprotective mechanism in paraquat-mimic PD modal in SH-SY5Y cells. Vasicinone rescued the paraquat-induced loss of cell viability and mitochondrial membrane potential. Subsequently, the accumulation of mitochondrial reactive oxygen species (ROS) was balanced by an increase in the expression of antioxidant enzymes. Furthermore, vasicinone restored paraquat-impaired autophagy and mitophagy regulators DJ-1, PINK-1 and Parkin in SH-SY5Y cells. The vasicinone mediated autophagy pathways were abrogated by treatment with the autophagy inhibitor 3-MA, which lead to increases α-synuclein accumulation and decreased the expression of p-ULK and ATG proteins and the autophagy marker LC3-II compared to that observed without 3-MA treatment. These results demonstrated that vasicinone exerted neuroprotective effects by upregulating autophagy and PINK-1/Parkin mediated mitophagy in SH-SY5Y cells.

The Ocular Protective Effects of Nano/Submicron Particles Prepared from Lycium barbarum Fruits Against Oxidative Stress in an Animal Model.

Purpose: To investigate the antioxidative properties of Lycium barbarum (LB) fruits in the eyes and to study whether LB fruits prepared with new nanotechnology have stronger antioxidative effects. Methods: Fourteen days post-supplementation with milled or blended LB fruits, intravitreal paraquat (PQ) was injected into Wistar rats to create oxidative stress. After an additional 14-day supplementation with LB fruits, the rats were sacrificed. An electroretinogram (ERG) was performed to evaluate retinal function before and after the PQ injection. Expression levels of antioxidative responders' mRNA in retina were detected by reverse transcription-polymerase chain reaction. Superoxide dismutase (SOD) and glutathione reductase activity in the aqueous humor (AqH) were analyzed by ELISA. Immunohistochemistry was conducted to evaluate the morphological changes of retina and the levels of oxidative biomarkers. The levels of cell apoptosis were assessed by the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. The reactive oxygen species (ROS) levels in AqH were measured by chemiluminescence methods. Results: The murine eyes supplemented with LB fruits exhibited several changes compared with the control group. The ERGs revealed significant improvement in retinal function. The mRNA expression levels of oxidative responders were downregulated in the retinas. The ROS was significantly reduced in the retinas, but the SOD meaningfully increased in the AqH. Immunohistochemistry staining and TUNEL assays showed decreased incidences of oxidative biomarkers and apoptosis in the retinas. Milled LB fruits exhibited better antioxidative effects than blended fruits. Conclusions: Milled LB fruits demonstrated superior protection against oxidative threats than blended fruits. Thus, these fruits could be an inexpensive supplement for many oxidative stress-related ocular diseases.

Melittin Exerts Beneficial Effects on Paraquat-Induced Lung Injuries In Mice by Modifying Oxidative Stress and Apoptosis.

Melittin (MEL) is a 26-amino acid peptide with numerous biological activities. Paraquat (PQ) is one of the most widely used herbicides, although it is extremely toxic to humans. To date, PQ poisoning has no effective treatment, and therefore the current study aimed to assess for the first time the possible effects of MEL on PQ-induced lung injuries in mice. Mice received a single intraperitoneal (IP) injection of PQ (30 mg/kg), followed by IP treatment with MEL (0.1 and 0.5 mg/kg) twice per week for four consecutive weeks. Histological alterations, oxidative stress, and apoptosis in the lungs were studied. Hematoxylin and eosin (H&E) staining indicated that MEL markedly reduced lung injuries induced by PQ. Furthermore, treatment with MEL increased superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activity, and decreased malonaldehyde (MDA) and nitric oxide (NO) levels in lung tissue homogenates. Moreover, immunohistochemical staining showed that B-cell lymphoma-2 (Bcl-2) and survivin expressions were upregulated after MEL treatment, while Ki-67 expression was downregulated. The high dose of MEL was more effective than the low dose in all experiments. In summary, MEL efficiently reduced PQ-induced lung injuries in mice. Specific pharmacological examinations are required to determine the effectiveness of MEL in cases of human PQ poisoning.

Reduning injection ameliorates paraquat-induced acute lung injury by regulating AMPK/MAPK/NF-κB signaling.

Reduning injection (RDN), a patented Chinese medicine, is broadly used for common cold and lung infection in clinic, but the mechanism underlying its effects on inflammation-related pulmonary injury remains unclear. Paraquat (PQ, bolus 15 mg/kg dose, ip) was administered for acute lung injury induction in mice, which were orally administered dexamethasone (2 mg/kg) or RDN (50 and 100 mg/kg/day) for 5 days. After treatment, plasma and lung tissue samples from the euthanized animals were obtained and analyzed by histological, biochemical and immunoblot assays. Histological observation demonstrated RDN alleviated PQ-induced lung damage. Meanwhile, RDN suppressed myeloperoxidase (MPO) activity, reduced the wet/dry (W/D) ratio and decreased the amounts of total leukocytes and neutrophils. Treatment also markedly decreased the amounts of malondialdehyde, MPO, and inflammatory cytokines while increasing superoxide dismutase activity in comparison with the PQ group. In immunoblot, RDN blocked the phosphorylation levels of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), JNK, ERK, p38, inhibitor of nuclear factor κB kinase and nuclear factor-κB (NF-κB) in lung tissue specimens in PQ-challenged animals, which was further verified in vitro. The above data indicated protective effects for RDN in PQ-induced lung damage, possibly through inhibition of the AMPK/MAPK/NF-κB pathway.

Tribolium castaneum as a whole-animal screening system for the detection and characterization of neuroprotective substances.

Parkinson's disease (PD) is a movement disorder caused by the progressive loss of dopaminergic neurons. Natural antioxidants and plant extracts with neuroprotective properties offer a promising new therapeutic approach for PD patients, but a suitable large-scale screening system is required for their discovery and preclinical analysis. Here we used the red flour beetle (Tribolium castaneum ) as a whole-animal screening system for the detection and characterization of neuroprotective substances. Paraquat was added to the diet of adult beetles to induce PD-like symptoms, which were quantified using a novel positive geotaxis behavioral assay. These paraquat-induced behavioral changes were reduced in beetles fed on diets supplemented with l-dihydroxyphenylalanine, ascorbic acid, curcumin, hempseed flour, or the Chinese herb gou-teng. T. castaneum is, therefore, a valuable model for the screening of neuroprotective substances in chemical libraries and plant extracts and could be developed as a model for the preclinical testing of therapeutic candidates for the treatment of neurodegenerative diseases, such as PD.

The effects of ω-3 fish oil emulsion-based parenteral nutrition plus combination treatment for acute paraquat poisoning.

OBJECTIVE: To investigate the effects of parenteral nutrition (PN) including ω-3 fish-oil emulsion on nutritional state, inflammatory response, and prognosis in patients with acute paraquat poisoning. METHODS: Patients randomized to receive medium chain triglycerides (MCT)/long chain triglycerides (LCT)-based PN (control group) or MCT/LCT-based PN containing ω-3 fish-oil emulsion (intervention group) were compared for 90-day survival and short-term treatment efficacy. RESULTS: Tumour necrosis factor-α levels were significantly lower in the intervention group ( n = 101) versus controls ( n = 73) on treatment days 4 and 7. Intervention group C-reactive protein (CRP) levels were significantly increased on day 4, decreased to baseline (day 1) levels on day 7, and were significantly lower than baseline on day 10. Control group CRP levels were significantly increased on days 4 and 7 versus baseline, and returned to baseline levels on day 10. On day 7, retinol binding protein had recovered to baseline levels in the intervention group only. Intervention group mortality rate (36.6%) was significantly lower than controls (57.5%). ω-3 fish-oil PN was associated with reduced risk of death (hazard ratio 0.52; 95% confidence interval 0.33, 0.82). CONCLUSION: In patients with acute paraquat poisoning, MCT/LCT with ω-3 fish-oil emulsion PN plus combination treatment advantageously attenuated the inflammatory response, modified the nutritional state, and was associated with significantly improved 90-day survival versus treatment without ω-3 fish oil.

Epigallocatechin-3-gallate alleviates paraquat-induced acute lung injury and inhibits upregulation of toll-like receptors.

AIMS: To evaluate the detoxifying effect of epigallocatechin-3-gallate (EGCG) on paraquat (PQ)-induced acute lung injury in mice, and to explore the action mechanisms. MAIN METHODS: Following administration of PQ, the mice received a low, a medium or a high dose of EGCG daily for three days. Histopathology of the lungs were examined by H&E staining. The levels of inflammatory cytokines, such as TNF-α, IL-1ß and IL-6, in the bronchoalveolar lavage fluid were measured by enzyme-linked immunosorbent assay. Activation of NF-κB was assessed by Western blot and electrophoretic mobility gel shift assay. The expression of toll-like receptor (TLR)-2, 4, 9 and TLR adaptors (MyD88 and TRAF6) was detected by Western blot and immunohistochemical staining. The protective effect of EGCG against PQ toxicity was validated in vitro using A549 lung cancer cell line. KEY FINDINGS: Treatment with EGCG dose-dependently attenuated PQ-induced acute lung injury in mice by reducing alveolar edema, hemorrhage, inflammatory cell infiltration and production of inflammatory cytokines. EGCG inhibited the activation of NF-κB and the upregulation of TLR 2, 4 and 9 as well as their adaptors MyD88 and TRAF6 in the lungs following PQ challenge. In addition, EGCG significantly reduced PQ-induced cell death, cytokine production, activation of NF-κB, and upregulation of TLRs and adaptors in A549 cells. SIGNIFICANCE: Our data suggest that TLR-mediated activation of NF-κB in the non-immune pulmonary cells could be involved in PQ-induced acute lung injury, and it may serve as a target of EGCG against PQ pulmonary toxicity.

Protective effect of Xuebijing injection on paraquat-induced pulmonary injury via down-regulating the expression of p38 MAPK in rats.

BACKGROUND: Exposure to paraquat results in acute lung injury. A systemic inflammatory response has been widely established as a contributor to paraquat-induced acute lung injury. Recent studies have reported that consumption of Xuebijing prevents inflammatory response-induced diseases. This study investigated whether consumption of Xuebijing protected rats against paraquat-induced acute lung injury. METHODS: Adult male Sprague Dawley rats were randomly divided into four groups: control group; paraquat group; paraquat + Xuebijing group; and paraquat + dexamethasone group. Rats in the paraquat, paraquat + Xuebijing and paraquat + dexamethasone groups were intraperitoneally injected with paraquat (30 mg/kg) or administered paraquat and Xuebijing at 8 mL/kg or dexamethasone at 5 mg/kg, respectively, via an injection into the tail vein. Lung p38 MAPK, NF-κB65, IkB, p-IκB-α, HIF-1α, Nrf2 and TGF-ß1 expression were essayed using western blotting. IL-6, TNF-α, IL-1ß, IL-10, TGF-ß1 and PIIIP were measured using ELISA. ROS, oxidised glutathione and glutathione activity were measured. RESULTS: After inducing acute lung injury with paraquat for 24 h, Xuebijing was observed to block lung p-p38 MAPK, NF-κB65, HIF-1α, p-IκB-α and TGF-ß1 expression, and increased Nrf2 and IkB expression. The numbers of neutrophils and lymphocytes and total number of cells were significantly lower in the Xuebijing group compared with the control group. IL-6, TNF-α, IL-1ß, TGF-ß1 and PIIIP levels were significantly decreased in the Xuebijing group. ROS and oxidised glutathione activity were markedly inhibited by Xuebijing. Histological evaluation showed attenuation of the effects of Xuebijing on paraquat-induced lung injury. Compared with the paraquat + dexamethasone group, the Xuebijing + paraquat group showed no significant differences. CONCLUSIONS: Inhibiting the expression of p38 MAPK and NF-κB65 was crucial for the protective effects of Xuebijing on paraquat-induced acute lung injury. The findings suggest that Xuebijing could effectively ameliorate paraquat-induced acute lung injury in rats. Xuebijing was as effective as dexamethasone at improving paraquat-induced lung injury by regulating lung inflammation, lung function and oxidative stress responses.

Silymarin- and melatonin-mediated changes in the expression of selected genes in pesticides-induced Parkinsonism.

Parkinson's disease (PD) is the second most unconcealed neurodegenerative disorder labelled with motor impairments. Two pesticides, manganese ethylene-1,2-bisdithiocarbamate (maneb) and 1,1'-dimethyl-4,4'-bipyridinium dichloride (paraquat), together, are reported to increase the incidence of PD in humans and Parkinsonism in mice. Conversely, silymarin and melatonin, two naturally occurring antioxidants, rescue from maneb- and paraquat-induced Parkinsonism. The study examined silymarin- and melatonin-mediated changes in the expression of selected genes in maneb- and paraquat-induced Parkinsonism employing mouse discover chips microarrays. The mice were treated intraperitoneally (i.p.), daily, with silymarin (40 mg/kg) or melatonin (30 mg/kg) for 9 weeks along with vehicles. Subsets of animals were also treated with maneb (30 mg/kg; i.p.) and paraquat (10 mg/kg; i.p.), twice a week, for 9 weeks. Whilst the expression of genes in the striatum was determined by microarray, the expression of randomly selected transcripts was validated by quantitative real-time polymerase chain reaction (qRT-PCR). Combined maneb- and paraquat-treatment altered the expression of several genes associated with apoptosis, inflammation, cell cycle, cell-signalling, etc. pathways. Silymarin and melatonin significantly resisted the changes in the expression of a few genes related to apoptosis, inflammation, cell cycle, cell-signalling, etc. The expression patterns of seven randomly selected genes were analyzed by qRT-PCR, which were found to follow the similar trends, as observed with microarray. The results obtained from the study thus demonstrate that despite resemblances, silymarin and melatonin differentially offset maneb- and paraquat-induced changes in transcriptome.

Ratios of biliary glutathione disulfide (GSSG) to glutathione (GSH): a potential index to screen drug-induced hepatic oxidative stress in rats and mice.

Hepatotoxicity of drug candidates is one of the major concerns in drug screening in early drug discovery. Detection of hepatic oxidative stress can be an early indicator of hepatotoxicity and benefits drug selection. The glutathione (GSH) and glutathione disulfide (GSSG) pair, as one of the major intracellular redox regulating couples, plays an important role in protecting cells from oxidative stress that is caused by imbalance between prooxidants and antioxidants. The quantitative determination of the GSSG/GSH ratios and the concentrations of GSH and GSSG have been used to indicate oxidative stress in cells and tissues. In this study, we tested the possibility of using the biliary GSSG/GSH ratios as a biomarker to reflect hepatic oxidative stress and drug toxicity. Four compounds that are known to alter GSH and GSSG levels were tested in this study. Diquat (diquat dibromide monohydrate) and acetaminophen were administered to rats. Paraquat and tert-butyl hydroperoxide were administered to mice to induce changes of biliary GSH and GSSG. The biliary GSH and GSSG were quantified using calibration curves prepared with artificial bile to account for any bile matrix effect in the LC-MS analysis and to avoid the interference of endogenous GSH and GSSG. With four examples (in rats and mice) of drug-induced changes in the kinetics of the biliary GSSG/GSH ratios, this study showed the potential for developing an exposure response index based on biliary GSSG/GSH ratios for predicting hepatic oxidative stress.

[Therapeutic effects of epidermal growth factor (EGF) combined with plasma cryoprecipitate (CRYO) on the corneal injury induced by paraquat].

OBJECTIVE: To evaluate the therapeutic effects of epidermal growth factor (EGF) combined with plasma cryoprecipitate (CRYO) on the corneal injury induced by paraquat (PQ). METHODS: According to the "Toxicological test methods of pesticides for registration" (GB 15670-1995), the conjunctival sacs of 18 health New Zealand rabbits were exposed to 100 µl 20% PQ, which were randomly divided into EGF, CRYO and EGF plus CRYO groups. The routine treatments (normal saline washing and antibiotic eyedrops) were administrated to the injured eyes of 3 groups, at the same time the left eyes of 3 groups were treated with EGF, CRYO and EGF plus CRYO, respectively. The injury of conjunctival, iris and corneal, fluorescent stranded and pathology changes of corneal were observed. The injury score was calculated and the recovery time of corneal injury was recorded. RESULTS: The recovery time of corneal injury in EGF and EGF plus CRYO groups were 19.50 ± 3.08 and 18.67 ± 2.73 days, respectively which were significantly lower than those (27.33 ± 2.58 and 26.83 ± 3.13 days) in corresponding routine treatment controls (P < 0.05). CONCLUSION: EGF and EGF plus CRYO could be used to treat the corneal injury induced by paraquat.

Ferulsinaic acid attenuation of advanced glycation end products extends the lifespan of Caenorhabditis elegans.

OBJECTIVES: Ferulsinaic acid is the first member of a new rearranged class of sesquiterpene coumarins of the genus Ferula. The genus Ferula can be used for the treatment of skin infections, hysteria and for stomach disorders, such as a febrifuge and a carminative agent. The effect of ferulsinaic acid on the lifespan of the nematode Caenorhabditis elegans has been examined. Novel data explaining the effect of ferulsinaic acid on the lifespan of C. elegans and its antioxidant power were obtained. METHODS: C. elegans was cultivated under standard laboratory conditions in absence and presence of different ferulsinaic acid. Also, animals were cultivated under heat and chemical stress conditions in absence and presence of ferulsinaic acid. Life span assay, determination of protein concentration, assay of malondialdehyde and ELISA for determination of AGEs were performed. KEY FINDINGS: Under standard laboratory conditions and in presence of ferulsinaic acid (500 nm, 10 µm and 100 µm), mean life span of wild type animals was significantly lengthened in a dose-dependent manner from 18.64 ± 0.19 days (control) to 19 ± 0.19 (P = 0.695), 20.76 ± 0.25 (P = 0.043) and 22.3 ± 0.29 (P = 0.0291), respectively. Interestingly, in C. elegans resistance for heat stress at 35°C and oxidative stress induced by paraquat were significantly improved with ferulsinaic acid. Ferulsinaic acid was found to significantly attenuate both lipid peroxidation and the formation of advanced glycation end products in the wild-type animals under standard laboratory conditions. CONCLUSIONS: Ferulsinaic acid had therapeutic efficacy as an antioxidant with the possibility of its use as an antioxidant drug.

Foetal rat lung epithelial (FRLE) cells: partial characterisation and response to pneumotoxins.

Cultured cell lines are routinely used for in vitro toxicity screens, reducing the requirement for animal studies during the development of new pharmaceutical, agrochemical and cosmetic products. The foetal rat lung epithelial (FRLE) cell line was originally derived from alveolar type II cells (ATII) of the lung. The aims of this study were to further characterise FRLE cells and investigate their potential for screening for pneumotoxins. The cells were found to have retained some of the features of their progenitor cells, namely the expression of cytokeratin proteins, specifically cytokeratin 18, and the ability to actively accumulate the non-selective contact herbicide paraquat. However, the cells have lost the ability to synthesise surfactant protein mRNA and no longer contain multiple lamellar bodies. Toxins that damage ATII cells in vivo (cadmium chloride, cobalt chloride and paraquat) were found to induce cytotoxicity in FRLE cells, as did the non-specific pneumotoxin nitrofurantoin, and hydrogen peroxide. However, the cells were less sensitive to the effects of compounds that require metabolic activation (1-nitronaphthalene, coumarin and butylated hydroxytoluene) and the hepatotoxin bromobenzene. Thus, FRLE cells appear to be a good in vitro model for monitoring the potential toxicity to ATII cells and could be used as an initial screen for pneumotoxicity.

Antioxidant mobilization in response to oxidative stress: a dynamic environmental-nutritional interaction.

In today's society, human activities and lifestyles generate numerous forms of environmental oxidative stress. Oxidative stress is defined as a process in which the balance between oxidants and antioxidants is shifted toward the oxidant side. This shift can lead to antioxidant depletion and potentially to biological damage if the body has an insufficient reserve to compensate for consumed antioxidants. This report focuses on the observation that oxidative stress resulting from inhalation of oxidant air pollutants mobilized vitamin E to the lung. A review of the literature showed that this mobilization is not limited to the lung; rather, a variety of situations in which oxidative stress occur can mobilize antioxidants. This antioxidant mobilization shows that a high antioxidant capacity in the body must be maintained for it to cope efficiently with environmental oxidative stress. Maintaining a high-antioxidant capacity in the body with the use of dietary supplementation was a convenient and acceptable method by test subjects, human or non-human. One mechanism that might explain the antioxidant mobilization is a dynamic interaction between environment and nutrition. In that mechanism, oxidative stress would alter certain bioactive molecules, followed by activation of signal transduction pathways that in turn would mobilize antioxidants to the target organ of the oxidant attack.

An epidemiological study of the health of Sri Lankan tea plantation workers associated with long term exposure to paraquat.

Pulmonary function tests (FVC, FEV1, FEV1/FVC%, TLCO, single breath CO diffusion), chest x ray film, renal function (serum creatinine and blood urea nitrogen), liver function (serum alanine aminotransferase, aspartate transferase, and alkaline phosphatase, bilirubin, total protein, and albumin), a haematological screen (haemoglobin and packed cell volume), and a general clinical examination were performed on 85 paraquat spraymen (mean spraying time 12 years) and on two control groups (76 factory workers and 79 general workers) frequency matched for age and years of occupational service. All the subjects were men. There were no clinically important differences in any of the measurements made between the study group and the two control groups. In particular the results of the lung function tests, appropriate for paraquat toxicity of the study group, were similar to those of the control groups. The same was true of blood tests for liver and kidney function. The incidence of skin damage, nose bleeds, and nail damage in the study group was slightly higher than in the control groups but lower than the incidence reported for paraquat workers in previous studies. The results of this study confirmed that long term spraying of paraquat, at the concentrations used, produced no adverse health effects, in particular no lung damage, attributable to the occupational use of the herbicide.

Aggravation of experimental allergic conjunctivitis by environmental chemical and physical factors.

The effects of trichlorfon (DEP, Dipterex, anticholinesterase pesticide) and paraquat dichloride (Gramoxon, inhibitor of superoxide dismutase) on passive anaphylactic reaction in guinea pig conjunctiva using Japanese cedar pollen were quantitatively studied. For estimation of allergic conjunctivitis, Evans blue after i.v. injection was extracted from conjunctiva and measured spectrophotometrically. Allergic conjunctivitis was apparently aggravated by extremely low dosages of organophosphorus pesticide (10(-5) mg/kg) and organochlorine herbicide (10(-4) mg/kg). The aggravation of allergic conjunctivitis was also observed after exposure to cathode ray tubes used in commercial television, possibly due to electromagnetic waves. IgE-mediated allergic reaction could be non-specifically potentiated by such environmental factors.

Use and misuse of epidemiologic data in the courtroom: defining the limits of inferential and particularistic evidence in mass tort litigation.

Medical epidemiology is the cornerstone for understanding the safety and efficacy of drugs and medical devices. Epidemiologic principles provide a statistical basis for determining correlations, and ultimately mathematical causation, between two series of events. Medical epidemiologic evidence and statistical inferences are useful and are now routinely accepted in the courtroom. The complex distribution systems that provide fungible goods throughout the country often preclude the identification of the specific source of an allegedly defective product. An expansion of the principles established in Summers v. Tice and Ybarra v. Spangard provide a logical and rational means for the courts to address products liability issues in cases involving multiple and unnamed defendants. This Article discusses the impact of epidemiology on the judicial process, both in the nature of judicial decision-making and in the nature of the law itself. Part III B discusses the "weak" and "strong" versions of the traditional preponderance of the evidence rule, as recast by recent products liability litigation. The remainder of the Article defines the useful and appropriate scope of epidemiologic evidence, concluding that "intentless" epidemiologic evidence alone cannot support an award of punitive damages.

Marijuana. Health and treatment issues.

Intermittent use of low-potency cannabis is not generally associated with obvious toxicity. In recent years, some cannabis users have been using high doses more frequently and seeking treatment. A large but incomplete literature indicates that cannabis can be harmful to health, and that virtually every system in the body is affected by cannabis. Cannabis pharmacology is complex; all recent scientific groups reviewing cannabis conclude it is clearly capable of causing adverse effects to health. Specific treatment procedures have not been developed for managing cannabis related problems. Strategies useful in treating other drug dependence problems are useful in treating dependence.