Lessons from case studies of metals: investigating exposure,bioavailability, and risk

Since metals are widely distributed in environmental matrices, humans are exposed to them by either anthropogenic activities or inadvertently by necessity. Selected metals: arsenic, mercury, iron, tin, lead and chromium were chosen on the basis of their economic and public health importance to illustrate the diversity of exposure pathways and differences in factors governing bioavailability. Bioavailability is central to the toxicity of metals and this is discussed from the health risk paradigm standpoint of risk assessment and risk management and the impacts of including or excluding bioavailability in such assessment. The lessons from the case studies of arsenic, mercury, tin and chromium provide a unified concept of methods that can be used in investigating and controlling outbreaks due to metal poisoning in other similar situations.     

Partial cortical deafferentation promotes development of paroxysmal activity

This study tested the hypothesis that early functional alterations in neuronal synchrony in the partially deafferented cortex may lead to spontaneously occurring electrographic seizures. In vivo experiments with partial deafferentation of cat suprasylvian gyrus after extensive undercut of the white matter were conducted using multi-site EEG, extracellular unit and intracellular recordings. The amplitudes of EEG waves were much higher in the areas surrounding deafferented cortical fields as compared with control and with undercut cortex. In 40% of animals with undercut cortex, paroxysmal activity occurred 2-3 h after the undercut and was initiated in the relatively intact cortex, adjacent to the more disconnected one. The seizures that followed the undercut consisted of spike-wave/polyspike-wave complexes and fast runs, resembling the electrographic patterns of some clinical epileptic syndromes. An increased local synchrony in the relatively intact cortex evolved into paroxysmal activity that ultimately spread to the deafferented cortex. The electrographic seizures were found only in animals that showed a propagation of the slow sleep-like oscillation in control conditions. The increase of long-range synchrony within a given seizure was associated with seizure termination. These results indicate that alterations in neuronal synchrony following neuronal trauma can be a critical factor triggering electrographic seizures.     

Hyperexcitability of intact neurons underlies acute development of trauma-related electrographic seizures in cats in vivo

Cortical trauma can lead to development of electrographic paroxysmal activities. Current views of trauma-induced epileptogenesis suggest that chronic neuronal hyperexcitability and extensive morphological reorganization of the traumatized cortex are required for the generation of electrographic seizures. However, the mechanisms responsible for the initiation of electrographic seizures shortly after cortical injury are poorly understood. Here we show that, in the experimental model of partially deafferented (undercut) cortex, an increase in intrinsic and synaptic excitability of neurons in areas adjacent to the undercut cortex is sufficient for the generation of electrographic paroxysmal activity within few hours after partial cortical deafferentation. Locally increased and spatially restricted neuronal excitability arose from the increased incidence of intrinsically bursting neurons, enhanced intrinsic and synaptic neuronal responsiveness, and slight disinhibition. These mechanisms only operate in neurons located in the vicinity of partially deafferented sites because, after the cortical injury, partially deafferented neurons are mostly silent and hypoexcitable. Our results suggest that trauma-induced electrographic seizures first arise in cortical fields that are closest to the site of injury and such seizures do not require long-term neuronal reorganization.     

Decreased survival in pancreatic cancer patients with high concentrations of organochlorines in adipose tissue

We analysed adipose tissue concentrations of persistent organic pollutants (POPs) in 21 cases with exocrine pancreatic cancer. The comparison group consisted of 59 subjects. Significantly increased concentrations of polychlorinated biphenyls (PCBs), hexachlorobenzene (HCB), sum of chlordanes and polybrominated diphenylethers (PBDEs) were found in the cases. For 1,1,-dichloro-2,2-bis(p-chlorophenyl)-ethylene (p,p'-DDE) no significant difference was seen. For PCBs no odds ratio (OR) could be calculated since all cases had concentration>median in controls used as a cut-off. HCB yielded OR=53.0, 95% confidence interval (CI)=4.64-605 and sum of chlordanes OR=18.4, 95% CI=2.71-124 whereas OR was not significantly increased for p,p'-DDE or PBDEs. Body mass index (BMI) at the time of tissue sampling was significantly lower for the cases. This might have influenced the results. Using BMI one year previously or decreasing the concentrations of POPs with the same percentage as weight loss among the cases did not change the results. Survival of the cases was shorter in the group with the concentration of POPs>median among cases, significantly so for the sum of PCBs (147 vs. 294 days), p,p'-DDE (134 vs. 302 days), and sum of chlordanes (142 vs. 294 days) in the high and low group, respectively. The results were based on a low number of cases and should be interpreted with caution.     

Induction of dermal-epidermal separation in mice by passive transfer of antibodies specific to type VII collagen

Epidermolysis bullosa acquisita (EBA) is a subepidermal blistering disorder associated with tissue-bound and circulating autoantibodies specific to type VII collagen, a major constituent of the dermal-epidermal junction. Previous attempts to transfer the disease by injection of patient autoantibodies into mice have been unsuccessful. To study the pathogenic relevance of antibodies specific to type VII collagen in vivo, we generated and characterized rabbit antibodies specific to a murine form of this antigen and passively transferred them into adult nude, BALB/c, and C57BL/6 mice. Immune rabbit IgG bound to the lamina densa of murine skin and immunoblotted type VII collagen. Mice injected with purified IgG specific to type VII collagen, in contrast to control mice, developed subepidermal skin blisters, reproducing the human disease at the clinical, histological, electron microscopical, and immunopathological levels. Titers of rabbit IgG in the serum of mice correlated with the extent of the disease. F(ab')(2) fragments of rabbit IgG specific to type VII collagen were not pathogenic. When injected into C5-deficient mice, antibodies specific to type VII collagen failed to induce the disease, whereas C5-sufficient mice were susceptible to blister induction. This animal model for EBA should facilitate further dissection of the pathogenesis of this disease and development of new therapeutic strategies.     

Similar behaviour of lecithin:cholesterol acyltransferase and pseudocholinesterase in liver disease and hyperlipoproteinemia

Using exogenous substrate for its assay, lecithin:cholesterol acyltransferase (LCAT) was found to be decreased in liver disease and higher than normal in endogenous hypertriglyceridemia. LCAT activity was positively correlated with serum cholesterol and triglyceride. However in the six patients with excessive hypertriglyceridemia (type V), LCAT activity was lower than in type IV hyperlipoproteinemia. LCAT activity was not changed significantly in type II-a hyperlipoproteinemia. A striking parallel was noted between plasma LCAT and serum pseudocholinesterase activity. It suggested that both these liver secretion enzymes might be induced by an accelerated turnover of serum lipids and lipoproteins. Pathogenical implications of these findings are briefly discussed.     

An electrophysiological marker of the desire to quit in smokers

For many smokers, the motivational state of craving is a central feature of their dependence on nicotine, and is often at odds with a general desire to quit. How this desire to quit may influence the craving for a cigarette, however, is unclear. In the current study, we manipulated the level of craving in 24 regular smokers, and recorded EEG measures of brain activity during a rare target detection task utilizing addiction‐unrelated stimuli. In response to the non‐targets, we observed that smokers wanting to quit showed an enhanced late frontal activation when they were craving vs. not craving, whereas smokers not wanting to quit showed the opposite pattern of activity. A dissociation was also present in the target‐related P300 response as a function of craving and desire to quit, with smokers who did not want to quit processing targets differentially between the states of craving and non‐craving. The data suggest that distinct top‐down control mechanisms during craving may be implemented by people who wish to quit smoking, as compared to those who do not wish to quit. This pattern of findings establishes this ERP activity as a potential biomarker that may help to differentiate people who want to quit their addiction from those who wish to continue to use their substance of choice.     

Correlation between symptoms of diabetic gastroparesis and results of gastric scintigraphy

Background  

delayed gastric emptying is detectable in 20–40% of patients with type 1 and type 2 diabetes. The prevalence of symptoms suggestive for diabetic gastroparesis is much lower. The aim of the study was to evaluate the gastric emptying and to correlate the results with dyspeptic symptoms.