"Old" and "new" contaminants and their management: learning from the past, looking to the future.

Within the 50 year lifetime of the Society for Environmental Geochemistry and Health (SEGH), we have seen a number of contaminants transfer from being the wonder chemical of their day through to becoming current contaminants of concern. This is also true for a variety of emerging contaminants such as plastic microbeads, pharmaceutical residues, and fire retardant chemicals, amongst others. This thought piece discusses the risk associated with a range of these emerging contaminants, their global nature, how existing models and frameworks can be applied to deal with their impacts, and research and management gaps and challenges.

Medical Abortion before Confirmed Intrauterine Pregnancy: A Systematic Review.

"Very early medical abortion" (VEMA) refers to medical abortion (with mifepristone and misoprostol) before intrauterine pregnancy is visualized on ultrasound. Our aim is to present the current evidence on efficacy, safety (focused on ectopic pregnancies), and how to assess treatment success of VEMA. We conducted a systematic review of studies reporting outcomes of VEMA. The field is small and so our objective was to map all relevant literature, without conducting meta-analysis. We searched PubMed, Medline, and Embase on April 19, 2022. We conducted a narrative synthesis of the evidence. A total of 373 articles were identified. Six articles (representing four observational and one pilot trial) were included in the final review. Across all included studies, treatment efficacy ranged between 91 and 100%. Prevalence of ectopic pregnancy was low and very few cases (n = 2) of ruptures were reported. Most studies used serial serum human chorionic gonadotrophin (s-hCG) levels to determine success of abortion; one study used low sensitivity urine hCG. From the available evidence, VEMA appears to be efficacious and does not appear to cause harm to ectopic pregnancies. Treatment can be assessed with pre- and postabortion s-hCG. Good quality, randomized controlled trial evidence is needed to best inform practice.

Increasing the delivery of upper limb constraint-induced movement therapy post-stroke: A feasibility implementation study.

INTRODUCTION: Few stroke survivors receive upper limb constraint-induced movement therapy (CIMT). The aims of this study were to evaluate whether a behaviour change program for occupational therapists increased the number of stroke survivors receiving CIMT, describe the time and process involved in delivering the first program, any adverse events, fidelity and dose of CIMT provided, and upper limb outcomes. METHODS: A feasibility pre-post implementation study design was used, with intervention and measures for therapists and stroke survivors. Intervention for occupational therapists was informed by the Behaviour Change Wheel and included CIMT training, barrier identification, mentoring and a community of practice. Therapists delivered 2-week CIMT programs with 1:1 supervision, first assisting stroke survivors to identify upper limb goals using the Canadian Occupational Performance Measure. The primary outcome was change in the number of stroke survivors receiving CIMT (program reach). Hours associated with program delivery, adverse events and participant repetitions were recorded (program fidelity and dose). Change in motor function was measured (fidelity) using the Motor Assessment Scale (Upper Limb), Box and Block Test, Nine Hole Peg Test and Motor Activity Log at baseline, program completion (2 weeks), 1 and 12 months. RESULTS: Program reach: Sixteen stroke participants were recruited (mean 15.3 months post-stroke, SD 11.9) and six CIMT programs conducted over 24 months, compared to none pre-implementation. The first CIMT program required a mean of 242 hours for preparation and delivery. All programs were student-assisted. Fidelity and dose: Stroke participants completed a mean of 360.6 repetitions/hour (SD 183.7), and 12,719.6 repetitions/program (SD 6,872.8). Statistically significant changes in upper limb motor function were recorded; some changes were clinically important. CONCLUSIONS: The behaviour change program resulted in multiple CIMT programs being delivered safely and with fidelity. Capacity building and skill development took many hours, as did preparation for the first CIMT program.

Unusual sensory variant of Guillain-Barré syndrome.

We describe a 52-year-old woman presenting with acute onset of severe burning paraesthesia in the hands and feet associated with allodynia and antalgic gait. At the time of admission to hospital no motor weakness was present. A diagnosis of Guillain-Barré syndrome (GBS) was considered when neurophysiological studies were completed showing convincing evidence of demyelination on motor conduction studies and sural sparing on sensory nerve studies.1 We describe this case as a sensory variant of GBS. Clinical improvement followed treatment with a single course of intravenous immunoglobulin (IVIG). The patient made a complete clinical recovery within 6 months of onset and repeat neurophysiological studies showed marked improvement. We encourage clinicians to consider an atypical variant of GBS in patients presenting with acute sensory complaints.

Capacity Building in Environment and Health (CBEH) project: strengthening health in environmental assessments in Slovenia: gap analysis and way forward

In the frame of the Capacity Building in Environment and Health (CBEH) project, co-funded by the European Commission, a workshop was held in Slovenia in order to analyse the specific capacity needs in the country in relation to the implementation of health impact assessment (HIA) and further integration of health in environmental assessments (EAs). During the workshop in Ljubljana in June 2012, ways to enhance capacity in health in EAs across Slovenia were examined. The aim was for experts in health and environment to review their experience in impact assessments. Discussion focused on the following types of impact assessment: HIA; environmental impact assessment (EIA); and strategic environmental assessment (SEA). One of the key findings was that, even though capacity-building activities in HIA and different HIA pilot projects have already taken place in Slovenia, there still seem to be unmet needs in various government departments. Furthermore, there is a need to define clear roles and responsibilities between environment and health in regard to HIA and further integration of health into EAs.

Capacity Building in Environment and Health (CBEH) project: strengthening health in environmental assessments in Estonia: gap analysis and way forward

In the frame of a project on Capacity Building in Environment and Health (CBEH), co-funded by the European Commission, a workshop took place in June 2012 to review the specific capacity needs of Estonia in relation to: implementation of health impact assessment (HIA); further integration of health in environmental assessments (EAs); and use of methods for quantitative risk assessment in local assessments.HIA is a prospective process – it looks at the potential effects of policies, plans, programmes and projects on health. One of the drivers for looking into HIA and its implementation in Estonia was the occurrence of a number of fires in the area of the city of Kunda. This focus provided a platform to examine ways of working between environment and health, and to develop a programme for HIA at a country level.One of the key findings was the need to define clear roles and responsibilities between environment and health for the implementation of risk assessment and HIA. Consequently, the main outcome was a plan for the integration of health in EAs. Using information provided by participants on existing EA activities, one project was specifically identified as being useful to develop those needs.

Familial cortical myoclonus with a mutation in NOL3.

OBJECTIVE: Myoclonus is characterized by sudden, brief involuntary movements, and its presence is debilitating. We identified a family suffering from adult onset, cortical myoclonus without associated seizures. We performed clinical, electrophysiological, and genetic studies to define this phenotype. METHODS: A large, 4-generation family with a history of myoclonus underwent careful questioning, examination, and electrophysiological testing. Thirty-five family members donated blood samples for genetic analysis, which included single nucleotide polymorphism mapping, microsatellite linkage, targeted massively parallel sequencing, and Sanger sequencing. In silico and in vitro experiments were performed to investigate functional significance of the mutation. RESULTS: We identified 11 members of a Canadian Mennonite family suffering from adult onset, slowly progressive, disabling, multifocal myoclonus. Somatosensory evoked potentials indicated a cortical origin of the myoclonus. There were no associated seizures. Some severely affected individuals developed signs of progressive cerebellar ataxia of variable severity late in the course of their illness. The phenotype was inherited in an autosomal dominant fashion. We demonstrated linkage to chromosome 16q21-22.1. We then sequenced all coding sequence in the critical region, identifying only a single cosegregating, novel, nonsynonymous mutation, which resides in the gene NOL3. Furthermore, this mutation was found to alter post-translational modification of NOL3 protein in vitro. INTERPRETATION: We propose that familial cortical myoclonus is a novel movement disorder that may be caused by mutation in NOL3. Further investigation of the role of NOL3 in neuronal physiology may shed light on neuronal membrane hyperexcitability and pathophysiology of myoclonus and related disorders.

Acetylcholine receptor antibody positive generalized myasthenia gravis in association with primary biliary cirrhosis.

Primary Biliary Cirrhosis and Myasthenia Gravis are both autoimmune conditions, however, there are only rare case reports of their association. This is a case report of acetylcholine receptor antibody positive generalized myasthenia gravis in a female patient with antimitochondrial antibody positive, liver biopsy-confirmed primary biliary cirrhosis.

Galantamine inhibits beta-amyloid aggregation and cytotoxicity.

The ability of galantamine (Reminyl) to inhibit the aggregation and toxicity of the beta-amyloid peptide (Abeta) was investigated. Galantamine showed concentration-dependent inhibition of aggregation of both Abeta 1-40 and Abeta 1-42, as determined by an ELISA method. Electron microscope studies of Abeta 1-40 incubated in the presence of galantamine revealed fibrils that were disordered and clumped in appearance. MTT and lactate dehydrogenase assays, employing SH-SY5Y human neuroblastoma cells, showed that galantamine reduced the cytotoxicity induced by Abeta 1-40. Galantamine also dramatically reduced Abeta 1-40-induced cellular apoptosis in these cells. There is some evidence that galantamine may not be acting purely as a symptomatic treatment. Disease-modifying effects of the drug could be due to an additional effect on Abeta aggregation and/or toxicity.

Properties of neurotoxic peptides related to the Bri gene.

Familial British dementia, a rare autosomal dominant neurodegenerative disorder, shares features with Alzheimer's disease, including amyloid plaque deposits, neurofibrillary tangles, neuronal loss,progressive dementia, but clinically presents with additional physical defects [1,2]. A mutation in the termination codon of the BRI gene produces a BRI precursor protein 11 amino acids longer than the wild-type protein [3,4]. Mutant and wild-type precursor proteins both may undergo furin cleavage between residues 243 and 244, producing a peptide of 34 amino acids in the case of ABri and 23 amino acids long in the case of the wild type peptide. The ABri 4kDa peptide is the main component of the amyloid deposits found in familial British dementia brains. A decamer duplication in the 3- region of the BRI gene originates the peptide Adan that is associated with dementia in Familial Danish dementia (FDD), similar to BDD clinically, but with additional hearing and eyesight loss [5]. The resulting reading frame is extended to 277 amino acid residues, and cleavage by furin releases a peptide of 34 residues, which is identical to Abri and WT in its N-terminal 22-residues, but contains a distinct C-terminal 10 residues composed of mainly hydrophobic residues. Here we demonstrate that C-terminal extensions of Abri and Adan are required to elongate initially-formed dimers to neurotoxic soluble oligomers and fibrils. In contrast, the shorter wild-type peptide does not aggregate under the same conditions and is not toxic. Conformational analyses indicate triple-beta-sheet structures. Soluble nonfibrillar oligomers of oxidised ABri and reduced Adan were observed in solution (pH7.4) of peptides prior to the appearance of mature fibrils.

Induction of cellular oxidative stress by the beta-amyloid peptide involved in Alzheimer's disease.

Beta-amyloid, the 39-43 amino acid peptide fragment originating from amyloid precursor protein, is today, generally accepted as the biological entity responsible for causing the debilitating human disorder Alzheimer's disease. Understanding the exact biological effects of beta-amyloid in vitro and in vivo is clearly important to provide therapeutic strategies for the disease. Recent in vitro studies have focused on the production of reactive oxygen species by aggregating beta-amyloid, but the cellular effects of beta-amyloid induced reactive oxygen species production have not been fully elucidated.

Both the D-(+) and L-(-) enantiomers of nicotine inhibit Abeta aggregation and cytotoxicity.

The underlying cause of Alzheimer's disease is thought to be the aggregation of monomeric beta-amyloid (Abeta), through a series of toxic oligomers, which forms the mature amyloid fibrils that accumulate at the center of senile plaques. It has been reported that L-(-)-nicotine prevents Abeta aggregation and toxicity, and inhibits senile plaque formation. Previous NMR studies have suggested that this could be due to the specific binding of L-(-)-nicotine to histidine residues (His6, His13, and His14) in the peptide. Here, we have looked at the effects of both of the L-(-) and D-(+) optical enantiomers of nicotine on the aggregation and cytotoxicity of Abeta(1-40). Surprisingly, both enantiomers inhibited aggregation of the peptide and reduced the toxic effects of the peptide on cells. In NMR studies with Abeta(1-40), both enantiomers of nicotine were seen to interact with the three histidine residues. Overall, our data indicate that nicotine can delay Abeta fibril formation and maintain a population of less toxic Abeta species. This effect cannot be due to a highly specific binding interaction between nicotine and Abeta, as previously thought, but could be due instead to weaker, relatively nonspecific binding, or to the antioxidant or metal chelating properties of nicotine. D-(+)-nicotine, being biologically much less active than L-(-)-nicotine, might be a useful therapeutic agent.

Oligomerization and neurotoxicity of the amyloid ADan peptide implicated in familial Danish dementia.

Familial Danish dementia (FDD) is a rare neurodegenerative disorder, which is pathologically characterized by widespread cerebral amyloid angiopathy, parenchymal protein deposits and neurofibrillary degeneration. FDD is associated with mutation in the BRI gene. In FDD a decamer duplication between codons 265 and 266 in the 3' region of the BRI gene originates an amyloid peptide named ADan, 11 residues longer than the wild-type peptide produced from the normal BRI gene. ADan deposits have been found widely distributed in the CNS of FDD cases. The deposits of ADan are predominantly non-fibrillar aggregates. We show here that synthetic ADan forms oligomers in vitro, seen by Tricine-PAGE and gel filtration, and higher aggregates, which are seen by atomic force spectroscopy and electron microscopy as carrot-shaped objects that bunch together. Here we report that oligomeric ADan is toxic to neuronal cell lines. We find that the soluble non-fibrillar oligomeric species of both the reduced and oxidized forms of ADan are toxic. These results support the idea that the non-fibrillar soluble aggregates are the pathogenic species, which may play a central role in the pathogenesis of FDD, and imply that similar mechanism may also be involved in other neurodegenerative diseases associated with amyloid deposits.

Use of a hemoglobin-based oxygen-carrying solution in cats: 72 cases (1998-2000).

OBJECTIVE: To determine clinical features and outcome associated with use of a hemoglobin-based oxygen-carrying (HBOC) solution in cats. DESIGN: Retrospective study. ANIMALS: 72 cats. PROCEDURE: Medical records of cats that received an HBOC solution were reviewed. RESULTS: The most common clinical signs and physical examination findings prior to infusion of the HBOC solution were associated with anemia; vomiting, neurologic signs, and respiratory abnormalities were also detected. The HBOC solution was given as a supportive measure in treatment of anemia in 70 cats, most often because compatible blood was not readily available. There were 80 separate HBOC solution infusion events (mean dose, 14.6 ml/kg [6.6 mg/lb]; mean rate of infusion, 4.8 ml/kg [2.2 ml/lb] per hour). Improvements in 37 of 43 of the more closely monitored cats included increased rectal temperature, blood hemoglobin concentration, blood pressure, appetite, and activity. Adverse events in 44 cats included pulmonary edema (n = 8), pleural effusion (21), mucous membrane discoloration (21), pigmenturia (11), vomiting (4), and neurologic abnormalities (4). Twenty-three cats were discharged from the hospital, and 49 cats died or were euthanatized. Necropsy examination of 23 cats did not reveal evidence of renal or hepatic toxicosis associated with HBOC administration. CONCLUSIONS AND CLINICAL RELEVANCE: Although administration of an HBOC solution may provide temporary support to anemic cats, the development of pulmonary edema or pleural effusion potentially associated with rapid infusion rate and large volume of infusion of the HBOC solution should be investigated further before use of the solution can be recommended in cats.

Factors associated with pregnancy or miscarriage after clomiphene therapy in WHO group II anovulatory women.

OBJECTIVES: The present study was designed to determine whether clinical and endocrine characteristics assessed on initial screening of normogonadotropic oligo/amenorrhoeic infertile patients could predict ovulation and then conception and successful live birth or miscarriage. STUDY DESIGN: Retrospective cohort study SETTING: Outpatient clinic. POPULATION: Eighty-two consecutive women receiving clomiphene citrate (CC) therapy from 1993 to 1998. RESULTS: A cumulative conception rate of 67% was reached after six or more CC-induced cycles. Patients with failure of ovulation after a full course of CC had more severe oligomenorrhoea (p < 0.001) and greater BMI (p < 0.05) at initial screening. There was no relationship with levels of LH or androgens. In contrast, among women who ovulated in response to CC, conception was associated with less frequent periods, and higher basal levels of LH, free testosterone and androstenedione. Conceptions with subsequent miscarriage were associated with intermediate levels of LH and numbers of spontaneous periods between non-conception and live births. CONCLUSIONS: These observations are consistent with the hypothesis that failure of ovulation after CC is related to different factors (overweight and severe oligomenorrhoea) from those that predispose to non-conception (low basal LH and androgen levels and mild oligomenorrhoea).