Water-saving strategies in the mining industry - The potential of mineral processing simulators as a tool for their implementation.

As the mining industry is facing an increasing number of issues related to its fresh water consumption, water-saving strategies are progressively being implemented in the mineral processing plants, often leading to variations in the process water chemistry. However, the impact of water chemistry variations on the process performance is rarely known beforehand, thus creating an obstacle to the implementation of those water-saving strategies. To tackle this problem, the effect the different dissolved species present in the process water have on the processing plant performance must be quantified, and this information must be digitalized in a practical and suitable form to be used in mineral processing simulators. To achieve this goal, a methodology to digitalize the influence of the process water composition on the flotation performance is presented in this paper. Using the flotation of a fluorite ore as case study, the relationship between process water composition and the flotation kinetics of that fluorite ore was determined. This relationship was digitalized in HSC Sim, a mineral processing simulator, turning it into a tool capable of simulating the flotation performance under a variety of process water compositions. Finally, the potential of this new tool to help implementing water-saving strategies on the mine site is discussed, and the challenges that need to be overcome in order to apply this tool at industrial scale are being addressed.

Cardiorespiratory fitness and risk of dementia: a prospective population-based cohort study.

Dementia is considered to be one of the major public health problems in light of the ageing population. Little is known about directly measured cardiorespiratory fitness as measured by maximal oxygen uptake and the risk of dementia. Our aim was to examine the relationship of cardiorespiratory fitness, as indicated by maximal oxygen uptake, with subsequent incidence of dementia. This was a population-based cohort study with an average follow-up of 22 (range 0.22-29.8) years from eastern Finland. About 2,031 men with a mean age of 52.8 years of age and no history of dementia or pulmonary disease at baseline participated in the study. Among these men, 208 cases of dementia occurred. Maximal oxygen uptake (ml/kg/min) was measured during exercise testing at baseline. One standard deviation increase in VO2max was associated with a 20% decrease in dementia. Cardiorespiratory fitness was inversely related to the risk of dementia. Men with low cardiorespiratory fitness (VO2max < 23.7 ml/kg/min, lowest quintile) had a 1.92-fold (1.24-2.967, P = 0.003), risk of dementia as compared with men who had high cardiorespiratory fitness (VO2max >36.5 ml/kg/min, highest quintile) after adjusting for age and examination years. In a multivariate model, low cardiorespiratory fitness was associated with a 1.95-fold (1.24-3.05, P = 0.003) risk of dementia. Our findings show that low cardiorespiratory fitness was associated with an increased risk of dementia.

Slowly progressive frontotemporal lobar degeneration caused by the C9ORF72 repeat expansion: a 20-year follow-up study.

A hexanucleotide expansion in chromosome 9 open-reading frame 72 (C9ORF72) has been found to be a major cause of frontotemporal lobar degeneration (FTLD). We describe a 20-year follow-up of a unique case with very slowly progressive FTLD caused by the C9ORF72 repeat expansion. In serial neuropsychological examinations, the patient's cognitive decline was exceptionally slow and after 20 years the patient still was mainly independent in activities of daily living. Our case indicates that there is great individual variation in the progression and duration of C9ORF72-associated FTLD, and also language variants or mixed phenotypes may be present.

Short-term rapamycin treatment increases life span and attenuates aortic aneurysm in a murine model of Marfan-Syndrome.

BACKGROUND: Marfan syndrome (MFS) is a genetic disorder leading to medial aortic degeneration and life-limiting dissections. To date, there is no causal prevention or therapy. Rapamycin is a potent and selective inhibitor of the mechanistic target of rapamycin (mTOR) protein kinase, regulating cell growth and metabolism. The mgR/mgR mice represent an accepted MFS model for studying aortic pathologies to understand the underlying molecular pathomechanisms. This study investigated whether rapamycin inhibits the development of thoracic aortic aneurysms and dissections in mgR/mgR mice. METHODS: Isolated primary aortic smooth muscle cells (mAoSMCs) from mgR/mgR mice were used for in vitro studies. Two mg kg/BW rapamycin was injected intraperitoneally daily for two weeks, beginning at 7-8 weeks of age. Mice were sacrificed 30 days post-treatment. Histopathological and immunofluorescence analyses were performed using adequate tissue specimens and techniques. Animal survival was evaluated accompanied by periodic echocardiographic examinations of the aorta. RESULTS: The protein level of the phosphorylated ribosomal protein S6 (p-RPS6), a downstream target of mTOR, was significantly increased in the aortic tissue of mgR/mgR mice. In mAoSMCs isolated from these animals, expression of mTOR, p-RPS6, tumour necrosis factor α, matrix metalloproteinase-2 and -9 was significantly suppressed by rapamycin, demonstrating its anti-inflammatory capacity. Short-term rapamycin treatment of Marfan mice was associated with delayed aneurysm formation, medial aortic elastolysis and improved survival. CONCLUSIONS: Short-term rapamycin-mediated mTOR inhibition significantly reduces aortic aneurysm formation and thus increases survival in mgR/mgR mice. Our results may offer the first causal treatment option to prevent aortic complications in MFS patients.

Increasing incidence of multiple sclerosis in women in Northern Finland.

BACKGROUND: The geographical distribution of multiple sclerosis (MS) means that prevalence rates increase with latitude north or south of the equator. Temporally, a tendency for increased incidences of MS has been observed over the past two decades. OBJECTIVES: Since epidemiological studies of MS in areas close to the Arctic Circle are rare, we evaluated the incidence and prevalence of MS in Northern Ostrobothnia by means of a retrospective cohort study covering the period 1992-2007. METHODS: Patients with a definite clinical diagnosis of MS based on the Poser criteria and the early McDonald criteria of 2001 were identified in the region of Northern Ostrobothnia (population 386,972) and the incidence was calculated at 1-year time intervals, both overall and by gender. RESULTS: The overall prevalence was 103/100,000 (95% CI, 93-113), with a female/male ratio of 2.17. The mean overall incidence was 6.3/100,000 (95% CI, 5.2-7.2). The incidence shows a tendency to increase over the 16-year period due to a pronounced rise in the female incidence. CONCLUSIONS: Our results show a high prevalence of MS in Northern Ostrobothnia and a disproportional increase in the female MS incidence. These recent epidemiological features may be associated with environmental risk factors such as a vitamin D deficit, low life-long UV radiation and the high-latitude geographical location.

Mutations in CHMP2B are not a cause of frontotemporal lobar degeneration in Finnish patients.

BACKGROUND: Frontotemporal lobar degeneration (FTLD) is a genetically complex disorder. The majority of mutations linked to FTLD families are found in the microtubule-associated protein tau (MAPT) and progranulin (PGRN) genes. Mutations in the chromatin-modifying protein 2B gene (CHMP2B) have been identified in a few families. However, CHMP2B has been showed to be a rare cause of FTLD. Our aim was to determine the frequency of CHMP2B mutations in a clinical series of patients with FTLD in Northern Finland. PATIENTS AND METHODS: We examined 72 (36 men) Finnish patients with FTLD. The mean age at onset was 58.9 (range 43­80). Symptoms of motor neuron disease (FTLDMND) were present in 12 patients (17%). Positive family history was detected in 28% of the patients. Mutations in MAPT and PGRN were excluded from these patients. All exons and exon­intron boundaries of the CHMP2B gene were sequenced. RESULTS: No pathogenic CHMP2B mutations were found. A rare polymorphism in the non-coding region of exon 1 (rs36098294) and three other previously reported polymorphisms were detected. CONCLUSIONS: Our results confirm that mutations in CHMP2B are not a common cause of FTLD. MAPT and PGRN mutations are also rare in Finnish population, suggesting that other, still unknown genetic factors may play a role in the pathogenesis of FTLD in Finnish population.

Gene transfer to the vascular system: Novel translational perspectives for vascular diseases.

Although vessels are directly exposed to the bloodstream, vascular gene transfer is rarely used as a tool for preclinical studies for several reasons: (i) viral and non-viral vectors show a low transduction efficiency in the vascular system; (ii) classical vascular gene therapy approaches such as treatment of peripheral or cardiac ischemia are focusing on non-vascular target cells; and (iii) vascular diseases are rarely monogenetic, thus gene replacement approaches are uncommon. Here, we provide an overview of recent approaches in developing novel vectors and modes of application for improved transduction efficiency of large and small vessels. Increased availability of such tools for vascular gene transfer has already facilitated preclinical studies addressing a broad variety of vascular diseases like transplant vasculopathy, atherosclerosis, and hereditary aortic diseases such as Marfan syndrome.

Low prevalence of progranulin mutations in Finnish patients with frontotemporal lobar degeneration.

BACKGROUND AND PURPOSE: Mutations in the progranulin (PGRN) gene have recently been associated with frontotemporal lobar degeneration (FTLD). The frequency of these mutations varies between populations. The aim of this study was to determine mutations and genetic variations of the PGRN gene in Finnish patients with FTLD and FTLD with associated motor neuron disease (FTLD-MND). SUBJECTS AND METHODS: All exons of the PGRN gene were sequenced from 69 Finnish patients with FTLD. The FTLD-MND phenotype was present in 13 of the 69 patients. RESULTS: No pathogenic PGRN mutations were identified in the cohort. Eleven sequence variations were detected, of which IVS8 + 15C>T, IVS4-51_-52insAGTC and IVS11 + 25G>A have not been reported previously. At least one single-nucleotide polymorphism (SNP) of PGRN was detected in 83% of patients. CONCLUSIONS: We conclude that mutations in PGRN are rare among Finnish patients with FTLD and FTLD-MND. However, SNPs were frequent suggesting high genetic variability of the PGRN gene.

Marfan syndrome: A therapeutic challenge for long-term care.

Marfan syndrome (MFS) is an autosomal dominant genetic disorder caused by mutations in the fibrillin-1 gene. Acute aortic dissection is the leading cause of death in patients suffering from MFS and consequence of medial degeneration and aneurysm formation. In addition to its structural function in the formation of elastic fibers, fibrillin has a major role in keeping maintaining transforming growth factor ß (TGF-ß) in an inactive form. Dysfunctional fibrillin increases TGF-ß bioavailability and concentration in the extracellular matrix, leading to activation of proinflammatory transcription factors. In turn, these events cause increased expression of matrix metalloproteinases and cytokines that control the migration and infiltration of inflammatory cells into the aorta. Moreover, TGF-ß causes accumulation of reactive oxygen species leading to further degradation of elastin fibers. All these processes result in medial elastolysis, which increases the risk of vascular complications. Although MFS is a hereditary disease, symptoms and traits are usually not noticeable at birth. During childhood or adolescence affected individuals present with severe tissue weaknesses, especially in the aorta, heart, eyes, and skeleton. Considering this, even young patients should avoid activities that exert additional stress and pressure on the aorta and the cardiovascular system. Thus, if the diagnosis is made and prophylactic treatment is initiated in a timely fashion, MFS and its preliminary pathophysiologic vascular remodeling can be successfully ameliorated reducing the risk of life-threatening complications. This commentary focuses on new research opportunities and molecular findings on MFS, discusses future challenges and possible long-term therapies.

Parkinsonism associated with the homozygous W748S mutation in the POLG1 gene.

Parkinsonism has been described in patients with mutations in POLG1 gene. The W748S mutation is one of the most common mutations in this gene and it has been found to be a frequent cause of autosomal recessive ataxia in adults and the Alpers syndrome in children. We found the W748S mutation in a 65-year-old man with a late-onset syndrome consisting of ataxia, parkinsonism, ophthalmoplegia, peripheral neuropathy, and sensorineural hearing loss. Parkinsonism is one of the phenotypic features associated also with the W748S mutation.

Frontotemporal dementia as a comorbidity to idiopathic normal pressure hydrocephalus (iNPH): a short review of literature and an unusual case.

Behavioural variant frontotemporal dementia (bvFTD) and idiopathic normal pressure hydrocephalus (iNPH) are neurodegenerative diseases that can present with similar symptoms. These include decline in executive functions, psychomotor slowness, and behavioural and personality changes. Ventricular enlargement is a key radiological finding in iNPH that may also be present in bvFTD caused by the C9ORF72 expansion mutation. Due to this, bvFTD has been hypothesized as a potential comorbidity to iNPH but bvFTD patients have never been identified in studies focusing in clinical comorbidities with iNPH. Here we describe a patient with the C9ORF72 expansion-associated bvFTD who also showed enlarged ventricles on brain imaging. The main clinical symptoms were severe gait disturbances and psychiatric problems with mild cognitive decline. Cerebrospinal fluid removal increased the patient's walking speed, so a ventriculoperitoneal shunt was placed. After insertion of the shunt, there was a significant improvement in walking speed as well as mild improvement in cognitive function but not in neuropsychiatric symptoms relating to bvFTD. Comorbid iNPH should be considered in bvFTD patients who have enlarged ventricles and severely impaired gait.

Mitochondrial DNA deletions in dilated cardiomyopathy: a clinical study employing endomyocardial sampling.

OBJECTIVES: The aim of this study was to assess the occurrence of the two most commonly encountered mitochondrial DNA (mtDNA) deletions in the hearts of patients with idiopathic dilated cardiomyopathy. BACKGROUND: The mutation frequency of mtDNA is high, and sporadic cases of cardiomyopathies associated with mtDNA deletions have been described. Reports of increases in mtDNA deletions with advancing age also exist. METHODS: We studied 15 consecutive patients with typical signs of idiopathic dilated cardiomyopathy, without a family history, together with 16 control hearts obtained at autopsy from patients who died of noncardiac causes. The patients underwent both right and left heart catheterization, during which endomyocardial biopsy samples were taken. The mtDNA in these samples and in the control hearts was analyzed by the polymerase chain reaction technique for the occurrence and proportion of 5- and 7.4-kilobase (kb) deletions (Cambridge sequence map positions from nucleotides 8469 to 13447 and 8637 to 16084, respectively). RESULTS: The 5-kb mtDNA deletion was observed in the hearts of all of the patients with idiopathic dilated cardiomyopathy, accounting for 0.32 +/- 0.05% (mean +/- SEM) of the total mtDNA. The 7.4-kb deletion was found in 7 of the 15 patients with idiopathic dilated cardiomyopathy and comprised 0.28 +/- 0.08% of the total. The 5- and 7.4-kb deletions were detected in 12 and 9 control hearts, respectively, quantitatively similar to the patients with idiopathic dilated cardiomyopathy. A sigmoidal age dependency of the mtDNA deletions was found both in the patients with cardiomyopathy and in the control hearts, but after elimination of the confounding age variable, there was no difference between these groups. CONCLUSIONS: Because of the similarity of the age-dependent increase in the frequency of mtDNA deletions in cardiomyopathic and control hearts, the deletions have no causal relation with idiopathic dilated cardiomyopathy. The present results confirm the notion of an increase in mtDNA deletions with advancing age and show that endomyocardial tissue sampling is a feasible method for detecting mtDNA defects in affected hearts.

Adult-onset diabetes mellitus and neurosensory hearing loss in maternal relatives of MELAS patients in a family with the tRNA(Leu(UUR)) mutation.

We describe a family with three cases of "clinically incomplete mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS) syndrome" in which heteroplasmic tRNA(Leu(UUR)) mutation at nucleotide 3243 of the mitochondrial DNA was present in three generations. The amount of mutant genome varied among tissues: it was 60% in the kidney, 72% in the cardiac muscle, and 91% in the liver of the female proband's affected brother and 63% in the kidney, 71% in the cardiac muscle, and 71% in the liver of the female proband's perinatally deceased son. The tRNA(Leu(UUR)) mutation was also carried by the siblings of the proband's affected mother. None of them had any clinical signs of MELAS syndrome. This syndrome has the new feature of being associated with adult-onset diabetes mellitus, neurosensory hearing loss, and short stature.

Demyelinating polyneuropathy in a patient with the tRNA(Leu)(UUR) mutation at base pair 3243 of the mitochondrial DNA.

A novel feature of demyelinating polyneuropathy was observed in a patient with the tRNA(Leu(UUR)) mutation at base pair 3243 of the mitochondrial DNA. Based on electrodiagnostic examination, the polyneuropathy was defined as being of the demyelinating, mixed (motor more than sensory) type. In a 1-year follow-up we observed approximately 7% reduction in both the motor and sensory conduction velocities. The other clinical features of the proband included a mild to moderate cognitive impairment and a combined hearing loss with a moderate sensorineural component. The proportion of the mutant genome found in the muscle of the proband was 29%, but the mutation was not found in his blood. A wide variability of the clinical phenotype was observed in the family of the proband. Heteroplasmic mutation was detected in the blood of most family members. The proportion of abnormal mitochondrial DNA was highest in the proband's brother, who had clinically definite mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, while the mutant genome was less frequent or absent in the subjects with less severe phenotypes and in healthy individuals. The findings on this pedigree emphasize the need for studies of complete families in the search for new clinical phenotypes of mutations in mitochondrial DNA.

Ubiquinone and nicotinamide treatment of patients with the 3243A-->G mtDNA mutation.

The efficacy and safety of ubiquinone (Q10) and nicotinamide were evaluated in a 6-month open-label trial in patients with the 3243A-->G mitochondrial DNA mutation. Blood lactate and pyruvate concentrations decreased, but there was little clinical improvement. Q10 and nicotinamide were well tolerated, but two patients died suddenly and unexpectedly during the trial. These deaths may have been unrelated to treatment. The unpredictable course of the disease makes evaluation of the clinical response difficult.

Fumarase deficiency: two siblings with enlarged cerebral ventricles and polyhydramnios in utero.

A family having two boys with progressive encephalomyopathy and fumaric aciduria due to fumarase deficiency is described. Both patients initially presented with polyhydramnios and enlarged cerebral ventricles in utero, with subsequent cerebral atrophy, severe developmental delay, infantile spasms, and hypsarythmia on electroencephalogram. Fumarase activity in blood mononuclear cells and in the mitochondrial and cytosolic fractions of cultured skin fibroblasts was less than 0.5% of the control mean or undetectable. The older boy died at the age of 5 years and 4 months and the younger one is now 2 years and 10 months. The unrelated parents are symptomless and the other three children in the family are clinically healthy. Fumarase activities in the blood mononuclear cells of the father, mother, sister, and two brothers were 59%, 52%, 52%, 120%, and 44% of the control mean, respectively. The results strongly support autosomal recessive inheritance of fumarase deficiency and suggest its consideration in children with congenital hydrocephalus, progressive brain atrophy, and infantile spasms.

Childhood encephalopathies and myopathies: a prospective study in a defined population to assess the frequency of mitochondrial disorders.

OBJECTIVES: To assess the frequency of mitochondrial abnormalities in muscle histology, defects in respiratory chain enzyme activities, and mutations in mitochondrial DNA (mtDNA) in children with unexplained psychomotor retardation in the population of Northern Finland. BACKGROUND: The frequency of mitochondrial diseases among patients with childhood encephalopathies and myopathies is not known. Frequencies are difficult to estimate because the clinical presentation of these disorders is variable. METHODS: A total of 116 consecutive patients with undefined encephalopathies and myopathies were enrolled during a 7-year period in a hospital serving as the only neurologic unit for a pediatric population of 97 609 and as the only tertiary level neurologic unit for a pediatric population of 48 873. Biochemical and morphologic investigations were performed on muscle biopsy material, including oximetric and spectrophotometric analyses of oxidative phosphorylation, histochemistry, electron microscopy, and molecular analysis of mtDNA. RESULTS: Ultrastructural changes in the mitochondria were the most common finding in the muscle biopsies (71%). Ragged-red fibers were found in 4 cases. An oxidative phosphorylation defect was found in 26 children (28%), complex I (n = 15) and complex IV (n = 13) defects being the most common. Fifteen percent of patients (n = 17/116) with unexplained encephalomyopathy or myopathy had a probable mitochondrial disease. Common pathogenic mutations were found in the mtDNA of only 1 patient (.9%). CONCLUSIONS: The common known mutations in mtDNA are rarely causes of childhood encephalomyopathies, which is in contrast to the considerable frequency of the common MELAS mutation observed among adults in the same geographical area. Biochemically and morphologically verified mitochondrial disorders were nevertheless common among the children, making the analysis of a muscle biopsy very important for clinical diagnostic purposes.

Neutrophil polarization and immunoelectrophoresis assays in the study of complement activation by biomaterials.

The neutrophil polarization assay, a technique used to measure chemotaxis, was adapted to examine complement activation. Complement activation in serum which had been incubated with metallic and polymeric biomaterials was examined using the neutrophil polarization assay and immunoelectrophoresis assay. In agreement with previous publications, nylon activated the complement cascade, but PTFE did not. The neutrophil polarization assay was found to be the most sensitive technique for examining complement activation by endotoxin but the immunoelectrophoresis assay is the technique most sensitive for detecting complement activation by cobalt powder. In both assays, complement activation was not detected in serum incubated with chromium powder. However, serum incubated with silver and nickel powder stimulated neutrophils to polarize indicating that these powders may activate complement.

Relationship between chemotaxis and complement activation by ceramic biomaterials.

This paper examines the relationship between complement activation by ceramic biomaterials and chemotaxis. Complement activation was examined by both neutrophil polarization (a technique which has previously been used to examine chemotaxis) and immunoelectrophoresis assays. The results suggest that at increasing serum concentrations of both calcium hydrogen phosphate and coral (calcium carbonate) powder, the quantity of C3 activation increased, as did the quantity of serum-derived chemotactic factors. In the case of tricalcium phosphate powder, the quantity of C3 activation and the neutrophil polarization response to serum were similar for serum levels between 20 and 80 mg/ml. Complement C3 was not activated in serum incubated with calcium hydrogen phosphate powder and serum incubated with this material was not chemotactic for neutrophils.

Immune response in biocompatibility.

Biocompatibility is concerned with the interactions that occur between biomaterials and host tissues. As foreign objects in that host tissue these materials may initiate several types of response. It has often been postulated that the immune response, by which the host normally defends itself against invasion by foreign organisms, can be involved in the response to biomaterials. This review discusses the mechanisms by which this could occur and the evidence that suggests the immune response is indeed of significance in biocompatibility.