Uterine transplantation: legal and regulatory implications in England.

Uterus transplantation (UTx) is fast evolving from an experimental to a clinical procedure, combining solid organ transplantation with assisted reproductive technology. The commencement of the first human uterus transplant trial in the United Kingdom leads us to examine and reflect upon the legal and regulatory aspects closely intertwined with UTx from the process of donation to potential implications for fertility treatment and the birth of the resultant child. As the world's first ephemeral transplant, the possibility of organ restitution requires consideration and is discussed herein. TWEETABLE ABSTRACT: Uterine transplantation warrants a closer look at the legal frameworks on fertility treatment and transplantation in England.

In vitro and in vivo anticancer effects of mevalonate pathway modulation on human cancer cells.

BACKGROUND: The increasing usage of statins (the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) has revealed a number of unexpected beneficial effects, including a reduction in cancer risk. METHODS: We investigated the direct anticancer effects of different statins approved for clinical use on human breast and brain cancer cells. We also explored the effects of statins on cancer cells using in silico simulations. RESULTS: In vitro studies showed that cerivastatin, pitavastatin, and fluvastatin were the most potent anti-proliferative, autophagy inducing agents in human cancer cells including stem cell-like primary glioblastoma cell lines. Consistently, pitavastatin was more effective than fluvastatin in inhibiting U87 tumour growth in vivo. Intraperitoneal injection was much better than oral administration in delaying glioblastoma growth. Following statin treatment, tumour cells were rescued by adding mevalonate and geranylgeranyl pyrophosphate. Knockdown of geranylgeranyl pyrophosphate synthetase-1 also induced strong cell autophagy and cell death in vitro and reduced U87 tumour growth in vivo. These data demonstrate that statins main effect is via targeting the mevalonate synthesis pathway in tumour cells. CONCLUSIONS: Our study demonstrates the potent anticancer effects of statins. These safe and well-tolerated drugs need to be further investigated as cancer chemotherapeutics in comprehensive clinical studies.

Effectiveness of a polyamide film releasing lactic acid on the growth of E. coli O157:H7, Enterobacteriaceae and Total Aerobic Count on vacuum-packed beef.

The suitability of a polyamide 6 monolayer film containing lactic acid for use as an antimicrobial package for fresh beef cuts was studied. The release of lactic acid in an aqueous environment was immediate (within 1h) and was from approx. 55 µg lactic acid/cm(2) film at 0-8°C to approx. 67 µg lactic acid/cm(2) film at 12-20°C. Beef was contaminated with an Escherichia coli O157:H7 isolate with known minimum inhibitory concentration against lactic acid (0.09% v/v), then wrapped with the lactic-acid polyamide film and vacuum packaged. During storage at 12°C, the numbers of E. coli were 1 log unit lower than that of a control (untreated polyamide film) and decreased by an additional 1 log during storage for 14 days.

Dynamic modeling of α-synuclein aggregation in dopaminergic neuronal system indicates points of neuroprotective intervention: experimental validation with implications for Parkinson's therapy.

Protein aggregation is the major pathological hallmark seen in neurodegenerative disorders such as Parkinson's disease (PD). Alpha-synuclein (αS) is the main component of protein aggregates that form Lewy bodies (LBs) in PD and dementia with LBs. There have been several attempts to intervene in the process of expression, modification, clearance, and aggregation of αS as a therapeutic strategy toward neuroprotection. In this study, we have employed a novel, predictive, system level approach in silico to study four different strategies of anti-aggregation therapies: (a) reduction in αS modifications such as phosphorylation, nitration, or truncation in an approach called "seed clearance;" (b) "anti-oligomerization" approach through blocking the early oligomers formation; (c) "oligomers clearance" process by increasing its lysosomal degradation; and (d) "anti-aggregation" that involves prevention of aggregate formation at a later stage. These strategies were tested in a virtual dopaminergic neuronal system triggered by overexpression (OE) of mutant αS-A53T with or without rotenone (Rot)-induced oxidative stress. The results were compared by analyzing markers related to various end points such as oxidative stress, dopamine (DA) metabolism, proteasome function, survival and apoptosis. The experimental system and anti-oligomerization strategies were recapitulated in vitro in M17 dopaminergic cells overexpressing mutant αS-A53T triggered with Cu(II)-mediated oxidative stress, and the experimental data prospectively corroborated with the predictive results. Through this analysis, we found that intervention in the early part of the aggregation pathway by prevention of oligomer formation and increased clearance is indeed a good neuroprotective strategy, whereas anti-aggregation efforts to break up the aggregate at later stages has negative effects on the system.

Quality traits of wild boar mould-ripened salami manufactured with different selections of meat and fat tissue, and with and without bacterial starter cultures.

Quality traits of wild boar mould-ripened salami were assessed in eight batches produced from two different assortments of meat (hind leg vs. shoulder), fat tissue (backfat from domestic pigs vs. fat tissue from wild boar), and with and without addition of a commercial bacterial starter culture. Chemical composition of finished products (day 35) were in compliance with national food codex. Batches produced with a bacterial starter culture were generally preferred by taste panels, had significantly lower concentrations of TBARS (<1.5 mgmalondialdehyde/kg) and peroxide values (POVs) and lower concentrations of cadaverine (<50 mg/kg), histamine (<10 mg/kg) and putrescine (<60 mg/kg). TBARS and POVs were inversely related to sensory preference scores (r(2)=0.84 and 0.88). Batches produced from shoulder muscles contained significantly higher concentrations of cadaverine, histamine and putrescine. TBARS were highest in batches manufactured with fat tissue from wild boars. These findings should be considered when guides to good practice for the manufacture of game meat products are developed.

Integrating glutathione metabolism and mitochondrial dysfunction with implications for Parkinson's disease: a dynamic model.

UNLABELLED: Oxidative/nitrosative stress and mitochondrial dysfunction have been implicated in the degeneration of dopaminergic neurons in the substantia nigra during Parkinson's disease (PD). During early stages of PD, there is a significant depletion of the thiol antioxidant glutathione (GSH), which may lead to oxidative stress, mitochondrial dysfunction, and ultimately neuronal cell death. Mitochondrial complex I (CI) is believed to be the central player to the mitochondrial dysfunction occurring in PD. We have generated a dynamic, mechanistic model for mitochondrial dysfunction associated with PD progression that is activated by rotenone, GSH depletion, increased nitric oxide and peroxynitrite. The potential insults independently inhibit CI and other complexes of the electron transport chain, drop the proton motive force, and reduce ATP production, ultimately affecting the overall mitochondrial performance. We show that mitochondrial dysfunction significantly affects glutathione synthesis thereby increasing the oxidative damage and further exacerbating the toxicities of these mitochondrial agents resulting in neurodegeneration. Rat dopaminergic neuronal cell culture and in vitro experiments using mouse brain mitochondria were employed to validate important features of the model. MAJOR CONCLUSIONS: Using a combination of experimental and in silico modeling approaches, we have demonstrated the interdependence of mitochondrial function with GSH metabolism in relation to neurodegeneration in PD.

Dynamic modeling of alpha-synuclein aggregation for the sporadic and genetic forms of Parkinson's disease.

Excessive accumulation of alpha synuclein (a-syn) in the brain has been implicated in several degenerative neurological disorders, most notably Parkinson's disease. The aggregation of a-syn is the major component of intraneuronal inclusions, Lewy bodies, which are neuropathological features, observed in Parkinson's disease, Lewy body dementia, and other synucleopathies. Diverse cellular events can contribute to a-syn accumulation, aggregation, and to subsequent Lewy body formation. These factors include genetic mutations of synuclein, parkin, or the deubiquitinating enzyme, ubiquitin C-terminal hydrolase (UCH-L1), leading to reduced clearance of a-syn by the ubiquitin proteasomal pathway (UPP). Furthermore, intracellular insults include environmental factors and an age-related decrement in antioxidant defense systems that increase oxidative stress and can affect either the accumulation or clearance of a-syn. We have dynamically modeled a-syn processing in normal and in several disease states; focusing upon alterations in the aggregation and clearance of a-syn as influenced by the UPP and the oxidative stress pathways. Simulation of increased oxidative stress generates a free radical profile analogous to that reported in vivo following exposure to the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Varying model parameters of oxidative stress, UPP dysfunction, or both pathways, simulate kinetics of a-syn that corresponds with the neuropathology described for the sporadic and genetic forms of Parkinson's disease. This in silico model provides a mathematical framework that enables kinetic appraisal of pathway components to better identify and validate important pharmacological targets.

Molecular pathogenesis of oral submucous fibrosis--a collagen metabolic disorder.

Oral submucous fibrosis (OSF) is a chronic debilitating disease and a premalignant condition of the oral cavity. It is characterized by a generalized submucosal fibrosis. The pathogenesis of the disease is not well established. Epidemiological evidences strongly indicate the association of the betel quid (BQ) habit and OSF. Various findings indicate the disease to be a consequence of disturbances in the homeostatic equilibrium between synthesis and degradation of extracellular matrix (ECM), wherein collagen forms a major component, thus can be considered as a collagen-metabolic disorder. Transforming growth factor-beta (TGF-beta) is a potent stimulator of production and deposition of the ECM. The objectives of this review are to highlight the molecular events involved in the overproduction of insoluble collagen and decreased degradation of collagen occurring via exposure to BQ and stimulation of the TGF-beta pathway, and elucidate the cell signaling that is involved in the etiopathogenesis of the disease process.

Role of the sarcoplasmic reticulum in regulating the activity-dependent expression of the glycogen phosphorylase gene in contractile skeletal muscle cells.

Nerve-evoked contractile activity in skeletal muscle regulates transcript and protein levels of many metabolic genes in a coordinate fashion, including the muscle isozyme of glycogen phosphorylase (MGP). Cellular signaling mechanisms mediating the activity-dependent modulation of MGP transcript levels were investigated in a spontaneously contractile rat skeletal muscle cell line (Rmo). Mechanisms regulating MGP mRNA levels in Rmo myotubes were compared with those previously shown to modulate the gene encoding the alpha subunit of the acetylcholine receptor (alphaAChR). Reducing the resting membrane potential from -78 to -30 mV, either electrochemically (KCl) or by increasing Na(+) permeability (veratridine): (1) prevented activation of transverse tubules, (2) impeded calcium release by the sarcoplasmic reticulum (SR), and (3) blocked Rmo contractility. MGP mRNA levels decreased to 30% of control levels and alphaAChR levels increased to 350% following 24 h of depolarization. Differing mechanisms appear to mediate this voltage-dependent regulation of MGP and alphaAChR. Inhibition of SR calcium efflux selectively decreased MGP mRNA levels by 30-50% when using dantrolene, thapsigargin, or a dose of ryanodine shown to inactivate Ca(2+)-induced SR Ca(2+) release (CICR). By contrast, blockade of voltage sensors in transverse tubules with nifedipine, a dihydroaminopyridine (DHAP) antagonist, selectively increased alphaAChR mRNA levels by twofold. These data indicate that the voltage-dependent regulation of AChR gene expression differs from that modulating the MGP gene. KCl-induced depolarization and dantrolene both inhibit pulsatile SR Ca(2+) efflux in Rmo myotubes, but by differing mechanisms. Depolarization and dantrolene comparably reduced MGP mRNA levels and decreased MGP transcript stability from a t(1/2) of 24 h to 14.5 and 16 h, respectively. Reduced transcript stability can account for the observed reduction in mRNA levels of MGP in noncontractile Rmo myotubes and could be a significant regulatory mechanism in skeletal muscle that coordinates the activity-dependent expression of MGP with other glycogenolytic genes.

Anthropometric and clinical nutrition status of workers in some Indian factories.

Anthropometric and clinical nutritional status of 195 male factory workers was assessed in Nainital, North India. Relationships between anthropometry and clinical scores and between nutritional status and either education or income were evaluated. Mean ± standard deviation values were: height 161.3 ± 6.0 cm, weight 52.7± 7.6 kg, BMI 20.2 ± 2.4 and MUAC 24.0 ± 2.3 cm. For BMI, 57% of the subjects were below 20, a value below which FAO predicts that there will be increased risk of work performance. Values corresponding to chronic energy undernutrition (below 18.5 BMI) were found in about 20% of workers. Clinical signs of nutritional deficiencies were found to be 10.76% for vitamin B complex, 2.05% for ascorbic acid and 2.05% for iron. Clinical scores and anthropometric values were negatively correlated with each other, indicating that clinical signs of nutritional deficiencies increased with decreasing anthropometric values. Education and per capita income appeared to have a positive influence on nutritional status.