Effective interventions in preventing gestational diabetes mellitus: A systematic review and meta-analysis.

BACKGROUND: Lifestyle choices, metformin, and dietary supplements may prevent GDM, but the effect of intervention characteristics has not been identified. This review evaluated intervention characteristics to inform the implementation of GDM prevention interventions. METHODS: Ovid, MEDLINE/PubMed, and EMBASE databases were searched. The Template for Intervention Description and Replication (TIDieR) framework was used to examine intervention characteristics (who, what, when, where, and how). Subgroup analysis was performed by intervention characteristics. RESULTS: 116 studies involving 40,940 participants are included. Group-based physical activity interventions (RR 0.66; 95% CI 0.46, 0.95) reduce the incidence of GDM compared with individual or mixed (individual and group) delivery format (subgroup p-value = 0.04). Physical activity interventions delivered at healthcare facilities reduce the risk of GDM (RR 0.59; 95% CI 0.49, 0.72) compared with home-based interventions (subgroup p-value = 0.03). No other intervention characteristics impact the effectiveness of all other interventions. CONCLUSIONS: Dietary, physical activity, diet plus physical activity, metformin, and myoinositol interventions reduce the incidence of GDM compared with control interventions. Group and healthcare facility-based physical activity interventions show better effectiveness in preventing GDM than individual and community-based interventions. Other intervention characteristics (e.g. utilization of e-health) don't impact the effectiveness of lifestyle interventions, and thus, interventions may require consideration of the local context.

The effect of any given intervention to prevent gestational diabetes (high blood sugar levels that arise during pregnancy) may depend on the way it is delivered (how, when, what, etc). This study reviewed published literature to investigate if the effects of interventions (diet, exercise, metformin, probiotics, myoinositol) to prevent gestational diabetes differ according to the way it is being delivered (e.g., online vs in-person, by health professionals or others, etc.). Exercise delivered to group settings, or those delivered at a healthcare facility worked better to prevent gestational diabetes. Although we did not observe any differences with other delivery characteristics (e.g., online vs in-person), it does not mean they are always equally effective, it is important to consider individual situations when prescribing or developing interventions.

Participant characteristics in the prevention of gestational diabetes as evidence for precision medicine: a systematic review and meta-analysis.

BACKGROUND: Precision prevention involves using the unique characteristics of a particular group to determine their responses to preventive interventions. This study aimed to systematically evaluate the participant characteristics associated with responses to interventions in gestational diabetes mellitus (GDM) prevention. METHODS: We searched MEDLINE, EMBASE, and Pubmed to identify lifestyle (diet, physical activity, or both), metformin, myoinositol/inositol and probiotics interventions of GDM prevention published up to May 24, 2022. RESULTS: From 10347 studies, 116 studies (n = 40940 women) are included. Physical activity results in greater GDM reduction in participants with a normal body mass index (BMI) at baseline compared to obese BMI (risk ratio, 95% confidence interval: 0.06 [0.03, 0.14] vs 0.68 [0.26, 1.60]). Combined diet and physical activity interventions result in greater GDM reduction in participants without polycystic ovary syndrome (PCOS) than those with PCOS (0.62 [0.47, 0.82] vs 1.12 [0.78-1.61]) and in those without a history of GDM than those with unspecified GDM history (0.62 [0.47, 0.81] vs 0.85 [0.76, 0.95]). Metformin interventions are more effective in participants with PCOS than those with unspecified status (0.38 [0.19, 0.74] vs 0.59 [0.25, 1.43]), or when commenced preconception than during pregnancy (0.21 [0.11, 0.40] vs 1.15 [0.86-1.55]). Parity, history of having a large-for-gestational-age infant or family history of diabetes have no effect on intervention responses. CONCLUSIONS: GDM prevention through metformin or lifestyle differs according to some individual characteristics. Future research should include trials commencing preconception and provide results disaggregated by a priori defined participant characteristics including social and environmental factors, clinical traits, and other novel risk factors to predict GDM prevention through interventions.

An individual's characteristics, such as medical, biochemical, social, and behavioural may affect their response to interventions aimed at preventing gestational diabetes, which occurs during pregnancy. Here, we evaluated the published literature on interventions such as diet, lifestyle, drug treatment and nutritional supplement and looked at which individual participant characteristics were associated with response to these interventions. Certain participant characteristics were associated with greater prevention of gestational diabetes through particular treatments. Some interventions were more effective when started prior to conception. Future studies should consider individual characteristics when assessing the effects of preventative measures.

Proteomic analysis in primary T cells reveals IL-7 alters T cell receptor thresholding via CYTIP/cytohesin/LFA-1 localisation and activation.

The ability of the cellular immune system to discriminate self from foreign antigens depends on the appropriate calibration of the T cell receptor (TCR) signalling threshold. The lymphocyte homeostatic cytokine interleukin 7 (IL-7) is known to affect TCR thresholding, but the molecular mechanism is not fully elucidated. A better understanding of this process is highly relevant in the context of autoimmune disease therapy and cancer immunotherapy. We sought to characterise the early signalling events attributable to IL-7 priming; in particular, the altered phosphorylation of signal transduction proteins and their molecular localisation to the TCR. By integrating high-resolution proximity- phospho-proteomic and imaging approaches using primary T cells, rather than engineered cell lines or an in vitro expanded T cell population, we uncovered transduction events previously not linked to IL-7. We show that IL-7 leads to dephosphorylation of cytohesin interacting protein (CYTIP) at a hitherto undescribed phosphorylation site (pThr280) and alters the co-localisation of cytohesin-1 with the TCR and LFA-1 integrin. These results show that IL-7, acting via CYTIP and cytohesin-1, may impact TCR activation thresholds by enhancing the co-clustering of TCR and LFA-1 integrin.

The Ozaki Procedure With CardioCel Patch for Children and Young Adults With Aortic Valve Disease: Preliminary Experience - a Word of Caution.

BACKGROUND: The Ozaki procedure is a surgical technique for patients with significant aortic stenosis or regurgitation or both where valve repair cannot be performed. Individual cusps are cut from glutaraldehyde-treated autologous pericardium or bovine pericardium and implanted into the aortic valve position. Encouraging results have been reported within the adult population. There are limited published data on success of this procedure in younger patients. METHODS: We present a series of five children and young adults who underwent the Ozaki procedure with neoaortic valve cusps made from CardioCel, a decellularized bovine pericardial patch treated with a monomeric glutaraldehyde. RESULTS: There were no complications in the initial postoperative period and short inpatient stay. At a mean follow-up of 29.6 months (range: 22-36 months), 4 patients had no evidence of stenosis and 3 patients had trivial or no regurgitation from the neoaortic valve. Overall, two patients had complications related to the valve and underwent reintervention during the follow-up period with a Ross procedure. One of these patients who was not taking long-term anticoagulation experienced a transient ischemic attack. CONCLUSIONS: Our experience demonstrates that the Ozaki procedure with CardioCel in pediatric and young adult patients should be approached with caution. Further research with larger groups of pediatric patients, comparison of different graft materials, and longer follow-up is required to ascertain long-term success in children.

Development of a Commercial Process To Prepare AMG 232 Using a Green Ozonolysis-Pinnick Tandem Transformation.

A robust process to manufacture AMG 232 was developed to deliver drug substance of high purity. Highlights of the commercial process development efforts include the following: (i) use of a novel bench-stable Vilsmeier reagent, methoxymethylene- N, N-dimethyliminium methyl sulfate, for selective in situ activation of a primary alcohol intermediate; (ii) use of a new crystalline and stable isopropyl calcium sulfinate reagent ensuring robust preparation of a sulfone intermediate; (iii) development of a safe ozonolysis process conducted in an aqueous solvent mixture in either batch or continuous manufacturing mode; and (iv) control of the drug substance purity by crystallization of a salt rejecting impurities effectively. The new process was demonstrated to afford the drug substance (99.9 LC area %) in 49.8% overall yield from starting material DLAC (1).

Climate change impacts on the conservation outlook of populations on the poleward periphery of species ranges: A case study of Canadian black-tailed prairie dogs (Cynomys ludovicianus).

Given climate change, species' climatically suitable habitats are increasingly expected to shift poleward. Some imperilled populations towards the poleward edge of their species' range might therefore conceivably benefit from climate change. Interactions between climate and population dynamics may be complex, however, with climate exerting effects both indirectly via influence over food availability and more directly, via effects on physiology and its implications for survival and reproduction. A thorough understanding of these interactions is critical for effective conservation management. We therefore examine the relationship between climate, survival and reproduction in Canadian black-tailed prairie dogs, a threatened keystone species in an imperilled ecosystem at the northern edge of the species' range. Our analyses considered 8 years of annual mark-recapture data (2007-2014) in relation to growing degree days, precipitation, drought status and winter severity, as well as year, sex, age and body mass. Survival was strongly influenced by the interaction of drought and body mass class, and winter temperature severity. Female reproductive status was associated with the interaction of growing degree days and growing season precipitation, with spring precipitation and with winter temperature severity. Results related to body mass suggested that climatic variables exerted their effects via regulation of food availability with potential linked effects of food quality, immunological and behavioural implications, and predation risk. Predictions of future increases in drought conditions in North America's grassland ecosystems have raised concerns for the outlook of Canadian black-tailed prairie dogs. Insights gained from the analyses, however, point to mitigating species management options targeted at decoupling the mechanisms by which climate exerts its negative influence. Our approach highlights the importance of understanding the interaction between climate and population dynamics in peripheral populations whose viability might ultimately determine their species' ability to track climatically suitable space.

1,1'-Carbonyldiimidazole (CDI) Mediated Coupling and Cyclization To Generate [1,2,4]Triazolo[4,3-a]pyridines.

An operationally efficient CDI mediated tandem coupling and cyclization reaction to generate [1,2,4]triazolo[4,3-a]pyridines has been reported. The reaction conditions and scope were investigated, and the methodology was demonstrated in batch mode as well as in a continuous process.

A non-canonical ESCRT pathway, including histidine domain phosphotyrosine phosphatase (HD-PTP), is used for down-regulation of virally ubiquitinated MHC class I.

The Kaposi's sarcoma-associated herpes virus (KSHV) K3 viral gene product effectively down-regulates cell surface MHC class I. K3 is an E3 ubiquitin ligase that promotes Lys(63)-linked polyubiquitination of MHC class I, providing the signal for clathrin-mediated endocytosis. Endocytosis is followed by sorting into the intralumenal vesicles (ILVs) of multivesicular bodies (MVBs) and eventual delivery to lysosomes. The sorting of MHC class I into MVBs requires many individual proteins of the four endosomal sorting complexes required for transport (ESCRTs). In HeLa cells expressing the KSHV K3 ubiquitin ligase, the effect of RNAi-mediated depletion of individual proteins of the ESCRT-0 and ESCRT-I complexes and three ESCRT-III proteins showed that these are required to down-regulate MHC class I. However, depletion of proteins of the ESCRT-II complex or of the ESCRT-III protein, VPS20 (vacuolar protein sorting 20)/CHMP6 (charged MVB protein 6), failed to prevent the loss of MHC class I from the cell surface. Depletion of histidine domain phosphotyrosine phosphatase (HD-PTP) resulted in an increase in the cell surface concentration of MHC class I in HeLa cells expressing the KSHV K3 ubiquitin ligase. Rescue experiments with wild-type (WT) and mutant HD-PTP supported the conclusion that HD-PTP acts as an alternative to ESCRT-II and VPS20/CHMP6 as a link between the ESCRT-I and those ESCRT-III protein(s) necessary for ILV formation. Thus, the down-regulation of cell surface MHC class I, polyubiquitinated by the KSHV K3 ubiquitin ligase, does not employ the canonical ESCRT pathway, but instead utilizes an alternative pathway in which HD-PTP replaces ESCRT-II and VPS20/CHMP6.

Methoxetamine toxicity reported to the National Poisons Information Service: clinical characteristics and patterns of enquiries (including the period of the introduction of the UK's first Temporary Class Drug Order).

OBJECTIVE: To report the demographic and clinical characteristics of cases of methoxetamine toxicity reported to The National Poisons Information Service (NPIS) by healthcare professionals. To assess the pattern of enquiries from health professionals to the UK NPIS related to methoxetamine, including the period of the making of the UK first Temporary Class Drug Order (TCDO). METHODS: All telephone enquiries to and user sessions for TOXBASE, the NPIS on-line information resource, related to methoxetamine (and synonyms 'MXE', 'mket' and '2-(3-methoxyphenyl)-2-(ethylamino)cyclohexanone') were reviewed from 1 April 2010 to 1 August 2012. Data were compared for the 3 months before and after the TCDO. RESULTS: There were 47 telephone enquiries and 298 TOXBASE sessions regarding methoxetamine during the period of study. Comparing the 3 months before and after the TCDO, TOXBASE sessions for methoxetamine fell by 79% (from 151 to 32) and telephone enquiries by 80% (from 15 to 3). Clinical features reported by enquirers were consistent with case reports of analytically confirmed methoxetamine toxicity and typical toxidromes were of stimulant (36%), reduced consciousness (17%), dissociative (11%) and cerebellar (6.4%) types, but also particularly featured acute disturbances in mental heath (43%). CONCLUSIONS: Structured NPIS data may reveal trends in drugs of abuse use and toxicity when interpreted within their limitations. Since April 2012, there have been fewer enquiries to NPIS from clinicians, indicating reduced presentations with suspected methoxetamine toxicity to healthcare services. It is unclear if this is related to the TCDO made on 5 April 2012.

Development of a mouse model mimicking key aspects of a viral asthma exacerbation.

Viral respiratory tract infections are known triggers of asthma exacerbations in both adults and children. The current standard of care, inhaled CS (corticosteroids) and LABAs (long-acting ß2-adrenoceptor agonists), fails to prevent the loss of control that manifests as an exacerbation. In order to better understand the mechanisms underlying viral asthma exacerbations we established an in vivo model using the clinically relevant aeroallergen HDM (house dust mite) and the viral mimetic/TLR3 (Toll-like receptor 3) agonist poly(I:C). Poly(I:C) alone induced a similar neutrophilic inflammatory profile in the BAL (bronchoalveolar lavage) to that of HRV1b (human rhinovirus 1b) alone, accompanied by both elevated BAL KC (keratinocyte-derived chemokine) and IL-1ß (interleukin-1ß). When mice allergic to HDM were also challenged with poly(I:C) the neutrophilic inflammatory profile was exacerbated. Increased CD8(+) T-cell numbers, increased CD4(+) and CD8(+) cell activation and elevated KC and IL-1ß were observed. No increases in Th2 cytokines or the eosinophil chemoattractant CCL11 [chemokine (C-C motif) ligand 11], above those induced by HDM alone, were observed. The poly(I:C)-exacerbated neutrophilia did not translate into changes in AHR (airways hyper-responsiveness), indicating that in this model inflammation and AHR are two mechanistically independent events. To test the clinical relevance of this model CS sensitivity was assessed using prednisone, a synthetic oral CS used to manage exacerbations in asthmatic patients already on maximal doses of inhaled CS. The increased neutrophils, and accompanying cytokines/chemokines KC and IL-1ß induced by poly(I:C) challenge of HDM-sensitized and challenged mice were insensitive to oral prednisone therapy. In summary we have described a CS-resistant mouse model mimicking the key aspects of viral asthma exacerbation using the clinically relevant aeroallergen HDM and the viral mimic poly(I:C). This model may provide better understanding of disease mechanisms underlying viral exacerbations and could be used to build early confidence in novel therapeutic axes targeting viral asthma exacerbations in Th2 asthmatics.

The role of interleukin-1 and interleukin-18 in pro-inflammatory and anti-viral responses to rhinovirus in primary bronchial epithelial cells.

Human Rhinovirus (HRV) is associated with acute exacerbations of chronic respiratory disease. In healthy individuals, innate viral recognition pathways trigger release of molecules with direct anti-viral activities and pro-inflammatory mediators which recruit immune cells to support viral clearance. Interleukin-1alpha (IL-1α), interleukin-1beta (IL-1ß) and interleukin-18 (IL-18) have critical roles in the establishment of neutrophilic inflammation, which is commonly seen in airways viral infection and thought to be detrimental in respiratory disease. We therefore investigated the roles of these molecules in HRV infection of primary human epithelial cells. We found that all three cytokines were released from infected epithelia. Release of these cytokines was not dependent on cell death, and only IL-1ß and IL-18 release was dependent on caspase-1 catalytic activity. Blockade of IL-1 but not IL-18 signaling inhibited up-regulation of pro-inflammatory mediators and neutrophil chemoattractants but had no effect on virus induced production of interferons and interferon-inducible genes, measured at both mRNA and protein level. Similar level of virus mRNA was detected with and without IL-1RI blockade. Hence IL-1 signaling, potentially involving both IL-1ß and IL-1α, downstream of viral recognition plays a key role in induction of pro-inflammatory signals and potentially in recruitment and activation of immune cells in response to viral infection instigated by the epithelial cells, whilst not participating in direct anti-viral responses.

S[+] Apomorphine is a CNS penetrating activator of the Nrf2-ARE pathway with activity in mouse and patient fibroblast models of amyotrophic lateral sclerosis.

Compelling evidence indicates that oxidative stress contributes to motor neuron injury in amyotrophic lateral sclerosis (ALS), but antioxidant therapies have not yet achieved therapeutic benefit in the clinic. The nuclear erythroid 2-related-factor 2 (Nrf2) transcription factor is a key regulator of an important neuroprotective response by driving the expression of multiple cytoprotective genes via its interaction with the antioxidant response element (ARE). Dysregulation of the Nrf2-ARE system has been identified in ALS models and human disease. Taking the Nrf2-ARE pathway as an attractive therapeutic target for neuroprotection in ALS, we aimed to identify CNS penetrating, small molecule activators of Nrf2-mediated transcription in a library of 2000 drugs and natural products. Compounds were screened extensively for Nrf2 activation, and antioxidant and neuroprotective properties in vitro. S[+]-Apomorphine, a receptor-inactive enantiomer of the clinically approved dopamine-receptor agonist (R[-]-apomorphine), was identified as a nontoxic Nrf2 activating molecule. In vivo S[+]-apomorphine demonstrated CNS penetrance, Nrf2 induction, and significant attenuation of motor dysfunction in the SOD1(G93A) transgenic mouse model of ALS. S[+]-apomorphine also reduced pathological oxidative stress and improved survival following an oxidative insult in fibroblasts from ALS patients. This molecule emerges as a promising candidate for evaluation as a potential neuroprotective agent in ALS patients in the clinic.

How nurses assess breakthrough cancer pain, and the impact of this pain on patients' daily lives--results of a European survey.

PURPOSE: To increase our knowledge of how nurses assess breakthrough cancer pain (BTCP); and whether they find it difficult to distinguish BTCP from background pain; how they estimate the impact of BTCP on patients' daily lives, and the factors that nurses consider to induce BTCP. Variations in their use of assessment tools and their ability to distinguish between different types of pain were also examined in terms of the number of years of oncology nursing experience and the practice in different countries. METHODS: In total, 1241 nurses (90% female) who care for patients with cancer, from 12 European countries, completed a survey questionnaire. KEY RESULTS: Half the sample had >9 years of experience in oncology nursing. Although 39% had no pain assessment tool to help them distinguish between types of pain, 95% of those who used a tool found it useful. Furthermore, 37% reported that they had problems distinguishing background pain from BTCP. Movement was identified as the factor that most commonly exacerbated BTCP across all countries. The nurses reported that BTCP greatly interfered with patients' everyday activities, and they rated the patients' enjoyment of life as most strongly affected. The use of tools and the ability to distinguish between different pains varied between European countries and with years of experience in oncology nursing. CONCLUSIONS: The nurses reported that BTCP greatly interfered with patients' lives, and many nurses had problems distinguishing between background pain and BTCP. Nurses require more knowledge about BTCP management, and guidelines should be developed for clinical use.

A European survey of oncology nurse breakthrough cancer pain practices.

PURPOSE OF THE RESEARCH: Breakthrough cancer pain (BTCP) is a prevalent type of pain in which the nurse can play an important role in improving patients' pain symptoms and overall well-being. Nurses' experience with BTCP (number of patients, and estimates of severity and frequency), the treatment of BTCP (pharmacological and nonpharmacological treatments normally used), ratings of the importance of treatment factors, and reasons given for not advising patients to take strong painkillers are presented in the present paper. METHODS AND SAMPLE: Nurses from 12 European countries, who cared for patients with cancer, took part in a survey. In total 1618 nurses were recruited and 1241 completed the survey questionnaire. KEY RESULTS: Almost 90% of the nurses were female, and 50.4% had >9 years of experience in oncology nursing. The majority of the nurses (47%) said that a patient typically suffered from BTCP 2-3 times a day, and the severity of the pain for the patients was described as severe by 75.5%. In all, 38.4% of the nurses were unaware that medications specifically intended for treatment of BTCP exist, and 57% reported that oral opioids were normally prescribed for BTCP at their workplace. While 38% said they did not use nonpharmacological treatments for BTCP, the most common treatment approach was positional change (used by 76.6%). The treatment varied between the European countries. CONCLUSION: Patients do not receive the appropriate medical treatment for their BTCP. Nurses need better training about BTCP in general, and BTCP assessment and management specifically.

A comparison of in vitro properties of resting SOD1 transgenic microglia reveals evidence of reduced neuroprotective function.

BACKGROUND: Overexpression of mutant copper/zinc superoxide dismutase (SOD1) in rodents has provided useful models for studying the pathogenesis of amyotrophic lateral sclerosis (ALS). Microglia have been shown to contribute to ALS disease progression in these models, although the mechanism of this contribution remains to be elucidated. Here, we present the first evidence of the effects of overexpression of mutant (TG G93A) and wild type (TG WT) human SOD1 transgenes on a set of functional properties of microglia relevant to ALS progression, including expression of integrin ß-1, spreading and migration, phagocytosis of apoptotic neuronal cell debris, and intracellular calcium changes in response to an inflammatory stimulus. RESULTS: TG SOD1 G93A but not TG SOD1 WT microglia had lower expression levels of the cell adhesion molecule subunit integrin ß-1 than their NTG control cells [NTG (G93A) and NTG (WT), respectively, 92.8 ± 2.8% on TG G93A, 92.0 ± 6.6% on TG WT, 100.0 ± 1.6% on NTG (G93A), and 100.0 ± 2.7% on NTG (WT) cells], resulting in decreased spreading ability, with no effect on ability to migrate. Both TG G93A and TG WT microglia had reduced capacity to phagocytose apoptotic neuronal cell debris (13.0 ± 1.3% for TG G93A, 16.5 ± 1.9% for TG WT, 28.6 ± 1.8% for NTG (G93A), and 26.9 ± 2.8% for NTG (WT) cells). Extracellular stimulation of microglia with ATP resulted in smaller increase in intracellular free calcium in TG G93A and TG WT microglia relative to NTG controls (0.28 ± 0.02 µM for TG G93A, 0.24 ± 0.03 µM for TG WT, 0.39 ± 0.03 µM for NTG (G93A), and 0.37 ± 0.05 µM for NTG (WT) microglia). CONCLUSIONS: These findings indicate that, under resting conditions, microglia from mutant SOD1 transgenic mice have a reduced capacity to elicit physiological responses following tissue disturbances and that higher levels of stimulatory signals, and/or prolonged stimulation may be necessary to initiate these responses. Overall, resting mutant SOD1-overexpressing microglia may have reduced capacity to function as sensors of disturbed tissue/cellular homeostasis in the CNS and thus have reduced neuroprotective function.

Contrasting effects of cerebrospinal fluid from motor neuron disease patients on the survival of primary motor neurons cultured with or without glia.

Motor neuronal (MN) degeneration in motor neuron disease (MND) often starts focally before spreading to neighbouring MN populations, suggesting soluble factors may contribute to disease propagation. Whether cerebrospinal fluid (CSF) from MND patients contains such factors has been difficult to prove. We aimed to determine the effect of glia on the response of MNs to CSF from MND patients. Primary rat spinal MNs grown in mono-culture or cocultured with glia were exposed to CSF from patients (MND-CSF) or controls (Con-CSF) and survival measured by cell counting. In mono-culture both MND-CSF and Con-CSF reduced MN survival with MND-CSF reducing MN survival by less than Con-CSF. In coculture MN survival was unchanged by exposure to MND-CSF while exposure to Con-CSF improved MN survival. In separate experiments, murine MNs grown in mono-culture and stressed by growth factor withdrawal were partially rescued by the application of monocyte chemoattractant protein-1 (MCP-1), a trophic factor previously found to be elevated in MND-CSF. Our results suggest that MND-CSF may contain factors harmful to MNs as well as factors protective of MNs, the interplay of which is altered by the presence of glial cells. These preliminary results further emphasize the importance of MN environment to MN health.

Oxidative stress in ALS: key role in motor neuron injury and therapeutic target.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by death of motor neurons leading to muscle wasting, paralysis, and death, usually within 2-3 years of symptom onset. The causes of ALS are not completely understood, and the neurodegenerative processes involved in disease progression are diverse and complex. There is substantial evidence implicating oxidative stress as a central mechanism by which motor neuron death occurs, including elevated markers of oxidative damage in ALS patient spinal cord and cerebrospinal fluid and mutations in the antioxidant enzyme superoxide dismutase 1 (SOD1) causing approximately 20% of familial ALS cases. However, the precise mechanism(s) by which mutant SOD1 leads to motor neuron degeneration has not been defined with certainty, and the ultimate trigger for increased oxidative stress in non-SOD1 cases remains unclear. Although some antioxidants have shown potential beneficial effects in animal models, human clinical trials of antioxidant therapies have so far been disappointing. Here, the evidence implicating oxidative stress in ALS pathogenesis is reviewed, along with how oxidative damage triggers or exacerbates other neurodegenerative processes, and we review the trials of a variety of antioxidants as potential therapies for ALS.

A case study evaluation of ethics review systems for multicentre clinical trials.

OBJECTIVE: To evaluate the difference in time taken for ethics and site governance approval for multicentre clinical trials using two different systems of ethics review. DESIGN: We evaluated the times to final ethics and governance approval for two international, multicentre clinical trials of treatment for metastatic colorectal cancer: the MAX trial, using a non-centralised ethics review system, and the CO.20 trial, using the new New South Wales centralised ethics review system. MAIN OUTCOME MEASURE: Time from trial submission to overall study approval. RESULTS: The median time taken to obtain ethics approval for the MAX trial at 16 NSW sites was 100 days (range, 36-161 days). The median time to obtain central ethics approval for the CO.20 trial at 14 NSW sites was 77 days, with an additional 60 days (range 20-79 days) required to obtain site-specific research governance approval. CONCLUSIONS: Any difference in time to approval between the review systems was outweighed by the overall time taken. However, the time spent by both the coordinating centre and local sites in collation, submission and correspondence was greatly reduced, and the centralised process allowed for standardised documentation at all study sites.

Mutant SOD1 G93A microglia have an inflammatory phenotype and elevated production of MCP-1.

The inflammatory response in amyotrophic lateral sclerosis (ALS) is well documented but the underlying cellular mechanisms have not been fully elucidated. We report that microglia isolated from the mutant human superoxide dismutase 1 (SOD1) G93A transgenic mouse model of ALS have an increased response to the inflammatory stimulus, lipopolysaccharide. Cell surface area and F4/80 surface marker, both indicators of cell activation, are increased relative to transgenic wild-type human SOD1 microglia. Monocyte chemoattractant protein-1, known to be increased in ALS, is produced at three-fold higher levels by SOD1 G93A than by wild-type human SOD1 microglia, under activating conditions. This novel finding implicates ALS microglia as a source of the increased monocyte chemoattractant protein-1 levels detected in ALS patients and in the ALS mouse model.