South Hampshire Research Articles

Characterization of neuropathology in ovine CLN5 and CLN6 neuronal ceroid lipofuscinoses (Batten disease).

Sheep with naturally occurring CLN5 and CLN6 forms of neuronal ceroid lipofuscinoses (Batten disease) share the key clinical features of the human disease and represent an ideal model system in which the clinical efficacy of gene therapies is developed and test. However, it was first important to characterize the neuropathological changes that occur with disease progression in affected sheep. This study compared neurodegeneration, neuroinflammation, and lysosomal storage accumulation in CLN5 affected Borderdale, CLN6 affected South Hampshire, and Merino sheep brains from birth to end-stage disease at ≤24 months of age. Despite very different gene products, mutations, and subcellular localizations, the pathogenic cascade was remarkably similar for all three disease models. Glial activation was present at birth in affected sheep and preceded neuronal loss, with both spreading from the visual and parieto-occipital cortices most prominently associated with clinical symptoms to the entire cortical mantle by end-stage disease. In contrast, the subcortical regions were less involved, yet lysosomal storage followed a near-linear increase across the diseased sheep brain with age. Correlation of these neuropathological changes with published clinical data identified three potential therapeutic windows in affected sheep-presymptomatic (3 months), early symptomatic (6 months), and a later symptomatic disease stage (9 months of age)-beyond which the extensive depletion of neurons was likely to diminish any chance of therapeutic benefit. This comprehensive natural history of the neuropathological changes in ovine CLN5 and CLN6 disease will be integral in determining what impact treatment has at each of these disease stages.

Discoloured skies and an orange‐tinged sun seen over Romsey, south Hampshire

Discoloured skies and an orange‐tinged sun seen over Romsey, south Hampshire

An exceptionally bright solar corona in thin altocumulus cloud, photographed from Hillier Gardens, south Hampshire

WeatherVolume 74, Issue 7 p. E1-E1 Inside Cover Photograph An exceptionally bright solar corona in thin altocumulus cloud, photographed from Hillier Gardens, south Hampshire First published: 05 July 2019 https://doi.org/10.1002/wea.3586Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume74, Issue7Special Issue: Student Conference 2018July 2019Pages E1-E1 RelatedInformation

A Quiet Coup: Balkanizing the U.S. by Eliminating the Electoral College

There are calls for US presidential elections to be changed. The existing Electoral College system, a method that has been in effect in every presidential election since the 1804 approval of the Twelfth Amendment to the US Constitution, is seen by those seeking change as an unjust way for selecting US presidents. Many Democrats remain enraged by the fact that Hillary Clinton received more votes than Donald Trump in 2016 but was not elected president due to the Electoral College’s state-by-state electoral system. A movement is taking place in some state legislatures to adopt a system called the National Popular Vote Interstate Compact [the Compact]. This is a key part of a strategy drafted in 2006 and not yet operative but gaining state signatories. At this point in May 2019 all the current 15 state signatories to the Compact represent states with Democratic-controlled legislatures. The District of Columbia has also voted to join the Compact, bringing the total count to 16. The Investors Business Daily published an analysis of the worst run and best run states from a fiscal perspective. The worst run states included Illinois, California, Massachusetts, New Jersey, Connecticut, Hawaii, New Mexico, New York, and Rhode Island. Each of these states is a signatory to the national popular vote Compact. The best run states included South Dakota, Tennessee, Nebraska, Florida, Utah, Alaska, Oklahoma, Wyoming, New Hampshire, and Montana. With the exception of New Hampshire they are all “Red” states. None is a signatory to the Compact. The National Popular Vote Interstate Compact is an attempt at a “quiet coup” seeking permanent voting control of the office of the US Presidency. As such it offers a perfect recipe for the balkanization of America, contradicting the wisdom of those such as James Madison, one of our Founding Fathers who played a critical role in the formation of our Constitution. Madison recognized the inevitable factionalism of competing interests and diverse cultures in America. The Compact seeks to effectively amend the US Constitution de facto while pretending otherwise. The advocates launched a strategy through the National Popular Vote Interstate Compact knowing they could not gain the required approval of three-fourths of US states to create a national vote simple majority or plurality amendment to the US Constitution in place of the Twelfth Amendment’s Electoral College system.

A Self-Management Programme of Activity Coping and Education - SPACE for COPD(C) - in primary care: The protocol for a pragmatic trial

IntroductionNational guidance for chronic obstructive pulmonary disease (COPD) suggests that self-management support be provided for patients. Our institution has developed a standardised, manual-based, supported self-management programme: Self-Management Programme of Activity...

West Hampshire Community Diabetes Service: re‐commissioning a sustainable model of care

West Hampshire Community Diabetes Service: re‐commissioning a sustainable model of care

Delivering sustainable public transport: The case of the Better Bus Area Fund

Transport for South Hampshire, a joint board responsible for transport planning for a conurbation of over one million people, successfully bid for the UK's Better Bus Area Fund. This will result in investments of £7.4 million over the period 2012 to 2014, of which £4.5 million will come from central government. Investments will include installation of Wi-Fi on vehicles, Near Field Communication (NFC) tags and Next Stop Displays and Announcement systems, along with marketing initiatives, the development of mobile apps and the refurbishment of buses. These investments will be complemented by other initiatives in the conurbation, not least some £27 million of investments from the Local Sustainable Transport Fund over the period 2012 to 2015, including the development of key interchange points and bus corridors.This paper will outline the methodology that has been developed to monitor and evaluate these investments and will detail the baseline surveys that have been undertaken, the anticipated impacts on attitudes to and usage of bus services and the results of the initial implementation of the investment programme. The extent to which such investments can revitalise bus services in an area where there has been a long run historic decline will be assessed.

Chronic oral administration of minocycline to sheep with ovine CLN6 neuronal ceroid lipofuscinosis maintains pharmacological concentrations in the brain but does not suppress neuroinflammation or disease progression.

BackgroundThe neuronal ceroid lipofuscinoses (NCLs; or Batten disease) are fatal inherited human neurodegenerative diseases affecting an estimated 1:12,500 live births worldwide. They are caused by mutations in at least 11 different genes. Currently, there are no effective treatments. Progress into understanding pathogenesis and possible therapies depends on studying animal models. The most studied animals are the CLN6 South Hampshire sheep, in which the course of neuropathology closely follows that in affected children. Neurodegeneration, a hallmark of the disease, has been linked to neuroinflammation and is consequent to it. Activation of astrocytes and microglia begins prenatally, starting from specific foci associated with the later development of progressive cortical atrophy and the development of clinical symptoms, including the occipital cortex and blindness. Both neurodegeneration and neuroinflammation generalize and become more severe with increasing age and increasing clinical severity. The purpose of this study was to determine if chronic administration of an anti-inflammatory drug, minocycline, from an early age would halt or reverse the development of disease.MethodMinocycline, a tetracycline family antibiotic with activity against neuroinflammation, was tested by chronic oral administration of 25 mg minocycline/kg/day to presymptomatic lambs affected with CLN6 NCL at 3 months of age to 14 months of age, when clinical symptoms are obvious, to determine if this would suppress neuroinflammation or disease progression.ResultsMinocycline was absorbed without significant rumen biotransformation to maintain pharmacological concentrations of 1 μM in plasma and 400 nM in cerebrospinal fluid, but these did not result in inhibition of microglial activation or astrocytosis and did not change the neuronal loss or clinical course of the disease.ConclusionOral administration is an effective route for drug delivery to the central nervous system in large animals, and model studies in these animals should precede highly speculative procedures in humans. Minocycline does not inhibit a critical step in the neuroinflammatory cascade in this form of Batten disease. Identification of the critical steps in the neuroinflammatory cascade in neurodegenerative diseases, and targeting of specific drugs to them, will greatly increase the likelihood of success.

Altered biometal homeostasis is associated with CLN6 mRNA loss in mouse neuronal ceroid lipofuscinosis

SummaryNeuronal ceroid lipofuscinoses, the most common fatal childhood neurodegenerative illnesses, share many features with more prevalent neurodegenerative diseases. Neuronal ceroid lipofuscinoses are caused by mutations in CLN genes. CLN6 encodes a transmembrane endoplasmic reticulum protein with no known function. We characterized the behavioural phenotype of spontaneous mutant mice modeling CLN6 disease, and demonstrate progressive motor and visual decline and reduced lifespan in these mice, consistent with symptoms observed in neuronal ceroid lipofuscinosis patients. Alterations to biometal homeostasis are known to play a critical role in pathology in Alzheimer's, Parkinson's, Huntington's and motor neuron diseases. We have previously shown accumulation of the biometals, zinc, copper, manganese and cobalt, in CLN6 Merino and South Hampshire sheep at the age of symptom onset. Here we determine the physiological and disease-associated expression of CLN6, demonstrating regional CLN6 transcript loss, and concurrent accumulation of the same biometals in the CNS and the heart of presymptomatic CLN6 mice. Furthermore, increased expression of the ER/Golgi-localized cation transporter protein, Zip7, was detected in cerebellar Purkinje cells and whole brain fractions. Purkinje cells not only control motor function, an early symptomatic change in the CLN6 mice, but also display prominent neuropathological changes in mouse models and patients with different forms of neuronal ceroid lipofuscinoses. Whole brain fractionation analysis revealed biometal accumulation in fractions expressing markers for ER, Golgi, endosomes and lysosomes of CLN6 brains. These data are consistent with a link between CLN6 expression and biometal homeostasis in CLN6 disease, and provide further support for altered cation transporter regulation as a key factor in neurodegeneration.

Democratic Accountability and Metropolitan Governance: The Case of South Hampshire, UK

This paper examines the notion of democratic accountability through an investigation of metropolitan governance in South Hampshire, UK. The author employs an interpretive approach to trace varying readings of democratic accountability and to analyse how these notions reflect and influence specific institutional arrangements. The paper highlights how accountability can be strategically deployed to accomplish and bolster diverse policy and political objectives and how these interpretations impact the quality of democratic engagement

Increased Zinc and Manganese in Parallel with Neurodegeneration, Synaptic Protein Changes and Activation of Akt/GSK3 Signaling in Ovine CLN6 Neuronal Ceroid Lipofuscinosis

Mutations in the CLN6 gene cause a variant late infantile form of neuronal ceroid lipofuscinosis (NCL; Batten disease). CLN6 loss leads to disease clinically characterized by vision impairment, motor and cognitive dysfunction, and seizures. Accumulating evidence suggests that alterations in metal homeostasis and cellular signaling pathways are implicated in several neurodegenerative and developmental disorders, yet little is known about their role in the NCLs. To explore the disease mechanisms of CLN6 NCL, metal concentrations and expression of proteins implicated in cellular signaling pathways were assessed in brain tissue from South Hampshire and Merino CLN6 sheep. Analyses revealed increased zinc and manganese concentrations in affected sheep brain in those regions where neuroinflammation and neurodegeneration first occur. Synaptic proteins, the metal-binding protein metallothionein, and the Akt/GSK3 and ERK/MAPK cellular signaling pathways were also altered. These results demonstrate that altered metal concentrations, synaptic protein changes, and aberrant modulation of cellular signaling pathways are characteristic features in the CLN6 ovine form of NCL.

Spatial Planning as an Integrative Mechanism: A Study of Sub-regional Planning in South Hampshire, England

This article examines the concept of integrated spatial planning through a case study of sub-regional working in South Hampshire, England. It argues that while the government's notion of integration was ill-defined and inconsistent, there were critical opportunities discernible for planning practice. We focus on three aspects of integration: across territories and fragmented spaces; between actors and stakeholders; and from policy development to delivery and implementation. However, the cautious re-scaling of governance activity to the sub-region limited the effectiveness of the overall integration programme. The article concludes with a review of contextual features that contributed to the distinct manner in which integration was employed in South Hampshire and how this might inform future policy-making.

The Siting of Metalwork Hoards in the Bronze Age of South-East England

AbstractThe paper discusses the siting of Middle and Late Bronze Age hoards in south Hampshire, Sussex and parts of Surrey and Kent. It presents the results of fieldwork at the findspots of a hundred metalwork deposits and discusses the most informative ways of studying them on the ground. On the coastal plain the hoards were not far from occupation sites, and can be associated with evidence of burnt mounds and occasionally with field systems. That was less common on the chalk. Throughout the study area these deposits were normally located along watercourses, with a special emphasis on small areas of ground beside, or overlooking springs and confluences. It seems as if the deposition of bronze metalwork was governed by certain conventions. For that reason it may be possible to predict the pattern of future discoveries.

Location and connectivity determine GABAergic interneuron survival in the brains of South Hampshire sheep with CLN6 neuronal ceroid lipofuscinosis

The neuronal ceroid lipofuscinoses (NCLs, Batten disease) are fatal inherited neurodegenerative diseases. Sheep affected with the CLN6 form provide a valuable model to investigate underlying disease mechanisms from preclinical stages. Excitatory neuron loss in these sheep is markedly regional, localized early reactive changes accurately predicting neuron loss and subsequent symptom development. This investigation of GABAergic interneuron loss revealed similar regional effects that correlate with symptoms. Loss of parvalbumin positive neurons from the affected cortex was apparent at four months and became profound by 19 months, as was somatostatin positive neuron loss to a lesser extent. Conversely calbindin and neuropeptide Y positive neurons were relatively preserved and calretinin staining temporarily increased. Staining of subcortical regions was more intense but subcortical architecture remained relatively intact. Discrete subcortical changes followed from cortical changes in interconnected regions. These data highlight cellular location and interconnectivity as the major determinants of neuron survival, rather than phenotype.

Unexpectedly high incidence of indigenous acute hepatitis E within South Hampshire: Time for routine testing?

Hepatitis E indigenous to developed countries (hepatitis EIDC) is a form of hepatitis E in persons with no travel history to highly endemic areas. It has been recognized recently as an emerging clinical entity in a significant number of economically developed countries including UK. However, it is still perceived as a rare disease and routine laboratory testing for hepatitis E is not performed. A series of 13 cases of hepatitis EIDC, diagnosed in a 13-month period from June 2005 within a single center in South Hampshire, UK, is presented. These patients were identified after implementing a novel-screening algorithm that introduced routine hepatitis E serological investigations. Patients were middle aged or elderly and males were affected more commonly. Four patients (31%) required hospital admission. All reverse transcriptase-polymerase chain reaction (RT-PCR) confirmed cases carried hepatitis E virus (HEV) genotype-3, which bore close sequence homology to HEV circulating in UK pigs. None of these patients recalled eating undercooked pork products or close contact with pigs during the 2 months preceding the onset of acute hepatitis. In comparison, during the same period, only two cases of hepatitis A and five cases of acute hepatitis B were diagnosed. These data illustrate the importance of introducing routine hepatitis E testing in all patients with unexplained acute liver disease and absence of relevant travel history. Routine testing can clarify hepatitis E epidemiology whilst improving the clinical management of patients with acute liver disease.

Metabolomic investigation of CLN6 neuronal ceroid lipofuscinosis in affected South Hampshire sheep

The neuronal ceroid lipofuscinoses (NCLs; Batten disease) are a group of fatal inherited neurodegenerative diseases in humans and animals distinguished by a common clinical pathology, characteristic storage body accumulation in cells, and gross brain atrophy. An (1)H NMR spectroscopy- and GC-MS-based metabolomic investigation of changes in the cerebellum, frontal and occipital lobes, and cerebrospinal fluid (CSF) of CLN6 NCL affected South Hampshire sheep charted changes from the preclinical state to advanced disease. Glutamine and succinate concentrations increased in all brain regions in affected sheep relative to controls, whereas concentrations of aspartate, acetate, glutamate, N-acetyl aspartate (NAA), and gamma-aminobutyric acid (GABA) decreased. Changes in the concentrations of inositols, NAA, and GABA were consistent with glial cell activation and neurodegeneration beginning in the frontal and occipital lobes, in agreement with previous histopathological data. Further metabolic deficits were defined in all regions at earlier time points, including the cerebellum, where very little neurological degeneration has been reported. Biochemical abnormalities in the CSF of affected sheep at 18-31 months include relative increases in lactate, acetate, tyrosine, and creatine/creatinine concentrations and decreases in myo- and scyllo-inositol and citrate concentrations. The changes detected in the CSF and brain tissue mirrored those previously apparent in NCL mouse models, suggesting that they are common to all NCLs. However, the changes in glutamate and glutamine concentrations in CSF occurred after clinical disease, indicating that any changes in glutamate/glutamine cycling occur as a consequence of the primary deficits associated with the NCLs.

A missense mutation (c.184C > T) in ovine CLN6 causes neuronal ceroid lipofuscinosis in Merino sheep whereas affected South Hampshire sheep have reduced levels of CLN6 mRNA

The neuronal ceroid lipofuscinoses (NCLs, Batten disease) are a group of fatal recessively inherited neurodegenerative diseases of humans and animals characterised by common clinical signs and pathology. These include blindness, ataxia, dementia, behavioural changes, seizures, brain and retinal atrophy and accumulation of fluorescent lysosome derived organelles in most cells. A number of different variants have been suggested and seven different causative genes identified in humans ( CLN1, CLN2, CLN3, CLN5, CLN6, CLN8 and CTSD). Animal models have played a central role in the investigation of this group of diseases and are extremely valuable for developing a better understanding of the disease mechanisms and possible therapeutic approaches. Ovine models include flocks of affected New Zealand South Hampshires and Borderdales and Australian Merinos. The ovine CLN6 gene has been sequenced in a representative selection of these sheep. These investigations unveiled the mutation responsible for the disease in Merino sheep (c.184C > T; p.Arg62Cys) and three common ovine allelic variants (c.56A > G, c.822G > A and c.933_934insCT). Linkage analysis established that CLN6 is the gene most likely to cause NCL in affected South Hampshire sheep, which do not have the c.184C > T mutation but show reduced expression of CLN6 mRNA in a range of tissues as determined by real-time PCR. Lack of linkage precludes CLN6 as a candidate for NCL in Borderdale sheep.

Handbook of Patient Care in Vascular Surgery. 3rd ed. J. W. Hallett Jr, D. C. Brewster and R. C. Darling Jr (eds). 204 × 110 mm. Pp. 330. Illustrated. 1995. Edinburgh: Little Brown and Company (Boston). £32.95

Journal Article Handbook of Patient Care in Vascular Surgery. 3rd ed. J. W. Hallett Jr, D. C. Brewster and R. C. Darling Jr (eds). 204 × 110 mm. Pp. 330. Illustrated. 1995. Edinburgh: Little Brown and Company (Boston). £32.95 Get access Handbook of Patient Care in Vascular Surgery. 3rd ed. J W Hallett Jr, D C Brewster and R C Darling Jr (eds). 204 × 110 mm. Pp. 330. Illustrated. 1995. Edinburgh: Little Brown and Company (Boston). £32.95 A D B Chant, A D B Chant Royal South Hampshire Hospital, Graham Road, Southampton SO9 4PE, UK Search for other works by this author on: Oxford Academic Google Scholar V Lidstone V Lidstone Royal South Hampshire Hospital, Graham Road, Southampton SO9 4PE, UK Search for other works by this author on: Oxford Academic Google Scholar British Journal of Surgery, Volume 82, Issue 11, November 1995, Page 1580, https://doi.org/10.1002/bjs.1800821140 Published: 08 December 2005

Debate: South Hampshire, ‘East Wessex’ and the Atlas of Rural Settlement in England

(2005). Debate: South Hampshire, ‘East Wessex’ and the Atlas of Rural Settlement in England. Landscape History: Vol. 27, No. 1, pp. 71-75.

Wessex Estate: Recollections of British Military and Imperial History in the Heart of Singapore

Although the island Republic of Singapore has been submitted to a systematic territorial revolution since the 1960s, some of its urban heritage has been preserved. This is the case with Wessex Estate, a quiet residential neighbourhood located in the low hills extending on the western flank of the central urban area. Made up of less than a dozen bungalows and 26 small blocks of flats, Wessex Estate is of no particular architectural interest, but it does represent a heritage through the names borne by the blocks of flats. Clearly printed on the façades of the 26 blocks of flats, these names all refer to military feats of British history. The study locates and briefly describes these events, several of which took place on European fronts, as far back as the early 18th century (such as Ramilies, Blenheim), others throughout the British Empire, starting from the middle of the same century (such as Plassey, Quebec, Khartoum, Pegu). Built just prior to or just following WWII, it seems that the flats housed non-commissioned British officers during the Malayan Emergency (1948–1960). Their names refer to battles or theatres of war in all of which a given British regiment, the 67th or South Hampshire Regiment, might have been involved. Whatever the case, it remains somewhat remarkable that so many reminders of the colonial past, even a good number with "no natural connection" to Singapore, have remained prominent in this city-state otherwise apparently prone to sever "colonial apron strings".