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Hippocampal size and neuron number are reduced in a number of conditions, including temporal lobe epilepsy and Alzheimer's disease. Furthermore, a decrease with advancing age has also been suggested. The present study examined the entire hippocampal formation of 12 subjects aged from 46 to 85 years and free from neurological disease. The volume of seven subregions (CA1, CA2-3, CA4, dentate gyrus, subiculum, presubiculum and white matter) was determined and the number of neurons estimated in each of these grey matter subregions using the optical dissector technique. There was a significant relationship between CA1 neurons number and cerebrum volume. Multivariate analysis showed the greater contribution to the variance in CA1 neuron number was made by cerebrum volume (69%) rather than age (2%) or sex (1%). The findings of this study show that, in neurologically normal individuals, brain size is a major determinant of the number of CA1 neurons [ABSTRACT FROM AUTHOR]

Aims: Pregnancies are increasingly affected by young-onset type 2 diabetes mellitus (YT2DM), an aggressive phenotype associated with a higher vascular risk profile compared to type 1 diabetes mellitus (T1DM). We compared pregnancy outcomes to illuminate areas where differing management guidance might be needed., Methods: This retrospective single-centre study (2010 2019) included 259 singleton pregnancies affected by pregestational T1DM (N = 124) or YT2DM (N = 135) diagnosed at < 40 years. Primary outcomes included preterm delivery, large for gestational age (LGA) infants, and pre-eclampsia., Results: The YT2DM cohort were older, with more obesity, greater apparent sociodemographic disadvantage, and lower measures of pregnancy preparedness. Overweight/obesity were also prevalent in the T1DM cohort (46 % affected). The second/third trimester mean HbA1c measurements were significantly higher in the T1DM cohort. Pre-eclampsia and preterm delivery rates were similar between the cohorts. Significantly lower rates of LGA infants, NICU admission, neonatal hypoglycaemia, and neonatal respiratory distress were seen in the YT2DM cohort (p < 0.05 for all)., Conclusions: In pregnancy, YT2DM appears to be the lower-risk cohort compared to T1DM despite higher obesity rates. Gaps in achieving glycaemic targets exist for both subtypes but particularly for T1DM. The relative impact of increasing BMI in pregnancies affected by T1DM requires further elucidation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aims: The impact of Ramadan exposure to Gestational Diabetes Mellitus (GDM) pregnancies is not known. We therefore aimed to assess the association of Ramadan with maternal and neonatal outcomes among pregnant women with GDM., Methods: Retrospective cohort study of 345 Muslim women with singleton pregnancies who attended a major Sydney teaching hospital during the period 1989-2010, was undertaken. Exposure to Ramadan was stratified by the: (1) total pregnancy days exposed to Ramadan, (2) duration (hours) of daily fasting and (3) trimester of exposure. Maternal and neonatal outcomes were examined by exposure status, and never exposed pregnancies were comparator in all three analyses. Fasting status was not recorded., Results: We found no significant effect of Ramadan exposure on mean birthweight, macrosomia and maternal outcomes. However, we found a significant trend for increased neonatal hyperbilirubinemia with increasing Ramadan days exposure and later trimester exposure (p trend  ≤ 0.02 for both), with adjusted OR 3.9 (p=0.03) for those with ≥ 21 days exposure to Ramadan and adjusted OR 4.3 (p=0.04) for third trimester exposure. Conversely longer Ramadan exposure and late trimester exposure were independently associated with a lower prevalence of neonatal hypoglycaemia (adjusted OR 0.4 and 0.3 for ≥ 21 days and third trimester exposure, respectively). Furthermore, neonatal hypoglycaemia decreased for the fasting period of > 15 h group (adjusted OR 0.2, p = 0.01)., Conclusions: Ramadan exposure is associated with reduced neonatal hypoglycaemia, with no effect on birthweight, implying more favourable glycaemic control. However, the fourfold excess of neonatal hyperbilirubinemia indicates a need for further study of Ramadan and GDM., (© 2021. The Author(s).)

Objective: Damage to locus ceruleus neurons could play a part in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis because of impairment of the blood-brain barrier and enhanced neuroinflammation. The locus ceruleus has connections throughout the brain and spinal cord, so the characteristic widespread multifocal pathology in these disorders could be due to damage to different subsets of locus ceruleus neurons. Previous studies have shown that only certain locus ceruleus neurons accumulate the neurotoxic metal mercury. To find out if concentrations of other toxic metals or of essential trace elements also vary between individual locus ceruleus neurons, we used synchrotron X-ray fluorescence microscopy on frozen sections of locus ceruleus neurons taken from people with multiple sclerosis, in whom the locus ceruleus is structurally intact., Materials and Methods: Paraffin embedded sections containing the locus ceruleus from seven people with multiple sclerosis were stained with autometallography that demonstrates accumulations of mercury, silver and bismuth. These were compared to maps of multiple elements obtained from frozen sections of locus ceruleus neurons from the same people using X-ray fluorescence microscopy. Neurons in the anterior pons from three of these donors were used as internal controls., Results: Autometallography staining was observed in scattered locus ceruleus neurons from three of the seven donors. X-ray fluorescence microscopy showed variations among individual locus ceruleus neurons in levels of mercury, selenium, iron, copper, lead, bromine, and rubidium. Variations between donors of locus ceruleus neuronal average levels of mercury, iron, copper, and bromine were also detected. Anterior pons neurons contained no mercury, had varied levels of iron, and had lower copper levels than locus ceruleus neurons., Conclusions: Individual human locus ceruleus neurons contain varying levels of toxic metals and essential trace elements. In contrast, most toxic metals are absent or at low levels in nearby anterior pons neurons. The locus ceruleus plays a role in numerous central nervous system functions, including maintaining the blood-brain-barrier and limiting neuroinflammation. Toxic metals, or alterations in essential trace metals within individual locus ceruleus neurons, could be one factor determining the non-random destruction of locus ceruleus neurons in normal aging and neurodegenerative diseases, and subsequently the sites of the widespread multifocal central nervous system pathology in these disorders., Competing Interests: The authors have declared that no competing interests exist.

Vapor deposition processes have shown promise for high-quality perovskite solar cells with potential pathways for scale-up to large area manufacturing. Here, we present a sequential close space vapor transport process to deposit CH 3 NH 3 PbI 3 (MAPI) perovskite thin films by depositing a layer of PbI 2 then reacting it with CH 3 NH 3 I (MAI) vapor. We find that, at T = 100 °C and pressure = 9 torr, a ∼225 nm-thick PbI 2 film requires ≥125 minutes in MAI vapor to form a fully-reacted MAPI film. Raising the temperature to 160 °C increases the rate of reaction, such that MAPI forms within 15 minutes, but with reduced surface coverage. The reaction kinetics can be approximated as roughly first-order with respect to PbI 2 , though there is evidence for a more complicated functional relation. Perovskite films reacted at 100 °C for 150 minutes were fabricated into solar cells with an SLG/ITO/CdS/MAPI/Spiro-OMeTAD/Au structure, and a device efficiency of 12.1% was achieved. These results validate the close space vapor transport process and serve as an advance toward scaled-up, vapor-phase perovskite manufacturing through continuous vapor transport deposition., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The solventogenic clostridia have long been known for their ability to convert sugars from complex feedstocks into commercially important solvents. Although the acetone-butanol-ethanol process fell out of favour decades ago, renewed interest in sustainability and 'green' chemistry has re-established our appetite for reviving technologies such as these, albeit with 21st century improvements. As CRISPR-Cas genome editing tools are being developed and applied to the solventogenic clostridia, their industrial potential is growing. Through integration of new pathways, the beneficial traits and historical track record of clostridial fermentation can be exploited to generate a much wider range of industrially relevant products. Here we show the application of genome editing using the endogenous CRISPR-Cas mechanism of Clostridium saccharoperbutylacetonicum N1-4(HMT), to generate a deletion, SNP and to integrate new DNA into the genome. These technological advancements pave the way for application of clostridial species to the production of an array of products., (© FEMS 2019.)

Background: Gestational diabetes mellitus is one of the most common complications of pregnancy. Women with Gestational diabetes are at increased risk of serious health outcomes, such as pre-eclampsia, obstructed labor, and the development of Type 2 diabetes later in life. Chinese migrants, the third largest cultural group in Australia, are more likely to develop Gestational diabetes than Australian-born women. However, to date, Gestational diabetes self-management has not been investigated in this population., Aim: To explore the understanding and self-management experiences of Gestational diabetes among Chinese migrants., Methods: Data were collected through individual semi-structured face-to-face interviews. Participants were recruited from the antenatal clinic at the Royal Prince Alfred Hospital. Interviews were audio-recorded, transcribed verbatim and thematically analyzed., Findings: Although the majority of participants demonstrated a good understanding of Gestational diabetes, some did not understand the principles behind healthcare advice and faced challenges in self-management. Confusion about self-monitoring of blood glucose and fear of insulin were also evident. Participants relied on both formal and informal sources of information. Some had difficulty obtaining adequate support. Cultural influences on self-management included meeting family needs, Chinese diet and use of Chinese medicines., Conclusion: To assist Chinese women with Gestational diabetes to better self-manage their condition, there is a need for clinicians to: (1) provide more effective diabetes education to ensure clear understanding of self-management principles; (2) actively elicit and respond to women's confusion and concerns; (3) provide women with adequate practical support; and (4) develop greater cultural awareness., (Copyright © 2018 Australian College of Midwives. Published by Elsevier Ltd. All rights reserved.)

Entubulating devices to repair peripheral nerve injuries are limited in their effectiveness particularly for critical gap injuries. Current clinically used nerve guidance conduits are often simple tubes, far stiffer than that of the native tissue. This study assesses the use of poly(glycerol sebacate methacrylate) (PGSm), a photocurable formulation of the soft biodegradable material, PGS, for peripheral nerve repair. The material was synthesized, the degradation rate and mechanical properties of material were assessed and nerve guidance conduits were structured via stereolithography. In vitro cell studies confirmed PGSm as a supporting substrate for both neuronal and glial cell growth. Ex vivo studies highlight the ability of the cells from a dissociated dorsal root ganglion to grow out and align along the internal topographical grooves of printed nerve guide conduits. In vivo results in a mouse common fibular nerve injury model show regeneration of axons through the PGSm conduit into the distal stump after 21 days. After conduit repair levels of spinal cord glial activation (an indicator for neuropathic pain development) were equivalent to those seen following graft repair. In conclusion, results indicate that PGSm can be structured via additive manufacturing into functional NGCs. This study opens the route of personalized conduit manufacture for nerve injury repair., Statement of Significance: This study describes the use of photocurable of Poly(Glycerol Sebacate) (PGS) for light-based additive manufacturing of Nerve Guidance Conduits (NGCs). PGS is a promising flexible biomaterial for soft tissue engineering, and in particular for nerve repair. Its mechanical properties and degradation rate are within the desirable range for use in neuronal applications. The nerve regeneration supported by the PGS NGCs is similar to an autologous nerve transplant, the current gold standard. A second assessment of regeneration is the activation of glial cells within the spinal cord of the tested animals which reveals no significant increase in neuropathic pain by using the NGCs. This study highlights the successful use of a biodegradable additive manufactured NGC for peripheral nerve repair., (Copyright © 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Context: The increasing prevalence of gestational diabetes mellitus (GDM) necessitates risk stratification directing limited antenatal resources to those at greatest risk. Recent evidence demonstrates that an early pregnancy glycated hemoglobin (HbA1c ≥5.9% (41 mmol/mol) predicts adverse pregnancy outcomes., Objective: To determine the optimal HbA1c threshold for adverse pregnancy outcomes in GDM in a treated multiethnic cohort and whether this differs in women diagnosed <24 vs ≥24 weeks' gestation (early vs standard GDM)., Design and Setting: This was a retrospective cohort study undertaken at the Royal Prince Alfred Hospital Diabetes Antenatal Clinic, Australia, between 1991 and 2011., Patients and Interventions: Pregnant women (N = 3098) underwent an HbA1c (single-laboratory) measurement at the time of GDM diagnosis. Maternal clinical and pregnancy outcome data were collected prospectively., Main Outcome Measure: The association between baseline HbA1c and adverse pregnancy outcomes in early vs standard GDM., Results: HbA1c was measured at a median of 17.6 ± 3.3 weeks' gestation in early GDM (n = 844) and 29.4 ± 2.6 weeks' gestation in standard GDM (n = 2254). In standard GDM, HbA1c >5.9% (41 mmol/mol) was associated with the greatest risk of large-for-gestational-age (odds ratio [95% confidence interval] = 2.7 [1.5-4.9]), macrosomia (3.5 [1.4-8.6]), cesarean section (3.6 [2.1-6.2]), and hypertensive disorders (2.6 [1.1-5.8]). In early GDM, similar HbA1c associations were seen; however, lower HbA1c correlated with the greatest risk of small-for-gestational-age (P trend = 0.004) and prevalence of neonatal hypoglycemia., Conclusions: Baseline HbA1c >5.9% (41 mmol/mol) identifies an increased risk of large-for-gestational-age, macrosomia, cesarean section, and hypertensive disorders in standard GDM. Although similar associations are seen in early GDM, higher HbA1c levels do not adequately capture risk-limiting utility as a triage tool in this cohort., (Copyright © 2017 by the Endocrine Society)

It is well-established that for a considerable period the United Kingdom has spent proportionally less of its gross domestic product (GDP) on health-related services than almost any other comparable country. Average European spending on health (as a % of GDP) in the period 1980 to 2013 has been 19% higher than the United Kingdom, indicating that comparable countries give far greater fiscal priority to its health services, irrespective of its actual fiscal value or configuration. While the UK National Health Service (NHS) is a comparatively lean healthcare system, it is often regarded to be at a 'crisis' point on account of low levels of funding. Indeed, many state that currently the NHS has a sizeable funding gap, in part due to its recently reduced GDP devoted to health but mainly the challenges around increases in longevity, expectation and new medical costs. The right level of health funding is a political value judgement. As the data in this paper outline, if the UK 'afforded' the same proportional level of funding as the mean average European country, total expenditure would currently increase by one-fifth., (© 2016 by Kerman University of Medical Sciences.)

Objective: Recent guidelines recommend testing at <24 weeks of gestation for maternal dysglycemia in "high-risk" women. Evidence to support the early identification and treatment of gestational diabetes mellitus (GDM) is, however, limited. We examined the prevalence, clinical characteristics, and pregnancy outcomes of high-risk women with GDM diagnosed at <24 weeks of gestation (early GDM) and those with pre-existing diabetes compared with GDM diagnosed at ≥24 weeks of gestation, in a large treated multiethnic cohort., Research Design and Methods: Outcomes from 4,873 women attending a university hospital antenatal diabetes clinic between 1991 and 2011 were examined. All were treated to standardized glycemic targets. Women were stratified as pre-existing diabetes (n = 65) or GDM diagnosed at <12 weeks of gestation (n = 68), at 12-23 weeks of gestation (n = 1,247), or at ≥24 weeks of gestation (n = 3,493)., Results: Hypertensive disorders in pregnancy including pre-eclampsia, preterm delivery, cesarean section, and neonatal jaundice (all P < 0.001) were more prevalent in women with pre-existing diabetes and early GDM. Macrosomia (21.8% vs. 20.3%, P = 0.8), large for gestational age (39.6% vs. 32.8%, P = 0.4), and neonatal intensive care admission (38.5% vs. 39.7%, P = 0.9) in women in whom GDM was diagnosed at <12 weeks of gestation were comparable to rates seen in women with pre-existing diabetes., Conclusions: Despite early testing and current best practice treatment, early GDM in high-risk women remains associated with poorer pregnancy outcomes. Outcomes for those in whom GDM was diagnosed at <12 weeks of gestation approximated those seen in pre-existing diabetes. These findings indicate the need for further studies to establish the efficacy of alternative management approaches to improve outcomes in these high-risk pregnancies., (© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

The peripheral nervous system has a limited innate capacity for self-repair following injury, and surgical intervention is often required. For injuries greater than a few millimeters autografting is standard practice although it is associated with donor site morbidity and is limited in its availability. Because of this, nerve guidance conduits (NGCs) can be viewed as an advantageous alternative, but currently have limited efficacy for short and large injury gaps in comparison to autograft. Current commercially available NGC designs rely on existing regulatory approved materials and traditional production methods, limiting improvement of their design. The aim of this study was to establish a novel method for NGC manufacture using a custom built laser-based microstereolithography (μSL) setup that incorporated a 405 nm laser source to produce 3D constructs with ∼ 50 μm resolution from a photocurable poly(ethylene glycol) resin. These were evaluated by SEM, in vitro neuronal, Schwann and dorsal root ganglion culture and in vivo using a thy-1-YFP-H mouse common fibular nerve injury model. NGCs with dimensions of 1 mm internal diameter × 5 mm length with a wall thickness of 250 μm were fabricated and capable of supporting re-innervation across a 3 mm injury gap after 21 days, with results close to that of an autograft control. The study provides a technology platform for the rapid microfabrication of biocompatible materials, a novel method for in vivo evaluation, and a benchmark for future development in more advanced NGC designs, biodegradable and larger device sizes, and longer-term implantation studies., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aims: To investigate the prevalence, clinical significance and antepartum to postpartum trajectory of zinc transporter 8 autoantibodies, a novel marker of islet autoimmunity, in women with gestational diabetes mellitus., Methods: A total of 302 consecutive women attending a multi-ethnic Australian gestational diabetes clinic were prospectively studied. Zinc transporter 8 autoantibodies were measured at gestational diabetes diagnosis and 3 months postpartum using an enzyme-linked immunosorbent assay, and were correlated with maternal phenotype, antepartum and postpartum glucose tolerance, treatment and perinatal outcomes., Results: Of the 302 women, 30 (9.9%) were positive for one islet autoantibody antepartum. No participant had multiple islet autoantibodies. Zinc transporter 8 autoantibodies were the most prevalent autoantibody [zinc transporter 8 autoantibodies: 13/271 women (4.8%); glutamic acid decarboxylase 7/302 women (2.3%); insulinoma-associated antigen-2: 6/302 women (2.0%); insulin: 4/302 women (1.3%)]. Zinc transporter 8 autoantibody positivity was associated with a higher fasting glucose level on the antepartum oral glucose tolerance test, but not with BMI, insulin use, perinatal outcomes or postpartum glucose intolerance. Five of the six women who tested positive for zinc transporter 8 autoantibodies antepartum were negative for zinc transporter 8 autoantibodies postpartum, which corresponded to a significant decline in titre antepartum to postpartum (26.5 to 3.8 U/ml; P=0.03). This was in contrast to the antepartum to postpartum trajectory of the other islet autoantibodies, which remained unchanged., Conclusions: Zinc transporter 8 autoantibodies were the most common islet autoantibody in gestational diabetes. Zinc transporter 8 autoantibody positivity was associated with slightly higher fasting glucose levels and, unlike other islet autoantibodies, titres declined postpartum. Zinc transporter 8 autoantibodies may be a marker for islet autoimmunity in a proportion of women with gestational diabetes, but the clinical relevance of zinc transporter 8 autoantibodies in pregnancy and gestational diabetes requires further investigation., (© 2014 The Authors. Diabetic Medicine © 2014 Diabetes UK.)

The formation of scar tissue following nerve injury has been shown to adversely affect nerve regeneration and evidence suggests that mannose-6-phosphate (M6P), a potential scar reducing agent that affects transforming growth factor (TGF)-β activation, may enhance nerve regeneration. In this study we utilized thy-1-YFP-H mice - a transgenic strain expressing yellow fluorescent protein (YFP) within a subset of axons - to enable visual analysis of axons regenerating through a nerve graft. Using this strain of mouse we have developed analysis techniques to visualize and quantify regeneration of individual axons across the injury site following the application of either M6P or vehicle to the site of nerve injury. No significant differences were found in the proportion of axons regenerating through the graft between M6P- and vehicle-treated grafts at any point along the graft length. Maximal sprouting occurred at 1.0mm from the proximal graft ending in both groups. The maximum change in sprouting levels for both treatment groups occurred between the graft start and 0.5-mm interval for both treatment groups. The difference between repair groups was significant at this point with a greater increase seen in the vehicle group than the M6P group. The average length of axons regenerating across the initial graft entry was significantly shorter in M6P- than in vehicle-treated grafts, indicating that they encountered less impedance. Application of M6P appears to reduce the disruption of regenerating axons and may therefore facilitate quicker recovery; this is likely to result from altered scar tissue formation in M6P grafts in the early stages of recovery. This study also establishes the usefulness of our methods of analysis using the thy-1-YFP-H mouse strain to visualize and quantify regeneration at the level of the individual axon., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: To explore the occupational backgrounds of English Non-Executive Directors (NED) on Acute National Health Service (NHS) Trusts., Design: Data extrapolated from Trust websites of NED' occupational backgrounds by gender and occupations, and inter-rater reliability test undertaken., Setting: Data were available on all but 24 of the 166 Acute Trusts' from all regions., Participants: Trust Chairs and NED were categorised by their dominant occupation., Main Outcome Measure: Differentiating NED with and without health or social care leadership experience., Results: The ratings of NED' occupations positively correlated (p < 0.001). Occupational categories were Commerce and Finance from private and public sectors or with Medical or Community leadership experience. Only 4% of Chairs were Medical, 2% from Community - the majority (61%) from Commerce and Finance. Of the 1001 NED, 8% and 6% respectively had Medical or Community leadership experience; most (86%) were Commerce, Finance and non-clinical Managerial backgrounds. Females made up 27% of NED., Conclusions: With a predominance of Chairs and NED without health or social care leadership experience, are current Boards equipped to avoid inadvertently 'doing the system's business' (Francis, 2013) rather than developing a more patient-centred, clinically led and integrated NHS? It is suggested that Boards need more NED with health and social care leadership experience and methods to identify the 'patient's agenda' to create 'a common culture' that places 'patients at the centre of everything we do' (Hunt, 2012). A key context for Trust Boards operations is funding, which Francis' terms of reference excluded, an issue that is briefly discussed.

In the English National Health Service (NHS), patients are now expected to choose the time and place of treatment and even choose the actual treatment. However, the theory on which patient choice is based and the implementation of patient choice are controversial. There is evidence to indicate that attitudes and abilities to make choices are relatively sophisticated and not as straightforward as policy developments suggest. In addition, and surprisingly, there is little research on whether making individual choices about care is regarded as a priority by the largest NHS patient group and the single largest group for most GPs-older people. This conceptual paper examines the theory of patient choice concerning accessing and engaging with healthcare provision and reviews existing evidence on older people and patient choice in primary care.

Background: The United States introduced human T-lymphotropic virus Type I (HTLV-I) screening of blood donors in 1988. The US military uses freshly collected blood products for life-threatening injuries when available stored blood components in theater have been exhausted or when these components are unsuccessful for resuscitation. These donors are screened after donation by the Department of Defense (DoD) retrospective testing program. All recipients of blood collected in combat are tested according to policy soon after and at 3, 6, and 12 months after transfusion., Case Report: A 31-year-old US Army soldier tested positive for HTLV-I 44 days after receipt of emergency blood transfusions for severe improvised explosive device blast injuries. One donor's unit tested HTLV-I positive on the DoD-mandated retrospective testing. Both the donor and the recipient tested reactive with enzyme immunoassay and supplemental confirmation by HTLV-I Western blot. The donor and recipient reported no major risk factors for HTLV-I. Phylogenetic analysis of HTLV-I sequences indicated Cosmopolitan subtype, Subgroup B infections. Comparison of long terminal repeat and env sequences revealed molecular genetic linkage of the viruses from the donor and recipient., Conclusion: This case is the first report of transfusion transmission of HTLV-I in the US military during combat operations. The emergency fresh whole blood policy enabled both the donor and the recipient to be notified of their HTLV-I infection. While difficult in combat, predonation screening of potential emergency blood donors with Food and Drug Administration-mandated infectious disease testing as stated by the DoD Health Affairs policy should be the goal of every facility engaged with emergency blood collection in theater., (© 2013 Henry M. Jackson Foundation. Transfusion © 2013 American Association of Blood Banks.)

Escherichia coli and Gram-negative bacteria that live in the human gut must be able to tolerate rapid and large changes in environmental pH. Low pH irreversibly denatures and precipitates many bacterial proteins. While cytoplasmic proteins are well buffered against such swings, periplasmic proteins are not. Instead, it appears that some bacteria utilize chaperone proteins that stabilize periplasmic proteins, preventing their precipitation. Two highly expressed and related proteins, HdeA and HdeB, have been identified as acid-activated chaperones. The structure of HdeA is known and a mechanism for activation has been proposed. In this model, dimeric HdeA dissociates at low pH, and the exposed dimeric interface binds exposed hydrophobic surfaces of acid-denatured proteins, preventing their irreversible aggregation. We now report the structure and biophysical characterization of the HdeB protein. The monomer of HdeB shares a similar structure with HdeA, but its dimeric interface is different in composition and spatial location. We have used fluorescence to study the behavior of HdeB as pH is lowered, and like HdeA, it dissociates to monomers. We have identified one of the key intersubunit interactions that controls pH-induced monomerization. Our analysis identifies a structural interaction within the HdeB monomer that is disrupted as pH is lowered, leading to enhanced structural flexibility., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Professor Jellinger first identified that striatal Aβ deposition at postmortem seemed to differentiate cases of dementia with Lewy bodies (DLB) from those with Parkinson's disease dementia (PDD), a finding subsequently questioned. Our replication study in 34 prospectively studied cases assessed the ability of striatal Aβ deposition to differentiate DLB from PDD, and also assessed the relationship between striatal and cortical Aβ deposition and α-synuclein-immunoreactive pathologies, using previously published protocols. Cases with DLB had significantly shorter durations and greater dementia severities compared with cases with PDD. Striatal Aβ-immunoreactive plaques were only consistently found in cases with DLB and correlated with both the severity (positive correlation) and duration (negative correlation) of dementia. Striatal Aβ-immunoreactive plaques also positively correlated with the severity of α-synuclein-immunoreactive pathologies as well as cortical Aβ-positive plaques. Striatal Aβ deposition positively predicted dementia in Lewy body cases with high specificity and had the greatest sensitivity to differentiate DLB from PDD with 100% negative predictive value. These data suggest that striatal Aβ deposition in Lewy body diseases contributes to early dementia and in these cases may impact on the efficacy of treatments targeting the striatum.

Objective: In order to conduct postmortem human brain research into the neuropatho-logical basis of schizophrenia, it is critical to establish cohorts that are well-characterized and well-matched. The aim of the present study was therefore to determine if specimen characteristics including: diagnosis, age, postmortem interval (PMI), brain acidity (pH), and/or the agonal state of the subject at death related to RNA quality, and to determine the most appropriate reference gene mRNAs., Methods: A matched cohort was selected of 74 subjects (schizophrenia/schizoaffective disorder, n = 37; controls, n = 37). Middle frontal gyrus tissue was pulverized, tissue pH was measured, RNA isolated for cDNA from each case, and RNA integrity number (RIN) measurements were assessed. Using quantitative reverse transcription-polymerase chain reaction, nine housekeeper genes were measured and a geomean calculated per case in each diagnostic group., Results: The RINs were very good (mean = 7.3) and all nine housekeeper control genes were significantly correlated with RIN. Seven of nine housekeeper genes were also correlated with pH; two clinical variables, agonal state and duration of illness, did have an effect on some control mRNAs. No major impact of PMI or freezer time on housekeeper mRNAs was detected. The results show that people with schizophrenia had significantly less PPIA and SDHA mRNA and tended to have less GUSB and B2M mRNA, suggesting that these control genes may not be good candidates for normalization., Conclusions: In the present cohort <10% variability in RINs was detected and the diagnostic groups were well matched overall. The cohort was adequately powered (0.80-0.90) to detect mRNA differences (25%) due to disease. The study suggests that multiple factors should be considered in mRNA expression studies of human brain tissues. When schizophrenia cases are adequately matched to control cases subtle differences in gene expression can be reliably detected.

Constraints on the structure of rifted continental margins and the magmatism resulting from such rifting can help refine our understanding of the strength of the lithosphere, the state of the underlying mantle and the transition from rifting to seafloor spreading. An important structural classification of rifts is by width, with narrow rifts thought to form as necking instabilities (where extension rates outpace thermal diffusion) and wide rifts thought to require a mechanism to inhibit localization, such as lower-crustal flow in high heat-flow settings. Observations of the magmatism that results from rifting range from volcanic margins with two to three times the magmatism predicted from melting models to non-volcanic margins with almost no rift or post-rift magmatism. Such variations in magmatic activity are commonly attributed to variations in mantle temperature. Here we describe results from the PESCADOR seismic experiment in the southern Gulf of California and present crustal-scale images across three rift segments. Over short lateral distances, we observe large differences in rifting style and magmatism--from wide rifting with minor synchronous magmatism to narrow rifting in magmatically robust segments. But many of the factors believed to control structural evolution and magmatism during rifting (extension rate, mantle potential temperature and heat flow) tend to vary over larger length scales. We conclude instead that mantle depletion, rather than low mantle temperature, accounts for the observed wide, magma-poor margins, and that mantle fertility and possibly sedimentary insulation, rather than high mantle temperature, account for the observed robust rift and post-rift magmatism.

The determination of melt distribution in the crust and the nature of the crust-mantle boundary (the 'Moho') is fundamental to the understanding of crustal accretion processes at oceanic spreading centres. Upper-crustal magma chambers have been imaged beneath fast- and intermediate-spreading centres but it has been difficult to image structures beneath these magma sills. Using three-dimensional seismic reflection images, here we report the presence of Moho reflections beneath a crustal magma chamber at the 9 degrees 03' N overlapping spreading centre, East Pacific Rise. Our observations highlight the formation of the Moho at zero-aged crust. Over a distance of less than 7 km along the ridge crest, a rapid increase in two-way travel time of seismic waves between the magma chamber and Moho reflections is observed, which we suggest is due to a melt anomaly in the lower crust. The amplitude versus offset variation of reflections from the magma chamber shows a coincident region of higher melt fraction overlying this anomalous region, supporting the conclusion of additional melt at depth.

Assessment of a series of 279 cases with Lewy body disease revealed 14 families having a family history consistent with autosomal dominant inheritance, eight of these with dominant Parkinsonism and six with dominant dementia. Analysis of the age at onset and genetic features in these families revealed significant anticipation only in a subset of parkinsonian families, with no pathological alleles for spinocerebellar ataxias or the common alpha-synuclein or LRRK2 point mutations.

The Earth's oceanic crust crystallizes from magmatic systems generated at mid-ocean ridges. Whereas a single magma body residing within the mid-crust is thought to be responsible for the generation of the upper oceanic crust, it remains unclear if the lower crust is formed from the same magma body, or if it mainly crystallizes from magma lenses located at the base of the crust. Thermal modelling, tomography, compliance and wide-angle seismic studies, supported by geological evidence, suggest the presence of gabbroic-melt accumulations within the Moho transition zone in the vicinity of fast- to intermediate-spreading centres. Until now, however, no reflection images have been obtained of such a structure within the Moho transition zone. Here we show images of groups of Moho transition zone reflection events that resulted from the analysis of approximately 1,500 km of multichannel seismic data collected across the intermediate-spreading-rate Juan de Fuca ridge. From our observations we suggest that gabbro lenses and melt accumulations embedded within dunite or residual mantle peridotite are the most probable cause for the observed reflectivity, thus providing support for the hypothesis that the crust is generated from multiple magma bodies.

Until recently, cortical Lewy body disease (CLB) was considered essentially the same as dementia with Lewy bodies (DLB). It is now known patients with Parkinson's disease (PD) with a later-onset dementia (PD-dementia) have the same pattern and extent of cortical Lewy body pathology. Inheritance patterns of CLB have not been evaluated previously. To identify genetic influence on CLB, all cases with this pathology need to be considered. We selected 180 cases meeting clinical and/or pathological criteria for DLB or PD (+/-dementia) from two patient groups: a PD and PD-dementia brain donor program, and a case-control study of Alzheimer's disease (AD). Cases meeting NINCDS-ADRDA criteria for probable AD were excluded and non-demented PD cases used as a comparison group. A detailed family history was taken analyzing onset and progression of dementia and PD phenotypes and a family tree constructed. The frequency of a positive family history of dementia and/or PD and risk of developing CLB in relatives was calculated. Fifty-five percent of dementia and 52% of PD cohorts did not have relatives with clinical disease. There was no increased frequency of familial disease in the CLB cohort compared with PD. However, in half the CLB families, rather than a dominant dementia, the clinical presentation varied (dementia and/or PD). Unlike PD, there was an increased risk of dementia if CLB was present in a parent ( approximately 20% risk) compared with another family member ( approximately 5% risk), suggesting CLB is more likely than PD to occur in a pattern consistent with autosomal dominant inheritance., (Copyright 2004 Wiley-Liss, Inc.)

The amygdala exhibits significant pathological changes in Parkinson's disease, including atrophy and Lewy body (LB) formation. Amygdala pathology has been suggested to contribute to some clinical features of Parkinson's disease, including deficits of olfaction and facial expression. The degree of neuronal loss in amygdala subnuclei and the relationship with LB formation in non-demented Parkinson's disease cases have not been examined previously. Using stereological methods, the volume of neurones and the number of neurones in amygdala subdivisions were estimated in 18 prospectively studied, non-demented patients with Parkinson's disease and 16 age- and sex-matched controls. Careful exclusion (all cortical disease) and inclusion (non-demented, levodopa-responsive, idiopathic Parkinson's disease or controls) criteria were applied. Seven Parkinson's disease cases experienced well-formed visual hallucinations many years after disease onset, while nine Parkinson's disease cases and three controls were treated for depression. Anatomically, the amygdala was subdivided into the lateral nucleus, the basal (basolateral and basomedial) nuclei and the corticomedial (central, medial and cortical nuclei) complex. LB and Lewy neurites were identified by immunohistochemistry for alpha-synuclein and ubiquitin and were assessed semiquantitatively. LB were found throughout the amygdala in Parkinson's disease, being present in approximately 4% of neurones. Total amygdala volume was reduced by 20% in Parkinson's disease (P = 0.02) and LB concentrated in the cortical and basolateral nuclei. Lewy neurites were present in most cases but did not correlate with any structural or functional variable. Amygdala volume loss was largely due to a 30% reduction in volume (P = 0.01) and the total estimated number of neurones (P = 0.007) in the corticomedial complex. The degree of neurone loss and the proportion of LB-containing neurones in the cortical nucleus within this complex were constant across Parkinson's disease cases and neither variable was related to disease duration (R(2 )< 0.03; P > 0.5). The cortical nucleus has major olfactory connections and its degeneration is likely to contribute to the early selective anosmia common in Parkinson's disease. There was a small reduction in neuronal density in the basolateral nucleus in all Parkinson's disease cases, but no consistent volume or cell loss within this region. However, the proportion of LB-containing neurones in the basolateral nucleus was nearly doubled in cases that exhibited visual hallucinations, suggesting that neuronal dysfunction in this nucleus contributes to this late clinical feature. Detailed quantitation of the other amygdala subdivisions failed to reveal any other substantial anomalies or any associations with depression. Thus, the impact of Parkinson's disease on the amygdala is highly selective and correlates with both early and late clinical features.

Background: Alzheimer's disease (AD) is characterised by functional impairment, cerebral atrophy, and degeneration of specific neuronal populations, especially pyramidal neurones of the cerebral cortex and hippocampal formation. Although patients with subcortical vascular dementia have been shown to have similar metabolic and volumetric deficits to those with AD, the underlying pathogenesis of these changes is poorly understood., Objective: To determine whether pyramidal cell loss occurs in small vessel disease (SVD) dementia by quantifying hippocampal volume and CA1 neurone number., Methods: Fifty four prospectively studied patients with dementia were screened, and four patients fulfilling criteria for SVD with no other significant neuropathological abnormality were identified. These were compared with five patients fulfilling criteria for AD and seven controls matched for age and sex. The hippocampal formation was serially sectioned, and the number of CA1 pyramidal neurones estimated using the optical dissector technique. Analysis of variance was used to evaluate group differences., Results: Patients in both the AD and SVD groups showed a substantial loss of pyramidal neurones from the CA1 region. The pattern of hippocampal atrophy and the degree of CA1 neuronal loss were similar in the two dementia groups., Conclusions: These findings support recent in vivo studies showing similar metabolic deficits and atrophy in AD and subcortical vascular dementia. In addition, they provide evidence that the underlying cause of these abnormalities is a similar loss of neurones. Whereas the cause of the neuronal loss in AD is related to the deposition of abnormal proteins, the cause in SVD is unknown. In the absence of other pathologies, damage to cerebral microvasculature should be considered a likely candidate.

Neurofibrillary tangle (NFT) formation in the CA1 region of the hippocampus is one of the early events in the pathogenesis of Alzheimer's disease (AD). As the disease progresses more NFTs form and there is substantial neuron loss. In this study we investigated whether NFT formation accounts for all the CA1 pyramidal neuron loss seen in AD. Using unbiased stereological techniques, we estimated the total number of neurons and the number of intra- and extra-cellular NFTs in the hippocampus of 10 patients with AD and 10 age-matched controls. Marked neuronal loss (approximately 60%) was identified in AD, although NFTs accounted for only a small proportion of this loss (2.2-17.2%, mean 8.1%). Analysis of NFT accumulation with duration of dementia showed a linear relationship, supporting the belief that NFTs progressively accumulate with time.

Consensus opinion characterizes dementia with Lewy bodies (DLB) as a progressive dementing illness, with significant fluctuations in cognition, visual hallucinations and/or parkinsonism. When parkinsonism is an early dominant feature, consensus opinion recommends that dementia within the first year is necessary for a diagnosis of DLB. If dementia occurs later, a diagnosis of Parkinson's disease with dementia (PDD) is recommended. While many previous studies have correlated the neuropathology in DLB with dementia and parkinsonism, few have analysed the relationship between fluctuating cognition and/or well-formed visual hallucinations and the underlying neuropathology in DLB and PDD. The aim of the present study was to determine any relationship between these less-studied core clinical features of DLB, and the distribution and density of cortical Lewy bodies (LB). The brains of 63 cases with LB were obtained over 6 years following population-based studies of dementia and parkinsonian syndromes. Annual, internationally standardized, clinical assessment batteries were reviewed to determine the presence and onset of the core clinical features of DLB. The maximal density of LB, plaques and tangles in the amygdala, parahippocampal, anterior cingulate, superior frontal, inferior temporal, inferior parietal and visual cortices were determined. Current clinicopathological diagnostic criteria were used to classify cases into DLB (n = 29), PDD (n = 18) or parkinsonism without dementia (n = 16) groups. Predictive statistics were used to ascertain whether fluctuating cognition or visual hallucinations predicted the clinicopathological group. Analysis of variance and regressions were used to identify any significant relationship(s) between the presence and severity of neuropathological and clinical features. Cognitive fluctuations and/or visual hallucinations were not good predictors of DLB in pathologically proven patients, although the absence of these features early in the disease course was highly predictive of PDD. Cases with DLB had higher LB densities in the inferior temporal cortex than cases with PDD. There was no association across groups between any neuropathological variable and the presence or absence of fluctuating cognition. However, there was a striking association between the distribution of temporal lobe LB and well-formed visual hallucinations. Cases with well-formed visual hallucinations had high densities of LB in the amygdala and parahippocampus, with early hallucinations relating to higher densities in parahippocampal and inferior temporal cortices. These temporal regions have previously been associated with visual hallucinations in other disorders. Thus, our results suggest that the distribution of temporal lobe LB is more related to the presence and duration of visual hallucinations in cases with LB than to the presence, severity or duration of dementia.

Hippocampal volume and neuron number were measured using stereological techniques in pathologically confirmed dementia with Lewy bodies (n = 8), Parkinson's disease only (n = 4), and controls (n = 9). We, and others, have previously shown considerable cell loss in the CA1 and subiculum subregions in Alzheimer's disease. In contrast, these regions were spared in dementia with Lewy bodies where a selective loss of lower presubiculum pyramidal neurons was found. These findings suggest a selective loss of frontally projecting hippocampal neurons in dementia with Lewy bodies versus those projecting to temporal lobe regions in Alzheimer's disease.

Dementia with Lewy bodies (DLB) and Parkinson's disease (PD) are distinguishable clinically but often not neuropathologically. This study aims to test whether the distribution of cortical Lewy bodies differs in these clinicopathological groups and to develop diagnostic protocols for their differentiation. Brains were obtained at autopsy from cases recruited from prospective clinical studies of dementia or movement disorders. All cases with significant pathologies other than Lewy bodies or plaques were excluded. Cases were categorised into either PD without dementia, DLB (dementia first or within 2 years of disease onset), or PD with a later onset of dementia (PDD). The distribution and density of Lewy bodies and Lewy neurites was determined using antibodies to ubiquitin and alpha-synuclein. Cortical Lewy body densities could not separate cases of DLB from those with PDD. However, semiquantitative thresholds in the parahippocampus could separate demented from non-demented cases with high sensitivity and specificity. Interactions between multiple pathologies were determined using factor analysis. Although many cases had CA2 Lewy neurites, this was not associated with severity or duration of either dementia or parkinsonism. Most DLB cases had significant plaque pathology, and severity and duration of dementia was related to both increasing parahippocampal Lewy body densities and neuritic plaque grade. Weighted kappa statistics revealed that the combination of these pathologies indicated a more severe dementia. These results suggest that dual pathologies cause DLB, and high densities of parahippocampal Lewy bodies indicate dementia regardless of additional pathologies.

Quantifying the melt distribution and crustal structure across ridge-axis discontinuities is essential for understanding the relationship between magmatic, tectonic and petrologic segmentation of mid-ocean-ridge spreading centres. The geometry and continuity of magma bodies beneath features such as overlapping spreading centres can strongly influence the composition of erupted lavas and may give insight into the underlying pattern of mantle flow. Here we present three-dimensional images of seismic reflectivity beneath a mid-ocean ridge to investigate the nature of melt distribution across a ridge-axis discontinuity. Reflectivity slices through the 9 degrees 03' N overlapping spreading centre on East Pacific Rise suggest that it has a robust magma supply, with melt bodies underlying both limbs and ponding of melt beneath large areas of the overlap basin. The geometry of melt distribution beneath this offset is inconsistent with large-scale, crustal redistribution of melt away from centres of upwelling. The complex distribution of melt seems instead to be caused by a combination of vertical melt transport from the underlying mantle and subsequent focusing of melt beneath a magma freezing boundary in the mid-crust.

There have been no previous three-dimensional volumetric studies of regional brain atrophy in patients with pathologically confirmed progressive supranuclear palsy (PSP). Postmortem cortical and subcortical volumes were compared with neuropathology in 9 patients with PSP, 15 patients with Parkinson's disease, 10 patients with dementia with Lewy bodies, and 23 controls. Cases with the neuritic pathology of Alzheimer's disease were excluded. The topography of brain atrophy differed according to clinicopathological phenotype. Patients with Parkinson's disease had atrophy confined to the amygdala. Atrophy of the frontal lobe was found in both PSP and dementia with Lewy bodies and correlated with increasing neurofibrillary tangle or Lewy body densities, respectively. Patients with PSP could be differentiated by their marked atrophy of the internal globus pallidus. Further analysis of variance revealed that trends for greater frontal lobe atrophy correlated with clinical dementia in PSP, whereas both greater frontal and hippocampal atrophy and higher densities of Lewy bodies and Lewy neurites correlated with clinical dementia in cases with Lewy bodies. The present study provides evidence for selective regional atrophy that correlates with the underlying pathology of PSP and Lewy body disease.

Background: There have been no previous studies on the role of inflammation in the brain for the second most common dementing disorder, dementia with Lewy bodies., Objective: To investigate the degree of cortical inflammation in dementia with Lewy bodies (DLB) compared with Alzheimer disease (AD) and control brains., Design and Main Outcome Measures: Post-mortem tissue collection from a brain donor program using standardized diagnostic criteria. Brains collected from January 1, 1993, through December 31, 1996, were screened and selected only for the presence or absence of tau neuritic plaques. Results of immunohistochemistry for HLA-DR were quantified using area fraction counts. Counts were performed by investigators who were unaware of the diagnosis. Results were compared across groups using analysis of variance and posthoc testing., Setting: A medical research institute in Sydney, Australia., Patients: Eight brains with DLB and without the tau neuritic plaques typical of AD, 10 brains with AD and no Lewy bodies, and 11 nondemented controls without significant neuropathological features were selected from a consecutive sample., Results: Compared with AD, DLB demonstrated significantly less inflammation in the form of HLA-DR-reactive microglia in all cortical regions (P<.001, posthoc). The level of inflammation in DLB was comparable to that seen in controls (P=.54, post hoc)., Conclusions: Inflammation appears related to the tau neuritic plaques of AD. Despite similar clinical presentations, therapeutic anti-inflammatory strategies are not likely to be effective for pure DLB. Arch Neurol. 2000.

The examination of neurofibrillary tangles is now recommended for the diagnosis of Alzheimer's disease as their location and density can distinguish early, intermediate and late disease stages. While the Braak tangle staging protocol can identify these stages, it uses an uncommon silver stain and hippocampal sample. The present study evaluates the Braak protocol using commonly used methods and cases fulfilling either CERAD criteria for Alzheimer's disease, criteria for dementia with Lewy bodies or without neurological disease. Temporal and occipital cortices from 72 cases were stained using tau immunohistochemistry and the Gallyas and modified Bielschowsky silver stains. The modified Bielschowsky silver stain was equivalent to the Gallyas silver stain for tangle staging. Semiquantitative evaluation of neurofibrillary tangles in the hippocampus and the inferior temporal cortex provided equivalent information to that obtained using the original Braak tangle staging protocol (kappa statistic of 0.97). Comparison of this modification with the CERAD criteria provided moderate agreement (0.51) between diagnostic categories when cases with dementia with Lewy bodies were included, but substantially increased agreement (0.74) when they were excluded. This simplification of the Braak tangle staging protocol is easy to apply, can be readily incorporated into existing CERAD procedures, and helps to distinguish cases with neurofibrillary tangles from those with Lewy bodies.

This study examines the effect of chronic alcohol consumption on the human cerebellum using operational criteria for case selection [Caine D. et al. (1997) J. Neurol. Neurosurg. Psychiat. 62, 51-60] and unbiased stereological techniques. We describe, for the first time, structural changes in different functional zones of the cerebellum of chronic alcoholics and correlate these changes with specific clinical symptoms. No consistent changes in the number of neurons or the structural volume for any cerebellar region were observed in the chronic alcoholics without the clinical signs of Wernicke's encephalopathy. In all cerebellar measures, these chronic alcoholics did not differ significantly from the non-alcoholic controls, suggesting that chronic alcohol consumption per se does not necessarily damage human cerebellar tissue. However, several cerebellar changes were noted in the thiamine-deficient alcoholics studied. There was a significant decrease in Purkinje cell density (reduced on average by 43%) and molecular layer volume (reduced by 32%) in the cerebellar vermis in all thiamine-deficient chronic alcoholics. A decrease in cell density and atrophy of the molecular layer, where the dendritic trees of the Purkinje cells are found, without significant cell loss suggests loss of cellular dendritic structure and volume. These thiamine-deficient alcoholics also had a significant decrease (36% loss) in the estimated Purkinje cell number of the flocculi, disrupting vestibulocerebellar pathways. These results indicate that cerebellar Purkinje cells are selectively vulnerable to thiamine deficiency. There is evidence that this damage contributes significantly to the clinical signs of Wernicke's encephalopathy. There was a 36% loss of Purkinje cells in the lateral lobe in alcoholics with mental state signs and 42% atrophy of vermal white matter in ataxic alcoholics. The finding of a 57% loss of Purkinje cells and a 43% atrophy of the molecular layer of the vermis in alcoholics with cerebellar dysfunction supports previous findings highlighting the importance of spinocerebellar pathways to these symptoms.

Pathological criteria have recently been developed to differentiate those cases where Lewy bodies contribute to the dementing process. We applied consensus criteria to 20 cases with a pathological diagnosis of Alzheimer's disease (all demented) and/or Parkinson's disease (three without dementia) and eight controls. In addition, we applied the criteria to the different cortical layers to determine whether the site of the semiquantification affected the diagnosis. In the parietal lobe, few Lewy bodies were observed, and this region could be excluded. Rare Lewy bodies present in the frontal association cortex in a number of Parkinson's disease cases resulted in their classification as limbic or transitional cases with Lewy bodies. Exclusion of this non-limbic association cortex resulted in many of these cases with rare cortical Lewy bodies being re-classified as having brain stem predominant Lewy bodies, thus improving the diagnostic accuracy of the criteria. Most of these cases were non-demented. No other case was re-classified by excluding these cortical regions from the analysis. Few Lewy bodies were present in cortical layers I and II, and these layers could be excluded from the semiquantitative procedure without change to the overall classification of cases. The occasional presence of possible Lewy bodies in cases with Alzheimer's disease and controls incorrectly classified these cases as having brain stem predominant Lewy body disease, although these cases had no brain stem Lewy bodies. These modifications to the consensus criteria for assessing Lewy body disease (i.e. exclude parietal and frontal lobe, cortical layers I and II, and cases without brain stem Lewy bodies), provide significant time and cost savings for neuropathologists and researchers using this criteria to diagnose and study dementia with Lewy bodies.

Wide-angle seismic data along the Mantle Electromagnetic and Tomography (MELT) arrays show that the thickness of 0.5- to 1. 5-million-year-old crust of the Nazca Plate is not resolvably different from that of the Pacific Plate, despite an asymmetry in depth and gravity across this portion of the East Pacific Rise. Crustal thickness on similarly aged crust on the Nazca plate near a magmatically robust part of the East Pacific Rise at 17 degrees15'S is slightly thinner (5.1 to 5.7 kilometers) than at the 15 degrees55'S overlapping spreading center (5.8 to 6.3 kilometers). This small north-south off-axis crustal thickness difference may reflect along-axis temporal variations in magma supply, whereas the across-axis asymmetry in depth and gravity must be caused by density variations in the underlying mantle.

Cerebral expression of c-fos protein was studied by immunocytochemistry in murine cerebral malaria (CM) and malaria without cerebral involvement (non-CM). c-fos expression, low in the brains of uninfected mice, increased in frequency, intensity, and distribution during the course of fatal CM (e.g., a 70-fold increase on day 7 after inoculation). These changes paralleled the timing and degree of the neurologic complications and histopathologic changes. Only a slight increase in c-fos expression was detectable in non-CM mice on day 7 after inoculation. Dexamethasone treatment (days 0 and 1 after inoculation) of the CM mice largely prevented the increased cerebral c-fos expression, histopathologic changes, cerebral complications, and death. Increased c-fos expression may indicate the specific neuronal pathways activated by the immunopathologic process of fatal murine CM and could be associated with the behavioral changes and neurologic complications in this model.

High alcohol consumption for long periods of time causes significant hippocampal neurodegeneration in rodents. A single study using neuronal density measures has reported similar findings in humans. The present study aims to substantiate these findings in human alcoholics using unbiased stereological techniques. Both amnesic (n = 5) and nonamnesic (n = 7) chronic alcoholics were selected and compared with nonalcoholic controls (n = 8) and patients with marked memory loss and hippocampal neurodegeneration caused by Alzheimer's disease (n = 4). Hippocampal volume was significantly reduced in the alcoholics and in patients with Alzheimer's disease. However, in alcoholics the volume reduction occurred exclusively in the white matter, whereas both the gray and white matter were reduced in the patients with Alzheimer's disease. Neuron loss occurred exclusively from the CA1 and subiculum subregions of the hippocampus in Alzheimer's disease. No neuron loss occurred from any subregion of the hippocampus in alcoholics. There were no correlations with age and any of the volume or neuron number measures. Hippocampal volume correlated with brain volume and with the regional gray and white matter volumes within the hippocampus. In addition, hippocampal gray matter volume correlated with the number of CA1 pyramidal neurons. These results do not support the theory that chronic alcohol consumption is neurotoxic to hippocampal pyramidal neurons in humans. Further, the present results suggest that changes observed in rodent models of alcoholism do not parallel those observed in humans, questioning the validity of such models.

A high-performance liquid chromatographic method with evaporative light-scattering detection was developed for the analysis of intact lipid classes in nervous tissue. The method had the ability to resolve plasmalogen-phosphatidyl-ethanolamine and diacyl-phosphatidylethanolamine along with other major phospholipid classes in a single run. This technique was employed for the investigation of the effects of chronic alcohol consumption on the membrane lipid class composition of human brains (alcoholics, n = 13; controls, n = 11). Measurements were performed on cholesterol, cerebrosides, sulfatides, phospholipids and sphingolipids in total lipid extracts of white matter, gray matter and cerebellar regions of human brains. No significant differences in the lipid class composition between the groups were observed.

The chronic consumption of alcohol significantly reduces the number of vasopressin-producing neurons in the rat supraoptic nucleus [Maderia et al. (1993) Neourscience 56, 657-672] suggesting this region is particularly vulnerable to alcohol neurotoxicity. As hypothalamic vasopressin producing neurons are necessary for fluid homeostasis, it is important to assess if similar changes occur in humans. We analysed arginine vasopressin-immunoreactive neurons in the magnocellular hypothalamic nuclei of ten chronic alcoholic men (consuming > 80 g of ethanol per day) and four age- and sex-matched controls (consuming < 10g of ethanol per day). Brains were collected at autopsy and fixed in formalin. Serial 50 mu m-thick-sections of the hypothalamus were stained and assessed. The volume of the paraventricular and supraoptic nuclei and number of neurons were estimated using Cavalieri's principle and the optical dissector technique. The volume of these nuclei significantly correlated with the number of neurons and the number of vasopressin-immunoreactive neurons, and these measures significantly correlated with the maximum daily intake of alcohol. There was a loss of neurons at consumption levels greater than 100 g of ethanol per day, principally affecting the supraoptic nucleus although neuron loss also occurred in the paraventricular nucleus in cases with long histories of alcohol consumption. These results indicate that chronic alcohol consumption is toxic to hypothalamic vasopressin-producing neurons in a concentration- and time-dependent manner. As these magnocellular neurons are osmo-receptive, neuronal loss may result in fluid imbalances.

Glial fibrillary acidic protein (GFAP) is the principal marker for brain astrocytes. The present study aims to examine the variability in GFAP immunohistochemistry in formalin-fixed human brain. Four commercially-available antisera were tested using standardised protocols in the cerebral cortex of three cases with prominent glial reactions and one control. GFAP immunoreactivity was largely confined to the pial surface and white matter in control cortex, with the number of astrocytic cell bodies and processes as well as intensity of staining markedly increased in damaged cortices. A dramatic difference in the pattern of GFAP staining using different antisera was observed and may account for discrepancies between past studies. This variance has important practical implications for the interpretation of results using GFAP immunohistochemistry in human tissue.

The aim of this study was to assess the number and proportion of vasopressin-producing neurons in the hypothalamic magnocellular nuclei in rats and humans. Accurate and unbiased neuronal counts were estimated using the optical disector method. Arginine vasopressin-containing neurons were immunohistochemically visualized in formalin-fixed tissue sections. The magnocellular neurons were similar in size and morphology in both species. While the human hypothalamus contained significantly more vasopressin-containing neurons compared with the rat (36-fold increase), the proportion of vasopressin-containing neurons between species was similar. In both species, the majority of supraoptic neurons contained vasopressin, however the proportion of vasopressin-containing neurons in the human paraventricular nucleus was double that of the rat (nearly a 100-fold increase in number). These results suggest that the paraventricular nucleus contributes significantly to the release of vasopressin from the posterior pituitary in humans, whereas in rats vasopressin is mainly released by supraoptic neurons.

Seismic reflection data from the East Pacific Rise between 17 degrees 05' and 17 degrees 35'S image a magma lens that varies regularly in depth and width as ridge morphology changes, confirming the notion that axial morphology can be used to infer ridge magmatic state. However, at 17 degrees 26'S, where the ridge is locally shallow and broad, the magma lens is markedly shallower and wider than predicted from regional trends. In this area, submersible dives reveal recent volcanic eruptions. These observations indicate that it is where the width and depth of the magma chamber differ from regional trends, indicating an enhanced magmatic budget, that is diagnostic of current magmatism.

Radiation damage to the dopamine tracts caused by enriched L-10B-p-boronophenylalanine (L-10BPA)-fructose and the boron neutron capture reaction was investigated using the mouse model. Following various treatments with L-10BPA and neutron irradiation of the head, the brain was perfusion fixed and removed; 50-microns frozen sections were cut. Dopaminergic neurons were visualized using immunohistochemistry for tyrosine hydroxylase. The administration of L-10BPA had no permanent effect on dopaminergic tracts. Neutron capture therapy with L-10BPA caused a reduction in tyrosine hydroxylase immunohistochemical activity within 4 h of irradiation, but by 48 h, this reduction reversed. No damage was observed at 120 h postirradiation.