Vitamin C Urinary Loss in Fabry Disease: Clinical and Genomic Characteristics of Vitamin C Renal Leak.

BACKGROUND: Reduced plasma vitamin C concentrations in chronic diseases may result from abnormal urinary excretion of vitamin C: a renal leak. We hypothesized that vitamin C renal leak may be associated with disease-mediated renal dysregulation, resulting in aberrant vitamin C renal reabsorption and increased urinary loss. OBJECTIVES: We investigated the prevalence, clinical characteristics, and genomic associations of vitamin C renal leak in Fabry disease, an X-linked lysosomal disease associated with renal tubular dysfunction and low plasma vitamin C concentrations. METHODS: We conducted a non-randomized cross-sectional cohort study of men aged 24-42 y, with Fabry disease (n = 34) and controls without acute or chronic disease (n = 33). To match anticipated plasma vitamin C concentrations, controls were placed on a low-vitamin C diet 3 wk before inpatient admission. To determine the primary outcome of vitamin C renal leak prevalence, subjects were fasted overnight, and matched urine and fasting plasma vitamin C measurements were obtained the following morning. Vitamin C renal leak was defined as presence of urinary vitamin C at plasma concentrations below 38 µM. Exploratory outcomes assessed the association between renal leak and clinical parameters, and genomic associations with renal leak using single nucleotide polymorphisms (SNPs) in the vitamin C transporter SLC23A1. RESULTS: Compared with controls, the Fabry cohort had 16-fold higher odds of renal leak (6% vs. 52%; OR: 16; 95% CI: 3.30, 162; P < 0.001). Renal leak was associated with higher protein creatinine ratio (P < 0.01) and lower hemoglobin (P = 0.002), but not estimated glomerular filtration rate (P = 0.54). Renal leak, but not plasma vitamin C, was associated with a nonsynonymous single nucleotide polymorphism in vitamin C transporter SLC23A1 (OR: 15; 95% CI: 1.6, 777; P = 0.01). CONCLUSIONS: Increased prevalence of renal leak in adult men with Fabry disease may result from dysregulated vitamin C renal physiology and is associated with abnormal clinical outcomes and genomic variation.

Tetrahydrobiopterin deficiency in the pathogenesis of Fabry disease.

Fabry disease is caused by deficient activity of α-galactosidase A and subsequent accumulation of glycosphingolipids (mainly globotriaosylceramide, Gb3), leading to multisystem organ dysfunction. Oxidative stress and nitric oxide synthase (NOS) uncoupling are thought to contribute to Fabry cardiovascular diseases. We hypothesized that decreased tetrahydrobiopterin (BH4) plays a role in the pathogenesis of Fabry disease. We found that BH4 was decreased in the heart and kidney but not in the liver and aorta of Fabry mice. BH4 was also decreased in the plasma of female Fabry patients, which was not corrected by enzyme replacement therapy (ERT). Gb3 levels were inversely correlated with BH4 levels in animal tissues and cultured patient cells. To investigate the role of BH4 deficiency in disease phenotypes, 12-month-old Fabry mice were treated with gene transfer-mediated ERT or substrate reduction therapy (SRT) for 6 months. In the Fabry mice receiving SRT but not ERT, BH4 deficiency was restored, concomitant with ameliorated cardiac and renal hypertrophy. Additionally, glutathione levels were decreased in Fabry mouse tissues in a sex-dependent manner. Renal BH4 levels were closely correlated with glutathione levels and inversely correlated with cardiac and kidney weight. In conclusion, this study showed that BH4 deficiency occurs in Fabry disease and may contribute to the pathogenesis of the disease through oxidative stress associated with a reduced antioxidant capacity of cells and NOS uncoupling. This study also suggested dissimilar efficacy of ERT and SRT in correcting pre-existing pathologies in Fabry disease.

Prevalence of Fabry Disease and Outcomes in Young Canadian Patients With Cryptogenic Ischemic Cerebrovascular Events.

BACKGROUND AND PURPOSE: Previous studies reported Fabry disease in 0% to 4% of young patients with cryptogenic ischemic stroke (IS). We sought to determine the prevalence of Fabry and outcomes among young Canadians with cryptogenic IS or transient ischemic attack (TIA). METHODS: We prospectively enrolled individuals aged 18 to 55 with IS or speech or motor TIA, and no cause identified despite predetermined investigation. α-galactosidase-A gene was sequenced for Fabry diagnosis. National Institutes of Health Stroke Scale score was measured at presentation to quantify stroke severity. Modified Rankin Scale determined functional outcomes ≤7 days after presentation and 6 months later. RESULTS: We enrolled 365 patients with IS and 32 with TIA. α-galactosidase-A sequencing identified a single carrier of a genetic variant of unknown significance (p.R118C) and no well-recognized pathogenic variants. Mean National Institutes of Health Stroke Scale score was 3.1. Proportion of patients with modified Rankin Scale of 0 to 2 was 70.7% at ≤7 days and 87.4% at 6 months. National Institutes of Health Stroke Scale score at presentation and diabetes mellitus predicted 6-month modified Rankin Scale. Thirteen patients experienced 5 recurrent IS and 9 TIA during follow-up. No patient died. Most patients (98.7%) returned home. Among previous workers, 43% had residual working limitations. CONCLUSIONS: In this Canadian cohort of patients with cryptogenic IS or TIA, the prevalence of Fabry was 0.3% if p.R118C variant is considered as pathogenic. This suggests that more cost-effective methods should be applied for diagnosis of Fabry rather than systematic genetic screening in this population. Overall, cryptogenic IS in young adults is associated with favorable outcomes.

An animal-to-human scaling law for blast-induced traumatic brain injury risk assessment.

Despite recent efforts to understand blast effects on the human brain, there are still no widely accepted injury criteria for humans. Recent animal studies have resulted in important advances in the understanding of brain injury due to intense dynamic loads. However, the applicability of animal brain injury results to humans remains uncertain. Here, we use advanced computational models to derive a scaling law relating blast wave intensity to the mechanical response of brain tissue across species. Detailed simulations of blast effects on the brain are conducted for different mammals using image-based biofidelic models. The intensity of the stress waves computed for different external blast conditions is compared across species. It is found that mass scaling, which successfully estimates blast tolerance of the thorax, fails to capture the brain mechanical response to blast across mammals. Instead, we show that an appropriate scaling variable must account for the mass of protective tissues relative to the brain, as well as their acoustic impedance. Peak stresses transmitted to the brain tissue by the blast are then shown to be a power function of the scaling parameter for a range of blast conditions relevant to TBI. In particular, it is found that human brain vulnerability to blast is higher than for any other mammalian species, which is in distinct contrast to previously proposed scaling laws based on body or brain mass. An application of the scaling law to recent experiments on rabbits furnishes the first physics-based injury estimate for blast-induced TBI in humans.

In silico investigation of intracranial blast mitigation with relevance to military traumatic brain injury.

Blast-induced traumatic brain injury is the most prevalent military injury in Iraq and Afghanistan, yet little is known about the mechanical effects of blasts on the human head, and still less is known about how personal protective equipment affects the brain's response to blasts. In this study we investigated the effect of the Advanced Combat Helmet (ACH) and a conceptual face shield on the propagation of stress waves within the brain tissue following blast events. We used a sophisticated computational framework for simulating coupled fluid-solid dynamic interactions and a three-dimensional biofidelic finite element model of the human head and intracranial contents combined with a detailed model of the ACH and a conceptual face shield. Simulations were conducted in which the unhelmeted head, head with helmet, and head with helmet and face shield were exposed to a frontal blast wave with incident overpressure of 10 atm. Direct transmission of stress waves into the intracranial cavity was observed in the unprotected head and head with helmet simulations. Compared to the unhelmeted head, the head with helmet experienced slight mitigation of intracranial stresses. This suggests that the existing ACH does not significantly contribute to mitigating blast effects, but does not worsen them either. By contrast, the helmet and face shield combination impeded direct transmission of stress waves to the face, resulting in a delay in the transmission of stresses to the intracranial cavity and lower intracranial stresses. This suggests a possible strategy for mitigating blast waves often associated with military concussion.

Prevalence of Fabry disease in young patients with cryptogenic ischemic stroke.

BACKGROUND: A German study diagnosed 4% of young cryptogenic ischemic stroke patients with Fabry disease, an X-linked lysosomal storage disease caused by mutations in the alpha-galactosidase A (α-GAL-A) gene resulting in an accumulation of glycosphingolipids. A lower prevalence was found in other geographic regions. AIM: To determine the prevalence of Fabry disease in a Canadian population of young cryptogenic ischemic stroke patients. MATERIALS AND METHODS: Patients with cryptogenic ischemic stroke at age 16-55 were retrospectively identified in our institutional stroke database and underwent a focused clinical evaluation. We sequenced the α-GAL-A gene and measured the levels of blood globotriaosylsphingosine in subjects with mutations of undetermined pathogenicity. Fabry disease was diagnosed in patients with pathogenic mutations or increased levels of blood globotriaosylsphingosine. RESULTS: Ninety-three of 100 study subjects had normal α-GAL-A gene polymorphisms. Seven had mutations of undetermined pathogenicity, including one with increased globotriaosylsphingosine (prevalence, 1%; 95% confidence interval, <.01%-6%). No subjects had angiokeratomas or other clinical manifestations of Fabry disease. Investigation results suggestive of Fabry disease (idiopathic hypertrophic cardiomyopathy, proteinuria, vertebrobasilar dolichoectasia, and the pulvinar sign) were found only in subjects with normal α-GAL-A genes. Apart from the 100 study subjects, our database included another patient with a family history of Fabry disease and a pathogenic mutation identified before her ischemic stroke presentation as the first clinical manifestation of Fabry disease. Both Fabry patients experienced recurrent ischemic stroke. CONCLUSIONS: Fabry disease accounts for a small proportion of young Canadians with cryptogenic ischemic stroke. Identification of Fabry biomarkers remains a research priority to delineate stroke patients disserving routine screening.

Blast-induced electromagnetic fields in the brain from bone piezoelectricity.

In this paper, we show that bone piezoelectricity-a phenomenon in which bone polarizes electrically in response to an applied mechanical stress and produces a short-range electric field-may be a source of intense blast-induced electric fields in the brain, with magnitudes and timescales comparable to fields with known neurological effects. We compute the induced charge density in the skull from stress data on the skull from a finite-element full-head model simulation of a typical IED-scale blast wave incident on an unhelmeted human head as well as a human head protected by a kevlar helmet, and estimate the resulting electric fields in the brain in both cases to be on the order of 10 V/m in millisecond pulses. These fields are more than 10 times stronger than the IEEE safety guidelines for controlled environments (IEEE Standards Coordinating Committee 28, 2002) and comparable in strength and timescale to fields from repetitive Transcranial Magnetic Stimulation (rTMS) that are designed to induce neurological effects (Wagner et al., 2006a). They can be easily measured by RF antennas, and may provide the means to design a diagnostic tool that records a quantitative measure of the head's exposure to blast insult.

Nanoplatforms for constructing new approaches to cancer treatment, imaging, and drug delivery: what should be the policy?

Nanotechnology is the design and assembly of submicroscopic devices called nanoparticles, which are 1-100 nm in diameter. Nanomedicine is the application of nanotechnology for the diagnosis and treatment of human disease. Disease-specific receptors on the surface of cells provide useful targets for nanoparticles. Because nanoparticles can be engineered from components that (1) recognize disease at the cellular level, (2) are visible on imaging studies, and (3) deliver therapeutic compounds, nanotechnology is well suited for the diagnosis and treatment of a variety of diseases. Nanotechnology will enable earlier detection and treatment of diseases that are best treated in their initial stages, such as cancer. Advances in nanotechnology will also spur the discovery of new methods for delivery of therapeutic compounds, including genes and proteins, to diseased tissue. A myriad of nanostructured drugs with effective site-targeting can be developed by combining a diverse selection of targeting, diagnostic, and therapeutic components. Incorporating immune target specificity with nanostructures introduces a new type of treatment modality, nano-immunochemotherapy, for patients with cancer. In this review, we will discuss the development and potential applications of nanoscale platforms in medical diagnosis and treatment. To impact the care of patients with neurological diseases, advances in nanotechnology will require accelerated translation to the fields of brain mapping, CNS imaging, and nanoneurosurgery. Advances in nanoplatform, nano-imaging, and nano-drug delivery will drive the future development of nanomedicine, personalized medicine, and targeted therapy. We believe that the formation of a science, technology, medicine law-healthcare policy (STML) hub/center, which encourages collaboration among universities, medical centers, US government, industry, patient advocacy groups, charitable foundations, and philanthropists, could significantly facilitate such advancements and contribute to the translation of nanotechnology across medical disciplines.

Computational biology - modeling of primary blast effects on the central nervous system.

OBJECTIVES: Recent military conflicts in Iraq and Afghanistan have highlighted the wartime effect of traumatic brain injury (TBI). The reason for the prominence of TBI in these particular conflicts as opposed to others is unclear but may result from the increased survivability of blast due to improvements in body armor. In the military context blunt, ballistic and blast effects may all contribute to CNS injury, however blast in particular, has been suggested as a primary cause of military TBI. While blast effects on some biological tissues, such as the lung, are documented in terms of injury thresholds, this is not the case for the CNS. We hypothesized that using bio-fidelic models, allowing for fluid-solid interaction and basic material properties available in the literature, a blast wave would interact with CNS tissue and cause a possible concussive effect. METHODS: The modeling approach employed for this investigation consisted of a computational framework suitable for simulating coupled fluid-solid dynamic interactions. The model included a complex finite element mesh of the head and intra-cranial contents. The effects of threshold and 50% lethal blast lung injury were compared with concussive impact injury using the full head model allowing upper and lower bounds of tissue injury to be applied using pulmonary injury as the reference tissue. RESULTS: The effects of a 50% lethal dose blast lung injury (LD(50)) were comparable with concussive impact injury using the DVBIC-MIT full head model. INTERPRETATION: CNS blast concussive effects were found to be similar between impact mild TBI and the blast field associated with LD(50) lung blast injury sustained without personal protective equipment. With the ubiquitous use of personal protective equipment this suggests that blast concussive effects may more readily ascertained in personnel due to enhanced survivability in the current conflicts.

Case report of a soldier with primary blast brain injury.

Primary blast injury of the central nervous system is described in a service-member exposed to a large ordinance explosion. Neuroimaging abnormalities are described together with normalization of the fractional anisotrophy on diffusion tensor imaging after follow-up imaging studies.

Head injury as a PTSD predictor among Oklahoma City bombing survivors.

BACKGROUND: The aim of the Oklahoma City (OKC) bombing retrospective review was to investigate the relationship between physical injury, environmental contributors, and psychiatric disorders such as posttraumatic stress disorder (PTSD) in an event-based, matched design study focused on injury. METHODS: The 182 selected participants were a random subset of the 1,092 direct survivors from the OKC bombing. Only 124 of these 182 cases had a full complement of medical/clinical data in the OKC database. These 124 cases were assessed to explore relationships among PTSD diagnoses, levels of blast exposure, and physical injuries. Associations among variables were statistically tested using contingency analysis and logistic regression. RESULTS: Comparison of the PTSD cases to symptoms/diagnoses reported in the medical records reveals a statistically significant association between PTSD and head/brain injuries associated with head acceleration. PTSD was not highly correlated with other injuries. Although blast pressure and impulse were highly correlated with head injuries, the correlation with PTSD was not statistically significant. Thus, a correlation between blast pressure and PTSD may exist, but higher fidelity pressure calculations are required to elucidate this potential relationship. CONCLUSIONS: This study provides clear evidence that head injury is associated with subsequent PTSD, giving caregivers' information on what physical injuries may suggest the development of psychologic disorders to aid them in developing a profile for the identification of future survivors of terrorist attacks and Warfighters with brain injuries and potential PTSD.

Globotriaosylceramide induces oxidative stress and up-regulates cell adhesion molecule expression in Fabry disease endothelial cells.

Fabry disease, an X-linked systemic vasculopathy, is caused by a deficiency of alpha-galactosidase A resulting in globotriaosylceramide (Gb(3)) storage in cells. The pathogenic role of Gb(3) in the disease is not known. Based on previous work, we tested the hypothesis that accumulation of Gb(3) in the vascular endothelium of Fabry disease is associated with increased production of reactive oxygen species (ROS) and increased expression of cell adhesion molecules. Gb(3)-loading resulted in increased intracellular ROS production in cultured vascular endothelial cells in a dose-dependent manner. Increased Gb(3) also induced expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin. Reduction of endogenous Gb(3) by treatment of the cells with an inhibitor of glycosphingolipid synthase or alpha-galactosidase A led to decreased expression of adhesion molecules. Plasma from Fabry patients significantly increased ROS generation in endothelial cells when compared with plasma from non-Fabry controls. This effect was not influenced by reduction of intracellular Gb(3). This study provided direct evidence that excess intracellular Gb(3) induces oxidative stress and up-regulates the expression of cellular adhesion molecules in vascular endothelial cells. In addition, other factors in patient's plasma may also contribute to oxidative stress in Fabry vascular endothelial cells.

Skin-impedance in Fabry Disease: a prospective, controlled, non-randomized clinical study.

BACKGROUND: We previously demonstrated improved sweating after enzyme replacement therapy (ERT) in Fabry disease using the thermo-regularity sweat and quantitative sudomotor axon reflex tests. Skin-impedance, a measure skin-moisture (sweating), has been used in the clinical evaluation of burns and pressure ulcers using the portable dynamic dermal impedance monitor (DDIM) system. METHODS: We compared skin impedance measurements in hemizygous patients with Fabry disease (22 post 3-years of bi-weekly ERT and 5 ERT naive) and 22 healthy controls. Force compensated skin-moisture values were used for statistical analysis. Outcome measures included 1) moisture reading of the 100th repetitive reading, 2) rate of change, 3) average of 60-110th reading and 4) overall average of all readings. RESULTS: All outcome measures showed a significant difference in skin-moisture between Fabry patients and control subjects (p < 0.0001). There was no difference between Fabry patients on ERT and patients naïve to ERT. Increased skin-impedance values for the four skin-impedance outcome measures were found in a small number of dermatome test-sites two days post-enzyme infusions. CONCLUSION: The instrument portability, ease of its use, a relatively short time required for the assessment, and the fact that DDIM system was able to detect the difference in skin-moisture renders the instrument a useful clinical tool.

Apoptotic abnormalities in differential gene expression in peripheral blood mononuclear cells from children with Fabry disease.

AIM: This study was designed to examine the effect of enzyme replacement therapy (ERT) on differential gene expression in peripheral blood mononuclear cells (PBMCs) of children with Fabry disease who had not previously been exposed to ERT. METHODS: Thirteen children with Fabry disease (age range, 6.5-17.0 years) were studied as part of a 6-month, open-label study of ERT with agalsidase alfa. Paired blood samples were taken at the start of the study and after 6 months of ERT. Further blood samples were also taken from 16 age-matched control subjects. PBMCs were isolated and, following RNA extraction, differential gene expression analysis was performed using the Human Genome U133 Plus 2.0 microarray. RESULTS: Twenty-one genes were determined to be differentially expressed in PBMCs of ERT-naïve children with Fabry disease compared with healthy controls; neuronal apoptosis inhibitory protein ranked as the most significantly differentially expressed gene. Comparison of gene expression in children with Fabry disease prior to and after ERT showed that two genes were significantly differentially expressed (p < or = 0.05) following treatment; the expressed sequence tag (probe set ID, 243259_at) was downregulated, while expression of apoptosis-inducing factor was increased, possibly as an antioxidant counter-regulatory response. CONCLUSION: This study identifies a number of genes that are differentially expressed in a small cohort of children with Fabry disease relative to healthy controls. These genes may relate to the underlying biological abnormalities in Fabry disease.

The cerebral vasculopathy of Fabry disease.

Fabry disease is an X-linked disorder affecting both males and females. It is associated with an increased risk of stroke in up to 4% of patients below 55 years of age in the general population. The cerebral vasculopathy consists of ischemic strokes involving large and small vessels. The neuronal accumulation of glycosphingolipids appears to have no clinical effect on the natural history of Fabry disease with the possible exception of some reported mild cognitive abnormalities. The pathogenesis of Fabry vasculopathy remains poorly understood but is associated with abnormal functional control of the vessel secondary to endothelial dysfunction, cerebral hyper-perfusion and a prothrombotic state with likely increased production of reactive oxygen species. These abnormalities are further modified by genetic and possibly other vascular risk factors. This vasculopathy illustrates the role of glycolipids in this and possibly other types of cerebral vasculopathies. Therapy is preventive relying on standard medical care and in particular on anti-platelet agents such as clopidogrel.

Enzyme replacement therapy in orphan and ultra-orphan diseases: the limitations of standard economic metrics as exemplified by Fabry-Anderson disease.

BACKGROUND: Fabry-Anderson disease is an x-linked deficiency of lysosomal alpha-galactosidase A (GALA), resulting in chronic renal failure, cardiac arrhythmia, hypertrophy, valvular disease, pain (acro-paraesthesiae) and stroke, together with premature mortality. The disease has a significant impact on quality of life (QOL), as illustrated by studies using the EQ-5D. A specific treatment is available for Fabry-Anderson disease consisting of intravenous enzyme replacement therapy (ERT) of the deficient enzyme. The variable clinical efficacy and cost of ERT has resulted in reluctance by some health providers to approve it. METHODS: We use the limited QOL data available in the Fabry-Anderson disease literature on ERT to derive standard economic metrics. These were derived by bootstrap estimates of the incremental net benefit (INB) statistics together with a cost-effectiveness acceptability curve relating the willingness to pay to the probability that the INB was >0. The estimates were further developed by adoption of a supplementary Bayesian approach utilising a sceptical and enthusiastic prior of the INB of ERT in Fabry-Anderson disease. RESULTS: ERT for Fabry-Anderson disease is not economically viable by standard health programme evaluation metrics. Based on current ERT costs (year 2005 values), derivation of the INB distribution, and a Bayesian analysis using an enthusiastic and sceptical prior of the INB, an upper (350,000 dollars over 1 year) and lower (175,000 dollars over 1 year) economic cost, respectively, of ERT was derived. CONCLUSION: The cost of ERT will always result in a net deficit to society under current costing and ERT efficacy as determined by the QALY metric. The rules of fair cooperation should govern decision making both for ERT in Fabry-Anderson disease and for funding therapeutic advances in other rare diseases belonging to the orphan and ultra-orphan categories.

Using peripheral blood mononuclear cells to determine a gene expression profile of acute ischemic stroke: a pilot investigation.

BACKGROUND: Direct brain biopsy is rarely indicated during acute stroke. This study uses peripheral blood mononuclear cells (PBMCs) to determine whether a systemic gene expression profile could be demonstrated in patients with acute ischemic stroke. METHODS AND RESULTS: Using oligonucleotide microarrays, we compared the gene expression profile of an index cohort of 20 patients with confirmed ischemic stroke on neuroimaging studies with that of 20 referent subjects. Validation studies used quantitative real-time polymerase chain reaction to measure the levels of 9 upregulated genes in the index cohort, and an independent cohort of 9 patients and 10 referent subjects was prospectively studied to determine the accuracy of the Prediction Analysis for Microarrays list to classify stroke. After correction for multiple comparisons with the Bonferroni technique, 190 genes were significantly different between the stroke and referent groups. Broad classes of genes included white blood cell activation and differentiation (approximately 60%), genes associated with hypoxia and vascular repair, and genes potentially associated with an altered cerebral microenvironment. Real-time polymerase chain reaction confirmed increased mRNA expression in 9 of 9 upregulated stroke-associated genes in the index cohort. A panel of 22 genes derived from the Prediction Analysis for Microarrays algorithm in the index cohort classified stroke in the validation cohort with a sensitivity of 78% and a specificity of 80%. Control for the Framingham stroke risk score revealed only a partial dependence of the stroke gene expression profile in PBMCs on vascular risk. CONCLUSIONS: This study demonstrated an altered gene expression profile in PBMCs during acute ischemic stroke. Some genes with altered expression were consistent with an adaptive response to central nervous system ischemia.

Fabry disease and vascular risk factors: future strategies for patient-based studies and the knockout murine model.

UNLABELLED: Fabry disease is secondary to deficiency of the lysosomal enzyme alpha-galactosidase A, leading to altered glycosphingolipid metabolism and accumulation that is often associated with endothelial dysfunction. Current evidence suggests that there is impairment of the vascular nitric oxide pathway, with abnormalities evident in the cerebral circulation and in the dermal vasculature of patients with Fabry disease. Some of these findings have been confirmed in a mouse model of Fabry disease. The murine model, however, allows investigation of Fabry disease at a non-clinical level and a near complete investigation of biological processes within an affected tissue. This is of particular utility in allowing gene expression analysis of clinically inaccessible tissues such as the aorta. CONCLUSION: Future developments in array technology for proteins and DNA single nucleotide polymorphism analysis, together with gene expression microarray analysis, may open a new chapter in our understanding of the biology of lysosomal storage disorders.

Is Blast Injury a Modern Phenomenon?: Early Historical Descriptions of Mining and Volcanic Traumatic Brain Injury With Relevance to Modern Terrorist Attacks and Military Warfare.

BACKGROUND: Given the recent interest in blast injury spurred by returning soldiers from overseas conflicts, we sought to research the early historical descriptions of blast injuries and their treatments. Consideration was given to specific descriptions of survivors of closed head injury and their treatment. METHODS: A review of the medical and nonmedical literature was undertaken, with particular emphasis on pre-1800 descriptions of volcanic eruptions and mining accidents. Compilations of accounts of the Etna eruptions dating from 126 BC were translated into English, and early mining texts from the 1600s and 1700s were reviewed. RESULTS: Accumulations of flammable gases were recorded in many medieval sources and this knowledge of toxic gas which could lead to blast injury was known in the mining community by 1316. No direct attribution of injuries to blast forces was present in the historical record examined before the 1300s, although mining accounts in the 1600s detail deaths due to blast. No specific descriptions of survivors of a closed head injury were found in the mining and volcanic eruption literature. CONCLUSIONS: Descriptions and warnings of blast forces were commonly written about in the medieval and Renaissance mining communities. Personal narratives as early as 1316 recognize the traumatic effects of blast injury. No mining or volcanic blast descriptions before 1800 detailed severe closed head injury survivors, suggesting greater mortality than morbidity from blast injury in the premodern era. This review also uncovered that there was no historical treatment or remedy recommended to survivors of blast injury. Blast explosions resulting in injury or death were frequently described, although in simplistic terminology.

Elevated cerebral blood flow velocities in Fabry disease with reversal after enzyme replacement.

BACKGROUND AND PURPOSE: Fabry disease is an X-linked inherited disorder resulting from a deficiency of alpha-galactosidase A. Cerebrovascular disease in Fabry disease includes small-vessel disease and larger-vessel ectasia in a predominantly posterior distribution. We assessed transcranial Doppler (TCD) blood flow velocities in naive and enzyme-treated Fabry patients. METHODS: TCD was used to noninvasively examine patients with Fabry disease for abnormal cerebral blood flow velocities. TCD measurements were also made during CO2 retention by breathholding to examine cerebrovascular vessel reactivity. Twenty-six patients were enrolled in a 6-month, double-blind, placebo-controlled trial of enzyme replacement therapy consisting of biweekly intravenous alpha-galactosidase A infusions, with a subsequent 18-month follow-up in an open-label trial. Statistical analysis consisted of applying a mixed-effects ANOVA model for correlated outcomes. RESULTS: Peak velocity, mean velocity, pulsatility index, and resistance index were found to be significantly higher in patients compared with control subjects. When the individual vessels were considered, elevated flow velocities were found in the middle cerebral M1 branch and the posterior cerebral artery. Enzyme replacement therapy significantly decreased peak, mean, and end-diastolic velocities and flow acceleration at the 18-month follow-up time point. CONCLUSIONS: Patients with Fabry disease have elevated cerebral blood flow velocities. These velocities significantly improved with enzyme replacement therapy.