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1.  Characterization of the host–guest complex of a curcumin analog with β-cyclodextrin and β-cyclodextrin–gemini surfactant and evaluation of its anticancer activity 
Curcumin analogs, including the novel compound NC 2067, are potent cytotoxic agents that suffer from poor solubility, and hence, low bioavailability. Cyclodextrin-based carriers can be used to encapsulate such agents. In order to understand the interaction between the two molecules, the physicochemical properties of the host–guest complexes of NC 2067 with β-cyclodextrin (CD) or β-cyclodextrin–gemini surfactant (CDgemini surfactant) were investigated for the first time. Moreover, possible supramolecular structures were examined in order to aid the development of new drug delivery systems. Furthermore, the in vitro anticancer activity of the complex of NC 2067 with CDgemini surfactant nanoparticles was demonstrated in the A375 melanoma cell line.
Physicochemical properties of the complexes formed of NC 2067 with CD or CDgemini surfactant were investigated by synchrotron-based powder X-ray diffraction, Fourier-transform infrared spectroscopy, and thermogravimetric analysis. Synchrotron-based small- and wide-angle X-ray scattering and size measurements were employed to assess the supramolecular morphology of the complex formed by NC 2067 with CDgemini surfactant. Lastly, the in vitro cell toxicity of the formulations toward A375 melanoma cells at various drug-to-carrier mole ratios were measured by cell viability assay.
Physical mixtures of NC 2067 and CD or CDgemini surfactant showed characteristics of the individual components, whereas the complex of NC 2067 and CD or CDgemini surfactant presented new structural features, supporting the formation of the host–guest complexes. Complexes of NC 2067 with CDgemini surfactants formed nanoparticles having sizes of 100–200 nm. NC 2067 retained its anticancer activity in the complex with CDgemini surfactant for different drug-to-carrier mole ratios, with an IC50 (half-maximal inhibitory concentration) value comparable to that for NC 2067 without the carrier.
The formation of host–guest complexes of NC 2067 with CD or CDgemini surfactant has been confirmed and hence the CDgemini surfactant shows good potential to be used as a delivery system for anticancer agents.
PMCID: PMC4298337  PMID: 25609956
inclusion complex; supramolecular arrangement; small-angle X-ray scattering; powder X-ray diffraction; cytotoxic activity
2.  Barium Aspiration in an Infant: A Case Report and Review of Management 
We describe a case of bilateral inhalation of barium in an infant following a barium swallow for investigation of dusky spells associated with feeds. A bronchoscopy subsequently revealed the presence of a mid-tracheal tracheo-esophageal cleft. To date, little has been reported on barium aspiration in children and there is no consensus for management. We review the literature on barium aspiration, its consequences, and make recommendations for management.
PMCID: PMC4013468  PMID: 24818122
barium; aspiration; tracheo-esophageal cleft; tracheo-esophageal fistula
3.  SOD1 Plasma Level as a Biomarker for Therapeutic Failure in Cutaneous Leishmaniasis 
The Journal of Infectious Diseases  2014;210(2):306-310.
We show that increased plasma superoxide dismutase 1 (SOD1) levels are statistically significant predictors of the failure of pentavalent antimony treatment for cutaneous leishmaniasis caused by Leishmania braziliensis. In Leishmania amazonensis–infected patients, host SOD1 levels can be used to discriminate between localized and drug-resistant diffuse cutaneous leishmaniasis. Using in situ transcriptomics (nCounter), we demonstrate a significant positive correlation between host SOD1 and interferon α/β messenger RNA (mRNA) levels, as well as interkingdom correlation between host SOD1 and parasite SOD2/4 mRNA levels. In human macrophages, in vitro treatment with SOD1 increases the parasite burden and induces a diffuse cutaneous leishmaniasis–like morphology. Thus, SOD1 is a clinically relevant biomarker and a therapeutic target in both localized and diffuse cutaneous leishmaniasis.
PMCID: PMC4073785  PMID: 24511100
Cutaneous leishmaniasis; Leishmania amazonensis; Leishmania braziliensis; Diffuse cutaneous leishmaniasis; Oxidative burst; Parasite escape mechanism; Interkingdom signaling; Superoxide dismutase; Biomarker; Therapeutic failure
4.  Characteristics of the Human Host Have Little Influence on Which Local Schistosoma mansoni Populations Are Acquired 
Brazil remains the country in the Americas with the highest prevalence of schistosomiasis. A combination of control efforts and development, however, has sharply reduced its intensity and distribution. The acquisition of specific schistosome populations may be dependent on host characteristics such as sex, age, geography, work, habits and culture. How these and other host characteristics align with parasite subpopulations may guide approaches to improve control.
A cohort of more than 90% of the residents in two rural communities in Brazil participated in an epidemiologic survey of demographic, socio-economic and behavioral characteristics. The variables sex, age, intensity of infection, socio-economic index, % lifetime spent on site, previous infection, and trips outside the district were used to group parasites infecting individuals. Schistosoma mansoni infection status was determined by examination of stools submitted on 3 different days. The aggregate of eggs collected from the whole stool was used to determine degree of population differentiation from allele frequencies for 15 microsatellites.
Infection prevalence was 41% for these communities, and the epidemiologic characteristics were similar to many of the endemic areas of Brazil and the world. Parasite population structuring was observed between the two communities (Jost's D 0.046, CI95% 0.042–0.051), although separated by only 8 km and connected by a highway. No structuring was observed when infected individuals were stratified by host's biologic, demographic or epidemiologic characteristics. Those most heavily infected best reflected the communities' overall parasite diversity. The lack of differentiation within villages suggests that individuals are likely to get infected at the same sites or that the same parasite multilocus genotypes can be found at most sites. The geographic structuring between villages and the lack of structuring by age of the host further supports the impression of a population little affected by migration or drift.
Author Summary
Schistosomiasis is one of the world's most important parasitic infections. Its elimination has proved difficult even in countries such as Brazil where access to treatment is readily available. Infection is the result of human contact with surface water where there are infected snails, so that human biology and habits may bring different individuals in contact with different groups of parasites. Identification of schistosome subpopulations may assist understanding transmission patterns and guide control efforts. We compared microsatellite allele frequencies from all of the infections in 2 small villages and determined that the movement of parasites between them was limited. Individual infections were distinct composites of parasites, but if infected humans were grouped by demographic and epidemiologic characteristics, there was no evidence that specific parasite subpopulations were being selected in these types of hosts. Infections were also not differentiated when stratified by host's age indicating that the populations were stable over time. Since the infection cycle requires human fecal contamination of water, local human behavior can to some degree be inferred from the patterns of schistosome subpopulation distribution.
PMCID: PMC3854954  PMID: 24340115
5.  Towards a More Precise Serological Diagnosis of Human Tegumentary Leishmaniasis Using Leishmania Recombinant Proteins 
PLoS ONE  2013;8(6):e66110.
Exposure to Leishmania induces a humoral immune response that can be used as a marker of parasite exposure.
Methodology/Principal Findings
Herein, ELISA was used to screen sera from patients with Tegumentary Leishmaniasis (TL) against different L. infantum-chagasi-derived recombinant proteins (rHSP70, rH2A, rH2B, rH3, rH4 and rKMP11). Among the recombinant proteins, rHSP70 and rH2A showed the best reactivity against human sera obtained from endemic areas of TL. Receiver-Operator Characteristics (ROC) curve analysis was used to identify the effectiveness of these proteins for serodiagnosis of TL. ROC curves confirmed the superior performance of rHSP70 and rH2A, in comparison to the other tested recombinant proteins. Additionally, we evaluated the specificity of the response to rHSP70 and rH2A by testing sera obtained from patients with Chagas' disease, Tuberculosis, Leprosy or Systemic Lupus Erythematosus. In this case, rHSP70 displayed an increased ability to discriminate diseases, in comparison to SLA.
Our results raise possibility of using rHSP70 for the serodiagnosis of TL
PMCID: PMC3680450  PMID: 23776617
6.  Sex Ratio, Conflict Dynamics, and Wounding in Rhesus Macaques (Macaca mulatta) 
Applied animal behaviour science  2011;137(3-4):137-147.
Rhesus macaques, like many other primates, live in stable, multi-male multi-female groups in which adult females typically outnumber adult males. The number of males in multi-male/multi-female groups is most commonly discussed in terms of mate competition, where the sex ratio is a function of an adult male’s ability to monopolize a group of females. However, the relationship between sex ratio and group stability is unclear because the presence of many males may either reduce stability by increasing mate competition or may improve stability if adult males are key conflict managers. We investigated the relationship between sex ratio, male intervention behavior, and trauma in seven groups of captive rhesus macaques. Our results show that high-ranking adult males intervene twice as frequently as adult females (P<0.0001) and are about twice as successful (P<0.0001). Furthermore, the type of adult males present in the group affects the relationship between intervention behavior and rate of traumas: males must be unrelated to the highest-ranking matrilines. Groups with a lower ratio of females per male unrelated to the alpha and beta matrilines had better intervention success (P<0.04) and fewer traumas requiring veterinary care (P=0.003). We conclude that conflict management behavior by adult males, particularly those unrelated to the highest-ranking matrilines, is the mechanism by which sex ratio influences the frequency of traumas, and thus group stability. We therefore suggest that monitoring and managing the sex ratio of captive primate groups is one of many measurements to predict group stability.
PMCID: PMC3357203  PMID: 22628902
intervention; conflict management; group stability; captivity; aggression; males
7.  Schistosoma mansoni population structure and persistence after praziquantel treatment in two villages of Bahia, Brazil 
International journal for parasitology  2011;41(10):1093-1099.
Praziquantel has been used to treat schistosome infections since 1979 and currently is the only chemotherapeutic agent in production for this purpose, raising concerns about the potential for the emergence of drug resistance. In practice, 10–20% of infected patients will continue to excrete eggs after treatment. It is not understood to what degree this represents selection of a resistant population or incomplete elimination due to the presence of immature worms at the time of treatment. We used a population genetics approach to test whether or not persistent Schistosoma mansoni parasites were drawn from the same population as susceptible parasites. In this study, stool samples were collected from 96% of individuals in two small Brazilian communities (populations 482 and 367) and examined for S. mansoni eggs. The combined prevalence of S. mansoni infections in the villages was 41%. Total egg DNA was extracted from each sample and was genotyped at 15 microsatellite markers. Day-to-day variation of the infrapopulation from an individual human host was low (median differentiation using Jost’s D = 0.010), so that a single stool was representative of the genotypes present in stool eggs, at least in the short term. Average pairwise analysis of D among all pre-treatment infrapopulations suggested moderate differentiation (mean D = 0.082 and 0.122 for the two villages), whereas the pre-treatment component population differentiation between the two communities was 0.047. The differentiation of the component population remaining after treatment from the fully susceptible component population was low (mean D = 0.007 and 0.020 for the two villages), suggesting that the persistent parasites were not selected by praziquantel treatment. We will continue to follow these communities for evidence of selection or changes in population structure.
PMCID: PMC3155667  PMID: 21784077
Praziquantel; Resistance; Microsatellite; Population genetics; Sampling; Genetic differentiation; Selection
8.  Effects of natal male alliances on aggression and power dynamics in rhesus macaques 
American Journal of Primatology  2010;73(8):790-801.
In the wild, male rhesus macaques disperse at sexual maturity. In captivity, however, males cannot disperse from their natal groups. Thus, the presence of natal males in captive rhesus social groups is unnatural and has the potential to negatively influence group dynamics and stability. A primary difference between natal males and non-natal (immigrant) males is that natal males have the opportunity to form long-term alliances with their maternal kin as well as nonkin. We investigated the factors associated with natal males’ kin alliances and the impact of these alliances on measures of natal male behavior, group dynamics, and group stability. We found that natal males more frequently formed alliances with maternal kin when they were from high-ranking matrilines, had more siblings, and were younger. More frequent kin alliances was associated with more frequent use of intense aggression, higher individual rank, and higher degree of integration within the male displacement network. Thus, it seems that natal males use their alliances to be more active and influential in the social group, which may affect group stability. It appears that juvenile natal males from high-ranking matrilines, in particular, have the largest impact on group stability. Younger natal males from high-ranking matrilines formed alliances with kin more frequently and used intense aggression more frequently than older or lower-ranking males. Furthermore, groups with a higher proportion of juvenile males from high-ranking matrilines also had higher rates of wounding. We suggest that the presence of natal males in rhesus groups may act in opposition to group stability.
PMCID: PMC3058123  PMID: 21698659
social network; coalition; primates; group stability; aggression
9.  Effects of increased hypothalamic leptin gene expression on ovariectomy-induced bone loss in rats 
Peptides  2011;32(8):1575-1580.
Estrogen deficiency results in accelerated bone turnover with a net increase in bone resorption. Subcutaneous administration of leptin attenuates bone loss in ovariectomized (ovx) rats by reducing bone resorption. However, in addition to its direct beneficial effects, leptin has been reported to have indirect (central nervous system-mediated) antiosteogenic effects on bone, which may limit the efficacy of elevated serum leptin to prevent estrogen deficiency-associated bone loss. The present study evaluated the long-term effects of increased hypothalamic leptin transgene expression, using recombinant adeno-associated virus-leptin (rAAV-Lep) gene therapy, on bone mass, architecture, and cellular endpoints in sexually mature ovx Sprague-Dawley rats. Ovx rats were implanted with cannulae in the 3rd ventricle of the hypothalamus and injected with either rAAV-Lep or rAAV-GFP (control vector encoding green fluorescent protein) and maintained for 10 weeks. Additional controls consisted of ovary-intact rats and ovx rats pair-fed to rAAV-Lep rats. Lumbar vertebrae were analyzed by micro-computed tomography and tibiae by histomorphometry. Cancellous bone volume was lower and osteoclast perimeter, osteoblast perimeter, and bone marrow adipocyte density were greater in ovx rats compared to ovary-intact controls. In contrast, differences among ovx groups were not detected for any endpoint evaluated. In conclusion, whereas estrogen deficiency resulted in marked cancellous osteopenia, increased bone turnover and marrow adiposity, increasing hypothalamic leptin transgene expression in ovx rats had neither detrimental nor beneficial effects on bone mass, architecture, or cellular endpoints. These findings demonstrate that the antiresorptive effects of subcutaneous leptin administration in ovx rats are mediated through leptin targets in the periphery.
PMCID: PMC3152665  PMID: 21640774
Bone marrow adiposity; White adipose tissue; μCT; Histomorphometry; Osteoclasts; Osteoblasts
10.  Lysine-functionalized nanodiamonds: synthesis, physiochemical characterization, and nucleic acid binding studies 
Detonation nanodiamonds (NDs) are carbon-based nanomaterials that, because of their size (4–5 nm), stable inert core, alterable surface chemistry, fluorescence, and biocompatibility, are emerging as bioimaging agents and promising tools for the delivery of biochemical molecules into cellular systems. However, diamond particles possess a strong propensity to aggregate in liquid formulation media, restricting their applicability in biomedical sciences. Here, the authors describe the covalent functionalization of NDs with lysine in an attempt to develop nanoparticles able to act as suitable nonviral vectors for transferring genetic materials across cellular membranes.
NDs were oxidized and functionalized by binding lysine moieties attached to a three-carbon-length linker (1,3-diaminopropane) to their surfaces through amide bonds. Raman and Fourier transform infrared spectroscopy, zeta potential measurement, dynamic light scattering, atomic force microscopic imaging, and thermogravimetric analysis were used to characterize the lysine-functionalized NDs. Finally, the ability of the functionalized diamonds to bind plasmid DNA and small interfering RNA was investigated by gel electrophoresis assay and through size and zeta potential measurements.
NDs were successfully functionalized with the lysine linker, producing surface loading of 1.7 mmol g−1 of ND. These modified NDs formed highly stable aqueous dispersions with a zeta potential of 49 mV and particle size of approximately 20 nm. The functionalized NDs were found to be able to bind plasmid DNA and small interfering RNA by forming nanosized “diamoplexes”.
The lysine-substituted ND particles generated in this study exhibit stable aqueous formulations and show potential for use as carriers for genetic materials.
PMCID: PMC3418073  PMID: 22904623
disaggregation; spectroscopy; dispersion; electrophoresis; size; zeta potential
11.  Lesion Size Correlates with Leishmania Antigen-Stimulated TNF-Levels in Human Cutaneous Leishmaniasis 
Cutaneous leishmaniasis (CL) is a worldwide disease endemic in several regions of the globe. The hallmark of CL is skin ulcers likely driven by efforts of the immune system to control Leishmania growth. Cytokines, such as tumor necrosis factor (TNF) and interferon-gamma can control disease progression in animal models. Nevertheless, the impact of these cytokines in CL ulcer outcome is not well established in humans. In this study, 96 CL patients from an endemic area of Leishmania braziliensis were enrolled for a follow-up study that consisted of clinical and immunological evaluations in a 2-year period. Statistical analysis revealed that healing time (P = 0.029), age (P = 0.002), and TNF levels (P = 0.0002) positively correlate with ulcer size at the time of the first clinical evaluation. Our findings suggest that ulcer size correlates with healing time and TNF levels support the use of TNF inhibitors combined with standard therapy to improve healing in CL patients with severe lesions.
PMCID: PMC3122347  PMID: 21734128
12.  Regional Differences in Susceptibility to Hypoxic-Ischemic Injury in the Preterm Brain: Exploring the Spectrum from White Matter Loss to Selective Grey Matter Injury in a Rat Model 
Models of premature brain injury have largely focused on the white matter injury thought to underlie periventricular leukomalacia (PVL). However, with increased survival of very low birth weight infants, injury patterns involving grey matter are now recognized. We aimed to determine how grey matter lesions relate to hypoxic-ischemic- (HI) mediated white matter injury by modifying our rat model of PVL. Following HI, microglial infiltration, astrocytosis, and neuronal and axonal degeneration increased in a region-specific manner dependent on the severity of myelin loss in pericallosal white matter. The spectrum of injury ranged from mild, where diffuse white matter abnormalities were dominant and were associated with mild axonal injury and local microglial activation, to severe HI injury characterized by focal MBP loss, widespread neuronal degeneration, axonal damage, and gliosis throughout the neocortex, caudate putamen, and thalamus. In sum, selective regional white matter loss occurs in the preterm rat concomitantly with a clinically relevant spectrum of grey matter injury. These data demonstrate an interspecies similarity of brain injury patterns and further substantiates the reliable use of this model for the study of preterm brain injury.
PMCID: PMC3317060  PMID: 22530125
13.  Evaluation of cellular uptake and intracellular trafficking as determining factors of gene expression for amino acid-substituted gemini surfactant-based DNA nanoparticles 
Gene transfer using non-viral vectors offers a non-immunogenic and safe method of gene delivery. Cellular uptake and intracellular trafficking of the nanoparticles can impact on the transfection efficiency of these vectors. Therefore, understanding the physicochemical properties that may influence the cellular uptake and the intracellular trafficking can aid the design of more efficient non-viral gene delivery systems. Recently, we developed novel amino acid-substituted gemini surfactants that showed higher transfection efficiency than their parent compound. In this study, we evaluated the mechanism of cellular uptake of the plasmid/gemini surfactant/helper lipid nanoparticles and their effect on the transfection efficiency.
Nanoparticles were incubated with Sf 1 Ep cells in the presence of different endocytic inhibitors and gene expression (interferon-γ) was measured using ELISA. Clathrin-mediated and caveolae-mediated uptake were found to be equally contributing to cellular internalization of both P/12-7NH-12/L (parent gemini surfactant) and P/12-7NGK-12/L (amino acid-substituted gemini surfactant) nanoparticles. The plasmid and the helper lipid were fluorescently tagged to track the nanoparticles inside the cells, using confocal laser scanning microscopy. Transmission electron microscopy images showed that the P/12-7NGK-12/L particles were cylindrical while the P/12-7NH-12/L particles were spherical which may influence the cellular uptake behaviour of these particles. Dye exclusion assay and pH-titration of the nanoparticles suggested that high buffering capacity, pH-dependent increase in particle size and balanced DNA binding properties may be contributing to a more efficient endosomal escape of P/12-7NGK-12/L compared to the P/12-7NH-12/L nanoparticles, leading to higher gene expression.
Amino-acid substitution in the spacer of gemini surfactant did not alter the cellular uptake pathway, showing similar pattern to the unsubstituted parent gemini surfactant. Glycyl-lysine substitution in the gemini spacer improved buffering capacity and imparted a pH-dependent increase of particle size. This property conferred to the P/12-7NGK-12/L nanoparticles the ability to escape efficiently from clathrin-mediated endosomes. Balanced binding properties (protection and release) of the 12-7NGK-12 in the presence of polyanions could contribute to the facile release of the nanoparticles internalized via caveolae-mediated uptake. A more efficient endosomal escape of the P/12-7NGK-12/L nanoparticles lead to higher gene expression compared to the parent gemini surfactant.
PMCID: PMC3298462  PMID: 22296763
cellular uptake; endosomal escape; non-viral gene delivery; clathrin-mediated endocytosis; caveolae-mediated endocytosis
15.  Effect of xanthine oxidase-generated extracellular superoxide on skeletal muscle force generation 
Skeletal muscle contractions increase superoxide anion in skeletal muscle extracellular space. We tested the hypotheses that 1) after an isometric contraction protocol, xanthine oxidase (XO) activity is a source of superoxide anion in the extracellular space of skeletal muscle and 2) the increase in XO-derived extracellular superoxide anion during contractions affects skeletal muscle contractile function. Superoxide anion was monitored in the extracellular space of mouse gastrocnemius muscles by following the reduction of cytochrome c in muscle microdialysates. A 15-min protocol of nondamaging isometric contractions increased the reduction of cytochrome c in microdialysates, indicating an increase in superoxide anion. Mice treated with the XO inhibitor oxypurinol showed a smaller increase in superoxide anions in muscle microdialysates following contractions than in microdialysates from muscles of vehicle-treated mice. Intact extensor digitorum longus (EDL) and soleus muscles from mice were also incubated in vitro with oxypurinol or polyethylene glycol-tagged Cu,Zn-SOD. Oxypurinol decreased the maximum tetanic force produced by EDL and soleus muscles, and polyethylene glycol-tagged Cu,Zn-SOD decreased the maximum force production by the EDL muscles. Neither agent influenced the rate of decline in force production when EDL or soleus muscles were repeatedly electrically stimulated using a 5-min fatiguing protocol (stimulation at 40 Hz for 0.1 s every 5 s). Thus these studies indicate that XO activity contributes to the increased superoxide anion detected within the extracellular space of skeletal muscles during nondamaging contractile activity and that XO-derived superoxide anion or derivatives of this radical have a positive effect on muscle force generation during isometric contractions of mouse skeletal muscles.
PMCID: PMC2806206  PMID: 19828843
contractile function; free radicals; exercise
16.  Mouthwash for anaphylaxis 
PMCID: PMC2658374  PMID: 18029533
17.  Supracondylar periprosthetic femoral fractures following total knee arthroplasty: treatment with a retrograde intramedullary nail 
International Orthopaedics  2008;33(4):981-985.
Total knee replacement surgery is occasionally complicated by a supracondylar periprosthetic fracture, and this presents a challenging problem in an often frail population. Multiple nonoperative and operative treatments have been described which have the aim of restoring the patient to their pre-injury status. This study retrospectively reviews the results of the largest series to date of 14 such fractures treated by retrograde intramedullary supracondylar nailing and is supportive of its continued use with good functional outcomes, low complication rates, and 100% fracture union.
PMCID: PMC2899005  PMID: 18535827
18.  Course and outcome of acute limbic encephalitis with negative voltage‐gated potassium channel antibodies 
Limbic encephalitis is a potentially treatable immunological condition. The presence of voltage‐gated potassium channel antibodies (VGKC‐Ab) in the cerebrospinal fluid (CSF) and serum of patients with the condition is a marker of the disease associated with a non‐paraneoplastic form and good response to treatment. Recent work has highlighted absent serum VGKC‐Ab and distinct immunology in patients with the paraneoplastic form of limbic encephalitis.
The cases of four patients with the typical clinical presentation, neuropsychological features and brain imaging of acute limbic encephalitis, in the absence of any evidence for associated cancer during a follow‐up of at least 18 months are described here.
All patients had negative testing for VGKC‐Ab measured during their acute presentation. All patients made some recovery, although they were left with marked cognitive deficits and persistent seizures.
These cases demonstrate that the absence of VGKC‐Ab in limbic encephalitis does not necessarily imply a paraneoplastic form. Further work is required to establish the immunological basis for the disorder in these patients, and the optimal treatment regimen.
PMCID: PMC2077800  PMID: 17098840
19.  Contrast sensitivity and visual hallucinations in patients referred to a low vision rehabilitation clinic 
To examine the association of reported visual hallucinations and measured visual parameters in adult patients referred for low vision rehabilitation.
All patients (N = 225) referred to a low vision rehabilitation clinic for a calendar year were asked a standardised question about symptoms of formed visual hallucinations. Best corrected visual acuity and contrast sensitivity using the Pelli‐Robson chart were measured. We conducted multiple logistic regression analysis of the association between visual hallucinations and visual parameters.
Of the total cohort, 78 (35%) reported visual hallucinations. Visual acuity and contrast sensitivity were considered in four quartiles. In multiple logistic regression controlling for contrast sensitivity, age, gender, report of depression and independence, measured acuity in each of the poorer three categories (compared to the best) was not associated with reported hallucinations. Contrast sensitivity in the three poorer quartiles (compared to the best) was strongly associated with the report of hallucinations (OR 4.1, CI 1.1, 15.9; OR 10.5, CI 2.6, 42.1; OR 28.1, CI 5.6, 140.9) after controlling for acuity, age, sex, depression and independence.
Lowest contrast sensitivity was the strongest predictor of reported hallucinations after adjusting for visual acuity.
PMCID: PMC1857683  PMID: 17035271
Charles Bonnet hallucinations; contrast sensitivity
20.  Multi-system neurological disease is common in patients with OPA1 mutations 
Brain  2010;133(3):771-786.
Additional neurological features have recently been described in seven families transmitting pathogenic mutations in OPA1, the most common cause of autosomal dominant optic atrophy. However, the frequency of these syndromal ‘dominant optic atrophy plus’ variants and the extent of neurological involvement have not been established. In this large multi-centre study of 104 patients from 45 independent families, including 60 new cases, we show that extra-ocular neurological complications are common in OPA1 disease, and affect up to 20% of all mutational carriers. Bilateral sensorineural deafness beginning in late childhood and early adulthood was a prominent manifestation, followed by a combination of ataxia, myopathy, peripheral neuropathy and progressive external ophthalmoplegia from the third decade of life onwards. We also identified novel clinical presentations with spastic paraparesis mimicking hereditary spastic paraplegia, and a multiple sclerosis-like illness. In contrast to initial reports, multi-system neurological disease was associated with all mutational subtypes, although there was an increased risk with missense mutations [odds ratio = 3.06, 95% confidence interval = 1.44–6.49; P = 0.0027], and mutations located within the guanosine triphosphate-ase region (odds ratio = 2.29, 95% confidence interval = 1.08–4.82; P = 0.0271). Histochemical and molecular characterization of skeletal muscle biopsies revealed the presence of cytochrome c oxidase-deficient fibres and multiple mitochondrial DNA deletions in the majority of patients harbouring OPA1 mutations, even in those with isolated optic nerve involvement. However, the cytochrome c oxidase-deficient load was over four times higher in the dominant optic atrophy + group compared to the pure optic neuropathy group, implicating a causal role for these secondary mitochondrial DNA defects in disease pathophysiology. Individuals with dominant optic atrophy plus phenotypes also had significantly worse visual outcomes, and careful surveillance is therefore mandatory to optimize the detection and management of neurological disability in a group of patients who already have significant visual impairment.
PMCID: PMC2842512  PMID: 20157015
deletions; dominant optic atrophy; hereditary spastic paraplegia; mitochondrial DNA; multiple sclerosis; OPA1
21.  DNA sequence and analysis of human chromosome 9 
Humphray, S. J. | Oliver, K. | Hunt, A. R. | Plumb, R. W. | Loveland, J. E. | Howe, K. L. | Andrews, T. D. | Searle, S. | Hunt, S. E. | Scott, C. E. | Jones, M. C. | Ainscough, R. | Almeida, J. P. | Ambrose, K. D. | Ashwell, R. I. S. | Babbage, A. K. | Babbage, S. | Bagguley, C. L. | Bailey, J. | Banerjee, R. | Barker, D. J. | Barlow, K. F. | Bates, K. | Beasley, H. | Beasley, O. | Bird, C. P. | Bray-Allen, S. | Brown, A. J. | Brown, J. Y. | Burford, D. | Burrill, W. | Burton, J. | Carder, C. | Carter, N. P. | Chapman, J. C. | Chen, Y. | Clarke, G. | Clark, S. Y. | Clee, C. M. | Clegg, S. | Collier, R. E. | Corby, N. | Crosier, M. | Cummings, A. T. | Davies, J. | Dhami, P. | Dunn, M. | Dutta, I. | Dyer, L. W. | Earthrowl, M. E. | Faulkner, L. | Fleming, C. J. | Frankish, A. | Frankland, J. A. | French, L. | Fricker, D. G. | Garner, P. | Garnett, J. | Ghori, J. | Gilbert, J. G. R. | Glison, C. | Grafham, D. V. | Gribble, S. | Griffiths, C. | Griffiths-Jones, S. | Grocock, R. | Guy, J. | Hall, R. E. | Hammond, S. | Harley, J. L. | Harrison, E. S. I. | Hart, E. A. | Heath, P. D. | Henderson, C. D. | Hopkins, B. L. | Howard, P. J. | Howden, P. J. | Huckle, E. | Johnson, C. | Johnson, D. | Joy, A. A. | Kay, M. | Keenan, S. | Kershaw, J. K. | Kimberley, A. M. | King, A. | Knights, A. | Laird, G. K. | Langford, C. | Lawlor, S. | Leongamornlert, D. A. | Leversha, M. | Lloyd, C. | Lloyd, D. M. | Lovell, J. | Martin, S. | Mashreghi-Mohammadi, M. | Matthews, L. | McLaren, S. | McLay, K. E. | McMurray, A. | Milne, S. | Nickerson, T. | Nisbett, J. | Nordsiek, G. | Pearce, A. V. | Peck, A. I. | Porter, K. M. | Pandian, R. | Pelan, S. | Phillimore, B. | Povey, S. | Ramsey, Y. | Rand, V. | Scharfe, M. | Sehra, H. K. | Shownkeen, R. | Sims, S. K. | Skuce, C. D. | Smith, M. | Steward, C. A. | Swarbreck, D. | Sycamore, N. | Tester, J. | Thorpe, A. | Tracey, A. | Tromans, A. | Thomas, D. W. | Wall, M. | Wallis, J. M. | West, A. P. | Whitehead, S. L. | Willey, D. L. | Williams, S. A. | Wilming, L. | Wray, P. W. | Young, L. | Ashurst, J. L. | Coulson, A. | Blöcker, H. | Durbin, R. | Sulston, J. E. | Hubbard, T. | Jackson, M. J. | Bentley, D. R. | Beck, S. | Rogers, J. | Dunham, I.
Nature  2004;429(6990):369-374.
Chromosome 9 is highly structurally polymorphic. It contains the largest autosomal block of heterochromatin, which is heteromorphic in 6–8% of humans, whereas pericentric inversions occur in more than 1% of the population. The finished euchromatic sequence of chromosome 9 comprises 109,044,351 base pairs and represents >99.6% of the region. Analysis of the sequence reveals many intra- and interchromosomal duplications, including segmental duplications adjacent to both the centromere and the large heterochromatic block. We have annotated 1,149 genes, including genes implicated in male-to-female sex reversal, cancer and neurodegenerative disease, and 426 pseudogenes. The chromosome contains the largest interferon gene cluster in the human genome. There is also a region of exceptionally high gene and G + C content including genes paralogous to those in the major histocompatibility complex. We have also detected recently duplicated genes that exhibit different rates of sequence divergence, presumably reflecting natural selection.
PMCID: PMC2734081  PMID: 15164053
22.  Charles Bonnet syndrome: visual loss and hallucinations 
PMCID: PMC2717672  PMID: 19652169
23.  Multivariate prediction of major adverse cardiac events after 9914 percutaneous coronary interventions in the north west of England 
Heart  2005;92(5):658-663.
To develop a multivariate prediction model for major adverse cardiac events (MACE) after percutaneous coronary interventions (PCIs) by using the North West Quality Improvement Programme in Cardiac Interventions (NWQIP) PCI Registry.
All NHS centres undertaking adult PCIs in north west England.
Retrospective analysis of prospectively collected data on 9914 consecutive patients undergoing adult PCI between 1 August 2001 and 31 December 2003. A multivariate logistic regression analysis was undertaken, with the forward stepwise technique, to identify independent risk factors for MACE. The area under the receiver operating characteristic (ROC) curve and the Hosmer‐Lemeshow goodness of fit statistic were calculated to assess the performance and calibration of the model, respectively. The statistical model was internally validated by using the technique of bootstrap resampling.
Main outcome measures
MACE, which were in‐hospital mortality, Q wave myocardial infarction, emergency coronary artery bypass graft surgery, and cerebrovascular accidents.
Independent variables identified with an increased risk of developing MACE were advanced age, female sex, cerebrovascular disease, cardiogenic shock, priority, and treatment of the left main stem or graft lesions during PCI. The ROC curve for the predicted probability of MACE was 0.76, indicating a good discrimination power. The prediction equation was well calibrated, predicting well at all levels of risk. Bootstrapping showed that estimates were stable.
A contemporaneous multivariate prediction model for MACE after PCI was developed. The NWQIP tool allows calculation of the risk of MACE permitting meaningful risk adjusted comparisons of performance between hospitals and operators.
PMCID: PMC1860907  PMID: 16159983
major adverse cardiac events; percutaneous coronary interventions; risk prediction
24.  Social deprivation and prognostic benefits of cardiac surgery: observational study of 44 902 patients from five hospitals over 10 years  
Objective To assess the effects of social deprivation on survival after cardiac surgery and to examine the influence of potentially modifiable risk factors.
Design Analysis of prospectively collected data. Prognostic models used to examine the additional effect of social deprivation on the end points.
Setting Birmingham and north west England.
Participants 44 902 adults undergoing cardiac surgery, 1997-2007.
Main outcome measures Social deprivation with census based 2001 Carstairs scores. All cause mortality in hospital and at mid-term follow-up.
Results In hospital mortality for all cardiac procedures was 3.25% and mid-term follow-up (median 1887 days; range 1180-2725 days) mortality was 12.4%. Multivariable analysis identified social deprivation as an independent predictor of mid-term mortality (hazard ratio 1.024, 95% confidence interval 1.015 to 1.033; P<0.001). Smoking (P<0.001), body mass index (BMI, P<0.001), and diabetes (P<0.001) were associated with social deprivation. Smoking at time of surgery (1.294, 1.191 to 1.407, P<0.001) and diabetes (1.305, 1.217 to 1.399, P<0.001) were independent predictors of mid-term mortality. The relation between BMI and mid-term mortality was non-linear and risks were higher in the extremes of BMI (P<0.001). Adjustment for smoking, BMI, and diabetes reduced but did not eliminate the effects of social deprivation on mid-term mortality (1.017, 1.007 to 1.026, P<0.001).
Conclusions Smoking, extremes of BMI, and diabetes, which are potentially modifiable risk factors associated with social deprivation, are responsible for a significant reduction in survival after surgery, but even after adjustment for these variables social deprivation remains a significant independent predictor of increased risk of mortality.
PMCID: PMC2664869  PMID: 19342410
25.  Presymptomatic Prediction of Sepsis in Intensive Care Unit Patients▿  
Postoperative or posttraumatic sepsis remains one of the leading causes of morbidity and mortality in hospital populations, especially in populations in intensive care units (ICUs). Central to the successful control of sepsis-associated infections is the ability to rapidly diagnose and treat disease. The ability to identify sepsis patients before they show any symptoms would have major benefits for the health care of ICU patients. For this study, 92 ICU patients who had undergone procedures that increased the risk of developing sepsis were recruited upon admission. Blood samples were taken daily until either a clinical diagnosis of sepsis was made or until the patient was discharged from the ICU. In addition to standard clinical and laboratory parameter testing, the levels of expression of interleukin-1β (IL-1β), IL-6, IL-8, and IL-10, tumor necrosis factor-α, FasL, and CCL2 mRNA were also measured by real-time reverse transcriptase PCR. The results of the analysis of the data using a nonlinear technique (neural network analysis) demonstrated discernible differences prior to the onset of overt sepsis. Neural networks using cytokine and chemokine data were able to correctly predict patient outcomes in an average of 83.09% of patient cases between 4 and 1 days before clinical diagnosis with high sensitivity and selectivity (91.43% and 80.20%, respectively). The neural network also had a predictive accuracy of 94.55% when data from 22 healthy volunteers was analyzed in conjunction with the ICU patient data. Our observations from this pilot study indicate that it may be possible to predict the onset of sepsis in a mixed patient population by using a panel of just seven biomarkers.
PMCID: PMC2446638  PMID: 18480235

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