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1.  C9ORF72 hexanucleotide repeat expansions in clinical Alzheimer’s disease 
JAMA neurology  2013;70(6):736-741.
Objective
Hexanucleotide repeat expansions in C9ORF72 underlie a significant fraction of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). This study investigates the frequency of C9ORF72 repeat expansions in clinically diagnosed late-onset Alzheimer’s disease (AD).
Design, setting and patients
This case-control study genotyped the C9ORF72 repeat expansion in 872 unrelated familial AD cases and 888 controls recruited as part of the NIA-LOAD cohort, a multi-site collaboration studying 1000 families with two or more individuals clinically diagnosed with late-onset-AD.
Main Outcome Measure
We determined the presence or absence of the C9ORF72 repeat expansion by repeat-primed PCR, the length of the longest non-expanded allele, segregation of the genotype with disease, and clinical features of repeat expansion carriers.
Results
Three families showed large C9ORF72 hexanucleotide repeat expansions. Two additional families carried more than 30 repeats. Segregation with disease could be demonstrated in 3 families. One affected expansion carrier had neuropathology compatible with AD. In the NIA-LOAD series, the C9ORF72 repeat expansions constituted the second most common pathogenic mutation, just behind the PSEN1 A79V mutation, highlighting the heterogeneity of clinical presentations associated with repeat expansions.
Interpretation
C9ORF72 repeat expansions explain a small proportion of patients with a clinical presentation indistinguishable from AD, and highlight the necessity of screening “FTD genes” in clinical AD cases with strong family history.
doi:10.1001/2013.jamaneurol.537
PMCID: PMC3681841  PMID: 23588422
2.  Exome sequencing reveals DNAJB6 mutations in dominantly-inherited myopathy 
Annals of Neurology  2012;71(3):407-416.
Objective
To identify the causative gene in an autosomal dominant limb-girdle muscular dystrophy (LGMD) with skeletal muscle vacuoles.
Methods
Exome sequencing was used to identify candidate mutations in the studied pedigree. Genome-wide linkage was then used to narrow the list of candidates to a single disease-associated mutation. Additional pedigrees with dominant or sporadic myopathy were screened for mutations in the same gene (DNAJB6) using exome sequencing. Skeletal muscle from affected patients was evaluated with histochemistry and immunohistochemical stains for dystrophy-related proteins, SMI-31, TDP43, and DNAJB6.
Results
Exome analysis in three affected individuals from a family with dominant limb-girdle muscular dystrophy and vacuolar pathology identified novel candidate mutations in 22 genes. Linkage analysis excluded all variants except a Phe93Leu mutation in the G/F domain of the DNAJB6 gene, which resides within the LGMD 1E locus at 7q36. Analysis of exome sequencing data from other pedigrees with dominant myopathy identified a second G/F domain mutation (Pro96Arg) in DNAJB6. Affected muscle showed mild dystrophic changes, vacuoles, and abnormal aggregation of proteins, including TDP-43 and DNAJB6 itself.
Interpretation
Mutations within the G/F domain of DNAJB6 are a novel cause of dominantly-inherited myopathy. DNAJB6 is a member of the HSP40/DNAJ family of molecular co-chaperones tasked with protecting client proteins from irreversible aggregation during protein synthesis or during times of cellular stress. The abnormal accumulation of several proteins in patient muscle, including DNAJB6 itself, suggest that DNAJB6 function is compromised by the identified G/F domain mutations.
doi:10.1002/ana.22683
PMCID: PMC3314127  PMID: 22334415
3.  The influence of moisture content variation on fungal pigment formation in spalted wood 
AMB Express  2012;2:69.
Eight fungal species known to produce wood pigmentation were tested for reaction to various moisture contents in two hardwood species. Fungal pigmentation by Trametes versicolor and Xylaria polymorpha was stimulated at low water concentrations in both Acer saccharum (sugar maple) and Fagus grandifolia (American beech), while Inonotus hispidus and Polyporus squamosus were stimulated above 22-28% and 34-38% moisture content in beech and in sugar maple respectively. Fomes fomentarius and Polyporus brumalis produced maximum pigmentation in beech at 26 - 41% and in sugar maple at 59 - 96% moisture content. The pink staining Scytalidium cuboideum pigmented both wood species at above 35% moisture content. This research indicates that controlling the moisture content values of wood substrates can stimulate the intensity of pigmentation of specific fungi when spalting wood for decorative and commercial purpose.
doi:10.1186/2191-0855-2-69
PMCID: PMC3577483  PMID: 23245292
Fungal melanin; Pigment; Moisture content; Spalting
4.  Stimulating growth and xylindein production of Chlorociboria aeruginascens in agar-based systems 
AMB Express  2012;2:15.
Four isolates of Chlorociboria aeruginascens were tested for possible stimulatory effects when grown on malt agar media containing wood additives. The addition of any of the four types of test wood (Acer saccharum, Populus tremuloides, spalted P. tremuloides, and Ailanthus altissima), stimulated colony growth and xylindein production in C. aeruginascens. Addition of any amount of wood produced more growth than no wood additions, while ground wood produced more growth than chopped wood. Of the wood types tested, A. saccharum wood stimulated all four isolates, while spalted Populus tremuloides stimulated three of the four isolates. High glucose and sucrose amounts may be partially responsible for the greater stimulatory affect of some woods over others. The development of this simple and reliable method for growth and pigment stimulation of C. aeruginascens in laboratory conditions will allow for further development of this fungus for decorative and commercial use.
doi:10.1186/2191-0855-2-15
PMCID: PMC3350399  PMID: 22409931
Chlorociboria; Green Pigment; Spalting; Xylindein
5.  How to avoid a misdiagnosis in patients presenting with transient loss of consciousness 
Postgraduate Medical Journal  2006;82(972):630-641.
Daily in the UK, frontline medical and paramedical staff are required to manage patients with “collapse ?cause”. This universal colloquialism refers to patients who have had an abrupt loss of postural tone. Some of these patients would have had a “blackout” or a transient loss of consciousness (T‐LOC). The three most important causes of T‐LOC are syncope, epilepsy and psychogenic blackouts. Determining the correct cause is an important challenge; if the initial clinical diagnosis is wrong, investigations may be misdirected, and the final diagnosis and treatment incorrect. Syncope is much more common than epilepsy and may present with symptoms akin to the latter. This fact is not well appreciated and often leads to misdiagnosis. This article deals with the clinical features of the three main causes of blackouts, the value of investigations in arriving at a diagnosis and the problem of misdiagnosis. Pathways for managing patients presenting with blackouts are suggested.
doi:10.1136/pgmj.2006.046565
PMCID: PMC2653900  PMID: 17068273
blackouts; syncope; epilepsy; psychogenic blackouts; misdiagnosis
6.  Diagnosis and management of patients with blackouts 
Heart  2006;92(4):559-568.
doi:10.1136/hrt.2005.068650
PMCID: PMC1860900  PMID: 16537784
blackout; transient loss of consciousness; epilepsy; syncope
7.  The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial 
Lancet  2007;369(9566):1000-1015.
Summary
Background
Carbamazepine is widely accepted as a drug of first choice for patients with partial onset seizures. Several newer drugs possess efficacy against these seizure types but previous randomised controlled trials have failed to inform a choice between these drugs. We aimed to assess efficacy with regards to longer-term outcomes, quality of life, and health economic outcomes.
Methods
SANAD was an unblinded randomised controlled trial in hospital-based outpatient clinics in the UK. Arm A recruited 1721 patients for whom carbamazepine was deemed to be standard treatment, and they were randomly assigned to receive carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate. Primary outcomes were time to treatment failure, and time to 12-months remission, and assessment was by both intention to treat and per protocol. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN38354748.
Findings
For time to treatment failure, lamotrigine was significantly better than carbamazepine (hazard ratio [HR] 0·78 [95% CI 0·63–0·97]), gabapentin (0·65 [0·52–0·80]), and topiramate (0·64 [0·52–0·79]), and had a non-significant advantage compared with oxcarbazepine (1·15 [0·86–1·54]). For time to 12-month remission carbamazepine was significantly better than gabapentin (0·75 [0·63–0·90]), and estimates suggest a non-significant advantage for carbamazepine against lamotrigine (0·91 [0·77–1·09]), topiramate (0·86 [0·72–1·03]), and oxcarbazepine (0·92 [0·73–1·18]). In a per-protocol analysis, at 2 and 4 years the difference (95% CI) in the proportion achieving a 12-month remission (lamotrigine-carbamazepine) is 0 (−8 to 7) and 5 (−3 to 12), suggesting non-inferiority of lamotrigine compared with carbamazepine.
Interpretation
Lamotrigine is clinically better than carbamazepine, the standard drug treatment, for time to treatment failure outcomes and is therefore a cost-effective alternative for patients diagnosed with partial onset seizures.
doi:10.1016/S0140-6736(07)60460-7
PMCID: PMC2080688  PMID: 17382827
8.  The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial 
Lancet  2007;369(9566):1016-1026.
Summary
Background
Valproate is widely accepted as a drug of first choice for patients with generalised onset seizures, and its broad spectrum of efficacy means it is recommended for patients with seizures that are difficult to classify. Lamotrigine and topiramate are also thought to possess broad spectrum activity. The SANAD study aimed to compare the longer-term effects of these drugs in patients with generalised onset seizures or seizures that are difficult to classify.
Methods
SANAD was an unblinded randomised controlled trial in hospital-based outpatient clinics in the UK. Arm B of the study recruited 716 patients for whom valproate was considered to be standard treatment. Patients were randomly assigned to valproate, lamotrigine, or topiramate between Jan 12, 1999, and Aug 31, 2004, and follow-up data were obtained up to Jan 13, 2006. Primary outcomes were time to treatment failure, and time to 1-year remission, and analysis was by both intention to treat and per protocol. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN38354748.
Findings
For time to treatment failure, valproate was significantly better than topiramate (hazard ratio 1·57 [95% CI 1·19–2·08]), but there was no significant difference between valproate and lamotrigine (1·25 [0·94–1·68]). For patients with an idiopathic generalised epilepsy, valproate was significantly better than both lamotrigine (1·55 [1·07–2·24] and topiramate (1·89 [1·32–2·70]). For time to 12-month remission valproate was significantly better than lamotrigine overall (0·76 [0·62–0·94]), and for the subgroup with an idiopathic generalised epilepsy 0·68 (0·53–0·89). But there was no significant difference between valproate and topiramate in either the analysis overall or for the subgroup with an idiopathic generalised epilepsy.
Interpretation
Valproate is better tolerated than topiramate and more efficacious than lamotrigine, and should remain the drug of first choice for many patients with generalised and unclassified epilepsies. However, because of known potential adverse effects of valproate during pregnancy, the benefits for seizure control in women of childbearing years should be considered.
doi:10.1016/S0140-6736(07)60461-9
PMCID: PMC2039891  PMID: 17382828
9.  S100 and Cytokine Expression in Caries  
Infection and Immunity  2004;72(7):4102-4108.
The molecular immune response of the pulpal tissue during chronic carious infection is poorly characterized. Our objective was to examine the expression of potential molecular mediators of pulpal inflammation, correlate their levels with disease severity, and determine the cellular localization of key molecules. Results indicated that there was significantly increased transcriptional activity in carious compared to healthy pulp, and the increase correlated positively with disease severity. Semiquantitative reverse transcriptase PCR analysis in 10 carious and 10 healthy pulpal tissue samples of the S100 family members S100A8, S100A9, S100A10, S100A12, and S100A13; the cytokines tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), IL-8, IL-6, and epithelial cell-derived neutrophil attractant 78 (ENA-78); and the structural protein collagen-1α indicated that all genes tested, with the exception of S100A10, were more abundantly expressed in carious teeth. In addition, we found that the closer the carious lesion front was to the pulpal chamber the higher the expression was for all genes except S100A10. Multiple-regression analysis identified a significant positive correlation between the expression levels of S100A8 and IL-1β, ENA-78, and IL-6 and between collagen-1α and S100A8, TNF-α, IL-1β, IL-8, IL-6, and ENA-78. Immunohistochemical studies in carious pulpal tissue indicated that S100A8 and the S100A8/S100A9 complex were predominantly expressed by infiltrating neutrophils. Gene expression analyses in immune system cells supported these findings and indicated that bacterial activation of neutrophils caused upregulation of S100A8, S100A9, and S100A13. This study highlights the complex nature of the molecular immune response that occurs during carious infection.
doi:10.1128/IAI.72.7.4102-4108.2004
PMCID: PMC427449  PMID: 15213155
10.  Perioperative Complications of Transseptosphenoidal Excision for Pituitary Adenomas 
Skull base surgery  1996;6(4):231-235.
Although complications of transseptosphenoidal (TSS) pituitary surgery have been discussed in the literature, there has not been an analysis of complication rates related to clinical features and the nature of the tumor. A retrospective review of 366 TSS procedures (354 patients) for excision of pituitary adenomas evaluated the incidence and management of perioperative complications. The mortality rate was 0.82%. The most frequently encountered complications were transient diabetes insipidus (8.74%) and cerebrospinal fluid (CSF) rhinorrhea (4.10%). Other complications included exacerbation of visual acuity and visual field defects, hemorrhage, hydrocephalus, and meningitis. The factors evaluated were gender, age, tumor size, hormone secretory status, and any history of prior pituitary surgery.
There was a significantly higher incidence of transient diabetes insipidus in patients with hormone-secreting tumors. Minor and total complication rates were significantly increased in microadenomas, hormone-secreting tumors, in female patients, and in patients less than 60 years of age reflecting the increased incidence of transient diabetes insipidus in young female patients with hormone-secreting tumors. Observed intraoperative CSF leaks predisposed to postoperative CSF rhinorrhea. There were no identifiable risk factors for major complications.
PMCID: PMC1656618  PMID: 17171014
12.  An evaluation of the A4 folder system in general practice 
All 63 general practices known to have introduced the A4 folder system were asked to complete questionnaires comparing A4 records with the traditional medical records envelope system. Of the 77 per cent who replied, an overwhelming majority favoured the A4 system and felt that it helped them to obtain higher standards of care for patients.
PMCID: PMC2159121  PMID: 480299

Results 1-12 (12)