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1.  Characteristics of Frontotemporal Dementia Patients with a Progranulin Mutation 
Annals of neurology  2006;60(3):374-380.
Mutations in the Progranulin gene (PGRN) recently have been discovered to be associated with frontotemporal dementia (FTD) linked to 17q21 without identified MAPT mutations. The range of mutations of PGRN that can result in the FTD phenotype and the clinical presentation of patients with PGRN mutations have yet to be determined.
In this study, we examined 84 FTD patients from families not known previously to have illness linked to chromosome 17 for identified PGRN and MAPT mutations and sequenced the coding exons and the flanking intronic regions of PGRN. We compared the prevalence, clinical characteristics, magnetic resonance imaging and 18-fluoro-deoxyglucose positron emission tomography results, and neuropsychological testing of patients with the PGRN R493X mutation with those patients without identified PGRN mutations.
We discovered a new PGRN mutation (R493X) resulting in a stop codon in two patients. This was the only PGRN mutation identified in our sample. The patients with the PGRN R493X mutation had a rapid illness course and had predominant right-sided atrophy and hypometabolism on magnetic resonance imaging and 18-fluoro-deoxyglucose positron emission tomography. The affected father of one of the patients with the PGRN R493X mutation showed frontal and temporal atrophy without neurofibrillary tangles on neuropathological examination.
Known PGRN and MAPT mutations were rare and of similar prevalence in our sample (2 compared with 1/84). The patients with the PGRN R493X mutation had a clinical presentation comparable with other behavior-predominant FTD patients. The neuropathology of an affected family member of a patient with the PGRN R493X mutation appears not to be Alzheimer’s disease.
PMCID: PMC2987739  PMID: 16983677
2.  A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis 
Human Molecular Genetics  2009;18(8):1524-1532.
The cause of sporadic amyotrophic lateral sclerosis (ALS) is largely unknown, but genetic factors are thought to play a significant role in determining susceptibility to motor neuron degeneration. To identify genetic variants altering risk of ALS, we undertook a two-stage genome-wide association study (GWAS): we followed our initial GWAS of 545 066 SNPs in 553 individuals with ALS and 2338 controls by testing the 7600 most associated SNPs from the first stage in three independent cohorts consisting of 2160 cases and 3008 controls. None of the SNPs selected for replication exceeded the Bonferroni threshold for significance. The two most significantly associated SNPs, rs2708909 and rs2708851 [odds ratio (OR) = 1.17 and 1.18, and P-values = 6.98 × 10−7 and 1.16 × 10−6], were located on chromosome 7p13.3 within a 175 kb linkage disequilibrium block containing the SUNC1, HUS1 and C7orf57 genes. These associations did not achieve genome-wide significance in the original cohort and failed to replicate in an additional independent cohort of 989 US cases and 327 controls (OR = 1.18 and 1.19, P-values = 0.08 and 0.06, respectively). Thus, we chose to cautiously interpret our data as hypothesis-generating requiring additional confirmation, especially as all previously reported loci for ALS have failed to replicate successfully. Indeed, the three loci (FGGY, ITPR2 and DPP6) identified in previous GWAS of sporadic ALS were not significantly associated with disease in our study. Our findings suggest that ALS is more genetically and clinically heterogeneous than previously recognized. Genotype data from our study have been made available online to facilitate such future endeavors.
PMCID: PMC2664150  PMID: 19193627
3.  Sigma ligands, but not N-methyl-d-aspartate antagonists, reduce levodopa-induced dyskinesias 
Neuroreport  2008;19(1):111-115.
Levodopa (l-DOPA) is the ‘gold standard’ to treat Parkinson's disease. Unfortunately, dyskinesias detract from its efficacy. Current dyskinesia treatments, including amantadine and dextromethorphan, are thought to work via N-methyl-d-aspartate (NMDA) antagonism, but this hypothesis has not been tested. The NMDA antagonists MK- 801and HA-966 failed to suppress expression of dyskinesias in the 6-hydroxydopamine rat. Dyskinesias, however, were suppressed by the NMDA and sigma (σ)-1receptor ligand dextromethorphan and by the σ-1 antagonist BMY-14802. Antidyskinetic effects of dextromethorphan may be mediated via mechanisms other than NMDA, including the σ-1 receptor and other binding sites common to dextromethorphan and BMY-14802.
PMCID: PMC2845294  PMID: 18281903
6-hydroxydopamine; levodopa-induced dyskinesias; N-methyl-d-aspartate; Parkinson's disease; rat; sigma
4.  Analysis of IFT74 as a candidate gene for chromosome 9p-linked ALS-FTD 
BMC Neurology  2006;6:44.
A new locus for amyotrophic lateral sclerosis – frontotemporal dementia (ALS-FTD) has recently been ascribed to chromosome 9p.
We identified chromosome 9p segregating haplotypes within two families with ALS-FTD (F476 and F2) and undertook mutational screening of candidate genes within this locus.
Candidate gene sequencing at this locus revealed the presence of a disease segregating stop mutation (Q342X) in the intraflagellar transport 74 (IFT74) gene in family 476 (F476), but no mutation was detected within IFT74 in family 2 (F2). While neither family was sufficiently informative to definitively implicate or exclude IFT74 mutations as a cause of chromosome 9-linked ALS-FTD, the nature of the mutation observed within F476 (predicted to truncate the protein by 258 amino acids) led us to sequence the open reading frame of this gene in a large number of ALS and FTD cases (n = 420). An additional sequence variant (G58D) was found in a case of sporadic semantic dementia. I55L sequence variants were found in three other unrelated affected individuals, but this was also found in a single individual among 800 Human Diversity Gene Panel samples.
Confirmation of the pathogenicity of IFT74 sequence variants will require screening of other chromosome 9p-linked families.
PMCID: PMC1764752  PMID: 17166276
5.  GIDEON: a comprehensive Web-based resource for geographic medicine 
GIDEON (Global Infectious Diseases and Epidemiology Network) is a web-based computer program designed for decision support and informatics in the field of Geographic Medicine. The first of four interactive modules generates a ranked differential diagnosis based on patient signs, symptoms, exposure history and country of disease acquisition. Additional options include syndromic disease surveillance capability and simulation of bioterrorism scenarios. The second module accesses detailed and current information regarding the status of 338 individual diseases in each of 220 countries. Over 50,000 disease images, maps and user-designed graphs may be downloaded for use in teaching and preparation of written materials. The third module is a comprehensive source on the use of 328 anti-infective drugs and vaccines, including a listing of over 9,500 international trade names. The fourth module can be used to characterize or identify any bacterium or yeast, based on laboratory phenotype. GIDEON is an up-to-date and comprehensive resource for Geographic Medicine.
PMCID: PMC1090610  PMID: 15847698
6.  Clinical Significance and Antibiotic Resistance Patterns of Leminorella spp., an Emerging Nosocomial Pathogen 
Journal of Clinical Microbiology  2000;38(8):3036-3038.
Although Leminorella spp., members of the family Enterobacteriaceae, were previously isolated from feces and urine specimens, clinical correlates have not been studied. We conducted a retrospective study to investigate the clinical significance and disease spectrum of these organisms, as well as their antibiotic susceptibility patterns. Identification and susceptibility testing were performed by an automated system. Eighteen cases were identified retrospectively during a 28-month period (1/97 to 4/99), representing an incidence of 11 cases per 100,000 patient admissions. The medical records of 14 patients were reviewed. The average patient age was 67 years, and 78% were males. Patients had multiple and diverse underlying conditions which might have predisposed them to infection. Leminorella spp. were classified as definite pathogens in 43% of the cases, probable pathogens in 29%, and possible pathogens in 21%. In one case of asymptomatic bacteriuria, the isolate had no clinical significance. All infections but one were nosocomial. Clinical syndromes included urinary tract infection in six patients, surgical site infection in three patients, and primary bacteremia, peritonitis, respiratory tract infection, and soft tissue infection in one patient each. Isolates were uniformly susceptible to imipenem. Other beta-lactam agents had poor activity against the isolates. We conclude that Leminorella spp. are significant nosocomial pathogens that are capable of causing a variety of clinical syndromes and are resistant to multiple antibiotic agents.
PMCID: PMC87180  PMID: 10921973
8.  Group VE-1 Septicemia 
Journal of Clinical Microbiology  1983;17(5):926-927.
A severely immunocompromised patient developed septicemia while under treatment for pancreatitis. An organism isolated from three separate blood cultures was identified as CDC group VE-1. The biochemical characteristics, taxonomy, and antibiotic sensitivity of this organism are presented.
PMCID: PMC272768  PMID: 6863512
9.  Penetration of Clindamycin into Decubitus Ulcers 
Forty tissue samples, primarily of skin and bone, were obtained from 29 patients undergoing excision of decubitus ulcers after intravenous injection of 600 mg of clindamycin. Antibiotic concentrations exceeded 2.5 μg/g in 80% of the samples. In 50% of the instances, tissue levels were greater than those simultaneously present in the serum.
PMCID: PMC352490  PMID: 708028
10.  Comparative Pharmacokinetics of Cefamandole, Cephapirin, and Cephalothin in Healthy Subjects and Effect of Repeated Dosing 
Cefamandole nafate, cephapirin, and cephalothin were administered intravenously in crossover fashion to 12 volunteers, in dosages of 2 g every 6 h for 16 doses. Mean peak levels of cefamandole were approximately 50% higher than those of the other agents. The serum concentration curves appeared to decline bi-exponentially, suggesting that a two-compartment model was most applicable for pharmacokinetic analysis; accordingly, the t½ of cefamandole was significantly longer when the serum peak was omitted from the analysis (0.86 versus 0.73 h, P < 0.05). The half-lives of cephalothin and cephapirin, 0.34 and 0.36 h, respectively, were probably underestimates reflecting the inclusion of distribution-phase values in the calculation. Repeated dosing had no effect on the peak serum levels, half-life, serum clearance, or apparent volume of distribution with one exception: peak serum levels of cephapirin were significantly lower after the sixteenth than after the first dose. Marked variations within a given subject were noted in the half-life and apparent volume of distribution of cefamandole in several instances. Renal clearances of cefamandole exhibited saturation kinetics similar to those of penicillin G.
PMCID: PMC429764  PMID: 984783
11.  Activity of Cefamandole and Other Cephalosporins Against Aerobic and Anaerobic Bacteria 
The activity of cefamandole was comparable to that of cephalothin, cefazolin, and cephaloridine against Staphylococcus aureus, Streptococcus pyogenes, and Diplococcus pneumoniae. In contrast, cefamandole was considerably more active than cephalothin, cefazolin, or cephaloridine against gram-negative facultative bacilli, including Haemophilus influenzae, the most striking disparities being noted with indole-positive Proteus and Enterobacter. Bacteroides fragilis was more susceptible to cefoxitin than to cefamandole or cefazolin (median minimal inhibitory concentration, approximately 8, 32, and 32 μg/ml, respectively); cephalothin exhibited still less activity against this species. The majority of other anaerobes were inhibited by relatively low concentrations of all four cephalosporins. The results indicate a potentially valuable role for cefamandole against facultative gram-negative bacilli, including H. influenzae, but no exceptional activity against anaerobes.
PMCID: PMC429632  PMID: 949182
12.  Comparative Incidence of Phlebitis Due to Buffered Cephalothin, Cephapirin, and Cefamandole 
Buffered cephalothin, cefamandole, and cephapirin were compared with respect to their tendency to produce phlebitis. Two grams of each agent was administered every 6 h for 4 days to 12 healthy volunteers in a double-blind crossover fashion. Approximately 50% of intravenous sites developed mild (grade 1) phlebitis and 25% developed moderate (grade 2) phlebitis. The frequency of grade 1 inflammation did not differ significantly among the three cephalosporins. The proportion of individuals eventually exhibiting grade 2 phelebitis was highest with cefamandole, lowest with cephalothin (P = 0.07), and intermediate with cephapirin; however, cephapirin required a substantially greater number of doses to produce grade 2 phelebitis than did the other two drugs. These findings, together with the results of other reports, suggest that interpretation of the phlebitogenic potential of these antibiotics must be made with caution.
PMCID: PMC429579  PMID: 5053

Results 1-12 (12)