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1.  Neuronal Nicotinic Receptor Agonists Improve Gait and Balance in Olivocerebellar Ataxia 
Neuropharmacology  2013;73:75-86.
Clinical evidence indicates that the nicotinic receptor agonist varenicline improves axial symptoms in patients with spinocerebellar ataxia type 3, but pharmacological evidence in an animal model of olivocerebellar degeneration has not been demonstrated. This study investigated whether varenicline and nicotine were efficacious for attenuating ataxia in rats induced by chemical destruction of the olivocerebellar pathway. Rats were trained to maintain their balance on a rotating rod and walk across a stationary beam; rod and beam performance, locomotor activity, and gait were assessed prior to and after administration of the neurotoxin 3-acetylpyridine (3-AP). The administration of 3-AP led to an 85% loss of neurons in the inferior olive at one week after administration without evidence of recovery over the following 4 weeks. The lesion was accompanied by a 72% decrease in rotorod activity, a 3.1-fold increase in the time required to traverse a stationary beam, a 19% decrease in velocity and 31% decrease in distance moved in the open field, and alterations in both forepaw and hindpaw gait parameters, with a 19% increase in hindpaw stride width. The daily administration of nicotine (0.33 mg free base/kg) improved rotorod performance by 50%, an effect apparent following the first week of administration, and which did not improve further over time. Nicotine also normalized the increased hindpaw stride width induced by the lesion. The ability of nicotine to alleviate both rotorod and gait deficits induced by 3-AP were prevented by the administration of the nicotinic antagonist mecamylamine (0.8 mg free base/kg) prior to the daily administration of nicotine. The effects of varenicline were dose-related and doses of 1.0 and 3.0 mg free base/kg daily improved rotorod performance by approximately 50% following the first week of administration. Further, varenicline did not alter the time required for animals to traverse the stationary beam, but did improve the ability of rats to maintain their balance on the beam by increasing lateral tail movements following 3 weeks of administration at doses of 0.3 and 1.0 mg free base/kg daily. Further, doses of nicotine and varenicline that improved the impaired balance and gait did not affect any measure of locomotor activity in the open field. Results provide evidence that nicotinic agonists are of benefit for alleviating some of the behavioral deficits in olivocerebellar ataxia and warrant further studies to elucidate the specific mechanism(s) involved.
PMCID: PMC3766486  PMID: 23711550
Ataxia; neuronal nicotinic receptors; nicotine; olivocerebellar degeneration; varenicline
2.  Seminoma and Embryonal Carcinoma Footprints Identified by Analysis of Integrated Genome-Wide Epigenetic and Expression Profiles of Germ Cell Cancer Cell Lines 
PLoS ONE  2014;9(6):e98330.
Originating from Primordial Germ Cells/gonocytes and developing via a precursor lesion called Carcinoma In Situ (CIS), Germ Cell Cancers (GCC) are the most common cancer in young men, subdivided in seminoma (SE) and non-seminoma (NS). During physiological germ cell formation/maturation, epigenetic processes guard homeostasis by regulating the accessibility of the DNA to facilitate transcription. Epigenetic deregulation through genetic and environmental parameters (i.e. genvironment) could disrupt embryonic germ cell development, resulting in delayed or blocked maturation. This potentially facilitates the formation of CIS and progression to invasive GCC. Therefore, determining the epigenetic and functional genomic landscape in GCC cell lines could provide insight into the pathophysiology and etiology of GCC and provide guidance for targeted functional experiments.
This study aims at identifying epigenetic footprints in SE and EC cell lines in genome-wide profiles by studying the interaction between gene expression, DNA CpG methylation and histone modifications, and their function in the pathophysiology and etiology of GCC. Two well characterized GCC-derived cell lines were compared, one representative for SE (TCam-2) and the other for EC (NCCIT). Data were acquired using the Illumina HumanHT-12-v4 (gene expression) and HumanMethylation450 BeadChip (methylation) microarrays as well as ChIP-sequencing (activating histone modifications (H3K4me3, H3K27ac)). Results indicate known germ cell markers not only to be differentiating between SE and NS at the expression level, but also in the epigenetic landscape.
The overall similarity between TCam-2/NCCIT support an erased embryonic germ cell arrested in early gonadal development as common cell of origin although the exact developmental stage from which the tumor cells are derived might differ. Indeed, subtle difference in the (integrated) epigenetic and expression profiles indicate TCam-2 to exhibit a more germ cell-like profile, whereas NCCIT shows a more pluripotent phenotype. The results provide insight into the functional genome in GCC cell lines.
PMCID: PMC4041891  PMID: 24887064
3.  Role of SOX2 in the Etiology of Embryonal Carcinoma, Based on Analysis of the NCCIT and NT2 Cell Lines 
PLoS ONE  2014;9(1):e83585.
The transcription factor SOX2, associated with amongst others OCT3/4, is essential for maintenance of pluripotency and self-renewal of embryonic stem cells. SOX2 is highly expressed in embryonal carcinoma (EC), the stem cell component of malignant nonseminomatous germ cell tumors, referred to as germ cell cancer (GCC). In fact, OCT3/4 together with SOX2 is an informative diagnostic tool for EC in a clinical setting. Several studies support the hypothesis that SOX2 is a relevant oncogenic factor in various cancers and recently, SOX2 has been suggested as a putative therapeutic target for early stage EC. We demonstrate the presence of genomic amplification of SOX2 in an EC cell line, NCCIT, using array comparative genome hybridization and fluorescence in situ hybridization. Down-regulation of SOX2 by targeted siRNA provokes NCCIT cells towards apoptosis, while inhibition of OCT3/4 expression induced differentiation, with retained SOX2 levels. Mice pluripotent xenografts from NCCIT (N-NCCIT and N2-NCCIT) show a consistent SOX2 expression, in spite of loss of the expression of OCT3/4, and differentiation, with retained presence of genomic amplification. No SOX2 amplification has been identified in primary pure and mixed EC in vivo patient samples so far. The data presented in this study are based on a single EC cell line with a SOX2 amplification, with NT2 as control EC cell line, showing no profound induction of apoptosis upon SOX2 downregulation. The findings are of relevance to identify mechanisms involved in the pathogenesis of EC tumors, and support the model of SOX2-oncogene dependency of EC, which however, does not exclude induction of differentiation. This finding is likely related to the presence of wild type p53 in GCC, resulting in expression of downstream target genes, amongst others miR-34a, miR-145 and SOX2, associated to the unique sensitivity of GCC to DNA damaging agents.
PMCID: PMC3880257  PMID: 24404135
4.  HOXC9 directly regulates distinct sets of genes to coordinate diverse cellular processes during neuronal differentiation 
BMC Genomics  2013;14:830.
Cellular differentiation is characterized by the acquisition of specialized structures and functions, cell cycle exit, and global attenuation of the DNA damage response. It is largely unknown how these diverse cellular events are coordinated at the molecular level during differentiation. We addressed this question in a model system of neuroblastoma cell differentiation induced by HOXC9.
We conducted a genome-wide analysis of the HOXC9-induced neuronal differentiation program. Microarray gene expression profiling revealed that HOXC9-induced differentiation was associated with transcriptional regulation of 2,370 genes, characterized by global upregulation of neuronal genes and downregulation of cell cycle and DNA repair genes. Remarkably, genome-wide mapping by ChIP-seq demonstrated that HOXC9 bound to 40% of these genes, including a large number of genes involved in neuronal differentiation, cell cycle progression and the DNA damage response. Moreover, we showed that HOXC9 interacted with the transcriptional repressor E2F6 and recruited it to the promoters of cell cycle genes for repressing their expression.
Our results demonstrate that HOXC9 coordinates diverse cellular processes associated with differentiation by directly activating and repressing the transcription of distinct sets of genes.
PMCID: PMC3906982  PMID: 24274069
Neuronal differentiation; Cell cycle arrest; DNA damage response; E2F6; HOXC9; Neuroblastoma
5.  Prevalence of the variant allele rs61764370 T>G in the 3′UTR of KRAS among Dutch BRCA1, BRCA2 and non-BRCA1/BRCA2 breast cancer families 
Recently, a variant allele in the 3′UTR of the KRAS gene (rs61764370 T>G) was shown to be associated with an increased risk for developing non-small cell lung cancer, as well as ovarian cancer, and was most enriched in ovarian cancer patients from hereditary breast and ovarian cancer families. This functional variant has been shown to disrupt a let-7 miRNA binding site leading to increased expression of KRAS in vitro. In the current study, we have genotyped this KRAS-variant in breast cancer index cases from 268 BRCA1 families, 89 BRCA2 families, 685 non-BRCA1/BRCA2 families, and 797 geographically matched controls. The allele frequency of the KRAS-variant was found to be increased among patients with breast cancer from BRCA1, but not BRCA2 or non-BRCA1/BRCA2 families as compared to controls. As BRCA1 carriers mostly develop ER-negative breast cancers, we also examined the variant allele frequency among indexes from non-BRCA1/BRCA2 families with ER-negative breast cancer. The prevalence of the KRAS-variant was, however, not significantly increased as compared to controls, suggesting that the variant allele not just simply associates with ER-negative breast cancer. Subsequent expansion of the number of BRCA1 carriers with breast cancer by including other family members in addition to the index cases resulted in loss of significance for the association between the variant allele and mutant BRCA1 breast cancer. In this same cohort, the KRAS-variant did not appear to modify breast cancer risk for BRCA1 carriers. Importantly, results from the current study suggest that KRAS-variant frequencies might be increased among BRCA1 carriers, but solid proof requires confirmation in a larger cohort of BRCA1 carriers.
PMCID: PMC3735357  PMID: 20676756
KRAS-variant; Let-7; Breast cancer susceptibility; Association; BRCA1
6.  Episodic ataxia and hemiplegia caused by the 8993T→C mitochondrial DNA mutation 
Journal of Medical Genetics  2007;44(12):797-799.
The m.8993T→C MTATP6 mutation of mitochondrial DNA (mtDNA) usually causes mitochondrial disease in childhood, but was recently described in a family with adult onset ataxia and polyneuropathy. Cytochrome c oxidase muscle histochemistry, which is the standard clinical investigation for mitochondrial disease in adults, is usually normal in patients with MTATP6 mutations. This raises the possibility that these cases have been missed in the past. We therefore studied 308 patients with unexplained ataxia and 96 patients with suspected Charcot–Marie–Tooth disease to determine whether the m.8993T→C MTATP6 mutation is common in unexplained inherited ataxia and/or polyneuropathy. We identified a three‐generation family with the m.8993T→C mutation of mtDNA. One subject had episodic ataxia (EA) and transient hemipareses, broadening the phenotype. However, no further cases were identified in an additional cohort of 191 patients with suspected EA. In conclusion, m.8993T→C MTATP6 should be considered in patients with unexplained ataxia, CMT or EA, but cases are uncommon.
PMCID: PMC2652821  PMID: 18055910
7.  Genetic Structure in African Populations: Implications for Human Demographic History 
The continent of Africa is the source of all anatomically modern humans that dispersed across the planet during the past 100,000 years. As such, African populations are characterized by high genetic diversity and low levels of linkage disequilibrium (LD) among loci, as compared to populations from other continents. African populations also possess a number of genetic adaptations that have evolved in response to the diverse climates, diets, geographic environments, and infectious agents that characterize the African continent. Recently, Tishkoff et al. (2009) performed a genomewide analysis of substructure based on DNA from 2432 Africans from 121 geographically diverse populations. The authors analyzed patterns of variation at1327 nuclear microsatellite and insertion/deletion markers and identified 14 ancestral population clusters that correlate well with self described ethnicity and shared cultural or linguistic properties. The results suggest that African populations may have maintained a large and subdivided population structure throughout much of their evolutionary history. In this chapter, we synthesize recent work documenting evidence of African population structure and discuss the implications for inferences about evolutionary history in both African populations and anatomically modern humans as a whole.
PMCID: PMC2953761  PMID: 20453204
8.  Designing Tailored Biomaterial Surfaces to Direct Keratinocyte Morphology, Attachment, and Differentiation 
Precisely engineering the surface chemistry of biomaterials to modulate the adsorption and functionality of biochemical signaling molecules that direct cellular functions is critical in the development of tissue engineered scaffolds. Specifically, this study describes the use of functionalized self-assembled monolayers (SAMs) as a model system to assess the effects of biomaterial surface properties on controlling fibronectin (FN) conformation and concentration as well as keratinocyte function. By systematically analyzing FN adsorption at low and saturated surface densities, we distinguished between SAM dependent effects of FN concentration and conformation on presenting cellular binding domains that direct cellular functions. Quantitative image analyses of immunostained samples showed that modulating the availability of the FN synergy site directly correlated with changes in keratinocyte attachment, spreading, and differentiation, through integrin mediated signaling mechanisms. The results of this study will be used to elucidate design features that can be incorporated into dermal equivalents and percutaneous implants to enhance the rate of reepithelialization and tissue regeneration. Furthermore, these findings indicate that SAM based model systems are a valuable tool for designing and investigating the development of scaffolds that regulate the conformation of extracellular matrix cues and cellular functions that accelerate the rate of tissue regeneration.
PMCID: PMC2725218  PMID: 18655147
9.  Effects of constitutively active GTPases on fibroblast behavior 
The GTP-binding proteins RhoA, Cdc42 and Rac1 regulate the organization and turnover of the cytoskeleton and cell-matrix adhesions, structures bridging cells to their support, and translating forces, external or generated within the cell. To investigate the specific requirements of Rho GTPases for biomechanical activities of clonal cell populations, we compared side-by-side stable lines of human fibroblasts expressing constitutively active (CA) RhoA, Cdc42 or Rac1. There was no marked effect of any CA GTPase on cell adhesion to different extracellular matrix proteins. Cell spreading was CA Rho GTPase specific and independent of the extracellular matrix proteins allowing adhesion. Mechanical properties were dramatically restricted by CA RhoA on bi- and in tri-dimensional surroundings, were boosted by CA Rac1 on bi-dimensional surroundings only, and were not or marginally affected by CA Cdc42. In conclusion, the action of Rho GTPases appears to depend on the task cells are performing.
PMCID: PMC2792356  PMID: 16378244
RhoA; Rac1; Cdc42; QL mutants; fibroblast; adhesion; contraction; migration; cytoskeleton
10.  Intracranial placement of nasopharyngeal airways: is it all that rare? 
PMCID: PMC2564185  PMID: 16858116
base of skull fracture; intracranial; nasopharyngeal airway
11.  Fractionated stereotactic radiotherapy in the treatment of pituitary macroadenomas 
Current Oncology  2008;15(6):286-292.
The use of fractionated stereotactic radiotherapy (fsrt) has evolved with technical advances in noninvasive immobilization, radiation delivery, and image guidance. The application of fsrt to pituitary tumours is aimed at reducing toxicity through improved dose conformality and reduced treatment margins. The aim of the present paper is to report our own experience and to review the published data on fsrt for pituitary macroadenomas.
Between September 2000 and October 2005, 13 patients with pituitary macroadenoma underwent fsrt at our institution. In 12 patients, radiotherapy treatment followed surgical resection (transsphenoidal resection in 8, frontal craniotomy in 3, and multiple transsphenoidal resections followed by craniotomy in 1). In 4 patients, the tumours were functional (2 adrenocorticotropic hormone–secreting, 1 prolactinoma, and 1 growth hormone–secreting); the tumours in the remaining patients were clinically non-secretory. Before radiation, 3 patients had panhypopituitarism, and 6 patients had visual field defects. All patients were treated with fsrt using non-coplanar micro–multileaf collimation portals. A median dose of 50.4 Gy (range: 45–60 Gy) was prescribed to the 76.9%–95.2% isodose surface and delivered in 1.8-Gy fractions. The median planning target volume (gross tumour plus 3 mm) was 33.5 cm3 (range: 3.2–75 cm3).
After a median follow-up of 24 months (range: 6–60 months), local control was 100%. One patient achieved clinical complete response. Treatment was well tolerated acutely for all patients. Neither radiation-induced optic neuropathy nor any radiation-related endocrine dysfunction was observed in our patients.
In accordance with published series, we found fsrt to be safe and effective in the management of large pituitary macroadenomas.
PMCID: PMC2601024  PMID: 19079630
Radiotherapy; fractionated stereotactic radiotherapy; macroadenoma; pituitary adenoma
12.  Combination treatment strategies in early rheumatoid arthritis 
Annals of the Rheumatic Diseases  2005;64(9):1252-1256.
PMCID: PMC1755668  PMID: 15860511
13.  Colonic IgA producing cells and macrophages are reduced in recurrent and non-recurrent Clostridiumdifficile associated diarrhoea 
Journal of Clinical Pathology  2004;57(9):973-979.
Background: In Clostridium difficile associated diarrhoea (CDAD), histological changes in the colonic mucosa range from minimal inflammation to pseudomembranous colitis (PMC). The disease also recurs in a considerable proportion of patients.
Aim: To investigate mucosal immune system cells in colonic biopsies of patients with CDAD.
Methods: Colonic biopsies were obtained from 12 control patients with diarrhoea, six patients with CDAD and minimal inflammation, and 10 patients with CDAD with pseudomembranous colitis (samples obtained from areas with and without inflammatory exudate). Immunohistochemical studies were performed using antibodies to T cells (CD3), macrophages (CD68), B/plasma cells (CD79α), and to IgA, IgM, and IgG. Labelled cells in lamina propria were quantified.
Results: In contrast to T cells, there were significant reductions in B/plasma cell and macrophage counts in all biopsies from patients with CDAD compared with controls (p<0.001). Studies using anti-immunoglobulin antibodies showed significant reductions in IgA producing cells in CDAD biopsies (p<0.05), with the greatest reduction in samples from patients with PMC. In contrast, there was a significant increase (p<0.05) in IgG producing cells in CDAD biopsies. Only patients with PMC relapsed. In these patients, B/plasma cell and IgA producing cell counts (in biopsies with and without inflammatory exudates) were significantly lower (p<0.01) in mucosal samples from those who subsequently relapsed (five) than those who did not.
Conclusions: A selective reduction in mucosal IgA producing cells and macrophages is associated with colonic disease in C difficile infected patients. Severe reduction in colonic IgA producing cells may predispose to recurrence of CDAD.
PMCID: PMC1770426  PMID: 15333661
B cells; Clostridium difficile toxins; plasma cells; mucosal immunology; pseudomembranous colitis
14.  Simple DNA Extraction Method for Dried Blood Spots and Comparison of Two PCR Assays for Diagnosis of Vertical Human Immunodeficiency Virus Type 1 Transmission in Rwanda 
Dried blood spots (DBS) on filter paper facilitate the collection, transport, and storage of blood samples for laboratory use. A rapid and simple DNA extraction procedure from DBS was developed and evaluated for the diagnosis of human immunodeficiency virus type 1 (HIV-1) infection in children by an in-house nested-PCR assay on three genome regions and by the Amplicor HIV-1 DNA prototype assay version 1.5 (Roche Molecular Systems). A total of 150 samples from children born to HIV-1-infected mothers were collected in Kigali, Rwanda, in parallel as DBS and as peripheral blood mononuclear cell (PBMC) pellets. The results obtained on DBS by the two PCR assays were compared to the results of nested PCR on PBMCs. Of 150 PBMC samples, 10 were positive, 117 were negative, and 23 were indeterminate for HIV-1 infection. In DNA extracted from filter papers and amplified by using the in-house nested PCR, 9 of these 10 positive samples (90%) were found to be positive, and 1 was found to be indeterminate (only the pol region could be amplified). All of the negative samples and all of the 23 indeterminate samples tested negative for HIV-1 infection. When we used the Amplicor DNA test on DBS, all of the 10 PBMC-positive samples were found to be positive and all of the 23 indeterminate samples were found to be negative. Of the PBMC-negative samples, 115 were found to be negative and 2 were found to be indeterminate. We conclude that this simple rapid DNA extraction method on DBS in combination with both detection methods gave a reliable molecular diagnosis of HIV-1 infection in children born to HIV-infected mothers.
PMCID: PMC321659  PMID: 14715726
15.  Attenuated Signature-Tagged Mutagenesis Mutants of Brucella melitensis Identified during the Acute Phase of Infection in Mice  
Infection and Immunity  2003;71(12):7053-7060.
For this study, we screened 1,152 signature-tagged mutagenesis mutants of Brucella melitensis 16M in a mouse model of infection and found 36 of them to be attenuated in vivo. Molecular characterization of transposon insertion sites showed that for four mutants, the affected genes were only present in Rhizobiaceae. Another mutant contained a disruption in a gene homologous to mosA, which is involved in rhizopine biosynthesis in some strains of Rhizobium, suggesting that this sugar may be involved in Brucella pathogenicity. A mutant was disrupted in a gene homologous to fliF, a gene potentially coding for the MS ring, a basal component of the flagellar system. Surprisingly, a mutant was affected in the rpoA gene, coding for the essential α-subunit of the RNA polymerase. This disruption leaves a partially functional protein, impaired for the activation of virB transcription, as demonstrated by the absence of induction of the virB promoter in the Tn5::rpoA background. The results presented here highlight the fact that the ability of Brucella to induce pathogenesis shares similarities with the molecular mechanisms used by both Rhizobium and Agrobacterium to colonize their hosts.
PMCID: PMC308902  PMID: 14638795
16.  Mining Microarray Datasets Aided by Knowledge Stored in Literature 
DNA microarray technology produces large amounts of data. For data mining of these datasets, background information on genes can be helpful. Unfortunately most information is stored in free text. Here, we present an approach to use this information for DNA microarray data mining.
PMCID: PMC1480300  PMID: 14728384
17.  Decreased Production of Local Immunoglobulin A to Pneumocystis carinii in Bronchoalveolar Lavage Fluid from Human Immunodeficiency Virus-Positive Patients 
Infection and Immunity  2000;68(3):1054-1060.
An enzyme-linked immunosorbent assay and a Western blot analysis were developed to study the antibody response to Pneumocystis carinii in serum and bronchoalveolar lavage fluid from 27 human immunodeficiency virus 27 (HIV)-infected patients with P. carinii pneumonia (Pcp), 32 patients without Pcp, and 51 HIV-negative controls. Urea was used for the correct dilution of epithelial lining fluid, and albumin was used to evaluate transudation from plasma for the assessment of local production of antibodies to P. carinii. By contrast with those of immunoglobulin G (IgG), IgA responses to P. carinii were increased in serum from HIV-positive patients compared to negative controls. Local production of antibodies to P. carinii, especially IgA, was decreased in patients with Pcp. In a study of 10 patients of each group, IgG and IgA responses to gp116 from P. carinii were lower in patients with Pcp than in other groups. These results suggest that, in addition to alveolar macrophages, local antibodies may play a role in host defense against P. carinii.
PMCID: PMC97248  PMID: 10678907
19.  Is day care equivalent to inpatient care for active rheumatoid arthritis? Randomised controlled clinical and economic evaluation 
BMJ : British Medical Journal  1998;316(7136):965-969.
Objective: To test the clinical equivalence and resource consequences of day care with inpatient care for active rheumatoid arthritis.
Design: Randomised controlled clinical trial with integrated cost minimisation economic evaluation.
Setting: Rheumatic diseases unit at a teaching hospital between 1994 and 1996.
Subjects: 118 consecutive patients with active rheumatoid arthritis randomised to receive either day care or inpatient care.
Main outcome measures: Clinical assessments recorded on admission, discharge, and follow up at 12 months comprised: the health assessment questionnaire, Ritchie articular index, erythrocyte sedimentation rate, hospital anxiety and depression scale, and Steinbrocker functional class. Resource estimates were of the direct and indirect costs relating to treatment for rheumatoid arthritis. Secondary outcome measures (health utility) were ascertained by time trade off and with the quality of well being scale.
Results: Both groups had improvement in scores on the health assessment questionnaire and Ritchie index and erythrocyte sedimentation rate after hospital treatment (P<0.0001) but clinical outcome did not differ significantly between the groups either at discharge or follow up. The mean hospital cost per patient for day care, £798 (95% confidence interval £705 to £888), was lower than for inpatient care, £1253 (£1155 to £1370), but this difference was offset by higher community, travel, and readmission costs. The difference in total cost per patient between day care and inpatient care was small (£1789 (£1539 to £2027) v £2021 (£1834 to £2230)). Quantile regression analysis showed a cost difference in favour of day care up to the 50th centile (£374; £639 to £109).
Conclusions: Day care and inpatient care for patients with uncomplicated active rheumatoid arthritis have equivalent clinical outcome with a small difference in overall resource cost in favour of day care. The choice of management strategy may depend increasingly on convenience, satisfaction, or more comprehensive health measures reflecting the preferences of patients, providers, and service commissioners.
Key messages Day care and conventional inpatient care are clinically equivalent for patients with active rheumatoid arthritis The overall resource costs of day care are slightly lower than those of inpatient care Day care is associated with lower hospital costs but higher costs to patient and family; nevertheless half of all patients studied expressed a preference for day care Clinical benefit from either day care or inpatient care is short lived
PMCID: PMC28498  PMID: 9550954
20.  Triggering Glutamate Excretion in Corynebacterium glutamicum by Modulating the Membrane State with Local Anesthetics and Osmotic Gradients 
Applied and Environmental Microbiology  1995;61(12):4334-4342.
Corynebacterium glutamicum can be triggered to excrete glutamate by the addition of local anesthetics, particularly tetracaine. Glutamate efflux is a carrier-mediated process and not due to unspecific membrane permeabilization. The concentration of local anesthetics triggering optimum excretion depended on the type of anesthetic and varied, ranging from 0.1 (chlorpromazine), 1.3 (tetracaine), and 2.6 mM (butacaine) to 15 mM (benzocaine), in close resemblance to the order of efficiency in anesthetic effect. The onset of glutamate excretion was not correlated to a change in the viscosity or fluidity of the membrane, as measured by electron spin resonance spectroscopy, nor was it related to an action of the anesthetic as an uncoupler. Tetracaine-triggered glutamate excretion was sensitive to changes in the transmembrane osmotic gradient, although an osmotic gradient alone could not trigger glutamate excretion. Tetracaine-triggered glutamate efflux was inhibited by an external rise in osmolality and stimulated by a corresponding decrease. The effects of osmotic gradients and the addition of local anesthetics on glutamate excretion were mutually exchangeable, indicating similar modes of action. We suggest that this common principle is a change in the membrane strain. C. glutamicum cells which excrete glutamate without manipulation of the membrane, e.g., biotin-limited cells or glutamate production mutants, were not stimulated by the addition of tetracaine.
PMCID: PMC1388651  PMID: 16535186
21.  Multicentric reticulohistiocytosis with arthritis and cardiac infiltration: regression following treatment for underlying malignancy. 
Annals of the Rheumatic Diseases  1992;51(6):815-817.
The case is reported of a 63 year old man presenting with a rapidly destructive symmetrical polyarthritis and widespread papular nodular skin lesions, confirmed by a biopsy to be due to multicentric reticulohistiocytosis. Biventricular cardiac failure developed secondary to extensive myocardial infiltration with multicentric reticulohistiocytosis, a complication of this disease which has not previously been reported. The joint, skin, and cardiac manifestations of multicentric reticulohistiocytosis substantially regressed following resection of an associated squamous cell carcinoma. This report adds to the small amount of published work which suggests that multicentric reticulohistiocytosis can be a paraneoplastic disease that may respond to treatment directed at the underlying tumour.
PMCID: PMC1004756  PMID: 1616373
22.  Ex vivo pharmacodynamic study of piperacillin alone and in combination with tazobactam, compared with ticarcillin plus clavulanic acid. 
Ten volunteers received piperacillin (4 g), piperacillin (4 g) plus tazobactam (0.5 g) (Tazocin), and ticarcillin (3 g) plus clavulanic acid (0.2 g) (Timentin) intravenously over 30 min in a cross-over blinded scheme. Blood samples were obtained 0.5 and 3 h after the end of infusion to measure by (high-pressure liquid chromatography) the concentration and bactericidal titers against 70 gram-negative bacilli. Serum time-kill curves were done against 35 strains to measure killing rates and area under the time-kill curve. Using the measure of serum bactericidal activity, ticarcillin-clavulanic acid and piperacillin-tazobactam were equally effective against Pseudomonas aeruginosa, Escherichia coli, Enterobacter cloacae, Serratia marcescens, and Bacteroides fragilis. Piperacillin-tazobactam was superior to ticarcillin-clavulanic acid against piperacillin-resistant Klebsiella pneumoniae (4 to 16 times) and S. marcescens (2 to 4 times). By using the area under the time-kill curve, piperacillin-tazobactam was equivalent to ticarcillin-clavulanic acid against piperacillin-susceptible strains; piperacillin-tazobactam was significantly more active than piperacillin against piperacillin-resistant strains and was more active than ticarcillin-clavulanic acid when the sample obtained 3 h after the end of infusion to volunteers was considered. Serum piperacillin concentrations (mean +/- standard error of the mean; in mg/liter) were 115 +/- 13 at 0.5 h and 7.4 +/- 1.4 at 3 h after the administration of piperacillin alone and 105.5 +/- 12.6 (0.5 h) and 7.7 +/- 1.6 after the administration of piperacillin-tazobactam. Serum tazobactam concentrations (in milligram per liter) were 13.1 +/- 1.4 at 0.5 h and 1.2 +/- 0.2 at 3 h. The piperacillin-tazobactam ratio was 8 +/- 0.3 at 0.5 h and 6.2 +/- 0.5 at 3 h. Piperacillin-tazobactam appears promising against beta-lactamase-producing gram-negative bacilli.
PMCID: PMC188083  PMID: 8239597
23.  Developing a district diabetes register. 
BMJ : British Medical Journal  1992;305(6858):893.
PMCID: PMC1883061  PMID: 1294105
24.  Ethics and the physician. 
PMCID: PMC1336366  PMID: 1521198
25.  Characterization of regulatory functions of the varicella-zoster virus gene 63-encoded protein. 
Journal of Virology  1992;66(6):3899-3903.
Varicella-zoster virus (VZV) gene 63 encodes a protein (IE63) with a predicted molecular mass of 30.5 kDa which has amino acid similarities to the immediate-early (IE) protein 22 (ICP22) of herpes simplex virus type 1. ICP22 is a polypeptide synthesized in herpes simplex virus type 1-infected cells, and as is the case for its VZV counterpart, its regulatory functions are unknown. On the basis of the VZV DNA sequence, it has been shown that IE63 exhibits hydrophilic and acidic properties, suggesting that this protein could play a regulatory role during the infectious cycle. We report in this article cotransfection experiments which demonstrate that the VZV gene 63 protein strongly represses, in a dose-dependent manner, the expression of VZV gene 62. On the other hand, transient expression of the VZV gene 63 protein can promote activation of the thymidine kinase gene but cannot affect the expression of the genes encoding glycoproteins I and II. The results of transient expression experiments strongly suggest that the VZV gene 63 protein could play a pivotal role in the repression of IE gene expression as well as in the activation of early gene expression.
PMCID: PMC241178  PMID: 1316489

Results 1-25 (37)