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Biomedical subjects

M Brenner

Publications and source records attributed to M Brenner.

At least 19 recordsLinked to original sources
PubMed2006

Broadband diffuse optical spectroscopy measurement of hemoglobin concentration during hypovolemia in rabbits.

Serial blood draws for the assessment of trauma patients' hemoglobin (sHgb) and hematocrit (sHct) is standard practice. A device that would allow for continuous real-time, non-invasive monitoring of hemoglobin and tissue perfusion would potentially improve recognition, monitoring and resuscitation of blood loss. We developed a device utilizing diffuse optical spectroscopy (DOS) technology that simultaneously measures tissue scattering and near-infrared (NIR) absorption to obtain non-invasive measurements of oxy- (Hb-O(2)), deoxyhemoglobin (Hb-R) concentrations and tissue hemoglobin concentration (THC) in an animal model of hypovolemic shock induced by successive blood withdrawals. Intubated New Zealand White rabbits (N = 16) were hemorrhaged via a femoral arterial line every 20 min until a 20% blood loss (10-15 cc kg(-1)) was achieved to attain hypovolemia. A broadband DOS probe placed on the inner thigh was used to measure muscle concentrations of Hb-O(2) and Hb-R, during blood withdrawal. THC and tissue hemoglobin saturation (S(T)O(2)) were calculated from DOS [Hb-O(2)] and [Hb-R]. Broadband DOS-measured values were compared against traditional invasive measurements: systemic sHgb, arterial oxygen saturation (S(a)O(2)) and venous oxygen saturation (S(v)O(2)) drawn from arterial and central venous blood. DOS and traditional invasive measurements versus blood loss were closely correlated (r(2) = 0.96) showing a decline with removal of blood. S(T)O(2) and [Hb-O(2)] followed similar trends with hemorrhage, while [Hb-R] remained relatively constant. These measurements may be limited to some extent by the inability to distinguish between hemoglobin and myoglobin contributions to DOS signals in tissue at this time. Broadband DOS provides a potential platform for reliable non-invasive measurements of tissue oxygenated and deoxygenated hemoglobin and may accurately reflect the degree of systemic hypovolemia and compromised tissue perfusion.

Animals↗
PubMed2006

Cia27 is a novel non-MHC arthritis severity locus on rat chromosome 10 syntenic to the rheumatoid arthritis 17q22-q25 locus.

Cia27 on rat chromosome 10 is a collagen-induced arthritis (CIA) severity quantitative trait locus originally identified in a study of (DA x ACI) F2. As an initial step towards the positional cloning of the Cia27 gene, a 17 cM (21 Mb) interval from the DA strain (arthritis-susceptible) containing the two-logarithm of odds support interval comprising Cia27 was introgressed into the ACI (arthritis-resistant) background through genotype-guided congenic breeding. ACI.DA(Cia27) congenics developed a significantly more severe form of arthritis (CIA), with a 5.9-fold increase in median arthritis severity index, a parameter known to correlate with synovial inflammation, and cartilage and bone erosions, compared with ACI (P< or =0.001). The arthritis severity enhancing effect could be detected from day 21 onwards. Rats heterozygous at the congenic interval developed a disease similar to ACI rats, suggesting that DA alleles operate in a recessive manner. Levels of autoantibodies anti-rat type II collagen did not correlate with arthritis severity. Synovial tissue mRNA levels of interleukin-1beta (IL-1beta) were significantly increased in ACI.DA(Cia27) congenics compared with ACI. These results demonstrate that Cia27 harbors a novel arthritis severity regulatory gene. The identification of this gene should facilitate the identification of the rheumatoid arthritis gene mapped to the human syntenic region on chromosome 17q22-q25.

Alleles↗
PubMed2006

Penile block in children, our first experience.

Penile block has been in use in penile surgery as a technique for perioperative analgesia for 25 years. The authors reintroduced penile block on the Department of Paediatric Anaesthetics and Intensive Care at the University Children's Hospital in Bratislava, Slovakia in June 2004 after 8 years. This prospective open observational study presents their experience with penile block for elective penile surgery in 96 paediatric patients (Tab. 3, Ref. 14).

Adolescent↗
PubMed2005

Thermal signature analysis as a novel method for evaluating inflammatory arthritis activity.

OBJECTIVE: To examine the potential usefulness of a novel thermal imaging technique to evaluate and monitor inflammatory arthritis activity in small joints using rat models, and to determine whether thermal changes can be used to detect preclinical stages of synovitis. METHODS: Three different rat strains were studied in a model of inflammatory arthritis of the ankle induced by an intra-articular (IA) injection of complete Freund's adjuvant (CFA), compared with the contralateral ankle injected with normal saline. Arthritis activity and severity scores, ankle diameters, pain related posture scores, and thermal images were obtained at 10 different times between 0 h (before induction) and day 7. The pristane induced arthritis (PIA) model was used to study preclinical synovitis. Thermal images were obtained at each time point using the TSA ImagIR system and were digitally analysed. RESULTS: Rats developed similar ankle arthritis detected six hours after the IA injection of CFA, which persisted for seven days. All ankle clinical indices, including arthritis activity and severity scores, correlated significantly with ankle thermal imaging changes in the monoarthritis model (p<0.003). No thermal imaging changes were detected in preclinical stages of PIA. However, PIA onset coincided with increased ankle thermal signature. CONCLUSIONS: Thermal measurements correlated significantly with arthritis activity and severity indices. The technique was highly sensitive and could measure directly two cardinal signs of inflammation (warmth and oedema, based on ankle diameter) in an area (ankle) that is less than half the size of a human interphalangeal joint, suggesting a potential use in drug trials or clinical practice.

Animals↗
PubMed2005

Two-dimensional and 3-dimensional optical coherence tomographic imaging of the airway, lung, and pleura.

BACKGROUND: Methods for obtaining real-time in vivo histologic resolution by means of noninvasive endoscopic optical imaging would be a major advance for thoracic surgical diagnostics and treatment. Optical coherence tomography is a rapidly evolving technology based on near-infrared interferometry that might provide these capabilities. The purpose of this study is to investigate the feasibility of real-time 2- and 3-dimensional optical coherence tomographic imaging of airway, pleural, and subpleural lung tissues in normal, inflammatory, and malignant animal models and patients with known or suspected airway malignancy. METHODS: Freshly excised lungs and pleural tissue obtained from rabbits with inhalation lung injury and induced empyema, metastatic sarcomas, and pleural sarcomas and from patients with airway disease were imaged by using 2- and 3-dimensional optical coherence tomography with a prototype superluminescent diode optical coherence tomographic system constructed in our laboratory. Lungs and pleural tissue were subsequently processed for standard hematoxylin and eosin histology for comparison with optical coherence tomography. RESULTS: Optical coherence tomographic imaging achieved an ex vivo resolution of 10 microm and an in vivo resolution of about 30 microm with a depth penetration of 1 to 2 mm with 2- and 3- dimensional reconstruction capabilities. Tumors as small as 500 microm were detectable with optical coherence tomography. The acquired images closely matched histologic images, demonstrating details at the level of mucosal layers, glands, alveoli, and respiratory bronchioles. CONCLUSIONS: Optical coherence tomography with near-infrared interferometric methods enables near real-time in vivo near-histologic resolution optical imaging. With further advances, optical coherence tomography has the potential for real-time accurate and early pleural and subpleural diagnostics by using small-diameter flexible fiberoptic endoscopic probes for a wide range of thoracic surgical applications.

Animals↗
PubMed2005

Differential expression of melanoma-associated growth factors in keratinocytes and fibroblasts by ultraviolet A and ultraviolet B radiation.

BACKGROUND: Besides the direct DNA-damaging effects of ultraviolet (UV) radiation on cells, indirect effects on the microenvironment of the skin may facilitate melanoma development. A stimulation of growth factor production by cells in the immediate environment of melanocytes may lead to a paracrine activation and proliferation of melanocytes that in turn become more susceptible to transformation. OBJECTIVES: We investigated whether the expression of growth factors for melanocytes can be modulated in keratinocytes and fibroblasts by UVA or UVB. METHODS: After irradiation with different doses of UVA or UVB, protein expression of basic fibroblast growth factor (bFGF), endothelin (ET)-1, transforming growth factor (TGF)-beta1, platelet-derived growth factor (PDGF)-AA, stem cell factor (SCF) and hepatocyte growth factor (HGF) was analysed by quantitative enzyme-linked immunosorbent assay. The mRNA expression of bFGF and ET-1 was analysed by quantitative real-time reverse transcriptase-polymerase chain reaction. RESULTS: In keratinocytes, UVB and UVA increased bFGF protein levels up to 2.6-fold. This increase was paralleled by elevated mRNA levels. UVB also induced ET-1 protein up to 1.8-fold, while UVA led to an 80% decrease. Secreted TGF-beta1 and PDGF-AA were downregulated by UVA by less than 50%, while there was no significant alteration by UVB. Secreted SCF was not changed significantly by UVA or UVB. In fibroblasts, bFGF protein levels were increased 11-64-fold by UVA and 34-61-fold by UVB. This was paralleled by elevated mRNA levels for bFGF up to 2.7-fold. HGF protein was stimulated by UVA up to 2.8-fold and by UVB up to 6.7-fold, while TGF-beta1 protein was increased up to 2.7-fold by UVB and 1.7-fold by UVA. CONCLUSIONS: UVA and UVB can stimulate and inhibit the production of growth factors for melanocytes in keratinocytes and fibroblasts dependent on the cell type and wavelength. We show for the first time that UVA and UVB can activate bFGF, HGF and TGF-beta1 in fibroblasts, while bFGF was the most inducible factor both in fibroblasts and in keratinocytes. The induction of bFGF and HGF in fibroblasts by UVA suggests that stroma cells in the dermis may be involved in the UV activation of melanocytes via paracrine ways and thus promote melanoma development.

Cells, Cultured↗
PubMed2002

Molecular findings in symptomatic and pre-symptomatic Alexander disease patients.

BACKGROUND AND OBJECTIVE: Alexander disease is a slowly progressive CNS disorder that most commonly occurs in children. Until recently, the diagnosis could only be established by the histologic finding of Rosenthal fibers in brain specimens. Mutations in the glial fibrillary acidic protein (GFAP) gene have now been shown in a number of biopsy- or autopsy-proven patients with Alexander disease. A prospective study on patients suspected to have Alexander disease was conducted to determine the extent to which clinical and MRI criteria could accurately diagnose affected individuals, using GFAP gene sequencing as the confirmatory assay. METHODS: Patients who showed MRI white matter abnormalities consistent with Alexander disease, unremarkable family history, normal karyotype, and normal metabolic screening were included in this study. Genomic DNA from patients was screened for mutations in the entire coding region, including the exon-intron boundaries, of the GFAP gene. RESULTS: Twelve of 13 patients (approximately 90%) were found to have mutations in GFAP. Seven of those 12 patients presented in infancy with seizures and megalencephaly. Five were juvenile-onset patients with more variable symptoms. Two patients in the latter group were asymptomatic or minimally affected at the time of their initial MRI scan. The mutations were distributed throughout the gene, and all involved sporadic single amino acid heterozygous changes that changed the charge of the mutant protein. Four of the nine changes were novel mutations. CONCLUSIONS: In symptomatic and asymptomatic patients with a predominantly frontal leukoencephalopathy by MRI, GFAP gene mutation analysis should be included in the initial diagnostic evaluation process for Alexander disease.

Adolescent↗
PubMed2002

ICP monitoring following bilateral carotid occlusion in GFAP-null mice.

To investigate the possible role of glial fibrillary acidic protein (GFAP) in cerebral ischemia, we have monitored the intracranial pressure (ICP) and local cerebral blood flow (ICBF) following bilateral carotid artery occlusion (BCAO) in GFAP-null mice and their wild type littermates. GFAP-null mice (B6, 129-GfaptmlMes) were obtained from Jackson Laboratories. The ICP and ICBF was continuously monitored during 15 minutes BCAO and reperfusion. The variation of the circle of Willis was also investigated in both GFAP-null and wild type mice. The breakdown of blood brain barrier (BBB) was assessed by immunohistochemical staining against mouse immunogloblins (IgG). A significantly more profound and immediate decrease in ICBF after BCAO was observed in GFAP-null mice (p < 0.04, ANOVA). GFAP-null mice also showed a significant increase (% change) in ICP after reperfusion (p < 0.05, ANOVA). There were no gross differences in the circle of Willis between GFAP-null and wild type mice. No abnormal IgG immuno-reactivity was observed in the forebrain of both animals. These results indicate a high susceptibility to cerebral ischemia in GFAP-null mice and suggest an important role for astrocytes and GFAP in the progress of ischemic brain damage and increased ICP after cerebral ischemia with reperfusion.

Animals↗
PubMed2001

A novel mutation in glial fibrillary acidic protein gene in a patient with Alexander disease.

Alexander disease is a rare, progressive, leukoencephalopathy whose hallmark is the widespread accumulation of Rosenthal fibers. The most common form affects infants and young children, and is characterized by progressive failure of central myelination, usually leading to death before adulthood. Definitive diagnosis of Alexander disease has required biopsy or autopsy to demonstrate the presence of Rosenthal fibers. However, missense mutations in the coding region of the glial fibrillary acidic protein (GFAP) gene have recently been associated with a high percentage of pathologically proven cases. Here we report that a 10-year-old Japanese patient who showed clinical signs of Alexander disease is heterozygous for a C to T transition in which predicts a novel A244V amino acid substitution in the conserved 2A alpha-helix domain of GFAP. The nucleotide change was not found in 65 normal individuals (130 alleles). These results provide further support for a causative role for GFAP mutations in Alexander disease, and suggest DNA sequencing as an alternative diagnostic to biopsy.

Alanine↗
PubMed2001

Infantile Alexander disease: spectrum of GFAP mutations and genotype-phenotype correlation.

Heterozygous, de novo mutations in the glial fibrillary acidic protein (GFAP) gene have recently been reported in 12 patients affected by neuropathologically proved Alexander disease. We searched for GFAP mutations in a series of patients who had heterogeneous clinical symptoms but were candidates for Alexander disease on the basis of suggestive neuroimaging abnormalities. Missense, heterozygous, de novo GFAP mutations were found in exons 1 or 4 for 14 of the 15 patients analyzed, including patients without macrocephaly. Nine patients carried arginine mutations (four had R79H; four had R239C; and one had R239H) that have been described elsewhere, whereas the other five had one of four novel mutations, of which two affect arginine (2R88C and 1R88S) and two affect nonarginine residues (1L76F and 1N77Y). All mutations were located in the rod domain of GFAP, and there is a correlation between clinical severity and the affected amino acid. These results confirm that GFAP mutations are a reliable molecular marker for the diagnosis of infantile Alexander disease, and they also form a basis for the recommendation of GFAP analysis for prenatal diagnosis to detect potential cases of germinal mosaicism.

Adolescent↗
PubMed2001

Characterization and expression of enzymatically active recombinant filarial prolyl 4-hydroxylase.

The cuticle of parasitic nematodes consists primarily of a network of collagen molecules. The enzyme responsible for collagen maturation is prolyl 4-hydroxylase, making this enzyme a central activity in cuticle biosynthesis and a potentially important chemotherapeutic target. Adult and embryonic Brugia malayi are shown to be susceptible to inhibitors of vertebrate prolyl 4-hydroxylase, with exposed parasites exhibiting pathologies consistent with a disruption in cuticle biosynthesis. A full-length cDNA (Ov-phy-1) encoding a catalytically active alpha-subunit of Onchocerca volvulus prolyl 4-hydroxylase was isolated and characterized. The derived amino acid sequence of Ov-phy-1 encoded a peptide that was most similar to the two Caenorhabditis elegans prolyl 4-hydroxylase homologues and to the isoform II enzymes of vertebrates. Expressed sequence tag (EST) analysis and developmental polymerase chain reaction (PCR) studies demonstrated that Ov-phy-1 was expressed in L3 and adult parasites. The gene encoding the Ov-phy-1 open reading frame contained 11 introns, similar in structure to the gene encoding human prolyl 4-hydroxylase isoform I. Genomic Southern blot, EST and genomic PCR studies demonstrated that the O. volvulus genome contained between three and eight genes closely related to Ov-phy-1. Co-expression of Ov-phy-1 with the O. volvulus homologue of protein disulfide isomerase in a baculovirus system resulted in the production of enzymatically active O. volvulus prolyl 4-hydroxylase. In vitro production of enzymatically active O. volvulus prolyl 4-hydroxylase should facilitate identification of specific inhibitors of the parasite enzyme.

Amino Acid Sequence↗
PubMed2001

Climate change as the dominant control on glacial-interglacial variations in C3 and C4 plant abundance.

Although C4 plant expansions have been recognized in the late Miocene, identification of the underlying causes is complicated by the uncertainties associated with estimates of ancient precipitation, temperature, and partial pressure of atmospheric carbon dioxide (PCO2). Here we report the carbon isotopic compositions of leaf wax n-alkanes in lake sediment cores from two sites in Mesoamerica that have experienced contrasting moisture variations since the last glacial maximum. Opposite isotopic trends obtained from these two sites indicate that regional climate exerts a strong control on the relative abundance of C3 and C4 plants and that in the absence of favorable moisture and temperature conditions, low PCO2 alone is insufficient to drive an expansion of C4 plants.

Alkanes↗
PubMed2001

The AMPA receptor/Na(+) channel blocker BIIR 561 CL is protective in a model of global cerebral ischaemia.

In this study, we investigated whether the novel neuroprotective compound dimethyl-[2-[2-(3-phenyl-[1,2,4]oxadiazol-5-yl)-phenoxy]-ethyl]-amine hydrochloride, BIIR 561 CL, a combined non-competitive antagonist of AMPA receptors and blocker of voltage-gated Na+ channels, is protective in a rat model of severe global ischaemia. BIIR 561 CL administered immediately after 10 min of ischaemia (occlusion of both carotid arteries plus reduction of arterial blood pressure to 38-40 mm Hg) significantly reduced hippocampal damage at 4 x 26.8 mg/kg (subcutaneous injections). The competitive AMPA receptor antagonist 2,3-dihydro-6-nitro-7-sulfamoyl-benz(F)quinoxaline, NBQX, was used as a reference compound and was protective at 3x30 mg/kg (intraperitoneal and/or subcutaneous administration). BIIR 561 CL significantly reduced the ischaemia-induced premature mortality from 33.6% in the controls to 14.3%, whereas NBQX treatment had no statistically significant effect.Thus, BIIR 561 CL could be shown to reduce hippocampal damage and premature mortality in a model of severe global ischaemia. A compound with these properties might be an interesting candidate for the treatment of disorders related to global cerebral ischaemia in man.

Animals↗
PubMed2001

Solar forcing of drought frequency in the Maya lowlands.

We analyzed lake-sediment cores from the Yucatan Peninsula, Mexico, to reconstruct the climate history of the region over the past 2600 years. Time series analysis of sediment proxies, which are sensitive to the changing ratio of evaporation to precipitation (oxygen isotopes and gypsum precipitation), reveal a recurrent pattern of drought with a dominant periodicity of 208 years. This cycle is similar to the documented 206-year period in records of cosmogenic nuclide production (carbon-14 and beryllium-10) that is thought to reflect variations in solar activity. We conclude that a significant component of century-scale variability in Yucatan droughts is explained by solar forcing. Furthermore, some of the maxima in the 208-year drought cycle correspond with discontinuities in Maya cultural evolution, suggesting that the Maya were affected by these bicentennial oscillations in precipitation.

Archaeology↗
PubMed2001

Differential cellular expression of tumor necrosis factor-alpha and Type I tumor necrosis factor receptor after transient global forebrain ischemia.

We examined the expression of tumor necrosis factor-alpha (TNF-alpha) and the Type I tumor necrosis factor receptor, (TNFR1), in relation to c-fos, a known regulator gene of immediate cellular responses, after an extended period of global ischemia. The number of TNF-alpha mRNA expressing cells peaked in most brain areas after 8 h of reperfusion. Significant increases in TNFR1 mRNA expression were evident in the cortex at 2 and 8 h of reperfusion and after 8 h of reperfusion in the CA3/CA4 region of the hippocampus. Transient neuronal c-fos mRNA expression preceded these responses. TNF-alpha immunoreactivity was seen in neurons>>>oligodendrocytes=perivascular cells=ependymal cells=vessel wall structures. After ischemia/reperfusion, increased TNF-alpha immunoreactivity was evident only in oligodendrocytes. TNFR1 immunoreactivity in sham brains manifested in bundles of cellular fibers of variable length and thickness. In post-ischemic brains, immunoreactivity in these cellular processes representing mainly astroglial extensions was suppressed at 2 h but recovered partially by 8 and 24 h of reperfusion. In contradiction, transient ischemia-induced TNFR1 immunoreactivity was observed in somas of large cortical neurons, in activated microglia/macrophages, perivascular and endothelial cells.Taken together, the increase in neuronal TNF-alpha mRNA appeared not to be followed by substantial translation to protein in the cerebral tissue after an extended period of global ischemia. However, there was increased neuronal TNFR1 immunostaining in conjunction with increased immunostaining for TNF-alpha in oligoglial elements, which suggests signaling to neurons by enhanced oligoglial TNF-alpha.

Animals↗
PubMed2001

hGFAP-cre transgenic mice for manipulation of glial and neuronal function in vivo.

With the goal of performing astrocyte-specific modification of genes in the mouse, we have generated a transgenic line expressing Cre recombinase under the control of the human glial fibrillary acidic protein (hGFAP) promoter. Activity was monitored by crossing the hGFAP-cre transgenics with either of two reporter lines carrying a lacZ gene whose expression requires excision of loxP-flanked stop sequences. We found that lacZ expression was primarily limited to the central nervous system, but therein was widespread in neurons and ependyma. Cell types within the brain that notably failed to activate lacZ expression included Purkinje neurons of the cerebellum and choroid plexus epithelium. Onset of Cre expression began in the forebrain by e13.5, suggesting that the hGFAP promoter is active in a multi-potential neural stem cell.

Animals↗
PubMed2001

Impact of a multidisciplinary day program on disease and healthcare costs in children and adolescents with severe asthma: a two-year follow-up study.

For patients whose asthma remains in poor control necessitating high utilization of medical services, a referral to a specialized "center of excellence" is often considered. A decade ago, we evaluated our pediatric asthma program of long-term hospitalization (median stay of 75 days) and found significant decreases in subjects' medical utilization following this intervention. In an effort to contain treatment costs, the former program was markedly altered to one of abbreviated stay with emphasis on family management of asthma. The purpose of the present study was to determine the outcome of children treated in the revised program with regard to disease severity, quality of life, and subsequent utilization of medical resources. Children with severe asthma who were admitted to the program and fulfilled study criteria were consecutively enrolled. Data was obtained concerning disease characteristics, treatment, and quality of life at admission, and at 1 and 2 years following discharge. Medical records for the year prior to program admission and for the 2 years following discharge were coded for medical care encounters. Ninety-eight children, aged 9 months to 18 years (mean age, 10.9 years), were enrolled. They participated in the program for a mean of 15.6 ( +/- 8 SD), median of 15.0, and range of 2-51 treatment days. The group showed significant improvement (P < 0.0001) from admission to 1- and 2-year follow-up in median corticosteroid use, asthma functional severity, perceived competence in asthma management, and quality of life for both caregiver and child. Medical record data showed significant improvement (P < 0.0001) at both 1- and 2-year follow-up in median number of corticosteroid bursts, emergency department visits, hospital days, and overall utilization of medical care encounters. A median total medical encounter cost/patient of $16,250 ($6,972-$25,714 interquartile range (IQR)) for the year prior to program participation was reduced to $1,902 ($505-$6,524 IQR) at 1-year and $690 ($185-$3,550 IQR) at 2- year follow-up (P < 0.0001). We conclude that multidisciplinary care in a short-term, outpatient, day treatment program can significantly contribute to improvement in asthma severity, quality of life, and reduction in healthcare costs.

Adolescent↗