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Biomedical subjects

M Berry

Publications and source records attributed to M Berry.

At least 55 records · Page 3Linked to original sources
PubMed2001

Gene therapy for central nervous system repair.

The amelioration of the sequelae of CNS injury by gene therapy requires three post-injury events to be addressed: scarring, neuron death and axon regeneration. Administering anti-apoptotic, and axon growth promoting genes to neurons is inefficient, using nonviral vectors, because access to the transcriptional machinery is restricted by an intact nuclear membrane in G0 cells. Viral vectors have better transfection rates but a higher incidence of deleterious effects than non-viral vectors. Discrete targeted transfection of astrocytes, for example, about the wound with antifibrotic genes is essential to control scarring and for the inhibition of axon growth locally by gene products without transfecting neighboring and distant cells. Either rational or forced evolutionary design of vectors will ultimately achieve efficient safe gene transduction. Recombinant protein treatments for CNS repair have proved disappointing, probably because axotomized neurons are difficult to access in multiple disparate sites in the CNS after penetrant injury. Gene therapy has the potential to overcome these difficulties since sustained antiscarring/neurotrophic regimes are achievable after a single delivery to the site of injury by uptake by local injury responsive cells in the wound, and by axon terminals. Subsequent retrograde axonal transport delivers the therapeutic genes to all axotomized neurons throughout the CNS.

Active Transport, Cell Nucleus↗
PubMed2000

Phosphorylation status of the SCR homeodomain determines its functional activity: essential role for protein phosphatase 2A,B'.

Sex combs reduced (SCR) is a Drosophila Hox protein that determines the identity of the labial and prothoracic segments. In search of factors that might associate with SCR to control its activity and/or specificity, we performed a yeast two-hybrid screen. A Drosophila homologue of the regulatory subunit (B'/PR61) of serine-threonine protein phosphatase 2A (dPP2A,B') specifically interacted with the SCR homeodomain. The N-terminal arm within the SCR homeodomain was shown to be a target of phosphorylation/dephosphorylation by cAMP-dependent protein kinase A and protein phosphatase 2A, respectively. In vivo analyses revealed that mutant forms of SCR mimicking constitutively dephosphorylated or phosphorylated states of the homeodomain were active or inactive, respectively. Inactivity of the phosphorylated mimic form was attributed to impaired DNA binding. Specific ablation of dPP2A,B' gene activity by double-stranded RNA-mediated genetic interference resulted in embryos without salivary glands, an SCR null phenotype. Our data demonstrate an essential role for Drosophila PP2A,B' in positively modulating SCR function.

Amino Acid Sequence↗
PubMed2000

Thrombomodulin as a new marker of lesion-induced astrogliosis: involvement of thrombin through the G-protein-coupled protease-activated receptor-1.

Because injury of the CNS causes an astrogliosis, characterized by cell swelling and proliferation, similar to the effects of the serine protease thrombin on astrocytes, we hypothesized that a high level of thrombin at the site of injury might initially induce an astrocyte reaction and later increase the expression of its specific inhibitor, thrombomodulin. Thrombomodulin could then stabilize the astroglial scar through its adhesive properties. Here, we studied the in vivo injury response of astrocytes in the anterior medullary velum of adult rat by immunostaining and in situ hybridization of thrombomodulin. Thrombomodulin was poorly expressed on astrocytes in normal tissue, increased up to 2 d after injury, and was still highly expressed at 6 d. To check that thrombin had a direct effect on thrombomodulin expression by astrocytes, we used brain cortical astrocyte primary cultures treated with either thrombin or the agonist peptide thrombin receptor-activating peptide-6, known to activate directly the thrombin G-protein-coupled receptor (GPCR) protease-activated receptor-1 (PAR-1). Modification of thrombomodulin expression was studied by Western blotting and quantitative reverse transcription-PCR. There was a dose-dependent increase in thrombomodulin after 48 hr of treatment, with gene expression peaking at 24 hr but falling to control levels by 48 hr. Together, these results show the following: (1) injury increases astrocyte thrombomodulin expression; (2) thrombin might mediate thrombomodulin expression via the specific receptor PAR-1; and (3) serine proteases, their inhibitors, and the new family of GPCR, PARs, are active on astrogliosis.

Animals↗
PubMed2000

Oligodendrocytes and the control of myelination in vivo: new insights from the rat anterior medullary velum.

The rat anterior medullary velum (AMV) is representative of the brain and spinal cord, overall, and provides an almost two-dimensional preparation for investigating axon-glial interactions in vivo. Here, we review some of our findings on axon-oligodendrocyte unit relations in our adult, development, and injury paradigms: (1) adult oligodendrocytes are phenotypically heterogeneous, conforming to Del Rio Hortega's types I-IV, whereby differences in oligodendrocyte morphology, metabolism, myelin sheath radial and longitudinal dimensions, and biochemistry correlate with the diameters of axons in the unit; (2) oligodendrocytes derive from a common premyelinating oligodendrocyte phenotype, and divergence of types I-IV is related to the age they emerge and the presumptive diameter of axons in the unit; (3) during myelination, axon-oligodendrocyte units progress through a sequence of maturation phases, related to axon contact, ensheathment, establishment of internodal myelin sheaths, and finally the radial growth and compaction of the myelin sheath; (4) we provide direct in vivo evidence that platelet-derived growth factor-AA (PDGF-AA), fibroblast growth factor (FGF-2), and insulin-like growth factor-I (IGF-I) differentially regulate these events, by injecting the growth factors into the cerebrospinal fluid of neonatal rat pups; (5) in lesioned adult AMV, transected central nervous system (CNS) axons regenerate through the putatively inhibitory environment of the glial scar, but remyelination by oligodendrocytes is incomplete, indicating that axon-oligodendrocyte interactions are defective; and (6) in the adult AMV, cells expressing the NG2 chondroitin sulphate have a presumptive adult oligodendrocyte progenitor antigenic phenotype, but are highly complex cells and send processes to contact axolemma at nodes of Ranvier, suggesting they subserve a specific perinodal function. Thus, axons and oligodendrocyte lineage cells form interdependent functional units, but oligodendrocyte numbers, differentiation, phenotype divergence, and myelinogenesis are governed by axons in the units, mediated by growth factors and contact-dependent signals.

Animals↗
PubMed2000

Sonographic findings in grade III dengue hemorrhagic fever in adults.

PURPOSE: Sonography has been used to evaluate children with dengue hemorrhagic fever, but to our knowledge no such studies have been conducted with adults. We present the sonographic findings in 40 adults with severe (grade III) dengue hemorrhagic fever (DHF). METHODS: Forty patients (30 men and 10 women, aged 16-65 years) given a presumptive diagnosis of grade III dengue hemorrhagic fever during a documented regional epidemic underwent abdominal sonography. Ten also underwent chest radiography. Serologic confirmation was obtained in 5 patients, and in the rest the diagnosis was based on epidemiologic and clinical findings. RESULTS: Sonographic findings included pleural effusion in 21 patients (53%), thickening of the gallbladder wall in 17 (43%), and mild ascites in 6 (15%). These findings were similar to those of previous studies of severe DHF in children, although the incidence of pleural effusion and ascites was slightly lower in our series. Neither pleural effusion nor ascites was apparent on clinical examination. Of the 10 patients who underwent both sonography and chest radiography, sonography detected pleural effusion in all 10, whereas radiography detected it in only 3. CONCLUSIONS: Sonographic findings in DHF in adults (pleural effusions, ascites, and gallbladder wall thickening) were similar to those described for children but seem to be of lesser severity. Abdominal sonography is a useful diagnostic tool for confirming suspected cases of DHF. Sonography was found to be superior to chest radiography in detecting pleural effusions in the 10 patients in whom radiographs were available.

Adolescent↗
PubMed2000

Tolerability and efficacy of nabumetone and naproxen in the treatment of rheumatoid arthritis.

OBJECTIVE: The purpose of this study was to compare the tolerability and efficacy of nabumetone and naproxen in the treatment of patients with rheumatoid arthritis (RA). The occurrence of gastrointestinal (GI) adverse events was compared. BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) have similar efficacy at equipotent doses, but the therapeutic response to various NSAIDs often differs in individual patients. METHODS: This was a 3-month, randomized, double-blind, multicenter, parallel-group study conducted in adult patients with RA. The study had 2 phases: a 3- to 14-day washout period and a 12-week treatment period. During the treatment phase, the tolerability and efficacy of nabumetone 2000 mg/d were compared with those of naproxen 1000 mg/d. The change from baseline in efficacy variables, including global assessments, number of tender or swollen joints, and pain, was evaluated. The study was sized to provide an 80% power to detect a 15% difference in the percentage improvement on the physician's global assessment (alpha = 0.05). GI safety was assessed by monitoring the occurrence of clinically important adverse GI events. RESULTS: A total of 346 RA patients at 31 US rheumatology centers were randomly assigned to treatment (173 patients per group). The study population was predominantly white (87.0%) and female (70.5%), with a mean age of 54 years. Both treatments improved the signs and symptoms of RA, with no statistically significant differences between groups for any efficacy variables. No serious GI adverse events occurred with either NSAID. The most frequent treatment-related adverse events in both groups were predominantly GI in origin, as were those that resulted in withdrawal from the study. Diarrhea with lower abdominal pain was the most common adverse event in the nabumetone group; upper abdominal pain was the most common adverse event in the naproxen group. The only significant difference between the 2 groups was a higher incidence of diarrhea (P < 0.01) in patients receiving nabumetone. CONCLUSIONS: Nabumetone 2000 mg/d was as effective as naproxen 1000 mg/d in relieving the signs and symptoms of RA. In this study, no serious GI adverse events were observed with either NSAID, but nabumetone was associated with a higher incidence of diarrhea.

Adult↗
PubMed2000

Colour Doppler flow imaging of focal hepatic lesions.

Fifty-four patients with focal liver lesions were evaluated with colour Doppler flow imaging (CDFI) and CT to assess whether CDFI could be used to differentiate various types of lesions based on the flow pattern in terms of peritumoral and intratumoral blood flow. Peritumoral flow was found to be of no significance in the differential diagnosis of various liver lesions. Intratumoral flow was graded into mild, moderate or marked depending on the relative number of blood vessels demonstrated within the lesion. Marked intratumoral flow on CDFI was seen in 12.5% of primary hepatic malignancies and in infantile haemangioendothelioma, while a moderate flow pattern was seen in 56.2% of primary hepatic malignancies and in 18.7% of metastases. Mild flow was seen in 33.3% of primary malignancies; 18.7% of metastases; and 16.7% of haemangiomas. No intratumoral flow was seen in 100% of inflammatory lesions; 83.3% of haemangiomas; 62.5% of metastases; and only one hepatocellular carcinoma (5.6%). It was therefore concluded that the presence or absence of flow on CDFI is not a reliable feature for differential diagnosis of focal liver lesions when it is used alone. The flow pattern as assessed on CDFI may point to the nature of the lesion and, when used along with other morphological imaging features, can assist in diagnosis or in narrowing the list of different diagnoses in a particular clinical situation.

Blood Flow Velocity↗
PubMed2000

High rate of GB virus type C/HGV transmission from mother to infant: possible implications for the prevalence of infection in blood donors.

BACKGROUND: Because GB virus type C(GBV-C)/HGV (GBV-C/HGV) is blood-borne and sexually transmitted, persons at risk of infection with such viruses have a high prevalence of GBV-C/HGV markers. However, adults with no apparent risk factors, such as blood donors, frequently are positive for GBV-C/HGV markers. Mother-to-infant transmission could explain this high prevalence, but it has been studied only through small series of GBV-C/HGV-infected mothers co-infected with HCV or HIV. STUDY DESIGN AND METHODS: To determine the rate of mother-to-infant transmission of GBV-C/HGV RNA in women who are HCV- or HIV-negative, a prospective study was performed in a cohort of 288 mothers screened for viral RNA and in the infants born to GBV-C/HGV-infected mothers. RESULTS: Thirteen mothers (4.5%) were found positive for GBV-C/HGV RNA. Of the infants in whom at least one blood sample was collected between the third and the ninth months of life, 89 percent were positive for viral RNA. The majority of these newborns were negative for GBV-C/HGV RNA at birth and positive after the third month. The viral RNA titers of infants born to GBV-C/HGV-infected mothers appeared as elevated as those of their mothers. All the GBV-C/HGV-infected infants remained positive for viral RNA during the entire study period. No clinical events possibly linked to a primary GBV-C/HGV infection were reported in infants. Serum ALT level and blood count remained within normal values throughout the follow-up of all GBV-C/HGV-infected infants. CONCLUSION: The frequency of mother-to-infant GBV-C/HGV transmission is elevated and could explain the high prevalence of GBV-C/HGV markers (viral RNA and E2 antibody) in adults at low risk for blood-borne or sexually transmitted viruses, such as blood donors.

Adult↗
PubMed2000

Sonography and CT of pancreatoblastoma in children.

OBJECTIVE: We reveal the sonography and CT findings of three children with pancreatoblastoma. CONCLUSION: Pancreatoblastomas are invasive tumors that encase adjacent vessels and infiltrate surrounding organs. Original and atypical findings include metastases to the omentum and lymph nodes of the neck and direct extension of the tumor to the portal vein and its branches.

Child↗
PubMed2000

Optic nerve cysticercosis: imaging findings.

We present the imaging findings of retrobulbar optic nerve cysticercosis in a 50-year-old woman with a 6-month history of vision loss. Contrast-enhanced CT revealed an approximately 7-mm ring-enhancing cyst with a mural nodule located in the anterior portion of the left optic nerve. A contrast-enhanced MR imaging study revealed a cystic lesion with peripheral enhancement of the mural nodule. Sonography showed a cystic mass with a focal area of increased echogenicity corresponding to the mural nodule.

Cysticercosis↗
PubMed2000

Membrane-associated mucins in normal human conjunctiva.

PURPOSE: To examine the presence of specific membrane-associated mucins in normal human conjunctiva. METHODS: Glycoconjugates were extracted from membranes with two detergents: octylglucoside and Triton X114. Mucins were separated by cesium chloride density gradient centrifugation. Size was assessed by gel filtration on Sepharose CL2B and charge by ion-exchange chromatography on MonoQ. Cross reaction with antibodies against mucin gene products was assessed in blots of electrophoresis gels. RESULTS: Extraction of total tissue membranes yielded material with a buoyant density typical of mucins. Gel filtration showed material reacting with antimucin antibodies in a range of molecular sizes. Agarose electrophoresis confirmed the presence of MUC1 and MUC4 and the absence of MUC2 or MUC5AC. Isolation of membrane mucins by sequential, exhaustive extraction with octylglucoside followed by Triton X114 suggested the existence of mucins in different membrane environments. Reagents to carbohydrate epitopes revealed high mobility material, comigrating with MUC1 and MUC4. Low mobility membrane-bound mucins did not cross-react with any antibodies to mucin genes known to be expressed in human conjunctiva. CONCLUSIONS: Membrane-associated mucins are distinct from secreted mucins in normal human conjunctiva. MUC1 and MUC4 mature products decorate the membranes of conjunctival epithelial cells. Their segregation between octyl glucoside and the detergent and aqueous phases of Triton X114 suggests a variety of membrane anchoring modes.

Cell Membrane↗
PubMed1999

In vivo actions of fibroblast growth factor-2 and insulin-like growth factor-I on oligodendrocyte development and myelination in the central nervous system.

The in vivo effects of fibroblast growth factor-2 (FGF-2) and insulin-like growth factor-I (IGF-I) on oligodendrocytes and CNS myelination were determined in the postnatal rat anterior medullary velum (AMV) following injection of both cytokines into the cerebrospinal fluid. Either FGF-2, IGF-I, or saline were administered via the lateral ventricle, twice daily commencing at postnatal day (P) 6. At P9, AMV were immunohistochemically labeled with the Rip antibody, to enable analysis of the numbers of myelin sheaths and of promyelinating and myelinating oligodendrocytes; promyelinating oligodendrocytes are a recognisable immature phenotype which express myelin-related proteins prior to forming myelin sheaths. In parallel experiments, AMV were treated for Western blot analysis to determine relative changes in expression of the myelin proteins 2', 3'-cyclic nucleotide 3'-phosphohydrolase (CNP) and myelin oligodendrocyte glycoprotein (MOG), which, respectively, characterise early and late stages of myelin maturation. In FGF-2-treated AMV, the number of promyelinating oligodendrocytes increased by 87% compared to saline-injected controls. The numbers of myelinating oligodendrocytes and myelin sheaths were not decreased, but conspicuous unmyelinated gaps within fibre tracts were indications of retarded myelination following FGF-2 treatment. Western blot analysis demonstrated decreased expression of CNP and a near-total loss of MOG, confirming that FGF-2 decreased myelin maturation. In contrast, IGF-I had no effect on the number of promyelinating oligodendrocytes, but increased the numbers of myelinating oligodendrocytes and myelin sheaths by 100% and 93%, respectively. Western blot analysis showed that the amount of CNP was increased following IGF-I treatment, correlating with the greater number of oligodendrocytes, but that MOG expression was lower than in controls, suggesting that the increased number of myelin sheaths in IGF-I was not matched by increased myelin maturation. The results provide in vivo evidence that FGF-2 and IGF-I control the numbers of oligodendrocytes in the brain and, respectively, retard and promote myelination.

Animals↗
PubMed1999

Decorin attenuates gliotic scar formation in the rat cerebral hemisphere.

The transforming growth factor-betas (TGF-betas) are potent fibrogenic factors implicated in numerous CNS pathologies in which fibrosis and neural dysfunction are causally associated. In this study, we aimed to demonstrate significant inhibition of fibrogenesis, glial scarring, and inflammation in penetrating incisional wounds of the rat brain using the proteoglycan decorin, which effectively inhibits TGF-beta activity. Adult rats were assigned to two treatment groups each receiving 14 daily intraventricular injections of 10 microliter total volume of: (i) saline plus 0.3% autologous rat serum = 30 microgram protein); or (ii) saline plus 30 microgram recombinant human decorin. On day 0 of the experiment, a stereotactically defined unilateral incisional lesion was placed through the cerebral cortex into the lateral ventricle and, after 14 days, brains were processed for immunohistochemical analysis of the lesion site. Specific antibodies were used to visualize the deposition within the wound of matrix molecules and the extent and nature of reactive astrocytosis and inflammation. Quantitative and qualitative image analysis of the fibrous scar was performed in sections from a defined anatomical plane through the wound to detect the antifibrotic effects of decorin treatment. Treatment of wounds with decorin led to a marked attenuation of all aspects of CNS scarring including matrix deposition, formation of an accessory glial limiting membrane, and inflammation. Our findings suggest that decorin is potentially applicable to a number of human CNS fibrotic diseases to arrest the deposition of excessive extracellular matrix components and maintain and/or restore functional integrity.

Animals↗