Biomedical subjects
E Cooper
Publications and source records attributed to E Cooper.
A comparison of topical formulations for the prevention of human schistosomiasis.
Recently, a dimeticone formulation has been shown to be effective at preventing Schistosoma cercariae infecting skin, while DEET (N,N-diethyl-m-toluamide), a highly effective insecticide, has been shown to have activity against cercariae. Seven formulations, 3 containing DEET, were prepared and applied to excised human skin in Franz cells for 1 h. Schistosoma cercariae were applied for 30 min at 1 and 24 h, and the number that penetrated the skin calculated (n = 9). DEET could not be incorporated into the dimeticone formulation, yet it remained the most effective at preventing cercarial penetration, both 1 and 24 h after application. The ointments that contained DEET did prevent penetration but their mode of action was due to the toxicity of DEET against the cercariae. The persistence of the protection afforded by the dimeticone formulation after washing suggests that the formulation may be interacting with the stratum corneum to prevent cercarial recognition of skin.
Regaining consciousness for prolonged comatose patients with right median nerve stimulation.
During the past half year, we have utilized right median nerve stimulation (produced by Empi. Co. USA) to awaken consciousness of patients on 6 cases, 2 with brain trauma, one with aneurysm rupture, one with hemorrhagic stroke and two with hypoxic encephalopathy. The comatose duration ranged from 6 to 17 weeks. All patients underwent SPECT scan for cerebral perfusion evaluation and neurotransmitter quantification before and after the stimulation. The stimulation time lasted from 8 to 10 hours on daytime. The stimulation persisted for 3 months in all patients. Four patients recovered from the consciousness within 35 days. There was no obvious clinical improvement in two patients. Brain perfusion increased in all cases through the SPECT study after stimulation. The elevation of neurotransmitter in CSF was found in 5 out of the 6 cases. Median nerve stimulation elevates the cerebral blood flow and may influence the patient's consciousness. Young patients (<40 years old) had better results than old patients. The stimulation could be initiated if the patient's acute stage was over. In our series, although increase in cerebral blood flow was found in all cases, some patients did not regain consciousness.
Potential transmission of Creutzfeldt-Jakob disease after low-risk surgery.
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Antibodies to myelin basic protein, myelin oligodendrocytes peptides, alpha-beta-crystallin, lymphocyte activation and cytokine production in patients with multiple sclerosis.
OBJECTIVE: To measure neurone-specific humoral and cellular immune parameters in MRI-positive patients with multiple sclerosis (MS). BACKGROUND: It has been postulated from animal models for MS and in situ evidence in MS patients that antibodies, activated T cells and proinflammatory cytokines are involved in the destruction of myelin sheaths and loss of oligodendrocytes in active areas. SUBJECTS AND METHODS: Blood samples were obtained from 20 healthy control subjects and 20 patients with abnormal MRI and clinical diagnosis of MS. Sera were tested for levels of IgG, IgM and IgA against myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG) peptides, and a small heat-shock protein, alpha-beta-crystallin. Lymphocytes were isolated and cultured in the presence or absence of MBP, MOG peptides and alpha-beta-crystallin, measured for stimulated T cells, cytokine production and compared with controls. RESULTS: Patients with MS showed the highest levels of IgG, IgM or IgA antibodies against one or all three tested antigens. Moreover, in the presence of MBP, MOG peptides or alpha-beta-crystallin, a significant percent- age of lymphocytes from MS patients underwent blast transformation, which resulted in high levels of interferon gamma (IFN-gamma), tumour necrosis factor alpha (TNF-alpha) and tumour necrosis factor beta (TNF-beta) production. Sensitivity of these assays was 60-80% and specificity, 65-70%. CONCLUSIONS: Detection of antibodies against MBP, MOG peptides, alpha-beta-crystallin, lymphocyte stimulation and production of proinflammatory cytokines in response to these antigens could be used as surrogate markers for the confirmation of MS diagnosis. A combination of antibodies, lymphocyte activation or cytokine production with abnormal MRI may significantly increase the sensitivity and specificity of MS diagnosis.
Role of the human cytomegalovirus major immediate-early promoter's 19-base-pair-repeat cyclic AMP-response element in acutely infected cells.
Prior studies have suggested a role of the five copies of the 19-bp-repeat cyclic AMP (cAMP)-response element (CRE) in major immediate-early (MIE) promoter activation, the rate-limiting step in human cytomegalovirus (HCMV) replication. We used two different HCMV genome modification strategies to test this hypothesis in acutely infected cells. We report the following: (i) the CREs do not govern basal levels of MIE promoter activity at a high or low multiplicity of infection (MOI) in human foreskin fibroblast (HFF)- or NTera2-derived neuronal cells; (ii) serum and virion components markedly increase MIE promoter-dependent transcription at a low multiplicity of infection (MOI), but this increase is not mediated by the CREs; (iii) forskolin stimulation of the cAMP signaling pathway induces a two- to threefold increase in MIE RNA levels in a CRE-specific manner at a low MOI in both HFF- and NTera2-derived neuronal cells; and (iv) the CREs do not regulate basal levels of HCMV DNA replication at a high or low MOI in HFF. Their presence does impart a forskolin-induced increase in viral DNA replication at a low MOI but only when basal levels of MIE promoter activity are experimentally diminished. In conclusion, the 19-bp-repeat CREs add to the robust MIE promoter activity that occurs in the acutely infected stimulated cells, although the CREs' greater role may be in other settings.
Depolarization strongly induces human cytomegalovirus major immediate-early promoter/enhancer activity in neurons.
Activity-dependent changes in gene expression involving the transcription factor cAMP-response element-binding protein (CREB) occur in learning and memory, pain, and drug addiction. This mechanism may also be important for cytomegaloviral infections of the brain. The human cytomegalovirus major immediate-early promoter/enhancer (hCMV promoter), rate-limiting for productive cytomegalovirus infection, contains five cAMP-response elements (CREs). Indirect evidence suggests that this promoter does not function in unstimulated neurons. Here we test the hypothesis that expression from the hCMV promoter in neurons is induced by membrane depolarization. For these experiments, we infected cultured sympathetic and hippocampal neurons with hCMV-green fluorescent protein (GFP) promoter/reporter constructs using adenoviral gene transfer techniques and measured transgene expression by quantifying GFP fluorescence and GFP mRNA levels. We found that depolarization up-regulates promoter activity by >90-fold. Moreover, our results from pharmacological experiments suggest that this induction occurred through a CREB-dependent pathway. Importantly, site-directed mutagenesis of all five CREs in the promoter blocked this up-regulation almost completely, whereas mutating four of them had no effect. We conclude that the hCMV promoter acts as a molecular switch in neurons and is strongly induced by membrane depolarization, neuronal activity, or other stimuli that activate CREB. These results may provide insight into molecular mechanisms of cytomegalovirus-related diseases of the brain.
A new role for ion channels in myoblast fusion.
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Molecular cloning and functional expression of Xenopus laevis oocyte ATP-activated P2X4 channels.
All cells contain mechanosensitive ion channels, yet the molecular identities of most are unknown. The purpose of our study was to determine what encodes the Xenopus oocyte's mechanosensitive cation channel. Based on the idea that homologues to known channels might contribute to the stretch channels, we screened a Xenopus oocyte cDNA library with cation channel probes. Whereas other screens were negative, P2X probes identified six isoforms of the P2X4 subtype of ATP-gated channels. From RNase protection assays and RT-PCR, we demonstrated that Xenopus oocytes express P2X4 mRNA. In expression studies, four isoforms produced functional ATP-gated ion channels; however, one, xP2X4c, had a conserved cysteine replaced by a tyrosine and failed to give rise to functional channels. By changing the tyrosine to a cysteine, we showed that this cysteine was crucial for function. We raised antibodies against a Xenopus P2X4 C-terminal peptide to investigate xP2X4 protein expression. This affinity purified anti-xP2X4 antibody recognized a 56 kDa glycosylated Xenopus P2X4 protein expressed in stably transfected HEK-293 cells and in P2X4 cDNA injected oocytes overexpressing the cloned P2X4 channels; however, it failed to recognize proteins in control, uninjected oocytes. This suggests that P2X4 channels and mechanosensitive cation channels are not linked. Instead, oocyte P2X4 mRNA may be part of the stored pool of stable maternal mRNA that remains untranslated until later developmental stages.
PI-3 kinase and IP3: partners in NT3-induced synaptic transmission.
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Population pharmacokinetics of dapsone in children with human immunodeficiency virus infection.
BACKGROUND: Previous studies of dapsone pharmacokinetics in children have been too small to allow assessment of the relationships between dapsone pharmacokinetic parameters and patient characteristics or markers of efficacy and toxicity. METHODS: We used population analysis to estimate dapsone pharmacokinetic parameters in children participating in a phase I/II study of daily and weekly dapsone in children with human immunodeficiency virus (HIV) infection. With use of the program NONMEM and a 1-compartment open model, the influence of demographic and clinical characteristics on oral clearance (CL/F) and oral volume of distribution (V/F) were examined. Measures of drug exposure (area under the concentration-time curve [AUC] and predicted concentrations just before and 2 hours after administration) were estimated for each patient and correlated with markers of efficacy and toxicity. RESULTS: Sixty children (median age, 3 years; age range, 2 months to 12 years) contributed 412 dapsone concentrations collected after 175 study doses. Final parameter estimates were 1.40 L/kg for V/F, 0.0283 L/kg/h for CL/F, and 2.66 for the absorption rate constant. Of the clinical characteristics evaluated, dapsone CL/F was significantly increased by 50% in children taking rifabutin, by 39% in black children, and by 38% in children younger than 2 years old. Although no significant correlations were found between any dapsone exposure parameter and markers of toxicity, increased AUC was associated with a decreased risk of Pneumocystis carinii pneumonia (PCP). CONCLUSION: Ethnicity, age, and concomitant rifabutin use were associated with dapsone CL/F, with more rapid clearance observed in black children, children younger than 2 years old, and children receiving rifabutin. Dapsone pharmacokinetic parameters were not associated with toxicity, but higher dapsone AUC was associated with decreased risk of PCP. Monitoring of serum dapsone levels may be needed for optimal management of dapsone for PCP prophylaxis in children.
Pilot study of electrical stimulation on median nerve in comatose severe brain injured patients: 3-month outcome.
PRIMARY OBJECTIVE: To determine if electrical stimulation (ES) benefits (waking time, 3-month outcomes) treated coma patients. RESEARCH DESIGN: Double blind randomized-controlled study. METHODS AND PROCEDURES: Ten coma patients; six treatment and four controls, using the 'Respond Select' by EMPI. EXPERIMENTAL INTERVENTIONS: Treatment group received radial nerve ES applied in 300 ms intermittent pulses at 40 Hz, 15-20m A 8 hours a day up to 14 days of coma; control group received sham stimulation. MAIN OUTCOMES AND RESULTS: ES group emerged from coma mean 2 days earlier than controls, although this result was not statistically significant. At 3 months post-injury, there was no group difference in Glasgow Outcome Scale, although the ES group had improved function over controls as measured by the FIM/FAM (mean of 114 and 64.5, respectively, n.s.). CONCLUSIONS: These data show an interesting trend, although statistical power was limited in this small pilot study, suggesting the need for a larger trial.
Nicotinic acetylcholine receptors on vagal afferent neurons.
Nicotinic acetylcholine receptors (nAChRs) play an important role in various processes involved in regulating systemic blood pressure. These receptors are expressed at excitatory cholinergic synapses between sympathetic preganglionic neurons and postganglionic sympathetic neurons and link the integrative activities of the CNS with peripheral effector mechanisms of the sympathetic nervous system. Nicotinic AChRs are also expressed on a subset of vagal afferent neurons, including those involved in baroreceptor reflexes. This review discusses the developmental expression of nAChRs on vagal afferent neurons and two factors that influence the differentiation of these neurons: ganglionic satellite cells and neurotrophins. In addition, this review discusses two important properties of neuronal nAChRs: inward rectification and calcium permeability. At the molecular level, intracellular polyamines, acting as gating particles, effectively block the receptor pore in a voltage-dependent manner, producing inward rectification. Moreover, a critical structural determinant underlies both the block by intracellular polyamines and calcium permeability. Finally, this review discusses the modulation and block of neuronal nAChRs by extracellular polyamines and the possible implications for neurodegenerative diseases.
Occupational exposure: there for your protection.
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Treatment for intestinal helminth infection. Message does not follow from systematic review's findings.
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Human immunodeficiency virus (HIV) type 1 antibodies in perinatal HIV-1 infection: association with human HIV-1 transmission, infection, and disease progression. For the Women and Infants Transmission Study.
Anti -human immunodeficiency virus (HIV) type 1 antibodies in 242 pregnant women and 238 infants were measured at birth and at 1, 2, 4, and 6 months after birth, to estimate their association with perinatal transmission and infant disease progression. Maternal anti-p24 (P=.01) and anti-gp120 (P=.04) antibodies were inversely associated with vertical transmission rates, independent of maternal percentage of CD4 cells, hard drug use, duration of ruptured membranes, serum albumin levels, serum vitamin A levels, and quantitative HIV-1 peripheral mononuclear blood cell culture, but not with maternal plasma immune complex dissociated p24 or HIV-1 RNA copy number, both of which were highly correlated with antibodies. From ages 1-2 months, anti-gp120, -gp41, -p31, and -p66 decayed to a greater extent in infected than in uninfected infants. Infected infants produced anti-p24 antibody by age 2 months, anti-p17 by 4 months, and anti-p41 and anti-gp120 by 6 months. As early as birth, infants with rapid disease progression had lower levels of anti-p24 than did infants whose disease did not rapidly progress, but not independently of HIV-1 RNA levels.
A molecular link between inward rectification and calcium permeability of neuronal nicotinic acetylcholine alpha3beta4 and alpha4beta2 receptors.
Many nicotinic acetylcholine receptors (nAChRs) expressed by central neurons are located at presynaptic nerve terminals. These receptors have high calcium permeability and exhibit strong inward rectification, two important physiological features that enable them to facilitate transmitter release. Previously, we showed that intracellular polyamines act as gating molecules to block neuronal nAChRs in a voltage-dependent manner, leading to inward rectification. Our goal is to identify the structural determinants that underlie the block by intracellular polyamines and govern calcium permeability of neuronal nAChRs. We hypothesize that two ring-like collections of negatively charged amino acids (cytoplasmic and intermediate rings) near the intracellular mouth of the pore mediate the interaction with intracellular polyamines and also influence calcium permeability. Using site-directed mutagenesis and electrophysiology on alpha(4)beta(2) and alpha(3)beta(4) receptors expressed in Xenopus oocytes, we observed that removing the five negative charges of the cytoplasmic ring had little effect on either inward rectification or calcium permeability. However, partial removal of negative charges of the intermediate ring diminished the high-affinity, voltage-dependent interaction between intracellular polyamines and the receptor, abolishing inward rectification. In addition, these nonrectifying mutant receptors showed a drastic reduction in calcium permeability. Our results indicate that the negatively charged glutamic acid residues at the intermediate ring form both a high-affinity binding site for intracellular polyamines and a selectivity filter for inflowing calcium ions; that is, a common site links inward rectification and calcium permeability of neuronal nAChRs. Physiologically, this molecular mechanism provides insight into how presynaptic nAChRs act to influence transmitter release.