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Biomedical subjects

J Harris

Publications and source records attributed to J Harris.

At least 55 records · Page 3Linked to original sources
PubMed2002

Potential role of endocrine gastrin in the colonic adenoma carcinoma sequence.

The role of hyper-gastrinaemia in the incidence of colonic cancer remains to be clarified. The aim of this study was to determine whether cholecystokinin-2 (CCK-2) receptor expression predicts the sensitivity of human colonic adenomas to the proliferative effects of serum hyper-gastrinaemia. Gene expression of the classical (74 kDa) CCK-2 receptor in human colonic adenoma specimens and cell lines, was quantified by real-time PCR. Western blotting, using a CCK-2 receptor antiserum, confirmed protein expression. A transformed human colonic adenoma was grown in SCID mice, with hyper-gastrinaemia induced by proton pump inhibitors. CCK-2 receptor blockade was achieved by using neutralising antiserum. Both human colonic adenoma cell lines and biopsies expressed CCK-2 receptor mRNA at levels comparable with CCK-2 receptor transfected fibroblasts and oxyntic mucosa. Western blotting confirmed immunoreactive CCK-2 receptor bands localised to 45, 74 and 82.5 kDa. Omeprazole and lansoprazole-induced hyper-gastrinaemia (resulting in serum gastrin levels of 34.0 and 153.0 pM, respectively) significantly increased the weight of the human adenoma grafts (43% (P=0.016) and 70% (P=0.014), respectively). The effect of hypergastrinaemia on tumour growth was reversed by use of antiserum directed against the CCK-2 receptor. Hyper-gastrinaemia may promote proliferation of human colonic adenomas that express CCK-2 receptor isoforms.

Adenocarcinoma↗
PubMed2002

Evaluation of 50 probands with early-onset Parkinson's disease for Parkin mutations.

BACKGROUND: Early onset PD has been associated with different mutations in the Parkin gene, including exon deletions and duplications. METHODS: The authors performed an extensive mutational analysis on 50 probands with onset of PD at younger than 50 years of age. Thirteen probands were ascertained from a registry of familial PD and 37 probands by age at onset at younger than 50 years, blind to family history. Mutational analysis was undertaken on the probands and available family members and included conventional techniques (single strand conformation polymorphism analysis and sequencing) and a newly developed method of quantitative duplex PCR to detect alterations of gene dosage (exon deletions and duplications) in PARKIN: RESULTS: Using this new technique, the authors detected eight alterations of gene dosage in the probands, whereas 12 mutations were found by conventional methods among the probands and another different mutation in an affected family member. In total, the authors identified compound heterozygous mutations in 14%, heterozygous mutations in 12%, and no Parkin mutation in 74% of the 50 probands. We expanded the occurrence of Parkin mutations to another ethnic group (African-American). CONCLUSION: The authors systematically screened all 12 Parkin exons by quantitative PCR and conventional methods in 50 probands. Eight mutations were newly reported, 2 of which are localized in exon 1, and 38% of the mutations were gene dosage alterations. These results underline the need to screen all exons and to undertake gene dosage studies. Furthermore, this study reveals a frequency of heterozygous mutation carriers that may signify a unique mode of inheritance and expression of the Parkin gene.

Adult↗
PubMed2002

Interactions between cutaneous afferent inputs to a withdrawal reflex in the decerebrated rabbit and their control by descending and segmental systems.

Previous studies have suggested that activation of nociceptive afferents from the heel recruits a supraspinal mechanism, which is modulated by adrenergic descending inhibition, that augments withdrawal reflexes in medial gastrocnemius (MG) motoneurones. To test this idea, we have studied the temporal evolution of reflexes evoked in MG by electrical stimulation of sural nerve A(beta)-, A(delta)- and C-fibre axons at 1 Hz, in decerebrated rabbits. Reflexes were analysed in three time bands, estimated to accord to afferent drive from A(beta)- (phase 1), A(delta)- (phase 2) and C-fibre (phase 3) inputs. Stimulation of A(delta)- and C-fibres gave significant temporal summation of all reflexes. The alpha(2)-adrenoceptor antagonist RX 821002 ((2-(2,3-dihydro-2-methoxy-1,4-benzodioxin-2-yl)-4,5-dihydro-1-H-imidazole)-HCl) (100 microg intrathecal (i.t.)) potentiated, and the alpha(2)-agonist dexmedetomidine (1-30 microg i.t.) depressed all reflexes per se, but the effects of these drugs on temporal summation were secondary to changes in baseline excitability. When C-fibres were stimulated, the N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (1 mg i.t.) reduced temporal summation of phase 2 and 3 but not phase 1 reflexes. Spinalisation at L1 in the absence of drugs increased phase 2 and 3 reflexes but had no effect on phase 1, whereas spinalisation after RX 821002 resulted in decreased phase 1 responses with no significant change in later phases. Spinalisation in the presence of dizocilpine resulted in small reductions in phase 3 reflexes only. In all cases spinalisation virtually abolished temporal summation. In spinalised animals, dizocilpine selectively reduced late reflexes, and the opioid antagonist naloxone (100 microg i.t.) augmented all reflexes but gave rise to temporal subtraction of reflexes when C-fibres were stimulated.The present experiments have revealed a number of novel and important features of the sural-MG reflex pathway: (i) activity in fine afferent axons augments the reflexogenic potential of all subsequent afferent input, thereby allowing all afferent drive from the sural field to contribute to withdrawal of the heel; (ii) endogenous adrenergic control of this reflex pathway is completely non-selective; (iii) there is a non-adrenergic element of descending inhibition that is selective for the late components of MG reflex responses, and this element is directed particularly against transmission through NMDA receptors; (iv) temporal summation in this reflex is dependent on NMDA receptor-dependent and -independent mechanisms; and (v) this temporal summation is in some way dependent on the integrity of descending pathways.

Adrenergic alpha-Agonists↗
PubMed2002

Oxytocin induces long-term depression on the rat dentate gyrus: possible ATPase and ectoprotein kinase mediation.

We studied the effects of the neuropeptide oxytocin (OT) on the long-term potentiation (LTP) paradigm in the dentate gyrus (DG) of urethane anesthetized rats. Intracerebroventricular injection of 1 microg of the hormone in 1 microl of physiological solution 2min before tetanization produced a significant decrease in both components of the perforant path evoked potentials (EP) in the DG. The effects appeared right after the tetanization stimuli and were more pronounced in the excitatory postsynaptic components of the EPs. The decrements lasted for the 2h of recording time. We concluded that OT induced and maintained long-term depression on the DG. In contrast, injection of OT in the absence of tetanic stimulation did not significantly affect perforant path EP in the DG. The results are discussed taking particular consideration of the inhibitory effects the OT has on (Ca(2+)+Mg(2+)) ATPase at membrane levels and the potential interference that this action may have with phosphorylation processes via an ectoprotein kinase isolated from membranes of hippocampal pyramidal neurons. Blocking of this ectoprotein kinase in vitro significantly impairs establishment and maintenance of LTP.

Action Potentials↗
PubMed2002

Effects of androstenedione on long term potentiation in the rat dentate gyrus. Relevance for affective and degenerative diseases.

We studied the effects of the androgenic hormone androstenedione, a 17-ketosteroid, on long term potentiation (LTP) in the dentate gyrus (DG) of intact, urethane anesthetized rats. Intravenous injection of 10mg of the hormone dissolved in Nutralipid produced a significant increase of the population spike (PS), but not of the excitatory post-synaptic potentials (EPSPs). The results are discussed in terms of the potential enhancement that androstenedione may have on some aspects of memory processes as reported for other androgenic steroids. Also noted are the plausible beneficial effects of the hormone on depression as well as in recovery following both central and peripheral neural injury.

Action Potentials↗
PubMed2002

Transfection of HEK cells via DNA-loaded PLGA and P(FASA) nanospheres.

HEK cells were transfected with the GFP gene using various vectors: naked DNA, lipofectamine, and both PLGA and P(FASA) plasmid-loaded nanospheres. All methods were assessed alone and with the use of chloroquine, a lysosomal enzyme inhibitor. Transfection efficiencies were determined and compared at various times post-incubation using a fluorescence standard curve. Neither naked DNA alone nor naked DNA and chloroquine were capable of transfecting cells. No differences were evident between lipofectamine with chloroquine and lipofectamine alone which transfected cells with a constant increase in efficiency up to 2 weeks. While transfection was not feasible with polymeric nanospheres alone, the addition of chloroquine allowed DNA released from nanospheres within cells to escape endosomal degradation and transfect the cells. The increase in transfection efficiency via nanospheres over time was exponential up to 1 week, as compared to the constant rate seen for the bolus-type administration of lipofectamine, indicating that nanospheres delivered DNA to the cells by a controlled release mechanism. Additionally, the effective dose delivered to cells via nanospheres was approximately 25% that of lipofectamine, indicating that transfection via PLGA and P(FASA) nanospheres might actually be more efficient.

Cell Line↗
PubMed2002

RX 821002 as a tool for physiological investigation of alpha(2)-adrenoceptors.

RX 821002 is the 2-methoxy congener of idazoxan. In binding and tissue studies it behaves as a selective antagonist of alpha(2)-adrenoceptors, with at least 5 times greater affinity for these receptors than any other binding site. It does not select between the different types of alpha(2)-receptor. Although this drug probably has no future as a therapeutic agent, it remains a good probe for physiological activity at alpha(2)-adrenoceptors in animal experiments. A particularly useful feature of this compound is its lack of binding at I(1) and I(2) imidazoline receptors. However, it has relatively high affinity for 5-HT(1A) receptors (at which it acts as an antagonist) and a tendency to behave as an inverse agonist at alpha(2A)-adrenoceptors in some cell culture systems. These potential drawbacks may be overcome by careful design of experiments, and the greater selectivity of RX 821002 renders it much superior to yohimbine or idazoxan as a tool for probing physiological actions at alpha(2)-receptors. It can be compared favorably with other selective antagonists such as atipamezole. In physiological studies, RX 821002 augments norepinephrine release in the frontal cortex and increases drinking behavior in rat. In rabbit, intrathecal administration of this drug enhances somatic and autonomic motor outflows, showing that tonic adrenergic descending inhibition of withdrawal reflexes and sympathetic pre-ganglionic neurons is strong in this species. The potentiation of reflexes may be considered a pro-nociceptive action. In the same model, RX 821002 antagonizes the inhibitory effects of the mu opioid fentanyl, indicating that exogenous opioids synergize with endogenously released norepinephrine in the spinal cord. Thus, the careful use of RX 821002 has revealed several aspects of the physiological activity of alpha(2)-adrenoceptors in rabbit spinal cord and rat brain. We recommend that RX 821002 and/or compounds with similar selectivity for alpha(2)-adrenoceptors (atipamezole, MK-912, RS-79948) should be used in preference to yohimbine or idazoxan in all future studies of this type.

Adrenergic alpha-Agonists↗
PubMed2001

RTOG 96-10: reirradiation with concurrent hydroxyurea and 5-fluorouracil in patients with squamous cell cancer of the head and neck.

PURPOSE: Patients with recurrent squamous cell cancer of the head and neck (SCH&N) are generally treated with systemic chemotherapy. Improvement in survival has not occurred, despite an increased objective response rate. This study was undertaken to explore the feasibility and toxicity, and estimate the therapeutic impact of, reirradiation (RRT) with concurrent hydroxyurea and 5-fluorouracil. METHODS AND MATERIALS: The eligibility requirements included SCH&N presenting as a second primary or recurrence > or =6 months after definitive RT to > or =45 Gy, with > or =75% of the tumor volume within the previous field. The cumulative spinal cord dose was limited to 50 Gy, and measurable disease was required. Four weekly cycles were given, each separated by 1 week of rest. A cycle consisted of 5 days, Monday through Friday, of 1.5-Gy twice-daily repeated RT, with the fractions separated by > or =6 h, with 1.5 g of hydroxyurea given 2 h and 300 mg/m2 of a 5-fluorouracil IV bolus given 30 min before each second daily fraction. RESULTS: Eighty-six patients were entered; 81 patients were assessable. The median prior radiation dose was 61.2 Gy. The 4 planned cycles were delivered in 79% of patients. Grade 3 mucositis occurred in 14% of patients, and Grade 4 in 5%. Grade 3 acute pharyngeal toxicity was seen in 17%. Grade 3 neutropenia occurred in 9%, Grade 4 in 10%, and Grade 5 in 7%. Six patients died of treatment-related toxicity. Two died of hemorrhage from the tumor site without thrombocytopenia. With a median follow-up of 16.3 months for living patients, the estimated median overall survival was 8.2 months and the estimated 1-year survival rate 41.7%. Patients treated >3 years after the previous RT had a 1-year survival rate of 48% compared with 35% for patients treated within 3 years (p = 0.017). The 1-year survival rate for patients with a second primary was 54% compared with 38% for patients with recurrence (p = 0.083). CONCLUSION: Repeated RT with concurrent chemotherapy as given in this study is a feasible approach for selected, previously irradiated patients with SCH&N and may produce increased median and 1-year survival rates compared with systemic chemotherapy trials reported in the literature. A randomized study should be conducted to compare these two different approaches.

Adult↗
PubMed2001

Endogenous adrenergic control of reflexes evoked by mechanical stimulation of the heel in the decerebrated rabbit.

In decerebrated rabbits, reflexes were evoked in medial gastrocnemius motoneurones by mechanical stimulation of the heel, using four pinch strengths from 183 (innocuous) to 4577 (noxious) mN. The alpha(2)-adrenoceptor antagonist idazoxan (1-156 microg intrathecal (i.th.) significantly increased responses to pinch strengths of 607 mN and above. Subsequent administration of the alpha(1) adrenoceptor selective antagonist prazosin (200 microg i.th.) decreased reflexes to 4577 mN pinches but had no other significant effects. The opioid antagonist (-)-quadazocine (25 microg i.th.) caused no further changes in reflexes. Spinal section at L1 in the presence of this drug combination enhanced gastrocnemius responses to 183 and 607 mN stimuli, had no effect on reflexes to 1866 mN and significantly decreased responses to 4577 mN pinches. These data confirm that reflexes evoked by 'natural' stimulation of heel mechanoreceptors are subject to powerful tonic descending inhibition mediated by alpha(2)-adrenoceptors. For the highest strength stimulus, the results of alpha(2) blockade involved enabling of descending facilitation as well as reduction of descending inhibition.

Adrenergic alpha-Antagonists↗
PubMed2001

Impairment of mycobacterial but not viral immunity by a germline human STAT1 mutation.

Interferons (IFN) alpha/beta and gamma induce the formation of two transcriptional activators: gamma-activating factor (GAF) and interferon-stimulated gamma factor 3 (ISGF3). We report a natural heterozygous germline STAT1 mutation associated with susceptibility to mycobacterial but not viral disease. This mutation causes a loss of GAF and ISGF3 activation but is dominant for one cellular phenotype and recessive for the other. It impairs the nuclear accumulation of GAF but not of ISGF3 in heterozygous cells stimulated by IFNs. Thus, the antimycobacterial, but not the antiviral, effects of human IFNs are principally mediated by GAF.

Adult↗
PubMed2001

Adaptive changes in withdrawal reflexes after noxious stimulation at the heel and the toes in the decerebrated rabbit.

In decerebrated rabbits, reflexes evoked by electrical stimulation of the toes in the ankle flexor tibialis anterior were enhanced for > 30 min after application of 20% mustard oil to the base of the toes, whereas responses of the ankle extensor medial gastrocnemius to stimulation of the heel were depressed for > 20 min by the same stimulus. Applied to the heel, mustard oil had inconsistent effects on the flexor reflex but potentiated the extensor response for approximately 1 h. Intrathecal co-administration of naloxone (25 microg) with the selective alpha(2)-adrenoceptor antagonist RX 821002 (200 microg) enhanced both reflexes to more than twice pre-drug values and reduced or abolished all effects of mustard oil. These data confirm that the location of a noxious stimulus is an important determinant of the subsequent adaptive changes in reflexes, and indicate roles for endogenous opioids and noradrenaline in these processes.

Adaptation, Physiological↗
PubMed2001

Effect of the APOE promoter polymorphisms on cerebral amyloid peptide deposition in Alzheimer's disease.

Polymorphisms in the promoter region of the apolipoprotein E gene (APOE) affect the amount of amyloid peptide (Abeta) in the brains of patients with Alzheimer's disease. We measured Abeta load immunohistochemically in regions 8 and 9 of Brodman's area in 74 people with Alzheimer's disease. The amount of Abeta deposition was independent of APOE genotype in our cohort. These findings in patients with confirmed Alzheimer's disease are consistent with the hypothesis that variation in APOE expression directly affects Alzheimer's disease pathology.

Aged↗
PubMed2001

Cannabinoidergic and opioidergic inhibition of spinal reflexes in the decerebrated, spinalized rabbit.

The present experiments were designed to investigate the role(s) of cannabinoid receptors in modulating transmission in the sural-medial gastrocnemius withdrawal reflex of the decerebrated, spinalized rabbit and how, if present, cannabinoid-mediated control might interact with opioid-mediated inhibitions known to impinge on this reflex pathway. The selective CB(1) receptor antagonist SR 141716A enhanced reflexes by a factor of two after a cumulative dose of 100 nmol kg(-1) i.v., but had no effect on the endogenous opioid-mediated inhibition generated by repetitive electrical stimulation of the common peroneal nerve, or on the suppression of reflexes caused by i.v. administration of the synthetic opioid fentanyl. Given at a dose of 10 nmol kg(-1) i.v., the potent, CB(1)--CB(2) cannabinoid receptor agonist HU 210 inhibited medial gastrocnemius reflexes to approximately 30% of controls and significantly decreased both heart rate and blood pressure, but did not alter the inhibition of reflexes resulting from common peroneal nerve stimulation or i.v. fentanyl. The effects of HU 210 were reversed by SR 141716A. HU 210 was just as effective in inhibiting reflexes in the presence of the opioid antagonist naloxone (5 micromol kg(-1)) as it was in untreated animals. The data show that cannabinoids, acting through CB(1) receptors, are inhibitory in rabbit spinal cord and that there appears to be some endogenous cannabinoid tone under the conditions of the present experiments. The evidence of this study is that the inhibitory effects of opioids and cannabinoids in rabbit spinal cord are completely independent of each other, and are additive rather than synergistic.

Animals↗
PubMed2001

The risk of acquiring hepatitis B or C among public safety workers: a systematic review.

CONTEXT: Determination of the occupational risk of hepatitis B and C to public safety workers is important in identifying prevention opportunities and has significant legal and policy implications. OBJECTIVES: Characterize the risk of occupationally acquired infection: (1) risk of exposure to blood and body fluids, (2) seroprevalence of hepatitis B and C in the source population, and (3) risk of infection after exposure. DATA SOURCES: Electronic search of MEDLINE (1991-1999), HealthStar (1982-1999), and CINAHL (1975-1999) supplemented by selected reference citations and correspondence with authors of relevant articles. STUDY SELECTION: Peer-reviewed journal articles (N=702) that addressed the transmission of hepatitis B and C in law enforcement, correctional, fire, emergency medical services, and healthcare personnel were identified. One hundred five (15.0%) articles were selected for full-text retrieval; 72 (68.6%) were selected for inclusion. DATA ABSTRACTION: Articles selected for inclusion were abstracted by two reviewers and checked by a third reviewer, using a standard reporting form. DATA SYNTHESIS: Evidence tables were constructed, using the standardized abstracts. The tables were designed to summarize data for the key elements of the risk analysis. CONCLUSIONS: Data suggest that emergency medical service (EMS) providers are at increased risk of contracting hepatitis B, but data have failed to show an increased prevalence of hepatitis C. EMS providers have exposure risks similar to those of hospital-based healthcare workers. Other public safety workers appear to have lower rates of exposure. Urban areas have much higher prevalence of disease, and public safety workers in those areas are likely to experience a higher incidence of exposure events.

Blood-Borne Pathogens↗
PubMed2001

Ignorance, information and autonomy.

People have a powerful interest in genetic privacy and its associated claim to ignorance, and some equally powerful desires to be shielded from disturbing information are often voiced. We argue, however, that there is no such thing as a right to remain in ignorance, where a fight is understood as an entitlement that trumps competing claims. This does not of course mean that information must always be forced upon unwilling recipients, only that there is no prima facie entitlement to be protected from true or honest information about oneself. Any claims to be shielded from information about the self must compete on equal terms with claims based in the rights and interests of others. In balancing the weight and importance of rival considerations about giving or withholding information, if rights claims have any place, rights are more likely to be defensible on the side of honest communication of information rather than in defence of ignorance. The right to free speech and the right to decline to accept responsibility to take decisions for others imposed by those others seem to us more plausible candidates for fully fledged rights in this field than any purported right to ignorance. Finally, and most importantly, if the right to autonomy is invoked, a proper understanding of the distinction between claims to liberty and claims to autonomy show that the principle of autonomy, as it is understood in contemporary social ethics and English law, supports the giving rather than the withholding of information in most circumstances.

Confidentiality↗
PubMed2001

Mutation of the matrix metalloproteinase 2 gene (MMP2) causes a multicentric osteolysis and arthritis syndrome.

The inherited osteolyses or 'vanishing bone' syndromes are a group of rare disorders of unknown etiology characterized by destruction and resorption of affected bones. The multicentric osteolyses are notable for interphalangeal joint erosions that mimic severe juvenile rheumatoid arthritis (OMIMs 166300, 259600, 259610 and 277950). We recently described an autosomal recessive form of multicentric osteolysis with carpal and tarsal resorption, crippling arthritic changes, marked osteoporosis, palmar and plantar subcutaneous nodules and distinctive facies in a number of consanguineous Saudi Arabian families. We localized the disease gene to 16q12-21 by using members of these families for a genome-wide search for homozygous-by-descent microsatellite markers. Haplotype analysis narrowed the critical region to a 1.2-cM region that spans the gene encoding MMP-2 (gelatinase A, collagenase type IV; (ref. 3). We detected no MMP2 enzymatic activity in the serum or fibroblasts of affected family members. We identified two family-specific homoallelic MMP2 mutations: R101H and Y244X. The nonsense mutation effects a deletion of the substrate-binding and catalytic sites and the fibronectin type II-like and hemopexin/TIMP2 binding domains. Based on molecular modeling, the missense mutation disrupts hydrogen bond formation within the highly conserved prodomain adjacent to the catalytic zinc ion.

Amino Acid Sequence↗