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Biomedical subjects

D J Martin

Publications and source records attributed to D J Martin.

At least 55 records · Page 3Linked to original sources
PubMed1999

Pharmacological and urodynamic changes in rat urinary bladder function after multiple pregnancies.

OBJECTIVE: To investigate the changes in bladder function after multiple pregnancies and parturition in rats, and to establish links between the changes in voiding profiles and in vitro pharmacological responses. MATERIALS AND METHODS: Cystometry was used in conscious virgin and multiparous female Wistar rats (2 weeks after the last parturition) with chronically implanted lines to continuously record bladder pressure during five reproducible voiding cycles. In vitro, detrusor muscle contractile responses induced by cumulative concentrations of KCl, carbachol, noradrenaline and alpha, beta-methylene-ATP (mATP) were compared. RESULTS: In multiparous rats, there was a significant increase in the amplitude of voiding pressure (+31%), bladder capacity (+83%) and residual volume (about threefold); 60% of the multiparous rats but only 10% of the virgin rats showed bladder instability during the filling phase. Cumulative concentration-response curves to KCl, expressed as the tension developed vs tissue weight, were identical in the two groups of rats. Contractile responses induced by carbachol (0.1-30 micromol/L) were significantly larger in multiparous than in virgin rats. Similarly, noradrenaline-induced contractions (0.3-10 micromol/L) were significantly higher for multiparous animals. However, the sensitivity of the detrusor muscle to mATP was not modified by multiple pregnancies. CONCLUSION: After multiple gestations, female rats develop bladder hypertrophy, bladder instabilities and a higher amplitude of voiding pressure associated with an increased residual volume. These altered patterns are similar to those found in rats after chronic infravesical outlet obstruction. We propose that pregnancies and parturition modify urinary bladder function, leading to a dysfunction similar to that induced by obstruction, and involving an increased sensitivity to adrenergic and cholinergic stimulation.

Adenosine Triphosphate↗
PubMed1999

Impaired interleukin-8-induced degranulation of polymorphonuclear neutrophils from human immunodeficiency virus type 1-infected individuals.

Degranulation of peripheral blood polymorphonuclear leukocytes (PMNLs) was monitored in human immunodeficiency virus (HIV) type 1 (HIV-1)-infected individuals with or without pulmonary tuberculosis (HIV/TB and HIV groups, respectively) by measuring the release of beta-glucuronidase induced by interleukin-8 (IL-8). This was increased in a dose-dependent manner in the control groups consisting of healthy blood donors and patients with pulmonary tuberculosis. In contrast, PMNLs from the HIV and HIV/TB groups responded reciprocally in the same assay; that is, higher IL-8 input concentrations resulted in the release of less enzyme than lower IL-8 input concentrations. The degranulation response of PMNLs from HIV-1-infected individuals was similarly altered for another agonist, N-formyl-methionyl-leucyl-phenylalanine, suggesting that impairment of the nonoxidative armature of PMNL was a more generalized phenomenon. However, impaired IL-8-induced degranulation was found to be associated with the reduced expression of both IL-8 receptors, A and B, on whole-blood PMNLs from HIV-1-infected patients compared with that on whole-blood PMNLs from healthy persons. The density of IL-8RA, in particular, was most reduced on the surfaces of PMNLs from those patients with the poorest degranulation in response to IL-8. Inefficient agonist-induced degranulation may contribute to the increased susceptibility of HIV-1-infected persons to secondary microbial infections, this being further exacerbated in HIV/TB patients who, in addition, display defects in phagocytosis and oxidative burst.

Adult↗
PubMed1999

Dysregulated production of interleukin-8 in individuals infected with human immunodeficiency virus type 1 and Mycobacterium tuberculosis.

Interleukin-8 (IL-8) production in vivo was monitored in four study groups: normal blood donors, patients with pulmonary tuberculosis (TB), patients with human immunodeficiency virus type 1 (HIV-1) infection, and dually infected (HIV/TB) patients. We show that whereas there was evidence of detectable levels of cell-associated IL-8 (mRNA and protein) in peripheral cells of healthy individuals, this was largely lost in the disease states studied. Coupled with this finding was significantly increased circulating levels of IL-8 in HIV-1-infected individuals with or without concomitant pulmonary TB (P < 0.001). On the other hand, the capacity of peripheral mononuclear cells to produce IL-8 spontaneously ex vivo was enhanced in HIV-1 and TB patients (P < 0.05) and many of the HIV/TB group, but their corresponding capacities to respond to various stimuli, in particular phytohemagglutinin, were significantly diminished compared to those of normal donors (P < 0.05). Circulating levels of IL-8 in a group of HIV/TB patients were significantly positively correlated with the percentage of polymorphonuclear leukocytes (PMN) in the peripheral circulation (r = 0.65; P = 0.01), the proportions of IL-8 receptor A (IL-8RA)-expressing (r = 0.86; P < 0.01) and IL-8RB-expressing (r = 0.77; P < 0.01) PMN, and the capacity of PMN to migrate in response to IL-8 as chemoattractant (r = 0.68; P < 0. 01). IL-8RB fluorescence intensity, however, was negatively correlated with plasma IL-8 levels (r = -0.73; P < 0.01). Our results suggest that altered regulation of IL-8 in HIV-1 may have important implications for antimicrobial defenses and for normal immune processes.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Preclinical pharmacology of alpha1-adrenoceptor antagonists.

The implication of a single adrenoceptor subtype in the contractility of prostatic and urethral smooth muscle cells led to the concept that drugs with selectivity for this subtype may exhibit functional uroselectivity. Comparison of the affinities of the alpha1-adrenoceptor antagonists revealed that few compounds show selectivity for one of the three cloned alpha1-adrenoceptor subtypes (alpha1a/A, alpha1b/B, alpha1d/D) whereas most of them had a similar affinity for the three subtypes. Moreover, data supporting a relationship between selectivity for the alpha1a/A-adrenoceptor subtype and functional uroselectivity are still lacking and recent data challenged the relevance of the selectivity for a given cloned alpha1-adrenoceptor subtype in predicting functional uroselectivity. In vivo data showed that alpha1-adrenoceptor antagonists without adrenoceptor subtype selectivity, like alfuzosin or to a minor extent doxazosin, showed functional uroselectivity whereas prazosin and terazosin were not shown to be uroselective. Compounds considered to be selective for the alpha1a/A-adrenoceptor, like tamsulosin or 5-Me-urapidil, did not show functional uroselectivity since they modified urethral and blood pressures in a manner which was not correlated to their selectivity for the cloned alpha1-adrenoceptor subtypes. Meanwhile, the identification in prostatic tissue, of a new sub-family of alpha1-adrenoceptors with low affinity for prazosin and denominated alpha1L gave rise to numerous studies. However, its functional role as well as the affinity of the known antagonists for this receptor subtype remains to be clarified. In conclusion, the existing alpha1-adrenoceptor antagonists have different pharmacological profiles in vivo which are yet not predictable from their receptor pharmacology based on the actual state of knowledge of the alpha1-adrenoceptor classification.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed1999

Anticoagulant and antithrombotic activity of maltodapoh, a novel sulfated tetrasaccharide.

Orally bioavailable anticoagulants are needed that exhibit rapid and predictable onset and offset kinetics. This study was designed to determine whether maltodapoh, a novel sulfated bis-maltobionic acid amide, exhibits anticoagulant and antithrombotic activity in vivo after oral administration. Maltodapoh exhibited a dose-dependent increase in activated partial thromboplastin time (aPTT) in both rabbit and human plasma in vitro. Maltodapoh also induced a dose-dependent increase in aPTT when administered either i.v. or p.o. in rabbits. After a single oral bolus (3 mg/kg), aPTT increased 2- to 3-fold between 4 and 8 h and remained elevated for at least 24 h. This dose doubled the time to the onset of thrombotic occlusion after electrical injury to the carotid artery (from 52 +/- 12 min in vehicle-treated, control rabbits, n = 7, to 98 +/- 12 min in maltodapoh-treated animals, n = 7, P <.001) and reduced by 84% the weight of thrombus in the superior vena cava induced over 2 h after insertion of a thrombogenic copper wire and thread device (from 37 +/- 10 mg in controls to 6 +/- 3 mg in maltodapoh-treated animals, P <.001). Thus, based on the in vivo activity after oral administration, favorable kinetic profile and efficacy for inhibition of both arterial and venous thrombosis, further testing of this class of compounds appears warranted.

Administration, Oral↗
PubMed1998

Haemocyanin and the binding of cadmium and zinc in the haemolymph of the shore crab Carcinus maenas (L.).

The trace metals cadmium and zinc are taken up from solution into haemolymph of the shore crab, Carcinus maenas, where they bind to the respiratory pigment haemocyanin. Investigations using FPLC and PAGE to separate the constituent dodecamer and hexamer aggregations of haemocyanin showed a difference between the distribution of cadmium and zinc between the two aggregate states. In the haemolymph, labelled cadmium binds not only to haemocyanin but, at least initially, it is also associated with low molecular size material or exists as free cadmium ions. The binding of cadmium to haemocyanin is not an immediate process. Initially the binding of cadmium favours the hexamer; only later is a more even distribution between the two aggregate states apparent. Newly taken up labelled zinc is rapidly bound to haemocyanin. The majority of both total and labelled zinc in the haemolymph is bound to haemocyanin, with the hexamer having a greater binding affinity for zinc than the dodecamer. This suggests that formation of the dodecamer leads to a blocking of zinc-binding sites and/or that the hexamer consists of subunits which possess a relatively high affinity for zinc.

Animals↗
PubMed1998

Genetic characterization of HIV type 1 from migrant workers in three South African gold mines.

The phylogenetic relationships between 44 HIV-1 isolates from 43 infected subjects employed by three adjacent South African gold mines were investigated. The patients were migrant workers originating from rural areas of South Africa and the neighboring countries of Lesotho, Botswana, Swaziland, and Mozambique. Proviral HIV-1 DNA was subtyped using a heteroduplex mobility assay (HMA) based on the 700-bp V3-V5 region of the env gene. DNA sequence analysis was used to confirm the subtype designation and to determine phylogenetic relationships between isolates. All 44 HIV-1 isolates were identified as env subtype C using both HMA and phylogenetic analysis. These isolates did not show a distinct phylogenetic relatedness based on the geographic origins of the migrant workers or show close homology to other subtype C sequences from southern Africa or India. However, five clusters of closely related sequences were identified, mainly involving miners of disparate geographic origins, suggesting possible epidemiological linkage in these few cases. The characteristic tetrapeptide sequence, GPGQ, at the tip of the V3 loop of subtype C viruses was conserved in the predicted amino acid sequences of most isolates. The heterogeneity of HIV-1 sequences among migrant workers in a mining cohort suggests multiple introductions of HIV-1 subtype C into this population that are not apparently linked to the geographic origins of the patients.

Adolescent↗
PubMed1998

Carotid ultrasound examination in Williams syndrome.

OBJECTIVE: To noninvasively measure arterial wall thickness in a group of patients with Williams syndrome (WS). METHODS: High-resolution, real-time B-mode ultrasonography was used to examine the carotid arteries of 20 patients with WS (ages 7 months to 24.9 years) and 25 control subjects (ages 2.5 years to 25.5 years). RESULTS: The mean combined intimal-medial wall thickness of the patients in the WS group was 0.86 mm +/- 0.08 mm compared with a mean of 0.54 mm +/- 0.05 mm in the control subjects (p < 0.0001). Within the WS group, arterial wall thickness did not vary significantly with gender, patient age, the presence or absence of stenotic cardiac disease, or the presence or absence of hypertension. CONCLUSIONS: The ultrasonographic finding of increased carotid arterial wall thickness across a wide range of patients with WS demonstrates the pervasive nature of the arteriopathy of this disorder. That increased arterial wall thickness was observed in all patients studied suggests that the arteriopathy of WS is related to haploinsufficiency for the elastin gene.

Adolescent↗
PubMed1998

Relationship between the effects of alfuzosin on rat urethral and blood pressures and its tissue concentrations.

This study was undertaken in order to establish the alpha1-antagonist effects of alfuzosin on phenylephrine-induced increases in urethral and arterial blood pressures at 1 and 6 hours post dosing (10 mg/kg, p.o.). At each time, plasma and prostatic concentrations of alfuzosin were measured and correlations between tissue concentrations and pharmacological effects were calculated. At one and six hours post dosing, alfuzosin markedly shifted the urethral and arterial dose response curve to phenylephrine. At one hour, prostatic concentration was 4.1 times greater than plasma concentration (363 ng/g vs 88 ng/ml) and at 6 hours this ratio reached 8.6 times (167 ng/g vs 20 ng/ml). By taking together the data points obtained at 1 and 6 hours we showed that the effects of alfuzosin on urethral pressure were correlated with prostate levels (r=0.906, p<0.01) and the effects on arterial blood pressure were correlated with plasma levels (r=0.941, p<0.01). These results suggest that a preferential distribution of alfuzosin in prostatic tissue may play a role in its functional uroselectivity.

Adrenergic alpha-Antagonists↗
PubMed1998

A conscious-rabbit model for the long-term observation of urethral and arterial pressures.

OBJECTIVE: To describe and evaluate a new experimental model for the simultaneous measurement of urethral (UP) and arterial (AP) pressures in the conscious rabbit, thereby avoiding the interference of anaesthesia which markedly reduces reflex activity and tone of smooth muscle. MATERIALS AND METHODS: Female rabbits were anaesthetized and catheters inserted into the urethra, abdominal aorta, jugular vein and bladder. After recovering from surgery, rabbits were trained to remain static in a sling for a period of 2 h, during which the UP and AP were recorded. The model was validated for short- and long-term stability before the effects of drugs were assessed; UP and AP were recorded for up to 60 min after drug/solvent administration to assess short-term stability, and long-term stability was assessed by comparing 60 min control periods between the first and fifth experimental session up to a month apart. RESULTS: Over 60 min in the control group, the UP remained steady, whereas the AP only decreased slightly. Recordings were made during five subsequent control periods, with at least 3 days of rest between successive assessments, and the UP and AP remained similar for up to 1 month. During a second phase, the effect of alpha 1-adrenoceptor agonists on both pressures were evaluated to characterize their functional uroselectivity. De-glymidodrine and L-phenylephrine (0.1 mg/kg) were administered intravenously; the UP increased by 18 cmH2O (146%) and 21 cmH2O (173%), respectively, whereas AP increased by 22 mmHg (31%) and 47 mmHg (63%), respectively. At 5 min after administering the drugs, the UP remained higher by 16 cmH2O (121%) with de-glymidodrine, whereas it had returned to basal values with L-phenylephrine. CONCLUSIONS: This conscious-animal model allows the simultaneous measurement of UP and AP in the absence of anaesthesia. It provides a useful means to directly evaluate the effects of a drug on the urogenital and cardiovascular systems, and thereby its functional uroselectivity.

Animals↗
PubMed1998

Reduced expression of interleukin-8 receptors A and B on polymorphonuclear neutrophils from persons with human immunodeficiency virus type 1 disease and pulmonary tuberculosis.

The expression of the two human interleukin (IL)-8 receptors, designated IL-8RA (CXCR-1) and IL-8RB (CXCR-2), on the surface of whole blood polymorphonuclear leukocytes (PMNL) was determined by use of receptor-specific monoclonal antibodies and flow cytometry. Sixteen subjects each were included in 4 study groups: healthy blood donors (ND), patients with pulmonary tuberculosis (TB), human immunodeficiency virus type 1-seropositive patients (HIV), and HIV-1-seropositive subjects with pulmonary tuberculosis (HIV/TB). A significant reduction in the percentage of PMNL expressing IL-8RA and IL-8RB and in their respective fluorescence intensities was found in TB, HIV, and HIV/TB groups compared with that obtained for the ND group. The greatest down-regulation of both receptors occurred in the HIV/TB group. Furthermore, associated with this reduced expression of IL-8 receptors was impairment of both intracellular calcium flux and migration of PMNL in response to IL-8 in a group of HIV/TB patients compared with that in healthy persons.

AIDS-Related Opportunistic Infections↗
PubMed1998

High human immunodeficiency virus type 1 RNA load in the cerebrospinal fluid from patients with lymphocytic meningitis.

Thirty-seven matched cerebrospinal fluid (CSF) and plasma samples from 34 human immunodeficiency virus type 1 (HIV-1)-infected patients with suspected meningitis were analyzed for levels of HIV-1 RNA and markers of inflammation. Patients with tuberculous (n = 9) or cryptococcal (n = 6) meningitis had the highest CSF virus loads, which in many cases exceeded the levels in plasma, compared with patients with meningococcal meningitis (n = 3), aseptic meningitis (n = 8), tuberculoma (n = 2), or AIDS dementia complex (n = 4) or with normal lumbar punctures (n = 3). CSF virus load correlated significantly with the number of infiltrating lymphocytes (r = .60, P < .001) but not with plasma virus load, the levels of beta2-microglobulin in the CSF, or the integrity of the blood-brain barrier. These data suggest significant intrathecal HIV-1 replication in patients with lymphocytic meningeal infections such as tuberculous and cryptococcal meningitis.

AIDS Dementia Complex↗
PubMed1998

Depressed phagocytosis and oxidative burst in polymorphonuclear leukocytes from individuals with pulmonary tuberculosis with or without human immunodeficiency virus type 1 infection.

Phagocytosis and oxidative burst in whole-blood granulocytes were assessed by flow cytometry with Phagotest and Bursttest kits, respectively. Seventy individuals were included in this study: 15 healthy, normal donors, 18 human immunodeficiency virus (HIV) type 1 (HIV-1)-seropositive patients, 19 patients with pulmonary tuberculosis (TB), and 18 patients co-infected with Mycobacterium tuberculosis and HIV-1 (TB-HIV). Granulocyte phagocytosis was assessed by incubating whole blood with fluorescence-labelled Escherichia coli and measuring the proportion of granulocytes with ingested bacteria and the capacity (fluorescence intensity) of each cell to phagocytose E. coli. The percentage of granulocytes converting nonfluorescent dihydrorhodamine to fluorescent rhodamine 123 on production of reactive oxygen intermediates (ROIs) and the mean channel shift were assessed as a measure of oxidative burst. No differences in the proportion of granulocytes that were capable of phagocytosing or producing ROIs in response to E. coli were observed between any of the study groups. Phagocytosis was significantly enhanced in granulocytes from HIV-1-infected individuals. On the other hand, granulocytes from individuals infected with M. tuberculosis alone or in combination with HIV-1 had a significantly reduced capacity to phagocytose E. coli and to produce ROIs in response to E. coli as an agonist. These results provide evidence that granulocytes from individuals with pulmonary TB with or without concomitant infection with HIV-1 have an impaired ability to phagocytose and to undergo oxidative burst, possibly contributing to the enhanced susceptibility to opportunistic infections in these patients.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Functional uroselectivity.

Alpha1-adrenoceptors mediating sympathetic tone to smooth muscle cells are located within the prostatic tissue, bladder base and in the proximal urethra, but are also widely distributed within a large number of tissues, especially the vascular beds and the central nervous system. Compounds clinically used in the symptomatic treatment of benign prostatic hyperplasia must therefore exhibit functional uroselectivity. This means that they should preferentially act on the lower urinary tract rather than the vasculature or central nervous system. Few clinically used alpha1-adrenoceptor antagonists show selectivity for the alpha1a/A-adrenoceptor subtype, whereas most of them have similar affinities for the three cloned subtypes (alpha1a-, alpha1b- and alpha1d-adrenoceptors). Recent data from in vitro studies assessing pharmacological uroselectivity and from in vivo models evaluating functional uroselectivity challenged the relevance of the affinity or the selectivity for a known alpha1-adrenoceptor subtype in predicting functional uroselectivity. They suggest instead that another subtype, like the alpha1L-adrenoceptor, might be functionally involved. In conclusion, the actual state of knowledge on alpha1-adrenoceptor subtype distribution and function, does not support a role of pharmacological uroselectivity in predicting functional uroselectivity. Furthermore, functional uroselectivity can be achieved in the absence of selectivity for the alpha1-adrenoceptor subtypes described so far.

Adrenergic alpha-Antagonists↗
PubMed1997

Synchrotron radiation study of the relation between structure and strain in polyurethane elastomers.

This paper describes a system for the study of the relation between structure and applied strain in thermoplastic polyurethane elastomers using the Australian National Beamline Facility at the Photon Factory, KEK, Tsukuba, Japan. The system uses the sagittal focusing monochromator at beamline 20B to provide a high-intensity focused beam which then falls on the specimen mounted in a miniature tensometer mounted in the unique vacuum diffractometer (BIGDIFF). Imaging plates were used to record simultaneously SAXS and WAXS patterns from the specimen at a particular strain. The change in SAXS and WAXS patterns with loading and unloading was recorded using a ten-plate imaging-plate changer.

Journal Article↗
PubMed1997

Programming of implantable cardioverter-defibrillators on the basis of the upper limit of vulnerability.

BACKGROUND: A patient-specific measure of defibrillation efficacy that requires a minimum number of ventricular fibrillation (VF) episodes would be valuable for programming implantable cardioverter-defibrillators (ICDs). The upper limit of vulnerability (ULV) is the weakest shock strength at or above which VF is not induced when a stimulus is delivered during the vulnerable phase of the cardiac cycle. It correlates with the defibrillation threshold (DFT) and can be determined with a single episode of VF. The objective of this study was to test the hypothesis that ICDs programmed on the basis of the ULV convert spontaneous ICD-detected VF reliably. METHODS AND RESULTS: We studied 100 consecutive patients at ICD implantation and during follow-up of 20 +/- 7 months. At implantation, the ULV and DFT were determined, and the ICD system was tested at a shock strength equal to the ULV + 3 J. During follow-up, the strength of the first shock was programmed to the ULV + 5 J for arrhythmias detected in the VF zone (cycle length < 292 +/- 17 ms). We reviewed stored detection intervals and electrograms from spontaneous episodes of ICD-detected VF to determine the success rate for appropriate first shocks. The programmed first-shock strength was 17.5 +/- 5.2 J. During follow-up, there were 120 appropriate first shocks in 37 patients. The arrhythmia was rapid monomorphic ventricular tachycardia (VT) in 70% of episodes (31 patients), VF in 11% (13 patients), polymorphic VT in 1%, and unclassified in 17% (15 patients). The first shock was successful in 119 of 120 episodes (99%; 95% CI, 93% to 100%). One unclassified episode required two shocks. No patient had syncope associated with an ICD shock or arrhythmic death. CONCLUSIONS: ICD shocks can be programmed on the basis of the ULV, a measurement made in regular rhythm, without a direct measure of defibrillation efficacy.

Aged↗