Search PubMed⌕ Search

Biomedical subjects

M J Martin

Publications and source records attributed to M J Martin.

At least 37 records · Page 2Linked to original sources
PubMed1999

Return of the internal jugular vein--development of collateral drainage following neonatal ligation of the vein.

The development of collateral venous drainage in the neck of a child, who as a neonate had undergone ligation and cannulation of the right internal jugular vein, is described. The resultant vessels were of sufficient calibre to be considered as potential sites for vascular access, although it is possible that their course in the thorax may preclude correct placement of a central venous catheter. Nevertheless, we feel that this case further illustrates the benefit of hand-held ultrasonography in visualizing the vascular structures of the neck. Moreover, ligation of a vein in the neonatal period should not be a contraindication to subsequent assessment of that site for vascular access.

Carotid Artery, Common↗
PubMed1998

Effects of cinitapride on gastric ulceration and secretion in rats.

OBJECTIVE AND DESIGN: The aim of the present study was to examine the effects of cinitapride, a novel prokinetic benzamide-stimulating gastrointestinal motility agent, on gastric secretion and ulceration in rats and elucidate some possible vascular and anti-oxidant mechanisms of such protection. MATERIAL: Male Wistar rats. TREATMENT: Cinitapride (CNT, Lab. Almirall, S.A.) (0.25, 0.5, and 1 mg/kg) and 5-hydroxytryptamine (5-HT, Sigma Chemical Co., St. Louis, MO, USA) (10 mg/kg), administered intraperitoneally (i.p.). METHODS: Gastric ulceration was induced by instillation of 1 mL/100 g animal of 50% (v/v) ethanol in distilled water and by pylorus-ligated rat model. Gastric microvascular changes, and the activity of myeloperoxidase (as a marker of neutrophil infiltration) and glutathione peroxidase (an important enzyme in scavenging of lipid peroxides) were determined. The results were compared with those of 5-HT. The data were evaluated using Student's t-test for paired data and the non-parametric Mann-Whitney U-test. RESULTS: In 4 h pyloric-ligated animals, i.p. CNT did not significantly reduce the incidence of gastric mucosal damage, and no significant differences were found in the values of total volume and acidity. However, CNT caused a marked and dose-dependent reduction of haemorrhagic lesions induced by 50% v/v ethanol. These protective effects were specifically related to a reduction of neutrophil infiltration. CNT at the dose of 1 mg/kg raised the decreased glutathione peroxidase activity to the control level. In contrast, pretreatment with 5-HT worsened the ethanol-induced erosions, but did not significantly induce any gastric microvascular changes. However, the myeloperoxidase activity rose markedly and the glutathione peroxidase levels decreased significantly in the mucosa injured by 50% v/v ethanol. CONCLUSIONS: This study demonstrates a new gastroprotective feature of CNT that could be partly explained not only through reduction of neutrophil toxicity but also by an increased synthesis of free-radical scavenging enzymes such as glutathione peroxidase. Furthermore, it is likely that serotonergic-dependent mechanisms are also involved via 5-HT2-receptor blockade and 5-HT1 receptor activation.

Animals↗
PubMed1998

Changes in human plasma melatonin profiles in response to 50 Hz magnetic field exposure.

The effects of power-frequency magnetic fields on nighttime plasma melatonin were studied in a group of 30 adult male human subjects. Exposure consisted of 20 microT (200 mG) at 50 Hz (circularly polarized) at certain times in relation to the predicted time of onset of rise in melatonin concentration for a particular individual (the time of onset was predicted from a previous screening night). Response to this exposure was compared to sham-exposure (in random order). When exposure preceded onset of rise, a significant delay in onset time relative to sham-exposure of approximately half an hour was observed, with indications (marginally significant) of a reduction in maximum melatonin level. Analysis of distribution of time-delays is consistent with two populations: those individuals who respond (around 20%) and those that do not. Magnetic fields generated by square-wave currents produce more marked reductions in the maximum level when compared to sinusoidal waveforms, but there was no significant difference in onset time.

Adolescent↗
PubMed1998

Major depression in medically ill patients.

Major depression is one of the most common psychiatric problems complicating the treatment and prognosis of patients with active medical illness. Recognizing and treating major depressive conditions in this population can often be challenging, even for the most seasoned clinicians. This article reviews the medical and neurologic conditions that have been associated with the high prevalence rates of major depression. Highlights of the evaluation process that help confirm this suspected diagnosis are addressed, and management issues are discussed. Brief reviews of supportive psychotherapeutic tools that the clinician may find helpful are included, as well as current advances in pharmacologic interventions.

Antidepressive Agents↗
PubMed1998

In vivo distribution and metabolism of a phosphorothioate oligonucleotide within rat liver after intravenous administration.

In the rat, the liver represents a major site of phosphorothioate oligodeoxynucleotide deposition after i.v. administration. For this reason, we examined the intracellular fate of ISIS 1082, a 21-base heterosequence phosphorothioate oligodeoxynucleotide, isolated from parenchymal and nonparenchymal cell types after systemic dosing using established perfusion and separation techniques followed by CGE. Isolated cells were further fractionated into nuclear, cytosolic and membrane constituents to assess the intracellular localization, distribution and metabolic profiles as a function of time and dose. After a 10-mg/kg i.v. bolus, intracellular drug levels where maximal after 8 hr and diminished significantly thereafter, suggesting an active efflux mechanism or metabolism. Nonparenchymal (i.e., Kupffer and endothelial) cells contained approximately 80% of the total organ cellular dose, and this was equivalently distributed between the two cell types, while the remaining 20% was associated with hepatocytes. Nonparenchymal cells contained abundant nuclear, cytosolic and membrane drug levels over a wide dose range. In contrast, at doses of less than 25 mg/kg, hepatocytes contained significantly less drug with no detectable nuclear-association. Doses at or above 25 mg/kg appeared to saturate nonparenchymal cell types, whereas hepatocytes continued to accumulate drug in all cellular compartments, including the nucleus. Our results suggest that although pharmacokinetic parameters vary as a function of hepatic cell type, significant intracellular delivery can be readily achieved in the liver after systemic administration.

Animals↗
PubMed1997

Structure-activity relationships of selective estrogen receptor modulators: modifications to the 2-arylbenzothiophene core of raloxifene.

The 2-arylbenzothiophene raloxifene, 1, is a selective estrogen receptor modulator which is currently under clinical evaluation for the prevention and treatment of postmenopausal osteoporosis. A series of raloxifene analogs which contain modifications to the 2-arylbenzothiophene core have been prepared and evaluated for the ability to bind to the estrogen receptor and inhibit MCF-7 breast cancer cell proliferation in vitro. Their ability to function as tissue-selective estrogen agonists in vivo has been assayed in a short-term, ovariectomized (OVX) rat model with end points of serum cholesterol lowering, uterine weight gain, and uterine eosinophil peroxidase activity. These studies have demonstrated that (1) the 6-hydroxy and, to a lesser extent, the 4'-hydroxy substituents of raloxifene are important for receptor binding and in vitro activity, (2) small, highly electronegative 4'-substituents such as hydroxy, fluoro, and chloro are preferred both in vitro and in vivo, (3) increased steric bulk at the 4'-position leads to increased uterine stimulation in vivo, and (4) additional substitution of the 2-aryl moiety is tolerated while additional substitution at the 4-, 5-, or 7-position of the benzothiophene results in reduced biological activity. In addition, compounds in which the 2-aryl group is replaced by alkyl, cycloalkyl, and naphthyl substituents maintain a profile of in vitro and in vivo biological activity qualitatively similar to that of raloxifene. Several novel structural variants including 2-cyclohexyl, 2-naphthyl, and 6-carbomethoxy analogs also demonstrated efficacy in preventing bone loss in a chronic OVX rat model of postmenopausal osteopenia, at doses of 0.1-10 mg/kg.

Adenocarcinoma↗
PubMed1997

Transgenic pigs expressing human CD59 and decay-accelerating factor produce an intrinsic barrier to complement-mediated damage.

We characterize a line of transgenic pigs that express the human complement-regulatory proteins human CD59 and human decay-accelerating factor. These genes, under the control of heterologous promoters, are expressed in a variety of organs, including the vasculature of the heart, kidney, and liver. We demonstrate that moderate levels of these gene products are sufficient to protect peripheral blood cells from human or baboon complement. Using pig to baboon heterotopic heart transplants, we show that expression of these proteins is sufficient to block the complement-mediated damage that is the hallmark of such xenografts, when nontransgenic organs are used. These results indicate that there is significant species specificity of intrinsic complement regulatory protein function. This specificity is evident in transgenic organs in which low levels of human CD59 and human decay-accelerating factor expression significantly effect the humoral immune response that causes xenograft rejection. This result suggests that transgenic organs with high levels of human complement-regulatory protein expression will be sufficient to alleviate the humoral immunological barriers that currently block the use of xenogeneic organs for human transplantation.

Animals↗
PubMed1997

Hypokalemia leading to torsades de pointes. Munchausen's disorder or bulimia nervosa?

A 45-year-old woman traveled over 1000 miles from a major metropolitan area to obtain another opinion for medically refractory diarrhea. She had an extremely complicated medical history with no outside records or family members accompanying her to give collateral history. She had multiple previous diagnostic evaluations including 13 surgical procedures and many therapeutic trials of various medications. She acknowledged a preoccupation with weight and appearance, described previous attempts to diet, and repetitively denied purging, including laxative abuse. During her hospitalization she had two episodes of torsades de pointes requiring cardiac defibrillation. Laboratory testing revealed hypokalemia at the time of these events, and a toxicology screen was positive for bisacodyl, confirming laxative abuse. When confronted by a combined team of cardiology, gastroenterology, and psychiatry specialist, she admitted her laxative abuse and surrendered her supply of Dulcolax tablets. The discussion addresses the procedures employed to detect her surreptitious medication use, the near lethal cardiac complications, and the appropriate psychiatric diagnosis.

Bulimia↗
PubMed1997

Evaluation of the major metabolites of raloxifene as modulators of tissue selectivity.

Raloxifene (LY139481 HCl) is a selective estrogen receptor modulator (SERM) which blocks the effects of estrogen on some tissues, such as the breast and uterus, while mimicking estrogen in other tissues, such as bone. To study the origins of this unique pharmacology, we have prepared the major metabolites of raloxifene as chemical probes for examining the estrogen receptor function in vitro and in vivo. In human breast cancer cell (MCF-7) related assays, these glucuronide conjugates show little affinity for the estrogen receptor and are more than two orders of magnitude less potent at inhibiting cell proliferation than raloxifene. In non-traditional estrogen target tissue, such as bone, these metabolites are less effective than the parent at inhibiting cytokine-stimulated bone resorbing activity in rat osteoclasts or producing transforming growth factor beta-3 (TGF-beta3). In animal models, tissue distribution studies with radiolabelled metabolite indicate that conversion to raloxifene occurs readily in a variety of tissues including the liver, lung, spleen, kidney, bone and uterus. Differential conversion of metabolite in target organs, such as bone and the uterus, is not observed indicating that the origin of raloxifene's pharmacology does not result from tissue-selective deconjugation of metabolite to parent.

Adenocarcinoma↗
PubMed1997

Melatonin protects against gastric ischemia-reperfusion injury in rats.

Lipid peroxidation and active oxygen metabolites have been suggested to play an important role in the pathogenesis of acute gastric mucosal injury induced by ischemia-reperfusion. The aim of this study was to examine the in vivo protective effects of melatonin on ischemia-reperfusion induced gastric damage in rats. The peroxidation of lipids and changes in the activities of related enzymes such as glutathione peroxidase and myeloperoxidase, as a marker of neutrophil infiltration, were also studied. Our results show that gastric injury was significantly increased after 30 min ischemia induced by clamping the celiac artery and 60 min reperfusion. Intraperitoneal administration of melatonin prevented postischemic mucosal injury. The mean ulcer indices of rats treated with 5, 10, and 20 mg kg(-1) were significantly lower (P<0.01, P<0.001) than that of control rats. These protective effects were likely in part related to a reduction of neutrophil infiltration (myeloperoxidase values). Lipid peroxidation in the stomach was increased by ischemia-reperfusion injury and this increase was inhibited by the administration of melatonin. In addition, treatment with melatonin limited the decreased glutathione peroxidase activity. The results suggest that melatonin confers a marked protection against ischemia-reperfusion gastric injury which could be due to melatonin's free radical scavenging activity and its ability to reduce neutrophil-induced toxicity.

Animals↗
PubMed1997

Trial of chlorhexidine gluconate for fungal corneal ulcers.

AIMS: Suppurative corneal ulcers due to filamentous fungi are a serious and intractable problem in many tropical developing countries. In vitro studies and a small pilot study have shown that chlorhexidine gluconate is effective. The aim was to establish the optimum concentration which would be appropriate to use in a larger randomized clinical trial. METHODS: A masked randomized clinical trial of three concentrations of chlorhexidine compared with natamycin 5% was carried out in consecutive patients with established corneal ulcers shown by microscopy to contain fungal hyphae and later proven to be culture positive. Topical treatments were applied 1/2-hourly to 2-hourly for up to 5 days, with reduced frequency thereafter, and all patients were re-assessed at 21 days. RESULTS: Of 60 patients entered in the trial, 2 were lost to follow-up, and 12 were classified as 'severe' with little prospect of recovery. At 5 days the response was related to the concentration of chlorhexidine, with 0.2% giving the best results. Compared with the response to natamycin as the referent, the relative efficacy was 1.17 with chlorhexidine 0.05%, 1.43 with 0.1%, and 2.00 with 0.2%. The superiority of 0.2% chlorhexidine over natamycin was statistically significant (relative efficacy 2.20, p = 0.043) in patients not having had prior antifungal treatment. CONCLUSIONS: This preliminary study justifies further trials of chlorhexidine as a primary treatment for fungal corneal ulcers in circumstances where specific antifungal agents are not available.

Administration, Topical↗
PubMed1997

Protein sequence annotation in the genome era: the annotation concept of SWISS-PROT+TREMBL.

SWISS-PROT is a curated protein sequence database which strives to provide a high level of annotation, a minimal level of redundancy and high level of integration with other databases. Ongoing genome sequencing projects have dramatically increased the number of protein sequences to be incorporated into SWISS-PROT. Since we do not want to dilute the quality standards of SWISS-PROT by incorporating sequences without proper sequence analysis and annotation, we cannot speed up the incorporation of new incoming data indefinitely. However, as we also want to make the sequences available as fast as possible, we introduced TREMBL (TRanslation of EMBL nucleotide sequence database), a supplement to SWISS-PROT. TREMBL consists of computer-annotated entries in SWISS-PROT format derived from the translation of all coding sequences (CDS) in the EMBL nucleotide sequence database, except for CDS already included in SWISS-PROT. While TREMBL is already of immense value, its computer-generated annotation does not match the quality of SWISS-PROTs. The main difference is in the protein functional information attached to sequences. With this in mind, we are dedicating substantial effort to develop and apply computer methods to enhance the functional information attached to TREMBL entries.

Amino Acid Sequence↗
PubMed1996

Reduction in the level of Gal(alpha1,3)Gal in transgenic mice and pigs by the expression of an alpha(1,2)fucosyltransferase.

Hyperacute rejection of a porcine organ by higher primates is initiated by the binding of xenoreactive natural antibodies of the recipient to blood vessels in the graft leading to complement activation. The majority of these antibodies recognize the carbohydrate structure Gal(alphal,3)Gal (gal epitope) present on cells of pigs. It is possible that the removal or lowering of the number of gal epitopes on the graft endothelium could prevent hyperacute rejection. The Gal(alpha1,3) Gal structure is formed by the enzyme Galbeta1,4GlcNAc3-alpha-D-galactosyltransferase [alpha(1,3)GT; EC 2.4.1.51], which transfers a galactose molecule to terminal N-acetyllactosamine (N-lac) present on various glycoproteins and glycolipids. The N-lac structure might be utilized as an acceptor by other glycosyltransferases such as Galbeta1,4GlcNAc 6-alpha-D-sialyltransferase [alpha(2,6)ST], Galbeta1,4GlcNAc 3-alpha-D-Sialyltransferase [alpha(2,3)ST], or Galbeta 2-alpha-L-fucosyltransferase [alpha(1,2)FT; EC 2.4.1.691, etc. In this report we describe the competition between alpha(1,2)FT and alpha(1,3)GT in cells in culture and the generation of transgenic mice and transgenic pigs that express alpha(1,2)Fr leading to synthesis of Fucalpha,2Galbeta- (H antigen) and a concomitant decrease in the level of Gal(alpha1,3)Gal. As predicted, this resulted in reduced binding of xenoreactive natural antibodies to endothelial cells of transgenic mice and protection from complement mediated lysis.

Animals↗
PubMed1996

Characterization of transgenic pigs expressing functionally active human CD59 on cardiac endothelium.

The critical shortage of human donor organs has generated interest in the potential for porcine to human xenotransplantation. The initial immunological barrier to xenotransplantation is hyperacute rejection, which is mediated by xenoreactive antibodies and complement, and results in rapid and irreversible tissue destruction. While endogenous complement regulatory proteins (CRPs) protect cells from injury caused by autologous complement, they are relatively species specific and most likely ineffectual in this setting. This has led to the hypothesis that expression of human CRPs in transgenic pigs may affect susceptibility to complement-mediated tissue injury in a porcine-to-human xenograft. Using specific lines of transgenic pigs that express low levels of human CD59, a CRP that acts at the terminal stage of the complement cascade, we present evidence that shows that the human CD59 protein inhibits membrane attack complex assembly and reduces tissue damage when the heart is transplanted to a baboon. Examination by immunohistochemistry of transgenic porcine hearts after transplantation revealed markedly reduced deposition of C5b and MAC, but a similar level of C3 deposition as compared with transplanted control hearts. This finding supports the concept that the species specific function of CRPs contributes to the humoral barrier to xenotransplantation and, given the low level of human CD59 protein expression in the porcine heart, argues that the human protein contributes a unique rather than an additive function in regulation of complement in a xenogeneic setting.

Animals↗
PubMed1996

Three keratin gene mutations account for the majority of dominant simplex epidermolysis bullosa cases within the population of Ireland.

We have located three extended families in Ireland (population 3.5 million) with autosomal dominant simplex forms of Epidermolysis Bullosa (EBS). A mutation within the keratin type I (K14) gene (Met-->272-->Arg) in one family suffering from the generalized simplex (Koebner) form of the disease has been previously described (Humphries et al., Hum Mutat 2:37-42, 1993). Here we report on the identification of mutations within the remaining two families, both of whom suffer from the Weber-Cockayne form of the disease. These mutations, within the type II keratin (K5) gene, are Asn-->193-->Lys and Met-->327-->Thr. They have been shown in each case to co-segregate with the disease and are not present in the normal population. Within the three families, a total of 44 living persons with such mutations have been identified, providing a minimum prevalence estimate for the disease in the Irish population of approximately 1 in 80,000, compared to an overall estimated global incidence at birth for all forms of EB of 1 in 50,000. Therefore, these three mutations probably account for the majority of cases of EBS within this population.

Amino Acid Sequence↗
PubMed1996

Role of endogenous sulphydryls and neutrophil infiltration in the pathogenesis of gastric mucosal injury induced by piroxicam in rats.

In the present report we studied the formation of severe gastric erosions produced in fasted rats by intragastric administration of piroxicam (PRX), an enolic acid-derived NSAID. The time course of gastric damage and the possible role of mucus secretion, endogenous sulphydryl compounds, changes of gastric vascular permeability and neutrophil infiltration in the development of PRX-induced gastric lesions were also investigated. PRX dose-dependently (1.25-20 mg/kg) caused acute gastric haemorrhagic erosion in the rat. The lesions increased with time until 9 hr after dosing. Mucus secretion did not change significantly with respect to the control group with 5, 10 and 20 mg/kg of PRX at different times (3 and 6 hours) of treatment. There was also no increase in the concentration of its components. In addition, oral pretreatment of the animals with PRX did not significantly change the amount of dye trapped in the stomach. In contrast, non-protein SH fraction was decreased after administration of PRX and MPO activity as an index of neutrophil infiltration was significantly increased. These results suggest that independently of the PRX dose, depletion of endogenous non-protein SH and neutrophil infiltration could play an important part in the pathogenesis of gastric mucosal injury induced by PRX.

Animals↗