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Biomedical subjects

W J Martin

Publications and source records attributed to W J Martin.

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

Bacteria-related sequences in a simian cytomegalovirus-derived stealth virus culture.

Extensive sequencing of cloned DNA isolated from the culture of an African green monkey simian cytomegalovirus-derived stealth virus has identified multiple regions of highly significant homology to various bacterial genes. The apparent acquisition of bacterial sequences extends the potential role of stealth viruses as natural vectors in the transfer of genetic information. The findings highlight the dynamic interface between viral and bacterial genomes and the potential of this interaction in the emergence and spread of novel pathogens. The term viteria is proposed for microorganisms that contain both eukaryotic-viral and prokaryotic-bacterial genetic sequences.

Animals↗
PubMed1999

Melanoma growth stimulatory activity (MGSA/GRO-alpha) chemokine genes incorporated into an African green monkey simian cytomegalovirus-derived stealth virus.

DNA isolated from the culture of an African green monkey simian cytomegalovirus (SCMV)-derived stealth virus has been cloned. A region of the virus that contains genes coding proteins homologous to the UL141, UL144, and UL145 proteins of human cytomegalovirus has recombined with cellular sequences encoding several distinct copies of the melanoma growth stimulatory activity (MGSA/GRO-alpha) chemokine gene. This finding illustrates the capacity of stealth viruses to capture, amplify, and mutate genes with potential oncogenic activity. The lack of introns in the assimilated cellular genes indicates a role for reverse transcription in the assembly of stealth viruses.

Amino Acid Sequence↗
PubMed1999

Stealth adaptation of an African green monkey simian cytomegalovirus.

DNA extracted from cultures of a cytopathic virus isolated from a patient with chronic fatigue syndrome was cloned into pBluescript plasmid. The nucleotide sequences of the plasmid inserts were analyzed using the BlastN and BlastX programs of the National Center for Biotechnology Information. In confirmation of earlier studies, many of the sequences show partial homology to various regions within the genome of human cytomegalovirus (HCMV). The matching regions were unevenly distributed throughout the HCMV genome. No matches were seen with either the UL55 or the UL83 genes, which provide the major antigenic targets for anti-HCMV cytotoxic T-cell-mediated immunity. This finding is consistent with the notion that certain viruses can avoid immune elimination by deleting genes required for effective antigenic recognition by the cellular immune system. The term "stealth" has been applied to such viruses. Comparisons were also made between the sequences of the stealth virus and the limited sequence data available on cytomegaloviruses from rhesus monkeys and from African green monkeys. These comparisons unequivocally establish that the virus was derived from an African green monkey simian cytomegalovirus.

Adult↗
PubMed1999

The neurobiology of cannabinoid analgesia.

The discovery of cannabinoid receptors and their putative endogenous ligands raises questions as to the nature of the effects produced by cannabinoids on neural circuits that mediate pain and whether endogenous cannabinoids produced by the brain or in the periphery serve naturally to modulate pain. A sizable body of previous work showed that cannabinoid agonists suppress pain behavior in a variety of models of acute and chronic pain. However, at appropriate doses, cannabinoids also profoundly suppress motor behavior (see Sañudo-Peña et al., this volume), which complicates the interpretation of behavioral analgesia since a motor response is the endpoint of virtually all such studies. Studies conducted in this laboratory used biochemical and neurophysiological measures to determine whether cannabinoids suppress nociceptive neurotransmission. The results showed that cannabinoids suppress nociceptive neurotransmission at the level of the spinal cord and the thalamus. These effects are reversible, receptor mediated, selective for painful as opposed to nonpainful somatic stimuli, and track the behavioral analgesia both in time course and potency.

Analgesia↗
PubMed1999

Differential effects of neurotoxic destruction of descending noradrenergic pathways on acute and persistent nociceptive processing.

Although many pharmacological studies indicate that bulbospinal noradrenergic projections contribute to antinociception, lesions of the major brainstem noradrenergic cell groups have provided conflicting evidence. Here we used a new immunotoxin, anti-dopamine beta-hydroxylase-saporin, to re-examine the contribution of noradrenergic pathways to nociception and to morphine analgesia. We treated rats intrathecally by lumbar puncture with the immunotoxin and examined dopamine beta-hydroxylase (DbetaH) immunoreactivity seven and 14 days after treatment. There was no change in DbetaH staining at 7 days; however, 14 days after treatment we demonstrated significant destruction of noradrenergic neurons in the locus coeruleus and in the A5 and A7 cell groups. There was a concomitant loss of noradrenergic axons in the dorsal and ventral horns of the lumbosacral and cervical cord. Consistent with the lack of anatomical changes, we found no difference in nociceptive responses in the hot-plate, tail-flick or formalin tests one week post-toxin. On day 14 we examined the behavioral response to injection of formalin into the hindpaw and found that responses during the second phase of pain behavior were significantly reduced. There was no change during the first phase. Formalin-evoked fos expression in the spinal cord was also reduced. We also evaluated morphine analgesia in the formalin test and found that toxin-treated animals exhibited enhanced morphine analgesia. These results establish the utility of using this immunotoxin to selectively destroy subpopulations of noradrenergic cell groups and provide evidence that acute and persistent nociception are differentially regulated by descending noradrenergic pathways.

Acute Disease↗
PubMed1999

Inflammation-induced up-regulation of protein kinase Cgamma immunoreactivity in rat spinal cord correlates with enhanced nociceptive processing.

Activation of various second messengers contributes to long-term changes in the excitability of dorsal horn neurons and to persistent pain conditions produced by injury. Here, we compared the time-course of decreased mechanical nociceptive thresholds and the density of protein kinase Cgamma immunoreactivity in the dorsal horn after injections of complete Freund's adjuvant in the plantar surface of the rat hindpaw. Complete Freund's adjuvant significantly increased paw diameter and mechanical sensitivity ipsilateral to the inflammation. The changes peaked one day post-injury, but endured for at least two weeks. In these rats, we recorded a 75-100% increase in protein kinase Cgamma immunoreactivity in the ipsilateral superficial dorsal horn of the L4 and L5 segments at all time-points. Electron microscopy revealed that the up-regulation was associated with a significant translocation of protein kinase Cgamma immunoreactivity to the plasma membrane. In double-label cytochemical studies, we found that about 20% of the protein kinase Cgamma-immunoreactive neurons, which are concentrated in inner lamina II, contain glutamate decarboxylase-67 messenger RNA, but none stain for parvalbumin or nitric oxide synthase. These results indicate that persistent changes in protein kinase Cgamma immunoreactivity parallel the time-course of mechanical allodynia and suggest that protein kinase Cgamma contributes to the maintenance of the allodynia produced by peripheral inflammation. The minimal expression of protein kinase Cgamma in presumed inhibitory neurons suggests that protein kinase Cgamma-mediated regulation of excitatory interneurons underlies the changes in spinal cord activity during persistent nociception.

Animals↗
PubMed1999

Differential diagnostic significance of the paucity of HLA-I antigens on metastatic breast carcinoma cells in effusions.

Distinction between benign reactive mesothelial cells and metastatic breast adenocarcinoma cells in effusions from patients with a known prior history of breast cancer is not the easiest task in diagnostic pathology. Here, we report the usefulness of testing the expression of class I HLA antigens (HLA A, B, C) in this respect. Cytospins were prepared from effusions of patients without the history of breast cancer (5 cases) and from effusions of patients with infiltrating ductal carcinoma (11 cases). Three effusions from cancerous patients were not malignant cytologically. The expression of HLA-A, B, C, HLA-DR and beta2-microglobulin as well as the macrophage antigen, CD14, was evaluated by immunocytochemistry. In 10 of 11 effusions the cytologically malignant cells expressed very weak or undetectable HLA-A,B,C as compared to the mesothelial cells and macrophages. The paucity of expression of HLA-A, B, C was detectable in those 3 cases where a definitive cytological diagnosis of malignancy could not be established. In contrast, mesothelial cells and macrophages from all samples were uniformly and strongly positive for both HLA-A, B, C and beta2-microglobulin. We conclude that the paucity of HLA-I antigens provides a marker helpful in distinguishing metastatic breast carcinoma cells from reactive mesothelial cells in effusions.

Adult↗
PubMed1999

Performance characteristics of three serum iron and total iron-binding capacity methods in acute iron overdose.

Accurate serum iron and total iron binding capacity (TIBC) measurements may be useful in acute iron overdoses. Two alumina column TIBC methods were found to measure increased TIBC when free iron was present. A homogeneous TIBC method gave consistent results until iron concentrations exceeded 500 micrograms/dL (90 mumol/L), when it began to underestimate the TIBC. Serious iron overdoses require chelation therapy with deferoxamine. Iron recovery was reduced by up to 50% for all 3 methods with clinically achievable concentrations of deferoxamine 8,400 micrograms/dL (150 mumol/L). TIBC measurements by both alumina column methods were reduced by deferoxamine in the presence of free iron and unaffected when the iron concentration was less than the TIBC. The homogeneous TIBC method yielded falsely elevated results in the presence of free deferoxamine. Procedures that measure TIBC by addition of excess ferric iron followed by alumina adsorption are not suitable for monitoring TIBC in acute iron overdose. The homogeneous TIBC assay can be used in acute iron overdose but underestimates TIBC when iron concentrations exceed 500 micrograms/dL (90 mumol/L). None of the methods examined are useful for measuring iron or TIBC in the presence of deferoxamine.

Acute Disease↗
PubMed1999

Gamma interferon stimulates rat alveolar macrophages to kill Pneumocystis carinii by L-arginine- and tumor necrosis factor-dependent mechanisms.

Pneumocystis carinii pneumonia remains a serious complication for immunocompromised patients. In the present study, P. carinii organisms interacted with gamma interferon (IFN-gamma)-stimulated alveolar macrophages (AMs) to activate the L-arginine-dependent cytocidal pathway involving reactive nitrogen intermediates (RNI) that were assayed as nitrite (NO2-). Unstimulated cultures of AMs produced negligible quantities of RNI. Addition of P. carinii organisms to IFN-gamma-primed AMs resulted in greatly enhanced production of RNI. NO2- levels increased from 0.8 +/- 0.4 to 11.1 +/- 3.8 microM as early as 6 h after P. carinii organisms were incubated with IFN-gamma-stimulated AMs and to 35.1 +/- 8.9 microM after a 24-h incubation, a near-maximum level. High levels of NO2- were produced by AMs primed with as little as 10 U of IFN-gamma per ml in the presence of P. carinii, and a 20-fold increase in IFN-gamma concentration resulted in only a further 65% increase in NO2- production. RNI-dependent killing of P. carinii was demonstrated by both a 51Cr release assay and a [35S]methionine pulse immunoprecipitation assay. Addition of either monoclonal tumor necrosis factor alpha (TNF-alpha) neutralizing antibody or 200 microM NG-monomethyl-L-arginine (L-NGMMA), a competitive inhibitor of the L-arginine-dependent pathway, significantly decreased NO2- production and reduced P. carinii killing. TNF-alpha alone had no effect on P. carinii viability. These results suggest that (i) the specific interaction of P. carinii organisms with IFN-gamma-primed AMs triggers the production of RNI, (ii) RNI are toxic to P. carinii, and (iii) TNF-alpha likely plays a central role in mediating P. carinii killing by IFN-gamma-stimulated AMs.

Animals↗
PubMed1999

Surfactant protein A suppresses reactive nitrogen intermediates by alveolar macrophages in response to Mycobacterium tuberculosis.

Mycobacterium tuberculosis attaches to, enters, and replicates within alveolar macrophages (AMs). Our previous studies suggest that surfactant protein A (SP-A) can act as a ligand in the attachment of M. tuberculosis to AMs. Reactive nitrogen intermediates (RNIs) play a significant role in the killing of mycobacteria. We have demonstrated that RNI levels generated by AMs were significantly increased when interferon-gamma-primed AMs were incubated with M. tuberculosis. However, the RNI levels were significantly suppressed in the presence of SP-A (10 microg/ml). The specificity of SP-A's effect was demonstrated by the use of F(ab')2 fragments of anti-SP-A monoclonal antibodies and by the use of mannosyl-BSA, which blocked the suppression of RNI levels by SP-A. Furthermore, incubation of deglycosylated SP-A with M. tuberculosis failed to suppress RNI by AMs, suggesting that the oligosaccharide component of SP-A, which binds to M. tuberculosis, is necessary for this effect. These results show that SP-A-mediated binding of M. tuberculosis to AMs significantly decreased RNI levels, suggesting that this may be one mechanism by which M. tuberculosis diminishes the cytotoxic response of activated AMs.

Animals↗
PubMed1998

An analgesia circuit activated by cannabinoids.

Although many anecdotal reports indicate that marijuana and its active constituent, delta-9-tetrahydrocannabinol (delta-9-THC), may reduce pain sensation, studies of humans have produced inconsistent results. In animal studies, the apparent pain-suppressing effects of delta-9-THC and other cannabinoid drugs are confounded by motor deficits. Here we show that a brainstem circuit that contributes to the pain-suppressing effects of morphine is also required for the analgesic effects of cannabinoids. Inactivation of the rostral ventromedial medulla (RVM) prevents the analgesia but not the motor deficits produced by systemically administered cannabinoids. Furthermore, cannabinoids produce analgesia by modulating RVM neuronal activity in a manner similar to, but pharmacologically dissociable from, that of morphine. We also show that endogenous cannabinoids tonically regulate pain thresholds in part through the modulation of RVM neuronal activity. These results show that analgesia produced by cannabinoids and opioids involves similar brainstem circuitry and that cannabinoids are indeed centrally acting analgesics with a new mechanism of action.

Analgesia↗
PubMed1998

Pain: nocistatin spells relief.

Tissue or nerve injury can dramatically alter the transmission of sensory stimuli by spinal cord neurons, so that a light touch produces pain. The discovery that peptide products of prepronociceptin processing either facilitate or inhibit these mechanisms suggests novel approaches to treating these conditions.

Analgesics, Opioid↗
PubMed1998

Cannabinoid receptor-mediated inhibition of the rat tail-flick reflex after microinjection into the rostral ventromedial medulla.

Systemic administration of cannabinoids produce profound antinociception in rodents. The purpose of this study was to examine the contribution of the rostral ventromedial medulla (RVM) to cannabinoid-mediated inhibition of the tail-flick reflex. Rats received direct injections of two selective cannabinoid agonists, WIN55,212-2 and HU210, into the RVM. Both compounds significantly elevated tail-flick latencies by over 50%. WIN55,212-3, the inactive enantiomer, was without effect. Furthermore, co-administration of the selective cannabinoid receptor antagonist, SR141716A greatly attenuated the antinociception produced by HU210. Finally, injections of WIN55,212-2 outside the region of the RVM did not affect tail-flick latencies. These results demonstrate that the cannabinoid receptor system participates in the descending control of nociception and raise the possibility that actions of endogenous cannabinoids in the RVM may modulate nociceptive responsiveness.

Analgesics↗
PubMed1998

Nitrated SP-A does not enhance adherence of Pneumocystis carinii to alveolar macrophages.

We investigated whether nitration of surfactant apoprotein (SP) A alters its ability to bind to mannose-containing saccharides on Pneumocystis carinii and its potential role in the mediation of P. carinii adherence to alveolar macrophages. Human SP-A was nitrated by incubation with tetranitromethane at pH 8.0 or synthetic peroxynitrite (ONOO-) at pH 7.4, which resulted in significant nitration of tyrosines in its carbohydrate recognition domain [0.63 +/- 0.001 (SE) and 1.25 +/- 0.02 mol nitrotyrosine/mol monomeric SP-A, respectively; n = 3 samples]. Binding of SP-A to P. carinii was calcium dependent and competitively inhibited by alpha-methyl-D-mannopyranoside. Nitration of SP-A by ONOO- or tetranitromethane decreases its binding to P. carinii by increasing its dissociation constant from 7.8 x 10(-9) to 1.6 x 10(-8) or 2.4 x 10(-8) M, respectively, without significantly affecting the number of binding sites (7.1 x 10(6)/P. carinii organisms, assuming that the native molecular mass of oligomeric SP-A is 650 kDa). Furthermore, ONOO--nitrated SP-A failed to mediate the adherence and phagocytosis of P. carinii to rat alveolar macrophages as observed with normal SP-A. Binding of SP-A to rat alveolar macrophages was not altered by nitration. These results indicate that nitration of SP-A interferes with its ability to serve as a ligand for P. carinii adherence to alveolar macrophages at the site of the SP-A moleculeP. carinii interaction.

Animals↗
PubMed1998

Cellular sequences in stealth viruses.

Cloned DNA obtained from the culture of an African green monkey simian cytomegalovirus-derived stealth virus contains multiple discrete regions of significant sequence homology (p values ranging from 4 x 10(-3) to 1 x 10(-20)) to portions of known human cellular genes. The stealth virus was cultured from a patient with chronic fatigue syndrome (CFS). Earlier studies had revealed considerable sequence heterogeneity within DNA fragments isolated from virus-infected cells. A set of polymerase chain reaction (PCR) primers generated different PCR products when tested on stealth virus cultures from 4 patients with CFS. Several of the PCR products also contain regions of significant partial homology to distinct cellular sequences, including sequences repetitively expressed throughout the cellular genome. Stealth viruses may play an important role in the origins and in the genetic diversity of both viral and cellular sequences.

Animals↗
PubMed1998

Pneumocystis carinii: the art and science of survival in the hostile environment of the alveolar spaces.

Pneumocystis carinii remains an important cause of pneumonia in immunocompromised patients, particularly in those who have acquired immune deficiency syndrome. Potential mechanisms by which P. carinii escapes elimination by lung defenses and proliferates are discussed. Evidence indicates that P. carinii attachment to alveolar epithelium is an important event in the establishment of infection and occurs through a variety of means. The binding of the organisms appears to be injurious to alveolar epithelial cells. Proliferation of the organism is associated with an ineffective and at times detrimental host inflammatory response. Additional studies indicate that P. carinii has the ability to invade tissues. Future investigations using new methodologies and strategies will be required to fully control this pathogen.

Animals↗
PubMed1997

Stealth virus epidemic in the Mohave Valley. I. Initial report of virus isolation.

Increasing numbers of patients within the Mohave Valley region of the United States are reporting symptoms attributable to atypical neurological illness. Many of these patients have experienced an acute-onset gastrointestinal illness during the spring and summer of 1996. Stealth viral cultures performed on the blood of 40 of these patients have been uniformly positive, yielding unequivocal transmissible cytopathic effect (CPE) in both human- and monkey-derived cell lines. One patient has died from a stealth-CPE-positive glioblastoma, while another patient has developed a plemorphic adenoma of the parotid. Viral cultures and epidemiological data support human-to-human, and probable human-to-dog, transmission of the Mohave stealth virus infection.

Animals↗