Search PubMed⌕ Search

Biomedical subjects

William J Martin

Publications and source records attributed to William J Martin.

At least 37 records · Page 2Linked to original sources

Comparative genomic analyses in Asparagus.

Garden asparagus (Asparagus officinalis L.) belongs to the monocot family Asparagaceae in the order Asparagales. Onion (Allium cepa L.) and Asparagus officinalis are 2 of the most economically important plants of the core Asparagales, a well supported monophyletic group within the Asparagales. Coding regions in onion have lower GC contents than the grasses. We compared the GC content of 3374 unique expressed sequence tags (ESTs) from A. officinalis with Lycoris longituba and onion (both members of the core Asparagales), Acorus americanus (sister to all other monocots), the grasses, and Arabidopsis. Although ESTs in A. officinalis and Acorus had a higher average GC content than Arabidopsis, Lycoris, and onion, all were clearly lower than the grasses. The Asparagaceae have the smallest nuclear genomes among all plants in the core Asparagales, which typically have huge genomes. Within the Asparagaceae, European Asparagus species have approximately twice the nuclear DNA of that of southern African Asparagus species. We cloned and sequenced 20 genomic amplicons from European A. officinalis and the southern African species Asparagus plumosus and observed no clear evidence for a recent genome doubling in A. officinalis relative to A. plumosus. These results indicate that members of the genus Asparagus with smaller genomes may be useful genomic models for plants in the core Asparagales.

Asparagus Plant↗

A novel approach to restore lung immunity during systemic immunosuppression.

Systemic immunosuppression accounts for significant morbidity and mortality worldwide. Pulmonary infections represent the most common cause of death in these patients. The resident inflammatory cell in the lung is the alveolar macrophage (AM) and its function is markedly diminished by immunosuppression. We hypothesized that AMs from normal mice with or without gene transfer of the gamma interferon gene inside the macrophages, can restore alveolar immunity in immunosuppressed mice with severe combined immunodeficiency syndrome (SCID). To test this hypothesis we intratracheally instilled normal and IFN-gamma activated macrophages to the lungs of SCID mice. We demonstrated that airway delivery of macrophages results in widespread alveolar distribution, improved phagocytic function and ability to clear opportunistic infections such as Pneumocystis carinii. Airway delivery of IFN-gamma expressing macrophages further increased the function of alveolar macrophages. Reconstitution of the lungs of immunosuppressed mice with normal or activated AMs can restore alveolar immunity despite ongoing systemic immunosuppression.

Animals↗

The behavioral and neuroanatomical effects of IB4-saporin treatment in rat models of nociceptive and neuropathic pain.

One distinguishing feature of primary afferent neurons is their ability to bind the lectin IB(4). Previous work suggested that neurons in the inner part of lamina II (IIi), onto which IB(4)-positive sensory neurons project, facilitate nociceptive transmission following tissue or nerve injury. Using an IB(4)-saporin conjugate (IB(4)-SAP), we examined the contribution of IB(4)-positive neurons to nociceptive processing in rats with and without nerve injury. Intrasciatic injection of IB(4)-SAP (5 mug/5 mul) significantly decreased IB(4)-labeling and immunoreactive P(2)X(3) in the spinal cord and delayed the behavioral and neuroanatomical consequences of L5 spinal nerve ligation (SNL) injury. In the absence of injury, thermal and mechanical nociceptive thresholds increased 2 weeks post-treatment only in IB(4)-SAP-treated, but not control (saline or saporin only), rats. Acute NGF-induced hyperalgesia was also attenuated following IB(4)-SAP treatment. In the SNL model, mechanical allodynia failed to develop 1 and 2 weeks post-injury, but was fully established by 4 weeks. Moreover, neuropeptide Y immunoreactivity (NPY-ir), which increases in the spinal cord after nerve injury, was unchanged in IB(4)-SAP-treated animals whereas immunoreactive PKCgamma decreased 2, but not 4, weeks post-injury. Quantitative RT-PCR revealed a reduction in P(2)X(3) mRNA in L4 DRG of IB(4)-SAP-treated animals, but no change in TrkA expression. Our results suggest that IB(4)-positive neurons in L4 are required for the full expression of NGF-induced hyperalgesia and participate in the behavioral and anatomical consequences that follow injury to the L5 spinal nerve.

Animals↗

A disubstituted succinamide is a potent sodium channel blocker with efficacy in a rat pain model.

Sodium channel blockers are used clinically to treat a number of neuropathic pain conditions, but more potent and selective agents should improve on the therapeutic index of currently used drugs. In a high-throughput functional assay, a novel sodium channel (Na(V)) blocker, N-[[2'-(aminosulfonyl)biphenyl-4-yl]methyl]-N'-(2,2'-bithien-5-ylmethyl)succinamide (BPBTS), was discovered. BPBTS is 2 orders of magnitude more potent than anticonvulsant and antiarrhythmic sodium channel blockers currently used to treat neuropathic pain. Resembling block by these agents, block of Na(V)1.2, Na(V)1.5, and Na(V)1.7 by BPBTS was found to be voltage- and use-dependent. BPBTS appeared to bind preferentially to open and inactivated states and caused a dose-dependent hyperpolarizing shift in the steady-state availability curves for all sodium channel subtypes tested. The affinity of BPBTS for the resting and inactivated states of Na(V)1.2 was 1.2 and 0.14 microM, respectively. BPBTS blocked Na(V)1.7 and Na(V)1.2 with similar potency, whereas block of Na(V)1.5 was slightly more potent. The slow tetrodotoxin-resistant Na(+) current in small-diameter DRG neurons was also potently blocked by BPBTS. [(3)H]BPBTS bound with high affinity to a single class of sites present in rat brain synaptosomal membranes (K(d) = 6.1 nM), and in membranes derived from HEK cells stably expressing Na(V)1.5 (K(d) = 0.9 nM). BPBTS dose-dependently attenuated nociceptive behavior in the formalin test, a rat model of tonic pain. On the basis of these findings, BPBTS represents a structurally novel and potent sodium channel blocker that may be used as a template for the development of analgesic agents.

Amides↗

Future directions in sarcoidosis research: summary of an NHLBI working group.

Sarcoidosis is a systemic granulomatous disease of unknown etiology that primarily affects the lungs. The etiology remains unclear; however, environmental, genetic, ethnic, and familial factors probably modify expression of the disease. As an example, African Americans are at greater risk of mortality and morbidity than are white Americans, and more often have a family history of sarcoidosis. Most patients with sarcoidosis recover spontaneously, but some develop chronic, debilitating disease. Corticosteroids and other drugs, although effective at controlling disease activity, may not influence the overall course of disease. Because of the many uncertainties about the pathogenesis, course, and management of sarcoidosis, the National Heart, Lung, and Blood Institute convened a working group to identify future research directions and opportunities for sarcoidosis. These include developing a tissue bank, using novel methods to identify genetic factors, studying the immunopathogenesis with human tissue and animal models, exploring new approaches to diagnose and manage disease, and, finally, conducting randomized controlled trials to assess new therapies.

Biomedical Research↗

Characterization of wide dynamic range neurons in the deep dorsal horn of the spinal cord in preprotachykinin-a null mice in vivo.

We previously reported that mice with a deletion of the preprotachykinin-A (pptA) gene, from which substance P (SP) and neurokinin A (NKA) are derived, exhibit reduced behavioral responses to intense stimuli, but that behavioral hypersensitivity after injury is unaltered. To understand the contribution of SP and NKA to nociceptive transmission in the spinal cord, we recorded single-unit activity from wide dynamic range neurons in the lamina V region of the lumbar dorsal horn of urethane-anesthetized wild-type and ppt-A null mutant (-/-) mice. We found that intensity coding to thermal stimuli was largely preserved in the ppt-A -/- mice. Neither the peak stimulus-evoked firing nor the neuronal activity during the initial phase (0-4 s) of the 41-49 degrees C thermal stimuli differed between the genotypes. However, electrophysiological responses during the late phase of the stimulus (5-10 s) and poststimulus (11-25 s) were significantly reduced in ppt-A -/- mice. To activate C-fibers and to sensitize the dorsal horn neurons we applied mustard oil (MO) topically to the hindpaw. We found that neither total MO-evoked activity nor sensitization to subsequent stimuli differed between the wild-type and ppt-A -/- mice. However, the time course of the sensitization and the magnitude of the poststimulus discharges were reduced in ppt-A -/- mice. We conclude that SP and/or NKA are not required for intensity coding or sensitization of nociresponsive neurons in the spinal cord, but that these peptides prolong thermal stimulus-evoked responses. Thus whereas behavioral hypersensitivity after injury is preserved in ppt-A -/- mice, our results suggest that the magnitude and duration of these behavioral responses would be reduced in the absence of SP and/or NKA.

Animals↗

Melanocortin receptors and erectile function.

OBJECTIVE: Review the historical and current evidence that suggests that activation of melanocortin receptors modulates erectile activity. METHODS: The available literature was reviewed. RESULTS: Melanocortin peptides derived from the pro-opiomelanocortin (POMC) precursor protein exert a host of diverse physiological effects in the periphery and in the CNS through interactions with one or more of the five cloned melanocortin receptors. Natural and synthetic melanocortin peptide agonists influence erectile and sexual function in a range of preclinical species. Emerging clinical evidence now suggests that the proerectile effects observed in preclinical species are evident in man as well. CONCLUSIONS: Preclinical and clinical results support the involvement of melanocortins in the modulation of erectile and sexual function. Current evidence indicates that the melanocortin 4 receptor subtype contributes to the proerectile effects observed with pan-receptor agonists. However, the putative receptor subtypes, pathways and mechanisms implicated in mediating the proerectile effects of melanocortins remain to be fully elucidated.

Humans↗

Amiodarone pulmonary toxicity.

The amount of literature on amiodarone pulmonary toxicity (APT) peaked in 1983-1984 with several hundred cases reported cumulatively, and declined thereafter. Since the mid-1990s, publications have increased, which suggests that APT remains a current problem in clinical practice. Amiodarone remains difficult to diagnose noninvasively, and although the outcome is good in the majority of patients, not all cases of APT can be controlled satisfactorily.

Amiodarone↗

Alveolar macrophages from HIV-infected subjects are resistant to Mycobacterium tuberculosis in vitro.

HIV-infected individuals frequently develop Mycobacterium tuberculosis (MTB) infection. Alveolar macrophages (AM) are the initial host defense against this organism. We measured MTB growth in AM from normal and HIV-infected subjects after in vitro exposure. Intracellular growth of MTB was reduced in AM from HIV-infected subjects compared with normal macrophages. This was confined to subjects with CD4 counts greater than 200/microl. Growth of avirulent mycobacteria in HIV macrophages was significantly less than virulent MTB. Because avirulent MTB is more sensitive to tumor necrosis factor-alpha (TNF-alpha), we examined the relationship between cytokine secretion and mycobacterial growth. Higher AM spontaneous TNF-alpha secretion was associated with reduced MTB growth in normal AM. This relationship was not seen in HIV-infected subjects, suggesting that other factors contributed to mycobacteria resistance. Mycobacteria-induced TNF-alpha secretion was inversely associated with growth in normal AM but not in HIV-infected subjects. Finally, binding and internalization of MTB was augmented in HIV macrophages compared with normal, demonstrating that reduced intracellular MTB growth was not due to impaired phagocytosis. In conclusion, the increased incidence of MTB infection in HIV-infected subjects does not appear to be due to a defect in macrophage innate immunity.

Adult↗

Medical risks of wilderness hiking.

PURPOSE: We sought to determine the extent to which injuries and illnesses limit long-distance or endurance outdoor recreational activities. METHODS: In a prospective surveillance study, 334 persons who hiked the Appalachian Trail for at least 7 days (mean [+/- SD] length of hike, 140 +/- 60 days) in 1997 were interviewed. At the end of their hike, subjects completed a questionnaire on injuries, illnesses, water purification methods, and hygiene practices. RESULTS: Of the 280 backpackers who responded (a combined 38,940 days of wilderness exposure), 69% (n = 192) achieved their goal. The most important reasons for ending a hike prematurely were injury, time limitation, and psychosocial reasons. The most common medical complaints were feet blisters (64%; n = 180), diarrhea (56%, n = 156), skin irritation (51%, n = 143), and acute joint pain (36%, n = 102). The incidence of vector-borne disease was 4% (n = 11); physician-diagnosed Lyme disease was the most common, and 24% of hikers (n = 68) reported tick bites. The risk of diarrhea was greater among those who frequently drank untreated water from streams or ponds (odds ratio [OR] = 7.7; 95% confidence interval [CI]: 2.7 to 23; P <0.0001), whereas practicing "good hygiene" (defined as routine cleaning of cooking utensils and cleaning hands after bowel movements) was associated with a decreased risk (OR = 0.46; 95% CI: 0.22 to 0.97; P =0.04). CONCLUSION: Diarrhea is the most common illness limiting long-distance hikers. Hikers should purify water routinely, avoiding using untreated surface water. The risk of gastrointestinal illness can also be reduced by maintaining personal hygiene practices and cleaning cookware.

Adult↗

Surfactant protein A decreases nitric oxide production by macrophages in a tumor necrosis factor-alpha-dependent mechanism.

Surfactant protein A (SP-A) modulates the lung defense system through regulation of cytokines and nitric oxide (NO) production by alveolar macrophages (AMs). Whether SP-A upregulates or downregulates production of proinflammatory cytokines and NO is controversial. This study demonstrates the molecular mechanism(s) by which SP-A suppresses NO production by activated murine AMs. NO production by interferon-gamma (IFN-gamma) and IFN-gamma plus Mycobacterium avium-stimulated AMs was mediated through tumor necrosis factor-alpha (TNF-alpha) production, as addition of neutralizing anti-TNF-alpha antibodies during AMs stimulation resulted in reduced NO production. SP-A suppressed NO production by activated AMs by inhibiting TNF-alpha production. The maximum inhibitory effect of SP-A on NO production was observed at 20 microg/ml of SP-A concentration. Furthermore, SP-A inhibited activation of nuclear factor-kappa B, a transcription factor required for induction of TNF-alpha and inducible NO synthase genes. These findings suggest that SP-A suppresses NO production by activated AMs by inhibiting TNF-alpha secretion and nuclear factor-kappa B activation. This study also highlights the importance of SP-A levels in the lung, as changes in SP-A levels may modulate the local lung defense system.

Animals↗

Evaluation of postoperative analgesia in a rat model of incisional pain.

Effective postoperative analgesia is essential for improving patient well-being and decreasing morbidity. Historical recommendations of postoperative analgesics have been based on their effectiveness in attenuating a nociceptive response in animals that have not undergone a surgical procedure, potentially leading to over- or underestimation of postoperative analgesia requirements. This study was designed to evaluate the efficacy of four analgesics in a model of postsurgical pain, which involves surgical incision of the plantar aspect of the hindpaw in halothane-anesthetized rats. The hindpaw was selected as the injury site because it permits quantitative assessment of mechanical sensitivity, which increases as a consequence of tissue damage. As the primary endpoints for postoperative recovery, mechanical sensitivity and weight gain were determined for 5 days. Analgesic regimens included buprenorphine (0.025, 0.05, and 0.1 mg/kg subcutaneously [s.c.]; 1 ml/kg), fentanyl (0.01 and 0.1 mg/kg intraperitoneally [i.p.]; 1 ml/kg), flunixin meglumine (1.1 and 2.5 mg/kg, s.c.; 1 ml/kg) and acetaminophen (100 and 300 mg/kg orally; approximately 3 & 10 ml/kg). Drugs were administered once daily on days 0, 1, and 2 postoperatively. Buprenorphine, fentanyl, and flunixin all significantly decreased mechanical sensitivity, but buprenorphine provided the highest degree of analgesia during the postoperative treatment period. However, rats treated with buprenorphine exhibited heightened mechanical sensitivity once treatment was discontinued on day 2. Moreover, buprenorphine also compromised weight gain as compared to that of vehicle-treated animals. These findings suggest that potent nonsteroidal anti-inflammatory agents, such as flunixin, may be useful alternatives to opioid-based agents for the control of acute postoperative pain associated with a minor surgical procedure and highlight the importance of assessing the risk-benefit ratio when selecting analgesics and dosing regimens.

Acetaminophen↗

Influence of postoperative analgesics on the development of neuropathic pain in rats.

Rodent models of neuropathic pain require extensive tissue manipulation to induce the lesion of interest which results in inflammation and postoperative pain that is unrelated to nerve injury per se. We sought to determine whether acute postoperative pain management affects the development of hallmark signs of neuropathic pain. Analgesic regimens (q 24 h x 3 days) were buprenorphine (0.05 and 0.1 mg/kg of body weight, s.c.), flunixin meglumine (1.1 and 2.5 mg/kg, s.c.), and fentanyl citrate (0.01 and 0.1 mg/kg, i.p.). The spared nerve injury model of neuropathic pain was used, and mechanical and cold allodynia as well as body weight gain were measured for 28 days. Buprenorphine and fentanyl alleviated mechanical sensitivity and prevented weight loss associated with the surgery (0 to 3 days), but opioid-related adverse effects were observed. Flunixin reduced wound inflammation and improved weight gain, but had no effect on nociceptive thresholds. Cold allodynia was unaltered by any treatment. By postoperative day 7, control and treatment groups did not differ with respect to weight gain or nociceptive thresholds. Our findings suggest that postsurgical inflammation and pain behavior can be ameliorated without substantially altering the long-term development of neuropathic pain, provided that the selection of agent(s) and treatment regimen(s) is appropriate and the neuropathic pain of interest is evaluated seven days after surgery.

Analgesics↗

Activation of melanocortin MC(4) receptors increases erectile activity in rats ex copula.

Melanocortin peptide agonists, alpha-melanocyte stimulating hormone (alpha-MSH) and melanotan-II, stimulate erectile activity in a variety of species, including man. Since neither peptide discriminates amongst melanocortin receptors, it is not clear which subtype mediates these pro-erectile effects. Here, we present data that melanocortin-induced erectogenesis is mediated by melanocortin MC(4) receptors. Systemic administration of a melanocortin MC(4) receptor agonist (N-[(3R)-1,2,3,4-tetrahydroisoquinolinium-3-ylcarbonyl]-(1R)-1-(4-chlorobenzyl)-2-[4-cyclohexyl-4-(1H-1,2,4-triazol-1ylmethyl)piperidin-1-yl]-2-oxoethylamine; THIQ) with high selectivity over other melanocortin receptors enhanced intracavernosal pressure and stimulated erectile activity in rats ex copula. THIQ dose-dependently (1-5 mg/kg, i.v.) increased the total number of erections, to an extent comparable or greater than that produced by apomorphine (0.025 mg/kg, s.c.). Central administration of THIQ (20 microg, intracerebroventricular (i.c.v.)) increased the number of reflexive penile erections; whereas administration of both a nonselective endogenous melanocortin MC(4) receptor antagonist (agouti-related protein (AgRP), 5.5. microg, i.c.v.) and a melanocortin MC(4) receptor preferring antagonist (MPB10, 1 mg/kg, i.v.) blocked THIQ-induced erectogenesis. These pro-erectile effects were also attenuated by systemic or central administration of an oxytocin antagonist (L-368899, 1 mg/kg, i.v.). Thus, melanocortin MC(4) receptor activation is sufficient for erectogenesis and these effects may involve oxytocinergic pathways.

Agouti-Related Protein↗

Morphologic detection and functional assessment of reconstituted normal alveolar macrophages in the lungs of SCID mice.

Alveolar macrophages (AMs) from immunocompetent animals were isolated from bronchoalveolar lavage and labeled with the fluorescent marker 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI). These AMs were administered intratracheally into mechanically ventilated SCID mice. From 1 to 28 days later, the recipient mice underwent bronchoalveolar lavage to isolate their AMs. To determine whether reconstituted AMs were still immunocompetent, the recovered AMs were assayed for their ability to phagocytose fluorescein-labeled zymosan-coated beads. After incubation with the beads, samples were assayed using a fluorescent-activated cell sorter to identify DiI-labeled reconstituted AMs, unlabeled resident AMs, and the proportion of these two groups undergoing phagocytosis. DiI-labeled AMs accounted for approximately 50% of all returned AMs. Additionally, the reconstituted AMs from normal BALB/c mice retained phagocytic activity compared with AMs from immunodeficient SCID mice. Reconstituted AMs demonstrated enhanced phagocytic activity compared with resident SCID AMs for up to 28 days following reconstitution. These results indicate that immunocompetent AMs can be successfully reconstituted into an immunodeficient host to partially restore alveolar host defense.

Animals↗

Design and pharmacology of N-[(3R)-1,2,3,4-tetrahydroisoquinolinium- 3-ylcarbonyl]-(1R)-1-(4-chlorobenzyl)- 2-[4-cyclohexyl-4-(1H-1,2,4-triazol- 1-ylmethyl)piperidin-1-yl]-2-oxoethylamine (1), a potent, selective, melanocortin subtype-4 receptor agonist.

Synthetic and natural peptides that act as nonselective melanocortin receptor agonists have been found to be anorexigenic and to stimulate erectile activity. We report the design and development of 1, a potent, selective (1184-fold vs MC3R, 350-fold vs MC5R), small-molecule agonist of the MC4 receptor. Pharmacological testing confirms the food intake lowering effects of MC4R agonism and suggests another role for the receptor in the stimulation of erectile activity.

Animals↗

A role for the melanocortin 4 receptor in sexual function.

By using a combination of genetic, pharmacological, and anatomical approaches, we show that the melanocortin 4 receptor (MC4R), implicated in the control of food intake and energy expenditure, also modulates erectile function and sexual behavior. Evidence supporting this notion is based on several findings: (i) a highly selective non-peptide MC4R agonist augments erectile activity initiated by electrical stimulation of the cavernous nerve in wild-type but not Mc4r-null mice; (ii) copulatory behavior is enhanced by administration of a selective MC4R agonist and is diminished in mice lacking Mc4r; (iii) reverse transcription (RT)-PCR and non-PCR based methods demonstrate MC4R expression in rat and human penis, and rat spinal cord, hypothalamus, brainstem, pelvic ganglion (major autonomic relay center to the penis), but not in rat primary corpus smooth muscle cavernosum cells; and (iv) in situ hybridization of glans tissue from the human and rat penis reveal MC4R expression in nerve fibers and mechanoreceptors in the glans of the penis. Collectively, these data implicate the MC4R in the modulation of penile erectile function and provide evidence that MC4R-mediated proerectile responses may be activated through neuronal circuitry in spinal cord erectile centers and somatosensory afferent nerve terminals of the penis. Our results provide a basis for the existence of MC4R-controlled neuronal pathways that control sexual function.

Animals↗