Biomedical subjects

A Simmons

Publications and source records attributed to A Simmons.

At least 145 records · Page 8Linked to original sources

PubMed1991

Induction of protective immunity with antibody to herpes simplex virus type 1 glycoprotein H (gH) and analysis of the immune response to gH expressed in recombinant vaccinia virus.

Passive administration of neutralizing monoclonal antibody (MAb) to glycoprotein H (gH) of herpes simplex virus type 1 (HSV-1) was found to protect mice from an HSV-1 strain SC16 challenge infection. To investigate further the protective potential of gH, recombinant vaccinia viruses were constructed which expressed the HSV-1 gH open reading frame under the control of the vaccinia virus 7.5K early/late promoter or the 4b late promoter. Immunization with recombinant viruses, however, did not induce the production of neutralizing antisera and the mice were not protected from zosteriform spread or the establishment of latent infection following viral challenge. The gH produced by the recombinant vaccinia viruses differed in electrophoretic mobility and antigenicity from authentic HSV-1 gH. Only one of three neutralizing MAbs specific for conformational epitopes on gH was able to immunoprecipitate gH synthesized in recombinant vaccinia virus-infected cells. In addition cell surface expression of gH was not detected in cells infected with the recombinant vaccinia viruses.

Animals↗

PubMed1991

Divergent molecular pathways of productive and latent infection with a virulent strain of herpes simplex virus type 1.

Mutants of herpes simplex virus (HSV) have been used to show that a variety of key genes associated with initiation of lytic infection or replication of viral DNA are not essential for establishment of latency. These observations are extended in the present study, in which a virulent strain of HSV type 1 that is not compromised in its ability to productively infect neurons under favorable conditions was used to demonstrate early divergence of molecular pathways leading to productive and latent infection. Our experimental strategy made unique use of the segmental innervation of the vertebrate trunk to study the spread of virus throughout the peripheral nervous system after inoculation of mouse flanks. Evidence of viral gene expression, including that of immediate-early genes, was transient, confined to ganglia directly innervating the inoculated skin (8th through 12th thoracic segments), and seen only at sites from which infectious virus could be recovered. In contrast, neurons containing latency-associated transcripts and reactivatable virus were more widely distributed (sixth thoracic through first lumbar segments), from which we conclude that replication-competent HSV type 1 can establish latency without initiating productive infection.

Acute Disease↗

PubMed1991

Hodgkin's disease presenting as liver abscesses.

A patient is reported who presented with sterile hepatic abscesses which proved to be the first manifestation of Hodgkin's disease. He failed to improve with antibiotic treatment but responded to combined chemotherapy. Liver involvement as the first sign of Hodgkin's disease is rare. Liver abscesses due to Hodgkin's disease seem to be previously unreported.

Adult↗

PubMed1991

The beneficial effect of lys-plasminogen upon the thrombolytic efficacy of urokinase in a dog model of peripheral arterial thrombosis.

The efficacy of thrombolytic therapy may be limited by local availability of plasminogen near a poorly perfused thrombus. The purpose of this study was to determine if the local (i.e., clot site) administration of 0.5 mg glu-plasminogen (glu-plg) or 0.5 mg lysplasminogen (lys-plg) could safely increase the thrombolytic efficacy of a 30-min intraarterial injection of 3,500 U kg-1 of two-chain urokinase plasminogen activator (UK) in a dog model of arterial thrombosis. Thrombolysis was measured by monitoring the continuous decrement of 125I-gamma emissions from a radiolabeled thrombus. Reflow was evaluated by a distally placed flowmeter and by direct visual examination. Forty-two dogs (mean weight 10.1 +/- 1.9 kg) were randomly sorted into six groups of 7 each. The dogs in each group were given either saline plus saline (group 1), saline plus UK (group 2), glu-plg plus saline (group 3), glu-plg plus UK (group 4), lys-plg plus saline (group 5), or lys-plg plus UK (group 6) by selective arterial catheterization 60 min after formation of an occlusive thrombus. Ninety minutes following drug administration, all groups which received UK (groups 2, 4, and 6) showed greater lysis (p less than 0.05) than the groups which received only saline or either glu- or lys-plg plus saline. Group 6, which received lys-plg plus UK, showed significantly greater lysis (34 +/- 4%) than both group 2 (23 +/- 2%), which received saline plus UK, and group 4 (19 +/- 3%), which received glu-plg plus UK (p less than 0.05). All dogs (7/7) in group 6 had reflow at 90 min whereas only 3/7 dogs had reflow in both groups 2 and 4.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

A successful decade of regionalized perinatal care in Tennessee: the neonatal experience.

We hypothesized that successful implementation of regionalized perinatal care would result in early identification and antenatal referral of high-risk neonates, and also improved stabilization before and during transport of those transferred postnatally. We conducted a retrospective study of demographic characteristics and transport outcome in two defined groups of neonates transported to regional perinatal centers in Tennessee, one group (n = 218) from the first year of regionalization (1975), and a second group (n = 261) from the 12th year (1986). The percentage of outborn infants decreased, from 50% of all admissions in 1975 to 22% in 1986 (P = .005). Likewise, the percentage of low-birthweight neonates transported after birth decreased, from 59% of all transports to 32% (P = .002). The frequency of stabilization measures performed before and during transport increased between study years (intravenous line placement: 12% to 58%, P = .0001; assisted ventilation: 10% to 33%, P = .001). The incidence of complications during transport decreased between study years (cyanosis: 25% to 8%, P = .0001; hypothermia: 30% to 3%, P = .0001; acidemia: 33% to 13%, P = .011). Both transport-related mortality and neonatal mortality decreased between study years (2.8% to 0.8%, P = .043; 17% to 7%, P = .0001, respectively). We conclude that regionalization during its first decade has been successful in improving perinatal care in Tennessee as indicated by favorable changes in referral patterns and improved outcome of transported neonates.

Humans↗

PubMed1990

The protective effect of heparin in a dog model of rethrombosis following pharmacologic thrombolysis.

Rethrombosis is an important clinical problem for patients who have benefitted from pharmacologic thrombolysis. The present study describes a dog model of arterial thrombosis, which includes endothelial denudation, intimal damage, and stenosis, and is suitable for studying the phenomena of both thrombolysis and subsequent rethrombosis. The model was used to determine the effect of tissue-type plasminogen activator (t-PA), high and low dose heparin, and saline upon the incidence of rethrombosis after t-PA-induced thrombolysis. Initial thrombolysis with reflow was achieved with 0.4 mg/kg t-PA, intravenous bolus injection, followed immediately by 0.4 mg/kg t-PA, 30 min infusion, in 40 of 42 dogs (95%) that had an occlusive, 125I-labelled thrombus created in a segment of femoral artery. The 40 dogs in which reperfusion was achieved were randomly sorted into 4 groups of 10 each which then received either saline, t-PA (0.4 mg kg-1 infused over 1 h), low dose heparin (500 U bolus injection then 250 U h-1 for 24 h), or high dose heparin (1,500 U bolus injection then 500 U h-1 for 24 h). Sixty percent (6/10) of the saline treated dogs showed occlusive rethrombosis at 24 h. The incidence of occlusive rethrombosis was 9/10 in the t-PA treated group (p = NS), 3/10 in the low dose heparin treated group (p = NS), and 0/10 in the high dose heparin treated group (p less than 0.01). Two smaller groups consisting of 5 dogs each were treated with either saline or high dose heparin alone (no t-PA). None of the dogs in either group showed thrombolysis with reflow.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

Cmv-1, a genetic locus that controls murine cytomegalovirus replication in the spleen.

The genetic basis of the control of acute splenic MCMV infection was studied after intraperitoneal inoculation of the virus. Classical Mendelian analyses using C57BL/6 (resistant) and BALB/c (susceptible) parental strains disclosed an autosomal dominant non-H-2 gene that regulates splenic virus replication. The probable location of this gene, to which we have assigned the symbol Cmv-1, is on chromosome 6 as defined by the strain distribution pattern of splenic MCMV replication in CXB recombinant inbred mice. Although there is a similar hierarchy of resistance to MCMV and HSV-1 with respect to the C57BL and BALB genetic backgrounds, the strain distribution pattern of HSV-1 replication in recombinant inbred mice suggests that Cmv-1 is not involved in restricting the spread of this virus. This is the first clear identification of a non-H-2 gene regulating the magnitude of MCMV infection. Elucidation of the function of this gene may be a fundamental step towards understanding the control of systemic CMV infection.

Animals↗

PubMed1990

An approach to trapping gamma-glutamyl radical intermediates proposed for vitamin K dependent carboxylase: alpha,beta-methyleneglutamic acid.

The vitamin K dependent carboxylase activates the glutamyl gamma-CH of substrate peptides for carboxylation by producing a gamma-glutamyl free radical, a gamma-glutamyl carbanion, or through a concerted carboxylation. We propose to intercept the putative gamma-glutamyl free radical by the intramolecular rearrangement of a substrate containing the alpha,beta-cyclopropane analogue of glutamic acid. The rearrangement of cyclopropylcarbinyl radicals into 2-butenyl radicals is rapid, exothermic, and considered diagnostic of free-radical formation. 1-Amino-2-(carboxymethyl)cyclopropane-1-carboxylate, the beta-cyclopropane analogue of glutamic acid, was synthesized starting from diethyl alpha-ketoglutarate. The alpha-keto ester was first treated with benzonitrile in sulfuric acid, to yield diethyl alpha,alpha-dibenzamidoglutarate. The alpha,alpha-dibenzamido acid was cleaved to produce the alpha,beta-dehydroamino acid and benzamide on treatment with p-toluenesulfonic acid in hot benzene. Diazomethane addition to the dehydroamino acid resulted in cycloaddition of diazomethane and production of the pyrazoline, which upon irradiation lost N2 to give the protected cyclopropane-containing amino acid analogue. Acidic hydrolysis of the N-benzoyl-alpha,beta-methyleneglutamate diethyl ester resulted in the production of the unprotected amino acid, alpha,beta-methyleneglutamic acid, in high yield. A single dehydroamino acid and a single methyleneglutamic acid isomer were produced in this synthesis; both are identified as the Z isomer, the former by NMR using the nuclear Overhauser effect and the latter through X-ray crystallographic analysis of N-benzoyl-alpha,beta-methyleneglutamate diethyl ester. Saponification of a N-protected methyleneglutamic acid dialkyl ester using limiting alkali was shown to selectively yield the alpha-alkyl ester gamma-acid. The reaction was used to produce alpha,beta-cyclopropane-containing analogues of the carboxylase substrates N-t-Boc-L-glutamic acid alpha-benzyl ester and N-benzoyl-L-glutamic acid alpha-ethyl ester. The cyclpropane-containing analogues were tested and found to be neither substrates for nor inhibitors of the rat liver microsomal vitamin K dependent carboxylase. The inability of the enzyme to recognize these substrate analogues is attributed to the alpha-alkyl substitution, which apparently abolishes substrate binding.

Animals↗

PubMed1989

Disseminated herpes simplex virus infection in an apparently immunocompetent woman.

A young, previously healthy woman developed bilateral exudative tonsillitis that was associated with severe systemic symptoms. This was followed by evidence of multisystem disease with acute abdominal pain, raised liver enzyme levels, respiratory difficulty, increasing drowsiness and multiple vesicular skin lesions. Herpes simplex virus type-1 was isolated from skin lesions and a throat swab and herpes simplex virus type-1 antigen was detected in a liver biopsy sample. She recovered rapidly without any sequelae after treatment with intravenously administered acyclovir.

Abdominal Pain↗

PubMed1989

Fatal rhabdomyolysis and renal failure associated with hand, foot and mouth disease.

Fatal severe rhabdomyolysis and anuric renal failure developed in a young man who had contracted hand, foot and mouth disease during an epidemic of this disease. Viral studies implicated coxsackievirus A16 as the infecting agent. This appears to be the first reported case of rhabdomyolysis that was associated with hand, foot and mouth disease and infection with coxsackievirus A16.

Adult↗

PubMed1989

Retention of chromosome 3 in extrapulmonary small cell cancer shown by molecular and cytogenetic studies.

In small cell lung carcinoma, one of the short arms of chromosome 3 is typically lost. To investigate chromosome 3 in extrapulmonary small cell carcinoma, we used DNA probes that detect restriction-fragment-length polymorphisms at loci on 3p. These probes were used to study DNA extracted from tumors and normal tissues and/or tumor cell lines from five patients with extrapulmonary small cell cancer. Tumor DNA from four of the five patients with extrapulmonary small cell cancer retained heterozygosity at loci on 3p. Cytogenetic studies of the tumor cell lines established from these four patients showed retention of both short arms of chromosome 3. We conclude that the loss of genetic material from 3p observed in small cell lung cancer is not typical in extrapulmonary small cell cancer.

Adult↗

PubMed1989

H-2-linked genes influence the severity of herpes simplex virus infection of the peripheral nervous system.

Infection of the peripheral nervous system was studied after inoculation of HSV into the flank skin of H-2 congenic mice. The amount of virus recovered from the sensory ganglia varied significantly between the mouse strains tested. Differences became apparent 7 d after infection, at which time the severity of disease in H-2k mice was two to three orders of magnitude greater than that in H-2d animals. The association of the H-2k haplotype with impaired ability to clear HSV from the nervous system is the first clear demonstration that genes within the MHC can influence the severity of primary herpetic infection, in spite of numerous studies on genetic resistance to this disease.

Animals↗

PubMed1989

Neural infection in mice after cutaneous inoculation with HSV-1 is under complex host genetic control.

The ability to restrict neural infection with herpes simplex virus is of potential importance because the nervous system is the main reservoir of virus between recrudescences. Genetic control of innate resistance to herpes simplex after intraperitoneal challenge is well established, but this route of infection does not mimic the progress of virus from skin to the sensory nervous system which occurs during natural infection. We show here, by Mendelian analysis, that the control of neural infection after cutaneous inoculation is complex, involving several (perhaps four) genetic loci, and is not accurately represented by genes which determine survival. The results are discussed in relation to possible underlying resistance mechanisms, particularly the control of early interferon production.

Animals↗

PubMed1988

The effectiveness of postischemic oxypurinol administration upon myocardial function in the isolated rat heart.

The Langendorff isolated rat heart preparation was used to determine the effect of oxypurinol, a xanthine oxidase inhibitor, on myocardial function when administered during reperfusion after 30 min of warm ischemia. Twenty rats were randomly sorted into 2 groups of 10, and an isolated heart preparation made from each rat. The isolated hearts were perfused for 15 min with a modified Krebs-Henseleit solution to permit stabilization of the preparation. Each heart was then subjected to 30 min of total ischemia at 37 degrees C followed by 40 min of reperfusion with either saline-treated perfusate or oxypurinol-treated perfusate (1.3 mM). The maximum power produced and the preload required to produce maximum power were both determined prior to ischemia and every 10 min after ischemia during 40 min of reperfusion. The saline-treated group, but not the oxypurinol-treated group, showed significantly less maximum power output at all testing times during reperfusion compared to the preischemic value (P less than 0.05). There was a significantly greater maximum power output (P less than 0.02) in the oxypurinol-treated group compared to the saline-treated group after 20, 30, and 40 min of reperfusion. There were no differences within either group, or between groups, for the preload required to produce maximum power at any of the testing times. Ultrastructural examination of myocardium after reperfusion showed severe mitochondrial and myofibrillar disruption in the saline-treated group but not in the oxypurinol-treated group. We conclude that oxypurinol administered following 30 min of total ischemia at the onset of reperfusion, can preserve myocardial function during the early reperfusion period in the isolated rat heart.

Animals↗

PubMed1987

Retrograde transneuronal transfer of herpes simplex virus type 1 (HSV 1) from motoneurones.

The use of Herpes simplex virus (HSV) as a retrograde transneuronal tracer would have the unique advantage that the virus would be replicated in the second order neurones, resulting in strong labelling. HSV was injected in the XII nerve (mice). The virus was detected immunohistochemically. Four stages in the brainstem distribution of HSV-positive neurones were distinguished. These stages were correlated with injected amounts/survival time. In stage 1, positive neurones were restricted to the XII nucleus; glial cells were present around the intramedullary XII rootlets. In stages 2-4, positive neurones and glial cells were also present outside the XII nucleus: (a) in the lateral reticular formation, Kölliker-Fuse nucleus, raphe and nucleus coeruleus; and (b) in the area around the XII rootlets, including parts of the inferior olive. In view of their distribution, many of the neurones in (a) must have received the virus by retrograde transneuronal transfer from XII motoneurones. The neurones in (b) were probably infected through a different route, i.e. local transfer of virus from XII axons via glial cells. This local transfer does not lead to extensive spread of the infection, yet, when using HSV for retrograde transneuronal tracing it may represent a source of error.

Afferent Pathways↗

PubMed1987

Protection from reperfusion injury in the isolated rat heart by postischaemic deferoxamine and oxypurinol administration.

A Langendorff isolated rat heart preparation was used to determine the effect of oxypurinol, a xanthine oxidase inhibitor, and deferoxamine, an iron binding agent, on the extent of myocardial reperfusion injury after 60 minutes of ischaemia. Thirty rats were divided into three groups of 10, and an isolated heart preparation made from each rat. The isolated hearts were perfused for 15 minutes with a modified Krebs-Henseleit perfusate solution to permit stabilisation of the preparation. Each heart was then subjected to 60 minutes of total ischaemia at 37 degrees C followed by 60 minutes of reperfusion with either saline treated perfusate, oxypurinol treated perfusate (1.3 mmol.litre-1), or deferoxamine treated perfusate (0.61 mmol.litre-1). Reperfusion injury was assessed by the total amount of creatine phosphokinase released into the perfusate, by changes in myocardial vascular resistance, and by morphological examination. The saline treated group released significantly more creatine phosphokinase into the perfusate than either the oxypurinol treated group (p less than 0.05) or the deferoxamine treated group (p less than 0.05). The mean vascular resistance increased for all groups during the 60 minutes of reperfusion compared with that just before ischaemia but was significantly greater in the saline treated group than in the drug treated groups (p less than 0.01). Ultrastructural examination of a randomly selected heart from each group after 60 minutes of reperfusion showed pronounced attenuation of mitochondrial and endoplasmic reticulum swelling, increased maintenance of membrane integrity, and diminished separation of myofilaments in the oxypurinol treated and deferoxamine treated hearts.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1987

Effect of B cell suppression on primary infection and reinfection of mice with herpes simplex virus.

During primary infection with herpes simplex virus type 1, elimination of the antibody response by B cell suppression did not interfere with clearance of virus from skin. However, spread of virus within the peripheral nervous system was more extensive in B cell-suppressed animals compared with that in fully immunocompetent mice. Mice that had previously recovered from herpes simplex virus infection of the ear pinna, when subsequently reinfected in the flank, showed restricted viral replication in the skin and cleared virus more rapidly than did animals experiencing primary infection. B cell suppression did not compromise the ability of mice to resist reinfection compared with the ability of normal immune animals. The implications of the above findings with regard to future immunoprophylaxis and the interpretation of experiments designed to test for immunity are discussed.

Animals↗

PubMed1985

Role of antibody in primary and recurrent herpes simplex virus infection.

When herpes simplex virus was inoculated into the flank of a BALB/c mouse by scarification, the local replication of virus was followed by the establishment of an acute ganglionic infection. The subsequent centrifugal spread of this virus along nerves to the skin of the whole dermatome led to the development of a bandlike "zosteriform" rash. This represents a highly reproducible system in which virus travels through the nervous system synchronously in large numbers of animals. The transection of peripheral nerves at various times after infection showed that the virus had completed the round trip 60 h after inoculation into the upper flank and was detectable as infectious virus by 74 h postinfection. After the administration of virus, neutralizing but not nonneutralizing antibodies prevented the development of the zosteriform rash. The target epitopes of the protective antibodies were not confined to a single glycoprotein. Neutralizing antibody was effective even when given up to 60 h postinfection and was protective even when administered after sensory neurotomy at this time. Antibody was therefore able to prevent clinically and virologically detectable infection of the skin, presumably by acting peripherally on virus emerging from nerve endings. A quantitative estimate of the action of one of the neutralizing monoclonal antibody preparations, AP7, showed that high titers (several times higher than those normally found in immune mice) were needed to prevent this type of infection. These results are discussed in relation to antibody prophylaxis.

Animals↗