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Biomedical subjects

G Simmons

Publications and source records attributed to G Simmons.

At least 37 records · Page 2Linked to original sources
PubMed2000

Carriage of N. lactamica in a population at high risk of meningococcal disease.

Carriage of Neisseria lactamica among household contacts of meningococcal disease (MCD) cases was investigated during an epidemic in Auckland, New Zealand. The overall carriage rate for N. lactamica was 10.5% (95% CI 7.4-13.5%) with a peak carriage rate in 2-year-olds of 61.5% (95% CI 26.6-88.1%). Factors associated with a significant (P < 0.05) increase in the likelihood of carriage included runny nose, the number of people per bedroom and youth. Genetic analysis of isolates revealed a striking correlation of strains within the same household but a high level of diversity between households, suggesting that household contact is an important factor in acquisition. For household contacts aged less than 5 years, there was a higher rate of carriage amongst those in contact with MCD cases under 8 years old than for contacts of cases aged 8 years and over. It is likely that development of MCD is a reflection of the nature and intensity of the exposure to a virulent strain of N. meningitidis, coupled with an absence of host resistance among those individuals not carrying N. lactamica.

Adolescent↗
PubMed2000

Co-receptor use by HIV and inhibition of HIV infection by chemokine receptor ligands.

Human and simian immunodeficiency viruses (HIV and SIV) require a seven transmembrane chemokine (7TM) receptor in addition to CD4 for efficient entry into cells. CCR5 and CXCR4 act as major co-receptors for non-syncytium-inducing and syncytium-inducing strains respectively. We have examined the co-receptor requirement for HIV-1 infection of cells of macrophage lineage. Both CCR5 and CXCR4 can operate as functional co-receptors for infection in these cell types. Other co-receptors utilised by multi-co-receptor-using strains of HIV-1, including CCR3 and STRL33, were not used for macrophage infection. HIV-2 and SIV strains, however, can replicate in both peripheral blood mononuclear cells (PBMCs) and other primary cell types such as fibroblasts independently of CCR5 or CXCR4. HIV co-receptors, particularly CCR5, will be major targets for new therapeutics in this decade. We have therefore investigated different chemokines and derivatives that bind co-receptors for their capacity to inhibit HIV infection. These included derivatives of a CCR5 ligand, RANTES, with modified N-termini as well as Kaposi's sarcoma-associated herpesvirus-encoded chemokines that bind a wide range of co-receptors, including CCR5, CXCR4, CCR3 and CCR8, as well as the orphan 7TM receptors GPR1 and STRL33. One compound, aminooxypentane or AOP-RANTES, was a particularly potent inhibitor of HIV infection on PBMCs, macrophages and CCR5+ cell lines and demonstrated the great promise of therapeutic strategies aimed at CCR5.

Chemokines↗
PubMed2000

Equivalence of ceftriaxone and rifampicin in eliminating nasopharyngeal carriage of serogroup B Neisseria meningitidis.

The efficacy of ceftriaxone in eliminating nasopharyngeal carriage of Neisseria meningitidis was compared with that of rifampicin during an epidemic of serogroup B meningococcal disease in Auckland, New Zealand. Household contacts of cases had a throat swab taken and were randomized to treatment. Carriers had a repeat swab taken 6 days later to determine efficacy of treatment. Ceftriaxone (98.2%) was equivalent to rifampicin (97.6%) in eliminating serogroup B N. meningitidis. It is cheaper than rifampicin and has the advantage of full compliance and fewer contraindications, but its acceptability by patients may limit its use as a first-line prophylactic agent.

Adolescent↗
PubMed1999

Coreceptor ligand inhibition of fetal brain cell infection by HIV type 1.

The capacity of a panel of HIV-1 isolates to infect primary mixed fetal brain cell cultures was estimated and their sensitivity to inhibition by a range of coreceptor ligands assessed. Our results show that (1) HIV-1 strains that predominantly use CCR5 or only CXCR4 are able to infect microglia in primary brain cell cultures, and (2) ligands to these two coreceptors can inhibit brain cell infection. CCR5 ligands (including AOP-RANTES, a potent inhibitor of CCR5-dependent infection), however, blocked infection only weakly, raising the possibility that alternative unidentified coreceptors are also used. Interestingly, vMIP-II, a chemokine encoded by the Kaposi sarcoma-associated herpes virus (KSHV), reduced brain cell infection by all HIV-1 strains tested, including both R5 and X4 viruses. Our results therefore indicate that novel drugs targeted to the major HIV-1 coreceptors will influence HIV replication in the brain, if they cross the blood-brain barrier.

Anti-HIV Agents↗
PubMed1999

Primary human immunodeficiency virus type 2 (HIV-2) isolates infect CD4-negative cells via CCR5 and CXCR4: comparison with HIV-1 and simian immunodeficiency virus and relevance to cell tropism in vivo.

Cell surface receptors exploited by human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) for infection are major determinants of tropism. HIV-1 usually requires two receptors to infect cells. Gp120 on HIV-1 virions binds CD4 on the cell surface, triggering conformational rearrangements that create or expose a binding site for a seven-transmembrane (7TM) coreceptor. Although HIV-2 and SIV strains also use CD4, several laboratory-adapted HIV-2 strains infect cells without CD4, via an interaction with the coreceptor CXCR4. Moreover, the envelope glycoproteins of SIV of macaques (SIV(MAC)) can bind to and initiate infection of CD4(-) cells via CCR5. Here, we show that most primary HIV-2 isolates can infect either CCR5(+) or CXCR4(+) cells without CD4. The efficiency of CD4-independent infection by HIV-2 was comparable to that of SIV, but markedly higher than that of HIV-1. CD4-independent HIV-2 strains that could use both CCR5 and CXCR4 to infect CD4(+) cells were only able to use one of these receptors in the absence of CD4. Our observations therefore indicate (i) that HIV-2 and SIV envelope glycoproteins form a distinct conformation that enables contact with a 7TM receptor without CD4, and (ii) the use of CD4 enables a wider range of 7TM receptors to be exploited for infection and may assist adaptation or switching to new coreceptors in vivo. Primary CD4(-) fetal astrocyte cultures expressed CXCR4 and supported replication by the T-cell-line-adapted ROD/B strain. Productive infection by primary X4 strains was only triggered upon treatment of virus with soluble CD4. Thus, many primary HIV-2 strains infect CCR5(+) or CXCR4(+) cell lines without CD4 in vitro. CD4(-) cells that express these coreceptors in vivo, however, may still resist HIV-2 entry due to insufficient coreceptor concentration on the cell surface to trigger fusion or their expression in a conformation nonfunctional as a coreceptor. Our study, however, emphasizes that primary HIV-2 strains carry the potential to infect CD4(-) cells expressing CCR5 or CXCR4 in vivo.

Animals↗
PubMed1999

Expanded tropism of primary human immunodeficiency virus type 1 R5 strains to CD4(+) T-cell lines determined by the capacity to exploit low concentrations of CCR5.

Human immunodeficiency virus type 1 (HIV-1) non-syncytium-inducing (NSI) strains predominantly use the chemokine receptor CCR5, while syncytium-inducing (SI) strains use CXCR4. In vitro, SI isolates infect and replicate in a range of CD4(+) CXCR4(+) T-cell lines, whereas NSI isolates usually do not. Here we describe three NSI strains that are able to infect two CD4(+) T-cell lines, Molt4 and SupT1. For one strain, a variant of JRCSF selected in vitro, replication on Molt4 was previously shown to be conferred by a single amino-acid change in the V1 loop (M.T. Boyd et al., J. Virol. 67:3649-3652, 1993). On CD4(+) cell lines expressing different coreceptors, these strains use CCR5 predominantly and do not replicate in CCR5-negative peripheral blood mononuclear cells derived from individuals homozygous for Delta32 CCR5. Furthermore, infection of Molt4 and SupT1 by each of these three strains is potently inhibited by ligands for CCR5, including 2D7, a monoclonal antibody specific for CCR5. CCR5 mRNA was present in both Molt4 and SupT1 by reverse transcription-PCR, although CCR5 protein could not be detected either on the cell surface or in intracellular vesicles. The expanded tropism of the three strains shown here is therefore not due to adaptation to a new coreceptor but due to the capacity to exploit extremely low levels of CCR5 on Molt4 and SupT1 cells. This novel tropism observed for a subset of primary HIV-1 isolates may represent an extended tropism to new CD4(+) cell types in vivo.

CD4-Positive T-Lymphocytes↗
PubMed1998

Aminooxypentane-RANTES induces CCR5 internalization but inhibits recycling: a novel inhibitory mechanism of HIV infectivity.

CCR5, a chemokine receptor expressed on T cells and macrophages, is the principal coreceptor for M-tropic HIV-1 strains. Recently, we described an NH2-terminal modification of the CCR5 ligand regulated on activation, normal T cell expressed and secreted (RANTES), aminooxypentane-RANTES (AOP-RANTES), that showed potent inhibition of macrophage infection by HIV-1 under conditions where RANTES was barely effective. To investigate the mechanism of AOP-RANTES inhibition of HIV infectivity we examined the surface expression of CCR5 using a monoclonal anti-CCR5 antibody, MC-1. We demonstrate that AOP-RANTES rapidly caused >90% decrease in cell surface expression of CCR5 on lymphocytes, monocytes/ macrophages, and CCR5 transfected Chinese hamster ovary (CHO) cells. RANTES also caused a loss of cell surface CCR5, although its effect was less than with AOP-RANTES. Significantly, AOP-RANTES inhibited recycling of internalized CCR5 to the cell surface, whereas RANTES did not. When peripheral blood mononuclear cells are cultured for prolonged periods of time in the presence of RANTES, CCR5 expression is comparable to that seen on cells treated with control medium, whereas there is no CCR5 surface expression on cells cultured in the presence of AOP-RANTES. Immunofluorescence indicated that both AOP-RANTES and RANTES induced downmodulation of cell surface CCR5, and that the receptor was redistributed into endocytic organelles containing the transferrin receptor. When RANTES was removed, the internalized receptor was recycled to the cell surface; however, the receptor internalized in the presence of AOP-RANTES was retained in endosomes. Using human osteosarcoma (GHOST) 34/CCR5 cells, the potency of AOP-RANTES and RANTES to inhibit infection by the M-tropic HIV-1 strain, SF 162, correlated with the degree of downregulation of CCR5 induced by the two chemokines. These differences between AOP-RANTES and RANTES in their effect on receptor downregulation and recycling suggest a mechanism for the potent inhibition of HIV infection by AOP-RANTES. Moreover, these results support the notion that receptor internalization and inhibition of receptor recycling present new targets for therapeutic agents to prevent HIV infection.

Animals↗
PubMed1998

Cardiovascular disease risk factors in 65-84 year old men and women: results from the Auckland University Heart and Health Study 1993-4.

AIM: To describe the distribution of the major cardiovascular risk factors among older men and women in the Auckland region, New Zealand. METHODS: Means and prevalences of the major cardiovascular risk factors were estimated for non-Maori, non-Pacific Islands men and women in the age groups 65-74 and 75-84 years using data from the 1993-4 survey of the University of Auckland Heart and Health Study, a cross-sectional, population-based study of cardiovascular risk factors. RESULTS: 996 people aged 65-84 years participated, with men and women and the two ten-year age groups almost equally represented. Fewer than half engaged in regular leisure time physical activity; around 35% were overweight (BMI 25-30) and 10% were obese (BMI > 30). Total mean cholesterol levels were higher in women and 46% of women had a cholesterol level > or = 6.5 mmol/L compared with only 17% of men. However, total cholesterol:HDL ratios were higher among men. Age and sex differences in blood pressure were small. Around 50% had raised blood pressure (BP > 150/90) or were currently on antihypertensive medication; only 8% smoked; around 6% were diabetic. Almost 8% had three or all of four major modifiable cardiovascular risk factors (elevated blood pressure, total cholesterol:HDL ratio > or = 6.5, current smoking and physical inactivity). CONCLUSIONS: These results are broadly comparable to those from other Western populations. Differences between 65-74 and 75-84 year age groups are few but important differences in cholesterol, smoking and physical activity between older men and women are noted. These findings indicate that there is considerable potential for prevention of cardiovascular disease among older people.

Aged↗
PubMed1998

CXCR4 as a functional coreceptor for human immunodeficiency virus type 1 infection of primary macrophages.

The coreceptors used by primary syncytium-inducing (SI) human immunodeficiency virus type 1 isolates for infection of primary macrophages were investigated. SI strains using only CXCR4 replicated equally well in macrophages with or without CCR5 and were inhibited by several different ligands for CXCR4 including SDF-1 and bicyclam derivative AMD3100. SI strains that used a broad range of coreceptors including CCR3, CCR5, CCR8, CXCR4, and BONZO infected CCR5-deficient macrophages about 10-fold less efficiently than CCR5(+) macrophages. Moreover, AMD3100 blocked infection of CCR5-negative macrophages by these strains. Our results therefore demonstrate that CXCR4, as well as CCR5, is used for infection of primary macrophages but provide no evidence for the use of alternative coreceptors.

HIV-1↗
PubMed1998

Artificial urinary sphincter in the treatment of urinary incontinence: preoperative urodynamics do not predict the need for future bladder augmentation.

PURPOSE: The artificial urinary sphincter has been used to treat urinary incontinence in pediatric patients with neurogenic bladders secondary to myelodysplasia. Frequently bladder augmentation is performed in conjunction with the artificial urinary sphincter implantation. Identifying patients with adequate urinary reservoirs who are candidates for implantation without bladder augmentation is a clinical challenge. We reviewed our experience with the artificial urinary sphincter in children with myelodysplasia to determine whether preoperative urodynamic findings predict the need for future augmentation cystoplasty. MATERIALS AND METHODS: We identified 38 patients younger than 18 years at artificial urinary sphincter implantation who did not undergo augmentation enterocystoplasty before or at implantation. We evaluated preoperative bladder capacity and compliance to determine whether these standard preoperative urodynamic measurements predict the eventual need for bladder augmentation in these patients. RESULTS: In the 15 patients who required eventual bladder augmentation after artificial urinary sphincter implantation mean bladder capacity plus or minus standard deviation was 62.9+/-29.9% of age expected capacity and mean bladder compliance was 8.0+/-4.8 ml./cm. water. In the 23 patients who did not require eventual bladder augmentation mean bladder capacity was 59.2+/-25.4% of age expected capacity and compliance was 7.0+/-3.3 ml./cm. water. There was no statistically significant difference between the 2 groups. CONCLUSIONS: Standard preoperative urodynamics do not predict the patients who undergo isolated artificial urinary sphincter implantation and eventually require bladder augmentation.

Adolescent↗
PubMed1997

A broad-spectrum chemokine antagonist encoded by Kaposi's sarcoma-associated herpesvirus.

Kaposi's sarcoma-associated herpesvirus encodes a chemokine called vMIP-II. This protein displayed a broader spectrum of receptor activities than any mammalian chemokine as it bound with high affinity to a number of both CC and CXC chemokine receptors. Binding of vMIP-II, however, was not associated with the normal, rapid mobilization of calcium from intracellular stores; instead, it blocked calcium mobilization induced by endogenous chemokines. In freshly isolated human monocytes the virally encoded vMIP-II acted as a potent and efficient antagonist of chemotaxis induced by chemokines. Because vMIP-II could inhibit cell entry of human immunodeficiency virus (HIV) mediated through CCR3 and CCR5 as well as CXCR4, this protein may serve as a lead for development of broad-spectrum anti-HIV agents.

Amino Acid Sequence↗
PubMed1997

CD4-independent infection by HIV-2 (ROD/B): use of the 7-transmembrane receptors CXCR-4, CCR-3, and V28 for entry.

We have assayed a variety of 7tm chemokine receptors (CCR-2b, CCR-3, CCR-4, CCR-5, CXCR-1, CXCR-4) and two orphan 7tm receptors (V28 and EBI.1) for their ability to allow infection of CD4-negative feline kidney CCC cells by the HIV-2 strains ROD/A and ROD/B. We found that ROD/B was able to use CXCR-4 transiently expressed in CCC cells, and infection by ROD/A was enhanced 15-fold in the presence of sCD4. Feline CCC cells also became permissive to ROD/B and ROD/A entry when transiently transfected with the chemokine receptor CCR-3 or the orphan 7tm receptor V2B, when cultured in the presence of sCD4. Entry of ROD/A into CCC cells expressing CCR-3 could be blocked by 800 ng/ml eotaxin, the natural ligand for CCR-3.

Animals↗
PubMed1997

Enough said.

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Crowns↗
PubMed1997

Potent inhibition of HIV-1 infectivity in macrophages and lymphocytes by a novel CCR5 antagonist.

The chemokine receptors CXCR4 and CCR5 have recently been shown to act as coreceptors, in concert with CD4, for human immunodeficiency virus-type 1 (HIV-1) infection. RANTES and other chemokines that interact with CCR5 and block infection of peripheral blood mononuclear cell cultures inhibit infection of primary macrophages inefficiently at best. If used to treat HIV-1-infected individuals, these chemokines could fail to influence HIV replication in nonlymphocyte compartments while promoting unwanted inflammatory side effects. A derivative of RANTES that was created by chemical modification of the amino terminus, aminooxypentane (AOP)-RANTES, did not induce chemotaxis and was a subnanomolar antagonist of CCR5 function in monocytes. It potently inhibited infection of diverse cell types (including macrophages and lymphocytes) by nonsyncytium-inducing, macrophage-tropic HIV-1 strains. Thus, activation of cells by chemokines is not a prerequisite for the inhibition of viral uptake and replication. Chemokine receptor antagonists like AOP-RANTES that achieve full receptor occupancy at nanomolar concentrations are strong candidates for the therapy of HIV-1-infected individuals.

Animals↗
PubMed1997

The effect of lossy discrete cosine transform compression on subtle bone fractures.

Extensive research efforts have been devoted to the feasibility of picture archiving and communication systems (PACS) in recent years. The advantages of PACS are numerous but mainly include reduced cost and improvement in the operational efficiency of a PACS-based radiology department. In digital radiography, images are viewed either in hard-copy or soft-copy format. Usually, these images are subsequently compressed and archived for future evaluation. There are various methods used in image compression. In this study, computed radiography images showing subtle pediatric bone fractures were compressed with the lossy method of image compression after they had been initially evaluated on workstation monitors. These studies were subsequently evaluated by observers, who were unaware of the interpretations of these images before compression, to determine if they could detect similar abnormalities. Our conclusion is that there is no difference in the interpretation of soft-copy computed radiographic images before or after lossy 10:1 compression in studies of subtle pediatric bone fractures. This is a US government work. There are no restrictions on its use.

Analysis of Variance↗