Biomedical subjects

A S Williams

Publications and source records attributed to A S Williams.

At least 37 records · Page 2Linked to original sources

PubMed1996

A single intra-articular injection of liposomally conjugated methotrexate suppresses joint inflammation in rat antigen-induced arthritis.

In this study, we sought to determine whether liposomal preparations containing a phospholipid conjugate of methotrexate and dimyristoylphosphatidylethanolamine (MTX-gamma-DMPE) incorporated within their lipid membranes are effective in suppressing established joint inflammation in a monoarticular model of arthritis in the rat. Arthritis was induced in the right knee joint of Lewis rats. The rats were treated with a single intra-articular injection of either free methotrexate (MTX), liposomal MTX [MTX-multilamellar vesicles (MLV)-1.2 microns or MTX-small unilamellar vesicles (SUV)-100 nm], control liposomes (E-LIPO) or saline into the inflamed knee 7 days after arthritis induction. There was no significant difference in knee swelling in MTX-, saline- and E-LIPO-treated rats up to 21 days after treatment. However, MTX-MLV treatment produced a significant reduction in knee swelling (26.5 +/- 6.0%: mean +/- S.E.M.) 1 day after intra-articular injection compared with MTX (3.5 +/- 3.5%) and MTX-SUV (14.4 +/- 2.4%), respectively. Over the next 20 days, knee swelling in MTX-MLV-treated rats fell progressively and almost returned to normal. MTX-MLV treatment also inhibited the cellular infiltration associated with the arthritis. Large multilamellar liposomal preparations of MTX-gamma-DMPE are more effective than free MTX and MTX-SUV in suppressing inflammation. Their differential effects in treating the antigen-induced arthritis model are related to their retention within the joint space.

Animals↗

PubMed1996

Predicting postnatal depression among pregnant women.

BACKGROUND: Depression after the birth of a baby is a common cause of maternal morbidity, and its prevalence in Australia is 10 to 15 percent at 6 to 9 months postpartum. This study assesses the prediction of postnatal depression at 6 weeks postpartum. METHOD: Women at 24 weeks' gestation or less were invited to complete a Modified Antenatal Screening Questionnaire (MASQ) that identified women more vulnerable to becoming depressed after childbirth. Of these 249 women, 144 (58%) screened more vulnerable, and were randomly allocated to receive either a supportive intervention to reduce postnatal depression or to receive no intervention. At 6 weeks postpartum the women completed the Edinburgh Postnatal Depression Scale (EPDS) to assess their mood after the birth. RESULTS: No difference occurred at 6 weeks postpartum between the MASQ vulnerable group (return rate 64/68) and the MASQ less vulnerable group (return rate 44/51) in the frequency of those who screened as potential candidates for major depression using the EPDS. For major depression the MASQ's sensitivity was 73 percent, specificity 43 percent, positive predictive value 17 percent, and negative predictive value 91 percent; for minor depression its sensitivity was 81, 48, 34, and 89 percent, respectively. The MASQ was able to predict minor depression. More women in the vulnerable group scored at increased risk of minor depression on the EPDS at 6 weeks postpartum. CONCLUSION: Further studies are needed to extend this work and develop a screening test with higher specificity and greater positive predictive value.

Adult↗

PubMed1996

Psychiatrists working in primary care: a survey of general practitioners' attitudes.

OBJECTIVES: To collect information on current working arrangements between general practitioners (GPs) and mental health professionals and to assess GPs' attitudes towards developing closer working practices with psychiatrists in the primary care setting. METHOD: Six hundred and three GPs from South Australia were surveyed with questionnaires. Main outcome measures included information about existing primary care links between GPs and mental health professionals, GPs' preferred working arrangements with psychiatrists in the primary care setting and their attitude towards developing these practices, including perceived obstacles, advantages and disadvantages. RESULTS: One hundred and eighty-one completed questionnaires were returned. One in 11 GPs returning the questionnaire (RGPs) had established primary care links with a psychiatrist, 1 in 6 with clinical psychologists and 1 in 17 with psychiatric nurses and social workers. RGPs held positive attitudes towards developing closer links at their work settings with psychiatrists when it le8ads to improved collaboration and access to psychiatrists. Reservations were expressed about the public weakening of the GPs' primary care role. CONCLUSIONS: The joint needs of clinical care and GPs' further training in psychiatry could be addressed by further development of schemes to attract psychiatrists to work in primary care settings. This is mostly viewed very positively by GPs, although the percentage of GPs responding make these conclusions tentative. It is more likely to occur with changes to current funding of both private psychiatric care and GP remuneration, with a recognition of time spent in liaison.

Adult↗

PubMed1995

The sequence of the stem and flanking sequences at the 3' end of histone mRNA are critical determinants for the binding of the stem-loop binding protein.

Complexes of different electrophoretic mobility containing the stem-loop binding protein, a 45 kDa protein, bound to the stem-loop at the 3' end of histone mRNA, are present in both nuclear and cytoplasmic extracts from mammalian cells. We have determined the effect of changes in the loop, in the stem and in the flanking sequences on the affinity of the SLBP for the 3' end of histone mRNA. The sequence of the stem is particularly critical for SLBP binding. Specific sequences both 5' and 3' of the stem-loop are also required for high-affinity binding. Expanding the four base loop by one or two uridines reduced but did not abolish SLBP binding. RNA footprinting experiments show that the flanking sequences on both sides of the stem-loop are critical for efficient binding, but that cleavages in the loop do not abolish binding. Thus all three regions of the RNA sequence contribute to SLBP binding, suggesting that the 26 nt at the 3' end of histone mRNA forms a defined tertiary structure recognized by the SLBP.

Animals↗

PubMed1995

Internalization of Staphylococcus aureus by cultured osteoblasts.

Staphylococcus aureus is the most common cause of both acute and chronic osteomyelitis; however, the pathogenesis of osteomyelitis is poorly understood. We investigated the ability of S. aureus to associate with chick osteoblasts in culture and have demonstrated internalization of bacteria by the osteoblasts. Two strains of S. aureus were examined that were ingested by osteoblasts to different extents, suggesting strain differences in uptake. Initial association of S. aureus strains with osteoblasts was independent of the presence of matrix collagen produced by the osteoblasts. Internalization of bacteria required live osteoblasts, but not live S. aureus, indicating osteoblasts are active in ingesting the organisms. The bacteria were not killed by the osteoblasts, since viable bacteria were cultured several hours after ingestion.

Animals↗

PubMed1995

Methods for assessing splenic macrophage depletion by liposome encapsulated clodronate.

Small unilamellar vesicles containing clodronate (SUVc) injected intravenously will deplete splenic macrophages and the degree of histological depletion can be assessed by determining the clearance and uptake of monoclonal antibody coated erythrocytes. Splenic Fc dependent clearance, assessed in decomplemented animals, provides a more sensitive index of the effects of large multilamellar liposome encapsulated clodronate (MLVc) and SUVc than does the clearance of complement coated erythrocytes on macrophage depletion in the spleen. MLVc were more efficient than SUVc in inducing a reduction in the number of red pulp macrophages within the spleen. Receptor specific red cell uptake in the spleen could be used as an alternative to histology when assessing splenic macrophage depletion. Encapsulation of clodronate is crucial to its depleting effect since the free drug in saline does not change splenic macrophage number or function.

Animals↗

PubMed1995

Clinical experience with the Baerveldt glaucoma drainage implant.

PURPOSE: To assess clinical outcomes in patients who were treated with the Baerveldt glaucoma drainage implant. METHODS: The authors performed a retrospective multicenter study of 100 patients (103 eyes) with medically uncontrollable glaucomas who underwent a one-stage implantation with either the 200-, 250-, 350-, or 500-mm2 Baerveldt implant. The authors defined surgical success as 5 mmHg less than intraocular pressure less than 22 mmHg without additional glaucoma surgery and without loss of light perception. RESULTS: With a mean follow-up of 13.6 +/- 0.9 months (range, 4-37 months), 74 eyes (71.8%) had successful outcomes. Cumulative life-table success rates were 90.3% at 3 months (n = 103), 72.6% at 6 months (n = 84), and 60.3% at 24 months (n = 34). Intraocular pressure (IOP) was reduced from a mean of 38.5 +/- 1.4 mmHg with 2.2 +/- 0.1 antiglaucoma medications to 15.1 +/- 0.8 mmHg (P < 0.0005) with 0.5 +/- 0.1 antiglaucoma medications (P < 0.0005). Visual acuity was improved or remained within one line of the preoperative visual acuity in 90 eyes (87.4%). Complications occurred in 74 eyes (71.8%). A significant portion of these complications (45%) was transient, resolving without any intervention. Only 8% were serious sight-threatening complications. The most common complications included shallow anterior chamber or hypotony (32%), choroidal effusion or hemorrhage (20.4%), corneal decompensation or edema (17.5%), hyphema (14.1%), and tube obstruction (12.6%). CONCLUSION: The Baerveldt implant is effective in lowering the IOP in patients with intractable glaucomas. Hypotony and other complications are common, which also have been reported in other nonvalved glaucoma drainage implants. However, the majority of these complications did not affect surgical outcome.

Adolescent↗

PubMed1995

The effect of liposomally conjugated methotrexate upon mediator release from human peripheral blood monocytes.

The ability of methotrexate (MTX) and a liposomal preparation containing a lipophilic conjugate of methotrexate (MTX-LIPO) to modulate pro-inflammatory mediator release from lipopolysaccharide-stimulated human peripheral blood monocytes was investigated. At non-toxic concentrations MTX-LIPO (10 micrograms MTX per 250 micrograms lipid) was a potent inhibitor of both IL-1 beta and TNF release resulting in 70.07 +/- 2.3% and 59.19 +/- 2.36% (mean +/- S.E.M.) inhibition, respectively, whereas empty liposomes (E-LIPO; 250 micrograms lipid/well) of the same lipid composition and free MTX (up to 100 micrograms/well) had no effect on either mediator.

Cell Survival↗

PubMed1995

Antenatal care in South Wales 1934-1962.

The records of the Special Antenatal Clinics held by the Rhondda Urban District Council between 1934 and 1962 at the Carnegie Welfare Centre in Trealaw, South Wales, were studied. An analysis is presented of structured samples taken from the clinics of one month in each quinquennium from 1934 to 1962. The collected material is then grouped into a period covering the pre-war and wartime years of 1934-1946, and a post-war period from 1950 to 1962. Examination of these sections shows developments in the mid-twentieth century both in the recording of medical histories and in the care of childbirth in this area of Wales.

Female↗

PubMed1995

Identification and gene expression of anaerobically induced enolase in Echinochloa phyllopogon and Echinochloa crus-pavonis.

Enolase (2-phospho-D-glycerate hydrolase, EC 4.2.1.11) has been identified as an anaerobic stress protein in Echinochloa oryzoides based on the homology of its internal amino acid sequence with those of enolases from other organisms, by immunological reactivity, and induction of catalytic activity during anaerobic stress. Enolase activity was induced 5-fold in anoxically treated seedlings of three flood-tolerant species (E. oryzoides, Echinochloa phyllopogon, and rice [Oryza sativa L.]) but not in the flood-intolerant species (Echinochloa crus-pavonis). A 540-bp fragment of the enolase gene was amplified by polymerase chain reaction from cDNAs of E. phyllopogon and maize (Zea mays L.) and used to estimate the number of enolase genes and to study the expression of enolase transcripts in E. phyllopogon, E. crus-pavonis, and maize. Southern blot analysis indicated that only one enolase gene is present in either E. phyllopogon or E. crus-pavonis. Three patterns of enolase gene expression were observed in the three species studied. In E. phyllopogon, enolase induction at both the mRNA and enzyme activity levels was sustained at all times with a further induction after 48 h of anoxia. In contrast, enolase was induced in hypoxically treated maize root tips only at the mRNA level. In E. crus-pavonis, enolase mRNA and enzyme activity were induced during hypoxia, but activity was only transiently elevated. These results suggest that enolase expression in maize and E. crus-pavonis during anoxia are similarly regulated at the transcriptional level but differ in posttranslational regulation, whereas enolase is fully induced in E. phyllopogon during anaerobiosis.

Amino Acid Sequence↗

PubMed1995

Differential effects of methotrexate and liposomally conjugated methotrexate in rat adjuvant-induced arthritis.

In this study we evaluated the comparative efficacy of free and liposomally conjugated methotrexate on both disease induction and suppression of acute inflammation in rat adjuvant-induced arthritis. Rats were given either empty liposomes (E-LIPO), free methotrexate (MTX) or the liposomally conjugated methotrexate (MTX-LIPO) at a dose of 100 micrograms/day for 7 consecutive days by the intravenous route. When MTX treatment was initiated on the day of arthritis induction the drug suppressed but did not abolish the development of joint inflammation. Free MTX had no significant anti-inflammatory effect upon an established arthritis when dosing was commenced on day 11 post-adjuvant induction. Conversely, MTX-LIPO did not affect the progression of the arthritis when dosing was started on day 0, but exerted a significant anti-inflammatory effect on an established arthritis. MTX-LIPO treatment was significantly less haematotoxic than free MTX.

Animals↗

PubMed1995

The effect of free and liposome-encapsulated clodronate on the hepatic mononuclear phagocyte system in the rat.

Clodronate, encapsulated within small unilamellar vesicles (SUVc) will deplete hepatic macrophages after intravenous injection. Functional studies, using probes to evaluate hepatic Fc and C3b uptake, showed a close correlation between the inhibition of receptor-mediated uptake and the depletion of hepatic macrophages. Twenty milligrams of clodronate encapsulated within SUVc produced > or = 90% inhibition of uptake and clearance of Fc- and C3b-coated erythrocytes and a comparable reduction of hepatic macrophage numbers. Inhibition of macrophage receptor-mediated uptake of these erythrocytes was closely related to the reduction in macrophage numbers. Repopulation of macrophages within the liver took place over 2 weeks. At 1 week after depletion, although repopulation was taking place, receptor-mediated function remained suppressed. In a preliminary experiment, treatment of rats with adjuvant arthritis with 20 mg clodronate encapsulated in SUV suppressed the inflammation and reversed the course of the disease, while treatment with 20 mg free clodronate in saline or 20 mg clodronate in multilamellar vesicles (MLVc) did not.

Animals↗

PubMed1995

Evaluation of antenatal and postnatal support to overcome postnatal depression: a randomized, controlled trial.

This randomized, controlled trial tested the hypothesis that women identified as more vulnerable to developing postnatal depression who attended two specific antenatal groups and one postnatal group have a reduced frequency of postnatal depression from 37 to 15 percent at 6 weeks, 12 weeks, and 6 months postpartum. A modified antenatal screening questionnaire was completed, and women identified as more vulnerable to postnatal depression were stratified by parity and randomly allocated to receive extra support groups or to a control group. The Edinburgh Postnatal Depression Scale (EPDS) was used to detect postnatal depression. Attendance at the support groups was low, 31 percent overall. At six weeks, in the intervention group, 8 (13%) of 64 women scored high (> 12) on the EPDS, compared with 11 (17%) controls. Similarly, at 12 weeks 7 (11%) of 63 versus 10 (15%) of 65 women scored higher than 12, and at 6 months, 9 (15%) of 60 versus 6 (10%) of 64 women scored higher than 12, indicating that the intervention did not reduce postnatal depression. It is possible that the method of applying the intervention, using groups separate from the standard antenatal classes, may have affected attendance. More research is required into ways of reaching and supporting women who may become depressed.

Adult↗

PubMed1994

Changes in the stem-loop at the 3' terminus of histone mRNA affects its nucleocytoplasmic transport and cytoplasmic regulation.

The stem-loop structure at the 3' end of replication-dependent histone mRNA is required for efficient pre-mRNA processing, localization of histone mRNA to the polyribosomes, and regulation of histone mRNA degradation. A protein, the stem-loop binding protein (SLBP), binds the 3' end of histone mRNA and is thought to mediate some or all of these processes. A mutant histone mRNA with two nucleotide changes in the loop was constructed and found to be transported inefficiently to the cytoplasm. The mutant histone mRNA, unlike the wild-type histone mRNA, was not rapidly degraded when DNA synthesis is inhibited, and was not stabilized upon inhibition of protein synthesis. The stem-loop binding protein (SLBP) has between a 20-50 fold greater affinity for the wild type histone stem-loop structure than for the mutant stem-loop structure, suggesting that the alteration in the efficiency of transport and the normal degradation pathway in histone mRNA may be due to the reduced affinity of the mutant stem-loop for the SLBP.

Animals↗

PubMed1994

Effect of liposomally encapsulated MTX-DMPE conjugates upon TNF alpha and PGE2 release by lipopolysaccharide stimulated rat peritoneal macrophages.

The ability of liposomally encapsulated preparations of methotrexate (MTX) and three of its lipophilic derivatives (MTX-gamma-DMPE, MTX-alpha-DMPE and MTX-alpha,gamma-diDMPE) to alter mediator release by lipopolysaccharide (LPS)-stimulated rat peritoneal macrophages (PM theta) was investigated. The viability of these macrophages when incubated with approximately 6.0 nmol/10(5) cells of the respective liposomal preparations (MTX-LIPO, MTX-gamma-LIPO, MTX-alpha-LIPO and MTX-di-LIPO) for 20 h was greater than 80%. Treatment of macrophages, which had been incubated with MTX-alpha-LIPO (5.5 nmol/10(5) cells), MTX-gamma-LIPO (6.9 nmol/10(5) cells) and MTX-di-LIPO (4.5 nmol/10(5) cells) for 20 h, with antibody-coated sheep red blood cells resulted in 105 +/- 9.6%, 80.6 +/- 5.6% and 91 +/- 11.4% phagocytosis respectively (mean +/- S.E.M.). At similar concentrations of MTX-alpha-LIPO, MTX-gamma-LIPO and MTX-di-LIPO (6.5 nmol/10(5) cells), PGE2 release from LPS-stimulated rat peritoneal macrophages was inhibited by 85.3 +/- 3.7%, 68.7 +/- 0.6% and 88.8 +/- 2.2%, respectively (mean +/- S.E.M., n = 4). Incubation of these macrophages with 12, 10 and 9.4 nmol/10(5) cells of the respective liposomal preparations resulted in 89 +/- 3.3%, 62 +/- 5.5% and 85 +/- 3.9% inhibition of TNF alpha release (mean +/- S.E.M., n = 4). However, at this concentration MTX-di-LIPO was toxic. Neither MTX (20-2.5 nmol/10(5) cells) nor MTX-LIPO (5.6 nmol/10(5) cells) affected TNF alpha release from LPS-stimulated macrophages. Whilst free MTX was also ineffective at inhibiting PGE2 from these cells, incubation with MTX-LIPO at the above concentration resulted in 76.9 +/- 2.6% inhibition of the prostaglandins release.

Adenosine Triphosphate↗

PubMed1994

Prostaglandin and tumor necrosis factor secretion by peritoneal macrophages isolated from normal and arthritic rats treated with liposomal methotrexate.

The effect of a novel liposomal preparation containing a phospholipid conjugate of methotrexate (MTX-LIPO) upon macrophage mediator release was investigated in normal and arthritic rats ex vivo. Peritoneal macrophages isolated from MTX-LIPO-treated arthritic rats and stimulated with lipopolysaccharide produced significantly less tumor necrosis factor (TNF) and prostaglandin (PGE2) than did macrophages isolated from saline-treated controls. In the same experimental system, free methotrexate only inhibited prostaglandin release, but it was more potent than MTX-LIPO in this respect. Additional studies are presently underway to investigate the effect of MTX-LIPO and MTX treatment upon the lipopolysaccharide-induced rise in plasma levels of various proinflammatory mediators in vivo. Haematopoietic toxicity was demonstrated in blood isolated from rats treated with free MTX, and this was as characterized by a significant reduction in reticulocyte count compared with MTX-LIPO and saline-treated rats.

Animals↗

PubMed1994

Suppression of adjuvant-induced arthritis by liposomally conjugated methotrexate in the rat.

A phospholipid conjugate of methotrexate was synthesized and liposomally formulated in order to determine whether such a formulation could modulate the severity of experimentally induced arthritis in the rat. Lewis rats were immunized with Mycobacterium butyricum and after the onset of joint inflammation were treated intravenously with methotrexate liposomes (MTX-LIPO). This preparation was significantly better in reducing established joint inflammation than comparable doses of the free drug or empty liposomes of identical lipid composition. Haematopoietic toxicity associated with MTX-LIPO was significantly less than seen with comparable doses of the free drug.

Animals↗

PubMed1994

Effect of three lipophilic methotrexate derivatives upon mediator release by lipopolysaccharide-stimulated rat peritoneal macrophages.

The ability of methotrexate and three lipophilic derivatives (methotrexate-gamma-dimyristoylphosphatidylethanolamine (M gamma D), methotrexate-alpha-dimyristoylphosphatidylethanolamine (M alpha D) and methotrexate-alpha-gamma-di-dimyristoylphosphatidylethanolamine (M alpha gamma D) to modulate mediator release by lipopolysaccharide-stimulated rat peritoneal macrophages was investigated. At nontoxic concentrations, approximately 10 nmol/10(5) cells, M alpha D and M gamma D produced 11.06 +/- 1.0 and 75.6 +/- 5.2%, respectively, inhibition of tumour necrosis factor (TNF) release (mean +/- s.e.m., n = 4). At this same dose M alpha gamma D resulted in 68.8 +/- 2.1% inhibition of TNF but cellular ATP levels were reduced by 80%. The inhibitory activity of all three derivatives was dose-dependent. Non-derivatized methotrexate at a concentration of 25 nmol/10(5) cells had no inhibitory effect upon TNF release (14.7 +/- 0.8%, n = 3). Determination of prostaglandin E2 (PGE2) levels in the same samples demonstrated that all three conjugates were powerful inhibitors of prostaglandin release. At a quarter of the conjugate concentrations described above the monoamides M alpha (3.1 nmol/10(5) cells) and M gamma D (2.5 nmol/10(5) cells) maintained their effects on PGE2 production with 73 +/- 2.3 and 71 +/- 2.0% (n = 4) inhibition, respectively. At this lower concentration, however, the diamide M alpha gamma D (3.1 nmol/10(5) cells) was less effective in reducing the amount of PGE2 released from the macrophages (29 +/- 18%, n = 4). Maximal PGE2 inhibition by each of the conjugates was attained at approximately 5 nmol/10(5) cells. Unconjugated methotrexate (range of 2.5-20 nmol/10(5) cells) did not inhibit the release of PGE2 from lipopolysaccharide-stimulated macrophages.

Animals↗