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Biomedical subjects

R Coombs

Publications and source records attributed to R Coombs.

At least 19 recordsLinked to original sources
PubMed2001

Treatment of primary human immunodeficiency virus type 1 infection with potent antiretroviral therapy reduces frequency of rapid progression to AIDS.

Immunologic data supporting immediate antiretroviral therapy in primary human immunodeficiency virus type 1 (HIV-1) infection are emerging; however, clinical benefit has not been demonstrated. The clinical and virologic course of 47 patients who were enrolled from September 1993 through June 1996 and who were not initially treated with potent therapy was compared with the course of 20 patients who immediately began therapy with zidovudine, lamivudine, and indinavir. Demographic and baseline laboratory data were comparable. During 78 weeks of follow-up, the early-treatment cohort showed a reduced frequency of opportunistic infections (5% vs. 21.3%; relative risk, 0.11; P=.02), less frequent progression to AIDS (13% vs. 0%), and significantly less frequent nonopportunistic mucocutaneous disorders and respiratory infections (P<.01). Plasma HIV-1 RNA levels were <50 copies/mL in all patients who continued therapy; however, after 9--12 months, HIV-1 remained detectable in latently infected CD4(+) T cells and in lymph node mononuclear cells. Combination antiretroviral therapy during primary HIV-1 infection demonstrated a decreased frequency of minor opportunistic infections, mucocutaneous disorders, and respiratory infections and reduced progression to AIDS.

AIDS-Related Opportunistic Infections↗
PubMed1999

Upper extremity kinematics and body roll during preferred-side breathing and breath-holding front crawl swimming.

Front crawl swimmers often restrict the number of breaths they take during a race because of the possible adverse effects of the breathing action on resistance or stroke mechanics. The aim of this study was to determine whether differences exist in the kinematics of the trunk and upper extremity used during preferred-side breathing and breath-holding front crawl swimming. Six male swimmers performed trials at their 200 m race pace under breathing and breath-holding conditions. The underwater arm stroke was filmed from the front and side using video cameras suspended over periscope systems. Video recordings were digitized at 50 Hz and the three-dimensional coordinates of the upper extremity obtained using a direct linear transformation algorithm. Body roll angles were obtained by digitizing video recordings of a balsa wood fin attached to the swimmers' backs. The swimmers performed the breathing action without any decrement in stroke length (mean +/- s: breathing 2.24 +/- 0.27 m; breath-holding 2.15 +/- 0.22 m). Stroke widths were similar in the breathing (0.28 +/- 0.07 m) and breath-holding (0.27 +/- 0.07 m) trials, despite swimmers rolling further when taking a breath (66 +/- 5 degrees) than when not (57 +/- 4 degrees). The timing of the four underwater phases of the stroke was also unaffected by the breathing action, with swimmers rolling back towards the neutral position during the insweep phase. In conclusion, the results suggest that front crawl swimmers can perform the breathing action without it interfering with their basic stroke parameters. The insweep phase of the stroke assists body roll and not vice versa as suggested in previous studies.

Adult↗
PubMed1999

Suppression of intimal hyperplasia with low molecular weight heparin in a sheep model.

BACKGROUND: Both unfractionated heparin (UH) and low molecular weight heparin (LMWH) in therapeutic anticoagulant doses have been shown to inhibit the development of intimal hyperplasia (IH) but with an increased risk of haemorrhage. In this study we investigated the effect of a "low dose" and "high dose" of UH and LMWH on the inhibition of IH together with their effect on plasma anti-Xa activity (AXa) and activated partial thromboplastin time (APTT) using a carotid artery sheep model. METHODS: A gelatin sealed Dacron patch graft was implanted into the common carotid artery of sheep which were randomly allocated to a control group (Group 1, n=10) or to one of four treatment groups receiving either low-dose LMWH enoxaparin 1 mg/kg/day (group 2, n=11), high-dose LMWH enoxaparin 2 mg/kg/day (Group 3, n=13), low-dose UH 125 u/kg/day (Group 4, n=10) or high-dose UH 250 u/kg/day (Group 5, n=10). The LMWH was administered subcutaneously once daily for four weeks and the UH in two divided doses per day for four weeks. During the treatment period, AXa and APTT were assayed from blood collected prior to and at 1 and 2 h after heparin administration on day 3, 7, 14, 21 and 28. On day 28, all animals were sacrificed and grafts were collected for analysis after taking blood samples prior to, then at 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 h following the last injection. Measurements of intimal thickness were obtained under light microscopy from eight transverse sections of each grafted artery using an eyepiece graticule. RESULTS: IH measurements (Mean+/-SD) were: Group 1 (controls) 288+/-86 microm, Group 2 (low-dose LMWH) 222+/-50 mm (p<0.05 compared to Group 1), Group 3 (high-dose LMWH) 203+/-78 microm (p<0.01), Group 4 (low-dose UH) 275+/-61 microm, and Group 5 (high-dose UH) 206+/-71 microm (p<0.01). There was no significant difference between Groups 2, 3 and 5. Groups 2, 3 and 5 demonstrated significant AXa during the 28 days period of which Groups 2 and 5 showed a significant increase in AXa levels with time. In the 24 h study after the last dose of treatment both Groups 2 and 3 showed longer AXa than group 5 (12-24 h vs 8 h). When compared to the control group, significant elevation of APTT was demonstrated in Groups 3 and 5. Group 5 had significantly longer APTT than Group 3. In the 24 h study, APTT reflected the changes of AXa in all groups. CONCLUSIONS: In this study the LMWH enoxaparin was effective in reducing the formation of IH both at a standard anticoagulant therapeutic dose of 2 mg/kg/day and also at a lower dose of 1 mg/kg/day.

Animals↗
PubMed1997

The MDA-180 coagulation analyser: a laboratory evaluation.

We have evaluated the technical performance of the MDA-180 automated coagulation analyser in a working diagnostic hemostasis laboratory environment. The analyser has been on site now for over 18 months, and has undergone considerable testing. More than 22,000 samples have been processed, with over 90% of these via the MDA-180's cap-piercing facility. The instrument has been primarily assessed for its technical ease of use and continued reliability, as well as its analytical performance. The instrument has also been successfully interfaced to, and used with, our Laboratory information (CERNER PATHNET) system. A major feature of our evaluation has been an assessment of the MDA-180's ability to perform assays currently performed using alternative methodology or instrumentation (eg; ELISA methodology or the Coagamate-X2 and ACL-300R instruments), as well as its potential to streamline the technical performance of some of these assays. We have co-evaluated the following assays: PT/INR, APTT, TT, Fibrinogen, Protein C, ATIII, Factors II, V, VII, VIII, IX, X, XI, and XII, Lupus anticoagulant (dRVVT), and heparin (alpha Xa). In addition, a number of different reagents (particularly for PT and APTT assays) have been tested on the instrument. Intra-assay and inter-assay variation appears to be remarkably low (five different plasmas tested: PT: 0.6 to 1.3% and 0.5 to 1.3% respectively; APTT: 0.7 to 3.2% and 0.6 to 3.6% respectively; single day analysis). Other comparative assessment data typically showed good correlation to existing test assay systems. A review of other features which may enhance or detract from the instrument's worth in a given hemostasis laboratory is also presented. In summary however, we conclude that the instrument is reliable, easy to use and capable of fast sample through-put.

Blood Coagulation Factors↗
PubMed1997

Perspective: validating surrogate markers--are we being naive?

Because of the difficulties in conducting studies of clinical efficacy of new therapies for human immunodeficiency virus infection and other diseases, there is increasing interest in using measures of biologic activity as surrogates for clinical end points. A widely used criterion for evaluating whether such measures are reliable as surrogates requires that the putative surrogate fully captures the "net effect"-the effect aggregated over all mechanisms of action-of the treatment on the clinical end point. The variety of proposed metrics for evaluating the degree to which this criterion is met are subject to misinterpretation because of the multiplicity of mechanisms by which drugs operate. Without detailed understanding of these mechanisms, metrics of "surrogacy" are not directly interpretable. Even when all of the mechanisms are understood, these metrics are associated with a high degree of uncertainty unless either treatment effects are large in moderate-size studies or sample sizes are large in studies of moderately effective treatments.

Biomarkers↗
PubMed1997

Exposure-response relationships for saquinavir, zidovudine, and zalcitabine in combination therapy.

The relationship of CD4+ cell response, level of RNA in plasma, and quantitative peripheral blood mononuclear cell (PBMC) titer to apparent drug exposure was investigated by using data from AIDS Clinical Trial Group protocol 229, a multicenter randomized study. Patients received either saquinavir, zalcitabine, or a combination of both, along with open-label zidovudine. Approximately 100 patients were enrolled in each arm, and the primary study duration was 24 weeks. Individual drug exposure, the area under the concentration-time curve, was estimated by using population-based pharmacokinetic methods. Response was defined as the maximum increase in CD4+ cell count or the maximum decrease in RNA in plasma or PBMC titer adjusted for baseline CD4+ cell count, RNA in plasma, and PBMC titer, respectively. Regression of responses on exposure demonstrated an exposure effect for saquinavir which was significant for the maximum increase in CD4+ cell count and the decrease in RNA in plasma. For the PBMC titer, no significant relationship could be demonstrated but the results suggested a trend similar to that of the other response variables. For all three response variables, the slope of the saquinavir exposure response was greater with the triple combination (saquinavir, zidovudine, and zalcitabine) than with the combination of saquinavir and zidovudine, suggesting possible synergism between saquinavir and zalcitabine.

Adult↗
PubMed1997

Congenital renal tubular dysplasia and skull ossification defects similar to teratogenic effects of angiotensin converting enzyme (ACE) inhibitors.

An apparently autosomal recessive syndrome of congenital renal tubular dysplasia and skull ossification defects is described in five infants from two separate, consanguineous, Pakistani Muslim kindreds. The clinical, pathological, and radiological features are similar to the phenotype associated with fetal exposure to angiotensin converting enzyme (ACE) inhibitors: intrauterine growth retardation, skull ossification defects, and fetal/ neonatal anuric renal failure associated with renal tubular dysplasia. There was no fetal exposure to ACE inhibitors in the affected infants. Phenotypic similarities between these familial cases and those associated with ACE inhibition suggest an abnormality of the "renin-angiotensin-aldosterone" system (RAS). It is postulated that the molecular pathology in this uncommon autosomal recessive proximal renal tubular dysgenesis could be related to mutations of the gene systems governing the RAS.

Abnormalities, Drug-Induced↗
PubMed1996

HIV viral load markers in clinical practice.

Plasma HIV RNA determinations are an important prognostic marker of disease progression and, when used appropriately, provide a valuable tool for the management of individual patients. But what constitutes appropriate use?

Antiviral Agents↗
PubMed1996

Evaluation of a quality assurance program for quantitation of human immunodeficiency virus type 1 RNA in plasma by the AIDS Clinical Trials Group virology laboratories.

A number of quantitative assays have been developed by using amplification techniques to measure human immunodeficiency virus type 1 RNA in the plasma of infected individuals. The Virology Committee of the AIDS Clinical Trials Group in the Division of AIDS, National Institute of Allergy and Infectious Diseases, has established a quality assurance program (QAP) for quantitative assays of HIV-1 RNA levels in plasma. The primary objective of the QAP was to ascertain that a laboratory could maintain the precision required to have a 90% power to detect a fivefold difference in RNA copy number between two samples in the same batch. To achieve this goal, the QAP required an intra-assay standard deviation of no greater than 0.15 log10 RNA copies per ml. Panels for proficiency testing consisted of coded replicate samples and a common set of standards. To date, 41 laboratories have participated in the program and have used both commercial and in-house assays. We demonstrated that 65% of the laboratories were capable of attaining the necessary level of intra-assay precision. The fitted regressions indicated that the differences among laboratories that used the same kit were generally greater than the differences among population-average regressions for the kits themselves. The use of an external QAP and a common set of standards reduced differences both among laboratories that used the same kit and among laboratories that used different kits. Thus, use of a common set of standards across clinical trial protocols would allow for cross-protocol comparisons.

Clinical Protocols↗
PubMed1996

Splenic macrophages in preterm infants: a necropsy study.

AIMS: To study the frequency and nature of histiocytes in the splenic red pulp of infants who died following complicated immaturity/prematurity. METHODS: Twenty four preterm/immature infants were investigated. Frozen sections of formalin fixed splenic tissue were stained with Oil Red O. Paraffin wax sections from the same tissue were conventionally stained with haematoxylin and eosin. Immunohistochemistry was carried out for a number of macrophage markers. The administration of Intralipid was compared with the presence and extent of tissue macrophages. RESULTS: The spleens of 10 infants showed varying degrees of Oil Red O positivity ranging from mild to strong. In all these cases varying numbers of macrophages were confirmed in the splenic parenchyma in ordinary sections. The immunomarkers indicated that the histiocytes belonged to the macrophage phagocytic system. Of the 10 cases with splenic macrophages all had received Intralipid. Of those not receiving Intralipid none showed splenic macrophages. Seven had received Intralipid but did not have splenic macrophages; they had either only received small amounts of Intralipid or Intralipid was discontinued before death. CONCLUSIONS: Splenic macrophages are common at necropsy in immature/preterm infants. The macrophages are most lucidly demonstrated using Oil Red O staining in frozen sections. There is a strong association between the presence of splenic macrophages and Intralipid administration.

Azo Compounds↗
PubMed1995

Phase I study of high-dose, intravenous rsCD4 in subjects with advanced HIV-1 infection.

In vitro, recombinant soluble CD4 (rsCD4) attaches to and inactivates human immunodeficiency virus (HIV). To determine if prolonged therapy with high-dose intravenous rsCD4 provides an in vivo benefit, we gave three HIV-1-infected patients with AIDS, whose isolates were susceptible in vitro to rsCD4, 10 mg/kg of rsCD4 for 4 weeks, 5 mg/kg for 4 weeks, and 1 mg/kg for 2 weeks. Single-dose pharmacokinetic studies performed prior to this showed transient in vivo decreases of HIV-1 plasma viremia in all three subjects. Surrogate markers of HIV activity, clinical status, HIV-1 p24 antigen, plasma HIV-1 titers, and peripheral blood mononuclear cell (PBMC) intracellular titers of virus were measured at entry, and every other week after onset of therapy. All subjects demonstrated rsCD4 concentration-dependent reduction in plasma viremia, with two subjects having complete neutralization of cell-free virus. The third subject's isolate was relatively resistant to the in vivo effects of rsCD4 and only partial reduction in plasma virus titers was obtained, even at the highest dose of 10 mg/kg. There was no change in the PBMC intracellular viral titer or surrogate markers of HIV-1 activity (including CD4 cell count and beta 2-microglobulin). There was subjective improvement in clinical symptoms, and all subjects gained weight with the highest doses of rsCD4. rsCD4 exhibited linear pharmacokinetics over the dose range studied. We conclude that high-dose intravenous rsCD4 can be safely given for up to 10 weeks and that it has a stable pharmacokinetic profile.(ABSTRACT TRUNCATED AT 250 WORDS)

Acquired Immunodeficiency Syndrome↗
PubMed1995

Filtered plasma as a potential cause of clinical misdiagnosis: inappropriate testing in a haematology laboratory.

We have identified situations in which filtered plasma is provided to the laboratory for combined assessment of lupus anticoagulant, as well as other diagnostic haemostasis laboratory procedures. On the basis of laboratory investigation, however, we report that significant errors in test result interpretation can arise should this occur and depending on the specimen processing procedure, and whether filtered plasma is used for multiple assays. Citrated plasma samples were obtained from 12 normal individuals and a portion of each sample filtered using a standard 0.22 micron filter. Small volumes were frozen for later analysis. We could detect a statistically significant difference (P < 0.01) between filtered plasma and non-filtered plasma in most test results. Most notable were changes in the APTT, fibrinogen, FVIII and vWF, where results often fell outside the normal reference range of the assay. Such assay results closely mimic those obtained with type 2 von Willebrand's disease (vWD) patients, thus should filtered plasma unknowingly be tested for vWF, a wrong conclusion of type 2 vWD could easily arise. Assay results for other parameters may similarly draw incorrect conclusions, such as mild haemophilia A and dysfibrinogenaemia. In summary, we report that following filtration not only are a variety of coagulation test results altered, but reduced plasma levels of some coagulation factors could potentially lead clinicians incorrectly to diagnose congenital or acquired deficiencies or defects. We recommend that laboratories note that (other than for lupus anticoagulant) filtered plasma is not appropriate for the coagulation laboratory, and that any abnormal haemostasis test result following such combined testing be considered a potential artifact and independently repeated to confirm any putative abnormality prior to drawing any clinical conclusions.

Blood Coagulation Disorders↗
PubMed1994

Combination therapy with zidovudine and didanosine selects for drug-resistant human immunodeficiency virus type 1 strains with unique patterns of pol gene mutations.

Drug resistance conferred by specific human immunodeficiency virus type 1 (HIV-1) pol gene mutations has been associated with clinical progression in HIV-infected patients receiving anti-retroviral therapy. This study examined drug susceptibilities and pol mutations of HIV-1 strains from patients treated for 1 year with zidovudine, didanosine (ddI), or zidovudine and ddI. Ten (42%) of 24 patients receiving combination therapy versus 8/26 (31%) receiving only zidovudine had HIV-1 strains with phenotypic zidovudine resistance or a zidovudine resistance pol mutation at codon 215 (P = .6). In contrast, a ddI resistance mutation at codon 74 was less common among patients receiving combination therapy (2/24) than among those receiving ddI only (17/26; P < .001). Two patients receiving combination therapy developed resistance to zidovudine and ddI; they had HIV strains with amino acid mutations at codons 62, 75, 77, 116, and 151. Combination therapy with zidovudine and ddI selects for zidovudine-resistant HIV-1 strains lacking a ddI resistance mutation and for multidrug-resistant strains containing novel pol mutations.

Amino Acids↗
PubMed1994

The safety and efficacy of combination N-butyl-deoxynojirimycin (SC-48334) and zidovudine in patients with HIV-1 infection and 200-500 CD4 cells/mm3.

We conducted a double-blind, randomized phase II study to evaluate the safety and activity of combination therapy with N-butyl-deoxynojirimycin (SC-48334) (an alpha-glucosidase I inhibitor) and zidovudine versus zidovudine alone. Patients with 200 to 500 CD4 cells/mm3 who tolerated < or = 12 weeks of prior zidovudine therapy received SC-48334 (1000 mg every 8 h) and zidovudine (100 mg every 8 h) or zidovudine and placebo. Sixty patients received combination therapy and 58, zidovudine and placebo. Twenty-three patients (38%) and 15 (26%), in the combination and zidovudine groups, respectively, discontinued therapy (p = 0.15). The mean SC-48334 steady-state trough level (4.04 +/- 0.99 micrograms/ml) was below the in vitro inhibitory concentration for human immunodeficiency virus (HIV). The mean increase in CD4 cells at week 4 was 73.8 cells/mm3 and 52.4 cells/mm3 for the combination and zidovudine groups, respectively (p > 0.36). For patients with prior zidovudine therapy, the mean change in CD4 cells in the combination and zidovudine groups was 63.7 cells/mm3 and 4.9 cells/mm3 at week 8 and 6.8 cells/mm3 and -45.1 cells/mm3 at week 16, respectively. The number of patients with suppression of HIV p24 antigenemia in the combination and zidovudine groups was six (40%) and two (11%) at week 4 (p = 0.10) and five (45%) and two (14%) at week 24 (p = 0.08), respectively. Diarrhea, flatulence, abdominal pain, and weight loss were common for combination recipients.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Deoxynojirimycin↗