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Biomedical subjects

S Little

Publications and source records attributed to S Little.

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

Evaluation of stereotactic core needle biopsy (SCNB) of the breast at a single institution.

Stereotactic core needle biopsy (SCNB) has become a popular method for diagnosis of occult breast abnormalities. There are few large series of SCNB from a single institution. Data on patients undergoing SCNB for mammographic abnormalities were collected prospectively over 43 months at a university hospital. Mammographic findings were categorized as benign, probably benign, indeterminate, suspicious or malignant. For lesions with SCNB pathology that were non-diagnostic, showed atypical hyperplasia or malignancy (in situ or invasive), or were discordant with the pre-biopsy mammogram findings, surgical excision was recommended. Subsequent surgical pathology was reviewed. All remaining lesions were followed mammographically after SCNB. SCNB was performed on 692 lesions in 607 patients. There were 79 malignancies, for a positive SCNB rate of 11.4%. The 349 SCNB performed for benign, probably benign and indeterminate lesions on mammography had a positive SCNB rate of only 4%. Surgery was recommended for 127 (18.3%) lesions, while 565 (81.6%) were followed mammographically after SCNB. A compliance rate of 61 % for at least one follow-up mammogram was obtained, with a median follow-up of 17.2 months and with no cancers found. The sensitivity for malignancy with SCNB was 93%. SCNB provides a minimally invasive method to assess mammographic abnormalities. Abnormalities considered radiographically to be other than malignant or suspicious yielded few cancers. In this series a low positive SCNB rate resulted in no false negatives on mammographic follow-up. The optimal positive biopsy rate for SCNB is debatable.

Biopsy, Needle↗
PubMed2000

Rapid accumulation of human immunodeficiency virus (HIV) in lymphatic tissue reservoirs during acute and early HIV infection: implications for timing of antiretroviral therapy.

The follicular dendritic cell network (FDC) in lymphoid tissues (LTs) is the major site of human immunodeficiency virus (HIV) storage in presymptomatic and late stages of disease. However, little is known about the rate of virus accumulation during the acute and early stages. In situ hybridization and quantitative image analysis were used to determine the amount of virus bound to the FDC network during the first year of infection. The FDC pool was already >7.0 log10 copies of HIV RNA/g LT in the first year, and 2 patients biopsied within 2-4 days of symptom onset had 7.3 and 8.2 log10 copies of HIV RNA/g LT, respectively. There was no correlation between duration of infection and accumulation of HIV into the FDC network. These data suggest that a large pool of infectious virus is established soon after infection and that initiation of antiretroviral therapy when symptoms of primary HIV infection are recognized is unlikely to prevent substantial accumulation of virus in the FDC network.

Acute Disease↗
PubMed2000

Transcription factor nuclear factor-kappa B is activated in neurons after focal cerebral ischemia.

Nuclear factor-kappa B (NF-kappaB) is a multisubunit transcription factor that when activated induces the expression of genes encoding acute-phase proteins, cell adhesion molecules, cell surface receptors, and cytokines. NF-kappaB is composed of a variety of protein subunits of which p50-and p65-kDa (RelA) are the most widely studied. Under resting conditions, these subunits reside in the cytoplasm as an inactive complex bound by inhibitor proteins, IkappaB alpha and IkappaB beta. On activation, IkappaB is phosphorylated by IkappaB kinase and ubiquitinated and degraded by the proteasome; simultaneously, the active heterodimer translocates to the nucleus where it can initiate gene transcription. In the periphery, NF-kappaB is involved in inflammation through stimulation of the production of inflammatory mediators. The role of NF-kappaB in the brain is unclear. In vitro, NF-kappaB activation can be either protective or deleterious. The role of NF-kappaB in ischemic neuronal cell death in vivo was investigated. Adult male rats were subjected to 2 hours of focal ischemia induced by middle cerebral artery occlusion (MCAO). At 2, 6, and 12 hours after reperfusion, the expression and transactivation of NF-kappaB in ischemic versus nonischemic cortex and striatum were determined by immunocytochemistry and by electrophoretic mobility gel-shift analysis. At all time points studied, p50 and p65 immunoreactivity was found exclusively in the nuclei of cortical and striatal neurons in the ischemic hemisphere. The contralateral nonischemic hemisphere showed no evidence of nuclear NF-kappaB immunoreactivity. Double immunofluorescence confirmed expression of p50 in nuclei of neurons. Increased NF-kappaB DNA-binding activity in nuclear extracts prepared from the ischemic hemisphere was further substantiated by electrophoretic mobility gel-shift analysis. Because the activation of NF-kappaB by many stimuli can be blocked by antioxidants in vitro, the effect of the antioxidant, LY341122, previously shown to be neuroprotective, on NF-kappaB activation in the MCAO model was evaluated. No significant activation of NF-kappaB was found by electrophoretic mobility gel-shift analysis in animals treated with LY341122. These results demonstrate that transient focal cerebral ischemia results in activation of NF-kappaB in neurons and supports previous observations that neuroprotective antioxidants may inhibit neuronal death by preventing the activation of NF-kappaB.

Animals↗
PubMed2000

Attempted transmission of Ehrlichia chaffeensis among white-tailed deer by Amblyomma maculatum.

A deer was needle-exposed intravenously to Ehrlichia chaffeensis (Rickettsiales: Ehrlichieae) in canine macrophage (DH82) cells and 7 days later was infested with laboratory-reared Amblyomma maculatum (Koch) (Acari:Ixodidae) nymphs for acquisition feeding. After molting, the adult ticks were allowed to feed on a naive deer. The organism was reisolated from the needle-exposed deer by cell culture and E. chaffeensis DNA was detected in the deer's blood by PCR. Similar isolation/recovery techniques were used for the tick-exposed deer and no evidence of infection was found. Although these findings must be considered as preliminary owing to inadequate controls, the data suggest that A. maculatum is probably not a suitable vector for E. chaffeensis.

Animals↗
PubMed2000

Comparison of the pharmacokinetic profiles of soluble aspirin and solid paracetamol tablets in fed and fasted volunteers.

The aim of this study was to investigate the absorption of popular preparations of two common analgesics--soluble aspirin and solid paracetamol tablets. An open, randomised, crossover study design was used to compare the pharmacokinetic parameters of soluble aspirin and solid paracetamol tablets in 16 healthy, male volunteers from the University of the Witwatersrand, South Africa, in both fed and fasted states. Plasma concentrations of paracetamol, aspirin and salicylic acid were measured. It was found that the rate of absorption was significantly faster for soluble aspirin than for solid paracetamol, regardless of fed or fasting state, considering time to maximum concentration (p < 0.01), time to first quantifiable concentrations (p < 0.05) and absorption rate (p < 0.01). Absorption rate was significantly affected by food for both soluble aspirin (p = 0.028) and for solid paracetamol (p = 0.0003). Time to maximum concentration was not significantly affected by food for soluble aspirin (p = 0.17) but significantly lengthened for solid paracetamol (p = 0.0003). The extent of absorption was affected by food in terms of maximum concentration for both drugs (p = 0.0001), with a reduction of 49% in the fed state for solid paracetamol compared to 18% for soluble aspirin, the difference between the drugs being statistically significant (p = 0.0024). The overall bioavailability of soluble aspirin was unaffected by food and the bioavailability of salicylic acid was increased in the fed state, whereas that of solid paracetamol was lowered in the fed state. Greater inter-individual variation was seen in paracetamol concentrations compared with aspirin or salicylic acid levels. In conclusion, these results show that the absorption of soluble aspirin is largely unaffected by food, whereas, in the same volunteers, the absorption of solid paracetamol tablets is greatly affected. In some volunteers, maximum plasma concentrations of paracetamol following food did not reach levels previously reported to be required for effective analgesia, and this may have implications for pain relief in some individuals. The practice in some individuals of taking aspirin tablets after food to minimise potential gastric disturbance should not affect the level of analgesia.

Acetaminophen↗
PubMed1999

Sexual transmission and propagation of SIV and HIV in resting and activated CD4+ T cells.

In sexual transmission of simian immunodeficiency virus, and early and later stages of human immunodeficiency virus-type 1 (HIV-1) infection, both viruses were found to replicate predominantly in CD4(+) T cells at the portal of entry and in lymphoid tissues. Infection was propagated not only in activated and proliferating T cells but also, surprisingly, in resting T cells. The infected proliferating cells correspond to the short-lived population that produces the bulk of HIV-1. Most of the HIV-1-infected resting T cells persisted after antiretroviral therapy. Latently and chronically infected cells that may be derived from this population pose challenges to eradicating infection and developing an effective vaccine.

Animals↗
PubMed1999

Reversibility of the pathological changes in the follicular dendritic cell network with treatment of HIV-1 infection.

Over the course of HIV-1 infection, the lymphoid follicles where the humoral immune response is generated initially increase in size and number and then progressively involute. In advanced disease, the network of the processes of follicular dendritic cells (FDCs) that serve as antigen repositories and anatomical substrate for B and T cells and antigen to interact is destroyed, contributing to the breakdown of the immune system. Because destruction of FDCs is associated with deposition of HIV-1, and much of the virus can be cleared from the network with antiretroviral therapy, we investigated the reversibility of damage. We measured the immunohistochemically stainable FDC compartment by quantitative image analysis, and we documented changes in this compartment at different stages of disease. We show that treatment, initiated even at advanced stages of HIV-1 disease, can slowly reverse pathological changes in the FDC network.

Anti-HIV Agents↗
PubMed1999

Cytosolic phospholipase A2 is induced in reactive glia following different forms of neurodegeneration.

Many recent studies have emphasized the deleterious role of inflammation in CNS injury. Increases in free fatty acids, eicosanoids, and products of lipid peroxidation are known to occur in various conditions of acute and chronic CNS injury, including cerebral ischemia, traumatic brain injury, and Alzheimer's disease. Although an inflammatory response can be induced by many different means, phospholipases, such as cytosolic phospholipase A(2) (cPLA(2)), may play an important role in the production of inflammatory mediators and in the production of other potential second messengers. cPLA(2) hydrolyzes membrane phospholipids and its activity liberates free fatty acids leading directly to the production of eicosanoids. We investigated the cellular localization of cytosolic phospholipase A(2) in the CNS following: (1) focal and global cerebral ischemia, (2) facial nerve axotomy, (3) human cases of Alzheimer's disease, (4) transgenic mice overexpressing mutant superoxide dismutase, a mouse model of amyotrophic lateral sclerosis, and (5) transgenic mice overexpressing mutant amyloid precursor protein, which exhibits age-related amyloid deposition characteristic of Alzheimer's disease. We show that in every condition evaluated, cytosolic phospholipase A(2) is present in reactive glial cells within the precise region of neuron loss. In conditions where neurons did not degenerate or are protected from death, cytosolic phospholipase A(2) is not observed. Both astrocytes and microglial cells are immunoreactive for cytosolic phospholipase A(2) following injury, with astrocytes being the most consistent cell type expressing cytosolic phospholipase A(2). The presence of cytosolic phospholipase A(2) does not merely overlap with reactive astroglia, as reactive astrocytes were observed that did not exhibit cytosolic phospholipase A(2) immunoreactivity. In most conditions evaluated, inflammatory processes have been postulated to play a pivotal role and may even participate in neuronal cell death. These results suggest that cytosolic phospholipase A(2) may prove an attractive therapeutic target for neurodegeneration.

Alzheimer Disease↗
PubMed1999

Detection of PCR products using self-probing amplicons and fluorescence.

Molecular diagnostics is progressing from low-throughput, heterogeneous, mostly manual technologies to higher throughput, closed-tube, and automated methods. Fluorescence is the favored signaling technology for such assays, and a number of techniques rely on energy transfer between a fluorophore and a proximal quencher molecule. In these methods, dual-labeled probes hybridize to an amplicon and changes in the quenching of the fluorophore are detected. We describe a new technology that is simple to use, gives highly specific information, and avoids the major difficulties of the alternative methods. It uses a primer with an integral tail that is used to probe an extension product of the primer. The probing of a target sequence is thereby converted into a unimolecular event, which has substantial benefits in terms of kinetics, thermodynamics, assay design, and probe reliability.

BRCA2 Protein↗
PubMed1999

In vitro correlate of immunity in an animal model of inhalational anthrax

The incidence of anthrax in humans is extremely low. Human vaccine efficacy studies for inhalational anthrax cannot be conducted. The identification of a correlate of protection that predicts vaccine efficacy is crucial for determining the immune status of immunized humans. This surrogate marker of immunity can only be established by using an appropriate animal model. Numerous studies showed that protective antigen (PA) is the principle protective antigen in naturally- or vaccine-induced immunity. However, attempts to correlate the quantity of anti-PA antibodies with protective immunity in the guinea pig model for anthrax and various vaccine formulations have failed. In these studies, we used the licensed anthrax vaccine adsorbed (AVA) in rabbits. Groups of New Zealand white rabbits, 10 or 20 per group, were immunized intramuscularly (two doses, 4 weeks apart) with varying doses of AVA, ranging from a human dose to 1:256 dilution in sterile phosphate-buffered saline (PBS). Control rabbits received PBS/Alhydrogel according to the same schedule. Each rabbit was bled 2 weeks after the second dose, and antibody levels to PA measured by both the quantitative anti-PA IgG ELISA and the toxin-neutralizing antibody (TNA) assay. Rabbits were aerosol-challenged 10 weeks from day 0 with a lethal dose of Ames spores. All the rabbits that received the undiluted and 1:4 dilution of vaccine survived, whereas those receiving the higher dilutions of vaccine (1:16, 1:64 and 1:256) had deaths in their groups. All the controls died. Rabbit survival was compared with the antibody response. Statistical models were used to test for significance of the peak antibody responses to predict survival. Results showed that both the amount of anti-PA IgG and TNA titres present in the sera at the time of the peak antibody response were significant (P < 0.0001) predictors of survival. These results demonstrate that the humoral immune response to AVA can predict protection in the rabbit model of inhalational anthrax.

Journal Article↗
PubMed1999

Epithelial lymphocyte and macrophage distribution in the adult and fetal equine lung.

Leucocytes in the lung epithelium play an important role in the ability of an animal to respond appropriately to inhaled pathogens. The distribution of lymphoid and myeloid cells associated with the lung epithelium was examined immunohistochemically throughout the respiratory tract of four horses, comprising two adults from an abattoir, one pregnant mare, and her fetus (in the final stage of gestation). Cross and tangential cryosections were labelled with monoclonal antibodies against T-cell, B-cell, macrophage/dendritic myeloid cell, and major histocompatibility Class (MHC) II surface antigens. Cell numbers were determined by microscopy. In the three adult horses, epithelial CD3+ T-cell numbers decreased progressively from the upper to the lower respiratory tract, but in the fetus there were low numbers of T cells (at most, 10% of those seen in the adult airways) and little variation in different parts of the respiratory tract. MHC Class II was expressed on the airway epithelium of the two abattoir horses, but not that of the mare and her fetus. In these two animals occasional large, mostly irregularly-shaped, Class II-positive cells were seen. Very few epithelium-associated cells in any animal were labelled by anti-CD21 antibody, which identifies B cells, or anti-myeloid cell antibodies; an anti-rat macrophage antibody (ED2) was shown, for the first time, to identify mature equine alveolar macrophages. Despite the small number of animals, the results suggest that in normal adult horses the greatest numbers of epithelial T cells are found where there is greatest contact with airborne antigens, and that there is constitutive epithelial MHC Class II expression. The low level of MHC Class II expression in the fetus, together with the reduced numbers of T cells, was consistent with the suggestion that the fetal immune system requires exposure to airborne stimuli for full development. The low level of MHC Class II expression in the mare may have reflected the immunosuppression that accompanies pregnancy.

Animals↗
PubMed1999

Changes in blood lymphocyte populations after multiple trauma: association with posttraumatic complications.

OBJECTIVE: To study the frequency of several lymphocyte subsets, circulating cytokines, and prostaglandin plasma values at their time course over a period of 14 days in severely injured trauma patients in relation to the development of sepsis and multiple organ failure (MOF). DESIGN: Prospective study. SETTING: An operative intensive care unit (ICU) of a university hospital. PATIENTS: Sixty-eight consecutive severely injured trauma patients. INTERVENTIONS: Patients were separated into patients without sepsis and MOF (group 1, n = 51), and patients who developed sepsis and MOF (group 2, n = 17) during their stay in the ICU. Therapy was adjusted to the standards of modern intensive care management by physicians who were not involved in the study. MEASUREMENTS AND MAIN RESULTS: In arterial blood samples, the profile of lymphocyte subset frequencies was performed by flow cytometry and, together with interleukin (IL)-1, IL-10, tumor necrosis factor (TNF)-alpha soluble TNF-alpha receptor 1 (sTNF-alpha r1 [p55]), and prostaglandin E2 (PGE2alpha)-alpha, serially measured after arrival in the ICU (baseline value) and during the next 14 days. Mean plasma IL-1 (29.3 +/- 5.8 [SD] pg/mL), TNF-alpha (138.5 +/- 22.4 pg/mL), and soluble TNF-alpha r1 (6.1 +/- 0.3 ng/mL) values were significantly higher in group 2 patients before clinical evidence of sepsis and MOF. With the onset of severe infections in group 2 patients, IL-1, TNF-alpha, and sTNF-alpha r1 values decreased, while immunosuppressive IL-10 (191.7 +/- 29.1 pg/mL) and PGE2alpha (87.7 +/- 20.4 pg/mL) values further increased and remained elevated during the time course. Analysis of lymphocyte subsets revealed a fall in total lymphocyte levels, in CD4+ T lymphocytes, and natural killer (NK) cells, but no change in CD8+ T lymphocyte subset. Despite a marked change in the T helper (CD4+) to T suppressor (CD8+) ratio (from 1:1.72 to 1:1.10), patients without MOF (group 1) had no significant difference in any of the markers tested compared with baseline values. In addition to the inverse CD4+/CD8+ T cell ratio (from 1:1.75 to 1:0.91) and increased activated T cells, each of these markers was significantly elevated and peaked before the onset of MOF in group 2 patients. CONCLUSIONS: A severely depressed cellular immune response associated with increased suppressive mediators might be closely related to the development of severe sepsis and MOF in trauma patients. Therefore, an in-depth understanding of the deficits in host defense following multiple trauma will provide the basis for therapeutic interventions.

Adult↗
PubMed1999

Functional regions of the Bacillus subtilis spore coat morphogenetic protein CotE.

The Bacillus subtilis spore is encased in a resilient, multilayered proteinaceous shell, called the coat, that protects it from the environment. A 181-amino-acid coat protein called CotE assembles into the coat early in spore formation and plays a morphogenetic role in the assembly of the coat's outer layer. We have used a series of mutant alleles of cotE to identify regions involved in outer coat protein assembly. We found that the insertion of a 10-amino-acid epitope, between amino acids 178 and 179 of CotE, reduced or prevented the assembly of several spore coat proteins, including, most likely, CotG and CotB. The removal of 9 or 23 of the C-terminal-most amino acids resulted in an unusually thin outer coat from which a larger set of spore proteins was missing. In contrast, the removal of 37 amino acids from the C terminus, as well as other alterations between amino acids 4 and 160, resulted in the absence of a detectable outer coat but did not prevent localization of CotE to the forespore. These results indicate that changes in the C-terminal 23 amino acids of CotE and in the remainder of the protein have different consequences for outer coat protein assembly.

Bacillus subtilis↗
PubMed1999

Painless left hemorrhagic pleural effusion: An unusual presentation of dissecting ascending aortic aneurysm.

Aortic dissection is a catastrophic event that is commonly associated with severe pain, massive hemorrhage, and high mortality. In this report, we present the case of a 31-year-old man who presented with painless, hemorrhagic left pleural effusion. Further investigation revealed a 9-cm dissecting ascending aortic aneurysm that was thought to be due to a congenitally bicuspid aortic valve. We suggest that ascending aortic aneurysm be included in the differential diagnosis of hemorrhagic pleural effusion, even in the absence of the classic features of aortic dissection, such as chest pain, advanced age, or history of hypertension.

Adult↗
PubMed1998

Memory-enhancing effects of secreted forms of the beta-amyloid precursor protein in normal and amnestic mice.

When administered intracerebroventricularly to mice performing various learning tasks involving either short-term or long-term memory, secreted forms of the beta-amyloid precursor protein (APPs751 and APPs695) have potent memory-enhancing effects and block learning deficits induced by scopolamine. The memory-enhancing effects of APPs were observed over a wide range of extremely low doses (0.05-5,000 pg intracerebroventricularly), blocked by anti-APPs antisera, and observed when APPs was administered either after the first training session in a visual discrimination or a lever-press learning task or before the acquisition trial in an object recognition task. APPs had no effect on motor performance or exploratory activity. APPs695 and APPs751 were equally effective in the object recognition task, suggesting that the memory-enhancing effect of APPs does not require the Kunitz protease inhibitor domain. These data suggest an important role for APPss on memory processes.

Amnesia↗
PubMed1998

Effects of the M1 agonist xanomeline on processing of human beta-amyloid precursor protein (FAD, Swedish mutant) transfected into Chinese hamster ovary-m1 cells.

Complementary DNA (cDNA) encoding human beta-amyloid precursor protein familial Alzheimer's disease (FAD) Swedish mutant (beta APPSM) form was cloned into a mammalian expression vector (PK255) containing the CMV promoter. The vector was transfected into Chinese hamster ovary cells containing human muscarinic m1 receptors (CHO-m1), and clonal cells stably expressing beta APPSM were isolated. The effects of m1-receptor activation by the selective m1 agonist xanomeline and the non-selective muscarinic agonist carbachol on processing of beta APPSM to release soluble APP (APPs) and beta-amyloid peptide (A beta) were compared. Xanomeline stimulated APP release with a potency 1000-fold greater than that observed for carbachol. Concentrations of carbachol and xanomeline producing maximal effects on APPs release reduced the secretion of A beta by 28 and 46%, respectively. These results extend previous studies with xanomeline and suggest that cholinergic replacement therapy for Alzheimer's disease may reduce amyloid deposition.

Alzheimer Disease↗