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Biomedical subjects

S A Miller

Publications and source records attributed to S A Miller.

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

Chlamydia pneumoniae activates nuclear factor kappaB and activator protein 1 in human vascular smooth muscle and induces cellular proliferation.

BACKGROUND: Observational data strongly suggest an association between Chlamydia pneumoniae and atherosclerotic cardiovascular disease. However, few studies have mechanistically linked C. pneumoniae to vascular remodeling. The purpose of the present study was to examine the mechanistic relationship between C. pneumoniae and human vascular smooth muscle cell (VSMC) physiology. We sought to determine the influence of human VSMC infection by C. pneumoniae on (1) VSMC proliferation and (2) activation of the proinflammatory and proliferative transcription factors nuclear factor kappaB (NF-kappaB) and activator protein 1 (AP-1). MATERIALS AND METHODS: C. pneumoniae was grown and isolated from Hep 2 cells. Human aortic VSMCs were inoculated with C. pneumoniae in the presence and absence of the azalide antibiotic azithromycin. Cell proliferation was assayed by direct cell counting 48 h following infection. Two hours following infection, nuclear extracts were isolated, and activation of both NF-kappaB and AP-1 was assessed by electrophoretic mobility shift assay. RESULTS: Compared with control, C. pneumoniae infection stimulated VSMC proliferation (P < 0.05) and induced both NF-kappaB and AP-1 DNA binding activity. These effects were eliminated by concurrent treatment with azithromycin. CONCLUSIONS: VSMC infection with C. pneumoniae activates proliferative intracellular signals and stimulates cell growth. These data implicate C. pneumoniae as a pathogenic mediator and a potential therapeutic target in the prevention of atherosclerotic disease.

Arteriosclerosis↗
PubMed2000

HER-2/neu blocks tumor necrosis factor-induced apoptosis via the Akt/NF-kappaB pathway.

Overexpression of HER-2/neu correlates with poor survival of breast and ovarian cancer patients and induces resistance to tumor necrosis factor (TNF), which causes cancer cells to escape from host immune defenses. The mechanism of HER-2/neu-induced TNF resistance is unknown. Here we report that HER-2/neu activates Akt and NF-kappaB without extracellular stimulation. Blocking of the Akt pathway by a dominant-negative Akt sensitizes the HER-2/neu-overexpressing cells to TNF-induced apoptosis and inhibits IkappaB kinases, IkappaB phosphorylation, and NF-kappaB activation. Our results suggested that HER-2/neu constitutively activates the Akt/NF-kappaB anti-apoptotic cascade to confer resistance to TNF on cancer cells and reduce host defenses against neoplasia.

3T3 Cells↗
PubMed2000

Retrobulbar pseudotumor of the orbit in a cat.

Idiopathic nonspecific inflammatory disease of the orbit (orbital pseudotumor) was diagnosed detected in a cat. The cat had progressive lagophthalmia, keratitis, and decreased motion of the right eye. Four months later, the left eye was affected in a similar manner. Response to antibiotics and immunosuppressive agents was not detected. Computed tomography of the brain and orbits revealed bilateral thickening of the sclera and episcleral tissues. Bilateral exenteration of the eyes was required because of worsening clinical signs or corneal perforation. Histologic examination revealed proliferation of spindle cells and fibrovascular tissue within and adjacent to the sclera.

Animals↗
PubMed2000

Costs and savings of investigational drug services.

The costs and savings resulting from two pharmacy-based investigational drug services (IDSs) for fiscal year 1996-97 were studied. The costs and savings associated with IDSs at two joint institutions were calculated by adding the cost-avoidance figures (money that would most likely have been spent, but was not because of a specific intervention or program) to the money received from services charged to study investigators or patients and subtracting salaries and overhead costs. Only drugs for which the authors could obtain prices were used to calculate cost-avoidance figures. The number of doses of marketed drugs that were provided free or for which the pharmacy was reimbursed by a drug study sponsor between July 1996 and June 1997 was tabulated from pharmacy dispensing records for each study. Investigational drugs that were not marketed or for which no marketed alternative was available were not included in the cost-avoidance calculation but were included in the charges for IDSs. The total cost of IDSs at the two institutions was $249,112. Income (representing cost avoidance and payments received) totaled $2,958,774, giving the IDSs an overall saving of $2,709,662. The two disease categories with the largest cost-avoidance figures were AIDS and oncology. In total, there was a cost avoidance of $2.9 million in drug costs, which is equivalent to 8% of the institutions' annual drug budget for 1996-97. IDSs in two institutions accounted for a combined one-year saving of over $2.7 million, most of which was attributable to cost avoidance from not having to purchase study drugs.

Academic Medical Centers↗
PubMed2000

Neural and behavioral teratological evaluation of rats exposed to ultra-wideband electromagnetic fields.

Several investigators have reported teratologic effects of electromagnetic field exposure. The majority of these studies have been performed at levels of exposure that could produce substantial heating of the animals. New and unique sources of ultra-wideband (UWB) electromagnetic fields are currently being developed and tested that are capable of generating nonthermalizing, high-peak-power, microwave (MW) pulses with nanosecond (ns) pulse widths, picosecond (ps) rise times, and an UWB of frequencies. Our study was performed to determine if teratological changes occur in rat pups as a result of (i) daily UWB exposures during gestation days 3-18, or (ii) as a result of both prenatal and postnatal (10 days) exposures. Dams were exposed either to (i) UWB irradiation from a Kentech system that emitted a 55 kV/m-peak E field, 300 ps rise time, and a 1.8 ns pulse width, average whole-body specific absorption rate 45 mW/kg; (ii) sham irradiation; or (iii) a positive control, lead (Pb) acetate solution (2000 microg/ml) continuously available in the drinking water. Offspring were examined for ontogeny (litter size, sex-ratios, weights, coat appearance, tooth-eruption, eye-opening, air-righting, and ultrasonic stress vocalizations). Male pups were tested on various performance measures (locomotor, water-maze learning, and fertilization capabilities). The pups postnatally exposed were examined for hippocampal morphology and operant behavior. Behavioral, functional, and morphological effects of UWB exposure were unremarkable with these exceptions: (i) The UWB-exposed pups emitted significantly more stress vocalizations than the sham-exposed pups; (ii) the medial-to-lateral length of the hippocampus was significantly longer in the UWB-exposed pups than in the sham-exposed animals; (iii) male offspring exposed in utero to UWB mated significantly less frequently than sham-exposed males, but when they did mate there was no difference in fertilization and offspring numbers from the sham group. There does not appear to be a unifying physiological or behavioral relationship among the significant differences observed, and our findings could be due to the expected spurious results derived when a large number of statistical comparisons are made. Significant effects found between our positive-controls and other groups on numerous measures indicates that the techniques used were sensitive enough to detect teratological effects. Bioelectromagnetics 21:524-537, 2000. Published 2000 Wiley-Liss, Inc.

Animals↗
PubMed2000

Endomyocardial biopsy in pediatric heart transplant recipients: a useful exercise? (Analysis of 1,169 biopsies).

The objective of this study was to define the diagnostic yield for endomyocardial biopsy (EMB) procedures performed for various indications in a large pediatric heart transplant population. Endomyocardial biopsy procedure has been employed as the 'gold standard' for rejection surveillance. Previous studies have questioned the value of surveillance EMB beyond the early post-transplant period. We retrospectively reviewed data on 82 pediatric heart transplant recipients with serial EMB. A total of 1,169 EMB were performed during a follow-up period of 2-149 months (median 41 months). EMB were classified by age at transplantation, time from transplant, immunosuppressive regimen used [tacrolimus vs. cyclosporin A (CsA)] and indication, i.e. surveillance, follow-up after rejection or lowering of immunosuppression, non-specific clinical symptoms and graft dysfunction. During the first year after heart transplantation, surveillance EMB demonstrated significant rejection [International Society for Heart and Lung Transplantation (ISHLT) grade > or = 3A] in 18% of biopsies with the yield being 14-43% for all other indications. Surveillance EMB 1-5 yr post-transplantation were found to have a lower diagnostic yield in infants (4%, vs. 13% in children) and in patients with favorable first-year rejection history (9% vs. 17% in 'frequent rejectors'). Tacrolimus-based immunosuppression was associated with significantly less rejection, but only in the first year post-transplantation (14% in tacrolimus vs. 24% in CsA surveillance EMB, p = 0.035). Surveillance EMB remains an important diagnostic tool for rejection surveillance during the first 5 years after pediatric heart transplantation. Endomyocardial biopsy is particularly warranted after reduction of immunosuppression and for monitoring for ongoing rejection after treatment of acute rejection episodes.

Adolescent↗
PubMed2000

Selective mitochondrial KATP channel opening controls human myocardial preconditioning: too much of a good thing?

BACKGROUND: Paradoxically, patients with noninsulin-dependent diabetes mellitus experience a higher cardiovascular mortality rate than patients with insulin-dependent diabetes mellitus. We have shown that K(ATP) channel inhibition, with oral sulfonylureas, prevents myocardial preconditioning and may explain the paradox of cardiovascular death in patients with noninsulin-dependent diabetes mellitus. Cardiac preconditioning is an attractive protective strategy against any elective ischemia/reperfusion (I/R) injury. The relationship between the K(ATP) channels and human myocardial preconditioning has not previously been elucidated. METHODS: Human atrial trabeculae were harvested, placed in organ baths, and paced (1 Hz). Developed force was recorded during simulated 37 degrees C I/R (30/45 or 45/60 minutes). Before I/R, trabeculae were treated transiently with a selective mitochondrial K(ATP) channel opener for 5 minutes, followed by a 10-minute washout, or were exposed to the channel opener throughout ischemia. Recovery of function is expressed as percentage of baseline developed force. Conserved creatine kinase activity (units per gram of wet tissue) was measured at the end of reperfusion as an indicator of cellular protection. RESULTS: Transient mitochondrial K(ATP) channel opening provided protection from both I/R insults. Surprisingly, there was no protection afforded by continuous mitochondrial K(ATP) channel opening. CONCLUSIONS: Transient selective mitochondrial K(ATP) channel opening protects both viability and function of human myocardium against I/R injury, although prolonged opening of the mitochondrial K(ATP) channel does not. These results reinforce the concept of preconditioning as a transient event that must be completed before the onset of ischemia.

Adenosine Triphosphate↗
PubMed2000

Chemokines as mediators of diseases related to surgical conditions.

Chemokines are important mediators of inflammation. Animal studies suggest that inhibition of chemokine action results in a decrease in inflammation. Novel anti-inflammatory agents directed against chemokines are now available. Surgeons are uniquely positioned to treat multiple chemokine-mediated diseases. In this article, we review the biology and nomenclature of chemokines as well as their role in neutrophil migration. Further, the potential role of chemokines in various diseases related to surgical conditions, including adult respiratory distress syndrome, atherosclerosis, inflammatory bowel disease, and solid organ rejection, is reviewed. Finally, the idea that chemokines could be targets for novel therapeutic agents is discussed.

Animals↗
PubMed2000

Unfit for further service: trends in medical discharge from the British Army 1861-1998.

Military service requires individuals who are free from ill-health and who are physically and mentally robust, and throughout history those who have become unfit for service have been discharged on medical grounds. This paper uses published historical records to examine trends in the rate of discharge for six key conditions for the period 1861-1998 and to draw conclusions. In the late 19th and early 20th centuries, communicable diseases such as tuberculosis and syphilis were a major problem together with ill-defined conditions such as "disordered action of the heart". By the mid-20th century, psychiatric and gastrointestinal disorders had become the principal causes of medical discharge, whereas in the late 20th century, the majority of discharges resulted from injuries and musculoskeletal disorders. The pattern of conditions leading to medical discharge from the Army tends to mirror conditions which are prevalent at that time in the civilian population.

Communicable Diseases↗
PubMed1999

Liposomal delivery of purified inhibitory-kappaBalpha inhibits tumor necrosis factor-alpha-induced human vascular smooth muscle proliferation.

Vessel injury results in the elaboration of various cytokines, including tumor necrosis factor-alpha (TNF-alpha), which may influence vascular smooth muscle cell (VSMC) function and contribute to atherogenesis. We tested the hypothesis that TNF-alpha-induced VSMC proliferation requires activation of the transcription factor nuclear factor-kappaB (NF-kappaB), which could be prevented by delivery of the NF-kappaB inhibitory peptide, IkappaBalpha. TNF-alpha induced concentration-dependent human VSMC proliferation, and neutralizing antibody to interleukin-6 reduced TNF-alpha-induced VSMC proliferation by 65%. In TNF-alpha-stimulated VSMCs, there was a 3-fold increase in NF-kappaB-dependent luciferase reporter activity that was associated with degradation of IkappaBalpha. To determine an essential role for NF-kappaB in TNF-alpha-induced VSMC proliferation, recombinant IkappaBalpha was introduced into VSMCs via liposomal delivery. Under these conditions, TNF-alpha-induced NF-kappaB nuclear translocation and DNA binding were inhibited, NF-kappaB-dependent luciferase activity was reduced by 50%, there was no degradation of native IkappaBalpha detected, interleukin-6 production was reduced by 54%, and VSMC proliferation was decreased by 60%. In conclusion, the mitogenic effect of TNF-alpha on human arterial VSMCs is dependent on NF-kappaB activation and may be prevented by exogenously delivered IkappaBalpha. Furthermore, liposomal delivery of endogenous inhibitory proteins may represent a novel, therapeutically accessible method for selective transcriptional suppression in the response to vascular injury.

Cell Division↗
PubMed1999

Domains of differential cell proliferation suggest hinged folding in avian gut endoderm.

A profile of proliferative growth assessed with tritium autoradiograms from White Leghorn embryo stages Hamburger-Hamilton 6-21 labeled in ovo presents evidence of hinged folding driven by localized differential cell proliferation in endoderm. There is a significant, bilateral pattern, and differences are most pronounced in axial levels that are folding and rotating. Highest proliferation is in cells producing folds; lowest proliferation is in median cells. Localized changes in cell shape are lacking, as are TUNEL markers and cell morphology that would suggest involvement of apoptosis. Folding endoderm to form gut tube appears to be a process that is driven by domains of high cell proliferation flanking a domain of significantly lower proliferation. When considered in the context of an epithelium attached to subjacent mesoderm, these differentials could produce a forced and directed buckling of endoderm into lateral folds that join and enclose a tube. Patterns suggest that endoderm folds about a median hinge. In the light of this new information, we suggest it is more precise to refine the term, median hinge point (MHP), to neural hinge point (NHP) and gut hinge point (GHP).

Analysis of Variance↗
PubMed1999

Optimal dosing of intravenous tacrolimus following pediatric heart transplantation.

BACKGROUND: Early experience with intravenous tacrolimus at high doses (0.1-0.15 mg/kg/day) was associated with frequent clinical toxicity. The optimal dosing regimen after pediatric heart transplantation is unknown. METHODS: We retrospectively reviewed data on the last 45 pediatric heart transplant recipients to document the time required to achieve therapeutic blood levels and the safety of 2 differing intravenous dosing regimens (tacrolimus 0.03 & 0.05 mg/kg/day as continuous i.v. infusion). Target plasma levels were (1.2-1.7 ng/ml) with levels >2.0 ng/ ml considered toxic, and target whole blood levels were 15-20 ng/ml with levels >25 ng/ml considered toxic. RESULTS: Mean age at transplantation was 7.5 +/- 5.6 years (0.1-18), and 14 were infants. Intravenous tacrolimus was commenced at a mean of 7 +/- 3 hours (range 2-16) after arrival in the ICU. Eight patients were excluded from analysis because of protocol modifications. Of the remaining 37 pts, 9 received initial infusion at 0.03 mg/kg/day; 3 (33%) achieved 'therapeutic' levels within 48 hours and 1 patient had a toxic level (27 ng/ml) at 36 hours. Twenty-eight patients received 0.05 mg/kg/day; 18 (64%) achieved therapeutic levels within 48 hours and 9 (32%) developed toxic levels. Patients with toxic whole blood levels had higher tacrolimus levels on first blood assay compared to those who did not develop toxicity (16.4 +/- 3.4 vs 9.3 +/- 3.9, p < .0001; level >10 ng/ml on first assay in 7/7 toxic patients vs 7/19 without toxicity, p = .004). Patients receiving the higher dose regimen had fewer episodes of moderate or severe rejection (> or =Grade 3A) at first biopsy than those receiving the lower dose infusion (32% vs 75%; p = .046). No patient required renal dialysis. CONCLUSIONS: Dosing below 0.05 mg/kg/day may result in clinically important delay in achieving therapeutic levels. Toxicity may be reduced by frequent monitoring of levels for the first 48 hours after transplantation especially when the initial level is >10 ng/ml.

Adolescent↗
PubMed1999

Precise detection and tracing of Trichoderma hamatum 382 in compost-amended potting mixes by using molecular markers.

Randomly amplified polymorphic DNA (RAPD) analysis and the PCR assay were used in combination with dilution plating on a semiselective medium to detect and enumerate propagules of Trichoderma hamatum 382, a biocontrol agent utilized in compost-amended mixes. Distinct and reproducible fingerprints were obtained upon amplification of purified genomic DNA of T. hamatum 382 with the random primers OPE-16, OPH-19, and OPH-20. Three amplified DNA fragments of 0.35 (OPE-16(0.35)), 0.6 (OPH-19(0.6)), and 0.65 (OPH-20(0.65)) kb were diagnostic for T. hamatum 382, clearly distinguishing it from 53 isolates of four other Trichoderma spp. tested. Some isolates of T. hamatum shared these low-molecular-weight fragments with T. hamatum 382. However, RAPD analysis of isolates of T. hamatum with all three random primers used in consecutive PCR tests distinguished T. hamatum 382 from other isolates of T. hamatum. These three RAPD amplicons were cloned and sequenced, and pairs of oligonucleotide primers for each cloned fragment were designed. Use of the primers in the PCR assay resulted in the amplification of DNA fragments of the same size as the cloned RAPD fragments from genomic DNA of T. hamatum 382. A combination of dilution plating on a semiselective medium for Trichoderma spp. and PCR, with the RAPD primers OPH-19, OPE-16, and OPH-20 or the three sequence-characterized primers, was used successfully to verify the presence of T. hamatum 382 propagules in nine different soil, compost, and potting mix samples. All 23 Trichoderma isolates recovered on semiselective medium from commercial potting mixes fortified with T. hamatum 382 were identified as T. hamatum 382, whereas 274 Trichoderma isolates recovered from the other nine samples were negative in the PCR assay. Thus, this highly specific combination of techniques allowed detection and enumeration of propagules of T. hamatum 382 in fortified compost-amended potting mixes. Sequence-characterized amplified region markers also facilitated the development of a very simple procedure to amplify DNA of T. hamatum 382 directly from fortified compost-amended potting mixes.

Base Sequence↗
PubMed1999

Epidemiology of malaria in the British Army from 1982-1996.

An epidemiological review was carried out of all known cases of malaria involving British soldiers between 1982-1996. Hospital records of 213 confirmed cases of malaria were obtained from the Defence Analytical Services Agency (DASA). More than half of the infections (52%) occurred as a result of military training in Kenya and 74% of these were due to Plasmodium falciparum which is potentially life-threatening. Mefloquine has been used as chemoprophylaxis by the British Army in Kenya since 1993 and the implications of this are discussed. There were no deaths in the series but malaria nevertheless remains a serious threat to the health of the British Soldier. The importance of adherence to chemoprophylaxis and of simple bite avoidance measures must continue to be emphasised.

Antimalarials↗
PubMed1999

Ultrawideband radiation and pentylenetetrazol-induced convulsions in rats.

New non-ionizing pulsed systems using ultrawideband (UWB) require safety assessment before they can be used by either military or civilian communities. The development of directed energy weaponry intended for use against electronically vulnerable targets, as well as ground-probing radar systems, have used fast-rise-time high-peak-power electromagnetic pulses characteristic of UWB emitters. It has been postulated that these ultrashort pulses might produce electromagnetic transients resulting in tissue damage. Several challenges to this notion have been posed, however. One report found that rats exposed to UWB after receiving a convulsant drug tended toward longer latency to the onset of convulsions than the no-exposure group. Although not statistically significant, the presence of this trend prompted the present study. An ED99 dose of the convulsant pentylenetetrazol (PTZ) or saline was given just before UWB or sham exposure and resultant seizure activity was recorded. The data from the current study show no effect of UWB exposure on PTZ-induced seizure activity, thereby not supporting the tissue damage concerns, at least for the exposure parameters used here.

Animals↗
PubMed1998

Right-left asymmetry of cell proliferation predominates in mouse embryos undergoing clockwise axial rotation.

BACKGROUND: Differential growth is fundamental to most mechanisms proposed for axial rotation in amniotes. Other mechanisms such as changes in cell shape are not consistently suggested by ultrastructure. Lateral asymmetries in cell proliferation exist in mouse and chick embryos undergoing normal, anticlockwise axial rotation, but there has been no investigation of inverse clockwise rotation that could test the correlation. METHODS: We used the BALB/cHu-iv/iv, situs inversus mouse to test the apparent correlation of lateral asymmetries with morphogenesis that we saw in cell division patterns of normally rotating mice. Proliferation indices were collected from tritium autoradiograms. RESULTS: Asymmetry of cell proliferation in inverse axial rotation is a mirror image of the pattern seen for normal axial rotation: right predominates over left. This asymmetry is statistically significant and correlates with morphology. Patterns of proliferation in constraining extraembryonic membranes, particularly visceral yolk sac, suggest that rotation could be pushed by uneven lateral growth as body and gut tubes form, for they are attached to these membranes. CONCLUSIONS: Data from iv/iv mice provide additional evidence that differential growth, constrained by contiguous extraembryonic membranes, may drive closure of body and gut walls and contribute to axial rotation. Asymmetries of cell proliferation are likely consequences of genetic cascades, and will need to be incorporated with in situ information on gene activity.

Animals↗
PubMed1998

Apoptosis in cavitation of middle ear space.

Mesenchyme cells surround early ossicles in the developing middle ear, then are replaced by space that is created by what has been described as an expansion of the pharyngeal pouch. Cell death has not been considered important in cavitation of chick middle ear (Jaskoll and Maderson [1978] Anat. Rec., 190:177-200), but an uncharacterized form of cell death has been reported to play a major role in cavitation of mouse middle ear (Jaskoll [1977] PhD thesis, CUNY). We investigated whether this uncharacterized cell death is the non-random form known as apoptosis. We examined the middle ear cavitation process using an in situ immunomarker for apoptosis. CBy RF mice during prenatal days 15-20 and postnatal days 1-3 and chick embryos representing HH stages 33-38 were investigated. Apoptotic cells were marked in mouse postnatal day 1. No indication of apoptosis was present in other prenatal and postnatal days of development included in this study, although morphology showed that cavitation proceeds over several perinatal days in the mouse. Apoptosis was not marked in the chick middle ear. Previously observed cell death in murine middle ear is the non-random form of cell death known as apoptosis. Cell death has not been reported in avian middle ear, and lack of apoptotic marker supports those observations. The limited occurrence of apoptosis in mice and apparent absence of apoptosis in chicks suggest that several mechanisms contribute to cavitation of vertebrate middle ear space.

Animals↗