Biomedical subjects

M Brown

Publications and source records attributed to M Brown.

At least 127 records · Page 7Linked to original sources

PubMed2000

Differential effects of right versus left stellate ganglion block on left ventricular function in humans: an echocardiographic analysis.

STUDY OBJECTIVES: To evaluate the effects of unilateral stellate ganglion blockade on left ventricular function. DESIGN: Prospective cohort of patients with chronic regional pain syndrome type I and II of the upper extremity requiring therapeutic stellate ganglion blockade. SETTING: University-affiliated hospital. PATIENTS: Fifteen adult ASA physical status I and II patients with the diagnosis of chronic regional pain syndrome type I and II of the arm were studied. Right stellate ganglion block was performed in nine subjects and a left in six. INTERVENTIONS: Stellate ganglion block was performed with 10 mL of 1% plain Xylocaine. Transthoracic echocardiograms were performed immediately prior and 30 min following the block. MEASUREMENTS: Heart rate and blood pressure were monitored at regular intervals. Global systolic function was determined by calculating ejection fraction. Regional systolic motion was evaluated on the short axis and four-chamber views using the American Society of Echocardiography criteria. Diastolic function was assessed with pulsed-wave Doppler of the left ventricular outflow tract and the mitral valve. Data collected included isovolumic relaxation time and early and atrial velocity patterns. MAIN RESULTS: A successful stellate ganglion block was achieved in all patients. Blood pressure and heart rate were not significantly different during data collection. Patients who underwent a right stellate ganglion block showed no significant differences in systolic or diastolic function. Following a left stellate ganglion block, global and regional systolic function remained unchanged. Isovolumic relaxation time was increased but did not reach statistical significance (80 +/- 13 ms to 88 +/- 9 ms; p = 0.09). Left ventricular end-diastolic (LVEDV) and end-systolic volumes (LVESV) were significantly increased (LVEDV from 73 +/- 9 mL to 100 +/- 9 mL, p < 0.02; LVESV from 31 +/- 4 mL to 37 +/- 4 mL, p < 0.03). CONCLUSIONS: In patients without cardiovascular disease, unilateral denervation of the left ventricle after stellate ganglion block produces no clinical deleterious effects on left ventricular function.

Adult↗

PubMed2000

Natural HPV immunity and vaccination strategies.

BACKGROUND: the task of preventing premature death in women may be delivered by vaccinating against the high-risk papillomaviruses associated with various malignancies. OBJECTIVES: we will discuss the immune mechanisms likely to be relevant to the control of an HPV infection in the cervix and assess the limited evidence for such immune recognition in the natural history of infection. CONCLUSION: the next generation of vaccination strategies should include the use of HPV 16 early (E2 and/or E6 and/or E7) and late gene targets (L1 and L2) expressed as VLPs with their clinical and immunological evaluation aimed at therapy as well as prophylaxis. Important clinical efficacy assessment may be deliverable in relatively short-term studies by targeting patients with HPV 16 associated vulval intraepithelial neoplasia.

Female↗

PubMed2000

The infection of human skin by schistosome cercariae: studies using Franz cells.

Franz cells (2-chambered, air/fluid phase static diffusion devices, previously used for the study of drugs across viable human skin) are utilized for the first time to investigate the process of infection of human skin by Schistosoma mansoni cercariae. Skin obtained from cosmetic surgery sources was used in the Franz cells to describe the temporal dynamics of the early interaction of cercariae with skin. At 38 degrees C, about 50% of cercariae applied in water to the epidermal surface of the skin were irreversibly attached within 1 min and after 5 min about 85%, were similarly irrecoverable. The technique also provides the means of following the early penetration path of cercariae by histological methods. Franz cell results on the dynamics of attachment/early penetration have been compared with those obtained using artificial skin equivalents and non-human mammalian skin models in the context of the physical and chemical differences between these systems and viable human skin. It is concluded that Franz cells provide a convenient system for directly investigating the early phases of S. mansoni cercariae interaction with human skin.

Animals↗

PubMed2000

High-resolution computed tomographic characteristics in acute farmer's lung and in its follow-up.

High resolution computed tomography (HRCT) scans are increasingly used in hypersensitivity pneumonitis (HP). This study looked at HRCT findings at different phases of farmer's lung (FL), a common form of HP. A cross sectional analysis of 95 HRCT scans of FL cases (20 acute, 75 with a history of FL, 48 still in contact (Ex +) (dairy farm), and 27 who had ceased contact (Ex-)) was made. All scans were read independently by two, and if needed by three, radiologists blinded to the category. The lungs were divided into six regions (fives lobes + lingula), and read for attenuation/mosaic, ground-glass, micronodules, fibrosis, and emphysema. A score of 0-3 was given for each region and each variable: 0 = absence, 1 =<25% of the surface, 2 = 25-50%, 3 =>50%. Mediastinal lymphadenopathy was also noted. Ground glass, predominating in the lower lobes, was the most frequent feature in the acute and Ex+ cases. Other abnormalities had no preferential distribution. Ex+ had more ground-glass than the Ex- (p=0.0025). Emphysema was more frequently seen than interstitial fibrosis (p=0.004). Mediastinal lymphadenopathy was present in 26 cases (9 acute, 10 Ex+ and 7 Ex-). In conclusion, in farmer's lung: 1) ground-glass predominates in the lower lobes while the other abnormalities have no anatomic predilection; 2) contact avoidance allows a better resolution of computed tomography abnormalities than continued exposure; 3) emphysema is a more frequent finding than interstitial fibrosis; and 4) the presence of mediastinal lymphadenopathy has no negative diagnostic value.

Acute Disease↗

PubMed2000

Angiocentric primary cutaneous T-cell-rich B-cell lymphoma: a case report and review of the literature.

BACKGROUND: T-cell-rich B-cell lymphoma (TCRBCL) is an uncommon B-cell lymphoma, which is characterized histologically by a small number of neoplastic B cells surrounded by large numbers of nonneoplastic T cells. Diagnosis is frequently difficult because the neoplastic 'B-cell population may be quite sparse, and immunohistochemical and molecular analysis to identify the B-cell origin and clonality of the cells is necessary. METHODS: In this report we present an additional case of primary cutaneous TCRBCL with immunohistochemical and gene rearrangement studies and review the literature of this unusual entity. RESULTS: The patient was a 52-year-old woman who had a slowly growing cutaneous lymphoma which fulfills the strictest criteria initially proposed for a diagnosis of TCRBCL. This case has additional features of a prominent angiocentric/angioinvasive histology and dual clonality, showing both immunoglobulin heavy chain and T-cell receptor gene rearrangements. CONCLUSIONS: Controversy surrounds the notion of TCRBCL as a distinct clinicopathological entity. There have only been 14 reported cases of TCRBCL with skin involvement in the literature and only seven of these cases have arisen in the skin. To better understand the histological and clinical characterisitcs of TCRBCL we have reviewed previously reported cases of TCRBCL with skin involvement, and contrast them with the present case.

Blood Vessels↗

PubMed2000

Toxicity evaluation of replication-competent herpes simplex virus (ICP 34.5 null mutant 1716) in patients with recurrent malignant glioma.

The herpes simplex virus (HSV) ICP34.5 null mutant 1716 replicates selectively in actively dividing cells and has been proposed as a potential treatment for cancer, particularly brain tumours. We present a clinical study to evaluate the safety of 1716 in patients with relapsed malignant glioma. Following intratumoural inoculation of doses up to 10(5) p.f.u., there was no induction of encephalitis, no adverse clinical symptoms, and no reactivation of latent HSV. Of nine patients treated, four are currently alive and well 14-24 months after 1716 administration. This study demonstrates the feasibility of using replication-competent HSV in human therapy.

Adult↗

PubMed2000

Dendritic cells infected with recombinant fowlpox virus vectors are potent and long-acting stimulators of transgene-specific class I restricted T lymphocyte activity.

The identification of dendritic cells (DC) as the major antigen-presenting cell type of the immune system, combined with the development of procedures for their ex vivo culture, has opened possibilities for tumour immunotherapy based on the transfer of recombinant tumour antigens to DC. It is anticipated that the most effective type of response would be the stimulation of specific, MHC class I restricted cytotoxic T lymphocytes capable of recognising and destroying tumour cells. In order to make this approach possible, methods must be developed for the transfer of recombinant antigen to the DC in such a way that they will initiate an MHC class I restricted response. Here, we demonstrate that murine DC infected with a recombinant fowlpox virus (rFWPV) vector stimulate a powerful, MHC class I restricted response against a recombinant antigen. A rFWPV containing the OVA gene was constructed and used to infect the DC line DC2.4. The infected DC2.4 cells were found to stimulate the T-T cell hybridoma line RF33. 70, which responds specifically to the MHC class I restricted OVA peptide SIINFEKL. The stimulatory ability of the rFWPV-infected DC2.4 cells lasted for at least 72 h after infection and was eventually limited by proliferation of uninfected cells. By comparison, DC2.4 cells pulsed with synthetic SIINFEKL peptide stimulated RF33.70 well initially, but the stimulatory ability had declined to zero by 24 h after pulsing. FWPV infection of DC2.4 up-regulated MHC and costimulatory molecule expression. rFWPV was also found to infect both immature and mature human DC derived from cord blood CD34+ progenitors and express transgenes for up to 20 days after infection. We conclude that rFWPV shows promise as a vector for antigen gene transfer to DC in tumour immunotherapy protocols.

Animals↗

PubMed2000

Low-intensity exercise as a modifier of physical frailty in older adults.

OBJECTIVE: To examine the effects of a 3-month low-intensity exercise program on physical frailty. DESIGN: Randomized clinical trial. SETTING: Regional tertiary-care hospital and academic medical center with an outpatient rehabilitation fitness center. PARTICIPANTS: Eighty-four physically frail older adults (mean age, 83 +/- 4 yrs). INTERVENTION: Three-month low-intensity supervised exercise (n = 48) versus unsupervised home-based flexibility activities (n = 36). MAIN OUTCOME MEASURES: Physical performance test, measures of balance, strength, flexibility, coordination, speed of reaction, peripheral sensation. RESULTS: Significant improvement was made by the exercise group on our primary indicator of frailty, a physical performance test (PPT) (29 +/- 4 vs 31 +/- 4 out of a possible 36 points), as well as many of the risk factors previously identified as contributors to frailty; eg, reductions in flexibility, strength, gait speed, and poor balance. Although the home exercise control group showed increases in range of motion, the improvements in flexibility did not translate into improvements in physical performance capacity as assessed by the PPT. CONCLUSIONS: Our results suggest that physical frailty is modifiable with a program of modest activities that can be performed by virtually all older adults. They also indicate that exercise programs consisting primarily of flexibility activities are not likely to reverse or attenuate physical frailty. Although results suggest that frailty is modifiable, it is not likely to be eliminated with exercise, and efforts should be directed toward preventing the condition.

Aged↗

PubMed2000

Non-typhoidal Salmonella bacteraemia without gastroenteritis: a marker of underlying immunosuppression. Review Of cases at St. Thomas' Hospital 1970-1999.

OBJECTIVES: To classify non-typhoidal salmonella bacteraemia according to clinical presentation, and to study how this correlates with the presence of underlying immunosuppression. METHODS: We analysed data collected prospectively for all 82 cases of non-typhoidal salmonella bacteraemia presenting to St. Thomas' Hospital between 1970 and 1999. RESULTS: Patients presented with one of three syndromes: diarrhoea, an extra-intestinal focus of infection, or isolated fever with no focus. Only 18% of those with diarrhoea had underlying immunosuppression, compared with 80% of those with extra-intestinal focal infections (P= 0.001) and 80% of those with no focus (P= 0.0001). There was no significant association between salmonella serotype and underlying immunosuppression. Salmonella enteritidis isolates, especially phage type 4, increased significantly during the last decade (P= 0.001). The presentation of non-typhoidal salmonella bacteraemia in the absence of diarrhoea prompted the diagnosis of HIV in two patients. CONCLUSION: Underlying immunosuppression should be excluded in patients presenting with non-typhoidal salmonella bacteraemia in the absence of gastroenteritis. This may lead to an earlier diagnosis of HIV.

Adult↗

PubMed2000

Models for predicting subjective quality of life in individuals with traumatic brain injury.

The objective of this study was to compare the utility of ICIDH-based models and needs-based models for predicting subjective quality of life in individuals with traumatic brain injury (TBI). Using an existing data base of individuals with TBI living in the community, seven predictive models were tested using multiple regression analyses. In comparing adjusted R2 associated with each of seven models, it was concluded that needs-based models using subjective indicators clearly predict more variance in measures of life satisfaction, or subjective well-being, than do either type of model relying on objective measures. It is suggested that, in documenting 'outcomes' of rehabilitation, the degree to which the focal individual's important needs are met defines more directly his/her well-being than do measures of impairment, disability or handicap.

Activities of Daily Living↗

PubMed2000

Physical and performance measures for the identification of mild to moderate frailty.

BACKGROUND: The relative importance and association of factors contributing to physical frailty in elderly persons are unclear. METHODS: Physical measures of upper and lower extremity strength, range of motion, balance, coordination, sensation, and gait were evaluated in relation to scores obtained on a 36-point physical performance test (PPT) in 107 elderly subjects. RESULTS: Scores on the PPT were significantly associated with the measures of strength and balance, gait, several range of motion values, and sensation. Subjects were also grouped according to score on the PPT as not frail (32-36 points), mildly frail (25-31 points), or moderately frail (17-24 points). ANOVA followed by Bonferroni post hoc analyses were used to examine the relationships of physical measures to this index of frailty. Balance measures, an obstacle course, the Berg scale, the full tandem portion of the Romberg test, and fast gait speed were significantly different among the three groups. Multiple stepwise regression analyses indicated that the strongest combination of variables, explaining 73% of all the variance in the PPT, included obstacle course performance, hip abduction strength, the semitandem portion of the Romberg test, and coordination (pegboard). CONCLUSIONS: Results provide further insight into the relative importance of factors that contribute to frailty and factors that should be considered in treatment planning for the remediation of physical frailty in old adults.

Aged↗

PubMed2000

Pharmacokinetics and burn eschar penetration of intravenous ciprofloxacin in patients with major thermal injuries.

Adequate penetration of antibiotics into burn tissue and maintenance of effective serum levels are essential for the treatment of patients sustaining major thermal injuries. The pharmacokinetics and burn eschar penetration of intravenous ciprofloxacin were determined in 12 critically ill patients with burn injuries. Mean age for the 12 patients was 45 +/- 17 (range 25-82 years), total body surface area burned (TBSAB) = 38 +/- 15% and Acute Physiology and Chronic Health Evaluation (APACHE) II score = 8 +/- 6. Patients received recommended doses of ciprofloxacin, 400 mg q12h iv, for three doses beginning 72 h post-burn. Serum concentrations were measured at t = 0, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 2.0, 4.0 and 12.0 h after the first and third doses. Burn eschar biopsies were obtained after the third ciprofloxacin dose. Three of these 12 patients (25%) manifested later signs of clinical sepsis (TBSAB = 61 +/- 6% and APACHE II score = 11 +/- 3) and underwent a second infusion of three doses of intravenous ciprofloxacin, blood sampling and eschar biopsy. Serum and eschar concentrations were determined by high performance liquid chromatography. Serum ciprofloxacin concentrations were comparable to those of normal volunteers (C(max) = 4.0 +/- 1 mg/L and AUC = 11.4 +/- 2 mg.h/L) during the immediate post-burn period after dose 1 (C(max1) = 4.8 +/- 3 mg/L and AUC(0-12) = 12.5 +/- 7 mg. h/L) and dose 3 (C(max3) = 4.9 +/- 2 mg/L and AUC(24-36) = 17.5 +/- 11 mg.h/L). Mean burn eschar concentration during the 72 h post-burn was significantly lower than that found during clinical sepsis (18 +/- 17 compared with 41.3 +/- 54 microg/g; P < 0.05 by t test). Similar serum concentrations were achieved in patients with clinical sepsis (C(max1) = 4.2 +/- 0.2 mg/L and AUC(0-12) = 15.0 +/- 3 mg. h/L; C(max3) = 5.0 +/- 1 mg/L and AUC(24-36) = 22.8 +/- 9 mg.h/L). A positive correlation between burn eschar concentrations and C(max) (r = 0.71, r(2) = 0.51, P = 0.01) was found by linear regression analysis. A C(max)/MIC ratio > 10 (MIC = 0.5 mg/L) and an AUC/MIC ratio > 100 SIT(-1).h (serum inhibitory titre) (MIC = 0.125 mg/L) were achieved. High burn eschar concentrations and serum levels, similar to those found in normal volunteers, can be achieved after intravenous ciprofloxacin infusion in critically ill burns patients.

Adult↗

PubMed2000

Utility of near-infrared spectroscopy in the diagnosis of lower extremity compartment syndrome.

OBJECTIVE: To determine the utility of near-infrared spectroscopy in the diagnosis of lower extremity compartment syndrome (CS). METHODS: Nine patients with CS confirmed by physical examination and elevated compartment pressures (64 +/- 17 mm Hg) were evaluated before and after fasciotomy. Control readings were also performed on 33 surgical patients who had no evidence of CS. The deltoid muscle was used as a reference value. RESULTS: The deltoid muscle oxygen saturation (StO2) readings revealed a mean = 84 +/- 17% prefasciotomy and mean = 83 +/- 12% postfasciotomy in the CS group. The control group had a mean StO2 of 83 +/- 11%. In the CS group, the leg compartment with the highest pressure had a StO2 mean = 56 +/- 27% before fasciotomy. This value was statistically significantly lower (p < 0.05) than either the postfasciotomy mean StO2 in that compartment (82 +/- 16%) or the values found in matched control patients with no evidence of CS (87 +/- 7%). CONCLUSION: Near-infrared spectroscopy-derived StO2 values in the lower extremities of trauma patients with CS were diminished relative to the control patients and usually normalized after fasciotomy. Near-infrared spectroscopy evaluation may offer a rapid, noninvasive method of assessing extremities at risk for CS.

Adult↗

PubMed2000

Stored red blood cells selectively activate human neutrophils to release IL-8 and secretory PLA2.

Packed red blood cell (PRBC) transfusion has been invoked previously with immunosuppression and increased infections, but it has now been demonstrated that stored PRBCs (>14 days) can prime PMNs and provoke multiple organ failure. Recently, the role of PMNs in the genesis of MOF has been extended to their release of inflammatory cytokines, notably IL-1, IL-8, TNFalpha, and secretory phospholipase A2 (sPLA2). We hypothesize that stored PRBCs can act as a second event via stimulating the release of inflammatory cytokines from PMNs. Isolated human PMNs were incubated for 24 h in RPMI with either 20% fresh plasma or plasma from 42 day old PRBC (day of outdate) and release of IL-8, IL-1beta, TNFalpha, and sPLA2 were measured. Plasma from stored PRBCs contained small amounts of IL-8, sPLA2, and TNFalpha (102.1 +/-5.6 pg/ml, 87.6+/-6.0 pg/ml and 9.7+/-.7 pg/ml). Levels of IL-1beta were below detection (<1 pg/ml). Day 42 PRBC plasma stimulated significant PMN release of both IL-8 and sPLA2 as compared to both control and day 0 plasma (*P < .05), but PRBC plasma did not stimulate PMN release of either IL-1beta or TNFalpha. Transfused blood is emerging as an inflammatory agent that is capable of producing PMN priming. In this study we have demonstrated that PRBC plasma selectively activates PMNs to release both IL-8 and sPLA2. Thus, transfusion of PRBCs may represent a preventable inflammatory insult via modification of both blood banking and transfusion practices.

Blood Preservation↗

PubMed2000

Low-fat, high-carbohydrate diets and atherogenic risk.

The debate surrounding the use of low-fat, high-carbohydrate diets has raised concerns regarding the atherogenicity of triglyceride-rich lipoproteins. A recent study has demonstrated that feeding a diet high in carbohydrate delays very low-density lipoprotein (VLDL) clearance. The same diet fed to mildly hyperinsulinemic subjects delays both VLDL and chylomicron clearance without affecting triglyceride production.

Arteriosclerosis↗

PubMed2000

Leaky scanning is the predominant mechanism for translation of human papillomavirus type 16 E7 oncoprotein from E6/E7 bicistronic mRNA.

Human papillomaviruses (HPV) are unique in that they generate mRNAs that apparently can express multiple proteins from tandemly arranged open reading frames. The mechanisms by which this is achieved are uncertain and are at odds with the basic predictions of the scanning model for translation initiation. We investigated the unorthodox mechanism by which the E6 and E7 oncoproteins from human papillomavirus type 16 (HPV-16) can be translated from a single, bicistronic mRNA. The short E6 5' untranslated region (UTR) was shown to promote translation as efficiently as a UTR from Xenopus beta-globin. Insertion of a secondary structural element into the UTR inhibited both E6 and E7 expression, suggesting that E7 expression depends on ribosomal scanning from the 5' end of the mRNA. E7 translation was found to be cap dependent, but E6 was more dependent on capping and eIF4F activity than E7. Insertion of secondary structural elements at various points in the region upstream of E7 profoundly inhibited translation, indicating that scanning was probably continuous. Insertion of the E6 region between Renilla and firefly luciferase genes revealed little or no internal ribosomal entry site activity. However when E6 was located at the 5' end of the mRNA, it permitted over 100-fold-higher levels of downstream cistron translation than did the Renilla open reading frame. Internal AUGs in the E6 region with strong or intermediate Kozak sequence contexts were unable to inhibit E7 translation, but initiation at the E7 AUG was efficient and accurate. These data support a model in which E7 translation is facilitated by an extreme degree of leaky scanning, requiring the negotiation of 13 upstream AUGs. Ribosomal initiation complexes which fail to initiate at the E6 start codon can scan through to the E7 AUG without initiating translation, but competence to initiate is achieved once the E7 AUG is reached. These findings suggest that the E6 region of HPV-16 comprises features that sponsor both translation of the E6 protein and enhancement of translation at a downstream site.

5' Untranslated Regions↗

PubMed2000

AIB1 is a conduit for kinase-mediated growth factor signaling to the estrogen receptor.

Growth factor modulation of estrogen receptor (ER) activity plays an important role in both normal estrogen physiology and the pathogenesis of breast cancer. Growth factors are known to stimulate the ligand-independent activity of ER through the activation of mitogen-activated protein kinase (MAPK) and the direct phosphorylation of ER. We found that the transcriptional activity of AIB1, a ligand-dependent ER coactivator and a gene amplified preferentially in ER-positive breast cancers, is enhanced by MAPK phosphorylation. We demonstrate that AIB1 is a phosphoprotein in vivo and can be phosphorylated in vitro by MAPK. Finally, we observed that MAPK activation of AIB1 stimulates the recruitment of p300 and associated histone acetyltransferase activity. These results suggest that the ability of growth factors to modulate estrogen action may be mediated through MAPK activation of the nuclear receptor coactivator AIB1.

Animals↗

PubMed2000

BRG-1 is recruited to estrogen-responsive promoters and cooperates with factors involved in histone acetylation.

Several factors that mediate activation by nuclear receptors also modify the chemical and structural composition of chromatin. Prominent in this diverse group is the steroid receptor coactivator 1 (SRC-1) family, which interact with agonist-bound nuclear receptors, thereby coupling them to multifunctional transcriptional coregulators such as CREB-binding protein (CBP), p300, and PCAF, all of which have potent histone acetyltransferase activity. Additionally factors including the Brahma-related gene 1 (BRG-1) that are involved in the structural remodeling of chromatin also mediate hormone-dependent transcriptional activation by nuclear receptors. Here, we provide evidence that these two distinct mechanisms of coactivation may operate in a collaborative manner. We demonstrate that transcriptional activation by the estrogen receptor (ER) requires functional BRG-1 and that the coactivation of estrogen signaling by either SRC-1 or CBP is BRG-1 dependent. We find that in response to estrogen, ER recruits BRG-1, thereby targeting BRG-1 to the promoters of estrogen-responsive genes in a manner that occurs simultaneous to histone acetylation. Finally, we demonstrate that BRG-1-mediated coactivation of ER signaling is regulated by the state of histone acetylation within a cell. Inhibition of histone deacetylation by trichostatin A dramatically increases BRG-1-mediated coactivation of ER signaling, and this increase is reversed by overexpression of histone deacetylase 1. These studies support a critical role for BRG-1 in ER action in which estrogen stimulates an ER-BRG-1 association coupling BRG-1 to regions of chromatin at the sites of estrogen-responsive promoters and promotes the activity of other recruited factors that alter the acetylation state of chromatin.

Acetylation↗