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Biomedical subjects

J Whitehouse

Publications and source records attributed to J Whitehouse.

18 recordsLinked to original sources
PubMed2006

Using intranasal lidocaine to reduce food intake.

OBJECTIVE: Develop a dose-response curve for the effect of intranasal lidocaine on food intake. DESIGN: Healthy obese subjects had food intake, ratings of hunger, desire to eat, craving and fullness measured at lunch after an overnight fast. Four treatments were given as nose drops (0.5-0.6 ml per nostril) 5 min before the meal in a double-blind manner with a four period crossover design including a 7-day washout between periods. The treatments were saline, 2.5, 10 and 25 mg lidocaine per nostril. The order of administration was randomly assigned to each subject. Electrocardiograms, vital signs, chemistry panels, complete blood counts (CBC) and nasal inspections were carried out before and after each dose. SUBJECTS: Forty-seven subjects were screened, 34 were randomized and 20 subjects completed all four study periods in the trial. The subjects were 39+/-12.5 (s.d) years of age, had a weight of 91+/-13.0 kg, a height of 167+/-10.3 cm, 56% were women, 47% were African-American and 53% were Caucasian. MEASUREMENTS: Food intake, rating of hunger, desire to eat, craving and fullness are measures of efficacy. Adverse events, electrocardiograms, vital signs, chemistry panels, nasal inspections, CBC and physical exams are measures of safety. RESULTS: The mean reduction in food intake vs saline control in the 20 subjects completing all four study periods was 3.3+/-7% (s.d), 4.2+/-8.5% and 7.4+/-7.3% in the 2.5 mg, 10 and 25 mg per nostril groups, respectively (P=NS). Hunger and desire to eat in subjects who completed at least one study period decreased dose dependently (P<0.03, at the 25 mg per nostril dose). There were no clinically significant changes in safety measures, electrocardiograms, vital signs, chemistry panels, CBC or nasal inspections. CONCLUSION: Intranasal lidocaine reduced hunger and the desire to eat, but this did not translate into a significant reduction in food intake suggesting that intranasal lidocaine will not have value in treating obesity.

Administration, Intranasal↗
PubMed2003

Hair follicle dermal cells differentiate into adipogenic and osteogenic lineages.

The adult hair follicle dermal papilla (DP) and dermal sheath (DS) cells are developmentally active cell populations with a proven role in adult hair follicle-cycling activity and unique inductive powers. In stem cell biology, the hair follicle epithelium has recently been the subject of a great deal of investigation, but up to now, the follicle dermis has been largely overlooked as a source of stem cells. Following the sporadic appearance of muscle, lipid and bone-type cells in discretely isolated follicle DP and DS cell primary cultures, we demonstrated that cultured papilla and sheath cell lines were capable of being directed to lipid and bone differentiation. Subsequently, for the first time, we produced clonal DP and DS lines that had extended proliferative capabilities. Dye exclusion has been reported to be an identifying feature of stem cells; therefore, clonal papilla and sheath lines with differing capacity to exclude rhodamine 123 were cultured in medium known to induce adipocyte and osteocyte differentiation. Both DS- and DP-derived clones showed the capacity to make lipid and to produce calcified material; however, different clones had varied behaviour and there was no obvious correlation between their stem cell capabilities and dye exclusion or selected gene expression markers. As a highly accessible source, capable of being discretely isolated, the follicle has important potentially as a stem cell source for tissue engineering and cell therapy purposes. It will also be interesting to compare follicle dermal stem cell properties with the broader stem cell capabilities discovered in skin dermis and investigate whether, as we believe, the follicle is a key dermal stem cell niche. Finally, the discovery of stem cells in the dermis may have implications for certain pathologies in which abnormal differentiation occurs in the skin.

Actins↗
PubMed2000

Risk factors for preterm birth, low birth weight, and intrauterine growth retardation in infants born to HIV-infected pregnant women receiving zidovudine. Pediatric AIDS Clinical Trials Group 185 Team.

OBJECTIVE: To evaluate independent contributions of maternal factors to adverse pregnancy outcomes (APO) in HIV-infected women receiving antiretroviral therapy (ART). DESIGN: Risk factors for preterm birth (< 37 weeks gestation), low birth weight (LBW) (< 2500 g), and intrauterine growth retardation (IUGR) (birth weight < 10th percentile for gestational age) examined in 497 HIV-infected pregnant women enrolled in PACTG 185, a perinatal clinical trial. METHODS: HIV RNA copy number, culture titer, and CD4 lymphocyte counts were measured during pregnancy. Information collected included antenatal use of cigarettes, alcohol, illicit drugs; ART; obstetric history and complications. RESULTS: Eighty-six percent were minority race/ethnicity; 86% received antenatal monotherapy, predominantly zidovudine (ZDV), and 14% received combination antiretrovirals. Preterm birth occurred in 17%, LBW in 13%, IUGR in 6%. Risk of preterm birth was independently associated with prior preterm birth [odds ratio (OR) 3.34; P < 0.001], multiple gestation (OR, 6.02; P = 0.011), antenatal alcohol use (OR, 1.91; P = 0.038), and antenatal diagnosis of genital herpes (OR, 0.24; P = 0.022) or pre-eclampsia (OR, 6.36; P = 0.025). LBW was associated with antenatal diagnosis of genital herpes (OR, 0.08; P = 0.014) and pre-eclampsia (OR, 5.25; P = 0.049), and baseline HIV culture titer (OR, 1.41; P = 0.037). IUGR was associated with multiple gestation (OR, 8.20; P = 0.010), antenatal cigarette use (OR, 3.60; P = 0.008), and pre-eclampsia (OR, 12.90; P = 0.007). Maternal immune status and HIV RNA copy number were not associated with APO. CONCLUSIONS: Risk factors for APO in antiretroviral treated HIV-infected women are similar to those reported for uninfected women. These data suggest that provision of prenatal care and ART may reduce APO.

Adult↗
PubMed2000

A cell cycle-specific requirement for the XRCC1 BRCT II domain during mammalian DNA strand break repair.

XRCC1 protein is essential for viability in mammals and is required for efficient DNA single-strand break repair and genetic stability following DNA base damage. We report here that XRCC1-dependent strand break repair in G(1) phase of the cell cycle is abolished by mutations created within the XRCC1 BRCT domain that interact with DNA ligase III. In contrast, XRCC1-dependent DNA strand break repair in S phase is largely unaffected by these mutations. These data describe a cell cycle-specific role for a BRCT domain, and we conclude that the XRCC1-DNA ligase III complex is required for DNA strand break repair in G(1) phase of the cell cycle but is dispensable for this process in S phase. The S-phase DNA repair process can remove both strand breaks induced in S phase and those that persist from G(1) and can in part compensate for lack of repair in G(1). This process correlates with the appearance of XRCC1 nuclear foci that colocalize with Rad51 and may thus function in concert with homologous recombination.

Amino Acid Sequence↗
PubMed2000

Complications according to mode of delivery among human immunodeficiency virus-infected women with CD4 lymphocyte counts of < or = 500/microL.

OBJECTIVE: We sought to describe rates of and risk factors for complications by delivery mode among human immunodeficiency virus-infected women with CD4 counts of < or = 500/microL. STUDY DESIGN: Complication rates were calculated by delivery mode, as follows: planned cesarean delivery performed without labor or rupture of membranes, other cesarean delivery performed after labor or rupture of membranes, or vaginal delivery. Risk factors were evaluated. RESULTS: Major complications in the planned cesarean delivery (n = 37), other cesarean delivery (n = 95), and vaginal delivery (n = 365) groups were amnionitis or endometritis (16%, 27%, and 7%, respectively), wound infection (5%, 8%, and <1%, respectively), and transfusion (8%, 6%, and 3%, respectively). Any peripartum infection occurred among 16 (18%) of those with a CD4 count of <200/microL and 43 (13%) with a CD4 count of > or =200/microL (P =.17). On multivariate analyses, factors associated with amnionitis-endometritis were cesarean delivery and African American race, and a factor associated with transfusion was third-trimester anemia. CONCLUSION: Endometritis and wound infection occurred more frequently among human immunodeficiency virus-infected women after cesarean than among women undergoing vaginal delivery; however, complication rates overall were within the range reported in human immunodeficiency virus-negative women. Measures to decrease complications in human immunodeficiency virus-infected women, such as greater use of prophylactic antibiotics, should be assessed.

Adult↗
PubMed1999

Risk factors for perinatal transmission of human immunodeficiency virus type 1 in women treated with zidovudine. Pediatric AIDS Clinical Trials Group Study 185 Team.

BACKGROUND: Maternal, obstetrical, and infant-related factors associated with the risk of perinatal transmission of human immunodeficiency virus type 1 (HIV-1) were identified before the widespread use of zidovudine therapy in pregnant women. The risk factors for transmission when women and infants receive zidovudine are not well characterized. METHODS: We examined the effects of maternal, obstetrical, and infant-related characteristics and maternal virologic and immunologic variables on the risk of perinatal transmission of HIV-1 among 480 women and their infants, all of whom received zidovudine. The women and infants were participating in a phase 3 trial of passive immunoprophylaxis for the prevention of perinatal transmission. RESULTS: In univariate analyses, the risk of perinatal transmission was associated with each of the following: decreased maternal CD4+ lymphocyte counts at base line; decreased maternal HIV p24 antibody levels at base line and delivery; increased maternal HIV-1 titer at base line and delivery; increased maternal HIV-1 RNA levels at base line and delivery; and the presence of chorioamnionitis at delivery. In multivariate analyses, the only independent risk factor was the maternal HIV-1 RNA level at base line (odds ratio for transmission, 2.4 per log increase in the number of copies; 95 percent confidence interval, 1.2 to 4.7; P=0.02) and at delivery (odds ratio, 3.4; 95 percent confidence interval, 1.7 to 6.8; P=0.001). There was no perinatal transmission of HIV-1 among the 84 women who had HIV-1 levels below the limit of detection (500 copies per milliliter) at base line or the 107 women who had undetectable levels at delivery. CONCLUSIONS: Among pregnant women and their infants, all treated with zidovudine, the maternal plasma HIV-1 RNA level was the best predictor of the risk of perinatal transmission of HIV-1. Antiretroviral therapy that reduces the HIV-1 RNA level to below 500 copies per milliliter appears to minimize the risk of perinatal transmission as well as improve the health of the women.

Analysis of Variance↗
PubMed1999

Cell damage-induced conformational changes of the pro-apoptotic protein Bak in vivo precede the onset of apoptosis.

Investigation of events committing cells to death revealed that a concealed NH2-terminal epitope of the pro-apoptotic protein Bak became exposed in vivo before apoptosis. This occurred after treatment of human Jurkat or CEM-C7A T-lymphoma cells with the mechanistically disparate agents staurosporine, etoposide or dexamethasone. The rapid, up to 10-fold increase in Bak-associated immunofluorescence was measured with epitope-specific monoclonal antibodies using flow cytometry and microscopy. In contrast, using a polyclonal antibody to Bak, immunofluorescence was detected both before and after treatment. There were no differences in Bak protein content nor in subcellular location before or after treatment. Immunofluorescence showed Bcl-xL and Bak were largely associated with mitochondria and in untreated cells they coimmunoprecipitated in the presence of nonioinic detergent. This association was significantly decreased after cell perturbation suggesting that Bcl-xL dissociation from Bak occurred on exposure of Bak's NH2 terminus. Multiple forms of Bak protein were observed by two dimensional electrophoresis but these were unchanged by inducers of apoptosis. This indicated that integration of cellular damage signals did not take place directly on the Bak protein. Release of proteins, including Bcl-xL, from Bak is suggested to be an important event in commitment to death.

Apoptosis↗
PubMed1999

Efficacy of zidovudine and human immunodeficiency virus (HIV) hyperimmune immunoglobulin for reducing perinatal HIV transmission from HIV-infected women with advanced disease: results of Pediatric AIDS Clinical Trials Group protocol 185.

Pediatric AIDS Clinical Trials Group protocol 185 evaluated whether zidovudine combined with human immunodeficiency virus (HIV) hyperimmune immunoglobulin (HIVIG) infusions administered monthly during pregnancy and to the neonate at birth would significantly lower perinatal HIV transmission compared with treatment with zidovudine and intravenous immunoglobulin (IVIG) without HIV antibody. Subjects had baseline CD4 cell counts </=500/microL (22% had counts <200/microL) and required zidovudine for maternal health (24% received zidovudine before pregnancy). Transmission was associated with lower maternal baseline CD4 cell count (odds ratio, 1.58 per 100-cell decrement; P=.005; 10.0% vs. 3.6% transmission for count <200 vs. >/=200/microL) but not with time of zidovudine initiation (5.6% vs. 4.8% if started before vs. during pregnancy; P=. 75). The Kaplan-Meier transmission rate for HIVIG recipients was 4. 1% (95% confidence interval, 1.5%-6.7%) and for IVIG recipients was 6.0% (2.8%-9.1%) (P=.36). The unexpectedly low transmission confirmed that zidovudine prophylaxis is highly effective, even for women with advanced HIV disease and prior zidovudine therapy, although it limited the study's ability to address whether passive immunization diminishes perinatal transmission.

Adult↗
PubMed1998

Role of the DNA ligase III zinc finger in polynucleotide binding and ligation.

Mammalian DNA ligase III exists as two distinct isoforms denoted alpha and beta. Both forms possess a motif that is homologous to the putative zinc finger present in poly(ADP-ribose) polymerase. Here, the role of this motif in the binding and ligation of nicked DNA and RNA substrates in vitro has been examined in both isoforms. Disruption of the putative zinc finger did not affect DNA ligase III activity on nicked DNA duplex, nor did it abolish DNA ligase III-alpha activity during DNA base excision repair in a cell-free assay. In contrast, disruption of this motif reduced 3-fold the activity of both DNA ligase III isoforms on nicked RNA present in RNA/DNA homopolymers. Furthermore, whereas disruption of the motif did not prevent binding of DNA ligase III to nicked DNA duplex, binding to nicked RNA homopolymers was reduced approximately 10-fold. These results suggest that the putative zinc finger does not stimulate DNA ligase III activity on simple nicked DNA substrates, but indicate that this motif can target the binding and activity of DNA ligase III to nicked RNA homopolymer. The implications of these results to the cellular role of the putative zinc finger are discussed.

Amino Acid Sequence↗
PubMed1998

Modelling the consultation process in a secondary referral unit for children.

This paper overviews a detailed study of a consultation service for children with severe and/or intractable speech and language difficulties. The Speech Therapy Clinical Unit at the University of Central England in Birmingham (UCE) offered multidisciplinary, in-depth assessment of such children to speech and language therapists, parents and other professions involved in their management. Documentary materials generated by the service were analysed using Grounded Theory to develop a model of the process of assessment and consultation employed in the Unit. The implications of this model for clinical education and practice are discussed.

Child↗
PubMed1993

Protein-fat bypass supplement for lactating dairy cows.

Holstein cows (n = 46) were fed free choice a silage mixture balanced weekly throughout lactation using 13 and 36% CP grains to individualize CP for each cow; grains contained 15 and 20% of distillers grains with solubles, respectively. Cows were blocked by parity (1 vs. > 1) and assigned at calving to receive a commercial bypass protein-fat supplement at 0 (control) or 6% of weekly projected 4% FCM yield throughout lactation. In peak lactation, supplementation raised dietary fat from 4.3 to 6.0% of DM, NE(L) from 1.64 to 1.70 Mcal/kg of DM, and undegradable protein from 42 to 47% of CP and contributed about 25 and 20% of total CP in early and late lactation. Supplement reduced forage and total DMI significantly, which negated the potential nutritional value of the supplement. Reduction in protein content of milk from supplemented cows was small but significant; BW and yields of milk, SCM, and 4% FCM were not significantly affected by treatment. Supplementation increased fat test in parity 1 cows and lowered it in older cows. In wk 5 to 8, 21 to 24, and 37 to 40 postpartum, cows consumed 100 to 116% of the NRC recommendations of undegradable protein but only 65 to 94% of degradable CP needs; NE(L) intake generally was adequate except for primiparous cows in early lactation. Supplementation lowered Lys intake in early lactation. Addition of rumen-protected fat and undegradable, high quality protein mixture to the diet of lactating cows cannot be effective if its use reduced DMI or if degradable protein intake is inadequate.

Animal Feed↗
PubMed1987

The magnitude and duration of itch produced by intracutaneous injections of histamine.

The magnitude and duration of itch sensation produced by intracutaneous injection of histamine were determined for humans with the procedure of magnitude estimation scaling. Thirteen subjects received a 10-microliter intracutaneous injection of histamine at doses of 0.0001, 0.001, 0.01, 0.1, 1, and 10 micrograms into the volar forearm; eight of these subjects also received a 100-microgram dose. One subject received multiple injections over several weeks to determine the reliability of the magnitude estimates of itch. Following each injection, the area of flare and duration of itch were also determined. Intracutaneous injection of histamine produced a pure sensation of itch, without pain. The magnitude of itch increased in a dose-dependent fashion. The lowest histamine dose that produced itch greater than the itch produced by vehicle was 0.01 micrograms. The greatest itch was produced by the 100-microgram dose. A power function fitted to the mean magnitude estimates had an exponent of 0.17, indicating a negatively accelerating relation between the magnitude of itch and histamine dose. The one subject who received histamine over several weeks gave fairly reproducible estimates of itch magnitude. The duration of itch and the area of flare also increased in a dose-dependent fashion. The lowest dose of histamine that produced a duration of itch longer than the itch produced by the vehicle was 0.1 microgram, while the 100-microgram dose produced the longest duration of itch. Although the area of flare increased with each increase in dose from 0.1 to 10 micrograms, the areas of flare produced by 10 and 100 micrograms of histamine did not differ. These results indicate that humans can scale the magnitude of itch produced by histamine in a dose-dependent manner. In addition, the duration of itch and the area of flare produced by histamine are dose-dependent, confirming results of previous investigators. Intracutaneous histamine is easily quantifiable and may thus be a useful stimulus in neurophysiological studies of the peripheral neural mechanisms of itch.

Dose-Response Relationship, Drug↗
PubMed1986

Tactile detection of a dot on a smooth surface: peripheral neural events.

The capacities of humans to detect the presence of a single raised dot of 550 micron diameter on a smooth plate and to judge the magnitude of evoked sensation were determined for dots of different heights, stroked at different velocities across the passive fingerpad. Evoked responses to the same stimuli were recorded from single, slowly adapting (SA), rapidly adapting (RA), and Pacinian (PC) mechanoreceptive peripheral nerve fibers innervating the fingerpad of anesthetized macaque monkeys. When the stroke velocity was 10 mm/s, dot height detection thresholds, as determined from measurements of detection sensitivity were between 1 and 3 microns for all human observers. From fiber recordings in monkeys, the RAs had dot height thresholds of 2-4 microns, i.e., within the range of human detection thresholds. The dot height thresholds were 8 microns or greater for SAs and 21 micron or greater for PCs. In contrast, force thresholds for punctate von Frey filaments did not differ for RAs and SAs and were lowest for PCs. The magnitude of sensation evoked in human increased with increases in dot height above threshold. Similarly, the number of nerve impulses evoked in monkey RAs increased with dot height as did the widths of RA receptive fields. Neither changes in stroke velocity from 10 to 40 mm/s nor changes in vertical force applied by the dot plate to the skin altered sensory magnitude evoked by a 15-microns high dot or the number of impulses evoked in RAs. However, a decrease in stroke velocity from 10 to 1.5 mm/s elevated sensory detection thresholds and, for the 15-microns high dot, decreased sensory magnitude, the number of impulses in RAs, and the widths of RA receptive fields. It was hypothesized that the mechanical event responsible for activating the RA was the lateral deformation of elevated regions of skin. In support of this, the number of impulses evoked in RAs by a dot was greater when the dot was stroked across, as opposed to along, the papillary ridges. Also, under certain stimulus conditions, a correspondence was observed between the occurrence of each action potential in an RA and the passage of the leading edge of the dot across the peak of a papillary ridge. It is concluded that the responses of RAs alone account for the sensory capacity to detect a dot of minimal height on a smooth surface with the fingerpad.(ABSTRACT TRUNCATED AT 400 WORDS)

Adaptation, Physiological↗
PubMed1986

Pain changes among men from before to after drinking: effects of expectancy set and dose manipulations with alcohol and tonic as mediated by prior experience with alcohol.

In an experiment that manipulated the set that one would consume (or not consume) an alcoholic beverage, pain reduction occurred among men (N = 52) told that they had consumed alcohol if they reported customarily drinking in large amounts or drinking in order to attain positive emotional states. When the men's belief that they had or had not consumed alcohol was taken into account, the propensity to drink for social-celebratory and personal-deficiency reasons was also associated with pain reduction.

Adult↗
PubMedDate not supplied

Adenovirus type 5 uptake by lung adenocarcinoma cells in culture correlates with Ad5 fibre binding is mediated by alpha(v)beta1 integrin and can be modulated by changes in beta1 integrin function.

BACKGROUND: Recombinant adenoviruses (Ad) have been employed as vectors for a wide variety of gene therapy applications, but their use has been hindered by problems relating to efficacy and safety. The efficiency of Ad-mediated gene transfer depends on the interaction of the fibre and penton base proteins with their corresponding cell receptors. Ad infection is initiated by the formation of a high affinity complex between the fibre protein and a host cell protein that for most Ad serotypes is CAR (the coxsackie B virus and Ad receptor). A second molecule, the MHC class I, may also be involved in Ad type 2 and Ad type 5 uptake. Ad internalization results from the interaction of the penton base protein with cell surface integrins alpha(v)beta3 and alpha(v)beta5. In this study, we addressed the interaction between Ad type 5 (Ad5) and its receptors on lung derived adenocarcinoma cells in culture. METHODS: Using flow cytometry, we determined the level of expression of attachment and internalization receptors that are expressed on the cell surface of A549, H322 and H441 lung-derived adenocarcinoma cells in culture. The level of alpha(v)beta1 cell surface integrin was assessed by immunoprecipitation. Measuring the level of luciferase gene expression at different viral titres quantitated Ad5 uptake by these cells. The kinetics of binding of Ad5 fibre knobs to A549, H322 and H441 cells was assessed in direct binding studies using 125I labelling of purified recombinant Ad5 fibre-knob domains. In order to assess the functionality of integrins, adhesion assays were performed in the presence or absence of activators of integrin function. In competition experiments, prior to exposure to the virus, the cells were pre-incubated with purified recombinant Ad5 fibre-knob domains, function blocking anti-integrin antibodies, or integrin activating agents, prior to the introduction of luciferase expressing Ad5. RESULTS: We found that Ad5-mediated gene transfer in A549, H322 and H441 adenocarcinoma cells in culture is highly variable and that this variation correlates with specific binding of Ad5 fibre-knob domain binding to the cell surface. We also found, for the first time, that Ad5 infection is mediated by integrin alpha(v)beta1 and that functional activation of beta1 integrin by means of the specific anti-beta1 monoclonal antibody, TS2/16, induced increased A549 cell adhesion to fibronectin and vitronectin and also enhanced Ad5 uptake by these cells. CONCLUSIONS: Our studies demonstrate that the Ad5 fibre-knob domain interaction with CAR represents a major determinant of Ad5-mediated gene transfer to lung-derived adenocarcinoma cells in culture. The finding that integrin alpha(v)beta1 is involved in Ad5 infection has implications for the use of recombinant Ad5 vectors for cancer gene therapy, since alpha(v)beta1 is expressed at high levels and acts as an alternative vitronectin receptor in many epithelial and some melanoma tumours which express no alpha(v)beta3 and constant low levels of alpha(v)beta5. The fact that the beta1 integrin-activating antibody TS2/16 can enhance alpha(v)beta1-mediated Ad5 infection suggests that the efficacy of Ad5-mediated gene transfer might be influenced not only by the level of cell surface expression of integrins but also by their state of activation.

Adenocarcinoma↗