Search PubMed⌕ Search

Biomedical subjects

J M White

Publications and source records attributed to J M White.

At least 55 records · Page 3Linked to original sources
PubMed2001

The acute effects of zolpidem compared to diazepam and lorazepam using radiotelemetry.

The present study used a radiotelemetric method to compare the muscle relaxant, hypothermic and locomotor depressant actions of the imidazopyridine zolpidem, with those of the benzodiazepines lorazepam and diazepam. Rats, n=7 per group, were divided into 3 dose-dependent treatment groups (highest, middle, and lowest). Each rat within a treatment group received a single dose of diazepam, lorazepam, zolpidem and vehicle. All three drugs induced dose-dependent decreases in body temperature, locomotor activity and electromyographic (EMG) activity. Administration of zolpidem (5 and 10 mg/kg) resulted in maximal decrements in locomotor activity that were comparable to those elicited by both diazepam (10 and 20 mg/kg) and lorazepam (12.5 and 25 mg/kg). Zolpidem (10 mg/kg) decreased EMG activity levels to approximately 45% of vehicle treated controls; a value similar to that induced by diazepam (2.5 mg/kg). These data suggest that the imidazopyridine zolpidem has a similar profile of acute effects in comparison to the benzodiazepines diazepam and lorazepam. However, the relative magnitude of the effects differed, with zolpidem producing less hypothermia and muscle relaxation than the two benzodiazepines.

Animals↗
PubMed2001

Sequence-specific interaction between the disintegrin domain of mouse ADAM 3 and murine eggs: role of beta1 integrin-associated proteins CD9, CD81, and CD98.

ADAM 3 is a sperm surface glycoprotein that has been implicated in sperm-egg adhesion. Because little is known about the adhesive activity of ADAMs, we investigated the interaction of ADAM 3 disintegrin domains, made in bacteria and in insect cells, with murine eggs. Both recombinant proteins inhibited sperm-egg binding and fusion with potencies similar to that which we recently reported for the ADAM 2 disintegrin domain. Alanine scanning mutagenesis revealed a critical importance for the glutamine at position 7 of the disintegrin loop. Fluorescent beads coated with the ADAM 3 disintegrin domain bound to the egg surface. Bead binding was inhibited by an authentic, but not by a scrambled, peptide analog of the disintegrin loop. Bead binding was also inhibited by the function-blocking anti-alpha6 monoclonal antibody (mAb) GoH3, but not by a nonfunction blocking anti-alpha6 mAb, or by mAbs against either the alphav or beta3 integrin subunits. We also present evidence that in addition to the tetraspanin CD9, two other beta1-integrin-associated proteins, the tetraspanin CD81 as well as the single pass transmembrane protein CD98 are expressed on murine eggs. Antibodies to CD9 and CD98 inhibited in vitro fertilization and binding of the ADAM 3 disintegrin domain. Our findings are discussed in terms of the involvement of multiple sperm ADAMs and multiple egg beta1 integrin-associated proteins in sperm-egg binding and fusion. We propose that an egg surface "tetraspan web" facilitates fertilization and that it may do so by fostering ADAM-integrin interactions.

ADAM Proteins↗
PubMed2001

The relationship between mood state and plasma methadone concentration in maintenance patients.

Although methadone maintenance is designed to stabilize opioid-dependent patients, some experience significant withdrawal in the latter part of the 24-hour interdosing interval. This study was designed to determine the mood changes that maybe associated with such withdrawal. Eighteen methadone patients, nine of whom experienced significant withdrawal, were tested over a single interdosing interval. During this time, 13 blood samples were collected to measure plasma racemic methadone concentrations, and the Profile of Mood States (POMS) was administered on 11 of these occasions. The POMS was also administered on 11 occasions over 24 hours to 10 drug-free healthy controls. In comparison with controls, methadone patients showed increased anger, depression, tension, confusion, and fatigue, as well as decreased vigor. For all scales, maximal differences from controls occurred at times of trough methadone concentration and minimal differences around the time of peak concentration. Changes in mood over the interdosing interval were more exaggerated in the nine patients who experienced significant withdrawal compared with those who did not. The composite Total Mood Disturbance (TMD) scores were calculated for each subject at each time point. The sigmoid Emax model was used to relate plasma concentrations to these data and to calculate the slope factor (N). This model could be fitted for 14 of the 18 patients with a mean +/- SEM slope factor of 2.2 +/- 0.5. TMD score was also shown to be inversely related to the rate of decline in methadone concentration from peak to trough. These results show that significant mood changes occur in response to changes in methadone concentration, and these are more pronounced in those who experience withdrawal. The concentration-effect relationships suggest that relatively small changes in plasma concentration will result in significant mood change. Differences in the degree of mood change between those who do and do not experience significant withdrawal may be explained by variation in the rate of decline in plasma concentration from peak to trough.

Adult↗
PubMed2001

Music as intervention: a notable endeavor to improve patient outcomes.

Music interventions have been used in medicine and nursing throughout history. Music therapy is an easy-to-administer, relatively inexpensive, noninvasive intervention that has been used to reduce heart rate, blood pressure, myocardial oxygen consumption, gastrointestinal function, anxiety, and pain. A review of theoretic and empirical base for the use of music therapy to improve patient outcomes in a variety of areas of clinical practice is presented. Implications for practice and future research are suggested.

Auditory Cortex↗
PubMed2000

A one-flask synthesis of Weinreb amides from chiral and achiral carboxylic acids using the deoxo-fluor fluorinating reagent.

[structure] The reagent [bis(2-methoxyethyl)amino]sulfur trifluoride (Deoxo-Fluor reagent) converts carboxylic acids to the corresponding acid fluorides, which then react with N,N-dimethylhydroxylamine to give the corresponding Weinreb amides in high yields. The reaction proceeds without racemization when optically active acids are used as the starting material. This method is operationally simple and provides the products in high purity.

Amides↗
PubMed2000

The transmembrane domain of influenza hemagglutinin exhibits a stringent length requirement to support the hemifusion to fusion transition.

Glycosylphosphatidylinositol-anchored influenza hemagglutinin (GPI-HA) mediates hemifusion, whereas chimeras with foreign transmembrane (TM) domains mediate full fusion. A possible explanation for these observations is that the TM domain must be a critical length in order for HA to promote full fusion. To test this hypothesis, we analyzed biochemical properties and fusion phenotypes of HA with alterations in its 27-amino acid TM domain. Our mutants included sequential 2-amino acid (Delta2-Delta14) and an 11-amino acid deletion from the COOH-terminal end, deletions of 6 or 8 amino acids from the NH(2)-terminal and middle regions, and a deletion of 12 amino acids from the NH(2)-terminal end of the TM domain. We also made several point mutations in the TM domain. All of the mutants except Delta14 were expressed at the cell surface and displayed biochemical properties virtually identical to wild-type HA. All the mutants that were expressed at the cell surface promoted full fusion, with the notable exception of deletions of >10 amino acids. A mutant in which 11 amino acids were deleted was severely impaired in promoting full fusion. Mutants in which 12 amino acids were deleted (from either end) mediated only hemifusion. Hence, a TM domain of 17 amino acids is needed to efficiently promote full fusion. Addition of either the hydrophilic HA cytoplasmic tail sequence or a single arginine to Delta12 HA, the hemifusion mutant that terminates with 15 (hydrophobic) amino acids of the HA TM domain, restored full fusion activity. Our data support a model in which the TM domain must span the bilayer to promote full fusion.

Amino Acid Sequence↗
PubMed2000

Heptad-repeat regions of respiratory syncytial virus F1 protein form a six-membered coiled-coil complex.

The Respiratory Syncytial Virus (RSV) fusogenic glycoprotein F(1) was characterized using biochemical and biophysical techniques. Two heptad-repeat (HR) regions within F(1) were shown to interact. Proteinase-K digestion experiments highlight the HR1 region (located proximal to the fusion peptide sequence) of the F(1) protein to which an HR2-derived (located proximal to the membrane-spanning domain) peptide binds, thus protecting both the protein and peptide from digestion. Solution-phase analysis of HR1-derived peptides shows that these peptides adopt helical secondary structure as measured by circular dichroism. Sedimentation equilibrium studies indicate that these HR1 peptides self-associate in a monomer/trimer equilibrium with an association constant of 5.2 x 10(8) M(-2). In contrast, HR2-derived peptides form random monomers in solution. CD analysis of mixtures containing peptides from the two regions demonstrate their propensity to interact and form a very stable (T(m) = 87 degrees C), helical (86% helicity) complex comprised of three HR1 and three HR2 members.

Amino Acid Sequence↗
PubMed2000

Recombination signal sequences restrict chromosomal V(D)J recombination beyond the 12/23 rule.

The genes encoding the variable regions of lymphocyte antigen receptors are assembled from variable (V), diversity (D) and joining (J) gene segments. V(D)J recombination is initiated by the recombinase activating gene (RAG)-1 and -2 proteins, which introduce DNA double-strand breaks between the V, D and J segments and their flanking recombination signal sequences (RSSs). Generally expressed DNA repair proteins then carry out the joining reaction. The conserved heptamer and nonamer sequences of the RSSs are separated by non-conserved spacers of 12 or 23 base pairs (forming 12-RSSs and 23-RSSs). The 12/23 rule, which is mediated at the level of RAG-1/2 recognition and cutting, specifies that V(D)J recombination occurs only between a gene segment flanked by a 12-RSS and one flanked by a 23-RSS. Vbeta segments are appended to DJbeta rearrangements, with little or no direct Vbeta to Jbeta joining, despite 12/23 compatibility of Vbeta 23-RSSs and Jbeta12-RSSs. Here we use embryonic stem cells and mice with a modified T-cell receptor (TCR)beta locus containing only one Dbeta (Dbeta1) gene segment and one Jbeta (Jbeta1) gene cluster to show that the 5' Dbeta1 12-RSS, but not the Jbeta1 12-RSSs, targets rearrangement of a diverse Vbeta repertoire. This targeting is precise and position-independent. This additional restriction on V(D)J recombination has important implications for the regulation of variable region gene assembly and repertoire development.

Alleles↗
PubMed2000

Sequence-specific interaction between the disintegrin domain of mouse ADAM 2 (fertilin beta) and murine eggs. Role of the alpha(6) integrin subunit.

Little is yet known about the biological and biochemical properties of the disintegrin-like domains of ADAM (a disintegrin and metalloprotease) proteins. Mouse ADAM 2 (mADAM 2; fertilin beta) is a sperm surface protein involved in murine fertilization. We produced recombinant proteins containing the disintegrin-like domain of mADAM 2 in both insect cells and in bacteria. The protein produced in insect cells (baculo D+C) contained a signal sequence followed by the disintegrin-like and cysteine-rich domains; it was purified from the medium of recombinant baculovirus-infected cells. A bacterial construct containing the disintegrin-like domain was produced in Escherichia coli as a glutathione S-transferase chimera. Baculo D+C, as well as the D domain of the bacterial construct (released with thrombin), bound to the microvillar surface of murine eggs. Using concentrations in the range of 1 to 5 microM, both recombinant proteins strongly inhibited sperm-egg binding and fusion; the baculovirus-produced protein exhibited a somewhat greater extent of inhibition (approximately 75 versus approximately 55% maximal inhibition). Substitution of alanine for each of the five charged residues within the disintegrin loop of mADAM 2 revealed a critical importance for the aspartic acid at position nine. Binding of both recombinant proteins to the egg was inhibited by the function blocking anti-alpha(6) monoclonal antibody, GoH3, but not by a nonfunction-blocking anti-alpha(6) monoclonal antibody. Binding was also inhibited by a peptide analogue of, and with an antibody against, the disintegrin loop of mADAM 2.

ADAM Proteins↗
PubMed2000

Long-term abecarnil administration produces tolerance and withdrawal signs in the rat.

Abecarnil is a non-benzodiazepine that possesses anxiolytic and anticonvulsant properties. Conflicting reports of tolerance and withdrawal signs following chronic abecarnil administration have emerged from animal studies using different species and different models of tolerance and dependence. This study used a radiotelemetric method to examine any emergence of tolerance and abstinence signs in the rat following long-term abecarnil administration. Hooded Wistar rats, n=6 per group, were administered either abecarnil (8 mg/kg/bidaily, i.p.) or vehicle for 24 days. Locomotor activity, body temperature and electromyographic (EMG) activity were measured daily immediately following abecarnil administration. Tolerance to the abecarnil-induced muscle relaxant effects and decreased locomotor activity developed within 21 days. Administration of the benzodiazepine antagonist flumazenil (25 mg/kg), 18 h after abecarnil cessation, precipitated abstinence signs that included decreases in body temperature, and large increases in locomotor activity and muscle tone. Moreover, continuous recording of these measures over the 4 days after flumazenil administration indicated a prolonged increase in daytime locomotor activity, suggestive of spontaneous withdrawal. These data support earlier findings that reported signs of tolerance during administration of abecarnil and abstinence signs following abecarnil cessation.

Animals↗
PubMed2000

The prevalence of alcohol, cannabinoids, benzodiazepines and stimulants amongst injured drivers and their role in driver culpability: part ii: the relationship between drug prevalence and drug concentration, and driver culpability.

Blood samples from 2,500 injured drivers were analysed for alcohol, cannabinoids (measured by the presence of THC), benzodiazepines and stimulants. The relationship between the prevalence and concentration of drugs and the culpability of the driver was examined using an objective method for assessing culpability. There were no significant differences between males and females with respect to culpability. However, there was a relationship between age and culpability: drivers under 26 years and over 60 years were more likely to be culpable. Drivers who tested positive for alcohol only, benzodiazepines only and the combinations of alcohol and THC and alcohol and benzodiazepines were significantly more likely to be culpable for the crash compared with the drug-free group. Conversely, a lower percentage of drivers who only tested positive for THC were culpable for the crash compared with drug-free drivers. This difference was not statistically significant. For car drivers in single-vehicle crashes, the majority of drivers were judged culpable irrespective of drug use. In multiple-vehicle crashes, car drivers testing positive for alcohol only or benzodiazepines only were more likely to be culpable for the crash compared with drug-free drivers. For motorcycle riders in both single- and multiple-vehicle crashes, there were no significant differences between the drug-positive and drug-free groups. A higher percentage of drug-free riders in multiple-vehicle crashes were culpable compared with riders who only tested positive for THC, but this difference was not statistically significant. There was a significant concentration-dependent relationship between alcohol and culpability: as blood alcohol concentration increased, so did the percentage of culpable drivers. When THC was used alone, there was no significant increase in culpability. For those drivers with benzodiazepines at therapeutic concentrations and above, there was a significant increase in culpability. The relationship between stimulants and culpability was not significant, although a higher proportion of stimulant-positive drivers were culpable compared with drug-free drivers. The combinations of alcohol and THC, and alcohol and benzodiazepines also produced a significant increase in culpability, but this increase was not significantly greater than that produced by alcohol alone.

Accidents, Traffic↗
PubMed2000

The prevalence of alcohol, cannabinoids, benzodiazepines and stimulants amongst injured drivers and their role in driver culpability: part i: the prevalence of drug use in drive the drug-positive group.

Blood samples from 2,500 injured drivers were analysed for alcohol, cannabinnoids, benzodiazepines and stimulants. Overall, three-quarters of drivers tested negative for drugs. Alcohol was the most frequently detected drug. Cannabinoids were also detected at high rates, but the majority of drivers tested positive for THC-acid, the inactive metabolite of THC. Benzodiazepines and stimulants were detected at low rates, and detection rates for combinations of drugs were also low. Males were more likely to test positive for drugs, especially alcohol and THC, whereas females were more likely to test positive for benzodiazepines. A similar proportion of car drivers and motorcycle riders tested positive for drugs, although riders were more likely to test positive for THC. Single-vehicle crashes were particularly associated with alcohol for both car driver and riders, and for riders, multiple-vehicle crashes were particularly associated with THC.

Accidents, Traffic↗
PubMed2000

Precipitated and spontaneous withdrawal following administration of lorazepam but not zolpidem.

Radiotelemetry was utilized to compare zolpidem and lorazepam tolerance and withdrawal in rats. Locomotor activity, electromyographic activity (EMG), and body temperatures were used to assess the acute drug effects, and as measures of tolerance and withdrawal. Lorazepam, zolpidem, or vehicle was administered for 12 days, and data were recorded daily, immediately, after treatment. Data were also recorded immediately after flumazenil (25 mg/kg, IP) precipitated withdrawal and during 4 days of spontaneous withdrawal. Complete tolerance to the acute effects of lorazepam administration developed within 7 days of treatment and both flumazenil-precipitated and spontaneous withdrawal were observed. In contrast, there was no tolerance to the sedative actions of zolpidem administration after 12 days, but complete tolerance to the hypothermic and muscle relaxant effects was apparent after 8 days of treatment. Despite the presence of tolerance, no evidence of either spontaneous or flumazenil-induced withdrawal was recorded in these rats. In conclusion, this model suggests that as a sedative zolpidem has significant advantages over the classic benzodiazepines.

Animals↗
PubMed2000

Differential behavioural and neurochemical effects of para-methoxyamphetamine and 3,4-methylenedioxymethamphetamine in the rat.

1. This study was prompted by recent deaths that have occurred after recreational administration of the substituted amphetamine para-methoxyamphetamine (PMA). Because relatively little is known regarding its mechanism(s) of action, its effects on physiological, behavioural and neurochemical parameters were compared with the well known effects of 3,4-methylenedioxymethamphetamine (MDMA). 2. Equivalent doses of PMA (5-20 mg/kg) produced greater hypothermia than MDMA at an ambient temperature of 20 degrees C. At 30 degrees C, PMA continued to evoke hypothermia except the highest dose where hyperthermia ensued. MDMA altered body temperature only at the highest dose where hyperthermia also resulted. 3. At both 20 and 30 degrees C, MDMA stimulated locomotor activity whereas PMA had modest effects and then, only at high doses. 4. In vivo chronoamperometry was used to measure the effect of MDMA and PMA on release, and inhibition of uptake, of serotonin (5-HT) and dopamine (DA) in the dorsal striatum of anaesthetised rats. As expected, MDMA evoked release of DA and inhibited uptake of both DA and 5-HT. By contrast, PMA was a relatively weak releasing agent and did not inhibit DA uptake. However, PMA potently inhibited uptake of 5-HT. 5. Taken together these data suggest that the acute adverse effects of PMA are more likely to be associated with alterations in serotonergic rather than dopaminergic neurotransmission.

Amphetamines↗
PubMed2000

Eradication of established tumors by CD8+ T cell adoptive immunotherapy.

We generated the DUC18 T cell receptor transgenic mouse expressing an H-2Kd -restricted transgenic T cell receptor specific for the syngeneic CMS5 fibrosarcoma rejection antigen mutated ERK2(136-144). DUC18 mice were capable of specifically eliminating lethal CMS5 tumor challenges, and transfer of DUC18 splenocytes to naive nontransgenic recipients conferred protection from subsequent and established CMS5 tumor burdens. Eradication of established tumor burdens by adoptive transfer of DUC18 splenocytes was dose and time dependent. Transferred tumor-specific T cells remained functional in vivo and capable of rejecting small tumors even in the presence of large, established tumor burdens. These findings highlight the kinetic battle between tumor growth and the production of a tumor-specific response and have critical implications for effective adoptive immunotherapy.

Animals↗
PubMed2000

UK measles outbreak in non-immune anthroposophic communities: the implications for the elimination of measles from Europe.

We describe the epidemiology of the first nationwide outbreak of measles infection in the UK since the implementation of a mass vaccination campaign. Notifications of infectious diseases, interview and postal questionnaire identified 293 clinical cases, 138 of which were confirmed by salivary IgM, measles virus isolation and PCR. Twelve were epidemiologically linked to confirmed cases. The outbreak began in London, after contact with measles infection probably imported from Italy. Measles genotyping determined by sequence analysis confirmed spread to other unimmunized anthroposophic communities in the north, south west and south coast of England. Only two cases had been vaccinated against measles infection, and 90% of cases were aged under 15 years. Measles virus can selectively target non-immune groups in countries with high vaccine uptake and broader herd immunity. Without harmonization of vaccination policies and uniform high coverage across Europe, the importation and spread of measles virus amongst non-immune groups may prevent the elimination of measles.

Adolescent↗
PubMed2000

CD34+ selection of hematopoietic blood cell collections and autotransplantation in lymphoma: overnight storage of cells at 4 degrees C does not affect outcome.

The purpose of this study was to investigate whether storing mobilized peripheral blood progenitor cell (PBPC) collections overnight before CD34+ selection may delay platelet count recovery after high-dose chemotherapy and CD34+-enriched PBPC re-infusion. Lymphoma patients underwent PBPC mobilization with cyclophosphamide 4 g/m2 i.v. and G-CSF 10 microg/kg/day subcutaneously. Patients were prospectively randomized to have each PBPC collection enriched for CD34+ cells with the CellPro CEPRATE SC System either immediately or after overnight storage at 4 degrees C. Thirty-four patients were randomized to overnight storage and 34 to immediate processing of PBPC; 15 were excluded from analysis due to tumor progression or inadequate CD34+ cell mobilization. PBPC from 23 patients were stored overnight, while 30 subjects underwent immediate CD34+ selection and cryopreservation. Median yield of CD34+ enrichment was 43.6% in the immediate processing group compared to 39.1% in the overnight storage group (P = 0.339). Neutrophil recovery >500 x 10(9)/l occurred a median of 11 days (range 9-16 days) in the overnight storage group compared to 10.5 days (range 9-21 days) in the immediate processing group (P = 0.421). Median day to platelet transfusion independence was 13 (range 7-43) days in the overnight storage group vs 13.5 (range 8-35) days in those assigned to immediate processing (P = 0.933). We conclude that storage of PBPC overnight at 4 degrees C allows pooling of consecutive-day collections resulting in decreased costs and processing time without compromising neutrophil and platelet engraftment after infusion of CD34+-selected progenitor cells. Bone Marrow Transplantation(2000) 25, 559-566.

Adolescent↗