Industrial genotoxicology group.
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Animals↗
Biomedical subjects
B Phillips
Publications and source records attributed to B Phillips.
Activation of heat shock factor 2 during hemin-induced differentiation of human erythroleukemia cells.
Hemin induces nonterminal differentiation of human K562 erythroleukemia cells, which is accompanied by the expression of certain erythroid cell-specific genes, such as the embryonic and fetal globins, and elevated expression of the stress genes hsp70, hsp90, and grp78/BiP. Previous studies revealed that, as during heat shock, transcriptional induction of hsp70 in hemin-treated cells is mediated by activation of heat shock transcription factor (HSF), which binds to the heat shock element (HSE). We report here that hemin activates the DNA-binding activity of HSF2, whereas heat shock induces predominantly the DNA-binding activity of a distinct factor, HSF1. This constitutes the first example of HSF2 activation in vivo. Both hemin and heat shock treatments resulted in equivalent levels of HSF-HSE complexes as analyzed in vitro by gel mobility shift assay, yet transcription of the hsp70 gene was stimulated much less by hemin-induced HSF than by heat shock-induced HSF. Genomic footprinting experiments revealed that hemin-induced HSF and heat shock-induced HSF, HSF2, and HSF1, respectively, occupy the HSE of the human hsp70 promoter in a similar yet not identical manner. We speculate that the difference in occupancy and/or in the transcriptional abilities of HSF1 and HSF2 accounts for the observed differences in the stimulation of hsp70 gene transcription.
Base Sequence↗
Treatment of snoring and obstructive sleep apnea.
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Adult↗
Carbon-13 nuclear magnetic resonance spectroscopy of lipids: differential line broadening due to cross-correlation effects as a probe of membrane structure.
We have obtained proton-coupled carbon-13 nuclear magnetic resonance (NMR) spectra of a variety of lipid-water and lipid-drug-water systems, at 11.7 T, as a function of temperature, using the "magic-angle" sample-spinning (MAS) NMR technique. The resulting spectra show a wide range of line shapes, due to interferences between dipole-dipole and dipole-chemical shielding anisotropy interactions. The differential line-broadening effects observed are particularly large for aromatic and olefinic (sp2) carbon atom sites. Coupled spectra of the tricyclic antidepressants desipramine and imipramine, in 1,2-dimyristoyl-sn-glycero-3-phosphocholine-water mesophases, show well-resolved doublets having different line shapes for each of the four aromatic methine groups, due to selective averaging of the four C-H dipolar interactions due to rapid motion about the director (or drug C2) axis. 2H NMR spectra of [2,4,6,8-2H4]desipramine (and imipramine) in the same 1,2-dimyristoyl-sn-glycero-3-phosphocholine-water mesophase exhibit quadrupole splittings of approximately 0-2 and approximately 20 kHz, indicating an approximate magic-angle orientation of the C2-2H(1H) and C8-2H(1H) vectors with respect to an axis of motional averaging, in accord with the 13C NMR results. Selective deuteration of imipramine confirms these ideas. Spectra of digalactosyl diglyceride [primarily 1,2-di[(9Z,12Z,15Z)-octadeca-9,12,15-trienoyl ]-3- (alpha-D-galactopyranosyl-1-6-beta-D-galactopyranosyl)-sn-glycerol]-H2O (in the L alpha phase) show a large differential line broadening for C9 but a reduced effect for C10, consistent with the results of 2H NMR of specifically 2H-labeled phospholipids [Seelig, J., & Waespe-Saracevic, N. (1978) Biochemistry 17, 3310-3315].(ABSTRACT TRUNCATED AT 250 WORDS)
Carbon Isotopes↗
Transcriptional regulation of human hsp70 genes: relationship between cell growth, differentiation, virus infection, and the stress response.
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Bacterial Proteins↗
A modeling framework for AIDS/HIV nonacute care services.
This paper describes the conceptual structure underlying the microcomputer-based modeling system developed by Mathematica Policy Research, Inc. The modeling system was developed to assist communities in planning nonacute care services for symptomatic human immunodeficiency virus (HIV)-infected persons. The modeling system is based on the assumptions that (1) the characteristics of the HIV epidemic and the availability of nonacute care service vary across communities and (2) combinations of nonacute care services can be appropriately substituted for one another and for hospital-based nonacute care to meet the varying medical and social needs of symptomatic HIV-infected persons.
Acquired Immunodeficiency Syndrome↗
Shift work, sleep quality, and worker health: a study of police officers.
The Planning and Analysis Unit of the Lexington Police Department changed from rotating to permanent shift assignments. We report herein the results of patrol officers' responses to the Florida Sleep Questionnaire, the SCL-90 (a symptom checklist), and absentee data. Sleep quality and sleep hygiene improved after changing from rotating to permanent shifts. The SCL-90 demonstrated improved psychologic well-being. Further, absentee rates fell from 1400 hours during the 6 months preceding the shift change to 883 hours during the 6 months following the change. We review the literature concerning the effects of shift work on worker performance.
Absenteeism↗
Attenuation of the heat shock response in HeLa cells is mediated by the release of bound heat shock transcription factor and is modulated by changes in growth and in heat shock temperatures.
When HeLa S3 cells are subjected to a continuous 42 degrees C heat shock, activation of heat shock transcription factor (HSF) and transcriptional activation of the heat shock genes hsp70, hsp89 alpha, and hsp60 is transient, peaking at 40-60 min of heat shock, and then attenuating. We have used in vivo genomic footprinting to demonstrate that attenuation of hsp70 transcription is mediated by release of bound HSF from the heat shock element (HSE) of the hsp70 gene promoter. Release of bound HSF in vivo occurs at a higher rate than would be predicted from in vitro measurements of dissociation. Attenuation of HSF activation and heat shock gene transcription occurs only when mild heat shock temperatures are employed (42 degrees C); increasing the heat shock temperature by 1 degree C elicits a much higher level of activation, which does not attenuate during a 4-hr heat shock. Surprisingly, altering the temperature at which cells are grown prior to heat shock modulates the magnitude and temporal pattern of the response to a given heat shock temperature. This finding suggests that HSF does not sense temperature directly but, instead, may be responsive to the magnitude of the difference between growth and heat shock temperatures.
Base Sequence↗
Pacemaker syndrome in a patient with DDD pacemaker for long QT syndrome.
A patient with long QT syndrome was treated with beta blockers and had a permanent DDD pacemaker implanted. The lower rate was set to 85 beats/min because this provided the best shortening of QT interval at the lowest paced heart rate. The atrioventricular (AV) delay was programmed to 250 msec to allow native AV conduction. Patient returned complaining of symptoms suggestive of pacemaker syndrome. ECG during one of these episodes showed AV sequential pacing. Doppler echocardiography of hepatic vein flow suggested atrial contraction against a closed tricuspid valve. Endocardial electrogram telemetry demonstrated ventriculoatrial (VA) conduction with the retrograde atrial electrogram falling within the atrial refractory period and thus was not sensed. The following atrial stimulus did not capture because of the atrial refractoriness. Ventricular pacing proceeded after the programmed AV delay. Reprogramming the AV delay to 200 msec restored AV synchrony by allowing the atrial stimulus to capture by placing it outside of the refractory period of the atrium. No further symptoms reported during six months of follow-up.
Atenolol↗
Analysis of the specificity and mechanism of transcriptional activation of the human hsp70 gene during infection by DNA viruses.
We have examined the transcriptional regulation of the 70-kDa (70K) heat shock gene family following infection of human and monkey cells with four different DNA viruses: adenovirus type 5 (Ad5), herpes simplex virus type 1 (HSV-1), simian virus 40, and vaccinia virus. Our results indicate that induction of these genes is not a general response to the stress of viral infection but is instead a highly specific response, both with regard to the inducing virus and with regard to the target gene. Of three 70K heat shock genes examined, only hsp70 was induced during viral infection, and induction occurred only after infection by Ad5 and HSV-1. As revealed by genomic footprinting analysis, the mechanism of transcriptional activation of hsp70 during Ad5 or HSV-1 infection does not involve changes in the avidity of binding of basal transcription factors to the hsp70 promoter. In HSV-1-infected HeLa cells, transcriptional activation of hsp70 was quite transient, following which transcription was rapidly repressed; this was accompanied by the release of bound factors from the hsp70 promoter. In addition to the selectivity which characterizes the viral activation of hsp70 transcription, our results indicate that the consequences of this activation, as measured by changes in hsp70 mRNA levels and protein synthesis, are also virus specific.
Adenovirus Early Proteins↗
Heat shock-induced interactions of heat shock transcription factor and the human hsp70 promoter examined by in vivo footprinting.
Genomic footprinting of the human hsp70 promoter reveals that heat shock induces a rapid binding of a factor, presumably heat shock transcription factor, to a region encompassing five contiguous NGAAN sequences, three perfect and two imperfect matches to the consensus sequence. Arrays of inverted NGAAN sequences have been defined as the heat shock element. No protein is bound to the heat shock element prior to or after recovery from heat shock. Heat shock does not perturb the binding of factors to other regulatory elements in the promoter which contribute to basal expression of the hsp70 gene.
Base Sequence↗
Auditory evoked potentials in anxiety disorder.
The pathophysiology of anxiety has received much recent attention. EEG findings in anxiety are nonspecific, and some changes in psychophysiological measures have been reported. We recorded short-latency brainstem auditory evoked potentials (BAEPs) and long-latency auditory event-related potentials (AEPs) in 12 patients with generalized anxiety disorder. All 12 patients had BAEP latencies within clinical norms, but I-V interpeak latencies were significantly longer in patients with anxiety than controls. N1, N2, P2, and P3 AEP components were within normal limits; N1 and P2 were reduced in amplitude in anxiety patients, but differences from controls were not significant. The BAEP findings may suggest altered brain-stem function in anxiety, which has been implied by biochemical studies of anxiety and depression. AEP differences may be related to difficulties in concentration and attention direction reported by anxious patients.
Adult↗
Neuropsychiatric aspects of psychogenic status epilepticus.
We studied 20 patients with continuous repetitive psychogenic seizures simulating status epilepticus. Most patients received intravenous doses of multiple anticonvulsants. Our definition used for status epilepticus was that of Delgado-Escueta et al, at least 30 minutes of repetitive seizures without regaining consciousness. Nineteen of 20 patients were young women, all but one under 40 years of age. Sixteen of these patients had a history of childhood seizures. In over 50% of patients, seizures continued until respiratory arrest and intubation occurred. Thorough neuropsychological testing and psychiatric interview were done after cessation of the acute episode. Long-term outcome and prognosis depended on definitive psychiatric diagnosis. Repetitive psychogenic seizures simulating status epilepticus are not uncommon, and such patients may incur serious iatrogenic complications from treatment for status epilepticus. Appropriate management and long-term prognosis may be determined by the type and severity of the underlying psychiatric disorder.
Adult↗
Setting up a fireguard bank.
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Accidents, Home↗
Amantadine hydrochloride for refractory generalized epilepsy in adults.
Amantadine hydrochloride has been shown in several open studies to benefit children with refractory generalized epilepsy. We used amantadine as adjunctive therapy in 10 adolescents and adults with generalized tonic-clonic, myoclonic, or absence seizures refractory to therapeutic levels of valproate, carbamazepine, phenytoin, and benzodiazepines. Seven patients were men and 3 were women aged 18-29 years, and 8 of 10 patients were mentally retarded. All patients had generalized epileptiform paroxysms on EEG, with generalized or absence seizure recorded in 9. Five patients had both absence and tonic-clonic seizures, and 2 had all three seizure types. Amantadine was added to the existing regimens in weekly increments to 400 mg/day. Two patients had greater than 90 per cent seizure reduction, both with vomiting and somnolence. Two patients had seizure reduction between 50 and 90 per cent, 1 with anorexia and sleepiness. Three patients had no change in seizures, and 3 had worse tonic-clonic seizures. Amantadine may have some antiepileptic efficacy of unknown mechanism, but it may worsen generalized tonic-clonic seizures and is likely to be of limited value in adults.
Adolescent↗
Nonwheezing bronchial asthma diagnosed by methacholine challenge.
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Adolescent↗
Secondary mania after ventral pontine infarction.
Secondary mania is increasingly recognized clinically, and consists of acute exhibition of manic symptoms without past or family history of affective disorder. It has been reported with toxic and metabolic disturbances, primary and metastatic brain tumors, epilepsy, and cerebrovascular events. A multifactorial etiology has been suggested. We report two men, 52 and 56 years old, who developed grandiosity, sleeplessness, irritable mood, hyperactivity, and paranoid and religious delusions, with attempted violence in one case. Both had no premorbid psychiatric history and were healthy except for hypertension. One patient had a normal neurologic examination, and the other had mild left hemiparesis and hyperreflexia. EEGs, brainstem auditory-evoked responses, and median nerve somatosensory-evoked potentials were normal. Magnetic resonance studies demonstrated infarction of the ventral pons (on the right in the patient with left-sided signs and on the left in the patient with normal neurologic examination). The two patients responded to lithium carbonate and neuroleptics and have not had further psychiatric symptoms in 18 months of follow-up. These cases emphasize the relationship of late-onset mania with predisposing brain disease, and they suggest that brainstem disturbances can influence mood, sleep, libido, and thought.
Bipolar Disorder↗
Brainstem auditory evoked responses in partial and generalized seizures.
This study presents clinical neurophysiologic evidence of altered upper brainstem function in patients with generalized epilepsy who do not otherwise differ clinically from the general population. While the differences in absolute latencies are not great enough to support the use of BAERs in routine evaluation, this data does support experimental studies implicating brainstem structures in the pathophysiology of primary generalized epilepsy. The lack of evidence of brainstem involvement in complex partial seizures may suggest a mechanism of seizure spread that is not dependent upon primary brainstem pathology, or may indicate that any brainstem abnormality in epilepsy may involve areas not mediating transmission of auditory stimuli and therefore not assessed by BAERs.
Adult↗