Biomedical subjects
Publications and source records attributed to R J Ellis.
Some proteins synthesized by growing eukaryotic cells are transferred along unidirectional pathways of molecular chaperones until the risk of aggregation has decreased and they can be released safely. Mature proteins denatured by stress may instead be handled by chaperones acting in branched, reversible networks.
Anticoagulation with heparin is required in the management of the burn patient if their clinical course is complicated by venous thrombosis. Heparin therapy is commonly monitored by the activated partial thromboplastin time (APTT) but this assay can be unreliable in patients with acute inflammation because of an increase in plasma factor VIII levels that result in an underestimation of the heparin concentration. We report an example of heparin resistance that occurred in a patient who developed venous thrombosis following extensive second-degree burns. Heparin doses in excess of 60,000 units per day were required to produce a significant elevation in the APTT. The plasma factor VIII level was found to be markedly elevated to 455% and the plasma heparin concentration as determined by the anti-factor Xa assay was disproportionately elevated in relation to the APTT. Physicians treating patients with burn injury complicated by venous thrombosis should be aware of the potential development of factor VIII-related heparin resistance when large amounts of heparin are required to obtain a satisfactory elevation in the APTT. Measurement of the plasma heparin concentration will avoid excessive heparin administration and the serious bleeding which can result.
The ability of newly synthesised protein chains to fold into their functional conformations has evolved within the complex intracellular environment. Until recently, however, this ability has been studied largely as the refolding of denatured mature proteins in dilute simple solutions. Recent work aimed at understanding how proteins fold in vivo has allowed some general statements to be postulated.
HIV infection often results in neuropsychological (NP) impairment. In order to assess the impact that HIV-related NP deficits may have on automobile driving, we evaluated 68 HIV-seropositive drivers using an NP battery and two PC-based driving simulations. Thirty-two participants were classified as NP impaired; most (72%) evidenced only mild impairment, and none met criteria for HIV-associated dementia. After controlling for degree of immunosuppression and disease stage, NP-impaired participants failed a previously validated driving simulation at a much higher rate than cognitively intact participants [OR = 5.3, 95% CI (1.7, 17.0), p = .006]. Similarly, on a simulation of city driving, NP impaired participants were more likely to fail based upon the number of accidents [OR = 6.1, 95% CI (1.5, 24.6), p = .01]. Simulator performance was predicted by functioning in a number of NP domains, with NP tests accounting for 13-30% of the variance on the simulations. Although it would be premature to extrapolate these findings to impairment in on-the-road driving, they do argue for greater attention to the impact that even mild HIV-related NP deficits may have on driving skills.
Dendritic and synaptic damage (without frank neuronal loss) may be seen in milder human immunodeficiency virus (HIV)-related cognitive disorders. Synapse volume estimates, performed by stereological methods, could enhance the ability to detect subtle neuronal changes that may accompany cognitive impairment in HIV infection. For the present study, synaptic density and neuronal number were assessed by combined stereology/confocal microscopy and these measures were then correlated with ante-mortem levels of cognitive performance in AIDS patients. Three-dimensional stereological measures showed a significant correlation between reduced synaptic density and poor neuropsychological performance. To evaluate the specificity of any observed associations, additional variables including viral burden, astrogliosis and number of calbindin-immunoreactive neurons were measured. Factor analysis of a set of neuropathological variables revealed two factors; one defined by synaptic density and volume fraction, calbindin pyramidal neuronal densities and viral burden; the second by astrocytosis and calbindin interneuron density. Only the first factor correlated significantly with neuropsychological functioning during life. It is concluded that a combination of factors including synaptic damage, specific neuronal loss and increasing viral load underlies HIV-associated cognitive impairment. As synaptic damage is potentially reversible, early diagnosis and treatment of mild cogntive disorders may improve functioning and prevent the progression of brain disease.
BACKGROUND: ProstaScint (Cytogen Corporation, Princeton, NJ) murine monoclonal antibody imaging is FDA-approved for imaging of prostate cancer patients at high risk for metastatic disease and patients postprostatectomy with a rising serum prostate-specific antigen (PSA) level. ProstaScint is a murine monoclonal antibody which targets prostate-specific membrane antigen (PSMA). PSMA expression is upregulated in primary and metastatic prostate cancer. FDA Cytogen (Princeton, NJ) protocol studies using 111indium-labeled ProstaScint revealed correlation between areas of increased concentration in the prostate and biopsy-proven tumors in patients imaged pretherapy. METHODS: In our study, four transverse, single-photon emission tomography (SPECT) images were isolated and regions of interest were selected and correlated with pretherapy prostate biopsy results. Prostate cancer and normal tissue prostate/muscle background (P/M) ratios were derived, so that postprostatectomy/radiation therapy patients could be evaluated for the presence of residual prostate cancer. Twenty-three pretherapy prostate cancer patients with quadrant/sextant biopsies had SPECT 96-hr 111indium ProstaScint pelvic images. The four transverse 1-cm slices above the midline penile blood pool were chosen, and four to six 27-30-pixel regions of interest were placed over the prostate bed. The background muscle region of interest was placed over the external obturator muscle region. The P/M ratio was calculated and compared to the quadrant/sextant prostatic biopsy result. The same procedure was applied to 17 posttherapy prostate cancer patients with rising PSA. RESULTS: In the 23 pretherapy prostate cancer patients, there was a correlation between the P/M ratio of at least 3.0 in 32 of 35 prostatic cancer biopsy regions, and there was correlation with P/M ratios less than 3.0 in 82 of 89 negative biopsy regions. Seventeen posttherapy patients underwent ProstaScint studies. Six underwent biopsy, with typically one biopsy site per patient. All 6 had P/M ratios greater than 3.0 in the biopsied region. Five out of six biopsies revealed residual prostate cancer. CONCLUSIONS: A prostate/muscle ratio was developed from 111indium ProstaScint regions of interest obtained on 1-cm SPECT transverse slices through the prostate bed in 23 patients preprostatic cancer therapy. A P/M ratio above 3.0 correlated in the majority of positive cases, and a P/M ratio below 3.0 was demonstrated in negative prostatic biopsy cases. The P/M ratio of above 3.0 or below 3.0 also separated those posttherapy prostate cancer patients with rising PSA who had residual prostate carcinoma in the prostate bed.
We measured the concentrations of the neuron-specific protein, tau, in the cerebrospinal fluid (CSF) of 32 neurologically characterized HIV-infected (HIVpos) subjects and nine matched seronegative (HIVneg) controls using a sensitive ELISA assay. Of 32 HIVpos subjects, nine had HIV-associated neurocognitive disorders, and nine had clinically diagnosed peripheral neuropathies. CSF tau levels in subjects with HIV-associated neurocognitive disorders were similar to those in HIVneg subjects (185 +/- 83 vs. 223 +/- 106 pg/ml; P = 57). CSF tau levels in HIVpos subjects with peripheral neuropathies did not differ from those without neuropathies (320 +/- 190 vs. 251 +/- 185; P = 23). In summary, CSF tau levels were not elevated in patients with HIV-associated neurologic disease.
The workshop was held at St Catherine's College, Oxford, from March 25-28, 1998, and attracted participants from 32 nations. Protein folding is one of the most important processes in biology since it adds functional flesh to the bare bones of genes, but it has traditionally been studied by people separated both intellectually and physically because they are training in different disciplines. The aim of the meeting was to bring together chemists and structural biologists studying how pure, denatured proteins refold spontaneously in the test tube, with biochemists and cell biologists who are concerned with how proteins fold inside living cells and medical scientists interested in the diseases that result when this process goes wrong. In this report we concentrate on general concepts and themes rather than on detailing every contribution.
OBJECTIVE: To compare rates and anatomical patterns of brain atrophy during 3 stages of human immunodeficiency virus (HIV) disease. DESIGN: Comparisons of multiple serial brain magnetic resonance images in men without HIV infection and HIV-infected men in Centers for Disease Control and Prevention (CDC, Atlanta, Ga) stages A, B, and C. SETTING: Longitudinal cohort study of the San Diego HIV Neurobehavioral Research Center, San Diego, Calif. PARTICIPANTS: Eighty-six HIV-1-positive (HIV-positive) and 23 HIV-negative men who were similar in age and risk group. The number of HIV-positive men in each CDC stage was as follows: A, 33; B, 19; C, 34. All HIV-positive men were free of clinically detectable opportunistic neurologic illness. MAIN OUTCOME MEASURES: Regional volumes of serial magnetic resonance images converted to standardized slope estimates of change in regional volumes of interest. RESULTS: Medically asymptomatic men (CDC stage A) and medically symptomatic men (CDC stage C) had more rapid loss of cortical tissues than did HIV-negative men as manifested by higher slopes (Tukey honestly significant difference test, P=.02 and P=.001, respectively) for cortical fluid volume. Accelerated ventricular volume enlargement occurred only in men with CDC stage C disease. Reduction in the volume of white matter was accelerated in participants with CDC stage C disease compared with participants with CDC stage A disease. Of the gray matter regions, only the caudate nucleus sustained accelerated volume loss during CDC stage C disease. Participants whose systemic disease progressed to a higher CDC stage had significantly accelerated ventricular volume increases and caudate atrophy. Rates of cortical and subcortical fluid volume increases and reductions in the volumes of white matter and the caudate nucleus were significantly related to the rate of decline in the CD4+ lymphocyte count. CONCLUSIONS: In the absence of cerebral opportunistic disease, HIV infection causes progressive atrophy within the gray and white matter in the brain. These changes were most severe in the most advanced stage of disease but were evident even in medically asymptomatic HIV-positive persons. Within the gray matter, the caudate nucleus exhibited progressive volume loss linked to disease stage and the rate of decline of the CD4+ cell count. Structural brain changes can begin in the early stages of HIV infection and accelerate during advanced illness.
OBJECTIVE: To determine the sensitivity and specificity of postmortem dementia diagnoses based on a retrospective informant interview by comparison with criterion standard neuropathological diagnoses and the results of previous clinical examinations. SETTING: Three university-based academic research centers. SUBJECTS: Fifty-four deceased elderly persons with Alzheimer disease, another dementing disorder, a neurologic disease resulting in functional impairment but no dementia, or no neurologic disorder. METHODS: Blinded nonclinician interviewers administered the Dementia Questionnaire (DQ) by telephone to informants, typically close relatives, who were familiar with the intellectual and functional status of the subjects before death. Two senior clinicians (LJ.T. and C.K.) rated each DQ for the presence or absence of a dementia syndrome during life and for the specific disorders causing the dementia, if present. Raters were blinded to the neuropathological findings and based their assessments only on data provided by responses to the DQ. Comparison was made with diagnoses based on neuropathological assessment. In most cases, the results of antemortem clinical examinations were also available as a check on the clinical diagnosis of the dementia syndrome. Sensitivity and specificity of the DQ diagnoses were computed, and chance-corrected agreement measures were calculated for the 2 independent DQ raters (LJ.T. and C.K.). RESULTS: Compared with antemortem clinical diagnosis, the average sensitivity of the DQ for the clinical syndrome of dementia was 92.8%, the specificity was 89.5%, and the interrater agreement was 98% (kappa = 0.96). Among 7 subjects with mild dementia (Mini-Mental State Examination score > or = 24 at the last clinical examination), 5 (71%) were correctly identified using the DQ. The DQ correctly indicated the absence of dementia in 8 (80%) of 10 subjects with other neurologic disorders causing functional impairment. Compared with the neuropathological diagnoses, the DQ differentiated Alzheimer disease from other primary causes of dementia with a sensitivity of 89% and a specificity of 72%. The interrater agreement was 93.8% (kappa = 0.85). CONCLUSIONS: Compared with the results of the antemortem clinical examinations, the DQ was sensitive to the presence of dementia, detected most cases of mild dementia, and discriminated dementia from other neurologic disorders causing functional impairment. Compared with the neuropathological diagnoses, the ability of the DQ to differentiate Alzheimer disease from other dementing disorders indicates that it may be useful as a research tool.
OBJECTIVE: The treatment of patients with stage I endometrial adenocarcinoma is often shorter and less expensive if total abdominal hysterectomy (TAH), bilateral salpingo-oophorectomy (BSO), and therapeutic lymphadenectomy are used rather than TAH, BSO, pelvic lymph node sampling, and pelvic external beam radiation. We studied whether the survival and morbidity of patients treated with therapeutic lymphadenectomy are equal to or better than with these alternative treatments. METHODS: We reviewed the medical records of patients with stage I endometrial adenocarcinoma who were enrolled in the MetroHealth Medical Center tumor registry between 1970 and 1993 after undergoing full pelvic lymph node dissection, in addition to total abdominal hysterectomy, bilateral salpingo-oophorectomy, and vaginal brachytherapy. The mean number of resected nodes was 33 (median, 31; interquartile range, 19). Patients were followed for 1. 6-20 years (median, 8 years; interquartile range, 5.8 years). Morbidity and survival rates were compared to published series using similar treatment strategies and to those from studies using pelvic external beam radiation and pelvic lymph node sampling rather than lymphadenectomy. RESULTS: Of 192 patients with pathologic stage I (FIGO 1988) endometrial adenocarcinoma, 178 patients had full pelvic lymph node dissection; 159 patients were evaluable. The 15-year overall survival was 98%; 10- and 15- year disease-free survivals were 96 and 94%, respectively. Overall morbidity was 18% (29/159), and moderate-to-severe morbidity was 13% (21/159). Recurrences were seen in 4.4% (7/159) of patients. Grade and myometrial invasion were not significant predictors of disease-free survival after full pelvic lymph node dissection (grade, P = 0.42; stage, P = 0.67). The results compare favorably with those of similar studies and with studies of pelvic external beam radiation. CONCLUSIONS: Primary surgical management with total abdominal hysterectomy, bilateral salpingo-oophorectomy, therapeutic pelvic lymphadenectomy, and vaginal brachytherapy is a viable and possibly preferable option for patients with stage I endometrial adenocarcinoma.
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Fatal pulmonary embolus is an infrequent cause of death in patients with Hodgkin's disease who respond to initial therapy. This patient had associated minimal change disease and nephrotic syndrome that was responding to therapy, but had this complication. The diagnosis was delayed by the presentation that suggested pneumonia. A high index of suspicion for thrombotic complications and an aggressive diagnostic pursuit thereof are merited in these patients.
BACKGROUND: Painful sensory neuropathy is a common complication of HIV infection. Based on prior uncontrolled observations, we hypothesized that amitriptyline or mexiletine would improve the pain symptoms. METHOD: A randomized, double-blind, 10-week trial of 145 patients assigned equally to amitriptyline, mexiletine, or matching placebo. The primary outcome measure was the change in pain intensity between baseline and the final visit. RESULTS: The improvement in amitriptyline group (0.31+/-0.31 units [mean+/-SD]) and mexiletine group (0.23+/-0.41) was not significantly different from placebo (0.20+/-0.30). Both interventions were generally well tolerated. CONCLUSIONS: Neither amitriptyline nor mexiletine provide significant pain relief in patients with HIV-associated painful sensory neuropathy.
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The involvement of two types of molecular chaperone in folding newly synthesized proteins can be rationalized in terms of the crowded nature of the intracellular environment. Recent work sheds light on how these chaperones recognise their substrates and protect them from the problems of macromolecular crowding.