Reduction of HIV persistence following transplantation in HIV-infected kidney transplant recipients.

Chronic inflammation may contribute to human immunodeficiency virus (HIV) persistence through a number of potential pathways. We explored the impact of immunosuppressant therapy on peripheral blood measures of HIV persistence following kidney transplantation. Stored plasma and peripheral blood mononuclear cells prior to transplantation and at weeks 12, 26, 52 and 104 posttransplant were obtained from 91 transplant recipients. In a multivariate model, higher pretransplant plasma HIV RNA level (p < 0.0001) and a longer duration of follow-up posttransplant (p = 0.09) were associated with higher posttransplant plasma HIV RNA levels. A higher baseline HIV DNA (p < 0.0001) was significantly associated with higher HIV DNA levels posttransplant, while higher CD4+ T cell count (p = 0.001), sirolimus use (p = 0.04) and a longer duration of follow-up (p = 0.06) were associated with lower posttransplant HIV DNA levels. The association between sirolimus exposure and lower frequency of cells containing HIV DNA levels posttransplant suggest that the immune-modifying drugs may affect the level of HIV persistence during effect therapy. Future studies of sirolimus as a reservoir-modifying agent are warranted.

Transfusion management of an IgA deficient patient with anti-IgA and incidental correction of IgA deficiency after allogeneic bone marrow transplantation.

A patient with multiple myeloma was noted to have an IgA deficiency during investigation of a possible transfusion reaction due to IgA deficiency and anti-IgA. Because of the patient's age, otherwise good health, and early stage of disease, he was enrolled in a research treatment protocol that involved an allogeneic bone marrow transplant (BMT). The BMT successfully put the patient in complete remission from his multiple myeloma and corrected his IgA deficiency. Class-specific IgG anti-IgA antibody that had been identified prior to BMT was no longer detectable in his plasma. Anaphylactic transfusion reactions were successfully avoided by using a combination of IgA-deficient and washed blood components including the marrow graft, and IgA-reduced intravenous immunoglobulin.

Clinical study of fetal mesencephalic intracerebral transplants for the treatment of Parkinson's disease.

This study reports our findings from 22 patients (ages ranging from 42 to 73 yr; mean = 55.2) with recalcitrant idiopathic Parkinson's disease (PD) who received implants of fetal ventral mesencephalic tissue using an MRI-guided stereotactic procedure and who have been followed for at least 6 mo postoperatively, employing the guidelines established by the Core Assessment Program for Intracerebral Transplantations. Evaluations were videotaped and were performed both on and off levodopa medications. To date, we have seven patients with 24 mo, three with 18 mo, three with 12 mo, and nine with 6 mo post-surgical assessments. Comparing surgical outcomes to levels prior to fetal transplants we found: 1) mean levodopa levels were reduced 46% at 6 mo, 12% at 12 mo, 20% at 18 mo, and 54% at 24 mo; 2) Unified Parkinson's Disease Rating Scale (UPDRS) scores with patients on levodopa were improved by an average of 38% (6 mo), 50.2% (12 mo), 69.3% (18 mo), and 73.9% (24 mo), while off medication scores showed reductions ranging from 24.7% at 6 mo to 55.1% at 24 mo. Other measures, including Hoehn-Yahr staging, Activities of Daily Living, and dyskinesia rating scales, were also significantly improved following fetal transplants. Timed motor tasks (finger dexterity, supination-pronation, foot tapping, and Stand-Walk-Sit) performance also demonstrated highly significant improvements. Patient's self-rating scores indicated that the patients typically perceived substantial improvements in their condition. However, substantial variability in the improvements following surgery still persists and range from nominal improvements in performance to significant changes that can be classified as altering the overall lifestyle of the patients. To date, 4 of the 22 subjects were considered by the physicians to be nonresponders; that is, there were no clinically relevant improvements in these patients' conditions.

MEG and ECoG localization accuracy test.

We tested the localization accuracy of magnetoencephalography (MEG) and electrocorticography (ECoG) for a current dipole in a saline filled sphere at depths ranging from 1 to 6 cm at 1 cm intervals. We used standard neuromagnetometer placements and subdural electrode grids, previously employed for patient studies, with precise measurements of sensor and electrode locations with a 3-dimensional spatial digitizer. MEG and ECoG had comparable accuracy with mean errors of 1.5 and 1.8 mm, respectively. It appears that use of the spatial digitizer increases accuracy for both MEG and EGoG localizations. The larger errors in the ECoG with increasing depths could be attributed to under-sampling of the spatial pattern of the field which spreads out with deeper sources. It should be noted that in clinical applications a grid of the dimensions used here would most typically be used for superficial sources on the cortex with depth recordings being preferred for investigations of deep epileptogenic activity. Results are encouraging for continued development of non-invasive MEG methods for further definition of epileptogenic zones in the brain.

Neuromagnetic evidence of a dynamic excitation pattern generating the N100 auditory response.

Evoked magnetic field recordings were used to localize multiple sources of the negative component of cortical responses to auditory stimuli. The negative cortical component of the auditory evoked response, often called the N100, has traditionally been of interest due to its sensitivity to both stimulation parameters and cognitive variables. Results indicate that this component appears to reflect spreading activation of adjacent cortical columns within the primary projection area of the temporal lobe, extending anteriorly for about 1 cm following the downward slope of the superior surface of the lobe.

Aetiological considerations and risk factors for multi-infarct dementia.

One hundred and seventy five multi-infarct dementia (MID) patients were evaluated for risk factors for stroke as well as for the types of cerebrovascular lesions that were present. The incidence of associated risk factors for stroke were as follows: hypertension (66%), heart disease (47%), cigarette smoking (37%), diabetes mellitus (20%), moderate alcohol consumption (19%) and hyperlipidaemia (21%). The most frequently occurring type of lesions were multiple lacunar infarctions of the brain (43%). These were combined with other types of stroke in an additional 21%. Atherosclerotic occlusive disease of the carotid and vertebrobasilar arteries occurred alone in 18% and was associated with other types of stroke in another 25%. Embolic cerebral infarctions were present alone in 8% and were combined with other types of stroke in 15%. MID was more frequent in men (62%) than women (p less than 0.002). Mean bihemispheric gray matter cerebral blood flow (CBF) values showed a fluctuating course and when results were pooled and compared between different types of MID, extracranial occlusive disease and/or multiple lacunar infarctions resulted in lowest CBF values. The location of cerebral infarctions was more importantly related to cognitive impairments than was the total volume of infarcted brain. Mortality rates among 125 MID patients followed for 31 months has been 5%. Correct clinical classification of the types of cerebrovascular lesions was confirmed in three necropsied cases.

Hyperlipidemia is a risk factor for decreased cerebral perfusion and stroke.

Possible effects of chronically elevated serum cholesterol and triglyceride levels on measurements of cerebral blood flow were investigated by between-group comparisons of individuals, with and without hyperlipidemia, among 56 neurologically normal elderly volunteers and among 102 age-matched patients with symptoms of transient ischemic attacks (TIAs). Results demonstrated significantly higher levels of serum cholesterol and triglyceride among the TIA patients compared with randomly selected age-matched normal controls of similar educational and environmental backgrounds. Cerebral blood flow levels were reduced among groups of TIA patients with elevated levels of either cholesterol or triglycerides compared with the TIA patients with normal lipid levels. Similar trends were seen among normal volunteers, but these did not reach levels of statistical significance because of the limited numbers available. Analysis of frequency distributions for risk factors other than hyperlipidemia indicated that hypertension, atherosclerotic heart disease, diabetes mellitus, and cigarette smoking were also more prevalent among TIA patients than among age-matched normal controls.

Additional predisposing risk factors for atherothrombotic cerebrovascular disease among treated hypertensive volunteers.

A 7-year prospective study of a cohort of 107 neurologically normal elderly hypertensive volunteers (mean age, 65.8 +/- 8.3 years) was undertaken to investigate the predictive validities of additional risk factors for atherothrombotic cerebrovascular disease including stroke, transient ischemic attacks, reversible ischemic neurological deficits, and multi-infarct dementia. This longitudinal study has been in progress now for 7 years with a mean follow-up interval of 50.12 +/- 5.76 months. Among 107 formerly symptom-free, normal hypertensive volunteers, 25 (23%) have developed cerebrovascular disease, 7 (6.5%) sustained a stroke, 10 (9.3%) developed multi-infarct dementia, and 18 (16.8%) have transient ischemic attacks. None have suffered intracranial hemorrhage. Mean gray matter cerebral blood flow (CBF) values measured at the initial visit were sensitive predictors of cerebrovascular disease. Eight of 16 hypertensives (50%) with initial CBF values below 60.0 ml/100 g/min now exhibit signs and symptoms of cerebrovascular disease, while 11 of 43 hypertensives (25.6%) with initial CBF values between 60.1 and 69.9 ml/100 g/min and only 6 of 48 (12.5%) with initial CBF levels above 70.0 developed cerebrovascular disease. Incidence of cerebrovascular disease among cigarette smoking hypertensive volunteers (32.5%) was significantly greater than among nonsmokers (17.2%).

Improved cognition after control of risk factors for multi-infarct dementia.

A cohort of 52 patients (30 men and 22 women) with multi-infarct dementia (MID) has been followed up prospectively for a mean interval of 22.2 months. Clinical course has been documented by serial history taking and interviews and neurological, medical, and psychological examinations, and correlated with measurements of cerebral blood flow. The clinical course and cognitive performance have been compared with those of age-matched normal volunteers and patients with Alzheimer's disease. Patients with MID were subdivided into hypertensive and normotensive groups, and also into those displaying stabilized or improved cognition and those whose condition deteriorated. Among hypertensive patients with MID, improved cognition and clinical course correlated with control of systolic blood pressure within upper limits of normal (135 to 150 mm Hg), but if systolic blood pressure was reduced below this level, patients with MID deteriorated. Among normotensive patients with MID, improved cognition was associated with cessation of smoking cigarettes.

Abstention from cigarette smoking improves cerebral perfusion among elderly chronic smokers.

A cross-sectional study of cerebral blood flow (CBF) levels in 268 neurologically normal volunteers contrasting nonsmokers, smokers who quit, and current cigarette smokers indicated that subjects who quit smoking had significantly higher cerebral perfusion levels than subjects who had continued to smoke but remained lower than subjects without a history of cigarette smoking. All subjects were matched for age and sex, and smoking groups were matched for duration and amount of smoking. A prospective study of 11 subjects who were able to stop smoking in which CBF levels were available both antecedent to and following cessation of the habit indicated that significant gains occurred in cerebral perfusion levels within one year following cessation of smoking. A control group of 22 subjects who continued to smoke (matched for age, sex, duration of smoking, and duration of time between baseline and follow-up) showed no change in CBF values. A correlation between magnitude of CBF change and duration of cessation of cigarette smoking demonstrated a significant linear increase in CBF during the one-year period. These results suggest that elderly individuals who have smoked for three to four decades can benefit substantially by abstaining from cigarette smoking and that significant improvement in cerebral circulation occurs within a relatively short period.

Long-term assessment of cerebral perfusion following STA-MCA by-pass in patients.

A prospective study of mean hemispheric cerebral blood flow (CBF) correlated with clinical status has now been completed for the past 54 months. Thirty-eight patients underwent superficial temporal to middle cerebral artery (STA-MCA) by-pass. They were compared with 22 patients with similar arteriographic lesions and clinical symptoms, treated medically throughout the same interval of time. Assignment to either treatment group was not randomized but depended solely on choice of patient or treating physician. Both groups were matched for age, clinical symptoms, angiographic abnormalities, and CBF values. All patients had proximal occlusion of one internal carotid artery or intracranial occlusive disease of the internal carotid or middle cerebral arteries. CBF measurements and clinical evaluations were repeated at regular intervals up to 54 months following surgery or institution of medical treatment. Mean follow up interval after STA-MCA by-pass was 28.7 months and for medical treatment was 29.7 months. Mean hemispheric CBF values for STA-MCA patients became significantly increased 2 weeks after operation. After that, CBF flow values decreased. At 24 months after surgery, flow values for surgically treated patients were significantly higher than among those treated medically, although there were no differences in flow values between the two groups at 3, 6, 12, 36 and 48 months. Prospective clinical evaluations after STA-MCA by-pass were as follows: 12 (32%) improved with cessation of TIAs and/or neurological improvement, 16 (42%) remained unchanged, 7 (18%) deteriorated (due to new or recurrent strokes) and 3 (8%) expired. Clinical results were the same for medical treatment: 6 (27%) improved, 10 (46%) unchanged, 4 (18%) deteriorated due to new or recurrent stroke, and 2 (9%) expired.

The effects of chronic cigarette smoking on cerebrovascular responsiveness to 5 per cent CO2 and 100 per cent O2 inhalation.

Effects of chronic cigarette smoking on cerebrovascular responsiveness of volunteers at risk for stroke and not at risk for stroke were evaluated by serial measurements of cerebral blood flow using the 133Xe inhalation method. Resting gray matter blood flow values (Fg) measured while breathing room air were compared with Fg values measured during inhalation of either 5 per cent CO2 in air or 100 per cent O2. Changes in Fg values during inhalation of 5 per cent CO2 were used to estimate cerebral vasodilator capacitance, and those during inhalation of 100 per cent O2 were used to estimate cerebral vasoconstrictor capacitance. Results indicated that chronic cigarette smokers have both reduced vasodilator (P less than 0.01) and reduced vasoconstrictor (P less than 0.02) capacitance when compared with nonsmokers of the same ages regardless of whether or not other risk factors for stroke were present. Vasodilator capacitance to 5 per cent CO2 inhalation was reduced among smokers compared with nonsmokers of the same age by 48 per cent in non-risk subjects and 56 per cent in risk-factored subjects, while vasoconstrictor capacitance to 100 per cent O2 inhalation among smokers was decreased by 24 per cent in non-risk subjects and 34 per cent in risk-factored subjects. In risk-factored subjects, combined effects of smoking and other risks appeared to be additive.

Cigarette smoking decreases cerebral blood flow suggesting increased risk for stroke.

Effects of chronic cigarette smoking on cerebral blood flow were investigated by measuring gray matter blood flow (Fg) using xenon 133 inhalation among 192 volunteers without cerebrovascular symptoms. There were 108 normal, healthy volunteers; 84 had risk factors for stroke (hypertension, hyperlipidemia, diabetes mellitus, and/or heart disease). Of both risk and nonrisk groups, 75 were habitual smokers (0.5 to 3.5 packs per day for 25 years). Comparisons of mean Fg values for both hemispheres showed significant reductions related to tobacco consumption and risk factors for stroke. Multiple-regression equations using smoking, age, risk, and alcohol consumption indicated a combined R2 value of 0.22. Smoking seems to be a potent risk factor decreasing cerebral blood flow probably by enhancing cerebral arteriosclerosis. Chronic cigarette smoking in persons with other risk factors further reduced Fg values in an additive manner when compared with subjects who had corresponding risk factors who did not smoke.