Reduced glucose uptake and Aß in brain regions with hyperintensities in connected white matter.

Interstitial concentration of amyloid beta (Aß) is positively related to synaptic activity in animal experiments. In humans, Aß deposition in Alzheimer's disease overlaps with cortical regions highly active earlier in life. White matter lesions (WML) disrupt connections between gray matter (GM) regions which in turn changes their activation patterns. Here, we tested if WML are related to Aß accumulation (measured with PiB-PET) and glucose uptake (measured with FDG-PET) in connected GM. WML masks from 72 cognitively normal (age 61.7 ± 9.6 years, 71% women) individuals were obtained from T2-FLAIR. MRI and PET images were normalized into common space, segmented and parcellated into gray matter (GM) regions. The effects of WML on connected GM regions were assessed using the Change in Connectivity (ChaCo) score. Defined for each GM region, ChaCo is the percentage of WM tracts connecting to that region that pass through the WML mask. The regional relationship between ChaCo, glucose uptake and Aß was explored via linear regression. Subcortical regions of the bilateral caudate, putamen, calcarine, insula, thalamus and anterior cingulum had WM connections with the most lesions, followed by frontal, occipital, temporal, parietal and cerebellar regions. Regional analysis revealed that GM with more lesions in connecting WM and thus impaired connectivity had lower FDG-PET (r = 0.20, p<0.05 corrected) and lower PiB uptake (r = 0.28, p<0.05 corrected). Regional regression also revealed that both ChaCo (ß = 0.045) and FDG-PET (ß = 0.089) were significant predictors of PiB. In conclusion, brain regions with more lesions in connecting WM had lower glucose metabolism and lower Aß deposition.

Association of social network and social support with health-related quality of life and fatigue in long-term survivors of Hodgkin lymphoma.

PURPOSE: As the number of survivors of Hodgkin's lymphoma (HL) increases, there has been a growing interest in long-term treatment-related side effects and their impact on the quality of life (QoL). The aim of this study was to assess the association of social network and social support with the QoL and fatigue among long-term HL survivors. METHODS: A total of 200 HL survivors were included. The generic Short Form-12 (SF-12) questionnaire, the QoL cancer survivor's questionnaire (QOL-CS), and the Multidimensional Fatigue Inventory were used to assess QoL and fatigue. Social network and social support were evaluated with the Social Support Survey. RESULTS: Social network and all social support measures were favorably associated with two or more SF-12 scales, mainly with physical functioning and the mental health scales. Social network and social support dimensions were also associated with better QOL-CS scores. Affective support, informational support, positive interaction, and emotional support were associated with less fatigue. CONCLUSIONS: Both social network and social support are associated with better QoL and lower levels of fatigue in HL survivors. This information may be useful to health professionals and community organizations in implementing effective interventions to improve these patients' quality of life.

Lack of association of tumor-associated macrophages with clinical outcome in patients with classical Hodgkin's lymphoma.

BACKGROUND: A recent study demonstrated that an increased number of CD68+ macrophages were correlated with primary treatment failure, shortened progression-free survival (PFS) and disease-specific survival (DSS) in patients with classical Hodgkin's lymphoma (cHL). PATIENTS AND METHODS: The aim of the present study was to verify the relationship between the number of CD68+ and CD163+ macrophages with clinical outcomes in a cohort of 265 well-characterized patients with cHL treated uniformly with the standard doxorubicin, bleomycin, vinblastine and dacarbazine chemotherapy regimen. Two pairs of hematopathologists carried out independent pathological evaluations of tissue microarray slides. RESULTS: There were no associations between clinical characteristics and the expression of CD68 or CD163. However, higher levels of CD68 and CD163 expression were correlated with the presence of Epstein-Barr virus-positive Hodgkin tumor cells (P = 0.01 and 0.037, respectively). The expression of CD68 or CD163 was not associated with either the PFS or the DSS. CONCLUSION: CD68 and CD163 expression require further evaluation before their use can be recommended for prognostic stratification of patients with cHL.

Activation primes human B lymphocytes to respond to heat shock.

Crosslinkage of the B cell antigen receptor by anti-mu beads or SAC results in the selective induction of hsp70. We have observed that activated cells, having enhanced expression of hsp70, survive lethal stimuli much better than their unactivated counterparts. These results are in accordance with the proposal that hsp70 is essential for cells to survive lethal environmental stresses. Moreover, the activation event itself primes B cells thereby enabling them to increase the expression of both hsp70 mRNA and protein. This is the first demonstration that triggering of B cells via crosslinkage of sIg is accompanied by the induction of thermotolerance without the need for a prior sublethal heat treatment.

Alcohol breath tests: gross errors in current methods of measuring alveolar gas concentrations.

Transitory contact of ethanol with the mucous membranes of the mouth or nasal passages, or both, is sufficient to drastically alter measurements of concentrations of ethanol in so-called "alveolar" gas for more than 20 minutes after such contact. Various concentrations of ethanol were taken into the mouth by human subjects and were expectorated. Readings of so-called "blood alcohol" were then taken at short intervals by means of the Breathalyzer(R) and were continued up to 1 hour after exposure. These readings were compared with blood-alcohol concentrations measured by quantitative chemical analysis of venous blood. When true concentrations of blood alcohol were at or close to zero (plus possible error of 0.0001 gram per 100 milliliters), readings of greater than 0.40 gram per 100 milliliters were obtained on the Breathalyzer. Repeated mouth washing and gargling with water, changes in the nature of the solvent, and stomach loading each had only a slight effect in diminishing these errors.

Feeding and core temperature in albino rats: changes induced by preoptic heating and cooling.

At an ambient temperature of 25 degrees C, selective cooling of the area preoptica medialis to 24 degrees +/- 1 degrees C produced a significant decrease in food intake together with hyperthermia. Heating the same area to 43 degrees +/- 1 degrees C resulted in the opposite effects. At an ambient temperature of 35 degrees C, heating the area preoptica medialis to 43 degrees C resulted in a decrease in food intake despite concomitant hypothermia.

Uses of tuberculosis mortality surveillance to identify programme errors and improve database reporting.

BACKGROUND: In 2006, 848 persons died from tuberculosis (TB) in Rio de Janeiro, Brazil, corresponding to a mortality rate of 5.4 per 100 000 population. No specific TB death surveillance actions are currently in place in Brazil. SETTING: Two public general hospitals with large open emergency rooms in Rio de Janeiro City. OBJECTIVE: To evaluate the contribution of TB death surveillance in detecting gaps in TB control. METHODS: We conducted a survey of TB deaths from September 2005 to August 2006. Records of TB-related deaths and deaths due to undefined causes were investigated. Complementary data were gathered from the mortality and TB notification databases. RESULTS: Seventy-three TB-related deaths were investigated. Transmission hazards were identified among firefighters, health care workers and in-patients. Management errors included failure to isolate suspected cases, to confirm TB, to correct drug doses in underweight patients and to trace contacts. Following the survey, 36 cases that had not previously been notified were included in the national TB notification database and the outcome of 29 notified cases was corrected. CONCLUSION: TB mortality surveillance can contribute to TB monitoring and evaluation by detecting correctable and specific programme- and hospital-based care errors, and by improving the accuracy of TB database reporting. Specific local and programmatic interventions can be proposed as a result.

Magnetic brain stimulation upregulates adhesion and prevents Eae: MMP-2, ICAM-1, and VCAM-1 in the choroid plexus as a target.

Clinical signs appearance and significant increases of ICAM-1 and MMP-2 expressions with the clusters of VCAM-1(+) immunoreactivity in the choroids plexus epithelium to transferred anti-myelin oligodendroglial antibodies into the third brain ventricle, indicate important role of choroids plexus in the induction of acute experimental autoimmune encephalomyelitis (EAE). Magnetic brain stimulation with AKMA micro-magnet flux density of 60 miliTesla, 5 mm in diameter, implanted upon the pineal gland (PG), immediately after antibody injection, significantly decreases the expression of MMP-2 and ICAM-1 in the choroids plexus of the rat brain and abruptly suppresses the induction of acute EAE.

Anti-B4-blocked ricin: a phase I trial of 7-day continuous infusion in patients with B-cell neoplasms.

PURPOSE: This phase I trial was undertaken to determine the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLTs) of the B-cell-restricted immunotoxin anti-B4-blocked ricin (anti-B4-bR) when it is administered by 7-day continuous infusion. PATIENTS AND METHODS: Thirty-four patients with relapsed and refractory B-cell neoplasms (26 non-Hodgkin's lymphoma [NHL], four chronic lymphocytic leukemia [CLL], four acute lymphoblastic leukemia [ALL]) received 7-day continuous infusion anti-B4-bR. Successive cohorts of at least three patients were treated at doses of 10 to 70 micrograms/kg/d for 7 days with the dose increased by 10 micrograms/kg/d for each cohort. The initial three cohorts of patients (10, 20, and 30 micrograms/kg/d x 7 days) also received a bolus infusion of 20 micrograms/kg before beginning the continuous infusion. RESULTS: The MTD was reached at 50 micrograms/kg/d x 7 days. The DLTs were National Cancer Institute Common Toxicity Criteria (NCI CTC) grade IV reversible increases in AST and ALT, and grade IV decreases in platelet counts. Adverse reactions included fevers, nausea, headaches, myalgias, hypoalbuminemia, dyspnea, edema, and capillary leak syndrome. Potentially therapeutic serum levels of anti-B4-bR could be sustained for 4 days in patients treated at the MTD. Two complete responses (CRs), three partial responses (PRs), and 11 transient responses (TRs) were observed. CONCLUSION: Anti-B4-bR can be administered safely by 7-day continuous infusion with tolerable, reversible toxicities to patients with relapsed B-cell neoplasms. Although occasional responses were seen, future trials will use anti-B4-bR in patients with lower tumor burdens to circumvent the obstacle of immunotoxin delivery to bulk disease.

Prevention of graft-versus-host disease by selective depletion of CD6-positive T lymphocytes from donor bone marrow.

PURPOSE: Acute and chronic graft-versus-host disease (GVHD) continues to be the major causes of morbidity and mortality after allogeneic bone marrow transplantation (BMT). In this study, we have evaluated the clinical effects of selective in vitro T-cell depletion of donor allogeneic bone marrow by using a single monoclonal antibody ([MoAb] anti-T12, CD6) and rabbit complement. This antibody recognizes mature T cells, but not other cellular elements such as natural-killer (NK) cells, B cells, and myeloid precursors. PATIENTS AND METHODS: From August 1983 to April 1991, 112 consecutive adult patients with hematologic malignancies underwent BMT with bone marrow from HLA-identical sibling donors. Marrow was harvested and depleted of mature T lymphocytes ex vivo by the use of three rounds of incubation with an anti-T12 antibody and rabbit complement. The preparative regimen consisted of cyclophosphamide and fractionated total body irradiation (TBI) in 108 patients. No patients received prophylactic immune suppression post-BMT. Purgation by anti-T12 was used as the only method for the prevention of GVHD. RESULTS: Twenty patients (18%) developed acute GVHD (grade 2 to 4); only eight patients developed chronic GVHD. The incidence of GVHD did not increase significantly with age. Only three of 112 patients (2.7%) exhibited acute graft failure. One patient developed late graft failure that was associated with cytomegalovirus (CMV) infection. Within the subset of 50 patients who had not previously undergone unsuccessful conventional therapy (acute leukemia in first remission or chronic myelogenous leukemia [CML] in stable phase), we estimated by the Kaplan-Meier method that the probability of disease-free survival was 50% at 3 years post-BMT, with a median follow-up of 44 months. The treatment-related mortality rate in this group was only 14% and was independent of patient age. CONCLUSIONS: We conclude that selective in vitro T-cell depletion with an anti-T12 monoclonal antibody effectively reduces the incidence of both acute and chronic GVHD after allogeneic BMT without compromising engraftment. Moreover, depletion of CD6-positive cells from donor marrow obviates the need to administer immune suppressive medications to the majority of patients. This approach reduces the morbidity and mortality of allogeneic BMT and permits the BMT of older patients.

Autologous bone marrow transplantation in poor-prognosis intermediate-grade and high-grade B-cell non-Hodgkin's lymphoma in first remission: a pilot study.

PURPOSE: Using high-dose therapy and autologous bone marrow transplantation (ABMT) to overcome cellular resistance and eradicate minimal disease, we initiated a pilot study during first remission in patients with non-Hodgkin's lymphoma (NHL) to examine whether the long-term disease-free survival (DFS) rate can be improved for patients with poor-prognosis intermediate/high-grade NHL. PATIENTS AND METHODS: Twenty-six patients with advanced-stage diffuse intermediate/high-grade B-cell NHL (including 16 patients with diffuse small cleaved-cell [DSC]) were selected at presentation by histologic and clinical characteristics to have less than a 25% probability of long-term DFS with conventional treatment. After induction chemotherapy, 16 patients were in complete remission (CR) and 10 were in a minimal disease state. Patients were then treated with high-dose cyclophosphamide, total-body irradiation (TBI), and anti-B-cell monoclonal antibody-purged ABMT. RESULTS: Following ABMT, no acute in-hospital treatment deaths occurred, and engraftment of granulocytes and platelets was significantly faster than for patients undergoing ABMT who were in second or subsequent remission. Of 26 patients, 21 remain in CR maintained without continued therapy, three relapsed in sites of prior nodal disease (4.8, 5.4, and 28 months post-ABMT), and two died in remission. The DFS rate is estimated to be 85% at 28 months and thereafter. The median follow-up period for the 21 patients who are alive and disease-free is 32 months. CONCLUSION: This pilot study suggests that consolidation of first remission with ABMT may improve the long-term DFS rate for diffuse intermediate/high-grade NHL patients at high risk for relapse.

Correlation between plasma and cerebrospinal levels of imipramine.

This study measured the levels of imipramine hydrochloride and desipramine hydrochloride (desmethylimipramine) in the plasma and cerebrospinal fluid (CSF) in 11 depressed patients. The oral doses correlated significantly with the plasma levels irrespective of different diagnostic categories. The CSF levels varied significantly. In the endogenous depressive group the CSF levels were significantly higher in responders as compared to nonresponders. The CSF levels of the nonresponders in the endogenous depressive group, and of both responders and nonresponders in the schizo-affective groups, were similar.

Interleukin-2 therapy for advanced chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is usually treated with either alpha-interferon or hydrea. Median survival is 6 years. Eventually, in most CML patients, the disease evolves to blast phase with clinical and morphologic characteristics of an acute leukemia. This phase is commonly associated with systemic symptoms and the appearance of new cytogenetic abnormalities. Therapy for this phase is of limited value, resulting in a mean survival of 4 months. We describe four consecutive patients seen at our clinic with advanced stage CML (three blast, one accelerated phase) who were treated with interleukin-2 (Proleukin). The mean survival in these patients was 22 months (range 9-35 months) and two are still alive 25 and 35 months after the start of therapy. One patient had a complete cytogenetic response and another a partial response. Toxicity was minimal and no patient had to discontinue therapy because of it.

Nutrient patterns and brain biomarkers of Alzheimer's disease in cognitively normal individuals.

OBJECTIVES: Epidemiological evidence linking diet, one of the most important modifiable lifestyle factors, and risk of Alzheimer's disease (AD) is rapidly increasing. However, there is little or no evidence for a direct association between dietary nutrients and brain biomarkers of AD. This study identifies nutrient patterns associated with major brain AD biomarkers in a cohort of clinically and cognitively normal (NL) individuals at risk for AD. DESIGN: Cross-sectional study. SETTING: Manhattan (broader area). PARTICIPANTS: Fifty-two NL individuals (age 54+12 y, 70% women, Clinical Dementia Rating=0, MMSE>27, neuropsychological test performance within norms by age and education) with complete dietary information and cross-sectional, 3D T1-weighted Magnetic Resonance Imaging (MRI; gray matter volumes, GMV, a marker of brain atrophy), 11C-Pittsburgh compound-B (PiB; a marker of fibrillar amyloid-ß, Aß) and 18F-fluorodeoxyglucose (FDG; a marker of glucose metabolism, METglc) Positron Emission Tomography (PET) scans were examined. MEASUREMENTS: Dietary intake of 35 nutrients associated with cognitive function and AD was assessed using the Harvard/Willet Food Frequency Questionnaire. Principal component analysis was used to generate nutrient patterns (NP) from the full nutrient panel. Statistical parametric mapping and voxel based morphometry were used to assess the associations of the identified NPs with AD biomarkers. RESULTS: None of the participants were diabetics, smokers, or met criteria for obesity. Five NPs were identified: NP1 was characterized by most B-vitamins and several minerals [VitB and Minerals]; NP2 by monounsaturated and polyunsaturated fats, including ω-3 and ω-6 PUFA, and vitamin E [VitE and PUFA]; NP3 by vitamin A, vitamin C, carotenoids and dietary fibers [Anti-oxidants and Fibers]; NP4 by vitamin B12, vitamin D and zinc [VitB12 and D]; NP5 by saturated, trans-saturated fats, cholesterol and sodium [Fats]. Voxel-based analysis showed that NP4 scores [VitB12 and D] were positively associated with METglc and GMV, and negatively associated with PiB retention in AD-vulnerable regions (p<0.001). In addition, both METglc and GMV were positively associated with NP2 scores [VitE and PUFA], and negatively associated with NP5 scores [Fats] (p<0.001), and METglc was positively associated with higher NP3 scores [Anti-oxidants and Fibers] (p<0.001). Adjusting for age, gender, ethnicity, education, caloric intake, BMI, alcohol consumption, family history and Apolipoprotein E (APOE) status did not attenuate these relationships. The identified 'AD-protective' nutrient combination was associated with higher intake of fresh fruit and vegetables, whole grains, fish and low-fat dairies, and lower intake of sweets, fried potatoes, high-fat dairies, processed meat and butter. CONCLUSION: Specific dietary NPs are associated with brain biomarkers of AD in NL individuals, suggesting that dietary interventions may play a role in the prevention of AD by modulating AD-risk through its effects on Aß and associated neuronal impairment.

Regulation of the 28 kDa heat shock protein by retinoic acid during differentiation of human leukemic HL-60 cells.

Dysregulation of hematopoietic cellular differentiation contributes to leukemogenesis. Unfortunately, relatively little is known about how cell differentiation is regulated. Considering that heat shock proteins (hsp) and specifically the small hsps have been increasingly linked to growth regulation, we sought to determine whether the mammalian small hsp (hsp28) is a growth-regulatory candidate during hematopoietic cell differentiation. Because of its effects on cell growth and differentiation and its increasing clinical use as a differentiating agent, we examined the effect of retinoic acid (RA) on hsp28 during differentiation of the human leukemic HL-60 cell line. Although hsp28 was constitutively expressed at low levels in untreated HL-60 cells, steady state hsp28 protein increased transiently, concomitant with the onset of G1 cell cycle arrest. Furthermore, hsp28 phosphorylation transiently increased within one hour following treatment with RA. Interestingly, in contrast to other differentiating agents the induction of hsp28 by RA was post-transcriptionally mediated with hsp28 protein and mRNA being discordantly regulated. These observations underscore the complex regulation of hsp28 by RA during granulocytic differentiation of human leukemic cells and indicate hsp28 as an intermediary in the pathway through which retinoids exert their growth and differentiative effects.

Analysis of the value of empiric vancomycin administration in febrile neutropenia occurring after autologous peripheral blood stem cell transplants.

We conducted a retrospective review of 125 patients undergoing high-dose therapy and stem cell rescue in order to evaluate the incidence of documented infection and the utility of the administration of vancomycin empirically. All patients received prophylactic oral quinolone therapy. Because neutropenia in this setting is relatively brief, 21 patients never manifested fever, and no patient died of infection. Of the remaining 104 patients, positive blood cultures were obtained in only 10, nine with a gram stain positive and one with a gram stain negative organism. Sixty-two patients without any evidence of gram positive infection received vancomycin according to the existing algorithm for care of neutropenic fevers. In this population of patients, empiric administration of vancomycin for neutropenic fevers without culture documentation appears to be unnecessary, could be discontinued safely and at substantial cost savings, and might slow the appearance of vancomycin-resistant organisms.

Monoclonal antibody-purged autologous bone marrow transplantation in adults with acute lymphoblastic leukemia at high risk of relapse.

The prognosis for adults with B lineage ALL who have relapsed after an initial remission is poor. High-dose chemoradiotherapy followed by autologous BMT can induce prolonged clinical remissions in some children with recurrent ALL. In this study, we evaluated the efficacy of autologous BMT in adults. Autologous marrow was treated in vitro with J5 and J2 monoclonal antibodies (CD10/CD9) plus rabbit complement to purge residual ALL cells. Twenty-two adults with B lineage ALL were treated with high-dose chemoradiotherapy followed by infusion of J2/J5 purged autologous BM. The median age was 28 years (range 18-54 years). Twenty-one of 22 patients had experienced at least one relapse prior to BMT. All patients achieved complete hematologic engraftment. Disease-free survival (DFS) in this cohort of patients was 20%, with all survivors alive and free of disease between 2.5 and 7.5 years post-BMT. Age at the time of BMT was an important prognostic factor, with patients < 28 years old faring much better than older individuals (DFS, 45% vs 0%, p = 0.01). Our experience suggests that high-dose chemoradiotherapy followed by infusion of J2/J5 purged autologous marrow is as efficacious in young adults as it is in children and is a reasonable alternative for patients who lack HLA-matched donors. Results in older adults are poor, however, and demonstrate the need for more effective transplant strategies in these individuals.

Application of the IDSA guidelines for the use of antimicrobial agents in neutropenic patients: impact on reducing the use of glycopeptides.

We evaluated the impact of applying the Infectious Diseases Society of America guidelines for febrile neutropenic patients in reducing the use of glycopeptides. Forty-five prior episodes of febrile neutropenia were compared to 97 episodes seen after application of the guidelines. Glycopeptide use was reduced from 73% to 43% of episodes (P=.0008), without changes in outcome.

Risk factors for death in patients with candidemia.

OBJECTIVE: To analyze possible risk factors for death among patients with nosocomial candidemia. To identify risk factors for death in patients with candidemia, we analyzed demographic, clinical, and microbiological data. SETTING: Six tertiary hospitals in Brazil. PATIENTS: A cohort of 145 patients with candidemia. DESIGN: 26 possible risk factors for death, including age, underlying disease, signs of deep-seated infection, neutropenia, number of positive blood cultures, removal of a central venous catheter, etiologic agent of the candidemia, susceptibility pattern of the isolate to amphotericin B, and antifungal treatment were evaluated by univariate stepwise logistic regression analysis. RESULTS: Non-albicans species accounted for 63.4% of the candidemias. Risk factors for death in univariate analysis were older age, catheter retention, poor performance status, candidemia due to species other than Candida parapsilosis, hypotension, candidemia due to species other than Candida parapsilosis, and no antifungal treatment. In multivariate analysis, older age and nonremoval of a central venous catheter were the only factors associated with an increased risk for death. CONCLUSIONS: These data suggest that patients with candidemia and a central venous catheter should have the catheter removed.

Old and new strategies in the conditioning of immune responses.

Classical (Pavlovian) conditioning of immune responses was demonstrated by Metal'nikov and his colleagues at the Pasteur Institute in Paris during the 1920s. These experiments, although controversial, were repeated and extended, largely in the Soviet Union, by Dolin, Krylov, Flerov, Luk'yanenko and many others during the 1950s and '60s. Both immunosuppression and immunoenhancement were reported, with many antigens and in several species including man. After a long hiatus, new interest in this subject was revived in the United States, starting with the work of Ader and Cohen on one-trial association learning leading to immunosuppression, and extending again to a new wave of reports from the United States, Canada, Germany and other countries on both conditioned suppression and conditioned enhancement of several host-defense systems, including natural killer cell activity. It already has been demonstrated that conditioning in mice can slow down the growth of tumors and, in some instances, even completely reverse tumor growth. This work is briefly discussed, with emphasis on some of the more recent findings. Applications to human subjects are suggested. The doors are just being opened: the possibilities for new research, for new discoveries, and for new clinical applications are endless.