Disrupted Neural Synchrony Mediates the Relationship between White Matter Integrity and Cognitive Performance in Older Adults.

Our main goal was to determine the influence of white matter integrity on the dynamic coupling between brain regions and the individual variability of cognitive performance in older adults. Electroencephalography was recorded while participants performed a task specifically designed to engage working memory and inhibitory processes, and the associations among functional activity, structural integrity, and cognitive performance were assessed. We found that the association between white matter microstructural integrity and cognitive functioning with aging is mediated by time-varying alpha and gamma phase-locking value. Specifically, better preservation of the inferior fronto-occipital fasciculus in older individuals drives faster task-related modulations of alpha and gamma long-range phase-locking value between the inferior frontal gyrus and occipital lobe and lower local phase-amplitude coupling in occipital lobes, which in turn drives better cognitive control performance. Our results help delineate the role of individual variability of white matter microstructure in dynamic synchrony and cognitive performance during normal aging.

Infections in the tissue material and their impact on the loss of transplants in the Laboratory of in vitro Cell and Tissue Culture with Tissue Bank in the years 2011-2015.

Radiation sterilization eliminates microbiological infections but causes the degradation of the cell factor. The negative result of microbiological examination for tissue transplants is one of the conditions for approval for distribution in patients. The study attempts to verify impact of the presence of microbes onto material for transplant loss. In the 2011-2015 period, we analyzed 293 donors of skin and amnion. Microbiological sampling was performed. The total of 21 strains of bacteria, molds and fungi was identified in collected tissue. The widest spectrum of strains was found in skin (17), followed by amnia (8). The total number of positive findings was 147 and was again highest in skin (129), while the number of positive findings in amnia was 18 only. The general percentage of fungal infections was very low. The presence of fungal strains was only observed in allogeneic skin (2%). Large number of microorganisms isolated from the skin before sterilization was observed, so it seems impossible to use allogeneic intravital skin. However, the intravital application of allogeneic amnion obtained from cesarean section remains to be considered.

FTO genotype and aging: pleiotropic longitudinal effects on adiposity, brain function, impulsivity and diet.

Although overweight and obesity are associated with poor health outcomes in the elderly, the biological bases of obesity-related behaviors during aging are poorly understood. Common variants in the FTO gene are associated with adiposity in children and younger adults as well as with adverse mental health in older individuals. However, it is unclear whether FTO influences longitudinal trajectories of adiposity and other intermediate phenotypes relevant to mental health during aging. We examined whether a commonly carried obesity-risk variant in the FTO gene (rs1421085 single-nucleotide polymorphism) influences adiposity and is associated with changes in brain function in participants within the Baltimore Longitudinal Study of Aging, one of the longest-running longitudinal aging studies in the United States. Our results show that obesity-related risk allele carriers of FTO gene show dose-dependent increments in body mass index during aging. Moreover, the obesity-related risk allele is associated with reduced medial prefrontal cortical function during aging. Consistent with reduced brain function in regions intrinsic to impulse control and taste responsiveness, risk allele carriers of FTO exhibit dose-dependent increments in both impulsivity and intake of fatty foods. We propose that a common neural mechanism may underlie obesity-associated impulsivity and increased consumption of high-calorie foods during aging.

Association of hearing impairment with brain volume changes in older adults.

Hearing impairment in older adults is independently associated in longitudinal studies with accelerated cognitive decline and incident dementia, and in cross-sectional studies, with reduced volumes in the auditory cortex. Whether peripheral hearing impairment is associated with accelerated rates of brain atrophy is unclear. We analyzed brain volume measurements from magnetic resonance brain scans of individuals with normal hearing versus hearing impairment (speech-frequency pure tone average>25 dB) followed in the neuroimaging substudy of the Baltimore Longitudinal Study of Aging for a mean of 6.4 years after the baseline scan (n=126, age 56-86 years). Brain volume measurements were performed with semi-automated region-of-interest (ROI) algorithms, and brain volume trajectories were analyzed with mixed-effect regression models adjusted for demographic and cardiovascular factors. We found that individuals with hearing impairment (n=51) compared to those with normal hearing (n=75) had accelerated volume declines in whole brain and regional volumes in the right temporal lobe (superior, middle, and inferior temporal gyri, parahippocampus, p<.05). These results were robust to adjustment for multiple confounders and were consistent with voxel-based analyses, which also implicated right greater than left temporal regions. These findings demonstrate that peripheral hearing impairment is independently associated with accelerated brain atrophy in whole brain and regional volumes concentrated in the right temporal lobe. Further studies investigating the mechanistic basis of the observed associations are needed.

American Society of Hematology 2020 guidelines for sickle cell disease: prevention, diagnosis, and treatment of cerebrovascular disease in children and adults.

BACKGROUND: Central nervous system (CNS) complications are among the most common, devastating sequelae of sickle cell disease (SCD) occurring throughout the lifespan. OBJECTIVE: These evidence-based guidelines of the American Society of Hematology are intended to support the SCD community in decisions about prevention, diagnosis, and treatment of the most common neurological morbidities in SCD. METHODS: The Mayo Evidence-Based Practice Research Program supported the guideline development process, including updating or performing systematic evidence reviews. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including GRADE evidence-to-decision frameworks, to assess evidence and make recommendations. RESULTS: The panel placed a higher value on maintaining cognitive function than on being alive with significantly less than baseline cognitive function. The panel developed 19 recommendations with evidence-based strategies to prevent, diagnose, and treat CNS complications of SCD in low-middle- and high-income settings. CONCLUSIONS: Three of 19 recommendations immediately impact clinical care. These recommendations include: use of transcranial Doppler ultrasound screening and hydroxyurea for primary stroke prevention in children with hemoglobin SS (HbSS) and hemoglobin Sß0 (HbSß0) thalassemia living in low-middle-income settings; surveillance for developmental delay, cognitive impairments, and neurodevelopmental disorders in children; and use of magnetic resonance imaging of the brain without sedation to detect silent cerebral infarcts at least once in early-school-age children and once in adults with HbSS or HbSß0 thalassemia. Individuals with SCD, their family members, and clinicians should become aware of and implement these recommendations to reduce the burden of CNS complications in children and adults with SCD.

Experience in Using Fetal Membranes: The Present and New Perspectives.

INTRODUCTION: The placenta is an accessible source of tissues for transplantation. Placental transplants have been used in wound treatment because of the basic function of the placenta and its nutritious properties and structure. PATIENTS AND METHODS: The aim of this work is to present the clinical usage of fetal membranes, including human amnion, on the basis of the burn treatment center's experience. The clinical use of amnion and different types of placental transplants are described. The initial results of research work within the MEDPIG project are presented regarding the application of placenta from transgenic pigs as a source of tissues for transplantation. RESULTS: From August 2011 to March 2017, 252,592 cm2 of biostatic human amnion transplants were prepared in our tissue bank. During this period they were transplanted to 528 patients, including 10 patients with Lyell syndrome. Initial studies were conducted in which placentas were collected from 5 transgenic pigs and 27,426 cm2 of amniotic grafts were prepared from them. DISCUSSION: The authors' own experience as well as the literature confirm the extraordinary efficiency of transplants prepared from placental tissues, especially from the amniotic membrane. CONCLUSIONS: The clinical effects confirm the effectiveness of using human amnion in wound treatment. Amniotic transplant is a new treatment standard in toxic epidermal necrolysis TEN (Lyell's syndrome), which has found confirmation in very good clinical outcomes. The collected placentas from transgenic animals enabled the preparation of significantly more grafts than in the case of human material, which is a great advantage of this source of placenta over human tissues.

Autologous and Allogeneic Skin Cell Grafts in the Treatment of Severely Burned Patients: Retrospective Clinical Study.

BACKGROUND: Transplantation of skin cells (keratinocytes and fibroblasts) cultured in vitro is a method of choice for the treatment of severe and extensive burns in patients with a deficit of donor sites for free split-thickness skin grafts, and when the grave medical condition of the patient excludes the possibility of an operation under general anesthetic. Appropriate amounts of keratinocytes and/or fibroblasts cultured in vitro are grafted as a suspension in platelet-leukocyte-rich gel directly on the prepared acceptor site. Approximately 3 weeks are needed for autologous cell culture to grow. Allogeneic cells are obtained from patients who died before their own autologous cell transplantation. Therefore allogeneic cells are considered as ready to use product. The aim of the study was to evaluate the efficiency of in vitro cultured autologous/allogeneic skin cell grafts in the treatment of burns. MATERIALS AND METHODS: In this study a group of 68 patients hospitalized in the Dr Stanislaw Sakiel Centre for Burn Treatment in Siemianowice Slaskie and treated with in vitro cultured skin cells suspended in platelet-leukocyte-rich gel were analyzed. RESULTS: Autologous/allogeneic keratinocytes and fibroblasts transplantation hastens wound closure. CONCLUSION: A major factor in burn treatment is early application of skin cells, so allogeneic cells are more appropriate, because these cells are an on-shelf product. It is especially important in groups of patients with third-degree burn greater than 40%. Allogeneic cells application does not increase hospitalization length in comparison to autologous cells, meaning usage of allogeneic cells in burns treatment is as efficient as autologous cells.

Autoimmunity to collagen in human lung cancer.

Autoantibodies have been described in human cancer patients as well as in animal models of malignancy. The extracellular matrix and especially basement membranes act as barriers for tumor cell invasion. Collagen, particularly types I, III, and IV, are major constituents of the extracellular matrix. We tested the hypothesis that autoimmunity to collagen antigens is present in lung cancer. Sera from 67 patients with lung cancer and 50 reference subjects were tested for anticollagen antibodies by using purified human collagen types I-V and for antibodies binding human cartilage aggrecan proteoglycan. Antibody levels were determined by using ELISA. The relationship of serum levels of these antibodies to patient survival, histology, treatment response, disease stage, and pack years of smoking was examined by using multiple regression and discriminant function analyses. A subgroup of 45 patients in whom a smoking history was available was analyzed separately. Within 1 month of the initiation of therapy, mean serum levels of antibodies binding fibrillar collagen types I-III and V were significantly higher (P < 0.025) than were those in control sera (43.2% of patients positive for one or more anticollagen antibodies). Antibodies binding aggrecan proteoglycan were not different between patients and control sera. In the lung cancer patients, the levels of serum antibodies binding types IV and V collagens contributed to the variance of progression-free survival days, survival days, and the duration of favorable response in opposite directions. Histological cell type contributed to the variance in the level of serum antibody binding collagen types IV and V. Lower levels of antibody binding type IV and higher levels of antibody binding type V were associated with small cell carcinoma. The pack-years of smoking only contributed to the variance in the level of serum antibody binding type V collagen. We conclude that autoantibodies to fibrillar collagen antigens are present frequently in lung cancer patients, and their levels may be related to histological cell type and to the duration of the response to treatment.

A phase I trial of recombinant interleukin-2 combined with recombinant interferon-gamma in patients with cancer.

Twenty-six patients with metastatic cancer were entered into a phase I trial of concurrent recombinant interleukin-2 (IL-2) and recombinant interferon-gamma (IFN-gamma). IL-2 was administered as a continuous intravenous infusion for 5 days. IFN-gamma was administered by a daily intramuscular (IM) injection during the 5 days of IL-2 administration. Treatment was repeated twice after 9-day rest periods. After a 2-week rest, patients without evidence of tumor progression were retreated. Natural killer (NK)- and lymphokine-activated killer (LAK)-cell activity were assayed in each patient before treatment, on day 1, and on day 5 of each cycle. Constitutional symptoms occurred in most patients but were not dose-limiting. Other toxicities included hypotension responsive to fluids, transient elevations in liver function tests, erythema/pruritus, eosinophilia, and transient leukopenia/thrombocytopenia. The maximum-tolerated dose (MTD) of the combination was 1 x 10(6) U/m2/d of IL-2 combined with 0.50 mg/m2/d of IFN-gamma. The dose-limiting toxicity was pulmonary manifesting as rales and shortness of breath. The dose of the combination that resulted in the optimal generation of in vivo LAK-cell activity was a dose of at least 0.25 mg/m2/d of IFN-gamma combined with 1 x 10(6) U/m2/d of IL-2. Objective clinical responses were seen in five of 26 patients. These included a partial response of 2 months duration in a patient with non-Hodgkin's lymphoma (NHL), mixed responses in a patient with NHL and two patients with renal cell carcinoma (RCC), and an ongoing assessable response in a patient with bone metastases from RCC. The recommended dose for phase II trials of this combination is 0.50 mg/m2 of IFN-gamma and 1 x 10(6) U of IL-2.

Randomized study of CODE versus alternating CAV/EP for extensive-stage small-cell lung cancer: an Intergroup Study of the National Cancer Institute of Canada Clinical Trials Group and the Southwest Oncology Group.

PURPOSE: To determine whether an intensive weekly chemotherapy regimen plus thoracic irradiation is superior to standard chemotherapy in the treatment of extensive-stage small-cell lung cancer (ESCLC). PATIENTS AND METHODS: Patients with ESCLC were considered eligible for the study if they were younger than 68 years, had a performance status of 0 to 2, and were free of brain metastases. Patients were randomized to receive cisplatin, vincristine, doxorubicin, and etoposide (CODE) or alternating cyclophosphamide, doxorubicin, vincristine/etoposide and cisplatin (CAV/EP). Consolidative thoracic irradiation and prophylactic cranial irradiation were given to patients responding to CODE and according to investigator discretion on the CAV/EP arm. RESULTS: The fidelity of drug delivery on both drug regimens was equal, and more than 70% of all patients received the intended protocol chemotherapy. Although rates of neutropenic fever were similar, nine (8.2%) of 110 patients on the CODE arm died during chemotherapy, whereas one (0.9%) of 109 patients died on the CAV/EP arm. Response rates after chemotherapy were higher (P =.006) with CODE (87%) than with CAV/EP (70%). However, progression-free survival (median of 0.66 years on both arms) and overall survival (median, 0.98 years for CODE and 0. 91 years for CAV/EP) were not statistically different. CONCLUSION: The CODE regimen increased two-fold the received dose-intensity of four of the most active drugs in small-cell lung cancer compared with the standard CAV/EP regimen while maintaining an approximately equal total dose. Despite supportive care (but not routine prophylactic use of granulocyte colony-stimulating factor), there was excessive toxic mortality with the CODE regimen. The response rate with CODE was higher than that of CAV/EP, but progression-free and overall survival were not significantly improved. In view of increased toxicity and similar efficacy, the CODE chemotherapy regimen is not recommended for treatment of ESCLC.

Brain activation during encoding and recognition of verbal and figural information in older adults.

Positron emission tomography (PET) patterns of cerebral blood flow associated with verbal and figural memory are described in relation to their value as functional probes for studying longitudinal changes that occur in the aging brain. Relative to a matching control task, verbal and figural encoding increase blood flow in prefrontal cortex (PFC), anterior cingulate, insular, lateral and medial temporal, occipital cortex and the cerebellum. Additionally, medial temporal regions exhibited greater activity during figural encoding relative to verbal encoding. During recognition, blood flow increases in prefrontal, cingulate, insular, and lateral temporal and Broca's areas. Analysis of hemispheric asymmetry reveals that the prefrontal cortex exhibits regionally dependent results. Prefrontal region BA 10 demonstrates more bilateral activation during encoding and retrieval, whereas BA 46 shows right greater than left activation during both encoding and retrieval. Overall, the two tasks activate diverse regions within the frontal, temporal and occipital lobes of the brain, including areas that show age-related structural changes, proving their usefulness in the longitudinal assessment of brain function in the elderly.

Phase I clinical trial of pyrazoloacridine NSC366140 (PD115934).

The pyrazoloacridine (PZA) analogue NSC366140 (PD115934) entered clinical trial based on unique preclinical characteristics including solid tumor selectivity in vitro, marked antitumor activity in vivo against murine solid tumors, selectivity against noncycling cells, and activity against multidrug-resistant tumor cells. After identification of the pre-clinical efficacy and an acceptable toxicity profile, a Phase I study of PZA was carried out. A total of 28 patients was entered and received a total of 67 treatment courses. The drug was administered via a 1-h infusion every 21 days. The starting dose was 30 mg/m2 with 2-fold dose escalations through 480 mg/m2. The next dose escalation was 50%, to 720 mg/m2. Grade I through grade IV toxicities were observed. Since no dose-limiting toxicities were observed at 480 mg/m2, and up to grade IV toxicities were observed at 720 mg/m2, an intermediate dose, 600 mg/m2, was evaluated. Dose-limiting toxicities at 720 mg/m2 were hematological (grade III and IV neutropenia) in four of six patients and neurological (up to grade III cerebral toxicities, including restlessness, dizziness, agitation/anxiety, personality changes, and nightmares, as well as myoclonus) in three of six patients treated. The pharmacokinetic parameters which helped predict these toxicities included area under the curve and peak plasma level. Pharmacokinetic studies showed interpatient variations in all parameters studied. The mean area under the curve levels of PZA at the highest two dose levels in patients were near the level detected in mice at their maximum tolerated total dose. The recommended starting dose for Phase II trials using this schedule is 600 mg/m2.

Antinuclear antibodies as potential markers of lung cancer.

There are multiple case reports of antinuclear antibodies (ANAs) in patients with malignancies, yet to date there has not been a systematic survey of ANAs in lung cancer. We have previously reported that autoantibodies to collagen antigens resembling those found in the connective tissue diseases are consistently detected in the sera from lung cancer patients. In this work, we looked for the presence of ANAs in the sera from these same patients. Sera from 64 patients with lung cancer and 64 subjects without a history of cancer were retrospectively tested for reactivity on immunoblots of nuclear extracts of HeLa, small cell carcinoma, squamous cell carcinoma, adenocarcinoma, large cell carcinoma of the lung, and of normal lung cells. Associations were sought between the reactivities on immunoblots and lung cancer cell type, diagnosis, and progression-free survival by the method of classification and regression trees (CARTs). Cross-validated CART analyses indicated that reactivities to certain bands in immunoblots are associated with different types of lung cancer. Some of these autoantibodies were associated with a prolonged survival without disease progression. Our data suggest that autoimmunity is often a prominent feature of lung cancer and that molecular characterization of these antigens may lead to the discovery of proteins with diagnostic and prognostic value.

Autoimmunity to the M(r) 32,000 subunit of replication protein A in breast cancer.

PURPOSE: We sought to identify autoantigens recognized by antibodies in breast cancer patient sera with potential diagnostic or prognostic significance. EXPERIMENTAL DESIGN: Serum from a female breast cancer patient exhibiting a high titer antinuclear antibody was used to screen a HeLa cDNA expression library, leading to the cloning of a cDNA for the M(r) 32,000 subunit of replication protein A (RPA32). RPA32 expression and localization were assayed in autologous tumor by monoclonal antibody staining. A specific ELISA using recombinant protein was used to screen sera from 801 breast cancer patients and 65 controls. RESULTS: A relationship between anti-replication protein A (RPA) antibodies and the ductal breast carcinoma of the proband was suggested by overexpression and aberrant localization of RPA32 in tumor cells as compared with surrounding normal ductal tissue and by the presence of anti-RPA32 antibodies before the diagnosis. The prevalence of anti-RPA32 antibodies was significantly higher (P < 0.01) among breast cancer patients (87 of 801 patients) than among noncancer controls (0 of 65 controls). Similarly, anti-RPA32 antibodies were present in 4 of 39 patients with intraductal in situ carcinoma. No associations were found between anti-RPA antibodies and survival, occurrence of a second tumor, metastases, or antibodies to p53. Reactivity to RPA32 also was detected in sera from 3 of 47 patients with other cancers. CONCLUSIONS: In view of the central role of RPA in DNA replication, recombination, and repair, we suggest that autoimmunity to RPA32 may reflect molecular changes involved in the process of tumorigenesis. The finding of antibodies to RPA32 before diagnosis and their prevalence in in situ carcinoma suggest that they are potentially useful markers of early disease.

Lithographically fabricated silicon microreactor for in situ characterization of heterogeneous catalysts­Enabling correlative characterization techniques.

We report on a new modular setup on a silicon-based microreactor designed for correlative spectroscopic, scattering, and analytic on-line gas investigations for in situ studies of heterogeneous catalysts. The silicon microreactor allows a combination of synchrotron radiation based techniques (e.g., X-ray diffraction and X-ray absorption spectroscopy) as well as infrared thermography and Raman spectroscopy. Catalytic performance can be determined simultaneously by on-line product analysis using mass spectrometry. We present the design of the reactor, the experimental setup, and as a first example for an in situ study, the catalytic partial oxidation of methane showing the applicability of this reactor for in situ studies.

Phase I trial of recombinant macrophage colony-stimulating factor by rapid intravenous infusion in patients with cancer.

Fourteen patients were entered into a phase I dose-escalation trial of macrophage colony-stimulating factor (M-CSF). M-CSF was administered to inpatients by rapid 15 min i.v. infusion every 8 h x 5 days, repeated after a 9-day rest. Dose levels evaluated were 20, 40, 80, 330, and 1,100 micrograms/m2. Monitoring of patients every 4 h included vital signs, daily complete blood count (CBC), and serum chemistries (SGOT, creatinine, and bilirubin) while receiving M-CSF. No clinical or laboratory evidence of toxicity was seen. The average serum t1/2 varied with dose level. At 330 and 1,100 micrograms/m2, the serum t1/2 was 25 and 84 min, respectively, implying a saturable mechanism of clearance. After 5 days of treatment, the t1/2 decreased by twofold, consistent with enhancement of the saturable mechanism. Monocyte cytotoxicity against the A375 melanoma cell line was evaluated pretreatment and day 5 of each cycle. No consistent enhancement of monocyte cytotoxicity was seen. No effect on peripheral blood monocyte number was seen until the 1,100 micrograms/m2 dose level. At this dose level, the mean monocyte number on day 5 was increased compared to baseline (1,300 mm3 vs. 300/mm3). Clinical activity was seen in two patients with previously progressive leiomyosarcoma metastatic to the liver. A partial response (PR) lasting 7 months occurred at the 330 micrograms/m2 dose level while a patient treated at 1,100 micrograms/m2 has had stable disease for 20+ months. The maximum tolerated dose (MTD) of M-CSF was not determined. Based on clinical responses, a phase II trial is warranted in patients with metastatic soft tissue sarcoma.

Determination of oxygen extraction ratios by magnetic resonance imaging.

The oxygen extraction ratio (OER) of a tissue describes the interplay between oxygen delivery and consumption and, as such, directly reflects the viability and activity of any organ. It is shown that OER can be quantified using a single magnetic resonance imaging observable, namely the relaxation time T2 of venous blood draining from the tissue. This principle is applied to study local OER changes in the brain on visual stimulation in humans, unambiguously demonstrating a mismatch between changes in blood flow and oxygen metabolism on activation.

Kinetic analysis of [11C]McN5652: a serotonin transporter radioligand.

The impulse response function of a radioligand is the most fundamental way to describe its pharmacokinetics and to assess its tissue uptake and retention pattern. This study investigates the impulse response function of [11C](+)McN5652, a radioligand used for positron emission tomography (PET) imaging of the serotonin transporter (SERT) in the brain. Dynamic PET studies were performed in eight healthy volunteers injected with [11C](+)McN5652 and subsequently with its pharmacologically inactive enantiomer [11C](-)McN5652. The impulse response function was calculated by deconvolution analysis of regional time-activity curves, and its peak value (f(max)), its retention value at 75 minutes (fT), and its normalized retention (f(rel) = fT/f(max)) were obtained. Alternatively, compartmental models were applied to calculate the apparent total distribution volume (DV(T)) and its specific binding component (DV(S)). Both the noncompartmental (fT,f(rel)) and the compartmental parameters (DV) were investigated with and without correction for nonspecific binding by simple subtraction of the corresponding value obtained with [11C](-)McN5652. The impulse response function obtained by deconvolution analysis demonstrated high tracer extraction followed by a slow decline in the form of a monoexponential function. Statistical analysis revealed that the best compartmental model in terms of analysis of variance F and condition number of the parameter variance-covariance matrix was the one that was based on a single tissue compartment with parameters k1 and k2 and that also included the parameter of regional cerebral blood volume (BV). The parameter f(rel) demonstrated low between-subject variance (coefficient of variation [CV] = 19%), a midbrain to cerebellum ratio of 1.85, and high correlation with the known density of SERT (r = 0.787 where r is the coefficient of linear correlation between the parameter and the known density of SERT). After correction for nonspecific binding, f(rel) demonstrated further improvement in correlation (r = 0.814) and midbrain to cerebellum ratio (3.09). The variance of the distribution volumes was acceptable when the logarithmic transform lnDV was used instead of DV (17% for the three-parameter model), but correlation of this compartmental parameter was slightly less (r = 0.652 for the three-parameter model) than the correlation of the noncompartmental f(rel) with the known density of SERT, and the midbrain to cerebellum ratio was only 1.5 (uncorrected) and 1.8 (corrected). At the expense of increasing variance, the correlation was increased after correction for nonspecific binding using the inactive enantiomer (r = 0.694; CV = 22%). These results indicate that the kinetics of [11C](+)McN5652 can best be described by a one-tissue compartment model with three parameters (k1, k2, and BV), and that both the noncompartmental parameter f(rel) and the compartmental distribution volumes have the potential for quantitative estimation of the density of SERT. Further validation of the radioligand in experimental and clinical situations is warranted.

Inhibition of tumor cell growth by p21WAF1 adenoviral gene transfer in lung cancer.

Gene replacement therapy is potentially a very powerful tool, targeting specific molecular mediators of cancer development and progression. p21WAF1 (p21) is a cyclin-dependent kinase inhibitor that is induced by p53 upon DNA damage or p53 overexpression, resulting in cell cycle arrest at the G1 checkpoint and inhibition of further cell proliferation. Using a replication-deficient recombinant adenovirus (AdV) ((rAd)-p21) as a p21 gene delivery system, we have evaluated the effect of p21 introduction in lung cancer cells in vitro as well as in vivo. In in vitro experiments, two human non-small cell lung cancer (NSCLC) cell lines, NCI-H460 and NCI-H322, showed dose-dependent p21 induction and concomitant cell growth inhibition following rAd/p21 infection. Flow cytometric analysis of the cell cycle revealed a significant increase in the percentage of NCI-H460 cells in G0/G1 following rAd/p21 infection compared with untreated cells, suggesting that p21-induced growth inhibition was due to G0/G1 arrest. We also tested the therapeutic efficacy of rAd/p21 in an in vivo human NSCLC model in SCID mice. Tumor-bearing mice were established by subcutaneous injections of NCI-H460 cells and treated by repeated intratumoral injections of rAd/p21. Intratumoral delivery of rAd/p21 significantly suppressed tumor growth and prolonged survival in rAd/p21-treated mice. Our in vitro and in vivo results provide strong preliminary evidence for the growth inhibition of NSCLC by rAd/p21. Collectively, these results justify further studies to evaluate the efficacy of rAd/p21 for gene therapy in human lung cancer.

Neural pathways in tactile object recognition.

OBJECTIVE: To define further the brain regions involved in tactile object recognition using functional MRI (fMRI) techniques. BACKGROUND: The neural substrates involved in tactile object recognition (TOR) have not been elucidated. Studies of nonhuman primates and humans suggest that basic motor and somatosensory mechanisms are involved at a peripheral level; however, the mechanisms of higher order object recognition have not been determined. METHODS: The authors investigated 11 normal volunteers utilizing fMRI techniques in an attempt to determine the neural pathways involved in TOR. Each individual performed a behavioral paradigm with the activated condition involving identification of objects by touch, with identification of rough/smooth as the control. RESULTS: Data suggest that in a majority of individuals, TOR involves the calcarine and extrastriatal cortex, inferior parietal lobule, inferior frontal gyrus, and superior frontal gyrus-polar region. CONCLUSIONS: TOR may utilize visual systems to access an internal object representation. The parietal cortices and inferior frontal regions may be involved in a concomitant lexical strategy of naming the object being examined. Frontal polar activation likely serves a role in visuospatial working memory or in recognizing unusual representations of objects. Overall, these findings suggest that TOR could involve a network of cortical regions subserving somatosensory, motor, visual, and, at times, lexical processing. The primary finding suggests that in this normal study population, the visual cortices may be involved in the topographic spatial processing of TOR.