Placental blood transplant: who will benefit?
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Adult↗
Biomedical subjects
M Brenner
Publications and source records attributed to M Brenner.
Combined chemokine and cytokine gene transfer enhances antitumor immunity.
The probability of producing a specific antitumor response should be increased by multiplying the number of T lymphocytes that encounter the malignant cells. We tested this prediction in a murine model, using a recently discovered T-cell chemokine, lymphotactin (Lptn). This chemokine increased tumor cell infiltration with CD4+ lymphocytes but generated little antitumor activity. Coexpression of the T-cell growth factor interleukin-2, however, greatly expanded the T lymphocytes attracted by Lptn, affording protection from the growth of established tumor in a CD4+ and CD8+ T cell-dependent manner. Lesser synergy was seen with GM-CSF. Hence coexpression of a T-cell chemokine and T-cell growth factor potentiates antitumor responses in vivo, suggesting a general strategy to improve cancer immunotherapy.
Animals↗
Pattern recognition system for focal liver lesions using "crisp" and "fuzzy" classifiers.
RATIONALE AND OBJECTIVES: To determine the diagnostic performance of an artificial intelligence system for classification of focal liver lesions, in comparison to human observers. METHODS: One hundred forty-three focal hepatic lesions were evaluated with dynamic computed tomography. The study comprised 59 hemangiomas, 24 other benign lesions (focal nodular hyperplasia, adenoma), and 60 malignant liver lesions (18 primary, 42 secondary). All lesions but the hemangiomas were histologically examined by needle biopsy. For delineation of the lesion, a region of interest was defined interactively. The pattern recognition was performed in two steps with initial extraction of textural features: training of a classifier and classification of the lesions. The accuracy of classification of hepatic lesions into three groups (hemangioma, other benign processes, malignant lesions) was tested. The results were compared with those achieved by human observers using receiver operating characteristic statistical analysis. RESULTS: The accuracy (total rate of correct diagnoses) was 90.2%. False classifications were found owing to small size, weak contrast enhancement after bolus injection, respiratory movement, and atypical morphology of the lesion. The area under the receiver operating characteristic curve was not significantly different for computer and human observers. CONCLUSIONS: The system demonstrated a diagnostic accuracy comparable to human observers. Further improvement with increasing numbers of typical computed tomographic series for training of the classifier can be expected.
Adenoma↗
CO2 and Nd:YAG laser-induced pulmonary parenchymal lung injury in a rabbit model.
Laser exposure of the pulmonary parenchyma during treatment of emphysema and other clinical indications causes acute lung injury. Animal investigations are needed to understand and control laser-induced lung injury. We hypothesized that lung injury is deeper from Nd:YAG laser exposures than CO2 exposures because of deeper penetration of Nd:YAG wavelength light. We compared the temporal evolution of histologic injury in rabbits resulting from continuous mode shallow CO2 and Nd:YAG laser pulmonary parenchymal exposures applied in rabbits. Forty-six New Zealand white (NZW) rabbits underwent treatment with CO2 laser (n=18), Nd:YAG laser (n=18), or sham thoracotomy control (n=10) to the visceral pleural surface using 1 min of exposure (5 watts, defocused to 70 W/cm2 power density for both lasers). Animals were killed at 0, 4, 7, 21, and 49 d after exposure. Lung injury, similar to that seen clinically in humans, developed in all laser-treated animals. Injury progressed from ischemia and vascular congestion, to edema and necrosis, followed by pleural and parenchymal fibrosis. The acute injury was qualitatively distinct and slightly deeper in CO2 than Nd:YAG-treated animals (p<0.02) despite the shallower depth of penetration of the CO2 laser. These findings may imply that higher absorption coefficient for CO2 laser energy results in greater focal temperatures and injury in the areas of direct exposure, and suggest that Nd:YAG laser exposure at these settings may cause shallower injury than CO2 lasers in humans undergoing clinical treatment.
Absorption↗
Mechanism of short-term improvement in lung function after emphysema resection.
We prospectively investigated the mechanism of airflow limitation before and after targeted emphysematous resection in 12 consecutively studied adult patients 68 +/- 4 yr of age (mean +/- SD) with very severe COPD undergoing bilateral thoracoscopic stapling techniques. Lung function, static lung elastic recoil, and airway conductance was measured 2 wk before and 5 to 6 mo after surgery. After surgery, there was a significant (p < 0.01) reduction in TLC (9.3 +/- 0.3 [mean +/- SEM] to 7.7 +/- 0.4 L), functional residual capacity, and residual volume. Airway conductance, FVC, and FEV1 (0.7 +/- 0.1 to 1.2 +/- 0.2 L) all improved significantly (p < 0.01). Lung elastic recoil increased markedly at TLC (from 10.3 +/- 0.5 to 14.6 +/- 1.0 cm H20; p < 0.001) as did maximal expiratory airflow in every patient. Analysis of maximal expiratory flow-static elastic recoil pressure curve indicated that conductance of the S segment (Gs) increased from 0.20 +/- 0.03 (mean +/- SEM) to 0.27 +/- 0.03 L/s/cm H20 (p < 0.01), and the critical transmural pressure (Ptm') decreased from 3.1 +/- 0.2 to 2.4 +/- 0.2 cm H20 (p < 0.02). Mean airway conductance increased from 0.14 to 0.22 L/s/cm H20 (p < 0.01). The improvement in maximal expiratory airflow can be primarily attributed to increased lung elastic recoil and its secondary effect on enlarging airway diameter causing increased airway conductance, increased Gs, and decreased Ptm'.
Aged↗
Contribution of lung and chest wall mechanics following emphysema resection.
OBJECTIVE: To determine the contributions of (1) chest wall (Pcw) and (2) lung elastic recoil pressure (PL) to (3) total elastic recoil pressure exerted by the respiratory system (Prs) in 18 patients (12 men) aged 66 +/- 6 years (mean +/- 1 SD) with severe emphysema who underwent video-assisted thoracoscopic bilateral lung volume reduction surgery under paralyzed (vecuronium) general anesthesia (isoflurane). DESIGN: We measured preoperative and 6-week postoperative lung function studies, and intraoperative inspiratory lung conductance (GL), PL, Pcw, and Prs (cm H2O) at end-expiratory lung volume (EELV), EELV plus 0.60 +/- 0.0 L, and EELV plus 1.15 +/- 0.0 L. All values are mean +/- SEM. RESULTS: Preoperative vs postoperative FVC was 1.9 +/- 0.1 L vs 2.3 +/- 0.1 L (p = 0.03); FEV1 was 0.6 +/- 0.1 L vs 0.9 +/- 0.1 L (p < 0.02); total lung capacity was 7.4 +/- 0.4 L vs 5.9 +/- 0.3 L (p < 0.001); functional residual capacity was 5.7 +/- 0.4 L vs 4.4 +/- 0.2 L (p = 0.001). At EELV preoperative vs postoperative, PL was 0.0 +/- 0.3 vs 1.1 +/- 0.05 (p = 0.04), Pcw was 5.0 +/- 0.7 vs 2.4 +/- 0.9 (p = 0.02), and Prs was 5.0 +/- 0.8 vs 3.5 +/- 0.7 (p = 0.08). AT EELV plus 0.60 L, PL was 3.2 +/- 0.6 vs 6.1 +/- 0.9 (p < 0.001), Pcw was 8.8 +/- 0.8 vs 7.0 +/- 0.9 (p = 0.12), and Prs was 12.0 +/- 0.8 vs 13.1 +/- 0.7 (p = 0.80). At EELV plus 1.15 L, PL was 6.8 +/- 0.9 vs 10.3 +/- 1.1 (p < 0.001), Pcw was 13.5 +/- 1.0 vs 11.2 +/- 1.2 (p = 0.12), and Prs was 20 +/- 1.2 vs 21.5 +/- 1.0 p = 0.93). AT EELV plus 0.06 L, GL was 0.09 +/- 0.00 L/S/cm H2O vs 0.16 +/- 0.01 (p < 0.01). At EELV plus 1.15 L, GL was 0.12 +/- 0.01 vs 0.21 +/- 0.03 (p < 0.05) with similar preoperative vs postoperative GL/PL slopes. CONCLUSION: The increase in PL and decrease in Pcw following LVRS for emphysema may be responsible for the increase in spirometry and airway conductance.
Aged↗
Lung volume reduction surgery for emphysema.
There has been dramatic resurgence of interest in surgical treatment of emphysema, particularly "lung volume reduction" procedures. Recent studies have demonstrated improvements in pulmonary function, lung mechanics, exercise tolerance, and quality of life in selected patients following volume reduction procedures. However, considerable uncertainty remains regarding overall benefit, optimal patient selection, operative techniques, and duration of response. This summarizes current approaches to lung volume reduction surgery, available clinical outcome information, selection criteria, and physiologic mechanisms of response, and discusses the potential role for surgical volume reduction in treatment of emphysema. Recent data appear to support the efficacy of bilateral staple lung volume reduction surgery in patients with severe symptomatic heterogeneously distributed emphysema. Further studies will be needed to determine relative value of different operative techniques and benefit in patients with other clinical presentations.
Algorithms↗
Combined operations for lung volume reduction surgery and lung cancer.
Fifty-three lung masses were found in 51 (16%) of 325 patients who underwent lung volume reduction surgery. This included 11 non-small cell lung cancers and 42 benign lung masses. Eleven patients (mean age, 69.4 years) underwent a combined lung volume reduction surgery and resection of clinical stage I lung cancers (lymph node dissection with either lobectomy [3] or wedge resection [8]). There were no deaths or major complications. The average length of stay was 8.7 days. The mean FEV1 was 654 mL (21.7% predicted) preoperatively and 1,079 mL (49% predicted) postoperatively. Patients who are screened for lung volume reduction surgery should be carefully evaluated for possible lung masses. Lung volume reduction surgery allows lung cancer surgery in patients who otherwise would be considered to have physiologically inoperable disease.
Aged↗
Lung function 12 months following emphysema resection.
OBJECTIVE: To investigate the mechanism of airflow limitation before and 6 and 12 months after targeted emphysematous resection in 10 male patients aged 67 +/- 8 years (mean +/- SD) with very severe COPD undergoing bilateral thoracoscopic stapling techniques. DESIGN: Lung function, including static lung elastic recoil, was measured 2 weeks before and 6 and 12 months after surgery. RESULTS: Twelve months after surgery, there was a significant (p < 0.001) reduction in total lung capacity (TLC), 9.5 +/- 0.3 L (mean +/- SEM) to 8.5 +/- 0.3 L, functional residual capacity, and residual volume. Airway conductance and FEV1, 0.71 +/- 0.1 L (mean +/- SEM) to 0.95 +/- 0.1 L, improved significantly (p < 0.01). Lung elastic recoil increased markedly at TLC from 11.7 +/- 0.7 cm H2O (mean +/- SEM) to 15.0 +/- 1.0 cm H2O (p < 0.01) as did maximum expiratory airflow in every patient. However, when compared with data obtained in each patient at 6 months, lung volumes are significantly increased, and expiratory airflow and lung elastic recoil pressures are significantly reduced (p < or = 0.05). Analysis of maximum expiratory flow-static elastic recoil pressure curve indicates conductance of the S airway segment (Gs) increased from 0.20 +/- 0.03 L/s/cm H2O (mean +/- SEM) to 0.28 +/- 0.04 L/s/cm H2O (p < 0.02), and critical transmural pressure in the collapsible segment (Ptm') decreased from 3.2 +/- 0.2 cm H2O (mean +/- SEM) to 2.5 +/- 0.2 cm H2O (p < 0.01). CONCLUSION: The improvement in maximal expiratory airflow can be attributed primarily to increased lung elastic recoil and its secondary effect on enlarging airway diameter causing increased airway conductance, increased Gs, and decreased Ptm'. The improvement in lung function and elastic recoil peaks at 6 months.
Aged↗
[Indicators of male fertility in a sample of Slovak students].
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Adolescent↗
Cryogenic spinal cord injury induces astrocytic gene expression of insulin-like growth factor I and insulin-like growth factor binding protein 2 during myelin regeneration.
To study injury-induced astrocytic responses associated with regrowth of axons and regeneration of myelin, the method of Collins and colleagues was used to make focal cryogenic lesions in spinal cords of adult rats (Collins et al.: J Neuropathol Exp Neurol 45: 742-757, 1986). The duration of cryogenic injury (CI), the size of the cryode, and its temperature were chosen to destroy all myelin sheaths and axons without producing cavities or hemorrhages. Messenger RNA and peptide distributions of insulin-like growth factor I (IGF-I), IGF-I receptor (IGFR-I), IGF binding protein 2 (IGFBP-2), glial fibrillary acidic protein (GFAP), and myelin basic protein (MBP) were studied 3-56 days after CI by in situ hybridization and immunocytochemistry. At 3 days, vimentin-positive, GFAP-negative astrocyte-like cells in the lesion expressed IGF-I mRNA and peptide and 7 days after CI, both were expressed by typical GFAP-positive, hypertrophic astrocytes, many of which also were vimentin-positive. Levels of IGF-I, IGFBP-2, and GFAP mRNA and peptide were higher in lesion astrocytes after 14 days. They attained maximum levels at 21-28 days before declining to near control levels at 56 days. Decreasing relative levels of oligodendroglial MBP mRNA were found in and around lesions 7-14 days after CI; subsequently, rising levels accompanied remyelination. At 28 and 56 days after CI, some transferrin-positive, oligodendroglia-like cells also were immunostained by anti-IGFR-I. Our findings suggest that early astrocytic production of IGF-I and IGFBP-2 may be involved in the myelin regeneration which occurs in this model of spinal cord injury.
Animals↗
Determination of DLCO and cardiac output from expired gas slopes with cardiogenic oscillations.
Effects of 'cardiogenic oscillations' on alveolar plateau gas concentration slope measurements, constant expiratory pulmonary capillary blood flow, and DLCO determination have not been previously described. We examined cardiogenic oscillations during constant expiratory maneuvers to assess factors influencing magnitude of oscillations as well as effect of oscillatory phase at the start and end of exhalation measurement period on alveolar gas slope. Five normal volunteers performed repeated single breath constant exhalation vital capacity maneuvers using test gas containing 2 physiologically 'inert' gases: Helium (He Mw 4) and argon (Ar Mw 40). The mixture contained 3 absorbable gases, acetylene (C2H2 Mw 26), carbon monoxide (C18O Mw 30), and oxygen. Alveolar plateau slope, magnitude of cardiogenic oscillations, relative signal to noise ratios, and effect of cardiogenic oscillation phase on measured slope were determined for each gas. Cardiogenic oscillations were present for all inert gases. Oscillations were less evident for CO. However, the effects on calculated Qc and DLCO were negligible. Cardiac oscillations of considerable magnitude are seen during single breath constant exhalation maneuvers and affect constant expiratory gas slope calculations. Cardiogenic oscillation phase does not have a significant effect on measured Qc and DLCO using constant expiratory techniques.
Adult↗
A novel glial fibrillary acidic protein mRNA lacking exon 1.
Glial fibrillary acidic protein (GFAP) is the major intermediate filament protein in the mature astrocytes. We have assayed for the presence of GFAP mRNA gene in mouse tissues outside the nervous system. Nuclease S1 protection experiments show that RNAs lacking exon 1 are transcribed in bone marrow. From a mouse bone marrow cDNA library we isolated GFAP cDNAs which start in the 3' part of intron 1 and contain all the downstream GFAP exons. The new GFAP mRNAs, which we call GFAP gamma mRNAs, are already present in the brain at embryonic day 15 and in adult forebrain and cerebellum. Their presence in astrocytic cell lines suggests that astrocytes may be the site of in vivo expression of these mRNAs. In addition we have detected GFAP gamma mRNAs in mouse spleen. Furthermore in human an analogous GFAP mRNA containing the 3' part of intron 1 and lacking the exon 1 is also present in adult brain. These results suggest a new regulation of the GFAP gene expression.
Animals↗
European School of Oncology position paper. Gene therapy for the medical oncologist.
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Animals↗
Stereotactic injection of herpes simplex thymidine kinase vector producer cells (PA317-G1Tk1SvNa.7) and intravenous ganciclovir for the treatment of progressive or recurrent primary supratentorial pediatric malignant brain tumors.
This study will evaluate the safety and efficacy of in vivo gene transfer of the herpes simplex thymidine kinase (HSV-Tk1) gene using PA317/G1Tk1SvNa.7 vector producer cells (VPC) in pediatric patients with progressive or recurrent primary supratentorial malignant brain tumors. Insertion of the HSV-Tk1 gene confers a sensitivity to the anti-herpes drug ganciclovir. It has been demonstrated that the direct injection of HSV-Tk vector producer cells into growing tumors in animals can result in their complete destruction with ganciclovir therapy. This selective destruction of growing tumors in situ is thought to result from the transfer of the HSV-Tk gene into the tumor cells and the production of toxic ganciclovir metabolites which result from the interaction of HSV-Tk and ganciclovir. This procedure can result in the cure of some experimental animals with limited systemic toxicity due to selective gene transfer into tumors. This clinical trial will focus on maximizing the relative number of vector producer cells to the tumor mass by stereotactically injecting VPCs into the tumor mass. Children with progressive or recurrent primary supratentorial malignant brain tumor which is accessible to stereotactic injection will be evaluated for the extent and location(s) of their disease before being entered into the study. Fifteen days after stereotactic injection of the tumor mass, ganciclovir will be administered at 5 mg/kg IV b.i.d. for 14 days. Upon completion of the treatment with HSV-Tk1 vector producer cells and ganciclovir, the patient will be followed monthly for the first three months, then every two months for the next twenty-one months, and annually for life thereafter.
Adolescent↗
Overexpression of TGF-beta 1 in the central nervous system of transgenic mice results in hydrocephalus.
Transforming growth factor beta (TGF-beta) has been proposed to play a number of roles in central nervous system (CNS) development and response to injury. To test these proposals, transgenic mice were generated which overproduce TGF-beta 1 in the CNS. Surprisingly, these mice developed severe hydrocephalus and died between birth and 3 weeks of age. Ovary transplantation from an affected female founder has permitted perpetuation of one of the lines as a hydrocephalus model whose genetic defect is known. These results also demonstrate that the developing CNS is highly sensitive to TGF-beta, and suggest a role for aberrant expression of TGF-beta in the pathogenesis of developmental disease of the CNS.
Animals↗
Astrocytes upregulate glial fibrillary acidic protein (GFAP), but not insulin-like growth factor-I (IGF-I) during experimental autoimmune neuritis (EAN).
T cell-mediated autoimmune neuritis produces rapid activation of spinal cord microglia. To determine whether this microglial response upregulates astrocytic expression of IGF-related proteins, we induced EAN and used in situ hybridization and immunocytochemistry to examine the mRNAs and peptides for glial fibrillary acidic protein (GFAP), insulin-like growth factor-I (IGF-I), IGF-I receptor (IGFR-I) and IGF binding protein-2 (IGFBP-2). Relative levels of GFAP mRNA and peptide were highest in the lumbar spinal cord 4-10 d following T cell transfer and significant GFAP elevations were still present after three weeks. The astrocytes expressing GFAP mRNA and peptide were localized around motoneurons which were related topographically to axons in peripheral nerve inflammatory lesions. In the nucleus gracilis, where terminals of dorsal root ganglion neurons are located, astrocytic levels of GFAP mRNA and peptide rose later and did not reach their highest levels until 21 d after T cell transfer. Even though microglia were activated in both locations 2-4 d after transfer, astrocytic levels of IGF-I, IGFR-I and IGFBP-2 mRNA and peptide did not differ significantly from those observed in controls. The dissociation of GFAP and IGF-I expression in EAN suggests that these astrocytic responses may be independently regulated. We also suggest that the type and severity of remote neuronal injury are probably more important inducers and regulators of these astrocytic responses than microglial cell activation.
Animals↗
Psychological effects of bone marrow transplantation on children and adolescents: preliminary report of a longitudinal study.
The number of pediatric bone marrow transplantation (BMT) survivors is growing rapidly, yet little is known about the long-term neuropsychologic and psychosocial sequelae of this procedure. Using a prospective, longitudinal design, 64 pediatric patients undergoing BMT were evaluated with standardized measures of global intelligence, academic achievement and selected tests of neuropsychologic function. In addition, adjustment was assessed with parent and patient report measures of social competence, behavior problems and self-esteem. Patients were evaluated prior to admission for BMT, and again in the period 6-12 months after BMT. Longitudinal findings are reported on an initial cohort of 25 survivors. Cognitive and neuropsychologic function remained stable during the study period. The few significant changes from baseline which were observed were in the direction of improvement, and may be attributed to practice effects. In contrast, declines were observed in patient social competence, self-esteem and general emotional well-being. BMT conditioning regimens appear not to be associated with significant neuropsychologic impairment in the first year after transplant. However, a longer period of follow-up is necessary before neuropsychologic late-effects can be ruled out. The first year after BMT is characterized by significant psychosocial difficulties for survivors. Adjustment issues may provide a more salient focus of study during this time frame.
Adolescent↗