Showing papers by "Drexel University published in 1999"

Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate into astrocytes after injection into neonatal mouse brains

Abstract: Stem cells are a valuable resource for treating disease, but limited access to stem cells from tissues such as brain restricts their utility. Here, we injected marrow stromal cells (MSCs) into the lateral ventricle of neonatal mice and asked whether these multipotential mesenchymal progenitors from bone marrow can adopt neural cell fates when exposed to the brain microenvironment. By 12 days postinjection, MSCs migrated throughout the forebrain and cerebellum without disruption to the host brain architecture. Some MSCs within the striatum and the molecular layer of the hippocampus expressed glial fibrillary acidic protein and, therefore, differentiated into mature astrocytes. MSCs also populated neuron rich regions including the Islands of Calleja, the olfactory bulb, and the internal granular layer of the cerebellum. A large number of MSCs also were found within the external granular layer of the cerebellum. In addition, neurofilament positive donor cells were found within the reticular formation of the brain stem, suggesting that MSCs also may have differentiated into neurons. Therefore, MSCs are capable of producing differentiated progeny of a different dermal origin after implantation into neonatal mouse brains. These results suggest that MSCs are potentially useful as vectors for treating a variety of central nervous system disorders.

The impact of stocks and flows of organizational knowledge on firm performance: an empirical investigation of the biotechnology industry

Abstract: The knowledge-based view of the firm is a recent approach to understanding the relationship between firm capabilities and firm performance. Specifically, this approach suggests that knowledge generation, accumulation and application may be the source of superior performance. Other research has conceptualized organizational knowledge in terms of stocks of accumulated knowledge in the firm and flows of knowledge into the firm. This paper tests the relationship between stocks and flows of organizational knowledge and firm performance in the biotechnology industry. We suggest that a firm’s geographic location, alliances with other institutions and organizations and R&D expenditures are representative of knowledge flows, while products in the pipeline, firm citations and patents are indicative of knowledge stocks. Through factor analysis, we develop an aggregated measure of location from several variables. A regression model suggests that location is a significant predictor of firm performance as are products in the pipeline and firm citations. A major contribution of this investigation is the operationalization of geographic location and its statistically significant link to firm performance. Copyright © 1999 John Wiley & Sons, Ltd.

Development of a multiple sclerosis functional composite as a clinical trial outcome measure

Abstract: The primary clinical outcome measure for evaluating multiple sclerosis in clinical trials has been Kurtzke's expanded disability status scale (EDSS). New therapies appear to favourably impact the course of multiple sclerosis and render continued use of placebo control groups more difficult. Consequently, future trials are likely to compare active treatment groups which will most probably require increased sample sizes in order to detect therapeutic efficacy. Because more responsive outcome measures will be needed for active arm comparison studies, the National Multiple Sclerosis Society's Advisory Committee on Cinical Trials of New Agents in Multiple Sclerosis appointed a Task Force that was charged with developing improved clinical outcome measures. This Task Force acquired contemporary clinical trial and historical multiple sclerosis data for meta-analyses of primary and secondary outcome assessments to provide a basis for recommending a new outcome measure. A composite measure encompassing the major clinical dimensions of arm, leg and cognitive function was identified and termed the multiple sclerosis functional composite (MSFC). The MSFC consists of three objective quantitative tests of neurological function which are easy to administer. Change in this MSFC over the first year of observation predicted subsequent change in the EDSS, suggesting that the MSFC is more sensitive to change than the EDSS. This paper provides details concerning the development and testing of the MSFC.

Propagation and senescence of human marrow stromal cells in culture: a simple colony-forming assay identifies samples with the greatest potential to propagate and differentiate.

Abstract: Marrow stromal cells (MSCs) were isolated from bone marrow obtained by aspirates of the iliac crest of normal volunteers. The cells were isolated by their adherence to plastic and then passed in culture. Some of the samples expanded through over 15 cell doublings from the time frozen stocks were prepared. Others ceased replicating after about four cell doublings. The replicative potential of the cells in culture was best predicted by a simple colony-forming assay in which samples from early passages were plated at low densities of about 10 cells per cm2. Samples with high colony-forming efficiency exhibited the greatest replicative potential. The colonies obtained by plating early passage cells at low density varied in size and morphology. The large colonies readily differentiated into osteoblasts and adipocytes when incubated in the appropriate medium. As samples were expanded in culture and approached senescence, they retained their ability to differentiate into osteoblasts. However, the cells failed to differentiate into adipocytes. The loss of multipotentiality following serial passage in culture may have important implications for the use of expanded MSCs for cell and gene therapy.

An evidence-based appraisal of reflux disease management — the Genval Workshop Report

Abstract: This report summarises conclusions from an evidence-based workshop which evaluated major clinical strategies for the management of the full spectrum of gastro-oesophageal reflux disease, with an emphasis on medical management. The disease was defined by the presence of oesophageal mucosal breaks or by the occurrence of reflux induced symptoms severe enough to impair quality of life. Endoscopy negative patients were recognised as the most common subgroup; most of these patients can be diagnosed by a well structured symptom analysis. There is a consistent hierarchy of effectiveness of available initial and long term therapies that applies for all patient subgroups. Lifestyle measures were judged to be of such low efficacy that they were rejected as a primary therapy for all patient subgroups. Proton pump inhibitor therapy was considered the initial medical treatment of choice because of its clearly superior efficacy which results in the most prompt achievement of desirable outcomes at the lowest overall medical cost. It was acknowledged that most of patients require long term management and that any maintenance therapy should be chosen by step down to the regimen that is still effective, but least costly. Endoscopic monitoring of routine long term therapy was considered inappropriate, on the basis that control of symptoms is an acceptably reliable indicator of healing in patients with oesophagitis. Laparoscopic antireflux surgery was recognised as a significant therapeutic advance, the results of which, however, depend substantially on the experience of the surgeon. There are currently no published direct comparisons of cost and efficacy outcomes of optimal medical and surgical therapies for reflux disease. To a significant degree, the choice between medical and surgical therapy should depend on informed patient preference. Substantial advances have occurred recently in the understanding and treatment of reflux disease. By contrast, there has been relatively little research into the best …

A comparison of exposure therapy, stress inoculation training, and their combination for reducing posttraumatic stress disorder in female assault victims.

Abstract: Ninety-six female assault victims with chronic posttraumatic stress disorder (PTSD) were randomly assigned to 4 treatment conditions: prolonged exposure (PE), stress inoculation training (SIT), combined treatment (PE-SIT), or wait-list control (WL). Treatment consisted of 9 twice-weekly, individual sessions. Independent evaluations were conducted at pretreatment; posttreatment; and 3-, 6-, and 12-month follow-ups. All 3 active treatments reduced severity of PTSD and depression compared with WL but did not differ significantly from each other, and these gains were maintained throughout the follow-up period. However, in the intent-to-treat sample, PE was superior to SIT and PE-SIT on posttreatment anxiety and global social adjustment at follow-up and had larger effect sizes on PTSD severity, depression, and anxiety. SIT and PE-SIT did not differ significantly from each other on any outcome measure.

Tissue Engineering: Orthopedic Applications

Abstract: ▪ Abstract Because of an aging population and increased occurrence of sports-related injuries, musculoskeletal disorders have become one of the major health concerns in the United States. Current treatments, although fairly successful, do not provide the optimum therapy. These treatments typically rely on donor tissues obtained either from the patient or from another source. The former raises the issue of supply, whereas the latter poses the risk of rejection and disease transfer. This has prompted orthopedic surgeons and scientists to look for viable alternatives. In recent years, tissue engineering has gained increasing support as a method to treat orthopedic disorders. Because it uses principles of engineering, biology, and chemistry, tissue engineering may provide a more effective approach to the treatment of musculoskeletal disorders than traditional methods. This chapter presents a review of current methods and new tissue-engineering techniques for the treatment of disorders affecting bone, ligament...

Apoptosis in heart failure: Release of cytochrome c from mitochondria and activation of caspase-3 in human cardiomyopathy

Abstract: Apoptosis has been shown to contribute to loss of cardiomyocytes in cardiomyopathy, progressive decline in left ventricular function, and congestive heart failure. Because the molecular mechanisms involved in apoptosis of cardiocytes are not completely understood, we studied the biochemical and ultrastructural characteristics of upstream regulators of apoptosis in hearts explanted from patients undergoing transplantation. Sixteen explanted hearts from patients undergoing heart transplantation were studied by electron microscopy or immunoblotting to detect release of mitochondrial cytochrome c and activation of caspase-3. The hearts explanted from five victims of motor vehicle accidents or myocardial ventricular tissues from three donor hearts were used as controls. Evidence of apoptosis was observed only in endstage cardiomyopathy. There was significant accumulation of cytochrome c in the cytosol, over myofibrils, and near intercalated discs of cardiomyocytes in failing hearts. The release of mitochondrial cytochrome c was associated with activation of caspase-3 and cleavage of its substrate protein kinase C δ but not poly(ADP-ribose) polymerase. By contrast, there was no apparent accumulation of cytosolic cytochrome c or caspase-3 activation in the hearts used as controls. The present study provides in vivo evidence of cytochrome c-dependent activation of cysteine proteases in human cardiomyopathy. Activation of proteases supports the phenomenon of apoptosis in myopathic process. Because loss of myocytes contributes to myocardial dysfunction and is a predictor of adverse outcomes in the patients with congestive heart failure, the present demonstration of an activated apoptotic cascade in cardiomyopathy could provide the basis for novel interventional strategies.

Replacement of the aortic root in patients with Marfan's syndrome.

Abstract: Background Replacement of the aortic root with a prosthetic graft and valve in patients with Marfan's syndrome may prevent premature death from rupture of an aneurysm or aortic dissection. We reviewed the results of this surgical procedure at 10 experienced surgical centers. Methods A total of 675 patients with Marfan's syndrome underwent replacement of the aortic root. Survival and morbidity-free survival curves were calculated, and risk factors were determined from a multivariable regression analysis. Results The 30-day mortality rate was 1.5 percent among the 455 patients who underwent elective repair, 2.6 percent among the 117 patients who underwent urgent repair (within 7 days after a surgical consultation), and 11.7 percent among the 103 patients who underwent emergency repair (within 24 hours after a surgical consultation). Of the 675 patients, 202 (30 percent) had aortic dissection involving the ascending aorta. Forty-six percent of the 158 adult patients with aortic dissection and a documented ao...

Plastic adherent stromal cells from the bone marrow of commonly used strains of inbred mice: variations in yield, growth, and differentiation.

Abstract: Bone marrow stroma contains a unique cell population, referred to as marrow stromal cells (MSCs), capable of differentiating along multiple mesenchymal cell lineages. A standard liquid culture system has been developed to isolate MSCs from whole marrow by their adherence to plastic wherein the cells grow as clonal populations derived from a single precursor termed the colony-forming-unit fibroblast (CFU-F). Using this liquid culture system, we demonstrate that the relative abundance of MSCs in the bone marrow of five commonly used inbred strains of mice varies as much as 10-fold, and that the cells also exhibit markedly disparate levels of alkaline phosphatase expression, an early marker of osteoblast differentiation. For each strain examined, the method of isolating MSCs by plastic adherence yields a heterogeneous cell population. These plastic adherent cells also exhibit widely varying growth kinetics between the different strains. Importantly, of three inbred strains commonly used to prepare transgenic mice that we examined, only cells derived from FVB/N marrow readily expand in culture. Further analysis of cultures derived from FVB/N marrow showed that most plastic adherent cells express CD11b and CD45, epitopes of lymphohematopoietic cells. The later consists of both pre-B-cell progenitors, granulocytic and monocytic precursors, and macrophages. However, a subpopulation of the MSCs appear to represent bona fide mesenchymal progenitors, as cells can be induced to differentiate into osteoblasts and adipocytes after exposure to dexamethasone and into myoblasts after exposure to amphotericin B. Our results point to significant strain differences in the properties of MSCs and indicate that standard methods cannot be applied to murine bone marrow to isolate relatively pure populations of MSCs.

Analysis of protein aggregation kinetics.

Abstract: Given a set of kinetic data, then, the preceding discussions suggest the following approach to its analysis. 1. 1. For purposes of establishing the reaction, ignore the final stages and concentrate on the initial 10–20% of the reaction at first. A globally optimized model may be based on a faulty assumption for the initial steps. Thus, although the whole data set may look reasonably well fit, the reaction could be misrepresented, and thus the fit unhelpful if accuracy at the later stages has come at the expense of the initial phase of the reaction. 2. 2. What is the time course of the initial reaction? (A) Is the reaction exponential? Exponential growth gives dramatic lag times (see Fig. 3), whereas nonexponential “lag times” have a visible signal from time 0 (i.e., Fig. 2). If the data set shows the abrupt appearance of signals after a period of quiescence, the chances are excellent that the time course is exponential. High sensitivity measurement of the signal at times during the lag phase should be used to confirm the exponential nature quantitatively. Exponential reactions mean a secondary pathway is operative. (a) A cascade ( t n ) can look similar to an exponential, but may proceed from a multistep single-path reaction. Thus the exponential needs to be ascertained with some accuracy. (b) It is possible that some or all of the lag results from a stochastic process, i.e., formation of a single nucleus being observed. This, however, is likely to be accompanied by a secondary process, as few techniques are sensitive enough to detect a single polymer at a time, and having one nucleus form many polymers is a hallmark of a secondary process. Thus, the reproducibility of the kinetics must be established to rule out stochastics. If data show wide variation, stochastic methods as described earlier may be employed. (c) Given a secondary process, one must separate the primary nucleation process from the secondary process (by stochastic means or by use of the product B 2 A , as described earlier). (B) If the reaction does not begin with an exponential, is it parabolic? If so, it falls in the general class of linear polymerizations. 3. 3. What is the concentration dependence of the reaction(s)? This will separate nucleation processes from growth, and so on. 4. 4. If the initial reaction is neither exponential nor parabolic, a reaction mechanism needs to be proposed and evaluated. Solving the resulting equations is best done by linearization, which has the best chance of giving equations whose solutions and their sensitivity to parameters are readily understood. If this proves fruitful, full numeric solutions may be useful. 5. 5. At this point, the full reaction may be considered to completion. 6. 6. The physical basis of the description (sizes of parameters and their dependencies) needs to be finally considered to ensure that the mathematical success of the description rests on tenable physical grounds.

Bunch: a clustering tool for the recovery and maintenance of software system structures

Abstract: Software systems are typically modified in order to extend or change their functionality, improve their performance, port them to different platforms, and so on. For developers, it is crucial to understand the structure of a system before attempting to modify it. The structure of a system, however, may not be apparent to new developers, because the design documentation is non-existent or, worse, inconsistent with the implementation. This problem could be alleviated if developers were somehow able to produce high-level system decomposition descriptions from the low-level structures present in the source code. We have developed a clustering tool called Bunch that creates a system decomposition automatically by treating clustering as an optimization problem. The paper describes the extensions made to Bunch in response to feedback we received from users. The most important extension, in terms of the quality of results and execution efficiency, is a feature that enables the integration of designer knowledge about the system structure into an otherwise fully automatic clustering process. We use a case study to show how our new features simplified the task of extracting the subsystem structure of a medium size program, while exposing an interesting design flaw in the process.

Transplants of Fibroblasts Genetically Modified to Express BDNF Promote Regeneration of Adult Rat Rubrospinal Axons and Recovery of Forelimb Function

Abstract: Adult mammalian CNS neurons do not normally regenerate their severed axons. This failure has been attributed to scar tissue and inhibitory molecules at the injury site that block the regenerating axons, a lack of trophic support for the axotomized neurons, and intrinsic neuronal changes that follow axotomy, including cell atrophy and death. We studied whether transplants of fibroblasts genetically engineered to produce brain-derived neurotrophic factor (BDNF) would promote rubrospinal tract (RST) regeneration in adult rats. Primary fibroblasts were modified by retroviral-mediated transfer of a DNA construct encoding the human BDNF gene, an internal ribosomal entry site, and a fusion gene of lacZ and neomycin resistance genes. The modified fibroblasts produce biologically active BDNF in vitro. These cells were grafted into a partial cervical hemisection cavity that completely interrupted one RST. One and two months after lesion and transplantation, RST regeneration was demonstrated with retrograde and anterograde tracing techniques. Retrograde tracing with fluorogold showed that ;7% of RST neurons regenerated axons at least three to four segments caudal to the transplants. Anterograde tracing with biotinylated dextran amine revealed that the RST axons regenerated through and around the transplants, grew for long distances within white matter caudal to the transplant, and terminated in spinal cord gray matter regions that are the normal targets of RST axons. Transplants of unmodified primary fibroblasts or Gelfoam alone did not elicit regeneration. Behavioral tests demonstrated that recipients of BDNF-producing fibroblasts showed significant recovery of forelimb usage, which was abolished by a second lesion that transected the regenerated axons.

Donor variation in the growth properties and osteogenic potential of human marrow stromal cells.

Abstract: Human marrow stromal cells (MSCs) were isolated from posterior illiac crest marrow aspirates obtained from 17 healthy donors, ages 19-45 years, with no apparent physical disability. First passage hMSCs exhibited growth rates in vitro that varied up to 12-fold between donors. No correlation between growth rate and the age or gender of the donor was evident (P

Axon pathology in Parkinson's disease and Lewy body dementia hippocampus contains alpha-, beta-, and gamma-synuclein.

Abstract: Pathogenic α-synuclein (αS) gene mutations occur in rare familial Parkinson’s disease (PD) kindreds, and wild-type αS is a major component of Lewy bodies (LBs) in sporadic PD, dementia with LBs (DLB), and the LB variant of Alzheimer’s disease, but β-synuclein (βS) and γ-synuclein (γS) have not yet been implicated in neurological disorders. Here we show that in PD and DLB, but not normal brains, antibodies to αS and βS reveal novel presynaptic axon terminal pathology in the hippocampal dentate, hilar, and CA2/3 regions, whereas antibodies to γS detect previously unrecognized axonal spheroid-like lesions in the hippocampal dentate molecular layer. The aggregation of other synaptic proteins and synaptic vesicle-like structures in the αS- and βS-labeled hilar dystrophic neurites suggests that synaptic dysfunction may result from these lesions. Our findings broaden the concept of neurodegenerative “synucleinopathies” by implicating βS and γS, in addition to αS, in the onset/progression of PD and DLB.

Influence of grain size and stacking-fault energy on deformation twinning in fcc metals

Abstract: This article investigates the microstructural variables influencing the stress required to produce deformation twins in polycrystalline fcc metals. Classical studies on fcc single crystals have concluded that the deformation-twinning stress has a parabolic dependence on the stacking-fault energy (SFE) of the metal. In this article, new data are presented, indicating that the SFE has only an indirect effect on the twinning stress. The results show that the dislocation density and the homogeneous slip length are the most relevant microstructural variables that directly influence the twinning stress in the polycrystal. A new criterion for the initiation of deformation twinning in polycrystalline fcc metals at low homologous temperatures has been proposed as (σ tw −σ 0)/G=C(d/b)A, where σ tw is the deformation twinning stress, σ 0 is the initial yield strength, G is the shear modulus, d is the average homogeneous slip length, b is the magnitude of the Burger’s vector, and C and A are constants determined to have values of 0.0004 and −0.89, respectively. The role of the SFE was observed to be critical in building the necessary dislocation density while maintaining relatively large homogeneous slip lengths.

The mammalian low-density lipoprotein receptor family

Abstract: The low-density lipoprotein (LDL) receptor (LDL-R) family consists of cell-surface receptors that recognize extracellular ligands and internalize them for degradation by lysosomes. The LDL-R is the prototype of this family, which also contains very-low-density lipoprotein receptors (VLDL-R), apolipoprotein E receptor 2, LRP, and megalin. The family members contain four major structural modules: the cysteine-rich complement-type repeats, epidermal growth factor precursor-like repeats, a transmembrane domain, and a cytoplasmic domain. Each structural module serves distinct and important functions. These receptors bind several structurally dissimilar ligands. It is proposed that instead of a primary sequence, positive electrostatic potential in different ligands constitutes a receptor binding domain. This family of receptors plays crucial roles in various physiologic functions. LDL-R plays an important role in cholesterol homeostasis. Mutations cause familial hypercholesterolemia and premature coronary artery disease. LDL-R-related protein plays an important role in the clearance of plasma-activated alpha 2-macroglobulin and apolipoprotein E-enriched lipoproteins. It is essential for fetal development and has been associated with Alzheimer's disease. Megalin is the major receptor in absorptive epithelial cells of the proximal tubules and an antigenic determinant for Heymann nephritis in rats. Mutations in a chicken homolog of VLDL-R cause female sterility and premature atherosclerosis. This receptor is not expressed in liver tissue; however, transgenic expression of VLDL-R in liver corrects hypercholesterolemia in experiment animals, which suggests that it can be a candidate for gene therapy for various hyperlipidemias. The functional importance of individual receptors may lie in their differential tissue expression. The regulation of expression of these receptors occurs at the transcriptional level. Expression of the LDL-R is regulated by intracellular sterol levels involving novel membrane-bound transcription factors. Other members of the family are not regulated by sterols. All the members are, however, regulated by hormones and growth factors, but the mechanisms of regulation by hormones have not been elucidated. Studies of these receptors have provided important insights into receptor structure-function and mechanisms of ligand removal and catabolism. It is anticipated that increased knowledge about the LDL-R family members will open new avenues for the treatment of many disorders.

Diabetes mellitus, other medical conditions and familial history of cancer as risk factors for pancreatic cancer.

Abstract: In a population-based case-control study of pancreatic cancer conducted in three areas of the USA, 484 cases and 2099 controls were interviewed to evaluate the aetiologic role of several medical conditions/interventions, including diabetes mellitus, cholecystectomy, ulcer/gastrectomy and allergic states. We also evaluated risk associated with family history of cancer. Our findings support previous studies indicating that diabetes is a risk factor for pancreatic cancer, as well as a possible complication of the tumour. A significant positive trend in risk with increasing years prior to diagnosis of pancreatic cancer was apparent (P-value for test of trend = 0.016), with diabetics diagnosed at least 10 years prior to diagnosis having a significant 50% increased risk. Those treated with insulin had risks similar to those not treated with insulin (odds ratio (OR) = 1.6 and 1.5 respectively), and no trend in risk was associated with increasing duration of insulin treatment. Cholecystectomy also appeared to be a risk factor, as well as a consequence of the malignancy. Subjects with a cholecystectomy at least 20 years prior to the diagnosis of pancreatic cancer experienced a 70% increased risk, which was marginally significant. In contrast, subjects with a history of duodenal or gastric ulcer had little or no elevated risk (OR = 1.2; confidence interval = 0.9-1.6). Those treated by gastrectomy had the same risk as those not receiving surgery, providing little support for the hypothesis that gastrectomy is a risk factor for pancreatic cancer. A significant 40% reduced risk was associated with hay fever, a non-significant 50% decreased risk with allergies to animals, and a non-significant 40% reduced risk with allergies to dust/moulds. These associations, however, may be due to chance since no risk reductions were apparent for asthma or several other types of allergies. In addition, we observed significantly increased risks for subjects reporting a first-degree relative with cancers of the pancreas (OR = 3.2), colon (OR = 1.7) or ovary (OR = 5.3) and non-significantly increased risks for cancers of the endometrium (OR = 1.5) or breast (OR = 1.3). The pattern is consistent with the familial predisposition reported for pancreatic cancer and with the array of tumours associated with hereditary non-polyposis colon cancer.

Optimism and rehospitalization after coronary artery bypass graft surgery

Abstract: Objective: To determine whether optimism predicts lower rates of rehospitalization after coronary artery bypass graft surgery for the 6 months after surgery. Methods: A prospective, inception cohort design was used. The sample consisted of all consenting patients (N = 309) from a consecutive series of patients scheduled for elective coronary artery bypass graft surgery at a large, metropolitan hospital in Pittsburgh, Pa. To be eligible, patients could not be scheduled for any other coincidental surgery (eg, valve replacement) and could not be in the cardiac intensive care unit or experiencing angina at the time of the referral. Participants were predominantly men (69.9%) and married (80.3%), and averaged 62.8 years of age. Recruitment occurred between January 1992 and January 1994. Results: Compared with pessimistic persons, optimistic persons were significantly less likely to be rehospitalized for a broad range of aggregated problems (including postsurgical sternal wound infection, angina, myocardial infarction, and the need for another bypass surgery or percutaneous transluminal coronary angioplasty) generally indicative of a poor response to the initial surgery (odds ratio = 0.50, 95% confidence interval = 0.33-0.76; P = .001). The effect of optimism was independent of traditional sociodemographic and medical control variables, as well as independent of the effects of self-esteem, depression, and neuroticism. Allcause rehospitalization also tended to be less frequent for optimistic than for pessimistic persons (odds ratio = 0.77, 95% confidence interval = 0.57-1.05; P = .07). Conclusions: Optimism predicts a lower rate of rehospitalization after coronary artery bypass graft surgery. Fostering positive expectations may promote better recovery. Arch Intern Med. 1999;159:829-835

An Allele of COL9A2 Associated with Intervertebral Disc Disease

Abstract: Intervertebral disc disease is one of the most common musculoskeletal disorders. A number of environmental and anthropometric risk factors may contribute to it, and recent reports have suggested the importance of genetic factors as well. The COL9A2 gene, which codes for one of the polypeptide chains of collagen IX that is expressed in the intervertebral disc, was screened for sequence variations in individuals with intervertebral disc disease. The analysis identified a putative disease-causing sequence variation that converted a codon for glutamine to one for tryptophan in six out of the 157 individuals but in none of 174 controls. The tryptophan allele cosegregated with the disease phenotype in the four families studied, giving a lod score (logarithm of odds ratio) for linkage of 4.5, and subsequent linkage disequilibrium analysis conditional on linkage gave an additional lod score of 7.1.

Antibodies to alpha-synuclein detect Lewy bodies in many Down's syndrome brains with Alzheimer's disease.

Abstract: Immunohistochemical examination of 20 Down's syndrome brains, using antibodies to alpha-, beta-, and gamma-synuclein, demonstrated many alpha-synuclein-positive Lewy bodies and dystrophic neurites in 50% of amygdala samples from Down's syndrome brains with Alzheimer's disease. Similar lesions were less common in other regions of these brains, none of which contained beta-synuclein or gamma-synuclein abnormalities. Thus, alpha-synuclein-positive Lewy bodies and neuritic processes frequently occur with Alzheimer's disease in Down's syndrome brains.

A prospective, randomized study comparing the results of open discectomy with those of video-assisted arthroscopic microdiscectomy.

Abstract: BackgroundThe usefulness of video-assisted arthroscopic microdiscectomy for the treatment of a herniated lumbar disc has been studied previously. In the current prospective, randomized study, the results of this procedure were compared with those of conventional open laminotomy and discectom

Dislocations, kink bands, and room-temperature plasticity of Ti 3 SiC 2

Abstract: Transmission electron microscopy (TEM) of aligned, macrograined samples of Ti3SiC2, deformed at room temperature, shows that the deformed microstructure is characterized by a high density of perfect basal-plane dislocations with a Burgers vector of 1/3〈112 0〉. The dislocations are overwhelmingly arranged either in arrays, wherein the dislocations exist on identical slip planes, or in dislocations walls, wherein the same dislocations form a low-angle grain boundary normal to the basal planes. The arrays propagate across entire grains and are responsible for deformation by shear. The walls form as a result of the formation of kink bands. A dislocation-based model, that builds on earlier ideas proposed for kink-band formation in hexagonal metallic single crystals, is presented, which explains most of the microstructural features. The basic elements of the model are shear deformation by dislocation arrays, cavitation, creation of dislocation walls and kink boundaries, buckling, and delamination. The delaminations are not random, but successively bisect the delaminating sections. The delaminations and associated damage are contained by the kink boundaries. This containment of damage is believed to play a major role in endowing Ti3SiC2 and, by extension, related ternary carbides and nitrides with their damage-tolerant properties.

Communication skills training in oncology. Description and preliminary outcomes of workshops on breaking bad news and managing patient reactions to illness.

Abstract: BACKGROUND Cancer clinicians do not receive routine training in the psychosocial aspects of patient care such as how to communicate bad news or respond to patients who have unrealistic expectations of cure. Postgraduate workshops may be an effective way to increase interpersonal skills in managing these stressful patient encounters. METHODS The authors conducted 2 half-day workshops for oncology faculty, one on breaking bad news and one on dealing with “problem situations.” Participants met in a large group for didactic presentations and then small groups in which they used role-play and discussion to problem-solve difficult cases from their practices. The small groups were assisted in their work by trained physician facilitators. The workshops were evaluated by means of a follow-up satisfaction questionnaire as well as a self-efficacy measure, which was administered before and after the workshops. RESULTS Twenty-seven faculty and 2 oncology fellows participated in the training programs. Satisfaction questionnaires showed that the programs met the educational objectives and were considered to be useful and relevant by the participants. Self-efficacy questionnaires revealed an increase in confidence in communicating bad news and managing problem situation cases from before to after the workshop. The majority of attendees welcomed the opportunity to discuss their difficult cases with colleagues. A number resolved to implement newly learned approaches to common patient problems they encountered frequently. CONCLUSIONS Communication skills workshops may be a useful modality to provide training to oncologists in stressful aspects of the physician-patient relationship. Further research is needed to assess whether long term benefits accrue to the participants. [See editorial on pages 738-40, this issue.] Cancer 1999;86:887–97. © 1999 American Cancer Society.

Automatic clustering of software systems using a genetic algorithm

Abstract: Large software systems tend to have a rich and complex structure. Designers typically depict the structure of software systems as one or more directed graphs. For example, a directed graph can be used to describe the modules (or classes) of a system and their static interrelationships using nodes and directed edges, respectively. We call such graphs "module dependency graphs" (MDGs). MDGs can be large and complex graphs. One way of making them more accessible is to partition them, separating their nodes (i.e. modules) into clusters (i.e. subsystems). In this paper, we describe a technique for finding "good" MDG partitions. Good partitions feature relatively independent subsystems that contain modules which are highly interdependent. Our technique treats finding a good partition as an optimization problem, and uses a genetic algorithm (GA) to search the extraordinarily large solution space of all possible MDG partitions. The effectiveness of our technique is demonstrated by applying it to a medium-sized software system.

Toward Creating Physician-Healers: Fostering Medical Students' Self-Awareness, Personal Growth, and Well-Being.

Abstract: To restore the "humanism" in medical care, medical education needs to espouse the goal of creating physician-healers. Critical, and often neglected, factors in healing are the personal development and well-being of the healer. Unexamined attitudes and biases and personal stress can interfere with patient care. Personal awareness and well-being can contribute to physicians' using their emotional reactions to patients for their patients' benefit. The authors suggest goals and objectives for medical education that can promote trainees' self-awareness, personal growth, and well-being, and comment on how medical educators might achieve and evaluate these goals and objectives.