The aim of this study was to quantify the global prevalence of chronic obstructive pulmonary disease (COPD) by means of a systematic review and random effects meta-analysis. PubMed was searched for population-based prevalence estimates published during the period 1990-2004. Articles were included if they: 1) provided total population or sex-specific estimates for COPD, chronic bronchitis and/or emphysema; and 2) gave method details sufficiently clearly to establish the sampling strategy, approach to diagnosis and diagnostic criteria. Of 67 accepted articles, 62 unique entries yielded 101 overall prevalence estimates from 28 different counties. The pooled prevalence of COPD was 7.6% from 37 studies, of chronic bronchitis alone (38 studies) was 6.4% and of emphysema alone (eight studies) was 1.8%. The pooled prevalence from 26 spirometric estimates was 8.9%. The most common spirometric definitions used were those of the Global Initiative for Chronic Obstructive Lung Disease (13 estimates). There was significant heterogeneity, which was incompletely explained by subgroup analysis (e.g. age and smoking status). The prevalence of physiologically defined chronic obstructive pulmonary disease in adults aged>> or =40 yrs is approximately 9-10%. There are important regional gaps, and methodological differences hinder interpretation of the available data. The efforts of the Global Initiative for Chronic Obstructive Lung Disease and similar groups should help to standardise chronic obstructive pulmonary disease prevalence measurement.

Tissue deposition of normally soluble proteins as insoluble amyloid fibrils is associated with serious diseases including the systemic amyloidoses, maturity onset diabetes, Alzheimer's disease and transmissible spongiform encephalopathy. Although the precursor proteins in different diseases do not share sequence homology or related native structure, the morphology and properties of all amyloid fibrils are remarkably similar. Using intense synchrotron sources we observed that six different ex vivo amyloid fibrils and two synthetic fibril preparations all gave similar high-resolution X-ray fibre diffraction patterns, consistent with a helical array of beta-sheets parallel to the fibre long axis, with the strands perpendicular to this axis. This confirms that amyloid fibrils comprise a structural superfamily and share a common protofilament substructure, irrespective of the nature of their precursor proteins.

Previous cohort studies of fat intake and risk of coronary heart disease (CHD) have been inconsistent, probably due in part to methodological differences and various limitations, including inadequate dietary assessment and incomplete adjustment for total energy intake. The authors analyzed repeated assessment of diet from the Nurses' Health Study to examine the associations between intakes of four major types of fat (saturated, monounsaturated, polyunsaturated, and trans fats) and risk of CHD during 14 years of follow-up (1980-1994) by using alternative methods for energy adjustment. In particular, the authors compared four risk models for energy adjustment: the standard multivariate model, the energy-partition model, the nutrient residual model, and the multivariate nutrient density model. Within each model, the authors compared four different approaches for analyzing repeated dietary measurements: baseline diet only, the most recent diet, and two different algorithms for calculating cumulative average diets. The substantive results were consistent across all models; that is, higher intakes of saturated and trans fats were associated with increased risk of CHD, while higher intakes of monounsaturated and polyunsaturated fats were associated with reduced risk. When nutrients were considered as continuous variables, the four energy-adjustment methods yielded similar associationS. However, the interpretation of the relative risks differed across models. In addition, within each model, the methods using the cumulative averages in general yielded stronger associations than did those using either only baseline diet or the most recent diet. When the nutrients were categorized according to quintiles, the residual and the nutrient density models, which gave similar results, yielded statistically more significant tests for linear trend than did the standard and the partition models.

Ten able adults with autism or Asperger syndrome and 10 normal volunteers were PET scanned while watching animated sequences. The animations depicted two triangles moving about on a screen in three different conditions: moving randomly, moving in a goal-directed fashion (chasing, fighting), and moving interactively with implied intentions (coaxing, tricking). The last condition frequently elicited descriptions in terms of mental states that viewers attributed to the triangles (mentalizing). The autism group gave fewer and less accurate descriptions of these latter animations, but equally accurate descriptions of the other animations compared with controls. While viewing animations that elicited mentalizing, in contrast to randomly moving shapes, the normal group showed increased activation in a previously identified mentalizing network (medial prefrontal cortex, superior temporal sulcus at the temporo-parietal junction and temporal poles). The autism group showed less activation than the normal group in all these regions. However, one additional region, extrastriate cortex, which was highly active when watching animations that elicited mentalizing, showed the same amount of increased activation in both groups. In the autism group this extrastriate region showed reduced functional connectivity with the superior temporal sulcus at the temporo-parietal junction, an area associated with the processing of biological motion as well as with mentalizing. This finding suggests a physiological cause for the mentalizing dysfunction in autism: a bottleneck in the interaction between higher order and lower order perceptual processes.

BACKGROUND

Patients' perspectives concerning impaired functioning provide important information. AIMS; To evaluate the reliability and validity of the Work and Social Adjustment Scale (WSAS).

METHODS

Data from two studies were analysed. Reliability analyses included internal scale consistency, test-retest and parallel forms. Convergent and criterion validities were examined with respect to disorder severity.

RESULTS

Cronbach's alpha measure of internal scale consistency ranged from 0.70 to 0.94. Test-retest correlation was 0.73. Interactive voice response administrations of the WSAS gave correlations of 0.81 and 0.86 with clinician interviews. Correlations of WSAS with severity of depression and obsessive-compulsive disorder symptoms were 0.76 and 0.61, respectively. The scores were sensitive to patient differences in disorder severity and treatment-related change.

CONCLUSIONS

The WSAS is a simple, reliable and valid measure of impaired functioning. It is a sensitive and useful outcome measure offering the potential for readily interpretable comparisons across studies and disorders.

OBJECTIVE

To describe barriers to participation of African Americans in research.

METHODS

Focus group interviews conducted in 1997.

METHODS

Thirty-three African-American adults presenting to an urban public hospital for outpatient medical care participated in one of five focus groups.

RESULTS

African-American patients' attitudes toward medical research were measured. Mistrust of doctors, scientists, and the government was reported consistently by the participants. Many participants described concerns about the ethical conduct of clinicians and investigators when poor or minority patients are involved and cited examples of exploitation as supporting evidence for their mistrust of the medical establishment. While participants were clear about the violation of human rights in the Tuskegee Syphilis Study, all were misinformed of the historical facts of the study. Few participants understood the concept of informed consent. Participants saw signing the document as relinquishing their autonomy and as a legal protection for physicians. Despite these concerns, participants gave recommendations to improve minority participation in research.

CONCLUSIONS

African-American participants in this study described distrust of the medical community as a prominent barrier to participation in clinical research. Participants described real and perceived examples of exploitation to support their distrust of researchers. The goal of the consent process, to inform patients of risks and benefits so as to facilitate self-determination, was misinterpreted by these participants. Understanding the importance of interpersonal trust within the clinical relationship may prove to be a significant factor in enhancing participation in clinical trials.

First conceptualized as a mechanism for the mitochondrial transport of long-chain fatty acids in the early 1960s, the carnitine palmitoyltransferase (CPT) system has since come to be recognized as a pivotal component of fuel homeostasis. This is by virtue of the unique sensitivity of the outer membrane CPT I to the simple molecule, malonyl-CoA. In addition, both CPT I and the inner membrane enzyme, CPT II, have proved to be loci of inherited defects, some with disastrous consequences. Early efforts using classical approaches to characterize the CPT proteins in terms of structure/function/regulatory relationships gave rise to confusion and protracted debate. By contrast, recent application of molecular biological tools has brought major enlightenment at an exponential pace. Here we review some key developments of the last 20 years that have led to our current understanding of the physiology of the CPT system, the structure of the CPT isoforms, the chromosomal localization of their respective genes, and the identification of mutations in the human population.

Cancer stem cells (CSCs) have been defined as a unique subpopulation in tumors that possess the ability to initiate tumor growth and sustain tumor self-renewal. Although the evidence has been provided to support the existence of CSCs in various solid tumors, the identity of gastric CSCs has not been reported. In this study, we have identified gastric cancer-initiating cells from a panel of human gastric cancer cell lines using cell surface marker CD44. Among six gastric cancer cell lines, three lines MKN-45, MKN-74, and NCI-N87 had a sizeable subpopulation of CD44(+) cells, and these cells showed spheroid colony formation in serum-free media in vitro as well as tumorigenic ability when injected into stomach and skin of severe combined immunodeficient (SCID) mice in vivo. The CD44(+) gastric cancer cells showed the stem cell properties of self-renewal and the ability to form differentiated progeny and gave rise to CD44(-) cells. CD44 knockdown by short hairpin RNA resulted in much reduced spheroid colony formation and smaller tumor production in SCID mice, and the CD44(-) populations had significantly reduced tumorigenic ability in vitro and in vivo. Other potential CSC markers, such as CD24, CD133, CD166, stage-specific embryonic antigen-1 (SSEA-1), and SSEA-4, or sorting for side population did not show any correlation with tumorigenicity in vitro or in vivo. The CD44(+) gastric cancer cells showed increased resistance for chemotherapy- or radiation-induced cell death. These results support the existence of gastric CSCs and may provide novel approaches to the diagnosis and treatment of gastric cancer.

The goal of this study was to estimate the incidence of Parkinson's disease by age, gender, and ethnicity. Newly diagnosed Parkinson's disease cases in 1994-1995 were identified among members of the Kaiser Permanente Medical Care Program of Northern California, a large health maintenance organization. Each case met modified standardized criteria/Hughes diagnostic criteria as applied by a movement disorder specialist. Incidence rates per 100,000 person-years were calculated using the Kaiser Permanente membership information as the denominator and adjusted for age and/or gender using the direct method of standardization. A total of 588 newly diagnosed (incident) cases of Parkinson's disease were identified, which gave an overall annualized age- and gender-adjusted incidence rate of 13.4 per 100,000 (95% confidence interval (CI): 11.4, 15.5). The incidence rapidly increased over the age of 60 years, with only 4% of the cases being under the age of 50 years. The rate for men (19.0 per 100,000, 95% CI: 16.1, 21.8) was 91% higher than that for women (9.9 per 100,000, 95% CI: 7.6, 12.2). The age- and gender-adjusted rate per 100,000 was highest among Hispanics (16.6, 95% CI: 12.0, 21.3), followed by non-Hispanic Whites (13.6, 95% CI: 11.5, 15.7), Asians (11.3, 95% CI: 7.2, 15.3), and Blacks (10.2, 95% CI: 6.4, 14.0). These data suggest that the incidence of Parkinson's disease varies by race/ethnicity.

BACKGROUND

Osteoporotic structural damage and bone fragility result from reduced bone formation and increased bone resorption. In a phase 2 clinical trial, strontium ranelate, an orally active drug that dissociates bone remodeling by increasing bone formation and decreasing bone resorption, has been shown to reduce the risk of vertebral fractures and to increase bone mineral density.

METHODS

To evaluate the efficacy of strontium ranelate in preventing vertebral fractures in a phase 3 trial, we randomly assigned 1649 postmenopausal women with osteoporosis (low bone mineral density) and at least one vertebral fracture to receive 2 g of oral strontium ranelate per day or placebo for three years. We gave calcium and vitamin D supplements to both groups before and during the study. Vertebral radiographs were obtained annually, and measurements of bone mineral density were performed every six months.

RESULTS

New vertebral fractures occurred in fewer patients in the strontium ranelate group than in the placebo group, with a risk reduction of 49 percent in the first year of treatment and 41 percent during the three-year study period (relative risk, 0.59; 95 percent confidence interval, 0.48 to 0.73). Strontium ranelate increased bone mineral density at month 36 by 14.4 percent at the lumbar spine and 8.3 percent at the femoral neck (P<0.001 for both comparisons). There were no significant differences between the groups in the incidence of serious adverse events.

CONCLUSIONS

Treatment of postmenopausal osteoporosis with strontium ranelate leads to early and sustained reductions in the risk of vertebral fractures.

We evaluated a semiquantitative culture technic for identifying infection due to intravenous catheters: rolling the catheter segment across blood agar. This method was compared to broth culture. Of 250 catheters studied, 225 (90%) had low-density colonization on semiquantitative culture (less than 15 colonies on the plate) although 49 (19.6%) of these grew some organisms in broth or on the plate. None of these catheters led to septicemia. Twenty-five catheters (10%) grew greater than or equal to 15 colonies by the semiquantitative technic; most gave confluent growth. Septicemia originated from four of these catheters (P = 0.008). Of 37 catheters exposed to bacteremias from distant foci of infection, four yielded matching growth in broth, whereas none were concordant with the blood isolate on semiquantitative culture. Local inflammation was associated with high-density colonization semiquantitative culture (P less than 0.001). The semiquantitative technic distinguishes infection (greater than or equal to 15 colonies) from contamination and is more specific in diagnosis of catheter-related septicemia than culture of the catheter in broth.

OBJECTIVE

Emerging evidence suggests muscle depletion predicts survival of patients with cancer.

METHODS

At a cancer center in Alberta, Canada, consecutive patients with cancer (lung or GI; N = 1,473) were assessed at presentation for weight loss history, lumbar skeletal muscle index, and mean muscle attenuation (Hounsfield units) by computed tomography (CT). Univariate and multivariate analyses were conducted. Concordance (c) statistics were used to test predictive accuracy of survival models.

RESULTS

Body mass index (BMI) distribution was 17% obese, 35% overweight, 36% normal weight, and 12% underweight. Patients in all BMI categories varied widely in weight loss, muscle index, and muscle attenuation. Thresholds defining associations between these three variables and survival were determined using optimal stratification. High weight loss, low muscle index, and low muscle attenuation were independently prognostic of survival. A survival model containing conventional covariates (cancer diagnosis, stage, age, performance status) gave a c statistic of 0.73 (95% CI, 0.67 to 0.79), whereas a model ignoring conventional variables and including only BMI, weight loss, muscle index, and muscle attenuation gave a c statistic of 0.92 (95% CI, 0.88 to 0.95; P < .001). Patients who possessed all three of these poor prognostic variables survived 8.4 months (95% CI, 6.5 to 10.3), regardless of whether they presented as obese, overweight, normal weight, or underweight, in contrast to patients who had none of these features, who survived 28.4 months (95% CI, 24.2 to 32.6; P < .001).

CONCLUSIONS

CT images reveal otherwise occult muscle depletion. Patients with cancer who are cachexic by the conventional criterion (involuntary weight loss) and by two additional criteria (muscle depletion and low muscle attenuation) share a poor prognosis, regardless of overall body weight.

Henle, Gertrude (Children's Hospital of Philadelphia, Philadelphia, Pa.), and Werner Henle. Immunofluorescence in cells derived from Burkitt's lymphoma. J. Bacteriol. 91:1248-1256. 1966.-Indirect immunofluorescence tests led to the brilliant staining of a small proportion of the cells in five different cultures derived from Burkitt's (African) lymphomas. The reaction was not restricted to the 17 sera from cases of this disease but extended to many sera from American individuals, whether healthy donors or patients suffering from a variety of illnesses. The incidence of positive sera increased with age from about 30% in childhood to>> 90% in adults. Fluorescein-isothiocyanate-conjugated human gamma-globulins were suitable for direct staining of the same proportion of cells. The stained cells appeared to be in varying stages of degeneration, but cultural conditions leading to an increase in the cellular death rates failed to result in a rise in fluorescent cells. Several observations suggest that the stainable cells might be those which are seen to harbor virus particles under the electron microscope. Two cell lines derived from leukemic patients in this country also contained a small fraction of stainable cells but two others, and numerous primary human leukocyte cultures, gave consistently negative results. Attempts to relate the staining to known viral antigens have failed to implicate herpes simplex, varicella, cytomegalo, and reo viruses types 1, 2, and 3. The nature of the virus carried by the lymphoma cells as well as of the staining reactions remains to be determined.

BACKGROUND

Reversal of the progressive increase in frequency of atopic disease would be an important breakthrough for health care and wellbeing in western societies. In the hygiene hypothesis this increase is attributed to reduced microbial exposure in early life. Probiotics are cultures of potentially beneficial bacteria of the healthy gut microflora. We assessed the effect on atopic disease of Lactobacillus GG (which is safe at an early age and effective in treatment of allergic inflammation and food allergy).

METHODS

In a double-blind, randomised placebo-controlled trial we gave Lactobacillus GG prenatally to mothers who had at least one first-degree relative (or partner) with atopic eczema, allergic rhinitis, or asthma, and postnatally for 6 months to their infants. Chronic recurring atopic eczema, which is the main sign of atopic disease in the first years of life, was the primary endpoint.

RESULTS

Atopic eczema was diagnosed in 46 of 132 (35%) children aged 2 years. Asthma was diagnosed in six of these children and allergic rhinitis in one. The frequency of atopic eczema in the probiotic group was half that of the placebo group (15/64 [23%] vs 31/68 [46%]; relative risk 0.51 [95% CI 0.32-0.84]). The number needed to treat was 4.5 (95% CI 2.6-15.6).

CONCLUSIONS

Lactobacillus GG was effective in prevention of early atopic disease in children at high risk. Thus, gut microflora might be a hitherto unexplored source of natural immunomodulators and probiotics, for prevention of atopic disease.

BETA-Lactamases (EC. 3.5.2.6) from strains of Gram-negative bacteria have been studied using analytical isoelectric focusing. This permits a visual comparison of the patterns of beta-lactamase bands produced by enzymes from different organisms. Purification of crude intracellular preparations is unnecessary and the technique is sufficiently sensitive to demonstrate beta-lactamase in mutants previously reported to lack the enzyme. R that have not been distinguished from one another biochemically or immunologically can be differentiated by isoelectric focusing. Conversely, the enzymes specified by the R factors RTEM, R1 and RGN14, with identical isoelectric focusing patterns have the same biochemical properties. Chromosomal and R-factor-mediated beta-lactamases from single strains have been separated and their identities confirmed by immunoisoelectric focusing. R factor-mediated enzymes gave identical isoelectric focusing patterns irrespective of the host strain. Isoelectric focusing can therefore be used to observe the transfer of beta-lactamases carried by R factors.

OBJECTIVE

To evaluate the diagnostic performance of real-time freehand elastography by using the extended combined autocorrelation method (CAM) to differentiate benign from malignant breast lesions, with pathologic diagnosis as the reference standard.

METHODS

This study was approved by the University of Tsukuba Human Subjects Institutional Review Board; all patients gave informed consent. Conventional ultrasonography (US) and real-time US elastography with CAM were performed in 111 women (mean age, 49.4 years; age range, 27-91 years) who had breast lesions (59 benign, 52 malignant). Elasticity images were assigned an elasticity score according to the degree and distribution of strain induced by light compression. The area under the curve and cutoff point, both of which were obtained by using a receiver operating characteristic curve analysis, were used to assess diagnostic performance. Mean scores were examined by using a Student t test. Sensitivity, specificity, and accuracy were compared by using the standard proportion difference test or the Delta-equivalent test.

RESULTS

For elasticity score, the mean +/- standard deviation was 4.2 +/- 0.9 for malignant lesions and 2.1 +/- 1.0 for benign lesions (P < .001). When a cutoff point of between 3 and 4 was used, elastography had 86.5% sensitivity, 89.8% specificity, and 88.3% accuracy. When a best cutoff point of between 4 and 5 was used, conventional US had 71.2% sensitivity, 96.6% specificity, and 84.7% accuracy. Elastography had higher sensitivity than conventional US (P < .05). By using equivalence bands for noninferiority or equivalence, it was shown that the specificity of elastography was not inferior to that of conventional US and that the accuracy of elastography was equivalent to that of conventional US.

CONCLUSIONS

For assessing breast lesions, US elastography with the proposed imaging classification, which was simple compared with that of the Breast Imaging Recording and Data System classification, had almost the same diagnostic performance as conventional US.

BACKGROUND

Mesenchymal stem cells (MSC) have immunomodulatory effects. The aim was to study the effect of MSC infusion on graft-versus-host disease (GVHD).

METHODS

We gave MSC to eight patients with steroid-refractory grades III-IV GVHD and one who had extensive chronic GVHD. The MSC dose was median 1.0 (range 0.7 to 9)x10(6)/kg. No acute side-effects occurred after the MSC infusions. Six patients were treated once and three patients twice. Two patients received MSC from HLA-identical siblings, six from haplo-identical family donors and four from unrelated mismatched donors.

RESULTS

Acute GVHD disappeared completely in six of eight patients. One of these developed cytomegalovirus gastroenteritis. Complete resolution was seen in gut (6), liver (1) and skin (1). Two died soon after MSC treatment with no obvious response. One of them had MSC donor DNA in the colon and a lymph node. Five patients are still alive between 2 months and 3 years after the transplantation. Their survival rate was significantly better than that of 16 patients with steroid-resistant biopsy-proven gastrointestinal GVHD, not treated with MSC during the same period (P = 0.03). One patient treated for extensive chronic GVHD showed a transient response in the liver, but not in the skin and he died of Epstein-Barr virus lymphoma.

CONCLUSIONS

MSC is a very promising treatment for severe steroid-resistant acute GVHD.

Pluripotent cells can be derived from fibroblasts by ectopic expression of defined transcription factors. A fundamental unresolved question is whether terminally differentiated cells can be reprogrammed to pluripotency. We utilized transgenic and inducible expression of four transcription factors (Oct4, Sox2, Klf4, and c-Myc) to reprogram mouse B lymphocytes. These factors were sufficient to convert nonterminally differentiated B cells to a pluripotent state. However, reprogramming of mature B cells required additional interruption with the transcriptional state maintaining B cell identity by either ectopic expression of the myeloid transcription factor CCAAT/enhancer-binding-protein-alpha (C/EBPalpha) or specific knockdown of the B cell transcription factor Pax5. Multiple iPS lines were clonally derived from both nonfully and fully differentiated B lymphocytes, which gave rise to adult chimeras with germline contribution, and to late-term embryos when injected into tetraploid blastocysts. Our study provides definite proof for the direct nuclear reprogramming of terminally differentiated adult cells to pluripotency.

A dosage formula has been derived from a retrospective analysis of carboplatin pharmacokinetics in 18 patients with pretreatment glomerular filtration rates (GFR) in the range of 33 to 136 mL/min. Carboplatin plasma clearance was linearly related to GFR (r = 0.85, P less than .00001) and rearrangements of the equation describing the correlation gave the dosage formula dose (mg) = target area under the free carboplatin plasma concentration versus time curve (AUC) x (1.2 x GFR + 20). In a prospective clinical and pharmacokinetic study the formula was used to determine the dose required to treat 31 patients (GFR range, 33 to 135 mL/min) with 40 courses of carboplatin. The target AUC was escalated from 3 to 8 mg carboplatin/mL/min. Over this AUC range the formula accurately predicted the observed AUC (observed/predicted ratio 1.24 +/- 0.11, r = 0.886) and using these additional data, the formula was refined. Dose (mg) = target AUC x (GFR + 25) is now the recommended formula. AUC values of 4 to 6 and 6 to 8 mg/mL. min gave rise to manageable hematological toxicity in previously treated and untreated patients, respectively, and hence target AUC values of 5 and 7 mg/mL min are recommended for single-agent carboplatin in these patient groups. Pharmacokinetic modeling demonstrated that the formula was reasonably accurate regardless of whether a one- or two-compartment model most accurately described carboplatin pharmacokinetics, assuming that body size did not influence nonrenal clearance. The validity of this assumption was demonstrated in 13 patients where no correlation between surface area and nonrenal clearance was found (r = .31, P = .30). Therefore, the formula provides a simple and consistent method of determining carboplatin dose in adults. Since the measure of carboplatin exposure in the formula is AUC, and not toxicity, it will not be influenced by previous or concurrent myelosuppressive therapy or supportive measures. The formula is therefore applicable to combination and high-dose studies as well as conventional single-agent therapy, although the target AUC for carboplatin will need to be redefined for combination chemotherapy.

Three enteropathogenic Escherichia coli (E.P.E.C.) strains (O127:K63:H6, O128:K67:H2, and O142:K86:H6) isolated from outbreaks of infantile diarrhoea and one strain from the "normal" colonic flora (E. coli HS) of a healthy adult were fed in doses of 10(6), 10(8), and 10(10) organisms in NaHCO3 to adult volunteers. The strains, which had been stored for 7--9 years, gave negative results in sensitive tests for heat-labile (L.T.) enterotoxin (Y-1 adrenal-cell test), heat-stable (S.T.) enterotoxin (infant mouse assay), invasiveness (guineapig eye test), and gross fluid accumulation (infant rabbit assay). Two strains (O142 and O127) caused diarrhoea. L.T. or S.T. enterotoxins were not found in E. coli stool isolates from individuals with diarrhoea and no one had a rise in L.T. antitoxin titre; the findings suggest that L.T. and S.T. enterotoxins were not involved in pathogenesis of the diarrhoea. Non-invasive E.P.E.C. strains probably induce diarrhoea by a mechanism (presumably an enterotoxin) distinct from L.T. or S.T. enterotoxins.

A long-standing conjecture in neuroscience is that aspects of cognition depend on the brain's ability to self-generate sequential neuronal activity. We found that reliably and continually changing cell assemblies in the rat hippocampus appeared not only during spatial navigation but also in the absence of changing environmental or body-derived inputs. During the delay period of a memory task, each moment in time was characterized by the activity of a particular assembly of neurons. Identical initial conditions triggered a similar assembly sequence, whereas different conditions gave rise to different sequences, thereby predicting behavioral choices, including errors. Such sequences were not formed in control (nonmemory) tasks. We hypothesize that neuronal representations, evolved for encoding distance in spatial navigation, also support episodic recall and the planning of action sequences.

Gas exchange in the lung occurs within alveoli, air-filled sacs composed of type 2 and type 1 epithelial cells (AEC2s and AEC1s), capillaries, and various resident mesenchymal cells. Here, we use a combination of in vivo clonal lineage analysis, different injury/repair systems, and in vitro culture of purified cell populations to obtain new information about the contribution of AEC2s to alveolar maintenance and repair. Genetic lineage-tracing experiments showed that surfactant protein C-positive (SFTPC-positive) AEC2s self renew and differentiate over about a year, consistent with the population containing long-term alveolar stem cells. Moreover, if many AEC2s were specifically ablated, high-resolution imaging of intact lungs showed that individual survivors undergo rapid clonal expansion and daughter cell dispersal. Individual lineage-labeled AEC2s placed into 3D culture gave rise to self-renewing "alveolospheres," which contained both AEC2s and cells expressing multiple AEC1 markers, including HOPX, a new marker for AEC1s. Growth and differentiation of the alveolospheres occurred most readily when cocultured with primary PDGFRα⁺ lung stromal cells. This population included lipofibroblasts that normally reside close to AEC2s and may therefore contribute to a stem cell niche in the murine lung. Results suggest that a similar dynamic exists between AEC2s and mesenchymal cells in the human lung.

1. In anaesthetized and decerebrate cats isometric exercise of the hind limb muscles was elicited by stimulating the spinal ventral roots L7-S1. This caused a rise in arterial blood pressure, with small increases in heart rate and pulmonary ventilation. These changes were abolished by cutting the dorsal roots receiving afferents from the exercising muscle.2. When the triceps surae muscle was made to exercise by ventral root stimulation, occlusion of the femoral artery and vein through and beyond the period of exercise caused the blood pressure to remain raised until the occlusion was removed. The ventilatory and heart rate responses were not markedly altered or prolonged by such circulatory occlusion.3. Injection of small volumes of 5% NaCl or isotonic KCl into the arterial blood supplying hind limb muscles gave cardiovascular and respiratory responses similar to those evoked by exercise. Like the responses to exercise, these responses were abolished by dorsal root section.4. Direct current anodal block of the dorsal roots receiving afferents from the exercising muscle was used to block preferentially large myelinated fibres: this form of block did not abolish the evoked cardiovascular and respiratory responses. Local anaesthetic block of the dorsal roots was used to block preferentially unmyelinated and small myelinated fibres: this form of block abolished the cardiovascular and respiratory responses. It is concluded that the reflex responses are mediated by fibres within groups III and IV (small myelinated fibres and unmyelinated fibres).

Affinity chromatography was used to identify a putative cell surface receptor for fibronectin. A large cell-attachment-promoting fibronectin fragment was used as the affinity matrix, and specific elution was effected by using synthetic peptides containing the sequence Arg-Gly-Asp, which is derived from the cell recognition sequence in the fibronectin cell attachment site. A 140 kd protein was bound by the affinity matrix from octylglucoside extracts of MG-63 human osteosarcoma cells and specifically eluted with the synthetic peptide Gly-Arg-Gly-Asp-Ser-Pro. The 140 kd protein was labeled by cell surface specific radioiodination and became incorporated into liposomes at a high efficiency. Liposomes containing this protein showed specific affinity toward fibronectin-coated surfaces, and this binding could be selectively inhibited by the synthetic cell-attachment peptide but not by inactive peptides. Affinity chromatography on wheat germ agglutinin-Sepharose showed that the 140 kd protein is a glycoprotein and, in combination with the fibronectin fragment chromatography, gave highly enriched preparations of the 140 kd protein. These properties suggest that the 140 kd glycoprotein is a membrane-embedded cell surface protein directly involved in the initial step of cell adhesion to fibronectin substrates.