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Biomedical subjects

K Brennan

Publications and source records attributed to K Brennan.

At least 37 records · Page 2Linked to original sources
PubMed1998

Breakdowns on the path of chronic illness: opportunities for learning.

An unusual case of calciphylaxis, presenting at the onset of end-stage renal disease and evolving into an extended and arduous hospital stay, is described. The medical approach to this case is addressed briefly, but the main focus of this paper is to describe, in the words of various participants, the events and interactions that occurred and to learn from this description how our management of such cases breaks down. When confronted by difficult circumstances, it is common for us to react emotionally in ways that are automatic and based on our own personal histories and behavior patterns. Such automatic reactions prevent us from seeing and understanding what we really need to know about a given situation and leave us vulnerable to discouragement and internal suffering when clinical events do not go well (A. Nierenberg, personal communication, April 1998). The result is often exasperation with patients and families, as well as emotionally laden interactions that do not forward problem solving. In retrospect, the appearance of such breakdowns is not only predictable in the course of chronic illness, but offers us the opportunity to observe our automatic reactions, to re-evaluate our approach, and to redesign our actions. We have written this review, not to find error or blame, but rather to emphasize that we are learning to view these breakdowns as signals first to step back from our automatic reactions and then to listen and communicate clearly as a means to navigating the best pathway through difficult and discouraging clinical challenges.

Calciphylaxis↗
PubMed1998

Cis-interactions between Delta and Notch modulate neurogenic signalling in Drosophila.

We find that ectopic expression of Delta or Serrate in neurons within developing bristle organs is capable of non-autonomously inducing the transformation of the pre-trichogen cell into a tormogen cell in a wide variety of developmental contexts. The frequencies at which Delta can induce these transformations are dependent on the level of ectopic Delta expression and the levels of endogenous Notch signalling pathway components. The pre-trichogen cell becomes more responsive to Delta- or Serrate-mediated transformation when the level of endogenous Delta is reduced and less responsive when the dosage of endogenous Delta is increased, supporting the hypothesis that Delta interferes autonomously with the ability of a cell to receive either signal. We also find that a dominant-negative form of Notch, ECN, is capable of autonomously interfering with the ability of a cell to generate the Delta signal. When the region of Notch that mediates trans-interactions between Delta and the Notch extracellular domain is removed from ECN, the ability of Delta to signal is restored. Our findings imply that cell-autonomous interactions between Delta and Notch can affect the ability of a cell to generate and to transduce a Delta-mediated signal. Finally, we present evidence that the Fringe protein can interfere with Delta- and Serrate-mediated signalling within developing bristle organs, in contrast to previous reports of the converse effects of Fringe on Delta signalling in the developing wing.

Animals↗
PubMed1997

An intrinsic dominant negative activity of serrate that is modulated during wing development in Drosophila.

The Serrate and Delta genes of Drosophila encode two transmembrane proteins that act as ligands for the Notch receptor. Both have been shown to promote Notch activity during wing development and the specification of cell fate during neurogenesis. This observation has led to the suggestion that Serrate and Delta are functionally equivalent ligands for Notch. In this study we compare the activities of these proteins during wing development. Our results show that Serrate can activate or inactivate Notch in a concentration-dependent manner. While the inactivation is likely to be mediated by a dominant negative effect over Notch, the activation is similar to that elicited by Delta and requires the product of the Suppressor of Hairless gene. These results indicate that regulation of the concentration of Serrate during development must be an important way of regulating its activity.

Animals↗
PubMed1997

Variations in the relative mRNA levels of actins and myosin heavy chains do not produce corresponding differences in their proteins in the adult human heart.

This paper examines the quantitative relationship between the expression of myosin heavy chain (MHC) and actin at both the levels of their mRNAs and their proteins. Explanted human left ventricle tissues were obtained from non-diseased (ND) individuals and from dilated cardiomyopathy (DCM) patients with terminally failing hearts who underwent heart transplantation. We found: (1) there are substantial differences in the stoichiometry of sarcomeric MHC and actin transcripts in hearts of DCM patients as well as in ND individuals; (2) there are substantial differences between levels of total sarcomeric actin transcripts from different individual patients; (3) by and large variations in transcript levels between samples from the same heart are much less than between samples from different hearts; and (4) the ratio of MHC to sarcomeric actin proteins expressed by different ND and DCM hearts remains essentially constant. We conclude that the human ventricle can accommodate a substantial imbalance between sarcomeric MHC and actin mRNA levels while maintaining a constant ratio of their corresponding proteins.

Actins↗
PubMed1997

Cyclic AMP phosphodiesterases in human lymphocytes.

The function of lymphocytes, like platelets, has been shown to be inhibited by agents which increase intracellular cyclic AMP. Two high-affinity cAMP phosphodiesterases (PDEs), the cyclic GMP-inhibited cAMP phosphodiesterase, PDE3, and the cAMP-specific phosphodiesterase PDE4, are known to regulate cAMP concentration in haemopoietic cells by degrading cAMP to AMP. We characterized the relative contribution of the two PDEs to total lymphocyte PDE activity. We then determined which of the different gene products, PDE3A, typical of myocardium and platelets, or PDE3B, typical of adipocytes, were present in lymphocytes. The PDE3-specific inhibitor, milrinone, and the PDE4 inhibitor, rolipram, suppressed hydrolysis by 70% and 30% respectively, which indicated that both PDE4 and PDE3 were present, and that PDE3 was predominant. RT-PCR yields the expected size fragment for the primer pair PDE3B and not for PDE3A. The DNA sequence obtained had >95% identity with PDE3B. PDE3B appears to be the major cAMP PDE in lymphocytes. In contrast to human platelets, human lymphocytes appear to contain the PDE3B subtype. Since PDE3B in adipocytes is subject to hormonal regulation, lymphocytes may be similarly modulated. Understanding the role of cAMP regulation and the involvement of cAMP in lymphocyte function may have important implications in drug development.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1997

A functional analysis of Notch mutations in Drosophila.

The Notch gene encodes a receptor protein that is involved in many processes during development. Its best understood role is during neurogenesis in a process called "lateral inhibition." However, it has been proposed that Notch also has a role in defining the proneural clusters in the first place. This raises the possibility that the Notch protein is acting as a multifunctional receptor. To test this hypothesis, we have carried out a genetic analysis of molecularly characterized Notch alleles to identify alleles that affect only one of the two proposed functions. Here we present evidence that Notch alleles can be identified that appear to affect the function of Notch during either lateral inhibition or the definition of proneural clusters. In addition our results indicate that there may be discrete regions of the Notch protein required for each function.

Alleles↗
PubMed1997

Impact of alpha-skeletal actin but not alpha-cardiac actin on myoblast morphology.

Muscle differentiation involves a profound change in cell cytoarchitecture. This is accompanied by extensive isoform replacement in which the major non-muscle isoforms of the actin filament system are replaced by their muscle isoform counterparts. We have tested whether the sequential expression of the actin isoforms is functionally significant by precociously expressing the two striated muscle actins (alpha-skeletal and alpha-cardiac) in mouse myoblasts. The human alpha-skeletal and alpha-cardiac actin genes were transfected into mouse C2 myoblasts and clones expressing the human genes at the highest level were identified. Expression of the human alpha-skeletal actin gene was low with the highest mRNA level found to be 4% of that in adult human skeletal muscle. Clones expressing alpha-cardiac actin accumulated the mRNA up to 13% of the level of alpha-skeletal actin in adult human skeletal muscle. Despite the low level of alpha-skeletal actin expression, myoblasts transfected with this gene displayed a profound decrease in cell spreading. In contrast, alpha-cardiac actin had no impact on cell spreading. Neither alpha-skeletal actin nor alpha-cardiac actin had any impact on the total actin protein pool nor on the levels of the high molecular weight tropomyosins. The organisation of actin and tropomyosin into stress fibres was similar between transfected and control cells. We conclude that precocious expression of alpha-skeletal actin, but not alpha-cardiac actin, compromises myoblast morphology but not the ability of the cell to assemble stress-fibre-like structures.

Actins↗
PubMed1995

Interobserver variability of sonographically determined second-trimester nuchal skinfold thickness measurements.

Twenty physicians experienced in fetal sonographic evaluation obtained fetal nuchal skinfold thickness measurements in each of five pregnant women between 16 and 18 weeks' gestation. A random effects analysis of variance model was used to explore the sources of variation in the set of measurements, to determine the interobserver variability of sonographically measured second-trimester nuchal skinfold thickness. It was possible to obtain 96 measurements. Four measurements (all in the same patient) were deemed unobtainable due to fetal position. All recorded measurements were between 1.7 and 4.5 mm. The means (and ranges) for the five patients were 2.7 (1.7-3.6), 2.9 (2.0-4.5), 2.7 (2.0-4.0), 3.3 (2.2-4.0), and 2.7 (1.8-4.0) mm. The standard deviation for interobserver variability, caused by the combined effect of physician and machine imprecision, was 0.56 mm and the overall coefficient of variation was 19.8%. Interpatient differences were statistically significant (p = 0.004). Interphysician differences were not (p = 0.11). We conclude that experienced physician sonographers using high-resolution ultrasound equipment are able to obtain second-trimester nuchal skinfold thickness measurements within 1.1 mm of the estimated true value with 95% probability.

Analysis of Variance↗
PubMed1995

Sequence-specific targeting of nuclear signal transduction pathways by homeodomain proteins.

Cells translate extracellular signals into specific programs of gene expression that reflect their developmental history or identity. We present evidence that one way this interpretation may be performed is by cooperative interactions between serum response factor (SRF) and certain homeodomain proteins. We show that human and Drosophila homeodomain proteins of the paired class have the ability to recruit SRF to DNA sequences not efficiently recognized by SRF on its own, thereby imparting to a linked reporter gene the potential to respond to polypeptide growth factors. This activity requires both the DNA-binding activity of the homeodomain and putative protein-protein contact residues on the exposed surfaces of homeodomain helices 1 and 2. The ability of the homeodomain to impart signal responsiveness is DNA sequence specific, and this specificity differs from the simple DNA-binding specificity of the homeodomain in vitro. The homeodomain imparts response to a spectrum of signals characteristic of the natural SRF-binding site in the c-fos gene. Response to some of these signals is dependent on the secondary recruitment of SRF-dependent ternary complex factors, and we show directly that a homeodomain can promote the recruitment of one such factor, Elk1. We infer that SRF and homeodomains interact cooperatively on DNA and that formation of SRF-homeodomain complexes permits the recruitment of signal-responsive SRF accessory proteins. The ability to route extracellular signals to specific target genes is a novel activity of the homeodomain, which may contribute to the identity function displayed by many homeodomain genes.

Animals↗
PubMed1992

Affect intensity and cardiac arousal.

Relationships between affect intensity and basal, evoked, and perceived cardiac arousal were investigated in 3 experiments. Affect intensity was assessed using Larsen and Diener's (1987) Affect Intensity Measure (AIM). Cardiac arousal was evoked with exercise in the 1st study and with mental arithmetic in the 2nd and 3rd. Perceived cardiac arousal was measured under optimal conditions using a standard heartbeat discrimination procedure. Women as a group scored higher on the AIM. Affect intensity was unrelated to basal or evoked cardiac arousal and was negatively related to perceived cardiac arousal in all 3 studies. Data suggest that affect intensity, although unrelated to actual physiological arousal, is negatively related to the accuracy with which individuals perceive their own arousal. Results are discussed within the context of an expanded arousal-regulation model (Blascovich, 1990).

Affect↗
PubMed1992

A multi-center trial with a modified design of the Sarns membrane oxygenator.

A redesigned hollow fiber bundle was incorporated into an existing oxygenator that underwent clinical trials at seven cardiovascular surgery centers. Clinical investigators were asked to assess gas transfer performance under clinical conditions that could be considered challenging to any microporous membrane oxygenator, i.e., with large body weight patients, long bypass times, or normothermic bypass and surgery. Sixty-six patients, ranging in weight from 54.5 kg to 143 kg, constituted the initial evaluation population. Enhanced oxygen transfer was noted by all of the investigators. Fi0 2 requirements for patients weighing 100 kg or more never exceeded .85, despite oxygen consumption levels reaching as high as 396 mL/min. Two centers documented a 15% to 18% reduction in Fi0 2 requirements compared to their standard oxygenator.

Adult↗
PubMed1988

Morphological and kinetic abnormalities of platelets in hypercholesterolemic rabbits.

Hypercholesterolemia (HC = hypercholesterolemia or hypercholesterolemic) was produced in rabbits by feeding them diets supplemented with cholesterol and peanut oil. Platelet counts and volumes, white cell counts, reticulocyte counts, and hematocrits were determined at intervals for 8-12 weeks in blood from HC animals and controls on a normal rabbit diet. Microthrombocytosis was a consistent occurrence in the presence of HC, developing as early as 2 weeks into the diet. Microthrombocytosis was generally associated with normal platelet counts, but mild thrombocytosis occurred late in the diet at the time of the highest levels of serum cholesterol (greater than 1300 mg/dl). Platelets from HC rabbits were morphologically normal by transmission electron microscopy. Survivals of 51Cr-labeled platelets from HC and non-HC rabbits were measured in HC and non-HC recipients. The results identified an intrinsic defect in the ability of HC platelets to survive in the circulation. They also confirmed previous findings of an environmental defect in HC that causes shortened platelet survival.

Animals↗
PubMed1987

Familial bladder cancer in an oncology clinic.

We have evaluated family history and cigarette smoking history on 49 consecutively ascertained patients with urinary bladder carcinoma and compared them with 956 consecutively ascertained patients with histologically verified cancer (all sites), all of whom were being treated in the same oncology clinics. Data was collected through interviews, questionnaires, and primary medical and pathology documents. Cancer risks were compared on the basis of anatomic sites involved and with cumulative risk estimated from data in the Third National Cancer Survey. A permutation test was also employed. Significant heterogeneity of risk (z = 4.85, p less than or equal to 0.02) for bladder cancer was found in relatives of probands with bladder cancer. Significant heterogeneity or increase in risk of bladder cancer was not observed when families with lung, other smoking related cancer, and nonsmoking related cancer were analyzed. Though based on a limited number of verified bladder cancer patients, we have provided statistical evidence in support of our hypothesis that bladder cancer may have a stronger familial etiologic component than heretofore recognized.

Humans↗
PubMed1986

Familial heterogeneity of colon cancer risk.

The authors have assembled detailed family histories of cancer on 857 cancer probands, of whom 180 manifested colorectal carcinoma. This study determines if some families had a greater risk for colorectal cancer than others, and if so, what factors were associated with an increase in risk. To test for the possibility of heterogeneity of risk, a parameter called the Z-score, was calculated for each family. The Z-score is a measure of the number of cancer cases in the family adjusted for the number of expected cases. A permutation test was employed to test whether or not the variance of Z-scores from the sample was greater then expected by random chance. The variance for families ascertained through colon cancer probands, but not in any of the other groups, was significantly increased. Of the colon group, 10.6% fell into a high-risk category, as did 5.56% of the rectal cancer families, but only 3.95% of the other groups combined were at high risk. Anatomic sites (in the proband) with the highest Z-score variances were sigmoid and transverse colon, whereas lower variances were seen for cecum and descending colon. Risk status therefore may be partially dependent upon exact anatomic sites within the colon. The effect of proband's age of diagnosis was not significant, but did show the possibility of an effect on heterogeneity of risk for both the younger and older groups.

Age Factors↗
PubMed1980

Population density as an indicator of urban-rural differences in cancer incidence, upstate New York, 1968-1972.

This report presents cancer incidence data (1968-1972) for cities and towns in upstate New York (New York State exclusive of New York City) with various levels of urbanization as measured by population density. A direct association between population density and incidence was observed for a number of anatomic sites. A statistically significant linear trend of increasing incidence with increasing population density was observed among males and females for cancers of the buccal cavity and pharynx, esophagus, bronchus and lung, stomach and colon. For carcinomas of the liver, gallbladder, pancreas, bladder, larynx and rectum, this association was observed only among males, while, for malignant neoplasms of the brain and nervous system, only females demonstrated a statistically significant relationship between these two variables. The geographic distribution of incidence rates for the remaining sites appeared not to be related to population density. The most striking feature of these data, however, was the U-shaped pattern the authors observed for carcinomas of the uterine cervix. The observed geographic patterns tended to be consistent with data from previously published urban-rural studies and with the distribution of suspected etiologic factors.

Female↗
PubMed1974

Evaluation of the Minitek system for identification of Enterobacteriaceae.

Clinical isolates (869) and stock cultures (35) of Enterobacteriaceae were tested in parallel with the Minitek and conventional systems. The Minitek correctly identified 822 of 904 cultures. When a deoxyribonuclease plate was inoculated along with the Minitek, it was possible to speciate Enterobacteriaceae within 24 h. False-positive hydrogen sulfide reactions were the major fault with this system. Reactions were clear-cut and easy for technologists to read.

Bacteriological Techniques↗