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PubMed1997

The PMAC code of marketing practices: time for improvement? Pharmaceutical Manufacturers Association of Canada.

In this issue (see pages 351 to 356) Dr. Joel Lexchin proposes reforms that could help the Pharmaceutical Manufacturers Association of Canada (PMAC) adapt its Code of Marketing Practices to changing times. The PMAC code reflects the ethical concerns of drug manufacturers and speaks to the need for high standards in promotional activities. The code is a commendable beginning, but it does not go far enough in ensuring ethical practice. The PMAC should take this opportunity to address the concerns raised by Lexchin. For example, proactive assessment of advertising would improve the current system.

Advertising↗
PubMed1985

Development and evolution of electrocardiographic Minnesota Q-QS codes in patients with acute myocardial infarction.

The development of ECG Minnesota Q-QS codes and their subsequent evolution were studied in the first 692 subjects to enter the POSCH program who had had one MI. The mean interval from MI to entry into the study was 2.2 years. Sixty-three percent of the subjects developed the most significant code with the infarction. By the time the subjects entered the study, the codes had commonly regressed to a lower level, disappearing altogether in 34%. The likelihood of complete regression varied inversely with the significance of the code. There was no significant difference between the groups with disappearance and with retention of a Q-QS code as to time since MI, the extent of coronary arterial disease, or the age or sex of the subject. In about half of the subjects the original code did not change with time and in 21% to 44% the code increased to one of a higher level of significance.

Adult↗
PubMed1991

Integrating behavior and cardiovascular responses: the code.

The next revolution in biology is predicted to be in the integrative domain, and the need to involve physiologists in this kind of research has been recognized. This paper represents an approach to providing some of the tools required for dealing with integrative physiology at the behavioral level. Video tape recordings are made of the activities of a group of five baboons (Papio hamadryas) while simultaneous recordings of arterial blood pressure, heart rate, renal blood flow, and mesenteric or iliac blood flow are telemetered from two of the members of the group. The telemetered cardiovascular information is recorded on the two audio channels of the videotape. Subsequently the videotape is viewed, and a two-dimensional code is used to record the behavior of the two animals with the telemetry equipment. The first dimension of the code categorizes the behavior changes precisely regarding those aspects of behavior that are related to cardiovascular dynamics and does so with an accuracy of 16 ms. The second dimension codes relevant environmental changes. The paper describes the code and presents illustrations of how the code reflects the cardiovascular dynamics associated with the behavioral changes.

Animals↗
PubMed1985

The mitochondrial genome of the fission yeast Schizosaccharomyces pombe. 7. Continuous gene for apocytochrome b in strain EF1 (CBS 356) and sequence variation in the region of intron insertion in strain ade 7-50h.

The third BamHI fragment, containing most of gene for apocytochrome b, has been cloned and sequenced in the Schizosaccharomyces pombe strain EF1 (CBS 356). In contrast to strain ade 7-50h- (50) from the Leupold collection, in which the gene is interrupted by an intron of group II (Lang et al. 1984), the homologous gene in strain EF1 is continuous. This demonstrates that the intron in the gene for apocytochrome b is optional. Aligning the EF1 sequence with the homologous regions in strain 50, 2 base pair changes were found in the leader and 14 in the coding region. These changes led to 12 altered triplets, but 9 of them specify the same amino acid. Seven base changes were clustered within a stretch of 30 base pairs in the region in which the intron is inserted in strain 50. Five out of the resulting six triplet changes were also silent. These sequence variations around the highly conserved splice point region may be linked to the insertion or excision of the intron.

Ascomycota↗
PubMed1995

Nucleotide and deduced amino acid sequences of the nucleocapsid protein of the virulent A75/17-CDV strain of canine distemper virus.

Virus persistence is essential in the chronic inflammatory canine distemper virus (CDV)-induced demyelinating disease. In the case of CDV there is a close association between persistence and virulence. Virulent CDV isolated from dogs with distemper shows immediate persistence in primary dog brain cell cultures (DBCC) and in different cell lines. We have evidence that the nucleocapsid (NP) protein plays an important role in the development of persistence. The NP-protein, the most abundant structural virus protein, also influences virus assembly and has some regulatory functions in virus transcription and replication. In this study we compared the nucleotide and deduced amino acid sequence of a virulent CDV strain (A75/17-CDV) to a culture-attenuated non-virulent strain (OP-CDV). Viral RNA was extracted from DBCC infected with virulent CDV. Virulent CDV retains its in vivo properties, such as virulence and ability to cause demyelination, when propagated in these DBCC. The viral RNA was reverse transcribed and the resulting cDNA amplified by polymerase chain reaction for subsequent cloning. The nucleotide sequences of these clones were determined by the dideoxy chain termination method. The number of nucleotides and the putative NP-protein of the virulent strain matched the attenuated CDV strain. We observed a total of 105 nucleotide differences. Three were localised within the 3' and five within the 5' non-coding region of the NP-gene. The 97 nucleotide changes within the coding region resulted in 22 amino acid differences. 10 of these amino acid (AA) modifications were within the N-terminal region (AA 1 to 159) and 12 within the C-terminal area (AA 351 to 523).(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1992

Metabolic, molecular genetic and toxicological aspects of the acetylation polymorphism in inbred mice.

Over the past 10 years, much fascinating information has been obtained concerning the biochemistry, genetics, toxicological implications and molecular genetics of the N-acetylation polymorphism in mice. Using C57BL/6J (B6) mice as representative of rapid acetylation and A/J (A) mice as representing slow acetylation, it has been shown that the polymorphism observed in N-acetyltransferase (NAT) activity in liver also occurs in kidney, bladder, blood, and other tissues. The development of congenic acetylator mouse lines derived from B6 and A, have provided the necessary tools to study the role of the acetylation polymorphism, on either the B6 or A genetic background, free of nearly all other genetic differences between these strains. Eliminating genes which modify and complicate the differences due to the acetylator genes make the congenic lines very useful in toxicology studies, particularly those involving carcinogenesis. The molecular genetic basis of the acetylator polymorphism in B6 and A mice involves two Nat genes. Nat-1 encodes a protein termed NAT1 which is identical in rapid and slow acetylator strains. Nat-2, however, differs between rapid and slow strains by a single nucleotide change in the coding region. The corresponding NAT2 proteins differ by a single change at amino acid 99: an hydrophilic asparagine in rapid acetylator NAT2 to an hydrophobic isoleucine in NAT2 from slow acetylators. The mechanistic basis for the differences between rapid and slow acetylation in mice appears to be that NAT2 from the rapid B6 strain is 15-fold more stable at 37 degrees C and is transcribed/translated with a maximal efficiency twice that of the enzyme from slow acetylator A mice. Results discussed in this review indicate that mice provide an excellent system for studying the N-acetyltransferase polymorphism and also are useful for modelling several aspects of the human N-acetyltransferase polymorphism.

Acetylation↗
PubMed1987

Evolution of anticodons: variations in the genetic code.

Clues to evolution of the genetic code can be found by comparing usage of anticodons in various organisms and organelles. GC content of DNA varies, as a result of directional mutation pressure (AT/GC pressure), especially in bacteria. Low GC in Mycoplasma is accompanied by use of UGA for tryptophan and, in ciliated protozoa, by use of UAA and UAG for glutamine. These are examples of "stop codon capture," which has been preceded by duplication of tRNA genes followed by nucleotide substitutions in their sequences, including mutational changes in their anticodons. Evolutionary changes in the code may have resulted from disappearance of codons and anticodons resulting from GC pressure and from their reappearance when the direction of the pressure was reversed. In this manner, codon UGA and anticodon UCA for tryptophan could have disappeared under GC pressure and reappeared in Mycoplasma under AT pressure. Stop codon UGA may have been the third of the three stop codons to appear, originating from mutations in UAA. Changes in the code are adaptive and nondeleterious. We propose that the number of anticodons has increased and that evolution continued until three existing forms of the universal code were produced: eukaryotic, eubacterial, and the code for halobacteria and methanococci. These three codes are distinguished from each other by their anticodon pattern. The eukaryotic code contains eight INN (ANN) anticodons that have replaced GNN anticodons as a result of AT pressure. Mitochondrial and chloroplast codes have evolved from the eubacterial code through genomic economization and AT pressure, leading to losses of GNN and CNN anticodons.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗
PubMed1995

Absence of somatic changes in p21 gene in non-Hodgkin's lymphoma and chronic myelogenous leukemia.

p21 is induced by and mediates the effects of p53 in response to DNA damage arresting the cell in G1 or G2, by inhibiting multiple cyclin-cyclin-dependent kinases (CDK) or binding to proliferating-cell nuclear antigen (PCNA), respectively. To determine whether p21 mutants occur in tumors we examined DNA from 188 primary non-Hodgkin's B-cell lymphoma (NHL) tumors and 84 chronic myelogenous leukemia samples for mutational changes in the coding region of p21 by single-strand conformation polymorphism (SSCP) analysis and direct sequencing of polymerase chain reaction (PCR)-amplified DNA. We did not find mutations in the coding region in these two tumor types. We identified a polymorphic nucleotide change in codon 31 in which a transversion from C to A substituted amino acid arginine for serine. Three of 188 NHL tumors were homozygous for this change, but they were not identified in 84 CMLs or in 97 normal controls. On the other hand, in one CML case a transition from G to A in codon 64 substituted amino acid threonine for alanine. These data do not indicate that derangements in the coding region of p21 contribute to the initiation and/or progression of these tumors.

Base Sequence↗
PubMed1995

[Subpartal diagnosis of umbilical cord encirclement using color-coded Doppler ultrasonography and correlation with cardiotocographic changes during labor].

Umbilical cord complications are the most common cause of pathologic fetal heart tones during delivery. The inauguration of colour-coded Doppler ultrasound in obstetrics has made the definite diagnosis of umbilical cord encirclement during delivery possible. The prospective study introduced here examines the question of how exactly an encirclement can be seen by Doppler during delivery, its influence on cardiotocographic results, delivery mode, and fetal outcome. 107 patients in labour with cervical dilatation were examined in a prospective study using colour-coded Doppler ultrasound to determine cases of umbilical cord encirclement. In 50 cases, encirclement could be visualised, 48 of which were confirmed post partum. Encirclement could be ruled out in 57 other cases. A sensitivity of 96% and specificity of 100% resulted. No significant differences could be found with regard to mode of delivery and fetal outcome. However, the umbilical cord in cases of encirclement was significantly longer than when no encirclement occurred. Assessment of fetal heart tones demonstrated a significantly higher rate of variable decelerations in the patient group with umbilical cord encirclement compared to that without. In conclusion, our results show that the early diagnosis of umbilical cord encirclement during delivery allows appropriate assessment of fetal heart tone changes,justifying temporising management under continuous monitoring with possible micro-blood analysis.

Asphyxia Neonatorum↗
PubMed1987

Structure and organization of the CyIII actin gene subfamily of the sea urchin, Strongylocentrotus purpuratus.

We describe here the organization of the CyIII subfamily of cytoskeletal actin genes in the sea urchin Strongylocentrotus purpuratus. The functional genes CyIIIa and CyIIIb are linked at a 6 X 10(3)-base distance. Gene CyIIIc appears to be a pseudogene that lacks 5' exons and displays unselected mutational changes. Gene CyIIIa codes for a protein that differs at only nine out of 376 residues from that coded by another cytoskeletal actin gene, CyI. However, five of these nine changes occur within an 11-amino acid region that could represent a functional specialization of the CyIIIa actin protein. The CyIIIa gene possesses three introns, located, respectively, 25 nucleotides upstream from the translation start site, between the codons for amino acids 121 and 122, and within the codon for amino acid 204. These intron positions have also been observed in other cytoskeletal sea urchin actin genes. Comparison of both intron and 3'-terminal sequences shows that the CyIIIa and CyIIIb genes are closely related, while no homology in these untranslated sequences is observed between the CyIII genes and the other cytoskeletal actin genes of the S. purpuratus genome. The CyIII genes probably arose by duplication events at least 40 X 10(6) years ago, prior to radiation of the genus Strongylocentrotus. Consideration of the biological role of the embryo and larval aboral ectoderm cells to which CyIIIa and CyIIIb transcripts are confined suggests that these actins might contribute to cytoskeletal elements that endow the larval body wall with its rigid structure.

Actins↗
PubMed1991

Development of otoacoustic emissions in gerbil: evidence for micromechanical changes underlying development of the place code.

The development of the acoustic distortion product (ADP) 2f1-f2 was studied in gerbils, beginning 12 days after birth (P12). ADPs were measured as a function of stimulus frequency region (1.0 to 13.0 kHz) and level (10 to 80 dB SPL). There was an orderly progression in the appearance and maturation of the emissions, with responses to high-frequency stimuli (f2 = 13.0 kHz) appearing first, at P13-14. Responses to mid and high frequencies (f2 = 3.9 to 13.0 kHz) matured earlier than responses to lower frequencies. Responses to low-frequency stimuli (f2 = 1.3 KHz) did not appear until P18-19 and were not mature until after one month of age. The first emissions to develop in a given frequency region had elevated thresholds, were reduced in amplitude, and displayed monotonic input-output functions. As the auditory system matured, emission growth functions became non-monotonic displaying saturation, but initially retained a reduced dynamic range. Data from the developing gerbil suggest that initially its cochlear mechanics are passive and that active elements associated with normal outer hair cell function mature first in the basal turn and last near the apex. Furthermore, the development of active nonlinear elements underlying ADP generation is consistent with the development of frequency selectivity and developmental shifts in the place code which have been demonstrated in the gerbil.

Acoustic Stimulation↗
PubMed1997

Discrimination and association processes for faces and non-faces: the effect of rotation.

Most current theories of face perception claim that inversion leaves the coding of non-face stimuli largely unaffected, while causing a qualitative change in the coding of faces. Empirical support for this hypothesis mainly stems from recognition studies which typically show a larger inversion decrement for faces than for other stimuli. Several recent studies using experimental paradigms that do not contain a substantial memory component have however yielded contradicting results. This observation suggests that the disproportionate effect of inversion for faces might be related to the presence, or absence, of a memory component in the experimental task. In order to explore this hypothesis we investigated the effect of inversion within a discrimination learning paradigm, which contains a memory component comparable to that included in a recognition paradigm. We compared the effect of rotation on discrimination and association processes for faces and cars, Subjects learned to discriminate pairs of similar faces and similar cars and to associated them with neutral responses. The stimulus pairs were presented upright, inverted, and additionally in two intermediate orientations. We found that discrimination performance was generally better for faces than for cars and that associations were learned faster for faces than for cars. However, we did not find any evidence that rotation affected discrimination and association processes for faces differently than for cars. In this sense, our results provide no evidence for the hypothesis that memory processes are responsible for disproportionate effect of inversion which is found in recognition experiments.

Adult↗
PubMed1990

Trends in asthma mortality in New Zealand, 1908-1986.

Trends in mortality from asthma in non-Maori New Zealanders aged 5 to 34 years were examined for the period 1908-1986. Two previously documented epidemics of death from asthma occurred in the 1960s and the late 1970s. These epidemics are most likely to have been due to changes in the management of asthma: the introduction of isoprenaline forte by metered dose inhaler in the 1960s and inhaled fenoterol in the 1970s. A previously unreported rise in mortality, which was more gradual in onset and less severe, occurred in the 1940s and 1950s; a similar pattern occurred in England and Wales during the same period. It is unlikely that this increase in mortality was solely due to changes in diagnostic fashion or disease coding. Possible explanations include changes in the management or prevalence of asthma, or in environmental factors. It is notable that mortality was below 0.5 per 100,000 person-years prior to 1940, but has subsequently increased considerably. Thus, while modern methods for treating asthma have improved the quality of life of many asthmatics, mortality has increased during the period of their introduction and use.

Adolescent↗
PubMed1987

Thyroid hormone induced changes in cardiac proteins and mRNAs.

Contraction of the hypothyroid heart is characterized by delayed diastolic relaxation and decreased velocity of systolic contraction. In order to determine if these alterations could be mediated by the changes in the mRNA coding for the Ca++ ATPase of the sarcoplasmic reticulum and alterations of the mRNAs coding for myosin heavy chain (MHC) alpha and beta, the levels of these specific mRNAs were quantitated using a Northern blotting technique. We find that the Ca++ ATPase mRNA was 3-fold lower in hypothyroid hearts. After T3 administration to hypothyroid rats, Ca++ ATPase mRNA increased to 66% of control levels within 2 hrs and to 100% of control levels 5 hrs after T3 administration. In the hypothyroid heart, MHC beta mRNA was the predominant message with MHC alpha mRNA barely detectable. Administration of 2 mg of T3 led to a significant increase in MHC alpha mRNA levels first detectable 2 hrs after T3 administration. Twenty-four hrs after T3 administration, MHC alpha mRNA levels had normalized. The results of these studies indicate that thyroid hormone mediates significant alterations in the level of the mRNA coding for the Ca++ ATPase of the sarcoplasmic reticulum and of the mRNAs coding for MHC alpha and beta. Changes in the level of these specific mRNAs resulting in lower levels of the corresponding proteins may explain the delayed diastolic relaxation and the decreased velocity of contraction of the hypothyroid heart.

Animals↗