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PubMed2001

The formation of plasmid DNA loaded pharmaceutical powders using supercritical fluid technology.

The invention of novel drugs based on biological macromolecules requires the development of specialized formulation methods. Supercritical fluid technology offers the possibility to produce dry powder formulations suitable for inhalation or needle-free injection. In this article we describe the first application of a process involving supercritical carbon dioxide for the production of plasmid DNA-loaded particles. The technique of solution enhanced dispersion by supercritical fluids (SEDS) is used to coformulate the 6.9 kb plasmid pSV beta with mannitol as excipient. After initial experiments showed a high degradation of the plasmid during powder formation, a systematic investigation of the process revealed pH effects to be crucial for the recovery of intact DNA. The application of high-buffer concentration led to an increase of the recovered supercoiled proportion from 7% to 80%.

Biotechnology↗

PubMed2000

Heated, humidified air for the common cold.

OBJECTIVES: To assess the effects of inhaling heated water vapour with the help of a rhinotherm (an equipment designed to deliver heated water vapour to a person's nasal cavity), in the treatment of the common cold by comparing a. symptoms b. viral shedding c. nasal resistance after a natural or experimentally induced common cold. SEARCH STRATEGY: We searched MEDLINE with MeSH headings: common cold, rhinopharyngitis, inhalation, steam, heated vapour, rhinothermy, till July 1999. EMBASE, Current Contents, review articles, cross references were also searched. Attempts were also made to contact the manufacturers for any unpublished data. SELECTION CRITERIA: Randomized trials using heated water vapour in a standardized way in patients with the common cold or volunteers with experimental induction of rhinovirus infection were included in the review. DATA COLLECTION AND ANALYSIS: All the articles retrieved were initially subjected to a review for inclusion / exclusion criteria. Review articles, editorials, abstracts with inadequate outcome description were excluded. Studies selected for inclusion were subjected to a methodological assessment. MAIN RESULTS: The results of a systematic review of six trials with 319 participants, support the use of warm vapour inhalations in the common cold in terms of relief of symptoms (Odds Ratio with 95 % CI 0.31, 0.16-0.60, Relative risk 0.56, 0.4-0. 79). Results on symptom score indices were equivocal. None of the studies demonstrated a worsening of clinical symptom scores. One study demonstrated increased nasal resistance one week after steam inhalation in contrast to an earlier study which showed improvement in the nasal resistance. There was no evidence of decreased viral shedding measured by virus isolation in the nasal secretions (Tyrrell 1989) or measurement of viral titres in nasal washings among treatment group. The rhinovirus titres in the nasal washings from the treatment group were the same as those of the placebo group on day one prior to the treatment and on all four days after the treatment. The area under curve (Hendley 1994) was also similar in the placebo and treatment groups for titres of virus in the nasal washings as were the average viral titres across five days of follow up, the maximum values after treatment, and viral shedding velocity i.e. amount of virus shed per day (Hendley 1994). Minor side effects due to thermal stress were reported in all the studies. REVIEWER'S CONCLUSIONS: Three trials demonstrated beneficial effects on the symptoms of the common cold. One study from Israel showed a decrease in nasal resistance measured by peak nasal expiratory and inspiratory flow rate. Studies done in North America failed to show any objective improvement in outcome measures with the study intervention. A multi-centre double blind randomised controlled trial testing this therapy with uniform outcome measures is recommended.

Air↗

PubMed2004

Heated, humidified air for the common cold.

BACKGROUND: Heated, humidified air is used by common cold sufferers since the invention of the steam kettle. There is scientific literature available investigating this mode of therapy using a rhinotherm. The present reviews addresses to the use of hot, humid air in common cold. OBJECTIVES: To assess the effects of inhaling heated water vapour with the help of a rhinotherm (an equipment designed to deliver heated water vapour to a person's nasal cavity), in the treatment of the common cold by comparing: a. symptoms b. viral shedding c. nasal resistance after a natural or experimentally induced common cold. SEARCH STRATEGY: In the initial review published in issue 3, 1999 of The Cochrane Library, we searched MEDLINE with MeSH headings: common cold, rhinopharyngitis, inhalation, steam, heated vapour, rhinothermy (January 1966 to July 1999). EMBASE, Current Contents, review articles, cross references were also searched. Attempts were also made to contact the manufacturers for any unpublished data. In this updated review, we have searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 4, 2003), MEDLINE (January 1966 to November Week 2, 2003), EMBASE (January 1990 to November 2003), and Current Contents (current five years). SELECTION CRITERIA: Randomized trials using heated water vapour in a standardized way in patients with the common cold or volunteers with experimental induction of rhinovirus infection were included in the review. DATA COLLECTION AND ANALYSIS: All the articles retrieved were initially subjected to a review for inclusion / exclusion criteria. Review articles, editorials, abstracts with inadequate outcome description were excluded. Studies selected for inclusion were subjected to a methodological assessment. MAIN RESULTS: The results of a systematic review of six trials with 319 participants, support the use of warm vapour inhalations in the common cold in terms of relief of symptoms (Odds Ratio with 95 % CI 0.31, 0.16-0.60, Relative risk 0.56, 0.4-0.79). Results on symptom score indices were equivocal. None of the studies demonstrated a worsening of clinical symptom scores. One study demonstrated increased nasal resistance one week after steam inhalation in contrast to an earlier study which showed improvement in the nasal resistance. There was no evidence of decreased viral shedding measured by virus isolation in the nasal secretions (Tyrrell 1989a) or measurement of viral titres in nasal washings among treatment group. The rhinovirus titres in the nasal washings from the treatment group were the same as those of the placebo group on day one prior to the treatment and on all four days after the treatment. The area under curve (Hendley 1994) was also similar in the placebo and treatment groups for titres of virus in the nasal washings as were the average viral titres across five days of follow up, the maximum values after treatment, and viral shedding velocity i.e. amount of virus shed per day (Hendley 1994). Minor side effects due to thermal stress were reported in all the studies. REVIEWERS' CONCLUSIONS: Three trials demonstrated beneficial effects on the symptoms of the common cold. One study from Israel showed a decrease in nasal resistance measured by peak nasal expiratory and inspiratory flow rate. Studies done in North America failed to show any objective improvement in outcome measures with the study intervention. A multi-centre double blind randomised controlled trial testing this therapy with uniform outcome measures is recommended.

Air↗

PubMed2006

The acquisition of myelin: a success story.

The myelin sheath, and hence the myelin-forming cells (i.e. Schwann cells in the PNS and oligodendrocytes in the CNS), have been a crucial acquisition of vertebrates. The major function of myelin is to increase the velocity of propagation of nerve impulses. Invertebrate axons are ensheathed by glial cells, but do not have a compact myelin. As a consequence, action potentials along invertebrate axons propagate at about 1 m/s, or less. This is sufficient, however, for the survival of small animals (between 0.1 and 30cm). Among invertebrates, only the cephalopods are larger. By increasing their axonal diameter to 1 mm or more, cephalopods have been able to increase the speed of propagation of action potentials and therefore adapt nerve conduction to their larger body size. However, due to the physical constraint imposed by the skull and vertebrae, vertebrates had to find an alternative solution. This was achieved by introducing the myelin sheath, which leads action potentials to propagate at speeds of 50-100m/s without increasing the diameter of their axons. Not all vertebrate axons, however, are myelinated. In the protovertebrates (lancelets, hagfishes, lampreys), which belong to the agnathes (jawless fishes), axons are not ensheathed by myelin. Among living vertebrates, the most ancient myelinated species are the cartilaginous fishes (sharks, rays), suggesting that acquisition of myelin is concomitant with the acquisition of a hinged-jaw, i.e. the gnathostoma. The close association between the apparition of a hinged-jaw and the myelin sheath has led to speculation that among the devonian fishes that have disappeared today, the jawless conodonts and ostracoderms were not myelinated, and that myelin was first acquired by the oldest gnathostomes: the placoderms. I also question where myelin first appeared: the PNS, the CNS or both? I provide evidence that, in fact, it is not the type of myelin-forming cell that is crucial, but the appearance of axonal signals, rendering axons receptive to inducing an ensheathing glial cell to wrap around the axon. Under certain circumstances or in some species, invertebrate ensheathing glial cells wrap around axon to form a pseudo-myelin sheath. Therefore, to form myelin it was not compulsory to 'invent' a new cell type. Hence my conclusion that myelination has most probably started simultaneously in the PNS and the CNS, using pre-existing ensheathing glial cells.

Action Potentials↗

PubMed1990

Commercial exploitation of the human genome: what are the problems?

Commercial activities frequently take place against a background of the ownership of intellectual property, for example patents or know-how. This is particularly true of human health care companies and companies operating in the field of biotechnology, where the high cost and long time frames of research and development demand a degree of exclusivity in order to achieve an acceptable return on the investment. It follows that any company with an interest in using biotechnology to generate human health care products will have a strong interest in the ownership of property, much of which will have its origins in knowledge of the human genome. Claims to the ownership of portions of the human genome have been made public in recent times and these have been treated with everything from disgust to derision. However, a more considered analysis of this question will be found to turn on the relationship between discovery and invention in this field. This paper examines this question in relation to current commercial activities where information from the human genome is being used and attempts to draw some conclusions about what may be the impact of knowledge of the genome on commercial activities in the future.

Biotechnology↗

PubMed1990

Human genetic information: the legal implications.

This paper provides a brief summary of some of the key legal issues raised by human genetic information and research as viewed from a British common law standpoint. The law is basically reactive rather than prospective and problems posed by futuristic medico-scientific discoveries are likely to be dealt with by reference to established legal principles and analogies made with decided cases. The acquisition and research into human genetic information in the form of DNA profiling may have wide-ranging legal implications. Human genetic information may provide an evidential tool in the legal process when the identity of a specific individual or his family connections and relationships are called into question. It may also pose problems of confidentiality which could conflict with a duty of disclosure. In the future it may be possible to identify a propensity to develop a disease which may be seriously disabling or terminal long before any symptoms are detectable. This sensitive information could be of considerable interest to any prospective employer, insurer, marriage partner or family member and is of serious concern to the individual himself. How far should or could such information lawfully be made available and to whom? Legal debates are also likely to focus on ownership of human genetic information, the patenting of techniques to unravel it, and therapies and medicines developed therefrom. The law will be invoked to safeguard any intellectual property which may exist and to patent any inventive steps in the field.(ABSTRACT TRUNCATED AT 250 WORDS)

Confidentiality↗

PubMed1992

Roles of secondary metabolites from microbes.

The common feature of the seemingly diverse array of biological activities exhibited by microbial secondary metabolites is their survival value for the producing organism. The propensity to form these compounds is unevenly distributed in microbial taxa and seems more closely associated with existence in a competitive environment than with phylogeny. The characteristic multibranched elaboration of secondary biosynthetic pathways and the marked species specificity of the end products are consistent with their evolution by an 'inventive' mechanism. The species specificity suggests that distinctive terminal reactions may be of recent origin. However, comparisons of the nucleotide sequence of genes involved in the biosynthesis of phenazine and polyketide metabolites with related genes of primary pathways indicate that the secondary pathways have not evolved exclusively within the organisms in which they are now found. Sequence similarities with related primary pathway genes in phylogenetically distant organisms suggest that gene transfer has played an important part in the evolution of secondary metabolism. The diversity of products may reflect the many roles for which secondary metabolites have been selected after the genes for their biosynthesis have transferred to organisms with different physiologies and different environment challenges.

Bacteria↗

PubMed1992

Useful functions of microbial metabolites.

The mood-enhancing effects of fungi and their medicinal properties have been recognized for centuries. Ergot was initially used by midwives to speed childbirth in the Middle Ages. More recently their pharmacological action on dopamine receptors has been exploited to treat post-partum bleeding, migraine, Parkinson's disease and senile dementia. Further indications of the potential value of microbial metabolites are exemplified by the discovery and development of cyclosporin, to treat organ rejection, and mevinolin, a cholesterol-lowering drug. Such discoveries are not unexpected because we have known for some time that fungi regulate morphogenesis, differentiation and sexuality via hormonal molecules, ranging from peptides through to steroidal molecules similar in structure to human sex hormones. A combination of the power of molecular biology to design screens based on isolated disease mechanisms with the chemical inventiveness of microorganisms is providing numerous new pharmacophores for drug development.

Drug Evaluation, Preclinical↗

PubMed1993

The relationship between early giftedness and later achievement.

Although some prodigies grow up to become creative masters as adults, there is no necessary link between early signs of talent and ultimate achievement. Four possible relations between early and late achievement are explored here. The analysis draws upon two lines of evidence: (1) a new theoretical approach that posits the existence of multiple intelligences and examines the important role of the domains and fields in which individuals work; (2) case studies of seven highly creative individuals who lived at the turn of the century. A strong contrast emerges between the adult creator, who must discover the domain in which he or she can excel and the child prodigy, who must invent a creative personality.

Achievement↗

PubMed1977

Where did our infectious diseases come from? The evolution of infectious disease.

Infectious diseases have been evolving from the earliest days of life on earth. Major factors influencing their developments include the splitting of continents (continental drift), the radiation of early primates into present-day forms, migrations of man around the world, the ending of the Ice Age, the invention of agriculture, the domestication of animals, the increase in populations, and the urbanization of societies. The impact of such basic changes on infectious diseases is reviewed.

Agriculture↗

PubMedDate not supplied

Cellular life histories and bow tie biology.

Considering the life-long influences of fetal growth biology, it is of interest to further elucidate the nature of the fetal growth process itself. Previous analyses of longitudinal fetal ultrasound data led to the hypothesis that hypoxia signals were important aspects of normal growth biology and directed attention to the place of oxygen as a basic nutrient. From the perspective of the cell, both hypoxia and lack of energy substrate trigger a common adaptive pathway through their effects on ATP availability. Comparative data from animal studies and cell culture provide evidence for an integrated energy/oxygen signaling system that acts redundantly and hierarchically with cellular differentiation programs, providing opportunities for developmental flexibility in response to variable ecologic or environmental challenge. The multinodal and interactive design of the fetal growth process suggests that it follows what has been described as the "bow tie" model of metabolism, with implications for robust and inventive approaches to cell, organ, and whole organism construction.

Adaptation, Physiological↗

PubMed1981

The genetic dynamics of disease.

The notional principles of the genetics of disease are broadly discussed. Disease is an intrinsically vague term that represents the incongruity between the inner milieu of the organism and the environment. Its dynamics, then, cannot be reduced to naive statements about selection which may operate, and operate conflictingly, on several different levels or organization. Evolutionary selection results from the advantage of complexity, and the fundamental theorem of genetic dynamics - that mutational debts must eventually be paid in full-may be false or, at best approximate. The traditional models (mendelian, galtonian, and threshold) are set in a context that identifies certain features of disease that hitherto have been totally ignored. Neither invention nor traditional analysis has been adequate. Models should be made individually adequate for the study of diseases; the diseases should not be trimmed to fit the models.

Biological Evolution↗

PubMed2002

New tool use by wild Sumatran orangutans (Pongo pygmaeus abelii).

Two forms of tool use by wild Sumatran orangutans are reported from the Agusan Monitoring Station, a new research site in Indonesia. One form, a branch "hook" used in locomotion, has not been reported previously in wild orangutans. The second form, a leaf "pad" used to protect the hands and feet from thorns while feeding, shares similarities in form and function with a tool type used by orangutans at Ketambe, a nearby research site. Both instances of tool use occurred in areas of disturbance, and appear to be spontaneous inventions under novel conditions, although habitual use of the tool in other ecological contexts is plausible. A summary of the distribution of tool use types in wild orangutans is presented.

Animals↗

PubMed2005

Learning the ropes: The ontogeny of locomotion in red-shanked douc (Pygathrix nemaeus), Delacour's (Trachypithecus delacouri), and Hatinh langurs (Trachypithecus hatinhensis) I. positional behavior.

Recent studies at the Endangered Primate Rescue Center (EPRC) in the Socialist Republic of Vietnam's Cuc Phuong National Park by Byron et al. ([2002] Am. J. Phys. Anthropol. [Suppl.] 34:51) and Covert and Byron ([2002] Caring for Primates) revealed unexpected locomotor and postural behaviors in the red-shanked douc langur (Pygathrix nemaeus). This paper further elucidates the question of red-shanked douc suspensory behavior, and provides initial positional behavior data for two other rare Asian colobines, by comparing the ontogenetic positional behavior of red-shanked douc langurs, Delacour's langurs (Trachypithecus delacouri), and Hatinh langurs (Trachypithecus hatinhensis) at the EPRC. Two hundred and seven hours of positional behavior data were collected, with approximately equal amounts of data on each species, and equal amounts on adults and those less than 18 months in age. All young animals were more active than adults, used a wider repertoire of locomotor behaviors, and expressed suspensory behaviors more frequently than did the adults. Young animals also "invented" one new locomotor and two new postural behaviors. These differences are due to both play and explorative behavior, as well as to the youths' changing musculoskeletal systems. The number of positional behaviors utilized by the adults of these species is quite similar to one another (23-32), as is that utilized by the young (51-56). Douc langurs in both age categories used suspensory behaviors more frequently than did Delacour's and Hatinh langurs. Because the uniformity of enclosures offers a control, the results of this study generate hypotheses regarding adaptive radiations and niche partitioning in wild populations.

Animals↗

PubMed2004

Controlled microwave heating in modern organic synthesis.

Although fire is now rarely used in synthetic chemistry, it was not until Robert Bunsen invented the burner in 1855 that the energy from this heat source could be applied to a reaction vessel in a focused manner. The Bunsen burner was later superseded by the isomantle, oil bath, or hot plate as a source for applying heat to a chemical reaction. In the past few years, heating and driving chemical reactions by microwave energy has been an increasingly popular theme in the scientific community. This nonclassical heating technique is slowly moving from a laboratory curiosity to an established technique that is heavily used in both academia and industry. The efficiency of "microwave flash heating" in dramatically reducing reaction times (from days and hours to minutes and seconds) is just one of the many advantages. This Review highlights recent applications of controlled microwave heating in modern organic synthesis, and discusses some of the underlying phenomena and issues involved.

Chemistry, Organic↗

PubMed2004

Modern synthetic methods for fluorine-substituted target molecules.

Fluorine has come to be recognized as a key element in materials science: in heat-transfer agents, liquid crystals, dyes, surfactants, plastics, elastomers, membranes, and other materials. Furthermore, many fluorine-containing biologically active agents are finding applications as pharmaceuticals and agrochemicals. Progress in synthetic fluorine chemistry has been critical to the development of these fields and has led to the invention of many novel fluorinated molecules as future drugs and materials. As a result of the electronic effects of fluorine substituents, fluorinated substrates and reagents often exhibit unusual and unique chemical properties, which often make them incompatible with established synthetic methods. Thus, the problem of how to control the unusual properties of compounds with fluorine substituents deserves much attention, so as to promote the design of facile, efficient, and environmentally benign methods for the synthesis of valuable organofluorine targets.

Chemistry, Agricultural↗

PubMed2001

Gross anatomy in the surgical curriculum in Switzerland: improved cadaver preservation, anatomical models, and course development.

The invention of new techniques for surgery and interventional radiology demand improved training for ongoing specialists. The Anatomical Institutes in Switzerland support these requirements by establishing hands-on practical training courses by using new procedures for cadaver embalming and model construction. Improvements allow courses to provide students with more realistic simulations of both established and experimental surgical methods. Through these changes, the value of in-depth gross anatomy is enhanced as a topic of fundamental importance for the postgraduate medical and surgical curriculum. The web site http://www.unifr.ch/sgahe/snga.html contains information on courses using the Thiel embalming solution. Details about training courses in Switzerland using anatomical models are available at http://www.heartlab.org, http://www.vascular-international.org, and http://www.elastrat.com.

Anatomy↗

PubMed2002

The human cadaver in the age of biomedical informatics.

Major national and international critiques of the medical curriculum in the 1980s noted the following significant flaws: (1) over-reliance on learning by rote memory, (2) insufficient exercise in analysis and synthesis/conceptualization, and (3) failure to connect the basic and clinical aspects of training. It was argued that the invention of computers and related imaging techniques called to question the traditional instruction based on the faculty-centered didactic lecture. In the ensuing reform, which adopted case-based, small group, problem-based learning, time allotted to anatomical instruction was severely truncated. Many programs replaced dissection with prosections and computer-based learning. We argue that cadaver dissection is still necessary for (1) establishing the primacy of the patient, (2) apprehension of the multidimensional body, (3) touch-mediated perception of the cadaver/patient, (4) anatomical variability, (5) learning the basic language of medicine, (6) competence in diagnostic imaging, (7) cadaver/patient-centered computer-assisted learning, (8) peer group learning, (9) training for the medical specialties. Cadaver-based anatomical education is a prerequisite of optimal training for the use of biomedical informatics. When connected to dissection, medical informatics can expedite and enhance preparation for a patient-based medical profession. Actual dissection is equally necessary for acquisition of scientific skills and for a communicative, moral, ethical, and humanistic approach to patient care. Anat Rec (New Anat) 269:20-32, 2002.

Anatomy↗