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Otto Lowenstein: neurologic and ophthalmologic testing methods during his lifetime.

Lowenstein's work on the pupil is well known in this country and in Europe. It constituted, however, only one of many of his fields of interest. In all of them his contributions were based on experiments in which accurate, objective recording replaced mere observation with the unaided eye. The resulting traces, obtained under stable conditions and with well-defined stimuli, revealed specific normal or pathologic reaction patterns, and these, in turn, allowed recognition, quantification and localization of the underlying physiologic mechanisms or pathologic defects. During the early decades of this century Lowenstein invented and built his own instruments. And as more advanced technical means became available, he adopted these, so that his methods became more elegant and less time-consuming. This history forms an interesting parallel to the development of work done by others throughout the twentieth century.

Diagnostic Techniques, Neurological↗

The historical discovery of macular edema.

The occurrence of macular edema, or of intraretinal fluid in general, was largely unknown prior to the invention of the ophthalmoscope. One of the first reports on 'Retinitis in Glycosuria', a disease complex, which today would partly be described as diabetic maculopathy, was published in 1856 by Jaeger. His observations were confirmed less than twenty years later by Nettleship in London, and in 1875 Appolinaire Bouchardat from Paris described fluid and lipid accumulation in the macula which led--in his words--to a glucose induced amblyopia. The first pathophysiological hypotheses of fluid accumulation in the posterior pole were then put forward in 1882 by Tartuferi, who thought the edema represented swelling of photoreceptor sheaths. In 1896, the Frenchman Nuel coined the term 'oedème maculaire' which he had observed in a retinitis pigmentosa patient. However, it was not until the end of the first World War, that the Swiss ophthalmologist Alfred Vogt observed macular edema in a variety of other ocular conditions such as iridocyclitiOFF macular edema to a macular hole. A quarter of a century later Bangerter coined the German term 'Zystoides Makulaödem', and in 1950, Hruby was the first to draw attention to the development of macular edema after cataract extraction. Three years later this was followed by Irvine's classical paper on cystoid macular edema after intra- and extracapsular cataract extraction which had been complicated by incarceration of the vitreous in the anterior segment with consecutive tugging on the macula. A decade later, the phenomenon of cystic fluid accumulation in the macula after cataract extraction was further characterised by Gass and Norton using fluorescein angiography. The ensuing years saw the emergence of new concepts regarding the blood-retinal barrier and the paramount role of its dysfunction in the development of macular edema.

Fluorescein Angiography↗

Meningeosis leukaemica in adult acute lymphoblastic leukaemia.

This review addresses diagnosis of CNS involvement, incidence and treatment of CNS disease at time of diagnosis, prophylaxis and treatment of CNS relapse and risk factors for meningeal recurrence in adult acute lymphoblastic leukaemia (ALL). At the time of diagnosis meningeosis leukaemica is present in about 6% (1-10%) of the adult ALL patients with a higher incidence in ALL subgroups T-ALL (8%) and B-ALL (13 %). With the invention of early additional CNS directed therapy it no longer represents an unfavourable prognostic factor. In the absence of prophylaxis meningeal relapses occur in approximately one third of adults with ALL. A literature review including more than 4000 adult ALL patients showed for the different prophylactic treatment approaches the following CNS relapse rates: intrathecal therapy alone 13% (8-19%), intrathecal therapy and CNS irradiation 15% (6-22%), high dose chemotherapy 14% (10-16%), high dose chemotherapy and intrathecal therapy 8% (2-16%) and high dose chemotherapy, intrathecal therapy together with CNS irradiation 5% (1-12%). It became obvious that the early onset of intrathecal therapy and CNS irradiation and the continuation of intrathecal administrations throughout maintenance are essential. The most favourable results where achieved with high dose chemotherapy combined with intrathecal therapy and/or CNS irradiation. The majority of treatment regimens in adult ALL already include high dose chemotherapy in order to reduce the risk of bone marrow relapse. The outcome of patients with CNS relapse is still poor. Although a remission can be induced in the majority of patients (> 60%) it is usually followed by a bone marrow relapse and the survival is poor (< 5-10%). Bone marrow transplantation might be in adults at present the only curative approach.

Adult↗

Predictors of success in radiofrequency catheter ablation of atrial flutter.

Radiofrequency catheter ablation of typical atrial flutter at the isthmus between the tricuspid annulus and the inferior vena cava is established. However in selected patients, the creation of a continuous linear lesion at the targeted isthmus requires a lengthened procedure or is not feasible at all and atrial flutter recurrences are common. In a retrospective analysis, we found that an intraoperatively determined distance between the tricuspid annulus and the inferior vena cava of <.2.5 cm is an independent predictor of a lengthened or failed ablation procedure. Additional equipment, e.g., long introducer sheaths, adapted ablation catheter design, or irrigated tip ablation, as well as alternative ablation approaches, e.g., linear lesions between the tricuspid annulus and Eustachian ridge, have been invented in order to increase the acute success rate or decrease fluoroscopy and procedure time. In a prospective study on the effects of various conduction properties at the isthmus between tricuspid annulus and inferior vena cava following radiofrequency ablation of atrial flutter, we showed previously that others than a complete bidirectional conduction block predicts a high recurrence rate of atrial flutter. For determination of transisthmal conduction properties following ablation, established mapping approaches are documentation of double potentials at the ablation line and right atrial activation sequence following posteroseptal and low lateral right atrial pacing. Novel threedimensional mapping systems, i.e., Carto(R) and EnSite(R), may further enhance the accuracy of conventional mapping techniques.

Atrial Flutter↗

;Evolution of Photosynthesis' (1970), re-examined thirty years later.

I have re-examined my 1970 article 'Evolution of Photosynthesis' (Olson JM, Science 168: 438-446) to see whether any of my original proposals still survive. My original conviction that the evolution of photosynthesis was intimately connected with the origin of life has been replaced with the realization that photosynthesis may have been invented by the Bacteria after their divergence from the Archea. The common ancestor of all extant photosynthetic bacteria and cyanobacteria probably contained bacteriochlorophyll a, rather than chlorophyll a as originally proposed, and may have carried out CO(2) fixation instead of photoassimilation. The first electron donors were probably reduced sulfur compounds and later ferrous iron. The common ancestor of all extant reaction centers was probably similar to the homodimeric RC1 of present-day green sulfur bacteria (Chlorobiaceae) and heliobacteria. In the common ancestor of proteobacteria and cyanobacteria, the gene for the primordial RC1 was apparently duplicated and one copy split into two genes, one for RC2 and the other for a chlorophyll protein similar to CP43 and CP47 in extant cyanobacteria and chloroplasts. Homodimeric RC1 and homodimeric RC2 functioned in series as in the Z-scheme to deliver electrons from Fe(OH)(+) to NADP(+), while RC1 and/or RC2 separately drove cyclic electron flow for the production of ATP. In the line of evolution leading to proteobacteria, RC1 and the chlorophyll protein were lost, but RC2 was retained and became heterodimeric. In the line leading to cyanobacteria, both RC1 and RC2 replaced bacteriochlorophyll a with chlorophyll a and became heterodimeric. Heterodimeric RC2 further coevolved with a Mn-containing complex to utilize water as the electron donor for CO(2) fixation. The chlorophyll-protein was also retained and evolved into CP43 and CP47. Heliobacteria are the nearest photosynthetic relatives of cyanobacteria. The branching order of photosynthetic genes appears to be (1) proteobacteria, (2) green bacteria (Chlorobiaceae plus Chloroflexaceae), and (3) heliobacteria plus cyanobacteria.

Journal Article↗

Energetic stimulation of the heart.

The management of patients with acute heart failure includes frequently the use of positive inotropic agents in order to increase cardiac output and hence to maintain adequate tissue perfusion. The concept of energetic stimulation of the heart was invented in order to avoid deleterious effects of conventional inotropes, i.e. catecholamines and phosphodiesterase-inhibitors, on myocardial oxygen consumption and energy reserves and to circumvent potential dangerous side effects of the drugs. Metabolic support with glucose-insulin-potassium has proven efficious of improving cardiac performance and prognosis in the setting of the ischemic and postischemic heart. The glycolytic intermediate pyruvate increases contractile performance in isolated animal and human myocardium and improves short-time hemodynamics in patients with congestive heart failure, which is discussed in detail in the present article. Energetic stimulation with pyruvate could therefore be a new promising approach to the treatment of acute heart failure, if conventional therapy fails.

Amino Acids↗

Friction and wear of hydroxyapatite reinforced high density polyethylene against the stainless steel counterface.

Hydroxyapatite (HA) reinforced high density polyethylene (HDPE) was invented as a biomaterial for skeletal applications. In this investigation, tribological properties (e.g. wear rate and coefficient of friction) of unfilled HDPE and HA/HDPE composites were evaluated against the duplex stainless steel in dry and lubricated conditions, with distilled water or aqueous solutions of proteins (egg albumen or glucose) being lubricants. Wear tests were conducted in a custom-built test rig for HDPE and HA/HDPE containing up to 40 vol % of HA. It was found that HA/HDPE composites had lower coefficients of friction than unfilled HDPE under certain conditions. HA/HDPE also exhibited less severe fatigue failure marks than HDPE. The degradation and fatigue failure of HDPE due to the presence of proteins were severe for low speed wear testing (100 rpm) as compared to high speed wear testing (200 rpm). This was due possibly to the high shear rate at the contact which could remove any degraded film instantaneously at high sliding speed, while with a low sliding speed the build-up of a degraded layer of protein could occur. The degraded protein layer would stay at the contact for a longer time and mechanical activation would induce adverse reactions, weakening the surface layer of HDPE. Both egg albumen and glucose were found to be corrosive to steel and adversely reactive for HDPE and HA/HDPE composites. The wear modes observed were similar to that of ultra-high molecular weight polyethylene. Specimens tested with egg albumen also displayed higher wear rates, which was again attributed to corrosion accelerated wear.

Journal Article↗

The Human Genome Project and the future of diagnostics, treatment and prevention.

The Human Genome Project, the mapping of our 30,000-50,000 genes and the sequencing of all of our DNA, will have major impact on biomedical research and the whole of therapeutic and preventive health care. The tracing of genetic diseases to their molecular causes is rapidly expanding diagnostic and preventive options. The increased insights into molecular pathways, gained from high-throughput 'functional genomics', using DNA-chip and protein-chip approaches and specially designed animal model systems, will open great prospects for pharmacological and genetic therapies. Powerful bioinformatics and biostatistics will further improve our pattern recognition and accelerate progress. A rapidly expanding area of high expectations is that of 'pharmacogenomics': the design of more effective drugs with lower toxicity through tailoring of drug treatment to individual, genetically determined differences in drug metabolism. Not only will this decrease the cost of health care through reduction of adverse drug reactions, but a better stratification of populations will also provide more statistical power farther upstream in drug trials. However, the optimal benefits from the current explosion of 'data mining' will only be realized when the basic data are made and kept publicly accessible, while at the same time safeguarding the protection of intellectual property arising from downstream inventions. This is one of the goals of HUGO, the international Human Genome Organization, established 13 years ago to assist coordination of data acquisition and exchange and societal implementation of the genome project. Additional points of attention in this historic endeavour are the prevention of stigmatization and discrimination and the safeguarding of a worldwide balance in the contribution by--and benefits to--different populations, while respecting the diversity in cultures and traditions.

Ethics, Medical↗

Determination of [Mg(2+)]i - an update on the use of Mg(2+)-selective electrodes.

Since their invention, ion-selective microelectrodes have become an indispensable tool for investigations of intracellular ion regulation and transport. While highly selective sensors for all major intracellular monovalent ions have been available for decades, the development of sensors for divalent cations seems to have presented more difficulties. As ion-selective microelectrodes typically have time-constants in the range of 0.5 to several seconds they turned out to be inapt for the investigation of intracellular Ca2+. The development of sensors for Mg2+-selective electrodes has made its most striking progress only over the past few years. While the first Mg2+ sensor, ETH 1117, was barely able to detect physiological Mg2+ concentrations in the presence of other mono- and divalent cations, the newest sensors allow measurements in the micromolar range. When used in macroelectrodes, the most recent developments, ETH 5506 and ETH 5504, have even been reported to do so in the presence of millimolar Ca2+ concentrations. Although there is still room for improvement to make these sensors applicable in microelectrodes, some preliminary data look extremely promising and indicate that a new era for Mg2+-selective microelectrodes is about to start.

Animals↗

The commercialization of human stem cells: ethical and policy issues.

The first stage of the human embryonic stem (ES) cell research debate revolved around fundamental questions, such as whether the research should be done at all, what types of research may be done, who should do the research, and how the research should be funded. Now that some of these questions are being answered, we are beginning to see the next stage of the debate: the battle for property rights relating to human ES cells. The reason why property rights will be a key issue in this debate is simple and easy to understand: it costs a great deal of money to do this research, to develop new products, and to implement therapies; and private companies, researchers, and health professionals require returns on investments and reimbursements for goods and services. This paper considers arguments for and against property rights relating to ES cells defends the following points: (1) It should be legal to buy and sell ES cells and products. (2) It should be legal to patent ES cells, products, and related technologies. (3) It should not be legal to buy, sell, or patent human embryos. (4) Patents on ES cells, products, and related technologies should not be excessively broad. (5) Patents on ES cells, products, and related technologies should be granted only when applicants state definite, plausible uses for their inventions. (6) There should be a research exemption in ES cell patenting to allow academic scientists to conduct research in regenerative medicine. (7) It may be appropriate to take steps to prevent companies from using patents in ES cells, products, and related technologies only to block competitors. (8) As the field of regenerative medicine continues to develop, societies should revisit issues relating to property rights on a continuing basis in order to develop policies and develop regulations to maximize the social, medical, economic, and scientific benefits of ES cell research and product development.

Biotechnology↗

Unresolved issues in scientific sexology.

A number of unresolved issues in sexology research and practice are reviewed. Penile volume assessment of sexual arousal has consistently proved more sensitive than penile circumference assessment and requires much shorter exposure to the erotic stimuli eliciting the arousal, reducing the subjects' ability to modify their responses. Failure to acknowledge this has allowed acceptance of evidence based on penile circumference assessment that behavioral treatments such as directed masturbation can increase the ability of sex offenders to be heterosexually aroused and aversive therapy can reduce their deviant urges whereas penile volume assessment indicates these procedures are ineffective. A randomized controlled trial of relapse prevention versus no treatment for sex offenders found more treated than untreated subjects reoffended after a mean follow-up period of 4 years. Researchers and therapists accepted that a post hoc statistical manipulation of the results provided evidence of a treatment effect. Subsequently it has been recommended that randomized controlled evaluations of treatments of sex offenders be abandoned. Meta-analysis of outcome studies has been used uncritically. The majority of men and women who report homosexual feelings and/or behavior report predominant heterosexual feelings and behavior and do not identify as homosexual. These consistent findings remain ignored. Studies of the etiology and development of homosexuality and heterosexuality treat them as distributed categorically rather than dimensionally and investigate only self-identified homosexuals and heterosexuals. With this methodology the predominantly heterosexual majority are excluded or misclassified. The belief that the European concept of the homosexual is a late 19th-century invention is based on an inadequate reading of literature. Limitations of the DSM classification of sexual and gender identity disorders are pointed out. The validity of self-report of sexual behavior has been questioned on the basis that men report a markedly higher average number of sexual partners than women. Possible sex differences in reporting the number of partners who are of the same sex, casual, or perpetrators or victims of sexual coercion and child abuse have not been taken into account. Failure of sexology to progress due to lack of resolution of conflicting issues may contribute to the low impact factor of its journals.

Female↗

Secretory compartments as instances of dynamic self-evolving structures.

Biological objects are often "constructive dynamic systems" whose structures evolve as a consequence of their internal dynamics, which in turn is affected by the overall structure. As very few tools are presently adapted to tackle constructive dynamic systems, they constitute fascinating challenges for modeling/simulation. In cell biology, the secretory process in eukaryotic cells corresponds to this type of system, as it appears to autonomously generate new structures as a result of its molecular dynamics. Here I briefly review the only documented case of a membrane-bounded intracellular compartment whose very existence strictly depends on its continued functioning. Indeed, the Golgi apparatus of the yeast Saccharomyces cerevisiae appears at steady-state as a continuously renewed set of transitory membrane-bounded structures that self-mature, rather than as a permanent entity. On the basis of this case and of recent advances in related molecular studies, a detailed model is proposed, that encompasses the birth of a yeast Golgi element and bridges its molecular and morphogenetic aspects. This model is extended to briefly outline three evolutionary "inventions", from S. cerevisiae to another yeast, Pichia pastoris, on to plant, and on to animal cells: stacking, stabilizing and aggregating the primary Golgi elements.

Animals↗

The role of nitric oxide in vascular headache.

Shortly after the invention of nitroglycerin (NTG), it was noticed that this substance is capable of inducing a violent headache. Only recently, it became known that this was due to the release of nitric oxide (NO) by NTG. As the molecular mechanism of migraine pain remains to be determined, NTG, being pro-drug for NO, has been used to study the aetiology and pathophysiology of migraine. Such studies with NTG- and also histamine-induced headaches, have led to propose that NO may be the causative molecule in migraine pain. The evidence supporting the role of NO in migraine is discussed, e.g. substances capable of inducing experimental vascular headache do so with NO as the common mediator, while drugs with antimigraine activity inhibit NO and the cascade of intracellular reactions triggered by NO. The importance of NO as a potential initiator of the migraine attack opens new directions for the pharmacological treatment of migraine and other vascular headaches.

Histamine↗

Inpatient treatment of war-related posttraumatic stress disorder: a 20-year perspective.

These papers show that long-stay inpatient PTSD programs provide treatment that is quite different from other programs but that they are neither as effective, from a psychometric perspective, nor as helpful, from the veterans' subjective perspective, as has been expected. VA treatment of PTSD is changing its focus and is being influenced by three distinct societal forces, in addition to data from studies like these: (1) the continuing effort of American society to come to terms with its Vietnam War experience; (2) the crisis of U.S. health care costs; and (3) the emergence of a movement to "re-invent" government and to increase public accountability through performance data.

Combat Disorders↗

Patenting nonassociated polymeric structures (NAPS): implications for structural genomic data release.

The intellectual property laws that govern patent rights should provide a reasonable balance between the competing concerns of open access and exclusivity. Open access can facilitate knowledge dissemination and collaboration in furthering science. On the other hand, exclusivity can ensure interest and financial investment in scientific research and development. In recent days, the appropriate balance between open access and exclusivity has been a focus of public debate, particularly with regard to genomic inventions and their applications. In seeking to reconcile the timing of structural genomic data release with certain efforts to secure intellectual property rights, the International Structural Genomics Organisation joins others confronting this controversy. This paper seeks to inform the discussion with an overview of the U.S. standards for patenting nonassociated polymeric structures (NAPS), which include polynucleotides or polypeptides of unknown biological significance, and their corresponding structural data. In the United States, the present ability to obtain patent rights to these discoveries appears problematic given the requirement of specific, substantial and credible utility, among other things. Without demonstrable utility, NAPS and NAPS-related data likely will not be entitled to patent protection, whether the U.S. Patent & Trademark Office rejects NAPS claims as unpatentable in the first instance, or the U.S. federal courts invalidate NAPS claims in later patent litigation. As such, the improbability of obtaining enforceable patent rights to NAPS might undermine the rationale for delaying structural genomic data release to allow for the filing of patent applications in this regard.

Expressed Sequence Tags↗

[What must the family practitioner know about spinal injuries].

Spine injuries in a general practitioner's environment are mainly related to osteoporosis fractures in the elderly as well as cervical spine injuries in the elderly especially fractures of the odontoid process that need to be excluded if there is any suspicion. For osteoporotic spine fractures the invention of vertebroplasty offers a new treatment option and therefore patients should be transferred to a spine surgeon for further evaluation. The fracture of the odontoid process can end up in a non-union problem if not treated early; therefore this injury must be excluded in patients after sustaining any head contusion and complaints of neck pain afterwards.

Emergencies↗

[Diagnosis and treatment of common pediatric supraventricular tachycardias].

The incidence of paediatric supraventricular tachycardias is approximately 0.1-0.4%. AV node and AV reentrant tachycardias represent the most common supraventricular tachycardias in children. Atrial ectopic tachycardias are the second most common group of pediatric arrhythmias with a predominance in younger children. All these arrhythmias may result in a significant morbidity and necessitate therapy. During the last decade the widespread use of newer antiarrhythmic agents and the invention of radiofrequency catheter ablation have revolutionized the treatment of supraventricular tachycardias in children. A thorough knowledge of these various treatments options is essential to achieve a safe and effective management of supraventricular tachycardias in children. This article focuses on diagnostic and therapeutic aspects of the most frequent supraventricular tachycardias.

Catheter Ablation↗

[Does vaccination cause disease?].

Not many inventions in medical history have influenced our society as much as vaccination. The concept is old and simple. When Edward Jenner published his work on cowpox, "variolation" was quite common. In this procedure, pus of patients with mild smallpox was transferred to healthy individuals. Meanwhile smallpox has been eradicated worldwide. Diseases such as poliomyelitis, diphtheria or tetanus almost disappeared in industrialized countries. The same happened with epiglottitis and meningitis due to Haemophilus influenzae type b (Hib) after vaccination against Hib was introduced in Switzerland in 1990. This success was possible because of routine vaccination. Immunization is a save procedure and adverse events are much lower than complications in the natural course of the prevented diseases. However vaccinations were accused to cause diseases themselves such as asthma, multiple sclerosis, diabetes mellitus, chronic arthritis or autism. Hitherto no large cohort study or case-control-study was able to proof responsibility of vaccines in any of these diseases. Public media are eager to publish early data from surveillance reports or case reports which are descriptive and never a principle of cause and effect. In large controlled trials there was no proof that vaccination causes asthma, hepatitis-B-vaccination causes multiple sclerosis or macrophagic myofasciitis, Hib-vaccination causes diabetes mellitus, rubella-vaccination causes chronic arthritis, measles-mumps-rubella-vaccination causes gait disturbance or thiomersal causes autism. These results are rarely published in newspapers or television. Thus, many caring parents are left with negative ideas about immunization. Looking for the best for their children they withhold vaccination and give way to resurgence of preventable diseases in our communities. This must be prevented. There is more evidence than expected that vaccination is safe and this can and must be told to parents.

Evidence-Based Medicine↗