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Kurt Semm and the fight against skepticism: endoscopic hemostasis, laparoscopic appendectomy, and Semm's impact on the "laparoscopic revolution".

In the 1970s, Semm developed thermocoagulation, adapted the Roeder Loop, and further invented extra- and intracoporeal endoscopic knotting to achieve endoscopic hemostasis. His numerous technical inventions, especially the electronic insufflator, allowed more complex operations to be performed laparoscopically. His technique, however, was not quickly adopted by the surgical community. When the first fully laparoscopic appendectomy was carried out by Semm in 1980, a veritable storm broke loose. In the opinion of many prominent surgeons, Semm exaggerated the problem of adhesions, and laparoscopic technique itself was regarded as very dangerous. Misunderstood by medical scientists, Semm displayed an ability to force his ideas through despite skepticism and suspicion. He realized that endoscopic surgery had tremendous potential, and promoted laparoscopic technique not only in his field of gynecology but among general surgeons as well. In 1985, Muhe, of Boblingen, Germany, used Semm's technique to remove the first gallbladder in the world laparoscopically. Three years later when Semm presented a videotape of his laparoscopic appendectomy in Baltimore, he gave impetus to McKernan and Save of Marietta. Georgia, to carry out the first laparoscopic cholecystectomy in the United States.

Appendectomy↗

Status, sale and patenting of human genetic material: an international survey.

Following a decade of debate, the European Directive on the Legal Protection of Biotechnological Inventions was adopted by the European Parliament and the Council of the European Union on July 6, 1998. The Directive constitutes a legal and social policy landmark in biotechnology, taking an explicit position on the contentious issue of the patentability of higher life forms. It fails, however, to provide definitive statements on the legal status of human genetic material or the possibility of personal financial gain in relation to such material. An overview of the international, regional and national positions (as found in laws and official policy statements) on the status, commodification and patentability of human genetic material indicates that, although the Directive represents a consolidation of opinions, many issues remain unresolved.

Commerce↗

Adolescent health and social problems. A method for detection and early management. The Dartmouth Primary Care Cooperative Information Project (COOP).

OBJECTIVE: To develop and test a method for identification and early management of the health and social problems of adolescents, many of which go undetected and untreated. METHODS: Picture-and-word charts for the measurement of health and social problems formed the core of a brief, self-teaching lesson. Other sections of the lesson were designed to help teenagers interpret, invent solutions for, and communicate concerns about these problems. We examined the impact of the lesson on teenagers' understanding of themselves, their feelings, and their actions. Two hundred ninety-one adolescents served as subjects for this research. RESULTS: Less than 5% of the respondents found the chart-based lesson difficult or bothersome in the way it probed personal topics. Ninety percent reported that the lesson would have some positive impact on their actions or feelings. Three to six weeks after completing the lesson, their opinion of its impact remained high, and 36% of the students reported that they had shown it to others outside the school. CONCLUSION: A chart-based lesson is well accepted by adolescents and can be used to overcome obstacles for the detection and early management of adolescents' health and social problems.

Adolescent↗

Autotoxicity and Alzheimer disease.

I mmunological responses are considered to be either humoral, resulting from cloning of B lymphocytes, or cell mediated, resulting from cloning of T lymphocytes. Autoimmune diseases occur when the cloned products attack host tissue. Inflammation is considered a nonspecific response to injury, characterized by exudation of serum into damaged tissue, and identified by the cardinal signs of rubor, calor, dolor, and tumor. However, these classic mechanisms do not fit pathological observations of Alzheimer disease (AD)-affected brain tissue. Although many of the components prominently associated with peripheral immunological and inflammatory states are present in AD lesions, there are no identifiable B lymphocytes or antibodies, and T cells are sparse. Furthermore, the blood-brain barrier is intact, excluding exudation of exogenous serum proteins. Although "neuroinflammation" is the term commonly used to describe the pathological changes, it fails to define adequately the process that is taking place. The reaction is neither a nonspecific response to injury, as classically implied for inflammatory reactions, nor an autoimmune reaction, despite the directed attack against plaques and extracellular tangles. It is most appropriately defined as an innate immunoreaction. The fact that such a reaction can be mounted by brain, an organ frequently described as being immunologically privileged, suggests that a reevaluation is required of the dimensions of the innate immune system, including how it operates at the tissue level. The innate immune system is primitive, while the adaptive immune system, which is directed by peripheral immune organs, is an invention of vertebrates. Even in vertebrates, however, the innate immune system is the first line of defense. Much more needs to be learned about the operation of the innate immune system in health and disease. Arch Neurol. 2000.

Acute-Phase Proteins↗

150 years since Babbage's ophthalmoscope.

The discovery of the ophthalmoscope in 1851 is rightly attributed to Hermann von Helmholtz. However, 4 years earlier, in 1847, Charles Babbage nearly invented the instrument that was to revolutionize ophthalmological examination so dramatically.

England↗

Group support for patients with metastatic cancer. A randomized outcome study.

The effects of weekly supportive group meetings for women with metastatic carcinoma of the breast were systematically evaluated in a one-year, randomized, prospective outcome study. The groups focused on the problems of terminal illness, including improving relationships with family, friends, and physicians and living as fully as possible in the face of death. We hypothesized that this invention would lead to improved mood, coping strategies, and self-esteem among those in the treatment group. Eighty-six patients were tested at four-month intervals. The treatment group had significantly lower mood-disturbance scores on the Profile of Mood States scale, had fewer maladaptive coping responses, and were less phobic than the control group. This study provides objective evidence that a supportive group intervention for patients with metastatic cancer results in psychological benefit. Mechanisms underlying the effectiveness of this group intervention are explored.

Adaptation, Psychological↗

Immunoaugmentative therapy. An unproven cancer treatment.

While it is statistically true that clinical cancer occasionally occurs following development of immune incompetency, the fact remains that the most common forms of cancer (ie, breast, lung, and colon) are not experienced by immunosuppressed individuals. Since there is strong scientific evidence that the unprovoked, normal immune system does not recognize and destroy cancer cells that arise spontaneously, the concept of an immune surveillance system that continuously protects clinically normal humans from cancer remains an appealing but unproven hypothesis. Burton's theory of immune surveillance against cancer appears to be nothing more than a rehash of the hypotheses of many other investigators, embellished with his postulate that four specific anticancer protein factors exist and function in the normal human immune system. The IAT he invented as a treatment for cancer is based on his presumption that he has proven the existence of these factors. But neither his declarations nor those of his proponents offer any objective evidence to support such a conclusion. They have not proven that the IAT components exist or can be extracted from blood without the loss of biologic activity. The tests that are described cannot quantitatively measure the specific IAT proteins and there is no evidence that the IAT fractions possess any immunologic activity. Thus, Burton's tumor antibody has never been shown to be a tumor specific immunoglobulin that can interact with tumor antigens and activate complement. His tumor complement fraction has no complement activity (written communication, G.J. Gray, PhD, June 21, 1984), his blocking protein has not been shown to block anything, his deblocking protein has not been shown to deblock anything, and his human tumor cells have never been shown to lyse following the interaction of tumor antibody and tumor complement. Finally, since there is no information on the quality control procedures being used in the manufacture of the IAT materials, there is the possibility that they may be unsterile and, therefore, hazardous for use in humans. Patients who are considering IAT as treatment for cancer should be made aware of these facts when attempting to reach an informed decision regarding its safety and potential efficacy. While this paper was being reviewed for publication, an IAT proponent newsletter called The Cancer Chronicles published the news that Lawrence Burton died of a heart attack in March 1993. The editor of this newsletter, Ralph Moss, PhD, stated that Burton's clinic would remain open under the direction of its medical director, R. John Clement, MD, and would continue to offer IAT to cancer patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Complementary Therapies↗

What makes Hephaestus lame?

Hephaestus (or Hephaistos) is an Olympian Greek god, the divine smith, famed for inventions, who taught men glorious crafts. The fixed epithet for Hephaestus, used from the eighth century B.C. by Homer, Hesiod, and other ancient authors until the fifth century A.D., is "Amphiguéeis," i.e., with both feet crooked. He is also called "Kullopodíou," i.e., clubfooted. His body and his gait were described by Homer: "He spake, and from the anvil rose, a huge, panting bulk, halting the while, but beneath him his slender legs moved nimbly ... and with a sponge wiped his face and his two hands withal, and his mighty neck and shaggy breast, ... and grasped a stout staff, and went forth halting; but there moved swiftly to support their lord handmaidens wrought of gold in the semblance of living maids." His anomaly was congenital, as we learn from Hephaestus himself ("I was born misshapen") and from his mother Hera ("But my son Hephaestus whom I bare was weakly among all the blessed gods and shrivelled of foot."). Vase paintings of the sixth century B.C. depict Hephaestus' lameness, but his lameness is not emphasized in the fifth century and thereafter. It is most likely that bilateral congenital clubfeet made Hephaestus lame. Two sons of Hephaestus, Palaemonius and Periphetes, were also reported as having deformed feet.

Clubfoot↗

High prevalence of HTLV-I infection among the family members of a patient with adult T-cell leukemia/lymphoma from northeastern Japan.

Human T-cell lymphotropic virus type I (HTLV-I) is transmitted through infected lymphocytes mostly by breast feeding. In the present study, high prevalence of HTLV-I infection was disclosed in the family members of a patient with adult T-cell leukemia/lymphoma (ATL), all of whom were residents of Iwate, northeastern Japan. Long-term follow-up is necessary for people with HTLV-I infection because of the risk of developing ATL after a certain period of latency. New inventive treatments for the acute and lymphomatous types of ATL are needed.

Female↗

The role of biostatistics in the prevention, detection and treatment of fraud in clinical trials.

Recent cases of fraud in clinical trials have attracted considerable media attention, but relatively little reaction from the biostatistical community. In this paper we argue that biostatisticians should be involved in preventing fraud (as well as unintentional errors), detecting it, and quantifying its impact on the outcome of clinical trials. We use the term 'fraud' specifically to refer to data fabrication (making up data values) and falsification (changing data values). Reported cases of such fraud involve cheating on inclusion criteria so that ineligible patients can enter the trial, and fabricating data so that no requested data are missing. Such types of fraud are partially preventable through a simplification of the eligibility criteria and through a reduction in the amount of data requested. These two measures are feasible and desirable in a surprisingly large number of clinical trials, and neither of them in any way jeopardizes the validity of the trial results. With regards to detection of fraud, a brute force approach has traditionally been used, whereby the participating centres undergo extensive monitoring involving up to 100 per cent verification of their case records. The cost-effectiveness of this approach seems highly debatable, since one could implement quality control through random sampling schemes, as is done in fields other than clinical medicine. Moreover, there are statistical techniques available (but insufficiently used) to detect 'strange' patterns in the data including, but no limited to, techniques for studying outliers, inliers, overdispersion, underdispersion and correlations or lack thereof. These techniques all rest upon the premise that it is quite difficult to invent plausible data, particularly highly dimensional multivariate data. The multicentric nature of clinical trials also offers an opportunity to check the plausibility of the data submitted by one centre by comparing them with the data from all other centres. Finally, with fraud detected, it is essential to quantify its likely impact upon the outcome of the clinical trial. Many instances of fraud in clinical trials, although morally reprehensible, have a negligible impact on the trial's scientific conclusions.

Biometry↗

Intramural drug delivery by direct injection within the arterial wall: first clinical experience with a novel intracoronary delivery-infiltrator system.

Local drug delivery at the lesion site in patients with coronary artery disease is being intensively studied to prevent restenosis after percutaneous coronary intervention. However, the effective penetration of the delivered agents into the vessel wall and delivery time remain considerable problems for all currently existing devices. A unique, new catheter has been invented, the infiltrator Angioplasty Balloon Catheter (IABC), which has the capability to allow intramural drug delivery by direct injection within the arterial wall. We describe the first clinical experience with this catheter. IABC is an angioplasty catheter with 3 lumens: one for inflating the balloon, one central for the guidewire, and a third for drug delivery. On the surface of the balloon there are 3 longitudinal strips of 6 injection needles, which on inflation stand 0.01" high, and are connected to the drug-delivery lumen. With inflation of the balloon, the needles penetrate the lesion, allowing drug delivery into the media of the vessel wall. We used the IABC in 17 patients (age = 58 +/- 9 years) undergoing coronary angioplasty. All patients were symptomatic, with significant lesions (13 LAD, 3 LCX, 1 RCA) and documented ischemia. Following initial dilatation with a conventional angioplasty balloon (stenosis from 72 +/- 8% to 26 +/- 14%, P < 0.001), the IABC was used to infiltrate the lesion with 0.4 ml (6,000 IU) of low-molecular-weight heparin (Fraxiparine). For the delivery, the IABC was inflated to 1-2 atm for 30-45 s, and the heparin was injected by hand in 5 s. Lesion residual stenosis and morphology remained unchanged after IABC use (26 +/- 14% to 22 +/- 11%, P = NS). In 10 patients, stent placement followed the IABC use. The decision to proceed with stent placement was made after the initial dilatation with the conventional balloon, and it was not influenced by the IABC use. Stent placement greatly improved the final result (for the whole patient group: 22 +/- 11% to 5 +/- 18%, for the stented patients: 22 +/- 13% to -7 +/- 10%, P < 0.001 for both). Hospital course was uneventful, with no electrocardiogram changes and normal cardiac enzymes for all patients. We have shown that the use of a unique new catheter (IABC) for intramural drug delivery in human patients undergoing coronary angioplasty is feasible and safe. This catheter is the first of a new generation of catheters and represents a significant step in local drug delivery. It is very promising as a vehicle to modify plaque behavior and potentially influence restenosis after angioplasty.

Adult↗

Sequence and context effects on origin function in mammalian cells.

Jacob and Brenner proposed a model for control of DNA replication in which a trans-acting initiator protein binds to a cis-acting replicator to effect initiation of nascent DNA chains at a fixed locus. Although replicators have been identified in prokaryotic and simple eukaryotic genomes, it has been much more difficult to demonstrate their presence in mammalian chromosomes. Owing to the lack of genetic approaches for identifying mammalian replicators, investigators have directed attention to localizing nascent strand start sites, which should lie close to replicators. Toward this end, a variety of clever techniques have been invented for analyzing replication intermediates, but only rarely have more than one of these techniques been applied to a single locus. However, virtually all have been used to analyze the dihydrofolate reductase locus in CHO cells. The picture that has developed in this locus is that initiation can occur at any of a large number of sites scattered throughout a broad zone, but somewhat more frequently near two sites that may correspond to true genetic replicators. Furthermore, it appears that local transcriptional activity, as well as appropriate torsional stress (as imparted by local attachment to the nuclear matrix), may have profound effects on origin activity.

Animals↗

The hybridoma revolution: an offshoot of basic research.

In this narrative, I describe how my interest in the nature and origin of antibody diversity led me to tackle the problem by using somatic cell genetic techniques. The first hybridoma (an immortal antibody-secreting cell line derived by fusion of a short-lived lymphocyte and a myeloma cell line) was an offshoot of this approach. Although not intended for such purposes, it soon became obvious that this invention had widespread potential in basic research and industry. Indeed, the technique opened new inroads into the study of complex biological substances and became the method of choice to define new differentiation markers. Hybridomas also allowed us to dissect the immune response to a simple antigen and to demonstrate the critical role of somatic mutations in the generation of high affinity antibodies. Now, monoclonal antibodies can be derived and manipulated in vitro, leading to important new developments in therapeutic applications. BioEssays 1999;21:966-973.

Animals↗

Brave little yeast, please guide us to thebes: sphingolipid function in S. cerevisiae.

Sphingolipids typically cover the exoplasmic leaflet of the plasma membrane of eukaryotic cells. They differ from the more abundant glycerophospholipids in that they contain ceramide instead of diacylglycerol as a hydrophobic anchor. Why did nature choose to invent this complex class of lipids, and why do eukaryotic cells follow elaborate remodelling pathways in order to generate dozens to hundreds of different molecular species of sphingolipid, depending on cell type? Yeast may, once again, serve as a model to dissect sphingolipid function at various levels. Almost the complete pathway for sphingolipid synthesis in yeast has been uncovered during the past two decades. More recently, key enzymes in sphingolipid degradation and signalling have been identified. Together with a wealth of genetic data obtained from the characterization of various suppressor mutants, this information now allows for an unprecedented analysis of sphingolipid function in this organism. This overview summarizes recent data on sphingolipid function in cell signalling, their role in the heat-stress response and Ca(2+) homeostasis, and addresses their function in transport of glycosylphosphatidylinositol-anchored proteins.

Calcium↗

An integrated head-holder/coil for intraoperative MRI in open neurosurgery.

With the invention of "open" magnetic resonance imaging (MRI) systems, access to the patient is possible during the imaging procedure. An important application of these systems is intraoperative MRI to control the extent of resection during tumor surgery. Up to now flexible surface coils wrapped around, or placed at each side of the head, were used for imaging. These flexible coils have several disadvantages such as unreliability, interindividual problems, difficult handling, poor hygienic properties, and often unsatisfactory or inhomogeneous image quality. To solve most of these problems, an MR-compatible head-holder in combination with an integrated surface coil for use in a 0.2 T C-shaped magnet was developed. Forty-eight patients with known cranial tumors underwent MRI intraoperatively. In 32 patients (67%), residual tumor was found, and additional surgical resection was performed. The integrated head-holder/coil is a safe and practical tool for intraoperative MRI, providing efficient and reliable resection control during neurosurgical procedures.

Brain↗

Microplate array diagonal gel electrophoresis for mutation research in DNA banks.

Molecular genetic epidemiology, association and linkage studies in populations, human or other species, is now yielding powerful new insights into disease and susceptibility genes. Inter alia, the subject requires laboratory analytical methodologies focused on achieving high throughput. Here we review one suite of methodology suitable for such laboratories. Microplate array diagonal gel electrophoresis (MADGE) was invented for molecular genetic epidemiological studies. It combines direct compatibility with microplates, convenient polyacrylamide gel electrophoresis and economy of time and reagents, at minimal capital cost, and enables one user to run up to several thousand gel lanes per day for direct assay of single-base variations. Melt-MADGE combines temporal thermal ramp apparatus to achieve similar throughput for de novo mutation scanning.

Animals↗

Development of high-throughput tools to unravel the complexity of gene expression patterns in the mammalian brain.

Genomes of animals contain between 15000 (e.g. Drosophila) and 50000 (human, mouse) genes, many of which encode proteins involved in regulatory processes. The availability of sequence data for many of these genes opens up opportunities to study complex genetic and protein interactions that underlie biological regulation. Many examples demonstrate that an understanding of regulatory networks consisting of multiple components is significantly advanced by a detailed knowledge of the spatiotemporal expression pattern of each of the components. Gene expression patterns can readily be determined by RNA in situ hybridization. The unique challenge emerging from the knowledge of the sequence of entire genomes is that assignment of biological functions to genes needs to be carried out on an appropriately large scale. In terms of gene expression analysis by RNA in situ hybridization, efficient technologies need to be developed that permit determination and representation of expression patterns of thousands of genes within an acceptable time-scale. We set out to determine the spatial expression pattern of several thousand genes encoding putative regulatory proteins. To achieve this goal we have developed high-throughput technologies that allow the determination and visualization of gene expression patterns by RNA in situ hybridization on tissue sections at cellular resolution. In particular, we have invented instrumentation for robotic in situ hybridization capable of carrying out in a fully automated fashion, all steps required for detecting sites of gene expression in tissue sections. In addition, we have put together hardware and software for automated microscopic scanning of gene expression data that are produced by RNA in situ hybridization. The potential and limitations of these techniques and our efforts to build a Web-based database of gene expression patterns are discussed.

Animals↗

Coherent membrane supports for parallel microsynthesis and screening of bioactive peptides.

Since its invention the SPOT-synthesis methodology has become one of the most efficient strategies for the miniaturized assembly of large numbers of peptides. The combination of a facile synthetic method with high throughput solid- and solution-phase screening assays qualifies the SPOT-technique as a valuable tool in biomedical research. Recent developments such as the introduction of novel polymeric surfaces, new linker and cleavage strategies as well as automated robot systems extended the scope of practical chemical reactions that can be accommodated as well as the numbers of compounds obtainable by this technique. Thus, highly complex spatially addressed compound arrays have become accessible. Together with the introduction of novel screening assays, the method is excellently suited to elucidate recognition events on the molecular level.

Adsorption↗