BACKGROUND: Survey studies suggest that patients with various dermatologic conditions experience concomitant psychologic distress. OBJECTIVE: The purpose of this study was to determine which types of psychologic distress may be correlated with dystrophic disease of the nail in nonpsychiatric patients. METHODS: Fifty-seven adult subjects presenting for treatment of nail dystrophies completed a survey instrument, which included 5 psychometric measures. RESULTS: On average, patients rated the severity of their nail dystrophy and functional deficit higher (7.40/10 and 6.00, respectively) than investigators (6.15 and 3.75, respectively). Compared with age- and sex-matched nonpsychiatric patients, subjects in the study were moderately more anxious and minimally to mildly more depressed. Subjects had moderately depressed total self-concept, but their body image was approximately normal. Overall, subjects exhibited markedly more severe psychologic symptoms (84th percentile) than the normal sample, with the scores on the psychoticism, obsessive-compulsive, and paranoid ideation subscales being the most elevated. CONCLUSION: The subjects with nail dystrophy had markedly exacerbated psychologic symptoms compared with age- and sex-matched nonpsychiatric patients.

As we enter the third millennium, we witness the rapid continuation of the unprecedented explosion of scientific information. Today, we are fortunate to have access to Medline and to electronic journals covering the mammoth fields of biological sciences. It presumably assures us that we can no longer miss important relevant recent publications crucial to the continuation of our original line of research. Unfortunately, we witness today a dangerous trend that despite having access to Index Medicus and additional abstracting systems covering the literature prior to 1960, younger investigators tend to refrain from citing "older" publications, assuming that they are already passe. Obviously, it necessitates spending time in libraries. But who, in these "modern" computerized days, has time to wait? Over the last few years, I tried to find out what was behind this behavior. I took the liberty of writing to authors who published papers in my own field of research and who failed to cite crucial key publications from the pre-Medline era, without which I believe they cannot even start to understand the evolution of their own current research. The following are only several of the responses I received: "I do not read the Journals which you claimed had included papers relevant for my research paper." "I was unaware of the publications you proposed, but will be happy to read them if you can send them to me. I might consider citing them in my future review on the subject." "Restrictions over the numbers of reference permissible prevented me from citing the proposed articles." "The library at my university gives me a hard time trying to retrieve older literature." "The focus of my article was to narrow down only on the most relevant current information available on the subject." "Reviews covering the topic of my current investigations had recently been published." (However, no such review was cited by the author.) "I do not have the time to comment on your thoughts in a scholarly fashion. However, bear in mind that the papers you had listed have not gone completely unnoticed." (Really?) "You will recognize that it is not easy to find papers from several years unless they are cited by others, as there is literally too much information about" "As a newcomer to this field of research, I neglected to read relatively old articles and I restricted myself to critically report the most common views on the subject. Besides, I was unable to receive the older articles you mentioned, because they are unavailable in the library of our relatively new university." "I had, as you guessed, not seen your work. I am unfamiliar with most of the journals in which you publish—-and also I am not an immunologist." The following is also a reminder how certain line of research might become extinct. A review on the role of proteinases in tissue damage concluded that proteinases might also synergize with oxidants and with additional pro-inflammatory agents. Yet, publications since 1960 which had described this phenomenon had not been included either in this particular paper or in any of the papers on the subject. A main line of research had proposed that cationic proteins from leukocytes might kill bacteria by altering the permeability of their membranes. Yet, none of a very large series of investigations by others since the early 1970s, which had proposed an alternative possible mechanism suggesting that cationic proteins might kill microorganisms also by their ability to induce bacteriolysis, are ever cited anywhere. Because of a change in nomenclature, pioneering investigations from 1951-1957, which had described the properties and mechanisms of action of bacterial cell-sensitizing agents (HF), had literally been eliminated because today this factor is called lipoteichoic acid (LTA). One simple sentence, and including proper citations stressing that LTA was previously called HF, might have sufficed to prevent unnecessary repetitions of the same experiments. The following proposals might be adopted by editorial boards of journals to assure and also fight against the "disregard syndrome." (i) Every paper should include an introductory historical coverage of the "pioneering" investigations on which the current research is based. (ii) Emeriti professors, who might have read "older investigations" in a particular field of research, be nominated as referees. This might also stimulate emeriti professors to be reinvolved in the activities of the scientific community. (iii) A "Letters to the Editor" section in every Journal be established where authors can alert their readers to the existence of "old" literature on the subject. (iv) To combat the unacceptable attitude where publications which do not "fit" current thoughts and ideas are simply concealed from the modern reader. This is unethical and also self-defeating. Only a strong stand by Editorial Boards against the "disregard syndrome" might help to advance honest science.

We are witnessing the continuation of an accelerated, unprecedented explosion of scientific information that might make the life of a serious investigator unbearably complicated. Unlike our pioneering investigators, however, we are fortunate to have access to modern information-retrieving pools such as Medline, Biological Abstracts, and more recently selected electronic journals. These allow us, at the press of a key, to choose desired scientific citations. A search for articles in the medical

INTRODUCTION Why Have Clinical Trials of Sepsis Been Unsuccessful? It is disconcerting that entering the third millennium, severe microbial infections and their sequelae e.g., sep- sis, septic shock, ARDS, “flesh-eating syndromes,” still claim the lives of numerous patients annually. Further- more, it is of great interest that while immunomodu- lating agents have proved beneficial in the treatment of inflammatory conditions such as rheumatoid arthri- tis, a large series of clinical trials which have been con- ducted in the last decade and which have mainly tested only single immunomodulating agents as therapies for septic shock, have been mostly unsuccessful. In 1996, Verhoef et al. (1) have stated that reviewing the liter- ature on sepsis therapies “the area of immunomodula- tion has now become an area of more realism and the results of early trials have forced investigators to go back to the drawing board to re-investigate the whole con- cept of immunotherapy and immunoprophylaxis. In a more recent Point of View in Critical Care Medicine, entitled “Sepsis research: We must change course,” Dr. Nasraway has hit the nail on its head (2). Reviewing the disappointing results of no less than 29 prospec- tive controlled studies of human sepsis performed in the last decade, he has questioned whether “it is rational to attempt to alter the inflammatory responses by admin- istering a single immunomodulating agent while simul- taneously failing to control for the many interventions that also alter cytokine expression?” He has also raised serious doubts about the morality of any future trials of sepsis if conducted in the present manner. Baue (3), Opal and Yu (4), Cross et al. (5), Teplick and Ruben (6) and Abraham (7), have recently assessed the state of the art in sepsis research prevention and treatment, the reasons why the trials of sepsis have invariably failed to prolong the lives of septic patients, the hazards involved in the future use of multidrug strategies in sepsis, and the con- tributions of animal models to the development effec- tive therapeutic regimens in humans. Reading through the extensive literature on sepsis research and treatment, it was surprising to realize that no less than 35 different anti-inflammatory agents and strategies have been rec- ommended, usually singly, to cope with post-infectious sequelae (in 1–13). It is however important to stress that, at the bedside, anti-inflammatory agents are too often administered to patients when the deleterious pathophys- iological cascades leading to septic shock and organ fail- ure have already been irreversibly initiated. Therefore, one cannot avoid assuming that the recommendations to test only one antagonist, at time, to suppress the patho- physiological cascades in sepsis and septic shock, might have been unrealistic to begin with and also erroneous. Presumably, these have been based on the concept that there might exist a single “omnipotent” pro-inflamma- tory agonist generated following microbial invasions of the blood stream, which is efficiently neutralized, on time, might inhibit the multiple pathophysiological cas- cades responsible for the sepsis syndrome. Also, the use of multidrug strategies (4, 5, 8, 13) has been ham- pered by reports warning against the hazards of combi- nation therapies in sepsis (4, 5, 16). Is it possible that, today, sepsis research has reached a dead end because of “flawed concept or faulty implementation?” (5). Results from animal models have clearly indicated that the inhibition of septic shock induced either by endotoxin (LPS), lipoteichoic acid (LTA), peptidogly- can (PPG) or by viable microbial cells, has been mostly successful only if the anti-inflammatory agent has been administered prior to microbial challenge. This strongly suggests that the main obstacle facing clinicians at the bedside is that once sepsis symptoms have appeared, it might already be too late to effectively prevent the pathophysiological cascades leading to tissue damage and organ failure. Therefore, strategies to prevent sep- tic shock and of additional post-infectious sequelae in humans should inonvolve distinct preventive measures especially in defined groups of high-risk patients (3–13).

A large series of publications1-9 has proposed that cationic peptides from leukocytes kill bacteria primarily by causing a depolarization of their membranes leading to enhanced permeability. One group of cationic peptides from human neutrophils was even coined bactericidal/permeability-increasing proteins.3Surprisingly, however, none of a large series of other publications that had proposed a concept that cationic agents from neutrophils might be bactericidal also by virtue of their capacity to activate the bacterial autolytic wall enzymes (muramidases), leading to bacteriolysis and cell death,10-22 has ever been cited in any of the publications by the leading authors in this field of research.1-9 For the information of your readers, there exist a series of 16 publications since 1974 entitled “Effect of leukocyte hydrolases on bacteria” and several additional publications on the same subject under different titles, many of them published in journals covered by Medline; the references contain a selected list of these.10-22 24 These had proposed that many of the highly cationic agents either present in plasma or generated by activated phagocytes (eg, lysozymes, PLA2, elastase, cathepsin G, myeloperoxidase, bactericidal/permeability-increasing proteins, defensins, etc) might kill bacteria not simply by acting on the membranes to cause depolarization and enhanced permeability1-7 but also by an indirect mechanism. This involves a deregulation, by the cationic agents, of the anionic and amphiphilic regulators of the autolytic wall enzymes(muramidases) (lipoteichoic acid in Gram-positives and Forssman antigens in Gram-negatives)16 17 23-25 resulting in hydrolysis of the peptidoglycan, in bacteriolysis, and in cell death. It is of great clinical importance that the bacteriolysis-inducing activity of cationic agents mimics that of beta-lactam antibiotics.26 Furthermore, the observations that a variety of highly negatively charged, sulfated anionic agents can act as potent inhibitors of the cationic agent– and beta-lactam–induced bacteriolysis11 12 14 16 17 27-30further stress the importance of the autolytic systems in bacterial killing. This phenomenon might also be of great clinical significance especially in selecting measures to control postinfectious sequelae that undoubtedly are triggered by the release of bacterial components, especially following bacteriolysis. Regrettably, attempts to bring these issues to the awareness of the leading investigators in the field of cationic proteins1-9and of clinicians involved is the clinical aspects of sepsis control have not been successful. If the concept that cationic agents might be bactericidal also because of their bacteriolysis-inducing properties is reasonable and scientifically sound, it is expected that publications describing this phenomenon should be cited by authors studying the bactericidal effects of cationic agents. If on the other hand one deems that this concept is for some reason erroneous, nonsensical, and scientifically unacceptable, such publications should definitely be cited but properly discussed, challenged, and even also ridiculed. But it is totally unacceptable and unreasonable that such publications be simply ignored! Unfortunately, the avoidance of relevant citations and the disregard for concepts that might perhaps not “fit” current dogma and beliefs have reached epidemic levels. This is how pioneering publications proposing “novel approaches and ideas”16 17 29 30 to explain additional mechanisms of microbial killing might be lost forever. More importantly, these concepts will probably never reach the attention of clinicians interested in the pathogenesis of inflammation, infection, postinfectious sequelae, and the mechanisms of host defense.29-31 But what is even more disturbing, concerning, and unacceptable is that the expert referees selected by the editorial boards of journals and who should have been knowledgeable of the relevant literature failed to alert the authors to the existence of key publications on bacteriolysis so relevant to the subject of the papers and of the reviews they had been assigned to judge. Am I wrong to assume that the task of a journal's editorial board is to ensure that all viewpoints and ideas, both “conventional” and nonconventional, be equally represented? Excuses either that limitations to the number of references permissible were the reason for not citing basic and pioneering publications or that the authors had been “instructed” to discuss only a narrow field of research and to disregard others fields with direct relevance are unacceptable. A failure to give credit to relevant papers is also unacademic, self-defeating, unethical, and therefore unacceptable by all standards. Furthermore, are papers older than 15 years, or so, already passéand, therefore, unworthy of being acknowledged?