A diagnostic support system based on pain drawings: binary and k-disease classification of EDS, GBS, FSHD, PROMM, and a control group with Pain2D.

BACKGROUND AND OBJECTIVE: The diagnosis of rare diseases (RDs) is often challenging due to their rarity, variability and the high number of individual RDs, resulting in a delay in diagnosis with adverse effects for patients and healthcare systems. The development of computer assisted diagnostic decision support systems could help to improve these problems by supporting differential diagnosis and by prompting physicians to initiate the right diagnostic tests. Towards this end, we developed, trained and tested a machine learning model implemented as part of the software called Pain2D to classify four rare diseases (EDS, GBS, FSHD and PROMM), as well as a control group of unspecific chronic pain, from pen-and-paper pain drawings filled in by patients. METHODS: Pain drawings (PDs) were collected from patients suffering from one of the four RDs, or from unspecific chronic pain. The latter PDs were used as an outgroup in order to test how Pain2D handles more common pain causes. A total of 262 (59 EDS, 29 GBS, 35 FSHD, 89 PROMM, 50 unspecific chronic pain) PDs were collected and used to generate disease specific pain profiles. PDs were then classified by Pain2D in a leave-one-out-cross-validation approach. RESULTS: Pain2D was able to classify the four rare diseases with an accuracy of 61-77% with its binary classifier. EDS, GBS and FSHD were classified correctly by the Pain2D k-disease classifier with sensitivities between 63 and 86% and specificities between 81 and 89%. For PROMM, the k-disease classifier achieved a sensitivity of 51% and specificity of 90%. CONCLUSIONS: Pain2D is a scalable, open-source tool that could potentially be trained for all diseases presenting with pain.

[Rare diseases in the differential diagnosis of myalgia]. / Seltene Erkrankungen in der Differenzialdiagnose bei Myalgien.

Myalgia describes pain in the skeletal muscles. According to the current German clinical guidelines from 2020 (AWMF register number: 030/051), the initial diagnostic assessment consists of the anamnesis, clinical examination, electrophysiological examination and standard laboratory tests. Additional special examinations, such as molecular genetic investigations, special laboratory tests, medical imaging and muscle biopsy are only needed in certain cases. This article focuses on rare neurological diseases that are classically associated with myalgia. In this context etiologically different diseases are considered, whereby some genetically linked diseases (fascioscapulohumeral dystrophy, FSHD, dystrophia myotonica, McArdle's disease, Pompe's disease, limb girdle muscular dystrophy) are contrasted with diseases with an (auto)immune-related pathogenesis (stiff-person syndrome, Isaacs syndrome). The aspects relevant for the diagnosis are particularly highlighted. The therapeutic aspects of the diseases are not part of this article.

[Rare diseases in the differential diagnosis of myalgia]. / Seltene Erkrankungen in der Differenzialdiagnose bei Myalgien.

Myalgia describes pain in the skeletal muscles. According to the current German clinical guidelines from 2020 (AWMF register number: 030/051), the initial diagnostic assessment consists of the anamnesis, clinical examination, electrophysiological examination and standard laboratory tests. Additional special examinations, such as molecular genetic investigations, special laboratory tests, medical imaging and muscle biopsy are only needed in certain cases. This article focuses on rare neurological diseases that are classically associated with myalgia. In this context etiologically different diseases are considered, whereby some genetically linked diseases (fascioscapulohumeral dystrophy, FSHD, dystrophia myotonica, McArdle's disease, Pompe's disease, limb girdle muscular dystrophy) are contrasted with diseases with an (auto)immune-related pathogenesis (stiff-person syndrome, Isaacs syndrome). The aspects relevant for the diagnosis are particularly highlighted. The therapeutic aspects of the diseases are not part of this article.

[Pain management in rare diseases]. / Schmerztherapie bei seltenen Erkrankungen.

In this article we address the relevance of rare diseases and their peculiarities with respect to pain therapy. Towards this end, four rare diseases (hemophilia, Morbus Fabry, dermatomyositis, and facioscapulohumeral dystrophy (FSHD)) will be presented and fundamental aspects of their pain therapies described. The diseases were chosen to showcase a pain therapy based on the WHO-step-by-step plan (hemophilia), a complex but established pain therapy (M. Fabry), and two less well established, individually adapted pain therapies (dermatomyositis, FSHD).

[Pain management in sickle cell disease]. / Schmerztherapie bei Sichelzellkrankheit.

Sickle cell disease is associated with numerous symptoms and complications. Acute painful crisis is the most characteristic manifestation of the disease. In addition, many patients report chronic pain. As both acute and chronic pain severely diminish quality of life, adequate pain management is crucial. Recommendations for the treatment of acute painful crises are based on the World Health Organization analgesic ladder, which has been developed for cancer-related pain. Chronic pain can be treated with basic long-acting opioids and on-demand short-acting opioids. If patients show signs of neuropathic pain, administration of anticonvulsants, antidepressants or possibly ketamine should be considered.

[Pain management in osteoporosis]. / Schmerztherapie bei Osteoporose.

Osteoporosis is a very common disease all over the world, in which a reduction in bone density can lead to an increased risk of fractures and a diminished physical height. Osteoporosis is also associated with acute and chronic pain, which especially occurs in the back and can significantly reduce the quality of life. To provide sufficient care for affected patients, it is essential to know the particularities of pain management in osteoporosis, such as pharmacological and nonpharmacological treatment options. This article gives a comprehensive review of pain management in osteoporosis and also explains the underlying pathomechanisms, risk factors, and diagnostic procedures.

[Pain management in osteoporosis]. / Schmerztherapie bei Osteoporose.

Osteoporosis is a very common disease all over the world, in which a reduction in bone density can lead to an increased risk of fractures and a diminished physical height. Osteoporosis is also associated with acute and chronic pain, which especially occurs in the back and can significantly reduce the quality of life. To provide sufficient care for affected patients, it is essential to know the particularities of pain management in osteoporosis, such as pharmacological and nonpharmacological treatment options. This article gives a comprehensive review of pain management in osteoporosis and also explains the underlying pathomechanisms, risk factors, and diagnostic procedures.

[Cannabis and cannabinoids-easier access, hype and disappointment : What has been confirmed in therapy?] / Cannabis und Cannabinoide ­ erleichterter Zugang, Hype und Enttäuschung : Was ist gesichert in der Therapie?

BACKGROUND: Cannabis products are being increasingly liberalized all over the world and there is a huge interest in cannabis-based medicine. OBJECTIVES: Presentation of current studies on the efficacy of different cannabis-based medicine for the treatment of various diseases CURRENT DATA: In German pharmaceutical legislation, nabiximols is approved for the treatment of moderate to severe therapy-resistant spasticity in multiple sclerosis and nabilone is approved for the treatment of therapy-resistant chemotherapy-associated nausea and vomiting. In case of therapy failure cannabinoids, as part of an individual therapeutic attempt, may be considered for the treatment of chronic pain (neuropathic pain, cancer pain, non-neuropathic noncancer pain), cachexia in human immunodeficiency virus as well as for Dravet and Lennox-Gastaut syndrome. From the authors' perspective there is not enough evidence for the use in chemotherapy-associated nausea and vomiting and chronic non-neuropathic pain. CONCLUSIONS: Currently, a wide use of cannabinoids does not seem probable in the near future. Further studies involving more patients and evaluating long-term effects are necessary.

[Cannabinoid therapy in practice]. / Cannabinoidtherapie in der Praxis.

BACKGROUND: In recent years, the media and scientists have shown increased interest in cannabis-based drugs. OBJECTIVES: Background information about cannabis-based drugs and their mechanism of action as well as discussion of possible applications as supportive therapy or in palliative medicine, respectively, are presented. MATERIALS AND METHODS: The recent literature was examined and evaluated. RESULTS: In many medical fields, we do not have sufficient evidence for the efficacy of cannabinoids. In German pharmaceutical legislation, the use of nabiximols for the treatment of intermediate to severe, therapy-resistant spasticity in multiple sclerosis is the only approved indication for cannabis-based drugs. Furthermore, in view of the current evidence cannabinoids, combined with established treatments and as part of an individual therapeutic attempt, can be used for neuropathic pain, cancer-associated pain and human immunodeficiency virus (HIV)-related cachexia. CONCLUSIONS: In most cases, today's assessment of cannabinoids relies on studies that are classified as low evidence. Therefore, further studies which involve more participants and evaluate long-term effects are needed.

Protocol for the Electroencephalography Guidance of Anesthesia to Alleviate Geriatric Syndromes (ENGAGES) study: a pragmatic, randomised clinical trial.

INTRODUCTION: Postoperative delirium, arbitrarily defined as occurring within 5 days of surgery, affects up to 50% of patients older than 60 after a major operation. This geriatric syndrome is associated with longer intensive care unit and hospital stay, readmission, persistent cognitive deterioration and mortality. No effective preventive methods have been identified, but preliminary evidence suggests that EEG monitoring during general anaesthesia, by facilitating reduced anaesthetic exposure and EEG suppression, might decrease incident postoperative delirium. This study hypothesises that EEG-guidance of anaesthetic administration prevents postoperative delirium and downstream sequelae, including falls and decreased quality of life. METHODS AND ANALYSIS: This is a 1232 patient, block-randomised, double-blinded, comparative effectiveness trial. Patients older than 60, undergoing volatile agent-based general anaesthesia for major surgery, are eligible. Patients are randomised to 1 of 2 anaesthetic approaches. One group receives general anaesthesia with clinicians blinded to EEG monitoring. The other group receives EEG-guidance of anaesthetic agent administration. The outcomes of postoperative delirium (≤5 days), falls at 1 and 12 months and health-related quality of life at 1 and 12 months will be compared between groups. Postoperative delirium is assessed with the confusion assessment method, falls with ProFaNE consensus questions and quality of life with the Veteran's RAND 12-item Health Survey. The intention-to-treat principle will be followed for all analyses. Differences between groups will be presented with 95% CIs and will be considered statistically significant at a two-sided p<0.05. ETHICS AND DISSEMINATION: Electroencephalography Guidance of Anesthesia to Alleviate Geriatric Syndromes (ENGAGES) is approved by the ethics board at Washington University. Recruitment began in January 2015. Dissemination plans include presentations at scientific conferences, scientific publications, internet-based educational materials and mass media. TRIAL REGISTRATION NUMBER: NCT02241655; Pre-results.

Progress toward the development of a safe and effective agent for treating reentrant cardiac arrhythmias: synthesis and evaluation of ibutilide analogues with enhanced metabolic stability and diminished proarrhythmic potential.

A series of ibutilide analogues with fluorine substituents on the heptyl side chain was prepared and evaluated for class III antiarrhythmic activity, metabolic stability, and proarrhythmic potential. It was found that fluorine substituents stabilized the side chain to metabolic oxidation. Many of the compounds also retained the ability to increase the refractoriness of cardiac tissue at both slow and fast pacing rates. The potential for producing polymorphic ventricular tachycardia in the rabbit model was dependent on the chirality of the benzylic carbon. The S-enantiomers generally had less proarrhythmic activity than the corresponding racemates. One compound from this series (45E, trecetilide fumarate) had excellent antiarrhythmic activity and metabolic stability and was devoid of proarrhythmic activity in the rabbit model. It was chosen for further development.

Treatment of common cutaneous herpes simplex virus infections.

Herpes simplex virus infection is increasingly common in the United States. New antiviral medications have expanded treatment options for the two most common cutaneous manifestations, orolabial and genital herpes. Acyclovir therapy remains an effective and often less expensive option. Famciclovir and valacyclovir offer improved oral bioavailability and convenient oral dosing schedules but are more expensive than acyclovir. Patients who have six or more recurrences of genital herpes per year can be treated with one of the following regimens: acyclovir, 400 mg twice daily; valacyclovir, 1 g daily; or famciclovir, 250 mg twice daily. These regimens are effective in suppressing 70 to 80 percent of symptomatic recurrences. Episodic treatment of recurrent genital herpes is of questionable benefit, but it may be helpful in appropriately selected patients. There is little evidence indicating benefit from treatment of recurrent orolabial herpes, which tends to be mild and infrequent.

Substituent effects on the antibacterial activity of nitrogen-carbon-linked (azolylphenyl)oxazolidinones with expanded activity against the fastidious gram-negative organisms Haemophilus influenzae and Moraxella catarrhalis.

A series of new nitrogen-carbon-linked (azolylphenyl)oxazolidinone antibacterial agents has been prepared in an effort to expand the spectrum of activity of this class of antibiotics to include Gram-negative organisms. Pyrrole, pyrazole, imidazole, triazole, and tetrazole moieties have been used to replace the morpholine ring of linezolid (2). These changes resulted in the preparation of compounds with good activity against the fastidious Gram-negative organisms Haemophilus influenzae and Moraxella catarrhalis. The unsubstituted pyrrolyl analogue 3 and the 1H-1,2,3-triazolyl analogue 6 have MICs against H. influenzae = 4 microgram/mL and M. catarrhalis = 2 microgram/mL. Various substituents were also placed on the azole moieties in order to study their effects on antibacterial activity in vitro and in vivo. Interesting differences in activity were observed for many analogues that cannot be rationalized solely on the basis of sterics and position/number of nitrogen atoms in the azole ring. Differences in activity rely strongly on subtle changes in the electronic character of the overall azole systems. Aldehyde, aldoxime, and cyano azoles generally led to dramatic improvements in activity against both Gram-positive and Gram-negative bacteria relative to unsubstituted counterparts. However, amide, ester, amino, hydroxy, alkoxy, and alkyl substituents resulted in no improvement or a loss in antibacterial activity. The placement of a cyano moiety on the azole often generates analogues with interesting antibacterial activity in vitro and in vivo. In particular, the 3-cyanopyrrole, 4-cyanopyrazole, and 4-cyano-1H-1,2,3-triazole congeners 28, 50, and 90 had S. aureus MICs

Sexually transmitted diseases in women. Gonorrhea and syphilis.

Gonorrhea has been declining since its 1975 peak. Risk factors include age 15 to 19 years, multiple or casual sexual contacts, sexual activity related to drug use, and low socioeconomic status. Infection is usually mild but may be asymptomatic. While no physical signs are specific to the gonococcus, pelvic inflammatory disease is a common complication and cause of infertility and should be treated if it is suspected. Diagnosis of gonorrhea is typically by culture. Newer, more accurate tests are available but are more expensive. For treatment, the CDC recommends only highly effective regimens. Patients need to refer recent sexual partners for treatment and abstain from sexual intercourse until completion of therapy and resolution of symptoms. The incidence of syphilis appears to be declining in the United States, but it should be considered if an ulcer is found in the genital region. If untreated, the disease progresses through primary, secondary, latent, and tertiary phases, and systemic symptoms can mimic other conditions. Positive standard screening tests should be confirmed by fluorescent treponemal antibody absorption testing. Darkfield microscopy is appropriate for diagnosis of an ulcer. The treatment of choice for all phases of syphilis is a single dose of intramuscular benzathine penicillin. Other components of therapy include partner notification and patient follow-up. The spread of HIV is closely linked to STD transmission. Therefore, testing for HIV is strongly encouraged when another STD has been diagnosed.

Sexually transmitted diseases in women. Chlamydia trachomatis and herpes simplex infections.

C trachomatis infection is the most commonly reported STD in the United States, and the majority of women infected are asymptomatic. Screening is recommended for those at high risk, including women who are between 15 and 21 years of age, live in urban areas, are single, or have new or multiple sexual partners. The "gold standard" for diagnosis is chlamydial culture; however, techniques that use DNA and RNA amplification are nearly 100% sensitive and specific and may prove cost-effective. Doxycycline is a recommended first-line therapy, but certain other antibiotics may also be effective. Herpes simplex virus affects more than one third of the world's population. It is diagnosed by observation of shallow, tender ulcerations around the genitalia and by viral isolation using tissue culture. Initial treatment is with antiviral drugs, which may also be necessary episodically or as a suppressive regimen for recurrences. Patient education about prevention of these and other STDs, as well as the impact of such disease on sexual partners, is critical. Physicians should therefore become comfortable questioning and counseling patients about sexual issues and risks for STDs.

The role of vitamin E in the prevention of heart disease.

Data from the 1970s first suggested that vitamin E may be effective in decreasing mortality from cardiovascular disease. As the understanding of the antioxidant effect of this vitamin evolved, researchers began to further study the biologic effects of vitamin E. In vitro studies have shown vitamin E to have several potentially cardioprotective effects, including antagonizing the oxidation of low-density lipoproteins, inhibiting platelet aggregation and adhesion, preventing smooth muscle proliferation, and preserving normal coronary dilation. Several prospective studies, including the US Nurses' Health Study and the US Health Professionals' Follow-up Study, found a 34% and 39% reduction, respectively, in the risk of having a cardiac event for those taking vitamin E supplements. The Iowa Women's Health Study found a 47% reduction in cardiac mortality. Results of randomized, controlled clinical trials have not found consistent benefit, however. The best known of these trials, the Cambridge Heart Antioxidant Study, found a 47% reduction in fatal and nonfatal myocardial infarction in patients with proven coronary atherosclerosis who were given 400 or 800 IU of vitamin E daily. There was, however, no effect on mortality. While emerging and promising data suggest the potential benefit of vitamin E for high-risk cardiac patients, physicians should be alert to the results of randomized, controlled clinical trials already in progress.

The three-dimensional structure of a helix-less variant of intestinal fatty acid-binding protein.

Intestinal fatty acid-binding protein (I-FABP) is a cytosolic 15.1-kDa protein that appears to function in the intracellular transport and metabolic trafficking of fatty acids. It binds a single molecule of long-chain fatty acid in an enclosed cavity surrounded by two five-stranded antiparallel beta-sheets and a helix-turn-helix domain. To investigate the role of the helical domain, we engineered a variant of I-FABP by deleting 17 contiguous residues and inserting a Ser-Gly linker (Kim K et al., 1996, Biochemistry 35:7553-7558). This variant, termed delta17-SG, was remarkably stable, exhibited a high beta-sheet content and was able to bind fatty acids with some features characteristic of the wild-type protein. In the present study, we determined the structure of the delta17-SG/palmitate complex at atomic resolution using triple-resonance 3D NMR methods. Sequence-specific 1H, 13C, and 15N resonance assignments were established at pH 7.2 and 25 degrees C and used to define the consensus 1H/13C chemical shift-derived secondary structure. Subsequently, an iterative protocol was used to identify 2,544 NOE-derived interproton distance restraints and to calculate its tertiary structure using a unique distance geometry/simulated annealing algorithm. In spite of the sizable deletion, the delta17-SG structure exhibits a backbone conformation that is nearly superimposable with the beta-sheet domain of the wild-type protein. The selective deletion of the alpha-helical domain creates a very large opening that connects the interior ligand-binding cavity with exterior solvent. Unlike wild-type I-FABP, fatty acid dissociation from delta17-SG is structurally and kinetically unimpeded, and a protein conformational transition is not required. The delta17-SG variant of I-FABP is the only wild-type or engineered member of the intracellular lipid-binding protein family whose structure lacks alpha-helices. Thus, delta17-SG I-FABP constitutes a unique model system for investigating the role of the helical domain in ligand-protein recognition, protein stability and folding, lipid transfer mechanisms, and cellular function.

FlyBase: a Drosophila database. The FlyBase consortium.

FlyBase is a database of genetic and molecular data concerning Drosophila. FlyBase is maintained as a relational database (in Sybase) and is made available as html documents and flat files. The scope of FlyBase includes: genes, alleles (and phenotypes), aberrations, transposons, pointers to sequence data, clones, stock lists, Drosophila workers and bibliographic references. The Encyclopedia of Drosophila is a joint effort between FlyBase and the Berkeley Drosophila Genome Project which integrates FlyBase data with those from the BDGP.

The European Bioinformatics Institute (EBI) databases.

This paper describes the databases and services of the European Bioinformatics Institute (EBI). In collaboration with DDBJ and GenBank/NCBI, the EBI maintains and distributes the EMBL Nucleotide Sequence Database, Europe's primary nucleotide sequence data resource. The EBI also maintains and distributes the SWISS-PROT Protein Sequence Database, in collaboration with Amos Bairoch of the University of Geneva. Over thirty additional specialist molecular biology databases, as well as software and documentation of interest to molecular biologists, are also available. The EBI network services include database searching, entry retrieval, and sequence similarity searching facilities.