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Common to the biosynthesis of all known tetrapyrroles is the condensation of two molecules of 5-aminolevulinic acid to the pyrrole porphobilinogen catalyzed by the enzyme porphobilinogen synthase (PBGS). Two major classes of PBGS are known. Zn2+-dependent PBGSs are found in mammals, yeast and some bacteria including Escherichia coli, while Mg2+-dependent PBGSs are present mainly in plants and other bacteria. The crystal structure of the Mg2+-dependent PBGS from the human pathogen Pseudomonas aeruginosa in complex with the competitive inhibitor levulinic acid (LA) solved at 1.67 A resolution shows a homooctameric enzyme that consists of four asymmetric dimers. The monomers in each dimer differ from each other by having a “closed” and an “open” active site pocket. In the closed subunit, the active site is completely shielded from solvent by a well-defined lid that is partially disordered in the open subunit. A single molecule of LA binds to a mainly hydrophobic pocket in each monomer where it is covalently attached via a Schiff base to an active site lysine residue. Whereas no metal ions are found in the active site of both monomers, a single well-defined and highly hydrated Mg2+is present only in the closed form about 14 A away from the Schiff base forming nitrogen atom of the active site lysine. We conclude that the observed differences in the active sites of both monomers might be induced by Mg2+-binding to this remote site and propose a structure-based mechanism for this allosteric Mg2+in rate enhancement.

To assess the frequency of shedding of cytomegalovirus (CMV) in saliva, the distribution of CMV glycoprotein B (gB) genotypes, and the occurrence of CMV diseases, we screened 98 human immunodeficiency virus (HIV)-seropositive patients without CMV disease. CMV was detected by culture more frequently in saliva (45 [46%] of 98 patients) than in blood (7 [7.5%] of 93) and was associated with CD4 cell counts

Background Inherited epidermolysis bullosa (EB) comprises a group of rare disorders that have multi-system effects and patients present with a number of both acute and chronic pain care needs. Effects on quality of life are substantial. Pain and itching are burdensome daily problems. Experience with, and knowledge of, the best pain and itch care for these patients is minimal. Evidence-based best care practice guidelines are needed to establish a base of knowledge and practice for practitioners of many disciplines to improve the quality of life for both adult and pediatric patients with EB. Methods The process was begun at the request of Dystrophic Epidermolysis Bullosa Research Association International (DEBRA International), an organization dedicated to improvement of care, research and dissemination of knowledge for EB patients worldwide. An international panel of experts in pain and palliative care who have extensive experience caring for patients with EB was assembled. Literature was reviewed and systematically evaluated. For areas of care without direct evidence, clinically relevant literature was assessed, and rounds of consensus building were conducted. The process involved a face-to-face consensus meeting that involved a family representative and methodologist, as well as the panel of clinical experts. During development, EB family input was obtained and the document was reviewed by a wide variety of experts representing several disciplines related to the care of patients with EB. Results The first evidence-based care guidelines for the care of pain in EB were produced. The guidelines are clinically relevant for care of patients of all subtypes and ages, and apply to practitioners of all disciplines involved in the care of patients with EB. When the evidence suggests that the diagnosis or treatment of painful conditions differs between adults and children, it will be so noted. Conclusions Evidence-based care guidelines are a means of standardizing optimal care for EB patients, whose disease is often times horrific in its effects on quality of life, and whose care is resource-intensive and difficult. The guideline development process also highlighted areas for research in order to improve further the evidence base for future care. Electronic supplementary material The online version of this article (doi:10.1186/s12916-014-0178-2) contains supplementary material, which is available to authorized users.

• Central nervous system cysticercosis, caused by infection with the larva of the pork tapeworm, is common throughout the world. Infection occurs after ingestion of fecal contaminants containing the ova of Taenia solium . The clinical manifestations depend on the number, age, and location of the larval cysts disrupting neural tissues. Several disease patterns are apparent: (1) basilar cysticercosis resulting in chronic meningitis or progressive hydrocephalus, (2) parenchymal cysts with focal symptoms, (3) diffuse parenchymal cysts with intracranial hypertension, (4) ventricular localization with episodic acute hydrocephalus, and (5) spinal cord cysticercosis mimicking mass lesions. Mixtures of these basic patterns may occur, and asymptomatic infections are common. In the United States, meningeal cysticercosis is often mistaken for tuberculous or fungal meningitis. A diagnosis of CNS cysticercosis should be considered in any patient with these syndromes who has resided in an area of high prevalence of T solium . ( Arch Intern Med 140:1309-1313, 1980)

Respiratory syncytial virus disease was documented in 11 immunocompromised adults, aged 21 to 50. Underlying conditions included bone marrow transplant (6 patients), renal transplant (3 patients), renal and pancreas transplants (1 patient), and T-cell lymphoma (1 patient). Diagnosis of infection was based on specimens from bronchoalveolar lavage, sputum, throat, sinus aspirate, and lung biopsy. The virus was detected simultaneously by antibody in either an immunofluorescence or enzyme-linked immunosorbent assay in 3 of 4 patients whose culture results were positive for respiratory syncytial virus. The virus was an unexpected finding, despite widespread infection in the community. Clinical symptoms included low-grade fever, nonproductive cough, rhinorrhea or nasal congestion, and radiographic evidence of interstitial infiltrates and sinusitis. Aerosolized ribavirin therapy was used in the 6 recipients of bone marrow transplants, 3 of whom required assisted ventilation but died. Death caused by virus infection was documented in 4 of 11 patients. Respiratory syncytial virus disease must be considered in the differential diagnosis of fever and pulmonary infiltrates in immunocompromised adults.

ENLARGED lymph nodes occur in many conditions, either as a reaction to a local inflammatory process or associated with a systemic disease whose central focus is not in the lymph system. In some patients enlarged nodes are the initial or the most prominent manifestation of whatever disease is present and are the starting point for investigation. The algorithm presented here develops guidelines for evaluation of lymph node enlargement of the primary or secondary type. Scope and Limitations This algorithm is designed to be applied only to adolescents and adults, because a different array of diseases underlies enlarged lymph nodes in infants and children. It does not include therapy for any of the conditions detected. Following the model of protocols or clinical algorithms for primary care, it does not include diagnostic evaluation of rare diseases. On the other hand, nonspecific findings are included to alert the reader to consider more remote

Thirty-one immunocompromised patients with severe cytomegalovirus (CMV) disease were treated with intravenous ganciclovir. Twenty-one patients had received transplants—15 bone marrow recipients, five renal allograft recipients, and one liver transplant recipient—while the other ten were immunocompromised due to acquired immunodeficiency syndrome (six), hematologic malignancies (three), and systemic lupus erythematosus (one). They presented with one or more of the following syndromes: CMV pneumonitis (19), CMV of the gastrointestinal tract (six), CMV retinitis (seven), and CMV hepatitis (three). Seventeen (55%) of 31 patients demonstrated clinical improvement during ganciclovir therapy, with the best response seen in the transplant recipients. Viremia ceased in 14 (93.3%) of 15 patients after a mean of 4.7 days of therapy; viruria ceased in eight (53.3%) of 15 patients after a mean of 11 days of therapy. Ganciclovir plasma concentrations at a dosage of 2.5 mg/kg/three times a day were as follows: mean peak, 16.04 μmol/L; mean trough, 2.38 μmol/L. Neutropenia occurred in 11 (35%) of 31 patients and in nine (60%) of 15 bone marrow transplant recipients. We conclude that ganciclovir exerted an antiviral effect against CMV and may play a role in the treatment of CMV disease in patients with depressed immunity, especially bone marrow and organ transplant recipients. ( JAMA 1987;257:3082-3087

The herpesviruses that infect humans characteristically establish a latent infection that may be reactivated later. The consequences of reactivation range from asymptomatic shedding to severe disseminated infection. Varicella-zoster and herpes simplex viruses are both highly neurotropic, establishing nonreplicating infections in sensory ganglia. Latent herpes simplex virus is known to reside in neurons, and the virus-cell interactions involved have been defined to an extent. Cytomegalovirus and Epstein-Barr virus interact with peripheral blood leukocytes. Latent cytomegalovirus infection of human leukocytes has not been proved, although studies in a murine model have implicated B lymphocytes as a repository of latent virus. Epstein-Barr virus is known to persist in a non-replicating state as extrachromosomal DNA in B lymphocytes and to cause "immortalization" of the infected cell; persistence of the viral genome in epithelial cells may also result in malignant transformation, such as nasopharyngeal carcinoma.

Four patients were treated with antibiotics and simple bed rest for pyogenic vertebral osteomyelitis. The initial clinical response to therapy was good in all patients, with a rapid fall in temperature and a marked decrease in back pain within two or three days. The duration of hospitalization averaged 42 days and all four patients were ambulatory when discharged. Spontaneous intervertebral fusion occurred in three patients and all have returned to work. The duration of follow-up has ranged from 17 to 30 months and no relapses or complications have occurred. The fourth patient died of a myocardial infarction ten days after discharge. At autopsy, the vertebral bodies and disk space were sterile and reparative bony sclerosis had begun. In these four cases, the clinical response to bed rest and antibiotics was equivalent to that obtained with rigid immobilization. This regimen avoids the inconvenience and hazards of body casts and the duration of hospitalization may be shortened.

In recent years increasing attention has been devoted to a group of pulmonary diseases characterized by a host reaction to the inhalation of various organic dusts. Thermophilic actinomycetes have been implicated as respiratory allergens in bagassosis and farmers' lung1,2while avian and animal proteins have been found to be etiologically important in pigeon breeders' disease and pituitary snuff-takers' lung.3,4Although these disorders are well-known in this country, reports of a similar but more complex syndrome, allergic bronchopulmonary aspergillosis, have come primarily from Great Britain.5The reason for this is unclear since spores of the causative fungus, Aspergillus fumigatus(Fig 1) are frequently inhaled by the population at large and are a relatively common cause of allergic bronchial asthma in the United States.6,7This report describes two patients with allergic bronchopulmonary aspergillosis and evaluates the role of immunologic tests in the diagnosis

International audience; Time series prediction is one of the major applications of neural networks. After a short introduction into the basic theoretical foundations we argue that the iterated prediction of a dynamical system may be interpreted as a model of the system dynamics. By means of RBF neural networks we describe a modeling approach and extend it to be able to model instationary systems. As a practical test for the capabilities of the method we investigate the modeling of musical and speech signals and demonstrate that the model may be used for synthesis of musical and speech signals.