Nonmonotonic Dose-Response Curves Occur in Dose Ranges That Are Relevant to Regulatory Decision-Making.

Non-monotonic dose response curves (NMDRCs) occur in cells, tissues, animals and human populations in response to nutrients, vitamins, pharmacological compounds, hormones and endocrine disrupting chemicals (EDCs). Yet, regulatory agencies have argued that NMDRCs are not common, are not found for adverse outcomes, and are not relevant for regulation of EDCs. Under the linear dose response model, high dose testing is used to extrapolate to lower doses that are anticipated to be 'safe' for human exposures. NMDRCs that occur below the toxicological no-observed-adverse-effect level (NOAEL) would falsify a fundamental assumption, that high dose hazards can be used to predict low dose safety. In this commentary, we provide examples of NMDRCs and discuss how their presence in different portions of the dose response curve might affect regulatory decisions. We provide evidence that NMDRCs do occur below the NOAEL dose, and even below the 'safe' reference dose, for chemicals such as resveratrol, permethrin, chlorothalonil, and phthalates such as DEHP. We also briefly discuss the recent CLARITY-BPA study, which reported mammary adenocarcinomas only in rats exposed to the lowest BPA dose. We conclude our commentary with suggestions for how NMDRCs should be acknowledged and utilized to improve regulatory toxicity testing and in the calculation of reference doses that are public health protective.

Burden of disease and costs of exposure to endocrine disrupting chemicals in the European Union: an updated analysis.

A previous report documented that endocrine disrupting chemicals contribute substantially to certain forms of disease and disability. In the present analysis, our main objective was to update a range of health and economic costs that can be reasonably attributed to endocrine disrupting chemical exposures in the European Union, leveraging new burden and disease cost estimates of female reproductive conditions from accompanying report. Expert panels evaluated the epidemiologic evidence, using adapted criteria from the WHO Grading of Recommendations Assessment, Development and Evaluation Working Group, and evaluated laboratory and animal evidence of endocrine disruption using definitions recently promulgated by the Danish Environmental Protection Agency. The Delphi method was used to make decisions on the strength of the data. Expert panels consensus was achieved for probable (>20%) endocrine disrupting chemical causation for IQ loss and associated intellectual disability; autism; attention deficit hyperactivity disorder; endometriosis; fibroids; childhood obesity; adult obesity; adult diabetes; cryptorchidism; male infertility, and mortality associated with reduced testosterone. Accounting for probability of causation, and using the midpoint of each range for probability of causation, Monte Carlo simulations produced a median annual cost of €163 billion (1.28% of EU Gross Domestic Product) across 1000 simulations. We conclude that endocrine disrupting chemical exposures in the EU are likely to contribute substantially to disease and dysfunction across the life course with costs in the hundreds of billions of Euros per year. These estimates represent only those endocrine disrupting chemicals with the highest probability of causation; a broader analysis would have produced greater estimates of burden of disease and costs.

Designing Endocrine Disruption Out of the Next Generation of Chemicals.

A central goal of green chemistry is to avoid hazard in the design of new chemicals. This objective is best achieved when information about a chemical's potential hazardous effects is obtained as early in the design process as feasible. Endocrine disruption is a type of hazard that to date has been inadequately addressed by both industrial and regulatory science. To aid chemists in avoiding this hazard, we propose an endocrine disruption testing protocol for use by chemists in the design of new chemicals. The Tiered Protocol for Endocrine Disruption (TiPED) has been created under the oversight of a scientific advisory committee composed of leading representatives from both green chemistry and the environmental health sciences. TiPED is conceived as a tool for new chemical design, thus it starts with a chemist theoretically at "the drawing board." It consists of five testing tiers ranging from broad in silico evaluation up through specific cell- and whole organism-based assays. To be effective at detecting endocrine disruption, a testing protocol must be able to measure potential hormone-like or hormone-inhibiting effects of chemicals, as well as the many possible interactions and signaling sequellae such chemicals may have with cell-based receptors. Accordingly, we have designed this protocol to broadly interrogate the endocrine system. The proposed protocol will not detect all possible mechanisms of endocrine disruption, because scientific understanding of these phenomena is advancing rapidly. To ensure that the protocol remains current, we have established a plan for incorporating new assays into the protocol as the science advances. In this paper we present the principles that should guide the science of testing new chemicals for endocrine disruption, as well as principles by which to evaluate individual assays for applicability, and laboratories for reliability. In a 'proof-of-principle' test, we ran 6 endocrine disrupting chemicals (EDCs) that act via different endocrinological mechanisms through the protocol using published literature. Each was identified as endocrine active by one or more tiers. We believe that this voluntary testing protocol will be a dynamic tool to facilitate efficient and early identification of potentially problematic chemicals, while ultimately reducing the risks to public health.

Cryoglobulinemia associated with Purtscher-like retinopathy.

PURPOSE: To report a case of Purtscher-like retinopathy in a young man with chronic hepatitis C--associated cryoglobulinemia. METHODS: Case report. RESULTS: A 44-year-old Caucasian man with chronic hepatitis C developed sudden loss of vision in the left eye and abdominal pain. Ocular fundus examination revealed peripapillary cotton-wool spots and superficial retinal whitening in the macula. Systemic evaluation revealed markedly elevated rheumatoid factor, hypertension, and acute renal insufficiency. A renal biopsy demonstrated intravascular deposition of immunoglobulins IgG and IgM and complement consistent with type II mixed cryoglobulinemia. CONCLUSION: Clinicians should consider cryoglobulinemia in the differential diagnosis of a patient with Purtscher-like retinopathy and history of infection with hepatitis C.

Transcranial stimulation excites virtually all motor neurons supplying the target muscle. A demonstration and a method improving the study of motor evoked potentials.

Transcranial stimulation has become an established method in the evaluation of corticospinal tract function. Clinical studies mainly address slowing of conduction through measurement of increased central conduction time (CCT) and 'failures' of conduction through observation of marked reductions in the size of the motor evoked potential (MEP). While CCT is of great interest in detecting subclinical slowing of conduction, the method discloses only gross failures of conduction, since the size of the MEP varies markedly between normal subjects and from one stimulus to another, leading to a broad range of normal values. Furthermore, transcranial stimulation does not appear to achieve depolarization of all spinal motor neurons leading to the target muscles, since in most normal subjects MEPs are smaller in amplitude than the responses evoked by peripheral nerve stimulation. We have developed a triple stimulation technique (TST) which, through two collisions, links central to peripheral conduction and suppresses desynchronization of MEPs. This technique shows that transcranial stimulation does achieve depolarization of all, or nearly all, spinal motor neurons supplying the target muscle in healthy subjects. Our data thus demonstrate that the amplitudes of MEPs are (i) smaller than those of peripheral responses, mostly due to phase cancellation of the action potentials caused by the desynchronization occurring within the corticospinal tract or at spinal cell level and (ii) variable between normal subjects and from one stimulus to another, mostly due to variability of this desynchronization. This technique provides new insights into normal corticospinal tract conduction. It will improve detection and quantification of central motor conduction failures.

Nosocomial fungemia in a large community teaching hospital.

This report reviews 48 episodes of hospital-acquired fungemia that occurred over a four-year period at a large community teaching hospital. The incidence of hospital-acquired fungemia increased eightfold during the study period. Candida albicans (58%), Candida tropicalis (25%), and Candida parapsilosis (15%) were the most common fungal pathogens isolated from blood cultures. Twenty-one patients (44%) had concomitant bacteremia. Intravascular catheters (100%), antibiotic administration (98%), urinary catheters (81%), surgical procedures (65%), parenteral alimentation (60%), and corticosteroid administration (54%) were the most common predisposing factors. The overall mortality rate was 75%. Hospitalization on the medical service, age greater than 60 years, and hospital stay less than 100 days were associated with a significantly increased mortality rate.

Ecología y conservación del playero blanco (Calidris alba) en el Perú / Ecology and conservation of white sandpiper (Calidris alba) in Peru

The authors presents the results of their studies on the peruvian coast of the sand pipe (caladris alba), reporting on its distribution, its general characteristics, its activity patterns and individual behavior patterns.

Los autores presentan los resultados de sus estudios en la costa del Perú, reportando la distribución y abundancia, las características generales, los patrones de actividad y los movimientos individuales del playero blanco.

Cryptococcemia due to Cryptococcus albidus.

We have described a patient with cryptococcemia due to Cryptococcus albidus. Although usually nonpathogenic, C albidus and other non-neoformans cryptococcal species may occasionally be the causative agents in severe infections in man. The latex agglutination test for cryptococcal polysaccharide capsular antigen appears to be specific for C neoformans and thus may be falsely negative in serious infections caused by non-neoformans cryptococci, as seen in our patient with C albidus fungemia. Severe infections caused by C albidus appear to respond to treatment with amphotericin B with or without 5-fluorocytosine but so few cases are available for analysis that no firm conclusions can be made in this regard at present.

Enterococcal bacteremia in two large community teaching hospitals.

This report reviews 55 episodes of enterococcal bacteremia at two large community teaching hospitals. Fifty-eight percent of the patients were older than 60 years, and 84 percent of the patients had some underlying illness. The most common sources of bacteremia were the urinary tract (24 percent), cutaneous wound infection (11 percent), and intra-abdominal infection (11 percent). Five patients had enterococcal endocarditis. Antimicrobial therapy in the week preceding enterococcal bacteremia (42 percent) and polymicrobial bacteremia (38 percent) were common. Despite the institution of appropriate antimicrobial therapy in 75 percent of the patients (41 of 55 patients), the overall mortality rate was 44 percent. Male sex and the presence of a rapidly or ultimately fatal underlying illness were the only factors that showed a statistical tendency toward adversely influencing the mortality risk in enterococcal bacteremia.

Post-craniotomy wound infection caused by Pseudallescheria boydii. Case report.

The authors describe the first reported case of post-craniotomy wound infection due to Pseudallescheria boydii. The patient was a 24-year-old man who sustained a direct blunt injury to the calvaria, resulting in a large subdural hematoma that was surgically evacuated. Subsequently, the surgical wound became infected with a fungus, P. boydii, and was successfully treated with intravenous miconazole.

Mycotic endophthalmitis caused by Penicillium sp. after parenteral drug abuse.

A 30-year-old man developed endophthalmitis three weeks after an intravenous injection of hydromorphone hydrochloride. Penicillium species was recovered from a vitreous aspirate. Treatment with amphotericin B and flucytosine resulted in documented sterilization of the vitreous. At a six-month follow-up examination, the visual acuity of the involved eye was still limited to light perception.

Curbside consultation in infectious diseases: a prospective study.

This study prospectively evaluates curbside (unofficial, informal) consultation (CSC) directed to the hospital-based Infectious Disease Consultation Service (IDCS) in a 1,000-bed university-affiliated, general teaching hospital. Official consultation (OC) was neither solicited nor discouraged. During a one-year period, the IDCS was consulted officially about 532 patients (503 inpatients, 29 outpatients) and unofficially about 269 patients. Only 31 (11.5%) of the 269 CSCs subsequently resulted in OCs. Problems discussed during a CSC ranged from simple to complicated and life threatening, with pneumonia, hepatitis, and syphilis being the illnesses most frequently discussed. Forty-two percent of the CSCs were sought by the internal medicine housestaff, whereas approximately 29% were sought by internal medicine staff physicians. It may be concluded that a CSC in infectious diseases is common, that it sometimes involves complicated and/or life-threatening illnesses but usually does not result in a subsequent OC, and that it requires a considerable expenditure of time by the Infectious Disease Service. A CSC may also involve the exchange of inaccurate or insufficient information between inquiring physicians and the Infectious Disease Service.

Bacteremia due to methicillin-resistant Staphylococcus aureus.

During a three-year period, Staphylococcus aureus phage type D11/83A/85 that was resistant to methicillin, cephalothin, and multiple aminoglycosides was recovered from 260 infected patients in an urban general hospital in Cincinnati, Ohio. This methicillin-resistant S. aureus (MRSA) was recovered from 30% of all blood cultures positive for S. aureus and represented 50% of all episodes of nosocomial bacteremia due to S. aureus. Bacteremia due to MRSA occurred most often in surgical patients (especially burn patients), occurred late in hospitalization, and was recovered frequently from wounds and intravascular catheters. Infection with S. aureus was the direct cause of death of 44% of the patients with bacteremia due to MRSA. Nine of 10 MRSA-infected patients who were treated with vancomycin alone responded to therapy compared with seven of 15 who were treated with other antistaphylococcal antibiotics (P less than 0.05). The present study defines the epidemiologic characteristics of bacteremia due to MRSA, demonstrates the virulence of MRSA, and proves that vancomycin is effective as therapy.

Case report. Tularemia in Ohio: report of two cases and clinical review.

Although unusual, human tularemia continues to be reported from areas of the United States which are not heavily endemic for the disease. Two patients with ulceroglandular tularemia diagnosed in Ohio are described. The causative microorganism, Francisella tularensis, is a small, pleomorphic gram negative coccobacillus which requires special microbiological media for laboratory isolation. In nature, the organism is usually transmitted to man by the handling of infected animal tissues and body fluids or by an arthropod vector. There are several clinical forms of tularemia of which the ulceroglandular type is most common. Laboratory diagnosis is usually made by demonstrating a four-fold increase in the serologic agglutinating antibody titer to Francisella tularensis. Streptomycin is the drug of choice in the treatment of tularemia.

Pediatric Legionnaires' disease: diagnosis by direct immunofluorescent staining of sputum.

Legionnaires' disease occurred in a 3-year-old boy with Down's syndrome. His illness was characterized by bilateral pneumonia, high fever, and response to erythromycin. The diagnosis was made by demonstrating Legionella pneumophila, serogroup 1, in sputum with a direct fluorescent antibody stain. L pneumophila antigen was detected in urine by an enzyme-linked immunospecific assay. The diagnosis was confirmed by a more than fourfold rise in serum antibody titer. Although Legionnaires' disease appears to be uncommon in children, it should be included in the differential diagnosis of pneumonia in the immunocompromised child.