Elizabeth Gaskell (1810-1865) and the medical world.

Elizabeth Gaskell had several relatives who were doctors, two of whom became well known, and she met many practitioners and specialists. This led to interesting portraits of doctors in her novels and also leads to speculation as to why she includes some real individuals and certain diagnoses and why she gave herself a poor prognosis.

Effect of grain constraint on the field requirements for magnetocaloric effect in Ni45Co5Mn40Sn10 melt-spun ribbons.

The influence of grain constraint on the magnetic field levels required to complete the isothermal martensitic transformation in magnetic shape memory alloys has been demonstrated for a NiCoMnSn alloy, and the magnetocaloric performance of an optimally heat treated alloy was quantified. Ni45CoxMn45-xSn10 melt spun ribbons with x = 2, 4, 5, and 6 were characterized. The x = 5 sample was determined to exhibit the lowest transformation thermal hysteresis (7 K) and transformation temperature range during transformation from paramagnetic austenite to nonmagnetic martensite, as well as a large latent heat of transformation (45 J kg-1 K-1). For this composition, it was found that increasing the grain size to thickness ratio of the ribbons from 0.2 to 1.2, through select heat treatments, resulted in a decrease in the magnetic field required to induce the martensitic transformation by about 3 T due to the corresponding reduction in the martensitic transformation temperature range. This decrease in the field requirement ultimately led to a larger magnetocaloric entropy change achieved under relatively smaller magnetic field levels. The giant inverse magnetocaloric effect of the optimized alloy was measured and showed that up to 25 J kg-1 K-1 was generated by driving the martensitic transition with magnetic fields up to 7 T.

Postapplication Fipronil Exposure Following Use on Pets.

Fipronil is a pyrazole acaricide and insecticide that may be used for insect, tick, lice, and mite control on pets. Residents' short-term and long-term postapplication exposures to fipronil, including secondary environmental exposures, were estimated using data from chemical-specific studies. Estimations of acute (24-h) absorbed doses for residents were based on U.S. Environmental Protection Agency (U.S. EPA) 2012 standard operating procedures (SOPs) for postapplication exposure. Chronic exposures were not estimated for residential use, as continuous, long-term application activities were unlikely to occur. Estimated acute postapplication absorbed doses were as high as 0.56 µg/kg-d for toddlers (1-2 yr) in households with treated pets based on current U.S. EPA SOPs. Acute toddler exposures estimated here were fivefold larger in comparison to adults. Secondary exposure from the household environment in which a treated pet lives that is not from contacting the pet, but from contacting the house interior to which pet residues were transferred, was estimated based on monitoring socks worn by pet owners. These secondary exposures were more than an order of magnitude lower than those estimated from contacting the pet and thus may be considered negligible.

Implications of estimates of residential organophosphate exposure from dialkylphosphates (DAPs) and their relevance to risk.

Recent epidemiological studies have claimed to associate a variety of toxicological effects of organophosphorus insecticides (OPs) and residential OP exposure based on the dialkyl phosphates (DAPs; metabolic and environmental breakdown products of OPs) levels in the urine of pregnant females. A key premise in those epidemiology studies was that the level of urinary DAPs was directly related to the level of parent OP exposure. Specific chemical biomarkers and DAPs representing absorbed dose of OPs are invaluable to reconstruct human exposures in prospective occupational studies and even in non-occupational studies when exposure to a specific OP can be described. However, measurement of those detoxification products in urine without specific knowledge of insecticide exposure is insufficient to establish OP insecticide exposure. DAPs have high oral bioavailability and are ubiquitously present in produce at concentrations several-fold greater than parent OPs. Studies relying on DAPs as an indicator of OP exposure that lack credible information on proximate OP exposure are simply measuring DAP exposure and misattributing OP exposure.

Expression of periodontal interleukin-6 protein is increased across patients with neither periodontal disease nor diabetes, patients with periodontal disease alone and patients with both diseases.

BACKGROUND AND OBJECTIVE: Epidemiological studies have established that patients with diabetes have an increased prevalence and severity of periodontal disease. Interleukin (IL)-6, a multifunctional cytokine, plays a role in the tissue inflammation that characterizes periodontal disease. Our recent study has shown a trend of increase in periodontal IL-6 expression at the mRNA level across patients with neither periodontal disease nor diabetes, patients with periodontal disease alone and patients with both diseases. However, the periodontal IL-6 expression at the protein level in these patients has not been investigated. MATERIAL AND METHODS: Periodontal tissue specimens were collected from eight patients without periodontal disease and diabetes (group 1), from 17 patients with periodontal disease alone (group 2) and from 10 patients with both periodontal disease and diabetes (group 3). The frozen sections were prepared from these tissue specimens and IL-6 protein expression was detected and quantified. RESULTS: The nonparametric Kruskal-Wallis test showed that the difference in IL-6 protein levels among the three groups was statistically significant (p = 0.035). Nonparametric analysis using the Jonckheere-Terpstra test showed a tendency of increase in periodontal IL-6 protein levels across group 1 to group 2 to group 3 (p = 0.006). Parametric analysis of variance (ANOVA) on IL-6 protein levels showed that neither age nor gender significantly affected the difference of IL-6 levels among the groups. CONCLUSION: Periodontal IL-6 expression at the protein level is increased across patients with neither periodontal disease nor diabetes, patients with periodontal disease alone and patients with both diseases.

Pesticide exposure monitoring databases in applied risk analysis.

Faced with the need to evaluate under what conditions chemicals can be used with "reasonable certainty of no harm" to workers and consumers, industry and government agencies have embraced quantitative risk analysis as a science-based approach for product development, regulatory evaluations, and associated risk management decision making. Beginning in the 1990s, a variety of industry-sponsored task forces have been formed to develop exposure-related data to support safety evaluations for pesticide chemicals used in agricultural, industrial, institutional, residential, and other settings. Human exposure assessment and the underlying data (e.g., personal exposure and biological monitoring measurements, media-specific residue measurements, product use, and time-activity information) represent a critical component of the risk assessment process and a rapidly advancing science. While task forces have been created to develop databases for supporting the continued safe use of products, the development of these databases has served to advance general understanding of the basic principles underlying exposure assessment methodology and thereby provide the basis for improved science-based risk management by both industry and government. Given that developing chemical-specific data for every product use pattern and associated worker or consumer exposure scenario (e.g., professional mixer, loader and applicator activities associated with the use of a low-pressure sprayer, consumer residential lawn application via a ready-to-use hose-end sprayer product) is prohibitively expensive and time consuming, alternative approaches have been developed based upon meta-analyses and generalizations derived from databases of exposure monitoring studies for multiple chemicals, sorted by significant exposure covariates such as formulation type, method of application, amount of active ingredient applied, site of application, protective equipment and clothing, and task or activity. These generalizations can be used for predictive exposure analyses and have clearly demonstrated the value of "generic databases." Although data in these databases and associated generalizations are subject to interpretation, e.g., during the regulatory decision-making processes, and may be used in conjunction with additional considerations or assessment methods that result in conservative biases, the role of generic databases for risk management decision making, and advancing the science of applied exposure analysis continues to be realized.

Biphasic dissipation kinetics for dislodgeable foliar residues in estimating postapplication occupational exposures to endosulfan.

Agricultural workers are exposed to pesticide residues via dermal contact with foliage upon entry of treated fields. Restricted Entry Intervals (REIs) are established based on both toxicity and exposure. Key factors for estimation of potential worker exposures are dislodgeable foliar residues (DFRs) and the manner in which DFRs dissipate over time. DFR dissipation curves vary in form and shape, and are often biphasic, reflecting different rate processes, chemical-physical influences, and partitioning. Biphasic dissipation behavior for endosulfan [6,7,8,9,10,10-hexachloro-1,5,5a,6,9,9a-hexahydro-6,9-methano-2,4,3-benzodioxathiepin 3-oxide] previously reported for tomatoes and peppers has been confirmed here for endosulfan on melon, grape, and peach foliage. Use of biphasic kinetics results in more robust r2 values for the regression curves that describe foliar dissipation of endosulfan compared to use of simple first-order kinetics. For endosulfan, the use of biphasic kinetics to describe the overall dissipation accurately predicts daily DFR values. In contrast, first order kinetics may overestimate DFRs and, potentially, postapplication worker exposures during the critical period when entry of treated fields is most likely to occur.

Stromal testis tumors in children: a report from the prepubertal testis tumor registry.

PURPOSE: Stromal testis tumors are rare and generally exhibit a benign behavior in prepubertal patients. We reviewed the Prepubertal Testis Tumor Registry to elucidate further the behavior of these tumors. MATERIALS AND METHODS: Epidemiological and clinical information on stromal testis tumors was compiled and reviewed from the Prepubertal Testis Tumor Registry. In addition, original pathology reports were requested for all patients registered as having undifferentiated stromal tumors. RESULTS: There were 43 patients registered with stromal tumors. Of the 21 patients with unspecified stromal tumors pathology reports were obtained on 11. Eight patients had truly mixed or undifferentiated stromal tumors. Mean patient age at presentation was 38 months (Leydig cell 70, Sertoli cell 52.5, juvenile granulosa cell 1.5 and mixed/undifferentiated 41.2). No patient with a Leydig cell, Sertoli cell or juvenile granulosa cell tumor had metastases at presentation or metastatic disease during an average 24.6 months of followup. One undifferentiated tumor demonstrated malignant behavior by presenting with metastatic disease. Pathological examination revealed a poorly differentiated tumor with extension into the adjacent tunica and frequent mitotic figures. While other stromal tumors displayed mitotic figures, none showed local invasion. CONCLUSIONS: Stromal testis tumors are rare. Data from the Prepubertal Testis Tumor Registry confirms the benign behavior of most of these tumors. However, undifferentiated stromal tumors may exhibit metastatic behavior. A high index of suspicion is appropriate when there are a large number of mitotic figures, the tumor is poorly differentiated or when local invasion is present in the primary tumor. Metastatic evaluation and close followup are warranted for this select group of patients.

Laparoscopic cross-trigonal Cohen ureteroneocystostomy: novel technique.

PURPOSE: We describe a novel technique of laparoscopic transvesical cross-trigonal Cohen anti-reflux ureteroneocystostomy. MATERIALS AND METHODS: A 10, an 11 and a 32-year-old patient with symptomatic unilateral vesicoureteral reflux underwent laparoscopic cross-trigonal ureteral reimplantation. Two 5 mm. balloon tip ports were suprapubically inserted into the bladder. Using a transurethral resectoscope with a Collins knife a 4 to 5 cm. cross-trigonal submucosal trough was created from the refluxing ureteral orifice to the contralateral side of the bladder. The refluxing ureteral orifice and intramural ureter were completely mobilized intravesically, advanced transtrigonally and secured to the detrusor muscle at the apex of the trough with 3 deep interrupted sutures. The elevated mucosal flaps of the trough were suture approximated over the ureter to create a submucosal tunnel. All suturing was performed by freehand laparoscopic technique. RESULTS: Operative time was between 2.5 and 4.5 hours and blood loss was 10 to 50 cc. Adequate submucosal trough creation, ureteral extravesical mobilization and intravesical advancement, and bladder mucosal flap reapproximation were done to create a submucosal tunnel in all cases. Satisfactory transtrigonal anchoring of the neoureteral orifice to the detrusor muscle and mucosa was achieved with 3 stitches. Hospital stay was 2, 2 and 1 days in the 3 cases, and the Foley catheter remained in place for 3, 1 and 1 week, respectively. At 6 months reflux had resolved in 2 patients, while in 1 grade II reflux persisted, which was improved from grade IV preoperatively. All patients have remained infection-free without antibiotics. CONCLUSIONS: Laparoscopic transvesical cross-trigonal antireflux ureteral reimplantation is technically feasible. Intravesical laparoscopic suturing is possible. Potential advantages include a decreased hospital stay, decreased narcotic requirement and better cosmesis. Further experience is necessary to refine the technical nuances and evaluate outcomes compared to the open technique.

Renal neoplasms in adult survivors of childhood Wilms tumor.

PURPOSE: Survivors of childhood Wilms tumor have been followed by large collaborative studies for approximately 31 years. In this time a number of second malignant neoplasms have been documented in these Wilms tumor survivors and they are at higher risk for such development compared with the general population. To our knowledge no renal neoplasms have been previously reported in patients successfully treated for Wilms tumor in childhood. MATERIALS AND METHODS: We reviewed the cases of 4 adults in whom Wilms tumor was treated in childhood by radical nephrectomy and adjuvant therapy and who presented to our institution with complex cystic or solid renal masses in the contralateral kidney. Parameters, including patient age at Wilms tumor diagnosis, Wilms tumor treatment modalities, age at second malignant neoplasm presentation and resected renal lesion pathology were outlined. A thorough literature review was performed to identify the development of renal malignancies as second malignant neoplasms in survivors of Wilms tumor in childhood. RESULTS: The International Society of Pediatric Oncology and National Wilms Tumor Study have followed patients treated for Wilms tumor for no greater than 31 years. Renal neoplasms, including 2 renal cell carcinomas, 1 oncocytoma and 1 atypical cyst, in the solitary remaining kidney of relatively young adults 34 to 50 years old who were treated for Wilms tumor greater than 31 years ago were successfully treated with partial nephrectomy at our institution. Neither the International Society of Pediatric Oncology nor National Wilms Tumor Study has identified renal cell carcinoma as a second malignant neoplasm in patients successfully treated for Wilms tumor. CONCLUSIONS: Our experience suggests that relatively young adults with a history of childhood treatment for Wilms tumor may be at increased risk for renal neoplasms at ages not yet achieved by those enrolled in large multicenter trials. This possibility should be considered when planning the long-term followup of these patients. The potential to develop this type of second malignant neoplasm again raises the clinical issue of performing a primary nephron sparing procedure in children presenting with Wilms tumor.

Could pesticide toxicology studies be more relevant to occupational risk assessment?

Pesticide toxicology study design has evolved from concern for oral exposure via food residues. The emphasis on the oral route does not generally apply to workers that are exposed primarily via the dermal route either handling pesticides or re-entering treated fields. As a result numerous assumptions about how oral toxicology results relate to dermal exposure must be made when conducting worker risk assessments. These assumptions introduce a high degree of uncertainty. Alternative toxicology study designs are suggested to reduce uncertainty when assessing risk. Because the dermal route is so important to characterizing occupational risk, methods to improve the accuracy of dermal absorption estimates are suggested, including the use of human subjects to study dermal absorption. Additional suggestions include tailoring dermal, oral and inhalation kinetic study designs to reflect worker exposure dosages. Suggestions are made to routinely conduct a single dose toxicity study patterned after the neurotoxicity study design to distinguish single dose effects and NOAELs from those resulting from multiple doses. Finally, interspecies pharmacokinetics studies are proposed to determine which toxicology study regimen of dosing best reflects intermittent worker exposure.

Biomonitoring of persons exposed to insecticides used in residences.

Pesticides used indoors inevitably result in some unintentional and unavoidable exposures of residents. Measured dosages of residents are well below toxic levels. Exposures (microg/kg-day) are substantially less and occur over a longer time than suggested by unvalidated estimates derived from previous extreme, conservative default assumptions based solely on environmental residues. Human chlorpyrifos exposures were monitored following three different types of applications: fogger, broadcast, and crack-and-crevice. Persistence of total residue on carpet was substantially greater than the persistence of transferable residue (microg/cm(2)). Low-level (microg/kg) exposures of family members persisted for periods of weeks to a month after pesticide use. Although few children who resided with their parents in pest-protected homes have been monitored, they eliminated more biomarker than their parents on a kg body weight-day basis when absorbed dosages (microg/kg-day) were derived from spot urine specimens corrected for volume by an age-specific creatinine correction. Ultimately environmental residues may become useful elements of predictive residential exposure models, but their potential contribution to indirect exposure assessments must include careful determination of residue availability for contact transfer to clothing or skin and biological validation. When environmental data from monitoring studies reported here were used to estimate residential exposure according to Residential Exposure Assessment Standard Operating Procedures (SAP meeting, 1997), measured exposures were substantially less than assessments. Experimental and situational monitoring of exposed persons is essential for meaningful and responsible predictive resident exposure model building.

Needlescopic surgery for cryptorchidism: the initial series.

PURPOSE: The aim of this study is to report the initial experience with needlescopic surgery (2-mm optics and instrumentation exclusively) for the cryptorchid testicle. METHODS: Ten patients (age 8 months to 37 years) underwent 12 needlescopic procedures: orchiopexy (n = 8), orchiectomy (n = 2), and diagnostic exploration with attempted excision of testicular remnant (n = 2). Two patients underwent bilateral needlescopic orchiopexy. Needlescopic (2 mm) optics and instrumentation were used exclusively in the pediatric patients. RESULTS: All procedures were completed successfully by needlescopic techniques. Mean surgical time was 110 minutes (range, 60 to 180 minutes), and blood loss was 6 mL (range, 0 to 20 mL). There were no intraoperative complications. All procedures were performed on an outpatient basis. In all 8 orchidopexies, the testis was successfully brought to a scrotal position. CONCLUSIONS: Needlescopic techniques allow safe performance of various procedures for a cryptorchid testicle. The cosmetic result is excellent.

Pheochromocytoma. Special considerations in children.

Pheochromocytoma is a rare but important tumor in children. Appropriate evaluation and management are essential for a favorable outcome. Pheochromocytomas are more often multifocal and extra-adrenal in children when compared with adults. This pattern makes the diagnosis, localization, and surgical management more challenging. Nonetheless, the standard biochemical evaluation is usually diagnostic, and MR imaging is currently the best tool for tumor localization. The possibility of a familial syndrome must always be considered and should always be thoroughly evaluated when children present with a pheochromocytoma. Conversely, children with a familial syndrome should undergo annual screening for pheochromocytoma from a young age. Given the greater likelihood of a metachronous recurrence in children, consideration should be given to adrenal-sparing surgery in selected patients. When managed appropriately, the outlook for pheochromocytoma in children is excellent. Unfortunately, the uncommon malignant tumors are still difficult to treat. Perhaps the unique genetic characteristics of pheochromocytoma will ultimately be exploited in the management of the aggressive forms of this disease.

Penile adhesions after neonatal circumcision.

PURPOSE: The appropriate management of penile adhesions in circumcised boys is unclear. An important consideration is whether adhesions resolve spontaneously. We studied the incidence of penile adhesions as a function of patient age to assess the natural history. MATERIALS AND METHODS: We evaluated all circumcised boys presenting to our pediatric urology clinic. A standard form was used to classify adhesions as grade 0-no adhesions, 1-fine adhesions to the corona, 2-adhesions covering less than 50% of the glans and 3-adhesions covering greater than 50% of the glans. All boys were evaluated by 1 of 2 pediatric urologists. Previous treatment of adhesions was assessed and skin bridges were also noted. RESULTS: We enrolled in our study 254 boys 1 month to 19 years 8 months old. Only 7 patients had a history of treatment of adhesion, of whom 3 had recurrent adhesions at evaluation. Patients were divided into groups based on age, including younger than 12 months (61), 13 to 60 (78), 61 to 108 (51) and 109 months old or older (64). In these groups we noted an adhesion rate of 71%, 28%, 8% and 2%, respectively. The rate of adhesions more severe than grade 1 was 30%, 10% and 0% in boys 12 months old or younger, 13 to 60 and 61 months old or older, respectively. The oldest patient with grade 3 adhesions was 31 months old. Skin bridges in 6 cases involved the circumcision line in 4. CONCLUSIONS: Penile adhesions develop after circumcision and the incidence decreases with patient age. Although there is debate on whether to lyse these adhesions manually, our findings suggest that adhesions resolve without treatment. Based on our results we do not recommend lysing penile adhesions, except perhaps those involving the circumcision line.

Biomonitoring and whole body cotton dosimetry to estimate potential human dermal exposure to semivolatile chemicals.

Current methods of estimating absorbed dosage (AD) of chemicals were evaluated to determine residue transfer from a carpet treated with chlorpyrifos (CP) to humans who performed a structured exercise routine. To determine the dislodgeability of residue, a California Department of Food and Agriculture (CDFA) roller was applied to a flat cotton cloth upon a treated carpet. Levels ranged from 0.06 to 0.99 microg CP/cm2. Cotton whole body dosimeters (WBD) were also used to assess residue transfer. The dosimeters retained 1.5 to 38 mg CP/person. Urine biomonitoring (3 days) for 3,5,6-trichloro-2-pyridinol (TCP) of persons who wore only swimsuits revealed a mean AD of 176 microg CP equivalents/person. The results show that the AD depends on the extent of contact transfer and dermal absorption of the residue. Default exposure assessments based upon environmental levels of chemicals and hypothetical transport pathways predict excessive exposure. The cotton WBD retains chemical residues and may be effectively used to predict dermal dose under experimental conditions.

Conservatism in pesticide exposure assessment.

Three important factors are commonly encountered in exposure assessment that when combined could overestimate the exposure to pesticides by as much as two orders of magnitude. The three factors discussed are dermal absorption from laboratory animal studies, daily dose extrapolated from partial day monitoring, and nonbolus dose from dermal or inhalation exposure. Conservatism built into the process by each of these three factors is substantiated with available empirical data. The dose overestimation from these factors varies discriminatively by exposure scenarios and peculiarities of a given chemical. It is for this reason that a generic overestimation factor cannot be ascribed. Following the empirical illustrations, the authors conclude that the most effective approach for dealing with the problem is to generate the most appropriate data possible. This means producing human rather than laboratory animal dermal absorption data, conducting full-day exposure monitoring studies, and whenever feasible generating dermal rather than oral toxicology data (or alternatively data on both oral and dermal pharmacokinetics) in those cases where the dermal route predominates.

Analysis of chlorpyrifos exposure and human health: expert panel report.

This report summarizes the deliberations of an eight-member panel of scientists convened by Dow AgroSciences in cooperation with the U.S. Environmental Protection Agency (EPA). The panel was charged with evaluating the scientific literature on the health effects potentially associated with exposure to the insecticide chlorpyrifos. Specifically, the panel was asked to (1) evaluate human experience data available and address the adequacy of the available current literature; (2) develop a list of recommendations for epidemiology studies, including appropriate endpoints and study populations, and strengths and weaknesses of each approach; and (3) draft a report to summarize its recommendations. The panel assessed the quality of the existing epidemiologic literature on chlorpyrifos and specific outcomes such as neuropathy (including organophosphate induced delayed neurotoxicity), behavior (cognition and affect), immunologic, and multiple complaints (also referred to as multiple chemical sensitivities). The majority of panel members (five members) agreed that the literature reviewed provided little or no scientific evidence that chlorpyrifos exposure causes harm to human health other than its known cholinergic effects associated with acute poisoning. Those panel members voting in the minority (three members) agreed that the studies reviewed provided inadequate evidence to preclude the possibility of adverse effects to human health from chlorpyrifos exposure at levels associated with its manufacture or professional application. Those voting in the minority suggested further investigation of cohort(s) of workers engaged in either the manufacture or the professional application of chlorpyrifos, or both. Compared to the general population, these groups have relatively high levels of exposure to chlorpyrifos. The primary health outcomes recommended for study were cognitive and affective disorders, with consideration of the assessment of peripheral neuropathy also suggested for at least a subset of the cohort.