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Mesoamerican nephropathy (MeN) is a progressive kidney disease found on the Pacific coast of Central America primarily in young male agricultural workers without typical kidney disease risk factors. While it is generally accepted that environmental exposures contribute to MeN, we hypothesized that there was also an important genetic component. We performed a genome-wide association study comparing individuals with MeN versus individuals with normal kidney function. We found that Native American ancestry was strongly associated with increased risk of MeN. We also identified candidate variants in the OPCML gene, which encodes a protein that binds opioid receptors, that were associated with ~sixfold reduced odds of MeN (allele frequency 0.029 in controls and 0.005 in cases, OR = 0.16; P = 4 × 10 -8 ). Sugarcane workers with the protective OPCML variants had markedly increased urine osmolality suggesting greater ability to defend against hypovolemia. Experiments with Opcml knock-out mice revealed roles for OPCML in fluid balance and temperature regulation consistent with our findings in humans. Our data suggest that heritable differential sensitivity to heat stress and dehydration contributes to high rates of kidney disease in Central America., Competing Interests: Competing interests statement:The authors declare no competing interest.

Video 1Video describing the case, procedure, and outcomes., Competing Interests: The authors did not disclose any financial relationships., (© 2024 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc.)

Video 1Endoscopic retrieval of a whole apple from the sigmoid colon., (© 2023 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc.)

Video 1., (© 2023 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc.)

Purpose: As the prevalence of chronic kidney disease of non-traditional origin (CKDnt) rises in low-resource settings, there is a need for reliable point-of-care creatinine testing. The purpose of this analysis was to assess the accuracy of two commonly used point-of-care creatinine devices, the i-STAT handheld (Abbott, Princeton, NJ, USA) and the StatSensor Creatinine (Nova Biomedical, Waltham, MA, USA) in comparison to venipuncture serum creatinine measures. The affordability, sensitivity, specificity, ease of use, and other considerations for each device are also presented., Methods: Three paired data sets were compared. We collected 213 paired i-STAT and venipuncture samples from a community study in Nicaragua in 2015-2016. We also collected 267 paired StatSensor Creatinine and venipuncture samples, including 158 from a community setting in Nicaragua in 2014-2015 and 109 from a Guatemala sugarcane worker cohort in 2017-2018. Pearson correlation coefficients, Bland-Altman plots, and no intercept linear regression models were used to assess agreement between point-of-care devices and blood samples., Results: The i-STAT performed the most accurately, overestimating creatinine by 0.07 mg/dL (95% CI: 0.02, 0.12) with no evidence of proportional bias. The StatSensor Creatinine performed well at low levels of creatinine (Mean (SD): 0.87 (0.19)). Due to proportional bias, the StatSensor Creatinine performed worse in the Nicaragua community setting where creatinine values ranged from 0.31 to 7.04 mg/dL., Discussion: Both devices provide acceptable sensitivity and specificity. Although adequate for routine surveillance, StatSensor Creatinine is less accurate as the values of measured creatinine increase, a consideration when using the point-of-care device for screening individuals at risk for CKDnt. Research, clinical, and screening objectives, cost, ease of use, and background prevalence of disease must all be carefully considered when selecting a point-of-care creatinine device., Conclusion: POC testing can be more accessible in resource-limited settings. The selection of the appropriate device will depend on the use-case., Competing Interests: University of Colorado and Pantaleon are separate, independent organizations. University of Colorado employed appropriate research methods in keeping with academic freedom, based conclusions on critical analysis of the evidence and reported findings fully and objectively. The terms of this arrangement have been reviewed and approved by the University of Colorado in accordance with its conflict of interest policies. Boston University and Comite Nacional de Productores de Azucar (CNPA) are separate, independent organizations. Although CNPA provided partial funding for the studies through which the data were collected, the contract was no longer in place at the time the conceptualization and analysis for this manuscript were initiated. The remaining authors declare that they have no relevant financial interests., (Copyright: © 2023 The Author(s).)

6G is already being planned and will employ much higher frequencies, leading to a revolutionary era in communication between people as well as things. It is well known that weather, especially rain, can cause increased attenuation of signal transmission for higher frequencies. The standard methods for evaluating the effect of rain on symbol error rate are based on long-term averaging. These methods are inaccurate, which results in an inefficient system design. This is critical regarding bandwidth scarcity and energy consumption and requires a more significant margin of effort to cope with the imprecision. Recently, we have developed a new and more precise method for calculating communication system performance in case of rain, using the probability density function of rain rate. For high rain rate (above 10 mm/h), for a typical set of parameters, our method shows the symbol error rate in this range to be higher by orders of magnitude than that found by ITU standard methods. Our model also indicates that sensing and measuring the rain rate probability is important in order to provide the required bit error rate to the users. This will enable the design of more efficient systems, enabling design of an adaptive system that will adjust itself to rain conditions in such a way that performance will be improved. To the best knowledge of the authors, this novel analysis is unique. It can constitute a more efficient performance metric for the new era of 6G communication and prevent disruption due to incorrect system design.

The clinical efficacy of remote dielectric sensing (ReDS) monitoring is not well known. Digital databases were searched to identify relevant articles. Pooled unadjusted odds ratio (OR) for dichotomous outcomes were calculated using a random-effects model. Findings were reported as a point estimate with its 95% confidence interval (CI). A total of 985 patients across seven studies were included in the meta-analysis. Patients with heart failure monitored with ReDS had significantly lower odds of hospital readmission compared with non-ReDS patients (OR = 0.40; 95% CI 0.29-0.56; z = 5.43 p = 0.000, I2 = 0%). Subgroup analysis based on the duration of follow-up showed a lower odd of readmission within 30 days (OR = 0.36; 95% CI 0.18-0.71; z = 2.93; p = 0.003; I2 5.7%), as well as between 1 and 3 months (OR = 0.42; 95% CI 0.29-0.61; z = 4.54; p = 0.000; I2 = 0.0%). ReDS effect of lower readmissions of HF was observed irrespective of the duration of follow-up (<1-month vs 1-3 months). ReDS monitoring significantly lowers the odds of HF readmission within 3 months compared to participants not using ReDS., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group on behalf of Greater Baltimore Medical Center.)

A randomized, double-blind, placebo-controlled, 52-week study (no. NCT03068468) evaluated gosuranemab, an anti-tau monoclonal antibody, in the treatment of progressive supranuclear palsy (PSP). In total, 486 participants dosed were assigned to either gosuranemab (n = 321) or placebo (n = 165). Efficacy was not demonstrated on adjusted mean change of PSP Rating Scale score at week 52 between gosuranemab and placebo (10.4 versus 10.6, P = 0.85, primary endpoint), or at secondary endpoints, resulting in discontinuation of the open-label, long-term extension. Unbound N-terminal tau in cerebrospinal fluid decreased by 98% with gosuranemab and increased by 11% with placebo (P < 0.0001). Incidences of adverse events and deaths were similar between groups. This well-powered study suggests that N-terminal tau neutralization does not translate into clinical efficacy., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Progressive supranuclear palsy is a rare neurodegenerative movement disorder and little is known about its epidemiology. Objective: Estimate age-adjusted prevalence of progressive supranuclear palsy and describe antecedent diagnoses and progressive supranuclear palsy patient features in the 5 years before first diagnostic code. Methods: In a nested case-control study in the IBM MarketScan Commercial and Medicare Supplemental Databases, a large set of US insurance databases containing medical service and prescription drug claims from employer-based commercial and Medicare supplemental health insurance plans, progressive supranuclear palsy cases (identified via International Statistical Classification of Diseases 9th/10th revision codes) and controls were included if enrollment was ≥1 month in the study period (October 1, 2015-October 31, 2017). Two controls with no diagnosis codes for PSP were matched to cases on birth year, sex, enrollment time in the database, and pharmacy benefit eligibility. Controls were assigned a randomly selected index date from their eligibility period. Prevalence of progressive supranuclear palsy was estimated in 2016 among patients with ≥1 month of continuous enrollment in that year. Prevalence ratios for comorbidities (claim/diagnosis codes) were examined in the ≤ 5 years before index date (first progressive supranuclear palsy claim date). Results: Age-adjusted progressive supranuclear palsy prevalence was 2.95/100,000 in 2016. The most common diagnosis codes in cases vs. controls in the 5 years pre-index were gait abnormalities (79.3 vs. 21.8%), pain in joint (54.9 vs. 36.0%), Parkinson's disease (54.6 vs. 1.0%), fatigue (49.8 vs. 21.6%), and cerebrovascular disease (45.6 vs. 16.4%). Conclusions: In this large database analysis, based on preliminary analyses, the prevalence of diagnosed progressive supranuclear palsy was 2.95/100,000, which is lower than many prior studies. Typical symptoms suggestive of progressive supranuclear palsy were present before index date, indicating a potential delay in time to diagnosis. The identification of diagnostic codes for clinical features of progressive supranuclear palsy that occurred before index date may be used to develop predictive models to identify potential progressive supranuclear palsy patients earlier in their disease course., Competing Interests: EV, TD, LL, HK, SE, SH, and JK are/were employees of and hold shares/share options in Biogen. IL is supported by the National Institutes of Health grants: 5P50AG005131-33, 2R01AG038791-06A, U01NS090259, 1U54 NS 092089, U01NS100610, U01NS80818, R25NS098999, P20GM109025; Parkinson Study Group, Michael J Fox Foundation, Lewy Body Association, AbbVie, Biogen and Roche. She was member of a Lundbeck Advisory Board and participated in a symposium organized by Sunovion. She receives her salary from the University of California San Diego and as Chief Editor of Frontiers in Neurology. MJ was a contract employee of Biogen and is presently employed by MJ Analytics Ltd. GH received research support from GE Healthcare and Neuropore; has ongoing research collaborations with Orion and Prothena; serves as a consultant for AbbVie, AlzProtect, Asceneuron, Biogen, Biohaven, Lundbeck, Novartis, Roche, Sanofi, UCB; received honoraria for scientific presentations from AbbVie, Biogen, Roche, Teva, UCB, and Zambon; and holds a patent on PERK Activation for the Treatment of Neurodegenerative Diseases (PCT/EP2015/068734)., (Copyright © 2021 Viscidi, Litvan, Dam, Juneja, Li, Krzywy, Eaton, Hall, Kupferman and Höglinger.)

A major challenge in use of the optical spectrum for communication and imaging applications is the scattering of light as it passes through diffuse media. Recent studies indicate that light beams with orbital angular momentum (OAM) can penetrate deeper through diffuse media than simple Gaussian beams. To the best knowledge of the authors, in this paper we describe for the first time an experiment examining transmission of OAM beams through biological tissue with thickness of up to a few centimeters, and for OAM modes reaching up to 20. Our results indicate that OAM beams do indeed show a higher transmittance relative to Gaussian beams, and that the greater the OAM, the higher the transmittance also up to 20, Our results extend measured results to highly multi scattering media and indicate that at 2.6 cm tissue thickness for OAM of order 20, we measure nearly 30% more power in comparison to a Gaussian beam. In addition, we develop a mathematical model describing the improved permeability. This work shows that OAM beams can be a valuable contribution to optical wireless communication (OWC) for medical implants, optical biological imaging, as well as recent innovative applications of medical diagnosis.

Optical interrogation of tissues is broadly considered in biomedical applications. Nevertheless, light scattering by tissue limits the resolution and accuracy achieved when investigating sub-surface tissue features. Light carrying optical angular momentum or complex polarization profiles, offers different propagation characteristics through scattering media compared to light with unstructured beam profiles. Here we discuss the behaviour of structured light scattered by tissue-mimicking phantoms. We study the spatial and the polarization profile of the scattered modes as a function of a range of optical parameters of the phantoms, with varying scattering and absorption coefficients and of different lengths. These results show the non-trivial trade-off between the advantages of structured light profiles and mode broadening, stimulating further investigations in this direction.

The Rac1-specific guanosine triphosphatase (GTPase)-activating protein Slit-Robo GAP2 (Srgap2) is dramatically upregulated during RANKL-induced osteoclastogenesis. Srgap2 interacts with the cell membrane to locally inhibit activity of Rac1. In this study, we determined the role of Srgap2 in the myeloid lineage on bone homeostasis and the osteoclastic response to TNFα treatment. The bone phenotype of mice specifically lacking Srgap2 in the myeloid lineage (Srgap2 f/f :LysM-Cre; Srgap2 conditional knockout [cKO]) was investigated using histomorphometric analysis, in vitro cultures and Western blot analysis. Similar methods were used to determine the impact of TNFα challenge on osteoclast formation in Srgap2 cKO mice. Bone parameters in male Srgap2 cKO mice were unaffected. However, female cKO mice displayed higher trabecular bone volume due to increased osteoblast surface and bone formation rate, whereas osteoclastic parameters were unaltered. In vitro, cells from Srgap2 cKO had strongly enhanced Rac1 activation, but RANKL-induced osteoclast formation was unaffected. In contrast, conditioned medium from Srgap2 cKO osteoclasts promoted osteoblast differentiation and had increased levels of the bone anabolic clastokine SLIT3, providing a possible mechanism for increased bone formation in vivo. Rac1 is rapidly activated by the inflammatory cytokine TNFα. Supracalvarial injection of TNFα caused an augmented osteoclastic response in Srgap2 cKO mice. In vitro, cells from Srgap2 cKO mice displayed increased osteoclast formation in response to TNFα. We conclude that Srgap2 plays a prominent role in limiting osteoclastogenesis during inflammation through Rac1, and restricts expression of the paracrine clastokine SLIT3, a positive regulator of bone formation. © 2019 American Society for Bone and Mineral Research., (© 2019 American Society for Bone and Mineral Research.)

Rationale & Objective: In Central America, there is a high prevalence of chronic kidney disease (CKD) of nontraditional etiology often observed among agricultural workers. Few studies have assessed CKD prevalence among workers in nonagricultural occupations, which was the objective of this investigation., Study Design: Prospective cohort study., Setting & Participants: Male and female workers (n = 224) employed by artisanal brickmaking facilities in La Paz Centro, Nicaragua., Predictors: Age, sex, education, smoking status, body mass index, alcohol consumption, water consumption, first-degree relative(s) with CKD, years worked, hours worked per week, job category, study visit (baseline and follow-up), and self-reported hypertension and diabetes., Outcomes: CKD defined as estimated glomerular filtration rate (eGFR) < 60mL/min/1.73m 2 at 2 time points 4 months apart and CKD stage., Analytical Approach: A linear mixed-effects model with an unstructured covariance matrix was used to evaluate the association between demographics, occupational risk factors, and eGFR at baseline. The interaction between risk factors and time with change in eGFR was also evaluated. Multivariable logistic regression models were used to evaluate predictors of CKD., Results: The CKD prevalence was 12.1% (n = 27), 100% of cases were male, 30% had stage 5 CKD (eGFR < 15mL/min/1.73m 2 ), and 22% were younger than 35 years. Proportions of participants with eGFRs < 60mL/min/1.73m 2 at baseline and follow-up were 13.8% and 15.2%, respectively. Linear regression analysis demonstrated significant predictors of lower kidney function at baseline including oven work, older age, lack of education, and having an immediate family member with CKD. Predictors of CKD identified using logistic regression analysis included oven work and lack of education., Limitations: Crude job classification measures, loss to follow-up, self-reported exposures., Conclusions: The prevalence of CKD is high in this population of brick workers, suggesting that the epidemic of CKD affecting Mesoamerica is not limited to agricultural workers. These results are consistent with the hypothesis that occupational heat exposure is a risk factor for kidney disease in this region., (Copyright © 2019 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Rationale & Objective: Mesoamerican nephropathy (MeN), a form of chronic kidney disease (CKD) of unknown cause in Central America, affects young individuals working in physically strenuous occupations. Repeated episodes of work-related kidney injury may lead to CKD in this setting. We aimed to better understand the burden and natural history of acute kidney injury (AKI) in workers at risk for MeN., Study Design: Cross-sectional study of active sugarcane workers, followed by prospective follow-up of individuals with AKI., Setting & Participants: 326 sugarcane workers with normal preharvest serum creatinine (Scr) values and no history of CKD in an MeN hotspot in Nicaragua near the end of the harvest, and prospective follow-up of workers with AKI., Predictor: AKI during the harvest, as defined by Scr level increase ≥ 0.3mg/dL over baseline to a level ≥ 1.3mg/dL., Outcomes: Kidney function trajectory and development of CKD over 12 months., Analytical Approach: Linear regression models were used to analyze the association between job category and kidney function. For workers with AKI, the effect of time on Scr level was evaluated using linear mixed effects., Results: 34 of 326 participants were found to have AKI, with a median late-harvest Scr level of 1.64mg/dL in the AKI group. Workers without AKI had a median Scr level of 0.88mg/dL. AKI was more common among cane cutters compared with other field workers. Participants with AKI had variable degrees of kidney function recovery, with median 6- and 12-month Scr values of 1.25 and 1.27mg/dL, respectively (P < 0.001 for each follow-up value compared to late-harvest Scr). When we compared workers' kidney function before the AKI episode to their kidney function at last follow-up, 10 participants with AKI developed de novo estimated glomerular filtration rate < 60mL/min/1.73m 2 and 11 had a >30% decrease in estimated glomerular filtration rate., Limitations: Follow-up limited to 1 year and some loss to follow-up in the prospective component of the study. Broad definition of AKI that includes both acute and subacute kidney injury., Conclusions: In a group of sugarcane workers with normal preharvest kidney function, newly decreased kidney function developing during the harvest season was common. Of those with kidney injury, nearly half had established CKD 12 months later., (Copyright © 2018 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

We present the theory of a direct detection receiver for vortex beams for an optical wireless communication system. The proposed receiver has an array of annular detectors, which enables analysis of power distribution of the vortex beam. We give a detailed description, numerical optimization, and different options for its design. One possible application of this receiver could be high security communication systems, and another could be intra data center communication. Using a given set of parameters, we find that a seven-ring symmetrically spaced detector is comparable to a three-ring detector with an optimized ring area.

Background: Mesoamerican nephropathy (MeN) is a kidney disease of unknown cause that mainly affects working-age men in Central America. Despite being a major cause of morbidity and mortality in this region, its clinical characteristics have not been well defined., Study Design: Cross-sectional family-based study., Setting & Participants: 266 members of 24 families with high chronic kidney disease (CKD) burdens in a MeN hotspot in Northwestern Nicaragua. We compared clinical and biochemical characteristics of affected individuals first with their unaffected relatives and then with NHANES (National Health and Nutrition Examination Survey) participants with CKD in order to reveal identifying features of MeN., Predictor: CKD defined as serum creatinine level ≥ 1.5mg/dL in men and ≥1.4mg/dL in women., Outcomes: Clinical and biochemical parameters, including serum sodium, potassium, bicarbonate, calcium, magnesium, phosphorus, and uric acid., Results: Hyperuricemia, in many cases severe, was common among patients with MeN. Uric acid levels in patients with MeN were higher than those in NHANES participants (mean, 9.6 vs 7.4mg/dL for men in each group) despite more frequent use of uric acid-lowering medications in Nicaraguan individuals (71.7% vs 11.2%). In multivariable linear mixed-effects regression analysis, uric acid levels were 2.0mg/dL (95% CI, 1.0-3.0; P<0.001) higher in patients with MeN compared with their NHANES counterparts after adjusting for age, estimated glomerular filtration rate, and uric acid-lowering therapies. In contrast to prior reports, hyponatremia and hypokalemia were not common., Limitations: CKD defined by single serum creatinine measurement; population likely not representative of full MeN phenotype spectrum across Central America; major differences between MeN and NHANES groups in important characteristics such as age, ancestry, and recruitment method., Conclusions: Hyperuricemia out of proportion to the degree of decreased kidney function was common among Nicaraguan patients with MeN. Our results suggest that rather than being solely a consequence of CKD, hyperuricemia may play a role in MeN pathogenesis, a hypothesis that deserves further study., (Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Although hypertension is known to have an adverse impact on health-related quality of life (HRQoL) in adults, little is known about the effects of hypertension and use of antihypertensive medications on HRQoL in hypertensive children with chronic kidney disease (CKD)., Methods: Cross-sectional and longitudinal assessment of impact of elevated blood pressure (BP) and antihypertensive medication use on HRQoL scores obtained in children enrolled in the Chronic Kidney Disease in Children (CKiD) Study. Blood pressure was measured both manually and by ambulatory blood pressure monitoring. HRQoL was assessed with the PedsQL survey., Results: The study sample included 551 participants with sufficient data for cross-sectional and longitudinal analyses. Cross-sectional analysis of presence of prehypertension or hypertension and impact on HRQoL found mild associations between elevated BP and HRQoL scores with overall PedsQL parent and child scores averaging 79 vs. 76.5 and 83 vs. 78.5, respectively. However, no associations persisted under longitudinal multivariate analysis., Conclusions: Despite apparent small effects of elevated BP on HRQoL at baseline, no association was found between the presence of elevated BP and HRQoL over time in children with mild-to-moderate CKD. In addition, antihypertensive medication use did not appear to have an impact on HRQoL in this population.

Background: An epidemic of chronic kidney disease (CKD) of non-traditional aetiology has been recently recognized by health authorities as a public health priority in Central America. Previous studies have identified strenuous manual work, agricultural activities and residence at low altitude as potential risk factors; however, the aetiology remains unknown. Because individuals are frequently diagnosed with CKD in early adulthood, we measured biomarkers of kidney injury among adolescents in different regions of Nicaragua to assess whether kidney damage might be initiated during childhood., Methods: Participants include 200 adolescents aged 12-18 years with no prior work history from four different schools in Nicaragua. The location of the school served as a proxy for environmental exposures and geographic locations were selected to represent a range of factors that have been associated with CKD in adults (e.g. altitude, primary industry and CKD mortality rates). Questionnaires, urine dipsticks and kidney injury biomarkers [interleukin-18, N-acetyl-d-glucosaminidase (NAG), neutrophil gelatinase-associated lipocalin (NGAL) and albumin-creatinine ratio] were assessed. Biomarker concentrations were compared by school using linear regression models., Results: Protein (3.5%) and glucose (1%) in urine measured by dipstick were rare and did not differ by school. Urine biomarkers of tubular kidney damage, particularly NGAL and NAG, showed higher concentrations in those schools and regions within Nicaragua that were defined a priori as having increased CKD risk. Painful urination was a frequent self-reported symptom., Conclusions: Although interpretation of these urine biomarkers is limited because of the lack of population reference values, results suggest the possibility of early kidney damage prior to occupational exposures in these adolescents., (© The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Objective: To compare the reliability of blood pressure (BP) readings obtained with an oscillometric device with those obtained by auscultation and assess for differences in BP status classification based on the 2 techniques., Study Design: Resting BP was measured by auscultation and with an oscillometric device at the same encounter in 235 subjects enrolled in the Chronic Kidney Disease in Children study. Resting auscultatory BP values were averaged and compared with averaged oscillometric readings. BP agreement by the 2 methods was assessed using Bland-Altman plots, and BP status classification agreement was assessed by calculation of kappa statistics., Results: Oscillometric BP readings were higher than auscultatory readings, with a median paired difference of 9 mm Hg for systolic BP (SBP) and 6 mm Hg for diastolic BP (DBP). Correlation for mean SBP was 0.624 and for mean DBP was 0.491. The bias for oscillometric BP measurement was 8.7 mm Hg for SBP (P < .01) and 5.7 mm Hg for DBP (P < .01). BP status classification agreement was 61% for SBP and 63% for DBP, with Kappa values of .31 for SBP and .20 for DBP., Conclusions: Compared with auscultation, the oscillometric device significantly overestimated both SBP and DBP, leading to frequent misclassification of BP status., (Copyright © 2012 Mosby, Inc. All rights reserved.)

How was the world created? This question has received attention from many perspectives including religion, culture, philosophy, mysticism, and science. While it may not seem like a query amenable to scientific measurement, it has led scientists to pose fascinating ideas and observations including the Big Bang, the concept of inflation, the fact that most of the universe is made up of dark matter and dark energy that can not be perceived, and more. Scientists cannot claim to know the definitive answer, but they can approach the question from a scientific viewpoint. This begins by examining data, which, thanks to new technology, yields more information than has been previously available. Using novel scientific methods and techniques to analyze the data, fresh perspectives concerning the creation of the world have emerged. This process and its main findings will be described.

We report the case of an 8-year-old girl diagnosed with atypical hemolytic uremic syndrome (aHUS) with a complement factor B (CFB) gene mutation. aHUS is a disease of complement dysregulation. In approximately 50% of patients, mutations are identified in genes encoding regulators of complement-complement factor H (CFH), membrane cofactor protein or complement factor I (CFI)-or activators of complement-complement factor B (CFB) or C3. The mutation in this patient was identified in exon 12 of CFB and changes a lysine at amino acid position 533 to an arginine (c.1598A>G p.Lys533Arg). The two other mutations previously reported in CFB associated with aHUS are c.858C>G, p.F286L in exon 6 and c.967A>Gp.K323E in exon 7.

Nitric oxide and nitrovasodilators induce vascular smooth muscle cell relaxation in part by cGMP-dependent protein kinase I (PKG-Ialpha)-mediated activation of myosin phosphatase (MLCP). Mechanistically it has been proposed that protein-protein interactions between the N-terminal leucine zipper (LZ) domain of PKG-Ialpha ((PKG-Ialpha(1-59)) and the LZ and/or coiled coil (CC) domain of the myosin binding subunit (MBS) of MLCP are localized in the C terminus of MBS. Although recent studies have supported these interactions, the critical amino acids responsible for these interactions have not been identified. Here we present structural and biophysical data identifying that the LZ domain of PKG-Ialpha(1-59) interacts with a well defined 42-residue CC motif (MBS(CT42)) within the C terminus of MBS. Using glutathione S-transferase pulldown experiments, chemical cross-linking, size exclusion chromatography, circular dichroism, and isothermal titration calorimetry we identified a weak dimer-dimer interaction between PKG-Ialpha(1-59) and this C-terminal CC domain of MBS. The K(d) of this non-covalent complex is 178.0+/-1.5 microm. Furthermore our (1)H-(15)N heteronuclear single quantum correlation NMR data illustrate that this interaction is mediated by several PKG-Ialpha residues that are on the a, d, e, and g hydrophobic and electrostatic interface of the C-terminal heptad layers 2, 4, and 5 of PKG-Ialpha. Taken together these data support a role for the LZ domain of PKG-Ialpha and the CC domain of MBS in this requisite contractile complex.

Renal and urological anomalies in Down syndrome (DS) have received little attention compared with the nephrourological findings described in other chromosomal abnormalities. Renal hypoplasia, hydroureteronephrosis, ureterovesical and ureteropelvic junction obstruction, and vesicoureteral reflux, but not posterior urethral valves, have been associated with DS. We report the occurrence of posterior urethral valves in three male infants with DS at a single institution. All had multiple urological procedures for correction or palliation of obstruction. Children with DS may have an increased risk for developing posterior urethral valves and obstructive uropathy. Furthermore, they may also develop chronic renal failure secondary to posterior urethral valves. Therefore, we suggests that infants with DS be screened with ultrasonography for renal and urological abnormalities early in life and, if abnormal, a contrast voiding cystourethrogram be performed to rule out posterior urethral valves or other bladder or urethral abnormalities. A review of the renal and urological anomalies in DS reported in the literature since 1960 is presented.

The megacystis-microcolon-intestinal hypoperistalsis syndrome is a congenital disorder characterized by urinary bladder distension and hypoperistalsis throughout the entire gastrointestinal tract. We present a new case with the typical clinical, radiological, and pathological findings of the syndrome. The diagnosis should be suspected in a patient who present clinically with intestinal obstruction and urinary retention, and confirmed with imaging studies, including abdominal plain films, urinary tract ultrasonography, and contrast studies of the colon and the bladder. The prognosis is generally very poor. Our patient died secondary to sepsis on day 5 of life.

Between 1965 and 1988, at the Children's Hospital of Buenos Aires, 22 children developed two successive malignant tumors of different histology. The first tumor was diagnosed between 3 months and 12 years of age: 13 retinoblastoma, 2 rhabdomyosarcoma, 2 non-Hodgkin lymphoma, 2 Hodgkin disease, 1 brain stem glioma, 1 endodermal sinus tumor and 1 Ewing sarcoma. Familial cancer was registered in 6 patients. Children were treated with surgery, intensive chemo and radiotherapy. The second malignancy developed after 2 to 13 years: 10 osteosarcoma, 2 Ewing sarcoma, 2 rhabdomyosarcoma, 2 glioblastoma, 1 medulloblastoma, 1 synoviosarcoma, 1 fibrosarcoma, 1 thyroid carcinoma, 1 acute lymphoblastic leukemia and 1 acute myeloblastic leukemia. In 17 patients, the tumor developed in irradiated field. There was no evidence of the first tumor and only 1 patient was still under chemotherapy. Oncologic treatment was frustrating for these second tumors and 18 children died. Three are alive with no evidence of disease at 2 years, 2 years and 4 months and 3 years after diagnosis. One patient was lost to follow-up. It if postulated that second malignant tumors are consecutive to genetic predisposition and/or to the oncogenic effect of chemo and radiotherapy. The intensity of each treatment modality must be reduced as much as possible to obtain survival while limiting the secondary effects.