MEN2 phenotype in a family with germline heterozygous rare RET K666N variant.

Summary: Multiple endocrine neoplasia type 2 (MEN2) is a hereditary cancer syndrome caused by germline-activating pathogenic variants in the RET proto-oncogene. MEN2A is the most common subtype, with a risk for medullary thyroid cancer (MTC), pheochromocytoma (PHEO), and primary hyperparathyroidism (PHPT), whereas MEN2B is less common and associated with MTC and PHEO along with mucosal neuromas. Little is known about the specific RET germline heterozygous variant K666N. This variant has been described in very few families, and in most cases, patients were diagnosed with a very indolent MTC as the only feature. There is one case of MTC and bilateral PHEO. The RET K666N variant is not stratified yet by the American Thyroid Association, and data are limited on pathogenicity; therefore, appropriate screening and treatment of asymptomatic RET K666N carriers are unclear. Here, we report a family with a heterozygous germline RET K666N variant. The proband was identified when she experienced cardiogenic shock and multi-organ failure after an elective hysterectomy and subsequently was found to have PHEO, with genetic testing revealing the RET K666N germline variant. Patient consent was obtained through IRB protocol COMIRB #15-0516. Learning Points: The specific RET germline heterozygous variant K666N is rare and described in very few families, and in most cases, patients were diagnosed with a very indolent MTC as the only feature. Our proband is much younger and has PHEO, MTC, and PHPT. The RET K666N germline variant appears to be a low penetrance variant for MEN2.

Screening of Fracture Risk and Osteoporosis Among Older Long-term Care Residents: A Prospective Study.

This prospective study assessed the effectiveness of screening older long-term care residents (LTCRs) for fracture risk and osteoporosis in Taiwan. Fracture risk screening was done using the Fracture Risk Assessment Tool (FRAX), and those with high or moderate risk were offered osteoporosis workup and treatment at the hospital. Among 785 LTCRs screened, 338 men (mean age 75.6) and 447 women (mean age 81.2) were included. Only 5.2% of women and no men were using anti-osteoporosis medication. Based on the Bone Health and Osteoporosis Foundation (BHOF) recommendations, 69.2% of men and 92.6% of women were classified as high fracture risk. In 110 participants willing to receive bone mineral density examination, osteoporosis was diagnosed in 86.2% of women and half of men. FRAX could effectively differentiate fracture risk in 648 LTCRs who completed 2-year follow-ups; no fracture occurred in the low-risk group. The study emphasizes the importance of fracture risk screening to enhance osteoporosis diagnosis and treatment among LTCRs.

Docosahexaenoic acid inhibits ethanol/palmitoleic acid-induced necroptosis in AR42J cells.

Fatty acid ethyl esters (FAEEs), non-oxidative metabolites of ethanol, are the main causative agents of severe acute pancreatitis resulting from alcohol abuse. Pancreatic acinar cells exposed to ethanol in combination with the fatty acid palmitoleic acid (EtOH/POA) display increased levels of palmitoleic acid ethyl ester and cell death. Oxidative stress and acinar cell necroptosis are implicated in the pathology of severe acute pancreatitis. Docosahexaenoic acid (DHA) serves as a powerful anti-oxidant that reduces pancreatic inflammation and improves the outcomes of patients with acute pancreatitis. We investigated whether treatment of EtOH/POA, as an in vitro model of alcoholic pancreatitis, increases reactive oxygen species (ROS), necroptosis-regulating proteins, and cell death by increasing nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and intracellular calcium. Also, we investigated whether DHA inhibits EtOH/POA-induced alterations in pancreatic acinar AR42J cells. As a result, EtOH/POA increased intracellular and mitochondrial ROS levels, NADPH oxidase activity, necroptosis-regulating proteins, and cell death, which was inhibited by NADPH oxidase inhibitor apocynin, the Ca2+ chelator BAPTA, and DHA. However, DHA did not reduce EtOH/POA-induced increases in Ca2+ oscillation or levels in AR42J cells. Furthermore, EtOH/POA induced mitochondrial dysfunction by reducing mitochondrial membrane polarization and hence, adenosine triphosphate (ATP) production. DHA treatment attenuated EtOH/POA-induced mitochondrial dysfunction. In conclusion, DHA inhibits EtOH/POA-induced necroptosis by suppressing NADPH oxidase activity, reducing ROS levels, preventing mitochondrial dysfunction, and inhibiting activation of necroptosis-regulating proteins in AR42J cells.

Intranasal midazolam and fentanyl for procedural sedation and analgesia in infants in the neonatal intensive care unit.

BACKGROUND: The intranasal route is a minimally invasive method for rapidly delivering midazolam and fentanyl to provide short-term analgesia and sedation in infants. However, intranasal use of midazolam and fentanyl is not labeled for infants and safety data are sparse. The objective of this study is to evaluate the safety of intranasal midazolam and intranasal fentanyl in infants admitted to the Neonatal Intensive Care Unit (NICU). METHODS: We retrospectively identified all infants receiving intranasal midazolam or fentanyl in the NICU from 2009 to 2015. We recorded indication for use and vital signs and determined the proportion of infants experiencing the following adverse events: death within 24 hours, hypotension, bradycardia, worsening respiratory status, and chest wall rigidity. Vital signs 4 hours before and after each dose were compared using the Wilcoxon signed-rank test. RESULTS: We identified 17 infants (gestational ages 23- 41 weeks) receiving 25 intranasal doses. None of the infants died or developed hypotension, bradycardia, or chest wall rigidity. Intranasal delivery was most commonly used for sedation during magnetic resonance imaging studies. Other indications include analgesia or sedation for retinopathy of prematurity surgery, intubation, and peripherally inserted central catheter placement. One infant receiving intranasal midazolam experienced worsening respiratory status. Vital signs before and after dosing were not significantly different. CONCLUSIONS: Intranasal midazolam and fentanyl use in term and preterm infants appeared safe and well-tolerated in this small cohort of infants. Larger, prospective studies evaluating the safety and efficacy of intranasal midazolam and fentanyl use in infants are warranted.

Formation and alteration of airborne particles in the subway environment.

Most particles in the rail subway environment are sub-micron sized ferruginous flakes and splinters generated mechanically by frictional wear of brake pads, wheels and rails. To better understand the mechanisms of formation and the alteration processes affecting inhalable particles in subways, PM samples (1-2.5 µm and 2.5-10 µm) were collected in the Barcelona Metro and then studied under a scanning electron microscope. Most particles in these samples are hematitic (up to 88%), with relatively minor amounts of mineral matter (up to 9%) and sulphates (up to 5%). Detailed microscopy (using back scattered and TEM-DRX imaging) reveals how many of the metallic particles comprise the metallic Fe nucleus surrounded by hematite (Fe2O3) and a coating of sulphate and chloride salts mixed with mineral matter (including Ca-carbonates, clay minerals and quartz). These observations record the emission of fine to ultrafine FePM by frictional wear at elevated temperatures that promote rapid partial (or complete) oxidation of the native metal. Water condensing on the PM surface during cooling leads to the adsorption of inorganic mineral particles that coat the iron oxide. The distinctively layered polymineralic structure that results from these processes is peculiar to particles generated in the subway environment and very different from PM typically inhaled outdoors.

Risk factors for group B streptococcal disease in neonates of mothers with negative antenatal testing.

OBJECTIVE: The aim of this study was to identify risk factors for early-onset group B Streptococcus (EOGBS) disease in neonates of mothers with negative antenatal screening. STUDY DESIGN: We performed a retrospective cohort study of neonates born to mothers with negative antenatal GBS screening between 2002 and 2012. Our primary outcome was EOGBS infection. We used multivariable logistic regression to assess factors associated with EOGBS. RESULTS: EOGBS was confirmed in 492 of the 179 818 neonates that met the study inclusion criteria. Risk factors for EOGBS included black race (reference: white, odds ratio (OR) =1.81 (95% confidence interval: 1.43, 2.31)), maternal age <18 years (reference: >35 years, OR=2.63 (1.54, 4.51)) and maternal age 18 to 35 years (reference: >35 years, OR=1.94 (1.30, 2.88)). CONCLUSION: Maternal age <18 years and black race were the strongest predictors of EOGBS. Further research investigating contributors to the discordance between screening results and neonatal outcomes in these populations is needed.

High baseline bilirubin and low albumin predict liver decompensation and serious adverse events in HCV-infected patients treated with sofosbuvir-containing regimens.

To conduct surveillance and determine the safety profile of new hepatitis C virus treatments in real-world clinical practice. Hepatic decompensation and other serious adverse events were investigated in an observational cohort study of 511 patients treated with regimens containing sofosbuvir, December 2013-June 2014. Among 499 previously stable patients (no history of hepatic decompensation during the previous 12 months), a nested case-control study was performed to identify predictors of decompensation/serious adverse event. Cases and controls were matched 1:5 based on treatment regimen and duration. Matched conditional logistic regression was used for analysis. Providers scored the likelihood that events were treatment-related (scale = 0-4). The cumulative incidence of decompensation/events was 6.4% for the total cohort. Among 499 previously stable patients, the incidence of decompensation/events was 4.5%; the mortality rate was 0.6%. Sixteen of the 499 experienced one or more serious complications considered to be at least potentially treatment-related, and the sustained virological response rate was 7/16 (44%). Two cases, both on sofosbuvir/simeprevir (without interferon or ribavirin), had complications consistent with autoimmune events (score 3, 'likely treatment-related'), and one experienced a flare of autoimmune hepatitis. Compared to controls, cases had higher baseline median model for end-stage liver disease scores (14 vs 8, P < 0.01). Decompensation/events was independently associated with lower baseline albumin (OR = 0.12/g/dL, P = 0.01) and higher total bilirubin (OR = 4.31/mg/dL, P = 0.01). Reduced hepatic function at baseline increased the risk of liver decompensation/events.

The ZmCLA4 gene in the qLA4-1 QTL controls leaf angle in maize (Zea mays L.).

Maize architecture is a major contributing factor to their high level of productivity. Maize varieties with an erect-leaf-angle (LA) phenotype, which increases light harvesting for photosynthesis and grain-filling, have elevated grain yields. Although a large body of information is available on the map positions of quantitative trait loci (QTL) for LA, little is known about the molecular mechanism of these QTL. In this study, the ZmCLA4 gene, which is responsible for the qLA4-1 QTL associated with LA, was identified and isolated by fine mapping and positional cloning. The ZmCLA4 gene is an orthologue of LAZY1 in rice and Arabidopsis. Sequence analysis revealed two SNPs and two indel sites in ZmCLA4 between the D132 and D132-NIL inbred maize lines. Association analysis showed that C/T/mutation667 and CA/indel965 were strongly associated with LA. Subcellular localization verified the functions of a predicted transmembrane domain and a nuclear localization signal in ZmCLA4. Transgenic maize plants with a down-regulated ZmCLA4 RNAi construct and transgenic rice plants over-expressing ZmCLA4 confirmed that the ZmCLA4 gene located in the qLA4 QTL regulated LA. The allelic variants of ZmCLA4 in the D132 and D132-NIL lines exhibited significant differences in leaf angle. ZmCLA4 transcript accumulation was higher in D132-NIL than in D132 during all the developmental stages and was negatively correlated with LA. The gravitropic response was increased and cell shape and number at the leaf and stem junctions were altered in D132-NIL relative to D132. These findings suggest that ZmCLA4 plays a negative role in the control of maize LA through the alteration of mRNA accumulation, leading to altered shoot gravitropism and cell development. The cloning of the gene responsible for the qLA4-1 QTL provides information on the molecular mechanisms of LA in maize and an opportunity for the improvement of plant architecture with regard to LA through maize breeding.

Integrated multiple population analysis of leaf architecture traits in maize (Zea mays L.).

Leaf morphology in maize is regulated by developmental patterning along three axes: proximodistal, mediolateral, and adaxial-abaxial. Maize contains homologues of many genes identified as regulators of leaf development in other species, but their relationship to the natural variation of leaf shape remains unknown. In this study, quantitative trait loci (QTLs) for leaf angle, leaf orientation value, leaf length, and leaf width were mapped by a total of 256 F(2:3) families evaluated in three environments. Meta-analysis was used to integrate genetic maps and detect QTLs across several independent QTL studies, on the basis of the previously reported experimental results for leaf architecture traits. Candidate gene sequences for leaf architecture were mapped in the integrated consensus genetic map. In total, 21 QTLs and 17 meta-QTLs (mQTLs) were detected. Among these QTLs, qLA1-1 and qLA2 were consistently detected in five and three populations respectively, and six of seven QTLs with contributions (R(2)) >10% were integrated in mQTLs. Six key mQTLs (mQTL1-1, mQTL2-1, mQTL3-3, mQTL5-1, mQTL7-2, and mQTL8-1) with R(2) of some initial QTLs >10% included 4-6 initial QTLs associated with 2-4 traits. Therefore, the chromosome regions for six mQTLs with high QTL co-localization might be hot spots of the important QTLs for the associated traits. Fifteen key candidate genes controlling leaf architecture traits coincided with 11 corresponding mQTLs, namely DWARF4, KAN3, liguleless1, TAC1, ROT3, AS2/liguleless2, PFL2, yabby9/SE/LIC/yabby15, mwp1, CYCD3;2, and CYCB1. In particular, DWARF4, liguleless1, AS2/liguleless2, yabby9/SE/LIC/yabby15, and CYCD3;2 were mapped within the important mQTL1-1, mQTL2-1, mQTL3-3, mQTL5-1, and mQTL7-2 intervals, respectively. Fine mapping or construction of single chromosome segment lines for genetic regions of these five mQTLs is worth further study and could be put to use in marker-assisted breeding. In conclusion, the results provide useful information for further research and help to reveal the molecular mechanisms with regard to leaf architecture traits.

Quantitative trait loci mapping of leaf angle and leaf orientation value in maize (Zea mays L.).

A major limiting factor for high productivity of maize (Zea mays L.) in dense planting is light penetration through the canopy. Plant architecture with a narrower leaf angle (LA) and an optimum leaf orientation value (LOV) is desirable to increase light capture for photosynthesis and production per unit area. However, the genetic control of the plant architecture traits remains poorly understood in maize. In this study, QTL for LA, LOV, and related traits were mapped using a set of 229 F(2:3) families derived from the cross between compact and expanded inbred lines, evaluated in three environments. Twenty-five QTL were detected in total. Three of the QTL explained 37.4% and five of the QTL explained 53.9% of the phenotypic variance for LA and LOV, respectively. Two key genome regions controlling leaf angle and leaf orientation were identified. qLA1 and qLOV1 at nearest marker umc2226 on chromosome 1.02 accounted for 20.4 and 23.2% of the phenotypic variance, respectively; qLA5 and qLOV5 at nearest bnlg1287 on chromosome 5 accounted for 9.7 and 9.8% of the phenotypic variance, respectively. These QTL could provide useful information for marker-assisted selection in improving performance of plant architecture with regard to leaf angle and orientation.

Genetic analysis of photoperiod sensitivity in a tropical by temperate maize recombinant inbred population using molecular markers.

Photoperiod sensitivity is an important consideration in maize cultivation. Flowering time is affected by photoperiod and sensitivity to it limits the potential for successful exchange of germplasm across different latitudes. For resolving the genetic basis of photoperiod sensitivity in maize, a set of 207 recombinant inbred lines derived from a temperate and tropical inbred line cross was evaluated for 2 years in a long-day and short-day environment. Genetic linkage maps were constructed using 237 SSR markers with a total length 1,974.3 cM, and an average space between two makers of 8.33 cM. Twenty-nine QTL were detected for the five measured photoperiod sensitivity traits using composite interval mapping and multiple interval mapping. QTL for flowering time, plant height and leaf number, under long-day conditions, were found clustered on chromosome 10, while QTL for short-day conditions resided on chromosome 3. The QTL in the bin 10.04 region of chromosome 10 were detected associated with photoperiod sensitivity and related traits during long days. These results indicated that this region might contain an important photoperiod sensitivity element.

The fragile X mental retardation protein inhibits translation via interacting with mRNA.

Fragile X syndrome is a frequent form of inherited mental retardation caused by functional loss of the fragile X mental retardation protein, FMRP. The function of FMRP is unknown, as is the mechanism by which its loss leads to cognitive deficits. Recent studies have determined that FMRP is a selective RNA-binding protein associated with polyribosomes, leading to the hypothesis that FMRP may be involved in translational regulation. Here we show that purified recombinant FMRP causes a dose-dependent translational inhibition of brain poly(A) RNA in rabbit reticulocyte lysate without accelerated mRNA degradation. In our translation reaction FMRP interacts with other messenger ribonucleoproteins and pre-exposure of FMRP to mRNA significantly increased the potency of FMRP as a translation inhibitor. Translation suppression by FMRP is reversed in a trans-acting manner by the 3'-untranslated portion of the Fmr1 message, which binds FMRP, suggesting that FMRP inhibits translation via interacting with mRNA. Consistently FMRP suppresses translation of the parathyroid hormone transcript, which binds FMRP, but not the beta-globin transcript, which does not bind FMRP. Moreover, removing the FMRP-binding site on a translation template abolishes the inhibitory effect of FMRP. Taken together, our results support the hypothesis that FMRP inhibits translation via interactions with the translation template.

Left out: immigrants' access to health care and insurance.

Recent policy changes have limited immigrants' access to insurance and to health care. Fewer noncitizen immigrants and their children (even U.S.-born) have Medicaid or job-based insurance, and many more are uninsured than is the case with native citizens or children of citizens. Noncitizens and their children also have worse access to both regular ambulatory and emergency care, even when insured. Immigration status is an important component of racial and ethnic disparities in insurance coverage and access to care.

Adolescents' reports of reproductive health education, 1988 and 1995.

CONTEXT: Reproductive health education is a key strategy for promoting safe sexual behavior among teenagers. In the last decade, new initiatives in response to AIDS and growing interest in abstinence education may have changed the prevalence, content or timing of the reproductive health education provided by schools and parents. METHODS: Formal reproductive health education and communication with parents about reproductive health among males aged 15-19 were analyzed using data from the 1988 and 1995 National Surveys of Adolescent Males. Young men's reports of formal instruction were compared with reports by adolescent females from the 1995 National Survey of Family Growth. RESULTS: Between 1988 and 1995, formal reproductive health education became nearly universal among adolescent males: In 1988, 93% of teenage males received some formal instruction, compared with 98% in 1995. The percentage of teenage males who received instruction about AIDS increased from 73% to 97% and the proportion who received instruction about how to say no to sex increased from 58% to 75%. Adolescent males who had dropped out of school received significantly less reproductive health education than those who had stayed in school, however. In addition, the median age at initial instruction decreased from age 14 to 13. Many males did not receive instruction prior to first intercourse, with non-Hispanic blacks being significantly less likely than other males to receive education prior to first intercourse. In 1995, 54% of black males had received reproductive health education before they first had sex, compared with 68% of Hispanic males and 76% of non-Hispanic white males. A smaller share of adolescent males than females received reproductive health education, and males were less likely than females to receive instruction prior to first intercourse. CONCLUSIONS: During the last decade, many types of formal reproductive health education for adolescents expanded. Further efforts should focus on assuring access to timely, comprehensive and high-quality reproductive health education for all teenagers and reducing gaps in access related to race, gender and school attendance.

Use of reproductive health services among young men, 1995.

PURPOSE: To analyze the extent to which teenage males receive preventive reproductive health services and identify demographic and health factors associated with their receipt. METHODS: Bivariate and multivariate analyses of nationally representative data from the 1995 National Survey of Adolescent Males were conducted using logistic regression to determine which factors predicted whether teenagers had a physical examination and whether they discussed reproductive health topics with a medical professional, had a human immunodeficiency virus (HIV) test, or had a sexually transmitted disease (STD) test. RESULTS: Although 71% of males aged 15-19 years received a physical examination in the past year, only 39% of them received any of the three reproductive health services. Less than one-third of all young men discussed reproductive health with their doctor or nurse. Among sexually experienced males, one-sixth had an STD test and one-quarter an HIV test. In multivariate analysis, males who had a physical examination were more likely to have an STD or HIV test, but were no more likely to discuss reproductive health topics. Minority and low-income youth were more likely to receive these reproductive health services, as were young men with multiple sex partners and those with health problems. CONCLUSIONS: In general, the proportion of teenage men receiving reproductive health services is low, although levels are higher among minority youth and certain groups at risk. To reduce rates of teen pregnancy and STDs, physicians and nurses need to incorporate reproductive health care into routine health services for teenage males, as well as females.

Characterization of Vibrio parahaemolyticus isolates obtained from foodborne illness outbreaks during 1992 through 1995 in Taiwan.

Vibrio parahaemolyticus is an important foodborne pathogen in Taiwan and many other Asian countries. A total of 371 isolates of V. parahaemolyticus collected from patients involved in foodborne illness outbreaks in Taiwan from 1992 to 1995 were characterized. These isolates had typical biochemical characteristics and only 4% were urease positive. The most frequently isolated serovars were O5:K15 (18.5%), O4:K8 (16.2%), O3:K29 (12.5%), O1:K56 (8.3%), O2:K3 (6.5%), and O4:K12 (6.0%). Most of the isolates were susceptible to nalidixic acid, tetracycline, tobramycin, cephalothin, and gentamicin. About 10% of the isolates were resistant to seven or more antibiotics. Approximately 92.4% of these V. parahaemolyticus showed beta-hemolysis on Wagatsuma blood agar plate and approximately 62.1% of these isolates exhibited detectable amounts of thermostable direct hemolysin. Most of the isolates examined exhibited two copies of tdh genes on the 1.3- and 2.5-kb HindIII-digested chromosome fragments with several variations on other fragments. A pulsed-field gel electrophoresis (PFGE) subspecies typing scheme was used to analyze these domestic isolates and the O3:K6 strains from Japan, Korea, and Taiwan. Fifty seven patterns were differentiated with A, B, C, E, and H being the major domestic types (cumulatively 76% of isolates), while O3:K6 strains (PFGE type I), abruptly occurring since 1996, were genetically distant from the major domestic types.

Older, but not wiser: how men get information about AIDS and sexually transmitted diseases after high school.

CONTEXT: As they reach adulthood, young men are less likely to use condoms and are at increased risk for exposure to AIDS and other sexually transmitted diseases (STDs). Little is known about which prevention efforts reach men in their 20s. METHODS: Longitudinal data from the 1988, 1990-1991 and 1995 waves of the National Survey of Adolescent Males are used to identify sources of information about AIDS and STDs among 1,290 young men aged 22-26. Information receipt from four main sources, the topics covered by each source and the personal characteristics associated with getting more information are all explored. RESULTS: Twenty-two percent of men surveyed discussed disease prevention topics with a health provider in the last year, 48% attended a lecture or read a brochure, 51% spoke to a partner, friend or family member, and 96% heard about AIDS or STDs from the media (e.g., television advertisements, radio or magazine). Excluding media sources, 30% of young men reported getting no STD or AIDS prevention messages in the last year. Being black or Hispanic, having had a physical exam or an AIDS test in the last year, and having discussions about AIDS or STDs with parents or a health care provider in the past were associated with receiving more information. CONCLUSIONS: Although young men who are at higher risk for STD or HIV infection are more likely than other young men to get information about disease prevention, young adult men are much less likely than adolescents to receive AIDS or STD prevention education. More prevention efforts need to be aimed at young adults.