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Objectives. To assess the impact of the COVID-19 pandemic on immunization services across the life course. Methods. In this retrospective study, we used Michigan immunization registry data from 2018 through September 2020 to assess the number of vaccine doses administered, number of sites providing immunization services to the Vaccines for Children population, provider location types that administer adult vaccines, and vaccination coverage for children. Results. Of 12 004 384 individual vaccine doses assessed, 48.6%, 15.6%, and 35.8% were administered to children (aged 0–8 years), adolescents (aged 9–18 years), and adults (aged 19‒105 years), respectively. Doses administered overall decreased beginning in February 2020, with peak declines observed in April 2020 (63.3%). Overall decreases in adult doses were observed in all settings except obstetrics and gynecology provider offices and pharmacies. Local health departments reported a 66.4% decrease in doses reported. For children, the total number of sites administering pediatric vaccines decreased while childhood vaccination coverage decreased 4.4% overall and 5.8% in Medicaid-enrolled children. Conclusions. The critical challenge is to return to prepandemic levels of vaccine doses administered as well as to catch up individuals for vaccinations missed. (Am J Public Health. 2021;111(11):2027–2035. https://doi.org/10.2105/AJPH.2021.306474 )

Background: Human papillomavirus (HPV) vaccine effectiveness (VE) evaluations provide important information for vaccination programs. We established a linkage between statewide central registries in Michigan to estimate HPV VE against in situ and invasive cervical lesions (CIN3+). Methods: We linked females in Michigan's immunization and cancer registries using birth records to establish a cohort of 773,193 women with known vaccination history, of whom 3,838 were diagnosed with CIN3+. Residential address histories from a stratified random sample were used to establish a subcohort of 1,374 women without CIN3+ and 2,900 with CIN3+ among continuous Michigan residents. VE and 95% confidence intervals (CI) were estimated using cohort and case–cohort methods for up-to-date (UTD) vaccination and incomplete vaccination with 1 and 2 doses, and stratified by age at vaccination. Results: Both analytic approaches demonstrated lower CIN3+ risk with UTD and non-UTD vaccination vs. no vaccination. The cohort analysis yielded VE estimates of 66% (95% CI, 60%–71%) for UTD, 33% (95% CI, 18%–46%) for 2 doses-not UTD, and 40% (95% CI, 27%–50%) for 1 dose. The case–cohort analysis yielded VE estimates of 72% (95% CI, 64%–79%) for UTD, 39% (95% CI, 10%–58%) for 2 doses-not UTD, and 48% (95% CI, 25%–63%) for 1 dose. VE was higher for vaccination at age Conclusions: The statewide registry linkage found significant VE against CIN3+ with incomplete HPV vaccination, and an even higher VE with UTD vaccination. Impact: Future VE evaluations by number of doses for women vaccinated at younger ages may further clarify dose-related effectiveness.

On March 13, 2020, the United States declared a national state of emergency to control the pandemic spread of SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19) (1). Public health response measures to mitigate the pandemic have centered on social distancing and quarantine policies, including shelter-in-place and stay-at-home orders. Michigan implemented a stay-at-home order on March 23, 2020, to facilitate social distancing (2). Such strategies might result in decreased accessibility to routine immunization services, leaving children at risk for vaccine-preventable diseases and their complications (3). To evaluate whether vaccination coverage has changed during the pandemic, data from the Michigan Care Improvement Registry (the state's immunization information system) (MCIR) were analyzed. Changes in vaccine doses administered to children and the effects of those changes on up-to-date status were examined for vaccinations recommended at milestone ages corresponding to the end of an Advisory Committee on Immunization Practices (ACIP) recommendation period for one or more vaccines (4).

Background and aims Pollen grains of flowering plants display a fascinating diversity of forms, including diverse patterns of apertures, the specialized areas on the pollen surface that commonly serve as the sites of pollen tube initiation and, therefore, might play a key role in reproduction. Although many aperture patterns exist in angiosperms, pollen with three apertures (triaperturate) constitutes the predominant pollen type found in eudicot species. The aim of this study was to explore whether having three apertures provides selective advantages over other aperture patterns in terms of pollen survival, germination and reproductive success, which could potentially explain the prevalence of triaperturate pollen among eudicots. Methods The in vivo pollen germination, pollen tube growth, longevity and competitive ability to sire seeds were compared among pollen grains of Arabidopsis thaliana with different aperture numbers. For this, an arabidopsis pollen aperture series was used, which included the triaperturate wild type, as well as mutants without an aperture (inaperturate) and with more than three apertures. Key results Aperture number appears to influence pollen grain performance. In most germination and longevity experiments, the triaperturate and inaperturate pollen grains performed better than pollen with higher aperture numbers. In mixed pollinations, in which triaperturate and inaperturate pollen were forced to compete with each other, the triaperturate pollen outperformed the inaperturate pollen. Conclusions Triaperturate pollen grains might provide the best trade-off among various pollen performance traits, thus explaining the prevalence of this morphological trait in the eudicot clade.

Alteplase is an effective treatment for ischaemic stroke patients, and it is widely available at all primary stroke centres. The effectiveness of alteplase is highly time-dependent. Large tertiary centres have reported significant improvements in their door-to-needle (DTN) times. However, these same improvements have not been reported at community hospitals.Red Deer Regional Hospital Centre (RDRHC) is a community hospital of 370 beds that serves approximately 150,000 people in their acute stroke catchment area. The RDRHC participated in a provincial DTN improvement initiative, and implemented a streamlined algorithm for the treatment of stroke patients. During this intervention period, they implemented the following changes: early alert of an incoming acute stroke patient to the neurologist and care team, meeting the patient immediately upon arrival, parallel work processes, keeping the patient on the Emergency Medical Service stretcher to the CT scanner, and administering alteplase in the imaging area. Door-to-needle data were collected from July 2007 to December 2017.A total of 289 patients were treated from July 2007 to December 2017. In the pre-intervention period, 165 patients received alteplase and the median DTN time was 77 minutes [interquartile range (IQR): 60-103 minutes]; in the post-intervention period, 104 patients received alteplase and the median DTN time was 30 minutes (IQR: 22-42 minutes) (plt; 0.001). The annual number of patients that received alteplase increased from 9 to 29 in the pre-intervention period to annual numbers of 41 to 63 patients in the post-intervention period.Community hospitals staffed with community neurologists can achieve median DTN times of 30 minutes or less.L’altéplase est un traitement efficace dans le cas de patients victimes d’AVC ischémiques et demeure largement disponible dans les centres de soins de niveau primaire dédiés aux AVC. Cela dit, son efficacité dépend fortement des délais en fonction desquels on peut l’administrer. À cet égard, les centres de soins de niveau tertiaire ont fait état d’importantes améliorations en ce qui regarde leurs délais entre l’arrivée de patients et l’injection d’un traitement thrombolytique. Toutefois, il semble que de telles améliorations n’ont pas été signalées dans les hôpitaux communautaires.Le Red Deer Regional Hospital Centre (RDRHC) est un hôpital communautaire de 370 lits qui dessert approximativement 150 000 personnes dans sa zone d’attraction. Cet hôpital a participé à une initiative provinciale de réduction des délais mentionnés ci-dessus. Pour ce faire, il a mis au point un algorithme simplifié en vue du traitement de patients victimes d’AVC. Au cours de cette période d’intervention, les mesures de changement suivantes ont donc été adoptées : des alertes précoces transmises à un neurologue et aux équipes soignantes au moment de l’admission de patients victimes d’AVC aigus ; des rencontres immédiates avec les patients, et ce, dès leur arrivée à l’hôpital ; des processus de travail menés de façon parallèle ; le maintien des patients dans une civière d’ambulance jusqu’à temps qu’on puisse les conduire à un tomodensitomètre ; enfin, le fait d’administrer l’altéplase en fonction de la zone atteinte révélée par imagerie. Soulignons enfin que nos données en matière de réduction des délais ont été collectées de juillet 2007 à décembre 2017.Au total, 289 patients ont été traités durant cette période. Au cours de la période antérieure à l’initiative évoquée précédemment, 165 patients ont bénéficié d’un traitement à l’altéplase ; les délais médians entre l’arrivée des patients et l’injection de ce médicament thrombolytique étaient alors de 77 minutes (EI : 60-103 minutes). Une fois mise en place l’initiative de réduction des délais, 104 patients ont reçu un traitement à l’altéplase ; cette fois, les délais médians du RDRHC étaient de 30 minutes (EI : 22-42 minutes ; p0,001). Fait à noter, le nombre annuel de patients ayant bénéficié de l’altéplase est passé de 9 à 29 durant la période pré-initiative et de 41 à 63 lors de la période post-initiative.Dans le cas des hôpitaux communautaires disposant de neurologues réguliers, il est possible de parvenir à des délais de 30 minutes ou moins entre l’arrivée de patients et l’injection d’un traitement thrombolytique.

Female control of nonrandom mating has never been genetically established, despite being linked to inbreeding depression and sexual selection. In order to map the loci that control female-mediated nonrandom mating, we constructed a new advanced intercross recombinant inbred line (RIL) population derived from a cross between Arabidopsis (Arabidopsis thaliana) accessions Vancouver (Van-0) and Columbia (Col-0) and mapped quantitative trait loci (QTLs) responsible for nonrandom mating and seed yield traits. We genotyped a population of 490 RILs. A subset of these lines was used to construct an expanded map of 1,061.4 centimorgans with an average interval of 6.7 ± 5.3 centimorgans between markers. QTLs were then mapped for female- and male-mediated nonrandom mating and seed yield traits. To map the genetic loci responsible for female-mediated nonrandom mating and seed yield, we performed mixed pollinations with genetically marked Col-0 pollen and Van-0 pollen on RIL pistils. To map the loci responsible for male-mediated nonrandom mating and seed yield, we performed mixed pollinations with genetically marked Col-0 and RIL pollen on Van-0 pistils. Composite interval mapping of these data identified four QTLs that control female-mediated nonrandom mating and five QTLs that control female-mediated seed yield. We also identified four QTLs that control male-mediated nonrandom mating and three QTLs that control male-mediated seed yield. Epistasis analysis indicates that several of these loci interact. To our knowledge, the results of these experiments represent the first time female-mediated nonrandom mating has been genetically defined.

Background Concerns regarding vaccine safety and pain have prompted certain parents to limit the number of shots their child receives per visit. We estimated the prevalence of shot-limited children in Michigan, described their characteristics, assessed whether shot-limited children were up-to-date on recommended vaccinations, and investigated possible intervention points for vaccination education. Methods We analyzed vaccination registry and birth record data of children born in Michigan during 2012 who had ⩾2 vaccination visits, with ⩾1 visits after age 5 months. Shot-limited was defined as receiving ⩽2 shots at all visits through age 24 months. Nonlimited children received >2 shots at ⩾1 visits. Up-to-date vaccination was based on receipt of a seven-vaccine series and was determined at ages 24 months and 35 months. Risk ratios (RR) were calculated using risk regression. Results Of 101,443 children, a total of 2,967 (3%) children were shot-limited. Mothers of shot-limited children were more likely to be white (RR: 1.2; 95% confidence interval [CI]: 1.2–1.2), college graduate (RR: 1.9; 95% CI: 1.9–2.0), and married (RR: 1.5; 95% CI: 1.5–1.5). Compared with nonlimited children, shot-limited children were more likely to be born in a nonhospital setting (RR: 11.7; 95% CI: 9.4–14.6) and have a midwife attendant (RR: 1.9; 95% CI: 1.7–2.1). Shot-limited children were less likely to be up-to-date on recommended vaccinations (RR: 0.2; 95% CI: 0.2–0.3); this association was stronger for those with a midwife birth attendant (RR: 0.1; 95% CI: 0.1–0.2) rather than a medical doctor (RR: 0.3; 95% CI: 0.2–0.3). Conclusions Shot-limited children are less likely to be up-to-date on vaccinations, possibly leading to increased risk for vaccine-preventable diseases. This association was stronger for those with a midwife birth attendant. This analysis should prompt targeted education, such as to midwives, concerning risks associated with shot-limiting behavior.

Exine, the outer plant pollen wall, has elaborate species-specific patterns, provides a protective barrier for male gametophytes, and serves as a mediator of strong and species-specific pollen-stigma adhesion. Exine is made of sporopollenin, a material remarkable for its strength, elasticity, and chemical durability. The chemical nature of sporopollenin, as well as the developmental mechanisms that govern its assembly into diverse patterns in different species, are poorly understood. Here, we describe a simple yet effective genetic screen in Arabidopsis (Arabidopsis thaliana) that was undertaken to advance our understanding of sporopollenin synthesis and exine assembly. This screen led to the recovery of mutants with a variety of defects in exine structure, including multiple mutants with novel phenotypes. Fifty-six mutants were selected for further characterization and are reported here. In 14 cases, we have mapped defects to specific genes, including four with previously demonstrated or suggested roles in exine development (MALE STERILITY2, CYP703A2, ANTHER-SPECIFIC PROTEIN6, TETRAKETIDE α-PYRONE REDUCTASE/DIHYDROFLAVONOL-4-REDUCTASE-LIKE1), and a number of genes that have not been implicated in exine production prior to this screen (among them, fatty acid ω-hydroxylase CYP704B1, putative glycosyl transferases At1g27600 and At1g33430, 4-coumarate-coenzyme A ligase 4CL3, polygalacturonase QUARTET3, novel gene At5g58100, and nucleotide-sugar transporter At5g65000). Our study illustrates that morphological screens of pollen can be extremely fruitful in identifying previously unknown exine genes and lays the foundation for biochemical, developmental, and evolutionary studies of exine production.

Sporopollenin is the major component of the outer pollen wall (exine). Fatty acid derivatives and phenolics are thought to be its monomeric building blocks, but the precise structure, biosynthetic route, and genetics of sporopollenin are poorly understood. Based on a phenotypic mutant screen in Arabidopsis (Arabidopsis thaliana), we identified a cytochrome P450, designated CYP704B1, as being essential for exine development. CYP704B1 is expressed in the developing anthers. Mutations in CYP704B1 result in impaired pollen walls that lack a normal exine layer and exhibit a characteristic striped surface, termed zebra phenotype. Heterologous expression of CYP704B1 in yeast cells demonstrated that it catalyzes ω-hydroxylation of long-chain fatty acids, implicating these molecules in sporopollenin synthesis. Recently, an anther-specific cytochrome P450, denoted CYP703A2, that catalyzes in-chain hydroxylation of lauric acid was also shown to be involved in sporopollenin synthesis. This shows that different classes of hydroxylated fatty acids serve as essential compounds for sporopollenin formation. The genetic relationships between CYP704B1, CYP703A2, and another exine gene, MALE STERILITY2, which encodes a fatty acyl reductase, were explored. Mutations in all three genes resulted in pollen with remarkably similar zebra phenotypes, distinct from those of other known exine mutants. The double and triple mutant combinations did not result in the appearance of novel phenotypes or enhancement of single mutant phenotypes. This implies that each of the three genes is required to provide an indispensable subset of fatty acid-derived components within the sporopollenin biosynthesis framework.

Compatible pollinations from many different taxa display nonrandom mating. Here we describe a system for examining questions of nonrandom mating in Arabid- opsis thaliana. Using this system, we demonstrate that Arabidopsis thaliana displays nonrandom mating between distinct accessions. Statistical analysis of these data dem- onstrates aspects of both pollen competition and male- female complementarity in these matings. Cytological experiments implicate pollen germination and pollen tube growth rates as possible causal factors in these nonrandom mating efficiencies.

Jose A Vazquez,1 Anthony C Arnold,2 Robert N Swanson,3 Pinaki Biswas,3 Matteo Bassetti4 1Section of Infectious Diseases, Medical College of Georgia, Georgia Regents University, Augusta, GA, USA; 2UCLA Department of Ophthalmology, Jules Stein Eye Institute, Los Angeles, CA, USA; 3Clinical Research, Global Innovative Pharmaceutical, Pfizer Inc., New York, NY, USA; 4Infectious Diseases Division, Santa Maria della Misericordia University Hospital, Udine, Italy Objective: The objective of this study was to assess the long-term safety of linezolid in patients with chronic infections requiring treatment for ≥6weeks. Enhanced monitoring for optic neuropathy was included to characterize the early development of this side effect and to identify ophthalmologic tests that might be valuable in early detection of this event. Methods: This was a multicenter, open-label, pilot study of patients aged ≥18years on long-term linezolid therapy. Matched control patients were included for baseline assessment comparison. Patients were assessed at study entry, monthly while on treatment, at the end of treatment, and 30days following the last dose. Aggregate ocular safety data were reviewed. Response to treatment was reported. Results: The study was terminated owing to slow enrollment. Twenty-four patients received linezolid; nine patients were included as matched controls. Linezolid was prescribed for a median of 80.5days (range, 50–254days). In patients with a reported clinical outcome, the majority were considered improved or cured. Common treatment-related adverse events (AEs) included anemia, peripheral neuropathy, polyneuropathy, vomiting, and asthenia, and were consistent with the known safety profile. Most AEs resolved or stabilized with discontinuation of treatment. Results of ophthalmologic tests in the one case adjudicated as probable linezolid-associated optic neuropathy revealed abnormal color vision, characteristic changes in the optic disk, and central scotomas in each eye. Conclusion: In our small population, linezolid was generally well tolerated and AEs were consistent with the known safety profile. Extensive ophthalmologic testing of all 24 linezolid-treated patients identified one case adjudicated as probable, linezolid-associated optic neuropathy. Keywords: linezolid, oxazolidinones, optic nerve diseases, peripheral nervous system diseases,safety

CONTEXT The Advisory Committee on Immunization Practices (ACIP) publishes annual recommendations for the prevention and control of seasonal influenza. Between 2011 and 2013, the ACIP recommended 2 approaches that providers could use to determine how many influenza vaccine doses children aged 6 months through 8 years should receive. One did not consider doses received prior to the 2010-2011 season; the other considered complete influenza immunization history, such as that available in immunization information system (IIS). OBJECTIVES To use Michigan's IIS, the Michigan Care Improvement Registry (MCIR), to compare the number of children recommended to receive 2 doses of influenza vaccine under each ACIP approach, and to determine the potential for overimmunization of Michigan children with influenza vaccine if providers do not use the data in MCIR. DESIGN Cross-sectional analysis in the 2011-2012 to 2013-2014 influenza seasons. SETTING We used the seasonal influenza and 2009 H1N1 monovalent vaccine doses in MCIR to determine the number of influenza vaccine doses children should receive using both ACIP approaches each season. PARTICIPANTS We analyzed data for more than 900 000 children aged 6 months through 8 years in each influenza season. MAIN OUTCOME MEASURE Number of children recommended 2 doses of influenza vaccine using each ACIP approach in each influenza season. RESULTS Our evaluation showed that using MCIR could prevent the overimmunization with a second influenza vaccine dose for 70 323 children during the 2011-2012 influenza season, 126 076 children during the 2012-2013 season, and 81 635 children during the 2013-2014 season. CONCLUSIONS This is the first study to use an IIS to quantify the difference between ACIP's approaches for 2-dose influenza vaccine recommendations. The immunization history and 2-dose forecasting algorithm available through MCIR minimizes overimmunization and has potential cost-saving implications. Our study illustrates the value of a centralized repository provided by IISs to immunization providers, public health, and caregivers.

Objective:To quantify the association of initial ED serum cardiac markers with the risk for life-threatening events (LEs) or need for lifesaving interventions (Lis) or administration of IV nitroglycerin. Methods: A prospective, observational study was performed using a cohort of hemodynamically stable, hospitalized patients (age > 25 years) presenting with nontraumatic chest discomfort. Patients with ST-segment elevation on their initial ECGs were excluded. Presenting serum samples were assayed for serum myoglobin and creatine kinase-MB isomer (CK-MB) using the Opus and Stratus systems. Target cases were defined as patients having LEs (e.g., cardiogenic shock, ventricular fibrillation, cardiac arrest), requiring Lis (e.g., intubation, cardioversion, pacing, reperfusion therapy), or needing IV nitroglycerin within 48 hours. Manufacturer's thresholds defined abnormal marker levels. Abnormal ECGs were defined using the Brush criteria. Results: Of the 178 eligible patients, 44 (25%) were target cases. Most (55%) target cases had blood drawn for assays within four hours of chest discomfort onset. The relative risk and sensitivity of the serum markers and the ECG for target cases follow: Of the seven patients with an LE/LI, six had blood drawn four hours or less after symptom onset; two LE/LI patients had abnormal myoglobin levels' no LE/LI patient had an abnormal CK-MB level. Conclusions: Isolated serum myoglobin and CK-MB levels obtained at patient ED presentation were not strongly associated with the 48-hour risk for LEs, Lis, or the use of IV nitroglycerin. Future studies of risk stratification should address the merits of serial serum marker measurements that extend up to 12 hours beyond patient symptom onset.

Objective: To demonstrate that creatine kinase-MB fraction (CK-MB) elevations within three hours of presentation in the emergency department (ED) are associated with subsequent ischemic events in clinically stable chest pain patients. Methods: Prospective cohort study at two university-affiliated teaching hospitals. Participants were consenting ED chest pain patients 25 years old or older without evidence of rhythm or hemodynamic instability (n = 449). Exclusions included ST-segment elevation ≥0.1 mV in ≥2 electrocardiogram leads, chest wall trauma, abnormal x-ray studies, and incomplete data collection. Measurements included presenting and three-hour CK-MB levels, presenting ECG, initial clinical impression of coronary care unit need, and clinical follow up. Monitored adverse events included myocardial ischemia necessitating coronary angioplasty or cardiac bypass surgery, recurrent in-hospital myocardial infarction, bradycardia requiring pacing, emergent cardioversion, cardiogenic shock, ventricular fibrillation, and death. Results: Overall, nine (2%) of 449 patients experienced an ischemic event within the first 48 hours. All nine patients required either coronary angioplasty or bypass surgery. Four (44%) of the nine patients with 48-hour ischemic events had elevated CK-MB levels. Of 23 patients who had complications within one week of ED presentation, seven (30%) had elevated ED CK-MB levels. An elevated CK-MB level was associated with an ischemic event both within 48 hours (risk ratio 9.5; 95% CI 2.7–33.7) and within one week (risk ratio 5.2; 95% CI 2.3–11.7). Conclusions: An elevated CK-MB level within three hours of ED presentation is associated with a subsequent ischemic event in the clinically stable chest pain patient without ST-segment elevation. However, the ED CK-MB identifies only a minority of otherwise low-risk patients who develop ischemic events; other markers for diagnosing myocardial ischemia in the ED are needed.

Postpollination nonrandom mating among compatible mates is a widespread phenomenon in plants and is genetically undefined. In this study, we used the recombinant inbred line (RIL) population between Landsberg erecta and Columbia (Col) accessions of Arabidopsis (Arabidopsis thaliana) to define the genetic architecture underlying both female- and male-mediated nonrandom mating traits. To map the genetic loci responsible for male-mediated nonrandom mating, we performed mixed pollinations with Col and RIL pollen on Col pistils. To map the genetic loci responsible for female-mediated nonrandom mating, we performed mixed pollinations with Col and Landsberg erecta pollen on RIL pistils. With these data, we performed composite interval mapping to identify two quantitative trait loci (QTLs) that control male-mediated nonrandom mating. We detected epistatic interactions between these two loci. We also explored female- and male-mediated traits involved in seed yield in mixed pollinations. We detected three female QTLs and one male QTL involved in directing seed number per fruit. To our knowledge, the results of these experiments represent the first time the female and male components of seed yield and nonrandom mating have been separately mapped.

Optimisation of a screening hit incorporating both TRPV1 activity and solubility was conducted. Substitution of the isoxazole-3-carboxamide with the bespoke 1S, 3R-3-aminocyclohexanol motif afforded the requisite balance of potency and solubility. Compounds 32 and 40 were found to have antihyperalgesic effects in the rat CFA Hg assay and induce a mechanism based hyperthermia.

The discovery, synthesis and preliminary structure-activity relationships (SARs) of a novel class of CB1 antagonists is described. Initial optimization of benzimidazole-based screening hit 4 led to the identification of 'inverted' indole-based lead compound 18c with improved properties versus compound 4 including reduced AlogP, improved microsomal stability and improved aqueous solubility. Compound 18c demonstrates in vivo CB1 antagonist efficacy (CB1 agonist induced hypothermia model) and is orally bioavailable in rat.

We isolated lap3-1 and lap3-2 mutants in a screen for pollen that displays abnormal stigma binding. Unlike wild-type pollen, lap3-1 and lap3-2 pollen exine is thinner, weaker, and is missing some connections between their roof-like tectum structures. We describe the mapping and identification of LAP3 as a novel gene that contains a repetitive motif found in b-propeller enzymes. Insertion mutations in LAP3 lead to male sterility. To investigate possible roles for LAP3 in pollen development, we assayed the metabolite profile of anther tissues containing devel- oping pollen grains and found that the lap3-2 defect leads to a broad range of metabolic changes. The largest changes were seen in levels of a straight-chain hydrocarbon non- acosane and in naringenin chalcone, an obligate compound in the flavonoid biosynthesis pathway.

Study objective: To analyze the effect of creatine kinase isoenzyme (CKMB) results on decision making in the evaluation of emergency department patients with chest pain. Design: Prospective, controlled observational study of clinical decision making. Setting: EDs of two teaching hospitals, a Veterans Affairs medical center, and a medical school university hospital. Type of participants: Patients more than 30 years old complaining of chest discomfort warranting an ECG. Excluded were hemodynamically unstable patients and patients with ECG evidence of an acute myocardial infarction (AMI). Interventions: After the initial assessment including ECG but not CKMB data, physicians answered questions regarding estimated probability of AMI and disposition plans. CK-MB levels were drawn every hour for as long as three hours (from one to four CK-MBs) with results readily available. Physicians could admit their patients into the hospital at any time. At disposition after reviewing a second ECG and all available CK-MB data, the physicians answered the same questions and rank ordered the contribution to disposition of the following six factors: initial and serial clinical evaluations, initial and serial ECGs, and initial and serial CK-MB enzymes, respectively. The absolute log likelihood ratio test measured the contribution of CK-MB to decision certainty. Measurements and main results: Three hundred seventy-six patients were studied: 29 (7.7%) with AMI and 347 without AMI (nonAMI). Physicians indicated that CK-MB levels were useful for more than one third of study patients. When considered useful, CK-MB results strengthened the impression of AMI in AMI patients and decreased the impression of AMI for nonAMI patients; CK-MB also correlated with the perceived need for cardiac care unit admission in AMI patients and with a reduced need to admit nonAMI patients. The use of CK-MB results did not significantly increase ED release rates. Conclusion: The rapid availability of serial CK-MB results appears to affect decision making in one third of ED patients with chest pain and nondiagnostic ECGs. CK-MB levels appear to complement clinical evaluation of the ED chest pain patient in a manner analogous to the ECG.

Background Callose (β-1,3 glucan) separates developing pollen grains, preventing their underlying walls (exine) from fusing. The pollen tubes that transport sperm to female gametes also contain callose, both in their walls as well as in the plugs that segment growing tubes. Mutations in CalS5, one of several Arabidopsis β-1,3 glucan synthases, were previously shown to disrupt callose formation around developing microspores, causing aberrations in exine patterning, degeneration of developing microspores, and pollen sterility. Results Here, we describe three additional cals5 alleles that similarly alter exine patterns, but instead produce fertile pollen. Moreover, one of these alleles (cals5-3) resulted in the formation of pollen tubes that lacked callose walls and plugs. In self-pollinated plants, these tubes led to successful fertilization, but they were at a slight disadvantage when competing with wild type. Conclusion Contrary to a previous report, these results demonstrate that a structured exine layer is not required for pollen development, viability or fertility. In addition, despite the presence of callose-enriched walls and callose plugs in pollen tubes, the results presented here indicate that callose is not required for pollen tube functions.

This project examined which child health data would be appropriate and useful to integrate with an existing real-time Michigan Department of Community Health (MDCH) application, such as the Michigan Childhood Immunization Registry. A consultant was secured to conduct data gathering analysis activities. An advisory committee of MDCH Administrators convened to guide the project. Interviews were conducted with MDCH administrators, program managers and representatives from the public and private health care provider community. These interviews focused on answering three main questions: (1) What MDCH data resources do you currently use? (2) How do you use and access these data? and (3) What is your vision for expanding, enhancing, and linking these data to meet Michigan's future health goals? Acceptance of the Michigan Childhood Immunization Registry by the pediatric and family practice community demonstrates the utility of providing more information electronically to the medical community in Michigan. The MDCH has completed a stakeholders analysis and is moving forward with requirements gathering sessions in order to create an integrated child health data system. The integrated child health data system will include data from immunizations, newborn screening, newborn hearing, lead, the Women, Infants, and Children program, and Medicaid.

▪ Abstract For pollination to succeed, pollen must carry sperm through a variety of different floral tissues to access the ovules within the pistil. The pistil provides everything the pollen requires for success in this endeavor including distinct guidance cues and essential nutrients that allow the pollen tube to traverse enormous distances along a complex path to the unfertilized ovule. Although the pistil is a great facilitator of pollen function, it can also be viewed as an elaborate barrier that shields ovules from access from inappropriate pollen, such as pollen from other species. Each discrete step taken by pollen tubes en route to the ovules is a potential barrier point to ovule access and waste by inappropriate mates. In this review, we survey the current molecular understanding of how pollination proceeds, and ask to what extent is each step important for mate discrimination. As this field progresses, this synthesis of functional biology and evolutionary studies will provide insight into the molecular basis of the species barriers that maintain the enormous diversity seen in flowering plants.

An investigation into the structure–activity relationship of a lead compound, prolyl-5-aminopentanoic acid 4 , led to the identification of a novel series of 4-piperidinylacetic acid, 1-piperazinylacetic acid, and 4-aminobenzoic acid derivatives as potent VLA-4 antagonists with low nanomolar IC 50 values. A representative compound morpholinyl-4-piperidinylacetic acid derivative ( 13d : IC 50 = 4.4 nM) showed efficacy in the Ascaris -antigen sensitized murine airway inflammation model by oral administration.

The ornate surfaces of male and female reproductive cells in flowering plants have long attracted attention for their variety and evolutionary significance. These structures, and the molecules involved in sexual interactions, remain among the most rapidly evolving and diverse characteristics known.

Our studies of the yeast ubiquitin-proteasome pathway have uncovered a number of general principles that govern substrate selectivity and proteolysis in this complex system. Much of the work has focused on the destruction of a yeast transcription factor, MATα2. The α2 protein is polyubiquitinated and rapidly degraded in α–haploid cells. One pathway of proteolytic targeting, which depends on two distinct endoplasmic reticulum–localized ubiquitin–conjugating enzymes, recognizes the hydrophobic face of an amphipathic helix in α2. Interestingly, degradation of α2 is blocked ina/α–diploid cells by heterodimer formation between the α2 anda1 homeodomain proteins. The data suggest that degradation signals may overlap protein–protein interaction surfaces, allowing a straightforward steric mechanism for regulated degradation. Analysis of α2 degradation led to the identification of both 20S and 26S proteasome subunits, and several key features of proteasome assembly and active–site formation were subsequently uncovered. Finally, it has become clear that protein (poly)ubiquitination is highly dynamicin vivo, and our studies of yeast de–ubiquitinating enzymes illustrate how such enzymes can facilitate the proteolysis of diverse substrates.

Proteolysis by the ubiquitin-proteasome pathway is often regulated, but the mechanisms underlying such regulation remain ill-defined. In Saccharomyces cerevisiae, cell type is controlled by the MAT transcription factors. The alpha2 repressor is a known ubiquitin pathway substrate in alpha haploid cells. We show that a1 is rapidly degraded in a haploids. In a/alpha diploids, alpha2 and a1 are stabilized by heterodimerization. Association depends on N-terminal coiled-coil interactions between a1 and alpha2. Residues in alpha2 important for these interactions overlap a critical determinant of an alpha2 degradation signal, which we delimit by extensive mutagenesis. Our data provide a detailed description of a natural ubiquitin-dependent degradation signal and point to a molecular mechanism for regulated turnover in which proteolytic signals are differentially masked in alternative multiprotein complexes.

Serial creatine kinase-MB (CK-MB) levels provide more accurate predictive information regarding myocardial infarction than serial ECGs in emergency department patients with chest discomfort and no ST-segment elevation on the initial ECG.Prospective, observational study.University hospital and university-affiliated Veterans Affairs Medical Center EDs.Two hundred sixty-one patients 30 years or older with chest discomfort warranting an ECG and consenting to observation. Exclusions included hemodynamic or rhythm instability and ST-segment elevation of 0.1 mV or more in two or more electrically contiguous leads at presentation.ECGs were obtained at presentation and three to four hours after presentation. Significant serial ECG changes sought on comparison of initial and three- to four-hour ECGs were 0.05 mV or more ST elevation or depression, Q-wave development, or T-wave inversion changes in two or more electrically contiguous leads. CK-MB levels were obtained at presentation and hourly for three hours (positive level, 8 or more ng/mL). Myocardial infarction was determined by record review and was based on independent CK-MB measurements.Twenty-eight (11%) patients were diagnosed with a myocardial infarction. Thirty-eight (15%) patients had a serial ECG change. Eleven of the myocardial infarction patients (39%) had a serial ECG change compared with 27 (12%) of the non-myocardial infarction patients (P.001). Sensitivities and specificities of a serial ECG change versus serial CK-MBs for myocardial infarction were 39% versus 68% (sensitivity) and 88% versus 95% (specificity), respectively. Serial CK-MBs were more accurate than a serial ECG change for predicting myocardial infarction (P.03).Serial changes in ECGs during a three- to four-hour interval were associated with the diagnosis of myocardial infarction but were infrequent and less accurate than serial CK-MB levels obtained for the same interval.

In two unrelated cases, a 7-year-old boy and a 21-year-old woman died suddenly while receiving chronic imipramine therapy. In the boy, concentrations of imipramine were: Left femoral blood 0.5 mg/L, right femoral blood 1.2 mg/L, aorta blood 1.0 mg/L, liver 68 mg/Kg, and for the active metabolite, desipramine, left femoral blood 6.7 mg/L, right femoral blood 9.9 mg/L, aorta blood 8.7 mg/L, liver 400 mg/Kg. In the woman, the imipramine concentrations were: Femoral blood 0.6 mg/L, liver 37 mg/Kg, and of the active metabolite, desipramine, femoral blood 3.74 mg/L, liver 261 mg/Kg. In both cases, the scene investigation strongly indicated that neither individual had ingested an acute overdose. The very high ratios of desmethyl metabolite to parent drug are consistent with this observation. Impaired metabolism due to a genetically determined "slow metabolizer" phenotype of cytochrome CYP2D6, and/or concurrent therapy with phenothiazines, is suggested as a possible mechanism for the apparent fatal accumulation of these tricyclic antidepressants.

Parathyroid hormone (PTH) assays are becoming available to clinical chemistry laboratories for in-house use. We evaluated the clinical utility of two mid-molecule PTH assays in comparison to a sensitive but technically demanding component assay. A normal reference population, and an abnormal population including cases of primary and secondary hyperparathyroidism, hypoparathyroidism, and humoral hypercalcemia of malignancy were tested. PTH determinations with each assay system and total serum calcium determinations were done on all specimens. The Endocrine Metabolic Center (EMC) kit assay and the Immuno Nuclear Corp. (INC) kit assay demonstrated adequate standard curve reproducibility and precision for clinical use. With the aid of calcium determinations each assay performed well in the separation of abnormal patient groups, and in the separation of abnormal from normal PTH-calcium homeostasis. PTH values for the reference population differed among the three assays. The component assay and the EMC assay had a negative correlation with serum calcium, but the INC assay had a positive correlation with serum calcium.

21-deoxycortisol has been identified by others (1) in the plasma of a patient with the 21-hydroxylase deficiency variant of the adrenogenital syndrome. Because 21-deoxy cortisol* is similar in chemical structure to cortisol,** we tested the relative ability of this steroid to react as “cortisol” in three commonly employed methods of assaying cortisol: competitive protein binding, fluorometric and the phenylhydrazine (Porter-Silber) reaction. On an equal weight basis, 21-deoxycortisol gave 87% of the value of cortisol in the competitive protein binding assay; and 27% of the value of cortisol in the fluorometric assay. The phenylhydrazine reaction with 21-deoxycortisol was negative so that this steroid did not interfere in the Porter-Silber assay. It is concluded that falsely elevated values of plasma “cortisol” may be found in patients with 21- hydroxylase deficiency when cortisol is determined by the fluorometric or competitive binding methods.

The clinical course of a 29-month-old girl who was referred for evaluation after ingesting ninety 0.2-mg tablets of levothyroxine is reported. Despite an initial thyroxine (T4) level of 282 μg/dl and a triiodothyronine (T3) level of 1,837 ng/dl at 48 hours postingestion, her symptoms were mild and included irritability, vomiting, tremor, and tachycardia. Treatment was limited to activated charcoal and propranolol. Thyroid hormone levels fell to normal by 13 days postingestion. The child's clinical course was benign.Even after massive acute ingestions of levothyroxine, children's symptoms are usually mild and may be controlled with propranolol. This conservative approach should be considered before expensive and potentially dangerous therapies are undertaken.