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Fusarium head blight (FHB) is a devastating fungal disease responsible for significant yield losses in wheat and other cereal crops across the globe. FHB infection of wheat spikes results in grain contamination with mycotoxins, reducing both grain quality and yield. Breeding strategies have resulted in the production of FHB-resistant cultivars, however, the underlying molecular mechanisms of resistance in the majority of these cultivars are still poorly understood. To improve our understanding of FHB-resistance, we performed a transcriptomic analysis of FHB-resistant AC Emerson, FHB-moderately resistant AC Morley, and FHB-susceptible CDC Falcon in response to Fusarium graminearum . Wheat spikelets located directly below the point of inoculation were collected at 7-days post inoculation (dpi), where dual RNA-sequencing was performed to explore differential expression patterns between wheat cultivars in addition to the challenging pathogen. Differential expression analysis revealed distinct defense responses within FHB-resistant cultivars including the enrichment of physical defense through the lignin biosynthesis pathway, and DON detoxification through the activity of UDP-glycosyltransferases. Nucleotide sequence variants were also identified broadly between these cultivars with several variants being identified within differentially expressed putative defense genes. Further, F. graminearum demonstrated differential expression of mycotoxin biosynthesis pathways during infection, leading to the identification of putative pathogenicity factors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Mark F. Belmonte, Curt A. McCartney and His Majesty the King in Right of Canada, as represented by the Minister of Agriculture and Agri-Food Canada for the contribution of Philip L. Walker, Brent D. McCallum, Harpinder S. Randhawa and Maria A. Henriquez.)

The causative agent of white mold, Sclerotinia sclerotiorum, is capable of infecting over 600 plant species and is responsible for significant crop losses across the globe. Control is currently dependent on broad-spectrum chemical agents that can negatively impact the agroecological environment, presenting a need to develop alternative control measures. In this study, we developed transgenic Arabidopsis thaliana (AT1703) expressing hairpin (hp)RNA to silence S. sclerotiorum ABHYDROLASE-3 and slow infection through host induced gene silencing (HIGS). Leaf infection assays show reduced S. sclerotiorum lesion size, fungal load, and ABHYDROLASE-3 transcript abundance in AT1703 compared to wild-type Col-0. To better understand how HIGS influences host-pathogen interactions, we performed global RNA sequencing on AT1703 and wild-type Col-0 directly at the site of S. sclerotiorum infection. RNA sequencing data reveals enrichment of the salicylic acid (SA)-mediated systemic acquired resistance (SAR) pathway, as well as transcription factors predicted to regulate plant immunity. Using RT-qPCR, we identified predicted interacting partners of ABHYDROLASE-3 in the polyamine synthesis pathway of S. sclerotiorum that demonstrate co-reduction with ABHYDROLASE-3 transcript levels during infection. Together, these results demonstrate the utility of HIGS technology in slowing S. sclerotiorum infection and provide insight into the role of ABHYDROLASE-3 in the A. thaliana-S. sclerotiorum pathosystem., (© 2023. The Author(s).)

White mold is caused by the fungal pathogen Sclerotinia sclerotiorum and leads to rapid and significant loss in plant yield. Among its many brassicaceous hosts, including Brassica napus (canola) and Arabidopsis, the response of individual tissue layers directly at the site of infection has yet to be explored. Using laser microdissection coupled with RNA sequencing, we profiled the epidermis, mesophyll, and vascular leaf tissue layers of B. napus in response to S. sclerotiorum. High-throughput tissue-specific mRNA sequencing increased the total number of detected transcripts compared with whole-leaf assessments and provided novel insight into the conserved and specific roles of ontogenetically distinct leaf tissue layers in response to infection. When subjected to pathogen infection, the epidermis, mesophyll, and vasculature activate both specific and shared gene sets. Putative defense genes identified through transcription factor network analysis were then screened for susceptibility against necrotrophic, hemi-biotrophic, and biotrophic pathogens. Arabidopsis deficient in PR5-like RECEPTOR KINASE (PR5K) mRNA levels were universally susceptible to all pathogens tested and were further characterized to identify putative interacting partners involved in the PR5K signaling pathway. Together, these data provide insight into the complexity of the plant defense response directly at the site of infection., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Synechococcus elongatus UTEX 2973, the fastest-growing cyanobacterial strain known, optimally grows under extreme high light (HL) intensities of 1,500-2,500 μmol photons m -2 s -1 , which is lethal to most other photosynthetic microbes. We leveraged the few genetic differences between Synechococcus 2973 and the HL sensitive strain Synechococcus elongatus PCC 7942 to unravel factors essential for the high light tolerance. We identified a novel protein in Synechococcus 2973 that we have termed HltA for H igh l ight t olerance protein A . Using bioinformatic tools, we determined that HltA contains a functional PP2C-type protein phosphatase domain. Phylogenetic analysis showed that the PP2C domain belongs to the bacterial-specific Group II family and is closely related to the environmental stress response phosphatase RsbU. Additionally, we showed that unlike any previously described phosphatases, HltA contains a single N-terminal regulatory GAF domain. We found hltA to be ubiquitous throughout cyanobacteria, indicative of its potentially important role in the photosynthetic lifestyle of these oxygenic phototrophs. Mutations in the hltA gene resulted in severe defects specific to high light growth. These results provide evidence that hltA is a key factor in the tolerance of Synechococcus 2973 to high light and will open new insights into the mechanisms of cyanobacterial light stress response. IMPORTANCE Cyanobacteria are a diverse group of photosynthetic prokaryotes. The cyanobacterium Synechococcus 2973 is a high light tolerant strain with industrial promise due to its fast growth under high light conditions and the availability of genetic modification tools. Currently, little is known about the high light tolerance mechanisms of Synechococcus 2973, and there are many unknowns overall regarding high light tolerance of cyanobacteria. In this study, a comparative genomic analysis of Synechococcus 2973 identified a single nucleotide polymorphism in a locus encoding a serine phosphatase as a key factor for high light tolerance. This novel GAF-containing phosphatase was found to be the sole Group II metal-dependent protein phosphatase that is evolutionarily conserved throughout cyanobacteria. These results shed new light on the light response mechanisms of Synechococcus 2973, improving our understanding of environmental stress response. Additionally, this work will help facilitate the development of Synechococcus 2973 as an industrially useful organism.

Sclerotinia sclerotiorum is a pathogenic fungus that infects hundreds of crop species, causing extensive yield loss every year. Chemical fungicides are used to control this phytopathogen, but with concerns about increasing resistance and impacts on non-target species, there is a need to develop alternative control measures. In the present study, we engineered Brassica napus to constitutively express a hairpin (hp)RNA molecule to silence ABHYRDOLASE-3 in S. sclerotiorum. We demonstrate the potential for Host Induced Gene Silencing (HIGS) to protect B. napus from S. sclerotiorum using leaf, stem and whole plant infection assays. The interaction between the transgenic host plant and invading pathogen was further characterized at the molecular level using dual-RNA sequencing and at the anatomical level through microscopy to understand the processes and possible mechanisms leading to increased tolerance to this damaging necrotroph. We observed significant shifts in the expression of genes relating to plant defense as well as cellular differences in the form of structural barriers around the site of infection in the HIGS-protected plants. Our results provide proof-of-concept that HIGS is an effective means of limiting damage caused by S. sclerotiorum to the plant and demonstrates the utility of this biotechnology in the development of resistance against fungal pathogens., Competing Interests: The authors have declared that no competing interests exist.

Aldehyde dehydrogenases (ALDHs) catalyze the conversion of various aliphatic and aromatic aldehydes into corresponding carboxylic acids. Traditionally considered as housekeeping enzymes, new biochemical roles are being identified for members of ALDH family. Recent work showed that AldA from the plant pathogen Pseudomonas syringae strain PtoDC3000 (PtoDC3000) functions as an indole-3-acetaldehyde dehydrogenase for the synthesis of indole-3-acetic acid (IAA). IAA produced by AldA allows the pathogen to suppress salicylic acid-mediated defenses in the model plant Arabidopsis thaliana. Here we present a biochemical and structural analysis of the AldA indole-3-acetaldehyde dehydrogenase from PtoDC3000. Site-directed mutants targeting the catalytic residues Cys302 and Glu267 resulted in a loss of enzymatic activity. The X-ray crystal structure of the catalytically inactive AldA C302A mutant in complex with IAA and NAD+ showed the cofactor adopting a conformation that differs from the previously reported structure of AldA. These structures suggest that NAD+ undergoes a conformational change during the AldA reaction mechanism similar to that reported for human ALDH. Site-directed mutagenesis of the IAA binding site indicates that changes in the active site surface reduces AldA activity; however, substitution of Phe169 with a tryptophan altered the substrate selectivity of the mutant to prefer octanal. The present study highlights the inherent biochemical versatility of members of the ALDH enzyme superfamily in P. syringae., (© 2020 The Author(s).)

Calcium channel blockers (CCBs) are commonly prescribed cardiovascular medications used in several disease states including hypertension, coronary artery disease, and atrial fibrillation. Inadvertent exposure or intentional overdose of CCBs may result in hypotension, bradycardia, dysrhythmias, conduction disturbances, and hyperglycemia. In the most severe cases, CCB toxicity can lead to rapid cardiovascular collapse. Given the risk of significant morbidity and mortality associated with CCB toxicity, it is important that health care professionals are able to recognize and treat patients who present with a potentially toxic ingestion. Due to the paucity of literature in managing pediatric patients with severe CCB toxicity, treatment strategies for pediatric patients are mostly limited to case reports and extrapolation from expert consensus recommendations for adults. All pediatric patients with a potentially toxic CCB ingestion should be evaluated in the emergency department. Activated charcoal may be considered for asymptomatic patients presenting within an hour of ingestion. Symptomatic patients should be placed under cardiac monitoring and treatments to stabilize the patient's hemodynamics should not be delayed. Traditional first-line IV therapies include small boluses of fluids, calcium, and vasopressors. High-dose insulin has been proposed to independently increase inotropy and improve CCB-induced hypoinsulinemia and insulin resistance that results from CCB inhibition of insulin release from pancreatic β-islet cells. High-dose insulin is recommended as first-line therapy for adults and shows promising efficacy and safety in several pediatric case reports. Intravenous lipid emulsion may be considered in patients who are refractory to first-line therapies, although the data for pediatric patients are extremely limited., Competing Interests: Disclosure The authors declare no conflicts or financial interest in any product or service mentioned in the manuscript, including grants, equipment, medications, employment, gifts, and honoraria., (Copyright Published by the Pediatric Pharmacy Advocacy Group. All rights reserved. For permissions, email: matthew.helms@ppag.org 2019.)

Sclerotinia sclerotiorum, the causal agent of white stem rot, is responsible for significant losses in crop yields around the globe. While our understanding of S. sclerotiorum infection is becoming clearer, genetic control of the pathogen has been elusive and effective control of pathogen colonization using traditional broad-spectrum agro-chemical protocols are less effective than desired. In the current study, we developed species-specific RNA interference-based control treatments capable of reducing fungal infection. Development of a target identification pipeline using global RNA sequencing data for selection and application of double stranded RNA (dsRNA) molecules identified single gene targets of the fungus. Using this approach, we demonstrate the utility of this technology through foliar applications of dsRNAs to the leaf surface that significantly decreased fungal infection and S. sclerotiorum disease symptoms. Select target gene homologs were also tested in the closely related species, Botrytis cinerea, reducing lesion size and providing compelling evidence of the adaptability and flexibility of this technology in protecting plants against devastating fungal pathogens.

Transcription factors and their associated DNA binding sites are key regulatory elements of cellular differentiation, development, and environmental response. New tools that predict transcriptional regulation of biological processes are valuable to researchers studying both model and emerging-model plant systems. SeqEnrich predicts transcription factor networks from co-expressed Arabidopsis or Brassica napus gene sets. The networks produced by SeqEnrich are supported by existing literature and predicted transcription factor-DNA interactions that can be functionally validated at the laboratory bench. The program functions with gene sets of varying sizes and derived from diverse tissues and environmental treatments. SeqEnrich presents as a powerful predictive framework for the analysis of Arabidopsis and Brassica napus co-expression data, and is designed so that researchers at all levels can easily access and interpret predicted transcriptional circuits. The program outperformed its ancestral program ChipEnrich, and produced detailed transcription factor networks from Arabidopsis and Brassica napus gene expression data. The SeqEnrich program is ideal for generating new hypotheses and distilling biological information from large-scale expression data.

The hemibiotrophic fungal pathogen Leptosphaeria maculans is the causal agent of blackleg disease in Brassica napus (canola, oilseed rape) and causes significant loss of yield worldwide. While genetic resistance has been used to mitigate the disease by means of traditional breeding strategies, there is little knowledge about the genes that contribute to blackleg resistance. RNA sequencing and a streamlined bioinformatics pipeline identified unique genes and plant defense pathways specific to plant resistance in the B. napus-L. maculans LepR1-AvrLepR1 interaction over time. We complemented our temporal analyses by monitoring gene activity directly at the infection site using laser microdissection coupled to quantitative PCR. Finally, we characterized genes involved in plant resistance to blackleg in the Arabidopsis-L. maculans model pathosystem. Data reveal an accelerated activation of the plant transcriptome in resistant host cotyledons associated with transcripts coding for extracellular receptors and phytohormone signaling molecules. Functional characterization provides direct support for transcriptome data and positively identifies resistance regulators in the Brassicaceae. Spatial gradients of gene activity were identified in response to L. maculans proximal to the site of infection. This dataset provides unprecedented spatial and temporal resolution of the genes required for blackleg resistance and serves as a valuable resource for those interested in host-pathogen interactions., (© 2017 The Authors The Plant Journal © 2017 John Wiley & Sons Ltd.)

There are many causes of raised serum ferritin concentrations including iron overload, inflammation and liver disease to name but a few examples. Cases of extreme hyperferritinaemia (serum ferritin concentration equal to or greater than 10 000 ug/l) are being reported in laboratories but the causes of this are unclear. We conducted an audit study to explore this further. Extreme hyperferritinaemia was rare with only 0.08% of ferritin requests displaying this. The main causes of extreme hyperferritinaemia included multiple blood transfusions, malignant disease, hepatic disease and suspected Still's disease.

In four cases it is already known that the product of two distinct Jacobian theta functions having the same variable z and the same nome q is a multiple of a single Jacobian theta function, with the multiple independent of z. The main purpose of the present note is to show that this property also applies in the remaining two cases.

Purine nucleoside phosphorylase (PNPase) deficiency is an autosomal recessive disorder affecting purine degradation and salvage pathways. Clinically, patients typically present with severe immunodeficiency, neurological dysfunction, and autoimmunity. Biochemically, PNPase deficiency may be suspected in the presence of hypouricemia. We report biochemical and genetic data on a cohort of seven patients from six families identified as PNPase deficient. In all patients, inosine, deoxyinosine, guanosine, and deoxyguanosine were elevated in urine, and mutation analysis revealed seven different mutations of which three were novel. The mutation c.770A>G resulted in the substitution p.His257Arg. A second novel mutation c.257A>G (p.His86Arg) was identified in two siblings and a third novel mutation, c.199C>T (p.Arg67X), was found in a 2-year-old female with delayed motor milestones and recurrent respiratory infections. A review of the literature identified 67 cases of PNPase deficiency from 49 families, including the cases from our own laboratory. PNPase deficiency was confirmed in 30 patients by genotyping and 24 disease causing mutations, including the three novel mutations described in this paper, have been reported to date. In five of the seven patients, plasma uric acid was found to be within the pediatric normal range, suggesting that PNPase deficiency should not be ruled out in the absence of hypouricemia.

Aims: To review the incidence of multiple tumour marker (TM) requesting in the primary care setting and determine whether the rationale for requesting a TM panel is in agreement with evidence-based guidelines., Methods: Data-mining software was used to retrospectively identify multiple TM requests and requesting practices of GP surgeries over a 34-month period for α-fetoprotein, CA125, CA15-3, CA19-9, carcinoembryonic antigen and prostate-specific antigen. The appropriateness of each test was reviewed by a clinical biochemist in accordance with National Association of Clinical Biochemistry best-practice guidelines., Results: 505 multiple TM requests were identified which corresponded to 1304 TM tests. Comparison with best-practice guidelines suggested that 68% of request cards contained no appropriate TM request, and 84% of the tests requested were inappropriate., Conclusion: A review of requesting practices in primary care for TMs highlights the need for laboratories to be more proactive in educating their users on their clinical utility and limitations.

Identifying group affinity from human crania is a long-standing problem in forensic and physical anthropology. Many craniofacial differences used in forensic skeletal identification are difficult to quantify, although certain measurements of the midfacial skeleton have shown high predictive value for group classifications. This study presents a new method for analyzing midfacial shape variation between different geographic groups. Three-dimensional laser scan models of 90 crania from three populations were used to obtain cross-sectional midfacial contours defined by three standard craniometric landmarks. Elliptic Fourier transforms of the contours were used to extract Fourier coefficients for statistical analysis. After cross-validation, discriminant functions based on the Fourier coefficients provided an average of 86% correct classifications for crania from the three groups. The high rate of accuracy of this method indicates its usefulness for identifying group affinities among human skeletal remains and demonstrates the advantages of digital 3D model-based analysis in forensic research., (© 2011 American Academy of Forensic Sciences.)

Objective: To evaluate the risk of adrenal insufficiency following a single dose of etomidate in patients with suspected sepsis requiring rapid sequence intubation., Data Sources: A literature search was conducted using PubMed, MEDLINE, EMBASE, and International Pharmaceutical Abstracts from the dates of database inception until April 2010, utilizing the terms adrenal insufficiency, etomidate, and sepsis., Study Selection and Data Extraction: Data were synthesized in a qualitative manner, as variable study designs were identified. All studies that evaluated the clinical association between etomidate-induced adrenal insufficiency and sepsis in adults were reviewed and included., Data Synthesis: A search of the literature revealed 7 studies that specifically evaluated clinical endpoints in septic adults receiving etomidate for induction prior to intubation. Three of the studies evaluated risk factors associated with adrenal insufficiency in critically ill patients. Each of these studies determined that etomidate exposure was independently associated with an inappropriate response to cosyntropin stimulation testing (CST). Two studies found no significant difference in hospital mortality rates when evaluating patients receiving induction with etomidate compared with alternative regimens. Three studies found an increased risk of adrenal insufficiency in patients exposed to etomidate. The majority of studies that evaluated the use of etomidate in sepsis were underpowered, leading to difficulty in establishing a causal relationship between drug-related adrenal insufficiency, morbidity, and mortality., Conclusions: Until further studies are available, etomidate should be reserved for hemodynamically unstable patients who cannot tolerate an alternative induction agent despite the administration of fluids or vasoactive agents.

Three-dimensional (3D) laser scanner models of human crania can be used for forensic facial reconstruction, and for obtaining craniometric data useful for estimating age, sex, and population affinity of unidentified human remains. However, the use of computer-generated measurements in a casework setting requires the measurement precision to be known. Here, we assess the repeatability and precision of cranial volume and surface area measurements using 3D laser scanner models created by different operators using different protocols for collecting and processing data. We report intraobserver measurement errors of 0.2% and interobserver errors of 2% of the total area and volume values, suggesting that observer-related errors do not pose major obstacles for sharing, combining, or comparing such measurements. Nevertheless, as no standardized procedure exists for area or volume measurements from 3D models, it is imperative to report the scanning and postscanning protocols employed when such measurements are conducted in a forensic setting.

We document evidence for trophy-taking and dismemberment with a new bioarchaeological database featuring 13,453 individuals from prehistoric central California sites. Our study reveals 76 individuals with perimortem removal of body parts consistent with trophy-taking or dismemberment; nine of these individuals display multiple types of trophy-taking and dismemberment for a total of 87 cases. Cases span almost 5,000 years, from the Early Period (3000-500 BC) to the Late Period (AD 900-1700). Collectively, these individuals share traits that distinguish them from the rest of the population: a high frequency of young adult males, an increased frequency of associated trauma, and a tendency towards multiple burials and haphazard burial positions. Eight examples of human bone artifacts were also found that appear related to trophy-taking. These characteristics suggest that trophy-taking and dismemberment were an important part of the warfare practices of central Californian tribes. Temporally, the two practices soared in the Early/Middle Transition Period (500-200 BC), which may have reflected a more complex sociopolitical system that encouraged the use of trophies for status acquisition, as well as the migration of outside groups that resulted in intensified conflict. Overall, trophy-taking and dismemberment appear to have been the product of the social geography of prehistoric central California, where culturally differentiated tribes lived in close proximity to their enemies.

Each year, approximately 55,000 individuals worldwide die from an infection due to the rabies virus. Rabies is a life-threatening disease caused by an RNA virus that is usually transmitted to humans through bites from rabid animals. More recently, reports of transmission by means of organ transplantation have been reported. Since human rabies is nearly 100% fatal if prophylactic measures are not followed, an increased awareness of who should receive prophylaxis and when prophylaxis should be administered is necessary. Preexposure prophylaxis entails the administration of the rabies vaccine to individuals at high risk for exposure to rabies viruses (e.g., laboratory workers who handle infected specimens, diagnosticians, veterinarians, animal control workers, rabies researchers, cave explorers). Preexposure prophylaxis involves a three-dose series of the rabies vaccine that may confer some protection from the virus while simplifying postexposure prophylaxis regimens. Postexposure prophylaxis consists of a multimodal approach to decrease an individual's likelihood of developing clinical rabies after a possible exposure to the virus. Regimens depend on the vaccination status of the victim and involve a combination of wound cleansing, administration of the rabies vaccine, and administration of human rabies immune globulin. If used in a timely and accurate fashion, postexposure prophylaxis is nearly 100% effective. Once clinical manifestations of rabies have developed, however, treatment options for rabies are limited, and to date, only seven individuals have survived rabies virus infection. Treatment of clinical rabies consists of medical support in an intensive care unit, using a multifaceted approach that includes supportive care, heavy sedation, analgesics, anticonvulsants, and antivirals. The recently developed Milwaukee Protocol added induction of therapeutic coma to supportive care measures and antivirals; however, its use has shown inconsistent outcomes.

Osteologists commonly assess the sex of skeletal remains found in forensic and archaeological contexts based on ordinal scores of subjectively assessed sexually dimorphic traits. Using known-sex samples, logistic regression (LR) discriminant functions have been recently developed, which allow sex probabilities to be determined. A limitation of LR is that it emphasizes main effects and not interactions. Chi-square automatic interaction detection (CHAID) is an alternative classification strategy that emphasizes the information in variable interactions and uses decision trees to maximize the probability of correct sex determinations. We used CHAID to analyze the predictive value of the 31 possible combinations of five sexually dimorphic skull traits that Walker used previously to develop logistic regression sex determination equations. The samples consisted of 304 individuals of known sex of English, African American, and European American origin. Based on practical considerations, selection criteria for the best sex predictive trait combinations (SPTCs) were set at accuracies for both sexes of 75% or greater and sex biases lower than 5%. Although several of the trees meeting these criteria were produced for the English and European American samples, none met them for the African American sample. In the series of out-of-sample tests we performed, the trees from the English and combined sample of all groups predicted best.

Porosities in the outer table of the cranial vault (porotic hyperostosis) and orbital roof (cribra orbitalia) are among the most frequent pathological lesions seen in ancient human skeletal collections. Since the 1950s, chronic iron-deficiency anemia has been widely accepted as the probable cause of both conditions. Based on this proposed etiology, bioarchaeologists use the prevalence of these conditions to infer living conditions conducive to dietary iron deficiency, iron malabsorption, and iron loss from both diarrheal disease and intestinal parasites in earlier human populations. This iron-deficiency-anemia hypothesis is inconsistent with recent hematological research that shows iron deficiency per se cannot sustain the massive red blood cell production that causes the marrow expansion responsible for these lesions. Several lines of evidence suggest that the accelerated loss and compensatory over-production of red blood cells seen in hemolytic and megaloblastic anemias is the most likely proximate cause of porotic hyperostosis. Although cranial vault and orbital roof porosities are sometimes conflated under the term porotic hyperostosis, paleopathological and clinical evidence suggests they often have different etiologies. Reconsidering the etiology of these skeletal conditions has important implications for current interpretations of malnutrition and infectious disease in earlier human populations., (Copyright 2009 Wiley-Liss, Inc.)

The United States National Science Foundation has recently funded a large collaborative project on "A History of Health in Europe from the Late Paleolithic Era to the Present," whose goal is to measure and analyzes the evolution of skeletal health by combining data from human remains with information gathered from sources in archaeology, climate history, geography, and history. The goal of this international collaborative project is to create a series of database that will allow researchers to reinterpret the history of human health in Europe from the late Paleolithic era to the early twentieth century. During this period, human health and welfare were transformed enormously by the transition from foraging to farming; the rise of cities and complex forms of social and political organization; European colonization; and industrialization. With a trans-Atlantic network of collaborators, we will undertake large-scale comparative studies of the causes and health consequences of these and other dramatic changes in arrangements for work, living, and human interaction.

The accuracy of sex determinations based on visual assessments of the mental eminence, orbital margin, glabellar area, nuchal area, and mastoid process was tested on a series of 304 skulls of known age and sex from people of European American, African American, and English ancestry as well as on an ancient Native American sample of 156 individuals whose sex could be reliably determined based on pelvic morphology. Ordinal scores of these sexually dimorphic traits were used to compute sex determination discriminant functions. Linear, kth-nearest-neighbor, logistic, and quadratic discriminant analysis models were evaluated based on their capacity to minimize both misclassifications and sex biases in classification errors. Logistic regression discriminant analysis produced the best results: a logistic model containing all five cranial trait scores correctly classified 88% of the modern skulls with a negligible sex bias of 0.1%. Adding age at death, birth year, and population affinity to the model did not appreciably improve its performance. For the ancient Native American sample, the best logistic regression model assigned the correct pelvic sex to 78% of the individuals with a sex bias of only 0.2%. Similar cranial trait frequency distributions were found in same-sex comparisons of the modern African American, European American, and English samples. The sexual dimorphism of these modern people contrasts markedly with that of the ancient Native Americans. Because of such population differences, discriminant functions like those presented in this paper should be used with caution on populations other than those for which they were developed., ((c) 2008 Wiley-Liss, Inc.)

Linear enamel hypoplasia (LEH) is an enamel defect that records the effects of physiological stress on tooth formation. Estimating the age at which LEH defects form is integral to the reconstruction of population health in bioarcheological studies. Two principal methods for aging LEH defects have been introduced in the literature. The conventional approach employs regression equations based on a linear model of tooth growth. The newer, Reid and Dean [Am J Phys Anthropol 113 (2000) 135-139] approach, is based upon a histologically derived curvilinear model of enamel development and therefore likely provides more accurate age estimates. However, the extent to which the Reid and Dean method produces estimated ages at defect formation differing from those of the regression equations has not, until now, been determined. This study quantifies the differences between these two methods. Evaluating the degree to which these methods differ is essential for interpreting the accuracy of LEH age estimates given in previous bioarcheological studies. Age estimates of LEH defects on 338 anterior teeth from the Hamann-Todd osteological sample were calculated using both methods. The resulting estimated ages were compared through a randomized block ANOVA. However, the mean differences between the estimated ages yielded by both methods range from 4 months or less depending on the tooth type with an overall average of 2.63 months. The discussion focuses on the degree to which this difference affects answers to bioarcheological questions., (2007 Wiley-Liss, Inc.)

Denileukin diftitox plus rituximab was evaluated in relapsed/refractory B-cell non-Hodgkin lymphoma patients. Of the 38 evaluable patients, 30 (80%) were rituximab-refractory. The overall response rate (ORR) was 32%, with six complete responses (CR) and six partial responses (PR). The median time to progression for responders was 8 months (range: 2-36+); two patients with rituximab-refractory follicular lymphoma were in CR at 25 and 36+ months. The ORR was 55% (4 CRs, 2 PRs) in 11/14 patients with rituximab-refractory follicular lymphoma, and 100% in the three patients with rituximab-sensitive tumour. Most toxicities were low grade and transient, and myelotoxicity was uncommon.

This phase II study evaluated the safety and efficacy of denileukin diftitox, an interleukin-2-diphtheria toxin fusion protein, in relapsed/refractory T-cell non-Hodgkin lymphoma (T-NHL), excluding cutaneous T-cell lymphoma. Eligible patients received denileukin diftitox 18 microg/kg/d x 5 d every 3 weeks for up to eight cycles. Tumour staging was performed every two cycles and the primary endpoint was the objective response rate [complete response (CR) + partial response (PR)]. For 27 patients enrolled, median age: 55 years (range 26-80 years), 70.4% male, and mean prior therapies: 2.5 (range 1-6). Objective responses (six CRs, seven PRs) were achieved in 13 patients (48.1%), stable disease in eight (29.6%) and six (22.2%) had progressive disease. An objective response was achieved in eight of 13 patients (61.5%) with CD25(+) tumours (four CR/four PR) and five of 11 patients (45.5%) with CD25(-) tumours (two CR/three PR). Median progression-free survival was 6 months (range, 1-38+ months). Most adverse reactions were grade 1/2 and transient. No grade 4-5 toxicities were reported. Denileukin diftitox had significant activity and was well tolerated in relapsed/refractory T-NHL, with responses observed in both CD25(+) and CD25(-) tumours. Further studies of denileukin diftitox in combination with other agents are warranted in previously untreated and relapsed/refractory T-NHL.

Autoregressive integrated moving average (ARIMA) models provide a powerful tool for detecting seasonal patterns in mortality statistics. The strength of ARIMA models lies in their ability to reveal complex structures of temporal interdependence in time series. Moreover, changes in model parameters provide an empirical basis for detecting secular trends and death seasonality patterns. This approach is illustrated by our analysis of changes in the mortality patterns of the population of the town of Es Mercadal on the island of Minorca between 1634 and 1997. These data reveal a transition from an early mortality pattern requiring a complex ARIMA model that accounts for a strong seasonal death pattern and periodic epidemic-related mortality crises to a much simpler 20th-century pattern that can be described by a simple single-parameter ARIMA model. These same data were also analyzed using standard seasonality tests. The results show that the reduction in the number of parameters required to fit the Es Mercadal mortality data coincides with the epidemiological transition in which the predominant causes of morbidly and mortality shift from infectious to degenerative causes.

Denileukin diftitox (DAB(389)IL-2 or Ontak) is a synthetic fusion protein with demonstrated efficacy in a number of lymphoproliferative disorders, including non-Hodgkin's lymphoma. We report the case of a 45-year-old man with progressive follicular large cell lymphoma following an autologous stem cell transplant treated with denileukin diftitox who developed a fatal skin rash associated with extensive erythema, edema and large bullae involving his entire body. The clinical features and pathology were compatible with toxic epidermal necrolysis. This is the first reported case of toxic epidermal necrolysis in the literature associated with denileukin diftitox.

Fourteen adult burials in a large (N = 224) prehistoric central California cemetery (CA-SCL-674) lack forearm bones. Twelve of these otherwise well-articulated primary interments have distal humeri bearing cutmarks with a distribution like that seen in fur seals butchered by Native Californians. Most of the burials with missing forearms are young adult males, a demographic profile that differs significantly from the full sample. Three of these males show evidence of perimortem trauma in addition to forearm amputation. Drilled and polished human radii and ulnae were recovered from the CA-SCL-674 cemetery in archaeological contexts separate from burials with missing forearms. A warfare-related trophy-taking practice is strongly suggested by these bioarchaeological data. Based on these data, it seems likely that 20% (N = 10) or more of the adult males (N = 59) in this population were victims of violence. Evidence of perimortem violence was much less common among women, with only about 2% (N = 2) of adult females (N = 86) subjected to trophy-taking. Examination of museum collections produced further evidence for perimortem forearm amputation among the Native American inhabitants of this area during the transition between the Early and Middle periods. The emergence of more hierarchical social systems during this period may have fostered warfare-related trophy-taking as a symbolic tool for enhancing the power and prestige of individuals within competing social groups., ((c) 2005 Wiley-Liss, Inc.)

The accuracy of a method for visually scoring sex differences in the greater sciatic notch was tested on 296 skeletons of known age and sex. The proportion of correct sex assignments is 80% when all specimens are classified, and 89% when os coxae assigned the score in which the sexes show the greatest overlap are excluded. Although many os coxae (35%) have this sexually intermediate morphology, excluding them has the advantage of substantially reducing sex biases in sexing errors. For both sexes, there is a strong relationship between age at death and sciatic notch score. People who die at a younger age tend to have wider, more feminine-appearing sciatic notches than people of greater longevity. There are also significant population differences. The 18th-19th century English sample from St. Bride's Church has a more feminine morphology than Americans of European or African ancestry. Environmental influences on skeletal development (vitamin D deficiency) appear to provide the most likely explanation for these population differences., ((c) 2005 Wiley-Liss, Inc.)

Background: T-cell non-Hodgkin lymphomas (T-NHL) are more aggressive and patients have a poorer prognosis compared with patients with the corresponding B-cell lymphomas. Although intensive treatments have been developed, it is unknown whether they are more effective than CHOP chemotherapy (cyclophosphamide, doxorubicin, oncovorin, and prednisone)., Methods: The authors' retrospective study evaluated the clinical outcome of 135 previously untreated patients with T-NHL who were treated at The University of Texas M. D. Anderson Cancer Center (Houston, TX) between 1996 and 2002. Lymphomas with T-cell histologies with the exception of mycosis fungoides were included., Results: The estimated median overall survival was 46 months. Thirty-seven percent of the patients received CHOP therapy, 48% received intensive therapy, and 15% received other therapy. The estimated 3-year overall survival rates were 62% for the patients treated with CHOP therapy and 56% for the patients who received intensive therapy. After the exclusion of patients with anaplastic large cell lymphoma (ALCL), who are known to have a better prognosis than patients with other T-NHLs, the estimated 3-year overall survival rates were 43% for the patients treated with CHOP therapy and 49% for the patients who received intensive therapy. Parameters that may be independent prognostic factors for survival in T-NHL, excluding ALCL, included ECOG performance status > or = 2, beta-2-microglobulin level > 2 mg/L, lactate dehydrogenase level higher than normal, bulky disease > or = 7 cm, and a higher international prognostic index and tumor score., Conclusions: The current study data suggested that patients treated with intensive therapies did not fare better than those treated with CHOP therapy. New treatment regimens need to be developed for patients with T-NHL.

Purpose: Denileukin diftitox is a fusion protein combining diphtheria toxin and interleukin-2 (IL-2) that targets tumor cells expressing the IL-2 receptor. Its efficacy has been shown in CD25+ cutaneous T-cell lymphoma, but not in B-cell non-Hodgkin's lymphoma (NHL). A phase II study was performed to evaluate the efficacy and tolerability of denileukin diftitox for relapsed or refractory B-cell NHL., Patients and Methods: Patients with relapsed or refractory B-cell NHL were eligible. Tumor CD25 expression was determined by immunohistochemistry or flow cytometry. Denileukin diftitox was administered intravenously at a dose of 18 microg/kg once daily for 5 days every 3 weeks, up to eight cycles., Results: Of the 45 patients assessable for response, 32 (71%) were refractory to the last chemotherapy treatment, and all were previously treated with rituximab. Three complete responses (6.7%) and eight partial responses (17.8%) were observed, for an overall response rate of 24.5%. Nine patients (20%) had stable disease. Objective response rates were similar in CD25+ (22%) and CD25- histologies (29%), as were stable disease rates (22% and 18%, respectively). For responding patients, the median time to treatment failure was 7 months, with a median follow-up in survivors of 18 months (range, 9 to 28 months), and the projected progression-free survival at 20 months was 24% (95% CI, 0% to 60%). Most toxicities were low-grade and transient., Conclusion: Denileukin diftitox seems to be effective in relapsed or refractory, CD25+ and CD25- B-cell NHL and is well-tolerated at the dosage evaluated. Evaluation of denileukin diftitox in combination with other agents may be warranted.

Non-Hodgkin's lymphoma (NHL) is a complex group of hematologic malignancies. The majority are B-cell lineage, with 10%-20% arising from T-cell lineage. Detailed knowledge of the subtypes and staging of NHL is essential to plan treatment and provide effective management of treatment-related side effects. Although numerous regimens have demonstrated efficacy in the treatment of NHL, some subtypes of lymphomas generally are not curable. The recent development of targeted therapies such as denileukin diftitox (Ontak, Ligand Pharmaceuticals, Inc., San Diego, CA) has resulted in potentially significant advances in the treatment of NHL. Oncology nurses must gain a better understanding of the unique mechanism of action of this agent and its side effects to successfully manage patients being treated with this novel therapy.

Pentostatin is an adenosine deaminase (ADA) inhibitor with antineoplastic activity. CD26 is a surface glycoprotein with a key role in T cell function as the ADA binding protein. We conducted a phase II study to evaluate pentostatin efficacy in relapsed T-non-Hodgkin's lymphoma (T-NHL) and to correlate response with tumor CD26 expression. We also examined the lymphopenic effect of pentostatin on CD26+ T lymphocytes. Eighteen patients were registered for the study. Pentostatin was administered as intravenous bolus daily over 3 days at an initial dose of 5 mg/m(2)/day, repeated every 4 weeks. CD26 surface expression on tumor cells and T lymphocytes was determined by flow cytometry. Out of 14 patients evaluable for response, there was 1 (7%) complete response (CR) and 6 (43%) partial responses (PR). Median progression-free survival for responders was 6 months (range: 2-15 months); median number of courses was 4 (range: 1-6). Responders included 1 of 2 CD26+ and 5 of 9 CD26- cases. Pentostatin also specifically depleted CD26+ rather than CD26- T lymphocytes, potentially associated with immunosuppression. We therefore conclude that while pentostatin is a safe and active agent for T-NHL regardless of CD26 expression, it may selectively deplete CD26+ T lymphocytes, with potentially significant clinical implications.

Background: Immunoassays are used in almost all medical and surgical specialties, but they suffer from interference from proteins such as antibodies in some patients' sera. Such interferences are usually reported in the literature only as case reports after the introduction of a new assay., Methods: We undertook a prospective observational study on 5310 patients for whom the common immunoassay tests for thyroid-stimulating hormone (TSH) and/or gonadotropins were requested. All TSH and gonadotropin results were critically assessed for a mismatch between the clinical details and analytical results to identify samples suspected of analytical unreliability. These were tested further by three approaches to screen for interference., Results: From the 5310 sets of results, 59 patients' samples were identified as suspect and were tested further. Analytically incorrect results were found in 28 (0.53% of the total studied). The magnitude of interference varied, but in 23 of 28 patients (82%), it was considered large enough to have a potentially adverse effect on cost and/or the clinical care of these patients. Two cases, described in detail, illustrate the adverse effect of error on patient care and cost, and the second highlights the difficulties and limitations of current approaches for identifying interference and inaccuracy in immunoassays., Conclusions: Because millions of TSH/gonadotropin tests are carried out in UK hospital laboratories alone, our data suggest that thousands of patients could be adversely affected by errors from interferences. Early identification of interference in cases with unusual results could be valuable.

Although most archaeologists recognize that valuable information about the social lives of ancient people can be obtained through the study of burial practices, it is clear that the symbolic nature of burial rituals makes interpreting their social significance a hazardous enterprise. These analytical difficulties can be greatly reduced using a research strategy that draws upon the strengths of a broad range of conceptually and methodologically independent data sources. We illustrate this approach by using archaeological data from cemeteries at Malibu, California, to explore an issue over which researchers are sharply divided: when did the simple chiefdoms of the Chumash Indians first appear in the Santa Barbara Channel area? First we establish the social correlates of Chumash burial practices through the comparison of historic-period cemetery data, ethnohistoric records, and ethnographic accounts. The resulting understanding of mortuary symbolism is then used to generate hypotheses about the social significance of prehistoric-period Malibu burial patterns. Finally, bioarchaeological data on genetic relationships, health status, and activity are used to independently test artifact-based hypotheses about prehistoric Chumash social organization. Together, these independent data sources constitute strong evidence for the existence of a ranked society with a hereditary elite during the late Middle period in the Santa Barbara Channel area.