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An 18-year-old woman developed Stevens-Johnson syndrome (SJS) with ocular involvement after taking ibuprofen. She was admitted to another hospital, received saline flushes and bacitracin ophthalmic ointment to the eyes, and became unable to open them. Upon transfer to this burn center 3 weeks after symptom onset, there was complete fusion of both eyelids with no visible cornea or sclera. She underwent bilateral operative scar release. After opening the lids, meticulous debridement of cicatricial membranes and release of symblephara were performed with subsequent placement of amniotic membrane grafts. Her vision slowly improved, though her long-term visual prognosis remains guarded. Early recognition and treatment of SJS or toxic epidermal necrolysis (TEN) with ocular involvement is imperative. Even mild cases may require intensive topical lubrication, steroids, and antibiotics, with early placement of amniotic membrane grafts in severe cases. Prompt intervention and daily evaluation are paramount in preventing lifelong visual disability., (Published by Oxford University Press on behalf of the American Burn Association 2021.)

Introduction: Diplopia and strabismus are known complications after corneal refractive surgery (CRS). Within the U.S. Armed Forces, refractive surgery is used to improve the operational readiness of the service member, and these complications could cause significant degradation to their capability. This study was performed in order to identify the incidence of strabismus and diplopia following CRS within the U.S. Military Health System., Methods: A retrospective review of all patients who underwent photorefractive keratectomy (PRK) or laser-assisted in situ keratomileusis (LASIK) in the Department of Defense from January 2006 through September 2013 was designed and approved by the Naval Medical Center Portsmouth Institutional Review Board. The military health system data mart was queried for all patients who underwent one of these procedures and subsequently had an International Classification of Disease-9 code for any strabismus or diplopia through 2014 allowing at least 1 year of follow-up. We then calculated the incidence of both diplopia and strabismus for these procedures as the primary measure and the overall prevalence as a secondary measure., Results: A total of 108,157 patients underwent PRK or LASIK during our study period with 41 of these patients subsequently having a diagnosis of diplopia or strabismus. After chart review, 16 of these patients were excluded resulting in 25 patients for inclusion in either the strabismus (23 patients, 0.02%) or diplopia (3 patients, 0.003%) cohorts with one patient having both. Of the 23 patients with postoperative strabismus, 4 were new cases giving an incidence of 0.004% and 2 new cases of diplopia for an incidence of 0.002%., Conclusion: Diplopia and strabismus are rare complications after CRS in the U.S. military population. These procedures continue to increase the operational readiness of our service members with minimal risk of these potentially debilitating complications. Overall, this study provides support for the continued use of PRK and LASIK despite study limitations related to the use of large databases for retrospective review. Future prospective studies using delineated preoperative and postoperative examinations with sensorimotor testing included may be able to resolve the limitations of this study., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2019.)

Introduction: Penetrating and perforating ocular trauma is often devastating and may lead to complete visual loss in the traumatized eye and subsequent compromise of the fellow eye. Enucleation is commonly utilized for management of a non-salvageable eye following penetrating and perforating ocular injuries. Recently, the use of evisceration for non-salvageable traumatized eyes has increased. As a technically easier alternative, evisceration offers several advantages to the ocular trauma surgeon to include faster surgical times, better cosmesis and motility, and improved patient outcomes. Debate still persists concerning whether or not evisceration is a viable option in the surgical management of a non-salvageable eye following ocular trauma given the theoretical increased risk of sympathetic ophthalmia and technical difficulty in construction of the scleral shell with extensive and complex corneoscleral lacerations. A retrospective analysis at a level 1 trauma center was performed to evaluate the practicality of evisceration in ocular trauma., Materials and Methods: Eyes that underwent evisceration or enucleation following ocular trauma at San Antonio Military Medical Center, a level 1 trauma center, between 01 January 2014 and 30 December 2016 were examined. Factors evaluated include mechanism of injury, defect complexity, ocular trauma score, and time from injury to surgical intervention. Surgical outcomes were assessed., Results: In total, 29 eyes were examined, 15 having undergone evisceration and 14 enucleation. The average size of the scleral defect before evisceration was 20 mm in length, and 23 mm before enucleation. The mechanism of injury and characterization of the defects among the two groups were relatively similar and described. Overall comparison of the two study groups in terms of surgical outcomes and complications was also relatively similar, as demonstrated. No cases of postoperative persistent pain, sympathetic ophthalmia, infection, or hematoma were identified for either group., Conclusions: The postoperative outcomes demonstrated for the evisceration group are comparable to enucleation, which is consistent with the recent literature. Defect size and complexity did not affect surgical construction of the scleral shell during evisceration. If consistently proven to be a safe and viable alternative to enucleation, evisceration can offer shorter surgical times and better cosmesis for patients. More research into the long-term complication rates and more cases of evisceration for use following ocular trauma should be assessed. Still, this analysis demonstrates that evisceration is a viable surgical alternative and perhaps superior to enucleation for the management of a non-salvageable eye following extensive ocular trauma in many cases., (Published by Oxford University Press on behalf of Association of Military Surgeons of the United States 2019. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

After the performance of the first peroral endoscopic myotomy (POEM) in 2008, POEM has now spread worldwide and has arguably become a first-line treatment option for achalasia. Recently, there is increasing debate regarding post-POEM gastroesophageal reflux (GER) and gastroesophageal reflux disease (GERD). The reported incidences of GERD vary widely, owing to the variability in the definitions used. The literature regarding GERD and achalasia patients with a focus on 24-hour pH testing, esophageal acid exposure, and fermentation and the definitions of GERD used in the POEM literature are examined. 24-hour pH testing in achalasia patients may be abnormal due to fermentation both pre- and post-treatment. It is vital that POEM operators ensure that fermentation is recognized during 24-hour pH testing and excluded in the analysis of acid exposure time (AET) used in the diagnosis of GERD. In untreated achalasia, 24-hour pH testing may suggest abnormal AET in over a third of patients. However, most abnormal AETs in untreated achalasia patients are due to fermentation rather than GER. In treated achalasia, up to half of the patients with abnormal AET may be attributable to fermentation. To have a candid discussion and appropriately address the questions surrounding post-POEM GERD, consistent definitions need to be applied. We suggest the recent definition of GERD from the Lyon Consensus to be utilized when diagnosing GERD in post-POEM patients. Further studies are required in establishing ideal parameters for 24-hour pH testing in achalasia patients., (© The Author(s) 2020. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Lessons Learned: The combination of irinotecan and etoposide showed modest efficacy in terms of response rate in the refractory setting for patients with metastatic breast cancer.The studied dose and schedule of irinotecan and etoposide is very toxic, with >70% grade 3 or 4 treatment-related adverse events., Background: As single agents, both irinotecan and etoposide have documented activity against breast cancer among patients who have received multiple lines of prior chemotherapy. Irinotecan interacts with topoisomerase I (Topo I) to stabilize its cleavable complex, and etoposide has an analogous interaction with topoisomerase II (Topo II). This stabilization without rapid resealing of the cleavage point results in apoptotic cell death and accounts for the antitumor activity of these agents. Topo II levels may increase after administration of a Topo I inhibitor, thus providing a rationale for combining these agents in practice. Based on preclinical data, we conducted a phase II trial of the Topo I inhibitor irinotecan combined with the Topo II inhibitor etoposide in patients with metastatic breast cancer (MBC)., Methods: This was a single-arm phase II clinical trial in patients with MBC refractory to prior anthracycline, taxane, and capecitabine therapy. All patients were treated with oral etoposide at 50 mg/day on days 1-14 and intravenous irinotecan at 100mg/m 2 on days 1 and 15. Treatment cycles were repeated every 28 days. The primary endpoint was median time to progression. Secondary end points included overall clinical response rate using RECIST criteria and assessing the toxicity and safety profile associated with this combination regimen., Results: We enrolled 31 women with refractory MBC to our trial. Median age was 54 (range, 36-84), with the majority (64%) having hormone receptor positive (HR+) human epidermal growth factor receptor 2 negative (HER2 neg) MBC. Median number of prior therapies was five (range, 3-14). Efficacy was evaluated in 24 patients. Seventeen percent had a partial response, and 38% had stable disease as best response. Median progression-free survival was 9 weeks (range, 3-59). All 31 patients were evaluable for toxicity assessment, and 22 patients (71 %) experienced treatment-related grade 3 or 4 adverse events (AEs; Table 1). The most common grade 3-4 AE was neutropenia. The study was terminated early based on interim analysis assessment that suggested toxicities outweighed the efficacy., Conclusion: Irinotecan and etoposide demonstrated only modest clinical activity and poor tolerability in patients with MBC refractory to anthracycline, taxane, and capecitabine therapy. Further studies testing a lower dose and/or different schedule could be considered given ease of administration and responses seen., (© AlphaMed Press; the data published online to support this summary are the property of the authors.)

Background: Gastrointestinal (GI) motility and functional disorders comprise over two-third of referrals to GI specialists yet training programs are disproportionately focused on endoscopy, inflammatory bowel disease and liver disease. Trainees at many centres receive minimal or no formal training in motility disorders and have little or no exposure to motility testing. Our purpose was to develop an educational intervention to address this learning need., Methods: We designed a formal training program comprised of didactic sessions, workshops and hands-on motility sessions with live demonstrations designed to be held over the course of a weekend. Faculty for the course were experienced GI motility experts from across Canada. Resident trainees from all Canadian GI fellowship programs were invited to attend. Pre- and post-tests were administered to measure the baseline learning needs and the impact of the program. Course evaluations were completed by attendees., Results: Three annual courses were offered over the past 3 years. Both adult and paediatric gastroenterology trainees attended the programs. The majority of training programs from Canada were represented. Baseline testing of attendees revealed a fundamental lack of understanding of GI motility concepts and their clinical implications. Postcourse test scores demonstrated a significant improvement in motility knowledge. Course evaluations of the content and faculty presentations received uniformly positive reviews., Conclusions: There is a pervasive lack of clinical knowledge of GI motility among Canadian GI subspecialty trainees. A focused weekend intensive course is one step in addressing this learning need., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Canadian Association of Gastroenterology.)

Purpose of the Study: Older adults in residential care and assisted living (RC/AL) are less healthy than the general elderly population, and some have needs similar to those in nursing homes, making this an important group in which to assess potential overuse or underuse of preventive services. We determined the health status of RC/AL residents and distinguished characteristics between those who may and may not benefit from preventive services requiring a life expectancy ≥5 years., Design and Methods: Cross-sectional survey of a nationally representative sample of RC/AL residents using 2010 data from the National Survey of Residential Care Facilities. The primary outcome was the weighted frequency distribution of health states using three predictive mortality indices: Charlson Comorbidity Index, 4-year mortality index, and 9-year mortality index., Results: A total of 666,700 of 733,300 (weighted) residents met criteria for inclusion. Based on the three indices, 10%-15% were in good health, 11%-70% in intermediate health, and 20%-76% in poor health., Implications: Using triangulation between 3 well-validated mortality indices, 10%-15% of RC/AL residents are in good health and highly likely to benefit from preventive services that require ≥5 year life expectancy. In addition, many residents have uncertain benefit and would benefit from shared decision making., (© The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Nearly 50 % of patients with chronic medical illness exhibit poor treatment adherence. When making treatment decisions, these patients must balance the probability of current side effects against the probability of long-term benefits. This study examines if the behavioral economic construct of probability discounting can be used to explain treatment decisions in chronic disease., Methods: Thirty-eight nonadherent and 39 adherent patients with multiple sclerosis (MS) completed a series of hypothetical treatment scenarios with varied risk and benefit probabilities., Results: As described by a hyperbolic probability discounting model, all patients reported decreased medication initiation as the probability of treatment efficacy decreased and the probability of treatment side effects increased. When compared to adherent patients, nonadherent patients significantly devalued treatment efficacy and inflated treatment risk., Discussion: The methods in this study can be used to identify optimal risk/benefit ratios for treatment development and inform the process by which patients make treatment decisions.

This article advances the discussion of treatment fidelity in social and behavioral intervention research by analyzing fidelity in an intervention study conducted within participating long-term care settings of the Collaborative Studies of Long-Term Care. The authors used the Behavior Change Consortium's (BCC) best practices for enhancing treatment fidelity recommendations in the areas of study design, provider training, treatment delivery, treatment receipt, and treatment enactment to evaluate fidelity-related decisions. Modifications to the original fidelity strategies were necessary in all areas. The authors revised their dose score and compared it with two constructed alternative measures of fidelity. Testing alternative measures and selecting the best measure post hoc allowed them to observe chance differences in relationship to outcomes. When the end result is to translate behavioral interventions into real practice settings, it is clear that some degree of flexibility is needed to ensure optimal delivery. Based on the relationship of program elements to the outcomes, a multicomponent intervention dose measure was more appropriate than one related to individual elements alone. By assessing the extent to which their strategies aligned with the BCC recommendations, the authors offer an opportunity for social work researchers to learn from their challenges and decision-making process to maximize fidelity.

Purpose of the Study: Descriptions of culture change adoption are often complex and varied, creating a challenge for those seeking guidance about which of the many components of culture change to adopt and in what order and combination., Design and Methods: To begin to address this question, members of The Research Initiative Valuing Eldercare (THRIVE) developed and distributed an online survey to 327 known culture change adopters. Of these, 164 (50%) completed the survey. Data were analyzed to identify adopted components, co-occurrence of adopted components, and differences in these across various types of nursing home models (i.e., traditional unit, household, and small house)., Results: Our findings support unique co-occurrence of components across nursing home models. Results also show that homes with more traditional environments have been able to implement certain culture change components without large capital investments required by renovations., Implications: The adoption patterns suggest that the co-occurrence of components should be considered when pursuing organizational transformations to support culture change.

The human head louse, Pediculus humanus capitis De Geer (Phthiraptera: Pediculidae), is an obligate ectoparasite that causes pediculosis capitis and has parasitized humans since the beginning of humankind. Head louse infestations are widespread throughout the world and have been increasing since the early 1990s partially because of ineffective pediculicides. In Argentina, the overuse of products containing pyrethroids has led to the development of resistant louse populations. Pyrethroid insecticides act on the nervous system affecting voltage-sensitive sodium channels. Three point mutations at the corresponding amino acid sequence positions M815I, T917I, and L920F in the voltage-gated sodium channel gene are responsible for contributing to knockdown resistance (kdr). The management of pyrethroid resistance requires either early detection or the characterization of the mechanisms involved in head louse populations. In the current study, we estimated the distribution of kdr alleles in 154 head lice from six geographical regions of Argentina. Pyrethroid resistance kdr alleles were found in high frequencies ranging from 67 to 100%. Of these, 131 (85.1%) were homozygous resistant, 13 (8.4%) were homozygous susceptible, and 10 (6.5%) were heterozygous. Exact tests for the Hardy-Weinberg equilibrium for each location showed that genotype frequencies differed significantly from expectation in four of the six sites studied. These results show that pyrethroid resistance is well established reaching an overall frequency of 88%, thus close to fixation. With 30 yr of pyrethroid-based pediculicides use in Argentina, kdr resistance has evolved rapidly among these head louse populations.

Long-term memory formation in Drosophila melanogaster is an important neuronal function shaping the insect's behavioral repertoire by allowing an individual to modify behaviors on the basis of previous experiences. In conditioned courtship or courtship suppression, male flies that have been repeatedly rejected by mated females during courtship advances are less likely than naïve males to subsequently court another mated female. This long-term courtship suppression can last for several days after the initial rejection period. Although genes with known functions in many associative learning paradigms, including those that function in cyclic AMP signaling and RNA translocation, have been identified as playing critical roles in long-term conditioned courtship, it is clear that additional mechanisms also contribute. We have used RNA sequencing to identify differentially expressed genes and transcript isoforms between naïve males and males subjected to courtship-conditioning regimens that are sufficient for inducing long-term courtship suppression. Transcriptome analyses 24 hours after the training regimens revealed differentially expressed genes and transcript isoforms with predicted and known functions in nervous system development, chromatin biology, translation, cytoskeletal dynamics, and transcriptional regulation. A much larger number of differentially expressed transcript isoforms were identified, including genes previously implicated in associative memory and neuronal development, including fruitless, that may play functional roles in learning during courtship conditioning. Our results shed light on the complexity of the genetics that underlies this behavioral plasticity and reveal several new potential areas of inquiry for future studies.

Using a comprehensive set of discovery and optimization tools, antibodies were produced with the ability to neutralize SARS coronavirus (SARS-CoV) infection in Vero E6 cells and in animal models. These anti-SARS antibodies were discovered using a novel DNA display method, which can identify new antibodies within days. Once neutralizing antibodies were identified, a comprehensive and effective means of converting the mouse sequences to human frameworks was accomplished using HuFR (human framework reassembly) technology. The best variant (61G4) from this screen showed a 3.5-4-fold improvement in neutralization of SARS-CoV infection in vitro. Finally, using a complete site-saturation mutagenesis methodology focused on the CDR (complementarity determining regions), a single point mutation (51E7) was identified that improved the 80% plaque reduction neutralization of the virus by greater than 8-fold. These discovery and evolution strategies can be applied to any emerging pathogen or toxin where a causative agent is known.

The Mouse Genome Database (MGD) forms the core of the Mouse Genome Informatics (MGI) system (http://www.informatics.jax.org), a model organism database resource for the laboratory mouse. MGD provides essential integration of experimental knowledge for the mouse system with information annotated from both literature and online sources. MGD curates and presents consensus and experimental data representations of genotype (sequence) through phenotype information, including highly detailed reports about genes and gene products. Primary foci of integration are through representations of relationships among genes, sequences and phenotypes. MGD collaborates with other bioinformatics groups to curate a definitive set of information about the laboratory mouse and to build and implement the data and semantic standards that are essential for comparative genome analysis. Recent improvements in MGD discussed here include the enhancement of phenotype resources, the re-development of the International Mouse Strain Resource, IMSR, the update of mammalian orthology datasets and the electronic publication of classic books in mouse genetics.

Methanotrophic bacteria play an important role in global cycling of carbon and co-metabolism of contaminants. Methanotrophs from pristine regions of the Snake River Plain Aquifer (SRPA; Idaho, USA) were studied in order to gain insight into the native groundwater communities' genetic potential to carry out TCE co-metabolism. Wells were selected that were proximal to a TCE plume believed to be undergoing natural attenuation. Methane concentrations ranged from 1 to >1000 nM. Carbon isotope ratios and diversity data together suggest that the SRPA contains active communities of methanotrophs that oxidize microbially produced methane. Microorganisms removed from groundwater by filtration were used as inocula for enrichments or frozen immediately and DNA was subsequently extracted for molecular characterization. Primers that specifically target methanotroph 16S rRNA genes or genes that code for subunits of soluble or particulate methane monooxygenase, mmoX and pmoA, respectively, were used to characterize the indigenous methanotrophs via PCR, cloning, RFLP analysis, and sequencing. Type I methanotroph clones aligned with Methylomonas, Methylocaldum, and Methylobacter sequences and a distinct 16S rRNA phylogenetic lineage grouped near Methylobacter. The majority of clone sequences in type II methanotroph 16S rRNA, pmoA, and mmoX gene libraries grouped closely with sequences in the Methylocystis genus. A subset of the type II methanotroph clones from the aquifer had sequences that aligned most closely to Methylosinus trichosporium OB3b and Methylocystis spp., known TCE-co-metabolizing methanotrophs.

The Mouse Genome Database (MGD) is one component of the Mouse Genome Informatics (MGI) system (http://www.informatics.jax.org), a community database resource for the laboratory mouse. MGD strives to provide a comprehensive knowledgebase about the mouse with experiments and data annotated from both literature and online sources. MGD curates and presents consensus and experimental data representations of genetic, genotype (sequence) and phenotype information including highly detailed reports about genes and gene products. Primary foci of integration are through representations of relationships between genes, sequences and phenotypes. MGD collaborates with other bioinformatics groups to curate a definitive set of information about the laboratory mouse and to build and implement the data and semantic standards that are essential for comparative genome analysis. Recent developments in MGD discussed here include an extensive integration of the mouse sequence data and substantial revisions in the presentation, query and visualization of sequence data.

Differences in sweetener intake among inbred strains of mice are partially determined by allelic variation of the saccharin preference (Sac) locus. Genetic and physical mapping limited a critical genomic interval containing Sac to a 194 kb DNA fragment. Sequencing and annotation of this region identified a gene (Tas1r3) encoding the third member of the T1R family of putative taste receptors, T1R3. Introgression by serial backcrossing of the 194 kb chromosomal fragment containing the Tas1r3 allele from the high-sweetener-preferring C57BL/6ByJ strain onto the genetic background of the low-sweetener-preferring 129P3/J strain rescued its low-sweetener-preference phenotype. Polymorphisms of Tas1r3 that are likely to have functional significance were identified using analysis of genomic sequences and sweetener-preference phenotypes of genealogically distant mouse strains. Tas1r3 has two common haplotypes, consisting of six single nucleotide polymorphisms: one haplotype was found in mouse strains with elevated sweetener preference and the other in strains relatively indifferent to sweeteners. This study provides compelling evidence that Tas1r3 is equivalent to the Sac locus and that the T1R3 receptor responds to sweeteners.

The ability of populations to undergo adaptive evolution depends on the presence of quantitative genetic variation for ecologically important traits. Although molecular measures are widely used as surrogates for quantitative genetic variation, there is controversy about the strength of the relationship between the two. To resolve this issue, we carried out a meta-analysis based on 71 datasets. The mean correlation between molecular and quantitative measures of genetic variation was weak (r = 0.217). Furthermore, there was no significant relationship between the two measures for life-history traits (r = -0.11) or for the quantitative measure generally considered as the best indicator of adaptive potential, heritability (r = -0.08). Consequently, molecular measures of genetic diversity have only a very limited ability to predict quantitative genetic variability. When information about a population's short-term evolutionary potential or estimates of local adaptation and population divergence are required, quantitative genetic variation should be measured directly.

Recent developments in basic immunology have revealed the importance of glutathione (GSH) and cellular redox balance in the generation of an immune response. In the liver, it has been shown that exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) alters cellular GSH and reactive oxygen intermediate (ROI) production. We have tested the hypothesis that TCDD mediates the suppression of the cytotoxic T lymphocyte (CTL) response to alloantigen by increasing oxidative stress. Total cellular GSH, GSSG, and GSH-protein adducts were analyzed by HPLC. Changes in intracellular GSH and ROI were simultaneously measured in isolated hepatocytes and individual subpopulations of spleen cells (CD4+, CD8+, B220+, and Mac-1+) following in vivo exposure to TCDD and antigenic challenge with P815 mastocytoma cells. Monochlorobimane was utilized to measure GSH levels, and two fluorescent probes were used to evaluate ROI levels: dichlorofluoroscein diacetate to monitor peroxides and dihydroethidine to assess superoxide anion. In hepatocytes, in vivo treatment with TCDD resulted in a transient, 2-fold increase in GSH, a 50% decrease in peroxide levels and a small (20-40%) decrease in superoxide anion levels. Although alloantigen challenge resulted in increased GSH and peroxide in spleen cells, in vivo exposure to TCDD had no effect on splenic ROI levels, nor did it consistently alter GSH levels in any subpopulation of spleen cells examined. Moreover, in vivo treatment with the antioxidant N-acetyl cysteine failed to affect the immune suppression caused by TCDD. These results suggest to us that although TCDD perturbs cellular redox balance in the liver, it does not exacerbate or diminish the normal increased GSH and ROI which occur in the spleen in response to antigenic challenge.

This study investigated whether the commonly observed higher prevalence of physical disability among women is due to higher incidence rates or to other factors such as selective mortality or poor recovery. Methods included observed measures of prevalent lower body physical disability and potential risk factors at baseline (1989-1991) and 4-year follow-up of 2,025 community-dwelling adults aged 55 years and older in Marin County, California. Incidence, recovery, and mortality rates were determined at the follow-up examination. Results indicated that women had higher age-specific and age-adjusted prevalence rates at both examinations (odds ratios = 1.66 and 1.60, p<0.001) but that incidence rates were not significantly different (odds ratio = 1.12, 95% confidence interval: 0.77, 1.64). In the classic formulation, prevalence = incidence x duration, the higher prevalence rates in women could not be due to a higher incidence rate, but could be explained by longer duration due to lower recovery and mortality rates in women. Incident physical disability was predicted by prevalent chronic illnesses, poor vision, obesity, physical inactivity, poor memory, fewer social activities, and higher depression scores, but not by sex. Prevention efforts should concentrate on reducing known risk factors in both men and women and on promoting higher recovery rates among women.

The capacity of the pituitary to suppress hormone secretion in response to somatostatin (SRIF) is markedly age dependent. Immature pituitaries are relatively resistant to SRIF effects, and increasing sensitivity to SRIF with advancing age is believed to cause characteristic developmental changes in pituitary hormone secretion in mammals. However, the cellular mechanism(s) underlying this developmental pattern of response to SRIF are not understood. Because somatostatin receptors (ssts) are critical mediators of SRIF's actions on target tissues, we investigated the expression of sst1, sst2, sst3, sst4, and sst5 messenger RNA (mRNA) in pituitaries of developing and mature rats. Animals were studied at embryonic day 19.5, and at postnatal days 2, 12, 30, 45, 70, and 1 yr; these ages correspond to major changes in circulating GH levels and pituitary responsiveness to SRIF. Pituitary levels of sst2 mRNA increased strikingly and progressively with advancing age after birth (F = 30.92, P < 0.0001). Compared with 2-day-old pituitaries, sst2 mRNA abundance rose 3.25-fold by 12 days of age and 6-fold by 70 days of age. Moreover, Western blot analysis indicated a marked increase in pituitary expression of sst2A protein with advancing age. By contrast, pituitary abundance of sst1, sst3, sst4, and sst5 mRNAs did not differ with age. To assess the role of endogenous SRIF in regulating perinatal sst2 gene expression, we also administered a well-characterized SRIF antiserum (or NSS as controls; 10 microl/10 g) sc daily from postnatal days 2 to 12 of life. Treatment with SRIF antiserum raised GH levels but did not alter pituitary sst2 mRNA abundance, compared with controls. Taken together, these data indicate that 1) the perinatal rat pituitary expresses the same complement of ssts as the adult pituitary; 2) expression of ssts is developmentally regulated in a highly subtype-specific manner; 3) pituitary sst2 mRNA and sst2A protein increase markedly and progressively with advancing age after birth; and 4) the perinatal rise in sst2 mRNA levels is unlikely to be regulated by endogenous SRIF. The finding of subtype-specific, developmentally determined sst expression indicates a novel and potentially fundamental mechanism of sst regulation, and suggests a molecular mechanism underlying developmental maturation in the capacity of the pituitary to respond to SRIF.

Ninety subjects with severe and disabling psychiatric conditions, predominantly schizophrenia, participated in a controlled-outcome trial of the cognitive component of Integrated Psychological Therapy (IPT), a group-therapy modality intended to reestablish basic neurocognitive functions. The cognitive therapy was delivered to subjects in the experimental condition during intensive 6-month treatment periods. Control subjects received supportive group therapy. Before, during, and after the intensive treatment period, all subjects received an enriched regimen of comprehensive psychiatric rehabilitation, including social and living skills training, optimal pharmacotherapy, occupational therapy, and milieu-based behavioral treatment. IPT subjects showed incrementally greater gains compared with controls on the primary outcome measure, the Assessment of Interpersonal Problem-Solving Skills, suggesting that procedures that target cognitive impairments of schizophrenia spectrum disorders can enhance patients' response to standard psychiatric rehabilitation, at least in the short term, in the domain of social competence. There was equivocal evidence for greater improvement in the experimental condition on the Brief Psychiatric Rating Scale disorganization factor and strong evidence for greater improvement on a laboratory measure of attentional processing. There was significant improvement in both conditions on measures of attention, memory, and executive functioning, providing support for the hypothesis that therapeutic procedures that target impaired cognition enhance response to conventional psychiatric rehabilitation modalities over a 6-month timeframe.

Research in psychopathology and the cognitive neurosciences suggests new applications in psychiatric rehabilitation. Analysis of performance deficits on laboratory tasks can contribute to treatment planning, individual and family counseling, and staff consultation, much like it does in cases of brain injury and other types of central nervous system neuropathology. Recognition of the nature of cognitive impairments in schizophrenia can inform design of psychosocial techniques such as social and living skills training. Cognitive impairments are increasingly seen as potential targets for pharmacological and psychosocial treatment and rehabilitation. In this article, three key issues for application of cognitive technology in psychiatric rehabilitation of schizophrenia and related disorders are formulated as straightforward, clinically relevant questions: (1) What is the prognostic significance of cognitive impairment in acute psychosis? (2) Can cognitive functioning improve in the chronic, residual course? (3) How does cognitive improvement benefit other aspects of recovery and rehabilitation? These questions are addressed through review of previous findings and new multivariate analyses of cognitive functioning in the acute, post-acute, and chronic residual phases of schizophrenia.

Among 1,433 men of Japanese ancestry living in Hawaii with blood pressure measured at four different physical examinations over a 10-year period, 110 events of definite coronary heart disease (CHD) occurred during 11.6 years of subsequent follow-up. Each subject's mean blood pressure, the slope of the regression of his blood pressure on age, and the variance of blood pressure about this regression line were tested for association with subsequent incident definite CHD. Adjusted for mean systolic blood pressure (SBP), the variance of SBP was significantly associated with CHD (p < 0.001); however, the slope was not significantly associated with CHD. Variation in body weight was an independent risk factor for CHD. The effect of variation in SBP was significantly higher among men not taking antihypertensive medication; among men taking antihypertension medication, the standardized relative risk was 1.00. Comparing men in the highest quintile of SBP variation with those in the lowest quintile, the relative risk of CHD was 2.0 among all subjects and 5.3 among the 1,007 men not taking antihypertensive medication (95% confidence interval 1.8-15.4). Some of the beneficial effect of taking antihypertensive medication may have been due to reducing the effect of SBP variance rather than simply lowering the average SBP.

To investigate the association between idiopathic Parkinson disease (IPD) and reduced frequency of prior cigarette smoking, the authors compared the 29-year follow-up mortality rates and IPD incidence rates of men who were either cigarette smokers or nonsmokers at the time of enrollment in the Honolulu Heart Study (1965-1968). Based on IPD cases detected up to June 30, 1994, the age-adjusted incidence rate in smokers was less than half that in nonsmokers: 34.4 versus 94.2 cases per 100,000 person-years of pre-illness follow-up, respectively. When data were stratified by 5-year age group, lower IPD incidence in smokers was observed at all ages between 50 and 90 years. Age-specific mortality trends for smokers and nonsmokers with and without IPD suggested that increased mortality in IPD patients was mostly associated with IPD itself and not with smoking. The slight excess mortality in smokers without IPD, versus nonsmokers without IPD, appeared insufficient to account for the "missing" incident IPD cases in smokers. These IPD incidence and mortality data are not highly consistent with the "selective mortality" hypothesis, which attributes reduced prior smoking frequency, typically reported by persons with IPD, to accelerated mortality in undiagnosed IPD-affected persons who smoke. The "protective" association of cigarette smoking with IPD occurrence may thus be real, suggesting the need for further study of biologic mechanisms of protection.

The ability to taste low concentrations of propylthiouracil (PROP) and related bitter compounds is heritable. The current analysis determines whether the distribution of PROP taste thresholds is consistent with an additive or a dominant mode of Mendelian transmission. To that end, the lowest concentration of PROP detectable was determined for 1015 subjects and models of bi- or tri-modal distributions of PROP taste thresholds were tested. The model with the greatest likelihood had three distributions and followed an additive model of PROP taste sensitivity if the variances associated with the distributions were assumed to be equal. However, if the taste thresholds were transformed to remove skewness, or if the variances were unequal, then three- or two-distribution models were equally likely. Resolution of the mode of inheritance for bitter taste perception awaits additional family studies and the characterization of the molecular basis of taste perception for these bitter compounds.

There is a need to monitor anticoagulation accurately, inexpensively, and rapidly. The accuracy and precision of a simple fingerstick method was studied in a large outpatient anticoagulation clinic using the Coumatrak method. The Coumatrak apparatus has been studied in the home setting, and three recent reports suggest that it is practical, accurate, and possibly superior to the standard method. These results differ from recently published studies. This technique was found to be less than acceptable in precision and accuracy. This method requires further study before it can be recommended for wide-spread use in making decisions for patient care.

The relationship between social competence and information processing among individuals with chronic schizophrenia was investigated. Thirty-eight inpatients participated in a role play test of social competence and completed a battery of information-processing tasks. Information processing was found to be significantly related to social competence, even after controlling for patient demographics, chronicity, and symptomatology. Higher global social competence was related to more efficient early information processing on a continuous performance/span of apprehension task. Composite indices of specific social competence (i.e., paralinguistic and nonverbal skills) were related to other aspects of information processing (e.g., reaction time). Implications for behavioral assessment and cognitive rehabilitation are discussed.

Experiments were conducted to elucidate the status of glutathione present in the oxidized (GSSG), reduced (GSH), and protein-mixed disulfide (GSSprotein) forms in preimplantation mouse embryos during development and after treatment with tertiary-butyl hydroperoxide (tBH) to cause oxidative stress. Glutathione was measured at picomolar levels by fluorimetric HPLC after derivatization of extracted embryonic samples with dansyl chloride. GSH content decreased approximately 10-fold from that in the unfertilized oocyte to 0.12 pmol/blastocyst, representing an estimated change in concentration from 7 to 0.7 mM. GSH levels were lower in embryos cultured in vitro than in embryos that developed in vivo. Addition of GSH to the culture medium improved in vitro development of mouse embryos, but surprisingly the addition of glutathione monoethyl ester did not. Addition of low levels of the oxidant tBH (13.2 microM) to culture medium decreased the percentage of two-cell and blastocyst stage embryos that exhibited further development. After 15-min exposure to 13.2 microM tBH, GSH levels were markedly decreased in the two-cell stage embryo (75%), but only slightly decreased (25%) in the blastocyst. The loss of GSH was accounted for by increases in GSSG and GSSprotein, indicating that the embryo was undergoing oxidative stress. These data indicate that preimplantation embryos are very sensitive to conditions that can cause oxidative stress and show also that their glutathione status changes dramatically during development.

A 26-year follow-up study of 8,006 men enrolled in the Honolulu Heart Program examined the effect of cigarette smoking on the risk of developing idiopathic Parkinson's disease. Cases were identified through an ongoing search of hospital records and by the review of death certificates and medical records of local neurologists. Men who had smoked cigarettes at any time prior to study enrollment in 1965 had a reduced risk of developing idiopathic Parkinson's disease (relative risk = 0.39). Examination of smoking by pack-years revealed an apparent dose-response effect on the risk of idiopathic Parkinson's disease, but not on the age of onset. Coffee drinking was also associated with reduced risk, apparently because of its association with cigarette smoking. Although the detrimental health effects of cigarette smoking would far outweight any possible protective effect for smoking and Parkinson's disease, the association of smoking with apparent protection may contribute to understanding the underlying pathogenetic mechanisms.

There has been a controversy regarding occupation, as defined by blue and white collar work, and coronary heart disease (CHD). In a large long-term prospective study of the Honolulu Heart Program cohort, there were no significant differences between these two occupational classifications and the incidence rates of fatal and non-fatal CHD. Nor were there significant differences in total mortality, stroke or total cancer although there were very small but significant differences in some CHD risk factors. Unlike the previous studies, this investigation was free of prevalent cases of CHD at baseline and controlled for the major risk factors of CHD. We question the utility of using this occupational classification to investigate the causes of CHD.

While the excess risk of clinical cardiovascular disease among persons with diabetes mellitus is well established, most autopsy studies have not been able to elucidate reasons for the excess, to assess potential selection bias, or to adjust for other cardiovascular risk factors. The purpose of this study was to examine the predictive relation between diabetes and autopsy evidence of coronary atherosclerosis and myocardial lesions. Among 8,006 Japanese-American men examined at baseline in 1965-1968 as part of the Honolulu Heart Program, 7,591 were free of cardiovascular disease, and 1,515 of these men died over a 17-year follow-up period. Protocol autopsies were performed for 83 diabetic men and 159 nondiabetic men. Diabetes status was defined using self-reported history and treatment at several examinations, as well as physician diagnoses during hospitalization between 1965 and 1984. An excess of coronary artery atherosclerosis, assessed by mean panel score (3.4 vs. 3.0, p = 0.017) and percentage of intimal surface with raised lesions (56.6% vs. 47.4%, p = 0.024), was present among diabetic men but diminished to nonsignificant levels (3.3 vs. 3.0, p = 0.102, and 53.9% vs. 48.8%, p = 0.183, respectively) after adjustment for other cardiovascular risk factors. Myocardial lesions (acute, healing, or fibrotic) occurred significantly more frequently among diabetics than among nondiabetics (77.7% vs. 63.4%, p = 0.035), even after adjustment for other risk factors. Potential autopsy selection bias assessed in several ways appeared minimal. Among men with mild atherosclerosis, diabetics had more small and large myocardial lesions than did nondiabetics, although differences were not statistically significant (p < 0.10). It appears that the more adverse risk factor profile among diabetics accounts for some of the observed excess of coronary atherosclerosis. However, diabetes was independently associated with myocardial lesions, and these findings suggest a role for nonatherosclerotic mechanisms, such as clotting abnormalities or microvascular disease, in accounting for the excess clinical heart disease found in persons with diabetes.

Recent studies have shown that tissue macrophages are capable of proliferation and that this capability is enhanced by various cytokines, including macrophage colony-stimulating factor (M-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Tumor-associated macrophages (TAM) have been demonstrated to proliferate in vitro, but no information is currently available on the ability of M-CSF and GM-CSF to enhance this response. To address this problem, limiting dilution analysis was utilized to examine the proliferative ability of macrophages isolated from two murine tumors of distinct origin following growth in secondary hosts. As a means of comparison, resident peritoneal macrophages (RPM) and thioglycolate-elicited macrophages (TEM) were also analyzed. Results indicate that a rare subset of TAM and RPM is capable of proliferation and that M-CSF and GM-CSF enhance the frequency of TAM and RPM which proliferate, but do not enhance the growth of TEM.

The purpose of this study was to determine if the major risk factors for clinical myocardial infarction also predicted coronary artery stenosis as defined by arteriography. Of a cohort of 7,591 men who were free of cardiovascular disease at entry, 357 had arteriographic studies during a 20-year follow-up period. Risk factor levels were therefore known prior to the onset of clinical symptoms and arteriographic studies. Men with arteriograms were divided into groups with and without prior clinical myocardial infarction. High blood pressure, serum cholesterol, obesity, and low alcohol intake predicted both severe coronary stenosis and incident myocardial infarction, thus indicating that these variables were associated with clinical events through the underlying process of atherosclerosis. Dietary intake of cholesterol and serum glucose also had similar but not always statistically significant patterns of association with both coronary stenosis and myocardial infarction. In contrast, serum triglyceride and cigarette smoking predicted clinical myocardial infarction, but not severe coronary stenosis. This suggests that these variables play a stronger role in the precipitation of acute clinical events than in the underlying process of atherosclerosis. The findings were quite different for several risk factors when analyzed in a case-control format using the arteriography series from this same data set. Examination of possible explanations for the differences raises questions concerning the use of arteriography series for etiologic studies of coronary atherosclerosis.

In prospective studies, subjects found to have the disease under investigation at the initial screening examination are commonly excluded from analyses. However, the possibility of bias due to prevalent conditions other than the disease of interest is usually not considered. In the present study, an algebraic development enables analysis of the effects of inclusion and exclusion of subjects with certain prevalent conditions upon risk estimates. Hypothetical data are presented for which an association between a risk factor and an incident disease could become null or even reversed after removing subjects with certain prevalent diseases. Bias appears even when the only association present is between risk factor and total disease incidence. Data from the Honolulu Heart Study also have been used to illustrate this finding, examining the association between coronary heart disease (CHD) incidence and smoking. Decisions regarding the inclusion or exclusion of subjects with prevalent diseases requires prior knowledge of alteration of usual risk factors levels by individuals with these diseases. Simply removing all subjects with prevalent diseases might on the contrary create bias. Therefore, people with prevalent diseases should be screened for potential alteration of their risk factor levels as a result of the diseases. The situation becomes still more complex when several risk factors and prevalent diseases need to be considered at the same time as it happens in multivariate analyses. Because this situation represents a bias, and not confounding or effect modification, controlling for the effect of prevalent diseases is not appropriate.

The "paradoxical" occurrence of high rates of stroke and low rates of coronary heart disease observed in Asian and other populations has been examined using accumulated clinical and autopsy data obtained during the long-term follow-up from 1965 to 1985 of cohorts of Japanese men living in Hawaii and Japan. The search for explanatory variables revealed three with the characteristics of having both opposing patterns of associations with clinical stroke compared with coronary heart disease and of being more prevalent in Japan than in Hawaii. These variables were low serum cholesterol levels, high intake of alcohol, and some aspect of an Oriental diet characterized by low intake of fat and protein from animal sources. Analysis of associations of these variables with measures of atherosclerosis in coronary and cerebral arteries revealed no paradoxical differences, with the possible exception of some dietary variables. Associations with autopsy-measured myocardial infarctions, cerebral infarction, and hemorrhage, however, showed opposing patterns similar to those found for clinical disease. The main inference from this work is that the paradoxically high risk of stroke observed in populations with low risk of coronary heart disease is not due to atherosclerosis in the major cerebral arteries. Rather, it is more likely due to lesions in the small intracerebral arteries and appears to be related to low levels of serum cholesterol, high alcohol intake, and some aspect of a traditional Oriental diet.

Nutrient intake was determined in over 8000 men of Japanese ancestry residing on the island of Oahu. Nutrient determination took place at the initial examination during the years 1965-1968. This report relates nutrient intake to the risk of developing coronary heart disease in the 10 years subsequent to the initial examination. Men who developed coronary heart disease had a lower average intake of calories, carbohydrates, starch, and vegetable protein than men who remained free of coronary heart disease. Men who developed coronary heart disease also had a higher mean intake of percentage of calories from protein, fat, saturated fatty acids, and polyunsaturated fatty acids than men who remained free of coronary heart disease. These men also had a significantly lower mean percentage of calories from carbohydrates and a higher mean ingestion of cholesterol per 1000 calories than men who remained free of coronary heart disease. In multivariate analyses including age, systolic blood pressure, serum cholesterol, cigarettes smoked per day, and physical activity index, carbohydrates, vegetable protein, percentage of calories from saturated fatty acids, and percentage of calories from polyunsaturated fatty acids are no longer significantly related to incidence.

The hypothesis that men in high "strain" occupations have an increased risk of developing coronary heart disease was tested during an 18-year follow-up study from 1965-1983 of a cohort of 8,006 men of Japanese ancestry in Hawaii. There were no significant associations between the incidence of coronary heart disease and the individual job components of high psychologic demands and low job control or for the high strain interaction of these two characteristics. There were, in fact, trends of associations opposite to that predicted by the job strain model which were of borderline significance in multivariate analyses. Stratified analyses by level of acculturation showed similar inverse associations of job strain and coronary heart disease for the more Westernized men and no association for the more traditional men. There were also no significant associations among the various job characteristics and the major risk factors for coronary heart disease in this cohort. The disagreement of these results with those from other studies may be due to methodologic differences of using men whose usual and current occupations were the same in this study compared with using only current occupation in the other studies, the use of different methods of measuring job strain, or the possibility that men in this cohort perceive or react to occupational strain differently.

Accumulated data from the Honolulu Heart Program cohort of men of Japanese ancestry were analysed for 19-year trends in coronary heart disease (CHD) mortality and incidence rates, case-fatality ratios, and changes in risk factor levels. From 1966 to 1984, there was an estimated average annual decline of 2.7% for CHD mortality rates for the population from which the cohort was drawn. This decline was similar to that of US white males of the same age distribution. Within the examined cohort of men who were free of prevalent CHD at entry into the study, the temporal pattern of incidence rates of definite CHD was quite similar to the pattern of CHD mortality rates. Thus, for the examined cohort, mortality rates were an accurate indication of incidence rates. There was no evidence that the decline in CHD mortality rates was due to reductions in case-fatality ratios. There were, however, significant decreases in the percentages of men who smoked cigarettes, in blood pressure level among treated hypertensives and in the intake of dietary cholesterol. These changes, and a drop in coronary artery atherosclerosis measured during the same time period, are all compatible with the concept that the decline of CHD mortality among Japanese men in Hawaii reflects primary prevention of new disease.