Evaluating the performance of herd-specific Long Short-Term Memory models to identify automated health alerts associated with a ketosis diagnosis in early lactation cows.

The growing use of automated systems in the dairy industry generates a vast amount of cow-level data daily, creating opportunities for using these data to support real-time decision-making. Currently, various commercial systems offer built-in alert algorithms to identify cows requiring attention. To our knowledge, no work has been done to compare the use of models accounting for herd-level variability on their predictive ability against automated systems. Long Short-Term Memory (LSTM) models are machine learning models capable of learning temporal patterns and making predictions based on time series data. The objective of our study was to evaluate the ability of LSTM models to identify a health alert associated with a ketosis diagnosis (HAK) using deviations of daily milk yield, milk FPR, number of successful milkings, rumination time, and activity index from the herd median by parity and DIM, considering various time series lengths and numbers of d before HAK. Additionally, we aimed to use Explainable Artificial Intelligence method to understand the relationships between input variables and model outputs. Data on daily milk yield, milk fat-to-protein ratio (FPR), number of successful milkings, rumination time, activity, and health events during 0 to 21 d in milk (DIM) were retrospectively obtained from a commercial Holstein dairy farm in northern Indiana from February 2020 to January 2023. A total of 1,743 cows were included in the analysis (non-HAK = 1,550; HAK = 193). Variables were transformed based on deviations from the herd median by parity and DIM. Six LSTM models were developed to identify HAK 1, 2, and 3 d before farm diagnosis using historic cow-level data with varying time series lengths. Model performance was assessed using repeated stratified 10-fold cross-validation for 20 repeats. The Shapley additive explanations framework (SHAP) was used for model explanation. Model accuracy was 83, 74, and 70%, balanced error rate was 17 to 18, 26 to 28, and 34%, sensitivity was 81 to 83, 71 to 74, and 62%, specificity was 83, 74, and 71%, positive predictive value was 38, 25 to 27, and 21%, negative predictive value was 97 to 98, 95 to 96, and 94%, and area under the curve was 0.89 to 0.90, 0.80 to 0.81, and 0.72 for models identifying HAK 1, 2, and 3 d before diagnosis, respectively. Performance declined as the time interval between identification and farm diagnosis increased, and extending the time series length did not improve model performance. Model explanation revealed that cows with lower milk yield, number of successful milkings, rumination time, and activity, and higher milk FPR compared with herdmates of the same parity and DIM were more likely to be classified as HAK. Our results demonstrate the potential of LSTM models in identifying HAK using deviations of daily milk production variables, rumination time, and activity index from the herd median by parity and DIM. Future studies are needed to evaluate the performance of health alerts using LSTM models controlling for herd-specific metrics against commercial built-in algorithms in multiple farms and for other disorders.

RNA-binding Protein Quaking Stabilizes Sirt2 mRNA during Oligodendroglial Differentiation.

Myelination is controlled by timely expression of genes involved in the differentiation of oligodendrocyte precursor cells (OPCs) into myelinating oligodendrocytes (OLs). Sirtuin 2 (SIRT2), a NAD+-dependent deacetylase, plays a critical role in OL differentiation by promoting both arborization and downstream expression of myelin-specific genes. However, the mechanisms involved in regulating SIRT2 expression during OL development are largely unknown. The RNA-binding protein quaking (QKI) plays an important role in myelination by post-transcriptionally regulating the expression of several myelin specific genes. In quaking viable (qkv/qkv ) mutant mice, SIRT2 protein is severely reduced; however, it is not known whether these genes interact to regulate OL differentiation. Here, we report for the first time that QKI directly binds to Sirt2 mRNA via a common quaking response element (QRE) located in the 3' untranslated region (UTR) to control SIRT2 expression in OL lineage cells. This interaction is associated with increased stability and longer half-lives of Sirt2.1 and Sirt2.2 transcripts leading to increased accumulation of Sirt2 transcripts. Consistent with this, overexpression of qkI promoted the expression of Sirt2 mRNA and protein. However, overexpression of the nuclear isoform qkI-5 promoted the expression of Sirt2 mRNA, but not SIRT2 protein, and delayed OL differentiation. These results suggest that the balance in the subcellular distribution and temporal expression of QKI isoforms control the availability of Sirt2 mRNA for translation. Collectively, our study demonstrates that QKI directly plays a crucial role in the post-transcriptional regulation and expression of Sirt2 to facilitate OL differentiation.

Does Sirt2 Regulate Cholesterol Biosynthesis During Oligodendroglial Differentiation In Vitro and In Vivo?

Sirtuin2 (SIRT2) is a deacetylase enzyme predominantly expressed in myelinating glia of the central nervous system (CNS). We have previously demonstrated that Sirt2 expression enhances oligodendrocyte (OL) differentiation and arborization in vitro, but the molecular targets of SIRT2 in OLs remain speculative. SIRT2 has been implicated in cholesterol biosynthesis by promoting the nuclear translocation of sterol regulatory element binding protein (SREBP)-2. We investigated this further in CNS myelination by examining the role of Sirt2 in cholesterol biosynthesis in vivo and in vitro employing Sirt2 -/- mice, primary OL cells and CG4-OL cells. Our results demonstrate that expression of cholesterol biosynthetic genes in the CNS white matter or cholesterol content in purified myelin fractions did not differ between Sirt2 -/- and age-matched wild-type mice. Cholesterol biosynthetic gene expression profiles and total cholesterol content were not altered in primary OLs from Sirt2 -/- mice and in CG4-OLs when Sirt2 was either down-regulated with RNAi or overexpressed. In addition, Sirt2 knockdown or overexpression in CG4-OLs had no effect on SREBP-2 nuclear translocation. Our results indicate that Sirt2 does not impact the expression of genes encoding enzymes involved in cholesterol biosynthesis, total cholesterol content, or nuclear translocation of SREBP-2 during OL differentiation and myelination.

Organotypic Cultures from the Adult CNS: A Novel Model to Study Demyelination and Remyelination Ex Vivo.

Experimental models of multiple sclerosis (MS) have significantly advanced our understanding of pathophysiology and therapeutic interventions. Although in vivo rodent models are considered to most closely represent the complex cellular and molecular disease states of the human central nervous system (CNS), these can be costly to maintain and require long timelines. Organotypic slice cultures maintain the cytotypic organization observed in the intact CNS, yet provide many of the experimental advantages of in vitro cell culture models. Cerebellar organotypic cultures have proven useful for studying myelination and remyelination, but this model has only been established using early postnatal tissue. This young brain tissue allows for neuro development ex vivo to mimic the 'mature' CNS; however, there are many differences between postnatal and adult organotypic cultures. This may be particularly relevant to MS, as a major barrier to myelin regeneration is age. This paper describes a modified protocol to study demyelination and remyelination in adult cerebellar tissue, which has been used to demonstrate neuroprotection with omega-3 fatty acids. Thus, adult cerebellar organotypic cultures provide a novel ex vivo platform for screening potential therapies in myelin degeneration and repair.

Dose escalation of definitive radiation is not associated with improved survival for cervical esophageal cancer: a National Cancer Data Base (NCDB) analysis.

For cervical esophageal cancer (CEC), National Comprehensive Cancer Network guidelines support RT to 50-50.4 Gy with chemotherapy but acknowledge higher doses may be appropriate. This study uses the National Cancer Database (NCDB) to characterize RT practices and identify if a dose-response relationship exists for overall survival (OS) for definitive treatment of CEC. We queried the NCDB for patients diagnosed with Stage I-III CEC from 2004 to 2013, and selected patients receiving definitive RT with doses between 50 and 74 Gy. Using multivariate logistic regression, the database was analyzed to determine factors associated with use of RT > 50.4 Gy. Patients were then stratified into three dose categories. Predictors of OS were analyzed with univariate and multivariate methods using the Kaplan-Meier curves, the log-rank test, and the Cox proportional hazards analysis. We stratified 789 patients with CEC who were treated with definitive radiation ± chemotherapy: 50-50.4 Gy ('standard'), >50.4 and <66 Gy ('medium'), and 66-74 Gy ('high'). Of these patients, 215 (27%) received standard doses, 375 (48%) received medium doses, and 199 (25%) received high doses. Patients with Medicaid insurance and those with Stage II disease were less likely (P < 0.05) to receive >50.4 Gy. Sex, histology, distance to treatment facility, and academic/community facility type were not significantly associated with receipt of >50.4 Gy. There was no association between dose and OS for the medium or high groups when using univariate analysis or analysis adjusted for demographic, facility, and clinical attributes. Stage III disease and the Charlson-Deyo scores of 1 or 2 were associated with higher mortality (P < 0.05), while female sex and use of chemotherapy were associated with lower mortality (P < 0.01). Nearly three-fourths of CEC patients in the United States are treated with RT > 50.4 Gy. Higher radiation doses were not associated with increased OS in CEC patients in the NCDB.

Current developments in pharmacogenomics of multiple sclerosis.

Pharmacogenomics has a significant potential to impact how we treat diseases. It involves targeting genetically identifiable populations with therapeutic interventions that promises to yield immediate positive health outcomes with lower or no side effects. The 'trial and error' method of treatment will no longer be necessary with the successful implementation of personalized medicine. The following is an overview of some new developments in pharmacogenomics of multiple sclerosis, and how it has the potential to improve future treatment.

Conditional Tet-regulated over-expression of Hoxa2 in CG4 cells increases their proliferation and delays their differentiation into oligodendrocyte-like cells expressing myelin basic protein.

Hoxa2 gene was reported to be expressed by oligodendrocytes (OLs) and down-regulated at the terminal differentiation stage during oligodendrogenesis in mice (Nicolay et al. 2004b). To further investigate the role of Hoxa2 in oligodendroglial development, a tetracycline regulated controllable expression system was utilized to establish a stable cell line (CG4-SHoxa2 [sense Hoxa2]), where the expression level of Hoxa2 gene could be up-regulated. The impact of Hoxa2 over-expression on the proliferation and differentiation of CG4-SHoxa2 cells was investigated. Up-regulation of Hoxa2 increased the proliferation of CG4-SHoxa2 cells. The mRNA levels of PDGFαR (platelet-derived growth factor [PDGF] alpha receptor), which is expressed by OL progenitor cells, were not different in CG4-SHoxa2 cells compared to wild-type CG4 cells. Semi-quantitative RT-PCR revealed that the mRNA levels of myelin basic protein (MBP) was lower in CG4-SHoxa2 cells than in wild-type CG4 cells indicating the differentiation of CG4-SHoxa2 cells was delayed when the Hoxa2 gene was up-regulated.

Age-related and cuprizone-induced changes in myelin and transcription factor gene expression and in oligodendrocyte cell densities in the rostral corpus callosum of mice.

During aging, there is a decrease both in the stability of central nervous system (CNS) myelin once formed and in the efficiency of its repair by oligodendrocytes (OLs). To study CNS remyelination during aging, we used the cuprizone (a copper chelator) mouse model. Inclusion of cuprizone in the diet kills mature OLs and demyelinates axons in the rostral corpus callosum (CC) of mice, which enabled us to characterize age-related changes (i.e., 2-16 months of age) in glial cell response during the recruitment (i.e., demyelination) and differentiation (i.e., remyelination) phases of myelin repair. We have found that the time between 12 and 16 months of age is a critical period during which there is an age-related decrease in the number of OL lineage cells (Olig2(Nuc)+ve/GFAP-ve cells) in the rostral CC of both control mice and mice recovering from cuprizone-induced demyelination. Our results also show there was an age-related impaired recruitment of progenitor cells to replace lost OLs in spite of there being no major age-related decrease in the size of the progenitor cell pool (PDGFalphaR+ve/GFAP-ve, and Olig2(Nuc) +ve/PDGFalphaR+ve cells). However, there were cuprizone-induced increased numbers of astrocyte progenitor cells (Olig2(Cyto)+ve/PDGFalphaR+ve) in these same mice; thus PDGFalphaR+ve progenitor cells in mice as old as 16 months of age retain the ability to differentiate into astrocytes, with this fate choice occurring following cytoplasmic translocation of Olig2. These data reveal for the first time age-related differences in the differentiation of PDGFalphaR+ve progenitor cells into OLs and astrocytes and lead us to suggest that during aging there must be a transcriptional switch mechanism in the progenitor cell fate choice in favor of astrocytes. This may at least partially explain the age-related decrease in efficiency of OL myelination and remyelination.

Advances in the treatment of relapsing-remitting multiple sclerosis: the role of pegylated interferon ß-1a.

Multiple sclerosis (MS) is a progressive, neurodegenerative disease with unpredictable phases of relapse and remission. The cause of MS is unknown, but the pathology is characterized by infiltration of auto-reactive immune cells into the central nervous system (CNS) resulting in widespread neuroinflammation and neurodegeneration. Immunomodulatory-based therapies emerged in the 1990s and have been a cornerstone of disease management ever since. Interferon ß (IFNß) was the first biologic approved after demonstrating decreased relapse rates, disease activity and progression of disability in clinical trials. However, frequent dosing schedules have limited patient acceptance for long-term therapy. Pegylation, the process by which molecules of polyethylene glycol are covalently linked to a compound, has been utilized to increase the half-life of IFNß and decrease the frequency of administration required. To date, there has been one clinical trial evaluating the efficacy of pegylated IFN. The purpose of this article is to provide an overview of the role of IFN in the treatment of MS and evaluate the available evidence for pegylated IFN therapy in MS.

Protocols for Cloning, Expression, and Functional Analysis of Sirtuin2 (SIRT2).

SIRT2 is a NAD(+)-dependent deacetylase that belongs to the sirtuin family, which is comprised of seven members (SIRT1-SIRT7) in humans. Furthermore, recent study shows that the Sirt2 gene has three transcript variants in mice. Several diverse proteins have been identified as SIRT2 substrates. SIRT2 activity involves multiple cell processes including growth, differentiation, and energy metabolism. However, little is known of SIRT2's role in oligodendrocytes or in the myelin sheath, where it is an important component. Here we describe procedures that detail Sirt2 gene cloning, identification, expression, and biological analysis in cultured cells.

Alterations of phasic coronary artery flow velocity in humans during percutaneous coronary angioplasty.

BACKGROUND AND OBJECTIVES: Studies using Doppler catheters to assess blood flow velocity and vasodilator reserve in proximal coronary arteries have failed to demonstrate significant improvement immediately after coronary angioplasty. Measurement of blood flow velocity, flow reserve and phasic diastolic/systolic velocity ratio performed distal to a coronary stenosis may provide important information concerning the physiologic significance of coronary artery stenosis. This study was designed to measure these blood flow velocity variables both proximal and distal to a significant coronary artery stenosis in patients undergoing coronary angioplasty. METHODS: A low profile (0.018-in.) (0.046-cm) Doppler angioplasty guide wire capable of providing spectral flow velocity data was used to measure blood flow velocity, flow reserve and diastolic/systolic velocity ratio both proximal and distal to left anterior descending or left circumflex coronary artery stenosis. These measurements were made in 38 patients undergoing coronary angioplasty and in 12 patients without significant coronary artery disease. RESULTS: Significant improvement in mean time average peak velocity was noted in distal coronary arteries after angioplasty (before 19 +/- 12 cm/s; after 35 +/- 16 cm/s; p less than 0.01). Increases in proximal average peak velocity after angioplasty were less remarkable (before 34 +/- 18 cm/s; after 41 +/- 14 cm/s; p = 0.04). Mean flow reserve remained unchanged after angioplasty both proximal (1.5 +/- 0.5 vs. 1.6 +/- 1; p greater than 0.10) and distal (1.6 +/- 1 vs. 1.5 +/- 0.8; p greater than 0.10) to a coronary stenosis. Before angioplasty, mean diastolic/systolic velocity ratio measured distal to a significant stenosis was decreased compared with that in normal vessels (1.3 +/- 0.5 vs. 1.8 +/- 0.5; p less than 0.01). After angioplasty, distal abnormal phasic velocity patterns generally returned to normal, with a significant increase in mean diastolic/systolic velocity ratio (1.3 +/- 0.5 vs. 1.9 +/- 0.6; p less than 0.01). Phasic velocity patterns and mean diastolic/systolic velocity ratio measured proximal to a coronary stenosis were not statistically different from values in normal vessels (1.8 +/- 0.8 vs. 1.8 +/- 0.5; p greater than 0.10) and did not change significantly after angioplasty (1.8 +/- 0.8 vs. 2.13 +/- 0.9; p greater than 0.10). CONCLUSIONS: Flow velocity measurements may be performed distal to a coronary stenosis with the Doppler guide wire. Phasic velocity measurements made proximal to a coronary stenosis differed from those in the distal coronary artery. Both proximal and distal flow reserve measurements made immediately after angioplasty were of limited utility. Changes in distal flow velocity patterns and diastolic/systolic velocity ratio appeared to be more relevant than the hyperemic response in assessing the immediate physiologic outcome of coronary angioplasty.

Pharmacogenomics of interferon-ß in multiple sclerosis: what has been accomplished and how can we ensure future progress?

Multiple sclerosis (MS) is a progressive disorder of the central nervous system, often resulting in significant disability in early adulthood. The field of pharmacogenomics holds promise in distinguishing responders from non-responders to drug treatment. Most studies on genetic polymorphisms in MS have addressed treatment with interferon-ß, yet few findings have been replicated. This review outlines the barriers that currently hinder the validity, reproducibility, and inter-study comparison of pharmacogenomics research as it relates to the use of interferon-ß. Notably, statistical power, varying definitions of responder status, varying assay and genotyping methodologies, and anti-interferon-ß neutralizing antibodies significantly confound existing data. Future work should focus on addressing these factors in order to optimize interferon-ß treatment outcomes in MS.

Handedness and the risk of tardive dyskinesia.

Previous results from five cross-sectional studies are conflicting about the relationship between hand preference and tardive dyskinesia (TD): two report a greater TD prevalence in left handers, and three report a greater prevalence in right handers. To help resolve these inconsistencies, the handedness-TD association was assessed in the Yale TD Study, a large prospective cohort investigation of outpatients maintained with neuroleptics. A consistent monotonic association was observed between the handedness score and TD incidence (p = 0.009). The estimated rate ratio, comparing left and mixed handers with pure right handers, adjusted for confounders, was 0.25 (95% confidence interval = 0.09, 0.70). The handedness effect (higher TD rate in right handers) was stronger for subjects with fewer negative symptoms, and it was stronger for men than for women. Although the specific biological mechanisms are unclear, these findings may reflect cerebral laterality in the pathophysiology of psychiatric disorders, possibly in combination with asymmetrical action of neuroleptic exposure.

A randomized, double masked, controlled trial of botulinum toxin type A in essential hand tremor.

OBJECTIVE: To evaluate the safety and efficacy of botulinum toxin type A injection in essential tremor of the hand. BACKGROUND: Botulinum toxin type A is an effective treatment for dystonia, spasticity, and other movement disorders and has been found to be useful in open-label studies and one double-masked study of essential hand tremor. METHODS: One hundred thirty-three patients with essential tremor were randomized to low-dose (50 U) or high-dose (100 U) botulinum toxin type A (Botox) or vehicle placebo treatment. Injections were made into the wrist flexors and extensors. Patients were followed for 16 weeks. The effect of treatment was assessed by clinical rating scales, measures of motor tasks and functional disability, and global assessment of treatment. Hand strength was evaluated by clinical rating and by a dynamometer. RESULTS: Both doses of botulinum toxin type A significantly reduced postural tremor on the clinical rating scales after 4 to 16 weeks. However, kinetic tremor was significantly reduced only at the 6-week examination. Measures of motor tasks and functional disability were not consistently improved with botulinum toxin type A treatment. Grip strength was reduced for the low- and high-dose botulinum toxin type A groups as compared with the placebo group. Adverse reactions consisted mainly of dose-dependent hand weakness. CONCLUSION: Botulinum toxin type A injections for essential tremor of the hands resulted in significant improvement of postural, but not kinetic, hand tremors and resulted in limited functional efficacy. Hand weakness is a dose-dependent significant side effect of treatment at the doses used in this study.

Radiation therapy of keratoacanthoma.

We report the radiation therapy of keratoacanthoma in 13 patients using orthovoltage X rays and electrons. All patients had an excellent cosmetic result, and time to regression was dose dependent up to a dose corresponding to TDF 50; increasing dose beyond this level did not accelerate time to regression past 2.4 months. We also note a heretofore undocumented association between keratoacanthoma and second malignancy.

Non-metastatic locally advanced cancer of the breast treated with radiation.

One hundred forty-seven female patients with retrospectively classified (AJCCS 1977) Stage III and nonmetastatic noninflammatory Stage IV breast carcinoma from June 1958 to December 1978 were studied to determine the effects of primary radiation on local recurrence and survival. Fifty-one patients recurred in the breast; 24 patients recurred in the local-regional area of breast and draining lymphatics and 15 patients recurred in the axilla only. Distant metastases developed in 97 patients. The 5 year actuarial survival was 24%. Decreased recurrence rates were associated with megavoltage and higher doses of radiation (34% vs. 65%); with smaller tumors (27% vs. 57%); with total extirpation of gross tumor (33% vs. 53%); and with those tumors that were given a "boost dose" (26% vs. 58%). The addition of systemic treatment did not appreciably alter either local-regional recurrence or survival. However, most of the patients received endocrine ablation or single-agent chemotherapy. Polyagent chemotherapy was used late in the series, making its true impact on survival difficult to evaluate.

Predicting the long-term risk of tardive dyskinesia in outpatients maintained on neuroleptic medications.

BACKGROUND: Tardive dyskinesia (TD) has been a source of great concern to the psychiatric community because of the iatrogenic nature of the illness. Little is known about the risk of developing TD if neuroleptic medications are continued. METHOD: This paper presents long-term risk estimates for TD in a prospective cohort study of 362 chronic psychiatric outpatients who were free of TD at baseline and who were maintained on neuroleptic medications. RESULTS: On the basis of 5 years of follow-up, we estimate the risk of persistent TD to be 32% after 5 years of neuroleptic exposure (95% confidence interval [CI] = 23%-43%), 57% after 15 years of exposure (95% CI = 47%-66%), and 68% after 25 years of exposure (95% CI = 58%-77%). For patients with 10 years of previous neuroleptic exposure, the risk is 15% after 5 more years of exposure (95% CI = 7.2%-27%) and 38% after 15 more years of exposure (95% CI = 24%-53%). Our results fall within the wide range of results found in other studies of TD incidence. Differences in incidence across studies may be explained in terms of patient characteristics and other methodological factors. CONCLUSION: One implication of this finding is that patients in the first 5 years of exposure could be targeted for prevention programs if resources are limited. A potential methodological problem encountered when studying chronically exposed patients is that they may have acquired TD (persistent) prior to the study and remitted before entry.

The contribution of predisposing and situational risk factors to serious fall injuries.

OBJECTIVES: The objectives were to identify situational risk factors associated with suffering a serious fall injury and to determine whether, and to what extent, predisposing and situational risk factors contributed independently to risk of suffering a serious fall injury. DESIGN: Nested cohort study. SETTING: General community. PARTICIPANTS: 568 members of a representative sample of community-living persons 72 years of age or older who fell during a median follow-up of 36 months. MEASUREMENTS: Candidate predisposing factors, identified during a baseline face-to-face home assessment, were the demographic, cognitive, medical, and physical performance measures associated with an increased risk of serious injury among fallers in a previous analysis of the cohort. Acute host, behavioral, and environmental factors present at the time of the participants' first reported fall constituted potential situational risk factors. The primary outcome was occurrence of a serious fall injury, defined as a fracture, joint dislocation, or head injury resulting in loss of consciousness and hospitalization, during the first fall recorded during follow-up. RESULTS: Sixty-nine subjects (12%) suffered a serious injury during their first reported fall. No acute host factor was associated with increased risk of injury. The environmental and activity factors associated independently with serious injury in multivariate analysis included falling on stairs (adjusted relative risk 2.0; 95% confidence intervals 1.1-3.5), during displacing activity (1.8; 1.0-3.0), and from at least body height (2.1; 1.0-4.7). The independent predisposing factors included female gender (2.1; 1.0-4.4), low body mass index (1.8; 1.2-2.9), and cognitive impairment (2.8; 1.7-4.7). Although 12% of first falls resulted in a serious injury overall, this percentage ranged from 0% to 36% as the number of predisposing risk factors increased from zero to three and from 5% to 40% as the number of situational risk factors increased from zero to three. Further, for any given number of predisposing risk factors, the percentage of fallers suffering a serious injury increased with the number of situational risk factors. CONCLUSIONS: Several environmental and behavioral factors contributed to the risk of serious fall injury; this contribution was independent of the effect of chronic predisposing risk factors. Preventive programs that address both predisposing and situational risk factors may result in the greatest injury reduction. These findings support previously recommended multicomponent intervention programs that combine medical, rehabilitative, and environmental components.

Risk factors for serious injury during falls by older persons in the community.

BACKGROUND: Serious fall injury represents a little studied, yet common and potentially preventable, cause of morbidity and mortality among older persons. We determined the frequency of, and risk factors for, experiencing serious fall injury events among older persons in the community. SUBJECTS: A representative sample of 1103 community-living persons aged 72 years and older underwent comprehensive baseline and 1-year evaluations. MAIN OUTCOME MEASURES: During a median 31 months of follow-up, fall data were obtained using fall calendars. Injury data were obtained from telephone interviews and from surveillance of emergency room and hospital records. RESULTS: At least one fall was experienced by 546 (49%) participants. A total of 123 participants, representing 23% of fallers and 12% of the cohort, experienced 183 serious fall injury events. The factors independently associated with experiencing a serious injury during a fall included cognitive impairment (adjusted odds ratios 2.2; 95% confidence interval 1.5, 3.2); presence of at least two chronic conditions (2.0; 1.4, 2.9); balance and gait impairment (1.8; 1.3, 2.7); and low body mass index (1.8; 1.2, 2.5). In a separate analysis, including only subjects who fell, female gender (1.8; 1.1, 2.9) as well as most of the above factors were associated with experiencing a fall injury. CONCLUSIONS: Several readily identifiable factors appeared to distinguish the subgroup of older fallers at risk for suffering a serious fall injury. These factors should help guide who and what to target in prevention efforts.

Coordinated expression of Hoxa2, Hoxd1 and Pax6 in the developing diencephalon.

Coordinated expression of Hoxa2, Hoxd1 and Pax6 proteins were found to coincide with the three developmental stages of the diencephalon, as described for the mouse brain. In the first stage (embryonic day (E) 10-12) Hoxa2, Hoxd1 and Pax6 (an early marker gene of the diencephalon) were expressed as early as E10.5 in prosomeres (p), p2 and p3. All three proteins continue to exhibit overlapping domains of expression at E12.5-13 (beginning of the second stage) when the primitive dense cell layer begins to differentiate into the internal germinal, external germinal and mantle layers. Towards the end of the second stage (E15), Pax6 expression was down-regulated whereas Hoxa2 and Hoxd1 continued to exhibit overlapping domains of expression for both protein and mRNA. Hoxd1 expression decreased significantly in the third stage of diencephalic development (E16-postnatal) such that only Hoxa2 expression persisted in the diencephalon of newborn mice. The temporal and spatial expression of these three proteins imply that coordinated waves of Hoxa2, Hoxd1 and Pax6 expression may be required to provide positional information for the specification of the diencephalon.