A randomized trial comparing balloon kyphoplasty and vertebroplasty for vertebral compression fractures due to osteoporosis.

BACKGROUND AND PURPOSE: Several trials have compared vertebral augmentation with nonsurgical treatment for vertebral compression fractures. This trial compares the efficacy and safety of balloon kyphoplasty and vertebroplasty. MATERIALS AND METHODS: Patients with osteoporosis with 1-3 acute fractures (T5-L5) were randomized and treated with kyphoplasty (n = 191) or vertebroplasty (n = 190) and were not blinded to the treatment assignment. Twelve- and 24-month subsequent radiographic fracture incidence was the primary end point. Due to low enrollment and early withdrawals, the study was terminated with 404/1234 (32.7%) patients enrolled. RESULTS: The average age of patients was 75.6 years (77.4% female). Mean procedure duration was longer for kyphoplasty (40.0 versus 31.8 minutes, P < .001). At 12 months, 7.8% fewer patients with kyphoplasty (50/140 versus 57/131) had subsequent radiographic fracture, and there were 8.6% fewer at 24 months (54/110 versus 64/111). The results were not statistically significant (P > .21). When we used time to event for new clinical fractures, kyphoplasty approached statistical significance in longer fracture-free survival (Wilcoxon, P = .0596). Similar pain and function improvements were observed. CT demonstrated lower cement extravasation for kyphoplasty (157/214 versus 164/201 levels treated, P = .047). For kyphoplasty versus vertebroplasty, common adverse events within 30 postoperative days were procedural pain (12/191, 9/190), back pain (14/191, 28/190), and new vertebral fractures (9/191, 17/190); similar 2-year occurrence of device-related cement embolism (1/191, 1/190), procedural pain (3/191, 3/190), back pain (2/191, 3/190), and new vertebral fracture (2/191, 2/190) was observed. CONCLUSIONS: Kyphoplasty and vertebroplasty had similar long-term improvement in pain and disability with similar safety profiles and few device-related complications. Procedure duration was shorter with vertebroplasty. Kyphoplasty had fewer cement leakages and a trend toward longer fracture-free survival.

The impact of different health dimensions on overall quality of life related to kyphoplasty and non-surgical management.

UNLABELLED: This study uses data from a previously published randomised trial where balloon kyphoplasty was compared to non-surgical management. Of the improved overall quality of life, 60 % was caused by decreased pain. However, ignoring other dimensions of quality of life would underestimate the procedure's effect. INTRODUCTION: Acute back pain has been viewed as the most important factor lowering quality of life (QoL) for patients suffering vertebral fractures. The objective of this study was to quantify the impact of different health dimensions on overall QoL using patient-reported outcome measurements (PROMs) collected in Fracture Reduction Evaluation (FREE) trial. METHODS: The analysis was based on patients included in the 2-year-long randomised controlled FREE trial studying the efficacy and safety of balloon kyphoplasty procedure (BKP) compared to non-surgical management (NSM). The PROMs included were EQ-5D, Short Form (SF)-36, visual analogue scale (VAS) pain and the Roland-Morris Disability Questionnaire (RMDQ). The health dimensional contribution to the overall QoL improvements was analysed by isolating the impact of each dimension on QoL in the SF-36 and EQ-5D, respectively. A correlation analysis of the QoL improvement was performed to investigate the relationships between the four instruments. RESULTS: Changes in pain explained 60 % of the quality-adjusted life years (QALY) gained in BKP vs. NSM followed by self-care (17 %), mobility (16 %) and usual activities (10 %) (EQ-5D). Health dimensions capturing the mental state had little impact on the QALY gained. The SF-36 dimensional analysis showed similar results. The correlation analysis showed that the correlation between VAS pain, RMDQ and QALY improvement was fairly weak. CONCLUSIONS: Changes in the pain dimension of health are the most important drivers for changes of overall QoL in patients treated with BKP or NSM. However, ignoring the impact of other dimensions would lead to an underestimation of the actual improvement in overall QoL.

A randomized trial comparing 2 techniques of balloon kyphoplasty and curette use for obtaining vertebral body height restoration and angular-deformity correction in vertebral compression fractures due to osteoporosis.

BACKGROUND AND PURPOSE: Vertebral compression fractures often result in pain and vertebral deformity. We compared 2 different balloon kyphoplasty techniques both using intraoperative curettage. MATERIALS AND METHODS: Adults 50 years of age or older with osteoporosis and 1 acute VCF were randomized to undergo bilateral BKP in which the curette was used first (n = 57) followed by inflatable bone tamps or in which IBTs were used first, followed by curettage and a second IBT inflation (n = 55). RESULTS: Mean procedure duration was 33.5 and 36.8 minutes, and fluoroscopy duration was 3.8 and 3.7 minutes for the CF and IBTF groups, respectively. Two-thirds of VCFs were wedge-shaped, and one-half had dynamic mobility. Anterior height restored postoperatively was 2.28 mm (95% CI, 1.49-3.08 mm; P < .001) and 2.78 mm (95% CI, 1.89-3.66 mm; P < .001) for CF and IBTF groups, representing ∼35% and 39% of lost height restored, but group differences were not significant (P = .4). Intraoperative anterior height gain attributed to dynamic mobility was 2.96 mm (95% CI, 1.92-4.00 mm; P < .001) and 3.05 mm (95% CI, 2.10-4.00 mm; P < .001); additional height attributed to IBT inflation was 1.09 mm (95% CI, 0.77-1.41 mm; P < .001) and 1.25 mm (95% CI, 0.68-1.82 mm; P < .001), representing a 37% and 41% increase. There was no significant height loss on IBT removal and cementation. Both groups had improved pain and ambulation. Asymptomatic leakage occurred in 15% of VCFs. There was 1 nonserious device-related hematoma (IBTF group). One new clinical VCF occurred in each group, but they were not device-related. CONCLUSIONS: Both techniques resulted in significant vertebral body height and pain improvement. Procedure and adverse event data demonstrated safe curette use in conjunction with balloon kyphoplasty procedures.

Description of International Caenorhabditis elegans Experiment first flight (ICE-FIRST).

Traveling, living and working in space is now a reality. The number of people and length of time in space is increasing. With new horizons for exploration it becomes more important to fully understand and provide countermeasures to the effects of the space environment on the human body. In addition, space provides a unique laboratory to study how life and physiologic functions adapt from the cellular level to that of the entire organism. Caenorhabditis elegans is a genetic model organism used to study physiology on Earth. Here we provide a description of the rationale, design, methods, and space culture validation of the ICE-FIRST payload, which engaged C. elegans researchers from four nations. Here we also show C. elegans growth and development proceeds essentially normally in a chemically defined liquid medium on board the International Space Station (10.9 day round trip). By setting flight constraints first and bringing together established C. elegans researchers second, we were able to use minimal stowage space to successfully return a total of 53 independent samples, each containing more than a hundred individual animals, to investigators within one year of experiment concept. We believe that in the future, bringing together individuals with knowledge of flight experiment operations, flight hardware, space biology, and genetic model organisms should yield similarly successful payloads.

DJ-1 binds androgen receptor directly and mediates its activity in hormonally treated prostate cancer cells.

The oncogene DJ-1 has been associated with multiple cancers, including prostate cancer, where it can be stabilized by androgens and antiandrogens. However, little data exist on the expression pattern and function of DJ-1 in prostate cancer. To address the function of DJ-1 in prostate, a yeast two-hybrid screen was done to identify novel DJ-1 binding proteins. The androgen receptor (AR) was identified and confirmed as a DJ-1 binding partner. This is the first evidence that DJ-1 directly interacts with AR. We also show that modulation of DJ-1 expression regulated AR transcriptional activity. Importantly, both the subcellular localization of DJ-1 and the interaction with AR are regulated by androgens and antiandrogens. Additionally, immunohistochemical staining on two human prostate cancer tissue arrays was done providing the first large-scale expression analysis of DJ-1 in prostate. DJ-1 expression did not change with Gleason pattern but increased after androgen deprivation therapy, indicating that it may be involved in the development of androgen independence. These data provide a novel mechanism where DJ-1-mediated regulation of AR may promote the progression of prostate cancer to androgen independence.

Androgen and anti-androgen treatment modulates androgen receptor activity and DJ-1 stability.

BACKGROUND: Mechanisms regulating the transition from hormone responsive to hormone refractory prostate cancer (PCa) have remained unclear. METHODS: We analyzed androgen and anti-androgen treatment on endogenous AR activity in primary human prostate epithelial (HPE) cells cultured directly from patient radical prostatectomy specimens utilizing a transiently infected gene reporter (TIGR) assay. RESULTS: Flutamide treatment exhibited agonist activities in HPE cells derived from tumor and non-tumor specimens which contained wild-type AR. After proteomic comparison of these cells to those where flutamide functioned normally as an antagonist, we identified DJ-1, a positive regulator of AR. DJ-1 expression increased in HPE and LNCaP cells during flutamide treatment as a result of DJ-1 protein stabilization. CONCLUSION: Stabilization of AR and its co-regulators in the absence of androgen may partially account for anti-androgen withdrawal syndrome and potentially contribute to the development of hormone refractory PCa.

A survey of laboratory 'critical (alert) limits' in the UK.

INTRODUCTION: Critical or alert limits are the values of laboratory measurements that are regarded as requiring urgent clinical action and should be communicated to a clinician urgently. Despite this, there has been little evaluation of these values in the UK. METHODS: We have conducted a survey of hospital biochemistry laboratories in the UK. RESULTS: Ninety-four laboratories responded to the questionnaire; the response rate was not recorded. Twenty-three laboratories had derived their action limits locally from a consensus with their clinicians, experience over many years, and the literature. Only two laboratories quoted literature to support their values. Seven laboratories did not submit actual critical values. There was considerable variance in the values defined as critical by the responding laboratories. DISCUSSION: Each laboratory needs to evaluate its own list of acutely important critical values and aim for a small number of analytes that are always communicated to the doctor, so that clinical needs are met without raising the risk of information overload.

Isolation and molecular characterization of Musca domestica delta-9 desaturase sequences.

We have isolated fatty acyl-CoA desaturase cDNA (Mdomd9) and genomic sequences from the housefly, Musca domestica. Two approximately 1.66 kb cDNAs were recovered. They had identical coding regions and 3' untranslated regions (UTRs), but differed in their 5' UTRs. The open reading frame encodes a 380 amino acid (aa) protein with 82% identity to Drosophila melanogaster desat1, and significant (> 50%) identity with other insect delta-9 desaturases. Functional analyses in a yeast expression system confirmed the cDNA encodes a delta9 desaturase. Northern analysis indicated two transcripts of 1.7 and 2.9 kb that hybridized specifically to the open reading frame. PCR amplification of genomic templates revealed three intron sites that are conserved among other insect species. Southern analysis of genomic DNA indicated at least two desaturase gene copies per haploid genome. There is a high degree of polymorphism, most of which appears to be due to variable intron sequences; curiously, individual flies had varying morphs of intron II and intron III. Together, the data suggest that there are more delta9 desaturase alleles within the population studied than there are loci within the genome, and support other studies suggesting that insect fatty acyl-CoA desaturases are a dynamically evolving gene family.

Chaperone-mediated regulation of hepatic protein secretion by caloric restriction.

Calorie restriction (CR) delays age-related physiological changes, reduces cancer incidence, and increases maximum life span in mammals. Here we show that CR decreased the expression of many hepatic molecular chaperones and concomitantly increased the rate and efficiency of serum protein secretion. Hepatocytes from calorie-restricted mice secreted twice as much albumin, 63% more alpha1-antitrypsin, and 250% more of the 31.5-kDa protein 2 h after their synthesis. A number of trivial explanations for these results, such as differential rates of protein synthesis and cell leakage during the assay, were eliminated. These novel results suggest that CR may promote the secretion of serum proteins, thereby promoting serum protein turnover. This may reduce the circulating level of damaging, glycoxidated serum proteins.

Managed care and community health centers.

This study has two objectives: (1) to examine the relationship between the involvement of community health centers (CHCs) in managed care and various center characteristics, including patient, provider, services, and financial characteristics, that are critically linked with the fulfillment of their mission and (2) to identify factors significantly associated with CHCs' involvement in managed care. Regarding the first objective, the study indicates that CHCs involved in managed care have more diversified sources of revenue and depend less on grant funding than other CHCs, and they serve a significantly smaller proportion of uninsured and homeless patients. Involvement in managed care is also associated with greater financial vulnerability, reflected in higher costs and net revenue deficits. Regarding the second objective, the study finds that CHCs have become involved in managed care largely in response to external market pressures, such as the prospect of reduced federal grant funding. Other significant factors include center size, location, and the percentage of users who are Medicaid patients.

Vitamin D receptor displays DNA binding and transactivation as a heterodimer with the retinoid X receptor, but not with the thyroid hormone receptor.

The vitamin D receptor (VDR) is a transcription factor believed to function as a heterodimer with the retinoid X receptor (RXR). However, it was reported [Schräder et al., 1994] that, on putative vitamin D response elements (VDREs) within the rat 9k and mouse 28k calcium binding protein genes (rCaBP 9k and mCaBP 28k), VDR and thyroid hormone receptor (TR) form heterodimers that transactivate in response to both 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) and triiodothyronine (T(3)). We, therefore, examined associations of these receptors on the putative rCaBP 9k and mCaBP 28k VDREs, as well as on established VDREs from the rat osteocalcin (rOC) and mouse osteopontin (mOP) genes, plus the thyroid hormone response element (TRE) from the rat myosin heavy chain (rMHC) gene. In gel mobility shift assays, we found no evidence for VDR-TR heterodimer interaction with any tested element. Further, employing these hormone response elements linked to reporter genes in transfected cells, VDR and TR mediated responses to their cognate ligands only from the rOC/mOP and rMHC elements, respectively, while the CaBP elements were unresponsive to any combination of ligand(s). Utilizing the rOC and mOP VDREs, two distinct repressive actions of TR on VDR-mediated signaling were demonstrated: a T(3)-independent action, presumably via direct TR-RXR competition for DNA binding, and a T(3)-dependent repression, likely by diversion of limiting RXR from VDR-RXR toward the formation of TR-RXR heterodimers. The relative importance of these two mechanisms differed in a response element-specific manner. These results may provide a partial explanation for the observed association between hyperthyroidism and bone demineralization/osteoporosis.

Calories and aging alter gene expression for gluconeogenic, glycolytic, and nitrogen-metabolizing enzymes.

We characterized the effects of calorie restriction (CR) on the expression of key glycolytic, gluconeogenic, and nitrogen-metabolizing enzymes in mice. Of the gluconeogenic enzymes investigated, liver glucose-6-phosphatase mRNA increased 1.7- and 2. 3-fold in young and old CR mice. Phosphoenolpyruvate carboxykinase mRNA and activity increased 2.5- and 1.7-fold in old CR mice. Of the key glycolytic enzymes, pyruvate kinase mRNA and activity decreased approximately 60% in CR mice. Hepatic phosphofructokinase-1 and pyruvate dehydrogenase mRNA decreased 10-20% in CR mice. Of the genes that detoxify ammonia generated from protein catabolism, hepatic glutaminase, carbamyl phosphate synthase I, and tyrosine aminotransferase mRNAs increased 2.4-, 1.8-, and 1.8-fold with CR, respectively. Muscle glutamine synthetase mRNA increased 1.3- and 2. 1-fold in young and old CR mice. Hepatic glutamine synthetase mRNA and activity each decreased 38% in CR mice. These CR-induced changes are consistent with other studies suggesting that CR may decrease enzymatic capacity for glycolysis and increase the enzymatic capacity for hepatic gluconeogenesis and the disposal of byproducts of muscle protein catabolism.

Insect pheromones--an overview of biosynthesis and endocrine regulation.

This overview describes, compares, and attempts to unify major themes related to the biosynthetic pathways and endocrine regulation of insect pheromone production. Rather than developing and dedicating an entirely unique set of enzymes for pheromone biosynthesis, insects appear to have evolved to add one or a few tissue-specific auxiliary or modified enzymes that transform the products of "normal" metabolism to pheromone compounds of high stereochemical and quantitative specificity. This general understanding is derived from research on model species from one exopterygote insect order (Blattodea) and three endopterygote insect orders (Coleoptera, Diptera, and Lepidoptera). For instance, the ketone hydrocarbon contact sex pheromone of the female German cockroach, Blattella germanica, derives its origins from fatty acid biosynthesis, arising from elongation of a methyl-branched fatty acyl-CoA moiety followed by decarboxylation, hydroxylation, and oxidation. Coleopteran sex and aggregation pheromones also arise from modifications of fatty acid biosynthesis or other biosynthetic pathways, such as the isoprenoid pathway (e.g. Cucujidae, Curculionidae, and Scolytidae), or from simple transformations of amino acids or other highly elaborated host precursors (e.g. Scarabaeidae and Scolytidae). Like the sex pheromone of B. germanica, female-produced dipteran (e.g. Drosophilidae and Muscidae) sex pheromone components originate from elongation of fatty acyl-CoA moieties followed by loss of the carbonyl carbon and the formation of the corresponding hydrocarbon. Female-produced lepidopteran sex pheromones are also derived from fatty acids, but many moths utilize a species-specific combination of desaturation and chain-shortening reactions followed by reductive modification of the carbonyl carbon. Carbon skeletons derived from amino acids can also be used as chain initiating units and elongated to lepidopteran pheromones by this pathway (e.g. Arctiidae and Noctuidae). Insects utilize at least three hormonal messengers to regulate pheromone biosynthesis. Blattodean and coleopteran pheromone production is induced by juvenile hormone III (JH III). In the female common house fly, Musca domestica, and possibly other species of Diptera, it appears that during hydrocarbon sex pheromone biosynthesis, ovarian-produced ecdysteroids regulate synthesis by affecting the activities of one or more fatty acyl-CoA elongation enzyme(s) (elongases). Lepidopteran sex pheromone biosynthesis is often mediated by a 33 or 34 amino acid pheromone biosynthesis activating neuropeptide (PBAN) through alteration of enzyme activities at one or more steps prior to or during fatty acid synthesis or during modification of the carbonyl group. Although a molecular level understanding of the regulation of insect pheromone biosynthesis is in its infancy, in the male California fivespined ips, Ips paraconfusus (Coleoptera: Scolytidae), JH III acts at the transcriptional level by increasing the abundance of mRNA for 3-hydroxy-3-methylglutaryl-CoA reductase, a key enzyme in de novo isoprenoid aggregation pheromone biosynthesis.

Glucose regulation of GRP78 gene expression.

The endoplasmic reticulum chaperone glucose-regulated protein 78 (GRP78) is essential for the proper glycosylation, folding and assembly of many membrane bound and secreted proteins. GRP78 mRNA is well known to be induced in cultured cells by lowering medium glucose concentrations from 4.5 to 0 mg/ml. Here we report a study designed to determine the effects of intermediate concentrations of glucose on GRP78 mRNA abundance. Progressive reduction in culture medium glucose from 4.5 to 1.0 mg/ml progressively reduced GRP78 mRNA to approximately 30% of the initial level. Induction of GRP78 mRNA by glucose starvation was observed in medium containing less than 1 mg/ml glucose. Determination of the amount of glucose consumed in these cultures showed that reduction of glucose concentrations led first to repression of GRP78 mRNA abundance, followed by induction of the mRNA only when glucose is nearly exhausted. Caloric restriction in mice both reduces fasting and mean 24 h glucose blood concentrations and GRP78 mRNA abundance in the liver. Thus, it is possible that negative regulation of GRP78 mRNA in the liver is due directly to reduced blood glucose concentrations.

Psychodynamic psychotherapy, religious beliefs, and self-disclosure.

The intersection of psychodynamic psychotherapy and religious beliefs may present technical challenges for the psychotherapists; particularly if patients request to know more about the therapist's religious beliefs. Contrary to a recent technical recommendation for therapists to self-disclose personal religious beliefs when asked to do so, I suggest that such a request is complex and requires a thoughtful grounding in psychotherapeutic theory. Disclosing personal beliefs to patients runs the risk of being off-task as well as holding oneself out as an exemplar for the patient. Rather than adopt a formulaic response to requests for information, to deepen the understanding of the patient and the work of therapy, the therapist needs a complex understanding based on a careful diagnostic assessment of the patient, as well as an assessment of the current status of the psychotherapeutic venture. The workings of patients' particular transferences are often evident in requests for personal information and require careful evaluation and consideration. Likewise, countertransference elements may influence the type of response offered by the therapist. Using ethical principles as a guide is different from using them as a rule. The nexus of religious belief, psychosocial context, psychotherapy, and self-disclosure provides a potentially rich source of understanding when explored in the psychotherapeutic situation.

Caloric intake alters the efficiency of catalase mRNA translation in the liver of old female mice.

The free radical theory of aging predicts that calorie restriction, which extends life span, should reduce oxidant damage. In mammals, the oxidative processes centered in the liver are a major source of free radicals. Liver catalase has the dominant role in the intracellular detoxification of hydrogen peroxide. In male rodents, published studies indicate that aging decreases catalase gene transcription and that calorie restriction obviates this effect. In females, published studies are inconsistent, and no molecular mechanisms have been identified. Here we report that, in female mice, aging can lead to an increase in the translational efficiency of hepatic catalase mRNA, and that calorie restriction obviates this effect. Consideration of these results and published studies leads us to propose that the variability in catalase results in females may arise from the small number of studies or from unique aspects of female physiology, perhaps the estrous cycle and its cessation with age.

Dietary energy tissue-specifically regulates endoplasmic reticulum chaperone gene expression in the liver of mice.

A number of putative molecular chaperones seem to play essential roles in the correct folding, assembly and glycosylation of membrane and secreted proteins in the endoplasmic reticulum. We have shown that life span-extending dietary energy restriction significantly and specifically reduces GRP78 mRNA and protein by 50-75% in mice. Here, 5-mo-old female C3B10RF1 mice were given free access to food after being fed 50% less dietary energy since weaning. Hepatic GRP78 mRNA increased linearly, reaching the same level after 2 wk as was found in the liver of 20-mo-old mice with free access to food. This increase took place with no change in body weight. The mRNA levels of endoplasmic reticulum, cytosolic and mitochondrial chaperones were determined in young (7-mo-old) and old (21- or 28-mo-old) female C3B10RF1 mice. Each age group was either 50% energy restricted or was fed approximately 10% less energy than consumed by mice given free access to food. In young and old energy-restricted mice, hepatic expression of the endoplasmic reticulum chaperones ERp57 (37%), GRP170 (51%), ERp72 (43%), calreticulin (54%) and calnexin (23%) was significantly and specifically reduced. The GRP78, GRP94, GRP170, ERp57 and calnexin mRNA response to diet occurred reproducibly only in liver, and not in adipose, brain, heart, kidney, lung, muscle or small intestine. The mRNA for GRP75, a mitochondrial chaperone, HSC70, a cytoplasmic chaperone, protein disulfide isomerase, an endoplasmic reticulum chaperone, and C/EBPalpha, a transcription factor, was not regulated. Hepatic C/EBPbeta was 15% higher in old energy-restricted mice. Thus the expression of nearly all endoplasmic reticulum chaperones responded rapidly and specifically to dietary energy in mice.

Cuticular hydrocarbons and their role in copulatory behavior in Phormia regina (Meigen).

The cuticular hydrocarbons from adult Phormia regina (Meigen) were characterized by gas chromatography-mass spectrometry. Both sexes had similar components in nearly identical quantities, consisting of complex mixtures of saturated n-, monomethyl- and dimethylalkanes from 23 to 33 total carbons. Although no diet-, age-, or sex-specific differences were observed, cuticular hydrocarbons were shown to be involved in copulatory behavior. Hydrocarbon profiles of wild, compared to laboratory reared flies, showed no major differences. Behaviorally, males responded the same to dead decoys of either sex. Removal of the hydrocarbons, using hexane, from either male or female decoys, did not affect the number of mating strikes, but markedly reduced the number of copulatory attempts and the amount of time males spent mounted on either decoy. House fly, Musca domestica L., males when paired with a female M. domestica decoy produced copulatory attempts: whereas, when P. regina males were placed with M. domestica female decoys, there were no copulatory attempts. It is concluded that the cuticular hydrocarbons of P. regina function as species-specific but not sex-specific mating cues and elicit species-specific copulatory behavior in males.