Sentinel lymph node (SLN) isolated tumor cells (ITCs) in otherwise stage I/II endometrioid endometrial cancer: To treat or not to treat?

OBJECTIVES: To assess associations between treatment and recurrence-free survival (RFS) among patients with isolated tumor cells (ITCs) in sentinel lymph nodes (SLN) and otherwise stage I/II endometrioid endometrial cancer (EC). METHODS: A multi-institutional retrospective study of patients with SLN ITCs (<200 cells and < 0.2 mm) was performed. Only patients with otherwise stage I/II EC, endometrioid histology, and no evidence of micro-or macrometastases were included. Univariate and multivariable Cox proportional hazard models were used to evaluate associations between treatment, tumor characteristics, and RFS. RESULTS: 175 patients were included. Median follow up time was 31 months. 39% stage IB and 12% stage II disease. 76 (43%) received no adjuvant therapy or vaginal brachytherapy only (NAT/VBT), 21 (12%) had external beam radiation (EBRT), and 78 (45%) received chemotherapy +/- radiation. Patients who received chemotherapy more often had tumors with deep myoinvasion, lymphovascular space invasion (LVSI), and higher grade. Nine (5.1%) patients recurred; 5 distant, 3 retroperitoneal, and 1 vaginal. Extra-vaginal recurrences were similar in patients with or without chemotherapy (5.2% vs 3.8%, p = 0.68). After controlling for stage, LVSI and grade, chemotherapy and EBRT were not associated with RFS (HR = 0.63, 95%CI 0.11-3.52, and HR = 0.90, 95%CI 0.22-3.61, respectively). Type of lymph node dissection and ITC detection method were not associated with RFS. CONCLUSIONS: Risk of retroperitoneal and/or distant recurrence is low (4.6%) for patients with stage I/II endometrioid EC and ITCs in SLNs regardless of treatment. Our preliminary data suggests that adjuvant therapy may not be significantly associated with RFS. However, longer follow-up time and a larger sample size are needed before definitive recommendations regarding adjuvant therapy for patients with EC and only ITCs in SLN can be made.

CD93 and related family members: their role in innate immunity.

CD93 belongs to a newly described family of transmembrane glycoproteins which also includes endosialin and thrombomodulin. These cell surface proteins are grouped into a family based on similar ectodomain architecture consisting of a C-type lectin-like domain, a series of EGF-like repeats and a highly glycosylated mucin-like domain. However, recent studies suggest overlapping functions in the regulation of processes involving innate immunity and inflammation. CD93 regulates phagocytosis of apoptotic cells in vivo, a function critical to development, tissue repair and maintenance of tissue homeostasis. In addition, in vitro studies have demonstrated a role for CD93 in phagocytosis of antibody and complement opsonized particles and also in leukocyte and endothelial cell adhesion. Analysis of CD93 expression on endothelial cells in the developing mouse embryo correlates with the remodeling of blood vessels suggesting a role for CD93 in regulating angiogenesis, a process tightly linked to acute and chronic inflammation and also required for tumor metastasis. Endosialin has been characterized as a tumor specific antigen and functions in angiogenesis. Thrombomodulin is best characterized as a natural anticoagulant; however, more recent reports have illuminated the importance of thrombomodulin in the regulation of inflammation. This review discusses similarities and differences in the family members, and focuses on known and speculated functions in regulation of innate immunity.

The DEBIT trial: an intervention to reduce antipsychotic polypharmacy prescribing in adult psychiatry wards - a cluster randomized controlled trial.

BACKGROUND: Clinical guidelines advise against prescribing more than one antipsychotic with limited exceptions. Despite this, surveys continue to report high antipsychotic polypharmacy rates. The aim of the study was to investigate the effectiveness of a multi-faceted intervention in reducing prescribing of antipsychotic polypharmacy on general adult psychiatry wards, compared with guidelines alone. METHOD: A pragmatic cluster randomized controlled trial recruited 19 adult psychiatric units (clusters) from the South West of England. Participants were all ward doctors and nurses. The multi-faceted intervention comprised: an educational/CBT workbook; an educational visit to consultants; and a reminder system on medication charts. RESULTS: The odds of being prescribed antipsychotic polypharmacy in those patients prescribed antipsychotic medication was significantly lower in the intervention than control group when adjusted for confounders (OR 0.43, 95% CI 0.21-0.90, p=0.028). There was considerable between-unit variation in polypharmacy rates and in the change in rates between baseline and follow-up (5 months after baseline). CONCLUSION: The intervention reduced levels of polypharmacy prescribing compared to guidelines alone although the effect size was relatively modest. Further work is needed to elicit the factors that were active in changing prescribing behaviour.

Evolution of sensory complexity recorded in a myxobacterial genome.

Myxobacteria are single-celled, but social, eubacterial predators. Upon starvation they build multicellular fruiting bodies using a developmental program that progressively changes the pattern of cell movement and the repertoire of genes expressed. Development terminates with spore differentiation and is coordinated by both diffusible and cell-bound signals. The growth and development of Myxococcus xanthus is regulated by the integration of multiple signals from outside the cells with physiological signals from within. A collection of M. xanthus cells behaves, in many respects, like a multicellular organism. For these reasons M. xanthus offers unparalleled access to a regulatory network that controls development and that organizes cell movement on surfaces. The genome of M. xanthus is large (9.14 Mb), considerably larger than the other sequenced delta-proteobacteria. We suggest that gene duplication and divergence were major contributors to genomic expansion from its progenitor. More than 1,500 duplications specific to the myxobacterial lineage were identified, representing >15% of the total genes. Genes were not duplicated at random; rather, genes for cell-cell signaling, small molecule sensing, and integrative transcription control were amplified selectively. Families of genes encoding the production of secondary metabolites are overrepresented in the genome but may have been received by horizontal gene transfer and are likely to be important for predation.

Genome of Geobacter sulfurreducens: metal reduction in subsurface environments.

The complete genome sequence of Geobacter sulfurreducens, a delta-proteobacterium, reveals unsuspected capabilities, including evidence of aerobic metabolism, one-carbon and complex carbon metabolism, motility, and chemotactic behavior. These characteristics, coupled with the possession of many two-component sensors and many c-type cytochromes, reveal an ability to create alternative, redundant, electron transport networks and offer insights into the process of metal ion reduction in subsurface environments. As well as playing roles in the global cycling of metals and carbon, this organism clearly has the potential for use in bioremediation of radioactive metals and in the generation of electricity.

foxD5a, a Xenopus winged helix gene, maintains an immature neural ectoderm via transcriptional repression that is dependent on the C-terminal domain.

Xenopus foxD5a, the full-length fork head gene previously described as a PCR fragment (XFLIP), is first detectable at stage II of oogenesis. Low-abundance maternal transcripts are localized to the animal hemisphere of the cleavage embryo, and protein can be translocated to the nucleus prior to the onset of zygotic transcription. Zygotic expression is strongest in the presumptive neural ectoderm at gastrula and neural plate stages, but there is minor paraxial mesodermal expression during primary gastrulation that becomes significant in the tail bud during secondary gastrulation. Expression of foxD5a in animal cap explants induces elongation and expression of mesodermal, neural-inducing, and early neural-specifying genes, indicating a role in dorsal axis formation. Zygotic foxD5a expression is induced strongly by siamois, moderately by cerberus, weakly by Wnt8 and noggin, and not by chordin in animal cap explants. Expression of foxD5a in whole embryos has differential dorsal and ventral effects. Ventral mRNA injection induces partial secondary axes composed of expanded mesodermal and epidermal tissues, but does not induce ectopic neural tissues. Dorsal mRNA injection causes hypertrophy of the neural plate and expansion of early neural genes (sox3 and otx2), but this is not the result of increased proliferation or expanded neural-inducing mesoderm. The neural plate appears to be maintained in an immature state because otx2 expression is expanded and expression of en2, Krox20, proneural genes (Xnrgn1, neuroD) and a neural differentiation gene (n-tubulin) is repressed in foxD5a-expressing cells. These results indicate that foxD5a maintains an undifferentiated neural ectoderm after neural induction. Expression of foxD5a constructs fused with the engrailed repressor domain or with the VP16 activation domain demonstrates that FoxD5a acts as a transcriptional repressor in axis formation and neural plate expansion. Deletion constructs indicate that this activity requires the C-terminal domain of the protein.

Isoform-specific localization of voltage-gated K+ channels to distinct lipid raft populations. Targeting of Kv1.5 to caveolae.

The precise subcellular localization of ion channels is often necessary to ensure rapid and efficient integration of both intracellular and extracellular signaling events. Recently, we have identified lipid raft association as a novel mechanism for the subcellular sorting of specific voltage-gated K(+) channels to regions of the membrane rich in signaling complexes. Here, we demonstrate isoform-specific targeting of voltage-gated K(+) (Kv) channels to distinct lipid raft populations with the finding that Kv1.5 specifically targets to caveolae. Multiple lines of evidence indicate that Kv1.5 and Kv2.1 exist in distinct raft domains: 1) channel/raft association shows differential sensitivity to increasing concentrations of Triton X-100; 2) unlike Kv2.1, Kv1.5 colocalizes with caveolin on the cell surface and redistributes with caveolin following microtubule disruption; and 3) immunoisolation of caveolae copurifies Kv1.5 channel. Both depletion of cellular cholesterol and inhibition of sphingolipid synthesis alter Kv1.5 channel function by inducing a hyperpolarizing shift in the voltage dependence of activation and inactivation. The differential targeting of Kv channel subtypes to caveolar and noncaveolar rafts within a single membrane represents a unique mechanism of compartmentalization, which may permit isoform-specific modulation of K(+) channel function.

Complications of laser resurfacing and their management.

PURPOSE: To describe complications associated with laser resurfacing along with specific treatment recommendations. METHODS: The authors' experiences with laser resurfacing complications are discussed in conjunction with a review of published reports. Current preoperative and postoperative regimens are also presented. RESULTS: Postoperative erythema occurs in all patients and is considered a transient side effect, not a complication. Postinflammatory hyperpigmentation, hypopigmentation, scarring, wound infections, milia, ectropion, pain, acneiform eruptions, pruritus, and contact dermatitis are reported by multiple authors. Specific interventions combined with the passage of time allow most of these complications to resolve, leaving the patient with an acceptable final result. CONCLUSIONS: Although laser resurfacing is a safe and effective method of facial rejuvenation, the cosmetic surgeon must be aware of the various complications that may be encountered. Prompt recognition of complications and appropriate management provide the best opportunity for an acceptable aesthetic outcome.

Surgical debulking of eyelid and anterior orbital plexiform neurofibromas by means of the carbon dioxide laser.

PURPOSE: To present the carbon dioxide laser as an effective tool for surgical debulking of eyelid and orbital neurofibromas. METHOD: Two patients with neurofibromatosis underwent surgical debulking of their eyelid and orbital plexiform neurofibromas by means of the carbon dioxide laser. RESULTS: Acceptable cosmetic results were obtained with the removal of eyelid and orbital neurofibromas with improved hemostasis and minimal destruction of surrounding tissue when compared with conventional methods of removal. CONCLUSIONS: The carbon dioxide laser may allow significant improvement in the removal of plexiform neurofibromas.

Luteinizing hormone response to controlled-release deslorelin in estradiol benzoate primed ovariectomized gilts.

Development of a controlled release formulation of gonadotropin releasing hormone that would stimulate a LH surge capable of reducing the time span of ovulations would greatly benefit reproductive management because a single timed insemination could be used. A dose-response study was conducted to determine if Deslorelin, a potent gonadotropin releasing hormone analogue, delivered via the SABER system, a biodegradable controlled release system, would stimulate an ovulatory-like LH surge in the pig. Twenty ovariectomized gilts, approximately 200 d old and 100 kg body weight (BW), received estradiol benzoate (15 microg/kg BW im) and 48 h later, the gilts were given deslorelin at 0, 12.5, 25.0, 50.0 or 100.0 microg im (n = 4 each treatment group). Compared to controls, mean blood deslorelin concentrations were still elevated at 30 h after deslorelin. Mean deslorelin magnitude, area under the curve and duration were sequentially greater (P<0.05) in a dose-dependent sequence. Compared to controls, serum LH concentrations were elevated (P<0.05) for 6 to 12 h after deslorelin. A dose-response relationship was absent for all parameters of LH secretion. Magnitude of the serum LH response was greatest (P<0.05) in the 12.5 microg and 50.0 microg groups, whereas area under the curve was lower (P<0.05) after 25.0 microg of deslorelin than after 12.5, 50.0 and 100.0 microg, which were not different from each other. Thus, no more than 12.5 microg of deslorelin is necessary to obtain maximum LH release in the model studied and doses less than 12.5 microg may also be effective.

The histone database: a comprehensive WWW resource for histones and histone fold-containing proteins.

The Histone Database (HDB) is an annotated and searchable collection of all full-length sequences and structures of histone and non-histone proteins containing the histone fold motif. These sequences are both eukaryotic and archaeal in origin. Several new histone fold-containing proteins have been identified, including Spt7p, and a few false positives have been removed from the earlier version of HDB. Database contents include compilations of post-translational modifications for each of the core and linker histones, as well as genomic information in the form of map loci for the human histone gene complement, with the genetic loci linked to Online Mendelian Inheritance in Man (OMIM). Conflicts between similar sequence entries from a number of source databases are also documented. Newly added to the HDB are multiple sequence alignments in which predicted functions of histone fold amino acid residues are annotated. The database is freely accessible through the WWW at http://genome.nhgri.nih.gov/histones/

The Borrelia burgdorferi 37-kilodalton immunoblot band (P37) used in serodiagnosis of early lyme disease is the flaA gene product.

The 37-kDa protein (P37) of Borrelia burgdorferi is an antigen that elicits an early immunoglobulin M (IgM) antibody response in Lyme disease patients. The P37 gene was cloned from a B. burgdorferi genomic library by screening with antibody from a Lyme disease patient who had developed a prominent humoral response to the P37 antigen. DNA sequence analysis of this clone revealed the identity of P37 to be FlaA, an outer sheath protein of the periplasmic flagella. Recombinant P37 expression was accomplished in Escherichia coli by using a gene construct with the leader peptide deleted and fused to a 38-kDa E. coli protein. The recombinant antigen was reactive in IgM immunoblots using serum samples from patients clinically diagnosed with early Lyme disease that had been scored positive for B. burgdorferi anti-P37 reactivity. Lyme disease patient samples serologically negative for the B. burgdorferi P37 protein did not react with the recombinant. Recombinant P37 may be a useful component of a set of defined antigens for the serodiagnosis of early Lyme disease. This protein can be utilized as a marker in diagnostic immunoblots, aiding in the standardization of the present generation of IgM serologic tests.

Autosomal dominant nanophthalmos (NNO1) with high hyperopia and angle-closure glaucoma maps to chromosome 11.

Nanophthalmos is an uncommon developmental ocular disorder characterized by a small eye, as indicated by short axial length, high hyperopia (severe farsightedness), high lens/eye volume ratio, and a high incidence of angle-closure glaucoma. We performed clinical and genetic evaluations of members of a large family in which nanophthalmos is transmitted in an autosomal dominant manner. Ocular examinations of 22 affected family members revealed high hyperopia (range +7.25-+13.00 diopters; mean +9.88 diopters) and short axial length (range 17.55-19.28 mm; mean 18.13 mm). Twelve affected family members had angle-closure glaucoma or occludable anterior-chamber angles. Linkage analysis of a genome scan demonstrated highly significant evidence that nanophthalmos in this family is the result of a defect in a previously unidentified locus (NNO1) on chromosome 11. The gene was localized to a 14.7-cM interval between D11S905 and D11S987, with a maximum LOD score of 5. 92 at a recombination fraction of .00 for marker D11S903 and a multipoint maximum LOD score of 6.31 for marker D11S1313. NNO1 is the first human locus associated with nanophthalmos or with an angle-closure glaucoma phenotype, and the identification of the NNO1 locus is the first step toward the cloning of the gene. A cloned copy of the gene will enable examination of the relationship, if any, between nanophthalmos and less severe forms of hyperopia and between nanophthalmos and other conditions in which angle-closure glaucoma is a feature.

Measuring the intelligence of college students with learning disabilities: a comparison of results obtained on the WAIS-R and the KAIT.

This study compared results obtained on the Wechsler Adult Intelligence Scale-Revised and the Kaufman Adolescent Test and Adult Intelligence; these tests were individually administered to college students with and without learning disabilities. Participants were 30 students with learning disabilities and 30 students without learning disabilities between the ages of 18 and 30. Students were administered both IQ tests and the Peabody Picture Vocabulary Test-Revised, used as a covariate measure. The results were analyzed through a repeated-measures analysis of variance. No significant differences were found between groups or between tests. A significant difference was found for both groups when Performance IQ and Fluid Scale scores were compared.

Diagnosis of lateralized lumbosacral disk herniation with magnetic resonance imaging.

A left-lateralized, lumbosacral intervertebral disk herniation, which was not apparent on epidurography, was diagnosed in a dog with magnetic resonance imaging. Precise, preoperative localization and characterization of the lesion allowed surgical approach and excision with minimum disruption of surrounding tissues.

The effect of aging on the utilization of chemotherapy for metastatic breast cancer: a population-based study.

Older women (i.e., > or = 65 years of age) receive less adjuvant chemotherapy than younger women, in part because chemotherapy has been less effective in postmenopausal than premenopausal women in clinical trials. Metastatic breast cancer, however, does not respond differently to chemotherapy by age. Therefore, to evaluate further the effect of age on chemotherapy utilization, we conducted a population-based study of the treatment of metastatic breast cancer. Patients (n = 132) were identified by cross-tabulating death certificates from 1984 to 1991 with breast cancer cases in the Washington County Cancer Registry. Treatment information was obtained from the Tumor Registry of the Washington Country Hospital and Hospital medical records. Forty patients (74%) < 65 years old received chemotherapy compared to 11 (42%) 65-74 and 6 (12%) > or = 75 (p < 0.0001). Adjusting for other medical conditions and whether or not the patient saw a medical oncologist, there was still a significant effect of age in patients > or = 75 (p < 0.001) and a trend (p = 0.17) for patients 65-74. The different patterns of chemotherapy utilization were not associated with survival differences. Radiation therapy was also utilized significantly less frequently in older than younger patients, but the age effect was not as pronounced as with chemotherapy. There was no age effect on the utilization of hormonal therapy. Less frequent utilization of chemotherapy in older patients is probably caused by a combination of patient and physician factors and may result in less effective palliation for older patients.

A goldfish Notch-3 homologue is expressed in neurogenic regions of embryonic, adult, and regenerating brain and retina.

Members of the Notch gene family are thought to be involved in the regulation of cell fate decisions in a variety of embryonic tissues, particularly in the developing central nervous system (CNS) in Drosophila and vertebrates. In goldfish the CNS continues to develop and add neurons well into adulthood and has the capacity to regenerate new neurons. Using probes derived from Xenopus Notch to screen an adult goldfish retinal cDNA library, followed by 5' RACE, we isolated a partial cDNA for a goldfish Notch homologue, G-Notch. Sequence alignment supported assignment of G-Notch to the Notch-3 class. Northern blot analysis revealed a single transcript of > 8 kb, and RNase protection assays indicated that G-Notch is expressed in eye and brain but not muscle of adult goldfish. The spatiotemporal pattern of expression of G-Notch was defined from early embryonic stages to adulthood by in situ hybridization. Expression in the embryonic CNS was localized to neurogenic regions and was downregulated in differentiated cell populations. In adult goldfish, expression persisted in and adjacent to the germinal zones in the retina and the brain. Weak expression was seen in scattered cells in the inner nuclear layer of the retina, which might include neurogenic stem cells. Following retinal lesions (puncture wounds or laser lesions restricted to photoreceptors in the outer nuclear layer), G-Notch was upregulated in proliferating cell populations throughout the retina, in association with a generalized mitogenic response. In the region of the laser lesion, where earlier studies have demonstrated that photoreceptors are regenerating at 1-3 weeks following the lesion, G-Notch expressing cells were abundant in the outer nuclear layer. These observations suggest that retinal regeneration involves the re-expression of an important developmental signaling molecule in neuroepithelial cells resident in the differentiated retina.