Metastatic melanoma to the ovary in pregnancy: A case report.

Metastatic melanoma to the ovary is an uncommon presentation. We report a case of metastatic melanoma to the ovary that presented as a growing left adnexal mass during pregnancy and was thought to be benign by imaging and frozen section pathology. Here we discuss the challenges in radiologic and pathologic diagnosis, as well as considerations for the mother and newborn.

Fbw7-dependent cyclin E regulation ensures terminal maturation of bone marrow erythroid cells by restraining oxidative metabolism.

The mechanisms that coordinate the final mitotic divisions of terminally differentiated bone marrow (BM) erythroid cells with components of their structural and functional maturation program remain largely undefined. We previously identified phenotypes resembling those found in early-stage myelodysplastic syndromes (MDS), including ineffective erythropoiesis, morphologic dysplasia and BM hyper-cellularity, in a knock-in mouse model in which cyclin E mutations were introduced at its two Cdc4 phosphodegrons (CPDs) to ablate Fbw7-dependent ubiquitination and degradation. Here, we have examined the physiologic consequences of cyclin E dysregulation in BM erythroid cells during terminal maturation in vivo. We found that cyclin E protein levels in BM erythroid cells are dynamically regulated in a CPD-dependent manner and that disruption of Fbw7-dependent cyclin E regulation impairs terminal erythroid cell maturation at a discrete stage before enucleation. At this stage of erythroid cell maturation, CPD phosphorylation of cyclin E regulates both cell-cycle arrest and survival. We also found that normal regulation of cyclin E restrains mitochondrial reactive oxygen species (ROS) accumulation and expression of genes that promote mitochondrial biogenesis and oxidative metabolism during terminal erythroid maturation. In the setting of dysregulated cyclin E expression, p53 is activated in BM erythroid cells as part of a DNA damage response-type pathway, which mitigates ineffective erythropoiesis, in contrast to the role of p53 induction in other models of dyserythropoiesis. Finally, cyclin E dysregulation and ROS accumulation induce histone H3 lysine 9 hyper-methylation and disrupt components of the normal terminal erythroid maturation gene expression program. Thus, ubiquitin-proteasome pathway control of G1-to-S-phase progression is intrinsically linked to regulation of metabolism and gene expression in terminally differentiating BM erythroid cells.

How migraines impact cognitive function: findings from the Baltimore ECA.

OBJECTIVE: To examine the cross-sectional and longitudinal relationship between migraine headaches and cognitive functioning. METHODS: The data were from Waves III (1993 through 1996) and IV (2004 through 2005) of the Baltimore Epidemiologic Catchment Area Study. Migraine headaches were diagnosed according to modified criteria of the International Headache Society. Scores on the immediate and delayed recall tests and the Mini-Mental State Examination (MMSE) were compared for migraineurs (n = 204) vs nonmigraineurs (n = 1,244). The longitudinal association between migraine and cognitive changes was assessed by generalized estimating equations. RESULTS: Migraineurs scored lower on tests of immediate and delayed memory at baseline, but declined by less over time than nonmigraineurs. These associations were specific to migraineurs with aura, who declined by 1.26 (p < 0.01) and 1.47 (p < 0.01) words less on the immediate and delayed recall tests over the 12 years of follow-up. The effects of migraine, specifically with aura, on the MMSE were restricted to those older than 50 years. Among those younger than 50 years, migraineurs with aura declined at the same rate on the MMSE as nonmigraineurs. However, among those older than 50 years, migraineurs with aura declined by 0.99 points (p < 0.01) less over the follow-up. CONCLUSIONS: Migraineurs, specifically those with aura, exhibited less decline on cognitive tests over time vs nonmigraineurs. For the Mini-Mental State Examination, these effects were only apparent among those who were older than 50 years.

A case of multiple AOT-like jawbone lesions in a young patient--a new odontogenic entity?

We assessed the immunohistochemical profile of an unusual case of multiple similarly looking tumors in the jawbone of a young patient. Histologically, the tumors exhibited features of adenomatoid odontogenic tumor (AOT) and adenomatoid dentinoma but showed no resemblance to any other defined odontogenic tumor entities. They expressed high amounts of cytokeratin (CK) 8 and 14 together with some Vimentin. A small rim of peripheral cells showed CK 5, 17, and 19 reactivity. Also, these lesions expressed some bcl-2 as well as p53 and Ki67. Histologically and immunohistochemically, the unusual multiple lesions differed in details from a simultaneously examined group of 24 classical AOT cases, suggesting that they may represent a hitherto less well-defined odontogenic tumor entity.

Alcohol misuse by women.

Alcohol misuse among women is an important and growing problem. There is epidemiological and metabolic evidence that risk factors for and consequences of alcohol misuse are significantly different for women than for men. Understanding these differences is imperative if effective preventative and treatment interventions are to be undertaken. This article reviews the epidemiology of alcohol misuse by women, effects of alcohol misuse on women, fetuses, and relationships, and assessment and treatment strategies. We then suggest directions for future research in this field.

Relationship between velocity and temporal variables of the flat shod running walk.

The running walk of the Tennessee Walking Horse is often described as a faster variation of the walk, indicating the importance of velocity on the mechanics of the gait. Variations in gait variables create difficulties in clearly identifying the normal and abnormal running walk in a clinical evaluation. The objectives of this study were, therefore, to describe the flat shod running walk and to determine the relationship between velocity and the running walk. From frame-by-frame analysis of 60 Hz film, temporal variables were averaged for 6 strides from 6 horses performing an 'easy' (slow) and 'strong' (fast) running walk during a flat shod, easy-rider Tennessee Walking Horse show class. The running walk at both velocities was a 4-beat, symmetrical stepping gait with a lateral footfall sequence and lateral couplets. The velocity ranged from mean +/- s.d. 2.66 +/- 0.34 to 3.80 +/- 0.18 m/s. For both velocities (slow, fast), hind stance as a percentage of stride duration (58 +/- 3%, 56 +/- 2%) was significantly longer than fore (51 +/- 5%, 48 +/- 1%); diagonal advanced placement (29 +/- 2%, 37 +/- 4%) and lift-off (35 +/- 5%, 39 +/- 2%) were significantly longer than lateral (advanced placement: 22 +/- 2%, 12 +/- 3%; lift-off: 18 +/- 4%, 10 +/- 2); and lateral bipedal support (50 +/- 9%, 67 +/- 7%) was significantly longer than diagonal (27 +/- 6%, 16 +/- 4%). Strong correlations were found between velocity and diagonal advanced placement (0.640), lateral lift-off (-0.924) and diagonal (-0.648) and lateral (0.904) bipedal support. Understanding the running walk and the gait variations due to velocity may be important to both the performance and soundness of the Tennessee Walking Horse.

Genetic heterogeneity in schizophrenia II: conditional analyses of affected schizophrenia sibling pairs provide evidence for an interaction between markers on chromosome 8p and 14q.

Information from multiple genome scans and collaborative efforts suggests that schizophrenia is a heterogeneous, complex disorder with polygenic and environmental antecedents. In a previous paper we demonstrated that stratification of families on the basis of co-segregating phenotypes (psychotic affective disorders (PAD) and schizophrenia spectrum personality disorders (SSPD) in first-degree relatives of schizophrenic probands increased linkage evidence in the chromosome 8p21 region (D8S1771) among families with co-segregating SSPD. We have now applied a method of conditional analysis of sib-pairs affected with schizophrenia, examining shared alleles identical-by-descent (IBD) at multiple loci. The method yields enhanced evidence for linkage to the chromosome 8p21 region conditioned upon increased allele sharing at a chromosome 14 region. The method produces a more refined estimate of the putative disease locus on chromosome 8p21, narrowing the region from 18 cM (95% confidence interval) in our previous genome scan, to approximately 9.6 cM. We have also shown that the affected siblings sharing two alleles IBD at the chromosome 8p21 region and one allele IBD at the chromosome 14 region differ significantly in clinical symptoms from non-sharing affected siblings. Thus the analysis of allele sharing at a putative schizophrenia susceptibility locus conditioned on allele sharing at other loci provides another important method for dealing with heterogeneity.

Bacterial peptidoglycan-induced tnf-alpha transcription is mediated through the transcription factors Egr-1, Elk-1, and NF-kappaB.

Bacteria and their ubiquitous cell wall component peptidoglycan (PGN) activate the innate immune system of the host and induce the release of inflammatory molecules. TNF-alpha is one of the highest induced cytokines in macrophages stimulated with PGN; however, the regulation of tnf-alpha expression in PGN-activated cells is poorly understood. This study was done to identify some of the transcription factors that regulate the expression of the tnf-alpha gene in macrophages stimulated with PGN. Our results demonstrated that PGN-induced expression of human tnf-alpha gene is regulated by sequences proximal to -182 bp of the promoter. Mutations within the binding sites for cAMP response element, early growth response (Egr)-1, and kappaB3 significantly reduced this induction. The transcription factor c-Jun bound the cAMP response element site, Egr-1 bound the Egr-1 motif, and NF-kappaB p50 and p65 bound to the kappaB3 site on the tnf-alpha promoter. PGN rapidly induced transcription of egr-1 gene and this induction was significantly reduced by specific mutations within the serum response element-1 domain of the egr-1 promoter. PGN also induced phosphorylation and activation of Elk-1, a member of the Ets family of transcription factors. Elk-1 and serum response factor proteins bound the serum response element-1 domain on the egr-1 promoter, and PGN-induced expression of the egr-1 was inhibited by dominant-negative Elk-1. These results indicate that PGN induces activation of the transcription factors Egr-1 and Elk-1, and that PGN-induced expression of tnf-alpha is directly mediated through the transcription factors c-Jun, Egr-1, and NF-kappaB, and indirectly through the transcription factor Elk-1.

Functional MR imaging assessment of a non-responsive brain injured patient.

Functional magnetic resonance imaging (fMRI) was requested to assist in the evaluation of a comatose 38-year-old woman who had sustained multiple cerebral contusions from a motor vehicle accident. Previous electrophysiologic studies suggested absence of thalamocortical processing in response to median nerve stimulation. Whole-brain fMRI was performed utilizing visual, somatosensory, and auditory stimulation paradigms. Results demonstrated intact task-correlated sensory and cognitive blood oxygen level dependent (BOLD) hemodynamic response to stimuli. Electrodiagnostic studies were repeated and evoked potentials indicated supratentorial recovery in the cerebrum. At 3-months post trauma the patient had recovered many cognitive & sensorimotor functions, accurately reflecting the prognostic fMRI evaluation. These results indicate that fMRI examinations may provide a useful evaluation for brain function in non-responsive brain trauma patients.

Markets for individual health insurance: can we make them work with incentives to purchase insurance?

Simple income-based incentives to purchase health insurance (tax credits or deductions, or subsidies) are unlikely to succeed in significantly reducing the number of uninsured because income is not a good predictor of the extent to which individuals use medical service. Proposals to provide incentives to low-income people so they will purchase individual health insurance need to address the inherent tension between the interests of low-risk and high-risk people who rely on individual coverage. If carriers are forced to cover all applicants and to community rate premiums, low-risk people will drop coverage or not apply for it because premiums will exceed their expected need for insurance. Concern for people who currently have access to individual coverage calls for careful examination of options to permit incentive programs to succeed with the individual insurance markets. In particular, attention should focus on using alternatives to simple income-based subsidies to spread the burden of high-risk people's costs broadly, rather than impose the costs on low-risk people who purchase individual coverage. This paper describes three such alternatives. One uses risk adjustments and two rely on reinsurance so that carriers are compensated for the higher costs of covering high-risk people who use incentives to buy insurance. One alternative also permits risk selection by insurance carriers.

Successful repair of esophageal injury using an elastin based biomaterial patch.

An esophageal injury with significant tissue loss is very difficult to repair. We conducted an in vivo study to test our elastin based acellular biomaterial patch to repair such defect. The patch was made from porcine aorta, by decellularization and sterilization. Collagen fibers were preserved to retain mechanical strength and enhance cellular in-growth. Ten domestic pigs underwent right thoracotomy. A 2 cm circular defect was made on the distal esophagus, excising half its circumference, and was repaired using the biomaterial patch and sutures. Soon after the procedure, the animals resumed oral feeding. They were followed for clinical status, weight gain, barium studies, and endoscopic studies, and were killed after 6 weeks to 4 months. All ten animals survived long term, with a procedure success rate of 100% (10 of 10). With the exception of one pneumothorax, no complications occurred, and all animals resumed oral feeding and gained weight. Endoscopic studies showed mucosal coverage by 6 weeks, with minimal stricture at the repair site. Excised specimens showed complete mucosal coverage with regeneration of all three layers. Our biomaterial patch can be used safely and reliably for repair of esophageal injury with significant tissue loss when repaired immediately as in our experiment.

A conceptual structure and methodology for the systematic approach to the evaluation and treatment of patients with chronic dizziness.

The patient with chronic dizziness should never be labeled with psychogenic dizziness. Chronic does not mean psychogenic. Chronic means that health care has been unsuccessful. A systematic approach that yields a comprehensive formulation and rational treatment plan will increase the probability of a successful outcome and return to health. The four perspectives of diseases, life stories, dimensions, and behaviors provide a comprehensive yet flexible methodology for the evaluation of the patient in distress with chronic and disabling dizziness. The design of a comprehensive treatment plan involves the determination of each perspective's contribution to the patient's distress and to what relative degree. This process recognizes that the perspectives are distinct from one another but complementary in illuminating the various reasons for a patient's distress. The perspectives come together as the formulation of the patient's case and offer a recipe for treatment rather than just a list of ingredients such as bio, psycho, and social.

The effectiveness of housing policies in reducing children's lead exposure.

OBJECTIVES: This study evaluated the relation of housing policies to risk of subsequent lead exposure in addresses where lead-poisoned children had lived. METHODS: Addresses where children with lead poisoning lived between May 1992 and April 1993 were selected from lead screening registries in 2 northeastern states differing in their enforcement of lead poisoning prevention statutes. Blood lead levels of subsequently resident children, exterior condition, tax value, age, and census tract characteristics were collected. The odds of elevated blood lead levels in subsequently resident children were calculated with logistic regression. RESULTS: The risk of identifying 1 or more children with blood lead levels of 10 micrograms/dL or greater was 4 times higher in addresses with limited enforcement. Controlling for major confounders had little effect on the estimate. CONCLUSIONS: Enforcement of housing policies interrupts the cycle of repeated lead exposure.

Interleukin-6 promotes post-traumatic healing in the central nervous system.

The central nervous system (CNS) is an immune-privileged site where the role of immune cells and mediators in traumatic brain injury is poorly understood. Previously we have demonstrated that interleukin (IL)-6, a cytokine that acts on a wide range of tissues influencing cell growth and differentiation, is an agonist for vascular endothelial growth factor (VEGF), in in vitro vascularization assays for brain microvessel endothelial cells. In this present work we focus on the role of IL-6 in promoting tissue repair in the CNS in vivo. An aseptic cerebral injury (ACI) was created in the right parietal cortex, using both wild type (C57Bl/6J) and IL-6-deficient (C57Bl/6J-IL-6-/-) mice to study the consequences of the absence of IL-6 on the pathology of brain injuries. We monitored the immediate, early, and late responses to this traumatic injury by characterizing several histologic features in the CNS at days 1, 4, 7 and 14 following injury. Acellular necrosis, cellular infiltration, and re-vascularization were characterized in the injured tissues, and each of these histologic features was individually graded and totaled to assign a healing index. IL-6-deficient mice were found to have a comparatively slower rate of recovery and healing. Furthermore, fluorescein isothiocyanate (FITC)-dextran intravenous injection demonstrated leaky vessels in IL-6-deficient but not in wild type animals following ACI. Additionally, chronic expression of IL-6 in the CNS using transgenic GFAP-IL-6 mice resulted in more rapid healing following ACI. The accelerated tissue repair in GFAP-IL-6 transgenic animals is primarily due to extensive re-vascularization as detected by endothelial cell markers. Combined, this data suggests an important role of IL-6 in tissue repair processes following traumatic injury in the CNS.

Helical structure of the COOH terminus of S3 and its contribution to the gating modifier toxin receptor in voltage-gated ion channels.

The voltage-sensing domains in voltage-gated K(+) channels each contain four transmembrane (TM) segments, termed S1 to S4. Previous scanning mutagenesis studies suggest that S1 and S2 are amphipathic membrane spanning alpha-helices that interface directly with the lipid membrane. In contrast, the secondary structure of and/or the environments surrounding S3 and S4 are more complex. For S3, although the NH(2)-terminal part displays significant helical character in both tryptophan- and alanine-scanning mutagenesis studies, the structure of the COOH-terminal portion of this TM is less clear. The COOH terminus of S3 is particularly interesting because this is where gating modifier toxins like Hanatoxin interact with different voltage-gated ion channels. To further examine the secondary structure of the COOH terminus of S3, we lysine-scanned this region in the drk1 K(+) channel and examined the mutation-induced changes in channel gating and Hanatoxin binding affinity, looking for periodicity characteristic of an alpha-helix. Both the mutation-induced perturbation in the toxin-channel interaction and in gating support the presence of an alpha-helix of at least 10 residues in length in the COOH terminus of S3. Together with previous scanning mutagenesis studies, these results suggest that, in voltage-gated K(+) channels, the entire S3 segment is helical, but that it can be divided into two parts. The NH(2)-terminal part of S3 interfaces with both lipid and protein, whereas the COOH-terminal part interfaces with water (where Hanatoxin binds) and possibly protein. A conserved proline residue is located near the boundary between the two parts of S3, arguing for the presence of a kink in this region. Several lines of evidence suggest that these structural features of S3 probably exist in all voltage-gated ion channels.

Family income and crowd out among children enrolled in Massachusetts Children's Medical Security Plan.

OBJECTIVE: To assess whether participation in a state publicly financed health insurance program, Massachusetts Children's Medical Security Plan (CMSP) , which is open to children regardless of income, was associated with disenrollment from private insurance. DATA SOURCES/STUDY DESIGN: A survey of participants in CMSP who were enrolled as of April 1998 was used. We conducted analyses to detect differences in access to and uptake of private insurance between Medicaid-eligible and in eligible children, and between children eligible for the State Children's Health insurance Program (SCHIP) and in eligible children. DATA COLLECTION METHODS: A stratified sample of children was drawn from administrative files. the sampling strategy allowed us to examine crowd out among children based on in come and eligibility for publicly funded coverage: those who were Medicaid-eligible (income pound 133 percent of the federal poverty level [FPL]) , those who were SCHIP-eligible (134-200 percent of FPL) , and those with family in comes that exceed SCHIP eligibility criteria (> 200 percent of FPL). The majority of telephone interviews were conducted with the child's parent/guardian between November 1998 and March 1999. The overall response rate was 61.8 percent , yielding a sample of 996 children. PRINCIPAL FINDINGS: Of the children in our sample whose recent health coverage was employer-sponsored insurance (59 percent), 70 percent were no longer eligible. Few children who had employer-sponsored insurance at enrollment dropped this coverage to enroll in CM SP (1 percent, 4 percent, and 2 percent by income). Compared to Medicaid-eligible children, children with incomes > 133 percent of FPL were significantly more likely to be eligible for employer-sponsored insurance but they were no more likely to have purchased offered coverage. Access to employer-sponsored insurance was limited (19 percent), and uptake was low (13 percent). We found no significant difference between SCHIP-eligible children and those whose family incomes exceeded SCHIP guidelines. CONCLUSIONS: The Massachusetts experience suggests that (1) coverage could be expanded to children with incomes up to 200 percent of FPL with little direct substitution of public coverage for private insurance, and (2) substitution among children with incomes > 200 percent of FPL, who paid a premium that may have restrained crowd out, did not differ from that among SCHIP-eligible children.