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BACKGROUND: Endometrial ablation has recently gained popularity as a treatment of menorrhagia in the general population. In the von Willebrand disease (VWD) patient, intuitively, it would appear that the failure rate would be higher because of the underlying hypocoaguability increasing the likelihood for re-bleeding. In a consecutive series of seven patients, we assessed the efficacy and safety of endometrial ablation in VWD-related menorrhagia. PATIENTS AND METHODS: We performed a retrospective analysis using chart review and a 21-item questionnaire administered to seven (six type 1, one type 2A) women who underwent endometrial ablation between the years 1997 and 2001. Parameters assessed included operative complications, the development of abdominal pains, recurrence of menstrual bleeding post-ablation and the change in the pre-/post-ablation quality of life (QOL). Three patients underwent endomyometrial resection and one each underwent rollerball, thermal, electrocautery and balloon ablation. All patients were pre-treated with i.v. desmopressin (DDAVP) except the 2A patient who received Humate P. Mean age of the patient was 41 +/- 6 years and follow-up was for 45 months (range 31-73) post-ablation. RESULTS: No significant perioperative bleeding complications were observed in any of the patients. All patients initially responded (two amenorrhoea, four hypomenorrhoea, one moderate improvement). In all patients, QOL assessed by 10 parameters improved significantly following the ablation procedure, regardless of the specific technique used. However, at the end of follow-up, only one patient remained amenorrheic, one was hypomenorrheic, one had moderate improvement and four patients experienced recurrence of menorrhagia, three eventually requiring a hysterectomy at a median of 11 months post-ablation. CONCLUSION: Endometrial ablation appears to be a safe procedure that improves the QOL in patients with VWD-related menorrhagia. However, its long-term efficacy appears to be lower in VWD patients when compared with women with menorrhagia without VWD.

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Previous research has shown that reductions in body weight prior to induction of acute inflammation can attenuate inflammation-induced anorexia in male rats. In the current study, potential mechanisms responsible for this observation were examined. Specifically, the effect of a 12% prior reduction in body weight on serum leptin, insulin, and corticosterone; levels of interleukin-1 (IL-1), interleukin-6 (IL-6) in the serum, liver, and spleen; neuropeptide Y (NPY) and POMC mRNA levels in the arcuate nucleus (ARC) of the hypothalamus were examined 8 h after induction of acute inflammation. Rats with prior weight reduction had significantly lower serum leptin levels and gene expression of POMC in the ARC than normal-weight rats. In contrast, prior weight reduction altered neither NPY mRNA in the ARC, nor IL-1alpha, IL-1beta, and IL-6 levels in the serum, liver, and spleen. These results suggest that the attenuation of inflammation-induced anorexia by prior weight reduction is not due to altered cytokine activity, but rather to changes in energy regulatory systems that moderate the anorexic actions of IL-1beta and IL-6. One potential change may be reduced activity of the CNS melanocortin system induced by decreased circulating leptin.

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STUDY OBJECTIVE: To determine the safety and efficacy of reoperative hysteroscopic surgery for women who fail endometrial ablation and resection. DESIGN: Retrospective chart review and follow-up (Canadian Task Force classification II-2). SETTING: Private office practice. PATIENTS: Twenty-six women who had undergone endometrial ablation or resection and experienced failure characterized by intolerable pain, bleeding, or asymptomatic hematometra. INTERVENTION: Sonographically guided hysteroscopic endomyometrial resection. MEASUREMENTS AND MAIN RESULTS: Mean length of time from initial treatment for abnormal uterine bleeding and reoperative hysteroscopic surgery was 41.2 +/- 47.9 months. Five (19.2%) women required simple dilatation and 21 (80.8%) required endocervical resection to achieve access to the uterine cavity. There were no operative complications. Mean operating time was 20.3 +/- 9.5 minutes. Mean specimen weight was 6.7 +/- 4.9 g. Adenomyosis was present in 15 (57.7%) specimens. Women were followed for a mean of 23.2 +/- 22.7 months. Twenty-three (88.5%) achieved satisfactory results and avoided hysterectomy. Three women (11.5%) eventually required hysterectomy because of recurrent pain or bleeding. CONCLUSION: Reoperative hysteroscopy is useful in managing women after failed endometrial ablation and resection. It produces excellent results in achieving amenorrhea and relief of cyclic pelvic pain, thereby avoiding hysterectomy in most patients.

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OBJECTIVE: To determine the efficacy of hysteroscopic endomyometrial resection in treating women with intractable uterine bleeding. METHODS: A retrospective analysis was carried out on 304 women with intractable uterine bleeding treated between August 1, 1991, and December 31, 1997. The average patient was 41.3 +/- 8.0 years old and was followed for a mean of 31.8 +/- 22.1 months (range 6-75 months). RESULTS: Eighty-three percent of women were amenorrheic at the time of their one-year follow-up. The overall amenorrhea rate was 85.5%. Only 0.8% of subjects reported no improvement during the study period. Histologic analysis of the endomyometrial specimens revealed that 17 (5.6%) women were found to have significant endometrial pathology not previously identified with routine preoperative screening. There was a total of 20 complications (6.6%), although only 2 (0.7%) were considered severe. Twenty-seven women (8.9%) eventually required subsequent surgery during the study period. Finally, 69 (22.7%) women with adenomyosis were identified. They did not appear to be at increased risk for subsequent surgery. CONCLUSIONS: Hysteroscopic endomyometrial resection produces superior results as measured by amenorrhea rates, the need for subsequent surgery and its low incidence of associated complications; and it produces an important histologic specimen. For patients with significant comorbidity, endomyometrial resection can be adapted to a single-stage procedure incorporating the diagnostic and treatment phases in women with abnormal uterine bleeding.

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A complex between the Tat protein, encoded by human immunodeficiency virus type 1 (HIV-1), and the cellular protein, Puralpha, has been implicated in activation of the late promoter of JC virus (JCV) and in enhancement of JCV DNA replication. JCV is the causative agent of progressive multifocal leukoencephalopathy (PML), an acquired immunodeficiency syndrome (AIDS) opportunistic infection of the brain. Puralpha also binds the HIV-1 TAR RNA element and activates HIV-1 transcription, suggesting a role for RNA binding in the action of this protein. Using immunoelectron microscopy, we find that in human glial cells expressing both proteins, Tat and Puralpha are colocalized in extranucleolar chromatin structural elements. The colocalized Puralpha and Tat are nearly exclusively nuclear, although individual proteins can be seen in both nucleus and cytoplasm, suggesting a preferential tropism of the complex for the nucleus. Analysis of the interaction between purified proteins indicates that the Tat-Puralpha interaction is strongly enhanced by the presence of RNA. Tat amino acids from 37-48 are essential for Tat binding. Residues 49-72, including the TAR RNA-binding domain, are critical for binding to Puralpha, while Cys(22), in the Tat transactivation domain, is responsible for an important global effect. Puralpha repeat II domains are involved in the interaction, and a polypeptide based on one such sequence inhibits binding. After RNase treatment of Puralpha enhancement of Tat binding can be partially restored by addition of a single-stranded JCV DNA PUR element, to which Tat does not bind. The results indicate that the Tat-Puralpha interaction is direct, rather than through an RNA link, and that RNA binding configures Puralpha for optimal interaction with Tat.

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In order to examine concentrations of cerebrospinal fluid (CSF) neurochemicals, the technique of lumbar puncture is typically used. However, the effect of the intrinsic stress of undergoing a lumbar puncture on CSF monoamine concentrations in humans has not yet been established. We used lumbar puncture followed 3 h later by continuous CSF sampling to examine the effect of lumbar puncture on levels of the dopamine and serotonin metabolites homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA), respectively. Additionally, we examined the effect of lumbar puncture on the CSF HVA to 5-HIAA ratio. Immediately post lumbar puncture, CSF concentrations of HVA and 5-HIAA were, respectively, only 51 and 54% of the mean levels detected hours later. However, the HVA to 5-HIAA ratio remained stable during lumbar puncture. While HVA and 5-HIAA levels in CSF obtained via lumbar puncture reflect highly variable responses to the stress of the procedure, the ratio of these metabolites is unaffected.

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Leptin (OB protein) is an important signal in the regulation of energy balance. Leptin levels correlate with adiposity, but also decrease acutely with caloric restriction and increase with refeeding. The brain is an established critical site of leptin function, yet little is known about leptin concentrations in the central nervous system relative to plasma levels, psychiatric diagnoses, and other endocrine parameters. Therefore, using a novel ultrasensitive leptin assay, we explored relationships of human plasma and cerebrospinal fluid (CSF) leptin levels to body mass index, smoking, posttraumatic stress disorder diagnosis, and levels of dopamine, monoamine metabolites, beta-lipotropin, glucocorticoid, and thyroid and cytokine hormones. A strong linear relation between CSF and plasma leptin levels in the am (r = 0.63; P < 0.002) and afternoon (r = 0.90; P < 0.0001) was revealed. CSF and plasma leptin concentrations decreased during a 12- to 20-h period of fasting. A strong association was found between plasma leptin and CSF dopamine levels (r = 0.74; P < 0.01) as well as between CSF leptin levels and urinary free cortisol (r = 0.73; P < 0.01). Both of these parameters covaried with leptin independently of adiposity, as estimated by body mass index. Implications for leptin transport, regulation, and its potential role in therapeutic strategies for obesity and diabetes are discussed.

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The interaction between two regulatory proteins plays a crucial role in the control of several biological events, including gene transcription. In this report, we demonstrate that the interaction between the cellular sequence-specific single-stranded DNA binding protein Puralpha and the HIV type 1 (HIV-1) Tat protein is mediated by specific ribonucleic acids. The region of Tat that is important for its interaction with Puralpha includes the region demonstrated to bind Tat's viral RNA target, TAR. A 10-nucleotide GC-rich consensus sequence identified in RNAs associated with Puralpha derived from human U-87MG cells plays an important role in the Puralpha:Tat interaction as examined by an in vitro reconstitution assay. Furthermore, expression of the Puralpha-associated RNA in these cells enhances transcriptional activation of the HIV-1 promoter by Tat and Puralpha.

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OBJECTIVE: To screen for dopaminergic abnormalities in tobacco smokers and patients with posttraumatic stress disorder (PTSD), the authors determined serial CSF and plasma concentrations of the dopamine metabolite homovanillic acid (HVA). METHOD: Continuous subarachnoid sampling was used to obtain 37 serial CSF samples over 6 hours in 13 normal volunteers and 11 patients with combat-related PTSD; 10 smoked and 14 had never smoked. The smokers were abstinent from tobacco for 1 1 to 17 hours. RESULTS: The smokers had markedly lower CSF, but not plasma, HVA levels. Their CSF HVA concentrations averaged only 54% of the concentrations of the nonsmokers, independent of diagnosis. CONCLUSIONS: Smokers' low CSF concentrations of HVA may be associated either with chronic inhalation of nicotine or other constituents of tobacco smoke or with acute abstinence. Any possible basal dopaminergic abnormalities in patients with PTSD are small relative to the abnormalities associated with smoking.

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Levels of the single-stranded DNA-binding protein Pur(alpha), previously implicated in control of both DNA replication and gene transcription, are altered during the CV-1 cell cycle. Just prior to the onset of S phase, Pur(alpha) levels drop precipitously, after which they recover nearly 8-fold throughout S and G2 to peak just after mitosis. As observed previously, Pur(alpha) binds the hypophosphorylated form of the retinoblastoma protein, Rb. Coimmunoprecipitation of Pur(alpha) and Rb reveals that the complex declines as cells enter S phase and does not reform as Pur(alpha) levels recover in S and G2. As Pur(alpha) levels recover, the protein is localized to nuclear foci containing newly replicated DNA, as determined by immunoelectron microscopy using different sized gold beads and antibodies against Pur(alpha) and bromodeoxyuridine-labeled DNA. These foci also contain cyclin A, and Pur(alpha) coimmunoprecipitates with cyclin A from extracts of cells in S and G2 phases. Pur(alpha) remains with these foci throughout G2, after the bulk of DNA synthesis has ceased. Changing levels of Pur(alpha) may affect Pur(alpha) functions at the onset of S phase and during progression to mitosis.

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BACKGROUND: Experiments in lower animals and humans have demonstrated the existence of functional interactions between serotonin and dopamine in neuronal tissue. However, the relationship between parameters of serotonin and dopamine neuronal activity over time within the central nervous system (CNS) of the individual human has not yet been established. METHODS: We used continuous cerebrospinal fluid (CSF) sampling over 6 hours to test the hypothesis that the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) and the dopamine metabolite homovanillic acid (HVA) significantly covary in concentration over time. Two groups of normal volunteers (total n = 16) were studied at separate hospitals and CSF was assayed for 5-HIAA and HVA by high-performance liquid chromatography (HPLC). Three subjects underwent repeat CSF-withdrawal procedures after a 6-week interval. RESULTS: Strong and sustained positive covariability in concentrations of HVA and 5-HIAA was observed in the CSF of individual humans. High intraindividual correlation coefficients were +0.897 and +0.871 in the two normal volunteer groups. The HVA to 5-HIAA concentration ratio in CSF was 2.2 +/- 0.7 with very little variability over intervals ranging from minutes to weeks. CONCLUSIONS: The balance between CSF dopamine and serotonin metabolite concentrations remains relatively constant over time in healthy humans. Serial measures of CSF dopamine and serotonin metabolites within the same person could be an effective model in which to explore the interrelationships between these systems in various psychiatric syndromes, in response to drug treatment, and during provactive testing.

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Sertindole is an antipsychotic with atypical in vitro and ex vivo binding profiles and little propensity to cause extrapyramidal symptoms. However, its potential usefulness in the treatment of psychosis resistant to the 'classical' neuroleptics has not been determined. In the present study we used a double blind, placebo-controlled trial of sertindole and observed dramatic, sustained resolution of formerly-chronic positive and negative psychotic symptoms in a schizophrenic patient. This patient had averaged 2.5 inpatient admissions per year for the 8 years preceding initiation of sertindole therapy, but has had no hospitalizations or psychosis in the 3.5 years since. Improved cognitive function has also been documented. This preliminary, but controlled, experience suggests that sertindole may possess a spectrum of clinical activity distinct from that of the typical antipsychotic agent.

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Opioid-mediated analgesia develops in experimental animals following traumatic stress and increased opioid-mediated analgesia has been observed in combat veterans with post-traumatic stress disorder (PTSD). These observations have led to the hypothesis that increased central nervous system (CNS) opioidergic activity exists in patients with PTSD. However, direct CNS data on opioid peptide concentrations and dynamics in patients with PTSD are lacking. We withdrew cerebrospinal fluid (CSF) via a flexible, indwelling subarachnoid catheter over a 6-h period and determined hourly CSF concentrations of immunoreactive beta-endorphin (ir beta END) in 10 well-characterized combat veterans with PTSD and nine matched normal volunteers. Blood was simultaneously withdrawn to obtain plasma for ir beta END. PTSD symptom clusters, as measured by the CAPS, were correlated with neuroendocrine data. Mean CSF ir beta END was significantly greater in patients with PTSD compared with normals and there was a negative correlation between the ir beta END and PTSD intrusive and avoidant symptoms of PTSD. No intergroup difference between plasma ir beta END was found, nor was there a significant correlation between CSF and plasma ir beta END. Immunoreactive beta-lipotropin (ir beta LPH) and pro-opiomelanocortin (irPOMC), both precursors of beta END, were much more plentiful in human CSF than was beta-endorphin itself, as has been previously reported. It remains to be determined whether the increased CNS opioid concentrations predate traumatic stress, thereby conferring a vulnerability to dissociative states and PTSD itself, or result from the trauma. The negative correlation between CSF ir beta END and avoidant and intrusive symptoms suggests that CNS hypersecretion of opioids might constitute an adaptive response to traumatic experience. Poor correlation between CSF and plasma ir beta END limits use of plasma measures to assess CNS opioid activity.

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A new method was developed to access the uterine cavity in women in whom cervical stenosis precludes hysteroscopic surgery. Thirty-three women with intractable uterine bleeding were chosen to undergo either hysteroscopic myometrial resection or myomectomy. All of them had cervical stenosis that would, in the authors' opinion, not permit safe dilatation to 9 mm, the minimum diameter necessary to introduce a gynecologic resectoscope. Endocervical resection was performed in all 33 patients, with safe, easy access to the uterine cavity. No cases of fluid overload or excess bleeding occurred. We conclude that hysteroscopic endocervical resection is a safe method to create a portal of entry to the uterine cavity in women with absolute or relative cervical stenosis.

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OBJECTIVE: To describe the use of methotrexate and misoprostol to induce abortion in pregnancies up to 8 weeks when uterine or cervical anomalies make suction curettage difficult or impossible. METHODS: Four consecutive women, 8 weeks pregnant or less and with failed suction curettage, were given methotrexate 50 mg per square meter intramuscularly followed by a misoprostol 800-microgram suppository 72 hours later. A repeat dose of a misoprostol 800-microgram vaginal suppository was administered on day 4 if there was no bleeding, and an additional dose was given if the repeat beta-hCG titer had not decreased by at least 50%. Subjects were followed-up with serum or urine hCG assays. Complete abortion was defined by vaginal bleeding and a negative urine pregnancy test. Subjects completed a daily symptom log and a satisfaction questionnaire when the abortion was complete. RESULTS: The four women referred after failed suction curettage had the following anatomic problems: a uterus bicornis bicollis, a bicornuate uterus, uterine leiomyomas, and cervical stenosis resulting from previous laser surgery. All subjects had a complete abortion from methotrexate and misoprostol. Mild gastrointestinal side effects were reported by all four subjects: nausea (two subjects), vomiting (two), and diarrhea (two). The satisfaction questionnaire revealed that all subjects agreed with the statements that "Overall, the procedure went well" and "I would recommend this procedure over a surgical abortion." CONCLUSION: Methotrexate and misoprostol can induce an abortion when uterine or cervical anomalies make suction curettage difficult or impossible.

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STUDY OBJECTIVE: To review the results of hysteroscopic myomectomy in 75 women with menorrhagia. DESIGN: A retrospective analysis of 75 women who were evaluated and treated between November 1, 1988, and March 3, 1994. SETTING: Private gynecologic practice. PATIENTS: Seventy-five women with menorrhagia with confirmed hysteroscopic evidence of one or more submucous myomata. INTERVENTIONS: Sixty-five women who had completed their childbearing underwent myomectomy and a concomitant procedure to destroy the endometrium. The remaining 10, who wished to retain their childbearing ability, underwent myomectomy alone. With two new techniques, large submucous myomata were removed rapidly and efficiently. Both laparoscopy and intraoperative ultrasound were performed when surgical guidance and control were thought to be necessary. MEASUREMENTS AND MAIN RESULTS: Myomectomy was performed in 55 (73%) of women without intraoperative control, and in 10 (13.4%) with laparoscopic and ultrasound control. No serious complications occurred. Three patients had leiomyomas of uncertain malignant potential, the significance of which underscores the importance of having all the tissue that is excised evaluated histologically. The outcome of a single operation was satisfactory to 84% of women. CONCLUSIONS: Hysteroscopic myomectomy to control menorrhagia appears to be a safe and effective procedure. Two new techniques should improve its efficiency. In addition, controlling with ultrasound may help to avoid perforation injuries and obviate the need for laparoscopic guidance.

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Thirty-five patients with menorrhagia and a normal uterine cavity underwent hysteroscopic endomyometrial resection. None underwent any form of medical or surgical preparation of the endometrium. A standard gynecologic resectoscope was used to excise a minimum of 3 mm of endomyometrium from the entire uterine cavity. This depth was reduced to 2 mm at the tubal ostia. All patients were followed for 3-6 months. Twenty-one of the 25 patients (84%) who were followed at 6 months reported amenorrhea. The mean dysmenorrhea scores improved from 2.84 to 0.56 postoperatively. Seven of the 35 patients were diagnosed with adenomyosis. One woman was found to have adenomatous hyperplasia of the endometrium. Hysteroscopic endomyometrial resection is a highly effective method for the treatment of menorrhagia. This technique produces a very high rate of amenorrhea, provides a histologic specimen of the endomyometrium, and obviates the need for medical or surgical preparation of the endometrium.

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