Prognostic significance of supradiaphragmatic lymph nodes at initial presentation in patients with stage III high-grade serous ovarian cancer.

PURPOSE: To identify the optimal size threshold and to assess the prognostic significance of supradiaphragmatic lymph nodes at initial presentation of patients with high-grade serous ovarian cancer (HGSC). METHODS: This IRB-approved, HIPAA-compliant retrospective study included baseline pretreatment staging abdominal CTs of 88 women (mean age 62 years, SD 10.4, range 29-85) with FIGO stage III HGSC. Patients with stage IV disease were excluded due to worse prognosis and management guided by distant metastases. Two fellowship-trained radiologists independently reviewed abdominal CTs to record the presence of supradiaphragmatic nodes, abdominal lymphadenopathy, peritoneal carcinomatosis, and ovarian mass. Progression-free survival (PFS) and overall survival (OS) were recorded after median 79 months follow-up (IQR 58-115, range 13-144). The optimal short-axis size threshold for supradiaphragmatic lymphadenopathy was determined by correlating 3, 4, 5, 6, 7, and 10 mm thresholds with PFS and OS using Log-rank test. Prognostic significance of supradiaphragmatic lymphadenopathy was assessed using Cox proportional hazards models. RESULTS: There was good interobserver agreement for presence (κ = 0.65, 95%CI 0.51-0.79) and size (ICC = 0.77, 95%CI 0.66-0.86) of supradiaphragmatic nodes. 5 mm short-axis size threshold was associated with significantly shorter PFS (median 14 months, IQR 11-17 vs. 23 months, IQR 12-59; p = 0.02) and OS (median 44 months, IQR 27-69 vs. 65 months, IQR 45-96; p = 0.03). Total 38/88 (43%) patients had supradiaphragmatic lymphadenopathy. On Cox proportion hazards analysis, supradiaphragmatic lymphadenopathy was significantly associated with shorter PFS (p = 0.02; HR 1.81, 95%CI 1.11-2.96) and OS (p = 0.008; HR 2.11, 95%CI 1.21-3.65). CONCLUSION: In patients with stage III HGSC, supradiaphragmatic lymphadenopathy is associated with shorter PFS and OS. Further studies would help determine its implications on staging, decision regarding neoadjuvant therapy, and surgical technique.

Relation between length of hospital stay and costs of care for patients with community-acquired pneumonia.

PURPOSE: Patients with pneumonia often remain hospitalized after becoming clinically stable, without demonstrated benefits on outcome. The purposes of this study were to assess the relation between length of hospital stay and daily medical care costs and to estimate the potential cost savings associated with a reduced length of stay for patients with pneumonia. SUBJECTS AND METHODS: As part of a prospective study of adults hospitalized with community-acquired pneumonia at a community hospital and two university teaching hospitals, daily medical care costs were estimated by multiplying individual charges by department-specific cost-to-charge ratios obtained from each hospital's Medicare cost reports. RESULTS: The median total cost of hospitalization for all 982 inpatients was $5, 942, with a median daily cost of $836, including $491 (59%) for room and $345 (41%) for non-room costs. Average daily non-room costs were 282% greater on the first hospital day, 59% greater on the second day, and 19% greater on the third day than the average daily cost throughout the hospitalization (all P <0.05), and were 14% to 72% lower on the last 3 days of hospitalization. Average daily room costs remained relatively constant throughout the hospital stay, with the exception of the day of discharge. A projected mean savings of $680 was associated with a 1-day reduction in length of stay. CONCLUSIONS: Despite institutional differences in total costs, patterns of daily resource use throughout hospitalization were similar at all institutions. A 1-day reduction in length of stay might yield substantial cost-savings.

Resuscitation after hemorrhage using recombinant human hemoglobin (rHb1.1) in rats: effects on nitric oxide and prostanoid systems.

OBJECTIVES: Hemoglobin-based oxygen carriers are designed to replace blood volume and to increase oxygen delivery to tissues after blood loss. The goals of the present study were two-fold: a) to determine the systemic and regional vascular effects of resuscitation with recombinant human hemoglobin (rHb1.1) in rats during controlled hemorrhage; and b) to determine whether nitric oxide (NO) or prostaglandins were involved in the observed responses. DESIGN: Paralyzed, ventilated rats were hemorrhaged (18 mL blood/kg body weight) during halothane anesthesia and allowed to stabilize for 30 mins. Systemic and regional hemodynamics and oxygen delivery were monitored at three time points, using the radioactive microsphere method. Microspheres were first infused at the end of the hemorrhage stabilization period (t=0 min). rHb1.1 (1 g/kg body weight) or rHb1.1 diluent (phosphate buffered saline, 36 mL/kg body weight) were infused over 20 mins and microspheres were administered again, 30 mins later (t=50 mins). Saline (0.5 mL), indomethacin (5 mg/kg to inhibit cyclooxygenase), or NG-monomethyl-L-arginine (L-NMMA, 100 mg/kg, to inhibit NO synthase) were then infused in rHb1.1-treated rats and microspheres injected once more (t=80 mins). SETTING: Research laboratory. SUBJECTS: Male Wistar rats (n=37). INTERVENTIONS: Recombinant human hemoglobin (rHb1.1), rHb1.1 diluent (phosphate buffered saline) resuscitation of hemorrhaged rats. Saline, L-NMMA, or indomethacin treatment after resuscitation. MEASUREMENTS AND MAIN RESULTS: Resuscitation with rHb1.1 increased mean arterial pressure (MAP), cardiac output, and systemic oxygen delivery significantly when compared with diluent. After rHb1.1 resuscitation, regional blood flows were significantly increased in skin, kidney, spleen, and heart compared with diluent resuscitation. Compared with saline treatment after rHb1.1 resuscitation, L-NMMA increased MAP and regional resistances in virtually all tissues; indomethacin did not alter MAP, but increased resistance in the brain. CONCLUSIONS: These data indicate that rHb1.1 resuscitation was more effective than diluent in improving systemic and regional hemodynamics and oxygen delivery, suggesting that rHb1.1 may be of benefit in the treatment of acute blood loss. Increased resistance after L-NMMA in the presence of rHb1.1 indicated that rHb1.1 resuscitation did not eliminate NO dependent circulatory control. Increased resistance after indomethacin in brain indicated that vasodilator prostanoids were important in regulating vascular resistance in these tissues after rHb1.1 resuscitation.

Glucocorticoids may alter antioxidant enzyme capacity in the brain: baseline studies.

Glucocorticoids (GCs), the adrenal steroids secreted during stress, have been shown to increase the vulnerability of hippocampal neurons to metabolic insults, potentially by altering the neuronal defense capacity against oxidative damage. These experiments assessed the effect of long term in vivo GC supplementation on basal activity of the antioxidant enzymes copper/zinc superoxide dismutase (Cu/Zn SOD), manganese superoxide dismutase (Mn SOD), catalase, and glutathione peroxidase (GSPx). Kinetic enzyme studies were done using brain tissue from the hippocampus, cortex, cerebellum, and also from liver as a peripheral control. Cu/Zn SOD activity was significantly lower in all brain regions of GC-treated rats, but higher in the liver. Mn SOD activity was unaffected by treatment. Catalase in the brain appeared largely unaffected by GC treatment, although liver catalase was significantly decreased. GSPx activity was significantly decreased by GCs at high peroxide levels in all tissues. These results indicate that the presence of GCs may lower the antioxidant capacity of tissues in a region-specific manner, and that the deficit may not appear until the tissue is challenged with supranormal levels of oxidative products (as seen with GSPx).

Glucocorticoids may alter antioxidant enzyme capacity in the brain: kainic acid studies.

Glucocorticoids (GCs) predispose hippocampal neurons to damage during metabolic stressors. One component of hippocampal GC-endangerment may be changes in neuronal defenses against oxidative challenge. Previous experiments showed a decrease in basal levels of copper/zinc superoxide dismutase (Cu/Zn SOD) and glutathione peroxidase (GSPx) in the brain of rats treated with GCs [L. McIntosh, K. Hong, R. Sapolsky, Glucocorticoids may alter antioxidant enzyme capacity in the brain: baseline studies, 1997.]. In this study we administered the excitotoxin kainic acid (KA) to generate reactive oxygen species (ROS) in the brain, and monitored the activity of four antioxidant enzymes over 24 h in GC-free and GC-supplemented rats. We tested the response pattern in three regions of the brain (hippocampus, cortex, cerebellum) and the liver as a peripheral control. In the hippocampus, KA induced Cu/Zn SOD and catalase, but GCs prevented the induction of catalase and maintained the lowered GSPx activity seen previously in the baseline studies. In the cortex, KA induced Cu/Zn SOD, Mn SOD and catalase activity, but there was no significant GC effect. There was no response to KA in the cerebellum, but GCs decreased GSPx activity. In the liver, KA produced a rise in Cu/Zn SOD and catalase activity, and GC-treated animals showed a slower return to baseline. These experiments indicate that the impairment of antioxidant enzyme defenses, particularly the hippocampal peroxidases, could be a component of GC-mediated neuroendangerment.

Increased susceptibility of Alzheimer's disease temporal cortex to oxygen free radical-mediated processes.

Reactive oxygen-mediated processes are though to contribute to the pathogenesis of Alzheimer's disease (AD). To investigate this hypothesis we studied autopsy tissue from 11 pairs of AD cases and control individuals matched for age, postmortem delay, and tissue storage time. The temporal neocortex, which is severely involved by AD pathology, and the cerebellum, which is spared, were analyzed for tissue markers of lipid peroxidation (LPO). The average chemiluminescence formed from bond breakage in tissue homogenates during a 3-h incubation, without the presence of catalysts such as metal ions or ascorbate, was significantly increased in the AD temporal cortex to 130% of matched controls. Basal tissue content of LPO products (thiobarbituric acid reactive substances--TBARs) was not different between groups. However, TBARs were significantly elevated in AD temporal cortex to 135% of control after the incubation. In contrast, in the cerebellum there was no difference between AD and control tissue, indicating a disease-specific tissue effect. Because the use of oral antioxidants have received considerable attention in the last few years, the results seen in the testing of an AD patient who took daily vitamin E supplements for 4 years is particularly interesting. The time course for CL reactivity in the temporal cortex was considerably delayed compared to all other samples. This observation is consistent with the hypothesis that antioxidants within tissue will quench ROS-mediated reactions. This study indicates that there is increased susceptibility to ROS in the AD temporal cortex that may contribute to the pathogenesis of the disease. Furthermore, our observation suggest that oral antioxidant supplementation may be protective against LPO in the human brain.

Regional vascular effects of rHb1.1, a hemoglobin-based oxygen carrier.

The goals of this study were to determine the effects of recombinant human hemoglobin (rHb1.1, 1 g/kg i.v.) on systemic hemodynamics, regional blood flows, and regional vascular resistances in rats. Cardiac output (CO) and regional blood flow in 13 tissues were determined by using the radiolabeled-microsphere method during halothane anesthesia. Microspheres were injected at three time points: before (control, t = 0), t = 30 [10 min after a 20-min infusion of vehicle (diluent) or rHb1.1], and at t = 120 min. Infusion of diluent did not alter CO, heart rate (HR), mean arterial pressure (MAP), or systemic vascular resistance (SVR) and had minimal effects on regional blood flows. Infusion of rHb1.1 did not alter CO or HR but did increase MAP and SVR compared with diluent. Infusion of rHb1.1 increased blood flow to the heart and decreased blood flow to the gastrointestinal tract (GIT) and liver. Compared with the corresponding values in the diluent-treated rats, resistance was increased after rHb1.1 in spleen, kidney, and hepatic artery. In conclusion, rHb1.1 administration increased MAP and SVR. The vasoconstriction was heterogeneous and was associated with increased coronary blood flow and with increased regional resistance in kidney, spleen, and hepatic artery, compared with diluent-infused controls.

Effects of tetrandrine on spontaneous and evoked release of acetylcholine at the mouse neuromuscular junction.

The action of tetrandrine on spontaneous and phasic acetyl-choline (ACh) release was investigated at the mouse neuromuscular junction recording miniature endplate potentials (MEPPs) and endplate potentials. Superfusion of muscles with tetrandrine (10 microM) in normal Krebs-Ringer solution induced an increase of the mean regular MEPP amplitude and the overall MEPP frequency. In addition a larger than normal proportion of high-amplitude MEPPs appeared, described as "giants." This enhancement by tetrandrine of spontaneous ACh release also occurred in the presence of tetrodotoxin (1 microM). In elevated magnesium Krebs-Ringer solution the mean amplitude as well as the quantal content of endplate potentials was reduced simultaneously with the enhancement of spontaneous ACh release. Superfusion of muscles with emetine (20 microM), an alkaloid chemically of the same kind as tetrandrine, induced an enhancement of spontaneous ACh release as recorded by MEPPs qualitatively similar to that of tetrandrine. These results suggest that the isoquinolines tetrandrine and emetine similarly increased the spontaneous ACh release. This action of tetrandrine appeared to be presynaptic and was accompanied by a decrease of phasic ACh release.

Glucocorticoids increase the accumulation of reactive oxygen species and enhance adriamycin-induced toxicity in neuronal culture.

Glucocorticoids (GCs), the adrenal steroids secreted during stress, are known to affect diverse processes involving reactive oxygen species, from exacerbation of ischemic damage to alteration of antioxidant enzyme activities. To determine whether GCs have a direct effect on oxidative processes, we constructed a dose-response curve using adriamycin, an oxygen radical generator, in primary neuronal cultures. In cultures derived from the hippocampus, which has the greatest concentration of corticosteroid receptors in the brain, higher levels of GCs significantly increased adriamycin toxicity, while not being toxic themselves. In cortical cultures, which contain lesser amounts of corticosteroid receptors, GCs had no effect on the adriamycin dose-response. Surprisingly, when tested with dichlorofluorescein for levels of reactive oxygen species (ROS), GCs increased ROS by approximately 10% basally and at all adriamycin doses in both hippocampal and cortical cultures. Thus, greater generation of ROS does not account for the increased susceptibility of the hippocampus to oxidative damage.

Endocrine modulators of necrotic neuron death.

In recent years, there has been extraordinary progress in understanding the cellular and molecular cascades that mediate neuron death following necrotic insults. With this knowledge has come the recognition of ways in which these cascades can be modulated by extrinsic factors, altering the likelihood of subsequent neuron death. In this review, we consider the ability of a variety of hormones to modulate necrotic death cascades. Specifically, we will examine the ability of the stress hormones glucocorticoids and corticotropin-releasing factor, of thyroid hormone, and of pre-ischemic exposure to catecholamines to augment necrotic neuron death. In contrast, estrogen, insulin and postischemic exposure to catecholamines appear to decrease necrotic neuron death. We review the heterogeneous mechanisms that are likely to mediate these hormone effects, some possible clinical implications and the therapeutic potentials of these findings.

Glucocorticoids may enhance oxygen radical-mediated neurotoxicity.

Modern populations are constantly exposed to a variety of compounds in the workplace and the environment that promote formation of reactive oxygen species (ROS) within susceptible tissues. Due to its high oxygen consumption, the brain may be particularly vulnerable to oxidative damage and degeneration. Agents that impact cellular oxidative homeostasis would therefore be expected to alter the toxicity of ROS generating compounds. We are testing this hypothesis using endogenous stress hormones, glucocorticoids, to perturb neuronal homeostasis, and adriamycin to generate ROS. Glucocorticoids (GCs) are hormones secreted by the adrenals in response to stress, and are also prescribed clinically to control inflammatory and autoimmune disorders in millions of people annually. Therefore, high GC levels may not be uncommon in individuals exposed to low levels of toxic compounds. Also, GCs appear to act on cellular pathways relevant to ROS as seen by their potentiation of neurodegeneration following insults such as stroke, hypoglycemia and seizure. Using rat primary neuronal culture, we determined neuronal susceptibility to adriamycin toxicity by cell counting (using MAP-2 staining). Dichlorofluorescein fluorescence confirmed ROS generation after adriamycin administration. Physiological levels of GCS (up to mM concentrations) in the culture media exacerbated both adriamycin toxicity and ROS generation. We hypothesize that GCs may exacerbate the toxicity of three neurotoxins whose mechanisms of action overlap GC pathways.

Ehlers-Danlos syndrome: relationship between joint hypermobility, urinary incontinence, and pelvic floor prolapse.

OBJECTIVE: To compare the incidence of joint hypermobility and prolapse in incontinent and continent women with Ehlers-Danlos syndrome (EDS). METHODS: Forty-six patients with EDS were evaluated by history and physical examination. The degree of joint mobility of shoulder, elbow, wrist, hip, knee, and ankle was evaluated by orthopedic surgeons and physical therapists. Joint range of motion measurements were obtained using an orthopedic goniometer. RESULTS: The two EDS groups, incontinent (n = 28) and continent (n = 18) women, had a statistically similar mean age, weight, and parity (p = NS). In the EDS population overall joint hypermobility averaged 34.3%. Individuals with EDS type 3 had significantly more joint hypermobility than those with type 1 and 2 EDS. However, logistic regression analysis demonstrated no significant relationship between prolapse and joint hypermobility. Wrist dorsiflexion (p < 0.05) and palmar flexion (p = 0.05) were the only variables related to incontinence. CONCLUSION: It has previously been reported that hypermobility was correlated with pelvic floor prolapse. Of 18 joint measures per patient, hypermobility of both wrist dorsiflexion and palmar flexion was associated with symptoms of incontinence. We were unable to document an association between joint hypermobility and prolapse in the EDS population.

Gynecologic disorders in women with Ehlers-Danlos syndrome.

OBJECTIVE: We characterized the population with Ehlers-Danlos syndrome with regard to genital prolapse, urinary incontinence, and other gynecologic disorders. METHODS: Forty-one adult women who had registered for a first-ever Ehlers-Danlos multidisciplinary clinic participated in the study. Each had a comprehensive standardized evaluation, including gynecologic history, physical examination, urodynamic testing, and physical therapy evaluation. Qualitative and quantitative data were analyzed to determine means for various gynecologic disorders of Ehlers-Danlos syndrome. RESULTS: The frequencies of incontinence complaints (59%), endometriosis (27%), dyspareunia (57%), and previous hysterectomy (44%) were higher than expected for a population with a mean age of 41 years. Incontinence could not be demonstrated objectively. Prolapse was diagnosed in 12 (29.3%). CONCLUSIONS: Careful attention should be paid to women with Ehlers-Danlos syndrome because of an association with many gynecologic complaints. Women with Ehlers-Danlos syndrome should be questioned regarding incontinence, genital prolapse, endometriosis, and dyspareunia.

Perinatal outcome of broken marriage in the inner city.

OBJECTIVE: To test the hypothesis that the erosion of family structure, epidemic substance abuse, and increased low birth weight (LBW) rates are interrelated. METHODS: In this cohort study, we analyzed information coded prospectively in a computerized perinatal data base. Separated, divorced, and widowed mothers were grouped as broken marriages. The setting was a predominantly urban, indigent population in a tertiary care hospital. The analysis included singleton pregnancies of 14,896 women receiving prenatal and intrapartum care at our hospital from 1986-1991. The main outcome measures included LBW, prematurity, small for gestational age, neonatal mortality, and neonatal intensive care unit admissions. RESULTS: Married mothers fared better than single mothers, but risks for adverse perinatal outcomes for women with broken marriages were consistently as high or higher than for single mothers. The rate of LBW infants was 43% higher in the broken marriage group than in the married group. The increased frequency of LBW among infants born into broken marriages was attributable mainly to reduced growth rather than to prematurity and was associated with substance abuse. CONCLUSION: Our findings indicate that mothers from broken marriages are at relatively higher risk for LBW infants than married mothers (odds ratio 1.5). Broken marriage warrants emphasis as an important perinatal risk factor.

30-minute evaluation of incontinence in the older woman.

The key to successful management of urinary incontinence in the older woman is accurate diagnosis of the underlying condition. A simple 30-minute in-office evaluation answers the important questions that increase the likelihood of reaching the correct diagnosis. This core evaluation includes a history and physical exam, urinalysis and other basic lab tests, assessment of urethral angulation, and a simple cystometrogram. A patient voiding diary may also help to pinpoint the severity of incontinence. Further testing is required if symptoms fail to resolve after empiric therapy.

Complications from permanent suture in surgery for stress urinary incontinence. A report of two cases.

Two cases reports are used to illustrate potential complications of permanent suture in vaginal and abdominal surgical procedures for urinary incontinence. The first case used permanent suture for an abdominal retropubic urethropexy. A portion of a glove finger remained attached to the suture and was not recognized until the patient developed a retropubic abscess two years later. In the second case, permanent suture used in a vaginal retropubic urethropexy eroded through the vagina. The patient presented with lower abdominal pain 18 months after the procedure; the pain was relieved with removal of the suture. Complications of using permanent suture in abdominal retropubic urethropexy have not been reported, but the attachment of a foreign body, such as a glove finger, can create an adverse outcome. The use of permanent suture in vaginal procedures should be used with the awareness that there are potential complications.

Pelvic floor rehabilitation in the treatment of incontinence.

This study assessed the effectiveness of a pelvic floor rehabilitation program in a clinical practice. A retrospective convenience sample of 48 women was evaluated pretreatment and posttreatment with follow-up interviews from six months to three years. This group consisted of 81% with stress urinary incontinence, 6% with unstable bladder and 10% with mixed incontinence. Fecal incontinence was present as well in 35% of the subjects. The patients were taught pelvic floor muscle exercises and instruction reinforced with electromyographic biofeedback. Neuromuscular electrical stimulation was used when clinically indicated. Two women did not continue the program beyond the first visit and were excluded. Sixty-two percent of patients with two or more visits demonstrated an improvement. Thirteen percent were completely dry, and 49% demonstrated a significant improvement. Patients with genuine stress urinary incontinence, unstable bladder and mixed incontinence showed a 66%, 33% and 50% improvement rate, respectively. Fecal incontinence was improved in 63% of women trained in pelvic floor muscle exercises. A significant decrease (P < .001) was found in the frequency of self-reported leakage at the six-month to three-year follow-up. The strength and duration of a pelvic muscle contraction was significantly greater between the first and last visit in all patients, regardless of the subjective improvement. A pelvic floor rehabilitation program was an effective alternative to surgical intervention in reducing the frequency of urinary leakage. Further studies are needed to identify factors predicting success and to determine the most cost-effective method of achieving pelvic floor rehabilitation.

Crystals of an ATPase fragment of bovine clathrin uncoating ATPase.

A 44,000 Mr amino-terminal, clathrin-independent ATPase fragment of the bovine clathrin uncoating ATPase has been crystallized in a form suitable for X-ray diffraction studies. The crystals are orthorhombic, space group P2(1)2(1)2(1), a = 145.3 A, b = 65.0 A, c = 46.9 A, with one protein molecule per asymmetric unit (1 A = 0.1 nm).