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To compare the risks of developing invasive squamous cell cervical cancer associated with screening intervals of 1, 2, and 3 years after a negative cervical smear. We conducted a matched case-control study of invasive squamous cell cervical cancer patients (n = 482) diagnosed between 1983 and 1995 among long-term members of a large health maintenance organization. Controls were matched for age, length of membership, and race (n = 934). Screening interval was time between the last negative cervical smear and the case diagnosis date. The main outcome measure was the relative odds of invasive disease associated with 1-year, 2-year, and 3-year intervals. The odds ratio for a 2-year versus a 1-year interval was 1.72 (95% confidence interval 1.12, 2.64, P =.013) and for a 3-year versus a 1-year interval was 2.06 (95% confidence interval 1.21, 3.50, P =.007). The odds ratio for a 3-year versus a 2-year interval was 1.20 (95% confidence interval 0.65, 2.21, P =.561). Controlling for ever having had an abnormal cervical smear or a previous consecutive negative smear did not substantially change these results. In this large health plan, the relative risks of invasive squamous cell cervical cancer were significantly greater for 2-year and 3-year cervical cancer screening intervals compared with a 1-year interval, but not for a 3-year interval compared with a 2-year interval. Our findings need to be placed in the context of the low absolute risks of developing invasive cervical cancer during the first 3 years after a negative cervical smear before making policy recommendation.

Objectives: To determine associations between advancing age and screening behavior and prognosis in long-term members of a prepaid health plan diagnosed with invasive cervical cancer (ICC)., Design: Case series., Setting: Prepaid health plan., Participants: All women diagnosed with ICC at Kaiser Permanente Medical Care Program-Northern California health plan from 1988 to 1994., Measurements: From medical records, we recorded participants' age, stage at diagnosis, tumor histology, and results of and reasons for all previous cervical smears. We limited our analysis to women who had been members of the health plan for at least 30 of the 36 months preceding diagnosis (n = 455)., Results: Women in older age groups were less likely than younger women to have been screened within the 3 years before diagnosis (P = .005 for trend). Nonadherence to follow-up of abnormal cervical smears was uncommon (17/455, 3.7%) and not age related (P = .932 for trend). The proportions of ICC that were interval cancers, defined as ICC diagnosed within 3 years of a negative screening smear, were highest in women under age 30 (P = .004 for trend). In multivariate analyses controlling for stage at diagnosis, women age 60 and older were not more likely to die of ICC within 3 years of diagnosis than were women younger than age 60 (odds ratio 1.30, 95% confidence interval 0.75-2.28)., Conclusion: The disproportionate burden of cervical cancer observed in older women appears to be largely attributable to lack of screening within the 3 years before diagnosis.

The discrepancy between dynamical mass measures of objects such as galaxies and the observed distribution of luminous matter in the universe is typically explained by invoking an unseen "dark matter" component. Dark matter must necessarily be nonbaryonic. We introduce a simple hypothesis to do away with the necessity for dark matter by introducing an additional non-gravitational force coupled to baryon number as a charge. We compare this hypothesis to Milgrom's modified Newtonian dynamics. The model ultimately fails when confronted with observation, but it fails in an interesting way.

The late infall of cold dark matter onto an isolated galaxy such as our own produces flows with definite velocity vectors at any physical point in the galactic halo. It also produces caustics which are places where the dark matter density is very large. The outer caustics are topological spheres whereas the inner caustics are rings. The self-similar model of galactic halo formation predicts that the caustic ring radii a(n) follow the approximate law a(n) approximately 1/n. In a recent study of 32 extended and well-measured galactic rotation curves, we found evidence for this law.

Background: Despite the widespread use of Papanicolaou (Pap) smear screening, substantial morbidity and mortality from cervical carcinoma continue in the U.S. Although access to screening is a major barrier to use of the Pap smear, invasive cervical carcinoma (ICC) still is observed in health plan members who have comprehensive preventive care coverage., Methods: For all women diagnosed with ICC between 1988 and 1994 in a large prepaid health plan, the authors retrospectively reviewed the medical records for prediagnosis Pap smear history to identify antecedents to ICC., Results: Of 642 women diagnosed as having ICC, 455 (71%) had been plan members for > or = 30 of the 36 months before diagnosis. Of these 455 women, 240 (53%) had no Pap smear during the 6-36 months prior to diagnosis (i.e., were nonadherent to screening), 127 (28%) had only "normal" Pap smear results, 42 (9%) had at least 1 abnormal Pap smear and were adequately followed, 17 (4%) had at least 1 abnormal result without adequate follow-up, and 29 (6%) were classified as "other." Compared with adherent women, more nonadherent women presented with later stage disease, were symptomatic at the time of diagnosis, were older, and were of a race/ethnicity other than non-Hispanic white., Conclusions: Nonadherence to screening recommendations was found to be the most important modifiable antecedent to ICC in this population. The rate of incidence of ICC could be reduced by interventions to increase screening in women who do not have Pap smears regularly and by the use of newer screening technologies to reduce the false-negative rate of Pap smears.

We intensively reviewed 137 smears initially classified as atypical glandular cells of undetermined significance (AGUS) to refine cytological criteria for evaluating these cases, evaluate histological outcomes, and assess the value of human papillomavirus (HPV) DNA testing in management. Consenting, nonpregnant study participants were identified from a cohort of 46,009 women receiving routine Pap smear screening in a managed care setting. Colposcopy was performed on all women, and at least one histological sample was obtained from each. Review diagnoses were assigned to smears and biopsy specimens by two separate panels of pathologists. DNA testing for cancer-associated HPV types was performed on rinses of cytological samplers after a smear and thin-layer slide had been made. On review, 47 (34%) smears were reclassified as negative, 44 (32%) as AGUS, 30 (22%) as atypical squamous cells of undetermined significance (ASCUS), and 16 (12%) as squamous intraepithelial lesions (SIL). The 19 smears interpreted as high-grade intraepithelial lesions on review included 13 high-grade SIL (HSIL), two HSIL with AGUS, favor neoplastic (endocervical adenocarcinoma in situ [AIS]), and four AGUS, favor neoplastic (AIS). Review histological diagnoses were negative in 105 (77%), squamous or glandular atypia in four (3%), low-grade SIL (LSIL) in nine (7%), HSIL in 12 (9%), AIS in five (4%, including two with concurrent HSIL), and endometrial carcinoma in one (1%). HPV testing identified 11 (92%) of 12 women with histologically confirmed HSIL and all five with AIS (100%). A high-grade intraepithelial lesion or carcinoma is detected in approximately 14% of women with community-based diagnoses of AGUS who are referred for immediate evaluation. Use of refined cytological criteria and HPV DNA testing may permit improved management of women with AGUS.

Dysphagia as an initial complaint in rheumatoid arthritis is rare. We describe the case of a 69-year-old woman with rheumatoid arthritis who presented with a 2-day history of acute dysphagia. Our evaluation revealed the cause of the dysphagia was the presence of rheumatoid pannus that involved the anterior cervical spine and compressed the esophagus. Although the otolaryngologic manifestations of rheumatoid arthritis usually relate to synovial involvement of the temporomandibular and cricoarytenoid joints, our case establishes that a rheumatoid pannus on the anterior cervical spine can cause dysphagia. We believe that this may be the first reported case of this clinical entity.

Objective: To identify potential missed opportunities and to suggest interventions for cervical cancer screening in members of a prepaid health plan by examining the membership histories and medical records of women who had no Pap smear performed in the 3 years prior to the diagnosis of ICC., Methods: Medical records of all 642 members of a prepaid health plan developing ICC during the period from 1988 to 1994 were reviewed and details of patient interaction with the health care system were abstracted. Assessment of screening history and history of clinic visits was limited to the period 36 months prior to diagnosis, but excluded the last 6 months prior to diagnosis, so as to avoid including smears or visits which were part of the evaluation that led to the recognition of ICC., Results: Of women developing ICC, 384/642 (60%) had not had a smear in the period from 36 months to 6 months preceding the diagnosis. Of these 384 unscreened women, 241 (63%) had been insured by our HMO for at least 30 of the 36 months prior to diagnosis. Contact with the medical system in one of the primary care outpatient clinics was documented in 180/241 (75%) of these long-standing members during the specified period. Considering only Internal Medicine and Family Practice clinic visits, 169/241 (70%) had been seen at least once and 101/241 (42%) had been seen 3 or more times., Conclusion: Most long-standing HMO members developing ICC without benefit of recent Pap smear screening were seen in primary care outpatient clinics in the 3 years preceding their diagnosis., (Copyright 1998 Academic Press.)

The novel aminosterol, squalamine, inhibits angiogenesis and tumor growth in multiple animal models. This effect is mediated, at least in part, by blocking mitogen-induced proliferation and migration of endothelial cells, thus preventing neovascularization of the tumor. Squalamine has no observable effect on unstimulated endothelial cells, is not directly cytotoxic to tumor cells, does not alter mitogen production by tumor cells, and has no obvious effects on the growth of newborn vertebrates. Squalamine was also found to have remarkable effects on the primitive vascular bed of the chick chorioallantoic membrane, which has striking similarities to tumor capillaries. Squalamine may thus be well suited for treatment of tumors and other diseases characterized by neovascularization in humans.

Objective: To evaluate the magnetic resonance imaging results (MRI) of patients with electronystagmography (ENG) suggestive of central vestibular dysfunction and to determine if MRI abnormalities correlate with ENG findings., Study Design: Retrospective blinded case review., Setting: A regional neurotology center., Patients: Patients with ENG suggesting central vestibular dysfunction were identified (n = 30). An age-matched group of patients with normal ENG results were used as controls (n = 28)., Main Outcome Measures: MRI abnormalities in cerebellum, brain stem, cerebellar peduncles, and central ENG findings., Results: Twenty-one patients with abnormal MRI results of the vestibular pathway were found, 15 with abnormal and 6 with normal ENG results. MRI correlation with ENG findings has a better predictive value in older patients than in younger patients. Sixteen patients had MRI evidence of vascular compression, seven of whom had abnormal and nine of whom had normal ENG results., Conclusions: This study suggests that a detailed review of MRI images of the vestibular pathway is warranted, and, in patients with central ENG abnormalities, MRI may support the diagnosis of central vestibular dysfunction. MRI cannot support central vestibular dysfunction caused by vascular compression.

The diazabicyclic amino acid phosphonate 15, [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid, was identified as a potent NMDA antagonist. It contains the alpha-amino acid bioisostere 3,4-diamino-3-cyclobutene-1,2-dione and an additional ring for conformational rigidity. Compound 15 was as potent as CGS-19755 (5) in the [3H]CPP binding assay, the stimulated [3H]TCP binding assay, and the NMDA-induced lethality model in mice. A single bolus dose of compound 15, administered intravenously following permanent occlusion of middle cerebral artery (MCA) in the rat, reduced the size of infarcted tissue by 57%. Structure-activity relationship (SAR) studies have indicated that the six- and eight-membered ring derivatives had diminished activity and that the two-carbon side chain length was optimum for NMDA receptor affinity. Substitution on the ring was found to be counterproductive in the case of sterically demanding dimethyl groups and of no consequence in the case of an H-bonding hydroxyl group. Replacement of the phosphonic acid group by either a carboxylic acid or a tetrazole group was unproductive. The potent bicyclic NMDA antagonists were synthesized efficiently by virture of their achiral nature and the ease of vinylgous amide formation from squaric acid esters. Compound 15, being a unique NMDA antagonist structural type with a favorable preclinical profile, may offer advantages over existing NMDA antagonists for the treatment of neurological disorders such as stroke and head trauma. Compound 15 is currently under clinical evaluation as a neuroprotective agent for stroke.

Objective: Primary surgical resection of locally advanced squamous cancer of the vulva may compromise the integrity of important midline structures such as the anus, clitoris, urethra, and vagina. Chemoradiation (synchronous radiation and cytotoxic chemotherapy) has been used as alternative initial treatment which may serve as definitive management for some patients, or may reduce the scope and functional sequelae of subsequent surgery in others. Inguinofemoral node dissection is associated with substantial risk of both acute and late morbidity, prompting consideration of elective inclusion of groin nodes within the irradiated volume and deletion of subsequent groin surgery. Concern that disease relapse in the groins is potentially fatal suggested the prudence of formal outcome assessment of our recent experience with prophylactic treatment of clinically uninvolved groin nodes in the context of concurrent chemoradiation for locally advanced primary vulvar cancer., Methods: A review was conducted of 23 previously untreated patients with locally advanced squamous cancer of the vulva (2 T2, 20 T3, 1 T4) and clinically uninvolved groin nodes (1969 FIGO stages 14 N0, 4 N1, and 5 N2 with negative node biopsies) who were treated since 1987 with chemoradiation administered to a volume electively including bilateral inguinofemoral nodes. These patients did not undergo subsequent groin surgery., Results: With follow-up from 6 to 98 months (mean, 45.3 months; median, 42 months), no patient has failed in the prophylactically irradiated inguinofemoral nodes. No patient has developed lymphedema, vascular insufficiency, or neurological injury in a lower extremity, and no patient has experienced aseptic necrosis of a femur., Conclusions: Elective irradiation of the groin nodes in the context of initial chemoradiation for locally advanced vulvar cancer is an effective therapy associated with acceptable acute toxicity and minimal late sequelae. It constitutes a sensible alternative to groin dissection in this patient population., (Copyright 1997 Academic Press.)

Objective: To catalog a series of rare lesions of the posterior fossa that appeared with unusual initial retrocochlear symptoms and signs and to make the reader more aware of these unusual lesions with a view to improving initial assessment and treatment planning., Study Design: The study was a retrospective case review of seven patients., Setting: Multidisciplinary team evaluation in a tertiary hospital referral center., Patients: Patients with unusual lesions of the cerebellopontine angle and posterior fossa with initial retrocochlear symptoms and signs were included., Interventions: Diagnostic and therapeutic., Main Outcome Measures: Hearing preservation and balance function., Results: The rare lesions presented include two aneurysms of the anterior inferior cerebellar artery, one giant basilar artery aneurysm, and one each of the following neoplasms: endodermal cyst, choroid plexus papilloma, cavernous angioma, and ependymoma., Conclusions: A close working relationship among the otolaryngologist, neurotologist, neurosurgeon, and neuroradiologist is necessary to accurately evaluate these unusual cerebellopontine angle lesions and effect the best treatment outcome.

Analogs of the aminosterol antimicrobial agent squalamine have been synthesized beginning from hyodeoxycholic acid. After carboxylic acid esterification and oxidation of both alcohol functions to ketones, the A/B ring junction was converted from cis to trans by acid-catalyzed isomerization. Different polyamines were added to the 3-keto group by reductive amination, yielding both the 3 alpha and 3 beta addition products. The synthetic products exhibited potent, broad-spectrum antimicrobial activity similar to that of the parent compound. Changing the identity of the polyamine or the stereochemistry of addition has little effect upon antimicrobial activity but appears to change the selectivity of the agents. The analogs are synthesized with high yield from inexpensive starting materials and are promising alternatives to squalamine as potential antibiotics.

NF-kappa B is a potent transcriptional activator that resides in latent form in the cytoplasm complexed to its inhibitor I kappa B. Phosphorylation of I kappa B by protein kinase C (PKC) releases NF-kappa B, enabling its translocation to the nucleus. Since PKC can activate NF-kappa B and PKC is activated by long-term potentiation (LTP), we investigated NF-kappa B expression after hippocampal LTP induced in vivo. We first described the expression of the NF-kappa B subunits, p50 and p65, and I kappa B alpha mRNAs, in each cell field of the hippocampus. In other brain locations I kappa B alpha mRNA exhibited a more selective expression than p50 and p65. We then demonstrated specific NF-kappa B-like DNA-binding activity in hippocampal whole-cell extracts and in synaptosomes using electrophoretic mobility shift assays by the following criteria: (1) latent binding was revealed after deoxycholate treatment; (2) binding was competed off by unlabeled kappa B oligonucleotides; and (3) antibodies to either p50 or p65 blocked binding. Since p50 gene expression is auto-regulated by NF-kappa B, we used its expression as a reporter for NF-kappa B activity using quantitative in situ hybridization. Both p50 and p65 increased their expression in response to either LTP-inducing or low-frequency control stimulation, although the increase in p65 mRNA levels was greater after LTP than control stimulation. In contrast to p50 and p65, I kappa B alpha hybridization levels were not increased, but were inversely correlated with the magnitude of LTP. Since NF-kappa B subunit gene expression in the hippocampus is increased by augmented synaptic activity, NF-kappa B activation may contribute to alterations in target gene expression that accompany activity-dependent synaptic plasticity, but only in a combinatorial fashion with other transcription factors.

The presence in hippocampus of a basic helix-loop-helix (bHLH) family of transcription factors (TFs) specifically binding in an electrophoretic mobility shift assay (EMSA) to the E-box recognition element was established by selective blockade of binding both by cold competition and by an antibody to MyoD1, an E-box TF. Protein source was from a micro-dissected preparation enriched in hippocampal granule cells. Specific E-box binding of hippocampal transcription factors was significantly reduced in kainate acid (KA) treated animals. This was observed at 24 and 72 h, but not before (3, 6 h) or after (96 h). This is the first report to our knowledge to study functional regulation of E-box binding protein in adult hippocampus. To determine the generality of this E-box regulatory event, we studied four other situations, in addition to kainate treatment, where axonal growth is known or has been suggested to increase: NGF treatment of PC12 cells, unilateral hilar lesions, long-term potentiation after 1 h, and postnatal rat hippocampal development. In all four cases, decreased E-box binding was observed. The recent link of F1/GAP-43 mRNA induction in hippocampal granule cells by KA to growth of their axons, the mossy fibers in the adult rat, suggests a potential role for the F1/GAP-43 5' flanking promoter region in regulating neurite outgrowth. Since in all cases decreased E-box binding preceded increased F1/GAP-43 mRNA expression, it is suggested that E-box binding to the F1/GAP-43 promoter in hippocampal granule cells could negatively regulate F1/GAP-43 gene expression. Indeed, analysis of recognition elements on the F1/GAP-43 gene revealed an arrangement, previously described in other genes, of multiple adjacent E-box elements. E-box binding of bHLH transcription factors is likely to occur on several different genes in addition to F1/GAP-43. It is, therefore, attractive to think that E-box binding is regulated by in vivo activation of the adult brain and that this gene regulatory event participates in the orchestration of molecular and cellular responses underlying axonal growth.

Women with recurrent endometrial carcinoma are usually not considered candidates for pelvic exenteration. To assess the efficacy of this procedure, the records of all patients undergoing pelvic exenteration for adenocarcinoma of the endometrium at four institutions from 1955 through 1988 were reviewed. Of the 31 procedures performed, 7 were for primary therapy and 4 were judged to be palliative in nature and were excluded from analysis. Of the 20 patients with recurrent endometrial cancer who underwent exenteration with curative intent, all had previously received pelvic radiotherapy, 14 as part of their primary treatment and 6 as part of the treatment of recurrent disease. Six of 20 patients also received chemotherapy or hormonal therapy prior to exenteration. The median patient age was 65 years (range 44-79 years). At most recent follow-up, 8 patients were alive and disease free, 2 were alive with disease, 6 had died of disease, and 4 had died of other causes. The median follow-up of living patients is 89 months. Twelve of 20 patients experienced major complications, the most common of which was neovaginal flap necrosis. Of the 20 patients, 1 patient (5%) died in 1963 of surgical complications. The Kaplan-Meier estimate of 5-year disease-free survival is 45%. Pelvic exenteration can produce an acceptable rate of disease-free survival in highly selected patients with local recurrence of endometrial adenocarcinoma who have exhausted other treatment modalities.

Review of the records of all patients undergoing radical hysterectomy for cervical cancer at our institution between 1956 and 1985 revealed 121 patients with stage IB or IIA lesions and metastasis to pelvic lymph nodes. A uniform part of our surgical practice is to record the findings from visual and palpatory examinations of the intra-abdominal and retroperitoneal structures at the beginning of the operative report. This information was available for 117 of 121 patients. Of these 117 patients, 51 (44%) had pelvic lymph nodes palpably involved with metastatic malignant disease at the time of exploration. The Kaplan-Meier estimate of 5-year disease-free survival for this group was 40% (median follow-up of disease-free patients was 20.5 years). Adjuvant pelvic radiotherapy was received by 29 of the 51 patients. The remaining 22 patients received no adjuvant treatment. Information on the sites of recurrence was available for 30 of 32 patients who had recurrence. The site of first recurrence included an extrapelvic component in 22 of the 30 (73%). Disease-free survival rates for these patients reflect the advanced nature of their tumors. In light of our experience and our current understanding of the relationship between radiotherapy dose, tumor volume, and efficacy, we regard the assertion that primary radiotherapy is preferable to surgery in this population to be counterintuitive, and we await with interest data demonstrating that disease-free survival with approaches that involve leaving macroscopic tumor on the pelvic sidewall is superior to that noted above.

Because of the well-documented morbidity of radical hysterectomy, it would appear desirable to isolate a subset of patients at low risk of parametrial spread or disease recurrence who might thereby be candidates for less radical surgical therapy. To this end, the records of all patients undergoing radical hysterectomy for cervical carcinoma at our institution between 1956 and 1985 were reviewed. Of the 387 patients treated for squamous carcinoma clinically confined to the cervix, 83 (21.4%) had tumors with depth of invasion greater than 3 mm (stage IB) but volume of tumor less than or equal to that of a sphere 2 cm in diameter (4.19 cm3) and no tumor in angiolymphatic spaces. Of the 83 patients, none had parametrial nodal metastasis. Median follow-up of this subgroup was 9.8 years, and the Kaplan-Meier estimate of 5-year disease-free survival was 97.6% (95% confidence interval, 94.3-100%). We consider patients in the subset described above to be candidates for modified radical hysterectomy and pelvic lymphadenectomy, with a decrease in morbidity associated with the less radical dissection, a low risk of failure to excise occult parametrial tumor, and the expectation of an excellent chance of long-term disease-free survival.

Background: Amiodarone-induced thyrotoxicosis (AIT) is a rare disorder that is frequently refractory to conventional pharmacologic therapy., Methods: An analysis of seven patients who underwent thyroidectomy for control of AIT between 1987 and 1993 was completed to examine the clinical manifestations and the indications for surgical therapy., Results: Five men and two women, 53 to 72 years of age, had AIT after 3 to 55 months of amiodarone treatment (mean, 21 months). The primary manifestations of AIT were ventricular tachycardia (five), exacerbation of chronic pulmonary disease (one), and occult hyperthyroidism (one). Medical therapy included propylthiouracil in doses up to 1200 mg/day in five patients, a beta-receptor antagonist in three, and withdrawal of amiodarone in five. Near-total or total thyroidectomy resulted in resolution of thyrotoxicosis in all patients. Morbidity included pneumonia (one) and cardiac dysrhythmias (two). One patient died of ventricular dysrhythmias 4 months after thyroidectomy. The mean thyroid weight was 50 gm (range, 17 to 216 gm). Microscopic examination showed destructive follicular lesions with fibrosis in all patients. Associated thyroid pathologic condition included multinodular goiter in four patients and a follicular adenoma in one., Conclusions: AIT may be clinically occult or manifested by unusual symptoms requiring a high index of suspicion for diagnosis. Near-total thyroidectomy is safe and effective in producing rapid resolution of AIT and is indicated for the initial treatment of patients who present with a resurgence of life-threatening cardiac arrhythmias and for all patients with AIT refractory to medical therapy.

The effects of aerobic exercise on the fitness level of adults with physical disabilities were examined in this research. Twenty-one individuals participated in a pretest-posttest research design that compared the effects of an aerobic exercise program upon experimental and control subjects, specifically, on body weight, resting, and exercise cardiorespiratory and metabolic parameters, and physical work capacity. Results indicate that aerobic exercise significantly improved physical work capacity by 23.1% and cardiorespiratory fitness as measured by maximal pulmonary ventilation and maximal oxygen consumption by 16.1% and 23.7% respectively, for the experimental group. In contrast, the control group demonstrated declines in these variables of 10.3%, 8%, and 17.1%, respectively. Findings from this research highlight the importance of exercise in promoting fitness and preventing secondary disabilities in adults with physical disabilities.

The behavioral regulation of transcription factor function in hippocampus, a brain region activated by novelty and important for information storage, has not been previously studied. Sixty min after a 4 min exploration of a novel space by adult albino rats, electrophoretic mobility shift assays revealed a selective increase in specific binding to particular consensus recognition elements. For both AP-1 and CRE, an upper and lower band were observed in the electrophoretic mobility shift assay. The upper band showed increased binding restricted to the 60 min time point after exploration; no increase was observed 30 min or less, or 120 min or more after the novel experience. Increased binding to the lower of either AP-1 or CREB was observed at 30 and 120 min. When the time of exploration was increased from 4 to 15 min, no alterations in either the upper or lower band were observed in the transcription factor binding to either the AP-1 or the CRE element. Since the animals ceased to explore the environment after 10 min, the lack of binding may reflect behavioral habituation, leading to transcription factor deactivation. We conclude that brief, naturalistic stimulation can activate brain transcription factors in a time-delimited fashion, suggesting post-translational control of protein-DNA binding. We propose that promoter elements of target genes critically involved in the storage of information are turned on by environmentally-activated transcription factors.

Eighty-four women with acuminate warts of the external genital tract were treated with two methods of laser vaporization. Patients were classified by lesion number and volume (1+, 2+, 3+). Thirty-three patients had only the lesions vaporized, whereas 51 had individual lesions vaporized followed by the "brushing" technique applied to the surrounding mucosa. Postoperative discomfort and pain were worse in those patients who had the brushing technique. The results were assessed colposcopically six to eight weeks postoperatively. Regardless of the method of laser vaporization, the majority of patients with extensive disease (2+ or 3+) had persistent lesions, although reduced in number in most instances. Patients with relatively few lesions (1+) had complete elimination of the warts whether or not brushing was employed. Based upon this study, reducing the burden of acuminate warts before laser vaporization is recommended.

Background: Although second-look laparotomy (SLL) remains the hallmark method for determining disease status after completion of adjuvant therapy, the inclusion of reassessment surgery in the treatment scheme of ovarian carcinoma has been challenged. Given the absence of prospective analyses addressing this issue, justification for continued use of SLL must demonstrate benefits regardless of the outcome of the procedure., Results: In the absence of residual disease, either the recurrence rate after SLL should be acceptably low or the outcome should permit identification of specific groups that would benefit from consolidation therapy. The characteristics associated with a significant risk for recurrence after a negative SLL include patient age, histologic grade, and the amount of residual disease after the primary cytoreduction operation. The postoperative benefits of positive SLL findings must be manifested in enhanced survival rates after secondary cytoreduction surgery, salvage therapy, or both. Recent evidence suggests that tumor reduction during SLL and contemporary salvage methods favorably influence specific subgroups of patients., Conclusions: The criteria for continued use of SLL in advanced epithelial ovarian cancer should include the availability of (and preferably prospective clinical trials for) both consolidation and salvage therapy to which all patients with ovarian cancer optimally would be afforded access.

In this report, a novel bioisostere of the alpha-amino acid, 3,4-diamino-3-cyclobutene-1,2-dione, has been incorporated into a series of compounds which are NMDA antagonists. These compounds, which are achiral and easily prepared, demonstrated good affinity at the NMDA receptor by their ability to displace [3H]CPP binding in vitro. In particular, the phosphonic acid 24 provided protection against NMDA-induced lethality in mice equivalent to 2-amino-7-phosphonoheptanoic acid (5). This was considered an encouraging result in lieu of the fact that 24, like 5, lacks the conformational rigidity of the more potent NMDA antagonists. In addition, analogs that incorporate the 1,2,4-oxadiazolidine-3,5-dione heterocycle of quisqualic acid and the unsaturation of kainic acid were prepared to explore selectivity at the non-NMDA receptor subtypes.

The perceptions of life satisfaction among adults with physical disabilities were examined in this research. Personal interviews were conducted with 790 adults who had a physical disability. Data were collected using the Center for Epidemiological Studies Depression Scale, Rosenberg's Self-esteem Scale, and the Life 3 Scale. Results from a stepwise multiple regression analysis (n = 344) indicated that leisure satisfaction was the most significant predictor of life satisfaction, explaining 42% of the variance in the life satisfaction scores for this population. An additional 11% of the variance in life satisfaction was explained by scores on financial status, self-esteem, health satisfaction, religious satisfaction, and marital status. Findings from this research highlight the role that leisure satisfaction plays in enhancing life satisfaction among individuals with physical disabilities. Furthermore, the findings suggest that leisure and life satisfaction levels are influenced by employment status and whether the disability was acquired. Discussion centers on the potential contribution that therapeutic recreation can have in the rehabilitation arena.

The prognostic significance of flow-cytometric DNA analysis was assessed in 375 stages IB and IIA squamous cell carcinoma patients treated with radical hysterectomy and lymphadenectomy at the Mayo Clinic between 1956 and 1985. Paraffin-embedded samples containing at least 20% tumor were dewaxed, rehydrated, stained with propidium iodide, and analyzed. Among 344 assessable samples, 136 (40%) were diploid and 208 (60%) were nondiploid (26 tetraploid, 158 aneuploid, and 24 polyploid). Diploid cases were further subclassified: 25 high proliferative phase (HPP) (S+G2M greater than 20%) and 111 low proliferative phase. No significant correlation was noted between DNA diploid patterns and stage, tumor size, grade, or histotype, but HPP diploid tumors had a significantly higher risk of nodal metastasis. With a mean follow-up period of 150 months, 62 patients died of disease. No significant difference was observed in survival rates (SR) between diploid and nondiploid tumors, but the subset of HPP diploid tumors had a prognosis significantly worse than that of any other group (P less than 0.01). Other significant variables included nodal metastases, parametrial extension, age, and clinical stage. While ploidy patterns did not assign additional risk to node-positive lesions, HPP diploid tumors in node-negative patients were associated with a significantly lower SR. Multivariate analyses in node-negative patients demonstrated that stage, histologic subtype, and HPP diploid patterns retained prognostic independence.

We examined nimodipine modification of bupivacaine toxicity in anesthetized male rats. Three minutes after pretreatment, group 1 (n = 11), group 3 (n = 10), and their respective control groups (n = 11 and n = 9) received intravenous bupivacaine LD50 (median lethal dose). After pretreatment, group 2 (n = 10), group 4 (n = 8), and their respective control groups (n = 10 and n = 8) received intravenous bupivacaine LD90 (90% lethal dose). Pretreatment was 200 micrograms/kg intravenous nimodipine in groups 1 and 2 and 500 micrograms/kg in groups 3 and 4. Control animals were pretreated with intravenous saline solution. Data were analyzed by chi 2-analysis and analysis of variance. Survival increased after 200 micrograms/kg nimodipine (P less than 0.05). In group 1, 9 (81%) of 11 survived compared with control animals (4 [36%] of 11). In group 2, 8 (80%) of 10 survived compared with control animals (2 [20%] of 10). Survival was not increased after 500-micrograms/kg nimodipine pretreatment. In group 3, 2 (22%) of 9 survived compared with control animals (4 [40%] of 10). In group 4, 4 (50%) of 8 survived compared with control animals (2 [25%] of 8). We conclude that nimodipine pretreatment with 200 micrograms/kg protects against fatal toxicity from LD50 and LD90 bupivacaine, but 500 micrograms/kg does not.

Both CT and MRI may play an important role in the initial assessment and subsequent management of patients with gynecologic cancer. The different capabilities of these examinations make the choice of test dependent on what portion of the body is visualized (e.g., chest, upper abdomen, or pelvis) and what information is sought. Body imaging can be scheduled appropriately when the findings from the study will have a significant impact on patient management (e.g., operative versus nonoperative management, selection of treating physician, and initial modality of treatment). However, the limitations of each modality must be appreciated. In general, a negative CT or MRI will not exclude the possibility of small volume disease involvement, and a critical positive study should, when practical, be histologically confirmed. Neither test stands alone, but each plays a role when integrated with careful clinical history, physical examination, and other laboratory and radiologic examinations.

From 1956 to 1988, 27 women (median age, 60 years) found to have occult invasive carcinoma of the cervix at total hysterectomy underwent radical reoperation consisting of radical parametriectomy, upper vaginectomy, and pelvic lymphadenectomy. Residual disease was present at reexploration in 4 (15%) of the 27 patients: in the pelvic lymph nodes in 2, in the parametrium in 1, and in the vagina and a para-aortic node in 1. All patients were followed a minimum of 18 months; there were no deaths within 3 months of operation. However, 2 (7%) of the 27 patients developed ureterovaginal fistulas. Recurrent disease was observed in 6 (22%) of the patients: 2 had successful salvage procedures, and 4 died of disease, all within 4 years of reoperation. Recurrence correlated with the presence of residual disease at reoperation and with nonsquamous histologic findings. At a median follow-up of 8.4 years, 23 of the 27 patients were alive and disease-free. The 5-year absolute survival estimate (Kaplan-Meier) was 82%. Radical reoperation can be performed safely in selected patients who have early-stage invasive carcinoma of the cervix at the time of total hysterectomy with the expectation of an acceptable rate of long-term disease-free survival.

The purpose of this study was to evaluate the effects of pretreatment with propranolol on the cardio-respiratory toxicity of bupivacaine, either plain or with epinephrine 1:200,000 (5 micrograms.ml-1) added. Adult male Sprague Dawley rats, anaesthetized with intraperitoneal pentobarbital, were divided into four groups. Groups I and III were pretreated with iv propranolol 150 micrograms.kg-1, and Groups II and IV received iv NS as a placebo. Three minutes later, rats in Groups I and II received plain 0.5% bupivacaine, 4 mg.kg-1, and Groups III and IV received 4 mg.kg-1 of 0.5% bupivacaine with epinephrine, 5 micrograms.ml-1 iv. Five of eight rats pretreated with propranolol survived (Group I), compared with uniform fatality with NS pretreatment (Group II) (P less than 0.05). Addition of epinephrine to the bupivacaine eliminated the protective effect of propranolol. All rats pretreated with propranolol (Group III) or NS (Group IV) died when given bupivacaine with epinephrine. In conclusion, acute propranolol pretreatment reduced the fatal cardiotoxicity due to iv bupivacaine in male Sprague Dawley rats, but the addition of epinephrine 5 micrograms.ml-1 to bupivacaine eliminated the protective effect of propranolol.

The purpose of our study was to examine the effect of intravenous (IV) nicardipine pretreatment (30 micrograms.kg-1), given three minutes before an IV bolus of bupivacaine to determine its effect on the incidence of fatal bupivacaine cardio-respiratory toxicity in adult male Sprague Dawley rats anaesthetized with intraperitoneal pentobarbital. Fifty rats were divided into four groups. Groups I and II (n = 10 each) received 3.5 mg.kg-1 0.5 per cent bupivacaine and Groups III and IV (n = 15 each) received 5.0 mg.kg-1, 0.5 per cent bupivacaine. Groups I and III received pretreatment with normal saline before bupivacaine, whereas Groups II and IV were given pretreatment with nicardipine, 30 mg.kg-1. There was no difference in the incidence of survival between the nicardipine pretreatment group and the saline placebo pretreatment group given 3.5 mg.kg-1, 0.5 per cent bupivacaine (no fatalities in either group). However, there was significant protection by nicardipine pretreatment in the group given 5 mg.kg-1, 0.5 per cent bupivacaine (13 of 15 survived, compared with only 4 of 15 in the saline pretreatment group, P less than 0.001). In conclusion, our data demonstrate that in rats given 0.5 per cent bupivacaine, 5 mg.kg-1, nicardipine pretreatment protected against fatal cardio-respiratory toxicity.

We studied the effects of epinephrine and phenylephrine on the cardiorespiratory toxicity of intravenously injected bupivacaine in Sprague-Dawley rats. Our data show that both epinephrine and phenylephrine significantly increased cardiorespiratory toxicity of intravenously injected bupivacaine (P less than 0.007, X2 analyses with Yates' correction). Our data suggest that epinephrine or phenylephrine added to bupivacaine may be more toxic to cardiorespiratory systems than plain bupivacaine or epinephrine alone or phenylephrine alone when injected intravenously in rats.

A series of substituted 2-pyridinecarbothioamides was synthesized and evaluated for gastric mucosal protectant activity in the rat. Out of this investigation N-(3,5-difluorophenyl)-2- pyridinecarbothioamide (23, AY-31,574) was identified. This compound was much more potent than sucralfate and ranitidine against ethanol-induced lesions. Compound 23 was equipotent with ranitidine against gastric injury caused by stress. Unlike ranitidine, 23 was found to be devoid of antisecretory activity in the pylorus-ligated rat model, making it a selective mucosal protectant. Such a potent selective mucosal protectant may provide a novel clinical approach in treating ulcers.

Chronic massive pancreatic pleural effusion is an uncommon and often unrecognized clinical syndrome which results from an internal pancreatic fistula and usually presents as an exudative effusion of unknown cause. The effusion frequently occurs without clinical evidence of pancreatitis, but occasionally it may be associated with a pseudocyst of the pancreas. Chronic massive pancreatic pleural effusion is usually recurrent and characterized by very high levels of amylase in the pleural fluid. Morbidity and mortality are reduced when a definite diagnosis is established and appropriate therapy rendered. In this report, three cases of chronic massive pancreatic pleural effusions are presented. Two of the three had no demonstrable pancreatic disease, and the condition responded to conservative therapy. The third patient had a pancreatic pseudocyst and an internal pancreatic fistula which was corrected only after multiple surgical procedures.

A series of 38 patients 65 years of age or older who underwent Wertheim hysterectomy for primary treatment of stages IB and IIA (FIGO) carcinoma of the cervix is reported. There were no ureteral fistulas and no perioperative mortality, but 4 of the patients required reoperation. A control population of 320 patients less than age 65 was identified who had been treated in the same fashion and who resembled the older group in regard to stage, histologic features, grade, and incidence of pelvic nodal metastasis. Transfusion requirements and incidence of postoperative lower extremity edema were similar between groups. Febrile morbidity was less frequent in the geriatric group (P = 0.03) but postoperative small bowel obstruction (P = 0.01), bladder dysfunction (P = 0.06), and pulmonary emboli were more frequent (P = 0.11). Five-year cancer-specific Kaplan-Meier survival estimates were 84 and 85% for the geriatric and younger patient populations, respectively.

In a retrospective study conducted at the University of Alabama at Birmingham, the University of Michigan, and the Mayo Clinic, 185 patients with previously untreated FIGO stage IB and IIA squamous cell carcinoma of the cervix were found to have nodal metastasis at the time of radical hysterectomy and pelvic lymphadenectomy. Of these patients, 103 received adjuvant pelvic irradiation. Cancer recurred in 76 patients; the median time to recurrence was 3.1 years. The prognostic significance of patient age, clinical stage, lesion diameter, number and location of nodal metastases, and use of adjuvant radiation therapy was determined by multivariate analysis. Only patient age (P = 0.0006), lesion diameter (P less than 0.0001), and number of nodal metastases (P = 0.0004) were noted to be significant factors in determining overall survival. Rates of recurrence were also related to these factors. Employment of these significant variables led to identification of four risk groups. In general, patients with small cervical lesions (diameter less than 1 cm) and no more than two nodes with metastases fell into the low-risk category; those patients with large cervical lesions (diameter greater than 4 cm) and more than two involved nodes fell into the high-risk category. All other patients were categorized into intermediate-risk groups. Ten-year survival was 92% in the low-risk group (n = 13), 70% in the low-intermediate-risk group (n = 66), 56% in the high-intermediate-risk group (n = 66), and 13% in the high-risk group (n = 20). This risk group classification identifies subgroups of early-stage cervical carcinoma patients found to have nodal metastasis at the time of radical hysterectomy that warrant appropriately selected adjuvant therapy.

Therapeutic Recreation is being increasingly recognized as a valuable element of a total rehabilitation approach. In order to be effectively utilized as a treatment tool however, recreation must be approached in a scientific manner which gears activities to individual skills, interests and rehabilitation goals. Many programs in the past have been based primarily on what the therapeutic recreation specialist thought was best, rather than relying on objective analysis of client needs. In actuality this should not be the case. A more scientific approach is evolving as professionals learn more about the physical and psychological ramifications of recreation participation. Analysis of activity demands and outcomes can be used to match participation with client needs and interests to provide a recreation program that is truly rehabilitative as well as enjoyable. This manuscript provides a review of the benefits of Therapeutic Recreation and describes why it is important to utilize scientific and objective criteria in program planning. A number of models are identified that have developed systems approaches to Therapeutic Recreation programming. A recent model, developed at New York University, is described in detail and some projections for the future are made.

In a retrospective study, 185 patients with previously untreated stage IB or IIA (International Federation of Gynecology and Obstetrics) squamous cell carcinoma of the cervix were found to have pelvic nodal metastasis at the time of Wertheim hysterectomy and bilateral pelvic lymphadenectomy. Of these patients, 103 received adjuvant whole-pelvis irradiation and 82 received no adjuvant therapy. Median dose of pelvic irradiation was 5000 cGy. Among the irradiated patients, in 75% the dose was 5000 cGy or greater. Matching irradiated and nonirradiated patients according to stage, tumor size, and number and location of positive nodes yielded 60 pairs. Mean length of follow-up was 3.9 years for the 60 irradiated patients and 5.8 years for the non-irradiated patients. Kaplan-Meier overall and cancer-specific survival estimates for the two groups were not significantly different (P greater than 0.30). During the follow-up period, 21 surgery-only patients and 22 patients treated with adjuvant radiotherapy had recurrence, but adjuvant radiotherapy decreased the proportion of recurrences occurring in the pelvis alone--27% compared with 67% in the surgery-only group (P = 0.01).