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Objective: The primary goal of this work was to determine the relative importance of sarcoplasmic reticulum inositol 1,4,5-triphosphate receptors and ryanodine receptors in the mechanism of intracellular calcium wave propagation in human uterine myocytes. A secondary goal was to identify the rate-determining step of calcium wave propagation., Study Design: Pregnant human myometrium was obtained at the time of cesarean delivery, enzymatically dispersed, and cultured through several passages. Intracellular calcium wave velocities were measured with video fluorescence microscopy and the calcium-dependent fluorescent dye calcium green 1. Experimental conditions were modified by exposure of the cells to ruthenium red (blocked ryanodine receptor), ryanodine (locked open ryanodine receptor), oxytocin (increased inositol-1,4,5-triphosphate), sodium butyrate (intracellular acidification), ammonium chloride (intracellular alkalinization), and elevation of temperature (from 19 degrees C to 30 degrees C)., Results: Wave velocities were found to be the same for spontaneously occurring (9.6 +/- 2.6 microm/s) and oxytocin-stimulated (10.3 +/- 3.4 microm/s) waves. Advance treatment of the cells with ryanodine or ruthenium red failed to change oxytocin-stimulated wave velocities from control values. The temperature dependence of calcium wave velocities was studied across the range 19 degrees C to 30 degrees C. Plots of wave velocities versus the inverse of the temperature yielded apparent activation energies that were the same for spontaneous (13.2 +/- 0.3 kcal/mol) and oxytocin-induced (14.3 +/- 1.6 kcal/mol) waves. After intracellular acidification by treatment with butyrate (20 mmol/L) wave velocities increased by 44%. Wave velocities decreased by 35% after treatment with ammonium chloride (20 mmol/L)., Conclusion: Propagation of intracellular calcium waves in cultured human uterine myocytes exhibited mechanisms of sarcoplasmic reticulum calcium release that could use either inositol 1,4,5-triphosphate receptors alone or ryanodine receptors alone, or both together. The rate-determining step for calcium wave propagation was diffusion of calcium though a highly buffered cytoplasm.

Objective: Indomethacin, an inhibitor of cyclooxygenase types 1 and 2, and nimesulide, a cyclooxygenase 2 selective inhibitor, are both well-known inhibitors of prostaglandin production. It has been assumed that the tocolytic mechanism of nimesulide and indomethacin is only through decreased prostaglandin production. The purpose of this study was to test the hypothesis that either nimesulide or indomethacin, or both, has a mechanism of action on human myocytes other than inhibition of prostaglandin production., Study Design: Human uterine myometrium was obtained from consenting patients during cesarean deliveries. Myocytes were cultured, plated, and loaded with a calcium-dependent fluorescent dye, calcium green 1. The relative concentrations of intracellular free calcium were determined by measurement of time-dependent fluorescence changes by means of a video fluorimeter. In all experiments, cells were stimulated with prostaglandin F2alpha, 30 micromol/L. Experiments were performed without pretreatment (control) or with pretreatment consisting of indomethacin, 10 micromol/L, or nimesulide, 30 micromol/L. The percentages of cells demonstrating calcium increases were counted and compared by means of the Fisher exact test. A P value =.05 was considered significant., Results: After prostaglandin F2alpha exposure, 33% of cells showed an increase in intracellular free calcium under control conditions. When pretreated with nimesulide, 39% of cells responded to prostaglandin F2alpha (P =.59). When pretreated with indomethacin, only 16% of cells responded to prostaglandin F2alpha (P =.019)., Conclusions: Pretreatment with nimesulide failed to reduce the fraction of cells that responded to prostaglandin F2alpha. In contrast, pretreatment with indomethacin significantly reduced the fraction of responding cells. These data suggest that, in vitro, indomethacin exhibits a mechanism of tocolysis other than inhibition of prostaglandin synthesis.

Results of pulmonary function tests (as an indicator of respiratory health) are from 11 to 13 percent lower in African Americans and other racial ethnic populations than in Caucasians when controlled for gender, age, and height. Environmental factors influencing these indices are circadian variation, altitude, air pollutants, technology, state of nutrition, smoking history, and other indicators of lifestyle. A combination of subtle, genetically determined anthropometric variants may also be operative, the extent of which is controversial. Population-based, population-specific standards are required to avoid erroneous diagnosis of cardiorespiratory disease, erroneous assessment of operative risk, unfair hiring practices when lung function tests are used for preemployment evaluation in dusty occupations, and unfair labeling when workers apply for disability compensation. Tailoring of statistical prediction standards from simple linear to more complex polynomial regression models will increase the accuracy of population prediction standards for pulmonary function variables into the 21st century.

Drawing on E. Goffman's concepts of face and strategic interaction, the authors define a tease as a playful provocation in which one person comments on something relevant to the target. This approach encompasses the diverse behaviors labeled teasing, clarifies previous ambiguities, differentiates teasing from related practices, and suggests how teasing can lead to hostile or affiliative outcomes. The authors then integrate studies of the content of teasing. Studies indicate that norm violations and conflict prompt teasing. With development, children tease in playful ways, particularly around the ages of 11 and 12 years, and understand and enjoy teasing more. Finally, consistent with hypotheses concerning contextual variation in face concerns, teasing is more frequent and hostile when initiated by high-status and familiar others and men, although gender differences are smaller than assumed. The authors conclude by discussing how teasing varies according to individual differences and culture.

The plasma membrane contains the key elements for the control of coupling excitation to contraction in smooth muscle. The superficial calcium buffer barrier, initially proposed by van Breemen for vascular smooth muscle, may participate in the regulation of calcium entry in other smooth muscle types. To investigate the relationship between the sarcoplasmic reticulum (SR) and the plasma membrane in myometrial smooth muscle cells, we performed experiments using videofluorescence imaging and cell-attached electrophysiology. The cell-attached patch was used as a reporter for the free calcium in the subplasmalemmal space by monitoring openings of the Maxi-K channel. Calcium green-1 was used to simultaneously monitor changes of the deep cytosolic calcium concentrations. The cell with the patch attached was stimulated via an intercellular calcium wave from an adjacent cell. In this fashion, release of SR calcium was accomplished with minimal disturbance of the plasma membrane and the subplasmalemmal space of the cell studied. With physiological bathing solution, six of seven calcium waves activated Maxi-K channels. Surprisingly, the Maxi-K channels began opening 6.3 +/- 4.7s (range 2.6-15.0s) after the wave passed the pipette location. When plasma membrane calcium fluxes were inhibited with 100 microM lanthanum, no Maxi-K channel openings were observed in six of seven experiments. These results are best explained by a subplasmalemmal space in which the calcium concentration is largely controlled by store-operated channels. These results suggest the superficial buffer barrier as merely one aspect of subplasmalemmal regulation of calcium dynamics, and emphasize the importance of store-operated calcium channels during dynamic calcium changes.

Objectives: Since plasma protein binding of tricyclic antidepressants may be relevant to treatment effects and can be influenced by age-associated factors, we examined both plasma ultrafiltrate and total concentrations of nortriptyline (NT) in patients and compared these to age. We hypothesized negative associations with age of both ultrafiltrate NT and the ratio of ultrafiltrate NT to total plasma NT., Methods: Patients with major depression at a psychiatric service treated with a stable dose of NT were studied. Trough plasma ultrafiltrate NT concentrations and total plasma NT concentrations were measured by high performance liquid chromatography. Concentrations were corrected for dose., Results: Eighty-seven patients aged 26 - 88 years were studied. Ultrafiltrate NT concentrations and the ratio of ultrafiltrate NT to total NT concentrations were both significantly negatively associated with age. Total NT concentrations were not significantly associated with age., Conclusions: Relatively low ultrafiltrate NT concentrations in older patients may reflect lower tissue exposure at a given total plasma NT concentration. This could be relevant to toxic and therapeutic effects. Studies of relationships between non-bound drug concentrations and NT treatment outcomes across the age span are needed., (Copyright 2000 John Wiley & Sons, Ltd.)

Problem: To ascertain if cervical epithelial epidermal growth factor receptor (EGF-R) and serum insulin-like growth factor II (IGF-II) levels are potential markers for cervical cancer., Method of Study: We tested cervical biopsies obtained from 18 controls, 3 women with cervical intraepithelial neoplasia (CIN) I, 17 women with CIN II and III, and 12 women with cervical cancer for EGF-R using a quantitative immunofluorescent antibody assay. We measured serum IGF-II levels using an enzyme-linked immunosorbent assay in 20 controls, 26 CIN patients, 12 with cervical cancer before therapy, 5 with cervical cancer for < 1 year, and 9 others > 1 year after therapy., Results: The levels of cervical EGF-R in women with CIN and cervical cancer were significantly higher (P<0.05 for CIN I; P<0.001 for patients with CIN II and III or cervical cancer) than in controls. Women with cervical cancer (P<0.001 vs. controls) or advanced CIN (P = 0.03) had elevated levels of serum IGF-II, while the women with CIN I had levels similar to controls. Women with cervical cancer in the post-therapy period had significantly lower serum IGF-II levels than the women with cervical cancer before therapy (P<0.001)., Conclusion: Cervical epithelial EGF-R and serum IGF-II levels may be used for the diagnosis and prognosis of cervical cancer.

Oxyhemoglobin dissociation curves measure the most important function of red blood cells - the affinity for oxygen and its delivery to the tissues. This function may be deranged in sickle cell anemia and some other hemoglobinopathies. An automated oxyhemoglobin dissociation curve analyzer constructed dissociation curves in 55 patients with hemoglobinopathies and in 24 control subjects while maintaining constant temperature and pH. Sigmoid curves were converted to rectilinear ones using the Hill equation. Oxygen affinity of red cells was assessed by calculation of P50 (the PO2 at which hemoglobin is half saturated). Results revealed separation of oxyhemoglobin dissociation Hill plots according to phenotype but with wide variability. Mean oxygen affinity of fetal hemoglobin was greatest, whereas that of sickle hemoglobin was least. Other hemoglobins were intermediate. A positive correlation between decreased oxygen affinity and carboxyhemoglobin confirmed the decreased oxygen affinity of sickle hemoglobin and decreased oxygen affinity and increased diphosphoglycerate in red cells. Hill plots are less sensitive discriminators of oxygen affinity than traditional sigmoid dissociation curves and offer no particular advantage. Serial studies in a subset of three sickle cell anemia patients treated conservatively suggest automated oxyhemoglobin dissociation curves may be useful in assessment of effectiveness of newer therapies of sickle cell anemia after refinement of the method and studies of larger populations.

Problem: Over-expression of epidermal growth factor-receptors (EGF-R) has been described in a variety of cancers, including cervical cancer. Nicotine may increase cellular proliferation rates through a mechanism involving EGF or EGF-R. In this study, we ascertain the effect of EGF antibodies on nicotine-enhanced proliferation rates in two cervical cancer cell lines., Method of Study: We studied (a) nicotine-induced increase in the cellular expression of EGF-R in human papillomavirus (HPV)-positive ME-180 and HPV-negative HT-3 cervical cancer cell line cultures, using a semi-quantitative immunofluorescent antibody assay; (b) alterations in cellular proliferation in association with changes in EGF-R levels; and (c) the EGF-R mediation by EGF., Results: Nicotine exposure at physiologically attainable plasma concentrations caused increased expression of EGF-R in both cervical cancer cell lines. Up-regulation of EGF-R was associated with increased cellular proliferation. Decreased expression of EGF-R was associated with decreased cellular proliferation. These data were consistent with EGF-R expression as a mechanism for the control of proliferation of the cervical cancer cells. The action of nicotine was abrogated when antibodies to EGF were added, implying that nicotine up-regulation of EGF-R may be mediated by EGF., Conclusions: Our data show that nicotine-induced proliferation of cervical cancer cells is mediated through EGF-R over-expression and that this action of nicotine utilizes EGF.

The optimal management of early stage ovarian cancer with poor prognostic features remains controversial. On the basis of results of studies in advanced ovarian cancer, paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in combination with a platinum agent has become part of adjuvant chemotherapy trials in early stage disease. Because the optimal number of chemotherapy cycles has not been determined, the Gynecologic Oncology Group is conducting a study comparing three cycles with six cycles of adjuvant paclitaxel/carboplatin in high-risk patients with early stage ovarian cancer. At a median follow-up period of 3 years, 290 (88%) of the 331 evaluable patients on both arms of the trial were alive and recurrence free. Regimen B (treatment groups have not yet been unblinded) was associated with a somewhat higher incidence of grade 3/4 leukopenia and a markedly higher frequency of grade 2-4 neurologic toxicity. Final results from this study will reveal any difference in overall or progression-free survival between the two regimens.

This article describes the action potential-calcium wave hypothesis of uterine contractility. Two known mechanisms of intercellular tissue-level signaling are merged into a single hypothesis of organ-level signaling. This hypothesis provides a framework with which to link cellular physiology with organ function. The two mechanisms of tissue-level signaling considered are action potential propagation and intercellular calcium waves. A great body of literature exists regarding the electrical excitability of smooth muscle and myometrium. Despite this knowledge, it does not seem possible to reconcile the familiar uterine contraction profile with known parameters of cellular physiology unless a second mechanism of intercellular communication is postulated. Intercellular calcium waves fit the requirements needed for the second mechanism: slow speed, ability to raise intracellular free calcium, and ability to signal over hundreds of micrometers. The premise of the action potential-calcium wave hypothesis is that action potentials propagate rapidly throughout the uterus, initiating intercellular calcium waves. As the intercellular calcium waves propagate slowly through the bundles, myocytes are recruited to participate in the contraction. This article reviews and summarizes the literature on calcium waves in human myometrium and presents evidence to support the combination of these mechanisms. Extension of the hypothesis suggests that the functional unit of the laboring human uterus is the smooth-muscle bundle, and that the frequency and strength of uterine contractions are separate but linked physiologic characteristics of labor.

Background: This study investigated the relationship of executive and memory impairment to relapse, recurrence, and course of residual depressive symptoms and signs after remission of geriatric major depression., Methods: Fifty-eight elderly subjects remitted from major depression received continuation nortriptyline treatment (plasma levels 60-150 ng/mL) for 16 weeks and then were randomly assigned to either nortriptyline maintenance therapy or placebo for up to 2 years. Diagnosis was made using the Research Diagnostic Criteria and the DSM-IV criteria after an interview using the Schedule for Affective Disorders and Schizophrenia. Executive dysfunction and memory were assessed with the Dementia Rating Scale, disability and social support were rated with the Philadelphia Multiphasic Instrument, and medical burden was assessed with the Cumulative Illness Rating Scale., Results: Abnormal initiation and perseveration scores, but not memory impairment, were associated with relapse and recurrence of geriatric depression and with fluctuations of depressive symptoms in the whole group and in subjects who never met criteria for relapse or recurrence during the follow-up period. Memory impairment, disability, medical burden, social support, and history of previous episodes did not significantly influence the outcome of depression in this sample., Conclusions: Executive dysfunction was found to be associated with relapse and recurrence of geriatric major depression and with residual depressive symptoms. These observations, if confirmed, will aid clinicians in identifying patients in need of vigilant follow-up. The findings of this study provide the rationale for investigation of the role of specific prefrontal pathways in predisposing or perpetuating depressive syndromes or symptoms in elderly patients.

Fox Chase Cancer Center developed a format for affiliation with community providers in 1986. Fox Chase Network was formed to establish hospital-based community cancer centers to increase access to patients involved in clinical research. Under this program, the Fox Chase Network now contributes 500 patients per year to prevention and clinical research studies. As relationships with community providers form, patient referrals have increased at Fox Chase Cancer Center and for each Fox Chase Network member. A dedicated staff is required to operate the central office on a day-to-day basis as well as at each affiliate. We have found this to be a critical element in each program's success. New challenges in the cancer business-increasing volumes with declining revenue-have caused us to reconfigure the services offered to affiliates, while maintaining true to our mission: to reduce the burden of human cancer.

A high-speed hybrid optical-digital correlator system was designed, constructed, modeled, and demonstrated experimentally. This correlator is capable of operation at approximately 3000 correlations/s. The input scene is digitized at a resolution of 512 x 512 pixels and the phase information of the two-dimensional fast Fourier transform calculated and displayed in the correlator filter plane at normal video frame rates. High-fidelity reference template images are stored in a phase-conjugating optical memory placed at the nominal input plane of the correlator and reconstructed with a high-speed acousto-optic scanner; this allows for cross correlation of the entire reference data set with the input scene within one frame period. A high-speed CCD camera is used to capture the correlation-plane image, and rapid correlation-plane processing is achieved with a parallel processing architecture.

Serum alpha(1)-acid glycoprotein (AAG) reportedly can increase with age in the normal population, especially among women. In 33 patients with unipolar major depression or bipolar disorder, serum AAG was measured by age. The authors noted a positive association with age, particularly in depressed female patients (n=18; r(s)=0.61; P<0.01). The authors discuss implications for drug pharmacokinetics. Investigation of AAG in mood disorders needs to take age and sex into consideration.

The vasoactive peptide bradykinin (BK) has been implicated in the pathophysiology of a number of vascular wall abnormalities, but the cellular mechanisms by which BK generates second messengers that alter vascular function are as yet undefined. Exposure of vascular smooth muscle cells (VSMC) to BK (10(-7) M) produced a rapid and transient rise in intracellular calcium, which preceded an increase in tyrosine phosphorylation of mitogen-activated protein kinase (MAPK). MAPK activation by BK was observed as early as 1 min, peaked at 5 min, and returned to baseline by 20 min. Treatment of cells with the intracellular calcium chelator EGTA-acetoxymethyl ester inhibited BK-stimulated MAPK activation, suggesting that intracellular calcium mobilization contributes to the activation of MAPK. The calmodulin inhibitor W-7 also markedly inhibited BK-induced MAPK phosphorylation in the cytoplasm as well as in the nucleus. Moreover, the BK-induced increase in c-fos mRNA levels was significantly inhibited by the calmodulin inhibitor, indicating that calmodulin is required for BK signaling leading to c-fos induction. These results implicate the calcium-calmodulin pathway in the mechanisms for regulating MAPK activity and the resultant c-fos expression induced by BK in VSMC.

Intracellular calcium stores of human uterine myocytes in primary and second passage cell culture were visualized using the low-affinity calcium-sensitive fluorescent dye, fluo-3FF. The calcium stores appeared as numerous small (0.2-0.5 microm diameter) focal fluorescences. The stores were not depleted by exposing the cells to oxytocin or ryanodine under standard conditions. The stores were rapidly depleted by oxytocin or ryanodine exposure when sarcoplasmic reticulum (SR) calcium re-uptake was inhibited by pretreatment with thapsigargin. Immunofluorescence experiments indicated that both ryanodine and inositol 1,4,5-trisphosphate (IP(3)) receptors were smoothly distributed throughout the SR, and neither receptor co-localized with the calcium stores. Since IP(3) and ryanodine calcium channels are tightly associated with their receptor, these results suggest that SR calcium release occurs via second messenger channels that are remote from the SR calcium stores. These observations are consistent only with a mechanism for release of calcium stores where the SR serves three functions: (1) as site of calcium storage, (2) as the structure that contains the IP(3)- and ryanodine receptors and their associated release channels, and (3) as a conduit between the calcium stores and the release channels.

Objective: To establish a mouse model system of human cervical epithelium that maintains the stratified squamous architecture overlying a well-defined basement membrane., Methods: Normal cervical tissue specimens were obtained from the transformation zone of hysterectomy specimens. Small (2 mm) cubes of tissue containing stroma and epithelium were placed subdermally into severe combined immunodeficient (SCID) mice and harvested between 7 and 45 days. Specimens were examined histologically for the presence of stroma, epithelium, and basement membrane., Results: In 49 xenograft attempts in 24 mice, 35 (71%) were identified microscopically. Of these, 28 (80%) had identifiable epithelium and 20 (57%) formed cysts lined with stratified squamous epithelium. A cuboidal basal layer clearly defined the basement membrane. Proliferation within the cyst epithelium was demonstrated by expression of the Ki67 proliferation marker and the presence of mitotic figures., Conclusions: A human to mouse xenograft model system is described that maintains, in high yield, stratified squamous epithelium overlying a well-defined basement membrane. Advantages of this model system include the following: (1) The tissue originates from readily available human specimens; (2) A stratified squamous epithelial architecture is maintained for a sufficient time to study viral effects on proliferation; (3) The basement membrane of the epithelium is well defined, allowing for investigation of connective tissue factors in cervical intraepithelial neoplasia and cervical cancer.

Background: Excess brain changes in geriatric manic patients have been hypothesized. Few neuroimaging studies are available., Methods: Brain computed tomography scans in geriatric patients with manic disorder (n = 30) were compared to those in same-age control subjects (n = 18). Ratings of cortical sulcal widening (CSW), lateral ventricle-brain ratio (VBR), and related linear measures were determined., Results: Patients had greater CSW scores (Exact p = .002) and VBR (t = 2.51, df = 46, p < .02) compared to control subjects. CSW was positively associated with age at illness onset (rs = .46, p < .01) and age at first manic episode (rs = .53, p < .005). VBR was poorly correlated with CSW and was not associated with these indices of illness course., Conclusions: These findings support the need for further investigation of relationships between brain structure and clinical features in geriatric mania.

In geriatric patients with major depression (N=15), the authors compared response to treatment with nortriptyline as it relates to brain morphology assessed by computed tomography. There was a significant negative association between ventricle-brain ratio and response to nortriptyline (rs=-0.63; P=0.015).

Objective: To identify the structural elements and describe the three-dimensional microanatomy of the term-pregnant human uterus., Methods: Biopsy specimens were taken from the funduses and the lower uterine segments of two term-pregnant uteri. Tissue was sectioned serially and stained with Masson trichrome. Microscope images were captured with a digital camera, aligned, and computer-processed. Computer-assisted three-dimensional reconstruction of structures was performed., Results: Five structures were identified: 1) fasciculus-the macroscopic organization of myocytes and connective tissue, 2) cylindric bundle-300+/-100-microm diameter cylinder of densely packed myocytes, 3) sheet-like bundle-densely packed sheet of myocytes, 4) fiber bundle-a loosely packed bundle of small numbers of myocytes, and 5) communicating bridge-a large cylindric bundle that bridges adjacent fasciculi. The cylindric bundles merged, dichotomized, and intertwined with each other and with sheet-like bundles. Essentially all myocytes except those in fiber bundles were contiguous., Conclusion: The microanatomy of the term-pregnant human uterus contains clearly defined structural elements. These structures merge with each other and potentially form an interlacing network, connecting the vast majority of the myocytes of the uterus in a contiguous pathway.

Following E. Goffman's (1967) face threat analysis of social interaction, it was hypothesized that the aggressive, playful content of teasing would vary according to social status and relational satisfaction, personality, role as teaser or target, and gender. These 4 hypotheses were tested in analyses of the teasing among fraternity members (Study 1) and romantic couples (Study 2). Consistent with a face threat analysis of teasing, low-status fraternity members and satisfied romantic partners teased in more prosocial ways, defined by reduced face threat and increased redressive action. Some findings indicate that disagreeable individuals teased in less prosocial ways, consistent with studies of bullying. Targets reported more negative emotion than teasers. Although female and male romantic partners teased each other in similar ways, women found being the target of teasing more aversive, consistent with previous speculation.

About one third of the women diagnosed with ovarian cancer present with localized disease. Accurate surgical staging is required to properly evaluate these patients, define appropriate treatment, and establish prognosis. A series of recent studies have clarified which patients can be managed with comprehensive surgical staging and disease removal alone, and which may benefit from adjuvant therapy. A series of national and international prospective randomized trials are evaluating a variety of adjuvant treatments that may enhance long-term survival in those patients with early ovarian cancer who do require additional therapy.

Previously [Appl. Opt. 36, p. 9212 (1997)] we examined the performance of the linear and nonlinear preprocessed difference-of-Gaussians filter, and it was shown that this operation results in greater tolerance to in-class variations while maintaining excellent discrimination ability. The introduction of nonlinearity was shown to provide greater robustness to the filter's response to noise and background clutter in the input scene. We incorporate this new operation into the synthesis of a modified synthetic discriminant function filter. The filter is shown to produce sharp peaks, excellent discrimination without the need to include out-of-class objects, and good invariance to out-of-plane rotation over a distortion range of up to 90 degrees . Additionally, the introduction of nonlinearity is shown to provide greater robustness of the filter response to background clutter in the input scene.

The aetiology of late-onset bipolar disorder is heterogeneous because the disease is more likely to have a secondary (i.e. a medical disorder or medication-induced) cause in older than in younger patients. Elderly patients with bipolar disorder typically require lithium dosages that are 25 to 50% lower than those used in younger individuals. Information on the use of valproic acid (sodium valproate) in elderly patients with bipolar disorder is limited but encouraging. In contrast, there is virtually no information regarding the use of carbamazepine or other drugs in this patient group. Electroconvulsive therapy is well tolerated by older people and can be useful for these patients.

Objective: The purpose of this study was to determine if P300 latency is prolonged in geriatric depression and if longer P300 latency and deficits in initiation and errors of perseveration in depressed elderly patients are related to risk factors for vascular disease., Method: Geriatric patients with unipolar depression (N = 43) and elderly comparison subjects (N = 24) were assessed for depressive symptoms, cognitive functions, risk factors for vascular disease, and P300 latency., Results: Depressed elderly patients had longer P300 latency than normal elderly subjects. In the depressed patients, P300 latency was related to deficits in initiation and errors in perseveration. Risk factors for vascular disease were associated not only with P300 latency but also with deficits in initiation and errors in perseveration., Conclusions: Functional impairment of the cortico-striato-pallido-thalamo-cortical pathways from vascular disease, implicated in late-life depressive disorders, may explain not only deficits in initiation and errors in perseveration but also longer P300 latency in depressed elderly patients. These results are preliminary and need further examination with brain imaging and more sensitive neuropsychological measures.

A useful filter for pattern recognition must strike a compromise between the conflicting requirements of in-class distortion tolerance and out-of-class discrimination. Such a filter will be bandpass in nature, the high-frequency response being attenuated to provide less sensitivity to in-class variations, while the low frequencies must be removed, since they compromise the discrimination ability of the filter. A convenient bandpass is the difference of Gaussian (DOG) function, which provides a close approximation to the Laplacian of Gaussian. We describe the effect of a preprocessing operation applied to a DOG filtered image. This operation is shown to result in greater tolerance to in-class variation while maintaining an excellent discrimination ability. Additionally, the introduction of nonlinearity is shown to provide greater robustness in the filter response to noise and background clutter in the input scene.

The authors describe major depression with delusions occurring for the first time in an elderly man receiving metoclopramide and review the literature concerning metoclopramide and depression.

Objective: To establish mechanisms of intercellular communication in human myometrium other than action potential propagation., Methods: Monolayer cultured human myometrium was used as a model system. The calcium-sensitive fluorescent dye, calcium green-1, was used as a probe for the concentration of intracellular free calcium. Intercellular calcium waves were initiated by mechanical stimulation and observed with video spectrofluorimetry. This technique allowed initiation of calcium waves from a known location at a known time while simultaneously controlling the flow rate of the bathing solution across the surface of the cells. Intercellular calcium waves were observed at bath flow rates between 0 and 5.1 mL/minute through a 0.4 mL chamber. Experiments were performed using low calcium, high potassium bathing solutions to eliminate the possibility of action potential signaling., Results: In still bathing solution, calcium waves radiated symmetrically from the site of initiation. With the bathing solution flowing, two mechanisms of intercellular calcium wave propagation were observed-one dependent on and one independent of the direction of bath flow. The calcium waves that were independent of bath flow used an intracellular mechanism for intercellular communication, were only observed within 100 microns of the site of wave initiation, and demonstrated mean (+/- standard deviation [SD]) wave speeds of 14.1 +/- 2.6 microns/second. The waves dependent on bath flow used an extracellular signaling mechanism, were observed at distances much greater than 100 microns, and exhibited downstream biasing. Mean (+/- SD) wave speeds of flow-dependent calcium waves were faster under flow conditions than still bath conditions (36.0 +/- 4.7 versus 6.2 +/- 1.3 microns/second; P < .001). By exposing the cells to flurbiprofen, a water soluble prostaglandin synthetase inhibitor, both types of calcium waves were inhibited., Conclusion: Human myocytes demonstrate paracrine and intracellular signaling mechanisms for intercellular communication that are distinctly different from action potential propagation.

Purpose: To evaluate the efficacy and toxicity of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP)/doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy plus mantle-field radiation therapy in the treatment of patients with massive mediastinal Hodgkin's disease of any stage., Patients and Methods: Eighty patients presented with Hodgkin's disease and a mediastinal mass greater than one third the greatest chest diameter on chest radiograph. Patients were staged and treated with MOPP alternated with ABVD chemotherapy for a total of six cycles. Patients then received 10 Gy mantle-field radiation therapy delivered to the original extent of disease followed by 25 to 35 Gy to the residual abnormalities., Results: The complete response (CR) rate was 89%. With a median follow-up duration of 10 years, disease-free survival of the complete responders is 78% at 15 years and overall survival is 75% at 15 years. For patients with stage I or II disease, disease-free survival was 76% at 15 years and overall survival was 79%; for those with stage III or IV disease, disease-free survival was 82% at 15 years and overall survival was 64%. Age, stage, sex, B symptoms, number of extranodal sites, lactate dehydrogenase (LDH) levels, erythrocyte sedimentation rate, and platelet count did not influence treatment outcome. Treatment-related pneumonitis was noted in 16% of patients (fatal in one), mainly in those older than age 35 years who received total doses of radiation therapy greater than 42 Gy. Fertility is more often preserved with MOPP/ABVD therapy than with MOPP chemotherapy and there appears to be less pulmonary and cardiac disease than with ABVD chemotherapy. Two patients have developed second solid tumors within radiation ports and one relapsed patient developed acute leukemia after MOPP salvage therapy., Conclusion: MOPP/ABVD followed by mantle-field radiation therapy is an effective treatment for all stages of Hodgkin's disease that present with a large mediastinal mass. Our data suggest that the large mediastinal mass is a more dominant determinant of prognosis than Ann Arbor stage or other clinical prognostic factors.

We propose that cerebrovascular disease may predispose, precipitate, or perpetuate some geriatric depressive syndromes. The "vascular depression" hypothesis is supported by the comorbidity of depression, vascular disease, and vascular risk factors and the association of ischemic lesions to distinctive behavioral symptoms. Disruption of prefrontal systems or their modulating pathways by single lesions or by an accumulation of lesions exceeding a threshold are hypothesized to be central mechanisms in vascular depression. The vascular depression concept can generate studies of clinical and heuristic value. Drugs used for the prevention and treatment of cerebrovascular disease may be shown to reduce the risk for vascular depression or improve its outcomes. The choice of antidepressants in vascular depression may depend on their effect on neurologic recovery from ischemic lesions. Research can clarify the pathways to vascular depression by focusing on the site of the lesion, the resultant brain dysfunction, the presentation of depression and time of onset, and the contribution of nonbiological factors.

Objective: The purpose of this study was to examine whether the brainstem evoked responses of geriatric depressed patients with vascular disease show greater changes in wave V latency after increased stimulation than do responses of geriatric depressed patients without vascular disease and elderly comparison subjects with and without vascular disease., Method: Geriatric patients with unipolar depression (N = 53) were recruited from a university psychiatric hospital. Elderly comparison subjects (N = 23) were recruited through advertisements. All subjects were assessed for depressive symptoms, cognitive performance, overall medical burden, vascular disease, and disability. Brainstem evoked response was elicited at stimulation rates of 11.4 and 80.0 clicks/sec., Results: The interaction between depression and vascular disease had a significant effect on change in wave V latency. This effect was synergistic, more than an additive effect. Post hoc comparisons showed that the depressed patients with vascular disease had greater changes in wave V latency that did the depressed patients without vascular disease, comparison subjects with vascular disease, and comparison subjects without vascular disease. Linear discriminant function analysis showed that 82% of the subjects with abnormal changes in wave V latency (sensitivity: 75%, specificity: 81%) could be identified on the basis of ratings for depression and vascular disease., Conclusions: Demyelination afflicting the pons and mesencephalon may explain the greater change in wave V latency for the brainstem evoked response in depressed patients with vascular disease. Further studies combining brainstem evoked response with brain imaging may determine whether depression develops only after vascular disease leads to demyelination.

Sarcoidosis is a systemic granulomatous disease of undetermined etiology in which the immune system is overstimulated. Management of the patient with sarcoidosis entails continuity of patient care far beyond disease, even into remission. Care is comprehensive, including all involved organ systems, coordination of specialty consultations and services, and includes diagnostic tests. Therapeutic decisions are the responsibility of the primary care practitioner. Prognosis of sarcoidosis is not uniformly good. Patients can die. Subacute sarcoidosis patients usually do not require pharmacologic therapy. Chronic sarcoidosis may require long-term treatment for years to indefinitely. Corticosteroids are still the drugs of choice and other therapy is now available. Health organizations and private nonprofit support groups are available for patient education and assistance. Close support must still come from the family unit. Sarcoidosis may occur in family members in different cohorts at all ages in life and in any racial or ethnic group. The second in a two-part series on management of the patient with sarcoidosis, this article describes coordination of care and considers community, prevention, and family aspects of the disease.

Objective: The authors' goal was to examine the clinical presentation of a group of depressed elderly patients with clinically defined risk factors for vascular depression compared with a group of elderly depressed patients without such risk factors., Method: Cognitive deficits, disability, and depressive symptoms were examined in 33 consecutively recruited elderly patients defined as having vascular depression and 32 patients defined as having nonvascular depression according to their scores on the Cumulative Illness Rating Scale-Geriatrics., Results: The patients with vascular depression had greater overall cognitive impairment and disability than those with nonvascular depression. Fluency and naming were more impaired in patients with vascular depression, and they had more retardation and less agitation as well as less guilt feelings and greater lack of insight., Conclusions: The symptoms of vascular depression are consistent with lesions that may damage striato-pallido-thalamo-cortical pathways and other areas. The concept of vascular depression can provide the impetus for investigations of prevention and treatment of cerebrovascular disease and for studies of the course of vascular depression and selection of antidepressants.

Objective: To simulate a uterine contraction using a novel computer model for uterine communication and to validate the assumptions of the computer model by comparing the simulated contraction with a real uterine contraction., Methods: The computer model assumed two known mechanisms of intercellular communication: action potential propagation and calcium wave propagation. Simulations were performed on a desktop computer using available programming language. Model validity was assessed by fitting the computer-simulated contraction to a real contraction and comparing the fit values with values measured independently., Results: The simulated contraction demonstrated five characteristics that are also observed in human labor: 1) gradual onset, 2) a linear rising segment, 3) a plateau region, 4) a symmetrical fall, and 5) gradual offset. The fit values agreed well with values determined experimentally and supported the model., Conclusions: Our results support the model, strongly suggesting that intercellular communication occurs throughout the uterus by action potentials and locally within the tissue by calcium waves.

The authors report a case of mania occurring in a woman in late life who had begun receiving hormone replacement therapy for osteoporosis. They discuss related literature reports of mania or rapid cycling after adjunctive estrogen administration for refractory depression.

Age effects on early-onset bipolar illness may include changes in affective features and recovery. Age effects on the pharmacokinetics of lithium are clinically relevant. Average age at onset is relatively late among geriatric bipolars. Late-onset bipolar disorder is associated with lower rate of familial illness than early-onset cases and greater medical and neurologic comorbidity. The limited literature available points to the need for further studies of geriatric bipolar disorder. In such investigation, the distinction between age and age at onset effects provides a framework within which to enhance knowledge of psychopathology, to expand understanding of natural history and the impact of therapeutic interventions, and to study mechanisms.

Sarcoidosis is a systemic granulomatous disease of undetermined etiology in which the immune system is overstimulated. Management of the patient with sarcoidosis entails continuity of patient care far beyond disease, even into remission. Care is comprehensive, including all involved organ systems, coordination of specialty consultations and services, and diagnostic tests. Therapeutic decisions are the responsibility of the primary care practitioner. Prognosis of sarcoidosis is not uniformly good. Patients can die. Subacute sarcoidosis patients usually do not require pharmacologic therapy. Chronic sarcoidosis may require long-term treatment for years to indefinitely. Corticosteroids are still the drugs of choice and other therapy is now available. Health organizations and private nonprofit support groups are available for patient education and assistance. Close support must still come from the family unit. Sarcoidosis may occur in family members in different cohorts at all ages in life and in any racial or ethnic group. This article is the first in a two-part series on management of the patient with sarcoidosis in the 21 st century by the primary are provider. Applications of principles of family medicine are emphasized. Part 1 considers continuity, comprehensiveness, and coordination of care. Part 2 will complete coordination of care, and consider community, prevention, and family aspects of this disease.

Among psychiatric inpatients with primary degenerative dementia, those with psychotic symptoms (N = 20) were older than those without (N = 20) (t = 3.48; p < 0.001). Persecutory delusions were the most frequent psychotic phenomena. Duration of dementia overlapped, but scores on the Global Deterioration Scale and the Cornell Scale for Depression in Dementia were lower in the psychotic group after correcting for age. The limited literature concerning demographic and clinical correlates of psychosis in dementia is reviewed; the age difference noted is consistent with two other reports.

A prospective case-control study was undertaken to assess respiratory disability in 133 former coal miners who were claimants for "black lung" benefits. Consecutive assignment was made to either case or control group based on their chest radiograph having shown coal workers' pneumoconiosis or no coal workers' pneumoconiosis. A respiratory occupational survey was completed with physical examination that placed special emphasis on the cardiorespiratory systems. Subjects underwent pulmonary function testing while 92 of these also received arterial blood gases to assess respiratory disability and pulmonary insufficiency. Arterial blood gases were superior to spirometry in assessment of pulmonary insufficiency/disability. Smoking interacts with coal workers' pneumoconiosis to cause pulmonary insufficiency. The most frequent spirometric pattern was obstructive. Disability was caused by occupational injuries and comorbidities, both of which occurred with greater frequency in miners with coal workers' pneumoconiosis than in controls. Pulmonary insufficiency appears to be a better discriminator than respiratory disability in coal miners, suggesting that arterial blood gases replace spirometry in their evaluation. Greater emphasis on smoking intervention among coal miners should be given.

Objective: The authors' purpose was to identify the relationship of disability to clinical measures that are part of a comprehensive psychiatric examination of depressed elderly patients., Method: The disability of 75 elderly inpatients and outpatients with major depression whose cognitive function ranged from normality to mild dementia was assessed with the Philadelphia Multilevel Assessment Instrument. Age at onset of depression, chronicity of depression, severity of depression, cognitive impairment, medical burden, social support and living environment were assessed with standardized instruments., Results: Impairment in instrumental activities of daily living was significantly associated with advanced age, severity of depression, and medical burden. The relationship of depressive symptoms to impairment in instrumental activities of daily living was not influenced by age or medical burden. Anxiety and depressive ideation as well as retardation and weight loss were significantly associated with impairment in instrumental activities of daily living. Interviewer-rated global disability was associated with advanced age at onset of depression, medical burden, and overall cognitive impairment. Specifically, a disturbance in initiation and perseveration was significantly related to global disability., Conclusions: Impairment in instrumental activities of daily living appears to be a relatively independent dimension of health status that is related to depressive symptoms, particularly anxiety and depressive ideation as well as retardation and weight loss. Global disability may be associated with impairment in initiation and perseveration and with late onset of depression. These findings provide a basis for studies investigating whether psychotherapy aimed at depressive ideation and rehabilitation efforts focused on instrumental activities of daily living can improve the outcome of geriatric depression.

Intracellular calcium waves were observed in cultured human myometrium using confocal laser scanning microscopy in the epifluorescence mode. Intracellular calcium waves were observed following stimulation of the cells with 10 mU ml-1 oxytocin in physiological bathing solution, or following substitution of tetraethylammonium chloride for NaCl. Intracellular wave speeds were 18.9 +/- 8.2 microns s-1 in physiological bathing solution. Intracellular calcium waves were also observed in cells bathed in calcium-free solutions, with no significant differences in wave speeds. Calcium waves that crossed cell boundaries were also observed. Some intercellular calcium waves travelled large distances (> 500 microns). Wave speeds for intercellular waves were 7.8 +/- 1.6 microns s-1. Attempts to use octanol to determine the contribution of gap junctions to intercellular calcium wave propagation were unsuccessful because of direct effects of 2 mM octanol on calcium oscillations. These data demonstrate that intra- and intercellular calcium waves are a means of tissue level communication in myometrium that is distinct from action potentials with regard to mechanisms of action, propagation speeds, responses to stimuli, and responses to inhibitors.

Background: Clinical characteristics of depression, age at illness onset, medical burden, disability, cognitive impairment, lack of social support, and poor living conditions may influence the course of depression. This study investigates the timetable of recovery and the role of the above factors in predicting recovery in elderly patients with major depression., Methods: Recovery was studied in 63 elderly (age >63 years) and 23 younger patients with depression who were followed up for an average of 18.2 months (SD, 13.1 months) under naturalistic treatment conditions. Diagnosis was assigned according to Research Diagnostic Criteria after administration of the Schedule for Affective Disorders and Schizophrenia. The Longitudinal Follow-up Interval Examination was used to identify recovery., Results: The recovery rate of depressed elderly patients was similar to that of younger depressed patients. In the elderly patients, age, antidepressant treatment, age at onset, and chronicity of episode were significantly associated with time to recovery since entry. Among these parameters, late age at onset was the strongest predictor of slow recovery. In younger patients, long time to recovery was predicted by weak social support, younger age, cognitive impairment, and low intensity of antidepressant treatment. In the elderly, the intensity of antidepressant treatment began to decline within 16 weeks from entry and approximately 10 weeks prior to recovery., Conclusions: These findings challenge the view that geriatric depression has a worse outcome than depression in younger adults. However, depressed patients with onset of first episode in late life may be at higher risk for chronicity. Antidepressant treatment prescribed by clinicians may decline prior to recovery despite evidence that high treatment intensity is effective in preventing relapse.