Abnormal tau induces cognitive impairment through two different mechanisms: synaptic dysfunction and neuronal loss.

The hyperphosphorylated microtubule-associated protein tau is present in several neurodegenerative diseases, although the causal relationship remains elusive. Few mouse models used to study Alzheimer-like dementia target tau phosphorylation. We created an inducible pseudophosphorylated tau (Pathological Human Tau, PH-Tau) mouse model to study the effect of conformationally modified tau in vivo. Leaky expression resulted in two levels of PH-Tau: low basal level and higher upon induction (4% and 14% of the endogenous tau, respectively). Unexpectedly, low PH-Tau resulted in significant cognitive deficits, decrease in the number of synapses (seen by EM in the CA1 region), reduction of synaptic proteins, and localization to the nucleus. Induction of PH-Tau triggered neuronal death (60% in CA3), astrocytosis, and loss of the processes in CA1. These findings suggest, that phosphorylated tau is sufficient to induce neurodegeneration and that two different mechanisms can induce cognitive impairment depending on the levels of PH-Tau expression.

Comparative NMR analysis of an 80-residue G protein-coupled receptor fragment in two membrane mimetic environments.

Fragments of integral membrane proteins have been used to study the physical chemical properties of regions of transporters and receptors. Ste2p(G31-T110) is an 80-residue polypeptide which contains a portion of the N-terminal domain, transmembrane domain 1 (TM1), intracellular loop 1, TM2 and part of extracellular loop 1 of the α-factor receptor (Ste2p) from Saccharomyces cerevisiae. The structure of this peptide was previously determined to form a helical hairpin in lyso-palmitoylphosphatidyl-glycerol micelles (LPPG) [1]. Herein, we perform a systematic comparison of the structure of this protein fragment in micelles and trifluoroethanol (TFE):water in order to understand whether spectra recorded in organic:aqueous medium can facilitate the structure determination in a micellar environment. Using uniformly labeled peptide and peptide selectively protonated on Ile, Val and Leu methyl groups in a perdeuterated background and a broad set of 3D NMR experiments we assigned 89% of the observable atoms. NOEs and chemical shift analysis were used to define the helical regions of the fragment. Together with constraints from paramagnetic spin labeling, NOEs were used to calculate a transiently folded helical hairpin structure for this peptide in TFE:water. Correlation of chemical shifts was insufficient to transfer assignments from TFE:water to LPPG spectra in the absence of further information.

Relapse of depression during pregnancy following antidepressant discontinuation: a preliminary prospective study.

OBJECTIVE: Pregnancy has frequently been referred to as a time of emotional well-being for patients. However, systematic data about the risk for relapse of depression during pregnancy are sparse. METHOD: We completed a longitudinal cohort study of thirty-two (N = 32) women with histories of depression who were euthymic at conception and who either discontinued or attempted to discontinue antidepressant therapy proximate to conception. Subjects were prospectively followed across pregnancy once per trimester using structured clinical interviews. Rates of relapse and time to relapse were examined. Factors distinguishing the population with respect to risk for relapse including demographic characteristics and illness history were also examined. RESULTS: Seventy-five percent (N = 24) of patients relapsed during pregnancy. The majority of relapses (79%, N = 19) occurred in the first trimester, and relapse was more prevalent in women with histories of more chronic depression. CONCLUSIONS: Pregnancy is not "protective" with respect to risk for relapse of depression. Careful treatment planning is necessary for those women on antidepressants who plan to conceive or who become pregnant.

Sex- and age-related differences in major depressive disorder with comorbid anxiety treated with fluoxetine.

OBJECTIVE: To examine sex- and age-related differences of treatment outcome in a cohort of outpatients with major depressive disorder (MDD), with and without comorbid anxiety, treated with fluoxetine. METHODS: Outpatients with a SCID-diagnosis of MDD aged 18 to 65 years were treated openly with fluoxetine (20 mg/day) for 8 weeks. The 17-item Hamilton Depression Rating Scale (HAM-D-17) was administered at baseline, and at weeks 2, 4, 6 and 8. Remission of MDD was defined as a HAM-D-17 score < or =7 at week 8. Rates of remission and change of depressive symptoms of MDD were compared among women aged < 45 years and > or =45 years. The analyses were then repeated in men. The presence of comorbid anxiety disorders was included in the prediction model for change of depressive symptoms of MDD across age and sex. RESULTS: 176 women and 153 men were included in this analysis. Remission of MDD occurred in 57.1% and 50% of younger and older women respectively. Similar rates were present in men (57.2% and 49.1%, respectively). Age did not predict remission of depression or change of depressive symptoms of MDD, in both women and men. Anxious and non-anxious subtypes of depression did not present sex- or age-related differences in treatment outcome. CONCLUSION: In this cohort of outpatients with MDD, we observed no sex- or age-related differences in response to an 8-week treatment with the SSRI fluoxetine. Similarly, there were no age-related differences among women with anxious and non-anxious subtype of depression.

Postpartum onset obsessive-compulsive disorder: diagnosis and management.

The postpartum period is associated with an increased risk of developing obsessive-compulsive disorder (OCD) in women. Postpartum onset OCD is often undiagnosed and untreated resulting in serious consequences for the patient, her family and the newborn. The symptoms of postpartum onset OCD may consist of obsessional intrusive thoughts about harming the newborn without compulsions or with both obsessions and compulsions. In this review, the phenomenology of postpartum onset OCD is described as well as strategies for screening and diagnosis. The review also characterizes the differences between postpartum onset OCD and postpartum depression and postpartum psychosis and explores strategies for managing postpartum onset OCD patients. Issues regarding pharmacologic treatment of OCD in breastfeeding mothers are also reviewed.

A33scFv-cytosine deaminase: a recombinant protein construct for antibody-directed enzyme-prodrug therapy.

A recombinant fusion protein of colon carcinoma binding A33 single chain antibody with cytosine deaminase displayed specific antigen binding and enzyme activity in surface plasmon resonance and is catalytic activity assay. In vitro, it selectively increased the toxicity of 5-FC to A33 antigen-positive cells by 300-fold, demonstrating the potency of this ADEPT strategy.

Demographic, family, and occupational characteristics associated with major depression: the Harvard study of moods and cycles.

OBJECTIVE: This study assesses the extent to which women with and without major depression differ by demographic, familial, and occupational characteristics. METHOD: From a community-based sample, the authors identified 332 women with and 644 women without current or past major depression based on Structured Clinical Interviews for DSM-IV. Demographic and background interviews were conducted in-person. RESULTS: Depressed women were more likely to have gained >or =35 lbs between age 18 and study enrollment (OR=1.6, 95% CI 1.1-2.5), experienced divorce (OR=2.0, 95% CI 1.4-2.8), or changed occupations (OR=1.5, 95% CI 1.1-2.1) compared with non-depressed women. Compared with women with no brothers, those with > or =1 brothers were less likely to have a history of depression (OR=0.8, 95% CI 0.6-1.1), whereas compared with women with no sisters, those with > or =1 sisters were more likely to have current or past depression (OR=1.4, 95% CI 1.0-1.9). These findings were not influenced by family sibship size. CONCLUSION: These results illustrate demographic differences between women with and without major depression and that sibship gender rather than size may also influence risk.

Prevalence of body dysmorphic disorder in a community sample of women.

OBJECTIVE: In a large population-based study, the authors examined the prevalence and correlates of body dysmorphic disorder, a debilitating and chronic condition characterized by an imagined defect in appearance. METHOD: Rates and diagnostic correlates of body dysmorphic disorder were examined by using data from the Harvard Study of Moods and Cycles. This study used in-person structured clinical interviews to characterize the diagnostic status of a population-based, cross-sectional sample of 318 depressed and 658 nondepressed women between the ages of 36 and 44 who were selected from seven Boston metropolitan area communities. RESULTS: The presence of body dysmorphic disorder was significantly associated with the presence of major depression and anxiety disorders. The authors estimated the overall point prevalence of body dysmorphic disorder as 0.7% in women in this age range in the community. CONCLUSIONS: The authors found that the presence of body dysmorphic disorder was linked to the presence of major depression and anxiety disorders, which is similar to findings in clinical studies. Their estimate of the point prevalence of body dysmorphic disorder is consistent with data from a community-based sample of Italian women and suggests a prevalence similar to that of other serious psychiatric disorders in women (e.g., schizophrenia and drug abuse and dependence). These prevalence data encourage the further development of treatment options for this debilitating condition.

Characteristics of women with premenstrual dysphoric disorder (PMDD) who did or did not report history of depression: a preliminary report from the Harvard Study of Moods and Cycles.

We examined the characteristics of 33 women with a diagnosis of premenstrual dysphoric disorder (PMDD) who did (n = 19) or did not (n = 14) report a history of major depression. Five hundred thirteen older premenopausal women (ages 36-44) from a community-based sample completed a prospective evaluation of PMDD with daily records. The diagnosis of PMDD was confirmed in 33 women (6.3%), and 14 subjects met criteria for PMDD with no history of depression. Demographic characteristics, cigarette smoking, and menstrual and reproductive history of subjects with PMDD who did or did not report a history of depression were compared. Women with PMDD and no history of depression were more educated and more frequently had a marital disruption (p < 0.05). No significant differences were observed with respect to reproduction-related characteristics or past cigarette smoking. These preliminary data suggest the existence of characteristics particularly related to women who meet criteria for PMDD and have no history of depression. Given the significant psychosocial impairment commonly associated with PMDD symptoms and the existing data that support its classification and adequate treatment as a distinct clinical entity, further studies are needed to better identify predictors of this syndrome unrelated to a lifetime history of depression.

Venlafaxine in the treatment of postpartum depression.

BACKGROUND: Although postpartum depression is a highly prevalent illness, antidepressant treatment studies of postpartum depression are sparse. Incomplete recognition and treatment of puerperal illness place women at risk for chronic depression and may have adverse effects on child development. METHOD: An 8-week, flexible-dose, open study of venlafaxine (immediate release; mean dose = 162.5 mg/day) was performed in a group of 15 women who met DSM-III-R criteria for major depressive disorder with onset within the first 3 months postpartum. Patients were assessed at baseline and every 2 weeks across the study. Measurements of outcome included the 17-item Hamilton Rating Scale for Depression (HAM-D), the Kellner Symptom Questionnaire, and the Clinical Global Impressions scale (CGI). RESULTS: Despite baseline scores of depression that were particularly high, response to treatment was robust. Twelve of 15 patients experienced remission of major depression (HAM-D score < or = 7 or CGI score < or = 2). Dramatic decrease in anxiety paralleled the decrease in depression across the sample. CONCLUSION: Venlafaxine is effective in the treatment of postpartum major depression. Early identification of women who suffer from postpartum mood disturbance is critical to minimize the morbidity associated with untreated mood disturbance and the effect of depression on children and families.

Serological analysis of human anti-human antibody responses in colon cancer patients treated with repeated doses of humanized monoclonal antibody A33.

Mouse monoclonal antibody A33 (mAb A33) recognizes a M(r) 43,000 cell surface glycoprotein (designated A33) expressed in human colonic epithelium and colon cancer but absent from most other normal tissues. In patients, mAb A33 localizes with high specificity to colon cancer and is retained for up to 6 weeks in the cancer but cleared rapidly from normal colon (5-6 days). As a carrier of (125)I or (131)I, mAb A33 has shown antitumor activity. Induction of strong human anti-mouse antibody (immunoglobulin; HAMA) responses in patients, however, limits the use of the murine mAb A33 to very few injections. A humanized version of this antibody (huAb A33) has been prepared for Phase I and II clinical studies in patients with colon cancer. In those studies, immunogenicity of huAb A33 has been monitored using a novel, highly sensitive BIACORE method, which allows measurement of human anti-human antibodies (HAHAs) without the use of secondary reagents. We found that 63% (26 of 41) of the patients treated with repeated doses of huAb A33 developed HAHAs against a conformational antigenic determinant located in the V(L) and V(H) regions of huAb A33. Detailed serological analysis showed two distinct types of HAHAs. HAHA of type I (49% of patients) was characterized by an early onset with peak HAHA levels after 2 weeks of treatment, which declined with ongoing huAb A33 treatment. HAHA of type II (17% of patients) was characterized by a typically later onset of HAHA than in type I and by progressively increasing HAHA levels with each subsequent huAb A33 administration. Colon cancer patients with type I HAHAs did not develop infusion-related adverse events. In contrast, HAHA of type II was indicative of infusion-related adverse events. By using this new method, we were able to distinguish these two types of HAHAs in patients while on antibody treatment, allowing patients to be removed from study prior to the onset of severe infusion-related adverse events.

The Expert Consensus Guideline Series. Treatment of depression in women.

OBJECTIVES: Women constitute two-thirds of patients suffering from common depressive disorders. The treatment of depression in women is therefore a substantial public health concern. High-quality, empirical data on depressive disorders specific to women are limited. As a result, there are no comprehensive evidence-based practice guidelines on the best treatment approaches for these illnesses. We conducted a consensus survey of expert opinion on the treatment of 4 depressive conditions specific to women: premenstrual dysphoric disorder (PMDD), depression in pregnancy, postpartum depression in a mother choosing to breast-feed, and depression related to perimenopause/menopause. METHOD: After reviewing the literature and convening a work group of leading experts, we prepared a written survey covering a total of 858 treatment options in 117 specific clinical situations. Depression severity (mild to severe) was specified for most clinical situations. Treatment options included a broad range of pharmacological, psychosocial, and alternative medicine approaches. Most options were scored using a modified version of the RAND 9-point scale for rating appropriateness of medical decisions. We identified 40 national experts, 36 (90%) of whom completed the survey. Consensus on each option was defined as a non-random distribution of scores by chi-square "goodness-of-fit" test. We assigned a categorical rank (first line/preferred choice, second line/alternate choice, third line/usually inappropriate) to each option based on the 95% confidence interval around the mean rating. Guideline tables indicating preferred treatment strategies were then developed for key clinical situations. RESULTS: The expert panel reached consensus on 76% of the options, with greater consensus in situations involving severe symptoms. For women with severe symptoms in each of the 4 central disorder areas we asked about, the first-line recommendation was for antidepressant medication combined with other modalities (generally psychotherapy), paralleling existing guidelines for severe depression in general populations. For milder symptoms in each situation, the panel was less uniform in recommending antidepressants. For the initial treatment of milder symptoms, the panel either gave equal endorsement to other treatment modalities (e.g., nutritional or psychobehavioral approaches in PMDD; hormone replacement in perimenopause) or preferred psychotherapy over medication (in conception, pregnancy, or lactation). In all milder cases, however, antidepressants were recommended as at least second-line options. Among antidepressants, selective serotonin reuptake inhibitors (SSRIs) as a class were recommended as first-line treatment in all situations. The specific SSRIs that were preferred depended on the particular clinical situation. Tricyclic antidepressants were highly rated alternatives to SSRIs in pregnancy and lactation. CONCLUSIONS: The experts reached a high level of consensus on the appropriateness of including both antidepressant medication, specifically SSRIs, and nonpharmacological modalities in treatment plans for severe depression in 4 key clinical situations unique to women. To evaluate many of the treatment options in this survey, the experts had to extrapolate beyond controlled data in comparing modalities with each other or in combination. Within the limits of expert opinion and with the expectation that future research data will take precedence, these guidelines provide some direction for addressing common clinical dilemmas in women. They can be used to inform clinicians and educate patients regarding the relative merits of a variety of interventions.

Three-dimensional power Doppler ultrasound improves the diagnostic accuracy for ovarian cancer prediction.

OBJECTIVE: The goal of this study was to determine if three-dimensional power Doppler ultrasound improves the specificity for ovarian cancer detection as compared with two-dimensional ultrasound. METHODS: Seventy-one women with a known complex pelvic mass were referred for a preoperative ultrasound evaluation with both two-dimensional and three-dimensional gray-scale ultrasonography. The 3D studies were performed with the Kretz Voluson 530D using a mechanized transvaginal probe. Surface rendering and power Doppler imaging were performed by the same gynecologic sonologist, and reassigned to one of four echo patterns: cystic, multicystic, complex, or solid. Sonographic criteria used for diagnosing ovarian cancer were based on a system that included morphological characteristics, histological prediction, and power Doppler imaging. RESULTS: Seventy-one women underwent surgical exploration: 14 (19.7%) had ovarian cancer (2 FIGO stage I, 2 stage II, 7 stage III, and 3 metastatic colon) and 2 had uterine cancer. Two-dimensional gray-scale ultrasound identified 40 masses as suspicious for cancer, including all 14 malignancies, yielding a sensitivity, specificity, and positive predictive value of 100, 54, and 35%, respectively. However, evaluation with 3D power Doppler identified only 28 cases as suspicious (including all 14 cancers), resulting in a sensitivity, specificity, and positive predictive value of 100, 75, and 50%, respectively. CONCLUSIONS: Three-dimensional power Doppler imaging better defines the morphological and vascular characteristics of ovarian lesions. All malignancies were correctly identified by both 2D and 3D imaging; however, the specificity significantly improved with the addition of 3D power Doppler. This improved diagnostic accuracy may promote improved patient care by separating complex benign masses from ovarian cancer, therefore facilitating appropriate physician referral.

Efficacy of estradiol for the treatment of depressive disorders in perimenopausal women: a double-blind, randomized, placebo-controlled trial.

BACKGROUND: Results of previous studies suggest that estrogen improves somatic and mild depressive symptoms experienced by perimenopausal women. This study investigated the efficacy of 17beta-estradiol for the treatment of clinically significant depressive disorders in endocrinologically confirmed perimenopausal women. METHODS: Perimenopausal women (aged 40-55 years, with irregular menstrual periods and serum concentrations of follicle-stimulating hormone >25 IU/L), meeting criteria for major depressive disorder, dysthymic disorder, or minor depressive disorder, according to DSM-IV, were randomized to receive transdermal patches of 17beta-estradiol (100 microgram) or placebo in a 12-week, double-blind, placebo-controlled study. A 4-week washout period followed the 12-week treatment phase. Outcome measures were the Montgomery-Asberg Depression Rating Scale and Blatt-Kupperman Menopausal Index scores. RESULTS: Fifty women were enrolled in the study; 26 met DSM-IV criteria for major depressive disorder, 11 for dysthymic disorder, and 13 for minor depressive disorder. Remission of depression was observed in 17 (68%) women treated with 17beta-estradiol compared with 5 (20%) in the placebo group (P =.001). Subjects responded similarly to estradiol treatment, regardless of DSM-IV diagnosis. Patients treated with estradiol sustained antidepressant benefit of treatment after the 4-week washout period, although somatic complaints increased in frequency and intensity. Treatment was well tolerated and adverse events were rare in both groups. CONCLUSION: Transdermal estradiol replacement is an effective treatment of depression for perimenopausal women.

Obstetrical and neonatal outcome following clonazepam use during pregnancy: a case series.

BACKGROUND: Given the high prevalence of panic disorder in women, treatment decisions are frequently made regarding the use of anti-panic medications during the childbearing years and during pregnancy. The objective of this case series was to evaluate obstetric and neonatal outcome associated with treatment with clonazepam during pregnancy. METHODS: Subjects were 38 women with histories of panic disorder who used clonazepam during pregnancy. Information regarding the amount and duration of clonazepam use during pregnancy was obtained. Obstetrical records describing pregnancy, labor and delivery and infant Apgar scores were obtained for all subjects. Neonatal nursery records were obtained for 27 subjects. RESULTS: Maternal outcome assessed by obstetrical records and acute neonatal outcome assessed by Apgar scores were positive. Based on neonatal records, there were no cases of orofacial anomalies, neonatal apnea, benzodiazepine withdrawal syndromes, or temperature or other autonomic dysregulation. In 2 infants born to the same mother, use of clonazepam and imipramine at the time of delivery was associated with transient neonatal distress. CONCLUSION: Clonazepam use during pregnancy did not appear to be directly related to any obstetric complications during pregnancy, labor, or delivery. There was no evidence of neonatal toxicity or withdrawal syndromes in babies born to mothers who took clonazepam during pregnancy. Absence of serious maternal or neonatal compromise following clonazepam use during pregnancy in these mothers and infants is somewhat reassuring. One case of hypotonia and 1 case of respiratory distress in babies who were exposed to clonazepam in combination with imipramine at the time of delivery may suggest that coadministration of benzodiazepines with other psychotropic medications may require close neonatal observation.

Investigation of the uterine cavity and fallopian tubes using three-dimensional saline sonohysterosalpingography.

OBJECTIVE: To compare three-dimensional saline sonohysterosalpingography (SHSG) to X-ray hysterosalpingography (HSG) for the evaluation of the uterine cavity and fallopian tubes. PATIENT POPULATION: Fifteen infertile women on whom X-ray HSG had been performed within 1 year prior to this study. METHOD: Fifteen infertile women underwent three-dimensional power Doppler examination of the uterus and fallopian tubes with three-dimensional SHSG during the follicular phase. Distension was achieved using sterile saline injected through a 5 French HSG catheter. Peritoneal accumulation of free fluid surrounding the ovary and tube was required for a diagnosis of a patent tube. Fluid accumulation in the cul-de-sac without visualization of the tubes was considered consistent with at least one tube being patent. RESULTS: three-dimensional saline SHSG was completed in 14 patients. One patient had cervical stenosis and the procedure could not be performed. No significant intrauterine pathology was identified by either X-ray HSG or sonography. Three-dimensional saline SHSG made false positive diagnoses of tubal occlusion in four out of seven fallopian tubes (57%). The sensitivity and specificity for detecting tubal occlusion was 75 and 83%, respectively, with a positive predictive value of 40% and negative predictive value of 95%. Detection of fallopian tube architecture was not possible with three-dimensional saline SHSG in any patient. Simultaneous use of three-dimensional Doppler did not clearly identify the flow of saline through the fallopian tubes. CONCLUSIONS: Transvaginal three-dimensional saline SHSG provides good visualization of the uterine cavity and myometrial walls in three orthogonal planes. However, it does not diagnose tubal occlusion or depict architecture of the fallopian tube as accurately as X-ray HSG. Although we were able to visualize the distal fallopian tube and fimbria with real-time imaging, we were not able to satisfactorily image the proximal tube with three-dimensional power Doppler. This technique may be reserved as an initial screening test to evaluate the uterine cavity and test patency. Patients at high risk for tubal disease by history or with suspected tubal occlusion on three-dimensional saline SHSG should be evaluated by either X-ray HSG or laparoscopy with chromopertubation. Further improvements of three-dimensional technology and contrast materials will, it is hoped, make this method comparable to X-ray HSG.