The depressed woman as a mother

Summary Maternal role performance was examined in a group of acutely depressed women and compared with matched normal controls. The depressed women were significantly more impaired mothers. Their impairments with the children included diminished emotional involvement, impaired communication, disaffection, increased hostility and resentment. These disturbances were examined clinically within the context of the family life cycle from post partum to the empty nest. The specific problems between mother and children were found to vary with the stages of the life cycle. Depressed mothers of infants were helpless in caring for the children, over concerned or directly hostile, laying the ground work for future problems with the child. Mothers of school age children were irritable, uninvolved and intolerant of the children's noise and activity. Most school age children, however, did not develop overt psychological symptoms. The most severe problems occurred with the adolescents who reacted to the mothers hostility and withdrawal with serious deviant behavior. While conflict existed between the depressed mothers and the children leaving home, most children were able to make the physical break from home. These findings are discussed in light of scattered reports about the effect of maternal depression on children. Early and intensive treatment of the depressed mother can facilitate major preventive work for the entire family.

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Zusammenfassung In einer Gruppe akut depressiver Frauen wurde die Erfüllung der mütterlichen Rolle untersucht und mit entsprechenden normalen Kontrollfällen verglichen. Die depressiven Frauen waren als Mütter signifikant mehr beeinträchtigt. Ihre Behinderung im Umgang mit den Kindern äusserte sich in verminderter emotionaler Zuwendung, schlechter Kommunikation, Unzufriedenheit, vermehrter Feindseligkeit und Ressentiment. Diese Störungen wurden klinisch innerhalb des Kontextes des familiären Lebenscyclus von der Geburt an bis zum leeren Nest untersucht. Danach variieren die besonderen Probleme zwischen Mutter und Kindern mit den jeweiligen Stadien des Lebenscyclus. Depressive Mütter von Säuglingen waren hilflos bei der Versorgung ihrer Kinder, übermäßig besorgt oder direkt feindselig und legten damit den Grund für zukünftige Probleme mit dem Kind. Mütter von Kindern im Schulalter waren reizbar, unengagiert und intolerant gegenüber dem Lärm und der Aktivität der Kinder. Die meisten Kinder im Schulalter entwickelten jedoch keine deutlichen psychischen Probleme. Die schwersten Probleme ereigneten sich mit Jugendlichen, die auf die Feindseligkeit und das Zurückziehen der Mütter mit ernstlich abnormen Verhaltensweisen reagierten. Obwohl zwischen den depressiven Müttern und den Kindern, wenn sie das Elternhaus verließen, ein Konflikt bestand, konnten die meisten Kinder sich physisch vom Elternhaus lösen. Diese Befunde werden im Hinblick auf verstreute Berichte über die Wirkung mütterlicher Depression auf Kinder diskutiert. Frühzeitige und intensive Behandlung der depressiven Mutter kann einen Großteil der präventiven Arbeit für die gesamte Familie erleichtern.

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Résumé L'accomplissement du rôle maternel a été examiné dans un groupe de femmes souffrant de dépression aiguë et comparé avec des cas normaux de contrôle correspondants. Les femmes déprimées présentaient, de façon significative, davantage de troubles dans leur fonction maternelle. Ce comportement pertubé avec leurs enfants se traduisait par une réduction de l'investissement émotionnel, des troubles de la communication, de l'indifférence, une augmentation de l'hostilité et du ressentiment. Ces troubles ont été examinés cliniquement dans le cadre du cycle de l'a vie familiale, du post-partum à ce qu'il est convenu d'appeler le moment du nid vide. On a trouvé que les problèmes spécifiques entre mère et enfants variaient selon les stades de ce cycle. Les mères déprimées d'enfants en bas âge étaient incapables de s'occuper convenablement d'eux, trop concernées ou carrément hostiles, jettant ainsi les bases des problèmes futurs avec l'enfant. Les mères d'enfants en âge scolaire étaient irritables, désinvesties et intolérantes au bruit et à l'activité des enfants. La plupart des enfants en âge scolaire, cependant, ne présentaient pas de symptômes psychologiques manifestes. Les problèmes les plus graves sont apparus chez les adolescents, qui réagissaient à l'hostilité et au désintérêt de leur mère par un comportement sérieusement perturbé. Bien qu'il existât un conflit entre les mères déprimées et les enfants quittant la maison, la plupart des enfants étaient capables de réaliser la rupture physique d'avec leur foyer. Ces résultats sont discutés à la lumière de travaux dispersés sur l'effet de la dépression maternelle sur les enfants. Un traitement précoce et intensif de la mère déprimée peut faciliter un important travail de prévention pour la famille tout entière.

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This study was supported by U. S. P. H. S. Grant MH 13738 from the National Institute of Mental Health, Department of Health, Education and Welfare. Mrs. Weissman is a Assistant Professor in Psychiatry, Yale University School of Medicine, 34 Park Street, New Haven, Connecticut, 06519. Drs. Paykel and Klerman were at Yale University when this research was done. Dr. Paykel is currently Consultant Psychiatrist, St. George's Hospital, London, S. W. 17, England and Dr. Klerman is Professor of Psychiatry, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts, 02114.     

Differential methylation of genes that regulate cytokine signaling in lymphoid and hematopoietic tumors

The perturbations of the cytokine signaling pathway play an important role in lymphoid/hematopoietic tumors. Aberrant promoter methylation is the major mechanism of gene silencing in tumors. We examined 150 lymphoid/hematopoietic tumors or potential premalignant specimens, 55 control specimens and 12 EBV-transformed B lymphoblastoid cultures and 10 lymphoma/leukemia (L/L) or multiple myeloma (MM) cell lines for the methylation (and, in cell lines, of the expression status) of three genes involved in the cytokine signaling pathway. The genes were: SHP1, a protein tyrosine phosphatase; SYK, a protein kinase; and SOCS1, a suppressor of cytokine signaling. Our major findings were: (1) one or more of the three genes was frequently methylated in L/L and MM cell lines and there was good concordance (90-100%) between methylation and loss of gene expression; (2) treatment of L/L cell lines with a demethylating agent resulted in re-expression of SHP1 protein and downregulation of phosphorylated STAT3 in L/L cell lines; (3) all 55 control specimens and the lymphoblastoid cultures were negative for methylation of the three genes; (4) non-Hodgkin's lymphomas (100%), and leukemias (94%) had almost universal methylation of SHP1 and relatively less frequent (<30%) methylation of SOCS1 and SYK; (5) MM and monoclonal gammopathy of unknown significance (MGUS) had infrequent methylation of SHP1 (<20%), and occasional methylation of SOCS1 and SYK; and (6) comparable methylation frequencies for SOCS1 were observed in MM and MGUS, suggesting that SOCS1 methylation is an early event in MM pathogenesis. At least one gene was methylated in 119 of 130 (93%) of the malignant and 12 of 20 (60%) of the MGUS samples. Our findings demonstrate that the perturbations of cytokine signaling via silencing of these three genes are almost universal in lymphoid/hematopoietic tumors but the patterns of gene methylated for L/L and plasma cell dyscrasias are different.     

Update on angiogenesis inhibitors

PURPOSE OF REVIEW: A number of therapeutic agents have been developed which have anti-angiogenic potential. Here we present the most recent data from clinical trials with some of the promising inhibitors of angiogenesis. RECENT FINDINGS: Agents that target the vascular endothelial growth factor signaling pathway are the furthest along in clinical development. The last year has brought US Food and Drug Administration approval of bevacizumab (Avastin), a recombinant humanized anti-vascular endothelial growth factor monoclonal antibody. Bevacizumab has demonstrated a survival advantage in combination with chemotherapy for patients with metastatic colorectal cancer. Other agents with early promising results include PTK787/ZK 222584 (Vatalanib), ZD6474, and BAY 43-9006 (Sorafenib). SUMMARY: Angiogenesis inhibitors show promise, but evaluation for optimal efficacy has been a problem, given that the mechanisms of action of these agents differ from conventional cytotoxic agents and surrogate markers for inhibition of angiogenesis are not available.     

High-dose radioimmunotherapy combined with fixed, low-dose paclitaxel in metastatic prostate and breast cancer by using a MUC-1 monoclonal antibody, m170, linked to indium-111/yttrium-90 via a cathepsin cleavable linker with cyclosporine to prevent human anti-mouse antibody.

PURPOSE: Although radioimmunotherapy alone is effective in lymphoma, its application to solid tumors will likely require a combined modality approach. In these phase I studies, paclitaxel was combined with radioimmunotherapy in patients with metastatic hormone-refractory prostate cancer or advanced breast cancer. EXPERIMENTAL DESIGN: Patients were imaged with indium-111 (111In)-1,4,7,10-tetraazacyclododecane-N,N',N',N'-tetraacetic acid-peptide-m170. One week later, yttrium-90 (90Y)-m170 was infused (12 mCi/m2 for prostate cancer and 22 mCi/m2 for breast cancer). Initial cohorts received radioimmunotherapy alone. Subsequent cohorts received radioimmunotherapy followed 48 hours later by paclitaxel (75 mg/m2). Cyclosporine was given to prevent development of human anti-mouse antibody. RESULTS: Bone and soft tissue metastases were targeted by 111In-m170 in 15 of the 16 patients imaged. Three prostate cancer patients treated with radioimmunotherapy alone had no grade 3 or 4 toxicity. With radioimmunotherapy and paclitaxel, two of three prostate cancer patients developed transient grade 4 neutropenia. Four breast cancer patients treated with radioimmunotherapy alone had grade 3 or 4 myelosuppression. With radioimmunotherapy and paclitaxel, both breast cancer patients developed grade 4 neutropenia. Three breast cancer patients required infusion of previously harvested peripheral blood stem cells because of neutropenic fever or bleeding. One patient in this trial developed human anti-mouse antibody in contrast to 12 of 17 patients in a prior trial using m170-radioimmunotherapy without cyclosporine. CONCLUSIONS: 111In/90Y-m170 targets prostate and breast cancer and can be combined with paclitaxel with toxicity limited to marrow suppression at the dose levels above. The maximum tolerated dose of radioimmunotherapy and fixed-dose paclitaxel with peripheral blood stem cell support has not been reached. Cyclosporine is effective in preventing human anti-mouse antibody, suggesting the feasibility of multidose, "fractionated" therapy that could enhance clinical response.     

Pharmacotherapy of onychomycosis

Fungal infections of the nails are frequent in some segments of the population. Dermatophytes, yeasts and moulds are potential pathogens. A series of antifungal treatments are available to the clinician, differing by both their mechanistic nature and mode of administration. The pharmacodynamic and pharmacokinetic properties of each antifungal agent are distinct. This review focuses on the characteristics of amorolfine, bifonazole, ciclopirox, fluconazole, griseofulvin, itraconazole, ketoconazole, ravuconazole, R126638 and terbinafine. Single drug treatments and combined therapies are presented. None of the current drug regimens have demonstrated reliable efficacy against all cases of onychomycosis. Treatment failures, relapses and reinfections remain stubborn problems in the management of onychomycosis.     

Deamidation of model beta-turn cyclic peptides in the solid state

To investigate the importance of secondary structure on peptide deamidation in the solid state, two cyclic beta-turn peptides and their linear analogs were used as models of Asn residues in structured and unstructured domains, and incorporated into poly(vinyl pyrrolidone) (PVP)-based lyophilized solids. The secondary structure of the model peptides was determined in solution and the solid state using a combination of nuclear magnetic resonance (NMR) spectroscopy, circular dichroism (CD), and Fourier transform infrared (FTIR) spectroscopy. The model beta-turn cyclic peptides were found to be type II beta-turns while the linear analogs were determined to be predominantly unstructured. Quantitatively, the cyclic peptides consisted of approximately 80% beta-turn while the linear analogs contained only 30%-35% beta-turn. To characterize the solid environment, T(g), and moisture content of the solid-state formulations were determined. Accelerated stability studies were conducted in the solid state at 37 degrees C using formulations lyophilized from solutions at pH 8.8 (0.1 M borate buffer). The effect of matrix mobility on solid-state deamidation was investigated by altering the moisture content through variation of relative humidity or the addition of a plasticizer. Cyclic peptides degraded 1.2-8 times slower than the linear analogs under all of the conditions studied. The observed rate constants, however, for all of the peptides decreased dramatically (four orders of magnitude) in the glassy solids. This suggests the greater importance of matrix mobility in solid-state degradation. Molecular dynamics (MD) simulations were also performed to explore the low energy, preferred state of the peptides, and determine the structure around the beta-turn.     

Joint action of polycyclic aromatic hydrocarbons: predictive modeling of sublethal toxicity

Polycyclic aromatic hydrocarbons (PAHs) typically contaminate the environment as complex assemblages of different chemical compounds. Modeling approaches provide a means of estimating the toxicity of these PAH mixtures. In the present study, we tested the hypothesis that the joint effects of four PAHs: pyrene, phenanthrene, fluoranthene and naphthalene, on the growth rate of the crustacean Daphnia magna during sub-chronic exposure could be accurately predicted using a mathematical algorithm for concentration addition based upon the assumption that these PAHs impact growth by a common mode of action. Assessment of the individual toxicity of the four PAHs confirmed that these compounds elicited the common effect of retarding growth of daphnids at concentrations below those that were lethal to the organisms. Using the experimentally derived toxicity parameters for the individual chemicals, the toxicity of multiple mixtures of these four PAHs was modeled. These mixtures were based on concentrations reported in the environment and on equi-toxic concentrations. The effects of over 140 combinations of four mixture formulations on the growth rate of daphnids were experimentally determined and compared to model predictions. The concentration addition models tended to over predict the joint toxicity of these PAH mixtures and experimental data was better represented by an alternative model based upon the concept of independent joint action. Mixtures at environmentally relevant concentrations were predicted and experimentally demonstrated to have no effect on daphnid growth rates. Results indicate that PAHs elicit toxicity to daphnids by multiple mechanisms and demonstrate an appropriate modeling approach to assess the toxicity of these mixtures.     

Phase I and pharmacokinetic study of Bay 38-3441, a camptothecin glycoconjugate, administered as a 30-minute infusion daily for five days every 3 weeks in patients with advanced solid malignancies

Bay 38-3441 is a camptothecin glycoconjugate which stabilizes the active lactone form of camptothecin and allows selective uptake into tumor cells. We conducted a phase I study of Bay 38-3441 administered as a 30-minute infusion daily for five consecutive days every 21 days. Thirty-one patients were enrolled at 8 dose levels. Most common nonhematologic side effects were diarrhea (29%), vomiting (19%), nausea (19%), lethargy (13%), and abdominal pain (10%). The main hematologic toxicity was prolonged neutropenia. Nine patients had a best response of stable disease with a median duration of 2.7 months (range: 2.3–20.6 months). The study was closed without reaching the maximum tolerated dose (MTD) due to excessive toxicity in a companion trial resulting in termination of development of this agent. Bay 38-3441 was well tolerated in this study with granulocytopenia as the main hematologic toxicity. This study showed that glycoconjugation is a feasible delivery technique for camptothecin.The study medication, Bay 43-9006 and a partial funding for the study were provided by Bayer Inc.