Depression in chronic medical illness: the case of coronary heart disease

Depression is an important predictor of morbidity and mortality in patients with coronary disease, particularly after myocardial infarction, independent of previous cardiac history or CAD severity. Depression also is associated with poor long-term psychosocial outcomes. The prevalence of major depression among post-MI patients is 15 to 20%, with an additional 27% reporting symptoms of minor depression. This article briefly reviews the literature on depression in patients with coronary disease, including previously published efforts to treat the disorder in this group. A case review then is provided, highlighting important aspects of treatment.     

The neutrophil: function and regulation in innate and humoral immunity

The neutrophil is a critical effector cell in humoral and innate immunity and plays vital roles in phagocytosis and bacterial killing. Discussed here are the neutrophil components necessary for these processes and the diseases in which these components are either lacking or dysfunctional, illustrating that normal neutrophil function is vital for health.     

Ordered recombination of immunoglobulin light chain genes occurs at the IGK locus but seems less strict at the IGL locus

Regulation of allelic and isotypic exclusion of human immunoglobulin (Ig) light-chain genes was studied in 113 chronic B-cell leukemias as a "single-cell" model that allowed complete analysis of each light chain allele. Our data show that monospecific Ig light chain expression is in about 90% of cases determined by ordered recombination: Igkappa gene (IGK) rearrangements, followed by IGK deletions and Iglambda gene (IGL) rearrangements, resulting in the presence of only one functional Ig light chain rearrangement. In about 10% (10 cases), 2 functional Ig light chain rearrangements (IGK/IGL or IGL/IGL, but not IGK/IGK) were identified. This might be explained by the fact that regulation of the ordered recombination process is not fully strict, particularly when the IGL locus is involved. Unfavorable somatic mutations followed by receptor editing might have contributed to this finding. Eight of these 10 cases indeed contained somatic mutations. In cases with 2 functional Ig light chain rearrangements, both alleles were transcribed, but monospecific Ig expression was still maintained. This suggests that in these cases allelelic exclusion is not regulated at the messenger RNA level but either at the level of translation or protein stability or via preferential pairing of Ig light and Ig heavy chains. Nevertheless, ordered rearrangement processes are the main determinant for monospecific Ig light chain expression.     

Effects of treating depression and low perceived social support on clinical events after myocardial infarction: the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) Randomized Trial

Context  Depression and low perceived social support (LPSS) after myocardial infarction (MI) are associated with higher morbidity and mortality, but little is known about whether this excess risk can be reduced through treatment. Objective  To determine whether mortality and recurrent infarction are reduced by treatment of depression and LPSS with cognitive behavior therapy (CBT), supplemented with a selective serotonin reuptake inhibitor (SSRI) antidepressant when indicated, in patients enrolled within 28 days after MI. Design, Setting, and Patients  Randomized clinical trial conducted from October 1996 to April 2001 in 2481 MI patients (1084 women, 1397 men) enrolled from 8 clinical centers. Major or minor depression was diagnosed by modified Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria and severity by the 17-item Hamilton Rating Scale for Depression (HRSD); LPSS was determined by the Enhancing Recovery in Coronary Heart Disease Patients (ENRICHD) Social Support Instrument (ESSI). Random allocation was to usual medical care or CBT-based psychosocial intervention. Intervention  Cognitive behavior therapy was initiated at a median of 17 days after the index MI for a median of 11 individual sessions throughout 6 months, plus group therapy when feasible, with SSRIs for patients scoring higher than 24 on the HRSD or having a less than 50% reduction in Beck Depression Inventory scores after 5 weeks. Main Outcome Measures  Composite primary end point of death or recurrent MI; secondary outcomes included change in HRSD (for depression) or ESSI scores (for LPSS) at 6 months. Results  Improvement in psychosocial outcomes at 6 months favored treatment: mean (SD) change in HRSD score, -10.1 (7.8) in the depression and psychosocial intervention group vs -8.4 (7.7) in the depression and usual care group (P<.001); mean (SD) change in ESSI score, 5.1 (5.9) in the LPSS and psychosocial intervention group vs 3.4 (6.0) in the LPSS and usual care group (P<.001). After an average follow-up of 29 months, there was no significant difference in event-free survival between usual care (75.9%) and psychosocial intervention (75.8%). There were also no differences in survival between the psychosocial intervention and usual care arms in any of the 3 psychosocial risk groups (depression, LPSS, and depression and LPSS patients). Conclusions  The intervention did not increase event-free survival. The intervention improved depression and social isolation, although the relative improvement in the psychosocial intervention group compared with the usual care group was less than expected due to substantial improvement in usual care patients.      

Toxicity of acetaminophen,salicylic acid,and caffeine for first-passage rat renal inner medullary collecting duct cells

Chronic excess ingestion of nonsteroid anti-inflammatory drugs causes renal medullary necrosis. Previously, using an immortalized line of mouse inner medullary collecting ducts cells (mIMCD3), we found that acetaminophen, salicylic acid, and caffeine are toxic, and the effects of acetaminophen and caffeine are strongly additive. Furthermore, toxicity was greater in proliferating than in nonproliferating cells. Important limitations were that mIMCD3 cells do not readily tolerate the high concentrations of salt and urea normally present in renal inner medullas and proliferate much more rapidly than inner medullary cells in vivo. Thus, these cells may not serve as an appropriate model for the in vivo IMCD. The present studies address these limitations by using passage-1 rat inner medullary collecting duct (p1rIMCD) cells, which tolerate high salt and urea and become contact inhibited when confluent. At 640 mOsmol/kg (the lowest normal inner medullary osmolality), the drugs, singly and in combination, reduce the number of proliferating (i.e., subconfluent) p1rIMCD cells more than they do confluent cells. Effects of acetaminophen and caffeine are strongly additive. Addition of as little as 0.1 mM caffeine significantly enhances the toxicity of acetaminophen plus salicylic acid. With confluent cells at 640 mOsmol/kg and very slowly growing cells at 1370 mOsmol/kg, combinations of drugs that include acetaminophen increase proliferation, accompanied by DNA damage and apoptosis. We conclude that these drugs are toxic to renal inner medullary collecting duct cells under the conditions of high osmolality normally present in the inner medulla, that combinations of the drugs are more toxic than are the drugs individually, and that the toxicity includes induction of proliferation of these cells that are otherwise quiescent in the presence of high osmolality.     

Natural T-helper immunity against human papillomavirus type 16 (HPV16) E7-derived peptide epitopes in patients with HPV16-positive cervical lesions: identification of 3 human leukocyte antigen class II-restricted epitopes

Tumor-specific T-helper (Th) immunity was found to play a pivotal role in the natural and vaccine-induced immune defense against tumors. Since the majority of cervical cancers express human papillomavirus type 16 (HPV16) E7 oncoprotein, it is important to investigate the Th response against this target antigen in detail. By means of PBMC cultures from HLA-typed healthy donors, we identified the central part of HPV16 E7 (E7(41-72)) as the major immunogenic region within this antigen. Furthermore, we mapped 3 distinct Th epitopes within this region (DR15/E7(50-62), DR3/E7(43-77), DQ2/E7(35-50)). In a parallel approach, employing IFN-gamma ELISPOT analysis, we detected Th immunity against HPV16 E7 in subjects with HPV16+ lesions. Several of these responses matched with the 3 Th epitopes defined in our study. A number of other HPV16+ subjects did not display any E7-specific type 1 cytokine-producing T-cell immunity, indicating failure of the immune response. Our combined data argue for more extensive as well as longitudinal analysis of HPV16-specific T-cell immunity using the ELISPOT assay described, as well as for HPV-specific vaccination of individuals with HPV+ lesions.     

Successful therapy with tetracycline and nicotinamide in cicatricial pemphigoid

We describe a case of cicatricial pemphigoid in a 92-year-old female with extensive mucocutaneous involvement. She developed extensive hemorrhagic blistering with severely bleeding lesions, that healed with scarring. The conjunctivae showed extensive synechia. The diagnosis was based on clinical and histopathological features as well as immunofluorescence findings and immunoblot analysis. There was no clinical response to topical corticosteroids. The patient was given tetracycline and nicotinamid and showed rapid improvement of the mucocutaneous lesions within a few weeks. The clinical features, differential diagnosis and various treatment modalities of cicatricial pemphigoid are briefly reviewed, whereby the use of tetracycline and nicotinamide is discussed as an alternative effective and safe therapy for this potentially incapacitating condition.     

Pre-clinical safety and efficacy of TA-CIN, a recombinant HPV16 L2E6E7 fusion protein vaccine, in homologous and heterologous prime-boost regimens

Human papillomavirus (HPV) E6 and E7 oncoproteins are attractive targets for T-cell-based immunotherapy of cervical intraepithelial neoplasia (CIN) and cancer. A newly designed vaccine, comprising the HPV16 L2, E6 and E7 as a single fusion protein (TA-CIN), was shown to elicit HPV16-specific CTL, T-helper cells and antibodies in a pre-clinical mouse model. These immune responses effectively prevented outgrowth of HPV16-positive tumour cells in a prophylactic setting as well as in a minimal residual disease setting. CTL immunity was optimally induced when TA-CIN was employed in heterologous prime-boost regimens in combination with TA-HPV, a clinical grade vaccinia-based vaccine. These data provide a scientific basis for the use of TA-CIN, alone or in combination with TA-HPV in future human trials.     

Pityriasis rosea – a virus-induced skin disease? An update

Summary.  Pityriasis rosea (PR) is an acute, inflammatory skin disease of unknown cause. Clinical and experimental findings indicate an infectious etiology of PR. Various infectious agents including viruses have been proposed as causative agents and their presence in PR samples has been extensively investigated. Recently, human herpesvirus 7 was linked to PR, but contradictory findings have been reported by various investigators. Here, we describe the features of PR that suggest an infectious cause and review the data from viral studies in PR reported in the literature. In addition, we present a pathogenetic model of PR which may be helpful in planning and evaluating studies for the search of a putative PR-associated virus. Based on the current state of knowledge, none of the known viruses could, so far, be conclusively associated with PR. Received February 22, 2000 Accepted March 17, 2000     

Randomized phase III trial of bleomycin, vindesine, mitomycin-C, and cisplatin (BEMP) versus cisplatin (P) in disseminated squamous-cell carcinoma of the uterine cervix: An EORTC Gynecological Cancer Cooperative Group study

Purpose:Three previous mitomycin–cisplatin-basedchemotherapy trials conducted within the EORTC Gynecological CancerCooperative Group (GCCG) in patients with disseminated squamous-cell carcinomaof the uterine cervix (SCCUC) suggested that with such regimens a higheroverall response rate and a higher complete response rate could be obtainedcompared to what might have been expected from cisplatin alone. In thatrespect the combination of bleomycin, vindesine (Eldesine®), mitomycin Cand cisplatin (BEMP) was the most promising. In the present study BEMP hasbeen compared with the best single agent, cisplatin (P) in the expectationthat improved response rates might translate into a better survival. Patients and methods:Eligible patients were those with SCCUC anddisseminated measurable disease outside previously irradiated areas, aged75 years, with a WHO performance status 2 and adequate bone marrow,renal, hepatic and pulmonary function, who gave consent according toregulations followed in individual institutions. Patients were randomized toBEMP: E 3 mg/m² day 1, P 50 mg/m² day 1, B 15 mg(24-hour infusion) day 2–4 and M 8 mg/m² (at alternatecycles), or P 50 mg/m². The first four cycles were given every 3weeks (induction phase). Subsequent cycles were given every four weeks(maintenance phase), during which B was deleted from BEMP (MEP). Patientsfailing on P could be treated with BEM. Of the 287 patients entered, 235 wereeligible and 201 evaluable for response. Results:BEMP induced a significantly higher response rate thanP (42% vs. 25%, P = 0.006). There was nodifference in complete response rate (11% vs. 7%). BEMP wassignificantly more toxic than P (±BEM), both with respect tohematologic and nonhematologic toxicities. After a median follow-up of 6.1years, survival curves were not significantly different. Medianprogression-free survival and overall survival were 5.3 and 10.1 months withBEMP and 4.5 and 9.3 months with P (±BEM), respectively. In amultivariate analysis of prognostic factors for survival, a lower age(P = 0.003), a lower performance status (P =0.0001) and a short (<1 year) interval since diagnosis(P = 0.0152) were all associated with an increased risk ofdying. For progression-free survival, lower age, prior radiotherapy,locoregional involvement and no prior surgery were associated with a highrisk. Treatment with BEMP or P had no significant impact on survival, but forprogression-free survival there was a trend in favor of BEMP(P = 0.0893). Adjusting for prognostic factors did not changethe effect of treatment. Conclusions:Combination chemotherapy with BEMP produces moretoxicity and more responses compared with cisplatin alone in patients withdisseminated SCCUC, but this does not translate into a better survival.Therefore, in the palliative setting single-agent cisplatin should remain thestandard therapy for these patients.*See Appendix on pages 972–973 for a list of co-authors