[New Radiopharmaceuticals Based on Prostate-Specific Inhibitors of Membrane Antigen for Diagnostics and Therapy of Metastatic Prostate Cancer].

About 10.7% cases of prostate cancer were registered in Russia in 2011 (40,000 patients). More than half of cancer cases were revealed in advanced (III-IV) stages when metastases inevitably developed quickly. Clinical problem of early diagnostics and treatment of metastatic prostate cancer is still not solved. Anatomical imaging techniques have low sensitivity and specificity for the detection of this disease. Metabolic visualization methods which use prostate specific antigen (PSA) as a marker are also ineffective. This article describes prostate-specific membrane antigens (PSMA) that are proposed as a marker for diagnostics and therapy of prostate cancer. The most promising PSMA-based radiopharmaceutical agent for diagnostics has been developed and clinically tested in the European countries. These pharmaceuticals are based on small peptide molecules modified with urea, and have the highest affinity to PSMA. Favorable phannacokinetics, rapid accumulation in the tumor and rapid excretion from the body are beneficial features of these pharmaceuticals.

Mutations in either the essential or regulatory light chains of myosin are associated with a rare myopathy in human heart and skeletal muscle.

The muscle myosins and hexomeric proteins consisting of two heavy chains and two pairs of light chains, the latter called essential (ELC) and regulatory (RLC). The light chains stabilize the long alpha helical neck of the myosin head. Their function in striated muscle, however, is only partially understood. We report here the identification of distinct missense mutations in a skeletal/ventricular ELC and RLC, each of which are associated with a rare variant of cardiac hypertrophy as well as abnormal skeletal muscle. We show that myosin containing the mutant ELC has abnormal function, map the mutant residues on the three-dimensional structure of myosin and suggest that the mutations disrupt the stretch activation response of the cardiac papillary muscles.

Freeze-fracture study on the erythrocyte membrane during malarial parasite invasion.

Invasion of erythrocytes by malarial merozoites requires the formation of a junction between the merozoite and the erythrocyte. Migration of the junction parallel to the long axis of the merozoite occurs during the entry of the merozoite into an invagination of the erythrocyte. Freeze-fracture shows a narrow circumferential band of rhomboidally arrayed particles on the P face of the erythrocyte membrane at the neck of the erythrocyte invagination and matching rhomboidally arrayed pits on the E face. The band corresponds to the junction between the erythrocyte and merozoite membranes observed in thin sections and may represent the anchorage sites of the contractile proteins within the erythrocyte. Intramembrane particles (IMP) on the P face of the erythrocyte membrane disappear beyond this junction. When the erythrocytes and cytochalasin B-treated merozoites are incubated together, the merozoite attaches to the erythrocyte membrane and a junction is formed between the two, but the invasion process does not advance further and no movement of the junction occurs. Although there is no entry of the parasite, the erythrocyte membrane still invaginates. Freeze-fracture shows that the P face of the invaginated erythrocyte membrane is almost devoid of the IMP that are found elsewhere on the membrane, suggesting that the attachment process in and of itself is sufficient to create a relatively IMP-free bilayer.

Skeletal muscle expression and abnormal function of beta-myosin in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy is an important inherited disease. The phenotype has been linked, in some kindreds, to the beta-myosin heavy chain (beta-MHC) gene. Missense and silent mutations in the beta-MHC gene were used as markers to demonstrate the expression of mutant and normal cardiac beta-MHC gene message in skeletal muscle of hypertrophic cardiomyopathy patients. Mutant beta-myosin, also shown to be present in skeletal muscle by Western blot analysis, translocated actin filaments slower than normal controls in an in vitro motility assay. Thus, single amino acid changes in beta-myosin result in abnormal actomyosin interactions, confirming the primary role of missense mutations in beta-MHC gene in the etiology of hypertrophic cardiomyopathy.

Abnormal contractile properties of muscle fibers expressing beta-myosin heavy chain gene mutations in patients with hypertrophic cardiomyopathy.

Missense mutations in the beta-myosin heavy chain (beta-MHC) gene cause hypertrophic cardiomyopathy (HCM). As normal and mutant beta-MHCs are expressed in slow-twitch skeletal muscle of HCM patients, we compared the contractile properties of single slow-twitch muscle fibers from patients with three distinct beta-MHC gene mutations and normal controls. Fibers with the 741Gly-->Arg mutation (near the binding site of essential light chain) demonstrated decreased maximum velocity of shortening (39% of normal) and decreased isometric force generation (42% of normal). Fibers with the 403Arg-->Gln mutation (at the actin interface of myosin) showed lowered force/stiffness ratio (56% of normal) and depressed velocity of shortening (50% of normal). Both the 741Gly-->Arg and 403Arg-->Gln mutation-containing fibers displayed abnormal force-velocity relationships and reduced power output. Fibers with the 256Gly-->Glu mutation (end of ATP-binding pocket) had contractile properties that were indistinguishable from normal. Thus there is variability in the nature and extent of functional impairments in skeletal fibers containing different beta-MHC gene mutations, which may correlate with the severity and penetrance of the disease that results from each mutation. These functional alterations likely constitute the primary stimulus for the cardiac hypertrophy that is characteristic of this disease.

Comparison of VEGF-producing cells in periprosthetic osteolysis.

The pro-angiogenic cytokine vascular endothelial growth factor (VEGF) has been implicated in periprosthetic osteolysis and subsequent aseptic loosening of implants following total hip arthroplasty (THA). The goal of this study was to investigate whether increased VEGF at the bone-implant interface is secondary to a greater number of VEGF-producing cells or to increased VEGF production by individual cells. Real time polymerase chain reaction (RT-PCR) techniques were used to assess the expression of VEGF mRNA (isoforms 121, 165, 189) in periprosthetic tissues from revision THAs. Immunofluorescence was used to determine both differences in overall cellularity and in VEGF-producing cell type (macrophages, fibroblasts, endothelial cells) between patients with periprosthetic osteolysis (OL) and a control group undergoing primary THA for osteoarthritis (OA). Quantitative analysis of VEGF release in periprosthetic membranes via RT-PCR demonstrated no significant difference in the per-cell mRNA production of VEGF isoforms 121 165, or 189 between OL and OA patient groups. Immunofluorescence showed both higher cellularity and higher overall VEGF expression in the OL group. Immunofluorescence also showed a significant increase in macrophages in the OL group, but no significant difference in the proportion of fibroblasts or endothelial cells between the OL and OA groups. Co-localization of CD68+ and CD11b+ macrophage fluorescent signals with VEGF signal was greater in the OL group than in the OA group. Our results demonstrate that increased VEGF in OL periprosthetic tissue compared to OA synovium is correlated to increased numbers of VEGF-producing CD68+ and CD11b+ macrophages. Impact statement: Aseptic loosening, caused in large part by OL, remains the major cause of failed THAs leading to revision surgery. At the bone-implant interface, we found increased numbers of macrophages-cellular mediators of OL-and increased VEGF expression. VEGF may be a possible target for therapeutic intervention in mitigating OL.

Association between polymorphism in the chemokine receptor CX3CR1 and coronary vascular endothelial dysfunction and atherosclerosis.

Fractalkine, a chemokine expressed by inflamed endothelium, induces leukocyte adhesion and migration via the receptor CX3CR1, and the CX3CR1 polymorphism V249I affects receptor expression and function. Here we show that this polymorphism is an independent risk factor for atherosclerotic coronary artery disease (CAD). Genotyping of the CX3CR1-V249I polymorphism was performed in a cohort of 339 white individuals who underwent cardiac catheterization (n=197 with and n=142 without CAD, respectively). In 203 patients, intracoronary acetylcholine 15 microg/min) and sodium nitroprusside (20 microg/min) were administered to test endothelium-dependent and -independent coronary vascular function, respectively. Change in coronary vascular resistance (DeltaCVR) was measured as an index of microvascular dilation. An association was observed between presence of the CX3CR1 I249 allele and reduced prevalence of CAD, independent of established CAD risk factors (odds ratio=0.54 [95% confidence interval, 0.30 to 0.96], P=0.03). Angiographic severity of CAD was also lower in these subjects (P=0.01). Furthermore, endothelium-dependent vasodilation was greater in these individuals compared with individuals homozygous for the CX3CR1-V249 allele (DeltaCVR during acetylcholine = -46+/-3% versus -36+/-3%, respectively, P=0.02), whereas DeltaCVR with sodium nitroprusside was similar in both groups (-55+/-2% versus -53+/-2%, P=0.45). The association between CX3CR1 genotype and endothelial function was independent of established risk factors and presence of CAD by multivariate analysis (P=0.02). Thus, the CX3CR1 I249 allele is associated with decreased risk of CAD and improved endothelium-dependent vasodilation. This suggests that CX3CR1 may be involved in the pathogenesis of CAD.

Insertion-deletion polymorphism of the ACE gene modulates reversibility of endothelial dysfunction with ACE inhibition.

BACKGROUND: The aim of this study was to examine whether angiotensin-converting enzyme (ACE) inhibition improves coronary endothelial dysfunction in patients with atherosclerosis and its risk factors and whether this was related to the ACE insertion-deletion (I/D) polymorphism. METHODS AND RESULTS: In 56 patients with atherosclerosis or its risk factors, we studied endothelium-dependent responses with acetylcholine and endothelium-independent function with sodium nitroprusside, before and after ACE inhibition with enalaprilat. Enalaprilat did not alter either resting coronary tone or vasodilation with sodium nitroprusside. However, it potentiated the coronary microvascular and epicardial responses with acetylcholine; coronary blood flow increased from 82+/-7 to 90+/-8 mL/min (P=0.05) after enalaprilat. Patients with depressed endothelial function (P<0.001) and those with ACE DD or ID genotypes (P=0.002) but not those homozygous for the I allele had the greatest improvement by multivariate analysis. Similarly, acetylcholine-mediated epicardial vasomotion improved in segments that initially constricted (endothelial dysfunction): from -10.1+/-1% to -1.4+/-2% (P<0.001) after enalaprilat. No augmentation was observed in segments that dilated (normal endothelial dysfunction) with acetylcholine. Patients with the D allele, hypercholesterolemia, and smokers (all P<0.05) had greater improvement. CONCLUSIONS: Acute ACE inhibition improves coronary epicardial and microvascular endothelium-dependent vasomotion in patients with atherosclerosis or its risk factors who have endothelial dysfunction and presence of the D allele.

The insertion/deletion polymorphism of the angiotensin-converting enzyme gene determines coronary vascular tone and nitric oxide activity.

OBJECTIVES: We investigated whether the insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme (ACE) gene modulates vasomotor tone and endothelial function. BACKGROUND: The deletion allele of the ACE I/D polymorphism has been associated with increased incidence of cardiovascular pathology. The risk is synergistically increased in patients who also possess the C allele at position 1,166 of the angiotensin type I (AT1) receptor gene. METHODS: In 177 patients with coronary atherosclerosis or its risk factors, we investigated endothelial function with intracoronary acetylcholine (ACH), endothelium-independent smooth muscle function with sodium nitroprusside (SNP) and basal nitric oxide activity with L-NG monomethyl arginine. RESULTS: Compared with ACE II genotype, patients with the ACE DD genotype had lower coronary microvascular and epicardial responses with SNP (coronary blood flow increase 196 +/- 26% vs. 121 +/- 11%, p = 0.003, and diameter increase 21.9 +/- 2% vs. 17 +/- 1%, p = 0.03, ACE II vs. DD, respectively). L-NG monomethyl arginine induced greater constriction in patients with the ACE DD compared with ACE II genotype (coronary blood flow -10 +/- 4% vs. 11 +/- 5%, p = 0.003, ACE DD vs. II and diameter constriction -6.3 +/- 1.2% vs. -1.9 +/- 1.2%, p = 0.01, respectively, in patients with atherosclerosis). No difference in ACH-mediated vasomotion was detected between the three ACE genotypes. The AT1 receptor polymorphism did not influence responses to either SNP or ACH. CONCLUSIONS: Patients possessing the D allele of the ACE gene have increased vascular smooth muscle tone. The enhanced tone appears to be counterbalanced by an increase in basal nitric oxide activity in patients with atherosclerosis.

Contribution of bradykinin receptor dysfunction to abnormal coronary vasomotion in humans.

OBJECTIVES: The aim of our study was to investigate coronary vascular kinin receptor function in patients with atherosclerosis or its risk factors. BACKGROUND: Although acetylcholine (ACH) is used as a probe for testing vascular function in vivo, endogenous bradykinin (BK) regulates resting and flow-mediated epicardial tone. METHODS: In 53 patients with mild atherosclerosis or its risk factors and 9 control subjects, endothelium-dependent vasomotion was tested with intracoronary ACH (30 microg/min) and BK (62.5 ng/min and 4 microg/min), and endothelium-independent function with sodium nitroprusside. Metabolic vasodilation was assessed during cardiac pacing (n = 19). Correlation with serum angiotensin-converting enzyme (ACE) levels and the ACE insertion/deletion genotype was performed. RESULTS: There was progressive impairment in ACH-mediated microvascular dilation with increasing numbers of risk factors (p = 0.025, analysis of variance). By contrast, BK- and sodium nitroprusside-mediated microvascular dilation was similar in all groups. Similarly, there was no correlation between epicardial coronary responses to ACH and BK; segments that constricted or dilated with ACH had similar dilator responses with BK. Bradykinin, but not ACH-mediated vasomotion, was depressed in epicardial segments that constricted with pacing. Finally, epicardial BK responses were depressed in patients with high ACE levels and in those with the ACE DD genotype. CONCLUSIONS: Endothelial dysfunction in atherosclerosis appears to be receptor-specific, involving the muscarinic receptor with relative sparing of the kinin receptor pathways. Abnormal reactivity of epicardial coronary arteries during physiologic stress is better represented by BK and not by ACH responses. Bradykinin activity and, hence, physiologic coronary vasomotion appears to be influenced by serum ACE levels and the ACE insertion/deletion genotype.

Predictions of therapeutic process and progress in conjoint family therapy.

Following initial diagnostic interviews with 20 families in an outpatient psychiatric clinic, a group of therapists made predictions of the anticipated responses of the families to therapy. Changes in family structure, organization, and transactional patterns were predicted with use of the Family Category Schema. The families' responses to the process of therapy was predicted in a questionnaire. The results showed poor predictions of response to process. However, a normative response picture of a family in therapy did emerge. Also, all predictions erred in the direction of underrating the overall effectiveness of conjoint family therapy.

Research on the results of psychotherapy: a summary of evidence.

The authors present a basic overview of recent research on the outcome of psychotherapy, considering different types of therapy and different diagnostic categories separately. In some studies psychotherapy was more efficacious than spontaneous remission or placebo effects, especially in cases of anxiety and in nonpsychotic depression. As an adjunct to drugs and/or ECT, psychotherapy was effective in lowering the relapse rate of schizophrenic outpatients. Psychotherapy appeared to be more effective when focusing on realistic, relevant issues and when teaching social skills. Family therapy may be the most robust mode in terms of consistent positive results with different problems. Although results continue to be mixed, methodological progress is apparent and optimism for continued progress is warranted.

12-month outcome of patients with major depression and comorbid psychiatric or medical illness (compound depression).

OBJECTIVE: Inpatients with major depressive illness often have coexistent nonaffective psychiatric and/or medical conditions. The authors' objective is to address the following questions: 1) What is the effect of comorbid illness on the severity of major depression and associated psychosocial factors? 2) How does the course of depression differ for patients with and without concurrent illness? 3) Do patients with compound depression differ in rate of recovery and time to recovery from patients with pure depression? METHOD: The subjects were 78 patients with a DSM-III diagnosis of major depression who were consecutively admitted to an acute care university-affiliated psychiatric hospital; 37 of these patients had major depression only and 41 had major depression compounded by a coexisting axis I, II, or III condition. The patients were studied while hospitalized and for 12 months after hospital discharge. Instruments used included the Modified Hamilton Rating Scale for Depression, the Global Assessment Scale, and the Social Readjustment Rating Scale. RESULTS: Patients with compound depression reported significantly poorer functioning over the 12-month follow-up period and had lower recovery rates than the patients with pure depression. There were no differences in recovery rates between men and women with compound depression, but significantly more men than women with pure depression recovered. CONCLUSIONS: Compound depression is a common clinical occurrence, the course of illness is more difficult for patients with compound depression than for patients with pure depression, and the recovery rate of patients with compound depression is lower than that of patients with pure depression.

Role of the family in recovery and major depression.

OBJECTIVE: Major depression is significantly influenced by the family environment of the depressed patient. In order to explore how family functioning relates to this illness, the authors examined changes in family functioning over a 1-year course of major depression. METHOD: Subjective (Family Assessment Device) and objective (McMaster Clinical Rating Scale) assessments of family functioning were collected at hospitalization and 6 and 12 months after discharge for 45 inpatients diagnosed with major depression and their family members. Patterns of family functioning were examined by subjective and objective perspectives, initial levels of functioning, and reports of patients and other family members. RESULTS: Approximately 50% of families with a depressed member perceived their own family functioning as unhealthy; clinicians rated 70% of the families as unhealthy. While family functioning improved significantly from hospitalization through 12 months after discharge, the improvement was not uniform across all areas of functioning. Further, patients with good family functioning at hospitalization generally maintained their healthy functioning and were more likely to recover by 12 months than patients with poor family functioning. Although steady improvement in family functioning characterized the subjective ratings, objective assessments of family functioning suggested initial improvement followed by a decline from month 6 to month 12. CONCLUSIONS: Results show a clear association between family functioning and recovery from major depression. Different aspects of family life respond differently to the depressive illness; no one family dimension was uniquely related to outcome.

Genetic evidence of dissociation (generational skips) of electrical from morphologic forms of hypertrophic cardiomyopathy.

The diagnosis of hypertrophic cardiomyopathy (HC) is traditionally based on the demonstration by echocardiography of left ventricular hypertrophy in the absence of apparent cause. This study reports on 5 adults in 4 families who are obligate or highly probable carriers of the HC gene by virtue of their position in the pedigree, but who have normal echocardiographic findings. Four of these 5 patients had abnormal signal-averaged electrocardiograms, a finding suggesting the presence of electrical disease despite the absence of left ventricular hypertrophy. The fifth patient, an identical twin of a patient with familial HC, had neither left ventricular hypertrophy nor a myocardial electrical abnormality. These data indicate that the spectrum of HC includes patients who have a potentially arrhythmogenic left ventricular substrate but who have no evidence of left ventricular hypertrophy. Our data demonstrating generational skips also imply that some instances of HC previously judged to be sporadic may indeed by familial.

Long-term culture of infant leukemia cells: dependence upon stromal cells from the bone marrow and bilineage differentiation.

Infant leukemia cells with 46XY,t(11; 17)(q23; p13) karyotype and a hybrid pre B myeloid phenotype (HLA-DR, (Ia), B4 and My7-positive and CALLA and T11-negative) and immunoglobulin heavy chain gene rearrangement were maintained in long-term culture for over 10 months. The in-vitro survival and growth of the leukemia cells were strictly dependent upon the presence of their autologous marrow stromal cells. The latter could be replaced by the 14F1.1 clone of preadipocytes derived from mouse bone marrow. Neither heterologous human marrow or foreskin fibroblasts nor fibroblast or endothelial like cell lines from mouse stroma could mimic the effect of autologous stroma or 14F1.1 adipocytes. The leukemia cells maintained their original phenotype throughout the 10-month culture period with either their autologous stroma or the 14F1.1 adipocytes. They could be induced to differentiate in two distinct directions. Phorbol myristate acetate induced adherence of the leukemia cells and development of macrophage properties. In contrast, conditioned medium from a hybridoma producing B-cell growth factor caused aggregation of the leukemia cells and expression of CALLA antigen and surface IgM. This bipotency of the leukemia cells and their dependence upon marrow stroma are properties in common with stem cells.

Relationship of the C242T p22phox gene polymorphism to angiographic coronary artery disease and endothelial function.

Patients with coronary artery disease (CAD) have impaired endothelial function in part due to an increase in vascular oxidant stress. p22phox, an essential component of the NADPH oxidase, is thought to play a critical role in the generation of superoxide anions in the vessel wall. The C242T polymorphism, located in the potential heme-binding site of the p22phox gene, has recently been reported to confer a protective effect on CAD risk in a Japanese study population. In a U.S. population of 252 patients (83% Caucasian) undergoing angiography for diagnosis of CAD, we investigated whether the C242T polymorphism was associated with the presence of CAD. In a subset of 142 patients, we studied whether the polymorphism manifests its potential protective effects through alteration of vascular endothelial function by measuring coronary epicardial and microvascular responses to intracoronary acetylcholine and sodium nitroprusside. Prevalence of the C242T allele was not different in 149 patients with CAD compared to 103 patients with angiographically normal coronary arteries (65.1% vs. 54.4%, P = 0.11). The C242T allele frequency in our population was nearly fourfold higher than reported previously in a Japanese population. There were also no significant differences in coronary epicardial or microvascular responses to acetylcholine or sodium nitroprusside between groups of patients with or without the C242T allele. In a U.S. population, the C242T polymorphism does not appear to confer protection from endothelial dysfunction or CAD. Am. J. Med. Genet. 86:57-61, 1999. Published 1999 Wiley-Liss, Inc.

The application of behavioral couples therapy to the assessment and treatment of agoraphobia: implications of empirical research.

The present review was undertaken to examine the literature regarding the role of the marital relationship in treatment of agoraphobia from a behavioral couples therapy (BCT) perspective. Both qualitative and quantitative analyses were conducted to evaluate (a) whether marital quality predicts treatment responsiveness and (b) how best to include the spouse in treatment of agoraphobia. Regarding the assessment of agoraphobics' relationship quality, it is recommended that subjectively experienced "satisfaction" with the relationship be distinguished from more descriptive measures of general and agoraphobia-specific relationship "adjustment." Treatment can include the partner as a "co-therapist" to assist with interventions directly targeted at the agoraphobia, or use BCT interventions to modify relationship interactions that might impede treatment gains. The application of BCT for these couples poses a number of challenges, including (a) the need to maintain a balanced treatment approach in an "unbalanced" system, (b) the need to target interventions at more than one treatment goal, and (c) the task of combining couple-focused interventions with those aimed at reducing phobic symptoms.

The role of cognitions in marital relationships: definitional, methodological, and conceptual issues.

Although there have recently been numerous investigations exploring the role of couples' cognitions in an attempt to understand marital distress, at present there is little cohesion and direction in the study of how couples think about their relationships. The current article asserts that this lack of direction results from at least three factors: (a) a lack of delineation of the important cognitive variables to be considered in marital functioning, (b) conceptual and methodological difficulties that arise in attempts to operationalize cognitive variables, and (c) a dearth of models of marital functioning that incorporate cognitions in a detailed manner. These three factors are discussed, along with a review of empirical investigations supporting the importance of cognitions in intimate relationships.

Depressed patients with dysfunctional families: description and course of illness.

Sixty-eight depressed patients were subdivided according to their family's level of family functioning into functional and dysfunctional groups. Patients from dysfunctional families did not differ from those from functional families on measures of severity of depression, chronicity of depression, depression subtypes, other nonaffective psychiatric diagnoses, history of depression, or neuroendocrine functioning. Patients from dysfunctional families did have significantly higher levels of neuroticism. A 12-month follow-up of these patients indicated that depressed patients with dysfunctional families had a significantly poorer course of illness, as manifested by higher levels of depression, lower levels of overall adjustment, and a lower proportion of recovered patients. Thus, impaired family functioning appears to be an important prognostic factor in major depression.