Effectiveness of the Incredible Years Parenting Program for Families with Socioeconomically Disadvantaged and Ethnic Minority Backgrounds

Families with socioeconomically disadvantaged and ethnic minority backgrounds are often hard to reach for the prevention and treatment of disruptive child behavior problems. We examined whether the Incredible Years parenting intervention can successfully reach and benefit families with socioeconomic disadvantaged and ethnic minority backgrounds in the Netherlands. One hundred fifty-four families from a wide range of socioeconomic and ethnic backgrounds were recruited in an outpatient clinic for child and adolescent psychiatry and in elementary schools serving deprived neighborhoods. Families were randomly assigned to the BASIC Incredible Years parenting intervention or a waiting list control condition. Children were 3–8 years old (M = 5.59, SD = 1.35; 62% boys, 66% ethnic minorities) and 65% of the children met Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.) criteria for oppositional defiant disorder, conduct disorder, and/or attention-deficit hyperactivity disorder. Incredible Years reduced parent-reported disruptive child behavior and teacher-reported hyperactive and inattentive child behavior and increased parent-reported use of praise and incentives and reduced harsh and inconsistent discipline. Incredible Years did not affect parent-reported hyperactive and inattentive child behavior; teacher-reported child conduct problems; and parent-reported use of appropriate discipline techniques, clear expectations, physical punishment, and parenting stress. Of importance, the effectiveness of Incredible Years did not differ across families with different socioeconomic and ethnic backgrounds. Effects were maintained at 3-month follow-up. This study shows that socioeconomically disadvantaged and ethnic minority families in disadvantaged neighborhoods can be engaged in and benefit from parenting interventions to reduce disruptive child behavior.     

C1q binding to surface-bound IgG is stabilized by C1r2s2 proteases

Complement is an important effector mechanism for antibody-mediated clearance of infections and tumor cells. Upon binding to target cells, the antibody’s constant (Fc) domain recruits complement component C1 to initiate a proteolytic cascade that generates lytic pores and stimulates phagocytosis. The C1 complex (C1qr₂s₂) consists of the large recognition protein C1q and a heterotetramer of proteases C1r and C1s (C1r₂s₂). While interactions between C1 and IgG-Fc are believed to be mediated by the globular heads of C1q, we here find that C1r₂s₂ proteases affect the capacity of C1q to form an avid complex with surface-bound IgG molecules (on various 2,4-dinitrophenol [DNP]-coated surfaces and pathogenic Staphylococcus aureus). The extent to which C1r₂s₂ contributes to C1q–IgG stability strongly differs between human IgG subclasses. Using antibody engineering of monoclonal IgG, we reveal that hexamer-enhancing mutations improve C1q–IgG stability, both in the absence and presence of C1r₂s₂. In addition, hexamer-enhanced IgGs targeting S. aureus mediate improved complement-dependent phagocytosis by human neutrophils. Altogether, these molecular insights into complement binding to surface-bound IgGs could be important for optimal design of antibody therapies.

Antibodies are important mediators of the human complement response, which offers critical protection against microbial infections and damaged host cells (1). In order to initiate a complement response, an antibody molecule first needs to bind antigens on the target cell via its antigen-binding (Fab) domains (2–5). Subsequently, the antibody’s constant (Fc) domain recruits the first complement protein complex, C1, to the cell surface (SI Appendix, Fig. S1A). The large C1 complex (also denoted as C1qr₂s₂, 766 kDa) consists of the recognition protein C1q (410 kDa) and a heterotetramer of serine proteases C1r and C1s (denoted C1r₂s₂, 356 kDa) (SI Appendix, Fig. S1B). While C1q is responsible for antibody recognition, its attached proteases C1r₂s₂ induce the activation of downstream enzymatic complexes (i.e., C3 convertases [C4b2b (6)]) that catalyze the covalent deposition of C3-derived molecules (e.g., C3b and its degradation product iC3b) onto the target cell surface (SI Appendix, Fig. S1A) (7, 8). C3b opsonizes the target cell surface and can induce formation of lytic pores (membrane attack complex [MAC]) in the target cell membrane (9–11). In contrast to human cells and gram-negative bacteria, gram-positive bacteria are not susceptible to the MAC due to their thick cell wall (12). On these bacteria, efficient decoration with C3b and iC3b is essential for triggering effective phagocytic uptake of target cells via complement receptors (CR) expressed on phagocytes of which the integrin CR3 (also denoted CD11b/CD18) is considered most important (13, 14).In recent years, our insights into IgG-dependent complement activation have increased significantly. A combination of structural, biophysical, and functional studies revealed that surface-bound IgG molecules (after Fab-mediated antigen binding) require organization into higher-ordered structures, namely hexamers, to induce complement activation most effectively (15–19). Hexamerized IgGs are being held together by noncovalent Fc–Fc interactions and form an optimal platform for C1q docking (SI Appendix, Fig. S1A). C1q has a “bunch of tulips–” like structure, consisting of six collagen arms that each end in a globular (gC1q) domain (SI Appendix, Fig. S1B) that binds the Fc region of an IgG. As the affinity of C1q for a single IgG is very weak (20, 21), avidity achieved through simultaneous binding of its globular domains to six oligomerized IgG molecules is paramount for a strong response (15, 17–19). Furthermore, it was found that IgG hexamerization could be manipulated by specific point mutations in the Fc–Fc contact region that enhance such oligomerization (15, 18, 22). While these hexamer-enhancing mutations in IgG potentiate the efficacy of MAC-dependent cytotoxicity on tumor cells and gram-negative bacteria (15, 23), their effect on complement-dependent phagocytosis is not known.Because complement is an important effector mechanism to kill bacteria and tumor cells, development of complement-enhancing antibodies represents an attractive strategy for immune therapies (1, 24). Immunotherapy based on human monoclonal antibodies is not yet available for bacterial infections (25–28). Such developments are mainly hampered by the fact that little is known about the basic mechanisms of complement activation on bacterial cells. For instance, we do not understand why certain antibodies induce complement activation on bacteria and others do not. In this study, we set out to investigate how antibacterial IgGs induce an effective complement response. By surprise, we noticed that C1q–IgG stability differs between human IgG subclasses. More detailed molecular investigations revealed that C1r₂s₂ proteases are important for generating stable C1q–IgG complexes on various target surfaces. Furthermore, we demonstrate that C1q–IgG stability is influenced by antibody oligomerization. These molecular insights into C1q binding to surface-bound IgGs may pave the way for optimal design of antibody therapies.     

Short-, medium-, and long-term follow-up after percutaneous transluminal coronary angioplasty for stable and unstable angina pectoris

The first 840 consecutive patients who underwent percutaneous transluminal coronary angioplasty (PTCA) performed in the same institution were retrospectively assessed at an average follow-up period of 25 months after the initial procedure. The study population consisted of 506 patients with stable angina pectoris (group 1) and 334 patients with unstable angina pectoris (group 2). Clinical end points were death, nonfatal myocardial infarction, recurrent angina pectoris necessitating bypass surgery or repeat PTCA, and event-free survival. The two groups were comparable with respect to age, sex, previous myocardial infarction, ejection fraction, and number of diseased vessels. PTCA was successful in 83.0% of group 1 and 87.1% of group 2. Follow-up rates were expressed as events per attempted PTCA in a patient group. No difference in survival was observed between the two groups, the mortality rate being approximately 2.8% at 25 months. In the group with stable angina pectoris there was a lower incidence of nonfatal myocardial infarction within the first 24 hours after angioplasty; 4.3% vs 9.0% (p less than 0.01). During long-term follow-up the increase in the incidence of nonfatal myocardial infarction was similar, resulting in an overall long-term follow-up infarction rate of 8.3% and 14.2%, respectively (p less than 0.01). A higher event-free survival was observed in group 1 within 24 hours after PTCA: 93.7% vs 84.2% (p less than 0.01). During subsequent follow-up the difference in event-free survival between the two groups was no longer significant: 68.5% vs 61.2%.(ABSTRACT TRUNCATED AT 250 WORDS)     

Incidence of restenosis after successful coronary angioplasty: a time-related phenomenon. A quantitative angiographic study in 342 consecutive patients at 1, 2, 3, and 4 months

Data from experimental, clinical, and pathologic studies have suggested that the process of restenosis begins very early after coronary angioplasty. The present study was performed to determine prospectively the incidence of restenosis with use of the four National Heart, Lung, and Blood Institute and the 50% or greater diameter stenosis criteria, as well as a criterion based on a decrease of 0.72 mm or more in minimal luminal diameter. Patients were recatheterized at 30, 60, 90, or 120 days after successful percutaneous transluminal coronary angioplasty (PTCA). After PTCA all patients received 10 mg nifedipine three to six times a day and aspirin once a day until repeat angiography. Of 400 consecutive patients in whom PTCA was successful (less than 50% diameter stenosis), 342 underwent quantitative angiographic follow-up (86%) by use of an automated edge-detection technique. A wide variation in the incidence of restenosis was found dependent on the criterion applied. The incidence of restenosis proved to be progressive to at least the third month for all except NHLBI criterion II. At 4 months a further increase in the incidence of restenosis was observed when defined as a decrease of 0.72 mm or more in minimal luminal diameter, whereas the criteria based on percentage diameter stenosis showed a variable response. The lack of overlap between the different restenosis criteria applied affirms the arbitrary nature of angiographic definitions currently in use. Restenosis should be assessed by repeat angiography, and preferably ascertained according to the change in absolute quantitative measurements of the luminal diameter.     

Myocardial resistance assessed by guidewire-based pressure-temperature measurement: in vitro validation.

By injecting a few cubic centimeters of saline into the coronary artery and using thermodilution principles, mean transit time (T(mn)) of the injectate can be calculated and is inversely proportional to coronary blood flow. Because microvascular resistance equals distal coronary pressure (P(d)) divided by myocardial flow, the product P(d). T(mn) provides an index of myocardial resistance (IMR). In this in vitro study in a physiologic model of the coronary circulation, we compared IMR to true myocardial resistance (TMR) at different degrees of myocardial resistance and at different degrees of epicardial stenosis. Absolute blood flow was varied from 42 to 203 ml/min and TMR varied from 0.39 to 1.63 dynes. sec/cm(5). Inverse mean transit time correlated well to absolute blood flow (R(2) = 0.93). Furthermore, an excellent correlation was found between IMR and TMR (R(2) = 0.94). IMR was independent on the severity of epicardial stenosis and thus specific for myocardial resistance. Thus, using one single guidewire, both fractional flow reserve and IMR can be measured simultaneously as indexes of epicardial and microvascular disease, respectively, enabling separate assessment of both coronary arterial and microvascular disease.     

An Optimal Measurement of Fixation Disparity Using Ogle’s Apparatus

ABSTRACT

Purpose: Fixation disparity (FD) is a small misalignment of the eyes within the normal alignment when viewing under binocular condition. Ogle’s apparatus measures FD. Standards of procedures vary, which may lead to different outcomes.

Methods: Students with normal ocular alignment, stereopsis ≤60 seconds of arc and visual acuity <0.1 logMAR, were included in this prospective comparative study. Four procedures (P1-P4) of measuring FD with Ogle’s apparatus were performed with divergent placement of the line (P1 and P3), or the line moving from subjective zero (P1 and P2: prisms of ascending strength; P3 and P4: prisms alternating base in base out; combined and P4). Differences in the FD curve were determined by looking at point zero, motor fusion amplitude, and the degree of FD.

Results: Twenty-six participants were examined by these 4 procedures. Point zero showed a significant difference between P1-P2 (P=0.006) and P3-P4 (P=0.001). P1 and P3 indicated the highest point zero: median of -1 and -1.5 minutes of arc exodisparity. Motor fusion amplitude showed a significant difference between P1-P2 (P=0.037), P1-P3 (P=0.004), and P2-P4 (P=0.002). P1 revealed the highest motor fusion amplitude (median of 34Δ) and P4 the lowest amplitude (median of 28Δ). No significant differences were found in esodisparity. In exodisparity there was a significant difference comparing P1-P2 (P=0.000), P3-P4 (P=0.000), and P1-P3 (P=0.021). P1 gave the highest exodisparity (median 22 minutes of arc) and P4 the lowest (median 10 minutes of arc).

Conclusion: Clinically relevant differences were found in exodisparity, mainly caused by difference in line shifting. Exodisparity was significantly lower, moving the line from subjective zero. The most accurate procedure is using prisms of ascending strength combined with divergent placement of the line (P1). These findings standardize a reliable procedure of measuring the FD curve for clinical use. Patients will not be misdiagnosed with reduced FD.     

Cognitive-behavioral therapy for women with lifelong vaginismus: a randomized waiting-list controlled trial of efficacy

Women with lifelong vaginismus (N=117) were randomly assigned to cognitive-behavioral group therapy, cognitive-behavioral bibliotherapy, or a waiting list. Manualized treatment comprised sexual education, relaxation exercises, gradual exposure, cognitive therapy, and sensate focus therapy. Group therapy consisted of ten 2-hr sessions with 6 to 9 participants per group. Assistance with minimal-contact bibliotherapy consisted of 6 biweekly, 15-min telephone contacts. Twenty-one percent of the participants left the study before posttreatment assessment. Intent-to-treat analysis revealed that successful intercourse at posttreatment was reported by 14% of the treated participants compared with none of the participants in the control condition. At the 12-month follow-up 21% of the group therapy participants and 15% of the bibliotherapy participants, respectively, reported successful intercourse. Cognitive-behavioral treatment of lifelong vaginismus was thus found to be efficacious, but the small effect size of the treatment warrants future efforts to improve the treatment.     

Quantification of striatal dopamine transporters with 123I-FP-CIT SPECT is influenced by the selective serotonin reuptake inhibitor paroxetine: a double-blind, placebo-controlled, crossover study in healthy control subjects.

Dopamine transporter (DAT) imaging with (123)I-FP-CIT ((123)I-N-omega-fluoropropyl-2beta-carbomethoxy-3beta-(4-iodophenyl)nortropane) SPECT is frequently used to detect loss of nigrostriatal cells in parkinsonism. Recent (123)I-beta-CIT ((123)I-2beta-carbomethoxy-3beta-(4-iodophenyl)tropane) studies have shown a significant increase in striatal-to-nonspecific beta-CIT binding ratios after treatment with selective serotonin reuptake inhibitors (SSRIs). Due to similarities between (123)I-beta-CIT and (123)I-FP-CIT (both are derived from cocaine and show relatively high affinity for the DAT and the serotonin transporter [SERT]), we hypothesized that quantification of striatal (123)I-FP-CIT binding may be influenced by SSRIs. Moreover, we hypothesized that (123)I-FP-CIT in humans binds not only to DATs but also to central and peripheral SERTs. METHODS: To study the influence of the SSRI paroxetine on (123)I-FP-CIT binding to DATs in the striatum, we conducted a double-blind, placebo-controlled, crossover study with paroxetine in 8 healthy young male control subjects. In addition, we studied whether paroxetine was able to block (123)I-FP-CIT binding in SERT-rich brain areas and in lung tissue, as lung tissue contains a considerable amount of SERTs. Participants were pretreated for 2 d with paroxetine (20 mg/d) or placebo at 2 sessions (crossover design), and brain SPECT was performed 1 and 3 h after (123)I-FP-CIT injection, whereas lung uptake was measured 2 h after injection. RESULTS: Compared with placebo pretreatment, we found after paroxetine pretreatment a statistically significant increase (approximately 10%) in specific striatal-to-nonspecific (123)I-FP-CIT binding ratios at 3 h after injection, a time point at which striatal (123)I-FP-CIT binding ratios are stable. In addition, after paroxetine treatment, statistically significantly lower binding ratios were found in SERT-rich brain areas (e.g., at 1 h after injection, midbrain-to-cerebellar ratios were approximately 90% lower) as well as significantly lower uptake in lung tissue was found (approximately 40% lower after paroxetine). CONCLUSION: In this study we show that the quantification of striatal (123)I-FP-CIT binding to DAT is significantly increased by the SSRI paroxetine in humans. To our knowledge, this is the first study which shows that (123)I-FP-CIT binds in vivo in humans not only to DATs but also to central SERTs and SERTs in lung tissue.     

Memory function and serotonin transporter promoter gene polymorphism in ecstasy (MDMA) users

Although 3,4-methylenedioxymethamphetamine (MDMA or ecstasy) has been shown to damage brain serotonin (5-HT) neurons in animals and possibly humans, little is known about the long-term consequences of MDMA-induced 5-HT neurotoxic lesions on functions in which 5-HT is involved, such as cognitive function. Because 5-HT transporters play a key element in the regulation of synaptic 5-HT transmission it may be important to control for the potential covariance effect of a polymorphism in the 5-HT transporter promoter gene region (5-HTTLPR) when studying the effects of MDMA as well as cognitive functioning.The aim of the study was to investigate the effects of moderate and heavy MDMA use on cognitive function, as well as the effects of long-term abstention from MDMA, in subjects genotyped for 5-HTTLPR. A second aim of the study was to determine whether these effects differ for females and males. Fifteen moderate MDMA users (<55 lifetime tablets), 22 heavy MDMA+ users (>55 lifetime tablets), 16 ex-MDMA+ users (last tablet > 1 year ago) and 13 controls were compared on a battery of neuropsychological tests. DNA from peripheral nuclear blood cells was genotyped for 5-HTTLPR using standard polymerase chain reaction methods.A significant group effect was observed only on memory function tasks (p = 0.04) but not on reaction times (p = 0.61) or attention/executive functioning (p = 0.59). Heavy and ex-MDMA+ users performed significantly poorer on memory tasks than controls. In contrast, no evidence of memory impairment was observed in moderate MDMA users. No significant effect of 5-HTTLPR or gender was observed.While the use of MDMA in quantities that may be considered "moderate" is not associated with impaired memory functioning, heavy use of MDMA use may lead to long lasting memory impairments. No effect of 5-HTTLPR or gender on memory function or MDMA use was observed.     

Clinical implications of sentinel nodes outside the axilla and internal mammary chain in patients with breast cancer

PURPOSE: The aim of this study was to determine the incidence, location, surgical identification rate, tumor status, and clinical implications of sentinel nodes outside the axilla and internal mammary chain. PATIENTS AND METHODS: In 785 breast cancer patients, pre-operative lymphoscintigraphy was performed after intratumoral injection of 116 MBq 99mTc-labeled nanocolloid (0.2 ml; 3.1 mCi). Sentinel nodes were pursued using a gamma-ray detection probe and vital blue dye. RESULTS: Lymphoscintigraphy visualized sentinel nodes outside the axilla and internal mammary chain in 91 of the 785 patients (12%). Sentinel nodes (106) were identified in 80 patients. These nodes were found in the following locations: 50 in the breast, 31 in the infraclavicular fossa, 19 between the pectoral muscles, and 6 within the supraclavicular bed. Eighteen nodes contained a metastasis (17%) and were removed from 16 patients. The treatment strategy was adjusted in 12 of them with the addition of adjuvant local or systemic therapy. Two additional patients with an unusually situated tumor-negative sentinel node were spared an axillary node dissection that would otherwise have been performed. CONCLUSION: Unusually situated sentinel nodes were visualized in 12% of the patients. The treatment was adjusted in 18% of patients in whom these nodes were identified.