[Systemic therapy for malignant melanoma]. / Medikamentöse Therapie des malignen Melanoms.

For decades dacarbazine was the standard in the therapy for metastatic melanoma even though response rates were low. In recent years multiple pharmacological approaches have led to new therapy options including immune modulators like anti-CTLA4 antibodies and kinase inhibitors of the MAPK signaling pathway that showed better response rates and increased overall survival. However, since immune modulators lead only in a small subgroup of patients to long-term responses and kinase inhibitors lose their function due to development of resistance after several months, continuation of clinical studies is strongly required. Classical chemotherapeutic drugs will remain a basic part of the therapy especially as combinations of different treatment options have to be focused on in order to achieve better long-term survival rates.

Monitoring and Tracking Changes in Sensitivity to Azoxystrobin Fungicide in Alternaria solani in Wisconsin.

Azoxystrobin is a common fungicide used by farmers of Solanaceous crops against Alternaria solani, but there was growing concern about decreased sensitivity with repeated applications. In 2002 and 2003, monitoring of A. solani from commercial potato fields in Wisconsin indicated increased frequency and a statewide distribution of isolates with decreased in vitro sensitivity to azoxystrobin. Mean effective concentration in inhibiting spore germination by 50% values gathered in 2002 and 2003 were approximately 20-fold higher than baseline isolates of A. solani collected in 1998 from fields that had never been treated with azoxystrobin. This sensitivity decrease was correlated with site-specific mutations in the cytochrome b detected by quantitative real-time polymerase chain reaction. The F129L and the G143A substitution have been shown to cause a reduction in sensitivity or resistance, respectively, to quinone outside inhibitors. All of the recovered A. solani isolates collected in 2002 and 2003 were wild type at position 143. However, all three mutations responsible for the F129L substitution (TTA, CTC, and TTG) were detected in our samples. In addition, the frequency of this amino acid substitution in A. solani isolates was statistically different across sampling sites and years, indicating that sensitivity changes depended on specific disease management practices.

Dynamics of QoI Sensitivity in Mycosphaerella fijiensis in Costa Rica During 2000 to 2003.

ABSTRACT From 1997 onward, the strobilurin fungicide azoxystrobin was widely used in the main banana-production zone in Costa Rica against Mycosphaerella fijiensis var. difformis causing black Sigatoka of banana. By 2000, isolates of M. fijiensis with resistance to the quinolene oxidase inhibitor fungicides were common on some farms in the area. The cause was a single point mutation from glycine to alanine in the fungal target protein, cytochrome b gene. An amplification refractory mutation system Scorpion quantitative polymerase chain reaction assay was developed and used to determine the frequency of G143A allele in samples of M. fijiensis. Two hierarchical surveys of spatial variability, in 2001 and 2002, found no significant variation in frequency on spatial scales <10 m. This allowed the frequency of G143A alleles on a farm to be estimated efficiently by averaging single samples taken at two fixed locations. The frequency of G143A allele in bulk samples from 11 farms throughout Costa Rica was determined at 2-month intervals. There was no direct relationship between the number of spray applications and the frequency of G143A on individual farms. Instead, the frequency converged toward regional averages, presumably due to the large-scale mixing of ascospores dispersed by wind. Using trap plants in an area remote from the main producing area, immigration of resistant ascospores was detected as far as 6 km away both with and against the prevailing wind.

Calcium measurement in living filamentous fungi expressing codon-optimized aequorin.

Calcium signalling is little understood in filamentous fungi largely because easy and routine methods for calcium measurement in living hyphae have previously been unavailable. We have developed the recombinant aequorin method for this purpose. High levels of aequorin expression were obtained in Neurospora crassa, Aspergillus niger and Aspergillus awamori by codon optimization of the aequorin gene. Three external stimuli (mechanical perturbation, hypo-osmotic shock and high external calcium) were found transiently to increase [Ca(2+)](c). Each of the calcium signatures associated with these physico-chemical treatments was unique, suggesting the involvement of three distinct calcium-mediated signal transduction pathways. The fungal calcium channel blocker KP4 inhibited the [Ca(2+)](c) responses to hypo-osmotic shock and high external calcium, but not to mechanical perturbation. The divalent cation chelator BAPTA inhibited [Ca(2+)](c) responses to mechanical perturbation and hypo-osmotic shock. The calcium agonists A23187 and cyclopiazonic acid increased [Ca(2+)](c) levels.

Behavioral and emotional problems among children of cocaine- and opiate-dependent parents.

OBJECTIVE: To test associations between parental drug abuse and children's problems, children of cocaine- and opiate-dependent parents were compared with demographically matched referred and nonreferred children. METHOD: Cocaine- and opiate-dependent parents in treatment completed the Child Behavior Checklist for 410 children (218 boys, 192 girls) from ages 2 through 18 years (mean = 7.9 years). Children of drug abusers (CDAs) were demographically matched to referred (RCs) and nonreferred children (NRCs). RESULTS: RCs scored lower than CDAs and NRCs on most competence scales, and higher than CDAs and NRCs on all problem scales. CDAs scored lower than NRCs on most competence scales, and higher than NRCs on Withdrawn, Thought Problems, Delinquent Behavior, Aggressive Behavior, Internalizing, Externalizing, and Total Problems. Group status also predicted clinical range scores on most competence and all problem scales. CONCLUSIONS: CDAs showed more internalizing and externalizing psychopathology relative to matched NRCs, but they showed significantly less psychopathology than shown by matched RCs. CDAs are an important group to target for preventive interventions.

Six-year predictors of problems in a national sample: IV. Young adult signs of disturbance.

OBJECTIVE: To identify adolescent predictors of young adult signs of disturbance. METHOD: Family variables and parent- and self-reported syndromes, competencies, and stressful experiences were tested as predictors of school dropout, unwed pregnancy, substance use, mental health services, suicidal behavior, police contacts, and being fired from jobs. RESULTS: Most signs were predictable with considerable accuracy, especially suicidal behavior and being fired from jobs among females. The Delinquent Behavior syndrome and poor school functioning predicted the most poor outcomes. Concurrent scores on young adult syndromes were significantly associated with most signs. CONCLUSIONS: Across the diversity of a national sample, young adult signs of disturbance were predictable from risk and protective factors assessed in adolescence. The predictors can help to identify youth at risk for particular signs. Parents are important contributors to assessment of young adults' problems.

Accelerated longitudinal comparisons of aggressive versus delinquent syndromes.

Accelerated longitudinal analyses revealed both similarities and differences between the developmental trajectories of empirically based aggressive versus delinquent syndromes in childhood and adolescence. Syndromes were scored from standardized ratings obtained from parents five times at 2-year intervals for seven birth cohorts of Dutch children initially assessed at ages 4 to 10 years. Scores for both the aggressive and delinquent syndromes declined from ages 4 to 10. After about age 10 years, scores for the aggressive syndrome continued to decline, but scores for the delinquent syndrome increased until about age 17. The aggressive syndrome was significantly more stable than the delinquent syndrome. Long-term predictive correlations between matched subjects from different cohorts were as high as predictive correlations between scores obtained by the same subjects, thus supporting the validity of accelerated longitudinal analyses. The results highlight important developmental distinctions between aggressive versus delinquent conduct problems. Failure to distinguish between aggressive and delinquent conduct problems could generate misleading conclusions about their respective developmental courses and limit the generalizability of results.

Clinical study of the relation of borderline personality disorder to Briquet's syndrome (hysteria), somatization disorder, antisocial personality disorder, and substance abuse disorders.

OBJECTIVE: The criteria for borderline personality disorder seem to select patients with very high rates of Briquet's syndrome (hysteria), somatization disorder, antisocial personality disorder, and substance abuse disorders. This study was undertaken to determine whether systematic assessment of patients with borderline personality disorder would reveal characteristic features of that condition which would distinguish it from these other disorders. METHOD: Eighty-seven white female patients (75 in St. Louis and 12 in Milan, Italy) who had borderline personality disorder according to both the DSM-III-R criteria and the Revised Diagnostic Interview for Borderlines were further examined with the DSM-III-R Checklist and the Perley-Guze Hysteria Checklist to determine their patterns of psychiatric comorbidity. RESULTS: Every patient had at least one additional DSM diagnosis. Patients in St. Louis and Milan averaged five and four additional diagnoses, respectively. Eighty-four percent of the patients in St. Louis met criteria for either somatization disorder, Briquet's syndrome, antisocial personality disorder, or substance abuse disorders. Patterns of comorbidity for panic (51%), generalized anxiety disorder (55%), and major depression (87%) in St. Louis were consistent with those in other studies. CONCLUSIONS: The data indicate that the boundaries for the borderline condition are not specific and identify a high percentage of patients with these other disorders. Furthermore, the comorbidity profiles closely resemble the psychiatric profiles of patients with these disorders. If the borderline syndrome is meant to include all of these disorders, its usefulness as a diagnosis is limited. Until the fundamental features of borderline personality disorder that distinguish it from the others are identified, it is recommended that clinicians carefully assess patients for these other diagnoses. Efforts should be made to change the borderline personality disorder criteria by shifting away from overlap with the criteria for the other disorders.

Predictors of cross-informant syndromes among children and youths referred for mental health services.

This study sought to identify which syndromes of initial problems predicted later syndromes among children and youths referred for mental health services. Standardized parent reports on the Child Behavior Checklist obtained at intake were compared to standardized parent, teacher, and self-reports obtained at follow-up. There were 1,103 subjects (774 males and 329 females) 4 to 18 years old, followed up an average of 6 years after referral. High quantitative and categorical stability was found for cross-informant syndromes within samples of younger and older subjects. Throughout childhood and into young adulthood, parent ratings of most syndromes at the time of referral predicted the counterpart cross-informant syndrome construct at follow-up, controlling for other types of problems at referral. There were multiple additional independent predictors of many syndromes, including Delinquent Behavior, Aggressive Behavior, and Shows Off for young adult males. Time 1 Social Problems and Attention Problems independently predicted diverse problems at Time 2 for younger males. A wide variety of problems also predicted younger males' self-ratings of withdrawal, anxiety, and depression. The stability of problems for the referred sample was similar to that found for demographically matched nonreferred subjects drawn from a national sample.

Six-year predictors of problems in a national sample: III. Transitions to young adult syndromes.

OBJECTIVE: To test developmental paths from adolescent syndromes and other candidate predictors to young adult syndromes. METHOD: A national sample assessed at ages 13 through 16 and 16 through 19 years was reassessed at 19 through 22 years in terms of six syndromes derived empirically from parent and self-reports, two syndromes derived only from parent reports, and one derived from self-reports. RESULTS: Several young adult syndromes were similar to adolescent syndromes and were strongly predicted by these syndromes. A new syndrome designated as Shows Off and an adult Aggressive Behavior syndrome were both predicted by the adolescent Aggressive Behavior syndrome. This indicates a developmental transition away from overt aggression among some aggressive youths but not others. A syndrome designated as Irresponsible was predicted by the adolescent Attention Problems syndrome and may be an adult phenotype of attention deficit disorder. Surprisingly, attention problems were associated with more diverse problems among females than males. CONCLUSIONS: There are strong predictive relations from adolescent to adult syndromes. Sex differences in predictive paths argue against basing assumptions about both sexes on findings for one sex.

Six-year predictors of problems in a national sample of children and youth: II. Signs of disturbance.

OBJECTIVE: To identify 1986 and 1989 variables that significantly predicted signs of disturbance assessed in 1992. METHOD: 1986 parent reports and 1989 parent, teacher, and self-reports of syndromes, competencies, family variables, and stressful experiences were tested as predictors of 1992 reports of academic problems, school behavior problems, receipt of mental health services, suicidal behavior, police contacts, substance abuse, and the sum of these six signs. RESULTS: The predictors accounted for large percentages of variance in most signs and predicted fairly accurately which members of case-control samples would manifest specific signs. Overall predictive accuracy was similar for both sexes, but many predictors differed for boys versus girls. The six signs were weakly associated with each other but were strongly associated with particular syndromes. CONCLUSIONS: Signs of disturbance were predictable over a 6-year period despite the diversity of a national sample. Previous manifestations of certain signs were modest predictors of the same signs. The Delinquent Behavior and Attention Problems syndromes, plus stressful experiences, predicted the most signs. Sex differences in predictors argue against generalizing findings and inferences from one sex to the other.

Six-year predictors of problems in a national sample of children and youth: I. Cross-informant syndromes.

OBJECTIVE: To illuminate the development of psychopathology by tracing 6-year predictive paths to outcomes assessed in terms of empirically based syndromes. METHOD: A national sample assessed at ages 4 through 12 years via parent reports was reassessed 3 and 6 years later via parent, teacher, and self-reports. RESULTS: For syndromes having the clearest DSM counterparts, cross-informant predictive paths revealed similar traitlike patterns for Aggressive Behavior in both sexes; Delinquent Behavior was less traitlike, with greater sex differences in predictive paths; the Attention Problems syndrome was developmentally stable, but, surprisingly, it was associated with more diverse difficulties among girls than boys; conversely, Anxious/Depressed was associated with more diverse difficulties among boys than girls. CONCLUSIONS: Quantification of problems via empirically based syndromes can detect important sex, age, and developmental variations that may be masked by uniform diagnostic cutoff points for both sexes and diverse ages. This may be especially true for diagnostic cutoff points derived mainly from clinical cases of one sex, such as depression for girls versus attention and conduct disorders for boys.

Three-year course of behavioral/emotional problems in a national sample of 4- to 16-year-olds: 3. Predictors of signs of disturbance.

We tested parent-reported family variables, problems, competencies, and stress as predictors of (a) academic problems, (b) school behavior problems, (c) receipt of mental health services, (d) child's need for additional help, (e) suicidal behavior, (f) police contacts, and (g) the sum of these 6 outcomes. Included in the study were 995 cases manifesting at least 1 sign of disturbance (from Outcomes a-f) and 995 matched controls from a national sample of 2,479 children assessed twice over a 3-year interval. Path analyses identified predictors that were significant across age and sex plus those specific to particular groups. The predictive models accounted for medium to large effects in Time 2 signs of disturbance. Time 2 Child Behavior Checklist scores were significantly associated with all Time 2 disturbance scores. The multiple significant risk factors associated with signs of disturbance indicated variations in pathways leading to particular signs of disturbance.

Three-year course of behavioral/emotional problems in a national sample of 4- to 16-year-olds: II. Predictors of syndromes.

This study examined relations between parents' ratings of children's behavioral/emotional problems, family variables, and stressful experiences as predictors of 3-year outcomes in a nationally representative sample of American children. Outcomes were measured by time 2 parent, teacher, and self ratings on eight empirically derived cross-informant syndromes. Path analyses indicated that parent ratings of each time 1 syndrome predicted parent ratings of the same time 2 syndrome. Family variables and intervening stressful experiences predicted parent and self ratings, but not teacher ratings of syndromes. The number of family members receiving mental health services was the family variable that predicted the most time 2 syndromes. Parent reports of stress predicted parent ratings of time 2 syndromes, whereas child reports of stress predicted self-ratings of time 2 syndromes.

Three-year course of behavioral/emotional problems in a national sample of 4- to 16-year-olds: I. Agreement among informants.

Quantitative and categorical indices of psychopathology are reported for a nationally representative longitudinal sample assessed via eight empirically derived cross-informants syndromes, internalizing, externalizing, and total problems. Results showed medium to large stabilities for parents' ratings during a 3-year interval on all comparable scales. Predictive correlations between time 1 parents' ratings and time 2 teacher and self-ratings were weaker than parent-to-parent correlations. Classification of children as deviant showed weaker predictive relations than did quantitative scores. Odds ratios showed that children classified as deviant by parents' time 1 ratings were much more likely to be deviant at time 2 on corresponding parent, teacher, and self-ratings than were children initially classified as nondeviant.

In utero cocaine exposure: observations of fetal behavioral state may predict neonatal outcome.

Components of fetal behavioral state organization reflect the successful integration of the central nervous system, have a specific developmental timetable, and can be studied with fetal ultrasonographic techniques. To test the hypothesis that evaluation of state organization is a marker of abnormal central nervous system maturation and a predictor of risk, we studied 20 fetuses and newborns exposed to cocaine in utero. Fetal assessments were accomplished by serial ultrasonographic examination, videotaped, and scored by a scheme developed by the authors to assess organization and regulation of behavioral states. Newborn neurobehavioral assessments also emphasized organization and regulation of behavioral state. Abnormal or delayed state behavior was identified in 13 of 20 fetuses. State organization was evaluated as suspect or abnormal for 16 of the 20 exposed newborns. Disorganized behavioral state in the fetus successfully predicted abnormal newborn behavior. These findings support the concepts that cocaine exposure disrupts central nervous system development and that fetal assessment of state is predictive of neonatal outcome.

Self development and self-conscious emotions.

In each of 2 studies, the mirror-rouge technique was used to differentiate children into those who showed self-recognition and those who did not. In Study 1, 27 children (aged 9-24 months) were observed in 2 experimental situations thought to differentially elicit fear and embarrassment behaviors. In Study 2, 44 children (aged 22 months) were seen in the situations of Study 1 and 3 additional contexts thought to elicit embarrassment behavior. The results of both studies indicate that embarrassment but not wariness was related to self-recognition.

Serial neuropsychological follow-up of a child following craniospinal irradiation.

Serial neuropsychological examinations were made of an eight-year-old girl following diagnosis and treatment of a pineocytoma. The tumor was resected and she received intensive radiation therapy to the entire neuraxis, with a boost to the pineal region. A battery of neuropsychological tests was administered every six to eight weeks, beginning before and continuing for 48 weeks after radiation therapy. Parental questionnaires on the patient's everyday behavior were obtained, as well as past and present school records. MRI studies were performed seven weeks, nine months and 14 months after treatment had ended. The only functional area showing deterioration over the follow-up period was memory, both verbal and spatial. The MRIs showed no abnormalities related either to the tumor or to the radiation therapy.