Psychodynamic therapy for adolescents suffering from co-morbid disorders of conduct and emotions in an in-patient setting: a randomized controlled trial.

BACKGROUND: Co-morbid disorders of conduct and emotions can be regarded as childhood antecedents of further negative developments (e.g. manifestation of personality disorders in adulthood). We evaluated a manualized psychodynamic therapy (PDT) for adolescents with these co-morbid disorders. METHOD: In a randomized controlled trial (RCT), 66 adolescents diagnosed with mixed disorders of conduct and emotions (F92 in ICD-10) were randomly assigned to a manualized in-patient PDT group or a waiting list/treatment-as-usual (WL/TAU) control condition. Diagnoses according to DSM-IV were also documented. Patients were compared using rates of remission as the primary outcome. The Global Severity Index (GSI) and the Strengths and Difficulties Questionnaire (SDQ) were used as secondary measures. Assessments were performed at baseline, post-treatment and at the 6-month follow-up. RESULTS: The sample consisted of severely impaired adolescents with high rates of further co-morbid disorders and academic failure. Patients in the treatment group had a significantly higher rate of remission [odds ratio (OR) 26.41, 95% confidence interval (CI) 6.42-108.55, p < 0.001]. Compared with the control group, the PDT group resulted in significantly better outcomes on the SDQ (p = 0.04) but not the GSI (p = 0.18), with small between-group effect sizes (SDQ: d = 0.38, GSI: d = 0.18). However, the scores of patients treated with PDT were post-treatment no longer significantly different from normative data on the GSI and within the normal range on the SDQ. The effects in the treatment group were stable at follow-up. Furthermore, most patients were reintegrated into educational processes. CONCLUSION: PDT led to remarkable improvement and furthered necessary preconditions for long-term stabilization. In future, PDT should be compared to other strong active treatments.

A physical map and candidate genes in the BRCA1 region on chromosome 17q12-21.

We have constructed a physical map of a 4 cM region on chromosome 17q12-21 that contains the hereditary breast and ovarian cancer gene BRCA1. The map comprises a contig of 137 overlapping yeast artificial chromosomes and P1 clones, onto which we have placed 112 PCR markers. We have localized more than 20 genes on this map, ten of which had not been mapped to the region previously, and have isolated 30 cDNA clones representing partial sequences of as yet unidentified genes. Two genes that lie within a narrow region defined by meiotic breakpoints in BRCA1 patients have been sequenced in breast cancer patients without revealing any deleterious mutations. These new reagents should facilitate the identification of BRCA1.

Origin of the West Nile virus responsible for an outbreak of encephalitis in the northeastern United States.

In late summer 1999, an outbreak of human encephalitis occurred in the northeastern United States that was concurrent with extensive mortality in crows (Corvus species) as well as the deaths of several exotic birds at a zoological park in the same area. Complete genome sequencing of a flavivirus isolated from the brain of a dead Chilean flamingo (Phoenicopterus chilensis), together with partial sequence analysis of envelope glycoprotein (E-glycoprotein) genes amplified from several other species including mosquitoes and two fatal human cases, revealed that West Nile (WN) virus circulated in natural transmission cycles and was responsible for the human disease. Antigenic mapping with E-glycoprotein-specific monoclonal antibodies and E-glycoprotein phylogenetic analysis confirmed these viruses as WN. This North American WN virus was most closely related to a WN virus isolated from a dead goose in Israel in 1998.

Antibody to dengue 1 detected more than 60 years after infection.

We investigated the duration of humoral responses to dengue virus infection in individuals who recalled experiencing dengue fever-like illnesses at the time of the Second World War, when dengue fever epidemics occurred throughout the Pacific and Southeast Asia. In July 1943 dengue fever reappeared in Hawaii following an interval of 31 years. Over the next 12 months a total of 1498 locally transmitted cases were reported, and at least 46 imported cases were identified, most of which were among members of the military returning from the Pacific Theatre of the war. Serum samples collected in 2005, more than 60 years after onset of symptoms, were tested for the presence of dengue-specific antibodies using a rapid ELISA test, and by plaque reduction neutralization test. Four of seven samples were positive for dengue-specific IgG and demonstrated neutralization titers >or=160 to dengue 1. We describe the existence of dengue-specific antibodies in the serum of people infected more than 60 years earlier.

Identification of three regions on chromosome 17q in primary human breast carcinomas which are frequently deleted.

We have examined the long arm of chromosome 17 in sporadic breast carcinomas for the loss of heterozygosity (LOH) at 18 polymorphic loci. At least three distinct regions could be identified by the frequency of LOH and confirmed by high density deletion maps of individual tumor DNAs. A proximal region affected by LOH is located in a 22-cM region defined by D17S73 and NME1 and thus is similar in location to the region thought to contain the BRCA1 gene associated with familial breast and breast/ovarian cancer. The central region affected by LOH is bordered by the D17S86 and D17S21 loci and is estimated to be 28 cM in size. The third region is bordered by the D17S20 and D17S77 loci which are 11 cM apart. These results define three independent regions of chromosome 17q which are likely to contain tumor suppressor genes relevant to the etiology of sporadic breast carcinoma.

Two distinct regions involved in 1p deletion in human primary breast cancer.

Alteration of chromosome 1 is the most consistent cytogenetic abnormality found in human breast carcinoma. Cytogenetic studies have shown independent alterations on the two arms of chromosome 1, increased copy number of the long arm and loss of the short arm of chromosome 1. These deletions are thought to coincide with the location of tumor suppressor gene(s). We carried out deletion analysis of the 1p region by using restriction fragment length polymorphism markers mapping to the long (six markers) and short arm (22 markers). Thirty-five of the 74 (47.3%) human breast tumors tested showed somatic loss of heterozygosity at one or more loci on the short arm. Two commonly deleted regions, 1p13-p21 and 1p32-pter, were identified. The latter region is frequently involved in other types of tumors, suggesting that it harbors a common tumor suppressor gene. Our findings suggest that two tumor suppressor genes involved in the development of human breast carcinoma may occur on the short arm of the chromosome 1.

Frequent alteration of the DF3 tumor-associated antigen gene in primary human breast carcinomas.

The gene for the human DF3 breast carcinoma-associated antigen contains a conserved (G + C)-rich 60-base pair tandem repeat and maps to chromosome 1q21-24. In the present study we isolated and characterized 1220 base pairs of nonrepetitive adjacent sequences. Multiple alleles were identified by fragment size. Signal intensity of hybrids with the tandem and unique sequence probes indicated that allelic variation is due to different numbers of repeats. Probes for both the tandem and the unique sequences were used to study the DF3 locus in human breast tumor DNAs. Seventy of 110 breast tumor DNAs were informative at the DF3 locus. Of these, 20 (29%) showed a loss of heterozygosity, while eight (11%) had an increased copy number of one allele. In some cases, the loss of heterozygosity or increased copy number did not extend to other markers on chromosome 1q or 1p. These data indicate that the chromosomal region around the DF3 locus is affected by mutations at high frequency.

Somatic allelic deletion of nm23 in human cancer.

Tumor progression to the metastatic phenotype is accompanied in certain cell types by reduced expression of the nm23 gene. We have localized human nm23-H1 to chromosome 17 by somatic cell hybrid analysis. Regional localization in the CEPH database and in situ hybridization is reported. Somatic allelic deletion of nm23-H1 was observed in human breast, renal, colorectal, and lung carcinoma DNA samples, as compared to DNA from matched normal tissues. A homozygous deletion of nm23-H1 was observed in a lymph node metastasis of a colorectal carcinoma, indicating that nm23-H1 can be recessively inactivated. The data identify nm23-H1 as a novel, independent locus for allelic deletion in human cancer, a characteristic shared with previously described suppressor genes.

Evidence for involvement of BRCA1 in sporadic breast carcinomas.

The hereditary breast cancer gene BRCA1 previously has been localized to chromosome 17q21. We looked for evidence of involvement of this region of chromosome 17 in 130 sporadic breast cancers. Seventeen polymorphic sequence tagged site markers were examined in these tumors between the D17S250 and D17S579 loci to screen for deletions as measured by loss of heterozygosity. The smallest common region that was deleted occurred in the approximately 120-kilobase interval between the D17S846 and D17S746 loci within the BRCA1 region. Delineation of this commonly deleted area should accelerate attempts to identify the involved gene(s) and its relationship to BRCA1.

The role of protein kinase-C in gonadotropin-induced ovulation in the in vitro perfused rabbit ovary.

Tumor-promoting phorbol esters are believed to affect ovarian granulosa cell progesterone and prostaglandin (PG) production and possibly ovulation by activating protein kinase-C (PKC). The effects of phorbol esters and PKC inhibitors on ovulation, progesterone, and PG production were examined in an in vitro perfused rabbit ovary. The effect of tranexamic acid, an inhibitor of the conversion of plasminogen activator to plasmin, on phorbol ester-induced ovulation was also examined. Phorbol 12,13-dibutyrate (PdBU), a PKC stimulator, induced ovulation in a dose-related manner in the absence of gonadotropins (56%, 200 nM PdBU; 0%, 0 nM PdBU; P < 0.05). Perfusate progesterone levels were increased only after 600 nM PdBU treatment, and perfusate PGF2 alpha, PGE2, and 6-keto-PGF1 alpha were increased in a dose-dependent fashion (P < 0.05). Staurosporine, a potent inhibitor of the catalytic domain of PKC, and calphostin-C, a specific inhibitor of the diacylglycerol-binding region, inhibited hCG-induced ovulation in a dose-related manner. Gonadotropin-induced ovulation decreased from 73% without staurosporine to 19% with 1.0 microM staurosporine (P < 0.01). Calphostin-C reduced ovulatory efficiency from 60% to 24% (P < 0.01). However, neither inhibitor decreased progesterone or PGF2 alpha production by ovaries exposed to hCG. hCG-induced oocyte maturation was also unaffected by exposure to either staurosporine or calphostin-C. Tranexamic acid reduced phorbol ester-induced ovulatory efficiency from 67% to 37% (P < 0.05). These findings demonstrate that the calcium-dependent PKC pathway is instrumental in gonadotropin-mediated follicular rupture in the rabbit. Although PGs may play an important role in ovulation, they do not appear to be directly responsible for PKC-mediated follicular rupture.

Detection of loss of heterozygosity in tumor DNA samples by PCR.

We demonstrate that PCR amplification of human genomic DNA can be used for the detection of loss of heterozygosity (LOH) in tumor samples. A 250-bp fragment containing codon 72 of the human p53 gene was amplified, ThaI digested and electrophoresed. Tumor LOH is detectable both by ethidium bromide staining and autoradiography, despite 25% contamination with normal DNA. This technique provides a fast and reproducible alternative to conventional Southern blotting and has minimal sample requirements.

Clinical pharmacokinetics in the 21st century. Does the evidence support definitive outcomes?

Clinical pharmacokinetics emerged as a clinical discipline in the late 1960s and early 1970s. Clinical pharmacokinetic monitoring (CPM) helped many pharmacists to enter the clinical arena, but the focus was more on the pharmacists and tools. With the widespread acceptance of pharmaceutical care and patient-focused pharmacy, we now must take a sobering look at how clinical pharmacokinetics fits into the pharmaceutical care process. The existing literature is laden with articles that evaluate the effect of CPM on surrogate end-points. Many pharmacists have also had personal experiences that attest to the usefulness of CPM. Decreased mortality, decreased length of treatment, decreased length of hospital stay, decreased morbidity, and decreased adverse effects from drug therapy have been examined in an effort to measure and evaluate the impact of CPM on patient outcomes. While many of these studies demonstrated significant positive outcomes, several showed that CPM did not have a significant impact on specific patient outcomes. A few studies even found a negative impact on specific patient outcomes. Ultimately, there is good evidence in only a few specific patient groups to support the benefit of CPM. Despite the limitations of data supporting the routine use of CPM in managing drug therapy in diverse populations, many pharmacists continue to expend considerable time and effort in this activity. We need to define those patients who are most likely to benefit from CPM and incorporate this into our provision of pharmaceutical care, while minimising the time and money spent on CPM that provides no value. In redefining the patients who will benefit from CPM, we need to critically re-evaluate clinical studies on the relationship between drug concentration and response. Similarly, we need to pay special attention to recent studies evaluating the impact of CPM on outcomes in specific subpopulations. In the absence of specific studies demonstrating the value of CPM in particular patients, we propose that a more comprehensive decision-making process be undertaken that culminates in the quintessential question: 'Will the results of the drug assay make a significant difference in the clinical decision-making process and provide more information than sound clinical judgement alone?' We also need to consider opportunities to expand the use of CPM for new drugs and where new evidence suggests benefit. Even when there is strong evidence that CPM is useful in managing therapy in particular patient groups, clinicians need to remember that the therapeutic range is no more than a confidence interval and, therefore, we need to 'treat the patient and not the level'. We need to incorporate the patient-specific and outcome-oriented principles of pharmaceutical care into our CPM, even as we utilise CPM as an essential tool in pharmaceutical care.

Mutations in breast cancer.

The genetics of spontaneous breast cancer is reviewed. We have identified three regions of amplification and nine chromosomal arms with deletions in the genome. The significance and interrelations of these mutations is discussed with respect to the complex genetics of breast carcinoma. Recent work identifying a commonly deleted region between D17S846 and D17S746 is presented, which is approximately 0.5-1.0 Mb centromeric to the newly described BRCA1 gene candidate. Possible explanations for the different locations of our deleted region and the BRCA1 gene are presented.

Evaluation of an IgM immunoblot kit for dengue diagnosis.

A commercial IgM immunoblot kit was evaluated for dengue diagnosis with a panel of serum specimens collected from patients in a dengue endemic area. The kit is not recommended for use in its present form because of its undesirable rate of false-positive results. However, by substituting internal controls with the reference positive and negative controls that are more representative of those seen in endemic areas and by modifying the positive and negative scoring criteria, sensitivity and specificity of 80.3% and 94.5%, respectively, were obtained. These results are comparable with those obtained with the IgM ELISA on specimens, most of which were obtained from outpatient health care facilities. With further technical modifications, inclusion of a visual guide to ensure scoring standardization, and a more complete elaboration of the limitations of the test, wide application of the kit in diagnostic laboratories should be possible.

Experimental infection of house sparrows (Passer domesticus) with Rocio virus.

Rocio encephalitis is a new epidemic flaviviral infection of man, first described in São Paulo State, Brazil in 1975. The ecology of the viral transmission cycle remains largely unknown. Experimental studies were undertaken to assess the role of a wild avian species, the House Sparrow, as a maintenance or amplifying host. Approximately two-thirds of nesting and adult sparrows developed 2- to 3-day viremias of low to moderate magnitude (2.0--4.3 log/ml). Rocio-immune birds were not protected against challenge with St. Louis encephalitis (SLE) virus, but prior SLE viral infection prevented detectable viremia in birds challenged with Rocio virus. These studies provide some support for the hypothesis that birds are hosts for Rocio virus, but the House Sparrow probably plays a relatively minor role in viral transmission. Because sparrows are relatively inefficient viremic hosts, they would be expected to play a minor role in transmission should Rocio virus be introduced into the United States.

Arbovirus infections among laboratory personnel in Ibadan, Nigeria.

Laboratory-acquired infections encountered between 1963 and 1977 among personnel of the Virus Research Laboratory, Ibadan, Nigeria, are reported. Two cases of chikungunya infection occurred and one each with Dugbe, Wesselsbron, and dengue viruses. In each case, virus was isolated or development of antibody demonstrated. Among virus and two each to chikungunya and Rift Valley fever viruses, without experiencing any clinically recognized disease.

Yellow fever monoclonal antibodies: type-specific and cross-reactive determinants identified by immunofluorescence.

Monoclonal antibodies directed against the envelope glycoprotein and the NV3 non-structural viral protein of yellow fever (YF) were tested by the indirect fluorescent antibody technique against a variety of YF virus strains and heterologous flaviviruses. Monoclonal antibodies directed against the envelope glycoprotein exhibited YF strain-specificity, YF type-specificity, broad group cross-reactivity, or limited subgroup reactivity (YF + Banzi or YF + Koutango + Zika + Usutu + Uganda S). Monoclonal antibodies directed against NV3 reacted either with YF + Koutango or with YF + Banzi. These findings generally correlated with the results of biological tests reported previously. Monoclonal antibodies that were type-specific to YF will be useful for the rapid specific identification of YF virus isolates and are available from the Centers for Disease Control on request.

Effect of human gamma interferon on yellow fever virus infection.

We studied yellow fever virus infection in two species of monkey: Saimiri sciureus (squirrel monkeys) and Macaca mulatta (rhesus monkeys). Human gamma interferon was administered intravenously in five equal doses, one was given 24 hr before infection followed by four doses 24 hr apart. Interferon reduced the levels and duration of viremia and the severity of hepatitis in squirrel monkeys. Interferon prolonged survival time and delayed the appearance of viremia and hepatitis in infected rhesus monkeys, but it did not change overall mortality.

Arbovirus investigations in Argentina, 1977-1980. II. Arthropod collections and virus isolations from Argentine mosquitoes.

Prospective surveys for arboviruses were carried out in Santa Fe, Corrientes, and Chaco provinces, Argentina, aperiodically during 1977-1980. A total of 313,233 mosquitoes and 598 biting flies other than mosquitoes were collected and tested for virus in 5,197 and 45 pools, respectively. Forty virus strains were isolated, all from mosquitoes, as follows: Santa Fe Province: 4 Gamboa group viruses from Aedeomyia squamipennis, 1 strain each of St. Louis encephalitis virus from Culex pipiens quinquefasciatus and Culex (Culex) spp.; Corrientes Province: a single strain of a newly discovered Anopheles A serogroup virus, Las Maloyas, from Anopheles albitarsis; and Chaco Province: 4 Gamboa group viruses from Ad. squamipennis, 6 strains of new Bunyaviridae (1 Antequera, 1 Barranqueras, and 4 Resistencia) from Culex (Melanoconion) delpontei, 3 strains of a new subtype of western equine encephalitis virus and 1 strain of Para virus from the Cx. (Mel.) ocossa group, 12 strains of a newly discovered subtype (VI) of the Venezuelan equine encephalitis complex from Cx. (Mel.) delpontei, and 1 strain each from Ad. squamipennis, Aedes scapularis, Ae. spp., Cx. (Cux.) spp., Cx. (Mel.) ocossa group, Mansonia spp., and Psorophora spp. Bloodmeals from 265 engorged mosquitoes were identified by precipitin test. These data, coupled with data on engorgement rates for 25,995 mosquitoes from bait collections, provide information on the host feeding patterns of several mosquito species. This information is discussed, along with data on relative abundance of mosquito species, within the context of the vector relationships of the species from which viruses were isolated. The association of Cx. (Mel.) delpontei with 18 strains of 4 different viruses in Chaco Province, plus its catholic feeding habits, clearly indicate for the first time the importance of this species as an arbovirus vector.

Arbovirus investigations in Argentina, 1977-1980. III. Identification and characterization of viruses isolated, including new subtypes of western and Venezuelan equine encephalitis viruses and four new bunyaviruses (Las Maloyas, Resistencia, Barranqueras, and Antequera).

Forty viruses isolated from mosquitoes between 1977 and 1980 in Argentina have been identified and characterized. Nineteen strains of VEE virus, identical by neutralization (N) tests, were shown by hemagglutination-inhibition tests with anti-E2 glycoprotein sera to represent a new subtype VI of the VEE complex. RNA oligonucleotide fingerprints of this virus were distinct from subtype I viruses. The virus was not lethal for English short-haired guinea pigs, indicating that it is probably not equine-virulent. Three strains of a member of the WEE virus complex were shown to differ by N tests in 1 direction from prototype WEE virus. The new WEE subtype was also found to be distinct by RNA oligonucleotide mapping. Its vector relationships indicate that it is an enzootic virus, and it has not been associated with equine disease. A new member of the Anopheles A serogroup was identified, shown to be most closely related to Lukuni and Col An 57389 viruses, and given the name Las Maloyas virus. A strain of Para virus (Bunyaviridae, Bunyavirus) was identified. Six isolates, representing 3 new viruses morphologically resembling bunyaviruses are described; the names Antequera, Barranqueras, and Resistencia are proposed for these agents, which were all isolated from Culex (Melanoconion) delpontei in Chaco Province. No serologic relationships between these viruses and other bunyaviruses were found. Since they are antigenically interrelated, they form a new (Antequera) serogroup. Eight Gamboa serogroup viruses and 2 strains of St. Louis encephalitis virus were also identified.