Regulation of thyroid hormone metabolism in rat liver fractions

The nature of the conversion of thyroxine (T₄) to triiodothyronine (T₃) and reverse triiodothyronine (rT₃) was investigated in rat liver homogenate and microsomes. A 6-fold rise of T₃ and 2.5-fold rise of rT₃ levels determined by specific radioimmunoassays was observed over 6 h after the addition of T₄. An enzymic process is suggested that converts T₄ to T₃ and rT₃. For T₃ the optimal pH is 6 and for rT₃, 9.5. The converting activity for both T₃ and rT₃ is temperature dependent and can be suppressed by heat, H₂O₂, merthiolate and by 5-propyl-2-thiouracil. rT₃ and to a lesser degree iodide, were able to inhibit the production of T₃ in a dose related fashion. Therefore the pH dependendy, rT₃ and iodide may regulate the availability of T₃ or rT₃ depending on the metabolic requirements of thyroid hormones.     

Physiological loading of the mandibular osteosynthesis: development of an improved mandibular load simulator]

Loading conditions physiologically approximating those acting on the normal masticatory system were incorporated into a new mandibular load simulator. Separate tension wires attached to each ramus of the mandible simulated the resultant force vectors of the masticatory musculature. The muscle insertion points were chosen in accordance with the anatomical situation, and the maximum in vivo forces acting on the joint. In a first application, the stability of a 2.4 mm LC-WDCP was compared with that of a 2.7 mm EDCP in plastic mandible models. It was found that under largely physiological loading, the 2.4 mm LC-EDCP exerted a stabilizing effect similar to that of a 2.7 mm EDCP. Although of smaller dimensions, the 2.4 mm LC-EDCP appears to enable an osteosynthesis of similar stability in the treatment of fractures of the mandibular angle.     

An Individual Patient Data Meta-Analysis on Characteristics and Outcome of Patients with Papillary Glioneuronal Tumor,Rosette Glioneuronal Tumor with Neuropil-Like Islands and Rosette Forming Glioneuronal Tumor of the Fourth Ventricle

Background and Purpose

In 2007, the WHO classification of brain tumors was extended by three new entities of glioneuronal tumors: papillary glioneuronal tumor (PGNT), rosette-forming glioneuronal tumor of the fourth ventricle (RGNT) and glioneuronal tumor with neuropil-like islands (GNTNI). Focusing on clinical characteristics and outcome, the authors performed a comprehensive individual patient data (IPD) meta-analysis of the cases reported in literature until December 2012.

Methods

PubMed, Embase and Web of Science were searched for peer-reviewed articles reporting on PGNT, RGNT, and GNTNI using predefined keywords.

Results

95 publications reported on 182 patients (PGNT, 71; GNTNI, 26; RGNT, 85). Median age at diagnosis was 23 years (range 4–75) for PGNT, 27 years (range 6–79) for RGNT, and 40 years (range 2–65) for GNTNI. Ninety-seven percent of PGNT and 69% of GNTNI were located in the supratentorial region, 23% of GNTNI were in the spinal cord, and 80% of RGNT were localized in the posterior fossa. Complete resection was reported in 52 PGNT (73%), 36 RGNT (42%), and 7 GNTNI (27%) patients. Eight PGNT, 3 RGNT, and 12 GNTNI patients were treated with chemo- and/or radiotherapy as the primary postoperative treatment. Follow-up data were available for 132 cases. After a median follow-up time of 1.5 years (range 0.2–25) across all patients, 1.5-year progression-free survival rates were 52±12% for GNTNI, 86±5% for PGNT, and 100% for RGNT. The 1.5-year overall-survival were 95±5%, 98±2%, and 100%, respectively.

Conclusions

The clinical understanding of the three new entities of glioneuronal tumors, PGNT, RGNT and GNTNI, is currently emerging. The present meta-analysis will hopefully contribute to a delineation of their diagnostic, therapeutic, and prognostic profiles. However, the available data do not provide a solid basis to define the optimum treatment approach. Hence, a central register should be established.     

Mutation of the high affinity calcium binding sites in cardiac troponin C.

Fast skeletal and cardiac troponin C (TnC) contain two high affinity Ca2+/Mg2+ binding sites within the C-terminal domain that are thought to be important for association of TnC with the troponin complex of the thin filament. To test directly the function of these high affinity sites in cardiac TnC they were systematically altered by mutagenesis to generate proteins with a single inactive site III or IV (CBM-III and CBM-IV, respectively), or with both sites III and IV inactive (CBM-III-IV). Equilibrium dialysis indicated that the mutated sites did not bind Ca2+ at pCa 4. Both CBM-III and CBM-IV were similar to the wild type protein in their ability to regulate Ca(2+)-dependent contraction in slow skeletal muscle fibers, and Ca(2+)-dependent ATPase activity in fast skeletal and cardiac muscle myofibrils. The mutant CBM-III-IV is capable of regulating contraction in permeabilized slow muscle fibers but only if the fibers are maintained in a contraction solution containing a high concentration of the mutant protein. CBM-III-IV also regulates myofibril ATPase activity in fast skeletal and cardiac myofibrils but only at concentrations 10-100-fold greater than the normal protein. The pCa50 and Hill coefficient values for Ca(2+)-dependent activation of fast skeletal muscle myofibril ATPase activity by the normal protein and all three mutants are essentially the same. Competition between active and inactive forms of cardiac and slow TnC in a functional assay demonstrates that mutation of both sites III and IV greatly reduces the affinity of cardiac and slow TnC for its functionally relevant binding site in the myofibrils. The data indicate that although neither high affinity site is absolutely essential for regulation of muscle contraction in vitro, at least one active C-terminal site is required for tight association of cardiac troponin C with myofibrils. This requirement can be satisfied by either site III or IV.     

Small supernumerary marker chromosomes (SMCs): genotype-phenotype correlation and classification

Small supernumerary marker chromosomes (SMCs) are present in about 0.05% of the human population. In approximately 30% of SMC carriers (excluding the ~60% SMC derived from one of the acrocentric chromosomes), an abnormal phenotype is observed. The clinical outcome of an SMC is difficult to predict as they can have different phenotypic consequences because of (1) differences in euchromatic DNA-content, (2) different degrees of mosaicism, and/or (3) uniparental disomy (UPD) of the chromosomes homologous to the SMC. Here, we present 35 SMCs, which are derived from all human chromosomes, apart from chromosome 6, as demonstrated by the appropriate molecular cytogenetic approaches, such as centromere-specific multicolor fluoresence in situ hybridization (cenM-FISH), multicolor banding (MCB), and subcentromere-specific multicolor FISH (subcenM-FISH). In nine cases without an aberrant phenotype, neither partial proximal trisomies nor UPD could be detected. Abnormal clinical findings, such as psychomotoric retardation and/or craniofacial dysmorphisms, were associated with seven of the cases in which subcentromeric single-copy probes were proven to be present in three copies. Conversely, in eight cases with a normal phenotype, proximal euchromatic material was detected as partial trisomy. UPD was studied in 12 cases and subsequently detected in two of the cases with SMC (partial UPD 4p and maternal UPD 22 in a der(22)-syndrome patient), indicating that SMC carriers have an enhanced risk for UPD. At present, small proximal trisomies of 1p, 1q, 2p, 6p, 6q, 7q, 9p, and 12q seem to lead to clinical manifestations, whereas partial proximal trisomies of 2q, 3p, 3q, 5q, 7p, 8p, 17p, and 18p may not be associated with significant clinical symptoms. With respect to clinical outcome, a classification of SMCs is proposed that considers molecular genetic and molecular cytogenetic characteristics as demonstrated by presently available methods.Electronic database information: accession numbers and URLs for the data in this article are as follows:ENSEMBL-database, National Center for Biotechnology Information (NCBI), Genome Database (GDB), OMIM (Online Mendelian Inheritance in Man) Database,     

Attention-Deficit/Hyperactivity Disorder (ADHD) in Adulthood: Concordance and Differences between Self- and Informant Perspectives on Symptoms and Functional Impairment

Attention-deficit/hyperactivity disorder (ADHD) is a severe mental illness, associated with major impairment and a high comorbidity rate. Particularly undiagnosed ADHD in adulthood has serious consequences. Thus, a valid diagnosis is important. In adulthood, the diagnostic process for ADHD is complicated: symptoms may overlap with comorbid disorders, and the onset and progression of the disorder must be reconstructed retrospectively. Guidelines for the diagnostic process recommend the inclusion of additional informant ratings. Research into the relation between self- and informant ratings shows extremely heterogeneous results. The levels of agreement range from low to high. The focus of this study is the concordance and differences between self- and informant ratings on ADHD symptoms and impairments. In this regard, two possible influencing factors (gender and relationship type) are also examined. 114 people participated in this study, 77 with an ADHD diagnosis and 37 without a diagnosis. For all participants, either parents or partners also rated ADHD symptoms and impairments. Small to moderate concordance was found between self- and informant ratings, with females being slightly more concordant than males, particularly for ratings of problems with self-concept. Examination of the consistency within a particular perspective showed that people with ADHD seemed to be unaware of the causal relation between ADHD symptoms and their impairments. A close investigation found almost no influence of gender and relationship type on differences within perspectives. Based on these results, the implications for the diagnostic process are that additional informant information is clearly necessary and helpful.     

Primary hyperparathyroidism is associated with increased circulating bone marrow-derived progenitor cells

Recently, parathyroid hormone (PTH) was shown to support survival of progenitor cells in bone marrow. The release of progenitor cells occurs in physiological and pathological conditions and was shown to contribute to neovascularization in tumors and ischemic tissues. In the present study we sought to investigate prospectively the effect of primary hyperparathyroidism (PHPT) on mobilization of bone marrow-derived progenitor cells. In 22 patients with PHPT and 10 controls, defined subpopulations of circulating bone marrow-derived progenitor cells (BMCs) were analyzed by flow cytometry (CD45(+)/CD34(+)/CD31(+) cells indicating endothelial progenitor cells, CD45(+)/CD34(+)/c-kit(+) cells indicating hematopoietic stem cells, and CD45(+)/CD34(+)/CXCR4(+) cells indicating progenitor cells with the homing receptor CXCR4). Cytokine serum levels (SCF, SDF-1, VEGF, EPO, and G-CSF) were assessed using ELISA. Levels of PTH and thyroid hormone as well as serum electrolytes, renal and liver parameters, and blood count were analyzed. Our data show for the first time a significant increase of circulating BMCs and an upregulation of SDF-1 and VEGF serum levels in patients with PHPT. The number of circulating BMCs returned to control levels measured 16.7 +/- 2.3 mo after surgery. There was a positive correlation of PTH levels with the number of CD45(+)/CD34(+)/CD31(+), CD45(+)/CD34(+)/c-kit(+), and CD45(+)/CD34(+)/CXCR4(+) cells. However, there was no correlation between cytokine serum concentrations (SDF-1, VEGF) and circulating BMCs. Serum levels of G-CSF, EPO, and SCF known to mobilize BMCs were even decreased or remained unchanged, suggesting a direct effect of PTH on stem cell mobilization. Our data suggest a new function of PTH mobilizing BMCs into peripheral blood.     

Psychoanalytic and cognitive-behavior therapy of chronic depression: study protocol for a randomized controlled trial

ABSTRACT: BACKGROUND: Despite limited effectiveness of short-term psychotherapy for chronic depression, there is a lack of trials of long-term psychotherapy. Our study is the first to determine the effectiveness of controlled long-term psychodynamic and cognitive-behavioral (CBT) treatments and to assess the effects of preferential vs. randomized assessment. Methods / Design: Patients are assigned to treatment according to their preference or randomized (if they have no clear preference). Up to 80 sessions of psychodynamic or psychoanalytically oriented treatments (PAT) or up to 45 sessions of CBT are offered during the first year in the study. After the first year, PAT can be continued according to the "naturalistic", usual way of treating such patients within the system of German health care system (normally 240 up to 300 sessions), CBT therapists may extend their treatment up to 80 sessions, but focus mainly on maintenance and relapse prevention. We plan to recruit a total of 240 patients (60 per arm). A total of 11 assessments are conducted throughout treatment and up to 3 years after initiation of treatment. The primary outcome measures are the QIDS (independent clinician rating) and the BDI after year 1, 2 and 3. DISCUSSION: We combine an RCT and a naturalistic approach in order to investigate, how effectively chronic depression can be treated on an outpatient basis by the two forms of treatment reimbursed in the German health care system and we will determine the effects of treatment preference vs. randomization.