18q-syndrome: brain MRI shows poor differentiation of gray and white matter on T2-weighted images

PURPOSE: To study brain MRI findings in patients with 18q- syndrome and to correlate these findings with the results of the molecular breakpoint analysis. MATERIALS AND METHODS: Brain MR images of 17 patients with 18q- syndrome were evaluated. Segregation analysis was performed with 15 microsatellite markers to determine the deletion breakpoints and whether the deletion included the myelin basic protein (MBP) gene. RESULTS: One patient had an interstitial deletion of 18q which spared the MBP gene. He was the only one with normal brain MRI. All 16 patients with deletions including the MBP gene had abnormal white matter in MRI. The main finding was poor differentiation of gray and white matter on T2-weighted images due to increased white matter signal intensity. In addition, measured signal intensity of the white matter was significantly increased in patients compared with controls. CONCLUSIONS: Poor differentiation of gray and white matter on T2-weighted images is the most typical MRI finding of the 18q- syndrome. These results support the postulation that abnormal myelination in 18q- syndrome is due to haploinsufficiency at or near the MBP locus.     

PRRT2-related disorders: further PKD and ICCA cases and review of the literature

Recent studies reported mutations in the gene encoding the proline-rich transmembrane protein 2 (PRRT2) to be causative for paroxysmal kinesigenic dyskinesia (PKD), PKD combined with infantile seizures (ICCA), and benign familial infantile seizures (BFIS). PRRT2 is a presynaptic protein which seems to play an important role in exocytosis and neurotransmitter release. PKD is the most common form of paroxysmal movement disorder characterized by recurrent brief involuntary hyperkinesias triggered by sudden movements. Here, we sequenced PRRT2 in 14 sporadic and 8 familial PKD and ICCA cases of Caucasian origin and identified three novel mutations (c.919C>T/p.Gln307*, c.388delG/p.Ala130Profs*46, c.884G>A/p.Arg295Gln) predicting two truncated proteins and one probably damaging point mutation. A review of all published cases is also included. PRRT2 mutations occur more frequently in familial forms of PRRT2-related syndromes (80–100 %) than in sporadic cases (33-46 %) suggesting further heterogeneity in the latter. PRRT2 mutations were rarely described in other forms of paroxysmal dyskinesias deviating from classical PKD, as we report here in one ICCA family without kinesigenic triggers. Mutations are exclusively found in two exons of the PRRT2 gene at a high rate across all syndromes and with one major mutation (c.649dupC) in a mutational hotspot of nine cytosines, which is responsible for 57 % of all cases in all phenotypes. We therefore propose that genetic analysis rapidly performed in early stages of the disease is highly cost-effective and can help to avoid further unnecessary diagnostic and therapeutic interventions.     

Prolonged allogeneic islet graft survival by protoporphyrins

Transplantation of islets of Langerhans in patients with type 1 diabetes allows for improved metabolic control and insulin independence. The need for chronic immunosuppression limits this procedure to selected patients with brittle diabetes. Definition of therapeutic strategies allowing permanent engraftment without the need for chronic immunosuppression could overcome such limitations. We tested the effect of the use of protoporphyrins (CoPP and FePP), powerful inducers of the cytoprotective protein heme-oxygenase 1 (HO-1), on allogeneic islet graft survival. Chemically induced diabetic C57BL/6 mice received DBA/2 islets. Treatment consisted in peritransplant administration of CoPP or saline. Islets were either cultured in the presence of FePP or vehicle before implant. Short-course administration of CoPP led to long-term islet allograft survival in a sizable proportion of recipients. Long-term graft-bearing animals rejected third-party islets while accepting a second set donor-specific graft permanently, without additional treatment. Preconditioning of islets with FePP by itself led to improved graft survival in untreated recipients, and provided additional advantage in CoPP-treated recipients, resulting in an increased proportion of long-term surviving grafts. Preconditioning of the graft with protoporphyrins prior to implant resulted in reduction of class II expression. Administration of protoporphyrins to the recipients of allogeneic islets also resulted in transient powerful immunosuppression with reduced lymphocyte proliferative responses, increased proportion of regulatory cells (CD4+CD25+), decreased mononuclear cell infiltrating the graft, paralleled by a systemic upregulation of HO-1 expression. All these mechanisms may have contributed to the induction of donor-specific hyporesponsiveness in a proportion of the protoporphyrin-treated animals.     

A genome-wide analysis of population structure in the Finnish Saami with implications for genetic association studies

The understanding of patterns of genetic variation within and among human populations is a prerequisite for successful genetic association mapping studies of complex diseases and traits. Some populations are more favorable for association mapping studies than others. The Saami from northern Scandinavia and the Kola Peninsula represent a population isolate that, among European populations, has been less extensively sampled, despite some early interest for association mapping studies. In this paper, we report the results of a first genome-wide SNP-based study of genetic population structure in the Finnish Saami. Using data from the HapMap and the human genome diversity project (HGDP-CEPH) and recently developed statistical methods, we studied individual genetic ancestry. We quantified genetic differentiation between the Saami population and the HGDP-CEPH populations by calculating pair-wise F(ST) statistics and by characterizing identity-by-state sharing for pair-wise population comparisons. This study affirms an east Asian contribution to the predominantly European-derived Saami gene pool. Using model-based individual ancestry analysis, the median estimated percentage of the genome with east Asian ancestry was 6% (first and third quartiles: 5 and 8%, respectively). We found that genetic similarity between population pairs roughly correlated with geographic distance. Among the European HGDP-CEPH populations, F(ST) was smallest for the comparison with the Russians (F(ST)=0.0098), and estimates for the other population comparisons ranged from 0.0129 to 0.0263. Our analysis also revealed fine-scale substructure within the Finnish Saami and warns against the confounding effects of both hidden population structure and undocumented relatedness in genetic association studies of isolated populations.     

Oral contraceptive use before first birth and risk of breast cancer: a case control study

Background  

Our investigation sought to compare changes in sexual function following supracervical hysterectomy (SCH) and total abdominal hysterectomy (TAH).     

Neuromuscular function and balance of prepubertal and pubertal blind and sighted boys

Aim : To compare the neuromuscular function and balance of blind prepuberty- and puberty-aged boys to those with normal sight. Methods : Thirty-three prepubertal (aged 9–13 y) and pubertal (aged 15–18 y) blind and sighted boys were tested for muscle mass thickness, electromyography and maximal isometric strength, dynamic explosive actions, and balance. Results : There was no difference in the muscle mass thickness, maximal strength or vertical jump between the blind and sighted boys. However, fitness-ball throwing and five-jump distances were significantly shorter in both blind groups compared to the sighted groups. One-leg stance of the prepuberty-aged sighted boys was 109 (67) s and in blind boys 32 (12) s, and in the puberty-aged boys 120 (57) s and 31 (8) s, respectively. When vision was blocked in the sighted boys, differences between the blind and sighted boys disappeared.
Conclusion : The results showed comparable performance between prepubertal and pubertal blind and sighted boys in the static physical fitness tests. However, balance and performance in dynamic multi-joint tests did not improve similarly in the blind groups compared to sighted groups, indicating that maturation, learning and experience by themselves cannot compensate for the loss of sight.     

Modeling the Parameters Involved in Preparation of PLA Nanoparticles Carrying Hydrophobic Drug Molecules Using Artificial Neural Networks

Purpose

Artificial neural networks (ANNs) are used to optimize a formulation of poly(lactic acid) (PLA) nanoparticles containing hydrophobic drug molecules through a study of the critical parameters affecting nanoparticle size.

Methods

We evaluate the effect of input variables, including concentrations of PLA and Tween 80, amplitude of ultrasound wave, and sonication time on the formation of PLA nanoparticles, which were prepared using a solvent evaporation method. Budesonide was used as a model hydrophobic drug. An ANN model was created using training data and evaluated for prediction capability using validation data.

Results

The ANN model demonstrated that reducing PLA concentration and increasing Tween 80 concentration provided optimum conditions for the preparation of small particle size. Additionally, the simultaneous use of high sonication time and amplitude has an adverse effect on particle diameter.

Conclusion

By defining the effects of each parameter on the size of PLA nanoparticles, this study demonstrated the feasibility of using an ANN model to optimize the conditions for achieving minimum particle size in hydrophobic drug-loaded PLA nanoparticles.     

Angiographic and clinical results in 316 coil-treated basilar artery bifurcation aneurysms

OBJECT: The aim of this study was to analyze the effect of the endovascular treatment of basilar artery (BA) bifurcation aneurysms and to compare the results with those published by other neuroendovascular teams. METHODS: The authors performed a retrospective analysis of 316 aneurysms of the BA bifurcation that had been treated using endovascular coil occlusion between November 6, 1992, and February 12, 2005. After the initial embolization procedure, a 90 to 100% occlusion rate was achieved in 86% of the aneurysms. No complication was evident in 80% of the lesions, although periprocedural aneurysm rupture (3.2%) and thromboembolic events (12.3%) were the most frequent complications. Clinical outcome according to the Glasgow Outcome Scale (GOS) was a score of 5 or 4 in 77%, 3 in 11%, 2 in 5%, and 1 in 7% of patients. Initial follow-up angiography studies were obtained in 56% of patients at a mean of 19 months posttreatment and demonstrated a 90 to 100% occlusion rate in 70%. No recurrence was seen on 65% of the aneurysms. Coil compaction was evident on 24% of the follow-up angiograms. A second treatment was performed on 48 aneurysms (15%) a mean of 27 months after the first therapeutic session and resulted in 90 to 100% occlusion in 83% of the lesions. Complications were encountered in 19% of the aneurysms. Rupture did not occur during any of the procedures. Clinical outcome was rated as GOS Score 5 or 4 in 83% of the patients and Grade 3 in 17%. During a cumulative clinical follow up of 821 years in 237 patients, 182 patients (81%) were independent (GOS Score 5 or 4), 33 (14%) were dependent (GOS Score 3), eight (3%) were in a vegetative state, and two (1%) had died. Clinical outcome was significantly worse after previous aneurysm rupture and following procedural complications. CONCLUSIONS: These results are within the range of published data for coil treatment of BA tip aneurysms and confirm both the safety and efficacy of this endovascular treatment method.     

Amplification of fgfr4 gene in human breast and gynecological cancers

We have investigated gene amplification of fibroblast growth factor receptor-4 (FGFR4) gene in 30 primary breast tumor samples and 15 gynecological tumor samples. Ten percent of the breast tumors showed 2- to 4-fold amplification. Amplification was found more frequently in estrogen- and progesterone-receptor-positive tumors and in tumors with high lymph-node involvement. Breast tumor samples were also analyzed for the amplification of fgfr3 and erbB2 genes and the chromosome I Iq 13 located genes hst I Iint2lbci1 /sea. erbB2 gene was amplified 2- to 13-fold in 13% of the cases, but no amplification of int2/hst I/be/1/sea amplicon was found. Gynecological tumors were also analyzed for the amplification of fgfr4 and fgfr3 genes and for int2 and hst I oncogenes. Eleven of the 15 gynecological tumors were ovarian neoplasms including 2 benign tumors; the remainder comprised I ovarian metastasis of breast cancer; I endometrial cancer; I uterine leiomyosarcoma and I carcinosarcoma of the fallopian tube. In gynecological tumors, fgfr4 gene was found to be amplified in 2 ovarian tumors. Amplification of hst I was found in I benign ovarian tumor. Thus, the fgfr4 gene may be involved in breast and ovarian tumorigenesis.     

Doctor-managers as decision makers in hospitals and health centres

PURPOSE: This paper describes factors influencing doctor-managers' decision making in specialised health care, health centres and at different levels of management. DESIGN/METHODOLOGY/APPROACH: Data were collected as part of a survey on physicians graduating in 1977-1991 as drawn from the register of the Finnish Medical Association. The study sample was formed by selecting all physicians born on odd days (n=4144) from the baseline group (n=8232). The category of doctor-managers comprised physicians reporting as their main occupation: principal or assistant principal physician of hospital, medical director or principal physician of health centre, senior ward physician of hospital, and health centre physician in charge of a population area. FINDINGS: Independent of gender, all doctor-managers responding to the survey reported that the most important base for decision making was personal professional experience. Position in organisation (first-line manager, principal physician) had no impact on the base of decision making. Doctor-managers in primary health care utilised knowledge on norms and knowledge available from their organisation in support of their decision making to a greater degree compared with doctor-managers in specialised health care. RESEARCH IMPLICATIONS: Evolution discourse from public administration is not yet receiving much response in Finnish doctor-managers' activities, instead, they still act as clinicians. ORIGINALITY/VALUE: Facing the growing challenges of the future, the paper shows that doctor-managers should reconstruct their orientation and to act more like managers.