Clinical and polysomnographic effects of trazodone CR in chronic insomnia associated with dysthymia

Six middle aged subjects complaining of chronic insomnia associated with dysthymia were investigated in a 2-month single blind study: a 7-day placebo treatment period, followed by a 6-week phase with increasing doses of trazodone controlled release (CR) formulation (50 mg through days 8–10; 75 mg through days 11–13; 150 mg through days 14–49) and then a final 7-day withdrawal period under placebo. Medication was always administered at bedtime. Five polysomnographic recordings were accomplished by each subject (sleep 1: under baseline placebo; sleep 2-3-4: under active treatment; sleep 5: after drug discontinuation). A blind EEG reader analysed the traditional polysomnographic variables (macrostructure of sleep) and the amount and percentage ratio (CAP rate) of cyclic alternating pattern (CAP), the microstructural parameter that measures the instability of arousal during sleep. Visual analogue scales (VAS) for the evaluation of subjective sleep quality and the Hamilton rating scale for depression (HAM-D) were regularly assessed across the study. Statistical analysis was based on an ANOVA test with repeated measures completed by means of Bonferroni adjusted probabilities. No significant differences emerged from the macrostructural parameters referred to sleep initiation and maintenance, while significant overall modifications emerged from stage 2 (P<0.0005), slow wave sleep (P<0.0001), total CAP time (P<0.0001) and CAP rate (P<0.0001). Compared to the placebo baseline night, a significant increase of slow wave sleep (+40 min) and significant reductions of stage 2 (–67 min), CAP time (–90 min) and CAP rate (–23%) were already found on day 4 of treatment (sleep 2). These changes maintained significance throughout the active treatment period (sleep 3 and sleep 4), while a return to the baseline values occurred after drug discontinuation (sleep 5). The course of polysomnographic modifications was consistently associated with significant improvement of VAS and HAM-D scores during the active treatment period and by poor scores of the baseline and withdrawal periods. Trazodone appears to have a high affinity for 5-HT₂ receptors. The availability of an effective slow acting serotonin-related drug with both sedative and antidepressant properties may open new perspectives in the treatment of chronic insomnia.     

Thymoma and thymic carcinoma

Summary Based on the light microscopical features of normal thymic epithelial cells, human thymoma was divided in different types, namely cortical, medullary, and mixed ones, according to the epithelial cell (EC) type. Lymphoid cell populations with morphological features of either cortical or medullary thymocytes were found according to different types of EC in thymoma. The histological variation of the different types of thymoma are demonstrated. In a retrospective study of 58 thymomas and 13 thymic carcinomas, malignant invasive character as well as the occurrence of myasthenia gravis were both found to be related to the neoplastic proliferation of the cortical epithelial cells, whereas in the usual mixed type of thymoma and the medullary type no gross invasion or metastases were noticed.These results are discussed in view of recent concepts and immunological findings of thymus microarchitecture.This work has been supported by the Deutsche Forschungsgemeinschaft, SFB Project CN 2 and A 8. Part of the data were presented at the 68. Tagung der Deutschen Gesellschaft für PathologieSupported by the Deutscher Akademischer Austauschdienst     

Identification of fifteen novel mutations in the SLC12A3 gene encoding the Na-Cl Co-transporter in Italian patients with Gitelman syndrome

The SLC12A3 gene encodes the thiazide-sensitive Na-Cl co-transporter (NCCT) expressed in the apical membrane of the distal convoluted tubule of the kidney. Inactivating mutations of this gene are responsible for Gitelman syndrome (GS), a disorder inherited as an autosomal recessive trait. We searched for SLC12A3 gene mutations in 21 Italian patients with the clinical and biochemical features of GS (hypokalemia, hypomagnesemia, metabolic alkalosis, hypocalciuria, and the absence of nephrocalcinosis). All coding regions with their intron-exon boundaries were analyzed using PCR and SSCP techniques followed by sequencing analysis. We identified 21 different mutations evenly distributed throughout the gene without any mutation hot-spot. Fifteen are novel variants, including 12 missense mutations, one deletion, one deletion-insertion and one splice site mutation: R158Q, T163M, W172R, G316V, G374V, G463E, A464T, S615W, V677M, R852S, R958G, C985Y, 2114-2120delACCAAGT, 2144-2158delGCCTTCTACTCGGATinsTG, and 531-2A>G.     

Identification and functional characterization of five novel mutant alleles in 58 Italian patients with Gaucher disease type 1

Gaucher disease (GD) is the most frequent lysosomal glycolipid storage disorder due to an autosomal recessive deficiency of acid beta-glucosidase characterized by the accumulation of glucocerebroside. In this work we carried out the molecular analysis of the glucocerebrosidase gene (GBA) in 58 unrelated patients with GD type 1. We identified five novel genetic alterations: three missense changes c.187G>A (p.D63N), c.473T>G (p.I158S), c.689T>A (p.V230E), a gene-pseudogene recombinant allele and a non-pseudogene-derived complex allele [c.1379G>A;c.1469A>G] encoding [p.G460D;p.H490R]. All mutant alleles were present as compound heterozygotes in association with c.1226A>G (p.N409S), the most common mutation in GD1. The missense mutant proteins were expressed in vitro in COS-1 cells and analyzed by enzyme activity, protein processing and intracellular localization. Functional studies also included the c.662C>T (p.P221L) mutation recently reported in the Spanish GD population (Montfort et al., 2004). The missense mutant alleles retained an extremely low residual enzyme activity with respect to wild type; the complex allele expressed no activity. Processing of the mutant proteins was unaltered except for c.473T>G which was differently glycosylated due to the exposition of an additional glycosylation site. Immunofluorescence studies showed that protein trafficking into the lysosomes was unaffected in all cases. Finally, the characterization of the novel recombinant allele identified a crossover involving the GBA gene and pseudogene between intron 5 and exon 7.     

Vascularization of embryonic adrenal gland grafted onto chorioallantoic membrane

 Vascularization and endothelial phenotype expression were analysed in embryonic adrenal tissue grafted onto chorioallantoic membrane (CAM), by means of routine light microscopy and immunocytochemical staining, and of electron microscopy. Adrenal gland tissue from chick or quail embryos (donors) was grafted onto CAMs of chick or quail embryos (host). Vessels of chick origin were discriminated from those of quail origin by monoclonal antibodies, anti-MB1, specific for quail endothelial and haemopoietic cells, and QCPN, which labels quail cell nuclei. Vessels of adrenal type were distinguished from those of CAM-type by their ultrastructural endothelial phenotype – porous in the former and continuous in the latter. The observations carried out 6 days after implantation indicate that the adrenal gland develops and differentiates according to a virtually normal histological pattern. As regards the adrenal and CAM vascularization, the grafting procedure elicits angiogenic events consisting in the formation of peripheral anastomoses between the graft and the CAM original microvasculature and in new-growth of vessels from the CAM into the grafted tissue and vice versa. As to the endothelial phenotype, the ultrastructural results demonstrate that besides its own native vasculature, the adrenal tissue contains vessels with continuous endothelium and the CAM mesenchyme is supplied by adrenal-type, fenestrated vessels. Accepted: 27 April 1998     

Ultrasonography of the pancreas. 7. Intraoperative imaging

The usefulness of intraoperative ultrasonography (IOUS) has been documented in the Literature since the Eighties and, although its main applications are in hepatobiliary and pancreatic surgery, it has been used also in neurosurgery, cardiovascular and endocrine surgery. The continuous technical developments have led to an increase in the diagnostic accuracy of IOUS from the Eighties to now. The use of IOUS has increased in time together with the technical innovations until, mainly in the mid-Nineties, its value was recognized by many surgeons. This results have been obtained with scanners that allow to depict fine anatomical details and detect small lesions in real time with extremly high spatial resolution. IOUS is able to shows fine details, such as primary or secondary lesions not detectable with other preoperative imaging modalities or tumor extension and its relationship with vessels [14, 15]. Assessment of resectability by IOUS may determine important changes in therapeutic planning [13, 14, 16–18]. The role of IOUS, however, has recently been downsized, especially in those centers where preoperative imaging is advanced [20, 21]. This article will review the clinical role of pancreatic IOUS in the different pancreatic pathologies.     

Hybrid FDG-PET/MR compared to FDG-PET/CT in adult lymphoma patients

Purpose

The goal of this study is to evaluate the diagnostic performance of simultaneous FDG-PET/MR including diffusion compared to FDG-PET/CT in patients with lymphoma.

Methods

Eighteen patients with a confirmed diagnosis of non-Hodgkin’s (NHL) or Hodgkin’s lymphoma (HL) underwent an IRB-approved, single-injection/dual-imaging protocol consisting of a clinical FDG-PET/CT and subsequent FDG-PET/MR scan. PET images from both modalities were reconstructed iteratively. Attenuation correction was performed using low-dose CT data for PET/CT and Dixon-MR sequences for PET/MR. Diffusion-weighted imaging was performed. SUV_max was measured and compared between modalities and the apparent diffusion coefficient (ADC) using ROI analysis by an experienced radiologist using OsiriX. Strength of correlation between variables was measured using the Pearson correlation coefficient (r _p).

Results

Of the 18 patients included in this study, 5 had HL and 13 had NHL. The median age was 51 ± 14.8 years. Sixty-five FDG-avid lesions were identified. All FDG-avid lesions were visible with comparable contrast, and therefore initial and follow-up staging was identical between both examinations. SUV_max from FDG-PET/MR [(mean ± sem) (21.3 ± 2.07)] vs. FDG-PET/CT (mean 23.2 ± 2.8) demonstrated a strongly positive correlation [r _s = 0.95 (0.94, 0.99); p < 0.0001]. There was no correlation found between ADC_min and SUV_max from FDG-PET/MR [r = 0.17(?0.07, 0.66); p = 0.09].

Conclusion

FDG-PET/MR offers an equivalent whole-body staging examination as compared with PET/CT with an improved radiation safety profile in lymphoma patients. Correlation of ADC to SUV_max was weak, understating their lack of equivalence, but not undermining their potential synergy and differing importance.

     

Increasing days at work using function-centered rehabilitation in nonacute nonspecific low back pain: a randomized controlled trial

OBJECTIVE: To evaluate the effect of function-centered compared with pain-centered inpatient rehabilitation in patients whose absence from work is due to chronic nonspecific low back pain (LBP). DESIGN: Single-blinded randomized controlled trial with follow-up assessments immediately after treatment and at 3 months. SETTING: Center for work rehabilitation in Switzerland. PARTICIPANTS: Patients with more than 6 weeks of work absence due to chronic nonspecific LBP (N=174; 137 men, 37 women; mean age +/- standard deviation, 42+/-8 y; mean sick leave before study, 6.5 mo). INTERVENTIONS: Function-centered treatment (FCT) (4h/d, 6d/wk, for 3 wk) consisted of work simulation, strength, endurance, and cardiovascular training. Pain-centered treatment (PCT) (2.5h/d, 6d/wk, for 3 wk) used a mini back school, individually selected passive and active mobilization, stretching, and low-intensity strength training. MAIN OUTCOME MEASURES: The number of days at work in 3 months after treatment, self-efficacy, lifting capacity, pain, mobility, strength, and global perceived effect. Effect sizes (ESs) (Cohen d ) were defined as small (ES range, 0.2-0.5), moderate (ES range, 0.5-0.8), and large (ES, >0.8). RESULTS: Groups were comparable at baseline. Moderate ESs for the FCT group versus PCT group were found for days at work (25.9 d vs 15.8d, ES=.36, P =.029), self-efficacy (5.9 points vs -7.4 points, ES=.55, P =.003), and lifting capacity (2.3 kg vs 0.2 kg, ES=.54, P =.004). CONCLUSIONS: Function-centered rehabilitation increases the number of work days, self-efficacy, and lifting capacity in patients with nonacute nonspecific LBP.     

Bone ingrowth in porous titanium implants produced by 3D fiber deposition

3D fiber deposition is a technique that allows the development of metallic scaffolds with accurately controlled pore size, porosity and interconnecting pore size, which in turn permits a more precise investigation of the effect of structural properties on the in vivo behavior of biomaterials. This study analyzed the in vivo performance of titanium alloy scaffolds fabricated using 3D fiber deposition. The titanium alloy scaffolds with different structural properties, such as pore size, porosity and interconnecting pore size were implanted on the decorticated transverse processes of the posterior lumbar spine of 10 goats. Prior to implantation, implant structure and permeability were characterized. To monitor the bone formation over time, fluorochrome markers were administered at 3, 6 and 9 weeks and the animals were sacrificed at 12 weeks after implantation. Bone formation in the scaffolds was investigated by histology and histomorphometry of non-decalcified sections using traditional light- and epifluorescent microscopy. In vivo results showed that increase of porosity and pore size, and thus increase of permeability of titanium alloy implants positively influenced their osteoconductive properties.