bcl-2 proto-oncogene expression in normal and neoplastic human myeloid cells.

The present study provides immunobiochemical and molecular data on the differentiation-linked expression of the bcl-2 proto-oncogene in normal and neoplastic myeloid cells. Using a recently developed monoclonal antibody (MoAb) to the bcl-2 molecule, staining of normal bone marrow myeloblasts, promyelocytes, and myelocytes, but neither monocytes nor most polymorphonuclear cells, was demonstrated. By two-color flow cytometric analysis, bcl-2 was evidenced in CD33+ and CD33+/CD34+ myeloid cells as well as in the more primitive CD33-/CD34+ population. The leukemic cell lines HL-60, KG1, GM-1, and K562 were bcl-2 positive together with 11 of 14 acute myeloid leukemias (AML) and three of three chronic myeloid leukemias (CML) in blast crises; six of seven CML were negative. Among myelodysplastic cases, augmentation of the bcl-2 positive myeloblastic compartment was found in refractory anemia with excess of blasts (RAEB) and in transformation (RAEB-t). Western blots of myeloid leukemias and control lymphocytes extracts evidenced an anti-bcl-2 immunoreactive band of the expected size (26 Kd). Moreover, the HL-60 and KG1 cell lines, both positive for the bcl-2 protein, exhibited the appropriate size bcl-2 mRNA (7.5 Kb). These findings clearly indicate that the bcl-2 gene is operative in myeloid cells and that the anti-bcl-2 MoAb identifies its product and not a cross-reactive epitope. Induction of HL-60 differentiation toward the monocytic and granulocytic pathways was accompanied by a marked decrease in bcl-2 mRNA and protein levels; bivariate flow cytometric analysis showed that the fraction becoming bcl-2 negative was in the G1 phase of the cell cycle. These data establish that the bcl-2 proto-oncogene is expressed on myeloid cells and their progenitors and is regulated in a differentiation-linked manner.     

An anterior‐lateral thigh perforator flap on a recipient brachial‐radial vein graft for complex wound reconstruction: A case report

A case of challenging microsurgical reconstruction of a difficult defect in a radiated upper limb is reported. A difficult wound, with tendon and bone exposition, developed on the dorsum of the forearm in a 76‐year‐old patient; she had been radiated since almost 50 years and her left hand had also been revascularized twice with venous grafts between the humeral artery and the superficial palmar arch. After failure of a local flap, an anterior‐lateral thigh perforator flap was successfully transferred with end‐to‐side anastomoses on the arterialized venous graft. Up to date follow‐up shows a good outcome. The Authors discuss the case and review the indications for microsurgical reconstruction in difficult wounds after radiation and ischemic limb conditions. © 2009 Wiley‐Liss, Inc. Microsurgery, 2009.     

Pregabalin, celecoxib, and their combination for treatment of chronic low-back pain

Background  

The efficacy and safety of the association of celecoxib [a selective cyclooxygenase-2 (COX-2) inhibitor] and pregabalin (commonly used to control neuropathic pain), compared with monotherapy of each, were evaluated for the treatment of chronic low-back pain, a condition known to be due to neuropathic as well as nociceptive pain mechanisms.     

Adriamycin-induced myocardial toxicity: new solutions for an old problem?

Adriamycin is a potent and broad-spectrum antineoplastic agent that plays a major role in cancer chemotherapy. Unfortunately, its use has been hampered by conventional toxicities and cardiotoxicity manifested by congestive cardiomyopathy. Adriamycin is particularly toxic to heart tissue and constitutes a major cause of morbidity and mortality due to its complex pathogenesis. In this review, the different forms of cardiotoxicity produced by adriamycin as well as the biochemical changes induced by this drug are summarized. Secondly, the current hypotheses proposed to explain adriamycin-induced myocardial damage (the iron and free-radical hypothesis, the metabolic hypothesis, the "unifying hypothesis" and apoptosis) and the attempts to reduce adriamycin-induced myocardial toxicity are discussed (e.g. dose limitation, close cardiac monitoring, alteration of dosage schedules, development of new anthracycline analogs, and the administration of protective agents and liposomal encapsulation). Finally, we summarized our own experimental and clinical experience in ameliorating and or preventing adriamycin-induced cardiotoxicity and the latest attempts to prevent and/or monitor cardiac function. According to this, a combination of usual doses of calcium antagonist drugs plus vitamins A and E seems advisable.     

Effect of corpus callosum damage on ipsilateral motor activation in patients with multiple sclerosis: a functional and anatomical study

Functional MRI (fMRI) studies have shown increased activation of ipsilateral motor areas during hand movement in patients with multiple sclerosis (MS). We hypothesized that these changes could be due to disruption of transcallosal inhibitory pathways. We studied 18 patients with relapsing-remitting MS. Conventional T1- and T2-weighted images were acquired and lesion load (LL) measured. Diffusion tensor imaging (DTI) was performed to estimate fractional anisotropy (FA) and mean diffusivity (MD) in the body of the corpus callosum (CC). fMRI was obtained during a right-hand motor task. Patients were studied to evaluate transcallosal inhibition (TCI, latency and duration) and central conduction time (CCT). Eighteen normal subjects were studied with the same techniques. Patients showed increased MD (P < 0.0005) and reduced FA (P < 0.0005) in the body of the CC. Mean latency and duration of TCI were altered in 12 patients and absent in the others. Between-group analysis showed greater activation in patients in bilateral premotor, primary motor (M1), and middle cingulate cortices and in the ipsilateral supplementary motor area, insula, and thalamus. A multivariate analysis between activation patterns, structural MRI, and neurophysiological findings demonstrated positive correlations between T1-LL, MD in the body of CC, and activation of the ipsilateral motor cortex (iM1) in patients. Duration of TCI was negatively correlated with activation in the iM1. Our data suggest that functional changes in iM1 in patients with MS during a motor task partially represents a consequence of loss of transcallosal inhibitory fibers.     

Cornelia de Lange syndrome mutations in SMC1A or SMC3 affect binding to DNA

Cornelia de Lange syndrome (CdLS) is a clinically heterogeneous developmental disorder characterized by facial dysmorphia, upper limb malformations, growth and cognitive retardation. Mutations in the sister chromatid cohesion factor genes NIPBL, SMC1A and SMC3 are present in approximately 65% of CdLS patients. In addition to their canonical roles in chromosome segregation, the cohesin proteins are involved in other biological processes such as regulation of gene expression, DNA repair and maintenance of genome stability. To gain insights into the molecular basis of CdLS, we analyzed the affinity of mutated SMC1A and SMC3 hinge domains for DNA. Mutated hinge dimers bind DNA with higher affinity than wild-type proteins. SMC1A- and SMC3-mutated CdLS cell lines display genomic instability and sensitivity to ionizing radiation and interstrand crosslinking agents. We propose that SMC1A and SMC3 CdLS mutations affect the dynamic association between SMC proteins and DNA, providing new clues to the underlying molecular cause of CdLS.     

Inhibition of thalamic excitability by 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine-3-ol: a selective role for δ-GABAA receptors

The sedative and hypnotic agent 4,5,6,7‐tetrahydroisoxazolo[4,5‐c]pyridine‐3‐ol (THIP) is a GABA_A receptor (GABA_AR) agonist that preferentially activates δ‐subunit‐containing GABA_ARs (δ‐GABA_ARs). To clarify the role of δ‐GABA_ARs in mediating the sedative actions of THIP, we utilized mice lacking the α₁‐ or δ‐subunit in a combined electrophysiological and behavioural analysis. Whole‐cell patch‐clamp recordings were obtained from ventrobasal thalamic nucleus (VB) neurones at a holding potential of ?60 mV. Application of bicuculline to wild‐type (WT) VB neurones revealed a GABA_AR‐mediated tonic current of 92 ± 19 pA, which was greatly reduced (13 ± 5 pA) for VB neurones of δ^0/0 mice. Deletion of the δ‐ but not the α₁‐subunit dramatically reduced the THIP (1 μm )‐induced inward current in these neurones (WT, ?309 ± 23 pA; δ^0/0, ?18 ± 3 pA; α₁^0/0, ?377 ± 45 pA). Furthermore, THIP selectively decreased the excitability of WT and α₁^0/0 but not δ^0/0 VB neurones. THIP did not affect the properties of miniature inhibitory post‐synaptic currents in any of the genotypes. No differences in rotarod performance and locomotor activity were observed across the three genotypes. In WT mice, performance of these behaviours was impaired by THIP in a dose‐dependent manner. The effect of THIP on rotarod performance was blunted for δ^0/0 but not α₁^0/0 mice. We previously reported that deletion of the α₁‐subunit abolished synaptic GABA_A responses of VB neurones. Therefore, collectively, these findings suggest that extrasynaptic δ‐GABA_ARs vs. synaptic α₁‐subunit‐containing GABA_ARs of thalamocortical neurones represent an important molecular target underpinning the sedative actions of THIP.     

Implementation and evaluation of a parent training for language delayed children

Two-year old children speaking fewer than 50 words are language delayed and at a 50 % risk for a persistent language impairment (Grimm, 2000). The present study pioneers as it presents for the first time an evaluation of the parent program "It Takes Two to Talk" (from the Hanen Early Language Parent Program, Girolametto et al., 1986) in this country. A nonrandomized controlled pre-post study design was implemented with the experimental treatment group of 9 mothers of language delayed toddlers and the matched waiting-control group of 8 mothers of language delayed toddlers. The Hanen Parent Program was carried out in the treatment group. The main outcome measures included (a) expressive language (measured with ELFRA-2, Grimm u. Doil, 2000); (b) ratings of outcome and process quality by mothers and therapist (measured with FBB, Mattejat u. Remschmidt, 1998). The central findings were as follows: (a) In the two-factor ANOVA with repeated measures on one factor no significant interaction was demonstrated between group factor and pre-post factor for the expressive language scale "vocabulary" (p = 0.18); the average gain in the treatment group (increase from M(-pre) = 13,6 to M(-post) = 62,3 words) was numerically larger than the average gain in the control group (M(-pre) = 15,5, M(-post) = 44,1), while the pre-post differences were significant in both groups (t-test: p = 0.001 in EG; p = 0.03 in CG); (b) process and outcome qualities of the parent intervention were rated "positive" or "very positive" by parents and therapist. The conclusions drawn from this study are as follows: The experimental validity of the present clinical pilot study was influenced by several methodological limitations. The overall findings at least support the assumption that the early intervention parent program examined indicates some social validity. In order to evaluate the effectiveness of this program more conclusively, further research is urgently needed.     

Is smaller necessarily better? A systematic review comparing the effects of minilaparoscopic and conventional laparoscopic cholecystectomy on patient outcomes

Background  In recent years, minilaparoscopic cholecystectomy (MLC; total size of trocar incision <25 mm) has been increasingly advocated for the removal of the gallbladder, due to potentially better surgical outcomes (e.g., better cosmetic result, reduced pain, shorter hospital stay, quicker return to activity), but an evidence-based approach has been lacking. The current systematic review was undertaken to evaluate the importance of total size of trocar incision in improving surgical outcomes in adult laparoscopic cholecystectomy (LC). Methods  The literature was systematically reviewed using MEDLINE and EmBASE. Only randomized controlled trials in English, investigating minilaparoscopic versus conventional LC (total size of trocar incision ≥25 mm) and reporting pain scores were included. Quantitative analyses (meta-analyses) were performed on postoperative pain scores and other patient outcomes from more than one study where feasible and appropriate. Qualitative analyses consisted of assessing the number of studies showing a significant difference between the techniques. Results  Thirteen trials met the inclusion criteria. There was a trend towards reduced pain with MLC compared with conventional LC, without reduction in opioid use. Patients in the MLC group had slightly reduced length of hospital stay, but there were no significant differences for return to activity. The two interventions were also similar in terms of operating times and adverse events, but MLC was associated with better cosmetic result (largely patient rated). There was a significantly greater likelihood of conversion to conventional LC or to open cholecystectomy in the MLC group than there was of conversion to open cholecystectomy in the conventional LC group [OR 4.71 (95% confidence interval 2.67–8.31), p < 0.00001]. Conclusions  The data included in this review suggest that reducing the size of trocar incision results in some limited improvements in surgical outcomes after LC. However, it carries a higher risk of conversion to conventional LC or open cholecystectomy.