Multiple brain networks support processing speed abilities of patients with multiple sclerosis

Objectives: Many people affected by multiple sclerosis (MS) experience cognitive impairment, especially decreases in information processing speed (PS). Neural disconnection is thought to represent the neural marker of this symptom, although the role played by alterations of specific functional brain networks still remains unclear. The aim is to investigate and compare patterns of association between PS-demanding cognitive performance and functional connectivity across two MS phenotypes.

Methods: Forty patients with relapsing-remitting MS (RRMS) and 25 with secondary progressive MS (SPMS) had neuropsychological and MRI assessments. Multiple regression models were used to investigate the relationship between performance on tests of visuomotor and verbal PS, and on the verbal fluency tests, and functional connectivity of four cognitive networks, i.e. left and right frontoparietal, salience and default-mode, and two control networks, i.e. visual and sensorimotor.

Results: Patients with SPMS were older and had longer disease history than patients with RRMS and presented with worse overall clinical conditions: higher disease severity, total lesion volume, and cognitive impairment rates. However, in both patient samples, cognitive performance across tests was negatively correlated with functional connectivity of the salience and default-mode networks, and positively with connectivity of the left frontoparietal network. Only the visuomotor PS scores of the RRMS group were also associated with connectivity of the sensorimotor network.

Conclusions: PS-demanding cognitive performance in patients with MS appears mainly associated with strength of functional connectivity of frontal networks involved in the evaluation and manipulation of information, as well as the default mode network. These results are in line with the hypothesis that multiple neural networks are needed to support normal cognitive performance across MS phenotypes. However, different PS measures showed partially different patterns of association with functional connectivity. Therefore, further investigations are needed to clarify the contribution of inter-network communication to specific cognitive deficits due to MS.     

Model-Based Estimates of the Effects of Efavirenz on Bedaquiline Pharmacokinetics and Suggested Dose Adjustments for Patients Coinfected with HIV and Tuberculosis

Safe, effective concomitant treatment regimens for tuberculosis (TB) and HIV infection are urgently needed. Bedaquiline (BDQ) is a promising new anti-TB drug, and efavirenz (EFV) is a commonly used antiretroviral. Due to EFV''s induction of cytochrome P450 3A4, the metabolic enzyme responsible for BDQ biotransformation, the drugs are expected to interact. Based on data from a phase I, single-dose pharmacokinetic study, a nonlinear mixed-effects model characterizing BDQ pharmacokinetics and interaction with multiple-dose EFV was developed. BDQ pharmacokinetics were best described by a 3-compartment disposition model with absorption through a dynamic transit compartment model. Metabolites M2 and M3 were described by 2-compartment models with clearance of BDQ and M2, respectively, as input. Impact of induction was described as an instantaneous change in clearance 1 week after initialization of EFV treatment and estimated for all compounds. The model predicts average steady-state concentrations of BDQ and M2 to be reduced by 52% (relative standard error [RSE], 3.7%) with chronic coadministration. A range of models with alternative structural assumptions regarding onset of induction effect and fraction metabolized resulted in similar estimates of the typical reduction and did not offer a markedly better fit to data. Simulations to investigate alternative regimens mitigating the estimated interaction effect were performed. The results suggest that simple adjustments of the standard regimen during EFV coadministration can prevent reduced exposure to BDQ without increasing exposures to M2. However, exposure to M3 would increase. Evaluation in clinical trials of adjusted regimens is necessary to ensure appropriate dosing for HIV-infected TB patients on an EFV-based regimen.     

Autosomal dominant early-onset cortical myoclonus, photic-induced myoclonus, and epilepsy in a large pedigree

PURPOSE: Cortical tremor, a form of rhythmic cortical myoclonus (rhythmic CM), and epilepsy have been described in families with autosomal dominant inheritance. Linkage analyses revealed two putative loci on chromosome 2p and 8q. Clinical photosensitivity was not a prominent feature in such families. We describe a large Italian family with rhythmic CM, photosensitivity, and epilepsy. METHODS: Twenty-three individuals of a five-generation family were studied. Linkage analyses for the loci on chromosome 2p11.1 and 8q23.3 were performed. RESULTS: Of the 23 studied family members, 16 were affected. Rhythmic CM of childhood onset was present in all 16 individuals (onset ranging from 3 to 12 years), was associated with photic-induced myoclonic jerks in seven, and with epileptic seizures in six (onset ranging from 23 to 34 years). Five children of the V generation manifested also episodes of arousal with generalized tremor in early infancy ("tremulous arousals"). Jerk-locked back-averaging of rhythmic CM of six affected individuals, documented a premyoclonic EEG correlate. C-reflex at rest was present in two affected adults. Linkage analyses excluded mapping to the 2p11.1 and 8q23.3 loci. CONCLUSIONS: Clinical variability and severity of the phenotypes in this family are in line with those of previously described pedigrees with autosomal dominant cortical myoclonus and epilepsy. In this family, a progression of symptoms was found: rhythmic CM and tremulous arousals occurred in childhood, whereas visually induced manifestations and epileptic seizures occurred during adolescence-adulthood. Exclusion of linkage to the two known loci is consistent with genetic heterogeneity of such familial clustering of symptoms.     

Progressive knowledge loss: a longitudinal case study.

The evolution of the progressive loss of semantic knowledge of a patient, VZ, with lesions mainly affecting the infero-medial temporal lobes, was followed for two years. At the beginning of the study VZ's performance was mainly characterized by a category-specific deficit for living things and a modality-specific deficit for perceptual attribute knowledge. As time went on, VZ's disorder affected all categories by changing the relationship between category and attribute knowledge. Data show that dissociations may change in the course of progressive cognitive breakdown, depending on both degeneration stage and task demands. VZ's performance is discussed in the light of the most influential theoretical accounts. Methodological suggestions regarding longitudinal studies of degenerative patients are also put forward.     

B-cell concentration in the apheretic product predicts acute graft-versus-host disease and treatment-related mortality of allogeneic peripheral blood stem cell transplantation

BACKGROUND: The influence of the graft composition on the clinical outcome after allogeneic peripheral blood stem cell (PBSC) transplantation is not well established. METHODS: The cellular composition of the apheretic products obtained from 63 human leukocyte antigen-identical siblings was prospectively correlated with the outcome of patients with hematological malignancies undergoing an allogeneic PBSC transplant after myeloablative conditioning. The concentration of nuclear, mononuclear, CD34+, T-cell subsets, B cells, and natural killer cells in the graft has been analyzed. RESULTS: In univariate analysis, acute graft-versus-host disease (GVHD) correlated with the disease (P=0.002), with the phase of disease at transplant (P=0.01), and with the number of CD20+ cells infused (P=0.05). In multivariate analysis, a dose of CD20+ cells in the graft higher than the median dose remained the only factor negatively affecting the incidence of acute GVHD (P=0.01; 95% confidence interval [CI]: 0.12-0.78). In univariate analysis, treatment-related mortality (TRM) correlated with the disease (P=0.04) and was negatively affected by a dose of infused B cells greater than the median value (28% versus 50%; P=0.02). In multivariate analysis, TRM was close to statistical correlation with the dose of CD20+ cells (P=0.06; 95% CI: 0.02-1.05). No other clinical parameter was influenced by the composition of the graft. CONCLUSIONS: Our results suggest that the concentration of B cells in the apheretic product may predict the incidence of acute GVHD and TRM in patients undergoing an allogeneic PBSC transplantation and open the way to the new preventive and therapeutic strategies for the management of GVHD.     

Seven-year performance of the Edwards Prima Plus stentless valve with the intact non-coronary sinus technique

OBJECTIVES: Late results after stentless aortic valve replacement (AVR) may be jeopardized by progressive aortic dilatation. To define functional outcome using the intact non-coronary sinus technique, all patients operated using the stentless Edwards Prima Plus xenograft were assessed. METHODS: Between January 2000 and August 2007, 154 patients, aged 71 +/- 9 years, underwent stentless AVR using a technique, which replaces the non-coronary sinus and stabilizes two of three commissures. Indication was aortic valve stenosis (AS) in 103 (67%) patients: 33 (21%) had bicuspid valve and four endocarditis. Ninety-six (62%) patients were in NYHA III-IV, and 13 (8%) had LVEF <30%. Associated procedures were required in 59 (38%) patients (CABG, 34; ascending aorta, 22; others 3). Study endpoints were survival, freedom from valve-related events, clinical status, and graft function. RESULTS: There were two hospital and two late deaths during a 48 +/- 19 months (1-92) follow-up (97 +/- 3% survival at seven years). Seven-year freedom from structural failure, nonstructural failure, and endocarditis was 99 +/- 1%, 97 +/- 3%, and 98 +/- 2%. Follow-up NYHA (96 vs ten patients in class III-IV, p = 0.001), and cardiac function (13 vs one patient with LVEF <30%, p = 0.02) were improved. Xenograft performance was satisfactory: 0-2 + aortic insufficiency (AI) in 147 (98%) patients, mean trans-prosthetic pressure gradient 8 +/- 4 (0-25 mmHg). Aortic root diameters were comparable to postoperative values (sinus of Valsalva, 36 +/- 8 vs 35 +/- 9 mm, p = ns; sinotubular junction, 32 +/- 7 vs 34 +/- 8 mm, p = ns). CONCLUSIONS: Stentless AVR with non-coronary sinus replacement affords excellent late outcome and low rate of valve-related events, even in complex patients (bicuspid valve, LV failure, and endocarditis). Aortic root dimensions remain stable over time allowing rewarding xenograft function.     

Sperm quality improvement after natural anti-oxidant treatment of asthenoteratospermic men with leukocytospermia

Aim： To study the immune-modulating and anti-oxidant effects of beta-glucan, papaya, lactoferrin, and vitamins C and E on sperm characteristics of patients with asthenoteratozoospermia associated with leucocytosis. Methods： Fifty-one patients referred to our Sterility Center for semen analysis were selected. Sperm parameters were assessed before and after patient＇s treatment with beta-glucan, lactoferrin, papaya, and vitamins C and E. DNA damage was assessed by the acridine orange test and sperm structural characteristics were evaluated by transmission electron microscopy. Results： After 90 days of treatment, an increase in the percentage of morphologically normal sperm （17.0 ± 5.2 vs. 29.8 ± 6.5） and total progressive motility （19.0± 7.8 vs. 34.8 ± 6.8） were detected. Structural sperm characteristics as well as chromatin integrity were also improved after treatment. In terms of leukocyte concentration in seminal fluid, a significant reduction was recorded （2.2 ± 0.9 vs. 0.9± 0.2）. Conclusion： The treatment of an inflammatory process by the synergic action of immune modulators and anti-oxidants could protect sperm during maturation and migration, leading to improved sperm function. （Asian JAndrol 2008 Mar;. 10： 201-206）     

Polydeoxyribonucleotide stimulates angiogenesis and wound healing in the genetically diabetic mouse

Healing of diabetic wounds still remains a critical medical problem. Polydeoxyribonucleotide (PDRN), a compound having a mixture of deoxyribonucleotide polymers, stimulates the A2 purinergic receptor with no toxic or adverse effect. We studied the effects of PDRN in diabetes‐related healing defect using an incisional skin‐wound model produced on the back of female diabetic mice (db+/db+) and their normal littermates (db+/+m). Animals were treated daily for 12 days with PDRN (8 mg/kg/ip) or its vehicle (100 μL 0.9%NaCl). Mice were killed 3, 6, and 12 days after skin injury to measure vascular endothelial growth factor (VEGF) mRNA expression and protein synthesis, to assay angiogenesis and tissue remodeling through histological evaluation, and to study CD31, Angiopoietin‐1 and Transglutaminase‐II. Furthermore, we measured wound breaking strength at day 12. PDRN injection in diabetic mice resulted in an increased VEGF message (vehicle=1.0±0.2 n‐fold vs. β‐actin; PDRN=1.5±0.09 n‐fold vs. β‐actin) and protein wound content on day 6 (vehicle=0.3±0.07 pg/wound; PDRN=0.9±0.1 pg/wound). PDRN injection improved the impaired wound healing and increased the wound‐breaking strength in diabetic mice. PDRN also caused a marked increase in CD31 immunostaining and induced Transglutaminase‐II and Angiopoietin‐1 expression. Furthermore, the concomitant administration of 3,7‐dimethyl‐1‐propargilxanthine, a selective adenosine A2A receptor antagonist, abolished PDRN positive effects on healing. However, 3,7‐dimethyl‐1‐propargilxanthine alone did not affect wound healing in both diabetic mice and normal littermates. These results suggest that PDRN might be useful in wound disorders associated with diabetes.     

Surgical options in the treatment of GIST of the upper portion of the stomach. Report of two cases

Gastrointestinal stromal tumors are rare neoplasms arising from mesenchymal precursor cells of the gastrointestinal tract that may differentiate towards the interstitial cells of Cajal, pacemaker cells regulating autonomous motility of G.I. tract. Grading of GIST has been proven to be as difficult as their classification. Two thirds of GISTs are located in the stomach, 20-50% in the small bowel (one third in the duodenum), and 5-15% in colon and rectum; GISTs, however, may rarely be found also in the oesophagus, omentum, mesentery or the retroperitoneum. The distribuition of these tumors in the stomach is: pars media, 40%; antrum, 25%; pylorus, 20%; in less than 15%, GISTs location is next to the EGJ, in the cardia and in the iundus. The upper gastric third location of GISTs is not common, so their surgical management has been not yet well investigated. Total gastrectomy is considered the therapy of choice for the GIST located next to the EGJ, but wedge resection could be considered a surgical option in selected cases. The Authors describe 2 cases of GIST located just under the upper portion of the stomach and discuss about the different surgical options for GISTs of this region.