Coracoid tunnels in open and arthroscopic treatment of acromioclavicular dislocation: an experimental cadaveric study.

PURPOSE: Treatment of acromioclavicular joint (ACJ) dislocation is not encoded uniquely. Type I and II injuries are usually treated conservatively, while types IV, V and VI surgically. Controversy still exists over the treatment of type III injuries. In the operative approach, there is no agreement on the best surgical technique. Our purpose is to compare the mini-open and arthroscopic approach focusing on the evaluation of the anatomical precision of the coracoid drilling. METHODS: This is a controlled laboratory study. Ten fresh-frozen cadaveric shoulders were randomly assigned to the two techniques in order to compare them. We performed essential surgical gestures to drill the tunnel using MINAR® System (mini-open) and Dog-Bone® (ARTHREX, arthroscopic). The anatomical specimens were then subjected to CT-scan investigation. We statistically evaluated the precision of these two techniques analyzing DICOM files using two parameters. Parameter 1 evaluates the tunnel entry area on the superior side of the coracoid. Parameter 2 describes the orientation of the tunnel. RESULTS: There are no statistically significant differences (95% confidence level) between arthroscopic and mini-open approach about the precision in the location of the coracoid hole, regarding the entry area (p = 1.00) and the orientation (p = 0.196). CONCLUSION: The evidences collected enable the orthopedic surgeon to choose equally between the two techniques in the treatment of AC joint dislocation toward precision.

Oxytocin receptor mRNA expression in dorsolateral prefrontal cortex in major psychiatric disorders: A human post-mortem study.

There is growing interest in oxytocin as a putative treatment for various psychiatric disorders including major depressive disorder, bipolar disorder and schizophrenia/schizoaffective disorder. However, potential alterations in the endogenous brain oxytocin system in these disorders are poorly characterized. Brain expression of oxytocin and its receptor genes in patients with these psychiatric disorders has not been well studied outside the hypothalamus. We measured expression of mRNA for oxytocin and its receptor in the dorsolateral prefrontal cortex of postmortem brains using quantitative polymerase chain reaction in a total of 581 individuals. These individuals either were diagnosed with major depressive disorder (n = 135), bipolar disorder (n = 57), schizophrenia/schizoaffective disorder (n = 169), or were control subjects, defined as individuals with no lifetime history of any of these disorders (n = 220). Diagnoses of major depressive disorder and bipolar disorder were associated with significantly increased oxytocin receptor mRNA levels in the dorsolateral prefrontal cortex. This finding is discussed in light of the extant literature on the dysregulation of oxytocin signaling in individuals with major psychiatric disorders.

HCV NS3 sequencing as a reliable and clinically useful tool for the assessment of genotype and resistance mutations for clinical samples with different HCV-RNA levels.

OBJECTIVES: This study aims to evaluate the reliability and clinical utility of NS3 sequencing in hepatitis C virus (HCV) 1-infected patients who were candidates to start a PI-containing regimen. METHODS: NS3 protease sequencing was performed by in-house-developed HCV-1 subtype-specific protocols. Phylogenetic analysis was used to test sequencing reliability and concordance with previous genotype/subtype assignment by commercial genotyping assays. RESULTS: Five hundred and sixty-seven HCV plasma samples with quantifiable HCV-RNA from 326 HCV-infected patients were collected between 2011 and 2014. Overall, the success rate of NS3 sequencing was 88.9%. The success rate between the two subtype protocols (HCV-1a/HCV-1b) was similarly high for samples with HCV-RNA >3 log IU/mL (>92% success rate), while it was slightly lower for HCV-1a samples with HCV-RNA ≤3 log IU/mL compared with HCV-1b samples. Phylogenetic analysis confirmed the genotype/subtype given by commercial genotyping assays in 92.9% (303/326) of cases analysed. In the remaining 23 cases (7.1%), 1 was HCV-1g (previously defined as subtype 1a), 1 was HCV-4d (previously defined as genotype 1b) and 1 was HCV-1b (previously defined as genotype 2a/2c). In the other cases, NS3 sequencing precisely resolved the either previous undetermined/discordant subtype 1 or double genotype/subtype assignment by commercial genotyping assays. Resistance-associated variants (RAVs) to PI were detected in 31.0% of samples. This prevalence changed according to PI experience (17.1% in PI-naive patients versus 79.2% in boceprevir/telaprevir/simeprevir-failing patients). Among 96 patients with available virological outcome following boceprevir/telaprevir treatment, a trend of association between baseline NS3 RAVs and virological failure was observed (particularly for HCV-1a-infected patients: 3/21 failing patients versus 0/22 achieving sustained virological response; P = 0.11). CONCLUSIONS: HCV-NS3 sequencing provides reliable results and at the same time gives two clinically relevant pieces of information: a correct subtype/genotype assignment and the detection of variants that may interfere with the efficacy of PI.

Undetectable HCV-RNA at treatment-week 8 results in high-sustained virological response in HCV G1 treatment-experienced patients with advanced liver disease: the International Italian/Spanish Boceprevir/Peginterferon/Ribavirin Name Patients Program.

In many countries, first-generation protease inhibitors (PIs)/peginterferon/ribavirin (P/R) still represent the only treatment option for HCV-infected patients. Subjects with advanced disease and previous failure to P/R urgently need therapy, but they are under-represented in clinical trials. All treatment-experienced F3/4 Metavir patients who received boceprevir (BOC)+P/R in the Italian-Spanish Name Patient Program have been included in this study. Multivariate logistic regression analysis (MLR) was used to identify baseline and on-treatment predictors of SVR and adverse events (AEs). Four hundred and sixteen patients, mean age 57.7 (range 25-78 years), 70% males, 69.5% (289/416) F4, 14% (41/289) Child-Pugh class A6, 24% (70/289) with varices and 42% (173/416) prior null responders to P/R, were analysed. Overall, SVR rate (all 381 patients who received one dose of BOC) was 49%, (58% in F3, 45% in F4, 61% in relapsers, 51% in partial, 38% in null responders, and 72% in subjects with undetectable HCV-RNA at treatment-week (TW)8. Among patients with TW8 HCV-RNA ≥ 1000 IU/L, SVR was 8% (negative predictive value = 92%). Death occurred in 3 (0.8%) patients, while decompensation and infections were observed in 2.9% and 11%, respectively. At MLR, SVR predictors were TW4 HCV-RNA ≥ 1log10 -decline from baseline, undetectable TW8 HCV-RNA, prior relapse, albumin levels ≥3.5 g/dL and platelet counts ≥100 000/µL. Metavir F4, Child-Pugh A6, albumin, platelets, age and female gender were associated with serious and haematological AEs. Among treatment-experienced patients with advanced liver disease eligible for IFN-based therapy, TW8 HCV-RNA characterised the subset with either high or poor likelihood of achieving SVR. Using TW8 HCV-RNA as a futility rule, BOC/P/R appears to have a favourable benefit-risk profile.

Bone marrow-derived cell mobilization by G-CSF to enhance osseointegration of bone substitute in high tibial osteotomy.

PURPOSE: To evaluate granulocyte colony-stimulating factor (G-CSF) efficacy in accelerating bone regeneration following opening-wedge high tibial valgus osteotomy for genu varum. METHODS: A phase II trial was conducted for evaluating the preoperative administration of G-CSF given at 10 µg/kg/day for 3 consecutive days with an additional half-dose 4 h before the opening-wedge high tibial valgus osteotomy. Overall, 12 patients (Group A) received G-CSF treatment, and the subsequent 12 patients (Group B) underwent surgery without G-CSF. The osteotomy gap was filled by a bone graft substitute. Bone marrow cell (BMC) mobilization was monitored by CD34+ve cell and clonogenic progenitor cell analysis. All patients underwent a clinical (Lysholm Knee Scale and SF-36) and radiographic evaluation preoperatively, as well as at given intervals postsurgery. RESULTS: All patients completed the treatment program without major side effects; G-CSF was well tolerated. BMC mobilization occurred in all Group A patients, with median peak values of circulating CD34+ve cells of 110/µL (range 29-256). Circulating clonogenic progenitors paralleled CD34+ve cell levels. A significant improvement in Lysholm Knee Scale was recorded at follow-up in Group A compared to Group B. At the radiographic evaluation, there was a significant increase in osseointegration at the bone-graft junction in Group A at 1, 2, 3 and 6 months postsurgery compared to Group B. The computerized tomography scan of the grafted area at 2 months postsurgery showed no significant difference in the quality of the newly formed bone between the two Groups. CONCLUSIONS: Although the limited number of patients does not allow firm conclusions, the study suggests that G-CSF can be safely administered preoperatively in subjects undergoing opening-wedge high tibial valgus osteotomy; in addition, the clinical, radiographic and CT monitoring indicate that G-CSF and/or mobilized BMCs may hasten bone graft substitute osseointegration. LEVEL OF EVIDENCE: I.

Clinical trial: the combination of rifaximin with partially hydrolysed guar gum is more effective than rifaximin alone in eradicating small intestinal bacterial overgrowth.

BACKGROUND: Abnormal intestinal clearance is involved in the pathogenesis of small intestinal bacterial overgrowth (SIBO). It is known that partially hydrolysed guar gum affects intestinal motility. Eradication therapy of SIBO is based on antibiotic treatment: no data are available on the role of fibre supplementation in eradicating SIBO. AIM: To assess whether the combination of partially hydrolysed guar gum and rifaximin is more effective than rifaximin alone in the treatment of SIBO. METHODS: A 50 g-glucose breath test was given to 500 consecutive patients. Patients with a positive glucose breath test and predisposing conditions to SIBO entered into the study, and were randomized to receive rifaximin 1200 mg/day or rifaximin 1200 mg/day plus partially hydrolysed guar gum 5 g/day for 10 days. Patients completed a symptom questionnaire and glucose breath test both in basal condition and 1 month after withdrawal of therapy. RESULTS: Seventy-seven patients had SIBO. Eradication rate of SIBO was 62.1% in the rifaximin group (both on per-protocol and intention-to-treat analyses), and 87.1% (per-protocol, P=0.017) and 85.0% (intention-to-treat, P=0.036) in the rifaximin-plus-partially hydrolysed guar gum group. Clinical improvement was observed in 86.9% and 91.1% of eradicated cases in rifaximin and rifaximin-plus-partially hydrolysed guar gum groups respectively (P=0.677). CONCLUSION: The combination of rifaximin with partially hydrolysed guar gum seems to be more useful in eradicating SIBO compared with rifaximin alone.

Successful antiviral therapy determines a significant decrease in squamous cell carcinoma antigen-associated (SCCA) variants' serum levels in anti-HCV positive cirrhotic patients.

Aberrant squamous cell carcinoma antigen (SCCA) expression is an early event in hepatocarcinogenesis, and increasing serum levels of SCCA variants IgM immune complexes (SCCA-IgM IC) have been found in cirrhotic patients developing hepatocellular carcinoma (HCC). We longitudinally evaluated a cohort of cirrhotic patients with hepatitis C virus infection (HCV) who underwent pegylated interferon (PEG-IFN) and ribavirin treatment. SCCA-IgM IC levels were assessed in the sera of 33 cirrhotic patients with HCV (21 males, median age 57 years) before, at the end and at 6-month and 1-year follow-up after treatment with PEG-IFN and ribavirin. SCCA-IgM IC serum levels (arbitrary units/mL, AU/mL) were evaluated according to treatment outcome: sustained virological response (SVR) vs nonresponse (NR). Overall, 15 patients obtained a SVR to antiviral therapy (45%). There was no significant difference in baseline SCCA-IgM IC serum levels between SVR and NR patients. When compared to baseline (451.2 AU/mL), SVR patients showed a significant decrease in median SCCA-IgM IC serum levels at the end of treatment (186.8 AU/mL, P = 0.013) and at both 6-month (96.8 AU/mL, P < 0.001) and 1-year follow-up (52.4 AU/mL, P < 0.001), while no significant modification was observed in NR patients. In patients with HCV-related liver cirrhosis, successful antiviral therapy is associated with a dramatic and significant decrease in SCCA-IC serum levels. Because of the pathophysiological correlation between SCCA and liver carcinogenesis, it is hypothesized that in patients with liver cirrhosis, SVR may be accompanied by a decreased proliferative stimulation.

The Premorbid Adjustment Scale as a measure of developmental compromise in patients with schizophrenia and their healthy siblings.

Schizophrenia is associated with subtle developmental compromise, but the degree to which this is also associated with heritability and genetic risk is uncertain. The goal of the current study was to investigate the childhood, adolescent, and early adulthood social and academic function of patients with schizophrenia, their healthy siblings, and normal controls, using the Premorbid Adjustment Scale (PAS). Generalized Estimating Equations were conducted to account for nesting of subjects within families. Patients (N=286) scored significantly worse than their healthy siblings (N=315) at every age period; siblings scored significantly worse than controls (N=261) at every age period. In probands, PAS scores got worse after early adolescence while control and proband scores improved after late adolescence. Furthermore, patient PAS scores significantly predicted the scores of their own discordant siblings in childhood and late adolescence. This effect approached significance in early adolescence and in the general scale. Thus, the most premorbidly impaired patients tended to have non-ill siblings with worse premorbid adjustment scores than the siblings of less impaired probands. The results suggest that both patients and many of their siblings share poor adjustment in childhood and adolescence, possibly due to shared genetic or environmental risk factors.

Comparison of EPI distortion correction methods in diffusion tensor MRI using a novel framework.

Diffusion weighted images (DWIs) are commonly acquired with Echo-planar imaging (EPI). B0 inhomogeneities affect EPI by producing spatially nonlinear image distortions. Several strategies have been proposed to correct EPI distortions including B0 field mapping (B0M) and image registration. In this study, an experimental framework is proposed to evaluation the performance of different EPI distortion correction methods in improving DT-derived quantities. A deformable registration based method with mutual information metric and cubic B-spline modeled constrained deformation field (BSP) is proposed as an alternative when B0 mapping data are not available. BSP method is qualitatively and quantitatively compared to B0M method using the framework. Both methods can successful reduce EPI distortions and significantly improve the quality of DT-derived quantities. Overall, B0M was clearly superior in infratentorial regions including brainstem and cerebellum, as well as in the ventral areas of the temporal lobes while BSP was better in all rostral brain regions.

Serious obstetric complications interact with hypoxia-regulated/vascular-expression genes to influence schizophrenia risk.

The etiology of schizophrenia is thought to include both epistasis and gene-environment interactions. We sought to test whether a set of schizophrenia candidate genes regulated by hypoxia or involved in vascular function in the brain (AKT1, BDNF, CAPON, CHRNA7, COMT, DTNBP1, GAD1, GRM3, NOTCH4, NRG1, PRODH, RGS4, TNF-alpha) interacted with serious obstetric complications to influence risk for schizophrenia. A family-based study of transmission disequilibrium was conducted in 116 trios. Twenty-nine probands had at least one serious obstetric complication (OC) using the McNeil-Sjostrom Scale, and many of the OCs reported were associated with the potential for fetal hypoxia. Analyses were conducted using conditional logistic regression and a likelihood ratio test (LRT) between nested models was performed to assess significance. Of the 13 genes examined, four (AKT1 (three SNPs), BDNF (two SNPs), DTNBP1 (one SNP) and GRM3 (one SNP)) showed significant evidence for gene-by-environment interaction (LRT P-values ranged from 0.011 to 0.037). Although our sample size was modest and the power to detect interactions was limited, we report significant evidence for genes involved in neurovascular function or regulated by hypoxia interacting with the presence of serious obstetric complications to increase risk for schizophrenia.

Comprehensive approach for correction of motion and distortion in diffusion-weighted MRI.

Patient motion and image distortion induced by eddy currents cause artifacts in maps of diffusion parameters computed from diffusion-weighted (DW) images. A novel and comprehensive approach to correct for spatial misalignment of DW imaging (DWI) volumes acquired with different strengths and orientations of the diffusion sensitizing gradients is presented. This approach uses a mutual information-based registration technique and a spatial transformation model containing parameters that correct for eddy current-induced image distortion and rigid body motion in three dimensions. All parameters are optimized simultaneously for an accurate and fast solution to the registration problem. The images can also be registered to a normalized template with a single interpolation step without additional computational cost. Following registration, the signal amplitude of each DWI volume is corrected to account for size variations of the object produced by the distortion correction, and the b-matrices are properly recalculated to account for any rotation applied during registration. Both qualitative and quantitative results show that this approach produces a significant improvement of diffusion tensor imaging (DTI) data acquired in the human brain.

The neurodevelopmental hypothesis of schizophrenia: following a trail of evidence from cradle to grave.

This is a critical review of the literature related to the neurodevelopmental hypothesis of schizophrenia which posits that the illness is related to abnormal brain development. The review focuses on data deriving from clinical studies, and it is organized according to the life phase from which the data were collected: conception and birth, infancy and childhood up to the onset of the illness, after illness onset, and postmortem. The neurodevelopmental hypothesis is supported by several pieces of evidence, including increased frequency of obstetric complications in patients with schizophrenia: the presence of minor physical anomalies; the presence of neurological, cognitive, and behavioral dysfunction long before illness onset; a course and outcome of the illness itself that is incompatible in most cases with a degenerative illness; the stability of brain structural measures over time; and the absence of postmortem evidence of neurodegeneration. A historical perspective on how this research accumulated and a section addressing important areas of future investigation are also provided. We conclude that schizophrenia is certainly not a degenerative brain disorder, and that it is likely that a brain insult in utero or at birth plays a role in its expression. Current evidence cannot completely exclude the role of environmental variables after birth. In addition, it is possible that other psychiatric disorders may also have a neurodevelopmental component.

PET study of competition between intravenous cocaine and [11C]raclopride at dopamine receptors in human subjects.

OBJECTIVE: Animal data suggest that the strong euphoriant effects of cocaine are related to the drug's enhancement of available dopamine at the synaptic cleft. The authors' goal was to determine whether this mechanism is the same in humans because the development of putative pharmacological agents for treatment of cocaine dependence depends on this knowledge. METHOD: Positron emission tomography with [11C]raclopride was used to examine the effects of the intravenous administration of 48 mg of cocaine (a typical "street" dose) on the occupancy of dopamine 2 receptors in the putamen of 11 self-identified intravenous drug abusers. RESULTS: All 11 subjects reported subjective stimulation and euphoria in response to cocaine administration. Radioligand occupancy at dopamine receptors was decreased significantly after cocaine administration, suggesting that higher dopamine concentrations were competing at the receptor site. CONCLUSIONS: These results support the concept of dopamine system involvement in human cocaine abuse.

Dopamine transporters are markedly reduced in Lesch-Nyhan disease in vivo.

Dopamine (DA) deficiency has been implicated in Lesch-Nyhan disease (LND), a genetic disorder that is characterized by hyperuricemia, choreoathetosis, dystonia, and compulsive self-injury. To establish that DA deficiency is present in LND, the ligand WIN-35,428, which binds to DA transporters, was used to estimate the density of DA-containing neurons in the caudate and putamen of six patients with classic LND. Comparisons were made with 10 control subjects and 3 patients with Rett syndrome. Three methods were used to quantify the binding of the DA transporter so that its density could be estimated by a single dynamic positron emission tomography study. These approaches included the caudate- or putamen-to-cerebellum ratio of ligand at 80-90 min postinjection, kinetic analysis of the binding potential [Bmax/(Kd x Vd)] using the assumption of equal partition coefficients in the striatum and the cerebellum, and graphical analysis of the binding potential. Depending on the method of analysis, a 50-63% reduction of the binding to DA transporters in the caudate, and a 64-75% reduction in the putamen of the LND patients was observed compared to the normal control group. When LND patients were compared to Rett syndrome patients, similar reductions were found in the caudate (53-61%) and putamen (67-72%) in LND patients. Transporter binding in Rett syndrome patients was not significantly different from the normal controls. Finally, volumetric magnetic resonance imaging studies detected a 30% reduction in the caudate volume of LND patients. To ensure that a reduction in the caudate volume would not confound the results, a rigorous partial volume correction of the caudate time activity curve was performed. This correction resulted in an even greater decrease in the caudate-cerebellar ratio in LND patients when contrasted to controls. To our knowledge, these findings provide the first in vivo documentation of a dopaminergic reduction in LND and illustrate the role of positron emission tomography imaging in investigating neurodevelopmental disorders.

Comparison of functional MR and H2 15O positron emission tomography in stimulation of the primary visual cortex.

PURPOSE: To locate spoiled gradient-echo functional MR signal changes in relation to brain parenchyma. METHODS: The region of the primary visual cortex was evaluated using functional MR and H2 15O positron emission tomography in each of six male subjects who were being visually stimulated by means of red light-emitting diode flash goggles. RESULTS: The positron emission tomography technique demonstrated substantially greater relative signal change with visual stimulation than did the functional MR technique. Furthermore, the functional MR signal changes were concentrated in loci around the periphery of brain parenchyma exhibiting increased radiotracer activity, as opposed to being collocated. CONCLUSIONS: Signal changes found using functional MR based on gradient-echo techniques reflect primarily phenomena occurring within small veins and underrepresent activity intrinsic to brain parenchyma, thus introducing potential inaccuracies in locating regions of activated brain tissue. Positron emission tomography, however, directly measures changes in metabolically related activity within the parenchyma.

Positron emission tomography imaging of serotonin transporters in the human brain using [11C](+)McN5652.

This paper presents the first Positron Emission Tomography (PET) images of the serotonin (5-hydroxytryptamine, 5-HT) transporter in the living human brain. PET imaging was performed in three healthy subjects after administration of [11C](+)McN5652 (the (+) enantiomer of trans-1,2,3,5,6,10 beta-hexahydro- 6-[4-(methylthio) phenyl]pyrrolo-[2,1-a] -isoquinolone), a radioligand previously shown to selectively label the 5-HT transporter in vivo in the mammalian (mouse and baboon) brain. To demonstrate the specificity of [11C](+)McN5652 binding, additional images were obtained in the same subjects after injection of [11C](-)McN5652, the pharmacologically inactive enantiomer, and, in two of the subjects, with [11C](+)McN5652 after pretreatment with the 5-HT uptake site blocker fluoxetine. Highest accumulation of [11C](+)McN5652 was observed in the midbrain, putamen, caudate nucleus, hypothalamus, and thalamus, regions known to contain high densities of 5-HT transporters. In these areas [11C](+)McN5652 concentrations rose steadily over 120 min. In contrast, with [11C](-)McN5652 and when the [11C](+)McN5652 binding was inhibited with fluoxetine, radioactivity concentrations declined after reaching a maximum (at 20 to 30 min). Inhibition studies with fluoxetine suggest that only with [11C](+)McN5652, there is specific binding. In the cerebellum, a region relatively void of 5-HT transporters, both [11C](+)McN5652 with and without fluoxetine block and [11C](-)McN5652 were released at approximately the same rate. The results of the studies indicate that [11C](+)McN5652 labels 5-HT transporter sites in the human brain. Quantitative PET imaging studies with this new tracer should provide valuable information on the status of these sites in health and disease.