The Lynch syndrome (LS) is an inherited cancer syndrome showing a preponderance of colorectal cancer (CRC) in context with endometrial cancer and several other extracolonic cancers, which is due to pathogenic mutations in the mismatch repair (MMR) genes, MLH1, MSH2, MSH6, and PMS2. Some families were found to show a LS phenotype without an identified MMR mutation, although there was microsatellite instability and absence of MSH2 expression by immunohistochemistry. Studies of a subset of these families found a deletion at the 3′ end of the epithelial cell adhesion molecule (EPCAM) gene, causing transcription read-through resulting in silencing of MSH2 through hypermethylation of its promoter. The tumor spectrum of such families appears to differ from classical LS.
Our study of two large families (USA Family R and Dutch Family A) with an EPCAM deletion was carried out using each institution’s standard family study protocol. DNA was extracted from peripheral blood and EPCAM deletion analysis was performed.
Both families were found to harbor the same deletion at the 3′ end of EPCAM. Analysis showed that the deletion originated from a common ancestor. Family R and Family A members showed segregation of CRC with the presence of this EPCAM mutation. Compared with classic LS, there were almost no extracolonic cancers.
Members of Family R and Family A, all with the same EPCAM deletion, predominantly presented with CRC but no LS-associated endometrial cancer, confirming findings seen in other, smaller, LS families with EPCAM mutations. In these EPCAM mutation carriers, cancer surveillance should be focused on CRC.
The CorCap Cardiac Support Device (Acorn Cardiovascular, Inc.) is the first device that specifically addresses ventricular remodeling in heart failure by reducing wall stress. We previously reported outcomes from the Acorn randomized trial to a common closing date (22.9 months of follow up). This report summarizes results of extended follow up to 5 years.
107 patients were enrolled in the No-Mitral Valve Repair/Replacement stratum including 57 in the CorCap treatment group and 50 in the control (optimal medical therapy alone) group. Patients were assessed every year until completing 5 years of follow up, for survival, adverse events, major cardiac procedures, New York Heart Association (NYHA) functional status and echocardiograms, which were read at a core laboratory.
Overall survival rates were similar between the treatment and control groups demonstrating no late adverse effect on mortality. The treatment group had significant reductions in left ventricular end diastolic volume (p = 0.029) as well as a small increase in sphericity index. More patients in the treatment group improved by at least one NYHA functional class (p= 0.0005). There was no difference in rates of adverse events. In a subgroup of patients with an intermediate left ventricular end diastolic dimension, there was a significant reduction in the Kaplan Meier estimate of the freedom from the composite endpoint of death and major cardiac procedures (p= 0.04).
These cumulative data demonstrate the sustained reverse remodeling of the left ventricle and the long term safety and efficacy of the CorCap Cardiac Support Device as an adjunctive therapy for patients with heart failure who remain symptomatic despite optimal medical therapy.
The cognitive decline associated with normal aging was long believed to be due primarily to decreased synaptic density and neuron loss. Recent studies in both humans and non-human primates have challenged this idea, pointing instead to disturbances in white matter (WM) including myelin damage. Here, we review both cross-sectional and longitudinal studies in humans and non-human primates that collectively support the hypothesis that WM disturbances increase with age starting at middle age in humans, that these disturbances contribute to age-related cognitive decline, and that age-related WM changes may occur as a result of free radical damage, degenerative changes in cells in the oligodendrocyte lineage, and changes in microenvironments within WM.
Aging; White matter; Myelination
The study of diabetic cardiomyopathy (diabetic CM) is an area of significant interest given the strong association between diabetes and the risk of heart failure. Many unanswered questions remain regarding the clinical definition and pathogenesis of this metabolic cardiomyopathy. This article reviews the current understanding of diabetic CM with a particular emphasis on the unresolved issues that have limited translation of scientific discovery to patient bedside.
diabetic cardiomyopathy; mitochondria; heart failure; metabolism
To identify risk factors for cerebral lesions among survivors of TTTS treated with laser surgery.
A multilevel regression analysis examined risk factors for neonatal cerebral lesions identified by imaging. Imaging was routine in “high-risk survivors”, defined as those delivered at <32 weeks' gestation, and by clinical indications if born later. Severe lesions were defined as: intraventricular hemorrhage grade III–IV, cystic periventricular leukomalacia, ventriculomegaly and/or hydrocephalus, microcephaly, infarctions, porencephalic/Dandy-Walker cysts, or bilateral other cysts.
For 262 consecutive laser-treated TTTS patients, 18 neonates had severe lesions identified among 427 individual survivors (4.2%) and 242 “high-risk survivors” (7.4%). Forty-six newborns had any cerebral lesion, resulting in lesion rates of 10.8%–19.0%. Delivery <32 weeks' (OR=4.95, p<0.001) and <28 weeks' (OR=6.25, p<0.001) gestation were associated with increased likelihood of any cerebral lesion.
This cohort showed low rates (4–7%) of severe neonatal cerebral lesions, with prematurity being the primary risk factor.
cerebral lesions; imaging; neurological; outcome; twin-twin transfusion syndrome
This study assesses the two-year outcomes, costs, and financial sustainability of a medical care management intervention for community mental health settings.
A total of 407 psychiatric outpatients with serious mental illnesses were randomized to usual care or to a medical care manager, who provided care coordination and education. Two-year follow-up chart reviews and interviews assessed quality and outcomes of care, and costs from both the health system and managerial perspective.
Subjects in the intervention group had sustained improvements in quality of primary care preventive services (p<0.001), quality of cardiometabolic care (p<0.001), and mental health-related quality of life (p<0.001). From a health system perspective, by year 2, the program showed a $932 reduction in total costs (95% CI (−1973, 102) with a 92.3% probability that the program was associated with lower costs than usual care. From the community mental health center perspective, the program would break even (i.e., revenues would cover setup costs) if 58% or more of clients had Medicaid or another form of insurance. Given that only 40.5% of clients in the study had Medicaid, the program was not sustainable after grant funding ended.
The positive long-term outcomes and favorable cost profile provided evidence of the potential value of this model. However, the discrepancy between health system and managerial cost perspectives limited the program’s financial sustainability. With anticipated insurance expansions under health reform, there is likely to be a stronger business case for safety net organizations considering implementing these and other evidence-based interventions.
During macronuclear differentiation of the ciliate Tetrahymena thermophila, genome-wide DNA rearrangements eliminate nearly 50 Mbp of germline derived DNA, creating a streamlined somatic genome. The transposon-like and other repetitive sequences to be eliminated are identified using a piRNA pathway and packaged as heterochromatin prior to their removal. In this study, we show that LIA5, which encodes a zinc-finger protein likely of transposon origin, is required for both chromosome fragmentation and DNA elimination events. Lia5p acts after the establishment of RNAi-directed heterochromatin modifications, but prior to the excision of the modified sequences. In ∆LIA5 cells, DNA elimination foci, large nuclear sub-structures containing the sequences to be eliminated and the essential chromodomain protein Pdd1p, do not form. Lia5p, unlike Pdd1p, is not stably associated with these structures, but is required for their formation. In the absence of Lia5p, we could recover foci formation by ectopically inducing DNA damage by UV treatment. Foci in both wild-type or UV-treated ∆LIA5 cells contain dephosphorylated Pdd1p. These studies of LIA5 reveal that DNA elimination foci form after the excision of germ-line limited sequences occurs and indicate that Pdd1p reorganization is likely mediated through a DNA damage response.
The structure of the brain as a product of morphogenesis is difficult to reconcile with the observed complexity of cerebral connectivity. We therefore analyzed relationships of adjacency and crossing between cerebral fiber pathways in four nonhuman primate species and in humans by using diffusion magnetic resonance imaging. The cerebral fiber pathways formed a rectilinear three-dimensional grid continuous with the three principal axes of development. Cortico-cortical pathways formed parallel sheets of interwoven paths in the longitudinal and medio-lateral axes, in which major pathways were local condensations. Cross-species homology was strong and showed emergence of complex gyral connectivity by continuous elaboration of this grid structure. This architecture naturally supports functional spatio-temporal coherence, developmental path-finding, and incremental rewiring with correlated adaptation of structure and function in cerebral plasticity and evolution.
Objective. To develop and validate an evaluation tool to assess student pharmacists' performance in a simulation scenario involving a patient with Clostridium difficile infection (CDI).
Methods. The authors used an expert panel review process to establish content validity of the tool. Four faculty members used the tool to evaluate student pharmacist groups during 2011 and tested a modified version of the tool in 2012. The authors analyzed the results for each year to determine internal consistency and inter-rater reliability.
Results. The 2011 tool demonstrated sound internal consistency, but several items had poor inter-rater agreement. The revised 2012 tool demonstrated acceptable internal consistency and good to excellent inter-rater agreement for all items except one.
Conclusions. The tool facilitated reliable assessment of student pharmacists' clinical decision-making during simulation performance involving a patient with CDI.
assessment; simulation; evaluation tool; validation; clostridium difficile infection
To address the value of surgery in sporadic Zollinger-Ellison syndrome (ZES) patients with negative imaging studies.
Medical control of acid hypersecretion in patients with sporadic Zollinger-Ellison syndrome (ZES) is highly effective. This has led to these patients frequently not sent to surgery, especially if preoperative imaging studies are negative, due in large part because almost no data exists on the success of surgery in this group.
58 prospectively studied sporadic ZES patients (17% of total studied) had negative imaging studies and their surgical outcome was compared to 117 patients with positive imaging results.
35 patients had negative imaging in the pre-somatostatin receptor scintigraphy era (SRS) and 23 in the post-SRS era. The image negative patients had long disease histories prior to surgery (mean±SEM, from onset=7.9±1[range −0.25-35 yrs]) and 25% were followed ≥2yrs from diagnosis. At surgery, gastrinoma was found in 57/58 patients (98%). Tumors were small (mean=0.8cm, 60% < 1 cm). The most common primary sites were: duodenal 64%, pancreatic 17%, and lymph node (LN)(10%). 50% had a primary only, 41% primary + LN, and 7% had liver metastases. 35/58(60%) were cured immediately postoperatively and at last follow-up [mean-9.4yrs, range 0.2-22yrs], 27 patients (46%) remained cured. During follow-up 3 patients died, each was found to have liver metastases at surgery. In comparison to the image positive patients, those with negative imaging had lower preop fasting gastrin levels; a longer delay prior to surgery; more frequently had a small duodenal tumors; less frequently had a pancreatic tumor, multiple tumors or developed a new lesion postoperatively and had a longer survival.
Imaging negative sporadic ZES patients are not rare even in the post-SRS period. An experienced surgeon can find gastrinoma in almost every patient (98%) and nearly one-half (46%) are cured, a rate similar to imaging positive tumor patients. Because liver metastases were found in 7%, which may have been caused by a long delay in surgery and all the disease-related deaths occurred in this group, surgery should be routinely undertaken early in ZES patients despite negative imaging studies.
Gastrinoma; imaging negative; surgery; outcome
Magnesium plays an essential role in the synthesis and metabolism of vitamin D and magnesium supplementation substantially reversed the resistance to vitamin D treatment in patients with magnesium-dependent vitamin-D-resistant rickets. We hypothesized that dietary magnesium alone, particularly its interaction with vitamin D intake, contributes to serum 25-hydroxyvitamin D (25(OH)D) levels, and the associations between serum 25(OH)D and risk of mortality may be modified by magnesium intake level.
We tested these novel hypotheses utilizing data from the National Health and Nutrition Examination Survey (NHANES) 2001 to 2006, a population-based cross-sectional study, and the NHANES III cohort, a population-based cohort study. Serum 25(OH)D was used to define vitamin D status. Mortality outcomes in the NHANES III cohort were determined by using probabilistic linkage with the National Death Index (NDI).
High intake of total, dietary or supplemental magnesium was independently associated with significantly reduced risks of vitamin D deficiency and insufficiency respectively. Intake of magnesium significantly interacted with intake of vitamin D in relation to risk of both vitamin D deficiency and insufficiency. Additionally, the inverse association between total magnesium intake and vitamin D insufficiency primarily appeared among populations at high risk of vitamin D insufficiency. Furthermore, the associations of serum 25(OH)D with mortality, particularly due to cardiovascular disease (CVD) and colorectal cancer, were modified by magnesium intake, and the inverse associations were primarily present among those with magnesium intake above the median.
Our preliminary findings indicate it is possible that magnesium intake alone or its interaction with vitamin D intake may contribute to vitamin D status. The associations between serum 25(OH)D and risk of mortality may be modified by the intake level of magnesium. Future studies, including cohort studies and clinical trials, are necessary to confirm the findings.
Magnesium intake; Serum 25-hydroxyvitamin D levels; Vitamin D insufficiency; Vitamin D deficiency; Parathyroid hormone; Mortality; Colorectal cancer; Cardiovascular diseases
The discovery of functional magnetic resonance imaging (fMRI) has greatly impacted neuroscience. The blood oxygenation level-dependent (BOLD) signal, using deoxyhemoglobin as an endogenous paramagnetic contrast agent, exposes regions of interest in task-based and resting-state paradigms. However the BOLD contrast is at best a partial measure of neuronal activity, because the functional maps obtained by differencing or correlations ignore the total neuronal activity in the baseline state. Here we describe how studies of brain energy metabolism at Yale, especially with 13C magnetic resonance spectroscopy and related techniques, contributed to development of quantitative functional brain imaging with fMRI by providing a reliable measurement of baseline energy. This narrative takes us on a journey, from molecules to mind, with illuminating insights about neuronal-glial activities in relation to energy demand of synaptic activity. These results, along with key contributions from laboratories worldwide, comprise the energetic basis for quantitative interpretation of fMRI data.
calibrated fMRI; GABA; glutamate; glutamine; field potentials; multi-unit activity; neuroimaging
Ansamycins are very effective HSP90 inhibitors that showed significant beneficial effects in the treatment of EAE. However, their toxicity and poor stability in solution limit their clinical use. In the present study we have characterized the anti-inflammatory properties of a novel HSP90 inhibitor, PU-H71, and tested its effects in EAE. Our findings show that PU-H71 reduced lipopolysaccharide astrocyte activation but failed to reduce the inflammatory cytokine activation. In contrast to ansamycins, PU-H71 weakly affects EAE clinical course. In conclusion, although PU-H71 displayed some anti-inflammatory properties, it appeared in vivo less effective than the more toxic HSP90 inhibitors.
PU-H71; HSP90 inhibitors; Glial activation; EAE; Astrocytes; Microglia
In response to Catani et al., we show that corticospinal pathways adhere via sharp turns to two local grid orientations; that our studies have three times the diffusion resolution of those compared; and that the noted technical concerns, including crossing angles, do not challenge the evidence of mathematically specific geometric structure. Thus, the geometric thesis gives the best account of the available evidence.
To describe the prevalence of acute stress disorder (ASD) symptoms and examine proposed DSM-5 symptom criteria in relation to concurrent functional impairment in children.
From an international archive, datasets were identified which included assessment of acute traumatic stress reactions and concurrent impairment in children age 5 to 17. Data came from 15 studies conducted in the US, UK, Australia, and Switzerland with 1645 children. Dichotomized items were created to indicate the presence or absence of each of the 14 proposed ASD symptoms and functional impairment. The performance of a proposed diagnostic criterion (number of ASD symptoms required) was examined as a predictor of concurrent impairment.
Each ASD symptom was endorsed by 14% to 51% of children; 41% reported clinically-relevant impairment. Children reported from 0 to 13 symptoms (mean = 3.6). Individual ASD symptoms were associated with greater likelihood of functional impairment. The DSM-5 proposed 8-symptom requirement was met by 202 (12.3%) children, and had low sensitivity (.25) in predicting concurrent clinically-relevant impairment. Requiring fewer symptoms (three to four) greatly improved sensitivity while maintaining moderate specificity.
This group of symptoms appears to capture aspects of traumatic stress reactions that can create distress and interfere with children’s ability to function in the acute post-trauma phase. Results provide a benchmark for comparison with adult samples; a smaller proportion of children met the 8-symptom criterion than reported for adults. Symptom requirements for the ASD diagnosis may need to be lowered to optimally identify children whose acute distress warrants clinical attention.
acute stress disorder; DSM-5; diagnostic criteria
In 2011, Kaiser Permanente Northwest Region (KPNW) won the Lawrence Patient Safety Award for its innovative work in reducing hospital readmission rates. In 2012, Kaiser Permanente Southern California (KPSC) won the Transfer Projects Lawrence Safety Award for the successful implementation of the KPNW Region’s “transitional care” bundle to a Region that was almost 8 times the size of KPNW. The KPSC Transition in Care Program consists of 6 KPNW bundle elements and 2 additional bundle elements added by the KPSC team. The 6 KPNW bundle elements were risk stratification, standardized discharge summary, medication reconciliation, a postdischarge phone call, timely follow-up with a primary care physician, and a special transition phone number on discharge instructions. The 2 additional bundle elements added by KPSC were palliative care consult if indicated and a complex-case conference. KPSC has implemented most of the KPNW and KPSC bundle elements during the first quarter of 2012 for our Medicare risk population at all of our 13 medical centers. Each year, KPSC discharges approximately 40,000 Medicare risk patients. After implementation of bundle elements, KPSC Medicare risk all-cause 30-day Healthcare Effectiveness Data and Information Set readmissions observed-over-expected ratio and readmission rates from December 2010 to November 2012 decreased from approximately 1.0 to 0.80 and 12.8% to 11%, respectively.
We have previously shown that myelin abnormalities and loss characterize the normal aging process of the brain and that an age-associated reduction in Klotho is conserved across species. Predominantly generated in brain and kidney, Klotho overexpression extends life span, whereas loss of Klotho accelerates the development of aging-like phenotypes. While the function of Klotho in brain is unknown, loss of Klotho expression leads to cognitive deficits. In the present study, we found significant effects of Klotho on oligodendrocyte functions including induced maturation of rat primary oligodendrocytic progenitor cells (OPCs) in vitro and myelination. Phosphoprotein Western analysis indicated Klotho's downstream effects involve Akt and ERK signal pathways. Klotho increased OPCs maturation, and inhibition of Akt or ERK function blocked this effect on OPCs. In vivo studies of Klotho knockout mice and their control littermates revealed that knockout mice have a significant reduction in major myelin protein and gene expression. By immunohistochemistry, the number of total and mature oligodendrocytes was significantly lower in Klotho knockout mice. Strikingly, at the ultrastructural level, Klotho knockout mice exhibited significantly impaired myelination of the optic nerve and corpus callosum. These mice also displayed severe abnormalities at the nodes of Ranvier. In order to decipher the mechanisms by which Klotho affects oligodendrocytes, we used luciferase pathway reporters to identify the transcription factors involved. Taken together, these studies provide novel evidence for Klotho as a key player in myelin biology, which may thus be a useful therapeutic target in efforts to protect brain myelin against age-dependent changes.
It is unknown whether warfarin or aspirin therapy is superior for patients with heart failure who are in sinus rhythm.
We designed this trial to determine whether warfarin (with a target international normalized ratio of 2.0 to 3.5) or aspirin (at a dose of 325 mg per day) is a better treatment for patients in sinus rhythm who have a reduced left ventricular ejection fraction (LVEF). We followed 2305 patients for up to 6 years (mean [±SD], 3.5±1.8). The primary outcome was the time to the first event in a composite end point of ischemic stroke, intracerebral hemorrhage, or death from any cause.
The rates of the primary outcome were 7.47 events per 100 patient-years in the warfarin group and 7.93 in the aspirin group (hazard ratio with warfarin, 0.93; 95% confidence interval [CI], 0.79 to 1.10; P = 0.40). Thus, there was no significant overall difference between the two treatments. In a time-varying analysis, the hazard ratio changed over time, slightly favoring warfarin over aspirin by the fourth year of follow-up, but this finding was only marginally significant (P = 0.046). Warfarin, as compared with aspirin, was associated with a significant reduction in the rate of ischemic stroke throughout the follow-up period (0.72 events per 100 patient-years vs. 1.36 per 100 patient-years; hazard ratio, 0.52; 95% CI, 0.33 to 0.82; P = 0.005). The rate of major hemorrhage was 1.78 events per 100 patient-years in the warfarin group as compared with 0.87 in the aspirin group (P<0.001). The rates of intracerebral and intracranial hemorrhage did not differ significantly between the two treatment groups (0.27 events per 100 patient-years with warfarin and 0.22 with aspirin, P = 0.82).
Among patients with reduced LVEF who were in sinus rhythm, there was no significant overall difference in the primary outcome between treatment with warfarin and treatment with aspirin. A reduced risk of ischemic stroke with warfarin was offset by an increased risk of major hemorrhage. The choice between warfarin and aspirin should be individualized.
Weight gain is a major adverse effect of several second-generation antipsychotic medications. Rimonabant is a cannabinoid-1 receptor antagonist that promotes weight loss in the general population. We conducted a 16-week, double-blind, placebo-controlled study of rimonabant (20 mg/d) in people with schizophrenia or schizoaffective disorder, based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria, who were clinically stable on second-generation antipsychotics. Participants had a body mass index of 27 kg/m2 or higher with hyperlipidemia or body mass index of 30 kg/m2 or higher, and no current substance abuse/dependence (except nicotine), more than weekly cannabis use, or recent depressive symptoms/suicidality. An exercise and dietary counseling group was offered weekly. Target enrollment was 60; the trial was terminated early because of withdrawal of rimonabant from the European market. Fifteen participants were randomized (7 rimonabant, 8 placebo); 5 completed in each group. Rimonabant was associated with a greater reduction in Brief Psychiatric Rating Scale total score versus placebo (mean ± SE difference, −1.9 ± 0.8, P = 0.02), driven by differences in the Brief Psychiatric Rating Scale anxiety/depression (−1.4 ± 0.35, P = 0.0004) and hostility (−0.7 ± 0.3, P = 0.02) factors. Group differences were not significant for the Calgary Depression Scale total score (P = 0.24), Scale for the Assessment of Negative Symptoms total score (P = 0.13), weight, blood pressure, or fasting lipids or glucose. Rimonabant was well tolerated with no significant adverse events. No significant weight loss, metabolic effects, or adverse psychiatric effects were associated with the cannabinoid-1 receptor antagonist rimonabant in this small sample of people with schizophrenia. The endocannabinoid system remains a promising target for pharmacotherapy of schizophrenia and obesity.
rimonabant; schizophrenia; obesity; metabolic syndrome; depression
Macrophages respond to inflammatory stimuli by modulating the expression of hundreds of genes in a defined temporal cascade, with diverse transcriptional and post-transcriptional mechanisms contributing to the regulatory network. We examined pro-inflammatory gene regulation in activated macrophages by performing RNA-Seq with fractionated chromatin-associated, nucleoplasmic, and cytoplasmic transcripts. This methodological approach allowed us to separate the synthesis of nascent transcripts from transcript processing and the accumulation of mature mRNAs. In addition to documenting the sub-cellular locations of coding and non-coding transcripts, the results provide a high-resolution view of the relationship between defined promoter and chromatin properties and the temporal regulation of diverse classes of co-expressed genes. The data also reveal a striking accumulation of full-length yet incompletely spliced transcripts in the chromatin fraction, suggesting that splicing often occurs after transcription has been completed, with transcripts retained on the chromatin until fully spliced.
Presently there is no clinically feasible imaging modality that can effectively detect cortical demyelination in patients with multiple sclerosis (MS). The objective of this study is to determine if clinically feasible magnetization transfer ratio (MTR) imaging is sensitive to cortical demyelination in MS.
MRI were acquired in situ on 7 recently deceased patients with MS using clinically feasible sequences at 3 T, including relatively high-resolution T1-weighted and proton density–weighted images with/without a magnetization transfer pulse for calculation of MTR. The brains were rapidly removed and placed in fixative. Multiple cortical regions from each brain were immunostained for myelin proteolipid protein and classified as mostly myelinated (MMctx), mostly demyelinated (MDctx), or intermediately demyelinated (IDctx). MRIs were registered with the cortical sections so that the cortex corresponding to each cortical section could be identified, along with adjacent subcortical white matter (WM). Mean cortical MTR normalized to mean WM MTR was calculated for each cortical region. Linear mixed-effects models were used to test if mean normalized cortical MTR was significantly lower in demyelinated cortex.
We found that mean normalized cortical MTR was significantly lower in cortical tissue with any demyelination (IDctx or MDctx) compared to MMctx (demyelinated cortex: least-squares mean [LSM] = 0.797, SE = 0.007; MMctx: LSM = 0.837, SE = 0.006; p = 0.01, n = 89).
This result demonstrates that clinically feasible MTR imaging is sensitive to cortical demyelination and suggests that MTR will be a useful tool to help detect MS cortical lesions in living patients with MS.
Background and purpose
To determine the proper method for normalization of spinal cord volume.
Materials and Methods
A group of 34 multiple sclerosis (MS) patients (28 relapsing and 6 progressive) and 15 healthy controls had whole spinal cord 3 mm thick T2-weighted axial fast spin-echo MRI images obtained at 3T. For each participant, four volumes were measured (C2-3 volume, cervical cord volume, thoracic cord volume and whole cord volume). The volumes were normalized by the number of slices and three potential measures of body size (intracranial volume (ICV), body mass index, and body surface area) using the proportional method.
All raw volumes and volumes normalized by number of slices or ICV were significantly lower in progressive MS patients compared to relapsing MS patients/healthy controls (p<0.05). In addition, C2-3 volume and cervical cord volume were significantly correlated with EDSS score (p<0.05). All regional volumes showed high intercorrelation, and normalization by the number of slices significantly increased some correlations. Regarding reliability, whole cord volume regardless of normalization technique had lower coefficient of variation than C2-3 volume.
Since normalization factor had limited impact on reliability and the ability to detect differences, normalization by the number of slices is recommended.
3 Tesla imaging; multiple sclerosis; normalization; spinal cord atrophy
Carbon-13 NMR spectroscopy in combination with 13C-labeled substrate infusion is a powerful technique to measure a large number of metabolic fluxes non-invasively in vivo. It has been used to quantify glycogen synthesis rates, establish quantitative relationships between energy metabolism and neurotransmission and evaluate the importance of different substrates. All measurements can, in principle, be performed through direct 13C NMR detection or via indirect 1H-[13C] NMR detection of the protons attached to 13C nuclei. The choice for detection scheme and pulse sequence depends on the magnetic field strength, whereas substrate selection depends on the metabolic pathways that are studied. 13C NMR spectroscopy remains a challenging technique that requires several non-standard hardware modifications, infusion of 13C-labeled substrates and sophisticated processing and metabolic modeling. Here the various aspects of direct 13C and indirect 1H-[13C] NMR are reviewed with the aim of providing a practical guide.
NMR spectroscopy; direct 13C detection; indirect 1H-[13C] detection; broadband decoupling; RF power deposition; metabolism; metabolic modeling
Cannabis withdrawal occurs in frequent users who quit, but there are no accepted diagnostic criteria for a cannabis withdrawal syndrome (CWS). This study evaluated diagnostic criteria for CWS proposed in DSM-V and two earlier proposals.
A convenience sample of 384 adult, non-treatment-seeking lifetime cannabis smokers provided retrospective self-report data on their “most difficult” quit attempt without formal treatment, which was used in this secondary analysis. Prevalence, time of onset, and peak intensity (5-point Likert scale) for 39 withdrawal symptoms (drawn from the literature) were assessed via computer-administered questionnaire. Subject groups were compared using chi-square or ANOVA. Symptom clustering was evaluated with principal components analysis.
40.9% of subjects met the DSM-V criterion of ≥ 3 symptoms from a list of 7. There were no associations with sex, race, or type of cannabis preparation used. There were significant positive associations between duration or frequency of cannabis use prior to the quit attempt and experiencing CWS. Subjects with CWS had a significantly shorter duration of abstinence. Alternative syndromal criteria (dropping physical symptoms from DSM-V list; requiring ≥ 2or ≥ 4 symptoms from a list of 11) yielded a similar prevalence of CWS and similar associations with prior cannabis use and relapse. The PCA yielded 12 factors, including some symptom clusters not included in DSM-V.
Findings support the concurrent and predictive validity of the proposed DSM-V CWS, but suggest that the list of withdrawal symptoms and number required for diagnosis warrant further evaluation.
cannabis; diagnostic criteria; DSM-V; withdrawal