Aim
Recent studies have reported an association between low vitamin D levels and diabetic peripheral neuropathy. However, many of these did not differentiate between people with painful diabetic ...peripheral neuropathy and those with painless diabetic peripheral neuropathy, or assess major confounding factors including sunlight exposure and daily activity. Our study addressed these limitations and evaluated vitamin D levels in people with carefully phenotyped diabetic peripheral neuropathy and controls.
Methods
Forty‐five white Europeans with Type 2 diabetes and 14 healthy volunteers underwent clinical and neurophysiological assessments. People with Type 2 diabetes were then divided into three groups (17 with painful diabetic peripheral neuropathy, 14 with painless diabetic peripheral neuropathy and 14 with no diabetic peripheral neuropathy). All had seasonal sunlight exposure and daily activity measured, underwent a lower limb skin biopsy and had 25‐hydroxyvitamin D measured during the summer months, July to September.
Results
After adjusting for age, BMI, activity score and sunlight exposure, 25‐hydroxyvitamin D levels (nmol/l) (se) were significantly lower in people with painful diabetic peripheral neuropathy painful diabetic peripheral neuropathy 34.9 (5.8), healthy volunteers 62.05 (6.7), no diabetic peripheral neuropathy 49.6 (6.1), painless diabetic peripheral neuropathy 53.1 (6.2); ANCOVAP = 0.03. Direct logistic regression was used to assess the impact of seven independent variables on painful diabetic peripheral neuropathy. Vitamin D was the only independent variable to make a statistically significant contribution to the model with an inverted odds ratio of 1.11. Lower 25‐hydroxyvitamin D levels also correlated with lower cold detection thresholds (r = 0.39, P = 0.02) and subepidermal nerve fibre densities (r = 0.42, P = 0.01).
Conclusions
We have demonstrated a significant difference in 25‐hydroxyvitamin D levels in well‐characterized people with painful diabetic peripheral neuropathy, while accounting for the main confounding factors. This suggests a possible role for vitamin D in the pathogenesis of painful diabetic peripheral neuropathy. Further prospective and intervention trials are required to prove causality between low vitamin D levels and painful diabetic peripheral neuropathy.
What's new?
Although there have been consistent associations between vitamin D levels and diabetic peripheral neuropathy, many studies did not differentiate between people with painful and painless diabetic peripheral neuropathy, assess major confounding factors including seasonal sunlight exposure and daily activity, and lacked detailed assessment of peripheral neuropathy including measurement of skin intra‐epidermal nerve density.
Our study addressed these limitations and found a significant reduction in 25‐hydroxyvitamin D levels in well‐characterized people with painful diabetic peripheral neuropathy.
Further studies including prospective and intervention trials are required to prove the causality between low vitamin D levels and painful diabetic peripheral neuropathy. If causality is confirmed, this will have a significant impact on clinical practice as there would be a clear rationale for early screening and treatment for low vitamin D in people with painful diabetic neuropathy.
Background
Magnetic resonance imaging (MRI) of the brain and cervical spinal cord is often performed in diagnostic evaluation of suspected motor neuron disease/amyotrophic lateral sclerosis ...(MND/ALS). Analysis of MRI-derived tissue damage metrics in a common domain facilitates group-level inferences on pathophysiology. This approach was applied to address competing hypotheses of directionality of neurodegeneration, whether anterograde, cranio-caudal dying-forward from precentral gyrus or retrograde, dying-back.
Methods
In this cross-sectional study, MRI was performed on 75 MND patients and 13 healthy controls. Precentral gyral thickness was estimated from volumetric T1-weighted images using FreeSurfer, corticospinal tract fractional anisotropy (FA) from diffusion tensor imaging using FSL, and cross-sectional cervical cord area between C1-C8 levels using Spinal Cord Toolbox. To analyse these multimodal data within a common domain, individual parameter estimates representing tissue damage at each corticospinal tract level were first converted to
z
-scores, referenced to healthy control norms. Mixed-effects linear regression models were then fitted to these
z
-scores, with gradients hypothesised to represent directionality of neurodegeneration.
Results
At group-level,
z
-scores did not differ significantly between precentral gyral and intracranial corticospinal tract tissue damage estimates (regression coefficient − 0.24, 95% CI − 0.62, 0.14,
p
= 0.222), but step-changes were evident between intracranial corticospinal tract and C1 (1.14, 95% CI 0.74, 1.53,
p
< 0.001), and between C5 and C6 cord levels (0.98, 95% CI 0.58, 1.38,
p
< 0.001).
Discussion
Analysis of brain and cervical spinal MRI data in a common domain enabled investigation of pathophysiological hypotheses in vivo. A cranio-caudal step-change in MND patients was observed, and requires further investigation in larger cohorts.
In this study, we investigated brain mechanisms for the generation of subjective experience from objective sensory inputs. Our experimental construct was subjective tranquility. Tranquility is a ...mental state more likely to occur in the presence of objective sensory inputs that arise from natural features in the environment. We used functional magnetic resonance imaging to examine the neural response to scenes that were visually distinct (beach images vs. freeway images) and experienced as tranquil (beach) or non-tranquil (freeway). Both sets of scenes had the same auditory component because waves breaking on a beach and vehicles moving on a freeway can produce similar auditory spectral and temporal characteristics, perceived as a constant roar. Compared with scenes experienced as non-tranquil, we found that subjectively tranquil scenes were associated with significantly greater effective connectivity between the auditory cortex and medial prefrontal cortex, a region implicated in the evaluation of mental states. Similarly enhanced connectivity was also observed between the auditory cortex and posterior cingulate gyrus, temporoparietal cortex and thalamus. These findings demonstrate that visual context can modulate connectivity of the auditory cortex with regions implicated in the generation of subjective states. Importantly, this effect arises under conditions of identical auditory input. Hence, the same sound may be associated with different percepts reflecting varying connectivity between the auditory cortex and other brain regions. This suggests that subjective experience is more closely linked to the connectivity state of the auditory cortex than to its basic sensory inputs.
►Tranquil scenes effect enhanced connectivity between auditory cortex and other areas. ►Regions involved include medial prefrontal cortex and posterior cingulate gyrus. ►Also implicated are temporoparietal cortex and thalamus. ►This shows that visual context affects auditory connectivity and perception.
Summary
Background
(Meth)acrylates are potent sensitizers and a common cause of allergic contact dermatitis (ACD). The frequency of (meth)acrylate ACD has increased with soaring demand for acrylic ...nails. A preliminary audit has suggested a significant rate of positive patch tests to (meth)acrylates using aimed testing in patients providing a clear history of exposure. To date, (meth)acrylates have not been routinely tested in the baseline patch test series in the U.K. and Europe.
Objectives
To determine whether inclusion of 2‐hydroxyethyl methacrylate (2‐HEMA) 2% in petrolatum (pet.) in the baseline series detects cases of treatable (meth)acrylate ACD.
Methods
During 2016–2017, 15 U.K. dermatology centres included 2‐HEMA in the extended baseline patch test series. Patients with a history of (meth)acrylate exposure, or who tested positive to 2‐HEMA, were selectively tested with a short series of eight (meth)acrylate allergens.
Results
In total 5920 patients were consecutively patch tested with the baseline series, of whom 669 were also tested with the (meth)acrylate series. Overall, 102 of 5920 (1·7%) tested positive to 2‐HEMA and 140 (2·4%) to at least one (meth)acrylate. Had 2‐HEMA been excluded from the baseline series, (meth)acrylate allergy would have been missed in 36 of 5920 (0·6% of all patients). The top (meth)acrylates eliciting a positive reaction were 2‐HEMA (n = 102, 1·7%), 2‐hydroxypropyl methacrylate (n = 61, 1·0%) and 2‐hydroxyethyl acrylate (n = 57, 1·0%).
Conclusions
We recommend that 2‐HEMA 2% pet. be added to the British baseline patch test series. We also suggest a standardized short (meth)acrylate series, which is likely to detect most cases of (meth)acrylate allergy.
What's already known about this topic?
A significant rate of sensitization to (meth)acrylates has been demonstrated worldwide.
Increasing demand for acrylic nail fashion is putting consumers and nail technicians at risk of sensitization to (meth)acrylates.
What does this study add?
Inclusion of 2‐hydroxyethyl methacrylate (2‐HEMA) 2% in petrolatum (pet.) in the baseline series detects treatable (meth)acrylate allergic contact dermatitis (ACD).
Identifying (meth)acrylate ACD is important as it can have adverse health consequences for patients who require composite fillings, surgical glue and bone cement, all of which contain (meth)acrylates.
We recommend that 2‐HEMA 2% pet. be added to the British baseline patch test series, and to baseline series used in other countries.
Linked Comment: Goncalo. Br J Dermatol 2019; 181:663–664.
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Breast cancer is the most common type of cancer in women. Evaluation of axillary lymph node metastases is important for breast cancer staging and treatment planning.
To evaluate the diagnostic ...accuracy, cost-effectiveness and effect on patient outcomes of positron emission tomography (PET), with or without computed tomography (CT), and magnetic resonance imaging (MRI) in the evaluation of axillary lymph node metastases in patients with newly diagnosed early-stage breast cancer.
A systematic review of literature and an economic evaluation were carried out. Key databases (including MEDLINE, EMBASE and nine others) plus research registers and conference proceedings were searched for relevant studies up to April 2009. A decision-analytical model was developed to determine cost-effectiveness in the UK.
One reviewer assessed titles and abstracts of studies identified by the search strategy, obtained the full text of relevant papers and screened them against inclusion criteria. Data from included studies were extracted by one reviewer using a standardised data extraction form and checked by a second reviewer. Discrepancies were resolved by discussion. Quality of included studies was assessed using the quality assessment of diagnostic accuracy studies (QUADAS) checklist, applied by one reviewer and checked by a second.
Forty-five citations relating to 35 studies were included in the clinical effectiveness review: 26 studies of PET and nine studies of MRI. Two studies were included in the cost-effectiveness review: one of PET and one of MRI. Of the seven studies evaluating PET/CT (n = 862), the mean sensitivity was 56% 95% confidence interval (CI) 44% to 67% and mean specificity 96% (95% CI 90% to 99%). Of the 19 studies evaluating PET only (n = 1729), the mean sensitivity was 66% (95% CI 50% to 79%) and mean specificity 93% (95% CI 89% to 96%). PET performed less well for small metastases; the mean sensitivity was 11% (95% CI 5% to 22%) for micrometastases (≤ 2 mm; five studies; n = 63), and 57% (95% CI 47% to 66%) for macrometastases (> 2 mm; four studies; n = 111). The smallest metastatic nodes detected by PET measured 3 mm, while PET failed to detect some nodes measuring > 15 mm. Studies in which all patients were clinically node negative showed a trend towards lower sensitivity of PET compared with studies with a mixed population. Across five studies evaluating ultrasmall super-paramagnetic iron oxide (USPIO)-enhanced MRI (n = 93), the mean sensitivity was 98% (95% CI 61% to 100%) and mean specificity 96% (95% CI 72% to 100%). Across three studies of gadolinium-enhanced MRI (n = 187), the mean sensitivity was 88% (95% CI 78% to 94%) and mean specificity 73% (95% CI 63% to 81%). In the single study of in vivo proton magnetic resonance spectroscopy (n = 27), the sensitivity was 65% (95% CI 38% to 86%) and specificity 100% (95% CI 69% to 100%). USPIO-enhanced MRI showed a trend towards higher sensitivity and specificity than gadolinium-enhanced MRI. Results of the decision modelling suggest that the MRI replacement strategy is the most cost-effective strategy and dominates the baseline 4-node sampling (4-NS) and sentinel lymph node biopsy (SLNB) strategies in most sensitivity analyses undertaken. The PET replacement strategy is not as robust as the MRI replacement strategy, as its cost-effectiveness is significantly affected by the utility decrement for lymphoedema and the probability of relapse for false-negative (FN) patients.
No included studies directly compared PET and MRI.
Studies demonstrated that PET and MRI have lower sensitivity and specificity than SLNB and 4-NS but are associated with fewer adverse events. Included studies indicated a significantly higher mean sensitivity for MRI than for PET, with USPIO-enhanced MRI providing the highest sensitivity. However, sensitivity and specificity of PET and MRI varied widely between studies, and MRI studies were relatively small and varied in their methods; therefore, results should be interpreted with caution. Decision modelling based on these results suggests that the most cost-effective strategy may be MRI rather than SLNB or 4-NS. This strategy reduces costs and increases quality-adjusted life-years (QALYs) because there are fewer adverse events for the majority of patients. However, this strategy leads to more FN cases at higher risk of cancer recurrence and more false- positive (FP) cases who would undergo unnecessary axillary lymph node dissection. Adding MRI prior to SLNB or 4-NS has little effect on QALYs, though this analysis is limited by lack of available data. Future research should include large, well-conducted studies of MRI, particularly using USPIO; data on the long-term impacts of lymphoedema on cost and patient utility; studies of the comparative effectiveness and cost-effectiveness of SLNB and 4-NS; and more robust UK cost data for 4-NS and SLNB as well as the cost of MRI and PET techniques.
This study was funded by the Health Technology Assessment programme of the National Institute of Health Research.
High angular resolution diffusion tensor imaging (HARD) is an MRI technique that exploits the mobility of water molecules to yield maps of structural order and directionality of white matter tracts ...with greater precision than six-direction diffusion tensor imaging (DTI) schemes.
To assess whether HARD is more sensitive than conventional MRI or neurologic assessment in detecting the upper motor neuron (UMN) pathology of patients with ALS.
Twenty-five patients with definite UMN clinical signs and 23 healthy volunteers underwent conventional MRI. HARD datasets were collected from a subset of these participants plus four patients with isolated lower motor neuron (LMN) signs. ALS symptom severity was assessed by a neurologist, the conventional MR images were reviewed by neuroradiologists, and the DTI maps were subject to quantitative region of interest analysis.
Motor cortex hypointensity on T2-weighted images and corona radiata hyperintensity on proton density-weighted images distinguished patients with UMN involvement from volunteers with 100% specificity, but only 20% sensitivity. Fractional anisotropy (FA) was reduced in the posterior limb of the internal capsule in patients with UMN involvement compared to volunteers. A FA threshold value with a sensitivity of 95% to detect patients with ALS (including those with isolated LMN signs) had a specificity of 71%.
High angular resolution diffusion tensor imaging may be more sensitive than conventional MRI or neurologic assessment to the upper motor neuron (UMN) pathology of ALS, but it lacks the specificity required of a diagnostic marker. Instead, it is potentially useful as a quantitative tool for monitoring the progression of UMN pathology.
Abstract Purpose Sentinel lymph node biopsy (SLNB) and axillary lymph node dissection (ALND) are used to assess axillary nodal status in breast cancer, but are invasive procedures associated with ...morbidity, including lymphoedema. This systematic review evaluates the diagnostic accuracy of positron emission tomography (PET), with or without computed tomography (CT), for assessment of axillary nodes in early breast cancer. Methods Eleven databases including MEDLINE, EMBASE and the Cochrane Library, plus research registers and conference proceedings, were searched in April 2009. Study quality was assessed using the QUality Assessment of Diagnostic Accuracy Studies (QUADAS) checklist. Sensitivity and specificity were meta-analysed using a bivariate random effects approach. Results Across 26 studies evaluating PET or PET/CT ( n = 2591 patients), mean sensitivity was 63% (95% CI: 52–74%; range 20–100%) and mean specificity 94% (95% CI: 91–96%; range 75–100%). Across 7 studies of PET/CT ( n = 862), mean sensitivity was 56% (95% CI: 44–67%) and mean specificity 96% (90–99%). Across 19 studies of PET-only ( n = 1729), mean sensitivity was 66% (50–79%) and mean specificity 93% (89–96%). Mean sensitivity was 11% (5–22%) for micrometastases (≤2 mm; five studies; n = 63), and 57% (47–66%) for macrometastases (>2 mm; four studies; n = 111). Conclusions PET had lower sensitivity and specificity than SLNB. Therefore, replacing SLNB with PET would avoid the adverse effects of SLNB, but lead to more false negative patients at risk of recurrence and more false positive patients undergoing unnecessary ALND. The present evidence does not support the routine use of PET or PET-CT for the assessment of the clinically negative axilla.
That auditory hallucinations are voices heard in the absence of external stimuli implies the existence of endogenous neural activity within the auditory cortex responsible for their perception. ...Further, auditory hallucinations occur across a range of healthy and disease states that include reduced arousal, hypnosis, drug intoxication, delirium, and psychosis. This suggests that, even in health, the auditory cortex has a propensity to spontaneously "activate" during silence. Here we report the findings of a functional MRI study, designed to examine baseline activity in speech-sensitive auditory regions. During silence, we show that functionally defined speech-sensitive auditory cortex is characterized by intermittent episodes of significantly increased activity in a large proportion (in some cases >30%) of its volume. Bilateral increases in activity are associated with foci of spontaneous activation in the left primary and association auditory cortices and anterior cingulate cortex. We suggest that, within auditory regions, endogenous activity is modulated by anterior cingulate cortex, resulting in spontaneous activation during silence. Hence, an aspect of the brain's "default mode" resembles a (preprepared) substrate for the development of auditory hallucinations. These observations may help explain why such hallucinations are ubiquitous.
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