Corneal Confocal Microscopy Detects Neuropathy in Patients with Type 1 Diabetes without Retinopathy or Microalbuminuria

Objective

Corneal innervation is increasingly used as a surrogate marker of human diabetic peripheral neuropathy (DPN) however its temporal relationship with the other microvascular complications of diabetes is not fully established. In this cross-sectional, observational study we aimed to assess whether neuropathy occurred in patients with type 1 diabetes, without retinopathy or microalbuminuria.

Materials and Methods

All participants underwent detailed assessment of peripheral neuropathy [neuropathy disability score (NDS), vibration perception threshold (VPT), peroneal motor nerve conduction velocity (PMNCV), sural sensory nerve conduction velocity (SSNCV) and in vivo corneal confocal microscopy (IVCCM)], retinopathy (digital fundus photography) and albuminuria status [albumin: creatinine ratio (ACR)].

Results

53 patients with Type 1 diabetes with (n=37) and without retinopathy (n=16) were compared to control subjects (n=27). SSNCV, corneal nerve fibre (CNFD) and branch (CNBD) density and length (CNFL) were reduced significantly (p<0.001) in diabetic patients without retinopathy compared to control subjects. Furthermore, CNFD, CNBD and CNFL were also significantly (p<0.001) reduced in diabetic patients without microalbuminuria (n=39), compared to control subjects. Greater neuropathic severity was associated with established retinopathy and microalbuminuria.

Conclusions

IVCCM detects early small fibre damage in the absence of retinopathy or microalbuminuria in patients with Type 1 diabetes.     

Reliability and Validity of the Perfusion,Extent, Depth,Infection and Sensation (PEDIS) Classification System and Score in Patients with Diabetic Foot Ulcer

Aims

To validate the perfusion, extent, depth, infection and sensation (PEDIS) classification system and to make the clinical practice easier, we created a score system and compared this system with two previously published common score systems.

Methods

A retrospective cohort study was conducted on patients with diabetic foot ulcer (DFU) attending our hospital (n=364) from May 2007 to September 2013. Participants’ characteristics and all variables composing the PEDIS classification system were assessed.

Results

During a median follow-up of 25 months (range 6-82), ulcers healed in 217 of the 364 patients (59.6%), remained unhealed in 37 patients (10.2%), and were resolved by amputation in 62 patients (17.0%); 48 patients (13.2%) died. When measured using the PEDIS classification system, the outcome of DFU deteriorated with increasing severity of each subcategory. Additionally, longer ulcer history, worse perfusion of lower limb, a larger extent of the ulcer, a deeper wound, more severe infection, and loss of protective sensation were independent predictors of adverse outcome. More importantly, the new PEDIS score system showed good diagnostic accuracy, especially when compared with the SINBAD and Wagner score systems.

Conclusions

The PEDIS classification system, which encompasses relevant variables that contribute to the outcome of DFU and has excellent capacity for predicting the ulcer outcome, demonstrated acceptable accuracy. The PEDIS classification system might be useful in clinical practice and research both for the anticipation of health care costs and for comparing patient subgroups.     

The Effects of Aroma Foot Massage on Blood Pressure and Anxiety in Japanese Community-Dwelling Men and Women: A Crossover Randomized Controlled Trial

Objectives

The aim of this study was to investigate the effects of aroma foot massage on blood pressure, anxiety, and health-related quality of life (QOL) in Japanese community-dwelling men and women using a crossover randomized controlled trial.

Methods

Fifty-seven eligible participants (5 men and 52 women) aged 27 to 72 were randomly divided into 2 intervention groups (group A: n = 29; group B: n = 28) to participate in aroma foot massages 12 times during the 4-week intervention period. Systolic and diastolic blood pressure (SBP and DBP, respectively), heart rate, state anxiety, and health-related QOL were measured at the baseline, 4-week follow-up, and 8-week follow-up. The effects of the aroma foot massage intervention on these factors and the proportion of participants with anxiety were analyzed using a linear mixed-effect model for a crossover design adjusted for participant and period effects. Furthermore, the relationship between the changes in SBP and state anxiety among participants with relieved anxiety was assessed using a linear regression model.

Results

Aroma foot massage significantly decreased the mean SBP (p = 0.02), DBP (p = 0.006), and state anxiety (p = 0.003) as well as the proportion of participants with anxiety (p = 0.003). Although it was not statistically significant (p = 0.088), aroma foot massage also increased the score of mental health-related QOL. The change in SBP had a significant and positive correlation with the change in state anxiety (p = 0.01) among participants with relieved anxiety.

Conclusion

The self-administered aroma foot massage intervention significantly decreased the mean SBP and DBP as well as the state anxiety score, and tended to increase the mental health-related QOL scores. The results suggest that aroma foot massage may be an easy and effective way to improve mental health and blood pressure.

Trial Registration

University Hospital Medical Information Network 000014260     

Alterations in Functional and Structural Connectivity in Pediatric-Onset Multiple Sclerosis

Background

Reduced white matter (WM) integrity is a fundamental aspect of pediatric multiple sclerosis (MS), though relations to resting-state functional MRI (fMRI) connectivity remain unknown. The objective of this study was to relate diffusion-tensor imaging (DTI) measures of WM microstructural integrity to resting-state network (RSN) functional connectivity in pediatric-onset MS to test the hypothesis that abnormalities in RSN reflects changes in structural integrity.

Methods

This study enrolled 19 patients with pediatric-onset MS (mean age = 19, range 13–24 years, 14 female, mean disease duration = 65 months, mean age of disease onset = 13 years) and 16 age- and sex-matched healthy controls (HC). All subjects underwent 3.0T anatomical and functional MRI which included DTI and resting-state acquisitions. DTI processing was performed using Tract-Based Spatial Statistics (TBSS). RSNs were identified using Independent Components Analysis, and a dual regression technique was used to detect between-group differences in the functional connectivity of RSNs. Correlations were investigated between DTI measures and RSN connectivity.

Results

Lower fractional anisotropy (FA) was observed in the pediatric-onset MS group compared to HC group within the entire WM skeleton, and particularly the corpus callosum, posterior thalamic radiation, corona radiata and sagittal stratum (all p < .01, corrected). Relative to HCs, MS patients showed higher functional connectivity involving the anterior cingulate cortex and right precuneus of the default-mode network, as well as involving the anterior cingulate cortex and left middle frontal gyrus of the frontoparietal network (all p < .005 uncorrected, k≥30 voxels). Higher functional connectivity of the right precuneus within the default-mode network was associated with lower FA of the entire WM skeleton (r = -.525, p = .02), genu of the corpus callosum (r = -.553, p = .014), and left (r = -.467, p = .044) and right (r = -.615, p = .005) sagittal stratum.

Conclusions

Loss of WM microstructural integrity is associated with increased resting-state functional connectivity in pediatric MS, which may reflect a diffuse and potentially compensatory activation early in MS.     

An 'Importance' Map of Signs and Symptoms to Classify Diabetic Polyneuropathy: An Exploratory Data Analysis

Aims/Hypothesis

Early diagnosis of diabetic polyneuropathy (DPN) is critical for a good prognosis. We aimed to identify different groups of patients, based on the various common clinical signs and symptoms of DPN, that represent a progressive worsening of the disease before the onset of plantar ulceration or amputation. We also sought to identify the most important DPN-related variables that can discriminate between groups, thus representing the most informative variables for early detection.

Methods

In 193 diabetic patients, we assessed 16 DPN-related signs, symptoms, and foot characteristics, based on the literature and the International Consensus on the Diabetic Foot. We used multiple correspondence analysis and the Kohonen algorithm to group the variables into micro and macro-classes and to identify clusters of patients that represent different DPN conditions.

Results

Four distinct groups were observed. One group showed no indication of DPN. The remaining groups were characterized by a progressive loss of the vibration perception, without a worsening of symptoms or tactile perception. The 2 intermediate groups presented different aspects of DPN: one showed mostly DPN symptoms and the other showed the incipient vibration impairment, callus and crack formation, and foot arch alteration. The fourth group showed more severe foot and DPN conditions, including ulceration and amputation, absence of vibration and tactile perception (irrespective of how many compromised foot areas), and worse foot deformities and callus and crack formation.

Conclusion

Vibration perception was more informative than tactile sensitivity in discriminating early DPN onset because its impairment was evident in more groups. Symptoms and callus and cracks did not discriminate the severity status and should be interpreted in association with other clinical variables. Reconsideration of the current screening techniques is needed to clinically determine the early onset of neuropathy using tactile perception.     

The Effect of Comorbidity on Glycemic Control and Systolic Blood Pressure in Type 2 Diabetes: A Cohort Study with 5 Year Follow-Up in Primary Care

Aims

To explore the longitudinal effect of chronic comorbid diseases on glycemic control (HbA₁C) and systolic blood pressure (SBP) in type 2 diabetes patients.

Methods

In a representative primary care cohort of patients with newly diagnosed type 2 diabetes in The Netherlands (n = 610), we tested differences in the five year trend of HbA₁C and SBP according to comorbidity profiles. In a mixed model analysis technique we corrected for relevant covariates. Influence of comorbidity (a chronic disease already present when diabetes was diagnosed) was tested as total number of comorbid diseases, and as presence of specific disease groups, i.e. cardiovascular, mental, and musculoskeletal disease, malignancies, and COPD. In subgroup effect analyses we tested if potential differences were modified by age, sex, socioeconomic status, and BMI.

Results

The number of comorbid diseases significantly influenced the SBP trend, with highest values after five years for diabetes patients without comorbidity (p = 0.005). The number of diseases did not influence the HbA₁C trend (p = 0.075). Comorbid musculoskeletal disease resulted in lower HbA₁C at the time of diabetes diagnosis, but in higher values after five years (p = 0.044). Patients with cardiovascular diseases had sustained elevated levels of SBP (p = 0.014). Effect modification by socioeconomic status was observed in some comorbidity subgroups.

Conclusions

Presence of comorbidity in type 2 diabetes patients affected the long-term course of HbA₁C and SBP in this primary care cohort. Numbers and types of comorbidity showed differential effects: not the simple sum of diseases, but specific types of comorbid disease had a negative influence on long-term diabetes control parameters. The complex interactions between comorbidity, diabetes control and effect modifiers require further investigation and may help to personalize treatment goals.     

Foot Drop Caused by Lumbar Degenerative Disease: Clinical Features,Prognostic Factors of Surgical Outcome and Clinical Stage

Objective

The purpose of this study was to analyze the clinical features and prognostic factors of surgical outcome of foot drop caused by lumbar degenerative disease and put forward the clinical stage.

Methods

We retrospectively reviewed 135 patients with foot drop due to lumbar degenerative disease. The clinical features and mechanism were analyzed. Age, sex, duration of palsy, preoperative muscle strength of tibialis anterior (TA), sensation defect of affected lower limb, affected foot, diagnosis and compressed nerve roots were recorded and compared with surgical outcome.

Results

Foot drop was observed in 8.1% of all inpatients of lumbar degenerative disease. L5 nerve root compression was observed in 126 of all 135 patients (93.3%). Single, double and triple roots compression was observed respectively in 43, 83, and 9 patients (31.9%, 61.5%, and 6.6%). But there was no significant relationship between preoperative muscle strength of TA and the number of compressed roots. The muscle strength of TA was improved in 113 (83.7%) patients after surgery, but it reached to >=4 in only 21 (15.6%) patients. Improvement of the muscle strength of TA was almost stable at the 6-month follow-up. At the last follow-up, the muscle strength of TA was 1, 2, 3, 4, 5 respectively in 28, 24, 62, 13, 8 patients. Multivariate logistic regression showed duration of palsy (p=0.0360, OR=2.543), preoperative muscle strength of TA (p=0.0064, OR=5.528) and age (p=0.0309, OR=3.208) were factors that influenced recovery following an operation.

Conclusions

L5 nerve root was most frequently affected. The muscle strength of TA improved in most patients after surgery, but few patients can get a good recovery from foot drop. Patients of shorter duration of palsy, better preoperative muscle strength of TA and younger age showed a better surgical outcome.     

Treatment of diabetic polyneuropathy with the antioxidant thioctic acid (alpha-lipoic acid): a two year multicenter randomized double-blind placebo-controlled trial (ALADIN II). Alpha Lipoic Acid in Diabetic Neuropathy.

Short-term trials with the antioxidant thioctic acid (TA) appear to improve neuropathic symptoms in diabetic patients, but the long-term response remains to be established. Therefore, Type 1 and Type 2 diabetic patients with symptomatic polyneuropathy were randomly assigned to three treatment regimens: (1) 2 x 600(mg of TA (TA 1200), (2) 600)mg of TA plus placebo (PLA) (TA 600) or (3) placebo and placebo (PLA). A trometamol salt solution of TA of 1200 or 600 mg or PLA was intravenously administered once daily for five consecutive days before enrolling the patients in the oral treatment phase. The study was prospective, PLA-controlled, randomized, double-blind and conducted for two years. Severity of diabetic neuropathy was assessed by the Neuropathy Disability Score (NDS) and electrophysiological attributes of the sural (sensory nerve conduction velocity (SNCV), sensory nerve action potential (SNAP)) and the tibial (motor nerve conduction velocity (MNCV), motor nerve distal latency (MNDL)) nerve. Statistical analysis was performed after independent reviewers excluded all patients with highly variable data allowing a final analysis of 65 patients (TA 1200: n = 18, TA 600: n = 27; PLA: n = 20). At baseline no significant differences were noted between the groups regarding the demographic variables and peripheral nerve function parameters for these 65 patients. Statistically significant changes after 24 months between TA and PLA were observed (mean +/- SD) for sural SNCV: +3.8 +/- 4.2 m/s in TA 1200, +3.0+/-3.0m/s in TA 600, -0.1+/-4.8m/s in PLA (p < 0.05 for TA 1200 and TA 600 vs. PLA); sural SNAP: +0.6+/-2.5 microV in TA 1200, +0.3+/-1.4 microV in TA 600, -0.7 +/- 1.5 microV in PLA (p = 0.076 for TA 1200 vs. PLA and p < 0.05 for TA 600 vs. PLA), and in tibial MNCV: +/- 1.2 +/- 3.8 m/s in TA 1200, -0.3 +/- 5.2 m/s in TA 600, 1.5 +/- 2.9 m/s in PLA (p < 0.05 for TA 1200 vs. PLA). No significant differences between the groups after 24 months were noted regarding the tibial MNDL and the NDS. We conclude that in a subgroup of patients after exclusion of patients with excessive test variability throughout the trial, TA appeared to have a beneficial effect on several attributes of nerve conduction.     

Age- and Sex-Dependency of Laser Speckle Flowgraphy Measurements of Optic Nerve Vessel Microcirculation

Purpose

To investigate the relationship between various characteristics of a normal population and laser speckle flowgraphy (LSFG) measurements of mean blur rate (MBR) in the optic nerve head (ONH).

Methods

A total of 189 eyes of 189 normal subjects (93 male, 96 female, mean age 45 ± 14 years old, age range: 20–72) without any history of hypertension, hyperlipidemia or diabetes were enrolled. ONH microcirculation was measured with LSFG and overall MBR (MA), vessel-area MBR (MV), and tissue-area MBR (MT) were derived from these measurements. The statistical association of these measurements with characteristics such as sex, age, intraocular pressure (IOP) and systolic blood pressure (SBP) was then determined.

Results

There was a trend towards decreased IOP and MV and increased SBP with age (P = 0.002, P = 0.035, and P = 0.006, respectively). Furthermore, IOP, MV and SBP were correlated with age (r = -0.23, P = 0.011; r = -0.24, P < 0.001; and r = 0.30, P < 0.001, respectively). Separate multiple regression analyses of independent contributing factors revealed that sex and IOP contributed to MA (P < 0.001 and P = 0.002, respectively), sex, IOP, and age contributed to MV (P < 0.001, P = 0.003, and P = 0.024, respectively), while only IOP contributed to MT (P = 0.003).

Conclusion

In a normal population, MBR was affected by IOP in both the large vessel and capillary areas of the ONH, but not by SBP. MV was also affected by age and sex, while MT was stable independent of age or sex.     

Association of Insulin Resistance,Arterial Stiffness and Telomere Length in Adults Free of Cardiovascular Diseases

Background

Chronic inflammation and oxidative stress might be considered the key mechanisms of aging. Insulin resistance (IR) is a phenomenon related to inflammatory and oxidative stress. We tested the hypothesis that IR may be associated with cellular senescence, as measured by leukocyte telomere length (LTL), and arterial stiffness (core feature of arterial aging), as measured by carotid-femoral pulse wave velocity (c-f PWV).

Methods

The study group included 303 subjects, mean age 51.8 ±13.3 years, free of known cardiovascular diseases and regular drug consumption. For each patient, blood pressure was measured, blood samples were available for biochemical parameters, and LTL was analyzed by real time q PCR. C-f PWV was measured with the help of SphygmoCor. SAS 9.1 was used for statistical analysis.

Results

Through multiple linear regression analysis, c-f PWV is independently and positively associated with age (p = 0.0001) and the homeostasis model assessment of insulin resistance (HOMA-IR; p = 0.0001) and independently negatively associated with LTL (p = 0.0378). HOMA-IR seems to have a stronger influence than SBP on arterial stiffness. In all subjects, age, HOMA-IR, LTL, and SBP predicted 32% of the variance in c-f PWV. LTL was inversely associated with HOMA-IR (p = 0.0001) and age (p = 0.0001). In all subjects, HOMA-IR, age, sex, and SBP predicted 16% of the variance in LTL.

Conclusions

These data suggest that IR is associated with cell senescence and arterial aging and could, therefore, become the main target in preventing accelerated arterial aging, besides blood pressure control. Research in telomere biology may reveal new ways of estimating cardiovascular aging and risk.     

Cardiac Autonomic Nervous System Activation and Metabolic Profile in Young Children: The ABCD Study

Background

In adults, increased sympathetic and decreased parasympathetic nervous system activity are associated with a less favorable metabolic profile. Whether this is already determined at early age is unknown. Therefore, we aimed to assess the association between autonomic nervous system activation and metabolic profile and its components in children at age of 5–6 years.

Methods

Cross-sectional data from an apparently healthy population (within the ABCD study) were collected at age 5–6 years in 1540 children. Heart rate (HR), respiratory sinus arrhythmia (RSA; parasympathetic activity) and pre-ejection period (PEP; sympathetic activity) were assessed during rest. Metabolic components were waist-height ratio (WHtR), systolic blood pressure (SBP), fasting triglycerides, glucose and HDL-cholesterol. Individual components, as well as a cumulative metabolic score, were analyzed.

Results

In analysis adjusted for child’s physical activity, sleep, anxiety score and other potential confounders, increased HR and decreased RSA were associated with higher WHtR (P< 0.01), higher SBP (p<0.001) and a higher cumulative metabolic score (HR: p < 0.001; RSA: p < 0.01). Lower PEP was only associated with higher SBP (p <0.05). Of all children, 5.6% had 3 or more (out of 5) adverse metabolic components; only higher HR was associated with this risk (per 10 bpm increase: OR = 1.56; p < 0.001).

Conclusions

This study shows that decreased parasympathetic activity is associated with central adiposity and higher SBP, indicative of increased metabolic risk, already at age 5–6 years.     

Elevated Vibration Perception Thresholds in CIDP Patients Indicate More Severe Neuropathy and Lower Treatment Response Rates

Introduction

Vibration perception threshold (VPT) examination using a neurothesiometer provides objective, sensitive and specific information, and has been utilized mainly in patients with diabetic polyneropathy.

Objectives

Explore the utility of VPT examination in CIDP patients.

Methods

CIDP subjects attending the Neuromuscular clinic between 01/2013 and 12/2014 were evaluated. Demographic data, clinical history, physical examination, VPT values, and electrophysiologic data from their charts were extracted.

Results

70 charts were reviewed. 55 CIDP patients had elevated VPT, associated with higher frequency of abnormal sensory testing for various modalities (92.7% vs. 46.7%, p<0.0001), lower sensory and motor amplitudes and reduced conduction velocities on nerve conduction studies, and lower treatment response rates (54% vs. 93%, p = 0.01).

Conclusion

VPT examination is a simple tool, which is a reliable and sensitive measure not only for diabetic neuropathy, but also for CIDP. Moreover, in CIDP, elevated VPT values are also associated with lower treatment response rates.     

Protein Diet Restriction Slows Chronic Kidney Disease Progression in Non-Diabetic and in Type 1 Diabetic Patients,but Not in Type 2 Diabetic Patients: A Meta-Analysis of Randomized Controlled Trials Using Glomerular Filtration Rate as a Surrogate

Background/ Objective

Studies, including various meta-analyses, on the effect of Protein Diet Restriction on Glomerular Filtration Rate (GFR) in Chronic Kidney Disease (CKD) have reported conflicting results. In this paper, we have provided an update on the evidence available on this topic. We have investigated the reasons why the effect has been inconsistent across studies. We have also compared the effect on GFR in various subgroups including type 1 diabetics, type 2 diabetics and non-diabetics.

Method

We searched for Randomized Controlled Trials on this intervention from MEDLINE, EMBASE, and other information sources. The PRISMA guidelines, as well as recommended meta-analysis practices were followed in the selection process, analysis and reporting of our findings. The effect estimate used was the change in mean GFR. Heterogeneity across the considered studies was explored using both subgroup analyses and meta-regression. Quality assessment was done using the Cochrane risk of bias tool and sensitivity analyses.

Results

15 randomized controlled trials, including 1965 subjects, were analyzed. The pooled effect size, as assessed using random-effects model, for all the 15 studies was -0.95 ml/min/1.73m²/year (95% CI: -1.79, -0.11), with a significant p value of 0.03. The combined effect estimate for the non-diabetic and type 1 diabetic studies was -1.50 ml/min/1.73m²/year (95% CI: -2.73, -0.26) with p value of 0.02. The effect estimate for the type 2 diabetic group was -0.17 ml/min/1.73m²/year (95% CI: -1.88, 1.55) with p value of 0.85. There was significant heterogeneity across the included studies (I² = 74%, p value for Q < 0.0001), explained by major variations in the percentage of type 2 diabetic subjects, the number of subjects and overall compliance level to diet prescribed.

Conclusion

Our findings suggest that protein diet restriction slows chronic renal disease progression in non-diabetic and in type 1 diabetic patients, but not in type 2 diabetic patients.     

Laser-induced auto-fluorescence (LIAF) as a method for assessing skin stiffness preceding diabetic ulcer formation

Recurrent foot ulceration is a major cause of morbidity in diabetic patients. Discrepancy between the stiffness of the plantar skin and underlying soft tissues may influence the likelihood of ulceration. Tissue properties change with diabetes primarily due to high blood glucose which promotes intermolecular cross-linking of structural proteins thus leading to altered structure and function of these structural fibers. This study utilizes a non-invasive method for indirectly assessing skin tissue in the context of plantar ulcer formation in diabetic patients' feet. Control (C, n=13), and diabetic subjects with a history of ulceration (n=16) were matched based on gender, age (42-81years old) and BMI. Six subjects re-ulcerated (U) during their 1-year follow-up. At every visit, each subject's plantar skin was excited with a weak laser light (337nm) to induce tissue fluorescence at three locations on each foot. The spectral area under the curve (AUC) was calculated after background subtraction and normalization. The mean AUC was significantly higher for diabetics compared to control subjects, (mean AUC: 145.6+/-7.2, C=112.6+/-8.3, respectively, p=0.006). For those who re-ulcerated (U, n=6), skin site was not a significant factor, but AUC was diminished at the time of re-ulceration (p<0.05). The alteration of intermolecular bonds in diabetic subjects and thinning of skin prior to ulceration could account for these observations. The decrease in AUC prior to an ulcer formation suggests its potential as a marker of tissue changes, which precede ulceration in the diabetic foot.     

Symptoms Reported by Head and Neck Cancer Patients during Radiotherapy and Association with Mucosal Ulceration Site and Size: An Observational Study

Background

Self-reported pain and impairment of oral functions varies markedly and often in spite of extensive oral mucositis (OM). The aim of the current study was to appraise how patient-reported debilitation caused by OM is influenced by the extent and possibly location of the OM lesions.

Methods

Patients with head and neck cancer undergoing radiotherapy were examined before treatment, twice weekly during 6-7 weeks of therapy, and 3-4 weeks after therapy completion. OM signs of 33 participants were evaluated using the Oral Mucositis Assessment Scale (OMAS), while OM symptoms were recorded using Patient-Reported Oral Mucositis Symptom (PROMS)-questionnaires. Changes in OM experience as a function of OM signs was undertaken by comparing the aggregated and individual PROMS scale values at the point of transition of OMAS ulceration scores between 0 to 1, 1 to 2 and 2 to 3, respectively in the nine intra-oral locations designated in the OMAS. ANOVA with pairwise contrasts using the LSD procedure was applied for comparisons of mean changes of PROMS scale values for the participants who experienced an OMAS score of 2 or more during therapy (n=24).

Results

Impairment of eating hard foods was more when the OMAS score for ulceration anywhere in the mouth or in the soft palate changed from 1 to 2, compared to between score 0 and 1 (p=.002 and p=.05) or between score 2 and 3 (p=.001 and p=.02). Mouth pain increased more upon transition of OMAS score anywhere in the mouth from 1 to 2 compared to 0 to 1 (p=.05).

Conclusion

The relationship between patient-reported impairment of oral function and pain caused by OM ulceration is not linear, but rather curvilinear. Our findings should prompt investigators of future interventional trials to consider using a less severe outcome than maximum OM scores as the primary study outcome.     

Orthostatic Changes in Hemodynamics and Cardiovascular Biomarkers in Dysautonomic Patients

Background

Impaired autonomic control of postural homeostasis results in orthostatic intolerance. However, the role of neurohormones in orthostatic intolerance has not been explained.

Methods

Six-hundred-and-seventy-one patients (299 males; 55±22 years) with unexplained syncope underwent head-up tilt (HUT) with serial blood sampling. Systolic blood pressure (SBP) and heart rate (HR) supine, after 3min, and lowest BP/highest HR during HUT were recorded. Plasma levels of epinephrine, norepinephrine, renin, C-terminal-pro-arginine-vasopressin (CT-proAVP), C-terminal- endothelin-1 (CT-proET-1), and mid-regional-fragment of pro-atrial-natriuretic-peptide (MR-proANP) were determined at supine and 3min of HUT. Multivariate-adjusted logistic regression model was applied to compare 1^st (reference) with 4^th quartile of 3 min and maximal ΔSBP/ΔHR (i.e. pronounced hypotension or tachycardia) vs. changes in neuroendocrine biomarkers, respectively.

Results

Higher resting CT-proET-1 predicted BP fall at 3min (Odds ratio (OR) per 1 SD: 1.62, 95%CI 1.18–2.22; p = 0.003), and max BP fall during HUT (1.82, 1.28–2.61; p = 0.001). Higher resting CT-proAVP predicted BP fall at 3min (1.33, 1.03–1.73; p = 0.03), which was also associated with increase in CT-proAVP (1.86, 1.38–2.51; p = 0.00005) and epinephrine (1.47, 1.12–1.92; p = 0.05) during HUT. Lower resting MR-proANP predicted tachycardia at 3min (0.37, 0.24–0.59; p = 0.00003), and max tachycardia during HUT (0.47, 0.29–0.77; p = 0.002). Further, tachycardia during HUT was associated with increase in epinephrine (1.60, 1.15–2.21; p = 0.005), and norepinephrine (1.87, 1.38–2.53; p = 0.005).

Conclusions

Resting CT-proET-1 and CT-proAVP are increased in orthostatic hypotension, while resting MR-proANP is decreased in postural tachycardia. Moreover, early BP fall during orthostasis evokes increase in CT-proAVP and epinephrine, while postural tachycardia is associated with increase in norepinephrine and epinephrine.     

Peripheral Nerve Diffusion Tensor Imaging: Assessment of Axon and Myelin Sheath Integrity

Purpose

To investigate the potential of diffusion tensor imaging (DTI) parameters as in-vivo biomarkers of axon and myelin sheath integrity of the median nerve in the carpal tunnel as validated by correlation with electrophysiology.

Methods

MRI examinations at 3T including DTI were conducted on wrists in 30 healthy subjects. After manual segmentation of the median nerve quantitative analysis of fractional anisotropy (FA) as well as axial, radial and mean diffusivity (AD, RD, and MD) was carried out. Pairwise Pearson correlations with electrophysiological parameters comprising sensory nerve action potential (SNAP) and compound muscle action potential (CMAP) as markers of axon integrity, and distal motor latency (dml) and sensory nerve conduction velocity (sNCV) as markers of myelin sheath integrity were computed. The significance criterion was set at P=0.05, Bonferroni corrected for multiple comparisons.

Results

DTI parameters showed a distinct proximal-to-distal profile with FA, MD, and RD extrema coinciding in the center of the carpal tunnel. AD correlated with CMAP (r=0.50, p=0.04, Bonf. corr.) but not with markers of myelin sheath integrity. RD correlated with sNCV (r=-0.53, p=0.02, Bonf. corr.) but not with markers of axon integrity. FA correlated with dml (r=-0.63, p=0.002, Bonf. corr.) and sNCV (r=0.68, p=0.001, Bonf. corr.) but not with markers of axon integrity.

Conclusion

AD reflects axon integrity, while RD (and FA) reflect myelin sheath integrity as validated by correlation with electrophysiology. DTI parameters consistently indicate a slight decrease of structural integrity in the carpal tunnel as a physiological site of median nerve entrapment. DTI is particularly sensitive, since these findings are observed in healthy participants. Our results encourage future studies to evaluate the potential of DTI in differentiating axon from myelin sheath injury in patients with manifest peripheral neuropathies.     

The Effect of Axial Length on the Thickness of Intraretinal Layers of the Macula

Purpose

The aim of this study was to evaluate the effect of axial length (AL) on the thickness of intraretinal layers in the macula using optical coherence tomography (OCT) image analysis.

Methods

Fifty three randomly selected eyes of 53 healthy subjects were recruited for this study. The median age of the participants was 29 years (range: 6 to 67 years). AL was measured for each eye using a Lenstar LS 900 device. OCT imaging of the macula was also performed by Stratus OCT. OCTRIMA software was used to process the raw OCT scans and to determine the weighted mean thickness of 6 intraretinal layers and the total retina. Partial correlation test was performed to assess the correlation between the AL and the thickness values.

Results

Total retinal thickness showed moderate negative correlation with AL (r = -0.378, p = 0.0007), while no correlation was observed between the thickness of the retinal nerve fiber layer (RNFL), ganglion cell layer (GCC), retinal pigment epithelium (RPE) and AL. Moderate negative correlation was observed also between the thickness of the ganglion cell layer and inner plexiform layer complex (GCL+IPL), inner nuclear layer (INL), outer plexiform layer (OPL), outer nuclear layer (ONL) and AL which were more pronounced in the peripheral ring (r = -0.402, p = 0.004; r = -0.429, p = 0.002; r = -0.360, p = 0.01; r = -0.448, p = 0.001).

Conclusions

Our results have shown that the thickness of the nuclear layers and the total retina is correlated with AL. The reason underlying this could be the lateral stretching capability of these layers; however, further research is warranted to prove this theory. Our results suggest that the effect of AL on retinal layers should be taken into account in future studies.     

Circulating microRNAs and Outcome in Patients with Acute Heart Failure

Background

The biomarker value of circulating microRNAs (miRNAs) has been extensively addressed in patients with acute coronary syndrome. However, prognostic performances of miRNAs in patients with acute heart failure (AHF) has received less attention.

Methods

A test cohort of 294 patients with acute dyspnea (236 AHF and 58 non-AHF) and 44 patients with stable chronic heart failure (CHF), and an independent validation cohort of 711 AHF patients, were used. Admission levels of miR-1/-21/-23/-126/-423-5p were assessed in plasma samples.

Results

In the test cohort, admission levels of miR-1 were lower in AHF and stable CHF patients compared to non-AHF patients (p = 0.0016). Levels of miR-126 and miR-423-5p were lower in AHF and in non-AHF patients compared to stable CHF patients (both p<0.001). Interestingly, admission levels of miR-423-5p were lower in patients who were re-admitted to the hospital in the year following the index hospitalization compared to patients who were not (p = 0.0001). Adjusted odds ratio [95% confidence interval] for one-year readmission was 0.70 [0.53–0.93] for miR-423-5p (p = 0.01). In the validation cohort, admission levels of miR-423-5p predicted 1-year mortality with an adjusted odds ratio [95% confidence interval] of 0.54 [0.36–0.82], p = 0.004. Patients within the lowest quartile of miR-423-5p were at high risk of long-term mortality (p = 0.02).

Conclusions

In AHF patients, low circulating levels of miR-423-5p at presentation are associated with a poor long-term outcome. This study supports the value of miR-423-5p as a prognostic biomarker of AHF.     

Comparison of Rebound Tonometry,Perkins Applanation Tonometry and Ocular Response Analyser in Mucopolysaccharidosis Patients

Aims

To investigate the feasibility and to compare three devices measuring intraocular pressure (IOP) in mucopolysaccharidosis patients (MPS): iCare rebound tonometer (RT), Perkins applanation tonometer (PAT) and ocular response analyzer (ORA)

Methods

MPS patients who underwent at least two examinations out of: RT, PAT and ORA at the same visit were identified and retrospectively analyzed in this study.

Results

17 patients fulfilled the inclusion criterion. In all 17 patients IOP measurements were performed with RT (34 eyes) and ORA (33 eyes), while PAT measurement was possible in only 12 (24 eyes) patients. The RT, corneal-compensated intraocular pressure (IOPcc) and Goldmann-correlated intraocular pressure (IOPg) differed relevantly from IOP assessed with PAT. Corneal clouding in MPS patients correlated positively with PAT, RT and IOPg (r = 0.3, 0.5, and 0.5 respectively), but not with IOPcc (r = 0.07). The MPS-related corneal clouding correlated positively with biomechanical corneal parameters assessed with ORA: corneal hysteresis (r = 0.77) and corneal resistance factor (r = 0.77) either.

Conclusions

RT and ORA measurements were tolerated better than applanation tonometry in MPS patients. IOP measurements assessed with RT and ORA differed relevantly from PAT. Corneal-compensated IOP assessed with ORA seems to be less affected by the MPS-related corneal clouding than applanation or rebound tonometry. RT and ORA measurements should be preferred for IOP assessment in patients with MPS.