Pathological spontaneous activity as a prognostic marker in chronic inflammatory demyelinating polyneuropathy.

BACKGROUND AND PURPOSE: Monitoring of the disease course of patients with chronic inflammatory demyelinating polyneuropathy (CIDP) remains challenging because nerve conduction studies do not adequately correlate with functional disability. The prognostic value of pathological spontaneous activity (PSA) in needle electromyography (EMG) in different CIDP subgroups in a longitudinal context has, to date, not been analysed. We aimed to determine whether PSA was a prognostic marker or a marker of disease activity in a cohort of patients with CIDP. METHODS: A total of 127 patients with CIDP spectrum disorder were retrospectively analysed over 57 ± 47 months regarding the occurrence of PSA (fibrillations and positive sharp waves). The presence of PSA at diagnosis, newly occurring PSA, and continuously present PSA were longitudinally correlated with clinical disability using the Inflammatory Neuropathy Cause and Treatment Overall Disability Sum Score (INCAT-ODSS) and CIDP subtype. RESULTS: Pathological spontaneous activity occurred in 49.6% of all CIDP patients at first diagnosis. More frequent evidence of PSA was significantly associated with a higher INCAT-ODSS at the last follow-up. Continuous and new occurrence of PSA were associated with higher degree of disability at the last follow-up. The majority of patients with sustained evidence of PSA were characterized by an atypical phenotype, higher degree of disability, and the need for escalation of treatment. CONCLUSIONS: Pathological spontaneous activity was associated with a higher degree of disability and occurred more frequently in atypical CIDP variants according to the longitudinal data of a large cohort of patients with CIDP. Our results showed that EMG examination was an adequate marker for disease progression and should be evaluated during the disease course.

Measurements of scar properties by SkinFibroMeter® , SkinGlossMeter® , and Mexameter® and comparison with Vancouver Scar Scale.

BACKGROUND: An objective measurement of scar is important for evaluating treatment outcomes. However, to date, there is no 'gold standard' for quantitative measurement of properties of hypertrophic scar. Existing objective modalities are neither portable nor easy to use. OBJECTIVE: This study aims to validate the correlation between objective measurements with SkinFibrometer® , SkinGlossMeter® , and Mexameter® and subjective assessment with Vancouver Scar Scale (VSS) of keloid and hypertrophic scar. METHODS: A total of 25 patients with keloids and hypertrophic scars were enrolled in this study. Patients were treated with intralesional triamcinolone acetonide at 2-6 week intervals. Scar assessments using VSS, Skinfibrometer, Skinglossmeter, and Mexameter were performed in both scars and contralateral normal skin at each treatment session. Correlations between the measurements by these tools and VSS parameters were examined. RESULTS: We found statistically significant differences between scar and contralateral normal skin using Skinfibrometer, Skinglossmeter, and Mexameter. A strong correlation was found between the VSS pliability scores and the stiffness of skin of Skinfibrometer (r = 0.628, P < 0.001). VSS vascularity scores showed weak correlation with erythema index of Mexameter (r = 0.372, P < 0.001). However, no correlation appeared to exist between any parameters of VSS and Skinglossmeter and between VSS pigmentation scores and the melanin index of Mexameter. CONCLUSION: In our study, Skinfibrometer can be an objective noninvasive evaluation tool for pliability of the scar.

Development and characterization of 22 polymorphic microsatellite markers for the balloon flower Platycodon grandiflorum (Campanulaceae).

The balloon flower (Platycodon grandiflorum A. DC.) is a perennial flowering plant of the Campanulaceae family; it is the only member of the genus Platycodon. Information on the genetic diversity of balloon flower populations is of great importance for the conservation and germplasm utilization of this flowering plant. Twenty-two polymorphic microsatellite loci were developed and characterized with eight balloon flower accessions collected from South Korea and China. Eighty-one alleles were detected among the eight balloon flower accessions. The number of alleles per locus ranged from two to six, with a mean of four alleles per locus. The observed and expected heterozygosity values ranged from 0.000 to 0.875 (mean = 0.355) and 0.117 to 0.766 (mean = 0.489), respectively. The polymorphic information content values ranged from 0.110 to 0.733, with a mean of 0.449. These new microsatellite markers will be useful for population and conservation genetic studies of P. grandiflorum.

[Clinical application of pain-related evoked potentials]. / Klinische Anwendung schmerzevozierter Potenziale.

Pain-related evoked potentials (PREPs) represent a novel method for the evaluation of peripheral and central nociceptive pathways, e.g. in the diagnosis of small fiber neuropathy (SFN) or after therapeutic interventions for headache. Compared to contact heat-evoked and laser-evoked potentials, recording of PREPs is less stressful for the subjects and technically less demanding. The clinical usefulness of PREPs has been described for SFN associated with diabetes, HIV and hepatitis C infections as well as in headache and facial pain disorders. They have also been evaluated after interventional methods, such as direct current stimulation (tDCS). The article reviews and discusses the advantages and pitfalls of this technique in the context of recent clinical studies as compared to other paradigms of peripheral electrical stimulation and delineates perspectives and possible indications.

Prevalence of primary headaches in Germany: results of the German Headache Consortium Study.

We investigated the prevalence of migraine (MIG), tension-type headache (TTH), and chronic headache in a population-based sample in Germany. A total of 18,000 subjects aged between 18 and 65 years were screened from 2003 until 2005 using a validated questionnaire. Overall 9,944 participants (55.2%) responded (mean age 43 ± 13.1 years, 52.7% women). Headache frequency <15 days/month was reported by 5,350 (55.5%) subjects of whom 1,601 (16.6%, [95% confidence interval (95% CI): 15.9-17.4]) reported episodic MIG, 1,202 (12.5%, 95% CI 11.8-13.1) episodic TTH, and 1,150 (11.9%, [11.3-12.6]) episodic MIG + episodic TTH, 1,396 (14.5%, [13.8-15.2]) unclassifiable headache. In women, episodic MIG peaked between 36 and 40 years, episodic MIG + TTH between 18 and 35 years and episodic TTH between 56 and 66 years. In men, episodic MIG was predominant between 36 and 45 years, episodic MIG + TTH between 26 and 35 years and episodic TTH showed comparable frequency between 36 and 66 years. Headache ≥15 days/month was reported by 2.6% (n = 255, [95% CI 2.3-3]). Chronic MIG was reported by 1.1% (n = 108, [0.91-1.33]), chronic TTH (n = 50, [95% CI 0.4-0.7]), chronic MIG + TTH 0.8% (n = 74, 95% CI 0.6-0.9) and unclassifiable headache 0.2% (n = 23, [95% CI 0.1-0.3]). Chronic headache was more frequent in women compared to men with the highest prevalence between 46 and 65 years. It is of note that the number of subjects with chronic headache is small in all age groups. The results of our large, population-based study provide reliable, age- and sex-specific estimates of the prevalence of primary headache disorders in Germany. The prevalence with respect to episodic and chronic primary headache disorders in Germany is comparable to other European countries and the USA.

Chronic migraine: classification and comparisons.

OBJECTIVE: The objective of our study was to field test different chronic migraine (CM) criteria and compare CM epidemiological profiles, which include demographic, personal, and lifestyle characteristics, with high-frequency episodic migraine (HFEM) and low-frequency episodic migraine (LFEM). METHODS: Questionnaires were mailed to a random sample of 18,000 18-65-year-olds in demographically diverse regions of Germany. The epidemiological data for the three classifications of CM, LFEM and HFEM were assessed using descriptive statistics, Pearson Chi-square, and analysis of variance tests. RESULTS: Among 9350 respondents, CM_I was the most restrictive (N = 37, 0.4%), followed by CM_II (N = 45, 0.5%) and CM_III (N = 185, 2.0%). CM groups did not differ in distribution by age, gender, body mass index, education or smoking and alcohol consumption. Compared to those with LFEM and HFEM, those with CM (CM_III) had significantly different epidemiological profiles. CONCLUSIONS: CM prevalence varies by case definition. The epidemiological profiles of the three CM groups are similar but differ significantly from those of HFEM and LFEM. Optimal definitions for clinical practice and epidemiological research require additional field testing.

Phospholipase D1 is an effector of Rheb in the mTOR pathway.

The mammalian target of rapamycin (mTOR) assembles a signaling network essential for the regulation of cell growth, which has emerged as a major target of anticancer therapies. The tuberous sclerosis complex 1 and 2 (TSC1/2) proteins and their target, the small GTPase Rheb, constitute a key regulatory pathway upstream of mTOR. Phospholipase D (PLD) and its product phosphatidic acid are also upstream regulators of the mitogenic mTOR signaling. However, how the TSC/Rheb and PLD pathways interact or integrate in the rapamycin-sensitive signaling network has not been examined before. Here, we find that PLD1, but not PLD2, is required for Rheb activation of the mTOR pathway, as demonstrated by the effects of RNAi. The overexpression of Rheb activates PLD1 in cells in the absence of mitogenic stimulation, and the knockdown of Rheb impairs serum stimulation of PLD activation. Furthermore, the overexpression of TSC2 suppresses PLD1 activation, whereas the knockdown or deletion of TSC2 leads to elevated basal activity of PLD. Consistent with a TSC-Rheb-PLD signaling cascade, AMPK and PI3K, both established regulators of TSC2, appear to lie upstream of PLD as revealed by the effects of pharmacological inhibitors, and serum activation of PLD is also dependent on amino acid sufficiency. Finally, Rheb binds and activates PLD1 in vitro in a GTP-dependent manner, strongly suggesting that PLD1 is a bona fide effector for Rheb. Hence, our findings reveal an unexpected interaction between two cascades in the mTOR signaling pathways and open up additional possibilities for targeting this important growth-regulating network for the development of anticancer drugs.

Incidence and predictors of chronic headache attributed to whiplash injury.

We identified clinical, demographic and psychological predictive factors that may contribute to the development of chronic headache associated with mild to moderate whiplash injury [Quebec Task Force (QTF) ≤ II] and determined the incidence of this chronic pain state. Patients were recruited prospectively from six participating accident and emergency departments. While 4.6% of patients developed chronic headache attributed to whiplash injury according to the International Classification of Headache Disorders, 2nd edn criteria, 15.2% of patients complained about headache lasting > 42 days (QTF criteria). Predictive factors were pre-existing facial pain [odds ratio (OR) 9.7, 95% confidence interval (CI) 2.1, 10.4; P = 0.017], lack of confidence to recover completely (OR 5.5, 95% CI 2.0, 13.2; P = 0.005), sore throat (OR 5.0, 95% CI 1.5, 8.9; P = 0.013), medication overuse (OR 4.2, 95% CI 1.4, 12.3; P = 0.009), high Neck Disability Index (OR 4.0, 95% CI 1.3, 12.6; P = 0.019), hopelessness/anxiety (OR 3.8, 95% CI 1.3, 8.7; P = 0.024), and depression (OR 3.3, 95% CI 1.2, 9.4; P = 0.024). The lack of a control group limits the conclusions that can be drawn from this study. Identified predictors closely resemble those found in chronic primary headache disorders.

Prevalence of facial pain in migraine: a population-based study.

Unilateral head pain focused on frontal, orbital or parietal regions is a leading symptom of migraine attacks. Rarely, head pain in migraine can extend involving the maxillary or mandibular region of the face, sometimes isolated facial pain is the only and atypical presentation of migraine. The prevalence of these unusual symptoms in migraine is unknown. We aimed to estimate the true prevalence of facial pain in migraine in a population-based sample of 517 migraine patients in Germany. In 46 (8.9%) cases migraine pain involved the head and the lower half of the face. Patients with facial pain suffer more trigemino-autonomic symptoms than migraine patients (47.8% vs. 7.9%; alpha(2) = 66.23, P < 0.001). In one case isolated facial pain without headache was the leading symptom of migraine. Our results demonstrate that facial pain is not unusual in migraine, whereas isolated facial migraine is extremely rare.

Electrically evoked nociceptive potentials for early detection of diabetic small-fiber neuropathy.

BACKGROUND AND PURPOSE: This study investigated the utility of pain-related evoked potentials (PREP's) elicited by a nociceptive electrical stimulation of the skin (= electrically evoked nociceptive potentials) in early detection of diabetic small-fiber neuropathy. METHODS: We studied 36 'young' (19-35 years) and 24 'older' (36-65 years) healthy subjects as well as 35 patients (35-64 years) with diabetes and neuropathic symptoms and 22 patients (34-64 years) with diabetes without neuropathic symptoms. Only patients with normal standard nerve conduction testing were included. RESULTS: In patients with neuropathic symptoms, we found a significant increase in PREP latencies and decrease of amplitudes elicited from both, upper and lower limbs. In non-symptomatic diabetic patients, we observed PREP abnormalities from lower limbs only. CONCLUSIONS: These data suggest that the method of pain-related evoked potentials elicited by a nociceptive electrical stimulation of the skin may contribute to the early detection of diabetic sensory neuropathy.

Population-based validation of a German-language self-administered headache questionnaire.

We validated a German-language self-administered headache questionnaire for migraine (M), tension-type headache (TTH) and trigeminal autonomic cephalalgia (TAC) in a general population sample of people with headache. Randomly selected subjects (n = 240) diagnosed by the questionnaire as M (n = 60), TTH (n = 60), a combination of M and TTH (M+TTH, n = 60) and TAC (n = 60) were invited for examination by headache specialists. One hundred and ninety-three subjects (80%) were studied. Sensitivity and specificity for M were 0.85 and 0.85, for TTH 0.6 and 0.88, for M+TTH 0.82 and 0.87, respectively. Cohen's kappa was 0.6 (95% confidence interval 0.50, 0.71). Of 45 patients with TAC according to the questionnaire, physicians diagnosed cluster headache in two patients only. We conclude: (i) the questionnaire can be used to diagnose M, TTH and M+TTH, but not TAC; (ii) screening questionnaires for epidemiological research should be validated in a general population sample but not in a tertiary headache clinic.

Efficacy of pregabalin in the treatment of trigeminal neuralgia.

This prospective, open-label study aimed to evaluate the efficacy of pregabalin treatment in patients suffering from trigeminal neuralgia with and without concomitant facial pain. Fifty-three patients with trigeminal neuralgia (14 with concomitant chronic facial pain) received pregabalin (PGB) 150-600 mg daily and were prospectively followed for 1 year. The primary outcome was number of patients pain free or with reduction of pain intensity by > 50% and of attack frequency by > 50% after 8 weeks. Secondary outcome was sustained pain relief after 1 year. Thirty-nine patients (74%) improved after 8 weeks with a mean dose of 269.8 mg/day (range 150-600 mg/day) PGB: 13 (25%) experienced complete pain relief and 26 (49%) reported pain reduction > 50%, whereas 14 (26%) did not improve. Patients without concomitant facial pain showed better response rates (32 of 39, 82%) compared with patients with concomitant chronic facial pain (7 of 14, 50%, P = 0.020). Concomitant chronic facial pain appears to be a clinical predictor of poor treatment outcome. PGB appears to be effective in the treatment of trigeminal neuralgia.

Significance of E2F-1 overexpression in epithelial ovarian cancer.

E2F-1 is a downstream regulator of the Rb pathway and is a transcription factor that plays a key role in the control of cell cycle progression. Deregulation of E2F-1 expression and Rb pathway is involved in carcinogenesis. The aim of this study was to evaluate E2F-1 expression and Rb pathway alteration and to elucidate their correlation with clinical and pathologic parameters in epithelial ovarian cancer (EOC). We investigated overexpression of E2F-1 and alterations of p16(INK4a), cyclin D1, CDK4, and pRb using immunohistochemistry and tissue microarray methods in 72 EOC patients. Overexpression of E2F-1 was detected in 45.8% of samples. The overall abnormal expression frequencies of p16(INK4a), cyclin D1, CDK4, and pRb were 33.3%, 11.1%, 12.5%, and 38.9%, respectively. E2F-1 overexpression was not associated with alteration of the Rb pathway. E2F-1 overexpression was correlated with FIGO stage, histologic grade, and mitotic index; it was a valuable prognostic variable along with FIGO stage in the multivariated analysis. The results suggest that E2F-1 has a growth-promoting effect in EOC and that E2F-1 overexpression may provide a useful prognostic indicator for EOC.

High-Resolution Nerve Ultrasound and Electrophysiological Findings in Restless Legs Syndrome.

BACKGROUND AND PURPOSE: Restless legs syndrome (RLS) is a multifactorial network disorder of a sensorimotor system extending from dopaminergic and glutamatergic cerebral structures to the spinal neurons and peripheral nerves. The role of peripheral nerve damage in the causality and severity progression for RLS patients remains unclear. METHODS: We performed a clinical and epidemiological study on a cohort of 34 RLS patients focusing on RLS risk factors and disease severity. We investigated the peripheral nerves with nerve conduction studies and with high-resolution nerve ultrasound (HRUS). RESULTS: In 18 of the 34 patients (mean age 67.4 ± 15 years old), a sensorimotor axonal neuropathy was diagnosed. These patients presented with late-onset RLS were treated with membrane stabilizing agents, whereas no neuropathy predisposing comorbidity could be identified for the majority of them. We could show an inverse correlation between the amplitudes of the tibial nerve for the patients with polyneuropathy and the RLS severity index. Neuropathy patients were characterized by an increase of the cross-sectional area (CSA) of the tibial nerve in the popliteal fossa and by increased intranerve and internerve variability values showing an asymmetry of CSA distribution. This pattern resembles previous studies on diabetic neuropathy. CONCLUSIONS: Early diagnosis, characterization, and treatment of neuropathy are increasingly relevant for RLS patients as it correlates with disease severity. HRUS revealed a pattern resembling diabetic neuropathy, which implies a similar pathophysiology with metabolic and ischemic origin of RLS-related axonal neuropathy.

Injecting NMDA and Ro 25-6981 in insular cortex induce neuroplastic changes and neuropathic pain-like behaviour.

BACKGROUND: Neuropathic pain is associated with abnormal sensitivity of the central nervous system. Although the mechanism underlying the development of sensitization remains to be fully elucidated, recent studies have reported that neuroplastic changes in the pain circuitry may be involved in hypersensitivity associated with neuropathic pain. However, it is difficult to investigate such phenomena in existing animal pain model. Therefore, in this study, we developed a novel animal model - the circuit plasticity reconstruction (CPR) model - to mimic central sensitization associated with neuroplastic changes. METHOD: NMDA and Ro 25-6981 were injected into the right insular cortex of Sprague-Dawley rats, while electrical stimulation was delivered to the contralateral hind paw. Mechanical allodynia was tested by von Frey test with up-down method, and neuroplastic changes were confirmed by PSA-NCAM-positive immunostaining. RESULT: The mechanical withdrawal threshold of the left hind paw decreased beginning 1 day after CPR modelling and persisted until day 21 comparing to the modified CPR 1 (mod-CPR 1) group (CPR: 91.68 ± 1.8%, mod-CPR 1: 42.71 ± 3.4%, p < 0.001). In contrast, mod-CPR 2 surgery without electrical stimulation did not induce mechanical allodynia. Immunostaining for PSA-NCAM also revealed that neuroplastic changes had occurred in the CPR group. CONCLUSION: Our results demonstrated that CPR modelling induced neuroplasticity within the insular cortex, leading to alterations in the neural circuitry and central sensitization. SIGNIFICANCE: This article represents that the CPR model can mimic the neuropathic pain derived by neuroplastic changes. Our findings indicate that the CPR model may aid the development of novel therapeutic strategies for neuropathic pain and in elucidating the mechanisms underlying pain induced by central sensitization and neuroplastic changes.

Impact of paraaortic lymphadenectomy for endometrial cancer with positive pelvic lymph nodes: A Korean Radiation Oncology Group study (KROG 13-17).

AIM: We investigated the role of paraaortic lymph node dissection (PALND) in patients with stage IIIC1 endometrial carcinoma after surgery followed by adjuvant radiotherapy (RT) alone or chemoradiotherapy (CTRT). METHODS: We performed a subgroup analysis in 151 patients treated with adjuvant pelvic RT. Paraaortic-recurrence free survival, disease-free survival (DFS) and overall survival (OS) were analyzed. RESULTS: In adjuvant RT alone, PALND was significantly related to reduced risk of paraaortic recurrence (0% vs. 17.1%) and distant metastasis (4.5% vs. 19.5%) compared with the no PALND group. PALND affected 5-year DFS (90.2% vs. 58.9%, p = 0.016) and OS (100% vs. 83.1%, p = 0.022). For the CTRT group, the paraaortic recurrence rate was 19.5% for the no PALND group and 12.8% for the PALND group (p = 0.682). Of patients who underwent PALND in the CTRT group, less extensive PALND was significantly related to increased paraaortic recurrence (≤10 vs. >10 dissected LNs, 17.1% vs. 0%). In the no PALND group (n = 82), 5-year paraaortic-recurrence free survival was 79.4% for the CTRT group and 76.2% for the RT alone group (p = 0.941). In multivariate analysis, PALND was significantly associated with reduced risk of disease-specific death (HR, 0.50; 95% CI, 0.26-0.96; p = 0.037). CONCLUSION: PALND provided excellent paraaortic control and improved outcome in stage IIIC1 endometrial cancer with favorable tumor features treated with adjuvant RT alone. Less extensive PALND was associated with significantly increased paraaortic recurrence in patients with advanced tumor features treated with adjuvant CTRT. Combined CTRT did not affect disease control in the paraaortic region compared with RT alone.

Effects of methylprednisolone on ventricular arrhythmias during acute myocardial ischaemia.

The effects of methylprednisolone (50 mg.kg-1) on the incidence of ventricular tachycardia and fibrillation and on ventricular fibrillation threshold were studied during acute coronary occlusion in anaesthetised dogs. Ventricular tachycardia and/or ventricular fibrillation occurred in 11 of the 16 animals (69%) both before and after methylprednisolone pretreatment. The mean ventricular fibrillation threshold of 10 dogs was 10.1 +/- 1.8 mA before methylprednisolone and it increased slightly to 13.3 +/- 2.3 mA after the drug. This difference was not statistically significant (P greater than 0.2).

Postextrasystolic T wave changes in normal canine hearts.

Premature ventricular beats were induced at variable coupling intervals and postextrasystolic T wave changes were observed following various postextrasystolic cycle lengths in 19 closed chest dogs with normal hearts. Following relatively longer postextrasystolic cycle lengths, reversal of the T wave polarity was seen in six dogs (31%), only T wave amplitude changes were seen in 6 dogs (31%), and no significant T wave changes were seen in seven dogs (38%). It was concluded that postextrasystolic T wave changes occur in normal hearts and have no useful diagnostic values.

Bochum ultrasound score allows distinction of chronic inflammatory from multifocal acquired demyelinating polyneuropathies.

OBJECTIVE: The aim of this observational study was to evaluate the applicability of a recently introduced ultrasound score (Bochum ultrasound score; BUS) in distinguishing the chronic inflammatory demyelinating polyneuropathy (CIDP) from the multifocal motor neuropathy (MMN) or the multifocal acquired demyelinating sensory and motor neuropathy (MADSAM). METHODS: The BUS underwent prospective evaluation of its applicability in a group of 13 patients (mean age 47.2, SD ± 13.7, 9 women), who were referred to our department between January 2012 and August 2013 with the clinical picture of a chronic symmetrical or asymmetrical sensory/sensorimotor neuropathy. RESULTS: The cut-off value of ≥ 2 points in the "Bochum ultrasound score" showed a sensitivity of 80% and specificity of 87.5% (PPV=80%, NPV=87.5%) in distinguishing CIDP from MMN or MADSAM. CONCLUSIONS: The BUS seems to allow a reliable distinction of CIDP from multifocal acquired demyelinating polyneuropathies causing predominantly motor nerve dysfunction, such as MMN or MADSAM. Our ultrasound findings indicate a stronger relationship of MADSAM to MMN, than to CIDP.