Quantifying Cartilage Biomechanical Properties Using a Linearized Frequency-Domain Method

Articular cartilage function relies on its unique mechanical behavior. Cartilage mechanics have been described by several analytic models, whose parameters are usually estimated by fitting their constitutive equations to stress-relaxation data. This procedure can be long and is prone to experimental and fitting errors. Τhis study describes a novel methodology for estimating the biomechanical properties of cartilage samples based on their linearized frequency response, derived by applying a series of small-amplitude harmonic displacements superimposed to a bias strain. The proposed methodology, denoted as linearized frequency-domain method (LFM), was demonstrated by quantifying the effects of collagenase and hyaluronidase on cartilage, where it provided robust cartilage parameter estimates that overall agreed well with estimates obtained by stress-relaxation analysis. LFM was also applied to unveil the strain-dependent nature of porcine cartilage biomechanical parameters. Results showed that increasing the bias strain from 5% to 15% caused a significant decrease in cartilage permeability but did not have significant effect on the compression modulus and the Poisson’s ratio. Apart from cartilage, LFM can potentially quantify the strain-dependent nature of tissues and biomaterials, thereby enhance tissue-level understanding on organ physiology and pathology, lead to better computational tissue models, and guide tissue engineering research.     

Circadian patterns of generalized tonic-clonic evolutions in pediatric epilepsy patients

ObjectiveTo investigate the sleep/wake, day/night, and 24-h periodicity of pediatric evolution to generalized tonic–clonic seizures (GTC).MethodsCharts of 407 consecutive patients aged 0–21 years undergoing continuous video-EEG monitoring for epilepsy were reviewed for the presence of GTC evolution. Seizures were characterized according to 2001 ILAE terminology. Charts were reviewed for EEG seizure localization, MRI lesion, and for seizure occurrence in 3-h time blocks, out of sleep or wakefulness, and during the day (6 AM–6 PM) or night. Analysis was done with binomial testing. Regression models were fitted using generalized estimating equations with patients as the cluster level variable.Results71 patients (32 girls, mean age 12.63 ± 5.3 years) had 223 seizures with GTC evolution. Sleep/wake seizure distribution predicted tonic–clonic evolution better than time of day, with more occurring during sleep (p < 0.001). Tonic–clonic evolution occurred most frequently between 12–3 AM and 6–9 AM (p < 0.05). Patients with generalized EEG onset had more tonic–clonic evolution between 9 AM and 12 PM (p < 0.05). Patients with extratemporal focal seizures were more likely to evolve during sleep (p < 0.001); this pattern was not found in patients with temporal or generalized seizure onset on EEG. Patients without MRI lesions were more likely to evolve between 12 AM and 3 AM (p < 0.05), in the sleeping state (p < 0.001), and at night (p < 0.05). Logistic regression revealed that sleep and older patient age were the most important predictors of GTC evolution.ConclusionGTC evolution occurs most frequently out of sleep and in older patients. Our results may assist in seizure prediction, individualized treatment patterns, and potentially complication and SUDEP prevention.     

Dacrystic seizures: Demographic,semiologic, and etiologic insights from a multicenter study in long‐term video‐EEG monitoring units

Purpose: To provide an estimate of the frequency of dacrystic seizures in video‐electroencephalography (EEG) long‐term monitoring units of tertiary referral epilepsy centers and to describe the clinical presentation of dacrystic seizures in relationship to the underlying etiology. Methods: We screened clinical records and video‐EEG reports for the diagnosis of dacrystic seizures of all patients admitted for video‐EEG long‐term monitoring at five epilepsy referral centers in the United States and Germany. Patients with a potential diagnosis of dacrystic seizures were identified, and their clinical charts and video‐EEG recordings were reviewed. We included only patients with: (1) stereotyped lacrimation, sobbing, grimacing, yelling, or sad facial expression; (2) long‐term video‐EEG recordings (at least 12 h); and (3) at least one brain magnetic resonance imaging (MRI) study. Key Findings: Nine patients (four female) with dacrystic seizures were identified. Dacrystic seizures were identified in 0.06–0.53% of the patients admitted for long‐term video‐EEG monitoring depending on the specific center. Considering our study population as a whole, the frequency was 0.13%. The presence of dacrystic seizures without other accompanying clinical features was found in only one patient. Gelastic seizures accompanied dacrystic seizures in five cases, and a hypothalamic hamartoma was found in all of these five patients. The underlying etiology in the four patients with dacrystic seizures without gelastic seizures was left mesial temporal sclerosis (three patients) and a frontal glioblastoma (one patient). All patients had a difficult‐to‐control epilepsy as demonstrated by the following: (1) at least three different antiepileptic drugs were tried in each patient, (2) epilepsy was well controlled with antiepileptic drugs in only two patients, (3) six patients were considered for epilepsy surgery and three of them underwent a surgical/radiosurgical or radioablative procedure. Regarding outcome, antiepileptic drugs alone achieved seizure freedom in two patients and did not change seizure frequency in another patient. Radiosurgery led to moderately good seizure control in one patient and did not improve seizure control in another patient. Three patients were or are being considered for epilepsy surgery on last follow‐up. One patient remains seizure free 3 years after epilepsy surgery. Significance: Dacrystic seizures are a rare but clinically relevant finding during video‐EEG monitoring. Our data show that when the patient has dacrystic and gelastic seizures, the cause is a hypothalamic hamartoma. In contrast, when dacrystic seizures are not accompanied by gelastic seizures the underlying lesion is most commonly located in the temporal cortex.     

Depressive symptoms, vascular disease, and mild cognitive impairment: findings from the Cardiovascular Health Study

CONTEXT: Depressive symptoms are common in patients with dementia and may be associated with increased risk of developing dementia. It has been hypothesized that depressive symptoms and dementia may be attributable to underlying vascular disease in some older persons. OBJECTIVES: To test the hypotheses (1) that depressive symptoms are associated with increased risk of developing mild cognitive impairment (MCI), a preclinical state that often precedes dementia, and (2) that the association between depressive symptoms and MCI is attributable to underlying vascular disease. DESIGN: Prospective, population-based, longitudinal study. SETTING: Random sample of adults 65 years or older recruited from 4 US communities. PARTICIPANTS: Subjects were 2220 participants in the Cardiovascular Health Study Cognition Study with high cognitive function at baseline. Depressive symptoms were measured at baseline using the 10-item Center for Epidemiological Studies Depression Scale and were classified as none (0-2 points), low (3-7 points), and moderate or high (>/=8 points). Vascular disease measures at baseline included confirmed history of stroke, transient ischemic attack, diabetes mellitus, or hypertension; carotid artery stenosis; ankle-arm blood pressure index; and small or large infarcts or white matter disease on cerebral magnetic resonance imaging. Mild cognitive impairment was diagnosed after 6 years of follow-up based on the consensus of a team of dementia experts using standard clinical criteria. MAIN OUTCOME MEASURE: Diagnosis of MCI. RESULTS: Depressive symptoms at baseline were associated with increased risk of MCI (10.0%, 13.3%, and 19.7% for those with no, low, and moderate or high depressive symptoms, respectively). This association was diminished only slightly by adjustment for vascular disease measures and demographics. Vascular disease measures also were associated with increased risk of MCI, and these associations were not diminished by adjustment for depressive symptoms or demographics. CONCLUSION: Depressive symptoms were associated with increased risk of MCI, and this association was independent of underlying vascular disease.     

Long-term results with vagus nerve stimulation in children with pharmacoresistant epilepsy.

PURPOSE: To retrospectively review our experience with VNS in pediatric patients with pharmacoresistant epilepsy and examine the seizure-frequency outcome and rates of discontinuation in two age groups: adolescent and pre-adolescent children. RESULTS: Complete pre- and post-VNS data were available for 46/49 patients. Median age at implantation was 12.1 (range 2.3-17.9) and median duration of epilepsy 8.0 (1.9-16.9) years. Twenty-one patients (45.6%) were under 12 years at the time of surgery. Median follow-up was 2 years; follow-up exceeded 4 years in 9/46 patients. As compared to baseline, median seizure-frequency reduction in the setting of declining numbers was 56% at 3 months, 50% at 6, 63% at 12, 83% at 24 and 74% at 36 months. When a last observation carried forward analysis was employed median seizure-frequency reduction in the range of 60% was observed at 1, 2 and 3 years post-VNS. Twenty patients (43.5%) had >75% seizure-frequency reduction. No response (increase or <50% reduction) was observed in 19/46 (41.3%). Five patients (10.1%) were seizure-free for more than 6 months by their last follow-up. There was no difference in the number of AEDs used before and after VNS. The long-term discontinuation rate was 21.7% and reflected a lack of clinical response or infection. CONCLUSIONS: In this series VNS was well-tolerated and effective as add-on therapy for refractory seizures in children of all ages. Response was even more favorable in the younger group (<12 years at implantation). Infection and lack of efficacy were the most common reasons for discontinuation of long-term VNS therapy in this group.     

Immunocryosurgery for basal cell carcinoma: results of a pilot, prospective, open-label study of cryosurgery during continued imiquimod application

Background/aim  Theoretical considerations support the combination of cryosurgery and topical imiquimod to treat basal cell carcinomas (BCC). The aim of the present study was to test the feasibility and efficacy of 'cryosurgery during continued imiquimod application' ('immunocryosurgery') to treat 'high-risk-for-recurrence' BCCs.
Methods  Thirteen patients with 21 biopsy-proven tumours (4 of 21 relapses after prior surgery) were included. After 2–5 weeks (median, 3) of daily 5% imiquimod cream application, the tumours were treated by liquid N₂ cryosurgery (spray, two cycles, 10–20 s) and imiquimod was continued for additional 2–12 weeks (median, 4). The outcome after at least 18 months of follow-up (18–24 months) is currently reported.
Results  Nineteen of 21 tumours responded promptly to immunocryosurgery; two tumours required additional treatment cycles to clear. Thus, the clinical clearance rate was 100%. Only 1 of 21(5%) tumour relapsed after at least 18 months of follow-up (cumulative efficacy: 95%).
Conclusions  'Immunocryosurgery' is a promising non-surgical combination modality to treat 'high-risk-for-recurrence BCCs'. Initial evidence is suggestive of an at least additive effect of the two combined modalities. Further studies comparing immunocryosurgery directly with cryosurgery and imiquimod monotherapies will confirm the reported results.     

Antidepressant pharmacotherapy in the treatment of depression in the very old: a randomized, placebo-controlled trial

OBJECTIVE: This study determined the efficacy of antidepressant medication for the treatment of depression in the "old-old." METHOD: This randomized 8-week medication trial compared citalopram, 10-40 mg/day, to placebo in the treatment of patients 75 and older with unipolar depression. RESULTS: A total of 174 patients who were 58% women with a mean age of 79.6 years (SD=4.4) and a mean baseline Hamilton Depression Rating Scale score of 24.3 (SD=4.1) were randomly assigned to treatment at 15 sites. There was a main effect for site but not for treatment condition. The remission rate, defined as a final Hamilton depression scale score <10, was 35% for the citalopram and 33% for the placebo groups. However, patients with severe depression (baseline Hamilton depression scale score >24) tended to have a higher remission rate with medication than with placebo (35% versus 19%). CONCLUSIONS: In the oldest group of community-dwelling patients to be studied to date, medication was not more effective than placebo for the treatment of depression. However, given the considerable psychosocial support received by all patients, the placebo condition represents more than the ingestion of an inactive pill. Across sites, there was considerable range in response to medication, 18% to 82%, and to placebo, 16% to 80%.     

Placebo-controlled study of relapse prevention with risperidone augmentation in older patients with resistant depression.

OBJECTIVE: The effect of risperidone augmentation of citalopram for relapse prevention in older patients with antidepressant-resistant depression was evaluated. METHODS: Patients with major depression aged > or =55 years who had failed at least one adequate trial of an antidepressant received citalopram monotherapy (20-40 mg) for 4 to 6 weeks to confirm nonresponse (<50% reduction in Hamilton Rating Scale for Depression [HAM-D] scores). Those who achieved remission (HAM-D score < or =7 or Clinical Global Impressions severity score 1 or 2) after 4 to 6 weeks of open-label risperidone augmentation (0.25-1 mg) then entered a 24-week double-blind maintenance phase during which they received citalopram augmented with risperidone or placebo. RESULTS: The patients' mean age was 63.4 +/- 7.9 years; 58% were women; 61% had received two or more antidepressants during the current episode; 93 met the criterion for citalopram nonresponse and entered open-label risperidone augmentation. Of the 89 patients who completed risperidone augmentation, 63 achieved symptom resolution and entered the 6-month double-blind maintenance phase: 32 received risperidone augmentation and 31 received placebo augmentation. The median time to relapse (Kaplan-Meier estimates) was 105 days in the risperidone group and 57 days in the placebo group (Wilcoxon chi(2): 3.2, df = 1, p = 0.069). Overall, 18 of 32 (56%) from the risperidone group and 20 of 31 (65%) from the placebo group relapsed. Treatment was well tolerated. CONCLUSION: In older patients with resistant depression and poor response to standard treatments, risperidone augmentation resulted in symptom resolution in a substantial number of patients and a nonsignificant delay in time to relapse.