Apoptosis as a form of cell death in intracerebral hemorrhage

OBJECTIVE: The goals of this study were to identify and quantify the presence of programmed cell death (apoptosis) in intracerebral hemorrhage (ICH) among human subjects. Recent evidence from laboratory models suggests that cell death in the perihematoma region may involve apoptosis. METHODS: Retrospective clinical and histological analyses were performed for patients with spontaneous ICH who underwent surgical evacuation. Quantification of apoptotic cells was performed in sections obtained from the perihematoma region from 12 patients with ICH and stained with the terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphosphate nick-end labeling method. Necrosis was identified on the basis of morphological criteria, using hematoxylin and eosin staining. RESULTS: Evidence of apoptosis was present in surgical specimens obtained from 10 of the 12 patients. The mean number of apoptotic cells in the perihematoma region in each patient specimen was 38% (range, 0-90%). For five patients, more than one-half of the total cells observed were apoptotic. Apoptosis was observed in specimens obtained within 1 day, 2 days, and 5 days after the onset of symptoms. No terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphosphate nick-end labeling-positive cells were observed in specimens from the two patients with cerebellar hematomas. The mean proportion of necrotic cells in the perihematoma region in each patient specimen was 25% (range, 0-100%). There was a prominent excess of apoptotic cells, in comparison with necrotic cells, for 6 of the 12 patients who underwent hematoma evacuation. For five other patients, similar proportions of apoptotic and necrotic cells were observed. Necrosis was the predominant finding for only one patient, who underwent late surgical evacuation on Day 5. CONCLUSION: These observations suggest that apoptosis represents a prominent form of cell death associated with ICH in the perihematoma region. Further studies are required to define the mediators of apoptosis in ICH.     

Proximal femoral focal deficiency: radiologic analysis of 49 cases

Proximal femoral focal deficiency, an uncommon congenital anomaly, necessitates early radiologic classification for surgical planning and treatment. Objective radiographic criteria, including femoral length index, acetabular depth index, acetabular angle index, and shape of the proximal femur were determined in 49 patients before cartilaginous ossification of the femoral capital epiphysis; final classification was based on follow-up radiographs or findings at arthrography or surgery. These parameters were analyzed to determine the accuracy and contributions of each in classification. Correct classification into one of three groups was possible in 86% of cases with use of three of the parameters: femoral length index, acetabular depth index, and shape of the proximal femur. The acetabular angle was found to contribute insignificantly to classification. Magnetic resonance imaging, used in only one case, depicted the nonossified cartilaginous femoral capital epiphysis, thus obviating the need for invasive diagnostic procedures and facilitating early classification.     

44Sacral extracorporeal magnetic stimulation is an effective treatment for pelvic floor dyssynergia; Comparative study with biofeedback therapy

Background: Recent development of extracorporeal magnetic stimulation (ECMS) which uses current‐changing magnetic fields allows the induction of electrical stimulation in the desired deep tissue. Recent study showed the sacral nerve stimulation reduces corticoanal excitability that may play a functional role in anal continence mechanisms. Preliminary study shows that ECMS of sacral nerve can modify pelvic floor function and expel rectal balloon in patients with pelvic floor dyssynergia (PFD). Aims: To evaluate the effect of ECMS compared with biofeedback therapy (BF) in patients with PFD. Methods and Materials: Thirty‐eight patients who fulfilled Rome II criteria for PFD by colon transit time and anorectal function tests, were randomly treated with 8 sessions of ECMS (2/weeks; n = 19) at prone position or BF (2/weeks; n = 19) at sitting position. Stimulation parameters were set at 50–80% of maximum intensity, 10 and 50 Hz frequency, 3 s burst length with 3 and 6 s off using arm‐typed stimulator (BioCom‐1000, Mcube Co., Korea). Symptom scores for constipation with/without anorectal function test were repeatedly measured after each treatment. Response was defined as 50% or more decreased symptom score after treatment (partial response: 30–50%, poor: <30%). Results: Fifteen patients (age 49.1 ± 13.4 years, mean ± SD; 4 men) completed 8 session of BF and 14 patients (54.5 ± 17.6 years, 3 men) completed 8 session of ECMS. Four patients of BF group discontinued treatment due to unsatisfactory therapeutic effect (n = 1) and withdrew consent (n = 3) and 5 patients of ECMS group discontinued treatment because of same reasons (n = 1, 4). Total symptom scores were significantly decreased after treatment of 8 session in both treatment groups (13.4 ± 6.6 vs. 4.3 ± 4.0 for BF, p = 0.009; 14.9 ± 5.6 vs. 3.4 ± 4.0 for ECMS, p < 0.001). Bowel movements per week were also significantly increased after treatment in both groups (median 2 vs. 7 for BF, p = 0.035; median 2 vs. 7 for ECMS, p = 0.008). Thirteen out of 15 patients showed response in BF group and 12 out of 14 showed good response in ECMS group. No adverse effects in both groups. Conclusions: ECMS is as effective as BF for the treatment of PFD. Long‐term effect of ECMS for the patients with pelvic floor dyssynergia need to be evaluated in the near future.     

EZH2 expression in gliomas: Correlation with CDKN2A gene deletion/ p16 loss and MIB‐1 proliferation index

Enhancer of zeste homolog 2 (EZH2) mediated down‐regulation of CDKN2A/p16 has been observed in cell lines as well as in a few carcinomas. However, there is no study correlating EZH2 expression with CDKN2A/p16 status in gliomas. Hence, the present study was conducted to evaluate EZH2 expression in astrocytic and oligodendroglial tumors and correlate with CDKN2A/p16 status as well as MIB‐1 labeling index (LI). Gliomas of all grades (n = 118) were studied using immunohistochemistry to assess EZH2, p16 and MIB‐1 LI and fluorescence in situ hybrization to evaluate CDKN2A gene status. EZH2 expression and CDKN2A homozygous deletion (HD) were both significantly more frequent in high‐grade gliomas (HGG). Further, strong EZH2 expression (LI ≥ 25%) was significantly more common in HGGs without CDKN2A HD (48.7%; 19/39) as compared to cases with deletion (15.8%; 3/19). Loss of p16 expression was noted in 100% and 51.3% of CDKN2A deleted and non‐deleted tumors, respectively. Notably, 80% (16/20) of the CDKN2A non‐deleted HGGs with p16 loss had strong EZH2 expression, in contrast to only 15.8% (3/19) in the deleted group. Loss of p16 expression significantly correlated with MIB‐1 LI, irrespective of EZH2 status. Thus, this study shows that EZH2 expression correlates with tumor grade in both astrocytic and oligodendroglial tumors and hence can be used as a diagnostic marker to differentiate between low and HGGs. Further, this is the first report demonstrating an inverse correlation of strong EZH2 expression with CDKN2A HD in HGGs. Loss of p16 protein expression is mostly attributable to CDKN2A HD and correlates significantly with MIB‐1 LI. Notably, our study for the first time suggests a possible epigenetic mechanism of p16 loss in CDKN2A non‐deleted HGGs mediated by strong EZH2 expression. A hypothetical model for control of proliferative activity in low versus HGGs is therefore proposed.     

Intra-Arterial Thrombolysis Within Three Hours of Stroke Onset in Middle Cerebral Artery Strokes

Background and Purpose

The Prolyse in Acute Cerebral Thromboembolism II (PROACT II) trial showed improved outcomes in patients with proximal middle cerebral artery (MCA) occlusions treated with intra-arterial (IA) thrombolysis within 6 h of stroke onset. We analyzed outcomes of patients with proximal MCA occlusions treated within 3 h of stroke onset in order to determine the influence of time-to-treatment on clinical and angiographic outcomes in patients receiving IA thrombolysis.

Methods

Thirty-five patients from three academic institutions with angiographically demonstrated proximal MCA occlusions were treated with IA thrombolytics within 3 h of stroke onset. Outcome measures included outcomes at 30–90 day follow-up, recanalization rates, incidence of symptomatic intracranial hemorrhage, and mortality in the first 90 days. The endpoints were compared to the IA treated and control groups of the PROACT II trial.

Results

The median admission National Institutes of Health Stroke Scale (NIHSS) score was 16 (range 4–24). The mean time to initiation of treatment was 106 min (range 10–180 min). Sixty-six percent of patients treated, had a modified Rankin Scale (mRS) score of 2 or less at 1–3 month follow-up compared to 40% in the PROACT II trial. The recanalization rate was 77% (versus 66% in PROACT II). The symptomatic intracranial hemorrhage rate was 11% (versus 10% in PROACT II) and the mortality rate was 23% (versus 25% in PROACT II).

Conclusion

Time-to-treatment is just as important in IA thrombolysis as it is in IV thrombolysis, both for improving clinical outcomes and recanalization rates as well.     

Autonomic dysfunction in Parkinson's disease: A prospective cohort study

Background : Dysautonomia is a frequent and disabling complication of PD, with an estimated prevalence of 30‐40% and a significant impact on the quality of life. Objectives : To evaluate the rate of progression of dysautonomia and, in particular, orthostatic hypotension, in a cohort of unselected PD patients, and assess the extent to which the progression of dysautonomia affects activities of daily living, health‐related quality of life, and health care utilization in PD. Methods : We recruited 131 consecutive patients into a 12‐month, prospective, observational cohort study. Clinical measures included the International Parkinson and Movement Disorder Society/UPDRS, the Scale for Outcomes in Parkinson Disease‐Autonomic, the Orthostatic Hypotension Symptoms Assessment, and orthostatic blood pressure measurements. Health care utilization was quantified as the number of hospitalizations, emergency room visits, and outpatient clinic evaluations. Results : The overall severity of autonomic symptoms, as measured by the the Orthostatic Hypotension Symptoms Assessment total score, worsened by 20% over 12 months (P < 0.001), with an overall increase in orthostatic hypotension prevalence from 31.1% to 46.7% (P < 0.001). Worsening of autonomic symptoms was independently associated with deterioration in daily living activities (P = 0.021) and health‐related quality of life (P = 0.025) adjusting for disease duration, cognitive impairment, and motor severity. Regardless of symptomatic status, orthostatic hypotension was associated with greater deterioration in daily living activities, health care utilization, and falls (P ≤ 0.009) compared to patients without orthostatic hypotension. Conclusions : The severity of autonomic symptoms progressed by 20% over 1 year and was independently associated with impairments in daily living activities and health‐related quality of life. Symptomatic and asymptomatic orthostatic hypotension were both associated with increased prevalence of falls and health care utilization. © 2017 International Parkinson and Movement Disorder Society