Selective Patterns of Cognitive Impairment in Spinocerebellar Ataxia Type 6 and Idiopathic Late-Onset Cerebellar Ataxia.

PURPOSE: To determine cognitive impairment patterns in patients with spinocerebellar ataxia type 6 (SCA6) compared to patients with idiopathic late-onset cerebellar ataxia (ILOCA). METHODS: Neurocognitive testing was conducted on 21 SCA6, nine ILOCA, and 27 controls subjects. Intergroup differences were assessed using the Wilcoxon signed-ranked test or Student's t-test. Principal component analysis (PCA) was performed on nine cognitive variables, and Hotelling's T-squared test assessed group-specific differences. Pearson's correlations assessed changes in cognitive performance and disease progression. Intra-group differences among SCA6 were examined in a post-hoc analysis. RESULTS: SCA6 and ILOCA patients showed impairment in visuo-spatial executive function, phonemic verbal fluency, and semantic-verb word generation. ILOCA showed impairment in mental flexibility/response inhibition, verbal learning, semantic-noun verbal fluency, and forward numerical working memory. Within the first three principal components, SCA6 and ILOCA differed from controls and from each other. Verbal working and immediate visuo-spatial memory correlated with disease duration for SCA6. For ILOCA, Mini-Mental Status Exam and RCF copy correlated with disease duration. CONCLUSION: Differing patterns of cognitive dysfunction were seen in SCA6 and ILOCA. PCA suggested that distinct SCA6 subgroups may exist, SCA61 with significant ILOCA overlap in several cognitive deficits, and SCA62 showing deficits in visuo-spatial performance only.

Bone mineral density loss in thoracic and lumbar vertebrae following radiation for abdominal cancers.

PURPOSE: To investigate the relationship between abdominal chemoradiation (CRT) for locally advanced cancers and bone mineral density (BMD) reduction in the vertebral spine. MATERIALS AND METHODS: Data from 272 patients who underwent abdominal radiation therapy from January 1997 to May 2015 were retrospectively reviewed. Forty-two patients received computed tomography (CT) scans of the abdomen prior to initiation and at least twice after radiation therapy. Bone attenuation (in Hounsfield unit) (HU) measurements were collected for each vertebral level from T7 to L5 using sagittal CT images. Radiation point dose was obtained at each mid-vertebral body from the radiation treatment plan. Percent change in bone attenuation (Δ%HU) between baseline and post-radiation therapy were computed for each vertebral body. The Δ%HU was compared against radiation dose using Pearson's linear correlation. RESULTS: Abdominal radiotherapy caused significant reduction in vertebral BMD as measured by HU. Patients who received only chemotherapy did not show changes in their BMD in this study. The Δ%HU was significantly correlated with the radiation point dose to the vertebral body (R=-0.472, P<0.001) within 4-8 months following RT. The same relationship persisted in subsequent follow up scans 9 months following RT (R=-0.578, P<0.001). Based on the result of linear regression, 5 Gy, 15 Gy, 25 Gy, 35 Gy, and 45 Gy caused 21.7%, 31.1%, 40.5%, 49.9%, and 59.3% decrease in HU following RT, respectively. Our generalized linear model showed that pre-RT HU had a positive effect (ß=0.830) on determining post-RT HU, while number of months post RT (ß=-0.213) and radiation point dose (ß=-1.475) had a negative effect. A comparison of the predicted versus actual HU showed significant correlation (R=0.883, P<0.001) with the slope of the best linear fit=0.81. Our model's predicted HU were within ±20 HU of the actual value in 53% of cases, 70% of the predictions were within ±30 HU, 81% were within ±40 HU, and 90% were within ±50 HU of the actual post-RT HU. Four of 42 patients were found to have vertebral body compression fractures in the field of radiation. CONCLUSIONS: Patients who receive abdominal chemoradiation develop significant BMD loss in the thoracic and lumbar vertebrae. Treatment-related BMD loss may contribute to the development of vertebral compression fractures. A predictive model for post-CRT BMD changes may inform bone protective strategies in patients planned for abdominal CRT.

Cross-sectional imaging following surgical interventions for stress urinary incontinence in females.

Stress urinary incontinence (SUI) is a condition in which the weakness of the pelvic floor muscles causes unintentional loss of urine. For patients who are unable to achieve symptomatic improvement from lifestyle modification and pharmacotherapy, surgical placement of the pelvic slings or the use of urethral bulking agents has been shown to provide tremendous symptomatic improvement. Learning to recognize the pelvic slings and to identify their complications on imaging is invaluable; however, this is challenging because of the change in the local anatomy after surgical placement of the sling. In this paper, we present CT and MR imaging to demonstrate the surgical and non-surgical treatments of female SUI and their complications. Through this pictorial essay, our goal is to familiarize radiologists with recognizing the various forms of treatment for SUIs, the relevant pelvic anatomy, and complications that may occur secondary to the surgical placement of the pelvic slings.

Comparison of Glioblastomas and Brain Metastases using Dynamic Contrast-Enhanced Perfusion MRI.

PURPOSE: To compare glioblastoma and brain metastases using T1-weighted dynamic contrast-enhanced (DCE)-MRI perfusion technique. METHODS: 26 patients with glioblastoma and 32 patients with metastatic brain lesions with no treatment who underwent DCE-MRI were, retrospectively, analyzed. DCE perfusion parameters K(trans) and Vp were calculated for the whole tumor. Signal intensity time curves were quantified by calculating the area under the curve (AUC) and the logarithmic slope of the washout phase to explore the heterogeneous tumor characteristics. RESULTS: Glioblastoma did not differ from all brain metastases in K(trans) (P = .34) or Vp (P = .47). Glioblastoma and melanoma metastases differed from hypovascular metastases in AUC and log slope of the washout phase of the signal intensity time curve (P < .05); however, glioblastoma and melanoma metastases did not differ from each other (AUC: P = .78, Log slope: P = .77). Glioblastoma and melanoma metastases differed from hypovascular metastases in the ratio of Voxelneg /Voxelpos (P< .03); however, they did not differ from each other. Glioblastoma and melanoma metastases differed from each other in Voxelneg_threshold at higher negative log slope threshold. CONCLUSION: DCE-MRI showed that it has a potential to differentiate glioblastomas, melanoma metastases and hypovascular brain tumors. Logarithmic slope of the washout phase and AUC of the signal intensity time curve were shown to be the best discriminator between hypervascular and hypovascular neoplasms.

Increased reward in ankle robotics training enhances motor control and cortical efficiency in stroke.

Robotics is rapidly emerging as a viable approach to enhance motor recovery after disabling stroke. Current principles of cognitive motor learning recognize a positive relationship between reward and motor learning. Yet no prior studies have established explicitly whether reward improves the rate or efficacy of robotics-assisted rehabilitation or produces neurophysiologic adaptations associated with motor learning. We conducted a 3 wk, 9-session clinical pilot with 10 people with chronic hemiparetic stroke, randomly assigned to train with an impedance-controlled ankle robot (anklebot) under either high reward (HR) or low reward conditions. The 1 h training sessions entailed playing a seated video game by moving the paretic ankle to hit moving onscreen targets with the anklebot only providing assistance as needed. Assessments included paretic ankle motor control, learning curves, electroencephalograpy (EEG) coherence and spectral power during unassisted trials, and gait function. While both groups exhibited changes in EEG, the HR group had faster learning curves (p = 0.05), smoother movements (p

The impact of an external breast prosthesis on the gait parameters of women after mastectomy.

BACKGROUND: An integral part of the recovery process after mastectomy involves the consideration of restorative options, including external prosthesis use; however, only few studies regarding the influence of breast prostheses on functional status have been done. OBJECTIVE: This study aimed to determine whether wearing an external breast prosthesis affects gait in women after a mastectomy. METHODS: Spatiotemporal gait parameters were collected in 40 women, postmastectomy, aged 37 to 70 years, divided into age subgroups of 37 to 54 years and 55 to 70 years, and in 38 healthy controls, women aged 38 to 69 years. Gait parameters were assessed with and without the breast prosthesis, including walking velocity, cadence, step length, step time, and left-right step time asymmetry. RESULTS: Significant differences were found in the gait parameters of the younger age group with and without a prosthesis. No significant differences were found in the women of the older group with and without the prosthesis. CONCLUSION: Gait parameters of the younger age group were closer to those of the healthy control group when they were wearing an external prosthesis, as compared with when they were not. This suggests a positive influence of breast prosthesis use on the functional status of women after mastectomy. IMPLICATIONS FOR PRACTICE: Clinical practitioners should be aware of the study results suggesting a positive influence of breast prosthesis use on gait parameters after mastectomy surgery, which could improve the patient's functional status after surgery; however, further research is still needed on factors affecting changes in gait with a larger study population.

The effect of a hippotherapy session on spatiotemporal parameters of gait in children with cerebral palsy - pilot study.

BACKGROUND: Hippotherapy has been shown to produce beneficial effects by improving the most difficult motor functions, such as sitting, running, jumping, coordination, as well as balance and muscle strength in children with motor developmental delays. The aim of this study was to analyze the effect of hippotherapy on spatiotemporal parameters of gait in cerebrally palsied children. MATERIAL AND METHODS: 16 ambulatory cerebrally palsied children (GMFCS Level I-III; Female: 10, Male: 6; Age: 5.7-17.5 years old) qualified for hippotherapy were investigated. Basic spatiotemporal parameters of gait, including walking speed, cadence, step length, stride length and the left-right symmetry, were collected using a three-dimensional accelerometer device (DynaPort MiniMod) before and immediately after a hippotherapy session. The Wilcoxon test was used to verify the differences between pre- and post-session results. RESULTS: Changes of walking speed were statistically significant. With the exception of step length, all spatiotemporal parameters improved, i.e. were closer to the respective reference ranges after the session. However, these changes were not statistically significant. CONCLUSION: One session of hippotherapy may have a significant effect on the spatiotemporal parameters of gait in cerebrally palsied children.

Tandem enzymatic oxygenations in biosynthesis of epoxyquinone pharmacophore of manumycin-type metabolites.

Many natural products contain epoxyquinone pharmacophore with unknown biosynthetic mechanisms. Recent genetic analysis of the asukamycin biosynthetic gene cluster proposed enzyme candidates related to epoxyquinone formation for manumycin-type metabolites. Our biochemical studies reveal that 3-amino-4-hydroxyl benzoic acid (3,4-AHBA) precursor is activated and loaded on aryl carrier protein (AsuC12) by ATP-dependent adenylase (AsuA2). AsuE1 and AsuE3, both single-component flavin-dependent monooxygenases, catalyze the exquisite regio- and enantiospecific postpolyketide synthase (PKS) assembly oxygenations. AsuE1 installs a hydroxyl group on the 3,4-AHB ring to form a 4-hydroxyquinone moiety, which is epoxidized by AsuE3 to yield the epoxyquinone functionality. Despite being a single-component monooxygenase, AsuE1 activity is elicited by AsuE2, a pathway-specific flavin reductase. We further demonstrate that the epoxyquinone moiety is critical for anti-MRSA activity by analyzing the bioactivity of various manumycin-type metabolites produced through mutasynthesis.

The gait pattern in post-menopausal women. Pilot study.

BACKGROUND: Aging brings about a number of degenerative changes in the body. The aging process in-creases its pace after the menopause. Women notice functional limitations in their daily lives, including mobility problems, as early as in their forties. Gait is one of the most reliable parameters reflecting the body's overall function and condition. The aim of this study was to determine the effect of menopause on gait patterns in healthy women. MATERIAL AND METHODS: The study involved a group of 48 healthy women (divided into Group A of pre-menopausal women and Group B of post-menopausal women). Gait parameters were acquired by a DynaPort MiniMod accelerometer. The pre- and post-menopausal women's gait data, including spatio-temporal parameters, gait cycle phases and the variability, were analysed. RESULTS: There were no significant differences between Group A and B in walking speed, step length, cadence, and gait phase duration. Significant differences were only noted in gait cycle phases with regard to the onset of single-support of the right limb, the 1st double-support of the right limb and the 2nd double-support of the left limb. Gait variability did not show any significant differences between the groups. CONCLUSIONS: 1. A prolonged stance phase during the gait cycle observed in the post-menopausal women in this study is a typical finding in aged people. 2. However, stride-to-stride variability of gait was not affected in the study.

Principal component analysis of cerebellar shape on MRI separates SCA types 2 and 6 into two archetypal modes of degeneration.

Although "cerebellar ataxia" is often used in reference to a disease process, presumably there are different underlying pathogenetic mechanisms for different subtypes. Indeed, spinocerebellar ataxia (SCA) types 2 and 6 demonstrate complementary phenotypes, thus predicting a different anatomic pattern of degeneration. Here, we show that an unsupervised classification method, based on principal component analysis (PCA) of cerebellar shape characteristics, can be used to separate SCA2 and SCA6 into two classes, which may represent disease-specific archetypes. Patients with SCA2 (n=11) and SCA6 (n=7) were compared against controls (n=15) using PCA to classify cerebellar anatomic shape characteristics. Within the first three principal components, SCA2 and SCA6 differed from controls and from each other. In a secondary analysis, we studied five additional subjects and found that these patients were consistent with the previously defined archetypal clusters of clinical and anatomical characteristics. Secondary analysis of five subjects with related diagnoses showed that disease groups that were clinically and pathophysiologically similar also shared similar anatomic characteristics. Specifically, Archetype #1 consisted of SCA3 (n=1) and SCA2, suggesting that cerebellar syndromes accompanied by atrophy of the pons may be associated with a characteristic pattern of cerebellar neurodegeneration. In comparison, Archetype #2 was comprised of disease groups with pure cerebellar atrophy (episodic ataxia type 2 (n=1), idiopathic late-onset cerebellar ataxias (n=3), and SCA6). This suggests that cerebellar shape analysis could aid in discriminating between different pathologies. Our findings further suggest that magnetic resonance imaging is a promising imaging biomarker that could aid in the diagnosis and therapeutic management in patients with cerebellar syndromes.

MRI shows a region-specific pattern of atrophy in spinocerebellar ataxia type 2.

In this study, we used manual delineation of high-resolution magnetic resonance imaging (MRI) to determine the spatial and temporal characteristics of the cerebellar atrophy in spinocerebellar ataxia type 2 (SCA2). Ten subjects with SCA2 were compared to ten controls. The volume of the pons, the total cerebellum, and the individual cerebellar lobules were calculated via manual delineation of structural MRI. SCA2 showed substantial global atrophy of the cerebellum. Furthermore, the degeneration was lobule specific, selectively affecting the anterior lobe, VI, Crus I, Crus II, VIII, uvula, corpus medullare, and pons, while sparing VIIB, tonsil/paraflocculus, flocculus, declive, tuber/folium, pyramis, and nodulus. The temporal characteristics differed in each cerebellar subregion: (1) duration of disease: Crus I, VIIB, VIII, uvula, corpus medullare, pons, and the total cerebellar volume correlated with the duration of disease; (2) age: VI, Crus II, and flocculus correlated with age in control subjects; and (3) clinical scores: VI, Crus I, VIIB, VIII, corpus medullare, pons, and the total cerebellar volume correlated with clinical scores in SCA2. No correlations were found with the age of onset. Our extrapolated volumes at the onset of symptoms suggest that neurodegeneration may be present even during the presymptomatic stages of disease. The spatial and temporal characteristics of the cerebellar degeneration in SCA2 are region specific. Furthermore, our findings suggest the presence of presymptomatic atrophy and a possible developmental component to the mechanisms of pathogenesis underlying SCA2. Our findings further suggest that volumetric analysis may aid in the development of a non-invasive, quantitative biomarker.

14-Aminocamptothecins: their synthesis, preclinical activity, and potential use for cancer treatment.

14-Aminocamptothecins were synthesized in good yields by treating camptothecin (1a) and 7-ethylcamptothecin (1b) with 90% fuming nitric acid either neat or in acetic anhydride and then followed by reduction of the resulting 14-nitrocamptothecins (2). 14-Aminocamptothecin (3a) and 7-ethyl-14-aminocamptothecin (3b) demonstrated excellent cytotoxic potency against human tumor cell lines in vitro, and they are not substrates for any of the major clinically relevant efflux pumps (MDR1, MRP1, and BCRP). 3a and 3b showed similar cytotoxicity against human and mouse bone marrow progenitor cells. This is in contrast to many camptothecin analogues, which are substrates for efflux pumps and are dramatically more toxic to human marrow cells relative to murine. 3a and 3b demonstrated significant brain penetration when dosed orally in mice. 3b showed significantly better efficacy relative to topotecan when dosed orally in the three ectopic xenograft models, H460, HT29, and PC-3. On the basis of its favorable in vitro and in vivo profile, 3b warrants future development.