Cortico-cerebellar connectivity underlying motor control in chronic post-stroke individuals.

The robust, reciprocal anatomical connections between the cerebellum and contralateral sensorimotor cerebral hemisphere underscores the strong physiological interdependence between these two regions in relation to human behavior. Previous studies have shown that damage to sensorimotor cortex can result in a lasting reduction of cerebellar metabolism, the magnitude of which has been linked to poor rehabilitative outcomes. A better understanding of movement-related cerebellar physiology as well as cortico-cerebellar coherence (CCC) in the chronic, post-stroke state may be key to developing novel neuromodulatory techniques that promote upper limb motor rehabilitation. As a part of the first in-human phase-I trial investigating the effects of deep brain stimulation of the cerebellar dentate nucleus (DN) on chronic, post-stroke motor rehabilitation, we collected invasive recordings from DN and scalp EEG in subjects (both sexes) with middle cerebral artery stroke during a visuo-motor tracking task. We investigated the excitability of ipsilesional cortex, DN and the their interaction as a function of motor impairment and performance. Our results indicate that 1) event-related oscillations in the ipsilesional cortex and DN were significantly correlated at movement onset in the low-ß band, with moderately and severely impaired subjects showing desynchronization and synchronization, respectively. 2) Significant CCC was observed during isometric 'hold' period in the low-ß band, which was critical for maintaining task accuracy. Our findings support a strong coupling between ipsilesional cortex and DN in the low-ß band during motor control across all impairment levels which encourages the exploitation of the cerebello-thalamo-cortical pathway as a neuromodulation target to promote rehabilitation.Significance Statement:Cerebral infarct due to stroke can lead to lasting reduction in cerebellar metabolism resulting in poor rehabilitative outcomes. Thorough investigation of the cerebellar electrophysiology as well as cortico-cerebellar connectivity in humans that could provide key insights to facilitate development of novel neuromodulatory technologies, has been lacking. As a part of the first in-human phase-I trial investigating deep brain stimulation of the cerebellar dentate nucleus (DN) for chronic, post-stroke motor rehabilitation, we collected invasive recordings from DN and scalp EEG while stroke patients performed a motor task. Our data indicate strong coupling between ipsilesional sensorimotor cortex and DN in the low-ß band across all impairment levels encouraging the exploration of electrical stimulation of the DN.

Evaluation of the Impact of Magnetic Resonance Imaging with Susceptibility-weighted Imaging for Screening and Surveillance of Radiation-induced Cavernomas in Long-term Survivors of Malignancy.

AIMS: Radiation-induced cavernomas (RIC) are common late toxicities in long-term survivors of malignancy following cerebral irradiation. However, the natural history of RIC is poorly described. We report the first series of long-term surveillance of RIC using modern magnetic resonance imaging (MRI) including highly sensitive susceptibility-weighted imaging (SWI). The aims of this research were to better characterise the natural history of RIC and investigate the utility of MRI-SWI for screening and surveillance. MATERIALS AND METHODS: Eligibility required long-term survivors of malignancy with previous exposure to cerebral irradiation and RIC identified on MRI-SWI surveillance. The number and size of RIC were reported on Baseline MRI-SWI and last Follow-up MRI-SWI. RESULTS: In total, 113 long-term survivors with RIC underwent MRI-SWI surveillance; 109 (96%) were asymptomatic at the time of RIC diagnosis. The median age at cerebral irradiation was 9.3 years; the median radiotherapy dose was 50.4 Gy. The median time from cerebral irradiation to Baseline MRI-SWI was 17.9 years. On Baseline MRI-SWI, RIC multiplicity was present in 89% of patients; 34% had >10 RIC; 65% had RIC ≥4 mm. The median follow-up from Baseline MRI-SWI was 7.3 years. On Follow-up MRI-SWI, 96% of patients had multiple RIC; 62% had >10 RIC; 72% had RIC ≥4 mm. Of the 109 asymptomatic patients at RIC diagnosis, 96% remained free from RIC-related symptoms at 10 years. Only two required neurosurgical intervention for RIC; there was no RIC-related mortality. CONCLUSIONS: RIC are commonly multiple, asymptomatic and typically increase in size and number over time. Our findings suggest that MRI-SWI for screening of RIC is unlikely to influence longer term intervention in asymptomatic cancer survivors. In the absence of neurological symptoms, assessment or monitoring of RIC are insufficient indications for MRI-SWI surveillance for long-term survivors of malignancy with past exposure to cerebral irradiation.

In pursuit of equity: partnering to improve breast and prostate cancer outcomes among African Americans.

PURPOSE: Community-based participatory research (CBPR) is a collaborative partnership approach that leverages the strengths of academic-community groups to address local problems. CBPR emphasizes equity (e.g., co-learning, power-sharing, participatory decision-making) among groups to achieve goals and promote sustainability. This study examines group dynamics, and their influence on achieving shared goals, within a CBPR-guided partnership established to improve breast and prostate cancer outcomes among underserved African American communities in St. Louis, Missouri. METHODS: We conducted in-person, semi-structured interviews with key academic and community informants and surveyed via email community collaborators involved in outreach activities. Interviews were audiotaped, transcribed, and independently coded by two authors using an iterative, open-coding process to identify major themes. Surveys were summarized using similar coding criteria for open-ended responses and descriptive statistics for discrete responses. Using a grounded theory approach, we summarized and compared themes from each data source to identify similarities and differences and triangulated results to generate overarching thematic findings. RESULTS: Participants described benefits from the partnership (funding; clinical, public health and evaluation expertise; training and networking opportunities) and found beneficial ways to leverage the partners' strengths in collaborating Participants expressed long-term commitment to sustaining the partnership and building capacity to address cancer disparities, but faced challenges related to power-sharing and participatory decision-making. CONCLUSIONS: Using CBPR to address cancer disparities is an effective approach to capacity-building and achieving shared goals. By evaluating the structures and processes within CBPR collaborations through the lens of equity, partners may identify and address challenges that threaten long-term partnership sustainability.

Long-term Survival with 18-Fluorodeoxyglucose Positron Emission Tomography-directed Therapy in Non-small Cell Lung Cancer with Synchronous Solitary Brain Metastasis.

AIMS: At diagnosis, <1% of patients with non-small cell lung cancer (NSCLC) have synchronous solitary brain metastasis (SSBM). In prior cohorts without 18-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) staging, definitive treatment to intracranial and intrathoracic disease showed a 5-year overall survival (OS) of 11-21%. We investigated the long-term survival outcomes for patients with SSBM NSCLC, diagnosed in the FDG-PET/CT era and treated definitively with local therapies to both intracranial and intrathoracic sites of disease. MATERIALS AND METHODS: This retrospective study assessed patients staged with FDG-PET/CT who received definitive lung and SSBM treatment from February 1999 to December 2017. A lung-molecular graded prognostic assessment (lung-molGPA) score was assigned for each patient using age, performance status score, and, where carried out, molecular status. Overall survival and progression-free survival (PFS) were calculated using Kaplan-Meier methods. Cox proportional hazard models determined OS and PFS prognostic factors. RESULTS: Forty-nine patients newly diagnosed with NSCLC and SSBM had a median age of 63 years (range 34-76). The median follow-up of all patients was 3.9 years. Thirty-three patients (67%) had ≥T2 disease, 23 (47%) had ≥N2. At 2 years, 45% of first failures were intracranial only (95% confidence interval 30-59). At 3 and 5 years, OS was 45% (95% confidence interval 32-63) and 30% (95% confidence interval 18-51), respectively. In ≥N1 disease, 5-year OS was 34% (95% confidence interval 18-63). The 3- and 5-year PFS was 8% (95% confidence interval 3-22) and 0%, respectively. Higher lung-molGPA was associated with longer OS (hazard ratio 0.26, 95% confidence interval 0.11-0.61, P = 0.002). Higher lung-molGPA (hazard ratio 0.33, 95% confidence interval 0.15-0.71, P = 0.005) and lower N-stage (hazard ratio 1.56, 95% confidence interval 1.13-2.15, P = 0.007) were associated with longer PFS. CONCLUSIONS: Definitive treatment of patients with NSCLC and SSBM staged with FDG-PET/CT can result in 5-year survivors, including those with ≥N1 disease.

Incidence of transformation to aggressive lymphoma in limited-stage follicular lymphoma treated with radiotherapy.

BACKGROUND: The established treatment of limited-stage follicular lymphoma is radiotherapy (RT). There is an inherent risk of transformation of follicular lymphoma to aggressive lymphoma; however, the frequency and impact on the outcome are unknown in limited-stage patients. MATERIALS AND METHODS: We identified 237 patients with limited-stage follicular lymphoma treated with curative intent RT. Cases were reviewed to determine the frequency of transformation and subsequent survival. RESULTS: With a median follow-up of 7.4 years, the 10-year risk of transformation was 18.5%. With a median follow-up after transformation of 4.7 years, the 3-year post-transformation progression-free survival (PFS) and overall survival (OS) were 42% and 44%, respectively. The addition of rituximab improved the 3-year post-transformation PFS and OS compared with combination chemotherapy alone (78% versus 15%, P < 0.00001) and (87% versus 38.5%, P < 0.00001), respectively. In multivariate analysis, only rituximab was associated with OS [HR 0.07 (95% CI 0.015-0.312, P = 0.001)] and PFS [HR 0.19 (95% CI 0.55-0.626, P = 0.007)] following transformation. CONCLUSIONS: There is a moderate risk of transformation in limited-stage follicular lymphoma treated with curative intent RT, and it substantially impacts outcome in these patients. Treatment with rituximab at the time of transformation appears to improve survival in this otherwise poor-risk population.

Minimising critical organ irradiation in limited stage Hodgkin lymphoma: a dosimetric study of the benefit of involved node radiotherapy.

BACKGROUND: Chemotherapy plus radiotherapy is the standard of care for patients with limited stage Hodgkin lymphoma (HL). Radiotherapy is evolving from involved field radiotherapy (IFRT) to involved node radiotherapy (INRT) to decrease radiotherapy-related morbidity. In the absence of long-term toxicity data, dose-volume metrics of organs at risk (OAR) provide a surrogate measure of toxicity risk. PATIENTS AND METHODS: Ten female patients with stage I-IIA supradiaphragmatic HL were randomly selected. All patients had pre-chemotherapy computerised tomography (CT) and CT-positron emission tomography staging. Using CT planning, three radiotherapy plans were produced per patient: (i) IFRT, (ii) INRT using parallel-opposed beams and (iii) INRT using volumetric modulated arc therapy (VMAT). Radiotherapy dose was 30.6 Gy in 1.8 Gy fractions. OAR evaluated were lungs, breasts, thyroid, heart and coronary arteries. RESULTS: Compared with IFRT, INRT significantly reduced mean doses to lungs (P < 0.01), breasts (P < 0.01), thyroid (P < 0.01) and heart (P < 0.01), on Wilcoxon testing. Compared with conventional INRT, VMAT improved dose conformality but increased low-dose radiation exposure to lungs and breasts. VMAT reduced the heart volume receiving 30 Gy (V30) by 85%. CONCLUSIONS: Reduction from IFRT to INRT decreased the volumes of lungs, breasts and thyroid receiving high-dose radiation, suggesting the potential to reduce long-term second malignancy risks. VMAT may be useful for patients with pre-existing heart disease by minimising further cardiac toxicity risks.

Chromosomal alterations in oligodendroglial tumours over multiple surgeries: is tumour progression associated with change in 1p/19q status?

BACKGROUND: Oligodendroglial neoplasms have morphologic and genotypic heterogeneity. Loss of heterozygosity (LOH) of 1p and/or 19q is associated with increased treatment responsiveness and overall survival. However, the pathogenesis of treatment-resistance is unknown. We sought to determine if tumour progression is due to a proliferating sub-population of tumour cells with intact 1p, or if recurrent tumours retain 1p/19q LOH. METHODS: 24 patients with oligodendroglial neoplasms, possessing biopsy samples taken at diagnosis and at progression, were identified. 53 tumour specimens were available for LOH analysis of 1p and 19q, using PCR amplification of multiple microsatellite markers. 40 were also tested for 9p and 10q. RESULTS: At diagnosis, the median age was 34 (24-66) years, 14 were male. 19 tumours were WHO Grade II, and 5 were high grade. The most common genomic status was 19q LOH (70%). 13 (54%) tumours were 1p LOH at diagnosis: of these, 12 were 19q LOH, and 1 was 19q uninformative. All 12 patients with 1p/19q LOH primary tumours had persistent co-deletion at progression. 9 (38%) tumours were 1p intact at diagnosis, and 8 remained 1p intact in the progressed tumours. There was little heterogeneity of 9p and 10q between tumours at diagnosis and progression. CONCLUSION: 100% of oligodendroglial tumours with 1p/19q LOH, demonstrated persistent 1p/19q LOH in the progressed tumour. Therefore, progression of these tumours is not due to a proliferating sub-population of treatment-resistant, 1p intact tumour cells. We propose that additional mutations contribute to this aggressive phenotype, however, 9p LOH or 10q LOH are unlikely to be involved.

Kidney transplantation into an ileal conduit: a single center experience of 59 cases.

PURPOSE: Congenital and acquired conditions of the lower urinary tract can lead to renal failure requiring transplantation. Under these circumstances transplantation into a urinary diversion or an augmented bladder may be the only option. We report our experience with renal transplantation into ileal conduits in the last 22 years. MATERIALS AND METHODS: Between January 1980 and August 2002, 59 renal transplants were drained into an ileal conduit in 54 patients at our center, accounting for 2.3% of the total number of transplants during this period. Median patient age was 28 years (range 1 to 63) and 13 patients were children. There were 12 living related and 47 cadaveric kidneys transplanted. Spina bifida, the most common cause of end stage renal disease, was seen in 22 patients (41%). Patient and graft survival following transplantation into an ileal conduit were compared with that in the 2,579 other transplants done at this center between January 1980 and December 2001. RESULTS: Actuarial graft survival was 90% at 1 year, 63% at 5 years, 52% at 10 years and 52% at 15 years. Actuarial patient survival was 95% at 1 year, 83% at 5 years, 69% at 10 years and 69% at 15 years. Graft and patient survival was statistically similar to the outcome of the 2,579 other transplants done at our center between January 1980 and December 2001. At a mean followup of 4.6 years (range 0.1 to 20) mean serum creatinine in the 39 functioning grafts was 156 mmol/l. Of the surgical complications 21% were directly attributable to the ileal conduit and it could be considered a risk factor contributing to the complication in a further 39%. Symptomatic urinary tract infection was noted in 65% of the patients, although it did not lead to graft loss. At followup 7 patients had died with a functioning graft. Grafts were lost due to chronic allograft nephropathy in 3 cases, renal artery stenosis in 2, renal vein thrombosis in 2, and acute severe rejection, staghorn calculus and ureteroileal stricture in 1 each. CONCLUSIONS: Kidney transplant drainage into an ileal conduit for urinary diversion is an effective treatment for patients with end stage renal disease due to abnormal lower urinary tracts. Despite preexisting co-morbidity and the increased complication rate long-term graft and patient survival is comparable to that in the normal transplant population.

Tacrolimus is not associated with gingival overgrowth in renal transplant patients.

BACKGROUND: Cyclosporin A is used extensively to prevent the rejection of allogenic renal transplants. However, it is associated with a variety of undesirable side effects including gingival overgrowth. Tacrolimus (FK506), has been marketed as an effective alternative immunosuppressant to cyclosporin A and recent subjective reports suggest patients taking it complain infrequently of gingival problems. This clinical investigation was undertaken to confirm whether or not tacrolimus adversely affected the gingival health of renal transplant recipients. METHODS: Renal transplant patients (RTPs) under the care of the Renal Transplantation Service at the Manchester Royal Infirmary, who had received a renal allograft at least 18 months earlier, were recruited for this study. All but one of the RTPs had been taking tacrolimus since transplantation. The other had commenced tacrolimus therapy two months after receiving her allograft. A hospital based control group was recruited from non transplanted individuals attending the Turner Dental School, Manchester. Each patient underwent a detailed dental assessment and had dental impressions taken. The extent of gingival overgrowth was determined from plaster models. RESULTS: 25 renal transplant recipients and 26 control patients were included in the study. None of the individuals in either the tacrolimus or control groups had clinically significant overgrowth. The patients in the tacrolimus group with the highest overgrowth scores were those also taking calcium antagonists as treatment for hypertension. CONCLUSION: This study demonstrates that tacrolimus has no adverse effects on the gingival tissues and thus has potential as an alternative immunosuppressant for individuals susceptible to developing cyclosporin A-induced gingival overgrowth.

Three clusters of ciguatera poisoning: clinical manifestations and public health implications.

Between July 1997 and August 1998 we investigated three clusters (26 cases) of ciguatera poisoning in the inner Sydney area. Tropical reef fish were implicated in each cluster. Most of those affected had musculoskeletal, neurological and gastrointestinal symptoms. The clusters raise questions about the need for rapid diagnosis and enhanced surveillance mechanisms, the regulation of fish supply, and the lack of testing facilities for ciguatera toxin.

The calcium channel blocker used with cyclosporin has an effect on gingival overgrowth.

BACKGROUND/AIMS: To investigate whether the choice of calcium channel blocker, used in conjunction with cyclosporin A, affected the prevalence of gingival overgrowth. METHOD: A cohort of 135 renal transplant recipients who had been medicated with cyclosporin A in combination with either nifedipine (89) or amlodipine (46) since transplant, took part in the study. The inclusion criteria were that eligible subjects had been in receipt of a kidney transplant for at least 12 months, had at least 10 teeth and had not received specialist periodontal treatment. The age, gender, current drug regimen and dosage were recorded for each participant and alginate impressions taken of both arches. The presence and severity of gingival overgrowth were scored from plaster models. RESULTS: A higher proportion (72%) of the amlodipine group were categorised as having gingival overgrowth compared with only 53% of the nifedipine group, chi square=4.5, p<0.05. Logistic regression analysis was used to explore the relationship between the presence or absence of gingival overgrowth (dependent variable) and age, gender, time since transplant, dose of cyclosporin A, centre in which the patient was treated, and the calcium channel blocker used (independent variables). Independent predictors of gingival overgrowth in this multivariate analysis were whether the individual was treated with amlodipine or nifedipine (p=0.01) and whether the individual was young or old (p=0.01). Within the multivariate analysis, the odds ratio for amlodipine to be associated with gingival overgrowth compared with nifedipine was 3.0 (confidence interval 1.3-6.9). CONCLUSIONS: The prevalence of gingival overgrowth in renal transplant recipients maintained on cyclosporin A and nifedipine is lower than those treated with cyclosporin A and amlodipine.

Reduction in gingival overgrowth associated with conversion from cyclosporin A to tacrolimus.

BACKGROUND: Unsightly gingival overgrowth affects many individuals immunosuppressed with cyclosporin A (CsA). Current management involves repeated periodontal surgery and intensive hygienist support. Tacrolimus is an effective alternative immunosuppressive agent for renal transplantation which does not appear to produce gingival enlargement. AIMS: The purpose of the present study was to monitor the gingival response of 4 renal transplant patients (RTPs), with clinically significant CsA-induced gingival overgrowth, after their immunosuppressive therapy was switched to tacrolimus. METHODS: Intra-oral photographs and alginate impressions were taken both prior to the drug conversion and again, 6 to 9 months later. Gingival overgrowth scores were determined, from plaster models on both these occasions. RESULTS: All of the RTPs experienced significant resolution of their gingival enlargement within the time period studied; however, only one had complete regression. CONCLUSION: It is concluded that conversion of RTPs with gingival overgrowth from CsA to tacrolimus may provide an effective management strategy for this clinical problem.

Inhibition of the expression of conditioned cardiac responses in the developing rat.

It is generally recognized that during development the capacity to express learning in terms of changes in somatomotor activity is evident earlier than the capacity for learned changes in autonomic responding (e.g., heart rate). In this series of experiments, findings indicate that changes in heart rate to a visual conditioned stimulus (CS) paired with a footshock unconditioned stimulus (US) can be observed as early in development in the rat as freezing responses. However, cardiac responses are inhibited from being expressed by preweanlings (but not adults) during CS-US pairings, the time when heart rate responses are often measured. This inhibition appears to arise from US exposure, and dissipates completely within 2 hr of training. These findings are discussed with respect to developmental changes in US-evoked autonomic arousal and response system dissociations.

Utilizing sonography to follow fetal growth.

In utero diagnosis of fetal growth abnormalities continues to pose a clinical dilemma. Although significant advances have been made in the understanding of growth disturbances and their clinical importance, false-positive and false-negative diagnoses of IUGR and excessive fetal growth continue to affect the accuracy of antenatal diagnosis. Until more accurate methods are developed to aid in diagnosis, multiple biometric parameters should be assessed in patients either at risk for or with a suspected growth disturbance. Serial measurements obtained every 2 to 3 weeks may enhance diagnostic capabilities. Although antenatal diagnosis of IUGR has been shown to be of benefit in improving outcome, more study is needed to determine whether there is a benefit in antenatal diagnosis of macrosomia or LGA.

Autonomic and behavioral correlates of appetitive conditioning in rats.

The cardiac responses accompanying conditioned stimulus- (CS)-generated (orienting) and unconditioned stimulus- (US)-generated appetitively motivated behaviors (P. C. Holland, 1977) were investigated. On the basis of contemporary psychophysiological research, CS-generated responses were predicted to produce bradycardia, and US-generated responses to produce tachycardia. Pairing a 10-s visual CS with food delivery produced conditioned behavioral orienting (rearing) during the initial portion of the CS, followed by magazine approach (US-generated) responses as the CS progressed. CS onset produced a decrease in heart rate, mediated by an increase in parasympathetic stimulation of the heart, which persisted throughout the 10-s CS; no support for a biphasic cardiac response was observed. These data are discussed with respect to other conditioned autonomic responses and their relevance to foraging and food ingestion.

Emergence of conditioned cardiac responses to an olfactory CS paired with an acoustic startle UCS during development: form and autonomic origins.

Pairing an olfactory conditioned stimulus (CS) with an acoustic startle unconditioned stimulus (UCS) produced conditioned bradycardia in rats ranging from 12 days of age to adulthood but failed to produce conditioning in 10-day-olds (Experiment 1). The second experiment compared the effects of two different UCSs, acoustic startle and electric shock. The startle UCS produced conditioned bradycardia accompanied by immobility. In contrast, the shock UCS produced conditioned tachycardia accompanied by behavioral activation. Pharmacological analysis revealed that activation of the parasympathetic nervous system (PNS) produced the conditioned bradycardia (Experiment 3) and that activation of the sympathetic nervous system (SNS) produced the conditioned tachycardia (Hunt, Hess, & Campbell, 1994). Further comparisons revealed that the startle UCS established conditioning several days earlier in development than the shock UCS. The ability of the PNS to respond to phasic stimulation earlier in development than the SNS was discussed as a possible mechanism for the early development of conditioned bradycardia.

Developmental and pharmacological analysis of the cardiac response to an acoustic startle stimulus.

The purpose of this research was to study the cardiac response of preweanling and adult rats to 10 presentations of an acoustic startle stimulus (0 ms rise time, 100 ms, 130 dB, white noise stimulus). The first presentation of the startle stimulus produced a decrease in heart rate (HR) at both ages. With continued stimulus presentations, the response shifted to tachycardia in the adults but remained bradycardia in the preweanlings. Pharmacological analysis revealed that the startle stimulus activated only the parasympathetic system in the preweanling rats on all 10 trials. In contrast, the startle stimulus produced coactivation of the parasympathetic and sympathetic systems in the adults on the first trial, with the parasympathetic system predominating, and solely sympathetic activation on later trials. These results are discussed in terms of current psychophysiological models of (a) the cardiac response to startle stimuli and (b) autonomic space.

Megaloblastic anemia in pregnancy.

Megaloblastic anemia is one of the acquired nutritional anemias that may complicate pregnancy. It is most often secondary to folic acid deficiency because folate requirements are increased during gestation. When the diagnosis of megaloblastic anemia is confirmed, appropriate therapy will initiate a rapid reversal of the anemia process. Because of the association between neural tube defects and folate deficiency, it is recommended that women of reproductive age take folic acid supplementation.

Delayed development of conditioned heart rate responses to auditory stimuli in the rat.

This study examined heart rate responses to an auditory conditioned stimulus during development in the rat. The unconditioned stimulus (US) in all experiments was an acoustic startle stimulus. The conditioned stimulus elicited a monophasic bradycardia in animals 21 days of age and older, but no response in younger animals. These results are strikingly similar to an earlier study that used shock as the US (Campbell & Ampuero, 1985). Further, the conditioned cardiac response in adults was found to be mediated entirely through activation of the parasympathetic division of the autonomic nervous system (ANS) even though the US unconditionally activates the sympathetic system at that age. The delayed development of several different forms of conditioned fear is discussed.