Promise of Pharmacogenomics for Drug Discovery, Treatment and Prevention of Parkinson’s Disease. A Perspective

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by a heterogeneous array of motor and non-motor features. Anti-PD drugs that are in use target only the motor symptoms, may lose efficacy over time, and can cause serious adverse effects such as dyskinesia and psychosis. There are currently no preventative or disease modifying treatments. All attempts to develop disease modifying drugs have failed. Pharmacogenomics (PGx) has the potential to change the way new drugs are developed and the way drugs are prescribed. By using genetic markers that correlate with, and can therefore predict drug response, clinical trials can be designed to be enriched with individuals who are most likely to benefit from the drug, maximizing drug’s efficacy, minimizing its adverse effects, and boosting the odds of successful drug discovery. Clinical application of PGx will help physicians to quickly and accurately determine the right drugs and the right doses for individuals, avoiding the lengthy trial and error approaches and adverse effects. In combination with known protective factors such as nicotine and caffeine, PGx may enable development of personalized methods for PD prevention and, by extension, care.     

Analysis of the pentafecta learning curve for laparoscopic radical prostatectomy

Purpose

Laparoscopic radical prostatectomy (LRP) has a long learning curve; however, little is known about the pentafecta learning curve for LRP. We analysed the learning curve for a fellowship trained surgeon with regard to the pentafecta with up to 6-year follow-up.

Methods

A retrospective review was performed in 550 cases, by dividing these cases into 11 groups of 50 patients. Outcomes analysed were the following: (1) the pentafecta (complication rate, positive surgical margin (PSM) rate, continence, potency and biochemical recurrence); (2) operative time and blood loss; and (3) overall pentafecta attainment.

Results

The mean complication rate for the entire series was 9 %; this plateaued after 150 cases. The overall PSM rate for the series was 23.5 %, 16.3 % for pT2 and 40.5 % for pT3. PSM plateaued after 200 cases. Excluding the first 100 cases, the overall PSM rate for pT2 was 10.9 % and 37.8 % for pT3. The continence rate stabilised after approximately 250 cases. The rate of male sling/artificial urinary sphincter plateaued after 200 cases. The potency learning curve continues to improve after 250 cases of nerve-sparing (ns) endoscopic extraperitoneal radical prostatectomy (EERPE) as does the pentafecta learning curve which closely follows the pattern of the potency learning curve. The last group of nsEERPE achieved pentafecta in 63 %.

Conclusion

This study shows multiple learning curves: an initial for peri-operative outcomes, then stabilisation of oncologic outcomes and the final for stabilisation of functional outcomes. In this series over 250 cases were required to achieve the learning curve.     

Interneuron precursor transplants in adult hippocampus reverse psychosis-relevant features in a mouse model of hippocampal disinhibition

GABAergic interneuron hypofunction is hypothesized to underlie hippocampal dysfunction in schizophrenia. Here, we use the cyclin D2 knockout (Ccnd2^−/−) mouse model to test potential links between hippocampal interneuron deficits and psychosis-relevant neurobehavioral phenotypes. Ccnd2^−/− mice show cortical PV⁺ interneuron reductions, prominently in hippocampus, associated with deficits in synaptic inhibition, increased in vivo spike activity of projection neurons, and increased in vivo basal metabolic activity (assessed with fMRI) in hippocampus. Ccnd2^−/− mice show several neurophysiological and behavioral phenotypes that would be predicted to be produced by hippocampal disinhibition, including increased ventral tegmental area dopamine neuron population activity, behavioral hyperresponsiveness to amphetamine, and impairments in hippocampus-dependent cognition. Remarkably, transplantation of cells from the embryonic medial ganglionic eminence (the major origin of cerebral cortical interneurons) into the adult Ccnd2^−/− caudoventral hippocampus reverses these psychosis-relevant phenotypes. Surviving neurons from these transplants are 97% GABAergic and widely distributed within the hippocampus. Up to 6 mo after the transplants, in vivo hippocampal metabolic activity is lowered, context-dependent learning and memory is improved, and dopamine neuron activity and the behavioral response to amphetamine are normalized. These findings establish functional links between hippocampal GABA interneuron deficits and psychosis-relevant dopaminergic and cognitive phenotypes, and support a rationale for targeting limbic cortical interneuron function in the prevention and treatment of schizophrenia.Precursors of most γ-aminobutyric acid (GABA)-releasing interneurons of the cerebral cortex and the hippocampus originate in the embryonic medial ganglionic eminence (MGE) (1–3). A subpopulation of MGE-derived cells differentiates into fast-spiking, parvalbumin-expressing (PV⁺) interneurons that tightly regulate the activity and synchronization of cortical projection neurons (2, 4). Structural and functional deficits in PV⁺ interneurons are hypothesized as a pathophysiological mechanism in schizophrenia and psychotic disorders (4–6).Although psychotic disorders are clearly heterogeneous in etiology, disinhibition within temporolimbic cortical circuits is postulated as a core pathophysiology underlying positive symptoms (e.g., delusions and hallucinations) and a subset of cognitive disturbances that manifest with psychosis (4, 5, 7). Postmortem studies of brains from individuals with psychotic disorders show reduced molecular markers of the number and/or function of PV⁺ interneurons in the hippocampus (6, 8). Consistent with these observations, basal metabolic activity in the hippocampus, as measured with functional magnetic resonance imaging (fMRI), is increased in schizophrenia, a phenotype that predicts psychosis and positive symptom severity (5, 7). This abnormal resting activity is postulated to underlie abnormal recruitment of hippocampal circuits during cognitive performance (5, 9). Striatal dopamine (DA) release capacity is also increased and correlated with positive symptoms in schizophrenia and its risk states (10, 11). Importantly, hippocampal hyperactivity may contribute to DA dysregulation (12), because rodent studies show that caudoventral hippocampal (in the primate, anterior hippocampal) efferents regulate the activity of DA neurons and medial striatal DA release (13, 14).Thus, converging evidence implicates hippocampal disinhibition in the abnormal striatal DA transmission and cognitive impairment in schizophrenia. However, the role of hippocampal inhibitory interneurons in psychosis-relevant circuitry remains to be established. To this end, we used the cyclin D2 (Ccnd2) knockout mouse model (15), which displays a relatively selective deficit in cortical PV⁺ interneurons, and transplantation of interneuron precursors from the MGE to elucidate relationships between reduced hippocampal GABA interneuron function and multiple psychosis-relevant phenotypes, and to explore a novel treatment strategy for psychosis.     

The clinical utility of the test of playfulness

Occupational therapists' increased focus on play as an occupation has created a need for play assessments that reflect this perspective. This study examined the clinical utility of the recently developed Test of Playfulness (ToP) (Bundy, 1997a) when used with children with disabilities. Changes in the participant's views of the child, the therapy goals, and the intervention plans after using the ToP were explored. Fourteen paediatric occupational therapists assessed children using the ToP, completed a clinical utility questionnaire and attended a focus group. Participants found the ToP easy to administer and score, however some found interpreting the results difficult. The ToP highlights the interactions between the Child, activity and environment, and illustrates the child's strengths in his/her role as a player. The results suggest the ToP is a useful tool for assessing playfulness. Additional education and research is needed to provide further direction for intervention and incorporation into practice.     

A survey of coronary risk factors and B-type natriuretic peptide concentrations in cardiac nurses from Europe: do nurses still practice what they preach?

BACKGROUND: From a previous survey of cardiac nurses attending a scientific conference, we learned that these nurses adopted a healthier lifestyle than the general population. AIMS: The aim of this study was to determine the overall profile of cardiac risk factors in a similar cohort and determine whether cardiac nurses continue to 'practice what they preach' in this regard. Secondly, we examined the practical value of screening a large cohort of individuals within a short time frame (total of 8 hours screening time) and determined the range of BNP concentrations within a 'healthy' cohort. METHODS: Data on CHD risk factors were collected with a short self-report questionnaire. The sample consisted of 122 cardiac nurses from 19 countries attending a European cardiac nursing conference held in Stockholm. A venous blood sample was collected into a tube containing potassium ETDA. B-type natriuretic peptide was measured on-site with the use of a portable fluorescence immunoassay kit. RESULTS: Most participants were female (89%). Participants ranged in age from 23 to 60 years with a mean age of 41 (S.D. 9.4). Eleven percent - all female - reported they were current smokers, 27% (34) had a BMI >25 and 27% of the sample stated they did not exercise regularly. Almost half (48%) of the sample reported a family history of CHD. As expected, all BNP-values were within the normal range. There were significant differences in BNP on the basis of sex (P<0.05) and age (P<0.05) and a trend towards increasing BNP concentrations with progressively higher BMI scores (P=0.06). CONCLUSION: This study reconfirms the likelihood that many cardiac nurses heed their own advice on lifestyle modification to reduce cardiovascular risk and therefore provide a good role model for the promotion of primary and secondary prevention initiatives.     

Pathological upstaging of clinical T1 renal cell carcinoma: an analysis of 115,835 patients from National Cancer Data Base, 2004–2013

Purpose

Clinical staging is vital for treatment decision-making by renal cell carcinoma (RCC) patients. Some RCCs clinically appear T1 on CT, but are actually T3a due to extension into fat or renal vein, causing the tumor to be pathologically upstaged. The objective of this study to determine the rate, survival, and predictors of RCC upstaging, for patients with cT1 disease treated surgically.

Methods

Using the National Cancer Data Base Participant User File for RCC from 2004 to 2013, we selected AJCC cT1 patients, who underwent surgical resection and whose AJCC pathological T stage (pT) was available. Upstaging was characterized dichotomously—overall (any pT > T1) and pT3a-specific upstaging. Patient and tumor characteristics of those upstaged and not were compared using Chi-squared analyses. Multivariable logistic regression was used to analyze predictors of upstaging, and Cox proportional hazards regression was used to estimate overall survival hazards ratios.

Results

Overall upstaging (pT > T1) was observed in 8252 (7.1%) patients, and T3a-specific upstaging was observed in 3380 (5.4%) patients. Patients who were older, male, and had comorbidities, and tumors that were cT1b, underwent RN, and had high Fuhrman grade were at a higher risk of pathological upstaging. Upstaging led to a 40% increased risk of death compared to patients who were not upstaged.

Conclusion

The rate of upstaging is not negligible (5–7% of the time), negatively impacts survival, and various patient and tumor characteristics can be used to predict upstaging.