[18F]fallypride-PET/CT Analysis of the Dopamine D2/D3 Receptor in the Hemiparkinsonian Rat Brain Following Intrastriatal Botulinum Neurotoxin A Injection.

Intrastriatal injection of botulinum neurotoxin A (BoNT-A) results in improved motor behavior of hemiparkinsonian (hemi-PD) rats, an animal model for Parkinson's disease. The caudate-putamen (CPu), as the main input nucleus of the basal ganglia loop, is fundamentally involved in motor function and directly interacts with the dopaminergic system. To determine receptor-mediated explanations for the BoNT-A effect, we analyzed the dopamine D2/D3 receptor (D2/D3R) in the CPu of 6-hydroxydopamine (6-OHDA)-induced hemi-PD rats by [18F]fallypride-PET/CT scans one, three, and six months post-BoNT-A or -sham-BoNT-A injection. Male Wistar rats were assigned to three different groups: controls, sham-injected hemi-PD rats, and BoNT-A-injected hemi-PD rats. Disease-specific motor impairment was verified by apomorphine and amphetamine rotation testing. Animal-specific magnetic resonance imaging was performed for co-registration and anatomical reference. PET quantification was achieved using PMOD software with the simplified reference tissue model 2. Hemi-PD rats exhibited a constant increase of 23% in D2/D3R availability in the CPu, which was almost normalized by intrastriatal application of BoNT-A. Importantly, the BoNT-A effect on striatal D2/D3R significantly correlated with behavioral results in the apomorphine rotation test. Our results suggest a therapeutic effect of BoNT-A on the impaired motor behavior of hemi-PD rats by reducing interhemispheric changes of striatal D2/D3R.

The Cuprizone Model: Dos and Do Nots.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. Various pre-clinical models with different specific features of the disease are available to study MS pathogenesis and to develop new therapeutic options. During the last decade, the model of toxic demyelination induced by cuprizone has become more and more popular, and it has contributed substantially to our understanding of distinct yet important aspects of the MS pathology. Here, we aim to provide a practical guide on how to use the cuprizone model and which pitfalls should be avoided.

Continuous Blood Sampling in Small Animal Positron Emission Tomography/Computed Tomography Enables the Measurement of the Arterial Input Function.

For quantitative analysis and bio-kinetic modeling of positron emission tomography/computed tomography (PET/CT) data, the determination of the temporal blood time-activity concentration also known as arterial input function (AIF) is a key point, especially for the characterization of animal disease models and the introduction of newly developed radiotracers. The knowledge of radiotracer availability in the blood helps to interpret PET/CT-derived data of tissue activity. For this purpose, online blood sampling during the PET/CT imaging is advisable to measure the AIF. In contrast to manual blood sampling and image-derived approaches, continuous online blood sampling has several advantages. Besides the minimized blood loss, there is an improved resolution and a superior accuracy for the blood activity measurement. However, the major drawback of online blood sampling is the costly and time-consuming preparation to catheterize the femoral vessels of the animal. Here, we describe an easy and complete workflow for catheterization and continuous blood sampling during small animal PET/CT imaging and compared it to manual blood sampling and an image-derived approach. Using this highly-standardized workflow, the determination of the fluorodeoxyglucose ([18F]FDG) AIF is demonstrated. Further, this procedure can be applied to any radiotracer in combination with different animal models to create fundamental knowledge of tracer kinetic and model characteristics. This allows a more precise evaluation of the behavior of pharmaceuticals, both for diagnostic and therapeutic approaches in the preclinical research of oncological, neurodegenerative and myocardial diseases.

The state of health economic and pharmacoeconomic evaluation research in Zimbabwe: A review.

BACKGROUND: Economic evaluation of health care has developed into a substantial body of work, and its contribution to medical decision making is increasingly being recognized. OBJECTIVE: The aim of the study was to describe the characteristics and quality of health economic (including pharmacoeconomic) evaluation research studies related to Zimbabwe. METHODS: A review of the literature was conducted to identify published health economic evaluation studies related to Zimbabwe. HEED, PubMed, MEDLINE, HealthSTAR, EconLit, and PsycINFO databases and sociological and dissertation abstracts were used to search for economic analyses. The searches used the following terms alone and in combination: costs, budgets, fee, economics, health, pharmacy, pharmacy services, medicines, drugs, health economics, cost-effectiveness, cost-benefit, cost-minimization, cost utility analysis, and Zimbabwe. Only original applied economic evaluations addressing a health-related topic pertaining to Zimbabwe and published in full were included. Two reviewers independently evaluated and scored each study in the final sample using the data collection form designed for the study. RESULTS: Fifty-nine studies were identified in the database searches, 18 of which were excluded because they were not about Zimbabwe (3 studies) or were not health related (15). Of the 41 remaining studies, 8 were excluded after further review because they were not original research, 6 because they were not economic analyses, and 1 because it was not about Zimbabwe. The final 26 studies appeared in 13 different journals (based mostly [17 (65%)] outside of Zimbabwe). The mean (SD) number of authors of each study was 3.36 (2.13); most of the authors had medical/clinical training. The number of studies peaked between 1994 and 1997. Based on a 10-point scale, with 10 indicating the highest quality, the mean (SD) quality score for all studies was 5.40 (1.56); 8 of the studies (31%) were considered to be of poor quality (score ≤4). The quality of the studies reviewed was significantly (all, P < 0.05) associated with the country in which the journal was based (non-Zimbabwe = higher), the primary health intervention (services>pharmaceutical interventions), the number of authors (more authors = higher), and year of publication (more recent = higher). CONCLUSION: This study indicated that the use of health economic (including pharmacoeconomic) evaluation research in Zimbabwe was low, and 31 % of the studies were of poor quality. More and better quality health economic research in Zimbabwe is warranted.

Unilateral Botulinum Neurotoxin-A Injection into the Striatum of C57BL/6 Mice Leads to a Different Motor Behavior Compared with Rats.

Different morphological changes in the caudate-putamen (CPu) of naïve rats and mice were observed after intrastriatal botulinum neurotoxin-A (BoNT-A) injection. For this purpose we here studied various motor behaviors in mice (n = 46) longitudinally up to 9 months after intrastriatal BoNT-A administration as previously reported for rats, and compared both outcomes. Apomorphine- and amphetamine-induced rotational behavior, spontaneous motor behavior, as well as lateralized neglect were studied in mice after the injection of single doses of BoNT-A into the right CPu, comparing them with sham-injected animals. Unilateral intrastriatal injection of BoNT-A in mice induced significantly increased contralateral apomorphine-induced rotations for 1 to 3 months, as well as significantly increased contralateral amphetamine-induced rotations 1 to 9 months after injection. In rats (n = 28), unilateral BoNT-A injection also induced significantly increased contralateral apomorphine-induced rotations 3 months after injection, but did not provoke amphetamine-induced rotations at all. Lateralized sensorimotor integration, forelimb preference, and forelimb stepping were significantly impaired on the left side. The differences in motor behaviors between rats and mice may be caused by different BoNT-A effects on cholinergic and catecholaminergic fibers in rat and mouse striata, interspecies differences in striatal receptor densities, and different connectomes of the basal ganglia.

Acetylcholine Neurotransmitter Receptor Densities in the Striatum of Hemiparkinsonian Rats Following Botulinum Neurotoxin-A Injection.

Cholinergic neurotransmission has a pivotal function in the caudate-putamen, and is highly associated with the pathophysiology of Parkinson's disease. Here, we investigated long-term changes in the densities of the muscarinic receptor subtypes M1, M2, M3 (mAchRs) and the nicotinic receptor subtype α4ß2 (nAchRs) in the striatum of the 6-OHDA-induced hemiparkinsonian (hemi-PD) rat model using quantitative in vitro receptor autoradiography. Hemi-PD rats exhibited an ipsilateral decrease in striatal mAchR densities between 6 and 16%. Moreover, a massive and constant decrease in striatal nAchR density by 57% was found. A second goal of the study was to disclose receptor-related mechanisms for the positive motor effect of intrastriatally injected Botulinum neurotoxin-A (BoNT-A) in hemi-PD rats in the apomorphine rotation test. Therefore, the effect of intrastriatally injected BoNT-A in control and hemi-PD rats on mAchR and nAchR densities was analyzed and compared to control animals or vehicle-injected hemi-PD rats. BoNT-A administration slightly reduced interhemispheric differences of mAchR and nAchR densities in hemi-PD rats. Importantly, the BoNT-A effect on striatal nAchRs significantly correlated with behavioral testing after apomorphine application. This study gives novel insights of 6-OHDA-induced effects on striatal mAchR and nAchR densities, and partly explains the therapeutic effect of BoNT-A in hemi-PD rats on a cellular level.

A picture is worth more than a thousand words: enhancement of a pre-exam telephone consultation in dermatology with digital images.

OBJECTIVE: In addition to the assessment and the management of patients with skin diseases, a considerable portion of dermatology residency involves examining clinical images and generating differential diagnoses from these images. This training, though helpful for recognizing manifestations of rare disorders, goes unused by most practicing dermatologists after certification. In contrast, dermatology residents learn and master verbal descriptions of skin diseases and continue to use this skill throughout their careers. However, problems arise when a dermatologist is not available and a non-dermatologist attempts to verbally describe a skin condition. An accurate description of a cutaneous disorder can facilitate effective triage management of a patient when a dermatologist is not available. Unfortunately, an inaccurate description by the referring provider can lead to diagnostic bias and ineffective, or even harmful, initial treatment. In recent years, digital photography has facilitated the electronic transfer of clinical images over distances. However, despite the promise that this technique shows in providing teledermatologic services to specialty-underserved areas and the availability of low-cost digital cameras, telephone consultation is still the standard of care when a dermatologist is not available. The purpose of this study is to compare the reliability of dermatologic consultations that use the telephone with that of dermatologic consultations that use both the telephone and digital images. DESCRIPTION: After patient approval, an acute care provider randomly assigned patients with skin disorders of unclear etiology to two groups, with and without digital images. The acute care provider then performed an exam and took the patient's history. Telephone data, with or without digital images, were then presented to the consulting dermatologist, who formulated a pre-physical exam differential diagnosis and treatment plan. The consulting dermatologist immediately examined the patient in person and refined the diagnosis and management. The confidence in diagnosis, both before and after the in-person exam, was compared in the patient group with digital images and in the patient group without digital images using a five-point scale (1 = no confidence, 5 = most confident). DISCUSSION: The consulting dermatologist evaluated 12 patients (six with digital images and six without digital images). In the patient group with digital images, the consulting dermatologist's confidence in diagnosis varied very little from before to after the in-person exam (from no change in five cases to a one-point increase in the sixth case). In the patient group without digital images, the consulting dermatologist's confidence level increased significantly from before to after the in-person exam. This led to therapy changes for three of the six patients in the patient group without digital images, versus two of the six patients in the patient group with digital images. This study indicates that an acute care provider's verbal description of a skin condition may be less reliable compared with a provider's verbal description combined with digital images. Telephone-only descriptions may also lead to management discrepancies more frequently than telephone descriptions with digital images. This has at least two implications for medical education: (1) need for support of formal teaching of the language of dermatology to non-dermatologists and (2) justification of the time spent in two-dimensional clinical image interpretation by dermatology residents in light of digital image technology.

Effects of antiepileptic drug substitutions on epileptic events requiring acute care.

STUDY OBJECTIVES: To determine the odds of antiepileptic drug substitution among patients who had an epileptic event requiring acute care-ambulance service, emergency department visit, or hospitalization-relative to patients who did not have an event, and to compare these results with those from a recent study involving a similar method but different patients. DESIGN: Case-control analysis. DATA SOURCE: United States health care claims from the PharMetrics database. PATIENTS: A cohort of patients aged 12-64 years with a primary diagnosis of epilepsy between October 1, 2005, and December 31, 2006; 991 cases (patients who experienced an epileptic event requiring acute care) and 2973 controls (patients who did not have an event) were matched in a 1:3 ratio for sex, age, and type of epilepsy. MEASUREMENTS AND MAIN RESULTS: Using discordant pairs analysis, we calculated the odds ratio of an epileptic event that required acute care occurring in patients whose antiepileptic drug underwent substitution to an A-rated (therapeutically equivalent) alternative (switch from branded product to generic, generic to branded, or generic to generic) versus those whose drugs were not substituted. For matched data, 109 (11.0%) of 991 cases had an A-rated antiepileptic drug substitution in the 6 months before the event, whereas only 186 (6.3%) of 2973 controls had a substitution (odds ratio 1.84, 95% confidence interval 1.44-2.36). Our results were similar to those of a previous study involving a different patient database, which showed substitution rates of 11.3% for cases versus 6.5% for controls (odds ratio 1.81, 95% confidence interval 1.25-2.63). Our sensitivity analyses were robust, and we found a temporal relationship in that numerous substitutions occurred in the month before the acute event. CONCLUSION: Patients who had an epileptic event requiring acute care were about 80% more likely than matched controls without an acute event to have recently had an antiepileptic drug substitution. Our replication of a previously published case-control analysis revealed a similar association between substitution involving A-rated antiepileptic drugs and subsequent epileptic events requiring acute care, thereby lending credibility to the findings.