Perillyl Alcohol Mitigates Behavioural Changes and Limits Cell Death and Mitochondrial Changes in Unilateral 6-OHDA Lesion Model of Parkinson's Disease Through Alleviation of Oxidative Stress.

In this study, we aim to assess the phytomedicinal potential of perillyl alcohol (PA), a dietary monoterpenoid, in a unilateral 6-hydroxydopamine (6-OHDA) lesion rat model of Parkinson's disease (PD). We observed that PA supplementation alleviated behavioural abnormalities such as loss of coordination, reduced rearing and motor asymmetry in lesioned animals. We also observed that PA-treated animals exhibited reduced oxidative stress, DNA fragmentation and caspase 3 activity indicating alleviation of apoptotic cell death. We found reduced mRNA levels of pro-apoptotic regulator BAX and pro-inflammatory mediators IL18 and TNFα in PA-treated animals. Further, PA treatment successfully increased mRNA and protein levels of Bcl2, mitochondrial biogenesis regulator PGC1α and tyrosine hydroxylase (TH) in lesioned animals. We observed that PA treatment blocked BAX and Drp1 translocation to mitochondria, an event often associated with the inception of apoptosis. Further, 6-OHDA exposure reduced expression of electron transport chain complexes I and IV, thereby disturbing energy metabolism. Conversely, expression levels of both complexes were upregulated with PA treatment in lesioned rats. Finally, we found that protein levels of Nrf2, the transcription factor responsible for antioxidant gene expression, were markedly reduced in cytosolic and nuclear fraction on 6-OHDA exposure, and PA increased expression of Nrf2 in both fractions. We believe that our data hints towards PA having the ability to provide cytoprotection in a hemiparkinsonian rat model through alleviation of motor deficits, oxidative stress, mitochondrial dysfunction and apoptosis.

Resistant and refractory hypertension: two sides of the same disease? / Hipertensão resistente e refratária: duas faces de uma mesma doença?

Abstract Refractory hypertension (RfH) is an extreme phenotype of resistant hypertension (RH), being considered an uncontrolled blood pressure besides the use of 5 or more antihypertensive medications, including a long-acting thiazide diuretic and a mineralocorticoid antagonist. RH is common, with 10-20% of the general hypertensives, and its associated with renin angiotensin aldosterone system hyperactivity and excess fluid retention. RfH comprises 5-8% of the RH and seems to be influenced by increased sympathetic activity. RH patients are older and more obese than general hypertensives. It is strongly associated with diabetes, obstructive sleep apnea, and hyperaldosteronism status. RfH is more frequent in women, younger patients and Afro-americans compared to RFs. Both are associated with increased albuminuria, left ventricular hypertrophy, chronic kidney diseases, stroke, and cardiovascular diseases. The magnitude of the white-coat effect seems to be higher among RH patients. Intensification of diuretic therapy is indicated in RH, while in RfH, therapy failure imposes new treatment alternatives such as the use of sympatholytic therapies. In conclusion, both RH and RfH constitute challenges in clinical practice and should be addressed as distinct clinical entities by trained professionals who are capable to identify comorbidities and provide specific, diversified, and individualized treatment.

Resumo A Hipertensão Arterial Refratária (HARf) representa um fenótipo extremo da hipertensão arterial resistente (HAR), sendo considerada a falência ao tratamento apesar do uso de 5 ou mais classes de anti-hipertensivos, incluindo um diurético tiazídico de longa ação e um antagonista mineralocorticoide. A HAR é comum (10-20%) entre os hipertensos em geral, sendo decorrente de hiperatividade do Sistema Renina Angiotensina Aldosterona e retenção hidrossalina. Aqueles com HARf correspondem a 5-8% dos resistentes e parecem sofrer maior influência catecolaminérgica. Os resistentes tendem a ter maior idade, ao sobrepeso e à obesidade. Comorbidades incluem diabetes, apneia obstrutiva do sono e status de hiperaldosteronismo. Refratários são afro-americanos em maior proporção, mais jovens e, predominantemente, mulheres. Ambos são fortemente associados à elevada albuminúria, HVE, doenças cardio e cerebrovasculares, além da doença renal crônica. O fenômeno do jaleco branco parece ser mais evidente nos resistentes. Quanto ao tratamento, a intensificação da terapia diurética está indicada nos resistentes, enquanto na HARf, a falência à terapia impôs novas alternativas de tratamento ("simpaticolíticas"). Em conclusão, tanto a HAR quanto a HARf constituem-se desafios na prática clínica e devem ser abordadas como entidades clínicas distintas por profissionais especialistas que identifiquem comorbidades e venham a prover um tratamento específico, diversificado e individualizado.

Quality of life improves in vasovagal syncope patients after clinical trial enrollment regardless of fainting in follow-up.

BACKGROUND: Frequent syncope is linked to poorer health-related quality of life (HRQoL). Recurrent syncope has been observed to reduce in all groups after seeing a syncope expert and enrolling in a clinical trial. It is unknown if HRQoL improves with this reduction in syncope recurrence. OBJECTIVES: We examined the change in HRQoL over time in vasovagal syncope (VVS) patients seen by a syncope expert and enrolled in a trial. We also explored whether change differed with treatment or the frequency of fainting during follow up. METHODS: The Short Form Health Survey (SF36) was completed at baseline (BL), 6 m, and 12 m post-enrollment by VVS patients in the 1st and 2nd Prevention of Syncope Trials, which were multi-centered, randomized, placebo-controlled trials of metoprolol (POST) and fludrocortisone (POST2). Differences in HRQoL at BL, 6 m, and 12 m were analyzed and compared by faints in follow-up and randomization group. RESULTS: Complete study data were available for 143 VVS patients (40 ±â€¯17 years, 62% F). Over 12 months, patients reported improvement in all SF36 dimensions except for bodily pain. Post hoc analyses indicated that differences first occurred between BL and 6 m for all but general health. Fainting in follow-up or drug randomization group did not diminish the improvements. The baseline syncope burden was not different whether patients' HRQoL improved or not. CONCLUSION: HRQoL of VVS patients improves over time after enrolling in a clinical trial, even with recurrent faints or randomization to placebo. Improvements may result from alternative factors, such as interaction with experts or patient adjustment.

Resistant and refractory hypertension: two sides of the same disease?

Refractory hypertension (RfH) is an extreme phenotype of resistant hypertension (RH), being considered an uncontrolled blood pressure besides the use of 5 or more antihypertensive medications, including a long-acting thiazide diuretic and a mineralocorticoid antagonist. RH is common, with 10-20% of the general hypertensives, and its associated with renin angiotensin aldosterone system hyperactivity and excess fluid retention. RfH comprises 5-8% of the RH and seems to be influenced by increased sympathetic activity. RH patients are older and more obese than general hypertensives. It is strongly associated with diabetes, obstructive sleep apnea, and hyperaldosteronism status. RfH is more frequent in women, younger patients and Afro-americans compared to RFs. Both are associated with increased albuminuria, left ventricular hypertrophy, chronic kidney diseases, stroke, and cardiovascular diseases. The magnitude of the white-coat effect seems to be higher among RH patients. Intensification of diuretic therapy is indicated in RH, while in RfH, therapy failure imposes new treatment alternatives such as the use of sympatholytic therapies. In conclusion, both RH and RfH constitute challenges in clinical practice and should be addressed as distinct clinical entities by trained professionals who are capable to identify comorbidities and provide specific, diversified, and individualized treatment.

Orexinergic neurons are involved in the chemosensory control of breathing during the dark phase in a Parkinson's disease model.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra compacta (SNpc) and the only risk factor is aging. We showed that in 6-hydroxydopamine (6-OHDA)-model of PD there is a reduction in the neuronal profile within the brainstem ventral respiratory column with a decrease in the hypercapnic ventilatory response. Here we tested the involvement of orexin cells from the lateral hypothalamus/perifornical area (LH/PeF) on breathing in a 6-OHDA PD model. In this model of PD, there is a reduction in the total number of orexinergic neurons and in the number of orexinergic neurons that project to the RTN, without changing the number of CO2-activated orexinergic neurons during the dark phase. The ventilation at rest and in response to hypercapnia (7% CO2) was assessed in animals that received 6-OHDA or vehicle injections into the striatum and saporin anti-Orexin-B or IgG saporin into the LH/PeF during the sleep and awake states. The experiments showed a reduction of respiratory frequency (fR) at rest during the light phase in PD animals only during sleep. During the dark phase, there was an impaired fR response to hypercapnia in PD animals with depletion of orexinergic neurons in awake and sleeping rats. In conclusion, the degeneration of orexinergic neurons in this model of PD can be related to impaired chemoreceptor function in the dark phase.

Targeting multiple pathways reduces renal and cardiac fibrosis in rats with subtotal nephrectomy followed by coronary ligation.

AIM: Multiple interacting pathways contribute to progression of renal and cardiac damage in chronic kidney disease followed by chronic heart failure (renocardiac syndrome). We hypothesized that simultaneous pharmacological modulation of critical pathways implicated in renocardiac syndrome would effectively reduce fibrosis in and preserve function of heart and kidney. METHODS: Rats were subjected to subtotal nephrectomy followed 9 weeks later by coronary artery ligation. From week 11 until week 16, rats received vehicle or losartan, or a combination of the NF-kB inhibitor PDTC, the NO donor molsidomine and superoxide dismutase mimetic tempol, or a combination of all four of these plus metoprolol together. At week 16, renal and cardiac structure, function and gene expression were assessed. RESULTS: Individual and combined treatments were similarly effective in limiting cardiac fibrosis and further decline in systolic function. Combined treatment with all five drugs reduced renal fibrosis and CTGF gene expression more effectively than other strategies. Combining all five drugs reduced heart rate, inotropy and mean arterial pressure (MAP). CONCLUSION: Thus, in our model of chronic renocardiac syndrome, combined treatments similarly decreased cardiac fibrosis and stabilized systolic function as losartan alone, perhaps suggesting a dominant role for a single factor such as angiotensin II type 1 (AT1) receptor activation or inflammation in the network of aberrant systems in the heart. However, tubulointerstitial fibrosis was most effectively reduced by a five-drug regimen, pointing to additive effects of multiple pathophysiological pathways in the kidney.

Effects of in vitro, acute and chronic treatment with fluoxetine on the sympathetic neurotransmission of rat vas deferens.

It is described that fluoxetine treatment is able to induce ejaculatory disorders. However, the exact mechanism is still not fully understood. Therefore, this study was carried out to further evaluate the anti-ejaculatory effects of fluoxetine, using different approaches (in vitro or in vivo treatments), on the sympathetic neurotransmission of the rat vas deferens. Vas deferens from male Wistar rats were used to check the in vitro effects of fluoxetine 10-6M, 3.10-6M or 10-5M. Animals were also acutely (20mg/kg, i.p. 4h or 24h) or chronically (10mg/kg, i.p., 30days) treated with fluoxetine or drug-free vehicle. The vas deferens from non-treated and treated animals were isolated and mounted in an isolated organ bath for the study of the contractions induced by adrenergic agonists, tyramine, 5-HT, Ca2+ or electrical field stimulation. In vitro or acute treatment with fluoxetine decreased the contraction induced by agonists, Ca2+ or electrical field stimulation. The chronic treatment with fluoxetine decreased the contractions induced agonists, tyramine or Ca2+, but did not modify the contractions induced by electrical field stimulation. We have shown that in vitro or in vivo fluoxetine treatment is able to alter the sympathetic neurotransmission of the rat vas deferens which could be related to alterations in the calcium signalling.

The Role of Group II Metabotropic Glutamate Receptors in the Striatum in Electroacupuncture Treatment of Parkinsonian Rats.

AIMS: Glutamatergic transmission may play a critical role in the pathogenesis of Parkinson's disease (PD). Electroacupuncture (EA) has been demonstrated to effectively alleviate PD symptoms. In this study, a potential glutamate-dependent mechanism underlying the therapeutic action of EA was investigated. METHODS: The effects of EA stimulation on motor behaviors, dopamine contents, glutamate release, and group II metabotropic glutamate receptor (mGluR2/3) expression in unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats were examined. RESULTS: Unilateral 6-OHDA lesions of the nigrostriatal system caused a marked increase in glutamate content in the ipsilateral cortex and striatum. mGluR2/3 protein expression and mGluR3 mRNA expression were reduced in the striatum. Noticeably, prolonged EA stimulation at 100 Hz significantly reversed these changes in the striatal glutamate system. Behaviorally, EA improved the motor deficits induced by 6-OHDA lesions. Intrastriatal infusion of an mGluR2/3 antagonist APICA blocked the improving effect of EA. CONCLUSIONS: These data collectively demonstrate that the group II mGluR-mediated glutamatergic transmission in the striatum is sensitive to dopamine depletion and may serve as a substrate of EA for mediating the therapeutic effect of EA in a rat model of PD.

The Role of Primary Motor Cortex (M1) Glutamate and GABA Signaling in l-DOPA-Induced Dyskinesia in Parkinsonian Rats.

UNLABELLED: Long-term treatment of Parkinson's disease with l-DOPA almost always leads to the development of involuntary movements termed l-DOPA-induced dyskinesia. Whereas hyperdopaminergic signaling in the basal ganglia is thought to cause dyskinesia, alterations in primary motor cortex (M1) activity are also prominent during dyskinesia, suggesting that the cortex may represent a therapeutic target. The present study used the rat unilateral 6-hydroxydopamine lesion model of Parkinson's disease to characterize in vivo changes in GABA and glutamate neurotransmission within M1 and determine their contribution to behavioral output. 6-Hydroxydopamine lesion led to parkinsonian motor impairment that was partially reversed by l-DOPA. Among sham-lesioned rats, l-DOPA did not change glutamate or GABA efflux. Likewise, 6-hydroxydopamine lesion did not impact GABA or glutamate among rats chronically treated with saline. However, we observed an interaction of lesion and treatment whereby, among lesioned rats, l-DOPA given acutely (1 d) or chronically (14-16 d) reduced glutamate efflux and enhanced GABA efflux. Site-specific microinjections into M1 demonstrated that l-DOPA-induced dyskinesia was reduced by M1 infusion of a D1 antagonist, an AMPA antagonist, or a GABAA agonist. Overall, the present study demonstrates that l-DOPA-induced dyskinesia is associated with increased M1 inhibition and that exogenously enhancing M1 inhibition may attenuate dyskinesia, findings that are in agreement with functional imaging and transcranial magnetic stimulation studies in human Parkinson's disease patients. Together, our study suggests that increasing M1 inhibitory tone is an endogenous compensatory response designed to limit dyskinesia severity and that potentiating this response is a viable therapeutic strategy. SIGNIFICANCE STATEMENT: Most Parkinson's disease patients will receive l-DOPA and eventually develop hyperkinetic involuntary movements termed dyskinesia. Such symptoms can be as debilitating as the disease itself. Although dyskinesia is associated with dynamic changes in primary motor cortex physiology, to date, there are no published studies investigating in vivo neurotransmitter release in M1 during dyskinesia. In parkinsonian rats, l-DOPA administration reduced M1 glutamate efflux and enhanced GABA efflux, coincident with the emergence of dyskinetic behaviors. Dyskinesia could be reduced by local M1 modulation of D1, AMPA, and GABAA receptors, providing preclinical support for the notion that exogenously blunting M1 signaling (pharmacologically or with cortical stimulation) is a therapeutic approach to the treatment of debilitating dyskinesias.

α-Terpineol Induces Gastric Retention of Liquids by Inhibiting Vagal Parasympathetic Pathways in Rats.

α-Terpineol is a monoterpene with smooth muscle relaxant properties. In this study, its effects on the gastric emptying rate of awake rats were evaluated with emphasis on the mode by which it induces gastrointestinal actions. Administered by gavage, α-terpineol (50 mg/kg) delayed gastric emptying of a liquid test meal at 10 min postprandial. Hexamethonium or guanethidine did not interfere with the retarding effect induced by α-terpineol, but atropine and L-NG-nitroarginine methyl ester abolished it. In vagotomized rats, α-terpineol did not delay gastric emptying. In isolated strips of gastric fundus, concentration-effect curves in response to carbamylcholine were higher in magnitude after treatment with the monoterpene. α-Terpineol (1 to 2000 µM) relaxed sustained contractions induced by carbamylcholine or a high K+ concentration in a concentration-dependent manner. This relaxing effect was not affected by the presence of L-NG-nitroarginine methyl ester, 1 H-[1, 2, 4]oxadiazolo[4,3-a]quinoxalin-1-one, tetraethylammonium, or atropine. Smooth muscle contractions induced by electrical field stimulation were inhibited by α-terpineol. In conclusion, α-terpineol induced gastric retention in awake rats through mechanisms that depended on intact vagal innervation to the stomach, which involved cholinergic/nitrergic signalling. Such a retarding effect induced by α-terpineol appears not to result from a direct action of the monoterpene on gastric smooth muscle cells.

ENDOCRINE DILEMMA: Managing menopausal symptoms after breast cancer.

Managing the symptoms of menopause after a diagnosis of breast cancer offers some unique clinical challenges. For some women, vasomotor symptoms can be severe and debilitating, and hormone therapy is at least relatively contraindicated. Non-oestrogen therapies for hot flushes include SSRIs, clonidine, gabapentin and perhaps black cohosh extracts. Vulvovaginal atrophy can usually be alleviated by simple moisturizers, although some may need specialized physiotherapy such as vaginal dilators. In a small number, topical oestrogens may be the only treatment that works. The CO2 laser may be a novel, non-oestrogen therapy to alleviate this unpleasant symptom. Bone loss can be accelerated in some patients on AIs or those who had early menopause induced by chemotherapy.

Management of sleep bruxism in adults: a qualitative systematic literature review.

This paper updates the bruxism management review published by Lobbezoo et al. in 2008 (J Oral Rehabil 2008; 35: 509-23). The review focuses on the most recent literature on management of sleep bruxism (SB) in adults, as diagnosed with polysomnography (PSG) with audio-video (AV) recordings, or with any other approach measuring the sleep-time masticatory muscles' activity, viz., PSG without AV recordings or electromyography (EMG) recorded with portable devices. Fourteen (N = 14) papers were included in the review, of which 12 were randomised controlled trials (RCTs) and 2 were uncontrolled before-after studies. Structured reading of the included articles showed a high variability of topics, designs and findings. On average, the risk of bias for RCTs was low-to-unclear, whilst the before-after studies had several methodological limitations. The studies' results suggest that (i) almost every type of oral appliance (OA) (seven papers) is somehow effective to reduce SB activity, with a potentially higher decrease for devices providing large extent of mandibular advancement; (ii) all tested pharmacological approaches [i.e. botulinum toxin (two papers), clonazepam (one paper) and clonidine (one paper)] may reduce SB with respect to placebo; (iii) the potential benefit of biofeedback (BF) and cognitive-behavioural (CB) approaches to SB management is not fully supported (two papers); and (iv) the only investigation providing an electrical stimulus to the masseter muscle supports its effectiveness to reduce SB. It can be concluded that there is not enough evidence to define a standard of reference approach for SB treatment, except for the use of OA. Future studies on the indications for SB treatment are recommended.

Facile and rapid generation of 3D chemical gradients within hydrogels for high-throughput drug screening applications.

We propose a novel application of dielectrophoresis (DEP) to make three-dimensional (3D) methacrylated gelatin (GelMA) hydrogels with gradients of micro- and nanoparticles. DEP forces were able to manipulate micro- and nanoparticles of different sizes and materials (i.e., C2C12 myoblasts, polystyrene beads, gold microparticles, and carbon nanotubes) within GelMA hydrogels in a rapid and facile way and create 3D gradients of these particles in a microchamber. Immobilization of drugs, such as fluorescein isothiocyanate-dextran (FITC-dextran) and 6-hydroxydopamine (6-OHDA), on gold microparticles allowed us to investigate the high-throughput release of these drugs from GelMA-gold microparticle gradient systems. The latter gradient constructs were incubated with C2C12 myoblasts for 24h to examine the cell viability through the release of 6-OHDA. The drug was released from the microparticles in a gradient manner, inducing a cell viability gradient. This novel approach to create 3D chemical gradients within hydrogels is scalable to any arbitrary length scale. It is useful for making anisotropic biomimetic materials and high-throughput platforms to investigate cell-microenvironment interactions in a rapid, simple, cost-effective, and reproducible manner.

Switching ability of over trained movements in a Parkinson's disease rat model.

Patients with Parkinson's disease show unbalanced capability to manage self-paced vs externally driven movements, or automatic-associated movements with respect to the intended voluntary movements. We studied the effect of a selective loss of dopaminergic terminals within the striatum and the execution of a well-learned set-shifting task as revealed using tyrosine hydroxylase immunoreactivity and magnetic resonance imaging in the rat. We found that, both in the externally cued condition, and in the externally-internally driven switching task, the cue-dependent constraints interfered with motor readiness in over training condition. The unilateral dopaminergic striatal depletion enhanced the switch-induced performance differences in favour of the internally-externally cued transition. Dopamine depleted rats, in fact, were impaired to produce an alternative motion when task switching required to change from an over trained behaviour, towards an alternative self-paced response. The comparative analysis of behavioural, tyrosine hydroxylase immunoreactivity and magnetic resonance imaging data, revealed a shrinkage of the lesioned striatum, and an enlargement of the ipsilateral ventricle that could provide useful markers for monitoring pathological changes occurring during early stages of Parkinson's disease in vivo.

Reduction of motor disorder in 6-OHDA-induced severe parkinsonism rats by post treatment with granulocyte-colony stimulating factor.

Granulocyte-colony stimulating factor (G-CSF) induced regeneration of dopaminergic neurons and improved behavior deficit in moderate Parkinson's disease (PD) model mice. Post treatment of G-CSF in severe PD model has not been addressed. A very severe PD model in rats was induced by a high dose 6-hydroxydopamine (6-OHDA) injected into the right medial forebrain bundle to evaluate therapeutic effects of G-CSF. G-CSF (50 microg/kg/day for five days) was given on the 9th day after the 6-OHDA injection. Rotational behavior was examined on the 9th and 28th days. Rats were killed on the 28th day and survival dopaminergic neurons in the substantia nigra, dopaminergic axons and dopaminergic receptor 2 in the striatum were examined. We, for the first time, demonstrated that post treatment with G-CSF reduced abnormal rotational behavior and increased the lesion to non-lesion ratio of dopaminergic fibers in the striatum, but the treatment promoted neither the increase in survival dopaminergic neurons nor the increase in dopaminergic receptor 2 expression. We conclude that post treatment with G-CSF can reduce the abnormal rotational behavior of severe PD rats primarily through relative increases in dopaminergic fibers of the lesion side in the striatum. Results of our study suggest therapeutic potentials of G-CSF for treating severe PD patients.

Interventions for treating pain and disability in adults with complex regional pain syndrome.

BACKGROUND: There is currently no strong consensus regarding the optimal management of complex regional pain syndrome although a multitude of interventions have been described and are commonly used. OBJECTIVES: To summarise the evidence from Cochrane and non-Cochrane systematic reviews of the effectiveness of any therapeutic intervention used to reduce pain, disability or both in adults with complex regional pain syndrome (CRPS). METHODS: We identified Cochrane reviews and non-Cochrane reviews through a systematic search of the following databases: Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects (DARE), Ovid MEDLINE, Ovid EMBASE, CINAHL, LILACS and PEDro. We included non-Cochrane systematic reviews where they contained evidence not covered by identified Cochrane reviews. The methodological quality of reviews was assessed using the AMSTAR tool.We extracted data for the primary outcomes pain, disability and adverse events, and the secondary outcomes of quality of life, emotional well being and participants' ratings of satisfaction or improvement. Only evidence arising from randomised controlled trials was considered. We used the GRADE system to assess the quality of evidence. MAIN RESULTS: We included six Cochrane reviews and 13 non-Cochrane systematic reviews. Cochrane reviews demonstrated better methodological quality than non-Cochrane reviews. Trials were typically small and the quality variable.There is moderate quality evidence that intravenous regional blockade with guanethidine is not effective in CRPS and that the procedure appears to be associated with the risk of significant adverse events.There is low quality evidence that bisphosphonates, calcitonin or a daily course of intravenous ketamine may be effective for pain when compared with placebo; graded motor imagery may be effective for pain and function when compared with usual care; and that mirror therapy may be effective for pain in post-stroke CRPS compared with a 'covered mirror' control. This evidence should be interpreted with caution. There is low quality evidence that local anaesthetic sympathetic blockade is not effective. Low quality evidence suggests that physiotherapy or occupational therapy are associated with small positive effects that are unlikely to be clinically important at one year follow up when compared with a social work passive attention control.For a wide range of other interventions, there is either no evidence or very low quality evidence available from which no conclusions should be drawn. AUTHORS' CONCLUSIONS: There is a critical lack of high quality evidence for the effectiveness of most therapies for CRPS. Until further larger trials are undertaken, formulating an evidence-based approach to managing CRPS will remain difficult.

High frequency electro-acupuncture enhances striatum DAT and D1 receptor expression, but decreases D2 receptor level in 6-OHDA lesioned rats.

The direct effects of electro-acupuncture (EA) on the dopaminergic neurotransmitter system in Parkinson's disease (PD) patients remain elusive. In the present study, 0, 2 or 100Hz EA was applied to acupoints Sanyinjiao (SP6), Yanglingquan (GB34) and Zusanli (ST36) in a rat model unilaterally lesioned by 6-hydroxydopamine. Rotational behavior tests were performed and the animals were then decapitated. Levels of striatal dopamine (DA), dopamine transporter, and D1- and D2-like DA receptors were subsequently evaluated. EA at 100 Hz was shown to significantly enhance survival of dopaminergic neurons in the substantia nigra (52.10 ± 11.41% of the level on the non-lesioned rats vs. 21.22 ± 5.52% in the non-EA group, P<0.05) and reduce motor deficits (207.80 ± 31.14 vs. 476.11 ± 68.80 turns/30 min, P<0.05), whereas it only slightly restored the 6-hydroxydopamine-induced loss of striatal DA (P>0.05 vs. the non-EA group). There was a 253.78% increase in dopamine transporter protein expression in the striatum in the 100 Hz EA group (P<0.05 vs. the non-EA group). Moreover, high frequency EA induced increases in striatal D1-like receptor mRNA and protein levels of 81.88% and 62.62%, respectively (P<0.001 and P<0.05 vs. the non-EA group). However, the D2-like DA receptor up-regulation observed in the non-EA group was suppressed in high frequency group (P>0.05 vs. the sham operation group). These findings suggest that high-frequency EA might work by acting on presynaptic dopamine transporter and postsynaptic dopamine receptors simultaneously to achieve a therapeutic effect in PD patients and models. This might shed some light on the mechanism by which EA affects the DA neurotransmitter system.

Pharmacological prevention of combat-related PTSD: a literature review.

Preventing posttraumatic stress disorder (PTSD) could have a significant positive impact on military readiness and quality of life. Few studies have examined whether pharmacological agents may prevent PTSD, and there has not been a systematic and critical review of these studies in order to guide future research efforts. We performed a literature review of articles examining the use of pharmacological agents for the prevention of PTSD. A total of 27 articles met inclusion criteria for the review and their results are summarized. The review points to corticosteroids and propranolol as the most promising agents for future research. Gamma-Amino butyric acid mimetic drugs received the least support. Complementary approaches using psychotherapy and pharmacological agents could also yield good results. Research aimed at determining the potential efficacy of these agents could start being carried out in the field with smaller numbers of personnel that has not been personally injured but have witnessed traumatic events. In addition, psychological interventions immediately after postdeployment could be used in large numbers of soldiers. Preliminary studies regarding the use of pharmacologic agents for the secondary prevention of PTSD are promising. However, much larger studies are needed before implementation in generalized practice.

Deep brain stimulation of the subthalamic nucleus in the 6-hydroxydopamine rat model of Parkinson's disease: effects on sensorimotor gating.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is effectively used to treat motor symptoms in Parkinson's disease (PD). Recently more attention has been paid to behavioral disturbances caused by PD itself and by STN DBS. In the 6-hydroxydopamine (6-OHDA) PD rat model we investigated the effect of STN DBS on deficient prepulse inhibition (PPI) induced by the dopamine (DA) receptor agonist apomorphine, which is an operative measure for disturbed sensorimotor gating seen in certain neuropsychiatric disturbances. Male Sprague Dawley rats with bilateral lesions of the nigrostriatal DA system (striatal injection of 6-OHDA or vehicle for sham-lesion) were bilaterally implanted with electrodes for DBS into the STN. After determination of individual thresholds rats were stimulated (130Hz, 80µs pulse width) or sham-stimulated for epochs of six days. On the sixth day of each epoch rats were tested for PPI of the acoustic startle response after apomorphine or vehicle injection in a within randomized cross-over design. Stimulation of the STN improved PPI in vehicle-treated (control) rats, but deteriorated PPI after apomorphine treatment. This effect was more pronounced in sham-lesioned rats. Furthermore, in lesioned rats the startle reaction was marginally enhanced without effect of stimulation or apomorphine treatment. These data suggest that STN DBS interacts with dopaminergic action. With respect to functional neurosurgery, STN DBS alone may improve certain aspects of psychiatric disturbances, but may have a different impact when combined with dopaminergic medication.

Complex fractionated electrograms in the right atrial free wall and the superior/posterior wall of the left atrium are affected by activity of the autonomic nervous system.

BACKGROUND: Complex fractionated atrial electrograms (CFAEs) are supposed to be related to structural and electrical remodeling. Animal studies suggest a role of the autonomic nervous system (ANS). However, this has never been studied in humans. OBJECTIVE: The goal of this study was to investigate the influence of ANS on CFAEs in patients with idiopathic atrial fibrillation (AF). METHODS: Thirty-six patients (28 men, 55 ± 9 years) were included before undergoing catheter ablation. In the 24 hours preceding the procedure, 20 patients were in AF (group 1) and 16 were in sinus rhythm (SR, group 2). With 2 decapolar catheters, 1 in the right atrium (RA) and 1 in the left atrium (LA), 20 unipolar electrograms were simultaneously recorded during a 100-second AF-period (in group 2 after induction of AF). After atropine and metoprolol administration, a second 100-second AF-period was recorded 30 minutes later. Five patients of group 2 served as controls and did not receive atropine and metoprolol prior to the second recording. CFAEs were assessed and the prevalence of CFAEs was expressed as percentage of the recording time. RESULTS: The prevalence of CFAEs was greater in group 1 than in group 2 in both RA and LA (P = 0.026, P < 0.001, respectively). Atropine and metoprolol significantly reduced CFAEs in group 1 (P < 0.001) and prevented the time-dependent increase of CFAEs in group 2. CONCLUSION: The prevalence of CFAEs is greater in long-lasting AF episodes. Atropine and metoprolol administration reduces CFAEs in both atria. Thus, CFAEs are at least partly influenced by the ANS.