Abdullah Mosabbir

Association of pain, Parkinson's disease, and restless legs syndrome

BACKGROUND Many patients with restless legs syndrome (RLS) and Parkinsons disease (PD) report having pain, however, the impact of the combination of PD and RLS on pain has not been analyzed extensively. The objective of this study was to explore the potential relationship between RLS and pain in individuals with and without PD, the prevalence of RLS in PD, the prevalence and severity of pain in PD and RLS, and how these measures are related to PD patients and controls. METHODS The study included 127 PD patients and an equal number of non-PD patients who were assessed for pain and RLS-like symptoms by using RLS diagnostic survey, RLS rating scale and Brief Pain Inventory. RESULTS The results showed that 21.3% of PD patients had RLS, compared to only 4.7% in the control group, representing a highly significant difference (p<0.005). The frequency of reporting pain was also significantly higher among PD patients with RLS (p<0.005), but not in control group. However, the mean difference in average pain severity was not significantly different between the PD with RLS and non-PD with RLS, nor was the pain level and severity significantly correlated with RLS severity for either group. CONCLUSION The presence of pain in PD patients may be exacerbated by RLS or in RLS patients, having PD may exacerbate pain.

An Engineered Split Intein for Photoactivated Protein Trans-Splicing

Protein splicing is mediated by inteins that auto-catalytically join two separated protein fragments with a peptide bond. Here we engineered a genetically encoded synthetic photoactivatable intein (named LOVInC), by using the light-sensitive LOV2 domain from Avena sativa as a switch to modulate the splicing activity of the split DnaE intein from Nostoc punctiforme. Periodic blue light illumination of LOVInC induced protein splicing activity in mammalian cells. To demonstrate the broad applicability of LOVInC, synthetic protein systems were engineered for the light-induced reassembly of several target proteins such as fluorescent protein markers, a dominant positive mutant of RhoA, caspase-7, and the genetically encoded Ca2+ indicator GCaMP2. Spatial precision of LOVInC was demonstrated by targeting activity to specific mammalian cells. Thus, LOVInC can serve as a general platform for engineering light-based control for modulating the activity of many different proteins.

Restless leg syndrome: a risk factor of higher prevalence of anxiety and depression in Parkinson’s disease patients

Background: Many studies have assessed the relationship of depression and anxiety with Parkinson’s disease (PD), as well as examining restless leg syndrome (RLS) with depression and anxiety. Nonetheless, there has not been an extensive effort to show how the prevalence of RLS affects both depression and anxiety in PD patients. The objective of this study was to examine how the prevalence of RLS in PD patients affects the prevalence and severity of depression and anxiety and how they compare with each other. This study is the first of its kind that examines the effects of the combination of the two neurological conditions with depression and anxiety as well as comparing their prevalence and severity to each other. Methods: The study included 27 PD patients who also suffered from RLS, 27 PD patients not suffering from RLS, and 27 gender-matched healthy individuals. All were evaluated for caseness and severity of both anxiety and depression using the Hospital Anxiety and Depression Scale (HADS); HADS-A and HADS-D, respectively. Results: PD patients with RLS reported having the highest prevalence of both anxiety and depression. The least reported cases for both anxiety and depression were in the control group. In comparison, the results for severity of anxiety and depression within the three groups showed that PD patients with and without RLS had significantly higher severity scores for both anxiety and depression than the control group, but the scores did not significantly differ between the two PD patient groups. Conclusion: The presence of RLS in PD patients may increase the occurrence of both anxiety and depression, but the severity of the symptoms is not significant in the two groups of the PD patients.

Is action tremor in Parkinson’s disease related to resting tremor?

Abstract Objective: Action tremor (AT) and resting tremor (RT) have been widely cited in many studies with Parkinson’s disease (PD) patients, but studies looking at the association between the two tremor types are few and show inconsistent results. This study will look at the prevalence and association of AT and RT in a large sample of idiopathic PD patients, and will put the results into context with the literature. Methods: A retrospective chart review analysis of 332 patients with idiopathic PD was performed. Prevalence rates of particular tremor types were noted. The presence of AT was analyzed relative to the presence and severity of RT. Results: Nearly all individuals with AT also had RT. The concurrence of the two tremor types was found to be highly significant by statistical analysis (P < 0·0001). The severity of RT, measured by its laterality, may also be of importance, albeit to a much smaller extent if at all. Neither presence of tremor nor type of tremor present was influenced by patient gender, age, or Hoehn and Yahr stage of PD. Conclusions: The results indicate that AT has extensive presence in PD. This and its seemingly close relationship to RT suggest that AT may be considered a variant of RT, particularly in PD patients. The degree of association between RT and AT needs to be further analyzed in PD, as well as in essential tremor (ET) and ET-PD.

Differentiating nocturnal leg cramps and restless legs syndrome.

Leg pain and discomfort are common complaints in any primary physician’s clinic. Two common causes of pain or discomfort in legs are nocturnal leg cramps (NLC) and restless leg syndrome (RLS). NLC present as painful and sudden contractions mostly in part of the calf. Diagnosis of NLC is mainly clinical and sometimes involves investigations to rule out other mimics. RLS is a condition characterized by the discomfort or urge to move the lower limbs, which occurs at rest or in the evening/night. The similarity of RLS and leg cramps poses the issue of errors in diagnosing and differentiating the two. In this paper we review the pathopysiology of each entity and their diagnosis as well as treatment. The two conditions are then compared to appreciate the differences and similarities. Finally, suggestions are recommended for complete assessment.

Engineered Proteins Program Mammalian Cells to Target Inflammatory Disease Sites

Disease sites in atherosclerosis and cancer feature cell masses (e.g., plaques/tumors), a low pH extracellular microenvironment, and various pro-inflammatory cytokines such as tumor necrosis factor α (TNFα). The ability to engineer a cell to seek TNFα sources allows for targeted therapeutic delivery. To accomplish this, here we introduced a system of proteins: an engineered TNFα chimeric receptor (named TNFR1chi), a previously engineered Ca2+-activated RhoA (named CaRQ), vesicular stomatitis virus glycoprotein G (VSVG), and thymidine kinase. Upon binding TNFα, TNFR1chi generates a Ca2+ signal that in turn activates CaRQ-mediated non-apoptotic blebs that allow migration toward the TNFα source. Next, the addition of VSVG, upon low pH induction, causes membrane fusion of the engineered and TNFα source cells. Finally, after ganciclovir treatment cells undergo death via the thymidine kinase suicide mechanism. Hence, we assembled a system of proteins that forms the basis of engineering a cell to target inflammatory disease sites characterized by TNFα secretion and a low-pH microenvironment.

Ca(2+)-mediated rewiring of cell homing and fusion to VEGF sources.

Challenges of cell-based cancer therapy include effectively homing therapeutic cells to the disease site and producing a controlled response in recognition of the microenvironment. While stem cells have been intensively studied for treating cancer as they naturally home towards sites of injury, they have drawbacks due to their pluripotency. In this paper we have shown that a stable HEK293 cell line expressing VEGFR2 and CarQ (an engineered Ca2+-sensitive RhoA) can home towards a cell colony expressing VEGF. Upon VEGF binding to VEGFR2, a Ca2+ signal is produced that in turn activates CarQ-mediated cell blebbing. With the addition of VSVG, these homing cells can further initiate pH-dependent fusion upon reaching the cell colony. This protein system can form the basis of engineering cells for therapeutic intervention by homing and inhibiting tumour growth by pH-dependent fusion.

Factors associated with the development of impulse compulsive disorders in Parkinson patients.

Objective: The aim of this study is to identify the prevalence of impulse compulsive disorder (ICD) in Parkinsons disease (PD) patients and to study potential associative factors that may be related to the onset of ICD while on parkinsonian medications. Method: The study was conducted in two parts. In Part A, the prevalence of ICD in 140 PD patients was first assessed, followed by identifying any common variables that may be associated with the development of ICD. Finally, using a detailed chart review, Part B of the study examined the prevalence of ICD in all patients who presented with identical risk factors gathered in Part A. Results: Of the 140 patients, 8 patients developed symptoms of ICD. Seven of these patients were found to have five common variables that included gender (males), stages 1–2 of PD, young onset of PD, maximum dosage of the drug and the use of dopamine agonists (DAs). Of the 140 patients, 22 patients fit the above-mentioned five criteria and of those 22 patients, 33% developed symptoms of ICD. Conclusion: The use of DA therapy in the treatment of PD patients should be carefully monitored, especially in younger male patients who exhibit early signs of parkinsonian symptoms. As such, it is crucial for physicians to adjust DA dosages while also seeking alternative treatments to avoid the risk of ICD while on DAs.

Pharmacological therapies for pain in Parkinson’s disease – a review paper

ABSTRACT Introduction: Parkinson’s disease (PD) is a neurodegenerative movement disorder characterized by the loss of dopamine containing cells in the substantia nigra, with pain being one of the most common, yet frequently misunderstood symptoms. The prevalence of pain in PD populations ranges from 40–85% and is usually categorized under the following types: i) musculoskeletal pain ii) radicular and neuropathic pain iii) dystonia-related pain iv) akathitic pain and iv) central parkinsonian pain. Areas covered: The aim of this literature review was to document and present the common and uncommon pharmaceutical therapies that treat and/or alleviate these types of pain in PD. The PubMed database was searched with keywords: “Parkinson’s disease”, “Pain”, and “Pharmacological Therapies”. Research articles involving randomized, controlled trials were included as well as case studies and qualitative studies. Expert commentary: Given the increased prevalence of pain in PD populations, there is a need for a clear understanding of the types of pain treatments available and how they can be best combined to fit the specific needs of each patient.

Light directed migration of a cluster of cells in the centimeter scale

ABSTRACT Protein-based systems for light directed migration of cells have been demonstrated up to distances of several hundred microns, but larger distances in the centimeter scale would allow new possible applications. Light activated migration in mammalian cells can be achieved by cells expressing channelrhodopsin-2 and an engineered Ca2+ sensitive Rac1 protein called RACer. In this study, light was used to induce wound healing, localize cells into a region of interest, and move cells over centimeter scale distances. Given the spatially complex organization of different types of cells in real tissue, light directed migration over the centimeter scale could potentially organize cell type arrangement to help develop more realistic tissues for transplantation.