Jacob Cohen

Validation of a swallowing disturbance questionnaire for detecting dysphagia in patients with Parkinson's disease

Underreporting of swallowing disturbances by Parkinsons disease (PD) patients may lead to delay in diagnosis and treatment, alerting the physician to an existing dysphagia only after the first episode of aspiration pneumonia. We developed and validated a swallowing disturbance questionnaire (SDQ) for PD patients and compared its findings to an objective assessment. Fifty‐seven PD patients (mean age 69 ± 10 years) participated in this study. Each patient was queried about experiencing swallowing disturbances and asked to complete a self‐reported 15‐item “yes/no” questionnaire on swallowing disturbances (24 replied “no”). All study patients underwent a physical/clinical swallowing evaluation by a speech pathologist and an otolaryngologist. The 33 patients who complained of swallowing disturbances also underwent fiberoptic endoscopyic evaluation of swallowing (FEES). According to the ROC test, the “optimal” score (where the sensitivity and specificity curves cross) is 11 (sensitivity 80.5%, specificity 81.3%). Using the SDQ questionnaire substantially reduced Type I errors (specifically, an existing swallowing problem missed by the selected cutoff point). On the basis of the SDQ assessment alone, 12 of the 24 (50%) noncomplaining patients would have been referred to further evaluation that they otherwise would not have undergone. The SDQ emerged as a validated tool to detect early dysphagia in PD patients.

Self assembly of the transmembrane domain promotes signal transduction through the erythropoietin receptor

Hematopoietic cytokine receptors, such as the erythropoietin receptor (EpoR), are single membrane-spanning proteins. Signal transduction through EpoR is crucial for the formation of mature erythrocytes. Structural evidence shows that in the unliganded form EpoR exists as a preformed homodimer in an open scissor-like conformation precluding the activation of signaling. In contrast to the extracellular domain of the growth hormone receptor (GHR), the structure of the agonist-bound EpoR extracellular region shows only minimal contacts between the membrane-proximal regions. This evidence suggests that the domains facilitating receptor dimerization may differ between cytokine receptors. We show that the EpoR transmembrane domain (TM) has a strong potential to self interact in a bacterial reporter system. Abolishing self assembly of the EpoR TM by a double point mutation (Leu 240-Leu 241 mutated to Gly-Pro) impairs signal transduction by EpoR in hematopoietic cells and the formation of erythroid colonies upon reconstitution in erythroid progenitor cells from EpoR(-/-) mice. Interestingly, inhibiting TM self assembly in the constitutively active mutant EpoR R129C abrogates formation of disulfide-linked receptor homodimers and consequently results in the loss of ligand-independent signal transduction. Thus, efficient signal transduction through EpoR and possibly other preformed receptor oligomers may be determined by the dynamics of TM self assembly.

Video-assisted swallowing therapy for patients with Parkinson's disease

BACKGROUND Conventional swallowing therapy for patients with Parkinsons disease (PD) and swallowing difficulties has poor carryover to everyday life. Herein, we test the effectiveness of visual information while treating swallowing disturbances in patients with PD. METHODS Forty two non-demented PD patients with swallowing disturbances were randomly divided into two groups. An experimental group received video-assisted swallowing therapy (VAST) and a control group (n = 21) was given conventional therapy. Both groups were given 6 interventional sessions by the same speech and swallowing therapist. Patients in the VAST group were exposed to video of the swallowing process in general as well as of their own, as part of all therapy sessions. Swallowing function was assessed before and post-intervention by fiberoptic endoscopic evaluation of swallowing (FEES). Quality of life, quality of care and the degree of pleasure from eating were also assessed by questioners pre and post-intervention. RESULTS There was a significant improvement in swallowing functions following both interventions. The FEESs demonstrated a significantly greater reduction in food residues in the pharynx in the VAST group compared to the conventional treatment group. There were significant group improvement in some parameters of the quality of life, quality of care and pleasure of eating scales. CONCLUSION In cognitively intact patients with PD with swallowing disturbances VAST was associated with improved swallowing related QOL and less food residues in the pharynx.

Anxiety, depression and swallowing disorders in patients with Parkinson's disease

Swallowing disturbances (SDs), anxiety and depression are commonly present in Parkinsons disease (PD) patients. We hypothesized that there is an association between the presence of SDs and the PD affective state. Sixty-nine PD patients were assessed for the presence of SDs by undergoing cognitive screening with the Mini Mental State Examination (MMSE), completing three inventories: a swallowing disturbance questionnaire (SDQ), the Spielberger manual for the trait anxiety and Beck depression inventories. All patients underwent clinical swallowing evaluations by a speech and language pathologist (SLP). Patients diagnosed with SDs were also assessed by fiberoptic endoscopic evaluation of swallowing (FEES) performed by an ENT and SLP. Thirty-eight patients experienced SDs, the other 31 did not. The clinical characteristics of the two groups were matched. Patients with SDs experienced increased anxiety and depression compared to patients without SDs. Comparisons between patients who scored in the two opposite ends of the anxiety and depression ranges demonstrated that the most anxious and depressed patients reported more swallowing difficulties (SDQ scores) compared with the least anxious and depressed ones. In addition, the most anxious patients had significantly increased disease severity and decreased MMSE scores compared with the least anxious patients. Disease severity was also increased in the most depressed patients compared with the least depressed ones. Advanced disease emerged as being associated with high anxiety levels and greater numbers of SDs. The contribution of anxiety or depression to the development or worsening of SDs and their role in treatment strategy warrant further investigation.

Identification of a cytoplasmic motif in the erythropoietin receptor required for receptor internalization

Erythropoietin (EPO) promotes the viability, proliferation and differentiation of mammalian erythroid progenitor cells via its specific cell surface receptor. The EPO receptor (EPO‐R) is a member of the cytokine receptor superfamily and is comprised of one identified subunit which homodimerizes upon ligand binding. To study the role of the intracellular domain of the EPO‐R in the endocytosis of EPO, we compared the rate and extent of 125I‐EPO endocytosis by wild type (wt) EPO‐R and five cytoplasmically truncated EPO‐Rs: 1–251 EPO‐R, 1–257 EPO‐R, 1–267 EPO‐R, 1–276 EPO‐R and 1–306 EPO‐R which contain 4, 10, 20, 29 or 59 amino acids of the cytoplasmic domain, respectively. We also studied an EPO‐R mutant (PB) which lacks amino acid residues 281–300 of the cytoplasmic domain. The experiments were conducted in COS 7 cells transfected with the EPO‐R cDNAs and in Ba/F3 cells stably expressing the wt EPO‐R, 1–251 or 1–257 EPO‐R. Cells expressing wt EPO‐R, PB EPO‐R (Δ281–300), 1–276 EPO‐R or 1–306 EPO‐R internalized approximately 50% of 125I‐EPO bound to the cell surface, while cells expressing 1–251, 1–257 or 1–267 EPO‐R internalized only 25% of the bound 125I‐EPO. The steady‐state expression levels of these latter receptors on the cell surface were typically 2–5‐fold higher than wt EPO‐R. Our data indicate that amino acid residues 267–276 (FEGLFTTHK) of the EPO‐R cytoplasmic domain may have a role in receptor internalization. Metabolic labeling experiments suggest that in transiently transfected COS 7 cells most of the wt EPO‐R and 1–257 EPO‐Rs do not exit the ER and may be degraded there. The half‐life of both receptors was essentially similar and was in the range of 1 h. In Ba/F3 cells the mature Golgi processed 1–257 EPO‐R was more stable than the corresponding form of the wt EPO‐R, possibly contributing to its higher cell surface expression.

Smartphone-Based Hearing Test as an Aid in the Initial Evaluation of Unilateral Sudden Sensorineural Hearing Loss

Sudden sensorineural hearing loss (SSNHL) can cause significant morbidity. Treatment with steroids can improve outcome. Delay in initiation of treatment reduces the chance to regain hearing. For this reason SSNHL is considered an emergency. Diagnosis is based on history, physical examination and a standard audiogram, the latter requiring specialized equipment and personnel. Standard audiogram may not be available at the time and place of patient presentation. A smartphone or tablet computer-based hearing test may aid in the decision to prescribe steroids in this setting. In this study the uHear™ hearing test application was utilized. The output of this ear-level air conduction hearing test is reported in hearing grades for 6 frequencies ranging from 250 to 6000 Hz. A total of 32 patients with unilateral SSNHL proven by a standard audiogram were tested. The results of standard and iPod hearing tests were compared. Based on the accepted criterion of SSNHL (at least 30 dB loss - or 2 hearing grades - in 3 consecutive frequencies) the test had a sensitivity of 0.76 and specificity of 0.91. Using a less stringent criterion of a loss of 2 hearing grades over at least 2 frequencies the sensitivity was 0.96 and specificity 0.86. The correlation coefficient for the comparison of the average hearing grade across the 6 measured frequencies of the study and standard audiogram was 0.83. uHear more accurately reflected hearing thresholds at mid and high tones. Similarly to previously published data, low frequency thresholds could be artificially elevated. In conclusion, uHear can be useful in the initial evaluation of patients with single-sided SSNHL by providing important information guiding the decision to initiate treatment before a standard audiogram is available.

Amino acid residues 268-276 of the erythropoietin receptor contain an endocytosis motif and are required for erythropoietin-mediated proliferation

Erythropoietin (EPO) promotes viability, proliferation and differentiation of mammalian erythroid progenitor cells via its specific cell surface receptor (EPO‐R). We have previously shown that truncated EPO‐Rs containing 267 amino acids or less were defective in internalization of 125I‐EPO, whereas internalization via a receptor derivative containing 276 amino acids was unaffected, thus directing focus to the nine amino acid residues FEGLFTTHK at positions 268–276 [Levin, Cohen, Supino, Yoshimura, Watowich, Neumann, FEBS Lett. 427 (1998) 164–170]. Here, a panel of EPO‐R mutants was generated to determine the role of these residues in EPO endocytosis, down regulation of cell surface receptors and EPO‐mediated signaling. While linking amino acid residues 268–276 to a truncated EPO‐R (Δ+9 EPO‐R) conferred both ligand uptake and ligand‐independent down regulation of the respective receptor from the cell surface, Phe 272 was crucial for EPO endocytosis but not for ligand‐independent down regulation. Additional receptor motifs probably play a role in EPO endocytosis and receptor down‐regulation, as these processes were not adversely impaired in Δ268–276 EPO‐R. A central role of residues 268–276, in particular Phe, was demonstrated by the inability of Δ268–276 and F268,272A EPO‐Rs to support EPO‐mediated signal transduction.