Treatment Approaches for Altered Facial Expression: A Systematic Review in Facioscapulohumeral Muscular Dystrophy and Other Neurological Diseases.

Background: Facial weakness is a key feature of facioscapulohumeral muscular dystrophy (FSHD) and may lead to altered facial expression and subsequent psychosocial impairment. There is no cure and supportive treatments focus on optimizing physical fitness and compensation of functional disabilities. Objective: We hypothesize that symptomatic treatment options and psychosocial interventions for other neurological diseases with altered facial expression could be applicable to FSHD. Therefore, the aim of this review is to collect symptomatic treatment approaches that target facial muscle function and psychosocial interventions in various neurological diseases with altered facial expression in order to discuss the applicability to FSHD. Methods: A systematic search was performed. Selected studies had to include FSHD, Bell's palsy, Moebius syndrome, myotonic dystrophy type 1, or Parkinson's disease and treatment options which target altered facial expression. Data was extracted for study and patients' characteristics, outcome assessment tools, treatment, outcome of facial expression and or psychosocial functioning. Results: Forty studies met the inclusion criteria, of which only three studies included FSHD patients exclusively. Most, twenty-one, studies were performed in patients with Bell's palsy. Studies included twelve different therapy categories and results were assessed with different outcomes measures. Conclusions: Five therapy categories were considered applicable to FSHD: training of (non-verbal) communication compensation strategies, speech training, physical therapy, conference attendance, and smile restoration surgery. Further research is needed to establish the effect of these therapies in FSHD. We recommend to include outcome measures in these studies that cover at least cosmetic, functional, communication, and quality of life domains.

Psychosocial functioning in patients with altered facial expression: a scoping review in five neurological diseases.

PURPOSE: To perform a scoping review to investigate the psychosocial impact of having an altered facial expression in five neurological diseases. METHODS: A systematic literature search was performed. Studies were on Bell's palsy, facioscapulohumeral muscular dystrophy (FSHD), Moebius syndrome, myotonic dystrophy type 1, or Parkinson's disease patients; had a focus on altered facial expression; and had any form of psychosocial outcome measure. Data extraction focused on psychosocial outcomes. RESULTS: Bell's palsy, myotonic dystrophy type 1, and Parkinson's disease patients more often experienced some degree of psychosocial distress than healthy controls. In FSHD, facial weakness negatively influenced communication and was experienced as a burden. The psychosocial distress applied especially to women (Bell's palsy and Parkinson's disease), and patients with more severely altered facial expression (Bell's palsy), but not for Moebius syndrome patients. Furthermore, Parkinson's disease patients with more pronounced hypomimia were perceived more negatively by observers. Various strategies were reported to compensate for altered facial expression. CONCLUSIONS: This review showed that patients with altered facial expression in four of five included neurological diseases had reduced psychosocial functioning. Future research recommendations include studies on observers' judgements of patients during social interactions and on the effectiveness of compensation strategies in enhancing psychosocial functioning.

Negative effects of altered facial expression on psychosocial functioning are common and more abundant in women and in more severely affected patients with various neurological disorders.Health care professionals should be alert to psychosocial distress in patients with altered facial expression.Learning of compensatory strategies could be a beneficial therapy for patients with psychosocial distress due to an altered facial expression.

Low Quality of Reports on Blood Pressure in Patients Adrenalectomized for Unilateral Primary Aldosteronism.

CONTEXT: Adrenalectomy is the preferred treatment for unilateral primary aldosteronism but the results of long-term control of blood pressure (BP) are far from optimal. One possible explanation relates to the quality of the assessment of treatment effects on BP. PURPOSE OF THE STUDY: To examine the quality of reporting BP measurements in studies assessing the outcome of adrenalectomy on BP. METHODS: We conducted a systematic review searching 3 databases (PubMed, EMBASE, Web of Science) for articles published from January 1, 1990, onwards. Sixty-six studies, each reporting on more than 50 adrenalectomized patients, were eligible for full analysis. RESULTS: In 37 of the analyzed 66 studies (56.1%) BP values both before and after adrenalectomy were reported. In 19.7% (13/66) of the studies the method of BP measurement was described. The number of visits and number of BP recordings per visit on which BP results were based were reported in <15% of papers. The criteria for the diagnosis of hypertension were described in 72.7% (48/66) of the studies. The used definitions of improvement of BP control after adrenalectomy were variable, with 84.8% of the studies not providing any quantitative criteria to define reduction in BP. CONCLUSION: We conclude that the quality of reporting on BP control after adrenalectomy for primary aldosteronism shows substantial deficiencies and inconsistencies, thus impacting negatively on accurate assessment of effects of adrenalectomy on BP control. Future studies should adhere to accepted recommendations of correct BP measurement and should provide detailed description of the methods used for BP measurement.

Self-Reported Hindering Health Complaints of Community-Dwelling Older Persons: A Cross-Sectional Study.

PURPOSE: Proactive care for community-dwelling older persons targeting self-reported hindering health complaints might prevent a decline in function. We investigated the spectrum of self-reported hindering complaints of community-dwelling older persons, the association with functional outcomes, and help-seeking behavior for these complaints. METHODS: Within the ISCOPE trial, participants (aged ≥75 years) received the ISCOPE screening questionnaire, including the open-ended question "At the moment, which health complaints limit you the most in your day-to-day life?". After coding the answers with the ICPC-1-NL, we examined the prevalence and the association between the number and type of complaints and functional outcomes (Groningen Activities Restriction Scale, quality of life measured on Cantril's Ladder, Mini-Mental State Examination, Geriatric Depression Scale-15, and De Jong Gierveld Loneliness Scale). Electronic patient registers were searched for the most reported complaints. RESULTS: 7285 participants (median age: 81.0 years [IQR 77.8-85.3], 38.6% males) reported 13,524 hindering complaints (median 1, range 0-18); 32.7% reported no complaints. Participants mostly reported problems with walking/standing (22.1%), pain (20.8%) or weakness/tiredness (8.5%). These complaints were mentioned in the electronic patient registers in 28.3%, 91.3% and 55.5%, respectively. Higher numbers of hindering complaints were related to poorer scores on the number of domains with problems, Cantril's Ladder for quality of life, Groningen Activities Restriction Scale, Geriatric Depression Scale, and De Jong Gierveld Loneliness Scale. Self-reported weakness, problems with walking/standing, visual limitations, cognitive problems, dyspnea and back complaints were associated with poorer scores on the number of domains with problems, Groningen Activities Restriction Scale, MMSE or Geriatric Depression Scale. CONCLUSION: One third of the participants reported no hindering complaints. Problems with walking/standing, pain, and weakness/tiredness were most reported, but not always found in electronic patient registers. A higher number of, and specific self-reported hindering complaints, were associated with poorer scores on functional outcomes. It may be helpful for general practitioners to ask about these complaints and their influence on daily life.

Comparison of quadriceps strength and handgrip strength in their association with health outcomes in older adults in primary care.

Sarcopenia is thought to play a major role in the functional impairment that occurs with old age. In clinical practice, sarcopenia is often determined by measuring handgrip strength. Here, we compared the lower limb quadriceps strength to the handgrip strength in their association with health outcomes in older adults in primary care. Our study population consisted of older adults (n = 764, 68.2% women, median age 83) that participated in the Integrated Systemic Care for Older People (ISCOPE) study. Participants were visited at baseline to measure quadriceps strength and handgrip strength. Data on health outcomes were obtained at baseline and after 12 months (including life satisfaction, disability in daily living, GP contact-time and hospitalization). Quadriceps strength and handgrip strength showed a weak association (ß = 0.42 [95% CI 0.33-0.50]; R (2) = 0.17). Quadriceps strength and handgrip strength were independently associated with health outcomes at baseline, including quality of life, disability in daily living, GP contact-time, hospitalization, and gait speed. Combined weakness of the quadriceps and handgrip distinguished a most vulnerable subpopulation that presented with the poorest health outcomes. At follow-up, handgrip strength showed an association with quality of life (ß = 0.05; P = 0.002) and disability in daily living (ß = -0.5; P = 0.004). Quadriceps weakness did not further contribute to the prediction of the measured health outcomes. We conclude that quadriceps strength is only moderately associated with handgrip strength in an older population and that the combination of quadriceps strength and handgrip strength measurements may aid in the identification of older adults in primary care with the poorest health outcomes. In the prediction of poor health outcomes, quadriceps strength measurements do not show an added value to the handgrip strength.

Quantitative global phosphoproteomics of human umbilical vein endothelial cells after activation of the Rap signaling pathway.

The small GTPase Rap1 is required for proper cell-cell junction formation and also plays a key role in mediating cAMP-induced tightening of adherens junctions and subsequent increased barrier function of endothelial cells. To further study how Rap1 controls barrier function, we performed quantitative global phosphoproteomics in human umbilical vein endothelial cells (HUVECs) prior to and after Rap1 activation by the Epac-selective cAMP analog 8-pCPT-2'-O-Me-cAMP-AM (007-AM). Tryptic digests were labeled using stable isotope dimethyl labeling, enriched with phosphopeptides by strong cation exchange (SCX), followed by titanium(iv) immobilized metal affinity chromatography (Ti(4+)-IMAC) and analyzed by high resolution mass spectrometry. We identified 19 859 unique phosphopeptides containing 17 278 unique phosphosites on 4594 phosphoproteins, providing the largest HUVEC phosphoproteome to date. Of all identified phosphosites, 220 (∼1%) were more than 1.5-fold up- or downregulated upon Rap activation, in two independent experiments. Compatible with the function of Rap1, these alterations were found predominantly in proteins regulating the actin cytoskeleton, cell-cell junctions and cell adhesion.

Epac1 and PDZ-GEF cooperate in Rap1 mediated endothelial junction control.

Epac1 and its effector Rap1 are important mediators of cAMP induced tightening of endothelial junctions and consequential increased barrier function. We have investigated the involvement of Rap1 signalling in basal, unstimulated, barrier function of a confluent monolayer of HUVEC using real time Electric Cell-substrate Impedance Sensing. Depletion of Rap1, but not Epac1, results in a strong decrease in barrier function. This decrease is also observed when cells are depleted of the cAMP independent Rap exchange factors PDZ-GEF1 and 2, showing that PDZ-GEFs are responsible for Rap1 activity in control of basal barrier function. Monolayers of cells depleted of PDZ-GEF or Rap1 show an irregular, zipper-like organization of VE-cadherin and live imaging of VE-cadherin-GFP reveals enhanced junction motility upon depletion of PDZ-GEF or Rap1. Importantly, activation of Epac1 increases the formation of cortical actin bundles at the cell-cell junctions, inhibits junction motility and restores barrier function of PDZ-GEFs depleted, but not Rap1 depleted cells. We conclude that PDZ-GEF activates Rap1 under resting conditions to stabilize cell-cell junctions and maintain basal integrity. Activation of Rap1 by cAMP/Epac1 induces junctional actin to further tighten cell-cell contacts.

Analysis of allele-specific RNA transcription in FSHD by RNA-DNA FISH in single myonuclei.

Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) is likely caused by epigenetic alterations in chromatin involving contraction of the D4Z4 repeat array near the telomere of chromosome 4q. The precise mechanism by which deletions of D4Z4 influence gene expression in FSHD is not yet resolved. Regulatory models include a cis effect on proximal gene transcription (position effect), DNA looping, non-coding RNA, nuclear localization and trans-effects. To directly test whether deletions of D4Z4 affect gene expression in cis, nascent RNA was examined in single myonuclei so that transcription from each allele could be measured independently. FSHD and control myotubes (differentiated myoblasts) were subjected to sequential RNA-DNA FISH. A total of 16 genes in the FSHD region (FRG2, TUBB4Q, FRG1, FAT1, F11, KLKB1, CYP4V2, TLR3, SORBS2, PDLIM3 (ALP), LRP2BP, ING2, SNX25, SLC25A4 (ANT1), HELT and IRF2) were examined for interallelic variation in RNA expression within individual myonuclei. Sequential DNA hybridization with a unique 4q35 chromosome probe was then applied to confirm the localization of nascent RNA to 4q. A D4Z4 probe, labeled with a third fluorochrome, distinguished between the deleted and normal allele in FSHD nuclei. Our data do not support an FSHD model in which contracted D4Z4 arrays induce altered transcription in cis from 4q35 genes, even for those genes (FRG1, FRG2 and SLC25A4 (ANT1)) for which such an effect has been proposed.

A lentiviral vector-based adenovirus fiber-pseudotyping approach for expedited functional assessment of candidate retargeted fibers.

BACKGROUND: Many studies aimed at retargeting adenovirus (Ad) rationally focus on genetic modification of fiber, which is the primary receptor-binding protein of Ad. Retargeted fibers ultimately require functional validation in the viral context. METHODS: Lentiviral vectors (LV) were used to express fiber variants in cells. Infections with a fiber gene-deleted Ad vector yielded fiber-pseudotyped viruses. An enzyme-linked immunosorbent assay and slot blot-based assays probed target binding-ability of retargeted fibers. Differential treatments with an alkylating agent prior to western blot analysis allowed for examination of intra- and extracellular redox states of fibers. RESULTS: In the present study, LV-based fiber-pseudotyping of Ad is presented as an accelerated means to test new fibers. LV-mediated gene transfer yielded stable and uniform populations of fiber variant-expressing cells. These populations were found to effectively support fiber-pseudotyping of Ad. As a secondary objective of the study, we functionally assessed a chimeric fiber harboring a tumor antigen-directed single-chain antibody fragment (scFv). This fiber was shown to trimerize and achieve a degree of binding to its antigenic target. However, its capsid incorporation ability was impaired and, moreover, it was unable to confer a detectable level of target binding upon Ad. Importantly, subsequent analyses of this fiber revealed the improper folding of its scFv constituent. CONCLUSIONS: LV-based fiber-pseudotyping was established as a convenient method for testing modified fibers for functionality within Ad particles. Furthermore, a new chimeric fiber was found to be inadequate for Ad retargeting. The folding difficulties encountered for this particular fiber might be generally inherent to the use (i.e. for genetic Ad capsid incorporation) of complex, disulfide bridge-containing natural ligands.