SIGMA-1 Receptor Gene Variants Affect the Somatosensory Phenotype in Neuropathic Pain Patients

Pain sensitivity is characterized by interindividual variability, determined by factors including genetic variation of nociceptive receptors and pathways. The sigma-1 receptor (SIGMAR1) is involved in pain modulation especially under pre-sensitized conditions. However, the contribution of SIGMAR1 genetic variants to pain generation and sensitivity is unknown yet. This study aimed to identify effects of 5 SIGMAR1 variants on the somatosensory phenotype of neuropathic pain patients (n?=?228) characterized by standardized quantitative sensory testing. Principal component analysis revealed that the SIGMAR1 variants ?297G>T (rs10814130) and 5A>C (rs1800866) significantly lowered thermal detection and heat/pressure nociception in particular in neuropathic pain patients with mainly preserved somatosensory function. Compared to wild-type, the variant allele ?297T was associated with loss of warm detection (P?=?.049), lower heat-pain sensitivity (P?=?.027) and wind-up ratio (P?=?.023) as well as increased paradoxical heat sensation (P?=?.020). Likewise for 5A>C the strongest genotype-associated differences observed were reduced peripheral (less heat hyperalgesia; P?=?.026) and central sensitization (lower mechanical pain sensitivity; P?=?.026) in variant compared to wild-type carriers. This study indicates lack of association of SIGMAR1 ?297G>T and 5A>C genetic variants to susceptibility to develop chronic pain, but significant modulation of somatosensory function in neuropathic pain patients.

Carotid Atherosclerosis Is Associated With Poorer Hearing in Older Adults

ObjectivesCardiovascular disease may be linked to hearing loss through narrowing of the nutrient arteries of the cochlea, but large-scale population-based evidence for this association remains scarce. We investigated the association of carotid atherosclerosis as a marker of generalized cardiovascular disease with hearing loss in a population-based cohort.DesignCross-sectional.SettingA population-based cohort study.Participants3724 participants [mean age: 65.5 years, standard deviation (SD): 7.5, 55.4% female].MethodsUltrasound and pure-tone audiograms to assess carotid atherosclerosis and hearing loss.ResultsWe investigated associations of carotid plaque burden and carotid intima-media thickness (IMT) (overall and side-specific carotid atherosclerosis) with hearing loss (in the best hearing ear and side-specific hearing loss) using multivariable linear and ordinal regression models. We found that higher maximum IMT was related to poorer hearing in the best hearing ear [difference in decibel hearing level per 1-mm increase in IMT: 2.09 dB, 95% confidence interval (CI): 0.08, 4.10]. Additionally, third and fourth quartile plaque burden as compared to first quartile was related to poorer hearing in the best hearing ear (difference: 1.06 dB, 95% CI: 0.04, 2.08; and difference: 1.55 dB, 95% CI: 0.49, 2.60, respectively). Larger IMT (difference: 2.97 dB, 95% CI: 0.79, 5.14), third quartile plaque burden compared to first quartile (difference: 1.24 dB, 95% CI: 0.14, 2.35), and fourth plaque quartile compared to first quartile (difference: 2.12 dB, 95% CI: 0.98, 3.26) in the right carotid were associated with poorer hearing in the right ear.Conclusions and ImplicationsCarotid atherosclerosis is associated with poorer hearing in older adults, almost exclusively with poorer hearing in the right ear. Based on our results, it seems that current therapies for the prevention of cardiovascular disease may also prove beneficial for hearing loss in older adults by promoting and maintaining inner ear health.     

Impaired sense of smell and color discrimination in monogenic and idiopathic Parkinson's disease

Olfaction is typically impaired in idiopathic Parkinson's disease (IPD), but its role is uncertain in monogenic PD. Diminished color discrimination has been suggested as another early sign of dopaminergic dysfunction but not been systematically studied. Furthermore, it is unknown whether both deficits are linked. We examined 100 patients with IPD, 27 manifesting mutation carriers (MC), 20 nonmanifesting mutation carriers (NMC), and 110 controls. Participants underwent a standardized neurological examination, the University of Pennsylvania Smell Identification Test (UPSIT), the Farnsworth‐Munsell (FM) color discrimination test, and mutation testing in known PD genes. The monogenic group consisted of 15 Parkin (6MC/9NMC), 17 PINK1 (10MC/7NMC), 8 LRRK2 (4MC/4NMC), 3 SNCA (MC), and 4 ATP13A2 (MC) carriers. Olfaction was most impaired in IPD (UPSIT percentiles 10.1 ± 13.5) compared with all other groups (MC 13.8 ± 11.9, NMC 19.6 ± 13.0, controls 33.8 ± 22.4). Within MC, carriers of two mutations in Parkin and PINK1 showed higher UPSIT percentiles than LRRK2 and SNCA carriers. Color discrimination was reduced in IPD (FM total error score 134.8 ± 92.7). In MC (122.4 ± 142.4), the reduction was most pronounced in LRRK2, NMC (80.0 ± 38.8) were comparable with controls (97.2 ± 61.1). UPSIT and FM scores were correlated in the control (r = ?0.305; P = 0.002) and the IPD group (r = ?0.303; P = 0.006) but not among mutation carriers. First, we confirmed olfaction and color discrimination to be impaired in IPD and suggest olfaction to be a premotor sign. Second, olfaction differed between carriers with one and two mutations in Parkin/PINK1‐associated PD. Third, olfaction and color discrimination impairment do not necessarily evolve in parallel. © 2010 Movement Disorder Society     

Characterization of a hydrophobin of the ascomycete Paecilomyces farinosus

The entomopathogenic ascomycete Paecilomyces farinosus (alternative name Isaria farinosa) synthesized a hydrophobin, irrespective of being grown in submerged or surface culture. The protein was extracted using trifluoroacetic acid and purified using preparative HPLC and SDS-PAGE. Partial sequences were obtained using ESI-MS/MS. The peptides were used as a start to apply a 'template switching oligo' protocol to elucidate the complete open reading frame of P. farinosus hydrophobin 1 (pfah1). The deduced protein sequence comprised 107 amino acids (10.7 kDa) including a 16 amino acid long hydrophobic signal peptide, showed a calculated pI of 4.56, and was interrupted by one intron. Phylogenetic analyses revealed relationships to hydrophobins of the ascomycetes Magnaporthe grisea and Metarhizium anisopliae. Based on solubility, hydropathy pattern and phylogeny PfaH1 was assigned to the class Ia hydrophobins.     

Provision of counseling on diabetes self-management: Are there any age disparities?

Objective

To determine whether there are any age-related disparities in the frequency of provision of counseling and education for diabetes care in a large HMO in Central Texas.

Methods

EMR search from 13 primary care clinics on patients aged ≥18 years (n = 1300) who had been diagnosed with type 2 diabetes.

Results

There were no significant age differences in the frequency of provision of counseling about HBGM, diet, smoking or diabetes education. However, there were significant age differences in the provision of exercise counseling. Patients aged ≥75 were significantly less likely to have been provided exercise counseling than those aged <65 (adjusted OR = 0.60; 95% CI = 0.37–0.98). The mean HbA1c for patients aged ≥75 and 65–74 were significantly lower than that of patients aged <65 (8.9 vs. 9.0 vs. 9.7; P < 0.001).

Conclusion

While age-related variations in self-management protocols were not found, the provision of formal diabetes education was low (29.4%). The persistence of key risk factors in later life (e.g., obesity) underscores the need for better self-management protocols for older adults.

Practice Implications

Additional efforts on strategies to increase counseling about lifestyle habits and diabetes self-management care by appropriate health care providers is needed. Diabetes counseling should be individually tailored in older population.     

Tolerance induction towards cardiac allografts under costimulation blockade is impaired in CCR7-deficient animals but can be restored by adoptive transfer of syngeneic plasmacytoid dendritic cells

Deficiency of transplant recipients for the chemokine receptor CCR7 was originally described to slightly increase the survival time of vascularized solid organ grafts, probably due to a reduced priming of alloreactive T cells. Using a model of allotolerance induction by donor-specific splenocyte transfusion (DST) in combination with anti-CD40L mAb-mediated costimulation blockade (CSB), we show here a striking failure of CCR7-deficient (CCR7(-/-) ) recipients to tolerate cardiac allografts. Furthermore, in addition to the recently described lack of Treg, CCR7(-/-) mice were found to harbor significantly reduced numbers of plasmacytoid dendritic cells (pDCs) within peripheral as well as mesenteric lymph nodes (LNs), but not the bone marrow or spleen. pDCs had previously been suggested to function as tolerogenic APC during allograft transplantation, and a single transfer of syngeneic WT pDCs, but not conventional DCs, was indeed sufficient to rescue graft survival in DST+CSB-treated CCR7(-/-) recipients in a dose-dependent manner. We therefore conclude that the nearly complete absence of pDCs within LNs of CCR7(-/-) mice prevents the successful induction of DST+CSB-mediated allotolerance, leading to the observed acute rejection of cardiac allografts under tolerizing conditions.