Proteolipid protein modulates preservation of peripheral axons and premature death when myelin protein zero is lacking

Protein zero (P0) is the major structural component of peripheral myelin. Lack of this adhesion protein from Schwann cells causes a severe dysmyelinating neuropathy with secondary axonal degeneration in humans with the neuropathy Dejerine‐Sottas syndrome (DSS) and in the corresponding mouse model (P0^null‐mice). In the mammalian CNS, the tetraspan‐membrane protein PLP is the major structural myelin constituent and required for the long‐term preservation of myelinated axons, which fails in hereditary spastic paraplegia (SPG type‐2) and the relevant mouse model (Plp^null‐mice). The Plp‐gene is also expressed in Schwann cells but PLP is of very low abundance in normal peripheral myelin; its function has thus remained enigmatic. Here we show that the abundance of PLP but not of other tetraspan myelin proteins is strongly increased in compact peripheral myelin of P0^null‐mice. To determine the functional relevance of PLP expression in the absence of P0, we generated P0^null*Plp^null‐double‐mutant mice. Compared with either single‐mutant, P0^null*Plp^null‐mice display impaired nerve conduction, reduced motor functions, and premature death. At the morphological level, axonal segments were frequently non‐myelinated but in a one‐to‐one relationship with a hypertrophic Schwann cell. Importantly, axonal numbers were reduced in the vital phrenic nerve of P0^null*Plp^null‐mice. In the absence of P0, thus, PLP also contributes to myelination by Schwann cells and to the preservation of peripheral axons. These data provide a link between the Schwann cell‐dependent support of peripheral axons and the oligodendrocyte‐dependent support of central axons. GLIA 2016;64:155–174     

Surgical treatment of symptomatic cerebral cavernous malformations in eloquent brain regions

Background

Despite the increased risk of hemorrhage and deteriorating neurological function of once-bled cerebral cavernous malformations (CM), the management of eloquently located CMs remains controversial.

Methods

All eloquently located CMs (n?=?45) surgically treated between 03/2006 and 04/2011 in our department were consecutively evaluated. Eloquence was characterized according to Spetzler and Martin's definition. The following locations were approached: brainstem, n?=?16; sensorimotor, n?=?8; visual pathway, n?=?7; cerebellum (deep nuclei and peduncles), n?=?7; basal ganglia, n?=?4, and language, n?=?3. Follow-up data was available for 41 patients (91 %) with a median interval of 14 months. Outcomes were evaluated according to the Glasgow outcome and the modified Rankin scale.

Results

Immediately after surgery, 47 % (n?=?21) had a new deficit. At follow-up, 80 % (n?=?36) recovered to at least preoperative status or were better than before surgery, 9 % (n?=?4) exhibited a slight, and 7 % (n?=?3) had a moderate neurological impairment. Only two cases (4 %) with a new permanent severe deficit were observed, both related to dorsal brainstem surgery. The outcome after the surgery of otherwise located brainstem CMs was as beneficial as that for non-brainstem CMs. Patients with initially poor neurological performance fared worse than oligosymptomatic patients.

Conclusions

Despite the high postoperative transient morbidity, the majority improved profoundly during follow-ups. Compared with natural history, surgical treatment should be considered for all eloquent symptomatic CMs. Dorsal brainstem location and poor preoperative neurological status are associated with an increased postoperative morbidity.

     

[<Superscript>11</Superscript>C]choline PET/CT in prostate cancer patients with biochemical recurrence after radical prostatectomy

Objective  

To evaluate [¹¹C]choline positron emission tomography/computed tomography ([¹¹C]choline PET/CT) for the detection of a biochemical recurrence of prostate cancer after radical prostatectomy.     

Comparison of three remifentanil dose-finding regimens for coronary artery surgery

OBJECTIVES: To identify the remifentanil dosing regimen providing safe and optimal anesthetic conditions during coronary artery bypass graft surgery and to evaluate postoperative recovery characteristics. DESIGN: Open-label, randomized, parallel group. SETTING: Three centers in the United States. PARTICIPANTS: Seventy-two patients with left ventricular stroke volumes >or=50 mL. INTERVENTIONS: Patients were randomized to remifentanil doses of 1 microg/kg/min (group 1, n = 23); 2 microg/kg/min (group 2, n = 24), or 3 microg/kg/min (group 3, n = 25). Somatic, sympathetic, and hemodynamic responses indicating inadequate anesthesia were treated with bolus doses of remifentanil, 1 to 2 microg/kg, and infusion rate increases, and, if necessary, isoflurane 0.5% to 1.0% was added as a rescue anesthetic. In the intensive care unit, the remifentanil infusion was reset to 1 microg/kg/min, with midazolam administered for supplemental sedation and morphine for analgesia. MEASUREMENTS AND MAIN RESULTS: The durations of anesthesia, surgery, and cardiopulmonary bypass were similar for the 3 study groups. In addition, dose of lorazepam premedication, time to loss of consciousness, preoperative left ventricular ejection fraction, age, weight, and sex were similar for the 3 study groups. Remifentanil alone (infusion and boluses) prevented and controlled all responses to stimulation in 44% of group 3, 37% of group 2 and 9% of group 1 patients intraoperatively. Isoflurane (0.5%-1% inspired) rescue was successful in the remaining patients in each group. Hypotension indicating discontinuation of isoflurane and reductions of remifentanil infusion rates occurred in 64% to 75% of all patients. The optimal range of remifentanil infusion was 2 to 4 microg/kg/min with isoflurane to supplement the opioid. Fifty-one patients (71%) met the criteria for extubation within 6 hours postoperatively; because of surgical practice differences, only 30 patients (59%) were actually extubated. CONCLUSIONS: After lorazepam premedication, remifentanil infusion (2-4 microg/kg/min) supplemented intermittently with low inspired concentrations of isoflurane provided an effective anesthetic regimen for coronary artery bypass graft surgery. Early extubation times were feasible after remifentanil continuous infusions (1-5 microg/kg/min) used as the primary anesthetic component intraoperatively and for analgesia (相似文献   

Diskography outcomes in patients following lumbar diskectomy

The results of lumbar diskography at post-diskectomy and nonoperative disk levels in postoperative patients and patients without prior back surgery were reviewed over 3 years. Other possible predictive factors, including disk degeneration (per the Adam's classification), end-point resistance, gender, and age, also were reviewed. The results revealed that no statistically significant association was noted between the presence of a prior diskectomy and the outcome of diskography. However, disk degeneration classified as ruptured and fissured correlated statistically with positive diskography. Additionally, age between 30 and 39 years and male gender were statistically associated with a positive diskogram. Disk levels displaying a poor end point during diskography injection (not amendable to pressurization) were statistically related to ruptured or fissured disk levels and thus positive diskography. Based on these results, the assumption that disabling low-back pain presenting after lumbar procedure is due to diskogenic disease arising from the surgical level is not supported.     

Quantitative analysis of EBV-specific CD4/CD8 T cell numbers, absolute CD4/CD8 T cell numbers and EBV load in solid organ transplant recipients with PLTD

Post transplant lymphoproliferative disease (PTLD) in solid organ transplant (SOT) recipients is assumed to be the result of impaired Epstein-Barr Virus (EBV)-specific cellular immunity. We analyzed the absolute CD4 and CD8 T cell counts as well as the EBV-specific CD4 and CD8 T cell responses in relation to EBV load in SOT recipients with PTLD. A prospective, single center study was initiated and 10 immunosuppressed patients with diagnosis of PTLD were analyzed and compared to 3 patients without PTLD (2 SOT recipients with EBV-reactivation, 1 patient with Infectious Mononucleosis) and 6 healthy EBV positive controls. EBV-specific CD8 T cells were enumerated using HLA class I tetramers and the IFN-gamma cytokine secretion assay. EBNA1-specific CD4 T cells were analyzed after protein stimulation and EBV load was quantified by real-time PCR. Absolute CD8 T cell counts were highly variable in all 19 cases analyzed. In contrast, the absolute EBV-specific CD8 T cell count was found to be low in 7/9 patients with PTLD (<5/microl whole blood). These frequencies were similar to absolute EBV-specific CD8 T cell numbers observed in healthy EBV positive donors, but much lower compared to patients with EBV reactivation but no PTLD. Absolute CD4 T cell counts were significantly lower in PTLD patients (mean: 336/microl+/-161 vs. controls 1008/microl+/-424, p=0.0001), with EBNA1-specific CD4 T cell responses being also low, but highly variable. Moreover, low absolute CD4 T cell counts (<230/microl) were associated with an elevated EBV load (>1000 copies/microg DNA). We conclude that SOT recipients with PTLD have an inadequate functional EBV-specific T cell response. Our data suggest that the frequency and function of circulating EBV-specific CD8 T cells are dependent on absolute CD4 T cell counts. Further studies are needed to verify if a low absolute CD4 T cell count presents a risk factor for the development of PTLD in SOT recipients.     

Early Surgery in Prone Position for Associated Injuries in Patients Undergoing Non-operative Management for Splenic and Liver Injuries

Background

In patients undergoing non-operative management (NOM) of blunt splenic and/or liver injuries, no data exist on the safety of same-admission surgery in prone position for concomitant injuries.

Methods

Retrospective study including adult trauma patients with blunt splenic/liver injuries and attempted NOM from 01/2009 to 06/2015 was conducted. Patient and injury characteristics as well as outcomes [failed (f)NOM, mortality] of patients with/without surgery in prone position were compared (‘prone’ vs. ‘non-prone’ group).

Results

A total of 244 patients with blunt splenic/liver injury and attempted NOM were included. Forty patients (16.4%) underwent surgery in prone position on median post-injury day 2.0 [interquartile range (IQR) 3.0]. Surgery in prone position was mostly performed for associated spinal or pelvic injuries. The ISS was significantly higher, and the proportion of patients with high-grade injuries (OIS?≥?3) was significantly less frequent in the ‘prone? group (30.0?±?14.5 vs. 23.9?±?13.2, p?=?0.009 and 27.5 vs. 53.9%, p?=?0.002). In-hospital mortality as well as NOM failure rates were not significantly different between the ‘prone’ and ‘non-prone? group (2.5 vs. 2.9%, p?=?1.000; 0.0 vs. 4.4%, p?=?0.362). Eleven patients with high-grade injuries were operated in prone position at median day 3 (IQR 3.0). None of these patients failed NOM. However, one patient with a grade IV splenic injury required immediate splenectomy after being operated in right-sided position on the day of admission.

Conclusion

In this single-center analysis, surgery in prone position was performed in a substantial number of patients with splenic/liver injuries without increasing the fNOM rate. However, caution should be used in patients with grade IV/V splenic injuries.

     

Pathogenic mitochondrial mt-tRNAAla variants are uniquely associated with isolated myopathy

Pathogenic mitochondrial DNA (mtDNA) point mutations are associated with a wide range of clinical phenotypes, often involving multiple organ systems. We report two patients with isolated myopathy owing to novel mt-tRNA^Ala variants. Muscle biopsy revealed extensive histopathological findings including cytochrome c oxidase (COX)-deficient fibres. Pyrosequencing confirmed mtDNA heteroplasmy for both mutations (m.5631G>A and m.5610G>A) whilst single-muscle fibre segregation studies (revealing statistically significant higher mutation loads in COX-deficient fibres than in COX-positive fibres), hierarchical mutation segregation within patient tissues and decreased steady-state mt-tRNA^Ala levels all provide compelling evidence of pathogenicity. Interestingly, both patients showed very high-mutation levels in all tissues, inferring that the threshold for impairment of oxidative phosphorylation, as evidenced by COX deficiency, appears to be extremely high for these mt-tRNA^Ala variants. Previously described mt-tRNA^Ala mutations are also associated with a pure myopathic phenotype and demonstrate very high mtDNA heteroplasmy thresholds, inferring at least some genotype:phenotype correlation for mutations within this particular mt-tRNA gene.     

Fatigue is cross-sectionally not associated with objective assessments of inflammation,but changes in fatigue are associated with changes of disease activity assessments during biologic treatment of patients with established rheumatoid arthritis

Clinical Rheumatology - The associations between fatigue and disease activity in patients with rheumatoid arthritis (RA) have not been defined. The present objectives were to explore in RA patients...