[Comparison of efficacy and safety of insulin aspart injection Rishulin and NovoRapid for treatment of diabetes: a multicenter, randomized, open-labeled, controlled trial].

Objective: To compare the efficacy and safety of Tonghua Dongbao's insulin aspart injection (Rishulin) and NovoRapid (Novo Nordisk) in the treatment of diabetes. Methods: A 26-week, randomized, open-label, parallel-group, positive control drug and non-inferiority trial was conducted in 23 centers in China. A total of 563 diabetes with poor blood glucose control treated with insulin for at least 3 months before were included. The subjects were randomized(stratified block random method) into those receiving Rishulin or NovoRapid at a ratio of 3∶1. Both groups were combined with basal insulin (Lantus). The primary endpoint was the change in glycosylated hemoglobin (HbA1c) from baseline to the end of 24 weeks of treatment. Results: For full analysis set, after 24 weeks of treatment, HbA1c level of Ruishulin group decreased from (8.66±1.28)% to (7.77±1.09)% (P<0.001), and that of NovoRapid group decreased from (8.47±1.28) % to (7.65±0.97) % (P<0.001). Treatment difference in HbA1c (NovoRapid group-Ruishulin group) was -0.061% (95%CI -0.320-0.199). HbA1c<7.0% target reacing rates were 24.26% and 21.21% (P=0.456), and HbA1c<6.5% target reacing rates were 9.65% and 6.82% (P=0.310) in Ruishulin group and NovoRapid group, repectively. The standard 2 hours postprandial blood glucose (2hPG) in Ruishulin group decreased from (16.23±5.22) mmol/L to (12.65±4.57) mmol/L (P<0.001), and 2hPG in NovoRapid group decreased from (16.13±5.37) mmol/L to (11.91)±4.21) mmol/L (P<0.001). The fingertips blood glucose at 7-point of both groups exhibited varying degrees of reduction compared with those at baseline, repectively. Positive ratios of specific antibodies were 31.68% in Ruishulin group and 36.36% in NovoRapid group (P=0.320). Ratios of negative to positive were 7.43% and 10.61% (P=0.360), and ratios of positive to negative were 10.40% and 7.58% (P=0.360) in Ruishulin group and NovoRapid group, respectively. The incidence of hypoglycemia was 60.05% and 55.40% (P=0.371), and the incidence of adverse events was 76.60% and 77.70% (P=0.818) in Ruishulin group and NovoRapid group, respectively. Conclusions: Rishulin is not inferior to NovoRapid, and has shown good efficacy and safety. It can be an ideal choice for clinicians in patients with poor blood glucose control with insulin.

[Intranuclear cytoplasmic autophagosomes cause specific nucleolysis and cell death of liver cancer cells and liver cells].

The structure and performance of nuclear cytoplasmic autophagosomes was explored. Seventeen cases of hepatocellular carcinoma and liver cells with other diseases from liver tissues were selected. The nuclear cytoplasm were isolated and degraded by the nuclear membrane. Damaged cytoplasm had damaged its own membrane and the surrounding nuclear tissues other than the nuclear membrane, leading to specific nucleolysis and cell death of liver cancer cells and liver cells.

Therapeutic potential of amniotic fluid stem cells to treat bilateral ovarian dystrophy in dairy cows in a subtropical region.

Amniotic fluid is a rich source of multipotent mesenchymal stem cells (MSCs). Amniotic fluid stem cells (AFSCs) have become a new source of stem cells; they have low immunogenicity and are easily harvested. For this reason, they may be useful in clinical tissue engineering. Moreover, AFSCs have anti-inflammatory properties and can repair tissues. This study evaluated the utility of AFSC injection to treat bilateral ovarian dystrophy in Holstein-Friesian cows. Bovine AFSCs (BAFSCs) were collected at slaughter from Holstein-Friesian cows during the third or fourth month of pregnancy and cultured in vitro. The BAFSCs began to show a fibroblast-like morphology. They were positive for ß-integrin, CD44, CD73, CD106 and Oct4 and negative for CD34 and CD45. After induction, the cells differentiated into mesodermal lineages. Bilateral ovarian dystrophy was confirmed by ultrasonography in 16 lactating cows. The subsequent experiment lasted 15 weeks. Serum was collected weekly to analyse progesterone concentrations, and weekly ultrasonography recorded ovarian changes. Each cow was equipped with an automatic heat detection system to facilitate oestrus observation and breeding records. The progesterone concentration of two cows in the treatment group (25%) significantly increased during weeks 10-15. On ultrasonography, the treatment group demonstrated mature follicles after BAFSCs injection, and foetuses were visualized approximately 40 days after artificial insemination (AI). Oestrus rates in the control and treatment groups were 0% (0/8) and 50% (4/8), respectively; pregnancy rates were 0% (0/8) and 25% (2/8), respectively. Calves were successfully delivered in both cases of pregnancy. These results show that BAFSCs can alleviate bovine ovarian dystrophy and restore fertility.

Structural correlates of trait impulsivity in patients with bipolar disorder and healthy controls: a surface-based morphometry study.

BACKGROUND: Patients with bipolar disorder (BD) frequently exhibit impulsive behaviors independent of their mood state, and trait impulsivity is increasingly recognized as a crucial BD biomarker. This study aimed to investigate structural correlates of trait impulsivity measured using the Barratt Impulsiveness Scale (BIS) in healthy controls (HCs) and patients with BD. METHOD: We recruited 59 patients diagnosed with BD I or BD II (35.3 ± 8.5 years) and 56 age- and sex-matched HCs (33.9 ± 7.4 years). Participants underwent structural magnetic resonance imaging and clinical evaluations, and their BIS scores were evaluated. An automated surface-based method (FreeSurfer) was used to measure cortical thickness and generate thickness maps for each participant. Brain-wise regression analysis of the association between cortical thickness and BIS scores was performed separately for BD and HC groups by using a general linear model. RESULTS: Patients with BD obtained significantly higher BIS scores than HCs. In HCs, higher BIS scores were associated with a thinner cortex in the left inferior, middle and medial frontal cortices. By contrast, in BD patients, higher BIS scores were associated with a thicker cortex in the right insula. Patients with BD showed a thinner cortex than HCs in all these four structures. CONCLUSIONS: The findings indicate that the left prefrontal cortex plays a cardinal role in trait impulsivity of healthy individuals. Patients with BD have a different structural correlate of trait impulsivity in the right insula. However, the use of various psychotropics in patients with BD may limit our interpretation of BD findings.

[Evaluation of short-term effect of intense pulsed light combined with meibomian gland expression in the treatment of meibomian gland dysfunction].

Objective: To explore short-term effect of intense pulsed light (IPL) combined with meibomian gland expression in treating meibomian gland dysfunction (MGD). Methods: This study was a prospective, randomized, double-masked, controlled study. Forty-four MGD patients were enrolled in the study and received three consecutive IPL treatments with an interval of 4 weeks. One eye of each patient was randomly assigned as the study eye receiving the IPL therapy with an energy of 14-16 J/cm(2), and the fellow eye was as the control eye receiving a placebo therapy with 0 J/cm(2). Meibomian gland expression was immediately performed after the IPL treatment in both eyes. Efficacy was evaluated through assessment of the meibomian gland yielding secretion score (MGYSS) , SPEED questionnaire, tear film break-up time (TBUT), cornea fluorescein staining and infrared meibography. Safety was evaluated through best spectacle corrected visual acuity, intraocular pressure, slit lamp examination and fundus examination. These examinations were performed before and after each treatment. Results: Significant improvements were observed in the MGYSS and TBUT after IPL treatments (P<0.05). The improvements compared to the baseline of MGYSS at the upper eyelid in the treatment eyes were significantly higher than those in the control eyes after the first treatment (Z=-2.036, P=0.003). The improvements compared to baseline of MGYSS at the lower eyelid and the TBUT in the treatment eyes were significantly higher than those in the control eyes after the second treatment (Z=-2.999 and -2.036, respectively P=0.007 and 0.042, respectively). SPEED and cornea fluorescein staining were decreased in both eyes after IPL treatments, but there was no statistical difference between the two eyes. No obvious complication was observed in the study. Conclusions: IPL treatment combined with meibomian gland expression is an efficient and safe therapy, and can increase meibomian gland yielding secretion, increase the TBUT, relieve the symptoms and repair the corneal epithelium defects for MGD eyes. (Chin J Ophthalmol, 2017, 53: 675-681).

The prevalence of actinic keratosis in patients visiting dermatologists in two hospitals in China.

BACKGROUND: Actinic keratosis (AK) is one of the most common conditions treated by dermatologists in western countries. Studies have shown that AK prevalence in Europe, the U.S.A. and Australia is 4·5-60%. No data of AK prevalence in China has been reported. OBJECTIVES: This study aimed to explore the prevalence of AK in patients visiting dermatologists in two hospitals in China. METHODS: This study was conducted in the dermatology departments of two teaching hospitals (Peking University First Hospital, Beijing, and Fourth Military Medical University, Xi'an). All records for 5 years between 2008 and 2012 with clinically or pathologically diagnosed AKs were collected from the pathological databases of both hospitals. Data from these records were used to calculate the prevalence of AKs among patients who were seen by dermatologists in these hospitals. To estimate the reliability of data from the previous database, a cross-sectional study was conducted simultaneously in the two hospitals from 15 October to 8 December in 2012 after all dermatologists in the two departments were retrained through intensive courses on recognizing AK clinically. RESULTS: The prevalence of total clinical AKs through 2008-2012 was 0·52% in 1 590 817 patient visits in the two hospitals. The yearly prevalence of clinical AKs was 0·30-1·20%. In the cross-sectional study, 72 437 clinical patients were screened and 76 patients (1·05%) were identified to have clinically recognized AK. CONCLUSIONS: The overall prevalence of AKs in patients visiting dermatologists in the two hospitals in China was 0·52%, which is much lower than the prevalence in western countries.

Polymorphisms in genes in the RANKL/RANK/OPG pathway are associated with bone mineral density at different skeletal sites in post-menopausal women.

UNLABELLED: Association between 22 single nucleotide polymorphisms (SNPs) in the TNFSF11, TNFRSF11A, and TNFRSF11B genes in the RANKL/RANK/OPG pathway with bone mineral density (BMD) in 881 post-menopausal women. Our results suggest that TNFSF11 and TNFRSF11A, but not TNFRSF11B, genetic polymorphisms influence BMD mainly in the femoral neck in post-menopausal Chinese women. INTRODUCTION: The aim of this study was to assess the relationship of polymorphisms in the TNFSF11, TNFRSF11A, and TNFRSF11B genes in the RANKL/RANK/OPG pathway with bone mineral density (BMD) in a cohort of Chinese post-menopausal women. METHODS: A cross-sectional study was conducted in 881 post-menopausal women aged 50-89 years. All participants underwent lumbar spinal (LS) and femoral neck (FN) BMD evaluation by dual-energy X-ray absorptiometry. Twenty-two TNFSF11, TNFRSF11A, and TNFRSF11B SNPs were genotyped. We tested whether a single SNP or a haplotype was associated with BMD variations. RESULTS: Two SNPs in the TNFSF11 gene (rs2277439 and rs2324851) and one in the TNFRSF11A gene (rs7239261) were found to be significantly associated with FN BMD (p = 0.014, 0.013, and 0.047, respectively). Haplotype TGACGT of TNFSF11 rs9525641-rs2277439-rs2324851-rs2875459-rs2200287-rs9533166 was a genetic risk factor toward a lower FN BMD (beta = -0.1473; p = 0.01126). In contrary, haplotype TAGCGT of TNFSF11 rs9525641-rs2277439-rs2324851-rs2875459-rs2200287-rs9533166 was genetic protective factor for LS BMD (beta = 0.3923; p = 0.04917). CONCLUSIONS: Our findings suggest that TNFSF11 and TNFRSF11A, but not TNFRSF11B, genetic polymorphisms influence BMD mainly in the femoral neck in post-menopausal Chinese women. This contributes to the understanding of the role of genetic variation in this pathway in determining bone health.

Frequency and features of TP53 mutation in 30 Chinese patients with sporadic basal cell carcinoma.

BACKGROUND: Basal cell carcinoma (BCC) is a prevalent form of nonmelanoma skin cancer. Although numerous studies in white populations suggest that mutations in the TP53 gene play an important role in the development of BCC, it is not clear whether this is also the case in East Asian populations such as in China. AIM: To investigate the frequency and the features of TP53 mutation in sporadic BCC in a Chinese population. METHODS: In total, 30 patients with sporadic BCC, who had previously taken part in a study on PTCH1 mutations, were enrolled. BCC and control cells were obtained by laser-capture microdissection, and DNA was amplified and sequenced for analysis of TP53 mutations. RESULTS: In the 30 BCC samples, 6 TP53 point mutations were found (frequency of 20%), and 4 of these 6 mutations had ultraviolet (UV)-specific alterations. Combining these results with those of the previous study on PTCH1 mutations, we found that two patients with had three types of genetic alterations (each had two PTCH1 mutations and one TP53 point mutation). A further two patients each had one PTCH1 mutation and one UV signature TP53 mutation. In addition, the total number of UV-specific mutations of PTCH1 and TP53 accounted for 20% of the total patient group. CONCLUSIONS: The incidence of TP53 mutation in BCC in our Chinese subjects was lower than that reported for white populations. Many of the patients carried mutations of other genes in addition to of TP53. The majority of TP53 mutations were UV-induced specific alterations. However, the results of the two studies on TP53 and PTCH1 indicated that the incidence of UV-specific mutations is much lower in Chinese than in white populations.

Polymorphisms in the promoter region of myostatin gene are associated with carcass traits in pigs.

Higher average daily gain, more lean meat yield and less fat yield of porcine carcass increase selling profits for animal producers. Myostatin (MSTN), previously called GDF8, is a member of transforming growth factor-ß (TGF-ß) superfamily. It is a negative regulator for both embryonic development and adult homeostasis of skeletal muscle. In this study, the genotypes of the previously described SNPs MSTN g.435G>A and g.447A>G SNPs in 66 Duroc pigs, 33 Landrace pigs, 180 Duroc × Landrace (DL) pigs and 155 Duroc × Yorkshire × Landrace (DYL) pigs were determined by Taqman SNP Genotyping Assays. For Duroc and Landrace pigs, MSTN g.435GG/g.447AA individual had greater backfat thickness (p < 0.05) than g.435AA/g.447GG individual, whereas MSTN g.435AA/g.447GG had greater meat (p < 0.05) and meat percentage (p < 0.05) than g.435GA/g.447AG individual. For DL and DYL pigs, the MSTN g.435GG/g.447AA animals were greater in backfat at ultrasound 10th rib (p < 0.05) and carcass 10th rib (p < 0.01) than g.435AA/g.447GG individual. The MSTN g.435AA/g.447GG individual also had higher values than g.435GG/g.447AA for anterior-end meat (p < 0.05), posterior-end meat (p < 0.01), total meat weight (p < 0.01) and meat percentage (p < 0.01). This study confirmed evidence that MSTN g.435G>A and g.447A>G affected carcass traits in pigs. The effects of the mutated alleles were additive with the maximal effects resulting from two copies of the mutated allele. Selection for MSTN g.435A/g.447G allele is expected to increase muscle of limb and total meat production and decrease backfat thickness.

Unique features of PTCH1 mutation spectrum in Chinese sporadic basal cell carcinoma.

BACKGROUND: Alterations of the PTCH1 gene have been found to contribute to both familial and sporadic basal cell carcinoma (BCC), especially in Caucasian patients. Furthermore, the majority of PTCH1 gene mutations in sporadic BCCs in Caucasian patients carry ultraviolet (UV) signatures, suggesting the key role of UV light in BCC development. However, sporadic BCC in non-Caucasian population has a lower incidence, and the pathogenesis remains largely unknown. To date, there has been no mutation analysis on PTCH1 gene in Chinese patients with sporadic BCCs. OBJECTIVE: To investigate genetic alterations of the PTCH1 gene in Chinese sporadic BCCs. METHODS: Direct sequencing was used to screen for mutations in PTCH1 in 31 microdissected samples in Chinese sporadic BCCs. In addition, single nucleotide polymorphisms (SNPs) were studied for loss of heterozygosity (LOH). RESULTS: Nineteen PTCH1 mutations in 17 of the 31 BCCs (54.8%) were identified. SNP analysis revealed LOH of PTCH1 in 10 of 23 BCCs (43.5%). Interestingly, the majority of mutations identified (63.2%) were insertion/deletion, which was different from the results in Caucasian cases whose mutations are predominantly point mutations. Only two (10.5%) of the remaining seven mutations were UV-specific C → T transition or tandem CC → TT transitions. All mutations occurred evenly throughout the entire PTCH1 protein domain without a hot-spot detected. CONCLUSION: Mutations and LOH in PTCH1 were also highly prevalent in Chinese sporadic BCCs. However, UV light plays a less role in causing these mutations, suggesting other potential mechanisms in the development of sporadic BCC in Chinese patients.

Preliminary exploration of the clinical features of Chinese patients with skin malignancies and premalignancies: a retrospective study of 1420 cases from Peking University First Hospital.

BACKGROUND: The epidemiological and clinical characterization data of skin malignancies and premalignancies in Chinese population is scarce and inadequate. OBJECTIVE: To systematically investigate the clinical features and the trend of skin malignancies and premalignancies in 1420 Chinese cases. METHODS: A total of 1398 patients (presenting 1420 skin tumours) were included. Clinical and demographic information for every individual was collected, including age, age of onset, sex, lesion location, disease duration and tumour histology, which was analyzed for each type of skin tumours. RESULTS: The number of skin malignancies and premalignancies increased over time, with Basal cell carcinoma (BCC) as the most common type (30.5%). The majority of the patients were above 60 years of age both at onset and at diagnosis (52.8% and 62.9%, respectively), yet around one-third of patients were between 35-59 years (35.3% and 31.2%, respectively). Skin malignancies and premalignancies were mainly located in the head and neck (58.6%), followed by the trunk (18.3%) and the extremities (15.0%). Of all BCCs, nodular BCC was the most common histologic subtype (62.8%), while 15.8% were classified as aggressive subtypes. Malignant melanoma (MM) comprised the lowest proportion of 3.7%, with 75% located on extremities. The diagnostic accordance rates varied from 49.5% to 90.4%, with BCC being 67.9%. CONCLUSIONS: The clinical features of skin malignancies and premalignancies in this study showed some similarities with those observed in Caucasian and other Asian populations, with several distinguished features in Chinese patients also being recognized. Closer attention to suspicious lesions in young and middle-aged people is needed.

Effect of three polyether ionophores on pharmacokinetics of florfenicol in male broilers.

Drug-drug interactions (DDIs) may adversely affect the prevention and cure of diseases. The effects of three polyether ionophore antibiotics, salinomycin (SAL), monensin (MON), and maduramycin (MAD) on the pharmacokinetics of florfenicol (FFC) were investigated in broilers. The chickens were fed rations with or without SAL (60 mg/kg feeds), MON (120 mg/kg feeds), or MAD (5 mg/kg feeds) for 14 consecutive days. FFC was given to the chickens either intravenously (i.v.) or orally (p.o.) at a single dose of 30 mg/kg body weight. Blood samples were taken from each chicken at 0-24 h postadministration of FFC. The plasma concentration of FFC was detected by high-performance liquid chromatography. The plasma concentration of FFC decreased with i.v. or p.o. co-administration of SAL, MON, or MAD in broilers, implying occurrence of DDIs during the co-administration of FFC with these ionophores. Our findings suggest that more attention should be given to the use of FFC to treat bacterial infections in chickens supplemented with polyether ionophore antibiotics.

Predisposing factors of pituitary hemorrhage.

BACKGROUND AND PURPOSE: The clinical features of pituitary adenomas were retrospectively analyzed, focusing on the factors that contribute to the development of pituitary hemorrhage. Although many causes of pituitary adenoma hemorrhage have been identified, it is difficult to distinguish which conditions are truly causative. We determined the independent variables that contribute to pituitary hemorrhage in pituitary adenoma. METHODS: Two hundred and eighty-eight consecutive patients diagnosed as pituitary adenoma were enrolled. These patients underwent tumor removal through endoscopic transsphenoidal approach. The subjects were divided into hemorrhagic and non-hemorrhagic groups, based on magnetic resonance images and histological findings. The predisposing factors were reviewed in the medical records for all patients. Univariate and multivariate analyses were performed to assess the relationships between variables of pituitary adenoma hemorrhage. RESULTS: We investigated 81 patients in whom hemorrhage from pituitary adenoma occurred. The incidence of pituitary hemorrhage was 28.1% (81/288). The predisposing factors surveyed for pituitary hemorrhage were significantly associated with macroadenoma, non-functional adenomas, anticoagulation therapy, end-stage renal disease, dopamine agonist treatment, and underlying malignant disease (all P < 0.05). Sex, age, hypertension, diabetes mellitus, and previous radiation therapy were not related to pituitary hemorrhage. CONCLUSIONS: In this pooled cohort, the predisposing factors of pituitary adenoma characteristic for pituitary hemorrhage were macroadenoma and non-functional adenoma. Patients who received dopamine agonist and anticoagulation therapy are implicated as precipitating factors. Underlying end-stage renal disease and malignant disease are also factors that contribute to pituitary adenoma hemorrhage.

Dynamic cervical flexion/extension atlantodental interval and functional outcome of the Harms technique for posterior C1/2 fixation: A retrospective analysis of 16 atlantoaxial subluxation cases in a tertiary medical center.

BACKGROUND: The aim of this study was to assess the relationship between the atlantodental interval (ADI) on dynamic flexion/extension cervical radiographs and functional outcomes of posterior spinal fixation by the Harms technique for atlantoaxial subluxation (AAS). Dynamic flexion/extension on cervical radiographs is a standard assessment for evaluation of C1/2 instability in AAS patients. Most studies focused on postoperative ADI and functional outcome, including pain and fusion rate; only few studies compared dynamic ADI change pre- to post-operatively. MATERIAL AND METHODS: Retrospectively, we reviewed the medical records of 16 patients who underwent posterior spinal fixation in our center from 2018 to 2019. We used dynamic cervical flexion/extension radiographs to assess the pre- to postoperative change at 12 months in ADI of flexion (ADIf), ADI of extension (ADIe), ADI between flexion/extension (ADIΔ), C1/2 fusion rate and functional outcomes measured by the modified Japanese Orthopaedic Association scale (mJOA scale). Postoperative CT at 3∼12 months assessed screw positioning on the Gertzbein and Robbins classification. RESULTS: In the 16 patients included in this study, ADIf, ADIe and ADIΔ were significantly reduced, from respectively 8.0mm, 5.0mm and 3.0mm preoperatively to 4.6mm, 3.8mm and 0.8mm at 12 months' follow-up. The fusion rate was 81% and the mJOA score recovery rate was 34.9±14.7%. Although the screw malposition rate was higher than in other studies in C1(10%) and C2(20%), there were no new neurologic deficits or worsening of symptoms at follow-up. CONCLUSIONS: The ADIΔ showed significant reduction, showing that the Harms technique of posterior spinal fixation can effective in maintaining the stability of the atlantoaxial joint and improving functional outcome.

Neurofilaments and orthograde transport are reduced in ventral root axons of transgenic mice that express human SOD1 with a G93A mutation.

Mice engineered to express a transgene encoding a human Cu/Zn superoxide dismutase (SOD1) with a Gly93 --> Ala (G93A) mutation found in patients who succumb to familial amyotrophic lateral sclerosis (FALS) develop a rapidly progressive and fatal motor neuron disease (MND) similar to amyotrophic lateral sclerosis (ALS). Hallmark ALS lesions such as fragmentation of the Golgi apparatus and neurofilament (NF)-rich inclusions in surviving spinal cord motor neurons as well as the selective degeneration of this population of neurons were also observed in these animals. Since the mechanism whereby mutations in SOD1 lead to MND remains enigmatic, we asked whether NF inclusions in motor neurons compromise axonal transport during the onset and progression of MND in a line of mice that contained approximately 30% fewer copies of the transgene than the original G93A (Gurney et al., 1994). The onset of MND was delayed in these mice compared to the original G93A mice, but they developed the same neuropathologic abnormalities seen in the original G93A mice, albeit at a later time point with fewer vacuoles and more NF inclusions. Quantitative Western blot analyses showed a progressive decrease in the level of NF proteins in the L5 ventral roots of G93A mice and a concomitant reduction in axon caliber with the onset of motor weakness. By approximately 200 d, both fast and slow axonal transports were impaired in the ventral roots of these mice coincidental with the appearance of NF inclusions and vacuoles in the axons and perikarya of vulnerable motor neurons. This is the first demonstration of impaired axonal transport in a mouse model of ALS, and we infer that similar impairments occur in authentic ALS. Based on the temporal correlation of these impairments with the onset of motor weakness and the appearance of NF inclusions and vacuoles in vulnerable motor neurons, the latter lesions may be the proximal cause of motor neuron dysfunction and degeneration in the G93A mice and in FALS patients with SOD1 mutations.