A missense variant in CREBRF, rs373863828, is associated with fat-free mass, not fat mass in Samoan infants.

BACKGROUND/OBJECTIVES: In Samoa, where 80% of the adult population is living with obesity, understanding the determinants of adiposity and growth during infancy may inform prevention efforts. We examined the association of a missense variant, rs373863828, in the CREBRF gene with body composition in Samoan infants. Adults with one or more copies of the rs373863828 minor allele (A) have higher odds of obesity, based on body-mass index (BMI), but paradoxically decreased odds of diabetes compared to those without the allele. Our study may offer novel insight into the natural history and pathogenesis of this unexpected relationship. SUBJECTS/METHODS: In a prospective study, we measured body composition in early infancy, and at 2- and 4-months of age using anthropometry and dual-energy x-ray absorptiometry (DXA). We genotyped subjects at the CREBRF rs373863828 locus and compared infants with (AA/AG) and without (GG) the variant. In longitudinal analyses, we calculated the absolute change in each outcome from the early infant to the 4-month assessment, adjusting for baseline and other covariates. RESULTS: In cross-sectional analyses, there was no significant difference in infant BMI or fat mass by genotype. After adjusting for covariates, infants with the variant had 4.0 ± 1.8 g more bone mass (p = 0.026) and 210.9 ± 79.6 g more lean mass (p = 0.009) at 4-months and accumulated 176.9 ± 73.0 g more lean mass between the early infant and 4-month assessment (p = 0.017). CONCLUSIONS: The CREBRF rs373863828 minor allele (A) was not associated with increased BMI or adiposity in Samoan infants, but instead with increased lean and bone mass. Our findings suggest that lean (i.e., muscle) and bone mass accretion should be explored as pathways to explain the "protective" effect of the CREBRF variant against diabetes.

25 years or more after spinal cord injury: clinical conditions of individuals in the Florence and Stockholm areas.

SETTING: Retrospective analysis and retrospective follow-up. INTRODUCTION: Spinal cord injury (SCI) patients have today a nearly normal lifespan. Avoidance of medical complications is key to this end. The aim of the study was to analyse health in individuals surviving 25 years or more after traumatic SCI in Stockholm and Florence, and compare medical complications. METHODS: Data from the databases of the Spinal Unit of Florence and from the Spinalis, Stockholm were analysed. Patients included were C2-L 2, American Spinal Cord Association (ASIA) Impairment Scale (AIS) A-C, and ≥25 years post traumatic SCI. Patients underwent a thorough neurological and general examination, and were interviewed about medical events during those years. Analysed data include: gender, age at injury, current age, neurological level, AIS, cause of injury, presence of neuropathic pain (NP), and spasticity and medical complications. RESULTS: A total of 66 Italian patients and 74 Swedish patients were included. The only statistical difference between the groups was cause of injury due to falls was higher in the Florence group (P<0.01). Male/female ratio was 4:1. Traffic accidents were the most common cause of injury. In all, 60% were paraplegics. Pressure ulcers (PU) occurred in nearly 60% and 32% experienced NP. Respiratory complications (RC) occurred in 25% among tetraplegics. Neurological deterioration occurred in 14%. CONCLUSION: PU, bony fractures, spasticity and NP are important problems after SCI. RC are of clinical importance in the tetraplegics. Complications occur during all periods after injury. Many patients are otherwise healthy 25 years or more after SCI.

Physiological effects of lower extremity functional electrical stimulation in early spinal cord injury: lack of efficacy to prevent bone loss.

STUDY DESIGN: Controlled, repeat-measures study. OBJECTIVES: To determine if functional electrical stimulation (FES) can affect bone atrophy in early spinal cord injury (SCI), and the safety, tolerance and feasibility of this modality in bone loss remediation. SETTING: Spinal Injuries Units, Royal Adelaide Hospital and Hampstead Rehabilitation Centre, South Australia. METHODS: Patients with acute SCI (ASIA A-D) were allocated to FES (n=23, 28+/-9 years, C4-T10, 13 Tetra) and control groups (CON, n=10, 31+/-11 years, C5-T12, four Tetra). The intervention group received discontinuous FES to lower limb muscles (15 min sessions to each leg twice daily, over a 5-day week, for 5 months). Dual energy X-ray absorptiometry (DEXA) measured total body bone mineral density (tbBMD), hip, spine BMD and fat mass (FM) within 3 weeks, and 3 and 6 months postinjury. RESULTS: FES and CON groups' tbBMD differed significantly at 3 months postinjury (P<0.01), but not thereafter. Other DEXA measures (hip, spine BMD, FM) did not differ between groups at any time. No adverse events were identified. CONCLUSION: Electrically stimulated muscle activation was elicited, and tetanic effects were reproducible; however, there were no convincing trends to suggest that FES can play a clinically relevant role in osteoporosis prevention (or subsequent fracture risk) in the recently injured patient. The lack of an osteogenic response in paralysed extremities to electrically evoked exercise during subacute and rehabilitation/recovery phases cannot be fully explained, and may warrant further evaluation.

Intravenous infusion of 4-AP in chronic spinal cord injured subjects.

STUDY DESIGN: A prospective double blind cross over trial of intravenous 4-Aminopyridine (4-AP). OBJECTIVE: To determine the efficacy of this drug in the treatment of spinal cord injured (SCI) patients for neurologic impairment, pain and spasticity. SETTING: The post anesthesia care unit (PACU) of a tertiary care acute hospital. METHODS: Twelve paraplegic patients were enrolled in a double blind cross over intravenous trial of 4-Aminopyridine (4-AP). Thirty milligrams of 4-AP or placebo were administered over a 2 h period. Patients were serially examined during and after the infusion clinically for pain, sensorimotor function, hypertonicity and motor control using electromyography (EMG). Samples of blood and cerebrospinal fluid (CSF) were also analyzed at similar intervals. RESULTS: Despite penetration of 4-AP into the CSF, no significant differences were noted in the clinical and EMG parameters at the times measured. Individual changes in sensory function were reported by some patients in both the placebo and 4-AP trials, however mean values were not robust. Frequently, patients complained of unpleasant symptoms during the 4-AP infusion. CONCLUSION: The intravenous route may not be the best way to administer this drug as no short term benefits were observed.

Diversion colitis: a cause of abdominal discomfort in spinal cord injury patients with colostomy.

Diversion colitis is thought to result from nutritional deficiencies secondary to fecal diversion. Symptoms include hemorrhagic purulent rectal discharge, abdominal pain, and tenesmus. 5-Aminosalicylic acid (5-ASA) and N-butyrate enemas have been reported to help this condition non-spinal cord injury (SCI) patients. We report the case of a 49-year-old C6 ASIA B tetraplegic man who had received colostomy because of intractable ileus 10 years earlier. He presented with a 2-week history of rectal pain and bleeding. Abdominal and rectal examination on admission were unremarkable. Colonoscopy showed a partial stricture 70cm proximally to the rectum. The colonic mucosa appeared granular and friable with evidence of linear ulceration. Histopathologic study was consistent with colitis. The patient developed fever, abdominal distention, and extensive retroperitoneal air after endoscopy, suggesting colonic perforation. He was treated with daily 5-ASA suppository and total parenteral nutrition for the presumed diagnosis of diversion colitis, and intravenous antibiotics for perforated colon. After 6 weeks of treatment with 5-ASA, the patient had decreased rectal pain and bleeding. This experience suggests that diversion colitis may be a cause of abdominal discomfort in SCI patients and that 5-ASA may be used in the management of diversion colitis.

Effect of mexiletine on spinal cord injury dysesthetic pain.

Severe pain occurs in 5-30% of the spinal cord-injured (SCI) population and is difficult to treat. Subarachnoid lidocaine has been used in selected patients with some success. Mexiletine, an analog of lidocaine that acts at Na+/K+ channels in the peripheral nerve, has been found effective in persons with diabetic dysesthetic neuropathy. The effect of mexiletine in the treatment of spinal cord dysesthetic pain was examined in this study. Fifteen patients were enrolled, and 11 patients completed the prospective, randomized, placebo-controlled, double-blind, crossover design trial. Inclusion/exclusion criteria were carefully defined. A 1-wk washout period was followed by a 4-wk drug trial of either mexiletine (450 mg/day) or placebo. This was repeated for the second medication in the second arm of the study. Patients were followed weekly with McGill and visual analog pain scales. Baseline, midpoint, and endpoint Barthel function scores were recorded. The Wilcoxon's signed-rank test and paired t test were used for statistical analysis. Results showed no significant effect of mexiletine on SCI dysesthetic pain scales or Barthel index. In conclusion, in this trial, mexiletine did not appear to decrease spinal cord injury-related dysesthetic pain.

Verbal and facial measures of children's emotion and empathy.

The purpose of this study was to assess the relationship between two theoretically distinct aspects of children's emotional responses (Lewis & Michalson, 1983), their emotional experience (via verbal report) and emotional state (via nonverbal expression), in response to emotion-evoking stimuli. A related objective was to assess the concordance of these two verbal and nonverbal measures as indices of empathy, i.e., affective responses consistent with those of stimulus persons. Facial expressions of 60 10-year-old girls were unobtrusively videotaped while they individually viewed six stimulus vignettes. Half of these children pressed a button to indicate awareness of emotional arousal while viewing stimuli; half served as controls. Results indicated that emotional and empathic responses were not affected by the button press procedure, or by a social desirability response set. Expressive responses at button presses were microanalytically analyzed using AFFEX. Postviewing interviews assessed children's reported emotions and the affect match (empathy) between children's reported emotion for themselves and stimulus characters. Results indicated modest associations between the emotions children reported and those facially displayed and similar associations between children's verbal and facial empathy scores. Results address the concurrent validity of different measures of children's emotions, and contribute to the small number of extant multimethod studies on children's emotional responses and empathy.

Children's concordant emotions and cognitions in response to observed emotions.

Children's emotional and cognitive responses to observed scenarios were examined in 2 studies (N = 138 5-13-year-olds) investigating hypothesized developments in concordant emotion with stimulus persons, cognitive attributions for these emotions, and the effects of emotional intensity in self and stimulus persons. Results across studies confirmed age-related increases in children's emotional and cognitive responses. There were limited increases with age in concordant emotion, and continuous increases in the frequency and kinds of attributions explaining such emotion. Results also confirmed a model ordering expected developments in children's emotion attributions. As expected, stimulus persons' emotional intensity correlated with children's emotion intensity and affect match. However, as expected, empathy with others was lower when children's own intensity was higher than stimulus persons'. Present findings contribute to investigations of children's understanding of emotions and have implications for developmental studies of empathy.

Aphidicolin-induced topological and recombinational events in simian virus 40.

Highly compacted (40S) SV40 DNA replication intermediates formed in vivo during aphidicolin exposure and immediately broke down in two stages. In the rapid initial stage, single strand DNA breaks caused loss of superhelicity in the 40S replication intermediates. This DNA breakage was accompanied by the formation of strong, permanent protein-DNA crosslinks which reached a maximum as nicking of the aberrant DNA replication intermediates was completed. These protein-associated DNA strand breaks were not repaired. In the slower second stage of breakdown, the aberrant DNA replication intermediates remained nicked and strongly associated with protein as they underwent DNA replication fork breakage and recombinational changes to produce high molecular weight forms.

Hypersensitivity to low level cytotoxic stress in mouse cells with high levels of DHFR gene amplification.

Low level cytotoxic stress greatly accelerates the loss of unstably amplified dihydrofolate reductase (dhfr) genes from methotrexate-resistant mouse cell lines. To understand this drug-induced loss of amplified genes, the highly methotrexate-resistant mouse R500 cell line was flow sorted into two subpopulations with higher and lower average dhfr gene dosage respectively. The subpopulation with higher levels of gene amplification was much more sensitive to low level cytotoxic stress as judged by both cloning efficiency and growth in the presence of low concentrations of cytotoxic drugs. These results suggest that high levels of gene amplification can confer hypersensitivity to cytotoxic stressors such as anticancer drugs.

Rapid evaluation of topoisomerase inhibitors: caffeine inhibition of topoisomerases in vivo.

Caffeine was found to inhibit both type I and type II topoisomerases in vivo as judged by its effects on replicating simian virus 40 (SV40) chromosomes. The study was facilitated by the use of a rapid filter assay for the detection and characterization of topoisomerase inhibitors. The assay, which requires neither purified enzymes nor substrates, was able to identify both antagonists and poisons of type I and type II topoisomerases.

Swiveling and decatenation of replicating simian virus 40 genomes in vivo.

We have found that type II topoisomerase inhibitors have two effects on replicating simian virus 40 genomes in vivo: production of catenated dimers and slowed replication of the last 5% of the genome. This suggests that type II topoisomerase simultaneously decatenates and facilitates replication fork movement at this stage of DNA replication. On the basis of this observation, a detailed model is proposed for the roles of topoisomerases I and II in simian virus 40 DNA replication.