Aging pathways for organophosphate-inhibited human butyrylcholinesterase, including novel pathways for isomalathion, resolved by mass spectrometry.

Some organophosphorus compounds are toxic because they inhibit acetylcholinesterase (AChE) by phosphylation of the active site serine, forming a stable conjugate: Ser-O-P(O)-(Y)-(XR) (where X can be O, N, or S and Y can be methyl, OR, or SR). The inhibited enzyme can undergo an aging process, during which the X-R moiety is dealkylated by breaking either the P-X or the X-R bond depending on the specific compound, leading to a nonreactivatable enzyme. Aging mechanisms have been studied primarily using AChE. However, some recent studies have indicated that organophosphate-inhibited butyrylcholinesterase (BChE) may age through an alternative pathway. Our work utilized matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry to study the aging mechanism of human BChE inhibited by dichlorvos, echothiophate, diisopropylfluorophosphate (DFP), isomalathion, soman, sarin, cyclohexyl sarin, VX, and VR. Inhibited BChE was aged in the presence of H2O18 to allow incorporation of (18)O, if cleavage was at the P-X bond. Tryptic-peptide organophosphate conjugates were identified through peptide mass mapping. Our results showed no aging of VX- and VR-treated BChE at 25 degrees C, pH 7.0. However, BChE inhibited by dichlorvos, echothiophate, DFP, soman, sarin, and cyclohexyl sarin aged exclusively through O-C bond cleavage, i.e., the classical X-R scission pathway. In contrast, isomalathion aged through both X-R and P-X pathways; the main aged product resulted from P-S bond cleavage and a minor product resulted from O-C and/or S-C bond cleavage.     

Contribution of Calcium Channel Subtypes to the Intracellular Calcium Signal in Sensory Neurons: The Effect of Injury

Background: Although the activation-induced intracellular Ca2+ signal is disrupted by sensory neuron injury, the contribution of specific Ca2+ channel subtypes is unknown.

Methods: Transients in dissociated rat dorsal root ganglion neurons were recorded using fura-2 microfluorometry. Neurons from control rats and from neuropathic animals after spinal nerve ligation were activated either by elevated bath K+ or by field stimulation. Transients were compared before and after application of selective blockers of voltage-activated Ca2+ channel subtypes.

Results: Transient amplitude and area were decreased by blockade of the L-type channel, particularly during sustained K+ stimulation. Significant contributions to the Ca2+ transient are attributable to the N-, P/Q-, and R-type channels, especially in small neurons. Results for T-type blockade varied widely between cells. After injury, transients lost sensitivity to N-type and R-type blockers in axotomized small neurons, whereas adjacent small neurons showed decreased responses to blockers of R-type channels. Axotomized large neurons were less sensitive to blockade of N- and P/Q-type channels. After injury, neurons adjacent to axotomy show decreased sensitivity of K+-induced transients to L-type blockade but increased sensitivity during field stimulation.     

Biliopancreatic diversion with duodenal switch or gastric bypass for failed gastric banding: retrospective study from two institutions with preliminary results.

BACKGROUND: Of patients who have undergone gastric banding, 11-25% will require a major reoperation with band removal and conversion to another bariatric procedure after they have failed to lose sufficient weight or have developed dysphagia or reflux. The aim of this study was to evaluate the respective benefits of Roux-en-Y gastric band (RYGB) or biliopancreatic diversion with duodenal switch (BPD-DS) after failed gastric banding and whether 1 of the 2 procedures might be a better procedure for such cases. METHODS: RYGB or BPD-DS was performed according to the institutional protocols with synchronous band removal, irrespective of the reason for failure. RESULTS: Of the 53 patients, 32 underwent laparoscopic RYGB for a body mass index (BMI) of 43.1 +/- 6.4 kg/m(2) (BMI 45.8 +/- 6.4 kg/m(2) before laparoscopic adjustable gastric banding) and 21 underwent BPD-DS for a BMI of 46.0 +/- 5.5 kg/m(2) (BMI 49.6 +/- 5.2 kg/m(2) before laparoscopic adjustable gastric banding). BPD-DS required significantly longer operative times (239.7 +/- 55.8 versus 135 +/- 26.7 minutes) and resulted in more complications (62% versus 12.5%; P <.002). No patients died postoperatively. The 2 groups of patients had a similar BMI at 12 and 18 months after revision (BMI 33.4 +/- 5.6 kg/m(2) and 31.4 +/- 3.5 kg/m(2)). The weight loss was greater after BPD-DS than after RYGB compared with the prerevision weight loss (66.2% versus 58.8% excess weight loss) or initial weight (73% versus 61.8%), although this was not significant. CONCLUSION: Despite an excessive rate of complications that were, in part, related to the learning curve in this series, BPD-DS resulted in greater weight loss compared with RYGB. However, both procedures were successful after failed gastric banding. A more accurate definition of failure could help to determine the respective indications for revisional surgery.     

Goldenhar and cri-du-chat syndromes: a contiguous gene deletion syndrome?

We report a full-term male infant born to nonconsanguinous parents who had clinical features of Goldenhar syndrome and cri du chat syndrome. At birth, the infant was noted to have dysmorphic features with bilateral preauricular tags, rotated ears, bilateral epicanthic folds, a left epibulbar lipodermoid, and an accessory left nipple. After he was assessed for feeding difficulty and tachypnea, he was found to have esophageal atresia with tracheoesophageal fistula. In addition, he had a high-pitched, cat-like cry, characteristic of cri-du-chat syndrome. He also failed a hearing test. Chromosomal analysis and fluorescence in situ hybridisation studies showed an unbalanced karyotype with a terminal deletion of the segment p14 on the short arm of chromosome 5, which is consistent with the cri-du-chat locus. The association of Goldenhar syndrome and cri-du-chat syndrome in this patient suggests that the chromosome 5p14 locus may harbor a gene implicated with Goldenhar syndrome.     

Non-cultured cell transplantation in an ovine model of non-ischemic heart failure.

OBJECTIVE: Cell therapy may be a promising alternative or adjunct to current treatment modalities for ischemic heart failure. But little is known on the impact of myogenic cell transplantation in large animal models of non-ischemic cardiomyopathy. The aim of the present study was to explore whether an ovine model of toxin-induced heart disease could benefit from non-cultured skeletal muscle cell transplantation. METHODS: Sequential intracoronary injections of doxorubicin (0.75 mg/kg) were carried out every 2 weeks until echocardiographic detection of myocardial dysfunction. Sheep were then randomly assigned to either non-cultured cell transplantation (n=8) or placebo injection (n=5). For the cell therapy group, a skeletal muscle biopsy (about 10 g) was explanted from each animal approximately 3h before grafting. After thoracotomy, 20 epicardial injections were carried out. The animals were assessed one last time before sacrifice, 2 months after the thoracotomy. Cells were tracked with cmDiI (red fluorescence) and characterized with immunohistochemistry with monoclonal antibodies to a fast skeletal isoform of myosin heavy chain. RESULTS: Two months after intramyocardial grafting, tissue Doppler imaging and conventional echocardiographic assessment of the groups showed a marked improvement in the non-cultured cell therapy group. Ejection fraction (EF) (p<0.05) as well as systolic endocardial velocities (p<0.01) improved versus the placebo group. CmDiI and skeletal myosin heavy chain expression was detected in all animals at 2 months after implantation confirming engraftment of skeletal muscle cells. CONCLUSIONS: In conclusion, our data indicate that non-cultured muscle cell transplantation is feasible and may translate into a functional benefit in an ovine model of dilated heart failure.     

Primary Hemiarthroplasty for Proximal Humeral Fractures in the Elderly: Long-Term Functional Outcome and Social Implications

Abstract Background: Primary shoulder hemiarthroplasty is an established treatment modality for complex fractures of the proximal humerus. Long-term functional outcome is often disappointing. However, little is known about social implications particularly in the elderly. Methods: A single-institution case series of consecutive geriatric patients (age > 70 years) treated with shoulder hemiarthroplasty for complex fractures of the proximal humerus between 1994 and 1997 was analysed. Postoperative morbidity, long-term function, radiological outcome and social implications were evaluated. Results: Seventy-seven patients fulfilled the study criteria. Median age at the time of operation was 80 years (range 70–93 years). Systemic and local postoperative complications were observed in 8% including 2 patients (3%) with revision surgery. Postoperative mortality was 1%. Forty-eight patients (62%) were available for follow-up (median 49 months, range 25–80 months), 22 (29%) died from causes unrelated to hemiarthroplasty before follow-up and 7 patients (9%) did not attend follow-up examination. Median Constant-Murley score was 41 points (range 17–77 points). Long-term results concerning pain were satisfying. The Oxford shoulder score ranged from 14 to 40 (median 30). Forty-one patients (85%) still lived in their original environment and managed their daily life independently despite poor shoulder function. Four patients (8%) lived in a retirement home and 3 (6%) in a nursery home. Eighty percent of our patients were still able to use public transportation, do the daily shopping and wash their whole body by themselves. Conclusion: Most patients managed their daily life independently despite poor shoulder function.     

Intraoperative somatosensory evoked potential monitoring during anterior cervical discectomy and fusion in nonmyelopathic patients--a review of 1,039 cases.

BACKGROUND CONTEXT: Intraoperative somatosensory evoked potential (SSEP) monitoring has been shown to reduce the incidence of new postoperative neurological deficits in scoliosis surgery. However, its usefulness during cervical spine surgery remains a subject of debate. PURPOSE: To determine the utility of intraoperative SSEP monitoring in a specific patient population (those with cervical radiculopathy in the absence of myelopathy) who underwent anterior cervical discectomy and fusion (ACDF) surgery. STUDY DESIGN: Retrospective review. PATIENT SAMPLE: A total of 1,039 nonmyelopathic patients who underwent single or multilevel ACDF surgery. The control group (462 patients) did not have intraoperative SSEP monitoring, whereas the monitored group (577 patients) had continuous intraoperative SSEP monitoring performed. OUTCOME MEASURE: A new postoperative neurological deficit. METHODS: SSEP tracings were reviewed for all 577 patients in the monitored group and all significant signal changes were noted. Medical records were reviewed for all 1,039 patients to determine if any new neurological deficits developed in the immediate postoperative period. RESULTS: None of the patients in the control group had any new postoperative neurological deficits. In the monitored group there were six instances of transient SSEP changes (1 due to suspected carotid artery compression; 5 thought to be due to transient hypotension) which resolved with the appropriate intraoperative intervention (repositioning of retractors; raising the arterial blood pressure). Upon waking up from anesthesia, one patient in the monitored group had a new neurological deficit (partial central cord syndrome) despite normal intraoperative SSEP signals. CONCLUSIONS: ACDF appears to be a safe surgical procedure with a low incidence of iatrogenic neurological injury. Transient SSEP signal changes, which improved with intraoperative interventions, were not associated with new postoperative neurological deficits. An intraoperative neurological deficit is possible despite normal SSEP signals.