Inherited focal, episodic neuropathies

Hereditary neuropathy with liability to pressure palsies (HNPP; also called tomaculous neuropathy) is an autosomal-dominant disorder that produces a painless episodic, recurrent, focal demyelinating neuropathy. HNPP generally develops during adolescence, and may cause attacks of numbness, muscular weakness, and atrophy. Peroneal palsies, carpal tunnel syndrome, and other entrapment neuropathies may be frequent manifestations of HNPP. Motor and sensory nerve conduction velocities may be reduced in clinically affected patients, as well as in asymptomatic gene carriers. The histopathological changes observed in peripheral nerves of HNPP patients include segmental demyelination and tomaculous or “sausage-like” formations. Mild overlap of clinical features with Charcot-Marie-Tooth (CMT) disease type 1 (CMT1) may lead patients with HNPP to be misdiagnosed as having CMT1. HNPP and CMT1 are both demyelinating neuropathies, however, their clinical, pathological, and electrophysiological features are quite distinct. HNPP is most frequently associated with a 1.4-Mb pair deletion on chromosome 17p12. A duplication of the identical region leads to CMT1A. Both HNPP and CMT1A result from a dosage effect of the PMP22 gene, which is contained within the deleted/duplicated region. This is reflected in reduced mRNA and protein levels in sural nerve biopsy samples from HNPP patients. Treatment for HNPP consists of preventative and symptom-easing measures. Hereditary neuralgic amyotrophy (HNA; also called familial brachial plexus neuropathy) is an autosomal-dominant disorder causing episodes of paralysis and muscle weakness initiated by severe pain. Individuals with HNA may suffer repeated episodes of intense pain, paralysis, and sensory disturbances in an affected limb. The onset of HNA is at birth or later in childhood with prognosis for recovery usually favorable; however, persons with HNA may have permanent residual neurological dysfunction following attack(s). Episodes are often triggered by infections, immunizations, the puerperium, and stress. Electrophysiological studies show normal or mildly prolonged motor nerve conduction velocities distal to the affected brachial plexus. Pathological studies have found axonal degeneration in nerves examined distal to the plexus abnormality. In some HNA pedigrees there are characteristic facial features, including hypotelorism. The prognosis for recovery of normal function of affected limbs in HNA is good, although recurrent episodes may cause residual deficits. HNA is genetically linked to chromosome 17q25, where mutations in the septin-9 (SEPT9) gene have been found.     

The etiology, treatment, and prevention of nonorganic failure-to-thrive in infants

Nonorganic failure-to-thrive is a medical-psychological disorder reflecting lack of growth in an infant without apparent physical causes. Children who fail to thrive as infants are at high risk for developmental delays, personality problems, abuse, and death. This article focuses on environmental failure-to-thrive, describing the behavioral characteristics of the nonthriving infant and the family milieu. Aspects of early environments of NOFT infants are profiled, specific intervention strategies are discussed, and recommendations regarding the promotion of intense, consistent multi-disciplinary intervention strategies are advanced.     

Robotic-assisted heller myotomy versus laparoscopic heller myotomy for the treatment of esophageal achalasia: multicenter study

Laparoscopic Heller myotomy (LHM) has become the standard treatment option for achalasia. The incidence of esophageal perforation reported is about 5%–10%. Robotically assisted Heller myotomy (RAHM) is emerging as a safe alternative to LHM. Data comparing the two approaches are scant. The aim of this study was to compare RAHM with LHM in terms of efficacy and safety for treatment of achalasia. A total of 121 patients underwent surgical treatment of achalasia at three institutions. A retrospective review of prospectively collected perioperative data was performed. Patients were divided into two groups: group A (RAHM), 59 patients, and group B (LHM), 62 patients. All the operations were completed using minimally invasive techniques. There were 63 women and 58 men, with a mean age of 45 ±19 years (14–82 years). Fifty-one percent of patients in group A and 95% of patients in group B reported weight loss. Duration of symptoms was equal for both groups. Dysphagia was the main complaint in both groups (P = NS). There was no difference in preoperative endoscopic treatment in both groups (44% versus 27%, P = NS). Operative time was significantly shorter for LHM in the first half of the experience (141 ± 49 versus 122 ± 44 minutes, P < .05). However, in the last 30 cases there was no difference in operative time between the groups (P = NS). Intraoperative complications (esophageal perforation) were more frequent in group B (16% versus 0%). The incidence of postoperative heartburn did not differ by group. There were no deaths. At 18 and 22 months, 92% and 90% of patients had relief of their dysphagia. This study suggests that RAHM is safer than LHM, because it decreases the incidence of esophageal perforation to 0%, even in patients who had previous treatment. At short-term follow-up, relief of dysphagia was equally achieved in both groups. Presented at the Forty-Sixth Annual Meeting of The Society for Surgery of the Alimentary Tract, Chicago, Illinois, May 14–18, 2005 (oral presentation). This study was supported in part by a grant provided by Intuitive Surgical, Inc. and Ethicon Endo-Surgery, Inc.     

Middle-Down Fragmentation for the Identification and Quantitation of Site-Specific Methionine Oxidation in an IgG1 Molecule

A middle-down LC/MS approach, for the rapid quantitation and characterization of site-specific methionine oxidation in a recombinant monoclonal IgG1 molecule, is described. An IgG1 antibody was digested with endoprotease LysC under limited proteolytic conditions to produce two major components; an antigen binding fragment (Fab) and a crystallizable fraction (Fc). These fractions were then reduced to produce three major species; light chain (LC), Fc/2 which is the C terminal region of the heavy chain (HC) and the N-terminal heavy chain region (Fd). These three fragments were separated by reversed-phase HPLC using a diphenyl column. The diphenyl column resolved site-specific methionine oxidation in all three subunits. Middle- down N-terminal sequencing with a LCT premier mass spectrometer was used to identify the sites of oxidation in the LC. Sites of oxidation in the Fc/2 were identified using middle-down collision-induced dissociation (CID) on a Qtof premier. This method allowed for the rapid quantitation and identification of oxidation on each methionine residue in an IgG1 molecule.     

Comparison of novel computer detectors and human performance for spike detection in intracranial EEG.

OBJECTIVE: Interictal spikes in intracranial EEG (iEEG) may correlate with epileptogenic cortex, but review of interictal iEEG is labor intensive. Accurate automated spike detectors are necessary for understanding the role of spikes in epileptogenesis. METHODS: The sensitivity, accuracy and reproducibility of three automated iEEG spike detectors were compared against two human EEG readers using iEEG segments from eight patients. A consensus set of detections was generated for detector calibration. Spike verification was calculated after both human EEG readers independently reviewed all detections. RESULTS: Humans and two of the three automated detectors demonstrated comparable accuracy. In four patients, automated spike detection sensitivity was >70% and accuracy was >50%. In the remaining four patients, EEG background morphology resulted in poorer performance. Blinded human verification accuracy was 76.7+/-6.6% for computer-detected spikes, and 84.5+/-4.1% for human-detected spikes. CONCLUSIONS: Automated iEEG spike detectors perform comparably to humans, but sensitivity and accuracy are patient dependent. Humans verified the majority of computer-detected spikes. SIGNIFICANCE: In some patients automated detectors may be used for mapping spike occurrences in epileptic networks. This may reveal associations between spike distribution, seizure onset, and pathology.     

Acetylcholinesterase Adaptation to Voluntary Wheel Running is Proportional to the Volume of Activity in Fast, but not Slow, Rat Hindlimb Muscles

Chronic enhancement of neuromuscular activity by forced exercise training programmes results in selective adaptation of the G₄ acetylcholinesterase (AChE) molecular form in hindlimb fast muscles of the rat, with only minor and non-selective AChE changes in the soleus. In order to shed further light on the physiological significance of this G₄ adaptation to training, we turned to a voluntary exercise model. The impact of 5 days and 4 weeks of voluntary wheel cage running on AChE molecular forms was examined in four hindlimb fast muscles and the slow-twitch soleus from two rat strains. Inbred Fisher and Sprague– Dawley rats, placed in live-in wheel cages, exercised spontaneously for distances which progressively increased up to an average of ∼3 and 18 km/day, respectively, by the end of week 4. Fast muscles responded to this voluntary activity by massive G₄ increases (up to 420%) with almost no changes in A₁₂, so that by week 4 the tetramer became the main AChE component of these muscles. The additional G₄ was composed primarily of amphiphilic molecules, suggesting a membrane-bound state. The G₄ content of fast muscles was highly correlated with the distance covered by the rats during the 5 days before they were killed ( r = 0.850-0.879, P < 0.001 in three muscles). The soleus muscle, in turn, responded to wheel cage activity by a marked selective reduction of its asymmetric forms—up to 45% for A₁₂. This A₁₂ decline, already maximal by day 5 of wheel cage running, showed no relationship with the distance covered. The present results constitute strong new evidence suggesting that the role of AChE in neuromuscular transmission is not limited solely to the rapid inactivation of just-released acetylcholine.     

Labman and Linkman: A data management system specifically designed for genome searches of complex diseases

Two programs have been developed to manage linkage analysis data. The first program, LABMAN, is a comprehensive laboratory data management system organizing pedigrees, blood DNA samples, DNA markers, Southern blot or polyacrylamide gels, autoradiographs, and marker-allele typings generated from these samples. Output includes mendelization checks for genetic incompatibilities in typings and formatted files ready for linkage analysis. LABMAN can also compress highly polymorphic allele systems into smaller allele systems facilitating analysis of large systems. The second program, LINKMAN, provides data management for lod score output from linkage analyses. It reads linkage analysis output files, calculates lod scores by family, associates lod scores with specific marker and family identifiers, and stores these data in a database where they can be combined with lod scores from previous analyses. LINKMAN easily incorporates any of a wide variety of genetic models. It produces formatted output of lod scores by user-specified criteria for reports or as ASCII files for input to other programs. If desired, tests of homogeneity of linkage across families can be run via the HOMOG program [Ott, 1991] and their output included in reports. The programs include features critical for conducting genome searches of complex diseases: They are easy-to-use, well-tested, and reliable. Data from multi-center investigations can be easily combined for analysis. Moreover, they include extensive error-checking capabilities, and they are specifically set up to protect blindness between laboratory workers and data analysts. LABMAN and LINKMAN are currently available free of charge under DOS. © 1994 Wiley-Liss, Inc.     

Eliminating Intensive Postoperative Care in Same-day Surgery Patients Using Short-acting Anesthetics

Background: A multidisciplinary effort was undertaken to determine whether patients could safely bypass the postanesthesia care unit (PACU) after same-day surgery by moving to an earlier time point evaluation of recovery criteria.

Methods: A prospective, outcomes research study with a baseline month, an intervention month, and a follow-up month was designed. Five surgical centers (three community-based hospitals and two freestanding ambulatory surgical centers) were utilized. Two thousand five hundred eight patients were involved in the baseline period, and 2,354 were involved in the follow-up period. Outcome measures included PACU bypass rates and adverse events. Intervention consisted of a multidisciplinary educational program and routine feedback reports.

Results: The overall PACU bypass rate (58%) was significantly different from baseline (15.9%, P < 0.001), for patients to whom a general anesthetic was administered (0.4-31.8%, P < 0.001), and for those given other anesthetic techniques (monitored anesthesia care, regional or local anesthetics; 29.1-84.2%, P < 0.001). During the follow-up period, the average (SD) recovery duration for patients who bypassed the PACU was significantly shorter compared to that for patients who did not bypass, 84.6 (61.5) versus 175.1 (98.8) min, P < 0.001, with no change in patient outcome. Patients receiving only short-acting anesthetics were 78% more likely (P < 0.002) to bypass the PACU after adjusting for various surgical procedures.