A practical approach to incidental findings in neuroimaging research.

OBJECTIVE: We describe the systematic approach to incidental findings (IFs) used at the Mind Research Network (MRN) where all MRI scans receive neuroradiologist interpretation and participants are provided results. METHODS: From 2004 to 2011, 8,545 MRI scans were acquired by 45 researchers. As mandated by MRN's external institutional review board, all structural sequences were evaluated by a clinical neuroradiologist who generated a report that included recommendations for referral if indicated. Investigators received a copy of their participants' reports, which were also mailed to participants unless they specifically declined. To better understand the impact of the radiology review process, a financial analysis was completed in addition to a follow-up phone survey to characterize participant perceptions regarding receiving their MRI scan results. RESULTS: The radiologist identified IFs in 34% of the 4,447 participants. Of those with IFs (n = 1,518), the radiologist recommended urgent or immediate referral for 2.5% and routine referral for 17%. For 80.5%, no referral was recommended. Estimated annual cost for this approach including support for the neuroradiologist, medical director, and ancillary staff is approximately $60,000 or $24/scan. The results of the retrospective phone survey showed that 92% of participants appreciated receiving their MRI report, and the majority stated it increased their likelihood of volunteering for future studies. CONCLUSIONS: Addressing IFs in a cost-effective and consistent manner is possible by adopting a policy that provides neuroradiology interpretation and offers participant assistance with clinical follow-up when necessary. Our experience suggests that an ethical, institution-wide approach to IFs can be implemented with minimal investigator burden.

Different strategies for auditory word recognition in healthy versus normal aging.

To explore the effects of commonly encountered pathology on auditory recognition strategies in elderly participants, magnetoencephalographic (MEG) brain activation patterns and performance were examined in 30 elderly [18 controls and 12 elderly with mild cognitive impairment (MCI) or probable Alzheimer's disease (AD)]. It was predicted that participants with known pathology would reveal different networks of brain activation, compared to healthy elderly, which should correlate with poorer performance. Participants heard a list of words representing common objects, twice. After 20 minutes a list of new and old words was presented and participants judged whether each word was heard earlier. MEG responses were analyzed using a semiautomated source modeling procedure. A cluster analysis using all subjects' MEG sources revealed three dominant patterns of activity which correlated with IQ and task performance. The highest performing group revealed activity in premotor, anterior temporal, and superior parietal lobes with little contribution from prefrontal cortex. Performance and brain activation patterns were also compared for individuals with or without abnormalities such as white matter hyperintensities and/or volume reduction evidenced on their MRIs. Memory performance and activation patterns for individuals with white matter hyperintensities resembled the group of MCI/AD patients. These results emphasize the following: (1) general pathology correlates with cognitive decline and (2) full characterization of the health of elderly participants is important in studies of normal aging since random samples from the elderly population are apt to include individuals with subclinical pathology that can affect cognitive performance.

Fluororuby as a marker for detection of acute axonal injury in rat spinal cord.

Axonal damage is a common pathological consequence of spinal cord injury. Previous studies have detected axonal injury with silver stains for degeneration or immunohistochemistry for alterations in components such as beta-amyloid precursor protein, neurofilament or ubiquitin. Fluororuby has recently been introduced as a neuronal tracer in studies of spinal cord injury and regeneration. Our study was carried out to determine whether Fluororuby can be used to identify injured axons and monitor the time course of axonal damage. Adult rats underwent needle puncture injury to the white matter in the midline and lateral spinal cord at T11. At the same time, 0.05 microl of Fluororuby was injected into the cord at the same sites. After survival times ranging from 6 h to 3 weeks, spinal cords were cut into longitudinal frozen sections and examined with confocal microscopy. Fluororuby was found to label key features of axonal injury including axonal swelling, retraction balls and disrupted axons. Damaged axons close to the injury site were consistently labeled within 6 h, with indications of swollen and disconnected axons spreading further from the site during the first week. Fewer injured axons were labeled after 1 week survival, but the marker revealed longer distances of degenerating axons both distal and rostral to the injury site. Our findings indicate that Fluororuby is a quick, sensitive, reliable and technically simple fluorescent marker for early stages of acute axonal injury and degeneration.

A biologically motivated solution to the cocktail party problem.

We present a new approach to the cocktail party problem that uses a cortronic artificial neural network architecture (Hecht-Nielsen, 1998) as the front end of a speech processing system. Our approach is novel in three important respects. First, our method assumes and exploits detailed knowledge of the signals we wish to attend to in the cocktail party environment. Second, our goal is to provide preprocessing in advance of a pattern recognition system rather than to separate one or more of the mixed sources explicitly. Third, the neural network model we employ is more biologically feasible than are most other approaches to the cocktail party problem. Although the focus here is on the cocktail party problem, the method presented in this study can be applied to other areas of information processing.

Effects of dihydropyridine receptor II-III loop peptides on Ca(2+) release in skinned skeletal muscle fibers.

In skeletal muscle fibers, the intracellular loop between domains II and III of the alpha(1)-subunit of the dihydropyridine receptor (DHPR) may directly activate the adjacent Ca(2+) release channel in the sarcoplasmic reticulum. We examined the effects of synthetic peptide segments of this loop on Ca(2+) release in mechanically skinned skeletal muscle fibers with functional excitation-contraction coupling. In rat fibers at physiological Mg(2+) concentration ([Mg(2+)]; 1 mM), a 20-residue skeletal muscle DHPR peptide [A(S(20)); Thr(671)-Leu(690); 30 microM], shown previously to induce Ca(2+) release in a triad preparation, caused only small spontaneous force responses in approximately 40% of fibers, although it potentiated responses to depolarization and caffeine in all fibers. The COOH-terminal half of A(S(20)) [A(S(10))] induced much larger spontaneous responses but also caused substantial inhibition of Ca(2+) release to both depolarization and caffeine. Both peptides induced or potentiated Ca(2+) release even when the voltage sensors were inactivated, indicating direct action on the Ca(2+) release channels. The corresponding 20-residue cardiac DHPR peptide [A(C(20)); Thr(793)-Ala(812)] was ineffective, but its COOH-terminal half [A(C(10))] had effects similar to A(S(20)). In the presence of lower [Mg(2+)] (0.2 mM), exposure to either A(S(20)) or A(C(10)) (30 microM) induced substantial Ca(2+) release. Peptide C(S) (100 microM), a loop segment reported to inhibit Ca(2+) release in triads, caused partial inhibition of depolarization-induced Ca(2+) release. In toad fibers, each of the A peptides had effects similar to or greater than those in rat fibers. These findings suggest that the A and C regions of the skeletal DHPR II-III loop may have important roles in vivo.

Postulated role of interdomain interaction within the ryanodine receptor in Ca(2+) channel regulation.

Localized distribution of malignant hyperthermia (MH) and central core disease (CCD) mutations in N-terminal and central domains of the ryanodine receptor suggests that the interaction between these domains may be involved in Ca(2+) channel regulation. To test this hypothesis, we investigated the effects of a new synthetic domain peptide DP4 corresponding to the Leu(2442)-Pro(2477) region of the central domain. DP4 enhanced ryanodine binding and induced a rapid Ca(2+) release. The concentration for half-maximal activation by agonists was considerably reduced in the presence of DP4. These effects of DP4 are analogous to the functional modifications of the ryanodine receptor caused by MH/CCD mutations (viz. hyperactivation of the channel and hypersensitization of the channel to agonists). Replacement of Arg of DP4 with Cys, mimicking the in vivo Arg(2458)-to-Cys(2458) mutation, abolished the activating effects of DP4. An N-terminal domain peptide DP1 (El-Hayek, R., Saiki, Y., Yamamoto, T., and Ikemoto, N. (1999) J. Biol. Chem. 274, 33341-33347) shows similar activation/sensitization effects. The addition of both DP4 and DP1 produced mutual interference of their activating functions. We tentatively propose that contact between the two (N-terminal and central) domains closes the channel, whereas removal of the contact by these domain peptides or by MH/CCD mutations de-blocks the channel, resulting in hyperactivation/hyper-sensitization effects.

A postulated role of the near amino-terminal domain of the ryanodine receptor in the regulation of the sarcoplasmic reticulum Ca(2+) channel.

To test the hypothesis that interactions among several putative domains of the ryanodine receptor (RyR) are involved in the regulation of its Ca(2+) release channel, we synthesized several peptides corresponding to selected NH(2)-terminal regions of the RyR. We then examined their effects on ryanodine binding and Ca(2+) release activities of the sarcoplasmic reticulum isolated from skeletal and cardiac muscle. Peptides 1-2s, 1-2c, and 1 enhanced ryanodine binding to cardiac RyR and induced a rapid Ca(2+) release from cardiac SR in a dose-dependent manner. The order of the potency for the activation of the Ca(2+) release channel was 1-2c > 1 > 1-2s. Interestingly, these peptides produced significant activation of the cardiac RyR at near zero or subactivating [Ca(2+)], indicating that the peptides enhanced the Ca(2+) sensitivity of the channel. Peptides 1-2c, 1-2s, and 1 had virtually no effect on skeletal RyR, although occasional and variable extents of activation were observed in ryanodine binding assays performed at 36 degrees C. Peptide 3 affected neither cardiac nor skeletal RyR. We propose that domains 1 and 1-2 of the RyR, to which these activating peptides correspond, would interact with one or more other domains within the RyR (including presumably the Ca(2+)-binding domain) to regulate the Ca(2+) channel.

Involvement of the Glu724-Pro760 region of the dihydropyridine receptor II-III loop in skeletal muscle-type excitation-contraction coupling.

Our previous study (El-Hayek, R., Antoniu, B., Wang, J. P., Hamilton, S. L., and Ikemoto, N. (1995) J. Biol. Chem. 270, 22116-22118) suggested the hypothesis that skeletal muscle-type excitation-contraction coupling is regulated by two domains (activating and blocking) of the II-III loop of the dihydropyridine receptor alpha1 subunit. We investigated this hypothesis by examining conformational changes in the ryanodine receptor induced by synthetic peptides and by transverse tubular system (T-tubule) depolarization. Peptide A, corresponding to the Thr671-Leu690 region, rapidly changed the ryanodine receptor conformation from a blocked state (low fluorescence of the conformational probe, methyl coumarin acetamide, attached specifically to the ryanodine receptor) to an activated state (high methyl coumarin acetamide fluorescence) as T-tubule depolarization did. Peptide C, corresponding to the Glu724-Pro760 region, blocked both conformational changes induced by peptide A and T-tubule depolarization. Its ability to block peptide A-induced and depolarization-induced activation was considerably impaired by replacing the portion of peptide C corresponding to the Phe725-Pro742 region of the loop with cardiac muscle-type sequence. These results are consistent with the model that depolarization-induced activation of excitation-contraction coupling and blocking/repriming are mediated by the peptide A region and the peptide C region (containing the critical Phe725-Pro742 sequence) of the II-III loop, respectively.

Immunophenotypic pattern of childhood acute lymphoblastic leukemia.

Full text is available as a scanned copy of the original print version.

A cervical manikin procedure for chiropractic skills development.

OBJECTIVE: To determine whether chiropractic students can effectively acquire adjustive skills for the cervical spine by utilizing a Thrust in Motion Cervical (TMC) manikin and to evaluate its value as a teaching aid. A pilot study was formulated and incorporated into the skills tutorial program at Macquarie University. Centre for Chiropractic in Sydney, Australia. DESIGN AND SETTING: A prospective study was performed on chiropractic students with no prior experience in performing spinal adjustments. SUBJECTS: Twenty subjects were selected randomly from a population of 75 students about to commence their 4th-yr Master's of Chiropractic program. INTERVENTION: Students who formed the experimental group (n = 6) did not perform any thrusting maneuvers on human subjects while practicing Diversified chiropractic cervical spinal techniques. They practiced the adjustive thrust only on the TMC manikin. The control group (n = 14) learned in the established "hands-on" approach, performing thrusting maneuvers on fellow student subjects. Both groups were supervised, taught and examined in an otherwise identical fashion. RESULTS: The data indicate there is no significant difference between the examination scores of the student group that practiced on the TMC manikin (average, 2.17 points) compared with the controls (2.13 points), with a confidence interval at p = .985, assuming that 0.5 marks is clinically important in these examination results. Interexam reliability was acceptable (Pearson's r = .73) for both experimental and control examination performances. CONCLUSION: The null hypothesis is accepted, and no significant difference in student examination performance was found between those who learned thrusting on the manikin alone and those who learned on fellow students. Further, for the first time, a manikin has been shown to be effective in teaching chiropractic skills. The implications of the TMC manikin procedure will revolutionize the acquisition of motor learning skills that are essential for chiropractic skills training.

Identification of the minimum essential region in the II-III loop of the dihydropyridine receptor alpha 1 subunit required for activation of skeletal muscle-type excitation-contraction coupling.

We have previously shown that among several peptides encompassing various regions of the II-III loop of the dihydropyridine receptor alpha 1 subunit, only one peptide corresponding to the Thr671-Leu690 region (designated as peptide A) activated ryanodine binding to and induced calcium release from the sarcoplasmic reticulum [El-Hayek et al. (1995) J. Biol. Chem. 270, 22116-22118]. To further localize within peptide A the minimum unit essential for activating the sarcoplasmic reticulum calcium release channel, we synthesized variously truncated forms of peptide A and examined their ability to activate ryanodine binding. We found that the carboxy-terminal 10-residue region of peptide A encompassing Arg681-Leu690 (peptide As-10; s, skeletal muscle-type sequence) activated ryanodine binding in a RyR1-specific manner and induced calcium release even more efficiently than the 20-residue peptide A. Further truncation of one or more residue(s) of peptide As-10 virtually abolished both functions of activating ryanodine binding and inducing Ca2+ release. The activating ability of As-10 seems to be determined by at least two factors: (1) the distribution of the positively charged residues, and (2) the skeletal muscle-type amino acid sequence, as deduced from the comparison of various peptides with modified structures. These results provide evidence that the minimum essential unit for the in situ trigger of skeletal muscle excitation-contraction coupling is localized in the Arg681-Leu690 region of the II-III loop of the alpha 1 subunit of the dihydropyridine receptor.

Signal transmission and transduction in excitation-contraction coupling.

For the better understanding of the molecular mechanism of E-C coupling, two key questions remain to be resolved: (a) how the excitation signal elicited in the T-tubule membrane is transmitted to the ryanodine receptor, RyR (signal transmission), and (b) how the signal transmitted from the T-tubule to the RyR is translated into the action of opening the sarcoplasmic reticulum Ca2+ channel to induce Ca2+ release and muscle contraction (signal transduction). Our recent studies on E-C coupling with the use of the isolated triads and synthetic peptides have provided several pieces of new information. It appears that the signal transmission is mediated by the voltage-controlled binding of the Thr671-Leu690 region (Trigger) of the cytoplasmic II-III loop of the dihydropyridine receptor alpha 1 a subunit to the putative activator site on the RyR. The transmitted signal is translated to the action of channel opening by mediation of rapid conformational changes occurring in the RyR. Upon T-tubule polarization the Glu724-Pro760 region of the loop (Blocker) replaces the RyR-bound Trigger. This reprimes the RyR to the original conformational state.

Correlating motion palpation with functional x-ray findings in patients with low back pain.

Objectives: To determine whether a correlation between motion palpation findings and abnormal coupling patterns, as viewed in lumbar functional X-rays, can be demonstrated in low back pain (LBP) patients.Design: A prospective observational study of patients who present to a chiropractic clinic for assessment of low back pain.Subjects: The sample population consisted of 27 consecutive patients presenting with LBP between the ages of 20-50 year old and who were capable of pain free lateral lumbar flexion.Intervention: All subjects underwent motion palpation to determine whether a "fixation" at the L4/5 existed. All had lumbar spine X-rays in an anterior-posterior (AP) and bilateral AP lateral flexion position. X-rays were then analyzed to determine whether the coupling pattern at L4/5 was considered abnormal.Results: In those patients with a perceived L4/5 motion restriction no coupling patterns where found in 6 cases (22.4%) and normal coupling patterns in 13 cases (48%). In those patients who presented with LBP and no motion findings at L4/5 no coupling was observed in 4 cases (14.8%) and normal coupling in another 4 cases (14.8%). The chi-squared test demonstrated no statistical differences (p>0.05) between the motion fixation at L4/5 and coupling patterns from lateral flexion X-rays.Conclusion: It is of particular interest to note that the presence of the L4/5 fixation was not associated with abnormal coupling but conversely was frequently observed to be associated with normal coupling patterns. A simple correlation between a single motion palpation finding of a restriction at a L4/5 facet and an alteration in coupling patterns could not be supported.

Solitary intestinal fibromatosis: a rare cause of intestinal perforation in neonates.

Solitary intestinal fibromatosis (SIF) is very rare; only 9 cases have been described. A new case presenting unusually in a newborn is described and the previously reported cases are reviewed. SIF should be considered in the differential diagnosis of a newborn presenting with an intestinal perforation.

Elective, postoperative ventilation in the management of esophageal atresia and tracheoesophageal fistula.

The management of esophageal atresia (EA) with or without tracheoesophageal fistula (TEF) has undergone many changes. As a result of recent advances in neonatal intensive care and pediatric anesthesia, the survival of infants with EA and TEF has improved markedly, but the occurrence of anastomotic complications has remained constant. To overcome this problem, various techniques and suture materials have been used. This review of 20 consecutive cases of EA/TEF stresses the importance and influence of non-reversal of anesthesia, paralysis, and elective ventilation for protection of the esophageal anastomosis following repair of EA and TEF.

Effects of Focus Film Distance (FFD) variation on entrance testicular dose in lumbar-pelvic radiography.

INTRODUCTION: With the steady increase in public and professional concern regarding the biological effects of ionising radiation, there is a need for both the Chiropractic and Radiography professions to improve imaging techniques for the lowering of patient radiation doses. Lumbar radiographs are essential in chiropractic general practice for biomechanical diagnosis and postural analysis. Detailed anatomical measurements are taken from spinal radiographs for the determination of various biomechanical alterations for clinical purposes. The quality of spinal radiograph is dependent on a number of factors, including Focus Film Distance (FFD), magnification ratios, penumbra, contrast and density. Variation in FFD will vary magnification factor (MF) and Penumbra. OBJECTIVES: The study aims to investigate the relationship between FFD and received radiation dose to patients, where the radiation dose to the testes may be significantly lowered whilst still maintaining acceptable image quality. METHODS: Radiographic images and dosimetry were obtained with a Seimans wall-mounted X-ray unit. All anterior/posterior (AP) and lateral lumbar-pelvic radiographs were taken of an anthromorphological phantom that resembles human tissues, at both 100cm and 200cm FFD. Five central beam air doses were measured for all parameters to demonstrate patient entrance doses. RESULTS: For AP lumbar-pelvic radiography, increasing FFD by a factor of two resulted in an approximately 30% decrease in entrance dose to the testes. For lateral lumbar-pelvic radiography a two fold increase in FFD resulted in a 70% reduction in entrance dose. CONCLUSIONS: The study suggests for the first time that an FFD of 200 cm, which is largely utilised by the chiropractic profession, is an efficient method of minimising radiation dose to patient, during lumbar radiography.

Reciprocal control of the conformational state of the sarcoplasmic reticulum calcium channel protein by polarization and depolarization in the transverse tubule.

We attached the conformational probe methylcoumarin acetate (MCA) specifically to the junctional foot protein (JFP) moiety of triads, and monitored conformational changes in the JFP during polarization and depolarization of the T-tubule moiety. The MCA fluorescence decreased upon T-tubule polarization, and the fluorescence changes were blocked by preventing T-tubule polarization or by a nimodipine block of the T-tubule-to-sarcoplasmic reticulum communication. Depolarization of the T-tubule reversed the MCA fluorescence decrease which had been produced by T-tubule polarization. These results suggest that the conformational and functional states of the JFP are regulated by T-tubule polarization and depolarization in a reciprocal fashion.

Peptide probe of ryanodine receptor function. Imperatoxin A, a peptide from the venom of the scorpion Pandinus imperator, selectively activates skeletal-type ryanodine receptor isoforms.

We have used [3H]ryanodine binding experiments and single channel recordings to provide convergent descriptions of the effect of imperatoxin A (IpTxa), a approximately 5-kDa peptide from the venom of the scorpion Pandinus imperator (Valdivia, H. H., Kirby, M. S., Lederer, W. J., and Coronado, R. (1992) Proc. Ntl. Acad. Sc. U.S.A. 89, 12185-12189) on Ca2+ release channels/ryanodine receptors (RyR) of sarcoplasmic reticulum (SR). At nanomolar concentrations, IpTxa increased the binding of [3H]ryanodine to skeletal SR and, to a lesser extent, to cerebellum microsomes. The activating effect of IpTxa on skeletal SR was Ca(2+)-dependent, synergized by caffeine, and independent of other modulators of RyRs. However, IpTxa had negligible effects on tissues where the expression of skeletal-type RyR isoforms (RyR1) is small or altogether absent, i.e. cardiac, cerebrum, and liver microsomes. Thus, IpTxa may be used as a ligand capable of discriminating between RyR isoforms with nanomolar affinity. IpTxa increased the open probability (Po) of rabbit skeletal muscle RyRs by increasing the frequency of open events and decreasing the duration of the closed lifetimes. This activating effect was dose-dependent (ED50 = 10 nM), had a fast onset, and was fully reversible. Purified RyR from solubilized skeletal SR displayed high affinity for [3H]ryanodine with a KD of 6.1 nM and Bmax of approximately 30 pmol/mg of protein. IpTxa increased [3H]ryanodine binding noncompetitively by increasing Bmax to approximately 60 pmol/mg of protein. These results suggested the presence of an IpTxa-binding site on the RyR or a closely associated regulatory protein. This site appears to be distinct from the caffeine- and adenine nucleotide-regulatory sites. IpTxa may prove a useful tool to identify regulatory domains critical for channel gating and to dissect the contribution of skeletal-type RyRs to intracellular Ca2+ waveforms generated by stimulation of different RyR isoforms.