The human motor cortex after incomplete spinal cord injury: an investigation using proton magnetic resonance spectroscopy

OBJECTIVES—(1) A biochemical investigation of themotor cortex in patients with incomplete spinal cord injury and normalcontrol subjects using proton magnetic resonance spectroscopy (MRS).(2) To relate any altered biochemistry with the physiological changesin corticospinal function seen after spinal cord injury.
METHODS—a group of six patients with incompletespinal cord injury who showed good recovery of motor function wereselected. The patients were compared with five healthy controlsubjects. Electromyographic (EMG) responses of thenar muscles totranscranial magnetic stimulation (TMS) of the motor cortex showed thatinhibition of cortical output was weaker in the patients than thecontrols. Proton MRS data were collected from a plane at the level ofthe centrum semiovale. Two 4.5 cm³ voxels in the motorcortex and a third voxel in the ipsilateral occipital cortex wereexamined in the patients and control subjects.
RESULTS—The mean level ofN-acetylaspartate (NAA), expressed relative to thecreatine (Cr) peak (NAA/Cr), was significantly increased in the motorcortex of the patients compared with their ipsilateral occipital cortexor either cortical area in the controls. No differences betweenpatients and controls were seen for any of the other metabolite peaks(choline (Cho), glutamate/glutamine (Glx) or the aspartate component ofNAA (Asp^NAA)) relative to Cr. Choline relative to Cr(Cho/Cr) was higher in the motor cortex of the control subjects than intheir ipsilateral occipital cortex. This difference was not present inthe patients.
CONCLUSIONS—Raised NAA/Cr in the motorcortex of the patients probably results from increased NAA rather thana decrease in the more stable Cr. The possible relevance of a raisedNAA/Cr ratio is discussed, particularly with regard to the changedcorticospinal physiology and the functional recovery seen in the patients.

     

Single center study of 53 consecutive patients with pituitary stalk lesions

Background

The etiological spectrum of pituitary stalk lesions (PSL) is wide and yet specific compared to the other diseases of the sellar and suprasellar region. Because of the pituitary stalk’s (PS) critical location and role, biopsies of these lesions are rarely performed, and their underlying pathology is often a conundrum for clinicians. A pituitary MRI in association with a clinical context can facilitate their diagnosis.

Aim

To present the various causes of PSL—their clinical, hormonal, histopathological, and MRI characteristics in order to gain better insight into this pathology.

Method

A retrospective observational study consisting of 53 consecutive patients with PSL of the mean age 32?±?4.2 years (range 6–67), conducted at the Department for Neuroendocrinology, Clinical Center of Serbia 2010–2018.

Results

Congenital malformations were the most common cause of PSL in 25 of 53 patients (47.1%), followed by inflammatory (9/53; 16.9%) and neoplastic lesions (9/53; 16.9%). The exact cause of PSL was established in 31 (58.4%) patients, of whom 23 were with congenital PS abnormalities and 8 with histopathology of PSL (7 neoplastic and 1 Langerhans Cell Hystiocytosis). A probable diagnosis of PSL was stated in 12 patients (22.6%): 6 with lymphocytic panhypophysitis, while Rathke cleft cyst, tuberculosis, dissemination of malignancy in PS were each diagnosed in 2 patients. In 10 patients (18.8%), the etiology of PSL remained unknown.

Conclusion

Due to the inability of establishing an exact diagnosis, the management and prognosis of PSL are difficult in many patients. By presenting a wide array of causes implicated in this condition, we believe that our study can aid clinicians in the challenging cases of this pathology.

     

Corticospinal function studied over time following incomplete spinal cord injury

STUDY DESIGN: Longitudinal. OBJECTIVES: (1) To perform standard clinical neurological examinations and establish the pattern of clinical change with time following incomplete spinal cord injury (iSCI). (2) To establish the pattern of change in corticospinal electrophysiological function with time after iSCI. (3) To correlate clinical with electrophysiological findings. Setting: The National Spinal Injuries Centre, Stoke Mandeville Hospital, Aylesbury, UK and Imperial College School of Medicine, Charing Cross Hospital, London, UK. METHODS: Neurological assessments and classification were performed according to American Spinal Injuries Association and International Medical Society of Paraplegia (ASIA/IMSOP) standards. Twenty-one patients (ages 18 - 72 years) with iSCI (level C2 - C7, ASIA impairment grades C - D) and 10 healthy control subjects (ages 27 - 57 years) were studied. Electrophysiological tests of corticospinal function were carried out using transcranial magnetic stimulation (TMS) of the motor cortex and electromyographic (EMG) recordings from thenar muscles. Both tests were performed on a number of occasions, beginning 19 - 384 days and ending 124 - 1109 days post-injury, and the group data were pooled into time epochs of 50 or 100 days post-injury for analysis. Seven of the patients were studied on seven or more occasions and were also assessed individually. RESULTS: Individual and pooled data indicated that neurological scores improved progressively and tended to stabilise by around 300 days post-injury. When the patients were first assessed, the mean latency for motor evoked potentials (MEPs) and inhibition of voluntary EMG were significantly different from control values. There was no significant change in latency on subsequent sessions for either the grouped or individual patient data. There was no correlation between clinical assessment and electrophysiological data. CONCLUSION: We conclude that the weakened inhibition seen following iSCI is established within a few days of the time of spinal cord trauma. We argue that reduced corticospinal inhibition may be a prerequisite for the recovery of useful motor function. SPONSORSHIP: The work was supported by a project grant from The Wellcome Trust.     

Semiparametric Distributions With Estimated Shape Parameters

Purpose  To investigate the use of adaptive transformations to assess the parameter distributions in population modeling. Methods  The logit, box-cox, and heavy tailed transformations were investigated. Each one was used in conjunction with the standard (exponential) transformation for PK and PD parameters. The shape parameters of these transformations were estimated to allow the parameter distributions to more accurately resemble a wider range of parameter distributions. The transformations were tested both in simulated settings where the true distributions were known and in 30 models developed from real data. Results  In the simulated setting the transformations were better than the standard lognormal distribution at characterizing the true distributions. Improvement could also be seen in objective function value (OFV) and in simulation based diagnostics. In the real datasets, significant model improvement based on OFV could be seen in 22, 18, and 22 out of the 30 models for the three transformations respectively. Conclusion  Transformations with estimated shape parameters are a promising approach to relax the often erroneous assumption of a known shape of the parameter distribution. They offer a simple and straightforward way of handling and characterizing parameter distributions.     

Aberrant V(D)J recombination is not required for rapid development of H2ax/p53-deficient thymic lymphomas with clonal translocations

Histone H2AX is required to maintain genomic stability in cells and to suppress malignant transformation of lymphocytes in mice. H2ax(-/-)p53(-/-) mice succumb predominantly to immature alphabeta T-cell lymphomas with translocations, deletions, and genomic amplifications that do not involve T-cell receptor (TCR). In addition, H2ax(-/-)p53(-/-) mice also develop at lower frequencies B and T lymphomas with antigen receptor locus translocations. V(D)J recombination is initiated through the programmed induction of DNA double-strand breaks (DSBs) by the RAG1/RAG2 endonuclease. Because promiscuous RAG1/RAG2 cutting outside of antigen receptor loci can promote genomic instability, H2ax(-/-)p53(-/-) T-lineage lymphomas might arise, at least in part, through erroneous V(D)J recombination. Here, we show that H2ax(-/-)p53(-/-)Rag2(-/-) mice exhibit a similar genetic predisposition as do H2ax(-/-)p53(-/-) mice to thymic lymphoma with translocations, deletions, and amplifications. We also found that H2ax(-/-)p53(-/-)Rag2(-/-) mice often develop thymic lymphomas with loss or deletion of the p53(+) locus. Our data show that aberrant V(D)J recombination is not required for rapid onset of H2ax/p53-deficient thymic lymphomas with genomic instability and that H2ax deficiency predisposes p53(-/-)Rag2(-/-) thymocytes to transformation associated with p53 inactivation. Thus, H2AX is essential for suppressing the transformation of developing thymocytes arising from the aberrant repair of spontaneous DSBs.     

Regulation of sorting and post-Golgi trafficking of rhodopsin by its C-terminal sequence QVS(A)PA

Several mutations that cause severe forms of the human disease autosomal dominant retinitis pigmentosa cluster in the C-terminal region of rhodopsin. Recent studies have implicated the C-terminal domain of rhodopsin in its trafficking on specialized post-Golgi membranes to the rod outer segment of the photoreceptor cell. Here we used synthetic peptides as competitive inhibitors of rhodopsin trafficking in the frog retinal cell-free system to delineate the potential regulatory sequence within the C terminus of rhodopsin and model the effects of severe retinitis pigmentosa alleles on rhodopsin sorting. The rhodopsin C-terminal sequence QVS(A)PA is highly conserved among different species. Peptides that correspond to the C terminus of bovine (amino acids 324–348) and frog (amino acids 330–354) rhodopsin inhibited post-Golgi trafficking by 50% and 60%, respectively, and arrested newly synthesized rhodopsin in the trans-Golgi network. Peptides corresponding to the cytoplasmic loops of rhodopsin and other control peptides had no effect. When three naturally occurring mutations: Q344ter (lacking the last five amino acids QVAPA), V345M, and P347S were introduced into the frog C-terminal peptide, the inhibitory activity of the peptides was no longer detectable. These observations suggest that the amino acids QVS(A)PA comprise a signal that is recognized by specific factors in the trans-Golgi network. A lack of recognition of this sequence, because of mutations in the last five amino acids causing autosomal dominant retinitis pigmentosa, most likely results in abnormal post-Golgi membrane formation and in an aberrant subcellular localization of rhodopsin.     

Novel Dosing Strategies Increase Exposures of the Potent Antituberculosis Drug Rifapentine but Are Poorly Tolerated in Healthy Volunteers

Rifapentine is a potent antituberculosis drug currently in phase III trials. Bioavailability decreases with increasing dose, yet high daily exposures are likely needed to improve efficacy and shorten the tuberculosis treatment duration. Further, the limits of tolerability are poorly defined. The phase I multicenter trial in healthy adults described here investigated two strategies to increase rifapentine exposures: dividing the dose or giving the drug with a high-fat meal. In arm 1, rifapentine was administered at 10 mg/kg of body weight twice daily and 20 mg/kg once daily, each for 14 days, separated by a 28-day washout; the dosing sequence was randomized. In arm 2, 15 mg/kg rifapentine once daily was given with a high-fat versus a low-fat breakfast. Sampling for pharmacokinetic analysis was performed on days 1 and 14. Population pharmacokinetic analyses were performed. This trial was stopped early for poor tolerability and because of safety concerns. Of 44 subjects, 20 discontinued prematurely; 11 of these discontinued for protocol-defined toxicity (a grade 3 or higher adverse event or grade 2 or higher rifamycin hypersensitivity). Taking rifapentine with a high-fat meal increased the median steady-state area under the concentration-time curve from time zero to 24 h (AUC_0–24ss) by 31% (relative standard error, 6%) compared to that obtained when the drug was taken with a low-fat breakfast. Dividing the dose increased exposures substantially (e.g., 38% with 1,500 mg/day). AUC_0–24ss was uniformly higher in our study than in recent tuberculosis treatment trials, in which toxicity was rare. In conclusion, two strategies to increase rifapentine exposures, dividing the dose or giving it with a high-fat breakfast, successfully increased exposures, but toxicity was common in healthy adults. The limits of tolerability in patients with tuberculosis remain to be defined. (AIDS Clinical Trials Group study A5311 has been registered at ClinicalTrials.gov under registration no. {"type":"clinical-trial","attrs":{"text":"NCT01574638","term_id":"NCT01574638"}}NCT01574638.)