Positional cloning of the gene for X-linked retinitis pigmentosa 3: homology with the guanine-nucleotide-exchange factor RCC1

The gene for retinitis pigmentosa 3 (RP3), the most frequent form of X- linked RP (XLRP), has been mapped previously to a chromosome interval of less than 1000 kbp between the DXS1110 marker and the OTC locus at Xp21.1-p11.4. Employing a novel technique, YAC Representation Hybridization (YRH)', we have recently identified a small XLRP associated microdeletion in this interval, as well as several putative exons including the 3' end of a gene that was truncated by the deletion. cDNA library screening and sequencing of a cosmid centromeric to the deletion has now enabled us to identify numerous additional exons and to detect several point mutations in patients with XLRP. The predicted gene product shows homology to RCC1, the guanine-nucleotide- exchange factor (GEF) of the Ras-like GTPase Ran. Our findings suggest that we have cloned the long-sought RP3 gene, and that it may encode the GEF of a retina-specific GTP-binding protein.      

Short-Ti inversion-recovery pulse sequence: analysis and initial experience in cancer imaging

Inversion recovery (IR), commonly considered a pulse sequence capable of producing T1-weighted images with excellent display of normal anatomy, is versatile: The null point and peak time provide a useful, succinct summary of the properties of IR and its capacity for producing both T1- and T2-weighted images. Shortening of the inversion time (TI) and creation of a short-TI inversion-recovery (STIR) pulse sequence increases sensitivity to malignancy and other abnormalities by making the effects of prolonged T1 and T2 on signal intensity additive and by nulling the signal from fat. The authors examined over 300 patients with various malignancies and compared STIR images with T1- and T2-weighted images obtained at 0.5 T. In 43 cases, signal-difference-to-noise ratios (SD/Ns) were calculated between tumor, fat, and muscle. In general, STIR images demonstrated tumor as a conspicuously high-intensity area in a background of muted, discernible anatomic detail. The good contrast achieved with STIR sequences between tumor and fat (SD/N = 18.1) and tumor and muscle (SD/N = 12.9) consolidated into a single image the information contained separately on T1- and T2-weighted images, which facilitates efficient detection and localization of malignancy.     

The varied semiology of seizures in the context of small anterior temporal encephaloceles

Aims. Small encephaloceles of the anterior temporal pole have been increasingly recognised as an underlying epileptogenic substrate in patients with medically refractory epilepsy. The current report aims to expand on the current knowledge by emphasising that seizure semiology in such patients can vary significantly. Methods. Patients were selected from an epilepsy surgery database between 2012 and 2017. Results. Of the 143 patients who underwent epilepsy surgery, six patients had a temporal encephalocele. Four of these patients had stereo-EEG implantation. Of the four patients studied, each had a seizure semiology discordant with an ictal focus in the temporal lobe. Intracranial EEG assessment demonstrated, irrespective of this semiology, seizures originated from the anterior temporal pole. Seizures were observed to rapidly propagate to the orbitofrontal cortex, insula, temporo-occipital junction, and posterior language regions. Engagement of the mesial temporal structures could occur early or late, however, a good surgical outcome was achieved following a focused lesionectomy in either situation. Conclusion. The major finding was that seizures arising from anterior temporal encephaloceles can have an extra-temporal semiology. The varied clinical semiology and the rapid propagation to seemingly distant cortical regions could be explained by the connectivity of the anterior temporal lobe.     

Inactivation of purified human alpha 2-antiplasmin and purified human C1 inhibitor by synthetic fibrinolytic agents

3-Hydroxypropyl flufenamide (Flu-HPA) is one of a series of flufenamic acid derivatives that enhances blood clot lysis in vitro. Studies of possible mechanisms of action of Flu-HPA were undertaken. The profibrinolytic activity of Flu-HPA in clot lysis assays was found to be dependent on plasminogen. The influence of Flu-HPA on the ability of purified alpha 2-antiplasmin to inhibit purified plasmin was studied. Plasmin activity was determined using 125I-fibrin plates or the spectrophotometric tripeptide substrate, Val-Leu-Lys-paranitroanilide. At Flu-HPA concentrations greater than 1 mM, the inhibitory activity of alpha 2-antiplasmin was abolished in a time-dependent and concentration- dependent manner. The influence of Flu-HPA on the ability of purified Cl inhibitor to inhibit purified plasma kallikrein and beta-Factor XIIa was also studied. Cl inhibitor activity was abolished by Flu-HPA at concentrations greater than 2 mM. Notably, Flu-HPA up to 60 mM did not affect the amidolytic activities of plasmin, kallikrein, or beta-Factor XIIa. Flu-HPA did not release enzyme activity from preformed complexes of either alpha 2-antiplasmin and plasmin of Cl inhibitor and kallikrein. A water-soluble derivative of flufenamic acid, N-flufenamyl- glutamic acid, also inactivated alpha 2-antiplasm and Cl inhibitor. This inactivation was shown to be reversible. These results indicate that synthetic fibrinolytic compounds such as flufenamic acid derivatives may promote fibrinolysis by directly inactivating alpha 2- antiplasmin and Cl inhibitor.     

Evaluation of [18F]-JNJ-64326067-AAA tau PET tracer in humans

The [¹⁸F]-JNJ-64326067-AAA ([¹⁸F]-JNJ-067) tau tracer was evaluated in healthy older controls (HCs), mild cognitive impairment (MCI), Alzheimer’s disease (AD), and progressive supranuclear palsy (PSP) participants. Seventeen subjects (4 HCs, 5 MCIs, 5 ADs, and 3 PSPs) received a [¹¹C]-PIB amyloid PET scan, and a tau [¹⁸F]-JNJ-067 PET scan 0-90 minutes post-injection. Only MCIs and ADs were amyloid positive. The simplified reference tissue model, Logan graphical analysis distribution volume ratio, and SUVR were evaluated for quantification. The [¹⁸F]-JNJ-067 tau signal relative to the reference region continued to increase to 90 min, indicating the tracer had not reached steady state. There was no significant difference in any bilateral ROIs for MCIs or PSPs relative to HCs; AD participants showed elevated tracer relative to controls in most cortical ROIs (P < 0.05). Only AD participants showed elevated retention in the entorhinal cortex. There was off-target signal in the putamen, pallidum, thalamus, midbrain, superior cerebellar gray, and white matter. [¹⁸F]-JNJ-067 significantly correlated (p < 0.05) with Mini-Mental State Exam in entorhinal cortex and temporal meta regions. There is clear binding of [¹⁸F]-JNJ-067 in AD participants. Lack of binding in HCs, MCIs and PSPs suggests [¹⁸F]-JNJ-067 may not bind to low levels of AD-related tau or 4 R tau.     

High frequency of memory and effector gag specific cytotoxic T lymphocytes in HIV seropositive individuals

Human immunodeficiency virus type 1 (HIV-1) specific cytotoxic T lymphocytes (CTL) have been detected in most patients following infection. It has also been suggested that the specific CTL response, which may play an important role in delaying disease in infected humans, may decline during the course of disease progression. We have measured HIV peptide specific CTL precursor frequency by limiting dilution analysis in two healthy seropositive patients whose fresh peripheral blood mononuclear cells (PBM) specifically lysed MHC matched target cells (restricted by HLA B27 and B8 respectively). The frequency of HIV peptide specific CTL precursors is high (3 x 10(-3)-10(-4], but lower than estimates of circulating CTL with the same specific cytotoxic activity present directly in peripheral blood using the same sample (10(-2)-10(-3]. We suggest that this difference may result from terminal effector CTL differentiation in the T cell lineage. This implies that only a subset of CTL effectors have growth potential, whereas relatively higher levels of CTL with lytic activity can be detected in PBM of healthy HIV seropositive patients.     

An antigen processing polymorphism revealed by HLA-B8-restricted cytotoxic T lymphocytes which does not correlate with TAP gene polymorphism

In previous studies of antigen presentation through HLA-B27, we identified a healthy person whose lymphoblastoid cells do not present three B27-restricted viral epitopes to specific cytotoxic T lymphocytes (CTL), despite adequate cell surface expression of HLA-B2702 of normal sequence. Similar findings were observed in all members of his family sharing the HLA-A3-B2702 haplotype. The original donor, NW, carries HLA-B8 on his other class I haplotype, which his daughter, HW, has inherited. We now report a failure to present an HLA-B8-restricted epitope from influenza nucleoprotein following viral infection of NW cells, although exogenous added peptide is still presented normally. However, cells from HW, which do not carry the A3-B2702 haplotype, present the expected epitope after viral infection. Another B8-restricted epitope, from human immunodeficiency virus-gag, is presented equally well by both cell lines when infected with gag-vaccinia. This antigen processing phenotype does not correlate with any of the known human TAP-1 and TAP-2 polymorphisms.