Genetic predisposition to leprosy: A major gene reveals novel pathways of immunity to Mycobacterium leprae

The elucidation of the genetic control of susceptibility to common infectious diseases is expected to provide new and more effective tools for prevention and control of some of the most pressings health needs on a global scale. A major advantage of whole genome based genetic approaches is that no a priori assumptions about mechanisms of pathogenesis need to be made in these studies. Hence, genetic studies can identify previously unrecognized pathways of disease susceptibility and tag critical pathogenic events for further biochemical, immunological or physiological analysis. We have applied this strategy to leprosy, a disease that still claims 400,000 new cases each year. We identified genetic variants in the shared promoter region of the PARK2 and PACRG genes as major risk factors of leprosy susceptibility. Both encoded proteins are part of the cellular ubiquitination system. Specifically, PARK2, the cause of early onset Parkinson's disease, is an E3 ligase that likely is involved in controlled proteolysis, the cellular anti-oxidants response and the regulation of innate immune responsiveness. In addition, numerous E3 ligases have recently been shown to be critical regulators of immunity. While the specific role of PARK2/PACRG in leprosy pathogenesis remains unknown, a number of experimentally testable scenarios can be developed to further explore the role of these proteins in anti-Mycobacterium leprae host responsiveness.     

Protein synthesis is required for the enhancement of long-term potentiation and long-term memory by spaced training

Spaced training is generally more effective than massed training for learning and memory, but the molecular mechanisms underlying this trial spacing effect remain poorly characterized. One potential molecular basis for the trial spacing effect is the differential modulation, by distinct temporal patterns of neuronal activity, of protein synthesis-dependent processes that contribute to the expression of specific forms of synaptic plasticity in the mammalian brain. Long-term potentiation (LTP) is a type of synaptic modification that may be important for certain forms of memory storage in the mammalian brain. To explore the role of protein synthesis in the trial spacing effect, we assessed the protein synthesis dependence of hippocampal LTP induced by 100-Hz tetraburst stimulation delivered to mouse hippocampal slices in either a temporally massed (20-s interburst interval) or spaced (5-min interburst interval) fashion. To extend our studies to the behavioral level, we trained mice in fear conditioning using either a massed or spaced training protocol and examined the sensitivity of long-term memory to protein synthesis inhibition. Larger LTP was induced by spaced stimulation in hippocampal slices. This improvement of synaptic potentiation following temporally spaced synaptic stimulation in slices was attenuated by bath application of an inhibitor of protein synthesis. Further, the maintenance of LTP induced by spaced synaptic stimulation was more sensitive to disruption by anisomycin than the maintenance of LTP elicited following massed stimulation. Temporally spaced behavioral training improved long-term memory for contextual but not for cued fear conditioning, and this enhancement of memory for contextual fear was also protein synthesis dependent. Our data reveal that altering the temporal spacing of synaptic stimulation and behavioral training improved hippocampal LTP and enhanced contextual long-term memory. From a broad perspective, these results suggest that the recruitment of protein synthesis-dependent processes important for long-term memory and for long-lasting forms of LTP can be modulated by the temporal profiles of behavioral training and synaptic stimulation.     

β 1- andβ 2-adrenoceptor binding and functional response in right and left atria of rat heart

Summary The properties of ₁- and ₂-adrenoceptors in right and left atria of rat heart, and their roles in mediating chronotropic and inotropic responses to-adrenoceptor agonists were examined. [¹²⁵I](-)-pindolol (¹²⁵IPIN) bound saturably and specifically to a single class of high affinity sites in homogenates of both right and left atria. Thek ₁'s for association in right and left atria were 6.5×10⁹ l/mol-min and 2.3×10⁹ l/mol-min respectively, while thek _–1's for dissociation were 0.20 min^–1 and 0.17 min^–1. The kinetically determinedK _D's were 75 pmol/l in right and 30 pmol/l in left atria and were similar to the equilibriumK _D's determined from Scatchard analysis of saturation isotherms of specific¹²⁵IPIN binding. Inhibition of¹²⁵IPIN binding by-adrenoceptor antagonists was stereoselective and the order of potency was timolol > 1-propranolol > d-propranolol > sotalol. Inhibition by ₁- and ₂-adrenoceptor subtype selective antagonists yielded flat displacement curves with low Hill coefficients. Nonlinear regression analysis of displacement by ₁-selective (practolol, atenolol and metoprolol) and ₂-selective (ICI 118,551) antagonists gave estimates of the proportion of ₁- and ₂-adrenoceptors present in rat atria. Right atria contained 67±4.2% ₂-adrenoceptors and 33±4.2% ₂-adrenoceptor, while left atria contained 67±2.8% ₁- and 33±2.8% ₂-adrenoceptors. Increases in the rate of spontaneously beating right atria and the force of electrically driven left atria caused by-adrenoceptor agonists were also measured. pA₂ values for non-subtype selective-adrenoceptor antagonists in inhibiting isoprenaline-induced increases in rate and force were highly correlated withK _D values determined for specific¹²⁵IPIN binding. pA₂ values for ₁- and ₂-selective antagonists in inhibiting isoprenaline-induced increases in rate and force correlated well with the pK _D values of these drugs in binding to ₁-adrenoceptors, but not with the pK _D values in binding to ₂-adrenoceptors. Dose-response curves for stimulation of both rate and force by the ₂-selective agonists procaterol and zinterol were shifted to a much greater extent by selective blockade of ₁-adrenoceptors with metoprolol than by selective blockade of ₂-adrenoceptors with ICI 118,551, suggesting that these compounds caused their effects by activating ₁-adrenoceptors. These results suggest that ₁- and ₂-adrenoceptors coexist in both left and right atria of rat heart in approximately a 21 ratio, however only ₁-adrenoceptors mediate the chronotropic and inotropic effects of-adrenoceptor agonists.Supported by a grant from the American Heart Association — Georgia Affiliate     

Hyperactive vestibulo-ocular reflex in cerebellar degeneration: pathogenesis and treatment

We studied a patient with a cerebellar degeneration and hyperactive vestibulo-ocular reflex (VOR). He complained of oscillopsia and blurred vision with head movement. A twofold increase in VOR gain (peak eye velocity/peak head velocity) at high frequencies was associated with a VOR time constant of 6 seconds (low normal). Visual cancellation ("suppression") of the VOR and smooth pursuit were also abnormal. We hypothesized that his high VOR gain was due to dysfunction of olivocerebellar projections. Physostigmine reduced his VOR gain, consistent with the hypothesis that these projections are cholinergic.     

How is your life? understanding the relative importance of life domains amongst older adults,and their associations with self-perceived COVID-19 impacts

Quality of Life Research - This study aims to provide new knowledge on the relative importance of key life domains amongst older adults, and how the Coronavirus pandemic has influenced their life...     

Perioperative antibiotic, steroid, and nonsteroidal anti-inflammatory agents in cataract intraocular lens surgery

Ophthalmologists continue to choose topical antibiotics and corticosteroids more frequently than injectable agents for their current cataract surgical techniques. The preoperative use of povidone-iodine 5% and the postoperative use of impregnated soft contact lenses have helped augment our therapeutic armamentarium. NSAIDs play an important role in decreasing postoperative convalescence with fewer side effects. The intracameral administration of heparin and antibiotic solutions is discussed.     

Microdissection and microcloning of chromosomal alterations in human breast cancer

Summary The recognition of recurring sites of chromosome changes in malignancies has greatly facilitated the identification of genes implicated in the pathogenesis of human cancers. Based especially upon recent studies [1–4], it appears increasingly likely that a subset of recurring chromosome alterations will be recognized in human breast cancer. Currently recognized chromosome changes characterizing breast carcinoma include the recognition of cytologic features of gene amplification (e.g. double minutes [dmins] and homogeneously staining regions [HSRs]) [5–8]. As these and other chromosome regions are implicated in recurring abnormalities in breast cancer, it will become increasingly important to have band-or region-specific genomic libraries and probes in order to facilitate high resolution physical mapping and ultimately to clone breast cancer related genes [9]. Toward this end an important recent development in physical mapping has been the establishment of chromosome microdissection as a rapid and reproducible approach to rapidly isolate and characterize chromosome region-specific DNA, greatly facilitating the initial steps in positional cloning of disease-related genes [10–13]. In this brief report, we will highlight the application of chromosome microdissection to the generation of region-specific probes for both fluorescent in situ hybridization (FISH) and the generation of genomic microclone libraries. Additionally, efforts using this methodology to generate a microclone library encompassing the early onset breast/ovarian cancer (BRCA1) gene will be presented.Presented by Jeffrey M. Trent at the 16th Annual San Antonio Breast Cancer Symposium, San Antonio TX, USA, November 4, 1993; Minisymposium on Molecular Genetics in Breast Cancer.     

Do workers exposed to intermittent aircraft noise suffer from occupational deafness? A study in Alexandria airport

The study aimed at assessment of noise levels in Alexandria airport and measurement of hearing acuity--among other health parameters of the working personnel. By performing 65 sound pressure level measurements, a questionnaire and air conduction audiometry, significant hearing defects could be revealed. Deficiencies affected hearing levels at all frequencies but especially higher frequencies in workers exposed to noise of aircrafts and other airport activities at the exterior of the airport building. The importance of pre-employment and periodic ear and audiometric examinations is thus expressed.     

Comparative study between different diagnostic techniques in huge splenomegaly cases in El-Minia Province

Fifty four patients presenting by huge splenomegaly were admitted to Tropical Medicine Department, El-Minia University Hospital. Tissue biopsy revealed pure bilharziasis due to S. hematobium in 10 (19%) cases, liver cirrhosis in 23 (42%), mixed schistosomiasis and cirrhosis in 8 (15%), hepatoma in 3 (6%), lymphoma in 6 (11%) and hematological diseases in the form of chronic myeloid leukemia in 2 (3.5%) and thalassemia major in 2 (3.5%) cases. The sensitivity and specificity of abdominal ultrasonography was 100% and 97% in cases of schistosomiasis, 100% and 100% in cases of hepatoma, 87% and 100% in cases of liver cirrhosis, 33% and 100% in cases of lymphoma respectively. There was a positive significant correlation between endoscopic variceal grading, portal vein diameter, splenic vein diameter, size of the spleen and the grading of the portal tract thickenings. The pathological and ultrasonographic diagnosis was the same in 38 (70%) cases. Splenogram was characteristic but not diagnostic in cases of schistosomiasis and liver cirrhosis. It was diagnostic and similar to peripheral blood picture in the 2 cases of chronic myeloid leukemia and was normal in cases of thalassemia major. Splenic aspiration was able to diagnose all cases of lymphomas. It can be considered as a useful adjunct to the usual diagnostic procedures, both in staging and follow up, especially in cases presenting only by splenomegaly.