University of Texas Medical Branch

About: University of Texas Medical Branch is a education organization based out in Galveston, Texas, United States. It is known for research contribution in the topics: Population & Virus. The organization has 22033 authors who have published 38268 publications receiving 1517502 citations. The organization is also known as: The University of Texas Medical Branch at Galveston & UTMB.

Enhancement of spinothalamic neuron responses to chemical and mechanical stimuli following combined micro-iontophoretic application of N-methyl-D-aspartic acid and substance P.

Abstract: A role for sensitization of nociceptors in the generation of primary hyperalgesia is well documented. More recent work has begun to define a role of an increased excitability of neurons within the spinal cord in the generation of secondary hyperalgesia. The present study demonstrates increased responses of primate spinothalamic neurons following co-administration of N-methyl-D-aspartic acid (NMDA) and substance P (SP) by micro-iontophoresis. Wide dynamic range and high threshold STT neurons in laminae I-VI showed an increased frequency of discharges following application of NMDA which was characterized by a slow onset to peak discharge rate and a slow return to background levels of discharge. Combined application of NMDA with SP resulted in an enhancement of responses to NMDA that often long outlasted the administration of SP. This increase in response of the cells to NMDA was not produced by repeated application of NMDA alone or following combined application of NMDA with an SP analog. NMDA responses were reduced or prevented in all cases by co-application of an NMDA-receptor antagonist. Finally, long-lasting potentiation of NMDA responses by SP was paralleled by enhanced responses to mechanical stimulation of skin. It is proposed that a mechanism involving the combined synaptic release of excitatory amino acids and peptides leads to secondary hyperalgesia.

International Union of Basic and Clinical Pharmacology. CII: Pharmacological Modulation of H2S Levels: H2S Donors and H2S Biosynthesis Inhibitors.

Abstract: Over the last decade, hydrogen sulfide (H2S) has emerged as an important endogenous gasotransmitter in mammalian cells and tissues. Similar to the previously characterized gasotransmitters nitric oxide and carbon monoxide, H2S is produced by various enzymatic reactions and regulates a host of physiologic and pathophysiological processes in various cells and tissues. H2S levels are decreased in a number of conditions (e.g., diabetes mellitus, ischemia, and aging) and are increased in other states (e.g., inflammation, critical illness, and cancer). Over the last decades, multiple approaches have been identified for the therapeutic exploitation of H2S, either based on H2S donation or inhibition of H2S biosynthesis. H2S donation can be achieved through the inhalation of H2S gas and/or the parenteral or enteral administration of so-called fast-releasing H2S donors (salts of H2S such as NaHS and Na2S) or slow-releasing H2S donors (GYY4137 being the prototypical compound used in hundreds of studies in vitro and in vivo). Recent work also identifies various donors with regulated H2S release profiles, including oxidant-triggered donors, pH-dependent donors, esterase-activated donors, and organelle-targeted (e.g., mitochondrial) compounds. There are also approaches where existing, clinically approved drugs of various classes (e.g., nonsteroidal anti-inflammatories) are coupled with H2S-donating groups (the most advanced compound in clinical trials is ATB-346, an H2S-donating derivative of the non-steroidal anti-inflammatory compound naproxen). For pharmacological inhibition of H2S synthesis, there are now several small molecule compounds targeting each of the three H2S-producing enzymes cystathionine-β-synthase (CBS), cystathionine-γ-lyase, and 3-mercaptopyruvate sulfurtransferase. Although many of these compounds have their limitations (potency, selectivity), these molecules, especially in combination with genetic approaches, can be instrumental for the delineation of the biologic processes involving endogenous H2S production. Moreover, some of these compounds (e.g., cell-permeable prodrugs of the CBS inhibitor aminooxyacetate, or benserazide, a potentially repurposable CBS inhibitor) may serve as starting points for future clinical translation. The present article overviews the currently known H2S donors and H2S biosynthesis inhibitors, delineates their mode of action, and offers examples for their biologic effects and potential therapeutic utility.

The neutralizing antibody, LY-CoV555, protects against SARS-CoV-2 infection in nonhuman primates.

Abstract: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) poses a public health threat for which preventive and therapeutic agents are urgently needed. Neutralizing antibodies are a key class of therapeutics that may bridge widespread vaccination campaigns and offer a treatment solution in populations less responsive to vaccination. Here, we report that high-throughput microfluidic screening of antigen-specific B cells led to the identification of LY-CoV555 (also known as bamlanivimab), a potent anti-spike neutralizing antibody from a hospitalized, convalescent patient with coronavirus disease 2019 (COVID-19). Biochemical, structural, and functional characterization of LY-CoV555 revealed high-affinity binding to the receptor-binding domain, angiotensin-converting enzyme 2 binding inhibition, and potent neutralizing activity. A pharmacokinetic study of LY-CoV555 conducted in cynomolgus monkeys demonstrated a mean half-life of 13 days and a clearance of 0.22 ml hour-1 kg-1, consistent with a typical human therapeutic antibody. In a rhesus macaque challenge model, prophylactic doses as low as 2.5 mg/kg reduced viral replication in the upper and lower respiratory tract in samples collected through study day 6 after viral inoculation. This antibody has entered clinical testing and is being evaluated across a spectrum of COVID-19 indications, including prevention and treatment.

Experimental immobilization and remobilization of rat knee joints

Abstract: This is a histological study of rat knee joints that were subjected to limitation of motion alone or were remobilized after varying periods of restricted movement. A progression of morphological changes consequent to restriction of motion was found, and it was possible to gain some indication of the degree of reversibility of these changes after varying periods of immobilization and remobilization either by a single forced manipulation, or by active movement alone, or by repeated gentle passive movement. On the basis of this study, we have arrived at the following conclusions in regard to experimental joint immobilization and remobilization in the rat: 1. Rigid immobilization is not essential to produce structural change, and the maintenance of a slight range of motion will not prevent structural changes; 2. After prolonged immobilization, contracture of both the muscles and the capsule is responsible for restriction of motion, with shortening of the muscles being primarily at fault; 3. Proliferation of intracapsular connective tissue and the formation of adhesions are primary responses to limitation of motion—to a limited degree these changes are reversible; 4. Major cartilage alterations, such as matrix fibrillation, cleft formation and ulceration, as well as their adjacent subchondral lesions, result from abnormal friction and pressure in a joint compromised by limitation of motion—these changes are not reversible; 5. In the rat, the joint changes that are caused by restriction of motion appear to be reversible if the period of immobilization does not exceed thirty days—after sixty days of immobilization all major joint alterations consequent to the restriction of motion have appeared, and further immobilization after this time only causes changes in the degree of these alterations; 6. With forced remobilization there is tearing of the connective tissue that has proliferated within the joint, often in a plane different from that of the original joint cleft; subsequently, associated with continued motion of the joint, a cellular layer with the characteristics of synovial membrane forms about the surfaces of the new cleft; 7. Three methods of remobilization—forced, active, and passive—were used in these experiments, which were equally effective in restoring of the range of motion; after thirty-five days of remobilization by any means the joints were histologically indistinguishable.

Therapeutic alliance in depression treatment: controlling for prior change and patient characteristics.

Abstract: Although many studies report that the therapeutic alliance predicts psychotherapy outcome, few exclude the possibility that this association is accounted for by 3rd variables, such as prior improvement and prognostically relevant patient characteristics. The authors treated 367 chronically depressed patients with the cognitive-behavioral analysis system of psychotherapy (CBASP), alone or with medication. Using mixed effects growth-curve analyses, they found the early alliance significantly predicted subsequent improvement in depressive symptoms after controlling for prior improvement and 8 prognostically relevant patient characteristics. In contrast, neither early level nor change in symptoms predicted the subsequent level or course of the alliance. Patients receiving combination treatment reported stronger alliances with their psychotherapists than patients receiving CBASP alone. However, the impact of the alliance on outcome was similar for both treatment conditions.