TGF-beta signaling regulates CD8+ T cell responses to high- and low-affinity TCR interactions

Absence of transforming growth factor-beta (TGF-beta) signaling to T cells in mice results in an increase in T cell numbers, an activated CD44 high, CD69-, CD25- T cell phenotype and a T cell-mediated injury to many organs. It is not known if such T cell activation in the absence of TGF-beta signaling is spontaneous or due to aberrant T cell responses to a physiological stimulus. We used adoptive transfer of CD8+ T cells from mice double transgenic for the OT-1 TCR and the TGF-beta1-dominant negative transgene [OT-dominant-negative receptor (DNR)] to investigate the role of TGF-beta in regulating CD8+ T cell activation in vivo. The activation and expansion of single-transgenic OT and double-transgenic OT-DNR cells to oral antigens, high-affinity and low-affinity peptides were indistinguishable. Activation with high-affinity peptide and CFA however resulted in greater expansion of OT-DNR cells in comparison to OT cells. Low-affinity peptide and adjuvant did not result in OT cell activation or expansion but results in up-regulation of CD44 on OT-DNR cells. These data show that TGF-beta functions in vivo to limit the scale of CD8+ T cell expansion after high-affinity peptide-MHC interactions. TGF-beta also limits T cell activation to the highest affinity peptide-MHC interactions. The increase in T cell number and activation present in TGF-beta-deficient and TGF-beta DNR-expressing mice may be due to the loss of these two phenomena.     

HIV gp120 plus specific peptides are recognized in a similar manner to specific HLA plus peptide by HLA-restricted antigen-specific T-cell lines

HIV induces disease only following chronic activation of the immune system. Other retroviruses such as the mouse mammary tumour virus (MMTV) activate a large percentage of T cells by encoding a superantigen (SAg). To date there is no evidence that HIV encodes a SAg. An alternative way to induce pan-activation of the immune system is by allogeneic stimulation, which occurs following transplantation. Here we extend previous work which demonstrated that HIVpg120 could bind peptides in a similar manner to HLA, by demonstrating that human antigen presenting cells (APCs) expressing gp120 (but not DR1) can present a DR1-restricted peptide to induce proliferation of a DR1-restricted peptide-specific T-cell line in a similar manner to the same peptide presented by a DR1 expressing APC. Our data provide strong support for the hypothesis that the HLA-like regions of gp120 encode functional properties shared with HLA, and could explain the extraordinary clinical and immunological similarities between AIDS and chronic graft versus host disease.     

Management of Chronic Pain in Nursing Homes: Navigating Challenges to Improve Person-Centered Care

Despite the dynamic demands in the nursing home (NH), a definitive approach to managing chronic pain in older adults has yet to be established. Due to concerns for potential adverse pharmacologic effects, balancing appropriate pain management is a challenge among NH residents. The challenges encompass but are not limited to medical complexities, functional disabilities, and physical frailty. Barriers to the successful implementation of a comprehensive chronic pain management at the NH may include ambiguous directions on specific therapeutic interventions, insufficient guidance on treatment duration, and limited available treatment options. The Centers for Medicare and Medicaid Services’ reporting requirement of adequate pain control among NH residents coupled with widely variable clinician-prescribing habits highlights the difficulties in overcoming the preceding challenges and barriers. The Coronavirus Disease 2019 (COVID-19) pandemic has further complicated pain management due to its negative consequences on well-being of residents of NHs. Associated symptoms of psychosocial stress, anxiety and depression, and chronic pain symptoms can exacerbate during the COVID-19 pandemic, leading to increased requirement for pain medications including but not limited to opioids.Pain is a multidimensional symptom and requires a strategic multimodal approach for its management. Nonpharmacologic modalities are underutilized in the NH setting and are the preferred first steps for mild pain, and nonopioid pharmacological agents can be added as a second step for a synergistic effect for moderate to severe pain. Opioids should be used as a last resort. Short-acting opioids are preferred over extended-release/long-acting opioids for chronic pain. Clinicians are encouraged to engage residents in proactive strategies in managing their pain, and to set realistic expectations toward improving their quality of life, as complete elimination of pain is not feasible in most cases.This review article provides the interdisciplinary team with a contemporary perspective of the multitude of changes and challenges influencing the prescribing as well as deprescribing of various pain medications.     

Prophylactic ureteric catheters in colon surgery—How safe are they?

Preoperative placement of ureteral catheters has been recommended for prevention of ureteral injuries. During a three-year period, prophylactic ureteral catheters were inserted selectively in 59 patients undergoing colorectal surgery in whom a difficult dissection was anticipated. Three patients developed reflux anuria after the use of prophylactic ureteral catheters. The safety of these catheters is questioned, and the diagnoses and methods of preventing ureteral injuries are discussed.     

病灶清除内固定植骨治疗胸椎结核

目的;探讨手术治疗胸椎结核的更好方法。方法;自１９９０年以来,对２１例胸椎结核导致椎柱不稳的患者,应用病灶清除,哈氏棒内固定,椎间及椎板植骨的手术方法。本组平均３３．２岁。胸７椎体６例,胸８椎体８例,胸１０椎体７例,椎体压缩〈１／２椎体高度１３例,〉１／２椎体高度８例,并不全瘫１４例。手术中先行病灶清除,然后哈氏棒内固一,撑开后再次清除病灶,取肋骨和髂骨行椎间及椎板上植骨。术后化疗１２～１５月。结     

Expression of the retinoic Acid nuclear receptors (rars) and retinoid x-receptor (rxr) genes in estrogen-receptor positive and negative breast-cancer

Retinoid inhibition of breast carcinoma growth correlates with the estrogen receptor (ER) positivity and elevated retinoic acid nuclear receptor (RARalpha) mRNA levels. We therefore examined retinoid nuclear receptor mRNA levels in patient breast carcinoma biopsy specimens to determine if such a correlation exists between ER positivity and RARalpha mRNA levels. We have now shown that RARalpha mRNA levels are significantly higher in ER positive samples. RARgamma mRNA is expressed at relatively high levels in a majority of the tumor samples independent of the ER-status while RARbeta mRNA was expressed at low levels in only one tumor sample. We also found high RXRalpha mRNA levels in all of the tumor samples examined while RXRgamma mRNA could not be detected. Our study demonstrates that RARalpha mRNA levels are either low or absent in ER-negative patient samples and that RARalpha levels may serve as a potential marker to determine patient responsiveness to RA therapy.     

Blunt abdominal trauma: comparison of ultrasonography and computed tomography in a district general hospital

Ultrasonography has been proposed as a screening method for blunt abdominal trauma, but its specific role in comparison with other diagnostic modalities has yet to be defined. The aim of the present retrospective study was to compare the results of ultrasonography and CT of the abdomen in blunt trauma in a district general hospital. The hospital records of 25 patients who were admitted with blunt abdominal trauma to Southland Hospital, Invercargill, New Zealand, between January 1991 and November 1996 and who had both ultrasound and CT of the abdomen within 48 h of admission were reviewed. Ultrasound missed seven lesions in seven patients (7/25, 28%) compared with CT. Three of these were intestinal lesions that needed laparotomy. Ultrasound had a usefulness index of 1, 0.76, 0.72, 0.69 and 0, respectively, for detecting lesions of the kidneys, free intraperitoneal fluid, the liver, the spleen, and intestines. Although ultrasound can be used as an initial screening method for blunt abdominal trauma, CT is still the imaging modality of choice for detecting intra-abdominal lesions for stable patients in a district general hospital.     

Giant cell tumour of the temporal bone: case report and review of the literature

This paper presents an expansile lesion of the temporal bone, in a 14-year-old boy, that was initially diagnosed as intra-osseous meningioma from CT appearance. At histopathology a final diagnosis of giant cell tumour was made. A brief review of the literature is presented for this rare case.     

Generation of antigen specific CD8+ cytotoxic T cells following immunization with soluble protein formulated with novel glycoside adjuvants.

Presentation of peptide on MHC class I molecules is essential to elicit cytolytic T cell (CTL) activity. Such peptides are a result of the cytosolic, or class I, antigen processing pathway. Due to the segregation of the class I and the exogenous processing pathway, soluble protein cannot enter the class I pathway and is thus incapable of inducing CTL. However careful formulation with adjuvants can overcome this obstacle. In this study we evaluated the capacity of two novel amphiphilic adjuvants, better termed delivery vehicles, to elicit CTL activity in a C57Bl/6 murine model with ovalbumin (OVA) as an antigen. Incomplete Freund's adjuvant and aluminium hydroxide (Alhydrogel) were used as reference adjuvants. In addition the oil-in-water emulsion Provax was used throughout as a positive control adjuvant. Both amphiphile preparations were capable of eliciting potent CTL activity after administration of one immunizing dose of ovalbumin. CTL were CD8+ restricted as assessed by in vitro depletion of CD8+ and CD4+ T cells. CTL activity was also MHC-restricted as well as specific for the H-2Kb OVA motif SIINFEKL.