Assessing social support in elderly adults

We examined the relationship among stress, social support and health status in patients with symptomatic osteoarthritis. Further, we compared three approaches to measuring social support (i.e. objective measures, subjective indicators, and satisfaction). Generally, subjective, rather than objective, indicators of support were more strongly associated with satisfaction with the amount of support received. Regardless of how social support was assessed, we failed to find evidence that support buffers individuals from negative health-related consequences of exposure to stressors. Univariate analyses also demonstrated that being black, married, better educated, and having a higher income were positively associated with social support. Social support continues to be a complex concept in terms of its operational definition and identification of the mechanism by which it influences health outcomes.     

Dietary Carbohydrate as Glycemic Load,Not Fat,Coupled with Genetic Permissiveness Favoring Rapid Growth and Extra Calories,Dictate Metabolic Syndrome and Diabetes Induction in Nile Rats (Arvicanthis niloticus)

Objective: Whether dietary carbohydrate (CHO) or fat is more involved in type 2 diabetes (T2DM) induction uncomplicated by dietary fiber was addressed in a spontaneous diabetic model, the diurnal Nile rat that mimics the human condition. Methods: A total of 138 male Nile rats were fed plant-based and animal-based saturated fat where 10% energy as CHO and fat were exchanged across 5 diets keeping protein constant, from 70:10:20 to 20:60:20 as CHO:fat:protein %energy. Diabetes induction was analyzed by: 1. diet composition, i.e., CHO:fat ratio, to study the impact of diet; 2. quintiles of average caloric intake per day to study the impact of calories; 3. quintiles of diabetes severity to study the epigenetic impact on diabetes resistance. Results: High glycemic load (GLoad) was most problematic if coupled with high caloric consumption. Diabetes severity highlighted rapid growth and caloric intake as likely epigenetic factors distorting glucose metabolism. The largest weanling rats ate more, grew faster, and developed more diabetes when the dietary GLoad exceeded their gene-based metabolic capacity for glucose disposal. Diabetes risk increased for susceptible rats when energy intake exceeded 26 kcal/day and the GLoad was >175/2000 kcal of diet and when the diet provided >57% energy as CHO. Most resistant rats ate <25 kcal/day independent of the CHO:fat diet ratio or the GLoad adjusted to body size. Conclusion: Beyond the CHO:fat ratio and GLoad, neither the type of fat nor the dietary polyunsaturated/saturated fatty acid (P/S) ratio had a significant impact, suggesting genetic permissiveness affecting caloric and glucose intake and glucose disposition were key to modulating Nile rat diabetes. Fat became protective by limiting GLoad when it contributed >40% energy and displaced CHO to <50% energy, thereby decreasing the number of diabetic rats and diabetes severity.     

Effects of histamine-receptor antagonists on histamine-stimulated renin secretion

The effects of histamine H1- and H2-receptor antagonists on histamine-stimulated renin secretion were examined in anesthetized dogs. Tripelennamine (H1 blocker) further enhanced renin secretion in the presence of exogenous histamine. Moreover, tripelennamine alone increased renin secretion. These effects are probably due to non-specific properties of the drug and not to interaction of tripelennamine with H1 receptors. Conversely, cimetidine (H2 blocker) significantly inhibited histamine-induced increases in renin secretion, renal blood flow, and sodium excretion without any changes in mean arterial blood pressure or glomerular filtration rate. Cimetidine alone had no effect. We conclude that H2 receptors mediate the effect of histamine on renin secretion in dogs with innervated, intact kidneys.     

ATR inhibition sensitizes liposarcoma to doxorubicin by increasing DNA damage

Liposarcomas account for approximately 20% of all adult sarcomas and have limited therapeutic options outside of surgery. Inhibition of ataxia-telangiectasia and Rad3 related protein kinase (ATR) has emerged as a promising chemotherapeutic strategy in various cancers. However, its activation, expression, and function in liposarcoma remain unkown. In this study, we investigated the expression, function, and potential of ATR as a therapeutic target in liposarcoma. Activation and expression of ATR in liposarcoma was analyzed by immunohistochemistry, which was further explored for correlation with patient clinical characteristics. ATR-specific siRNA and the ATR inhibitor VE-822 were applied to determine the effect of ATR inhibition on liposarcoma cell proliferation and anti-apoptotic activity. Migration activity and clonogenicity were examined using wound healing and clonogenic assays. ATR (p-ATR) was overexpressed in 88.1% of the liposarcoma specimens and correlated with shorter overall survival in patients. Knockdown of ATR via specific siRNA or inhibition with VE-822 suppressed liposarcoma cell growth, proliferation, migration, colony-forming ability, and spheroid growth. Importantly, ATR inhibition significantly and synergistically enhanced liposarcoma cell line chemosensitivity to doxorubicin. Our findings support ATR as critical to liposarcoma proliferation and doxorubicin resistance. Therefore, the addition of ATR inhibition to a standard doxorubicin regimen is a potential treatment strategy for liposarcoma.     

Immunoglobulin gene analysis reveals 2 distinct cells of origin for EBV-positive and EBV-negative Burkitt lymphomas

The normal counterpart of the neoplastic B cells in Burkitt lymphoma (BL) is still unclear. Based on immunoglobulin gene rearrangement studies, some authors suggest an origin from germinal center cells and others from memory B cells. However, most of these studies rely on cell lines or on a small series of cases. To help clarify the cell of origin of BL, semi-nested polymerase chain reaction (PCR) was performed to amplify the VDJ rearrangements of the immunoglobulin heavy chain (V(H)) genes, and the resultant amplificates were sequenced for comparison with known germline V(H) segments. The results of this approach revealed that all cases (15 endemic BL [eBL], 10 sporadic BL [sBL], and 6 AIDS-related BL) harbor mutated V(H) genes, with different mutation ranges among the 3 types of BL. The eBL and AIDS-related forms showed considerably higher mutation rates than the sBL form (5.1%, 5.4%, and 1.5%, respectively). The mutations in eBL and AIDS-related BL also showed signs of antigen selection, whereas no signs of antigen selection were found in sBL. Finally, after subcloning the amplificates, sequence analysis revealed no signs of ongoing mutations in any of the cases analyzed. Given that one of the main differences between eBL and AIDS-related BL on the one hand and sBL on the other hand is the association with Epstein-Barr virus (EBV), we compared EBV-positive and EBV-negative BLs independently of their geographic origin and HIV status. The differences in the number of somatic mutations and antigen selection were even more evident when this approach was used. According to our molecular results, it appears that EBV-positive and EBV-negative BL may originate from 2 distinct subsets of B cells, pointing to a particular role for the germinal-center reaction in the pathogenesis of these tumors. The different types of C-MYC translocation reported in BL may also be related to the different stages of B-cell maturation.     

Can Intermittent Dosing Optimize Prolonged Linezolid Treatment of Difficult Multidrug-Resistant Tuberculosis?

We evaluated treatment with linezolid, dosed at 800 mg once daily for 1 to 4 months as guided by sputum culture status and tolerance and then at 1,200 mg thrice weekly until ≥1 year after culture conversion, in addition to individually optimized regimens among 10 consecutive patients with extensively drug-resistant tuberculosis or fluoroquinolone-resistant multidrug-resistant tuberculosis. All achieved stable cure, with anemia corrected and neuropathy stabilized, ameliorated, or avoided after switching to intermittent dosing. Serum linezolid profiles appeared better optimized.     

Long-term outcome after bone marrow transplantation for severe aplastic anemia

From January 1978 to December 2001, 133 patients with severe aplastic anemia (SAA) underwent non-T cell-depleted allogeneic bone marrow transplantation from an HLA-identical sibling donor, at the Hospital Saint Louis using either the combination of cyclophosphamide (Cy) and thoracoabdominal irradiation (TAI; n=100) or Cy and antithymocyte globulin (ATG; n=33), as a conditioning regimen. With 13.6 years of follow-up, the 10-year survival estimate was 64%. Four factors were associated with lower survival: older age, use of Cy-TAI, any form of treatment prior to transplantation (either androgens or immunosuppressive therapy, [IST]), and grade II to IV acute graft-versus-host disease (GvHD). TAI was the sole factor associated with the occurrence of acute GvHD. The risk of cancers (15-year cumulative incidence, 10.9%) was associated with older age and with the use of cyclosporine as IST before transplantation. Cumulative incidences and risk factors of nonmalignant late effect including avascular osteonecrosis and late bacterial, viral, and fungal infection were also analyzed. Improved results using Cy-ATG as conditioning can lead to more than 90% chance of cure in patients with SAA. Even if, in our experience, the role of Cy-ATG versus that of Cy-TAI remained inextricably related to the year of transplantation, the major detrimental role of the GvHD disease in the long-term outcome and its relation to TAI supports avoidance of irradiation in the conditioning regimen. Furthermore, avoidance of any IST before transplantation in patients with a sibling donor is a prerequisite for attaining such excellent results.     

Correlation of PD-L1 Expression with Tumor Mutation Burden and Gene Signatures for Prognosis in Early-Stage Squamous Cell Lung Carcinoma

Objectives

Anti–programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-L1) immunotherapy has demonstrated success in the treatment of advanced NSCLC. Recently, PD-1/PD-L1 blockade also has demonstrated interesting results in small trials of neoadjuvant treatment in stage IB to IIIA NSCLC. In addition, several clinical trials using anti–PD-1/PD-L1 immunotherapy as an adjuvant or neoadjuvant treatment in patients with resectable stage NSCLC are ongoing. However, few analyses of anti–PD-1/PD-L1 immunotherapy–related biomarkers in early-stage squamous cell lung carcinoma (SqCLC) have been reported. In this study, we evaluated PD-L1 protein expression, tumor mutation burden, and expression of an immune gene signature in early-stage SqCLC, providing data for identifying the potential role for patients with anti–PD-1/PD-L1 treatment in early-stage SqCLC.

Effects of Cling Film Draping Material on Body Temperature of Mice During Surgery

General anesthesia induces many systemic effects, including thermoregulatory impairment and subsequent perioperative hypothermia. Due to the animals’ small size, monitoring and maintaining body temperatures in laboratory rodents during anesthesia is important for successful surgical outcomes and prompt anesthetic recovery. Draping materials have the potential to aid in thermal support during surgical anesthesia. In this study, rectal and surface (infrared) temperatures were measured in C57BL/6 mice under isoflurane anesthesia every 5 min for the duration of a 35-min sham surgery. In addition to placement on a circulating water bath, mice (n = 6/group) were draped with commercial cling film (CF; Press''n Seal, Glad, Oakland, CA), a conventional paper drape (PD), or no drape (ND) during surgery. Results demonstrated that CF-draped animals had significantly higher rectal temperatures than nondraped animals. Furthermore, surface temperatures of CF-draped mice were considerably higher than those of both paper-draped and undraped animals. The data indicate that cling film is an effective material to help minimize hypothermia in mice and potentially in other laboratory rodents requiring general anesthesia.

Surgery and anesthesia introduce many challenges, especially in veterinary medicine, due to the diversity of species. One major challenge during general anesthesia involves changes in an animal''s thermoregulatory ability.^1,14 Body temperatures in mice and rats fall significantly during anesthesia if no thermal support is provided.^29,30 Hypothermia occurs due to drug-induced alterations to the thermoregulatory center, inadequate circulation, and a loss of body heat to the environment from evaporation, radiation, conduction, and convection.⁷ Mice are particularly susceptible to hypothermia, due to their large surface area per gram of body weight, which permits significant physiologic changes in response to fluctuations in the ambient temperature.³¹ Covering the animal''s body with towels, drapes, or blankets to reduce the area exposed to the environment can minimize heat loss.^6,7,13 Placing the animal on an insulated surface can limit conductive heat loss. In larger animals, warmed fluids can be given perioperatively, heated anesthetic gasses can be administered, and heated blankets and heat packs can be applied to body surfaces to provide exogenous heat.^1,7 Safer and more practical methods for rodents are circulating water heating blankets, thermal gel packs, and warming lamps, which are commonly used for thermal support during anesthesia.^5,14 Addressing all of these factors can contribute to maintaining normothermia during anesthesia.Risk of mortality is elevated during anesthesia and in the postoperative period, including in rodents.^1,13 Hypothermia induced by anesthesia can negatively affect rodents by altering vital parameters such as heart rate and blood pressure and delaying anesthetic recovery.^3,5,12,19 These risks require careful selection of an appropriate anesthetic protocol and careful monitoring of the patient throughout anesthesia until full recovery occurs. Strict anesthetic monitoring and the use of supplemental heat devices have been shown to reduce the likelihood of complications, improve overall postoperative recovery, and reduce mortality associated with surgical procedures.^1,7,15,16 However, due to these species’ small size, monitoring equipment must be specialized and is often costly. Cost-effective and practical alternative equipment and materials would facilitate monitoring and care of rodents.Various draping options are available for rodent surgery, and their use is vital for both sterile technique and heat retention. Traditionally, paper draping material has been a popular option, because it is relatively inexpensive and can be autoclaved together with surgical instruments.^15,16 Some institutions have adopted varying methods and types of draping, including no drape and paper draping. Commercial cling film (CF) has been used as draping due to its low cost, ease of use, and sterility straight out of the box.⁹ Our study team sought to evaluate the effects of draping material on intraoperative thermoregulation in mice by measuring rectal temperature (modified rectal probe) and surface temperature (infrared device) during a 35-min laparotomy procedure, with both temperature devices chosen for affordability and availability. We hypothesized that mice draped with CF would maintain a higher intraoperative body temperature under general anesthesia than would mice with traditional paper drapes or no drape.