Erin L. Manning

Critical decline in fine motor hand movements in human aging

BACKGROUND Slowing of motor movements in human aging is a well-known occurrence, but its biologic basis is poorly understood. Reliable quantitation may refine observations of this phenomenon to better aid research on this entity. METHODS A panel equipped with timing sensors under computer control was used to measure upper extremity movement times in two groups of healthy individuals: adults younger than 60 years of age (n = 56; range, 18-58 years) and adults older than 60 years of age (n = 38; range, 61-94 years). RESULTS Fine motor performance was better in the dominant hand (p = 0.0007) regardless of age. Adult and aged groups differed on two basic timing measures, which reflect coarse motor and fine motor performance (p < 0.0001). There were no gender differences on either measure. There was a strong effect of task difficulty with age on coarse motor (p < 0.01) and fine motor (p < 0.0001) measures. The fine motor measure of hand performance in healthy individuals correlated in a nonlinear fashion with age for more difficult tasks (r2 = 0.63) but showed a simple linear relation for less-demanding tasks (r2 = 0.5). CONCLUSION This technique sensitively detects age-related motor performance decline in humans. There may be a critical period in late midlife when fine motor performance decline either begins or abruptly worsens.

Influences of inbreeding and genetics on telomere length in mice

Abstract. We measured telomere lengths of blood leukocytes in several inbred and outbred mammalian species, using a telomere-specific fluorescent probe and flow cytometry. Humans, non-human primates, and three outbred populations of Peromyscus mice (Peromyscus leucopus, Peromyscus maniculatus, and Peromyscus polionotus) have short telomeres. Two common strains of laboratory mice, C57BL/6J and DBA/2J, have telomeres several times longer than most other mammals surveyed. Moreover, the two inbred laboratory mouse strains display significantly different telomere lengths, suggesting the existence of strain-specific genetic determinants. To further examine the effects of inbreeding, we studied three Peromyscus leucopus inbred lines (GS109, GS16A1, and GS16B), all derived from the outbred P. leucopus stock. Telomeres of all three inbred lines are significantly lengthened relative to outbred P. leucopus, and the three lines display strain-specific significantly different telomere lengths, much like the C57BL/6J and DBA/2J strains of M. musculus. To further characterize the genetic inheritance of telomere length, we carried out several crosses to obtain hybrid F1 mice between parental strains displaying the phenotype of long and short telomeres. In all F1 mice assayed, peripheral blood leukocyte telomere length was intermediate to that of the parents. Additionally, we generated F2 mice from a cross of the (P. leucopus outbred × GS16B)F1. Based on the distribution of telomere length in the F2 population, we determined that more than five loci contribute to telomere length regulation in Peromyscus. We concluded that inbreeding, through unknown mechanisms, results in the elongation of telomeres, and that telomere length for a given species and/or sub-strain is genetically determined by multiple segregating loci.

Packed red blood cells suppress T-cell proliferation through a process involving cell-cell contact.

BACKGROUND Packed red blood cell (PRBC) transfusion suppresses immunity and increases morbidity and mortality. Leukocyte reduction has failed to abrogate these effects, thus implicating red blood cells themselves or their components. PRBC impair proliferation of immortal (Jurkat) T cells by depleting arginine from the extracellular environment. The effect of PRBC on isolated ex vivo T-cell proliferation has not been reported. We hypothesize that PRBCs depress mitogen-stimulated proliferation in isolated human and mouse T cells. METHODS Human peripheral T cells were isolated by Ficoll-Hypaque gradient, purified by magnetic separation, and stimulated with anti-CD3 or anti-CD28. DO11.10 transgenic mouse splenic T cells were stimulated with ovalbumin. Cells were cultured at 1 x 10(6)/mL in 96-well plates or in 24-transwell plates in the presence of PRBC (0.015-5% by volume, stored for 4-6 weeks). In culture media, arginine and citrulline were varied. Proliferation was measured at 72 hours by thymidine incorporation. T-cell viability, apoptosis, and receptor zeta chain were measured by flow cytometry. RESULTS PRBC significantly depressed human peripheral and mouse splenic T-cell proliferation in a dose-dependent manner. PRBC arginase blockade by N-omega-hydroxy-nor-l-arginine only partly restored proliferation. Cell contact was required in both cell types for maximal effect. Depressed zeta chain in human peripheral T cells was partly restored by arginase blockade. Salvage by high-dose arginine and citrulline was unsuccessful. Decreased proliferation was not related to cell death. CONCLUSION PRBC suppresses mitogen-stimulated human and antigen-stimulated mouse T-cell proliferation by mechanisms independent of arginine depletion. This is a novel mechanism for transfusion-associated immune suppression.

Red blood cell arginase suppresses Jurkat (T cell) proliferation by depleting arginine

BACKGROUND Transfusion of packed red blood cells (PRBC) suppresses immunity, but the mechanisms are incompletely understood. PRBCs contain arginase, an enzyme which converts arginine to ornithine and depletes arginine in vitro. Arginine depletion suppresses proliferation of Jurkat T cells in other models. We hypothesize that PRBC arginase-mediated arginine depletion will suppress proliferation of T cells. METHODS A transfusion model was designed adding PRBC to culture RPMI media with or without an irreversible arginase blocker (nor-NOHA), incubating for 6-48 hours and then removing the PRBCs. Amino acid concentrations in the media were measured using liquid chromatography mass spectrometry. T cells were then added to the pre-conditioned media, cultured for 24 hours, and proliferation was measured. RESULTS PRBC depleted arginine significantly and increased ornithine in media compared to baseline PRBC treated wells and significantly decreased T cell proliferation. These effects were enhanced with volume of PRBC exposure. Nor-NOHA inhibition of arginase restored T cell proliferation in PRBC treated cultures. CONCLUSIONS Jurkat T cell proliferation was impaired by PRBC in clinically relevant volumes. The mechanism influencing T cell impairment appears to result from arginine depletion by arginase. Arginine depletion by PRBC arginase may be a novel mechanism for immunosuppression after transfusion.

A Smartphone-based Decision Support Tool Improves Test Performance Concerning Application of the Guidelines for Managing Regional Anesthesia in the Patient Receiving Antithrombotic or Thrombolytic Therapy.

Background:The American Society of Regional Anesthesia and Pain Medicine (ASRA) consensus statement on regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy is the standard for evaluation and management of these patients. The authors hypothesized that an electronic decision support tool (eDST) would improve test performance compared with native physician behavior concerning the application of this guideline. Methods:Anesthesiology trainees and faculty at 8 institutions participated in a prospective, randomized trial in which they completed a 20-question test involving clinical scenarios related to the ASRA guidelines. The eDST group completed the test using an iOS app programmed to contain decision logic and content of the ASRA guidelines. The control group completed the test by using any resource in addition to the app. A generalized linear mixed-effects model was used to examine the effect of the intervention. Results:After obtaining institutional review board’s approval and informed consent, 259 participants were enrolled and randomized (eDST = 122; control = 137). The mean score was 92.4 ± 6.6% in the eDST group and 68.0 ± 15.8% in the control group (P < 0.001). eDST use increased the odds of selecting correct answers (7.8; 95% CI, 5.7 to 10.7). Most control group participants (63%) used some cognitive aid during the test, and they scored higher than those who tested from memory alone (76 ± 15% vs. 57 ± 18%, P < 0.001). There was no difference in time to completion of the test (P = 0.15) and no effect of training level (P = 0.56). Conclusions:eDST use improved application of the ASRA guidelines compared with the native clinician behavior in a testing environment.

Role of Telomerase in Maintaining Hematopoietic Stem Cell Telomere Length during Replicative Stress and Aging

INTRODUCTION. Telomeres and telomerase expression have been implicated in neoplastic progression of human tumors and in replicative senescence of cultured cells. However, their role in replicative senescence and aging of cell populations in vivo is less certain, despite the fact that human telomere length is age-related in rapidly dividing tissues such as hematopoietic cells (1). Given that relatively short-lived inbred mice have telomeres several times longer than humans, the relevance of telomere shortening to aging in mice is even more doubtful. Using a Flow cytometry-based fluorescence in situ hybridization (Flow-FISH) method of measuring telomere length in individual cells, we have studied the effects of aging and sublethal irradiation on hematopoietic cells of long-lived (C57BL/6) and short-lived (DBA/2) mouse strains.

Hematopoietic stem cells and aging

Publisher Summary Self-renewing tissues rely on stem cell populations to continuously supply those mature cells with inherently short lifespans or those lost through wear and tear, disease, or accident. Despite an age-related increase in at least hematopoietic stem cell numbers, some functional capabilities of stem cells are compromised during aging. The majority of stem cells are maintained in a quiescent, noncycling state until needed and then one (or a few) at a time is recruited and activated to become the active clones. A stem cell population in toto may efficiently orchestrate an appropriate response to specific hematopoietic needs, whereas at the level of individual stem cells all mitotic options, symmetric and asymmetric, may be open to each cell but with variable probabilities that reflect the current needs. Thus, events at the individual cell level may be stochastic, but the population is responsive to physiological needs.

The rising tide of opioid use and abuse: the role of the anesthesiologist

Opioid use has risen dramatically in the past three decades. In the USA, opioid overdose has become a leading cause of unintentional death, surpassing motor vehicle accidents. A patient’s first exposure to opioids may be during the perioperative period, a time where anesthesiologists have a significant role in pain management. Almost all patients in the USA receive opioids during a surgical encounter. Opioids have many undesirable side effects, including potential for misuse, or opioid use disorder. Anesthesiologists and surgeons employ several methods to decrease unnecessary opioid use, opioid-related adverse events, and side effects in the perioperative period. Multimodal analgesia, enhanced recovery pathways, and regional anesthesia are key tools as we work towards optimal opioid stewardship and the ideal of effective analgesia without undesirable sequelae.

Rationalization, Development, and Implementation of a Preoperative Diabetes Optimization Program Designed to Improve Perioperative Outcomes and Reduce Cost

Diabetes is an increasingly common medical condition affecting ∼29 million people (8 million of whom are undiagnosed), or 9% of the U.S. population. The estimated health expenditures to prevent and treat diabetes and associated direct and indirect complications totaled

Fluid Management in the Elderly

245 billion in 2012, and this cost is on a trajectory to double by 2030 (1,2). An estimated 25% of patients with diabetes will require surgery (3). Twenty-eight percent of patients with diabetes are unaware that they have the disease (2). Furthermore, 5–10% of patients presenting for surgery are found to have previously unrecognized diabetes (4,5). This is particularly important because patients who are unaware of their diabetes have higher preoperative blood glucose levels (4) and a higher risk of perioperative mortality compared to patients who are aware of their diabetes (5). Diabetes is a well-known risk factor for postoperative infection, acute renal failure, ileus, and prolonged hospital stay (6–9). Poor preoperative glycemic control portends poor intraoperative glycemic control, which is an established risk factor for perioperative morbidity (10,11). Surgical patients with perioperative hyperglycemia (with and without underlying diabetes) have a greater risk for infection and related adverse outcomes after surgery compared to patients without hyperglycemia. Patients with diabetes are more prone to these surgical complications due to the microangiopathy (e.g., nephropathy and neuropathy) and macroangiopathy (e.g., atherosclerosis) intrinsic to the disease and also have mortality rates significantly greater than those of patients without diabetes (12–16). When patients with poorly controlled diabetes present for surgery, they impose a significant financial health resource burden, including prolonged ventilator dependence, longer hospital stay, and greater postoperative loss of productivity. As the prevalence of diabetes increases, optimal screening, management, and timing of elective surgery for patients with diabetes has become a matter of increasing …