Perceived Consumption of a High-Dose Caffeine Drink Delays Neuromuscular Fatigue.

ABSTRACT: Elhaj, HM, Imam, O, Page, BW, Vitale, JM, and Malek, MH. Perceived consumption of a high-dose caffeine drink delays neuromuscular fatigue. J Strength Cond Res 36(5): 1185-1190, 2022-The placebo effect is a concept in which a desired outcome arises, mainly from the belief that the treatment (i.e., supplement or drug) was beneficial although no active ingredient was given. The results of studies related to the placebo effect primarily examine functional performance. What remains unanswered, however, is whether these changes in performance are associated with neuromuscular alterations in the exercised muscles. The purpose of the study, therefore, was to determine the influence of the placebo effect on the physical working capacity fatigue threshold (PWCFT) for a continuous exercise paradigm. To achieve this aim, subjects were told that they were participating in a study to determine the dosage response (low or high) of caffeine on neuromuscular fatigue when in fact no caffeine was given during the experiment. We hypothesized that the perceived consumption of the high-dose caffeine drink would result in a higher PWCFT than the perceived consumption of the low-dose caffeine drink and placebo. Secondarily, we hypothesized that the perceived consumption of the high-dose caffeine drink would result in a higher power output than the perceived consumption of the placebo. Nine healthy college-aged men (mean ± SEM: age, 25.7 ± 1.3 years; body mass, 84.4 ± 3.1 kg; and height: 1.82 ± 0.02 m) volunteered to be in the study. For each of the visits, subjects were given an 8 oz. bottle of water with dissolved crystal light. After the drink was consumed, subjects rested in the laboratory for 1 hour before performing the incremental single-leg knee-extensor ergometry. Immediately after the termination of the incremental single-leg knee-extensor ergometry, the subject was asked which caffeine dose (placebo, low, or high) they believed they consumed for that visit. There were no significant mean differences for maximal power output for the 3 perceived conditions (placebo: 62 ± 3, low-dose caffeine: 62 ± 4, and high-dose caffeine: 65 ± 3 W). When the subjects perceived consuming the high-dose caffeine drink, there were significant mean differences (all p-values < 0.01), for PWCFT, between the other conditions (mean ± SEM: placebo: 23 ± 3 W, low-dose caffeine: 26 ± 2 W, and high-dose caffeine: 42 ± 3 W). This corresponded to a significant mean difference (all p-values < 0.01) when the PWCFT was presented as a percentage of the maximal power output (mean ± SEM: placebo: 37 ± 5%, low-dose caffeine: 42 ± 3%, and high-dose caffeine: 64 ± 3%). The application of our results may indicate that the subject's expectancy, to caffeine consumption, plays a critical role in delaying the onset of neuromuscular fatigue despite not receiving any caffeine in their drinks.

Incidence, Severity, and Detection of Blood Pressure Perturbations after Abdominal Surgery: A Prospective Blinded Observational Study.

BACKGROUND: Intraoperative and postoperative hypotension are associated with myocardial and kidney injury and 30-day mortality. Intraoperative blood pressure is measured frequently, but blood pressure on surgical wards is usually measured only every 4 to 6 h, leaving long intervals during which hypotension and hypertension may be undetected. This study evaluated the incidence and severity of postoperative hypotension and hypertension in adults recovering from abdominal surgery and the extent to which serious perturbations were missed by routine vital-sign assessments. METHODS: Blood pressure was recorded at 1-min intervals during the initial 48 h in adults recovering from abdominal surgery using a continuous noninvasive monitor. Caregivers were blinded to these measurements and depended on routine vital-sign assessments. Hypotension and hypertension were characterized as time under and above various mean arterial pressure thresholds. RESULTS: Of 502 available patients, 312 patients with high-quality records were analyzed, with a median measurement time of 48 [interquartile range: 41, 48] postoperative hours. Nearly a quarter experienced an episode of mean arterial pressure of less than 70 mm Hg lasting at least 30 min (24%; 95% CI, 20%, 29%), and 18% had an episode of mean arterial pressure of less than 65 mm Hg lasting at least 15 min. Nearly half the patients who had mean arterial pressure of less than 65 mm Hg for at least 15 min (47%; 95% CI, 34%, 61%) were undetected by routine vital-sign assessments. Episodes of mean arterial pressure greater than 110 mm Hg lasting at least 30 min were observed in 42% (95% CI, 37%, 48%) of patients; 7% had mean arterial pressure greater than 130 mm Hg for at least 30 min, 96% of which were missed by routine assessments. Episodes of mean arterial pressure less than 65 mm Hg and mean arterial pressure greater than 110 mm Hg captured by routine vital-sign assessments but not by continuous monitoring occurred in 34 and 8 patients, respectively. CONCLUSIONS: Postoperative hypotension and hypertension were common, prolonged, profound, and largely undetected by routine vital-sign assessments in a cohort of adults recovering from abdominal surgery. Frequent or continuous blood pressure monitoring may detect hemodynamic perturbations more effectively and potentially facilitate treatment.

Exchange of supraglottic airways for endotracheal tube using the Eschmann Introducer during simulated child resuscitation: A randomized study comparing 4 devices.

BACKGROUND: The aim of this study was to examine the application of the Eschmann tracheal tube introducer (ETTI) with 4 types of supraglottic airway devices (SADs) using a child-manikin. METHODS: A total of 79 paramedics were asked to exchange the 4 SADs for an endotracheal tube with the ETTI in 3 different scenarios using a randomized crossover study format: normal airway without chest compression; normal airway with uninterrupted chest compression; and difficult airway with uninterrupted chest compression. The primary outcome was time to SAD exchange, with the secondary outcome measuring the success of SAD exchange. Each attempt was assessed by a trained assistant. RESULTS: The mean exchange times for LMA, Cobra PLA, Air-Q, and SALT were as follows: 21, 23, 21, and 18, respectively for Scenario A; 23, 27, 22.5, and 21 for Scenario B; and 23, 28, 23, and 23 for Scenario C. The percent efficacy of SADs exchange with LMA, Cobra PLA, Air-Q and SALT were 98.7%, 94.9%, 100%, and 100% for scenario A; 98.7%, 88.6%, 98.7%, and 97.5% for scenario B; and 93.7%, 87.3%, 94.9%, and 93.7% for scenario C. CONCLUSIONS: In this model of pediatric resuscitation, the SAD exchange using an ETTI has (LMA, Cobra PLA, Air-Q and SALT) proved to be effective in paramedics with no previous experience. Furthermore, experimental findings indicated that SAD exchange can be achieved without interrupting chest compression.

Cleveland Clinic's summer research program in reproductive medicine: an inside look at the class of 2014.

BACKGROUND: The American Center for Reproductive Medicine's summer internship course in reproductive medicine and research at Cleveland Clinic is a rigorous, results-oriented annual program that began in 2008 to train both local and international students in the fundamentals of scientific research and writing. The foremost goal of the program is to encourage premedical and medical students to aspire toward a career as a physician-scientist. The internship provides participants with an opportunity to engage in original bench research and scientific writing while developing theoretical knowledge and soft skills. This study describes selected survey responses from interns who participated in the 2014 internship program. The objective of these surveys was to elicit the interns' perspective on the internship program, its strengths and weaknesses, and to obtain insight into potential areas for improvement. METHODS: Questionnaires were structured around the five fundamental aspects of the program: 1) theoretical knowledge, 2) bench research, 3) scientific writing, 4) mentorship, and 5) soft skills. In addition, an exit survey gathered information on factors that attracted the interns to the program, communication with mentors, and overall impression of the research program. RESULTS: The opportunity to experience hands-on bench research and scientific writing, personalized mentorship, and the reputation of the institution were appreciated and ranked highly among the interns. Nearly 90% of the interns responded that the program was beneficial and well worth the time and effort invested by both interns and faculty. CONCLUSION: The outcomes portrayed in this study will be useful in the implementation of new programs or refinement of existing medical research training programs.

Generation of transgenic mouse fluorescent reporter lines for studying hematopoietic development.

During the development of the hematopoietic system, at least eight distinct lineages are generated in the mouse embryo. Transgenic mice expressing fluorescent proteins at various points in the hematopoietic hierarchy, from hematopoietic stem cell to multipotent progenitors to each of the final differentiated cell types, have provided valuable tools for tagging, tracking, and isolating these cells. In this chapter, we discuss general considerations in designing a transgene and survey available fluorescent probes and methods for confirming and analyzing transgene expression in the hematopoietic systems of the embryo, fetus, and postnatal/adult animal.

Dystrophin-compromised sarcoglycan-δ-knockout diaphragm requires full wild-type embryonic stem cell reconstitution for correction.

Limb-girdle muscular dystrophy-2F (LGMD-2F) is an incurable degenerative muscle disorder caused by a mutation in the sarcoglycan-δ (SGδ)-encoding gene (SGCD in humans). The lack of SGδ results in the complete disruption of the sarcoglycan complex (SGC) in the skeletal and cardiac muscle within the larger dystrophin-glycoprotein complex (DGC). The long-term consequences of SG ablation on other members of the DGC are currently unknown. We produced mosaic mice through the injection of wild-type (WT) embryonic stem cells (ESCs) into SGδ-knockout (KO) blastocysts. ESC-derived SGδ was supplied to the sarcolemma of 18-month-old chimeric muscle, which resulted in the restoration of the SGC. Despite SGC rescue, and contrary to previous observations obtained with WT/mdx chimeras (a mouse rescue paradigm for Duchenne muscular dystrophy), low levels of ESC incorporation were insufficient to produce histological corrections in SGδ-KO skeletal muscle or heart. The inefficient process of ESC rescue was more evident in the SGδ-KO diaphragm, which had reduced levels of dystrophin and no compensatory utrophin, and needed almost full WT ESC reconstitution for histological improvement. The results suggest that the SGδ-KO mouse model of LGMD is not amenable to ESC treatment.

Model to predict mortality in critically ill adults with acute kidney injury.

BACKGROUND AND OBJECTIVES: Acute kidney injury (AKI) requiring dialysis is associated with high mortality. Most prognostic tools used to describe case complexity and to project patient outcome lack predictive accuracy when applied in patients with AKI. In this study, we developed an AKI-specific predictive model for 60-day mortality and compared the model to the performance of two generic (Sequential Organ Failure Assessment [SOFA] and Acute Physiology and Chronic Health Evaluation II [APACHE II]) scores, and a disease specific (Cleveland Clinic [CCF]) score. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Data from 1122 subjects enrolled in the Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network study; a multicenter randomized trial of intensive versus less intensive renal support in critically ill patients with AKI conducted between November 2003 and July 2007 at 27 VA- and university-affiliated centers. RESULTS: The 60-day mortality was 53%. Twenty-one independent predictors of 60-day mortality were identified. The logistic regression model exhibited good discrimination, with an area under the receiver operating characteristic (ROC) curve of 0.85 (0.83 to 0.88), and a derived integer risk score yielded a value of 0.80 (0.77 to 0.83). Existing scoring systems, including APACHE II, SOFA, and CCF, when applied to our cohort, showed relatively poor discrimination, reflected by areas under the ROC curve of 0.68 (0.64 to 0.71), 0.69 (0.66 to 0.73), and 0.65 (0.62 to 0.69), respectively. CONCLUSIONS: Our new risk model outperformed existing generic and disease-specific scoring systems in predicting 60-day mortality in critically ill patients with AKI. The current model requires external validation before it can be applied to other patient populations.

Differential requirement for utrophin in the induced pluripotent stem cell correction of muscle versus fat in muscular dystrophy mice.

Duchenne muscular dystrophy (DMD) is an incurable degenerative muscle disorder. We injected WT mouse induced pluripotent stem cells (iPSCs) into mdx and mdx∶utrophin mutant blastocysts, which are predisposed to develop DMD with an increasing degree of severity (mdx <<< mdx∶utrophin). In mdx chimeras, iPSC-dystrophin was supplied to the muscle sarcolemma to effect corrections at morphological and functional levels. Dystrobrevin was observed in dystrophin-positive and, at a lesser extent, utrophin-positive areas. In the mdx∶utrophin mutant chimeras, although iPSC-dystrophin was also supplied to the muscle sarcolemma, mice still displayed poor skeletal muscle histopathology, and negligible levels of dystrobrevin in dystrophin- and utrophin-negative areas. Not only dystrophin-expressing tissues are affected by iPSCs. Mdx and mdx∶utrophin mice have reduced fat/body weight ratio, but iPSC injection normalized this parameter in both mdx and mdx∶utrophin chimeras, despite the fact that utrophin was compromised in the mdx∶utrophin chimeric fat. The results suggest that the presence of utrophin is required for the iPSC-corrections in skeletal muscle. Furthermore, the results highlight a potential (utrophin-independent) non-cell autonomous role for iPSC-dystrophin in the corrections of non-muscle tissue like fat, which is intimately related to the muscle.

Developmental ablation of Id1 and Id3 genes in the vasculature leads to postnatal cardiac phenotypes.

The Id1 and Id3 genes play major roles during cardiac development, despite their expression being confined to non-myocardial layers (endocardium-endothelium-epicardium). We previously described that Id1Id3 double knockout (dKO) mouse embryos die at mid-gestation from multiple cardiac defects, but early lethality precluded the studies of the roles of Id in the postnatal heart. To elucidate postnatal roles of Id genes, we ablated the Id3 gene and conditionally ablated the Id1 gene in the endothelium to generate conditional KO (cKO) embryos. We observed cardiac phenotypes at birth and at 6 months of age. Half of the Id cKO mice died at birth. Postnatal demise was associated with cardiac enlargement and defects in the ventricular septum, trabeculation and vasculature. Surviving Id cKO mice exhibited fibrotic vasculature, cardiac enlargement and decreased cardiac function. An abnormal vascular response was also observed in the healing of excisional skin wounds of Id cKO mice. Expression patterns of vascular, fibrotic and hypertrophic markers were altered in the Id cKO hearts, but addition of Insulin-Like Growth Factor binding protein-3 (IGFbp3) reversed gene expression profiles of vascular and fibrotic, but not hypertrophic markers. Thus, ablation of Id genes in the vasculature leads to distinct postnatal cardiac phenotypes. These findings provide important insights into the role/s of the endocardial network of the endothelial lineage in the development of cardiac disease, and highlight IGFbp3 as a potential link between Id and its vascular effectors.

Injection of wild type embryonic stem cells into Mst1 transgenic blastocysts prevents adult-onset cardiomyopathy.

Embryonic stem cells have the capacity to differentiate into a wide range of cell types. We previously described that blastocyst injection of wild type (WT) embryonic stem cells (ESCs) into various knockout (KO) mouse models of human disease prevents disease from occurring. In this study we ask if the blastocyst approach can also correct defects in a mouse model of transgenic (Tg) overexpression of a pro-apoptotic factor. We injected ROSA26 (LacZ-marked) WT ESCs into human mammalian sterile 20 like-kinase 1 (Mst1) Tg blastocysts. Mst1 Tg mice overexpress Mst1, a pro-apoptotic factor, in a cardiac-specific manner. As a result, Mst1 Tg mice develop adult dilated cardiomyopathy driven by apoptosis, reduction in cell density and no hypertrophic compensation. Incorporation of WT ESCs generated WT/Mst1 chimeric mice with normal hearts at histological and functional levels. Accordingly, apoptosis and cell density parameters were normalized. The experiments suggest that an adult-onset cardiac myopathy induced by overexpression of the pro-apoptotic Mst1 can be reversed by developmental incorporation of WT ESCs. The findings also suggest that since forced expression of the Mst1 transgene is not abolished in the rescued chimeras, the WT ES-derived cells normalize pathways that lie downstream of Mst1. The results expand the therapeutic capability of the ESCs to mouse models that overproduce detrimental proteins.

Prevalence of antibodies to four human coronaviruses is lower in nasal secretions than in serum.

Little is known about the prevalence of mucosal antibodies induced by infection with human coronaviruses (HCoV), including HCoV-229E and -OC43 and recently described strains (HCoV-NL63 and -HKU1). By enzyme-linked immunosorbent assay, we measured anti-HCoV IgG antibodies in serum and IgA antibodies in nasal wash specimens collected at seven U.S. sites from 105 adults aged 50 years and older (mean age, 67 ± 9 years) with chronic obstructive pulmonary disease. Most patients (95 [90%]) had at least one more chronic disease. More patients had serum antibody to each HCoV strain (104 [99%] had antibody to HCoV-229E, 105 [100%] had antibody to HCoV-OC43, 103 [98%] had antibody to HCoV-NL63, and 96 [91%] had antibody to HCoV-HKU1) than had antibody to each HCoV strain in nasal wash specimens (12 [11%] had antibody to HCoV-229E, 22 [22%] had antibody to HCoV-OC43, 8 [8%] had antibody to HCoV-NL63, and 31 [31%] had antibody to HCoV-HKU1), respectively (P < 0.0001). The proportions of subjects with IgA antibodies in nasal wash specimens and the geometric mean IgA antibody titers were statistically higher for HCoV-OC43 and -HKU1 than for HCoV-229E and -NL63. A higher proportion of patients with heart disease than not had IgA antibodies to HCoV-NL63 (6 [16%] versus 2 [3%]; P = 0.014). Correlations were highest for serum antibody titers between group I strains (HCoV-229E and -NL63 [r = 0.443; P < 0.0001]) and between group II strains (HCoV-OC43 and -HKU1 [r = 0.603; P < 0.0001]) and not statistically significant between HCoV-NL63 and -OC43 and between HCoV-NL63 and -HKU1. Patients likely had experienced infections with more than one HCoV strain, and IgG antibodies to these HCoV strains in serum were more likely to be detected than IgA antibodies to these HCoV strains in nasal wash specimens.

Rescue of developmental defects by blastocyst stem cell injection: towards elucidation of neomorphic corrective pathways.

Stem cell-based therapy is an exciting area of high potential for regenerative medicine. To study disease prevention, we inject mouse embryonic stem cells (ESCs) into a variety of mouse blastocysts, most of which harbor mutations. Mice derived from these mutant blastocysts develop human-like diseases, either at developmental stages or in the adult, but blastocyst injection of ESCs prevents disease from occurring. Rather than entirely repopulating the affected organs, with just 20% of chimerism, the ESCs replenish protein levels that are absent in mutant mice, and induce novel or "neomorphic" signals that help circumvent the requirements for the mutations. We also show data indicating that the "neomorphic" mechanisms arise as a result of blastocyst injection of ESCs, regardless of the nature of the host blastocyst (mutant or wild-type). Thus, blastocyst injection of ESCs not only allows the study of disease prevention, but also unveils novel pathways whose activation may aid in the correction of congenital or acquired disease.

Blastocyst injection of embryonic stem cells: a simple approach to unveil mechanisms of corrections in mouse models of human disease.

Embryonic stem cell (ESC) research is a promising area of investigation with enormous therapeutic potential. We have injected murine wild type (WT) ESCs into a variety of mutant murine blastocysts, which are predisposed to develop a human-like disease, such as muscular dystrophy or the embryonic lethal "thin myocardial syndrome". In this review, we summarize data indicating that partial incorporation of ESCs is sufficient to prevent disease from occurring. We also present data indicating that blastocyst incorporation of ESCs may aid in the prevention of heart failure in stressed WT mice. In some cases, the rescue observed is predominantly non-cell autonomous and relies on the production of secreted factors from the ES-derived cells, but in others, cell replacement is required. Thus, congenital or acquired disease can be pre-emptively averted in mice by developmental injection of ESCs.

Blastocyst injection of wild type embryonic stem cells induces global corrections in mdx mice.

Duchenne muscular dystrophy (DMD) is an incurable neuromuscular degenerative disease, caused by a mutation in the dystrophin gene. Mdx mice recapitulate DMD features. Here we show that injection of wild-type (WT) embryonic stem cells (ESCs) into mdx blastocysts produces mice with improved pathology and function. A small fraction of WT ESCs incorporates into the mdx mouse nonuniformly to upregulate protein levels of dystrophin in the skeletal muscle. The chimeric muscle shows reduced regeneration and restores dystrobrevin, a dystrophin-related protein, in areas with high and with low dystrophin content. WT ESC injection increases the amount of fat in the chimeras to reach WT levels. ESC injection without dystrophin does not prevent the appearance of phenotypes in the skeletal muscle or in the fat. Thus, dystrophin supplied by the ESCs reverses disease in mdx mice globally in a dose-dependent manner.

Human coronavirus and acute respiratory illness in older adults with chronic obstructive pulmonary disease.

BACKGROUND: The clinical features and incidence of human coronavirus (HCoV) infections in chronically ill older adults need better definition. METHODS: HCoV infection was determined on the basis of a 4-fold increase in serum antibody and the detection of HCoV by reverse-transcription polymerase chain reaction. Laboratory-documented influenza (LDI) was detected by serologic assay and culture. HCoV illnesses were compared with other acute respiratory illnesses identified by active surveillance, during the 1998-99 winter respiratory-virus season, of 2215 patients with chronic obstructive pulmonary disease who were > or = 50 years old and who received influenza vaccines. RESULTS: HCoV-229E and HCoV-OC43 were associated with 90 (14%) of 665 illnesses (HCoV-229E in 22, HCoV-OC43 in 67, and both in 1), LDI with 107 (16%) of 678 illnesses. In multivariate logistic regression analysis, myalgia was less likely with HCoV infection than with LDI (OR, 0.27 [95% confidence limit, 0.13-0.58]). A majority of these HCoV and LDI illnesses exhibited each of 11 symptoms and signs of acute respiratory illness. Spirometric results worsened most often with LDI, and many acute respiratory illnesses, regardless of etiology, were associated with hospitalization. A total of 8 illnesses were associated with HCoV-NL63, 1 with HCoV-HKU1. CONCLUSIONS: The frequencies of HCoV and LDI illnesses were similar. HCoV illness was less severe than LDI illness, was accompanied by multiple respiratory and systemic symptoms, and was associated with hospitalization.

Pre-emptive conditioning of the ischemic heart.

Ischemic heart disease remains one of the most frequent causes of morbidity and mortality worldwide. Although the prognosis of myocardial ischemia has been dramatically improved by the techniques of early reperfusion, the prevention of irreversible ischemic damage remains a critical aspect of the treatment. An appealing novel therapeutic avenue for the prevention of myocardial ischemia relates to the possibility of a pre-emptive conditioning of the heart, in which an activation of survival pathways could be achieved in patients with ischemic heart disease who are at risk for a subsequent lethal ischemia. These patients would include those with unstable angina, or with severe and repetitive ischemic episodes, and patients scheduled for surgical revascularization. In these situations, the pre-emptive activation of survival signaling mechanisms would confer a prophylactic cardioprotection during the following ischemic stress. During the last twenty years, it became clear that the heart can trigger survival mechanisms when submitted to stress, in such conditions as myocardial stunning, hibernation and preconditioning. The goal of the pre-emptive conditioning is to activate such survival pathways as a prophylactic measure to prevent myocardial cell death when the heart is threatened by potentially lethal ischemia. Based on the experimental data collected at the bench side, we review how this approach could be applied in the clinical setting.

Lessons for successful study enrollment from the Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network Study.

BACKGROUND AND OBJECTIVES: Design elements of clinical trials can introduce recruitment bias and reduce study efficiency. Trials involving the critically ill may be particularly prone to design-related inefficiencies. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Enrollment into the Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network Study was systematically monitored. Reasons for nonenrollment into this study comparing strategies of renal replacement therapy in critically ill patients with acute kidney injury were categorized as modifiable or nonmodifiable. RESULTS: 4339 patients were screened; 2744 fulfilled inclusion criteria. Of these, 1034 were ineligible by exclusion criteria. Of the remaining 1710 patients, 1124 (65.7%) enrolled. Impediments to informed consent excluded 21.4% of potentially eligible patients. Delayed identification of potential patients, physician refusal, and involvement in competing trials accounted for 4.4, 2.7, and 2.3% of exclusions. Comfort measures only status, chronic illness, chronic kidney disease, and obesity excluded 11.8, 7.8, 7.6, and 5.9% of potential patients. Modification of an enrollment window reduced the loss of patients from 6.6 to 2.3%. CONCLUSIONS: The Acute Renal Failure Trial Network Study's enrollment efficiency compared favorably with previous intensive care unit intervention trials and supports the representativeness of its enrolled population. Impediments to informed consent highlight the need for nontraditional acquisition methods. Restrictive enrollment windows may hamper recruitment but can be effectively modified. The low rate of physician refusal acknowledges clinical equipoise in the study design. Underlying comorbidities are important design considerations for future trials that involve the critically ill with acute kidney injury.