Cardiorespiratory responses to exercise training after orthotopic cardiac transplantation

We have tested the feasibility and effectiveness of a 2 year (average 16 +/- 7 months) walk/jog exercise program on 36 male orthotopic cardiac transplant patients (21 to 57 years old) seen initially 2 to 23 months after surgery. Comparison of initial exercise test results with those in 45 age-matched normal men showed the patients to have a lesser lean body mass (56 +/- 7 vs 63 +/- 8 kg, p less than .001), with a higher resting heart rate (104 +/- 12 vs 77 +/- 14 beats/min, p less than .001) and systolic (138 +/- 16 vs 129 +/- 17 mm Hg, p less than .001) and diastolic (95 +/- 14 vs 84 +/- 10 mm Hg, p less than .001) blood pressures. Peak power output was less than normal (101 +/- 27 vs 219 +/- 41 W, p less than .001), as was peak heart rate (136 +/- 15 vs 176 +/- 13 beats/min, p less than .001), peak oxygen intake (VO2max) (22 +/- 5 vs 34 +/- 6 ml.kg.min-1, p less than .001), and absolute anaerobic threshold (1.18 +/- 0.40 vs 2.04 +/- 0.40 liters.min-1, p less than .001). Peak ventilatory equivalent was higher (48 +/- 9 vs 37 +/- 61.1-1, p less than .001). Cardiac output (Q), as estimated by the CO2 rebreathing method, was slightly above normal at rest (p less than .01), but below normal at two submaximal work rates. The group's average weekly training distance was 24 km, with eight highly compliant patients progressing to 32 km or more weekly. After training, lean tissue increased (+2.4 +/- 3.1 kg, p less than .001), and resting values were reduced for heart rate (-4 +/- 11 beats/min, p less than .05), systolic (-13 +/- 20 mm Hg, p less than .001), and diastolic (-9 +/- 17 mm Hg, p less than .001) blood pressures. There were significant reductions in submaximal values for minute ventilation (VE), ratings of perceived exertion, and diastolic blood pressure at equivalent workloads. Peak values increased for power output (+49 +/- 34 W, p less than .001), VO2max (+4.0 +/- 6.0 ml.kg.min-1, p less than .001), VE (+20 +/- 20 l.min-1, p less than .001), and heart rate (+13 +/- 17 beats/min, p less than .001), and decreased for diastolic blood pressure (-8 +/- 15 mm Hg, p less than .001).(ABSTRACT TRUNCATED AT 400 WORDS)     

Quantitation in gated perfusion SPECT imaging: the Cedars-Sinai approach.

Cedars-Sinai's approach to the automation of gated perfusion single photon emission computed tomography (SPECT) imaging is based on the identification of key procedural steps (processing, quantitation, reporting), each of which is then implemented, in completely automated fashion, by use of mathematic algorithms and logical rules combined into expert systems. Our current suite of software applications has been designed to be platform- and operating system-independent, and every algorithm is based on the same 3-dimensional sampling scheme for the myocardium. The widespread acceptance of quantitative software by the nuclear cardiology community (QGS alone is used at over 20,000 locations) has provided the opportunity for extensive validation of quantitative measurements of myocardial perfusion and function, in our opinion, helping to make nuclear cardiology the most accurate and reproducible modality available for the assessment of the human heart.     

Increased susceptibility of peripheral mononuclear cells of leukemic patients to HTLV-I infection in vitro

Peripheral mononuclear cells (MNC) collected from 12 healthy donors and 44 leukemic patients at various stages of the disease were tested for natural killer (NK) activity and for their susceptibility to HTLV-I infection in vitro, measured in terms of percentage of p19 positive cells. MNC from leukemic donors at any stage of leukemia (ie, onset or relapse, ON/REL; complete remission or off-therapy, CR/OT donors) were highly susceptible to HTLV-I infection. This was true for acute leukemias of lymphoblastic (ALL) or nonlymphoblastic (ANLL) type. MNC of ON/REL patients were more susceptible to HTLV-I than those of CR/OT donors. In addition, leukemic blasts were more rapidly infected (ie, within five to seven days) than the HTLV-I-susceptible normal cord- blood lymphocytes. However, the presence of circulating blasts was not essential to virus susceptibility, since CR/OT MNC, presumably free of leukemic blasts, were still more susceptible to HTLV-I than normal cells. Basal NK function of MNC from leukemic patients was significantly lower than that detectable in healthy controls. However, no correlation was found between susceptibility to HTLV-I infection and NK activity.     

Peak oxygen intake and cardiac mortality in women referred for cardiac rehabilitation

OBJECTIVES: This study investigated the prognostic importance of measured peak oxygen intake (VO(2peak)) in women with known coronary heart disease referred for outpatient cardiac rehabilitation. BACKGROUND: Exercise capacity is a powerful predictor of prognosis in men with known or suspected coronary disease. Similar findings are described in women, but fewer studies have utilized measured VO(2peak), the most accurate measure of exercise capacity. METHODS: A single-center design took data from 2,380 women, age 59.7 +/- 9.5 years (1,052 myocardial infarctions, 620 coronary bypass procedures, and 708 with proven ischemic heart disease), who underwent cardiorespiratory exercise testing. They were followed for an average of 6.1 +/- 5 years (median 4.5 years, range 0.4 to 25 years) until cardiac and all-cause death. RESULTS: We recorded 95 cardiac deaths and 209 all-cause deaths. Measured VO(2peak) was an independent predictor of risk, values > or =13 ml/kg/min (3.7 multiples of resting metabolic rate) conferring a 50% reduction in cardiac mortality (hazard ratio [HR] 0.5, p = 0.001). Considered as a continuous variable, a 1 ml/kg/min advantage in initial VO(2peak) was associated with a 10% lower cardiac mortality. Adverse predictors were diabetes (HR 2.73, p = 0.0005) and antiarrhythmic therapy (HR 3.93, p = 0.0001). CONCLUSIONS: As in men, measured VO(2peak) is a strong independent predictor of cardiac mortality in women referred for cardiac rehabilitation.     

Preclinical to Clinical Translation of CNS Transporter Occupancy of TD-9855, a Novel Norepinephrine and Serotonin Reuptake Inhibitor

Background:

Monoamine reuptake inhibitors exhibit unique clinical profiles that reflect distinct engagement of the central nervous system (CNS) transporters.

Methods:

We used a translational strategy, including rodent pharmacokinetic/pharmacodynamic modeling and positron emission tomography (PET) imaging in humans, to establish the transporter profile of TD-9855, a novel norepinephrine and serotonin reuptake inhibitor.

Results:

TD-9855 was a potent inhibitor of norepinephrine (NE) and serotonin 5-HT uptake in vitro with an inhibitory selectivity of 4- to 10-fold for NE at human and rat transporters. TD-9855 engaged norepinephrine transporters (NET) and serotonin transporters (SERT) in rat spinal cord, with a plasma EC₅₀ of 11.7ng/mL and 50.8ng/mL, respectively, consistent with modest selectivity for NET in vivo.Accounting for species differences in protein binding, the projected human NET and SERT plasma EC₅₀ values were 5.5ng/mL and 23.9ng/mL, respectively. A single-dose, open-label PET study (4–20mg TD-9855, oral) was conducted in eight healthy males using the radiotracers [¹¹C]-3-amino-4- [2-[(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile for SERT and [¹¹C]-(S,S)-methylreboxetine for NET. The long pharmacokinetic half-life (30–40h) of TD-9855 allowed for sequential assessment of SERT and NET occupancy in the same subject. The plasma EC₅₀ for NET was estimated to be 1.21ng/mL, and at doses of greater than 4mg the projected steady-state NET occupancy is high (>75%). After a single oral dose of 20mg, SERT occupancy was 25 (±8)% at a plasma level of 6.35ng/mL.

Conclusions:

These data establish the CNS penetration and transporter profile of TD-9855 and inform the selection of potential doses for future clinical evaluation.     

Biomarkers of senescence in non-human primate adipose depots relate to aging

Forty-three female African green monkeys (Chlorocebus aethiops sabaeus) were selected to represent young adult to advanced geriatric ages (7–24 years) to exhibit a wide range of obesity status (8–53% body fat) and diverse metabolic syndrome criteria such as diabetes, dyslipidemia, and hypertension. Subcutaneous and visceral adipose tissues were collected and evaluated for the presence of senescence cells in both whole tissue and single-cell isolates from subcutaneous sources, utilizing senescence-associated β-galactosidase (SAβ-gal) staining. Plasma samples were analyzed for selected metabolic and inflammatory biomarkers related to the senescence-associated secretory profile. Our results indicated that tissue staining scores did not differ between subcutaneous and intra-abdominal visceral depots and were highly related within individuals. Tissue staining was significantly associated with chronological age; however, no associations with fatness or metabolic syndrome criteria were observed. Associations with age were unchanged when obesity status was included in regression models. Isolated cell staining did positively relate to age but not tissue staining, suggesting some of the SAβ-gal-positive cells were stromal vascular cells or small adipocytes, but that mature large adipocytes, filtered out in the cell isolation process, are also likely to exhibit positive SAβ-gal staining. Plasminogen activator inhibitor-1 (PAI-1) concentration in circulation was the sole inflammation-related biomarker that positively associated with age and is considered to be a marker of senescent cell burden. Our study is the largest, most comprehensive assessment of adipose SAβ-gal staining in a relevant animal model of human aging, and confirms that this senescence-associated biomarker specifically indicates an age-related process.

     

A truncating PET100 variant causing fatal infantile lactic acidosis and isolated cytochrome c oxidase deficiency

Isolated mitochondrial complex IV (cytochrome c oxidase) deficiency is an important cause of mitochondrial disease in children and adults. It is genetically heterogeneous, given that both mtDNA-encoded and nuclear-encoded gene products contribute to structural components and assembly factors. Pathogenic variants within these proteins are associated with clinical variability ranging from isolated organ involvement to multisystem disease presentations. Defects in more than 10 complex IV assembly factors have been described including a recent Lebanese founder mutation in PET100 in patients presenting with Leigh syndrome. We report the clinical and molecular investigation of a patient with a fatal, neonatal-onset isolated complex IV deficiency associated with multiorgan involvement born to consanguineous, first-cousin British Asian parents. Exome sequencing revealed a homozygous truncating variant (c.142C>T, p.(Gln48*)) in the PET100 gene that results in a complete loss of enzyme activity and assembly of the holocomplex. Our report confirms PET100 mutation as an important cause of isolated complex IV deficiency outside of the Lebanese population, extending the phenotypic spectrum associated with abnormalities within this gene.     

Monocytoid B-cell lymphoma: its evolution and relationship to other low- grade B-cell neoplasms

Monocytoid B-cell lymphoma (MBCL) is a newly recognized B-cell neoplasm of uncertain histogenesis. The cytologic features of the neoplastic monocytoid B lymphocytes are virtually identical to those of hairy cell leukemia (HCL). As with HCL, progression of MBCL to a higher histologic grade is very unusual. However, whereas circulating leukemic cells are a characteristic feature of HCL, peripheral blood involvement has not been reported in MBCL. We recently studied a patient with MBCL of the spleen and axillary lymph nodes who developed peripheral blood involvement by MBCL cells. Unlike the cells of HCL, the circulating MBCL cells exhibited strong acid phosphatase activity that was tartrate sensitive. The leukemic cells had the antigenic phenotype IgM lambda, CD20+, CD11c+, CD5-, CD25(TAC)-, and PCA-1-. Immunogenetic studies of both lymph node and peripheral blood cells revealed identical immunoglobulin heavy-chain gene rearrangements. When compared with a series of HCL, the immunophenotype was similar except for the absence of PCA-1 and TAC. Progression of the MBCL to a large cell lymphoma, also expressing IgM lambda, was documented in an abdominal lymph node of this patient. Therefore, although rare, peripheral blood involvement by lymphoma cells may occur during the course of MBCL and should be distinguished from HCL with cytochemical and immunophenotypic studies. In addition, comparison of the clinical, pathologic, and immunologic features of MBCL with those of other low-grade B-cell neoplasms suggests that a close lineage relationship exists between MBCL and HCL.