Skeletal muscle abnormalities in rats with experimentally induced heart hypertrophy and failure

Background: In congestive heart failure (CHF), function and metabolism of skeletal muscles are abnormal. Aim: To evaluate whether the reduced oxidative capacity of skeletal muscles in CHF is due to impaired O₂ utilisation. Methods: CHF was induced in rats by injecting 50 mg/Kg monocrotaline. Several animals received the same dose of monocrotaline but only compensated right ventricular hypertrophy and no sign of congestion resulted. Two age- and diet-matched groups of control animals were also studied. In soleus and extensor digitorum longus (EDL) muscles, we studied skeletal muscle blood flow, oxidative capacity and respiratory function of skinned muscle fibres. Results: In CHF, we observed a decrease of muscle blood flow (statistically significant in the soleus, p < 0.05 vs. controls). In compensated rats, a similar trend in blood flow was observed. In both soleus and EDL, a significant reduction of high energy phosphate and a shift of the redox potential towards accumulation of reducing equivalents were observed. The reduction of energy charge was not correlated to the decrease of blood flow. In skinned myofibres, the ratio of O₂ utilised in the presence and in absence of ADP (an index of phoshorilating efficiency) was reduced from 8.9 ± 1.9 to 2.7 ± 0.2 (p < 0.001) and from 5.7 ± 1.0 to 2.0 ± 0.3 (p < 0.01) in soleus and EDL, respectively. Activity of the different complexes of respiratory chain was investigated by means of specific inhibitors, showing major abnormalities at the level of complex I. In fact, inhibition of VO₂ by rotenone was decreased from 83.5 ± 3.2 to 36.4 ± 9.6 % (p < 0.005) and from 81.8 ± 6.1 to 38.2 ± 7.4 % (p < 0.005) in soleus and EDL, respectively. Conclusions: In rats with CHF, abnormalities of oxidative phosphorylation of muscles occur and complex I of the respiratory chain seem to be primarily affected. The metabolic alterations of skeletal muscles in CHF may be explained, at least in part, by an impaired O₂ utilisation. Received: 22 February 2002, Returned for 1. revision: 14 March 2002, 1. Revision received: 5 June 2002, Returned for 2. revision: 21 June 2002, 2. Revision received: 23 August 2002, Accepted: 12 September 2002 Correspondence to: Dr. C. Ceconi     

Frequency and extent of contraction band necrosis in orthotopically transplanted human hearts. A morphometric study

BACKGROUND: The aims of the present study are to quantify forms of myocardial and coronary changes found at postmortem and to discuss their significance in relation to causes of death and cardiac arrest in orthotopic transplanted human hearts. METHODS: The examined material included (1) 46 orthotopic transplanted human hearts and, as "controls", hearts from (2) 25 sudden/unexpected coronary death cases, 38 patients with acquired immunodeficiency syndrome, 34 subjects with "silent" Chagas' disease who died suddenly, 27 non cardiac patients who died from intracranial hemorrhage due to a ruptured cerebral aneurysm and 45 healthy subjects dead from head trauma. RESULTS: Contraction band necrosis was observed in 85% of transplanted hearts, 66% of AIDS cases and in 100% Chagas' disease, 89% intracranial hemorrhage, 71% sudden coronary death, and 18% normal head trauma cases. Foci of lymphocytic infiltrate were present in 89% of transplanted heart, 50% AIDS, 100% Chagas' disease, 37% intracranial hemorrage and 64% head trauma groups. An allograft coronary vasculopathy was observed in four transplanted hearts with a survival greater than 202 days. In another 12 cases, who survived more than one year, atherosclerosis was the only coronary lesion found. No relation was observed between coronary lesions of any degree of stenosis and myocardial injuries. CONCLUSIONS: In the group studied acute rejection was the least frequent cause (2%) of graft failure at any time following transplantation and coronary vasculopathy a questionable cause of it in four cases. Rather, contraction band necrosis as an expression of catecholamine myotoxicity seemed to play a role in graft failure related to increased myocardial catecholamine sensitivity after global denervation.     

Functional and nonfunctional adrenocortical tumors demonstrate a high responsiveness to low-dose adrenocorticotropin

Aldosterone-producing adenomas (APAs) demonstrate exquisite sensitivity to endogenous ACTH. We previously showed an ACTH receptor overexpression in APAs compared with the other adrenal tumors. To evaluate the meaning of such findings, we investigated the response of aldosterone, cortisol, and 17OH progesterone (17OHP) to 1 microg ACTH in 42 patients with adrenocortical tumors (23 NHAs, 9 APAs, and 10 CPAs) and 10 normal subjects (C). All 52 subjects were responsive to ACTH, and hormone peak levels were reached at 30 min. The aldosterone peak level was significantly higher in APAs [mean +/- SEM: 84.3 +/- 13.1 ng/dl (2335.1 +/- 362.9 pmol/liter)] than in other tumors and control (C). Cortisol peak levels was higher in CPAs [37.1 +/- 3.9 microg/dl (1023.9 +/- 107.6 nmol/liter)] than in NHAs (P < 0.01), in C (P < 0.01) and in APAs (P = n.s.). 17OHP peak levels were significantly higher in patients with adrenocortical tumors toward C. In summary: 1) low-dose ACTH induces an important stimulation in all tumors, suggesting preservation of high responsiveness to ACTH; 2) this is especially true for aldosterone in APA and could be of primary importance when performing diagnostic tests for hyperaldosteronism; and 3) 17OHP-hyperresponsiveness to low-dose ACTH is the most common alteration both in functional and nonfunctional tumors.     

Effect of antiviral treatment in patients with chronic HCV infection and t(14;18) translocation

Hepatitis C virus (HCV) may be associated with the mixed cryoglobulinemia syndrome and other B-cell lymphoproliferative disorders (LPDs). The t(14;18) translocation may play a pathogenetic role. Limited data are available regarding the effects of antiviral therapy on rearranged B-cell clones. We evaluated the effects of interferon and ribavirin on serum, B-lymphocyte HCV RNA, and t(14; 18) in 30 HCV+, t(14;18)+ patients without either mixed cryoglobulinemia syndrome or other LPDs. The t(14;18) translocation was analyzed by both bcl-2/JH polymerase chain reaction and bcl-2/JH junction sequencing in peripheral blood mononuclear cells in all patients. Fifteen untreated patients with comparable characteristics served as controls. Throughout the study, the presence or absence of both t(14;18) and HCV RNA sequences were, in most cases, associated in the same cell samples. At the end of treatment, t(14;18) was no longer detected in 15 patients (50%) with complete or partial virologic response, whereas it was persistently detected in nonresponders (P <.05), as well as in 14 of 15 control patients. In 4 responder patients, t(14;18) and HCV RNA sequences were no longer detected in blood cells after treatment, but were again detected after viral relapse; the same B-cell clones were involved in the pretreatment and posttreatment periods. In conclusion, this study suggests that antiviral therapy may induce regression of t(14;18)-bearing B-cell clones in HCV+ patients and that this phenomenon may be related, at least in part, to the antiviral effect of therapy. This in turn suggests that antiviral treatment may help prevent or treat HCV-related LPDs.     

Factors influencing outcome and incidence of long-term complications in children who underwent autologous stem cell transplantation for acute myeloid leukemia in first complete remission

To evaluate factors influencing outcome and incidence of long-term complications, we analyzed, in a retrospective, multicenter study, 387 children who underwent autologous hematopoietic stem cell transplantation (HSCT) for acute myeloid leukemia (AML) in first complete remission (CR). Median follow-up time from transplantation was 60 months. Transplantation of bone marrow cells was performed in 318 children, whereas in 60 patients peripheral blood progenitor cells (PBPCs) were used. In multivariate analysis, we investigated the variables influencing probability of hematopoietic recovery, transplantation-related mortality (TRM), relapse, and leukemia-free survival (LFS). We found that use of PBPCs as stem cell sources and use of BCNU (N,N-bis[2-chloroethyl]-N-nitrosourea), amsacrine, VP-16, and cytosine arabinoside (BAVC) as a preparative regimen were associated with faster neutrophil recovery. Infusion of PBPCs, young age of patients, use of BAVCs, and absence of marrow purging predicted an accelerated platelet reconstitution. The 5-year Kaplan-Meier estimates of TRM, relapse, and LFS were 3% +/- 1%, 39% +/- 3% and 60% +/- 3%, respectively. Relapse probability was increased in children given the BAVC regimen, and it was decreased after in vitro purging of hematopoietic progenitors and in children with a French-American-British classification of M3 and a time interval of 170 days or more between CR and HSCT. These 2 latter variables favorably influenced the probability of LFS, which was, by contrast, reduced with the BAVC regimen. Thirty-three percent of patients surviving more than 18 months experienced at least one late sequela; use of total body irradiation was the only predictive factor. The results obtained in this analysis can be of help in designing prospective studies of autologous HSCT in children with AML in first CR.     

The role of lipid profile in determining the risk of ischemic stroke in the elderly: a case-control study

In this study, we investigated the association of lipids with ischemic stroke and its different subtypes in elderly patients. In particular, lipid parameters not extensively investigated so far in previous case-control studies specifically focused in the old population, such as lipoprotein Lp (a) and Apoproteins AI (ApoAI) and B (ApoB), have been taken into account. Seventy nine patients (mean age 83 +/- 7.4, range 67-99), consecutively admitted to a Geriatric Ward between January 1998 and June 2000 with acute stroke (first event) were studied. A complete clinical and laboratory assessment, including neurological evaluation, head CT scan, carotid ultrasonography and ECG, was employed to define the clinical and etiologic stroke subtype, according to standardized criteria. Fasting blood samples were collected within 48 h from admission, for determination of total cholesterol (TC), triglycerides (TG), High Density Lipoprotein-cholesterol (HDL-C), Lp(a), ApoAI and ApoB; Low Density Lipoprotein-Cholesterol (LDL-C) was estimated by Friedwald formula. Eighty eight age and sex-matched outpatients, referred to the hospital for non-inflammatory disorders of joints and musculoskeletal system, served as controls. Patients showed HDL-C and HDL-C/ApoAI ratio significantly lower than controls, with higher LDL-C/HDL-C ratio. Analysis on quartiles of lipoprotein concentrations showed also a significant increase in odds of stroke for LDL-C concentrations over 100 mg/dl, in absence of a linear relationship between LDL-C levels and risk. Multiple logistic regression, adjusting for non-lipid risk factors for stroke, confirmed the independent association of low HDL-C and HDL-C/ApoAI with all strokes, as well as with each subtype. In conclusion, these data suggest that lipids give some contribution to stroke risk even in the elderly, with a more prevalent role for HDL than LDL, and that lipid profile assessment must be taken into account in estimating the individual risk of stroke.     

KNOWLEDGE OF INJURY PREVENTION AND PREVALENCE OF RISK FACTORS FOR THROWING INJURIES IN A SAMPLE OF YOUTH BASEBALL PLAYERS

Background

Information on baseball injury prevention and pitch count recommendations is growing, however, the incidence of throwing injuries continues to rise. This study is the first to assess knowledge of safe throwing guidelines and risk factors from the perspective of youth athletes.

Purpose

The purpose of this study is two‐fold: (1) to evaluate knowledge of safe throwing guidelines and (2) to assess the reporting of risk factors for throwing injuries in a sample of youth baseball players.

Study Design

Survey study of 98 overhead athletes between the ages of 4 and 18.

Methods

A 35‐question survey was developed with questions related to knowledge of injury prevention, presence of risk factors associated with throwing injuries, and understanding and compliance with USA Baseball Medical & Safety Advisory Committee (USA BMSAC) overhead throwing guidelines.

Results

Respondents demonstrated variability in their knowledge of the USA BMSAC guidelines related to throwing frequencies. The 13‐16 year old age group displayed the least knowledge of USA BMSAC guidelines. The 9‐10 and 11‐12 year old age groups demonstrated the greatest knowledge of recommended BMSAC guidelines. Eighty‐five (82/98) percent of the respondents reported that they had never heard of the USA BMSAC guidelines. Sixty‐two percent (59/98) disagreed with the statement, “The more you throw, the more likely you are to get an injury”. Fifty‐seven percent of respondents (39/98) indicated that they would not seek medical help if they experienced a tired or sore arm during a game.

Conclusion

The results of this study suggest that young baseball players demonstrate the need for education on the following topics: the USA Baseball Medical and Safety Advisory Committee throwing guidelines, risk factors for developing throwing‐related injuries, the long‐term implications of playing with an injured or fatigued arm, and the benefit of seeking medical help when fatigue or soreness is experienced in the throwing arm.

Level of Evidence

Level 3     

Chemotherapeutic drugs may be used to enhance the killing efficacy of human tumor antigen peptide-specific CTLs

The effects of anticancer chemotherapy on antigen-specific cytotoxic T lymphocytes (CTLs) are mostly unknown. We tested the effects of cytotoxic drugs such as 5-fluorouracil, gemcitabine, and oxaliplatin on the functional activity of antigen-specific CTL cultures derived from the peripheral blood mononuclear cells of human donors. We found that a biweekly drug-exposure of human HLA-A(*)02.01+ CTLs derived from bulk cultures led to completely different effects if occurring early (day second) or late (day thirteenth) after the in vitro stimulations with the cognate peptides. In the first case, there was a significant CTL inhibition, whereas in the second, there was a marked enhancement of the antigen-specific cytolytic activity. Results of immunocytofluorimetric studies and CTL/natural killer inhibition assays suggested that the latter effect could be related to a more selective drug-mediated inhibition of cohabitant T regulatory (reg) cells. These results were translated in an in vivo therapeutic mouse model where humanized HLA-A(*)02.01 transgenic mice inoculated with EL-4/humanized HLA-A(*)02.01 transgenic mice showed a prolonged survival and the greatest rate of cure when receiving a combined treatment with a thymidylate synthase-specific peptide vaccine and a multidrug chemotherapy regimen administered late after immunization. Tumor samples derived from this group of mice showed a reduced expression of the target thymidylate synthase antigen, a marked reduction of T(reg)s, and a noteworthy infiltration of C8+ T cells. These results may have clinical implications for the design of new translational anticancer regimens aimed at combining chemotherapy and immunotherapy.     

Continuous and intermittent cardiac output measurement in hyperdynamic conditions: pulmonary artery catheter vs. lithium dilution technique

OBJECTIVE: This study aimed to assess the level of agreement of both intermittent cardiac output monitoring by the lithium dilution technique (CO(Li)) and continuous cardiac output monitoring (PulseCO(Li)) using the arterial pressure waveform with intermittent thermodilution using a pulmonary artery catheter (CO(PAC)). DESIGN: Prospective, single-center evaluation. SETTING: University Hospital Intensive Care Unit. PATIENTS: Patients (n=23) receiving liver transplantation. INTERVENTION: Pulmonary artery catheters were placed in all patients and CO(PAC) was determined using thermodilution. CO(Li) and PulseCO(Li) measurements were made using the LiDCO system. MEASUREMENTS AND MAIN RESULTS: Data were collected after intensive care unit admission and every 8h until the 48th hour. A total of 151 CO(PAC), CO(Li) and PulseCO(Li) measurements were analysed. Bias and 95% limit of agreement were 0.11lmin(-1) and -1.84 to + 2.05 lmin(-1) for CO(PAC) vs. CO(Li) (r=0.88) resulting in an overall percentage error of 15.6%. Bias and 95% limit of agreement for CO(PAC) vs. PulseCO(Li) were 0.29 lmin(-1) and -1.87 to + 2.46 lmin(-1) (r=0.85) with a percentage error of 16.8%. Subgroup analysis revealed a percentage error of 15.7% for CO(PAC) vs. CO(Li) and 15.1% for CO(PAC) vs. PulseCO(Li) for data pairs less than 8 lmin(-1), and percentage errors of 15.5% and 18.5% respectively for data pairs higher than 8 lmin(-1). CONCLUSION: In patients with hyperdynamic circulation, intermittent and continuous CO values determined using the LiDCO system showed good agreement with those obtained by intermittent pulmonary artery thermodilution.