Spasmogenic Effects of the Proteasome Inhibitor Carfilzomib on Coronary Resistance, Vascular Tone and Reactivity

Background: Carfilzomib (CFZ) is a new proteasome inhibitor used for the treatment of multiple myeloma. Besides heart failure, angina and myocardial ischemia occurred following administration of CFZ, which is not contraindicated in patients with recent myocardial infarction/unstable angina excluded from the safety trials. Aimof Study: To test the effects of CFZ (10−9 to 10−7 mol/L) on vascular tone and reactivity in the isolated rabbit heart and aorta. Methods and Results: CFZ administered by bolus injection to the isolated heart increased coronary perfusion pressure (CPP) at all tested concentrations and mildly raised left ventricular pressure and heart rate, only at the highest concentration. Addition of CFZ directly into the organ bath increased the basal tone of isolated aortic strips with contraction plateau reached after 10 min. This spasmogenic effect doubled following ablation of the endothelium. Pretreatment with CFZ amplified the vasospastic action exerted by KCl, noradrenaline (NA) and angiotensin II (A) on aortic strips, and impaired vasodilation following administration of nitroglycerin (NTG) and nifedipine (NFP) on the contraction plateau induced by KCl, NA and A. Aortic strips pretreatedwith CFZ exhibited impaired relaxation, as compared to untreated strips, following administration of acetylcholine (Ach), an endothelium- dependent vasodilating agent, on the plateau of NA contraction (p b 0.05). Conclusions: CFZ increased CPP, resting vasoconstricting tone and the spasmogenic effect of different agents. Preincubation with CFZ decreased the anti-spasmogenic activity of NTG and NFP, as well as reduced by over 50% the vasodilating effect of Ach, suggesting that CFZ can impair vasodilation via an endothelium dependent mechanism. Further studies are warranted to establish its clinical safety in patients with known CAD and prior history of coronary spasm

Decreased expression of Klotho in cardiac atria biopsy samples from patients at higher risk of atherosclerotic cardiovascular disease

Background. Klotho proteins (α- and β) are membrane-based circulating proteins that regulate cell metabolism, as well as the lifespan modulating activity of Fibroblast Growth Factors. Recent data has shown that higher plasma circulating Klotho levels reduce cardiovascular risk, suggesting Klotho has a protective role in cardiovascular diseases. However, although so far it has been identified in various organs, it is unknown whether cardiomyocytes express Klotho and Fibroblast Growth Factors(FGFs), and whether high cardiovascular risk could affect cardiac expression of Klotho, FGFs and other molecules. Methods. We selected 20 patients with an estimated 10-year high atherosclerotic cardiovascular disease and 10 age-matched control subjects with an estimated 10-year low risk undergone cardiac surgery for reasons other than coronary artery by-pass. In myocardial biopsies, we evaluated by immuno-histochemistry whether Klotho and FGFs were expressed in cardiomyocytes, and whether higher cardiovascular risk influenced the expression of other molecules involved in endoplasmic reticulum stress, oxidative stress, inflammation and fibrosis. Results. Only cardiomyocytes of patients with a higher cardiovascular risk showed lower expression of Klotho, but higher expressions of FGFs. Furthermore, higher cardiovascular risk was associated with increased expression of oxidative and endoplasmic reticular stress, inflammation and fibrosis. Conclusions. This study showed for the first time that Klotho proteins are expressed in human cardiomyocytes and that cardiac expression of Klotho is down-regulated in higher cardiovascular risk patients, while expression of stress-related molecules were significantly increased

In vitro susceptibility of gram-positive cocci to paldimycin

Paldimycin (U-70138F) is a new antimicrobial agent with activity against gram-positive cocci. Clinical isolates of staphylococci and streptococci were tested. MICs were higher in Mueller-Hinton broth than in nutrient broth. Change in pH had minimal effect on the MICs in either broth. When inoculum size was varied, an inoculum effect was observed. The gram-positive cocci tested were generally more susceptible to paldimycin than to vancomycin.</jats:p

Infective endocarditis in intravenous drug abusers: an update

Infective endocarditis despite advances in diagnosis remains a common cause of hospitalization, with high morbidity and mortality rates. Through literature review it is possible to conclude that polymicrobial endocarditis occurs mainly in intravenous drug abusers with predominance in the right side of the heart, often with tricuspid valve involvement. This fact can be associated with the type of drug used by the patients; therefore, knowledge of the patient's history is critical for adjustment of the therapy. It is also important to emphasize that the most common combinations of organisms in polymicrobial infective endocarditis are: Staphylococcus aureus, Streptococcus pneumonia and Pseudomonas aeruginosa, as well as mixed cultures of Candida spp. and bacteria. A better understanding of the epidemiology and associated risk factors are required in order to develop an efficient therapy, although PE studies are difficult to perform due to the rarity of cases and lack of prospective cohorts.This work was supported by Portuguese Foundation for Science and Technology (FCT) through the grants SFRH/BPD/47693/2008, SFRH/BPD/20987/2004 and SFRH/BPD/72632/2010 attributed to Claudia Sousa, Claudia Botelho and Diana Rodrigues, respectively

Recurrent Klebsiella Meningitis Following Trans-sphenoidal Hypophysectomy for Nelson\u27s Syndrome: Chloramphenicol resistance during relapse

Three episodes of meningitis due to Klebsiella pneumoniae occurred in a young man following cerebral surgery. The patient had the features of Nelson\u27s syndrome, and a chromophobe adenoma was removed by trans-sphenoidal resection. Intravenous chloramphenicol was effective in producing a temporary clinical response during the first episode of meningitis, but the organism became resistant to chloramphenicol during the second episode. Combined parenteral and intralumbar administration of gentamicin resulted in temporary improvement only. Subsequently, the subcutaneous cerebrospinal fluid (CSF) reservoir of Ommaya provided a safe, convenient way to administer prolonged intraventricular therapy which, combined with a definitive procedure to correct the cerbrospinal fluid rhinorrhea, ultimately cured the infection

Antimicrobial peptides as novel anti-tuberculosis therapeutics

"Available online 24 May 2016"Tuberculosis (TB), a disease caused by the human pathogen Mycobacterium tuberculosis, has recently joined HIV/AIDS as the world's deadliest infectious disease, affecting around 9.6 million people worldwide in 2014. Of those, about 1.2 million died from the disease. Resistance acquisition to existing antibiotics, with the subsequent emergence of Multi-Drug Resistant mycobacteria strains, together with an increasing economic burden, has urged the development of new anti-TB drugs. In this scope, antimicrobial peptides (AMPs), which are small, cationic and amphipathic peptides that make part of the innate immune system, now arise as promising candidates for TB treatment. In this review, we analyze the potential of AMPs for this application. We address the mechanisms of action, advantages and disadvantages over conventional antibiotics and how problems associated with its use may be overcome to boost their therapeutic potential. Additionally, we address the challenges of translational development from benchside to bedside, evaluate the current development pipeline and analyze the expected global impact from a socio-economic standpoint. The quest for more efficient and more compliant anti-TB drugs, associated with the great therapeutic potential of emerging AMPs and the rising peptide market, provide an optimal environment for the emergence of AMPs as promising therapies. Still, their pharmacological properties need to be enhanced and manufacturing-associated issues need to be addressed.Portuguese Foundation for Science and Technology (FCT) - UID/ BIO/04469/2013 unit ; COMPETE 2020 (POCI-01-0145-FEDER- 006684) ; SFRH/BPD/64958/2010Project RECI/BBB-EBI/0179/2012 (FCOMP-01-0124-FEDER-027462

The Emerging Role of HTLV-I/II and HIV-1 Among Intravenous Drug Users in Detroit

During 1987-1988, a seroprevalence study of the human immunodeficiency virus (HIV-1) and the human T-cell lymphoma/leukemia virus (HTLV-l/II) was performed among Detroit intravenous drug users unaffiliated with substance abuse programs. Seroprevalence data along with patient demographic information were compared to a similar study performed in 1985-1986. In the earlier study, 12 (12.5%) of 96 individuals tested positive for HIV-1. Of the 74 available negative samples retested in 1987-1988 for retroviruses, 7 (9.5%) tested positive for HTLV-I/II. Thus, the overall retroviral (HIV-1, HTLV-I/II) seropositive rate for 1985-1986 was 22%. In 1987-1988, 11 (15.7%) of 70 individuals tested positive for HIV-1 and 7 (10%) tested positive for HTLV-I/II. Concomitant infection with both viruses was found in 2 (2.9%) of the 70 individuals. Thus, retrovirus seroprevalence in 1987-1988 was 22.9%. In 1987-1988, significant differences between the retroviral-positive group and the retroviral-negative group consisted of intravenous drug use greater than 16 years (P = 0.059) for an odds ratio of 3.80 (Cl 1.12-12.89) and sex with female prostitutes (P = 0.029) for an odds ratio of 5.38 (Cl 1.38-20.95)

Predictors of prolonged length of stay in adult patients with respiratory syncytial virus infections – a multi-center historical cohort study

ObjectivesSeveral studies have reported risk factors for severe disease and mortality in hospitalized adults with RSV infections. There is limited information available regarding the factors that affect the duration of a patient’s hospital length of stay (LOS).MethodsThis was a multicenter historical cohort study of adult patients hospitalized for laboratory-confirmed RSV in Southeast Michigan between January 2017 and December 2021. Hospitalized patients were identified using the International Classification of Diseases, Tenth Revision 10 codes for RSV infection. Mean LOS was computed; prolonged LOS was defined as greater than the mean.ResultsWe included 360 patients with a mean age (SD) of 69.9 ± 14.7 years, 63.6% (229) were female and 63.3% (228) of white race. The mean hospital LOS was 7.1 ± 5.4 days. Factors associated with prolonged LOS in univariable analysis were old age, body mass index (BMI), smoking status, Charlson Weighted Index of Comorbidity (CWIC), home oxygen, abnormal chest x-ray (CXR), presence of sepsis, use of oxygen, and antibiotics at the time of presentation. Predictors for prolonged LOS on admission in multivariable analysis were age on admission (p &lt; 0.001), smoking status (p = 0.001), CWIC (p = 0.038) and abnormal CXR (p = 0.043).InterpretationOur study found that age on admission, smoking history, higher CWIC and abnormal CXR on admission were significantly associated with prolonged LOS among adult patients hospitalized with RSV infection. These findings highlight the significance of promptly recognizing and implementing early interventions to mitigate the duration of hospitalization for adult patients suffering from RSV infection

How can malnutrition affect autophagy in chronic heart failure? Focus and perspectives

Chronic heart failure (CHF) is a disease with important clinical and socio-economic rami-fications. Malnutrition and severe alteration of the protein components of the body (protein disar-rangements), common conditions in CHF patients, are independent correlates of heart dysfunction, disease progression, and mortality. Autophagy, a prominent occurrence in the heart of patients with advanced CHF, is a self-digestive process that prolongs myocardial cell lifespan by the removal of cytosolic components, such as aging organelles and proteins, and recycles the constituent elements for new protein synthesis. However, in specific conditions, excessive activation of autophagy can lead to the destruction of molecules and organelles essential to cell survival, ultimately leading to organ failure and patient death. In this review, we aim to describe the experimental and clinical evidence supporting a pathophysiological role of nutrition and autophagy in the progression of CHF. The understanding of the mechanisms underlying the interplay between nutrition and autophagy may have important clinical implications by providing molecular targets for innovative therapeutic strategies in CHF patients

Fluoroquinolone resistance during 2000–2005 : An observational study

<p>Abstract</p> <p>Background</p> <p>Moxifloxacin is a respiratory fluoroquinolone with a community acquired pneumonia indication. Unlike other fluoroquinolones used in our healthcare system, moxifloxacin's urinary excretion is low and thus we hypothesized that increased use of moxifloxacin is associated with an increase in fluoroquinolone resistance amongst gram negative uropathogens.</p> <p>Methods</p> <p>All antibiograms for Gram negative bacteria were obtained for 2000 to 2005. The defined daily dose (DDD) for each fluoroquinolone was computed according to World Health Organization criteria. To account for fluctuation in patient volume, DDD/1000 bed days was computed for each year of study. Association between DDD/1000 bed days for each fluoroquinolone and the susceptibility of Gram negative bacteria to ciprofloxacin was assessed using Pearson's Correlation Coefficient, r.</p> <p>Results</p> <p>During the study period, there were 48,261 antibiograms, 347,931 DDD of fluoroquinolones, and 1,943,338 bed days. Use of fluoroquinolones among inpatients decreased from 237.2 DDD/1000 bed days in 2000 to 115.2 DDD/1000 bed days in 2005. With the exception of <it>Enterobacter aerogenes</it>, moxifloxacin use was negatively correlated with sensitivity among all 13 Gram negative species evaluated (r = -0.07 to -0.97). When the sensitivities of all Gram negative organisms were aggregated, all fluoroquinolones except moxifloxacin were associated with increased sensitivity (r = 0.486 to 1.000) while moxifloxacin was associated with decreased sensitivity (r = -0.464).</p> <p>Conclusion</p> <p>Moxifloxacin, while indicated for empiric treatment of community acquired pneumonia, may have important negative influence on local antibiotic sensitivities amongst Gram negative organisms. This effect was not shared by other commonly used members of the fluoroquinolone class.</p