Post-transplant dyslipidemia: Mechanisms,diagnosis and management

Post-transplant dyslipidemia is highly prevalent and presents unique management challenges to the clinician. The two major outcomes to consider with post-transplant therapies for dyslipidemia are preserving or improving allograft function, and reducing cardiovascular risk. Although there are other cardiovascular risk factors such as graft dysfunction, hypertension, and diabetes, attention to dyslipidemia is warranted because interventions for dyslipidemia have an impact on reducing cardiac events in clinical trials specific to the transplant population. Dyslipidemia is not synonymous with hyperlipidemia. Numerous mechanisms exist for the occurrence of post-transplant dyslipidemia, including those mediated by immunosuppressive drug therapy. Statin therapy has received the most attention in all solid organ transplant recipient populations, although the effect of proper dietary advice and adjuvant pharmacological and non-pharmacological agents should not be dismissed. At all stages of treatment appropriate monitoring strategies for side effects should be implemented so that the benefits from these therapies can be achieved. Clinicians have a choice when there is a conflict between various transplant society and lipid society guidelines for therapy and targets.     

Valsalva and gravitational variability of the internal jugular vein and common femoral vein: ultrasound assessment

PURPOSE: Central venous cannulation via the common femoral vein is an important starting point for many interventions. The purpose of this study was to determine the optimum conditions for cannulation of the femoral vein and to compare these with the relative changes in the internal jugular vein. METHODS: High-resolution 2D ultrasound was utilised to determine variability of the calibre of the femoral and internal jugular veins in 10 healthy subjects. Venous diameter was assessed during the Valsalva manoeuvre and in different degrees of the Trendelenburg position. RESULTS: The Valsalva manoeuvre significantly increased the size of the femoral and internal jugular veins. There was a relatively greater increase in femoral vein diameter when compared with the internal jugular vein of 40 and 29%, respectively. Changes in body inclination (Trendelenburg position) did not significantly alter the luminal diameter of the femoral vein. However, it significantly increased internal jugular vein diameter. CONCLUSIONS: Femoral vein cannulation is augmented by the Valsalva manoeuvre but not significantly altered by the gravitational position of the subject.     

Mitral valve repair in chronic severe mitral regurgitation: short-term results and analysis of mortality predictors

IntroductionMitral valve repair is the accepted treatment for mitral regurgitation (MR) but lack of resources and socioeconomic concerns delay surgical referral and intervention in developing countries. We evaluated immediate and short-term results of mitral valve repair for non-ischemic MR at our centre and aimed to identify the predictors of in-hospital and follow-up mortality.Materials and methodsThe study was conducted at a tertiary-level hospital in South India. All patients >18 years with severe non-ischemic MR who underwent mitral valve repair over a period of 6 years were included. Perioperative data was collected from hospital records and follow-up data was obtained by prospective methods.ResultsThere were 244 patients (170 males). Most of the patients were in the age group 31–60 years (76.6%). Aetiology of MR was degenerative (n = 159; 65.2%), rheumatic (n = 34; 13.9%), structural (n = 42; 17.2%), or miscellaneous (n = 9; 3.7%). All patients underwent ring annuloplasty with various valve repair techniques. One hundred patients (44.7%) underwent additional cardiac procedures. At discharge, MR was moderate in 4 patients; the rest had no or mild MR. The mean hospital stay of survivors was 7.1 days (SD 2.52, range 5–25 days). There were 9 in-hospital deaths (3.68%) and 10 deaths during follow-up (4.2%). The mean follow-up period was 1.39 years, complete for 87.6%. Pre-operative left ventricle ejection fraction (LVEF) <60% (p = 0.04) was found to be significantly associated with immediate mortality. Logistic regression analysis detected age (p = 0.019), female sex (p = 0.015), and left ventricular (LV) dysfunction at discharge (p = 0.025) to be significantly associated with follow-up mortality.ConclusionPre-operative LV dysfunction was identified as a significant risk factor for in-hospital mortality. Female sex, age greater than 45 years, and LV dysfunction at discharge were found to be significantly associated with follow-up mortality. Hence, it is important to perform mitral valve repair in severe regurgitation patients before significant LV dysfunction sets in for a better outcome.     

Structural and functional analysis of the semitendinosus tendon after harvest for soft tissue reconstructive procedures: a dynamic ultrasonographic study

Purpose

To assess the potential for regeneration of the hamstring tendons after harvesting for various soft tissue reconstructive procedures, this study uses dynamic, high-resolution ultrasound to evaluate the presence of any tissue in the harvest gap and to characterize tissue functionality.

Methods

Patients who underwent ACL reconstruction using ipsilateral hamstring autograft were identified in the database of a single surgeon. Dynamic 12-MHz sonographic imaging was used to evaluate the ipsilateral and contralateral (control) semitendinosus tendons from their insertion sites to proximal muscle bellies. The presence or absence and echogenicity of tissue in the harvest defect, tissue appearance, degree of retraction of the proximal tendon stump, thickness of gap tissue, and motion of the proximal tendon stump were recorded. Data were analysed with Wilcoxon–Mann–Whitney, sign or binomial tests, with significance of P < 0.05.

Results

Eighteen knees in 15 patients (aged 17–51 years) were studied. The proximal amputated stump was retracted an average of 9.0 ± 7.6 cm (range, 0–18 cm; P = 0.0063). With dynamic testing, 9 of 15 knees demonstrated decreased excursion of the proximal tendon stump when compared to the native, contralateral muscle–tendon unit (P = 0.0039). Tissue was detected in the harvest gap in nine knees, five of which had harvest gap tissue with a disorganized appearance compared to the native tendon (P < 0.0001). Six of these nine knees had tissue in the gap demonstrating either less or no excursion with active knee flexion when compared to the native, contralateral side (P = 0.0313).

Conclusions

The presence of tissue in the harvest gap after ACL reconstruction is variable. When tissue is present, there is proximal retraction of the musculotendinous junction and disorganized appearance of the tissue that does not demonstrate normal excursion or physiological function similar to the native muscle-tendon unit.

Level of evidence

Case series, Level IV.     

The Attenuation of Early Benzo(a)Pyrene-Induced Carcinogenic Insults by Diallyl Disulfide (DADS) in MCF-10A Cells

Diallyl disulfide (DADS), a garlic organosulfur compound, has been researched as a cancer prevention agent; however, the role of DADS in the suppression of cancer initiation in nonneoplastic cells has not been elucidated. To evaluate DADS inhibition of early carcinogenic events, MCF-10A cells were pretreated (PreTx) with DADS followed by the ubiquitous carcinogen benzo(a)pyrene (BaP), or cotreated (CoTx) with DADS and BaP for up to 24 h. The cells were evaluated for changes in cell viability/proliferation, cell cycle, induction of peroxide formation, and DNA damage. BaP induced a statistically significant increase in cell proliferation at 6 h, which was attenuated with DADS CoTx. PreTx with 6 and 60 μM of DADS inhibited BaP-induced G2/M arrest by 68% and 78%, respectively. DADS, regardless of concentration or method, inhibited BaP-induced extracellular aqueous peroxide formation within 24 h. DADS attenuated BaP-induced DNA single-strand breaks at all time points through both DADS Pre- and CoTx, with significant inhibition for all treatments sustained after 6 h. DADS was effective in inhibiting BaP-induced cell proliferation, cell cycle transitions, reactive oxygen species, and DNA damage in a normal cell line, and thus may inhibit environmentally induced breast cancer initiation.     

A phase I study of liposomal-encapsulated docetaxel (LE-DT) in patients with advanced solid tumor malignancies

Background

Docetaxel is a taxane anticancer drug used in a wide variety of solid tumors. Liposomes are versatile drug carriers that may increase drug solubility, serve as sustained release systems, provide protection from drug degradation and toxicities, and help overcome multidrug resistance. This phase I study was conducted to determine the maximum tolerated dose, dose-limiting toxicities (DLTs), pharmacokinetics (PK), and clinical response of liposomal-encapsulated docetaxel (LE-DT) in patients with advanced solid tumor malignancies.

Methods

LE-DT was administered using a standard 3 + 3 dose escalation schema with dose levels of 50, 65, 85, 110, and 132 mg/m² IV on a 3-week cycle. Toxicities were assessed using the NCI-CTCAE version 3.0, and response was assessed using RECIST criteria (version 1.0). PK samples were drawn during cycle 1 and analyzed using a non-compartmental analysis.

Results

Twenty-four patients were treated for 1–30 cycles (median = 4). No DLTs were experienced through dose levels of 50, 65, 85, and 110 mg/m². Two out of two patients experienced grade 4 neutropenia at the 132 mg/m² dose level. When an additional three patients were treated at the expanded 110 mg/m² dose level, two experienced grade 4 neutropenia. The 85 mg/m² dose level was reassessed with an expanded group of three additional patients, and only one of three patients experienced grade 4 neutropenia. The protocol was amended to allow G-CSF during cycle 1, and an additional three patients were treated at 110 mg/m² with no DLTs experienced. No patient experienced significant neuropathy, even patients treated for 19, 20, and 30 cycles. PK followed a two-compartment elimination pattern; there was no correlation between PK and toxicity. Two patients with thyroid and neuroendocrine cancer had partial responses (PR, 8 %), and one patient with non-small-cell lung cancer had an unconfirmed PR. Eight patients (33 %) had stable disease lasting more than 3 months, for a clinical benefit rate of 41 %.

Conclusion

LE-DT was well tolerated with expected toxicities of neutropenia, anemia, and fatigue, but without neuropathy or edema. Clinical benefit (SD + PR) was observed in 41 % of the patients. The recommended phase II dose of LE-DT is 85 mg/m² without G-CSF or 110 mg/m² with G-CSF.     

Cucurbitacin B potently suppresses non-small-cell lung cancer growth: Identification of intracellular thiols as critical targets

Cucurbitacin B (CuB), has recently emerged as a potent anticancer agent; however, its efficacy in non-small-cell lung cancer (NSCLC) and the mechanism(s) initiating its biological effects remain largely unclear. In this study, CuB potently suppressed the growth of four NSCLC cells (H1299, A549, HCC-827 and H661) in vitro and the highly aggressive H1299 xenograft in vivo. CuB significantly altered the actin cytoskeletal assembly, induced G2/M cell-cycle arrest and mitochondrial apoptosis through the modulation of several key molecular targets mediating the aforementioned processes. Interestingly, all cellular effects of CuB were completely attenuated only by the thiol antioxidant N-acetylcysteine (NAC). Furthermore, pretreatment with glutathione synthesis inhibitor butithione-sulfoxime (BSO), significantly exacerbated CuB’s cytotoxic effects. To this end, cells treated with CuB revealed a rapid and significant decrease in the levels of protein thiols and GSH/GSSG ratio, suggesting disruption of cellular redox balance as the primary event in CuB’s cytotoxic arsenal. Using UV and FTICR mass spectrometry we also demonstrate for the first time a physical interaction of CuB with NAC and GSH in a cell-free system suggesting that CuB interacts with and modulates cellular thiols to mediate its anti-cancer effects. Collectively, our data sheds new light on the working mechanisms of CuB and demonstrate its therapeutic potential against NSCLC.     

Complexity quantification of cardiac variability time series using improved sample entropy (I-SampEn)

The sample entropy (SampEn) has been widely used to quantify the complexity of RR-interval time series. It is a fact that higher complexity, and hence, entropy is associated with the RR-interval time series of healthy subjects. But, SampEn suffers from the disadvantage that it assigns higher entropy to the randomized surrogate time series as well as to certain pathological time series, which is a misleading observation. This wrong estimation of the complexity of a time series may be due to the fact that the existing SampEn technique updates the threshold value as a function of long-term standard deviation (SD) of a time series. However, time series of certain pathologies exhibits substantial variability in beat-to-beat fluctuations. So the SD of the first order difference (short term SD) of the time series should be considered while updating threshold value, to account for period-to-period variations inherited in a time series. In the present work, improved sample entropy (I-SampEn), a new methodology has been proposed in which threshold value is updated by considering the period-to-period variations of a time series. The I-SampEn technique results in assigning higher entropy value to age-matched healthy subjects than patients suffering atrial fibrillation (AF) and diabetes mellitus (DM). Our results are in agreement with the theory of reduction in complexity of RR-interval time series in patients suffering from chronic cardiovascular and non-cardiovascular diseases.     

Prevalence of oral lesions in relation to habits: Cross-sectional study in South India.

BACKGROUND: Smoking, drinking and chewing tobacco product, common habits in India have been positively associated with oral lesions. No study has been conducted in this part of Tamilnadu regarding the prevalence of oral lesions in relation to habits. METHODS: A hospital based cross-sectional study was carried out at Ragas Dental College, Chennai. Already existing data of two thousand and seventeen consecutive patients from sub-urban areas of Chennai, who attended the outpatient department, at Ragas Dental College, for dental complaints during a period of three months in 2004, who underwent oral examination and interviewer based questionnaire was used. RESULTS: Oral soft tissue lesions were found in 4.1% of the study subjects. The prevalence of leukoplakia, OSF and oral lichen planus was 0.59%, 0.55%, and 0.15% respectively. The prevalence of smoking, drinking alcoholic beverages and chewing was 15.02%, 8.78% and 6.99% respectively. Smoking and chewing were significant predictors of leukoplakia in this population. DISCUSSION: The prevalence of leukoplakia, OSF and oral lichen planus in our study population is similar to those found in other populations. The prevalence of consumption of alcoholic beverages in our study population was higher when compared to the Indian National Sample Survey study. However the prevalence of smoking and chewing was found to be lower. Smokers were more likely to develop smoker's melanosis compared to other lesions. Among those who consumed alcoholic beverages alone, the prevalence of leukoplakia was higher compared to other lesions. OSF was the most prevalent lesion among those who chewed panmasala or gutkha or betel quid with or without tobacco.