Impact of Coexisting Coronary Artery Disease on the Occurrence of Cerebral Ischemic Lesions after Carotid Stenting

Background

Coronary artery disease (CAD) may coexist with extracranial carotid artery stenosis (ECAS), but the influence of CAD on procedure-related complications after carotid artery stenting (CAS) has not been well investigated. The study aimed to determine the impact of CAD on the occurrence of peri-CAS cerebral ischemic lesions on diffusion-weighted imaging (DWI) scanning.

Methods

Coronary angiography was performed within six months before CAS. DWI scanning was repetitively done within 1 week before and after CAS. Clinical outcome measures were stroke, angina, myocardial infarction and death within 30 days.

Results

Among 126 patients (69.5±9.0 years) recruited for unilateral protected CAS, 33 (26%) patients had peri-CAS DWI-positive lesions. CAD was noted in 79% (26 in 33) and 48% (45 in 93) of patients with and without peri-CAS DWI-positive lesions (OR, 4.0; 95% CI, 1.6–10.0; P = .0018), and the number of concomitant CAD on coronary angiography was positively correlated with the risk for peri-CAS DWI-positive lesions (P = .0032). In patients with no CAD (n = 55), asymptomatic CAD (n = 41) and symptomatic CAD (n = 30), the occurrence rates of peri-CAS DWI-positive lesions were 13%, 41% and 30% (P = .0048), and the peri-CAS stroke rates were 2%, 7% and 0% (P = .2120).

Conclusions

The severity of morphological CAD and the presence of either symptomatic or asymptomatic CAD are associated with the occurrence of peri-CAS cerebral ischemic lesions.     

Role of 2-[18F] Fluoro-2-Deoxy-D-Glucose-Positron Emission Tomography/Computed Tomography in the Post-Therapy Surveillance of Breast Cancer

Purpose

To evaluate the usefulness of 2-[¹⁸F] fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography (FDG-PET/CT) in the early detection of breast cancer tumor recurrences and its role in post-therapy surveillance.

Methods

FDG-PET/CT was performed on patients with increased serum CA 15-3 levels and/or clinical/radiologic suspicion of recurrence. A group of asymptomatic patients who underwent FDG-PET/CT in the post-therapy surveillance of breast cancer served as the controls. The results were analyzed based on the patients'' histological data, other imaging modalities and/or clinical follow-up. Recurrence was defined as evidence of recurrent lesions within 12 months of the FDG-PET/CT scan.

Results

Based on elevated serum CA15-3 levels (n = 31) and clinical/radiologic suspicion (n = 40), 71 scans were performed due to suspected recurrence, whereas 69 scans were performed for asymptomatic follow-up. The sensitivity and specificity of FDG-PET/CT were 87.5% and 87.1% in the patients with suspected recurrence and 77.8% and 91.7% in the asymptomatic patients. The positive predictive value in the patients with suspected recurrence (mainly due to elevated serum CA 15-3 levels) was higher than that in asymptomatic patients (P = 0.013). Recurrences were proven in 56.3% (40/71) of the patients with suspected recurrence and in 13% (9/69) of the asymptomatic patients (P<0.001). FDG-PET/CT resulted in changes in the planned management in 49.3% (35/71) of the patients with suspected recurrence and 10.1% (7/69) of the asymptomatic patients (P<0.001). After follow-up, 77.5% (55/71) of the patients with suspicious recurrences and 97.1% (67/69) of the asymptomatic patients were surviving at the end of the study (P<0.001).

Conclusions

FDG-PET/CT was able to detect recurrence, and the results altered the intended patient management in the post-therapy surveillance of breast cancer. FDG-PET/CT should be used as a priority in patients with increased serum CA 15-3 levels, or with clinical/radiologic suspicion of recurrence, and might be useful for asymptomatic patients.     

Changes in White Matter Integrity before Conversion from Mild Cognitive Impairment to Alzheimer’s Disease

Background

Mild cognitive impairment (MCI) may represent an early stage of dementia conferring a particularly high annual risk of 15–20% of conversion to Alzheimer’s disease (AD). Recent findings suggest that not only gray matter (GM) loss but also a decline in white matter (WM) integrity may be associated with imminent conversion from MCI to AD.

Objective

In this study we used Voxel-based morphometry (VBM) to examine if gray matter loss and/or an increase of the apparent diffusion coefficient (ADC) reflecting mean diffusivity (MD) are an early marker of conversion from MCI to AD in a high risk population.

Method

Retrospective neuropsychological and clinical data were collected for fifty-five subjects (MCI converters n = 13, MCI non-converters n = 14, healthy controls n = 28) at baseline and one follow-up visit. All participants underwent diffusion weighted imaging (DWI) and T1-weighted structural magnetic resonance imaging scans at baseline to analyse changes in GM density and WM integrity using VBM.

Results

At baseline MCI converters showed impaired performance in verbal memory and naming compared to MCI non-converters. Further, MCI converters showed decreased WM integrity in the frontal, parietal, occipital, as well as the temporal lobe prior to conversion to AD. Multiple regression analysis showed a positive correlation of gray matter atrophy with specific neuropsychological test results.

Conclusion

Our results suggest that additionally to morphological changes of GM a reduced integrity of WM indicates an imminent progression from MCI stage to AD. Therefore, we suggest that DWI is useful in the early diagnosis of AD.     

Liver Retransplantation in Adults: The Largest Multicenter Italian Study

This study is the largest Italian survey on liver retransplantations (RET). Data report on 167 adult patients who received 2 grafts, 16 who received 3 grafts, and one who received 4 grafts over a 11 yr period.There was no statistically significant difference in graft survival after the first or the second RET (52, 40, and 29% vs 44, 36, and 18% at 1,5,and 10 yr, respectively: Log-Rank test, p = 0.30).Survivals at 1, 5, and 10 years of patients who underwent 2 (n = 151) or 3 (n = 15) RETs, were 65, 48,and 39% vs 59, 44, and 30%, respectively (p = 0.59).Multivariate analysis of survival showed that only the type of graft (whole vs reduced) was associated with a statistically significant difference (HR = 3.77, Wald test p = 0. 05); the donor age appeared to be a relevant factor as well, although the difference was not statistically significant (HR = 1.91, Wald test p = 0.08).Though late RETs have better results on long term survival relative to early RETs, no statistically significant difference can be found in early results, till three years after RET.Considering late first RETs (interval>30 days from previous transplantation) with whole grafts the difference in graft survival in RETs due to HCV recurrence (n = 17) was not significantly different from RETs due to other causes (n = 53) (65–58 and 31% vs 66–57 and 28% respectively at 1–5 and 10 years, p = 0.66).     

Serum YKL-40 Levels Correlate with Infarct Volume,Stroke Severity,and Functional Outcome in Acute Ischemic Stroke Patients

Background and Purpose

YKL-40 is associated with various neurological disorders. However, circulatory YKL-40 levels early after onset of acute ischemic stroke (AIS) have not been systematically assessed. We aimed to identify the temporal changes and clinical usefulness of measuring serum YKL-40 immediately following AIS.

Methods

Serum YKL-40 and C-reactive protein (CRP) levels were monitored over time in AIS patients (n = 105) and compared with those of stroke-free controls (n = 34). Infarct volume and stroke severity (National Institutes of Health Stroke Scale; NIHSS) were measured within 48 hours of symptom onset, and functional outcome (modified Rankin Scale; mRS) was measured 3 months after AIS.

Results

Within 12 hours of symptom onset, levels of YKL-40 (251 vs. 41 ng/mL) and CRP (1.50 vs. 0.96 µg/mL) were elevated in AIS patients compared to controls. The power of YKL-40 for discriminating AIS patients from controls was superior to that of CRP (area under the curve 0.84 vs. 0.64) and YKL-40 (r = 0.26, P<0.001) but not CRP levels were correlated with mRS. On day 2 of admission (D2), YKL-40 levels correlated with infarct volume and NIHSS. High YKL-40 levels predicted poor functional outcome (odds ratio 5.73, P = 0.03). YKL-40 levels peaked on D2 and declined on D3, whereas CRP levels were highest on D3.

Conclusions

Our results demonstrate serial changes in serum YKL-40 levels immediately following AIS and provide the first evidence that it is a valid indicator of AIS extent and an early predictor of functional outcome.     

Quantification of Parasite Load in Clinical Samples of Leishmaniasis Patients: IL-10 Level Correlates with Parasite Load in Visceral Leishmaniasis

A rapid and accurate method to detect and quantify Leishmania parasite is urgently needed to facilitate early diagnosis of Leishmaniasis and monitoring of antileishmania therapy. In this study, real-time assay was applied to estimate parasite load in clinical samples of visceral leishmaniasis (VL) and post kala-azar dermal leishmaniasis (PKDL) patients. The mean parasite load in blood of VL patients (n = 31) was 8,372 parasites/ml, while the mean parasite load in bone marrow aspirate (BMA) was 194,962 parasites/million nucleated cells (n = 12). Parasite load was undetectable after treatment with amphotericin B (n = 9) in VL, while a residual parasite burden was detected in 2 of 6 patients following treatment with sodium antimony gluconate. Further, circulating levels of IFN-γ, TNF-α, IL-10, IL-6, IL-4 and IL-2 were analysed in VL patients (n = 29) by Cytometric Bead Array to evaluate correlation with parasitic load. Interestingly, IL-10 levels correlated significantly with parasite load (r = 0.82, P<0.0001). The mean parasite load in dermal lesions of PKDL patients was 9,502 parasites/µg tissue DNA at pre-treatment stage (n = 25), with no detectable parasites after therapy (n = 5). Parasite burden was distinctly higher (P<0.0001) in nodular lesions (n = 12) (19,586 parasites/µg tissue DNA) compared to papular/macular lesions (n = 13, 193 parasites/µg tissue DNA). Further, chronic PKDL lesions showed significantly (P = 0.0166) higher parasite load in comparison with acute lesions. Results indicate that chronic, nodular cases constitute the major parasite reservoir for anthroponotic transmission. Our results establish that the high parasite load in VL is strongly correlated with a high level of IL-10, implicating IL-10 as a marker of disease severity. The assay is applicable for diagnosis as well as prognosis of both VL and PKDL, providing a simple molecular tool to monitor the efficacy of antileishmanial drugs or vaccines.     

Early Hemoperfusion May Improve Survival of Severely Paraquat-Poisoned Patients

Background

Thousands of paraquat (PQ)-poisoned patients continue to die, particularly in developing countries. Although animal studies indicate that hemoperfusion (HP) within 2−4 h after intoxication effectively reduces mortality, the effect of early HP in humans remains unknown.

Methods

We analyzed the records of all PQ-poisoned patients admitted to 2 hospitals between 2000 and 2009. Patients were grouped according to early or late HP and high-dose (oral cyclophosphamide [CP] and intravenous dexamethasone [DX]) or repeated pulse (intravenous methylprednisolone [MP] and CP, followed by DX and repeated MP and/or CP) PQ therapy. Early HP was defined as HP <4 h, and late HP, as HP ≥4 h after PQ ingestion. We evaluated the associations between HP <4 h, <5 h, <6 h, and <7 h after PQ ingestion and the outcomes. Demographic, clinical, laboratory, and mortality data were analyzed.

Results

The study included 207 severely PQ-poisoned patients. Forward stepwise multivariate Cox hazard regression analysis showed that early HP <4 h (hazard ratio [HR] = 0.38, 95% confidence interval (CI) 0.16–0.86; P = 0.020) or HP <5 h (HR = 0.60, 95% CI: 0.39–0.92; P = 0.019) significantly decreased the mortality risk. Further analysis showed that early HP reduced the mortality risk only in patients treated with repeated pulse therapy (n = 136), but not high-dose therapy (n = 71). Forward stepwise multivariate Cox hazard regression analysis showed that HP <4.0 h (HR = 0.19, 95% CI: 0.05–0.79; P = 0.022) or <5.0 h (HR = 0.49, 95% CI: 0.24–0.98; P = 0.043) after PQ ingestion significantly decreased the mortality risk in repeated pulse therapy patients, after adjustment for relevant variables.

Conclusion

The results showed that early HP after PQ exposure might be effective in reducing mortality in severely poisoned patients, particularly in those treated with repeated pulse therapy.     

Tert-Butylhydroquinone Alleviates Early Brain Injury and Cognitive Dysfunction after Experimental Subarachnoid Hemorrhage: Role of Keap1/Nrf2/ARE Pathway

Tert-butylhydroquinone (tBHQ), an Nrf2 activator, has demonstrated neuroprotection against brain trauma and ischemic stroke in vivo. However, little work has been done with respect to its effect on early brain injury (EBI) after subarachnoid hemorrhage (SAH). At the same time, as an oral medication, it may have extensive clinical applications for the treatment of SAH-induced cognitive dysfunction. This study was undertaken to evaluate the influence of tBHQ on EBI, secondary deficits of learning and memory, and the Keap1/Nrf2/ARE pathway in a rat SAH model. SD rats were divided into four groups: (1) Control group (n = 40); (2) SAH group (n = 40); (3) SAH+vehicle group (n = 40); and (4) SAH+tBHQ group (n = 40). All SAH animals were subjected to injection of autologous blood into the prechiasmatic cistern once in 20 s. In SAH+tBHQ group, tBHQ was administered via oral gavage at a dose of 12.5 mg/kg at 2 h, 12 h, 24 h, and 36 h after SAH. In the first set of experiments, brain samples were extracted and evaluated 48 h after SAH. In the second set of experiments, changes in cognition and memory were investigated in a Morris water maze. Results shows that administration of tBHQ after SAH significantly ameliorated EBI-related problems, such as brain edema, blood-brain barrier (BBB) impairment, clinical behavior deficits, cortical apoptosis, and neurodegeneration. Learning deficits induced by SAH was markedly alleviated after tBHQ therapy. Treatment with tBHQ markedly up-regulated the expression of Keap1, Nrf2, HO-1, NQO1, and GSTα1 after SAH. In conclusion, the administration of tBHQ abated the development of EBI and cognitive dysfunction in this SAH model. Its action was probably mediated by activation of the Keap1/Nrf2/ARE pathway.     

IV t-PA Influences Infarct Volume in Minor Stroke: A Pilot Study

Background

There is an ongoing debate whether stroke patients presenting with minor or moderate symptoms benefit from thrombolysis. Up until now, stroke severity on admission is typically measured with the NIHSS, and subsequently used for treatment decision.

Hypothesis

Acute MRI lesion volume assessment can aid in therapy decision for iv-tPA in minor stroke.

Methods

We analysed 164 patients with NIHSS 0–7 from a prospective stroke MRI registry, the 1000+ study (clinicaltrials.org {"type":"clinical-trial","attrs":{"text":"NCT00715533","term_id":"NCT00715533"}}NCT00715533). Patients were examined in a 3 T MRI scanner and either received (n = 62) or did not receive thrombolysis (n = 102). DWI (diffusion weighted imaging) and PI (perfusion imaging) at admission were evaluated for diffusion - perfusion mismatch. Our primary outcome parameter was final lesion volume, defined by lesion volume on day 6 FLAIR images.

Results

The association between t-PA and FLAIR lesion volume on day 6 was significantly different for patients with smaller DWI volume compared to patients with larger DWI volume (interaction between DWI and t-PA: p = 0.021). Baseline DWI lesion volume was dichotomized at the median (0.7 ml): final lesion volume at day 6 was larger in patients with large baseline DWI volumes without t-PA treatment (median difference 3, IQR −0.4–9.3 ml). Conversely, in patients with larger baseline DWI volumes final lesion volumes were smaller after t-PA treatment (median difference 0, IQR −4.1–5 ml). However, this did not translate into a significant difference in the mRS at day 90 (p = 0.577).

Conclusion

Though this study is only hypothesis generating considering the number of cases, we believe that the size of DWI lesion volume may support therapy decision in patients with minor stroke.

Trial Registration

Clinicaltrials.org {"type":"clinical-trial","attrs":{"text":"NCT00715533","term_id":"NCT00715533"}}NCT00715533     

RASopathic Skin Eruptions during Vemurafenib Therapy

Purpose

Vemurafenib is a potent inhibitor of V600 mutant BRAF with significant impact on progression-free and overall survival in advanced melanoma. Cutaneous side effects are frequent. This single-center observational study investigates clinical and histological features of these class-specific cutaneous adverse reactions.

Patients and Methods

Patients were all treated with Vemurafenib 960 mg b.i.d. within local ethic committees approved clinical trials. All skin reactions were collected and documented prospectively. Cutaneous reactions were classified by reaction pattern as phototoxic and inflammatory, hair and nail changes, keratinocytic proliferations and melanocytic disorders.

Results

Vemurafenib was well tolerated, only in two patients the dose had to be reduced to 720 mg due to arthralgia. 26/28 patients (93%) experienced cutaneous side effects. Observed side effects included UVA dependent photosensitivity (n = 16), maculopapular exanthema (n = 14), pruritus (n = 8), folliculitis (n = 5), burning feet (n = 3), hair thinning (mild alopecia) (n = 8), curly hair (n = 2) and nail changes (n = 2). Keratosis pilaris and acanthopapilloma were common skin reactions (n = 12/n = 13), as well as plantar hyperkeratosis (n = 4), keratoacanthoma (n = 5) and invasive squamous cell carcinoma (n = 4). One patient developed a second primary melanoma after more than 4 months of therapy (BRAF and RAS wild type).

Conclusion

Vemurafenib has a broad and peculiar cutaneous side effect profile involving epidermis and adnexa overlapping with the cutaneous manifestations of genetic diseases characterized by activating germ line mutations of RAS (RASopathy). They must be distinguished from allergic drug reaction. Regular skin examination and management by experienced dermatologists as well as continuous prophylactic photo protection including an UVA optimized sun screen is mandatory.     

Reflections of Two Parallel Pathways between the Hippocampus and Neocortex in Transient Global Amnesia: A Cross-Sectional Study Using DWI and SPECT

Objectives

Two parallel pathways have been proposed between the hippocampus and neocortex. Recently, the anterior and posterior hippocampus showed distinct connectivity with different cortical areas in an fMRI study. We investigated whether the two parallel pathways could be confirmed in patients with transient global amnesia (TGA) which is a natural lesion model of a perturbation of the hippocampus. In addition, we evaluated the relationship between the location of the hippocampal lesion and various clinical variables.

Methods

A consecutive series of 37 patients were identified from the TGA registry database of Seoul National University Bundang Hospital. Based on the location of the diffusion-weighted imaging (DWI) lesion along the anterior-posterior axis of the hippocampus, they were divided into the following three groups: head (n = 15), body (n = 15) or tail (n = 7). To evaluate which cortical regions showed hypoperfusion according to the location of the DWI lesion, their SPECT images were compared between two groups using statistical parametric mapping. We performed hierarchical cluster analysis to group demographic and clinical variables, including the location of the DWI lesion, into clusters.

Results

Statistical parametric mapping analyses revealed that more anterior DWI lesions were associated with hypoperfusion of the anterior temporal and frontal areas, whereas more posterior lesions were associated with hypoperfusion of the posterior temporal, parietal, occipital and cerebellar areas. The difference was most prominent between the group of hippocampal lesions on the head and tail. Hierarchical cluster analysis demonstrated that vomiting was related to female gender and hippocampal head lesions, whereas vascular risk factors were related to male gender and hippocampal body lesions.

Conclusions

We confirmed the parallel pathways between the hippocampus and neocortex with DWI and SPECT images of patients with TGA. Patients with hippocampal head lesions and body lesions were clustered within different groups of clinical variables.     

18F-FDG PET Metabolic Parameters and MRI Perfusion and Diffusion Parameters in Hepatocellular Carcinoma: A Preliminary Study

Objectives

Glucose metabolism, perfusion, and water diffusion may have a relationship or affect each other in the same tumor. The understanding of their relationship could expand the knowledge of tumor characteristics and contribute to the field of oncologic imaging. The purpose of this study was to evaluate the relationships between metabolism, vasculature and cellularity of advanced hepatocellular carcinoma (HCC), using multimodality imaging such as ¹⁸F-FDG positron emission tomography (PET), dynamic contrast enhanced (DCE)-MRI, and diffusion weighted imaging(DWI).

Materials and Methods

Twenty-one patients with advanced HCC underwent ¹⁸F-FDG PET, DCE-MRI, and DWI before treatment. Maximum standard uptake values (SUV_max) from ¹⁸F-FDG-PET, variables of the volume transfer constant (K^trans) from DCE-MRI and apparent diffusion coefficient (ADC) from DWI were obtained for the tumor and their relationships were examined by Spearman’s correlation analysis. The influence of portal vein thrombosis on SUV_max and variables of K^trans and ADC was evaluated by Mann-Whitney test.

Results

SUV_max showed significant negative correlation with K^trans _max (ρ = −0.622, p = 0.002). However, variables of ADC showed no relationship with variables of K^trans or SUV_max (p>0.05). Whether portal vein thrombosis was present or not did not influence the SUV _max and variables of ADC and K^trans (p>0.05).

Conclusion

In this study, SUV was shown to be correlated with K_trans in advanced HCCs; the higher the glucose metabolism a tumor had, the lower the perfusion it had, which might help in guiding target therapy.     

Radiological Findings of Sexual Intercourse Related Emergency Department Admissions: A First Overview

Objectives

Sexuality is an essential aspect of human function, well-being and quality of life. Many people have sex without complications. However, there are some people who need to seek emergency medical help for related health problems. The aim of this study was to present a first overview of patients who received a radiological examination related to sexual intercourse based emergency department admission.

Methods

Our centralized electronic patient record database was reviewed for patients who had been admitted to our emergency department with an emergency after sexual intercourse between 2000 and 2011. The database was scanned for the standardized key words ‘sexual intercourse’ or ‘coitus’ retrospectively. For all patients identified in the electronic patient record database the radiological examinations were searched for manually in our Radiology Information System, and reviewed by three independent radiologists.

Results

One hundred and twenty nine out of 445 (29,0%) patients received a radiological examination after immediate emergency department admission related to sexual intercourse. Fifty two out of 129 (40.3%) patients had positive radiological findings while 77 (59.7%) did not. Eighty point seven percent (n = 42) of the radiological findings were a sexual intercourse-associated pathology and 19.2% (n = 10) were considered to be incidental findings. Age and male sex positively correlated with radiological imaging workup (p<0.001, respectively p<0.037). The most common sexual intercourse-associated pathology was headache attributed to cerebrovascular insult (n = 21, 40.3%) followed by epididymitis (n = 7, 16.6%) and obstructive uropathy (n = 5, 11.6%). Of the patients with headache attributed to non-traumatic intracranial hemorrhage, subarachnoid hemorrhage (n = 14, 66.6%) was the most common, followed by intracerebral bleeding (n = 4, 19.0%) and one subdural hemorrhage.

Conclusions

Pathological findings are manifold. Cerebral imaging is the most common type of radiological imaging performed. Further prospective and standardized studies should be performed to better evaluate the significance of radiological imaging in this patient collective with the aim to gain better knowledge on what patients profit from what type of radiological imaging when presenting with a sexual intercourse related emergency.

Advances in Knowledge

The present study provides a first overview on radiological findings of sexual intercourse related emergency department admissions.     

Surgically Acquired Deficits and Diffusion Weighted MRI Changes after Glioma Resection - A Matched Case-Control Study with Blinded Neuroradiological Assessment

Background

Acquired deficits following glioma resection may not only occur due to accidental resection of normal brain tissue. The possible importance of ischemic injuries in causing neurological deficits after brain tumor surgery is not much studied. We aimed to study the volume and frequency of early postoperative circulatory changes (i.e. infarctions) detected by diffusion weighted resonance imaging (DWI) in patients with surgically acquired neurological deficits compared to controls.

Methods

We designed a 1∶1 matched case-control study in patients with diffuse gliomas (WHO grade II–IV) operated with 3D ultrasound guided resection. 42 consecutive patients with acquired postoperative dysphasia and/or new motor deficits were compared to 42 matched controls without acquired deficits. Controls were matched with respect to histopathology, preoperative tumor volumes, and eloquence of location. Two independent radiologists blinded for clinical status assessed the postoperative DWI findings.

Results

Postoperative peri-tumoral infarctions were more often seen in patients with acquired deficits (63% versus 41%, p = 0.046) and volumes of DWI abnormalities were larger in cases than in controls with median 1.08 cm³ (IQR 0–2.39) versus median 0 cm³ (IQR 0–1.67), p = 0.047. Inter-rater agreement was substantial (67/82, κ = 0.64, p<0.001) for diagnosing radiological significant DWI abnormalities.

Conclusion

Peri-tumoral infarctions were more common and were larger in patients with acquired deficits after glioma surgery compared to glioma patients without deficits when assessed by early postoperative DWI. Infarctions may be a frequent and underestimated cause of acquired deficits after glioma resection. DWI changes may be an attractive endpoint in brain tumor surgery with both good inter-rater reliability among radiologists and clinical relevance.     

Cholesteryl Ester Transfer Protein Inhibitors in the Treatment of Dyslipidemia: A Systematic Review and Meta-Analysis

Cholesteryl ester transfer protein (CETP) inhibitors are gaining substantial research interest for raising high density lipoprotein cholesterol levels. The aim of the research was to estimate the efficacy and safety of cholesteryl ester transfer protein inhibitors as novel lipid modifying drugs. Systematic searches of English literature for randomized controlled trials (RCT) were collected from MEDLINE, EBASE, CENTRAL and references listed in eligible studies. Two independent authors assessed the search results and only included the double-blind RCTs by using cholesteryl ester transfer protein inhibitors as exclusively or co-administrated with statin therapy irrespective of gender in enrolled adult subjects. Two independent authors extracted the data by using predefined data fields. Of 503 studies identified, 14 studies met the inclusion criteria, and 12 studies were included into the final meta-analysis. Our meta-analysis revealed that CETP inhibitors increased the HDL-c levels (n = 2826, p<0.00001, mean difference (MD)  = 20.47, 95% CI [19.80 to 21.15]) and total cholesterol (n = 3423, p = 0.0002, MD = 3.57, 95%CI [1.69 to 5.44] to some extent combined with a reduction in triglyceride (n = 3739, p<0.00001, MD = −10.47, 95% CI [−11.91 to −9.03]) and LDL-c (n = 3159, p<0.00001, MD = −17.12, 95% CI [−18.87 to −15.36]) irrespective of mono-therapy or co-administration with statins. Subgroup analysis suggested that the lipid modifying effects varied according to the four currently available CETP inhibitors. CETP inhibitor therapy did not increase the adverse events when compared with control. However, we observed a slight increase in blood pressure (SBP, n = 2384, p<0.00001, MD = 2.73, 95% CI [2.14 to 3.31], DBP, n = 2384, p<0.00001, MD = 1.16, 95% CI [0.73 to 1.60]) after CETP inhibitor treatment, which were mainly ascribed to the torcetrapib treatment subgroup. CETP inhibitors therapy is associated with significant increase in HDL-c and decrease in triglyceride and LDL-c with satisfactory safety and tolerability in patients with dyslipidemia. However, the side-effect on blood pressure deserves more consideration in future studies.     

Assessing and Responding to Palliative Care Needs in Rural Sub-Saharan Africa: Results from a Model Intervention and Situation Analysis in Malawi

Introduction

Palliative care is rarely accessible in rural sub-Saharan Africa. Partners In Health and the Malawi government established the Neno Palliative Care Program (NPCP) to provide palliative care in rural Neno district. We conducted a situation analysis to evaluate early NPCP outcomes and better understand palliative care needs, knowledge, and preferences.

Methods

Employing rapid evaluation methodology, we collected data from 3 sources: 1) chart review of all adult patients from the NPCP’s first 9 months; 2) structured interviews with patients and caregivers; 3) semi-structured interviews with key stakeholders.

Results

The NPCP enrolled 63 patients in its first 9 months. Frequent diagnoses were cancer (n = 50, 79%) and HIV/AIDS (n = 37 of 61, 61%). Nearly all (n = 31, 84%) patients with HIV/AIDS were on antiretroviral therapy. Providers registered 112 patient encounters, including 22 (20%) home visits. Most (n = 43, 68%) patients had documented pain at baseline, of whom 23 (53%) were treated with morphine. A majority (n = 35, 56%) had ≥1 follow-up encounter. Mean African Palliative Outcome Scale pain score decreased non-significantly between baseline and follow-up (3.0 vs. 2.7, p = 0.5) for patients with baseline pain and complete pain assessment documentation. Providers referred 48 (76%) patients for psychosocial services, including community health worker support, socioeconomic assistance, or both. We interviewed 36 patients referred to the NPCP after the chart review period. Most had cancer (n = 19, 53%) or HIV/AIDS (n = 10, 28%). Patients frequently reported needing income (n = 24, 67%) or food (n = 22, 61%). Stakeholders cited a need to make integrated palliative care widely available.

Conclusions

We identified a high prevalence of pain and psychosocial needs among patients with serious chronic illnesses in rural Malawi. Early NPCP results suggest that comprehensive palliative care can be provided in rural Africa by integrating disease-modifying treatment and palliative care, linking hospital, clinic, and home-based services, and providing psychosocial support that includes socioeconomic assistance.     

The Comparison of the Effects of Three Physiotherapy Techniques on Hamstring Flexibility in Children: A Prospective,Randomized, Single-Blind Study

The aim of the study was to evaluate changes in hamstring flexibility in 120 asymptomatic children who participated in a 6-week program consisting of one physiotherapy session per week and daily home exercises. The recruitment criteria included age (10–13 years), no pain, injury or musculoskeletal disorder throughout the previous year, physical activity limited to school sport. Subjects were randomly assigned to one of the three groups: (1) post-isometric relaxation – PIR (n = 40), (2) static stretch combined with stabilizing exercises – SS (n = 40) and (3) stabilizing exercises – SE (n = 40). Hamstring flexibility was assessed with straight leg raise (SLR), popliteal angle (PA) and finger-to-floor (FTF) tests. The examinations were conducted by blinded observers twice, prior to the program and a week after the last session with the physiotherapist. Twenty-six children who did not participate in all six exercise sessions with physiotherapists were excluded from the analysis. The results obtained by 94 children were analyzed (PIR, n = 32; SS, n = 31; SE, n = 31). In the PIR and SS groups, a significant (P<0.01) increase in SLR, PA, FTF results was observed. In the SE group, a significant (P<0.001) increase was observed in the SLR but not in the PA and FTF (P>0.05). SLR result in the PIR and SS groups was significantly (P<0.001) higher than in the SE group. As far as PA results are concerned, a significant difference was observed only between the SS and SE groups (P = 0.014). There were no significant (P = 0.15) differences regarding FTF results between the three groups. Post-isometric muscle relaxation and static stretch with stabilizing exercises led to a similar increase in hamstring flexibility and trunk forward bend in healthy 10–13-year-old children. The exercises limited to straightening gluteus maximus improved the SLR result, but did not change the PA and FTF results.     

A Novel Acute Retroviral Syndrome Severity Score Predicts the Key Surrogate Markers for HIV-1 Disease Progression

Objective: Best long-term practice in primary HIV-1 infection (PHI) remains unknown for the individual. A risk-based scoring system associated with surrogate markers of HIV-1 disease progression could be helpful to stratify patients with PHI at highest risk for HIV-1 disease progression. Methods: We prospectively enrolled 290 individuals with well-documented PHI in the Zurich Primary HIV-1 Infection Study, an open-label, non-randomized, observational, single-center study. Patients could choose to undergo early antiretroviral treatment (eART) and stop it after one year of undetectable viremia, to go on with treatment indefinitely, or to defer treatment. For each patient we calculated an a priori defined “Acute Retroviral Syndrome Severity Score” (ARSSS), consisting of clinical and basic laboratory variables, ranging from zero to ten points. We used linear regression models to assess the association between ARSSS and log baseline viral load (VL), baseline CD4⁺ cell count, and log viral setpoint (sVL) (i.e. VL measured ≥90 days after infection or treatment interruption).

Results

Mean ARSSS was 2.89. CD4⁺ cell count at baseline was negatively correlated with ARSSS (p = 0.03, n = 289), whereas HIV-RNA levels at baseline showed a strong positive correlation with ARSSS (p<0.001, n = 290). In the regression models, a 1-point increase in the score corresponded to a 0.10 log increase in baseline VL and a CD4⁺cell count decline of 12/µl, respectively. In patients with PHI and not undergoing eART, higher ARSSS were significantly associated with higher sVL (p = 0.029, n = 64). In contrast, in patients undergoing eART with subsequent structured treatment interruption, no correlation was found between sVL and ARSSS (p = 0.28, n = 40).

Conclusion

The ARSSS is a simple clinical score that correlates with the best-validated surrogate markers of HIV-1 disease progression. In regions where ART is not universally available and eART is not standard this score may help identifying patients who will profit the most from early antiretroviral therapy.     

High Calcium Bioglass Enhances Differentiation and Survival of Endothelial Progenitor Cells,Inducing Early Vascularization in Critical Size Bone Defects

Early vascularization is a prerequisite for successful bone healing and endothelial progenitor cells (EPC), seeded on appropriate biomaterials, can improve vascularization. The type of biomaterial influences EPC function with bioglass evoking a vascularizing response. In this study the influence of a composite biomaterial based on polylactic acid (PLA) and either 20 or 40% bioglass, BG20 and BG40, respectively, on the differentiation and survival of EPCs in vitro was investigated. Subsequently, the effect of the composite material on early vascularization in a rat calvarial critical size defect model with or without EPCs was evaluated. Human EPCs were cultured with β-TCP, PLA, BG20 or BG40, and seeding efficacy, cell viability, cell morphology and apoptosis were analysed in vitro. BG40 released the most calcium, and improved endothelial differentiation and vitality best. This effect was mimicked by adding an equivalent amount of calcium to the medium and was diminished in the presence of the calcium chelator, EGTA. To analyze the effect of BG40 and EPCs in vivo, a 6-mm diameter critical size calvarial defect was created in rats (n = 12). Controls (n = 6) received BG40 and the treatment group (n = 6) received BG40 seeded with 5×10⁵ rat EPCs. Vascularization after 1 week was significantly improved when EPCs were seeded onto BG40, compared to implanting BG40 alone. This indicates that Ca²⁺ release improves EPC differentiation and is useful for enhanced early vascularization in critical size bone defects.     

Suitability of Pharmacokinetic Models for Dynamic Contrast-Enhanced MRI of Abdominal Aortic Aneurysm Vessel Wall: A Comparison

Purpose

Increased microvascularization of the abdominal aortic aneurysm (AAA) vessel wall has been related to AAA progression and rupture. The aim of this study was to compare the suitability of three pharmacokinetic models to describe AAA vessel wall enhancement using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).

Materials and Methods

Patients with AAA underwent DCE-MRI at 1.5 Tesla. The volume transfer constant (K^trans), which reflects microvascular flow, permeability and surface area, was calculated by fitting the blood and aneurysm vessel wall gadolinium concentration curves. The relative fit errors, parameter uncertainties and parameter reproducibilities for the Patlak, Tofts and Extended Tofts model were compared to find the most suitable model. Scan-rescan reproducibility was assessed using the interclass correlation coefficient and coefficient of variation (CV). Further, the relationship between K^trans and AAA size was investigated.

Results

DCE-MRI examinations from thirty-nine patients (mean age±SD: 72±6 years; M/F: 35/4) with an mean AAA maximal diameter of 49±6 mm could be included for pharmacokinetic analysis. Relative fit uncertainties for K^trans based on the Patlak model (17%) were significantly lower compared to the Tofts (37%) and Extended Tofts model (42%) (p<0.001). K^trans scan-rescan reproducibility for the Patlak model (ICC = 0.61 and CV = 22%) was comparable with the Tofts (ICC = 0.61, CV = 23%) and Extended Tofts model (ICC = 0.76, CV = 22%). K^trans was positively correlated with maximal AAA diameter (Spearman’s ρ = 0.38, p = 0.02) using the Patlak model.

Conclusion

Using the presented imaging protocol, the Patlak model is most suited to describe DCE-MRI data of the AAA vessel wall with good K^trans scan-rescan reproducibility.