The safety of rosuvastatin: effects on renal and hepatic function

Statins, or 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, have been shown to reduce elevated serum cholesterol resulting in a reduced risk of coronary artery disease and its complications. Rosuvastatin is the latest of the class of HMG-CoA reductase inhibitors and has the most potent reduction of low-density lipoprotein and elevation of high-density lipoprotein in the class. Questions have been raised about its safety. In a careful examination of the data, rosuvastatin has the same rate of elevations of hepatic enzymes as the other statins. Whether any of the statins actually cause significant liver injury is doubtful, and this raises questions about the usefulness of routine monitoring of liver enzymes in statin patients. Rosuvastatin has been noted to produce low levels of transient proteinuria. However, transient proteinuria is seen with other comparable statins. Long-term administration of rosuvastatin and other statins have been shown not to be associated with any decline in renal function, but instead have been shown to produce modest but clear improvement in glomerular filtration rate. Therefore, it is clear that rosuvastatin, and other statins, are very safe and useful agents and do not appear to present significant risks to hepatic or renal safety.     

Impaired CD4-cell immune reconstitution upon HIV therapy in patients with toxoplasmic encephalitis compared to patients with pneumocystis pneumonia as AIDS indicating disease

Objectives

There is only little data on immune reconstitution in antiretroviral naïve AIDS-patients with toxoplasmosis. The observation of several cases with reduced increase of CD4-cells upon start of antiretroviral treatment (ART) prompted us to investigate the topic using the ClinSurv cohort.

Methods

17 German HIV treatment centers contribute to ClinSurv, a multicentre observational cohort under the auspices of the Robert Koch Institute. We retrospectively selected all antiretroviral-naïve patients with toxoplasmic encephalitis (TE) and -as comparator group -with pneumocystosis (PCP) between January 1999 and December 2005.

Results

A total of 257 patients were included in the analysis, 61 with TE and 196 with PCP. Demographic baseline data showed differences with regard to gender, transmission group, and baseline CD4⁺ counts (60.9 vs. 44.7/μl, p = 0.022). After ART-initiation the increase in CD4⁺ lymphocytes was lower in the TE-versus the PCP-group in the first, second and fourth three-month-period (74.4 vs. 120.3/μl, p = 0.006; 96.6 vs. 136.2/μl, p = 0.021; 156.5 vs. 211.5/μl, p = 0.013). Viral load (VL) was higher in the PCP-group at baseline (4.46 log₁₀cop/ml vs. 5.00 log₁₀cop/ml, p = 0.008), while virological success of ART was equal.

Conclusions

Our data show for the first time that the average CD4⁺ T-cell increase of patients with toxoplasmosis is impaired compared to PCP-patients. Most clinicians would not be prepared to discontinue follow-up TE-therapy unless CD4⁺ counts of 200/μl are reached. Explanation for our finding might be the myelosuppressive side effect of pyrimethamine, possible interactions of toxoplasmosis therapy with ART, or an unknown direct biological influence of toxoplasmosis on immune restoration.     

Mental health treatments and associated factors amongst mid-aged Melbourne women

Summary The aim of this study was to describe lifetime treatment rate and the treatment modalities used for psychiatric problems and to identify variables associated with the history of psychiatric treatment among mid-aged Melbourne women. A longitudinal observational study was carried out using a population-based sample of 438 mid-aged women interviewed annually for eight years. The baseline data on sociodemographic profiles and premenstrual symptoms, and history of exposure to violence obtained at year 6 were included in this analysis. All other variables including psychiatric treatment history, psychosocial and lifestyle variables, chronic medical conditions and mood score were obtained at year 8. We found 22.2% of the women in this study had ever taken psychotropic medication. Antidepressants were the most used drugs. History of hospitalization for psychiatric problems was reported by 15 women (3.9%). 27 of 387 women (7%) reported they had received other types of treatment for psychiatric problems such as counseling or psychotherapy. Of all variables taken from the questionnaire about the treatment, only the history of psychotropic medication had a high enough frequency for regression analysis. History of psychotropic drug use was associated with interpersonal stresses, poor self-rated health, and prior history of depressive change during the premenstrual period. Socio-demographic variables, exposure to violence, lifestyle factors, and chronic physical conditions were not associated with psychotropic drug use.     

Integrated single-label liquid-phase assay of APOE codons 112 and 158 and a lipoprotein study in British women

BACKGROUND: Apolipoprotein E (APOE) is an important element of lipid metabolism and, hence, cardiovascular disorders. APOE has 3 main allelic variants: epsilon3, epsilon4, and epsilon2. Of these, epsilon3 is the most common, followed by epsilon4 and epsilon2. The associations of these isoforms with cardiovascular disorders and Alzheimer disease have been widely studied in different populations. Most of the genotyping in these studies has been performed with gel-based methods, which have important limitations, particularly for large epidemiologic studies. We therefore developed an integrated "one-tube" liquid-phase assay. METHODS: To measure APOE isoforms, we developed an integrated single-label liquid-phase fluorescence assay containing 2 PCR primers, 2 probes, and 2 quencher oligonucleotides. We used a 384-well LightTyper, but the assay would be generically applicable for use with any fluorescence detector with thermal ramp control. We validated this method and applied it in the British Women's Heart and Health Study. RESULTS: There were 4 melting peaks, at 41, 56, 61, and 69 degrees C, which generated 6 distinctive patterns representing genotypic combinations of epsilon3, epsilon4, and epsilon2. The magnitude and direction of the associations found with total cholesterol, HDL-cholesterol, triglycerides, and estimated LDL-cholesterol were consistent with previous reports. CONCLUSION: The one-tube LightTyper assay presented here enables accurate, convenient, and economical genotyping of APOE and can be used for large epidemiologic studies.     

Evaluation of Specificity of BP3385 for Bordetella pertussis Detection

BP3385 has been proposed as a diagnostic PCR target for discriminating between Bordetella pertussis and other Bordetella species that also infect humans. Our results demonstrate that this gene is also present in some strains of Bordetella hinzii and Bordetella bronchiseptica.Bordetella pertussis is an obligate human pathogen and the causative agent of whooping cough. Identification based on traditional culture and biochemical testing is the current diagnostic standard but is hampered by poor sensitivity and a slow turnaround time. Primers targeting a variety of genes have been proposed and evaluated for PCR-based identification strategies (11). These methods provide rapid and highly sensitive detection, but specificity is suboptimal since other species of Bordetella sometimes associated with respiratory disease in humans, including Bordetella bronchiseptica and Bordetella hinzii, may also possess the targeted sequences (4, 7, 9). Based on a comparison of the genomes of 22 isolates of B. bronchiseptica, 1 of human origin, and 10 isolates each of B. pertussis and B. parapertussis, it was suggested that open reading frame BP3385 of B. pertussis may be a highly specific diagnostic target (1). The authors of a subsequent study that included an unspecified number of B. bronchiseptica and B. hinzii isolates similarly concluded that BP3385 is specific for B. pertussis (3).The goal of the present study was to screen a large and genetically heterogeneous group of Bordetella strains, including many of human origin, to further evaluate the specificity of BP3385 as a diagnostic target for B. pertussis.A total of 142 Bordetella isolates originating from the United States, Europe, or Australia were evaluated using the previously described BP3385-specific real-time (RT)-PCR assay (3). These included 112 B. bronchiseptica isolates representing 31 unique PvuII ribotypes, 23 isolates of B. hinzii representing 4 PvuII ribotypes, and 7 B. avium isolates representing 6 PvuII ribotypes (5, 6, 8; K. B. Register, unpublished data). Twenty-five B. bronchiseptica isolates and 6 B. hinzii isolates were of human origin. The Tohama strain of B. pertussis, in which BP3385 was identified previously (1), was used as a positive control. The RB50 strain of B. bronchiseptica, which is missing BP3385 (1), was used as a negative control. Bacteria were cultured on Bordet-Gengou agar supplemented with 10% sterile, defibrinated sheep''s blood at 37°C for 18 to 36 h. Chromosomal DNA was purified using a commercially available kit (Promega, Madison, WI) and quantified with PicoGreen reagent (Invitrogen, Carlsbad, CA).Excepting the B. pertussis positive control, only B. bronchiseptica strain PV6 gave unequivocally positive results in the BP3385 RT-PCR assay. Results for an additional 8 isolates of B. bronchiseptica and 18 isolates of B. hinzii were interpreted as inconclusive on the basis of measurable, but elevated, cycle threshold (C_T) values (Table ​(Table1).1). All remaining isolates tested gave negative results.

TABLE 1.

Bordetella isolates with positive or inconclusive RT-PCR results for BP3385^a

The Oncosurgery Approach to Managing Liver Metastases from Colorectal Cancer: A Multidisciplinary International Consensus

An international panel of multidisciplinary experts convened to develop recommendations for the management of patients with liver metastases from colorectal cancer (CRC). The aim was to address the main issues facing the CRC hepatobiliary multidisciplinary team (MDT) when managing such patients and to standardize the treatment patients receive in different centers. Based on current evidence, the group agreed on a number of issues including the following: (a) the primary aim of treatment is achieving a long disease‐free survival (DFS) interval following resection; (b) assessment of resectability should be performed with high‐quality cross‐sectional imaging, staging the liver with magnetic resonance imaging and/or abdominal computed tomography (CT), depending on local expertise, staging extrahepatic disease with thoracic and pelvic CT, and, in selected cases, fluorodeoxyglucose positron emission tomography with ultrasound (preferably contrast‐enhanced ultrasound) for intraoperative staging; (c) optimal first‐line chemotherapy—doublet or triplet chemotherapy regimens combined with targeted therapy—is advisable in potentially resectable patients; (d) in this situation, at least four courses of first‐line chemotherapy should be given, with assessment of tumor response every 2 months; (e) response assessed by the Response Evaluation Criteria in Solid Tumors (conventional chemotherapy) or nonsize‐based morphological changes (antiangiogenic agents) is clearly correlated with outcome; no imaging technique is currently able to accurately diagnose complete pathological response but high‐quality imaging is crucial for patient management; (f) the duration of chemotherapy should be as short as possible and resection achieved as soon as technically possible in the absence of tumor progression; (g) the number of metastases or patient age should not be an absolute contraindication to surgery combined with chemotherapy; (h) for synchronous metastases, it is not advisable to undertake major hepatic surgery during surgery for removal of the primary CRC; the reverse surgical approach (liver first) produces as good an outcome as the conventional approach in selected cases; (i) for patients with resectable liver metastases from CRC, perioperative chemotherapy may be associated with a modestly better DFS outcome; and (j) whether initially resectable or unresectable, cure or at least a long survival duration is possible after complete resection of the metastases, and MDT treatment is essential for improving clinical and survival outcomes. The group proposed a new system to classify initial unresectability based on technical and oncological contraindications.     

Renal Thrombotic Microangiopathy after Hematopoietic Cell Transplant: Role of GVHD in Pathogenesis

Background and objectives: Thrombotic microangiopathy (TMA) is a known complication of hematopoietic cell transplantation (HCT). The etiology and diagnosis of TMA in this patient population is often difficult because thrombocytopenia, microangiopathic hemolytic anemia, and kidney injury occur frequently in HCT recipients, and are the result of a variety of insults.Design, setting, participants & measurements: The authors reviewed renal pathology and clinical data from HCT patients to determine the prevalence of TMA and to identify correlative factors for developing TMA in the kidney. Kidney tissue was evaluated from 314 consecutive autopsies on patients who died after their first HCT (received between 1992 and 1999). Renal pathology was classified into three groups: (1) no renal thrombus (65%), (2) TMA (20%), and (3) isolated thrombosis (15%). Logistic regression models estimated the associations between each histologic category and clinical parameters: donor and recipient gender, patient age, human leukocyte antigen (HLA) matching of the donor and recipient, total body irradiation (TBI), acute graft versus host disease (GVHD), acute kidney injury, medications, and viral infections.Results: In a multivariate analysis, TMA correlated with acute GVHD grades II to IV, followed by female recipient/male donor, TBI > 1200 cGy, and adenovirus infection. Grades II to IV acute GVHD and female gender were associated with isolated renal thrombus.Conclusions: TMA in HCT recipients is associated with acute GVHD grades II to IV, recipient/donor mismatch, TBI > 1200 cGy, and adenovirus infection.Thrombotic microangiopathy (TMA) encompasses a spectrum of clinical diseases characterized by systemic or intrarenal platelet aggregation, thrombocytopenia, and microvascular fragmentation of erythrocytes, resulting in ischemic organ injury. Endothelial damage is thought to represent the inciting factor in TMA syndromes (1). Once the endothelium is damaged, loss of endothelial resistance to thrombus formation, leukocyte adhesion, and increased vascular sheer stress ensues and may augment and perpetuate the injury (2). Although abnormalities in von Willebrand factor and complement pathways have also been associated with inherited and recurrent forms of TMA (2), they have not been found in patients who developed TMA after hematopoietic cell transplant (HCT) (3).The incidence of TMA syndromes in the setting of HCT ranges between 2% and 21% (4–6). Renal biopsy specimens are difficult to obtain immediately after HCT, and therefore much of the literature on TMA has relied on clinical and laboratory features alone. However, it is difficult to establish the diagnosis of TMA in HCT patients by clinical and laboratory features alone because anemia, thrombocytopenia, and elevations in lactate dehydrogenase (LDH) and creatinine occur frequently because of delayed engraftment, infections, medications, or graft versus host disease (GVHD). Clinical manifestations of TMA range from a fulminant presentation associated with severe acute renal failure and death to a more common, indolent course resulting in the eventual development of chronic kidney disease. In many cases, elevations in serum creatinine may not occur until late in the disease process despite endothelial injury in the kidney, and therefore the diagnosis may be delayed or missed. We hypothesize that renal endothelial injury, consistent with TMA, exists in the absence of a clinical diagnosis of TMA and that this early injury may set the stage for progression to chronic kidney disease. In this study, we examined the renal pathology and clinical data from HCT patients to more accurately identify the prevalence of and risk factors for the development of TMA in the kidney.     

Fractures of the pelvis

High energy fractures of the pelvis are a challenging problem both in the immediate post-injury phase and later when definitive fixation is undertaken. No single management algorithm can be applied because of associated injuries and the wide variety of trauma systems that have evolved around the world. Initial management is aimed at saving life and this is most likely to be achieved with an approach that seeks to identify and treat life-threatening injuries in order of priority. Early mortality after a pelvic fracture is most commonly due to major haemorrhage or catastrophic brain injury. In this article we review the role of pelvic binders, angiographic embolisation, pelvic packing, early internal fixation and blood transfusion with regard to controlling haemorrhage. Definitive fixation seeks to prevent deformity and reduce complications. We believe this should be undertaken by specialist surgeons in a hospital resourced, equipped and staffed to manage the whole spectrum of major trauma. We describe the most common modes of internal fixation by injury type and review the factors that influence delayed mortality, adverse functional outcome, sexual dysfunction and venous thromboembolism.