Inhibition of 3-Hydroxy-3-Methylglutaryl–Coenzyme A Reductase and Application of Statins as a Novel Effective Therapeutic Approach against Acanthamoeba Infections

Acanthamoeba is an opportunistic pathogen in humans, whose infections most commonly manifest as Acanthamoeba keratitis or, more rarely, granulomatous amoebic encephalitis. Although there are many therapeutic options for the treatment of Acanthamoeba, they are generally lengthy and/or have limited efficacy. Therefore, there is a requirement for the identification, validation, and development of novel therapeutic targets against these pathogens. Recently, RNA interference (RNAi) has been widely used for these validation purposes and has proven to be a powerful tool for Acanthamoeba therapeutics. Ergosterol is one of the major sterols in the membrane of Acanthamoeba. 3-Hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase is an enzyme that catalyzes the conversion of HMG-CoA to mevalonate, one of the precursors for the production of cholesterol in humans and ergosterol in plants, fungi, and protozoa. Statins are compounds which inhibit this enzyme and so are promising as chemotherapeutics. In order to validate whether this enzyme could be an interesting therapeutic target in Acanthamoeba, small interfering RNAs (siRNAs) against HMG-CoA were developed and used to evaluate the effects induced by the inhibition of Acanthamoeba HMG-CoA. It was found that HMG-CoA is a potential drug target in these pathogenic free-living amoebae, and various statins were evaluated in vitro against three clinical strains of Acanthamoeba by using a colorimetric assay, showing important activities against the tested strains. We conclude that the targeting of HMG-CoA and Acanthamoeba treatment using statins is a novel powerful treatment option against Acanthamoeba species in human disease.     

Return to dialysis after renal transplantation. Which would be the best way?

The exact moment to return to dialysis when a graft fails has not clearly been established. Furthermore, there is no agreement with respect to whether the guidelines accepted for patients entering dialysis for the first time are adequate for this subgroup of patients with advanced renal failure, due to the special characteristics of these patients, derived from the immunosuppressive medications they are taking among other accompanying factors. We reviewed a group of renal transplant patients who returned to dialysis and compared them with a group of patients entering dialysis for the first time. Patients with chronic renal failure due to graft failure had a poorer renal function at the time entering dialysis and a more profound anemia. Additionally, complications considered such as the number of hospital admissions during the first year after initiation of dialysis were considerably higher in the group of transplanted patients. We advocate for an earlier referral to the dialysis unit, a more aggressive erythropoietin therapy in the phase of advanced renal failure due to chronic allograft nephropathy, and in selected cases retransplantation before definitive graft loss.     

Elderly patients on chronic hemodialysis: Effect of the secondary hyperparathyroidism on the hemoglobin level

In patients on chronic hemodialysis (CHD)hyperparathyroidism (HPTH) is associated withanemia and resistance to erythropoietin (EPO). This study included 86 CHD elderly pts (meanage 74.8 y, mean time on CHD = 50.5 mos); theywere divided into two groups: I (n = 31) – PTH> 250 pg/mL and II (n = 55) – PTH < 250 pg/mL.All these patients had been on CHD for> 6 mos. No differences were found betweengroups in respect to age, sex distribution andtime on CHD. The levels of creatinine, BUN, Ca,Al, Fe, albumin and ferritin were similar.Group I had a higher P level (5.4 vs 4.3 mg/dL,p = 0.001) and Ca x P (53.5 vs 43.7, p =0.009). Also the Hct (31 vs 33.5%, p = 0.008)and the Hb (10.4 vs 11.2 g/dL, p = 0.009) values werelower in Group I. The EPO dose (88 vs 85 U/kg/week,p = ns) was similar in the two groups.Our data showed that elderly patients with HPTHhave lower Hct and Hb levels than do youngerpatients on a similar EPO dose. We believethese patients will need a more aggressivetherapy with calcitriol.     

Partial Portal Vein Ligation Plus Thioacetamide: A Method to Obtain a New Model of Cirrhosis and Chronic Portal Hypertension in the Rat

To obtain a new model of chronic portal hypertension in the rat, two classical methods to produce portal hypertension, partial portal vein ligation and the oral administration of thioacetamide (TAA), have been combined. Male Wistar rats were divided into four groups: 1 (control; n?=?10), 2 [triple partial portal vein ligation (TPVL); n?=?9], 3 (TAA; n?=?11), and 4 (TPVL plus TAA; n?=?9). After 3 months, portal pressure, types of portosystemic collateral circulation, laboratory hepatic function tests (aspartate aminotransferase, alanine aminotransferase, bilirubin, alkaline phosphatase, and gamma-glutamyl transpeptidase) and liver histology were studied. The animals belonging to group 2 (TPVL) developed extrahepatic portosystemic collateral circulation, associated with mesenteric venous vasculopathy without hepatic destructurization or portal hypertension. Animals from group 3 (TAA) developed cirrhosis and portal hypertension but not extrahepatic portosystemic collateral circulation, or mesenteric venous vasculopathy. Finally, the animals from group 4 (TPVL?+?TAA) developed cirrhosis, portal hypertension, portosystemic collateral circulation, and mesenteric venous vasculopathy. The association of TPVL and TAA can be used to obtain a model of chronic portal hypertension in the rat that includes all the alterations that patients with hepatic cirrhosis usually have. This could, therefore, prove to be a useful tool to study the pathophysiological mechanisms involved in these alterations.     

Breast cancer management in middle-resource countries (MRCs): consensus statement from the Breast Health Global Initiative

In middle resource countries (MRCs), cancer control programs are becoming a priority as the pattern of disease shifts from infectious diseases to non-communicable diseases such as breast cancer, the most common cancer among women in MRCs. The Middle Resource Scenarios Working Group of the BHGI 2010 Global Summit met to identify common issues and obstacles to breast cancer detection, diagnosis and treatment in MRCs. They concluded that breast cancer early detection programs continue to be important, should include clinical breast examination (CBE) with or without mammography, and should be coupled with active awareness programs. Mammographic screening is usually opportunistic and early detection programs are often hampered by logistical and financial problems, as well as socio-cultural barriers, despite improved public educational efforts. Although multidisciplinary services for treatment are available, geographical and economic limitations to these services can lead to an inequity in health care access. Without adequate health insurance coverage, limited personal finances can be a significant barrier to care for many patients. Despite the improved availability of services (surgery, pathology, radiology and radiotherapy), quality assurance programs remain a challenge. Better access to anticancer drugs is needed to improve outcomes, as are rehabilitation programs for survivors. Focused and sustained government health care financing in MRCs is needed to improve early detection and treatment of breast cancer.     

Relación entre concentración intraoperatoria de parathormona y evolución postoperatoria del hiperparatiroidismo primario

Introduction

The relationship between the intra-operative concentration of parathyroid hormone (IOPTH) and the long-term outcome of patients intervened due to primary hyperparathyroidism (PHPT).

Patients and methods

A prospective observational study was performed with 120 patients. Three determinations were made of PTH in blood: baseline, when the diseases gland was located, and 10 minutes after its extirpation. The calcium, PTH and vitamin D (25-OH-D3) levels were measured during follow up.

Results

A decrease in IOPTH > 50% was observed in 96 (80%) patients, and the post-extirpation value returned to the normal range (Group I), in 18 (15%) a decrease of > 50% but the final value remained higher than normal (Group II) and in 6 (5%) the decrease was < 50% (Group III). Persistent PHPT was detected during follow up in 6 patients (5%): one in Group I (1%), 3 (16.7%) in II and 2 (33.3%) in group III (P < .001). The risk of persistent PHPT was higher in Group II (odds ratio: 19; 95% CI: 1.85-194) and in Group III (odds ratio: 47; 95% CI: 3.53-639). There were no cases of recurrent PHPT. A normal calcium with an increased PTH was detected in 20 patients of Group I (20.8%), 11 (61.1%) in II and 3 (50%) in III (P < .001). These patients had a lower concentration of post-operative vitamin D (17 ng/ml, range: 24; compared to 28 ng/ml, range: 21) (P = .008) and higher frequency of hypovitaminosis D (70.6% compared to 26.2%) (P>.001).

Conclusion

The risk of persistent PHPT is higher when the IOPTH decreases more than 50% but still remains high.     

Removal of primary tumor improves survival in metastatic breast cancer. Does timing of surgery influence outcomes?

Background

Resection of intact primary tumor is controversial in metastatic breast cancer patients. The aim of this study is to review the impact of surgical resection of primary tumor on overall survival and to assess the role of timing of surgery on survival rates.

Methods

208 patients with metastatic breast cancer diagnosed between 1982 and 2005 in the Hospital Clinico of Valencia (Spain) were analysed. Exclusion criteria were age >80, PS 3–4, Charlson score 3 or follow-up < 90 days. 123 of these underwent surgery and 85 did not. In order to assess the role of timing, the "surgery" cohort was divided into two sub-groups: "before" (n = 78) or "after" (n = 45) diagnosis of disseminated disease.

Results

In the surgery group, patients underwent mastectomy with axillary dissection (82.9%), without axillary dissection (8.9%) and conservative surgery (8.1%). After a median follow-up of 29.68 months, median OS in the "surgery" and the "non-surgery" groups were, 40.4 and 24.3 months. Removal of the primary tumor therefore had a significant positive impact on survival rates (p < 0.001). Benefits of surgery were observed mainly in patients with visceral disease (p = 0.005); no statistical differences were found in those with bone disease (p = 0.79). Univariate analysis for overall survival (OS) identified surgery, performance status, clinical T stage, hormone receptors and number and type of metastases as variables that impacted on survival. In the multivariate test, only resection of primary tumor and estrogen receptors maintained statistical significance, surgery having a protective effect with an HR 0.52 (95% CI 0.35–0.77). No differences in survival were found between the two sub-groups according to the timing of surgery: "before" vs "after"(p = 0.996).

Conclusions

Resection of primary tumor should be considered not only as a palliative or preventive strategy but also as an approach that possibly contributes to the control of the disease in selected patients.