Methicillin-resistant Staphylococcus aureus, Clostridium difficile, and extended-spectrum beta-lactamase-producing Escherichia coli in the community: assessing the problem and controlling the spread

Although health care-associated methicillin resistant staphylococcus aureus and clostridium difficile strains are primarily a risk to hospital patients, people are increasingly concerned about their potential to circulate in the community and the home. They are thus looking for support in order to understand the extent of the risk, and guidance on how to deal with situations where preventing infection from these species becomes their responsibility. A further concern are the community-acquired MRSA and C. difficile strains, and other antibiotic resistant strains circulating in the community such as the Extended-spectrum beta-lactamase (ESBL) Escherichia coli. In response to concerns about such organisms in the community, the International Scientific Forum on Home Hygiene has produced a report evaluating MRSA, C. difficile, and ESBL-producing E. coli from a community viewpoint. The report summarizes what is known about their prevalence in the community, their mode of transmission in the home, and the extent to which they represent a risk. It also includes "advice sheets" giving practical guidance on what to do when there is a risk of infection transmission in the home.     

Metabolic Activity Determines Efficacy of Macroautophagic Clearance of Pathological Oligomeric α-Synuclein

Macroautophagy is an essential degradative pathway that can be induced to clear aggregated proteins, such as those found in Parkinson’s disease and dementia with Lewy bodies, a form of Parkinsonism. This study found that both LC3-II and beclin were significantly increased in brains from humans with Dementia with Lewy bodies and transgenic mice overexpressing mutant α-synuclein, as compared with respective controls, suggesting that macroautophagy is induced to remove α-syn, particularly oligomeric or mutant forms. Aged mutant animals had higher autophagy biomarker levels relative to younger animals, suggesting that with aging, autophagy is less efficient and requires more stimulation to achieve the same outcome. Disruption of autophagy by RNA interference significantly increased α-syn oligomer accumulation in vitro, confirming the significance of autophagy in α-syn clearance. Finally, rotenone-induced α-syn aggregates were cleared following rapamycin stimulation of autophagy. Chronic rotenone exposure and commensurate reduction of metabolic activity limited the efficacy of rapamycin to promote autophagy, suggesting that cellular metabolism is critical for determining autophagic activity. Cumulatively, these findings support the concept that neuronal autophagy is essential for protein homeostasis and, in our system, reduction of autophagy increased the accumulation of potentially pathogenic α-synuclein oligomers. Aging and metabolic state were identified as important determinants of autophagic activity. This study provides therapeutic and pathological implications for both synucleinopathy and Parkinson’s disease, identifying conditions in which autophagy may be insufficient to degrade α-syn aggregates.Parkinson’s disease (PD) is a major neurodegenerative disease that affects approximately 1 million people in the United States. The disease affects the motor system due to loss of dopaminergic neurons. The common pathological hallmark of the disease includes the formation of intracellular inclusions called Lewy bodies,^1,2,3,4 principally composed of the protein α-synuclein (α-syn). The protein misfolds and accumulates, initially as oligomers and ultimately as aggregates.^5,6,7,8 The first mutation linked to PD was found in the α-synuclein gene at position A53T,⁹ and mutant variants of the protein are more prone to aggregate compared with wild-type protein.^10,11,12,13Other genes linked to PD include Parkin,¹⁴ UCHL1,¹⁵ DJ-1,¹⁶ PINK1,^17,18 LrrK2,^19,20 and ATP13a2.²¹ Mutations in these genes are not all associated with synucleinopathy however. Some involve mitochondrial dysfunction (PINK1, parkin, DJ-1), aberrant proteasomal activity (UCHL1), or altered autophagic or lysosomal function (LrrK2 and ATP13a2).^21,22 Recently, mutations of the glucocerebrosidase gene, encoding a lysosomal enzyme, have been shown to be an important risk factor for PD^23,24,25,26 and dementia with Lewy bodies (DLB), another form of Parkinsonism.^24,27 The mechanism by which glucocerebrosidase mutations cause disease is currently unknown but alterations in glucocerebrosidase may affect lysosomal degradation and increase the likelihood of aberrant α-syn accumulation into Lewy bodies, and neurodegeneration.Previously, wild-type α-syn was shown to undergo chaperone-mediated autophagy,²⁸ a lysosomal process that degrades 40% of all proteins, while the mutant variant blocks this lysosomal action.^29,30 As a result, mutant forms of α-synuclein (especially the A53T variant) are more prone to oligomerization and aggregation and are less readily degraded than the wild-type. Thus, they are more likely to accumulate as pathological intracellular inclusions due to decreased lysosomal degradation.Macroautophagy (autophagy) is critical to neuronal health as impairment leads to aberrant protein accumulation, neuronal dysfunction, and cell death.^31,32 In addition to its constitutive activity, macroautophagy is inducible and dually regulated by the mTOR³³ and PI3kinase/beclin/vsp34^34,35 signaling pathways. Induction of autophagy results in the recruitment of multiple Atg proteins^36,37 that initiate formation of double-membrane, autophagic vacuoles (AVs) that envelop proximal cytoplasmic material including aggregated proteins and organelles.³⁸ The AVs subsequently acquire lysosomal hydrolases or fuse with lysosomes to complete the degradative process.^39,40 Normally, this constitutive process is highly efficient in neurons.Up-regulation of autophagy has been previously reported to reverse the pathogenic accumulation of intracellular inclusions. In Huntington’s disease, induction of autophagy promotes the clearance of polyglutamine huntingtin aggregates that are a hallmark of the disease.^41,42 However, induction is not always a beneficial process. In Alzheimer’s disease, it has been suggested that the accumulation of AVs results in increased production of the toxic peptide β-amyloid and may be attributed to reduced fusion or lysosomal degradation.^43,44 Thus, although it appears that cells may up-regulate autophagy to attenuate dysfunction, it cannot be assumed that this is the case and the opposite may, in fact, be true.These studies provide comprehensive pathological and biochemical evidence that macroautophagy is essential for maintaining the homeostasis of α-synuclein levels. Our studies show that autophagy was stimulated in human DLB, and in mutant α-syn-expressing mice to clear aberrant α-syn. In addition, this work provides evidence that blockage of autophagy results in the promotion of the pathogenic α-syn oligomers,^45,46 particularly the mutant variant of α-syn. Finally, clearance of α-synuclein via small molecule induction of macroautophagy is dependent on the metabolic state of the cells, as cells were able to clear oligomeric α-syn when not metabolically compromised following acute exposure to rotenone, but with chronic exposure to rotenone the autophagic capacity to degrade α-synuclein was significantly diminished.     

Comparison of inhibitors of superoxide generation in vascular smooth muscle cells

Background and purpose:

We compared the dose-dependent reductions in cellular superoxide anion (O₂⁻) by catalytic agents: superoxide dismutase (SOD), polyethylene glycol (PEG)-SOD and the nitroxide 4-hydroxy-2,2,6,6,-tetramethylpiperidine-1-oxyl (tempol) with uncharacterized antioxidants: 5,10,15,20-tetrakis (4-sulphonatophenyl) porphyrinate iron (III)(Fe-TTPS), (-)-cis-3,3′,4′,5,7-pentahydroxyflavane (2R,3R)-2-(3,4-dihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol (-epicatechin), 2-phenyl-1,2-benzisoselenazol-3(2H)-one (ebselen) and N-acetyl-L-cysteine (NAC) with the spin trap nitroblue tetrazolium (NBT) and with the vitamins or their analogues: ascorbate, α-tocopherol and 6-hydroxy-2,5,7,8-tetramethylkroman-2-carboxy acid (trolox).

Experimental approach:

O₂⁻ was generated in primary cultures of angiotensin II-stimulated preglomerular vascular smooth muscle cells from spontaneously hypertensive rats and detected by lucigenin-enhanced chemiluminescence.

Key results:

SOD, PEG-SOD, NAC and tempol produced a similar maximum inhibition of O₂⁻ of 80–90%. -Epicatechin, NBT, ebselen and Fe-TTPS were significantly (P < 0.0125) less effective (50–70%), whereas trolox, α-tocopherol and ascorbate had little action even over 24 h of incubation (<31%). Effectiveness in disrupted and intact cells was similar for the permeable agents, PEG-SOD and tempol, but was enhanced for SOD. Generation of O₂⁻ was increased by NAC and NBT at low concentrations but reduced at high concentrations.

Conclusions and implications:

Maximum effectiveness against cellular production of O₂⁻ requires cell membrane permeability and catalytic action as exemplified by PEG-SOD or tempol. NAC and NBT have biphasic effects on O₂⁻ production. Vitamins C and E or analogues have low efficacy.     

Renal transplantation in the United Kingdom for patients from ethnic minorities

BACKGROUND: To investigate any differences in access to transplant and post-transplant outcomes for ethnic minority patients in the United Kingdom, national data on ethnicity of patients on the waiting list, those receiving a transplant, and deceased donors were analyzed. METHODS: Adult patients and donors were included. Ethnic origin was classified as white, Asian, black, or "other." National data were analyzed, and 2001 U.K. National census data were used for comparative purposes. Median waiting times to transplant were obtained from Kaplan-Meier estimates for patients registered 1998-2000. Transplant survival was estimated for patients transplanted from 1998 to 2003. RESULTS: A total of 92% of the U.K. population was white, compared with 77% of waiting list patients, 88% of transplant recipients, and 97% of deceased donors. Median waiting time to transplantation for white patients was 719 days (95% confidence interval 680-758) compared with 1368 (1131-1605) days for Asian patients and 1419 (1165-1673) days for black patients. The degree of human leukocyte antigen matching achieved was inferior for Asian and black patients. There is some evidence of inferior 3-year transplant survival for black patients compared with white and Asian patients (P=0.03). CONCLUSIONS: There are imbalances in the ethnic make up of the waiting list, the donor pool, and renal transplant recipients. There are significant differences in both post-transplant outcomes and time to transplantation between patients of different ethnic origin. Waiting times are influenced by allocation schemes, and the 2006 U.K. National Kidney Allocation Scheme is designed to achieve greater equity of access to transplant for all patients, regardless of geography, blood group, or ethnicity.     

A comparison of hexaminolevulinate fluorescence cystoscopy and white light cystoscopy for the detection of carcinoma in situ in patients with bladder cancer: a phase III, multicenter study

PURPOSE: We compared hexaminolevulinate (Hexvix) fluorescence cystoscopy with white light cystoscopy for detecting carcinoma in situ. MATERIALS AND METHODS: In this multicenter study 298 patients with known or suspected bladder cancer underwent bladder instillation with 50 ml 8 mM hexaminolevulinate for 1 hour. Cystoscopy was then performed, first using standard white light and then hexaminolevulinate fluorescence cystoscopy. Lesions or suspicious areas identified under the 2 illumination conditions were mapped and biopsied for histological examination. In addition, 1 directed biopsy was obtained from an area appearing to be normal. RESULTS: Of 196 evaluable patients 29.6% (58 of 196) had carcinoma in situ, including 18 with carcinoma in situ alone, and 35 with carcinoma in situ and concomitant papillary disease, which was only detected on random biopsy in 5. Of the 18 patients with no concomitant papillary disease carcinoma in situ was detected only by hexaminolevulinate fluorescence in 4 and only by white light in 4. In the group with concomitant papillary disease carcinoma in situ was found only by hexaminolevulinate fluorescence in 5 patients and only by white light in 3. The proportion of patients in whom 1 or more carcinoma in situ lesions were found only by hexaminolevulinate cystoscopy was greater than the hypothesized 5% (p=0.0022). Overall more carcinoma in situ lesions were found by hexaminolevulinate than by white light cystoscopy in 22 of 58 patients (41.5%), while the converse occurred in 8 of 58 (15.1%). Biopsy results confirmed cystoscopy findings. Of a total of 113 carcinoma in situ lesions in 58 patients 104 (92%) were detected by hexaminolevulinate cystoscopy and 77 (68%) were detected by white light cystoscopy, while 5 were detected only on directed visually normal mucosal biopsy. Hexaminolevulinate instillation was well tolerated with no local or systemic side effects. CONCLUSIONS: In patients with bladder cancer hexaminolevulinate fluorescence cystoscopy with blue light can diagnose carcinoma in situ that may be missed with white light cystoscopy. Hexaminolevulinate fluorescence cystoscopy can be used in conjunction with white light cystoscopy to aid in the diagnosis of this form of bladder cancer.     

The association between body size, prostate volume and prostate-specific antigen

Increasing prostate volume contributes to urinary tract symptoms and may obscure prostate cancer detection. We investigated the association between obesity and prostate volume, prostate-specific antigen (PSA) and PSA density among 753 men referred for prostate biopsy. Among men with a negative biopsy, prostate volume significantly increased approximately 25% from the lowest to highest body mass index (BMI), waist or hip circumference or height categories. PSA was 0.7 ng/ml lower with a high waist-to-hip ratio. These associations were less consistent among subjects diagnosed with high-grade prostatic intraepithelial neoplasia or cancer. Our data suggest that obesity and height are independently associated with prostate volume..     

The evidence-based pathway for peri-operative management of open and robotically assisted laparoscopic radical prostatectomy

OBJECTIVE: To assess reports supporting the novel and comprehensive evidence-based pathway for radical prostatectomy (RP), as collaborative-care pathways have helped to optimize management of patients treated with RP and such clinical pathways provide an ideal framework for constructing an original evidence-based pathway for the complete peri-operative care of these patients. PATIENTS AND METHODS: We searched for articles on Medline via PubMed to identify reports describing consensus opinions on appropriate aspects of the peri-operative management of patients treated with RP, specifically seeking to discern information on preoperative antibiotic regimen, peri-operative laboratory testing, use of beta-blockers for those at cardiac risk, pulmonary treatment, deep venous thrombosis prophylaxis, diet advancement, pain management, anti-emetic use, bowel regimen, and catheter removal after RP. RESULTS: Available reports were used to substantiate each variable of our collaborative-care pathway for RP. When available, meta-analyses were used to provide a broad review of the recognized clinical research. Otherwise, many controlled studies and retrospective reviews were relied upon to provide evidence to construct a framework for clinical decision-making. CONCLUSIONS: This is the first pathway for the peri-operative management of major urological procedure that is well integrated into current literature. The critical aspects of clinical decision-making in the patient treated with RP were validated by the available research.