MCL-1 is a stress sensor that regulates autophagy in a developmentally regulated manner.

Apoptosis has an important role during development to regulate cell number. In differentiated cells, however, activation of autophagy has a critical role by enabling cells to remain functional following stress. In this study, we show that the antiapoptotic BCL-2 homologue MCL-1 has a key role in controlling both processes in a developmentally regulated manner. Specifically, MCL-1 degradation is an early event not only following induction of apoptosis, but also under nutrient deprivation conditions where MCL-1 levels regulate activation of autophagy. Furthermore, deletion of MCL-1 in cortical neurons of transgenic mice activates a robust autophagic response. This autophagic response can, however, be converted to apoptosis by either reducing the levels of the autophagy regulator Beclin-1, or by a concomitant activation of BAX. Our results define a pathway whereby MCL-1 has a key role in determining cell fate, by coordinately regulating apoptosis and autophagy.

Equity, waiting times, and NHS reforms: retrospective study.

OBJECTIVE: To determine whether observable changes in waiting times occurred for certain key elective procedures between 1997 and 2007 in the English National Health Service and to analyse the distribution of those changes between socioeconomic groups as an indicator of equity. DESIGN: Retrospective study of population-wide, patient level data using ordinary least squares regression to investigate the statistical relation between waiting times and patients' socioeconomic status. SETTING: English NHS from 1997 to 2007. PARTICIPANTS: 427,277 patients who had elective knee replacement, 406,253 who had elective hip replacement, and 2,568,318 who had elective cataract repair. MAIN OUTCOME MEASURES: Days waited from referral for surgery to surgery itself; socioeconomic status based on Carstairs index of deprivation. RESULTS: Mean and median waiting times rose initially and then fell steadily over time. By 2007 variation in waiting times across the population tended to be lower. In 1997 waiting times and deprivation tended to be positively related. By 2007 the relation between deprivation and waiting time was less pronounced, and, in some cases, patients from the most deprived fifth were waiting less time than patients from the most advantaged fifth. CONCLUSIONS: Between 1997 and 2007 waiting times for patients having elective hip replacement, knee replacement, and cataract repair in England went down and the variation in waiting times for those procedures across socioeconomic groups was reduced. Many people feared that the government's NHS reforms would lead to inequity, but inequity with respect to waiting times did not increase; if anything, it decreased. Although proving that the later stages of those reforms, which included patient choice, provider competition, and expanded capacity, was a catalyst for improvements in equity is impossible, the data show that these reforms, at a minimum, did not harm equity.

[Emergence of vancomycin-dependent enterococci following glycopeptide therapy: case report and review]. / Emergence d'entérocoque dépendant de la vancomycine à la suite d'un traitement par glycopeptide: cas clinique et revue.

INTRODUCTION: Outbreaks of vancomycin-resistant enterococci have been increasingly reported in France over the last three years. We report here, the emergence of a vancomycin-dependent enterococci isolate following glycopeptide therapy. PATIENTS AND METHODS: An Enterococcus faecium isolate that required vancomycin for growth was cultured from the stools of a liver transplant recipient who was colonised with vancomycin-resistant enterococci and who received vancomycin treatment for methicillin-resistant Staphylococcus aureus infection. The resistant isolate and the dependent isolate were typed by pulsed-field gel electrophoresis. The sequence of the ddl gene coding for the D-Ala: D-Ala ligase was analysed. RESULTS: The dependent isolate was primary cultured onto a vancomycin-containing screening medium and could not be subcultured in the absence of vancomycin. Both the resistant and dependent isolates harboured the vanA gene and they had the same DNA restriction pattern after pulsed-field gel electrophoresis. Dependence on vancomycin was associated with a 1-bp deletion in the D-Ala: D-Ala ligase gene leading to an early stop odon. CONCLUSION: Cultures onto vancomycin-containing media are warranted for clinical specimens from patients, who are known to carry vancomycin-resistant enterococci and receive vancomycin therapy.

Genetic background of Escherichia coli isolates from patients with spontaneous bacterial peritonitis: relationship with host factors and prognosis.

Spontaneous bacterial peritonitis (SBP) is a severe complication in patients with cirrhosis and ascites. It is predominantly caused by Escherichia coli. The phylogenetic group and virulence genotype of E. coli isolates causing SBP were investigated, and the association of these characteristics with host factors and prognosis was examined. Seventy-six episodes of E. coli SBP that occurred over a 9-year period were studied. The phylogenetic group of the isolates and the presence of 36 virulence factor genes were investigated. The influence of bacterial and host factors on in-hospital mortality was assessed by multiple logistic regression. Phylogenetic groups A, B1, B2 and D were found in 26%, 4%, 46% and 24% of the isolates, respectively. Virulence factor genes were more frequent in B2 isolates than in non-B2 isolates (mean virulence score 15.4 vs. 7.3, p <10(-4)). Ciprofloxacin resistance was significantly associated with non-B2 groups and a low virulence score. Host factors independently associated with a shift from B2 to non-B2 isolates were norfloxacin prophylaxis (OR 13.01, p 0.0213) and prothrombin ratio (OR 1.04 for a 10% decrease, p 0.0211). The model for end-stage liver disease (MELD) score (OR 1.83, p 0.0007) and hospital-acquired SBP (OR 4.13, p 0.0247) were independent predictors of in-hospital mortality. In contrast, outcome was not influenced by the phylogenetic group or the virulence profile. These findings indicate that the characteristics of E. coli isolates causing SBP vary with the severity of liver disease and with fluoroquinolone prophylaxis. Host factors are more important than bacterial factors in predicting in-hospital mortality.

Mcl-1 is a key regulator of apoptosis during CNS development and after DNA damage.

Despite the importance of Mcl-1, an anti-apoptotic Bcl-2 family member, in the regulation of apoptosis, little is known regarding its role in nervous system development and injury-induced neuronal cell death. Because germline deletion of Mcl-1 results in peri-implantation lethality, we address the function of Mcl-1 in the nervous system using two different conditional Mcl-1 mouse mutants in the developing nervous system. Here, we show for the first time that Mcl-1 is required for neuronal development. Neural precursors within the ventricular zone and newly committed neurons in the cortical plate express high levels of Mcl-1 throughout cortical neurogenesis. Loss of Mcl-1 in neuronal progenitors results in widespread apoptosis. Double labeling with active caspase 3 and Tuj1 reveals that newly committed Mcl1 deficient neurons undergo apoptosis as they commence migration away from the ventricular zone. Examination of neural progenitor differentiation in vitro demonstrated that cell death in the absence of Mcl1 is cell autonomous. Although conditional deletion of Mcl-1 in cultured neurons does not trigger apoptosis, loss of Mcl-1 sensitizes neurons to an acute DNA damaging insult. Indeed, the rapid reduction of Mcl-1 mRNA and protein levels are early events after DNA damage in neurons, and maintaining high Mcl-1 levels can protect neurons against death. Together, our results are the first to demonstrate the requirement of Mcl-1, an anti-apoptotic Bcl-2 family protein, for cortical neurogenesis and the survival of neurons after DNA damage.

[Development of an intravesial oxybutynin chloride solution: from formulation to quality control]. / Développement d'une solution de chlorhydrate d'oxybutynine pour instillation vésicale: de la formulation au contrôle qualité.

Intravesical oxybutynin chloride has demonstrated its efficacy in children with neurogenic bladder and urinary incontinence refractory to oral anticholinergic agents. We developed a 205 microg/ml oxybutynin chloride solution in accordance with the specifications of the European Pharmacopeae. To guarantee quality, we assessed and validated formulation, the preparation process, and packaging. The solution was obtained by disolving oxybutynin chloride in 0.9% saline and sterile filtration. The solution was then packaged in syringes. Physical properies for intravesical instillation were met: pH 5.76 +/- 0.03, osmolality 281 mosmol/kg. The unit dose package guarantees sterility of the solution until use. The medication is given by adapting the syringe on the Luer Lock exteremity of the urinary catheter. The solution remains stable up to one month at 4 degrees C.

The motivation and behaviour of hospital Trusts.

This paper explores the motivation and behaviour of hospitals, using data from UK hospital Trusts. Managers and consultants (hospital specialists) are identified as the main alternative sources of power within Trusts. It is hypothesised that consultants are interested in production or service (volume and quality) while managers are interested primarily in financial break-even, and that in the long run consultants will dominate. A survey of 1500 consultants and managers and a statistical analysis of the behaviour of 100 Trusts over 3 years yielded the empirical results that were largely but not entirely consistent with these hypotheses. Consultants did indeed consider production goals to be more important than financial breakeven, but within those goals, considered quality to be more important than service volume. While the break-even target was found to be the primary goal of managers on average, they proved to be a heterogeneous group with quality ranking as the main priority among those managers who are closest to service delivery. This is at odds with the apparent objective of Trusts, which both groups perceive as being the single-minded pursuit of financial targets, consistent with the formal, government-set requirements. We find that this strong and unequivocal financial driver is not owned or acted upon by either consultants or managers and it is inferred that, in accordance with the dominant motivation of consultants, the Trust's primary objective is to maintain service quality.

Incentives and health policy: primary and secondary care in the British National Health Service.

This paper argues that issues concerning incentives and motivation are crucial to recent reforms to the British National Health Service. It examines how the incentive structure of General Practitioners with respect to the interface between primary and secondary care changed with the introduction of GP fundholding, and how it might change further with the new Primary Care Groups. It concludes that the effectiveness of the internal incentive structure of the new groups will depend on the location of power within the PCGs, and that the external incentives involving the possibility of heavy central monitoring may affect the behaviour and motivation of GPs in potentially harmful ways.

Competition, cooperation, or control? Tales from the British National Health Service.

The British National Health Service (NHS) recently underwent a massive social experiment, inspired in large part by the ideas of U.S. experts. This involved the creation of an internal or quasi-market, separating purchaser from provider and encouraging competition among providers. After reviewing the evidence concerning the impact of this experiment, I conclude that the impact in fact was minimal, partly because of the retention of central government control and partly because the experiment was based on an inadequate understanding of professional and managerial motivations. The paper draws out general lessons of the experiment for other market-oriented health care systems and examines whether the lessons are reflected in the new batch of NHS reforms initiated by the recently elected Labour Government.

A new simple method to perform pressure-volume curves obtained under quasi-static conditions during mechanical ventilation.

OBJECTIVE: To describe a fast, simple method to acquire pressure-volume curves of the respiratory system and to compare this with a classic method in terms of reliability of the data and speed. DESIGN: Acquisition of pressure-volume curves by low flow inflation technique (P-Vlf) versus the occlusion technique (P-Vst) using the standard equipment of a Cesar ventilator. SETTING: General ICU - Aix en Provence Hospital. PATIENTS: Ten sedated, curarized patients undergoing mechanical ventilation. INTERVENTIONS: P-Vlf curves were acquired by setting the ventilator parameters at f = 5 c./min, duty time Ti/Ttot = 80 %, VT = 1100 ml, pause time = 0. The pressure and volume data were collected directly on the ventilator screen. P-Vst curves were acquired using an airway occlusion technique. The pressures obtained for the same inflation volumes and times necessary for performance of the two techniques were compared. RESULTS: The time needed to acquire a P-Vlf curve was 3 min versus 38 min for P-Vst curve. Concordance analysis between the two methods showed a 95 % confidence interval of (-0.5 cm H2O, + 1.8 cm H2O) for pressure. CONCLUSIONS: P-Vlf curves are close to P-Vst curves, are much less time-consuming, easy to acquire with Cesar ventilator equipment, and may be used in clinical routine to assess the elastic properties of the respiratory system.

[Enterobacter aerogenes pneumopathy treated by a cefepime-sulbactam-gentamicin combination]. / Pneumopathie à Enterobacter aerogenes traitée par l'association céfépime-sulbactam-gentamicine.

BACKGROUND: Enterobacter aerogenes is the fifth most frequent pathogen causing nosocomial infections. Several strains have developed multiple resistance by over-production of a natural cephalosporinase and by the presence of wide-spectrum betalactamases. CASE REPORT: A patient with chronic respiratory failure developed Enterobacter aerogenes pneumonia while under mechanical ventilation. The infection was successfully treated with a cefepime, sulbactam, gentamycin combination. DISCUSSION: Choosing the optimum antibiotic therapy is a difficult task in many nosocomial infections. In certain cases, combining a betalactamase inhibitor with the appropriate antibiotic can improve bactericidal activity and provide successful cure.

Cryogenic high-resolution X-ray spectrometers for SR-XRF and microanalysis.

Experimental results are presented obtained with a cryogenically cooled high-resolution X-ray spectrometer based on a 141 x 141 micro m Nb-Al-Al(2)O(3)-Al-Nb superconducting tunnel junction (STJ) detector in an SR-XRF demonstration experiment. STJ detectors can operate at count rates approaching those of semiconductor detectors while still providing a significantly better energy resolution for soft X-rays. By measuring fluorescence X-rays from samples containing transition metals and low-Z elements, an FWHM energy resolution of 6-15 eV for X-rays in the energy range 180-1100 eV has been obtained. The results show that, in the near future, STJ detectors may prove very useful in XRF and microanalysis applications.

Soft x-ray performance of high-resolution superconducting spectrometers.

We are developing high-resolution, broad-band, superconducting X-ray spectrometers for applications in materials science, astrophysics and biophysics. These spectrometers are superconducting microcalorimeters based on superconducting tunnel junction sensors made from thin films of niobium and aluminum. The energy resolution of these spectrometers can be more than an order of magnitude better than that of the best Si(Li) or Ge(Li) detectors. We present results of recent measurements characterizing the performance of these detectors for X-ray energies from 70 eV to 500 eV, where the energy resolution ranged from 4 eV FWHM (at 70 eV) to 12 eV FWHM (at 500 eV).

The development of quasi-markets in welfare provision in the United Kingdom.

In the late 1980s, governments in many western economies began to introduce competition between public agencies providing health, education, and other forms of social welfare. Government became a contracting agency separating funding from provision. The United Kingdom went farthest in legislation passed between 1988 and 1990. The authors review some possible explanations for this fundamental change. The article draws on public choice theory and broader political science approaches and reviews the evidence on the impact of the changes. The gains from these changes may be small, and the result may be only the build up of pressure for more spending in the longer term.

A cognitive model of dangerous delusional misidentification syndromes.

The hallmark of the delusional misidentification syndromes is the presence of a misidentification delusion of the self or others. Delusional misidentification may present with an increased risk for dangerous behaviors. Individuals suffering from delusional misidentification syndromes may express hostility in ways ranging from serious verbal threats to homicidal acts. The causes of dangerous misidentification delusions remain for the most part undetermined. In this article, we report a series of six cases of individuals who harbored dangerous misidentification delusions. These individuals were studied phenomenologically and forensically. They were also studied biologically, including neuropsychological testing. A cognitive hypothesis aimed at explaining dangerousness and delusional misidentification is proposed. Implications of the hypothesis for further research are briefly outlined.

Regional inequalities in mortality.

STUDY OBJECTIVE: To examine the hypothesis of sustained and persistent inequalities in health between British regions and to ask how far they are a consequence of using standardised mortality ratios as the tool of measurement. DESIGN, SETTING AND PARTICIPANTS: Data are regional, age specific death rates at seven points in time from 1931 to 1987-89 for the British regions, reconstructed to make them comparable with the 1981 regional definitions. Log variance is used to measure inequality; regional rankings are also used. MEASUREMENTS AND MAIN RESULTS: There has been a substantial convergence in age specific death rates between regions in younger but not in older age groups. In younger age groups the historic north/south gradient has disappeared; it persists in older groups. CONCLUSIONS: Use of standardised mortality ratios obscures differences in the convergence rates of age specific death rates between regions. Simple conclusions about the persistence of a north/south divide are not justified. Different processes of change seem to be at work in different age groups.