The response to ether anesthesia and to electric stimulation of glycolytic metabolites in a red and a white muscle of the rat

Summary Since ether anesthesia lowered ATP by 25% in red, but not in white muscle, and only when the spinal neurones were intact, we suggested that small or intermediate muscle units were activated under ether anesthesia [8].In order to prove this postulate, some glycolytic metabolites, known to rise under muscular activation, are studied in the white musculus adductor magnus and in the red musculus pyramidalis of the rat: glucose-1-phosphate, glucose-6-phosphate, fructose-6-phosphate, fructose-1-6-diphosphate, -glycerophosphate, lactate, pyruvate, and dihydroxyacetone phosphate.The conditions compared are: Inactin (5-ethyl-5(methyl-propyl)-2-thiobarbituric acid)-anesthesia, diethyl ether anesthesia, and tetanic contraction under Inactin anesthesia.The histological assay with Sudan-black B staining shows 34.2±7.3% dark fibers in m. pyramidalis and 0.2±4.8% dark fibers in m. adductor magnus.Glucose-1-phosphate, fructose-1-6-diphosphate, and -glycerophosphate are elevated under ether anesthesia in both muscles versus Inactin anesthesia by 100–200%.Lactate in both muscles and pyruvate in the red muscle are slightly elevated under ether (by 40%) versus Inactin anesthesia.Under tetanic contraction the metabolites studied rise considerably in both muscles.As glycogen is lowered in rat muscle under ether [9], the present results suggest an activation of glycogen phosphorylase and of phosphofructokinase in both the red and the white muscle under ether anesthesia, which results in augmented glycolysis.The comparatively small increment of pyruvate and lactate in the presence of a high increment of -glycerophosphate under ether anesthesia is considered to indicate an asynchronous activation of fibers with unimpaired circulation and oxidative metabolism.     

Mother and clinician experiences of a trial of a video feedback parent–infant intervention for mothers experiencing difficulties consistent with ‘personality disorder’: A qualitative interview study

Objectives

We explored mothers' and clinicians' experiences of a video feedback intervention adapted for perinatal ‘personality disorder’ (VIPP-PMH) and the acceptability of a randomised controlled trial (RCT) examining its effectiveness.

Design

In-depth qualitative interviews with participants from a two-phase feasibility study of the VIPP-PMH intervention. Participants were mothers experiencing enduring difficulties in managing emotions and relationships, consistent with a ‘personality disorder’, and their 6- to 36-month-old children.

Methods

Forty-four qualitative interviews were conducted, including all nine mothers receiving VIPP-PMH during the pilot phase, 25 of the 34 mothers participating in the RCT (14 allocated to the VIPP-PMH arm and 9 from the control arm), 11 of the 12 clinicians delivering VIPP-PMH and one researcher. Interview data were thematically analysed.

Results

Mothers described feeling motivated to take part in the research and understood the need for randomisation. Research visits were largely experienced positively, with some suggestions for improvement in questionnaire timing and accessibility. Almost all mothers initially felt anxious about being filmed, but reported positive experiences of the intervention, particularly valuing its non-judgemental, positive and child-focussed nature, their supportive relationship with the therapist and the insights they gained on their child.

Conclusions

The findings indicate the likely feasibility and acceptability of undertaking a future definitive RCT of the VIPP-PMH intervention in this population. In designing a future trial, a positive and non-judgemental therapeutic relationship will be important to allay mothers' anxieties about being filmed, and careful consideration should be given to the timing and accessibility of questionnaires used.     

The cost-effectiveness of routine postoperative radiotherapy after sector resection and axillary dissection for breast cancer stage I. Results from a randomized trial

Background: Cost-effectiveness of routine postoperative radiotherapyafter breast-conserving surgery has not been prospectively evaluatedearlier. In times of rationing of medical resources, valid assessments ofcost-effectiveness are important for rational allocation of resources.Purpose: Cost and cost-effectiveness of routine postoperativeradiotherapy was calculated in a prospective randomized trial comparingsector resection plus axillary dissection with (XRT group) or without(non-XRT group) postoperative radiotherapy in breast cancer stage I. Threehundred eighty-one patients were included. After a median follow-up of fiveyears 43 local recurrences, six of them in the XRT-group occurred (P <0.0001). No difference in regional and distant recurrence (P = 0.23) orsurvival (P = 0.44) was observed.Patients and methods: Direct medical costs as well as indirect costs interms of production lost during the treatment period and travel expenseswere estimated from data in the medical records and the national insuranceregistry of each patient. Average costs of different treatment activitiesand measures were estimated for the XRT-group and the non-XRT grouprespectively. From these estimates differences in costs and effectivenessbetween the groups were calculated and marginal cost-effectiveness ratioswere estimated. For the construction of QALYs each life-year wasquality-adjusted by a utility value depending on which health state thepatient was considered to perceive.Results: Taking into account the cost of primary treatment, the cost offollow-up, the cost of treatment of a local recurrence, travel expenses andindirect costs (production lost) excluding costs for treatment of regionaland distant recurrence the cost per avoided local recurrence at five yearswas SEK 337,727 ($44,438, £27,018).Adjustment for quality of life showed a cost for every gained QALY to beSEK 1.6 million, ($210,526, £128,000), range SEK0.2–3.9 million ($26,315–513,158;£16,000–312,000).Conclusion: The cost of routine postoperative radiotherapy after sectorresection and axillary dissection in breast cancer stage I per avoided localrecurrence and gained QALY is high. The cost per gained QALY show greatvariation depending on utility value, which in this study was derived fromexternal observers and not from the patients themselves. These results stressthe importance of identifying risk factors for local recurrence, betterunderstanding of impact on quality of life of a local recurrence and addingcost evaluations to clinical trials in early breast cancer.     

Hormone dependence of breast cancer cells and the effects of tamoxifen and estrogen:31P NMR studies

Many breast tumors appear to progress from estrogen-dependent growth to a more malignant phenotype characterized by estrogen-independent growth, antiestrogen resistance, and a high metastatic potential. Utilizing³¹P NMR spectroscopy on human breast cancer cells growingin vitro, we have investigated the effects of 17-estradiol and tamoxifen on the metabolic/bioenergetic spectra of a series of human breast cancer cells that vary in their estrogen and antiestrogen responsiveness. A comparison of baseline spectra associates higher levels of phosphodiesters and UDP-glucosides (e.g. UDP-glucose, UDP-N-acetylglucosamine), and lower phosphocholine/glycerylphosphocholine and phosphocholine/phosphoethanolamine ratios, with the acquisition of estrogen-independent growth in estrogen receptor expressing cells. No metabolic changes are clearly associated with the metastatic phenotype. Whilst estrogen treatment produces no consistently significant spectral changes in any of the cell lines, the estrogen-independent and estrogen-responsive MCF7/MIII cell line responds to tamoxifen treatment by significantly increasing all spectral resonances 30%-40% above baseline values. This may reflect a tamoxifen-induced change to a more differentiated or apoptotic phenotype, or an attempt by the cells to reverse the inhibitory effects of the drug. The ability to detect metabolic changes in response to tamoxifen by NMR spectroscopy may provide a novel means to identify those tumors that are responsive to antiestrogen therapy.Abbreviations CCS-IMEM steroid-deprived Improved Minimal Essential Medium - E2 17-estradiol - ER estrogen receptor - P_i inorganic phosphate - GPE glyceryl-phosphoethanolamine - GPC glyceryl-phosphocholine - PC phosphocholine - PE phosphoethanolamine - PDE phosphodiesters - PME phosphomonoesters - TAM tamoxifen (trans-1-(4--dimethylaminoethoxyphenyl)-1,2-diphenylbut-1-ene) - UDPG uridine diphosphoglycoside     

Alphacalcidol oral pulses normalize uremic hyperparathyroidism prior to dialysis

Alphacalcidol oral pulse therapy was given for secondary hyperparathyroidism to 22 children (mean age of 5.6 years) with renal insufficiency. At the beginning of the study, the glomerular filtration rate was <50% of normal, serum intact parathyroid hormone (PTH) was >100 ng/l and the serum phosphate and calcium concentrations were within the normal range. Alphacalcidol (0.5–3.0 g) was given orally thrice weekly in the evening and adjusted according to PTH, ionized calcium and phosphate concentrations. Serum PTH (mean ± SEM) decreased significantly from a pre-treatment level of 393±81 ng/l to 122±34 ng/l after 12 months, and stabilized at this level. Mean vitamin D metabolite concentrations were within the normal range. 1,25-Dihydroxyvitamin D did not increase during therapy, while PTH decreased. The estimated creatinine clearance remained almost unchanged (20±3 and 21±6 ml/min per 1.73 m²). Growth remained low normal (height standard deviation score –1.8±0.3 initially and –1.7±0.4 12 months later) and bone mineral density did not decrease. We concluded that feedback regulation of PTH with oral alphacalcidol pulse therapy is effective in the treatment of hyperparathyroidism in children with renal failure prior to dialysis.     

Adherence to antiretroviral medications in an inner-city population

Adherence to antiretroviral medications is essential for optimal treatment of HIV infection. We investigated nonadherence to antiretroviral medications in an inner-city population by using a confidential interview and a self-administered anonymous questionnaire. We estimated adherence on the day before and the month before the interview and asked reasons for nonadherence. Of 173 people who were taking antiretroviral medications, all participated in the confidential interview and 101 also completed the anonymous questionnaire. Results of the confidential interview and the anonymous questionnaire revealed rates of 6% and 28%, respectively, for nonadherence to any drug on the preceding day and of 11% and 39%, respectively, in the preceding month. The most common reasons for nonadherence in both methods were forgetfulness, inaccessibility of medications, and perceived or actual toxicity. On 12% of the anonymous questionnaires one reason for nonadherence was perceived or actual lack of drug efficacy: this reason was not given in any of the confidential interviews. Responses about the extent of nonadherence and the reasons for it may differ depending on the method of ascertainment. Interventions to improve adherence should focus on making medication dosages easier to remember, ensuring a continued supply of medications, and circumventing toxicities.     

Multileafkollimator: Erweiterte Qualit?tssicherung an einem GE-Linearbeschleuniger

Hintergrund: Ein Multileafkollimator stellt durch die Vielzahl der Lamellen sehr viel höhere Ansprüche an die Konstanzprüfverfahren als ein konventionelles Blendensystem. Zur täglichen Kontrolle der Lamellenpositionierung wird ein Qualitssicherungskonzept vorgestellt. Methode: Zwei Feldkonfigurationen, die bei maximaler Öffnung der Blockblenden sowohl maximale Öffnung als auch "Overtravel" einzelner Lamellen enthalten, werden in täglichem Wechsel online vom Verifikationssystem zum Linearbeschleuniger übertragen. Im Lichtfeld des Linearbeschleunigers erfolgt eine visuelle Kontrolle der Lamellenpositionen mit Hilfe eines speziellen Prüfkörpers. Abschließend wird die Lamellenpositionierung mittels eines Electronic-Portal-Imaging-Systems dokumentiert und nach Überlagerung eines Gitters mit einer Referenzaufnahme verglichen. Ergebnisse: Die Methode stellt eine schnelle und effektive Möglichkeit dar, die Funktionsfähigkeit des gesamten Systems durch Simulation des "Routinebetriebs" zu überprüfen. Schlußfolgerung: Der Arbeits- und Zeitaufwand für die Qualitätssicherung an einem Multileafkollimator unterscheidet sich nur unwesentlich von dem eines konventionellen Blendensystems. Background: In comparison to a conventional collimator, a multileaf collimator demands a great deal of quality assurance procedures due to its large number of leaves. A concept for daily quality assurance is presented, mainly concerning the positioning accuracy of the leaves. Material and Methods: Two leaf configurations including maximal opening as well as overtravel of single leaves, at a maximal opening of the jaws, are transmitted online in daily exchange from our record- and verify system to the linac. Aiming at a special test phantom a visual control of the positioning accuracy is performed. The leaf positioning is documented by an electronic portal imaging system and is compared with a reference shot by superposition of a grid. Results: This method of quality assurance offers a fast and effective possibility to guarantee the proper function of the whole system by simulating the routine treatment situation. Conclusions: Compared to a conventional collimator only a slightly greater workload is needed for quality assurance of a multileaf collimator.     

The estimated prevalence and incidence of HIV in 96 large US metropolitan areas.

OBJECTIVES: This study sought to estimate the size and direction of the human immunodeficiency virus (HIV) epidemic in US metropolitan statistical areas (MSAs) with populations greater than 500,000. METHODS: A "components model" from review of more than 350 documents, several large datasets, and information from 220 public health personnel was used. Data review focused on injection drug users, men who have sex with men, and high-risk heterosexual men and women. RESULTS: In the 96 MSAs, there are, broadly, an estimated 1.5 million injection drug users, 1.7 million gay and bisexual men, and 2.1 million at-risk heterosexuals, and, among them, an estimated 565,000 prevalent and 38,000 incident HIV infections. This implies about 700,000 prevalent and 41,000 new HIV infections yearly in the United States. Roughly half of all estimated new infections are occurring among injection drug users, most of them in northeastern cities, Miami, and San Juan. Gay and bisexual men still represent most prevalent HIV infections, although incidence--except in young and minority gay men--is much lower now than it was a decade ago. Relatively high prevalences of HIV in at-risk heterosexual persons in several cities indicate the potential for an increase in transmission among them. CONCLUSIONS: This review and synthesis outline the comparative epidemiology of HIV in major US cities and identify populations for interventions.     

Physicochemical Characterization of Protein-Free Low Density Lipoprotein Models and Influence of Drug Loading

Purpose. Drug free and drug loaded protein-free low density lipoprotein (LDL) models consisting mainly of phospholipids, cholesterol, cholesterol esters, and triglycerides in ratios found for physiological LDL have been prepared. Their physicochemical characteristics were compared with those of physiological LDL. Methods. Different characterization methods were used: photon correlation spectroscopy, transmission electron microscopy, X-ray solution scattering, and ¹H nuclear magnetic resonance spectroscopy (NMR). Results. Particle sizes are highly dependent on the preparation method and in particular on the homogenization conditions. Electron microscopy indicates that the size distributions of model systems are much broader than those of physiological LDL. The X-ray solution scattering patterns of the model systems display a temperature dependent maximum near 3.8 nm similar to that found in the patterns of physiological LDL. NMR indicates a comparable mobility of the lipid molecules in model particles and in physiological LDL. The influence of drug loading is similar to that found earlier for physiological LDL. In particular, the incorporation of the anti-cancer drug WB 4291 seems to have a fluidizing effect on the lipids in the core region of the particles. Conclusions. The preparation method of LDL model systems is of crucial importance as only the solvent evaporation method yielded systems in the size range of physiological LDL with acceptable high lipid concentrations. The fluidizing influence of temperature and drug incorporation (WB 4291) may be a disadvantage in drug targeting.     

Abrin Poisoning

Abrin is a toxic protein obtained from the seeds of Abrus precatorius (jequirity bean), which is similar in structure and properties to ricin. Abrin is highly toxic, with an estimated human fatal dose of 0.1–1 µg/kg, and has caused death after accidental and intentional poisoning. Abrin can be extracted from jequirity beans using a relatively simple and cheap procedure. This satisfies one criterion of a potential chemical warfare agent, although the lack of large scale production of jequirity seeds means that quantity is unavailable for ready mass production of abrin for weapons. This contrasts with the huge cultivation of Ricinus seeds for castor oil production. At the cellular level, abrin inhibits protein synthesis, thereby causing cell death. Many of the features observed in abrin poisoning can be explained by abrin-induced endothelial cell damage, which causes an increase in capillary permeability with consequent fluid and protein leakage and tissue oedema (the so-called vascular leak syndrome). Most reported cases of human poisoning involve the ingestion of jequirity beans, which predominantly cause gastrointestinal toxicity. Management is symptomatic and supportive. Experimental studies have shown that vaccination with abrin toxoid may offer some protection against a subsequent abrin challenge, although such an approach is unlikely to be of benefit in a civilian population that in all probability would be unprotected.