Mitochondria and Critical Illness.

Classically, mitochondria have largely been believed to influence the development of illness by modulating cell metabolism and determining the rate of production of high-energy phosphate compounds (eg, adenosine triphosphate). It is now recognized that this view is simplistic and that mitochondria play key roles in many other processes, including cell signaling, regulating gene expression, modulating cellular calcium levels, and influencing the activation of cell death pathways (eg, caspase activation). Moreover, these multiple mitochondrial functional characteristics are now known to influence the evolution of cellular and organ function in many disease states, including sepsis, ICU-acquired skeletal muscle dysfunction, acute lung injury, acute renal failure, and critical illness-related immune function dysregulation. In addition, diseased mitochondria generate toxic compounds, most notably released mitochondrial DNA, which can act as danger-associated molecular patterns to induce systemic toxicity and damage multiple organs throughout the body. This article reviews these evolving concepts relating mitochondrial function and acute illness. The discussion is organized into four sections: (1) basics of mitochondrial physiology; (2) cellular mechanisms of mitochondrial pathophysiology; (3) critical care disease processes whose initiation and evolution are shaped by mitochondrial pathophysiology; and (4) emerging treatments for mitochondrial dysfunction in critical illness.

[A woman in her forties with cancer, syncope and spasms]. / En kvinne i 40-årene med kreft, synkope og kramper.

A female in her forties with advanced incurable rectal cancer presented to our emergency department after loss of consciousness followed by brief myoclonic jerks in her legs. A cerebral MRI was normal. Her electrocardiogram showed a prolonged QTc interval of 596 milliseconds and hypokalemia was present. She had no family history of congenital long QT syndrome or of cardiovascular disease. She was not on any medication apart from having ingested 100 g caesium carbonate over the previous 11 days as an alternative cancer treatment. Caesium chloride is postulated to increase pH and thereby induce apoptosis in cancer cells. In treatment doses caesium competes with potassium for membrane transport proteins in the cardiac cell membrane and in the reabsorption tubuli of the kidneys. A result is hypokalemia shortly after depolarization during the cardiomyocytes' repolarisation phase or delayed post-depolarisation. Torsade de pointes ventricular arrhythmias, ventricular tachycardia, pump failure and death can follow. A few case reports of adverse effects from caesium ingestion have been published, as well as reports on how caesium is used in animal models to induce ventricular tachycardia, but the hazards of caesium ingestion and its long half-life are not well known in the medical care profession or among patients. As this patient's QTc interval normalised slowly to 413 milliseconds 60 days after stopping caesium ingestion, we consider caesium intoxication and convulsive syncope from a self-terminating ventricular tachycardia as the most probable aetiology. The main message from this case is that alternative medicine can have life-threatening side effects.

Torsades de pointes - a report of a case induced by caesium taken as a complementary medicine, and the literature review.

WHAT IS KNOWN AND OBJECTIVE: Complementary medicines are commonly used by many patients. Caesium, a complementary therapy said to be of benefit for cancer treatment, has been associated with cardiac arrhythmias in the literature. We report a case of caesium-induced torsades de pointes and provide an evidence review. CASE SUMMARY: A 46-year-old woman with syncope experienced torsades de pointes and cardiac arrest. Upon admission her QTc was 620 ms. The patient had taken caesium carbonate 10 g daily for 1 month prior to admission. The patient was successfully resuscitated and discharged home after 35 days in hospital. WHAT IS NEW AND CONCLUSION: Ten cases of caesium-induced cardiac arrhythmias have previously been reported in the literature. Treatment strategies differed significantly among the cases. However, all patients recovered from the event. Complementary and alternative medicines should not be overlooked as a potential cause of serious adverse events.

Prostate-specific antigen spikes with ¹³¹Cs brachytherapy. Is there a difference with other radioisotopes?

PURPOSE: There is a suggestion that a dose-rate effect exists for the prostate-specific antigen (PSA) spike after brachytherapy. ¹³¹Cs is a newer radioisotope with a half-life of 9.7 days that is being used for prostate brachytherapy. There is no published data on the PSA spike with this radioisotope and the goal of this study was to quantify PSA spikes with ¹³¹Cs and compare it with published data for other isotopes. METHODS AND MATERIALS: We have been maintaining a prospective database for all patients treated with ¹³¹Cs prostate brachytherapy at our institution. We selected patients for whom followup PSA was available for at least 24 months. The PSA spike was defined as an increase of 0.2 ng/mL, followed by a decline to prespike level. RESULTS: One hundred twenty-three patients had monotherapy, whereas 32 had external beam radiation therapy followed by a brachytherapy boost. Median followup was 36 months and mean numbers of PSAs obtained were 7. Forty-six (29.7%) patients had a PSA spike. The mean time and duration for the PSA spike were 12.5 and 8.8 months, respectively. The mean magnitude of increase and mean PSA value at increase were 0.63 and 1.56 ng/mL, respectively. CONCLUSIONS: The incidence of a PSA spike in our series is consistent with reported numbers for other radioisotopes. The occurrence of the spike at 12.5 months appears to be at the early end of the spectrum reported for (125)I, but the duration and magnitude are similar to other radioisotopes.

Clinical effects of cesium intake.

The knowledge about cesium metabolism and toxicity is sparse. Oral intake of cesium chloride has been widely promoted on the basis of the hypothesis referred to as "high pH cancer therapy", a complimentary alternative medicine method for cancer treatment. However, no properly confirmed tumor regression was reported so far in all probability because of neither theoretical nor experimental grounds for this proposal. The aim of the present review was to resume and discuss the material currently available on cesium salts and their applications in medicine. The presence of cesium in the cell does not guarantee high pH of its content, and there is no clinical evidence to support the claims that cancer cells are vulnerable to cesium. Cesium is relatively safe; signs of its mild toxicity are gastrointestinal distress, hypotension, syncope, numbness, or tingling of the lips. Nevertheless, total cesium intakes of 6 g/day have been found to produce severe hypokalemia, hypomagnesemia, prolonged QTc interval, episodes of polymorphic ventricular tachycardia, with or without torsade de pointes, and even acute heart arrest. However, full information on its acute and chronic toxicity is not sufficiently known. Health care providers should be aware of the cardiac complications, as a result of careless cesium usage as alternative medicine.

Cesium chloride-induced torsades de pointes.

The chloride salt of cesium, a group 1A element, is gaining popularity as an alternative treatment of advanced cancers. Cesium chloride has primarily been used in cardiovascular research for arrhythmogenesis in animals because of its potassium-blocking effects. The present report describes a 45-year-old woman with metastatic breast cancer who experienced repeated episodes of torsades de pointes polymorphic ventricular tachycardia after several months of oral cesium therapy. There was a clear temporal relationship between cesium ingestion and the arrhythmia, which later resolved following discontinuation of cesium therapy. Serial cesium plasma and whole blood levels were measured over the ensuing six months and pharmacokinetic analysis was performed.

Cesium chloride protects cerebellar granule neurons from apoptosis induced by low potassium.

Neuronal apoptosis plays a critical role in the pathogenesis of neurodegenerative disorders, and neuroprotective agents targeting apoptotic signaling could have therapeutic use. Here we report that cesium chloride, an alternative medicine in treating radiological poison and cancer, has neuroprotective actions. Serum and potassium deprivation induced cerebellar granule neurons to undergo apoptosis, which correlated with the activation of caspase-3. Cesium prevented both the activation of caspase-3 and neuronal apoptosis in a dose-dependent manner. Cesium at 8 mM increased the survival of neurons from 45 +/- 3% to 91 +/- 5% of control. Cesium's neuroprotection was not mediated by PI3/Akt or MAPK signaling pathways, since it was unable to activate either Akt or MAPK by phosphorylation. In addition, specific inhibitors of PI3 kinase and MAP kinase did not block cesium's neuroprotective effects. On the other hand, cesium inactivated GSK3beta by phosphorylation of serine-9 and GSK3beta-specific inhibitor SB415286 prevented neuronal apoptosis. These data indicate that cesium's neuroprotection is likely via inactivating GSK3beta. Furthermore, cesium also prevented H(2)O(2)-induced neuronal death (increased the survival of neurons from 72 +/- 4% to 89 +/- 3% of control). Given its relative safety and good penetration of the brain blood barrier, our findings support the potential therapeutic use of cesium in neurodegenerative diseases.

Blood and tissue concentration of cesium after exposure to cesium chloride: a report of two cases.

CONTEXT: Complementary alternative medicine therapies based on the use of cesium chloride preparations for the treatment of cancer and radiation poisoning, have generated therapeutic interest; but oral or intravenous administration of cesium chloride (CsCl) to cancer patients as an alternative mode of cancer therapy have not been approved by the US Food and Drug Administration (FDA). OBJECTIVE: Cesium (Cs) levels from human tissue were measured to determine exposure to an alternative medical treatment. Cesium levels are reported from two patients who were administered cesium chloride in conjunction with aloe vera as part of an alternative cancer treatment. DESIGN: The samples were analyzed by graphite furnace atomic absorption spectrometry with Zeeman background correction. As a reference, Cs was also determined in brain, liver, kidney, and whole blood from control case materials retrieved from the National Tissue Repository of the Armed Forces Institute of Pathology. RESULTS: High levels of cesium were found in brain, liver, kidney, bile, gastric content, and whole blood collected at autopsy as compared to reference levels. The administration of cesium chloride resulted in blood levels a factor of 1100 higher than normal. The highest Cs concentrations were found in the liver (1029 microg/g, dry wt), followed by the kidney (815 microg/g, dry wt) and brain (219 microg/g, dry wt). CONCLUSION: The high accumulation in the liver suggests that hepatotoxicity from Cs might be an initial presenting symptom in Cs-poisoning cases. This is the first report describing two cases with high Cs levels in human tissues.

Theoretical analysis and experimental evaluation of a Csl(TI) based electronic portal imaging system.

This article discusses the design and analysis of a portal imaging system based on a thick transparent scintillator. A theoretical analysis using Monte Carlo simulation was performed to calculate the x-ray quantum detection efficiency (QDE), signal to noise ratio (SNR) and the zero frequency detective quantum efficiency [DQE(0)] of the system. A prototype electronic portal imaging device (EPID) was built, using a 12.7 mm thick, 20.32 cm diameter, Csl(Tl) scintillator, coupled to a liquid nitrogen cooled CCD TV camera. The system geometry of the prototype EPID was optimized to achieve high spatial resolution. The experimental evaluation of the prototype EPID involved the determination of contrast resolution, depth of focus, light scatter and mirror glare. Images of humanoid and contrast detail phantoms were acquired using the prototype EPID and were compared with those obtained using conventional and high contrast portal film and a commercial EPID. A theoretical analysis was also carried out for a proposed full field of view system using a large area, thinned CCD camera and a 12.7 mm thick CsI(TI) crystal. Results indicate that this proposed design could achieve DQE(0) levels up to 11%, due to its order of magnitude higher QDE compared to phosphor screen-metal plate based EPID designs, as well as significantly higher light collection compared to conventional TV camera based systems.

Results of radical radiotherapy for recurrent endometrial cancer.

OBJECTIVES: The aims of this study were to determine the overall survival (OS) and local control (LC) achieved in patients developing a locoregional recurrence of endometrial carcinoma and to define those prognostic factors that predict for improved LC and OS. METHODS: Between 1984 and 1988, 958 women were referred to Princess Margaret Hospital (PMH) with a diagnosis of endometrial carcinoma. Of these, 58 were treated for recurrent disease with radical radiotherapy (RT). Forty-two were referred with recurrence and 16 relapsed during follow-up at PMH for their primary tumor. None had received prior RT. The majority (n = 49) were treated with combined external beam RT followed by an intracavitary cesium insertion. RESULTS: The median time to relapse from original diagnosis was 1.3 years (range 0.2-13.4 years). The actuarial 5- and 10-year OS was 53 and 41%, respectively. The respective results for LC were 65 and 62%. All end-points were measured from the time of relapse. The median total dose received was 81.5 Gy. Univariate analysis showed that favorable histological features at original diagnosis (<50% myometrial involvement, grade 1-2, P = 0.007) and Perez modified staging (P = 0.02) were significant predictors for OS. The Perez staging (P = 0.02) and size of recurrence (<2 cm versus >/=2 cm, P = 0.04) were predictors for LC. CONCLUSION: Patients with localized relapse of endometrial carcinoma in whom radical radiotherapy can be administered should be treated aggressively and may be cured in over half the cases treated. Pathological findings in the original surgical specimen, size of recurrent disease, and a modified vaginal carcinoma staging system are significant predictors of local pelvic control and survival.

[Brachytherapy in France in 1995. Final results of the national survey]. / La curiethérapie en France en 1995. Résultats définitifs de l'enquête nationale.

A survey questionnaire was sent to the 189 French departments of radiation Oncology and 166 responded by brachytherapy and 358 shielded rooms were available. In Low Dose Rate (LDR) 81 departments used Cesium sources (159 afterloaders, 1,060 sources). Iridium wires were used by 84 departments (673 meters used). Only six departments used other elements. Twenty-six departments were equipped with high dose rate after loaders (HDR) all of them also using LDR techniques for most of the patients. A total of 9,160 patients were treated: 7,868 with LDR and 1,292 with HDR. The common sites treated by LDR were uterovaginal (4,300), breast (1,415), head and neck (1,049), skin (610), anorectal (220) and urologic (70). HDR was used for vaginal cuff (628), bronchi (371), oesophagus (232). PDR just started (33 patients) for a feasibility trial. The rate of patients treated by brachytherapy is around 6-8% of the irradiated patients, but the indications vary is each department. The diffusion of the techniques, and new indications should increase the number of patients being treated by brachytherapy.

Reirradiation for recurrent nasopharyngeal carcinoma: factors affecting the therapeutic ratio and ways for improvement.

PURPOSE: To identify factors for maximizing local salvage and minimizing damages by reirradiation for recurrent nasopharyngeal carcinoma. METHODS AND MATERIALS: 654 patients with recurrent nasopharyngeal carcinoma treated by reirradiation during 1976-1992 were retrospectively analyzed. Various fractionation schedules had been used during primary treatment with the total dose ranging from 45.6-70 Gy, fractional dose (at different phases) 1.5-4.2 Gy, and overall time 36-101 days. The gap between the two courses ranged from 0.5-10.6 years. Eighty-two percent of patients were reirradiated with teletherapy, 6% brachytherapy, and 12% with both. For those treated with teletherapy alone, the total dose ranged from 7.5-70 Gy, fractional dose 1.8-5 Gy, and overall time 3-89 days. RESULTS: The 5-year actuarial local salvage and complication-free rates were 23% and 52%, respectively. Multivariate analyses showed that the extensiveness of local recurrence was the most significant factor affecting local salvage, while T-stage of primary tumor also influenced prognosis. Choice of method for reirradiation and fractional effect during both courses affected the risk of late complications. For patients treated by teletherapy alone, the hazard of local failure decreased by 1.7% per Biological Effective Dose (assuming alpha/beta ratio = 10) of the second course, while radiation factors during primary radiotherapy had no significant effect. On the other hand, the risk of late complications was predominantly affected by the primary treatment: the hazard increased by 4.2% per Biological Effective Dose (assuming alpha/beta ratio = 3) of the first course, while the corresponding impact of reirradiation failed to reach statistical significance. Length of the gap between the two courses did not affect the outcome. CONCLUSION: Early detection of local recurrence and adequate total dose by reirradiation are crucial for improving the chance of local salvage. Combination of teletherapy and brachytherapy should be considered whenever feasible and large fractional dose avoided to minimize late complications. Optimization of biological dose during primary treatment is important.

Mechanism of antiarrhythmic drug-induced changes in defibrillation threshold: role of potassium and sodium channel conductance.

OBJECTIVES: We sought to determine which ion current predominantly affects defibrillation outcomes by using specific pharmacologic probes (lidocaine [a sodium channel blocking agent] and cesium [an outward potassium channel blocking agent]) in 26 swine. BACKGROUND: The effect of a drug on sodium or potassium channel conductance, or both, may affect defibrillation threshold values. However, it is unknown which ion channel predominates. METHODS: Each pig was randomly assigned to one of four treatment groups with two treatment phases: group 1 = placebo (D5W) in treatment phase I followed by placebo plus cesium in treatment phase II (n = 6); group 2 = lidocaine followed by lidocaine plus placebo (n = 7); group 3 = lidocaine followed by lidocaine plus cesium (n = 7); group 4 = placebo followed by placebo plus placebo (n = 6). Defibrillation threshold values and electrocardiographic measurements were obtained at baseline and at treatment phases I and II. RESULTS: Lidocaine increased defibrillation threshold values from baseline by 71% in group 2 (p = 0.02) and by 92% in group 3 (p < 0.01). There were no changes in defibrillation threshold values from baseline to D5W in groups 1 and 4. When D5W was added to lidocaine in group 2 and D5W in group 4, there were no significant changes in defibrillation threshold values. However, when cesium was added to lidocaine in group 3, the elevated defibrillation threshold values (mean +/- SD) returned to baseline values (from 15.7 +/- 3.46 to 7.55 +/- 3.19 J, p < 0.01). Cesium added to D5W in group 1 also significantly reduced defibrillation threshold values from 7.10 +/- 1.27 to 4.14 +/- 1.75 J (p < 0.01). The effect of cesium on defibrillation threshold values was similar between groups 1 and 3, regardless of lidocaine, such that these values were reduced by 40 +/- 14% and 51 +/- 18%, respectively (p = 0.28). CONCLUSIONS: Cesium, through potassium blockade, reverses lidocaine-induced elevation in defibrillation threshold values. The magnitude of defibrillation threshold reduction when cesium was added to lidocaine was similar to the defibrillation threshold reduction when cesium was added to placebo. Thus, inhibiting outward potassium conductance and prolonging repolarization decreases defibrillation threshold values independent of sodium channel blockade.

Effects of high potassium and the bradycardic agents ZD7288 and cesium on heart rate of rabbits and guinea pigs.

The effects of 2 mM cesium (Cs+) and a novel selective bradycardic agent ZD7288 (0.64 microM) on sinoatrial Node (SAN) pacing rate were investigated in an isolated guinea pig SAN/atrial preparation, rabbit SAN preparation, and isolated working rabbit heart preparation. The effect of Cs+ and ZD7288 on the response of the preparations to increased extracellular potassium concentration ([K+]o) was also studied. Cs+ reduced beating frequency by 24% in isolated rabbit SAN (n = 16, p < 0.01) and by 21% in isolated working rabbit heart (n = 9, p < 0.01). ZD7288 decreased beating rate by 53% in guinea pig SAN (n = 7, p < 0.01) and by 38% in isolated working rabbit heart (n = 6, p < 0.01). In all three preparations, increased [K+]o significantly decreased the rate (p < 0.01) in normal Tyrode's solution but had no effect in the presence of Cs+ and caused tachycardia (p < 0.01) in the presence of ZD7288. We conclude that Cs+ and ZD7288 decrease pacing rate in rabbits and guinea pigs, possibly through modulation of the hyperpolarization-activated current (I(f)). ZD7288 is a more effective bradycardic agent than Cs+.

In vivo detection of a boron-neutron-capture agent in melanoma by proton observed 1H-10B double resonance.

The Cesium salt of BSSB (Cs4B24H22S2), a common boron-neutron-capture-therapy (BNCT) agent, was injected into M2R mouse melanoma xenografts, and detected in vivo by 1H-observed, 10B-edited NMR spectroscopy. The technique of spin-echo difference spectroscopy, in which a proton spin-echo is detected following the alternating presence and absence of a 10B 180 degrees pulse was used. This method provides much higher sensitivity than direct 10B NMR detection, and should thus be suitable for in vivo detection in patients about to undergo BNCT treatment, where the infused agents are 95% isotopically enriched in 10B.

Influence of microscopic residual disease on survival for stage IB and IIA carcinoma of the cervix following intracavitary irradiation.

From 1977 to 1982, 102 patients with Stage IB and IIA carcinoma of the cervix underwent preoperative intracavitary caesium irradiation followed by radical hysterectomy and pelvic lymphadenectomy at the Wessex Radiotherapy Centre. The actuarial 5-year survival rate for Stage IB is 80% and for Stage IIA is 62%. Patients who had microscopic residual disease in the hysterectomy specimen and negative nodes showed an actuarial 10-year survival rate of 62% as opposed to 82% in patients with no residual disease and negative nodes (P less than 0.05).

A comparison of remote afterloading and manually inserted caesium in the treatment of carcinoma of cervix.

Between 1982 and 1985, 240 patients with carcinoma of cervix were treated by radical radiotherapy, 140 using the selectron at the Royal Beatson Memorial Hospital (RBMH) and 100 with conventional caesium at the Western Infirmary. To allow for the increased dose rate to point A (1.2-1.4 Gy/h) during selectron treatment the overall intracavity dose was reduced by a mean value of 25%. Local recurrence rates were similar: 15% (selectron) against 14% (conventional). Three-year survival with local control was somewhat worse in the selectron group (77% against 81%) mainly because of an increased frequency of metastatic disease with local control (19.3% against 12.0%. The use of remote afterloading has not increased late morbidity (15.7% selectron, 15.0% conventional). The introduction of the selectron has brought about a marked reduction in staff radiation exposure. At the RBMH the mean recorded dose to nurses fell from 19 mSv in 1981 to 2.4 mSv in 1985.