Trends, challenges, and success factors in pharmaceutical portfolio management: Cognitive biases in decision-making and their mitigating measures.

Effective portfolio management is crucial for innovation and sustaining revenue in pharmaceutical companies. This article holistically reviews trends, challenges, and approaches to pharmaceutical portfolio management and focuses, in particular, on cognitive biases in portfolio decision-making. Portfolio managers strongly rely on external innovation and face increasing competitive pressure and portfolio complexity. The ability to address biases and make robust decisions remains a challenge. Portfolio management practitioners most commonly face confirmation bias, champion bias, or misaligned incentives, which they seek to mitigate through expert input, team diversity, and rewarding truth-seeking. Ultimately, highest-quality portfolio management decision-making could be enabled by three factors: high-quality data, structured review processes, and comprehensive mitigating measures against biases in decision-making.

New Generation of sGC Stimulators: Discovery of Imidazo[1,2-a]pyridine Carboxamide BAY 1165747 (BAY-747), a Long-Acting Soluble Guanylate Cyclase Stimulator for the Treatment of Resistant Hypertension.

Herein, we describe the identification, chemical optimization, and preclinical characterization of novel soluble guanylate cyclase (sGC) stimulators. Given the very broad therapeutic opportunities for sGC stimulators, new tailored molecules for distinct indications with specific pharmacokinetics, tissue distribution, and physicochemical properties will be required in the future. Here, we report the ultrahigh-throughput (uHTS)-based discovery of a new class of sGC stimulators from an imidazo[1,2-a]pyridine lead series. Through the extensive and staggered optimization of the initial screening hit, liabilities such as potency, metabolic stability, permeation, and solubility could be substantially improved in parallel. These efforts resulted ultimately in the discovery of the new sGC stimulators 22 and 28. It turned out that BAY 1165747 (BAY-747, 28) could be an ideal treatment alternative for patients with hypertension, especially those not responding to standard anti-hypertensive therapy (resistant hypertension). BAY-747 (28) demonstrated sustained hemodynamic effects up to 24 h in phase 1 studies.

No Placebo Effect beyond Regression to the Mean on the Six Minute Walk Test in Pulmonary Arterial Hypertension Trials.

In drug studies, patients are often included when the disease activity is high. This will make any treatment appear to lessen disease activity, although the improvement is biased by selection. This effect is known as regression towards the mean (RTM). We aimed at investigating drug trials in Pulmonary Arterial Hypertension (PAH) using the 6-minute walking distance test (6MWD) as a primary outcome for the phenomenon of RTM. An existing registry of 43 open label studies and 23 randomized controlled trials conducted between 1990 and 2009 was used as the data source. Data analysis was carried out for 18 randomized controlled trials (RCTs) and 24 open label studies out of this registry. Data were analyzed for verum and placebo arms of the RCTs separately, as well as for the open label arms. In the verum arms, the overall effect given as 33.2 m (95% CI: 25.7; 40.6]); 6MWD was slightly lower than the effect in the observational studies, with 44.6 m (95% CI: [25.4; 63.8]). After studying and interpreting the data, we found that regression towards the mean plays only a minor role in PAH studies. In particular, placebo effects in the RCTs were negligibly small, with a mean 6MWD of -2.5 m (95% CI: [-9.8; 4.7]) in the placebo arm. Therefore, our analysis indicates that results of non-randomized observational studies can be regarded as valid tools for gaining valid clinical effects in patients with PAH.

Future unmet medical need as a guiding principle for pharmaceutical R&D.

In pharmaceutical R&D the strategic focus is on addressing areas of high unmet medical need. 'Unmet medical need' is a widely used term in the healthcare sector but a common definition does not exist. The current standard of care determines the current unmet medical need, whereas the future unmet medical need (i.e., the unmet medical need when a new product reaches the market) and the extent to which the unmet need is addressed by the new product significantly impact its value. We have defined six dimensions as key drivers of (future) unmet medical needs of patients in a given setting. In the absence of quantifiable criteria, structured expert assessment techniques, such as the Delphi method, can guide portfolio strategies, especially for early-stage assets.

Discovery of the Soluble Guanylate Cyclase Stimulator Vericiguat (BAY 1021189) for the Treatment of Chronic Heart Failure.

The first-in-class soluble guanylate cyclase (sGC) stimulator riociguat was recently introduced as a novel treatment option for pulmonary hypertension. Despite its outstanding pharmacological profile, application of riociguat in other cardiovascular indications is limited by its short half-life, necessitating a three times daily dosing regimen. In our efforts to further optimize the compound class, we have uncovered interesting structure-activity relationships and were able to decrease oxidative metabolism significantly. These studies resulting in the discovery of once daily sGC stimulator vericiguat (compound 24, BAY 1021189), currently in phase 3 trials for chronic heart failure, are now reported.

Phosgene- and chlorine-induced acute lung injury in rats: comparison of cardiopulmonary function and biomarkers in exhaled breath.

This study compares changes in cardiopulmonary function, selected endpoints in exhaled breath, blood, and bronchoalveolar lavage fluid (BAL) following a single, high-level 30-min nose-only exposure of rats to chlorine and phosgene gas. The time-course of lung injury was systematically examined up to 1-day post-exposure with the objective to identify early diagnostic biomarkers suitable to guide countermeasures to accidental exposures. Chlorine, due to its water solubility, penetrates the lung concentration-dependently whereas the poorly water-soluble phosgene reaches the alveolar region without any appreciable extent of airway injury. Cardiopulmonary endpoints were continually recorded by telemetry and barometric plethysmography for 20h. At several time points blood was collected to evaluate evidence of hemoconcentration, changes in hemostasis, and osteopontin. One day post-exposure, protein, osteopontin, and cytodifferentials were determined in BAL. Nitric oxide (eNO) and eCO2 were non-invasively examined in exhaled breath 5 and 24h post-exposure. Chlorine-exposed rats elaborated a reflexively-induced decreased respiratory rate and bradycardia whereas phosgene-exposed rats developed minimal changes in lung function but a similar magnitude of bradycardia. Despite similar initial changes in cardiac function, the phosgene-exposed rats showed different time-course changes of hemoconcentration and lung weights as compared to chlorine-exposed rats. eNO/eCO2 ratios were most affected in chlorine-exposed rats in the absence of any marked time-related changes. This outcome appears to demonstrate that nociceptive reflexes with changes in cardiopulmonary function resemble typical patterns of mixed airway-alveolar irritation in chlorine-exposed rats and alveolar irritation in phosgene-exposed rats. The degree and time-course of pulmonary injury was reflected best by eNO/eCO2 ratios, hemoconcentration, and protein in BAL. Increased fibrin in blood occurred only in chlorine-exposed rats 1-day post-exposure. Hence, the analysis of NO and CO2 in exhaled breath, including endpoints in blood mirroring changes in the peripheral to pulmonary fluid distribution, seem to be sensitive diagnostic endpoints readily available for early prognostic assessment of severity of injury and efficacy of any chosen countermeasure.

Corticosteroids found ineffective for phosgene-induced acute lung injury in rats.

Various therapeutic regimes have been proposed with limited success for treatment of phosgene-induced acute lung injury (P-ALI). Corticoids were shown to be efficacious against chlorine-induced lung injury but there is still controversy whether this applies also to P-ALI. This study investigates whether different regimen of curatively administered budesonide (BUD, 10 mg/kg bw, i.p. bid; 100 mg/m(3)×30 min, nose-only inhalation), mometasone (MOM, 3 mg/kg bw, i.p. bid) and dexamethasone (DEX, 10, 30 mg/kg bw, i.p. bid), show efficacy to alleviate P-ALI. Efficacy of drugs was judged by nitric oxide (eNO) and carbon dioxide (eCO2) in exhaled air and whether these non-invasive biomarkers are suitable to assess the degree of airway injury (chlorine) relative to alveolar injury (phosgene). P-ALI related analyses included lung function (enhanced pause, Penh), morbidity, increased lung weights, and protein in bronchial alveolar lavage fluid (BALF) one day postexposure. One of the pathophysiological hallmarks of P-ALI was indicated by increased Penh lasting for approximately 20 h postexposure. Following the administration of BUD, this increase could be suppressed; however, without significant improvement in survival and lung edema (increased lung weights and BALF-protein). Collectively, protocols shown to be efficacious for chlorine (Chen et al., 2013) were ineffective and even increased adversity in the P-ALI model. This outcome warrants further study to seek for early biomarkers suitable to differentiate chlorine- and phosgene-induced acute lung injury at yet asymptomatic stage. The patterns of eNO and eCO2 observed following exposure to chlorine and phosgene may be suitable to guide the specialized clinical interventions required for each type of ALI.

Single high-dose dexamethasone and sodium salicylate failed to attenuate phosgene-induced acute lung injury in rats.

Life-threatening acute lung injury potentially occurs following high-level accidental exposures to phosgene gas. This situation was mirrored in rats exposed nose-only at 900-1000 mg phosgene/m(3)min. At this exposure level, previous studies on rats demonstrated sustained reflexively induced cardiopulmonary dysfunction and evidence of vascular fluid redistribution. These findings challenge the currently applied treatment strategies to mitigate the presumed non-cardiogenic lung edema by steroidal or non-steroidal anti-inflammatory drugs. This study investigates whether high doses of curatively administered dexamethasone (DX; 100 mg/kg bw, ip) and sodium salicylate (SS; 200 mg/kg bw, ip), alone or in combination, show efficacy to mitigate the phosgene-induced lung edema. Exhaled nitric oxide (eNO), animal morbidity and mortality, and increased lung weights one day postexposure served as endpoints of lung injury and drug efficacy. When applying this dosing regimen, SS showed minimal (if any) efficacy while DX, alone or in combination with SS, substantially aggravated the emerging lung edema (lung weights) with 40% mortality. The degree of acute lung injury (ALI) was mirrored by increased eNO. Its direct relationship to ALI-severity was evidenced by decreased eNO following NO-synthetase inhibitor administration (aminoguanidine-aerosol) and associated mitigation of ALI. All non-treated phosgene-exposed as well as treated but non-phosgene-exposed rats survived. This experimental evidence suggests that high-dose corticoid treatments may aggravate the pulmonary toxicity of phosgene. Similarly, this outcome supports the supposition that non-inflammatory, cardiogenic and/or neurogenic factors play a role in this type of acute lung injury.

Rat models of acute lung injury: exhaled nitric oxide as a sensitive, noninvasive real-time biomarker of prognosis and efficacy of intervention.

Exhaled nitric oxide (eNO) has received increased attention in clinical settings because this technique is easy to use with instant readout. However, despite the simplicity of eNO in humans, this endpoint has not frequently been used in experimental rat models of septic (endotoxemia) or irritant acute lung injury (ALI). The focus of this study is to adapt this method to rats for studying ALI-related lung disease and whether it can serve as instant, non-invasive biomarker of ALI to study lung toxicity and pharmacological efficacy. Measurements were made in a dynamic flow of sheath air containing the exhaled breath from spontaneously breathing, conscious rats placed into a head-out volume plethysmograph. The quantity of eNO in exhaled breath was adjusted (normalized) to the physiological variables (breathing frequency, concentration of exhaled carbon dioxide) mirroring pulmonary perfusion and ventilation. eNO was examined on the instillation/inhalation exposure day and first post-exposure day in Wistar rats intratracheally instilled with lipopolysaccharide (LPS) or single inhalation exposure to chlorine or phosgene gas. eNO was also examined in a Brown Norway rat asthma model using the asthmagen toluene diisocyanate (TDI). The diagnostic sensitivity of adjusted eNO was superior to the measurements not accounting for the normalization of physiological variables. In all bioassays - whether septic, airway or alveolar irritant or allergic, the adjusted eNO was significantly increased when compared to the concurrent control. The maximum increase of the adjusted eNO occurred following exposure to the airway irritant chlorine. The specificity of adjustment was experimentally verified by decreased eNO following inhalation dosing of the non-selective nitric oxide synthase inhibitor amoniguanidine. In summary, the diagnostic sensitivity of eNO can readily be applied to spontaneously breathing, conscious rats without any intervention or anesthesia. Measurements are definitely improved by accounting for the disease-related changes in exhaled CO2 and breathing frequency. Accordingly, adjusted eNO appears to be a promising methodological improvement for utilizing eNO in inhalation toxicology and pharmacological disease models with fewer animals.

Lipopolysaccharide-induced acute lung injury in rats: comparative assessment of intratracheal instillation and aerosol inhalation.

Acute lung injury (ALI) has many possible etiopathologies and is characterized by acute diffuse lung damage with poor prognosis. Lipopolysaccharide (LPS) is widely used as septic model of ALI in pharmacological research. This study compares intratracheal bolus instillation (IT) with dose-adjusted aerosol inhalation (IH) of LPS in Wistar rats using both non-invasive and terminal endpoints. The former comprised exhaled nitric oxide (NOE) and 'enhanced pause' (Penh) both measured in spontaneous breathing conscious rats. Terminal endpoints included lung weights, LDH, protein, total cell counts, and cytodifferentiation in bronchoalveolar lavage (BAL). Measurements were made 1, 3, 7, and 14 days after IT instillation (5 mg LPS/kg body weight) or 6-hour directed-flow nose-only inhalation exposure to respirable LPS-aerosol at 100 mg/m(3) (thoracic dose: 2.6 mgLPS/kg body weight). Controls received saline (IT) or air only (IH). LDH and protein were significantly different from the control in the LPS-IH group (days 1 and 3) with a somewhat inconclusive outcome in the LPS-IT group due to the effects occurring in the control. Total cell counts were equally elevated with similar time-course changes in the LPS-IT and -IH groups. Polymorphonuclear neutrophils (PMNs) were indistinguishable amongst LPS-dosed rats. Again, IT-dosed control rats displayed markedly higher background levels than those dosed by inhalation. Similarly NOE was significantly elevated on post-LPS day 1 as was Penh. In summary, the LPS-aerosol dose delivered by nose-only exposure over 6 h was equally potent as the 2-times higher LPS-IT bolus dose on post-LPS day 1 with somewhat faster recovery thereafter. The climax and discriminatory power of the non-invasive endpoints matched those determined terminally. This supports the conclusion that the pharmacological efficacy and side effects of inhalation pharmaceuticals designed to mitigate ALI can better be identified by LPS-aerosol than by LPS-IT. Non-invasive time-course measurements may deliver apt information both on the efficacious dose as well as the dosing intervals required to maintain the targeted efficacy using a minimum of experimental animals. The outcome of this comparative study supports the conclusion that the inhalation route produces a more uniform type of injury at lower, more meaningful dosages. When designing studies for screening of effective drugs this mode of delivery appears to better approximate the human condition with less dosimetric uncertainty, less experimental variability and better characterization of what was actually delivered to the entire respiratory tract.

Brain temperature by Biosensor Imaging of Redundant Deviation in Shifts (BIRDS): comparison between TmDOTP5- and TmDOTMA-.

Chemical shifts of complexes between paramagnetic lanthanide ions and macrocyclic chelates are sensitive to physiological variations (of temperature and/or pH). Here we demonstrate utility of a complex between thulium ion (Tm(3+)) and the macrocyclic chelate 1,4,7,10-tetramethyl 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate (or DOTMA(4-)) for absolute temperature mapping in rat brain. The feasibility of TmDOTMA(-) is compared with that of another Tm(3+)-containing biosensor which is based on the macrocyclic chelate 1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetrakis(methylene phosphonate) (or DOTP(8-)). In general, the in vitro and in vivo results suggest that Biosensor Imaging of Redundant Deviation in Shifts (BIRDS) which originate from these agents (but exclude water) can provide temperature maps with good accuracy. While TmDOTP(5-) emanates three major distinct proton resonances which are differentially sensitive to temperature and pH, TmDOTMA(-) has a dominant pH-insensitive proton resonance from a -CH(3) group to allow higher signal-to-noise ratio (SNR) temperature assessment. Temperature (and pH) sensitivities of these resonances are practically identical at low (4.0T) and high (11.7T) magnetic fields and at nominal repetition times only marginal SNR loss is expected at the lower field. Since these resonances have extremely short relaxation times, high-speed chemical shift imaging (CSI) is needed to detect them. Repeated in vivo CSI scans with BIRDS demonstrate excellent measurement stability. Overall, results with TmDOTP(5-) and TmDOTMA(-) suggest that BIRDS can be reliably applied, either at low or high magnetic fields, for functional studies in rodents.

Brain temperature and pH measured by (1)H chemical shift imaging of a thulium agent.

Temperature and pH are two of the most important physiological parameters and are believed to be tightly regulated because they are intricately related to energy metabolism in living organisms. Temperature and/or pH data in mammalian brain are scarce, however, mainly because of lack of precise and non-invasive methods. At 11.7 T, we demonstrate that a thulium-based macrocyclic complex infused through the bloodstream can be used to obtain temperature and pH maps of rat brain in vivo by (1)H chemical shift imaging (CSI) of the sensor itself in conjunction with a multi-parametric model that depends on several proton resonances of the sensor. Accuracies of temperature and pH determination with the thulium sensor - which has a predominantly extracellular presence - depend on stable signals during the course of the CSI experiment as well as redundancy for temperature and pH sensitivities contained within the observed signals. The thulium-based method compared well with other methods for temperature ((1)H MRS of N-acetylaspartate and water; copper-constantan thermocouple wire) and pH ((31)P MRS of inorganic phosphate and phosphocreatine) assessment, as established by in vitro and in vivo studies. In vitro studies in phantoms with two compartments of different pH value observed under different ambient temperature conditions generated precise temperature and pH distribution maps. In vivo studies in alpha-chloralose-anesthetized and renal-ligated rats revealed temperature (33-34 degrees C) and pH (7.3-7.4) distributions in the cerebral cortex that are in agreement with observations by other methods. These results show that the thulium sensor can be used to measure temperature and pH distributions in rat brain in vivo simultaneously and accurately using Biosensor Imaging of Redundant Deviation in Shifts (BIRDS).

Regional temperature changes in the brain during somatosensory stimulation.

Time-dependent variations in the brain temperature (Tt) are likely to be caused by fluctuations of cerebral blood flow (CBF) and cerebral metabolic rate of oxidative consumption (CMRO2) both of which are seemingly coupled to alterations in neuronal activity. We combined magnetic resonance, optical imaging, temperature sensing, and electrophysiologic methods in alpha-chloralose anesthetized rats to obtain multimodal measurements during forepaw stimulation. Localized changes in neuronal activity were colocalized with regional increases in Tt (by approximately 0.2%), CBF (by approximately 95%), and CMRO2 (by approximately 73%). The time-to-peak for Tt (42+/-11 secs) was significantly longer than those for CBF and CMRO2 (5+/-2 and 18+/-4 secs, respectively) with a 2-min stimulation. Net heat in the region of interest (ROI) was modeled as being dependent on the sum of heats attributed to changes in CMRO2 (Qm) and CBF (Qf) as well as conductive heat loss from the ROI to neighboring regions (Qc) and to the environment (Qe). Although tissue cooling because of Qf and Qc can occur and are enhanced during activation, the net increase in Tt corresponded to a large rise in Qm, whereas effects of Qe can be ignored. The results show that Tt increases slowly (by approximately 0.1 degrees C) during physiologic stimulation in alpha-chloralose anesthetized rats. Because the potential cooling effect of CBF depends on the temperature of blood entering the brain, Tt is mainly affected by CMRO2 during functional challenges. Implications of these findings for functional studies in awake humans and temperature regulation are discussed.

A multiparametric assessment of oxygen efflux from the brain.

A quantitative understanding of unidirectional versus net extraction of oxygen in the brain is required because an important factor in calculating oxidative metabolism by calibrated functional magnetic resonance imaging (fMRI) as well as oxygen inhalation methods of positron emission tomography (15O2-PET) and nuclear magnetic resonance (17O2-NMR)) is the degree of oxygen efflux from the brain back into the blood. Because mechanisms of oxygen transport from blood to brain are dependent on cerebral metabolic rate of oxygen consumption (CMRO2), cerebral blood flow (CBF), and oxygen partial pressure (pO2) values in intravascular (Piv) and extravascular (Pev) compartments, we implemented multimodal measurements of these parameters into a compartmental model of oxygen transport and metabolism (i.e., hemoglobin-bound oxygen, oxygen dissolved in plasma and tissue spaces, oxygen metabolized in the mitochondria). In the alpha-chloralose anesthetized rat brain, we used magnetic resonance (7.0 T) and fluorescence quenching methods to measure CMRO2 (2.5+/-1.0 micromol/g min), CBF (0.7+/-0.2 mL/g min), Piv (74+/-10 mm Hg), and Pev (16+/-5 mm Hg) to estimate the degree of oxygen efflux from the brain. In the axially distributed compartmental model, oxygen molecules in blood had two possible fates: enter the tissue space or remain in the same compartment; while in tissue there were three possible fates: enter the blood or the mitochondrial space, or remain in the same compartment. The multiparametric results indicate that the probability of unmetabolized (i.e., dissolved) oxygen molecules reentering the blood from the tissue is negligible and thus its inclusion may unnecessarily complicate calculations of CMRO2 for 15O-PET, 17O-NMR, and calibrated fMRI methods.

Late results after PTCA for coronary stenosis after the arterial switch procedure for transposition of the great arteries.

BACKGROUND: The arterial switch operation has become the surgical approach of choice for d-transposition of the great arteries, but there is an increased awareness of adverse sequelae in some survivors. Long-term patency and normal function of the translocated coronary arteries must be achieved. It is reported that dependent of the prior coronary status, 3% to 11% of all survivors have proximal coronary stenosis or complete occlusion develop after arterial switch operations. However, treatment of these stenoses is still a matter of debate. Late results after percutaneous transluminal coronary angioplasty (PTCA) for coronary stenosis after the arterial switch operation for d-transposition of the great arteries are reported. METHODS: Seven children after arterial switch operation for d-transposition of the great arteries who had subsequently undergone PTCA for coronary stenosis were angiographically re-evaluated 3 to 15 months after the initial PTCA and again after 3 to 5 years. RESULTS: All children survived the initial PTCA procedure. There were no late deaths. The degree of stenosis before PTCA ranged from 74% to 97%; immediately after PTCA from 5% to 10%; at 3 to 15 months after PTCA from zero to 6%; and at 3 to 5 years after PTCA from zero to 3%. Three to 5 years after PTCA all children showed normal development of the treated coronary artery. CONCLUSIONS: Primary PTCA of stenotic proximal coronary arteries after the arterial switch procedure for d-transposition of the great arteries seems to be an effective treatment with excellent long-term results.

Variability analysis of oscillatory airway resistance in children.

Testing pulmonary function in preschool children is problematic since individual cooperation is often insufficient to yield adequate results. This is especially the case when repetitive measurements are carried out, e.g., during provocation tests in order to diagnose bronchial hyperresponsiveness. We therefore sought to determine whether the variability of the oscillatory airway resistance, which can be measured with minimal patient cooperation, might serve as an approach to separate asymptomatic children with asthma from age-matched healthy controls. Monofrequent forced oscillation technique was used to measure the oscillatory resistance (Ros) continuously at a repetition rate of 10 Hz. Forty consecutive values of Ros at the end of expiration (Ros(pe)) and at the end of inspiration (Ros(pi)) were used to calculate variability measures [standard deviation (SD), averaged deviation (LD), root mean square successive differences (RMSSD)] known from heart rate variability analysis to describe the airway diameter variability in 36 asthmatics and 21 healthy controls. Airway diameter variability of Ros(pi) and Ros(pe) as expressed by SD from the mean (P = 0.01 and 0.05, respectively), from LD (P = 0.01 and 0.21, respectively) and from the RMSSD (P = 0.006 and 0.03, respectively) was greater in patients with asthma. Mean values of Ros(pi) and Ros(pe) were not different between groups. Airway diameter variability is higher in asymptomatic children with asthma than in healthy controls. Future research should evaluate whether the measurement of the variability of Ros(pi), which does not require the patient's cooperation, can give similar information as challenge tests with respect to bronchial hyperresponsiveness.

A novel approach for selective brain cooling: implications for hypercapnia and seizure activity.

OBJECTIVE: During selective brain cooling (SBC) the brain temperature (TB) is reduced while the core temperature (TC) remains unchanged. This animal study investigated changes in brain temperature induced by a novel approach of cooling the brain from the pharynx (pSBC) and whether these temperature changes are related to commonly encountered clinical situations (i.e., seizure activity and hypercapnia). DESIGN: Experimental animal study. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: pSBC was achieved by a heat exchanger placed in the pharynx; hypercapnia and seizure activity were induced by adding CO2 to the respiratory gases and by intravenous injection of bicuculline, respectively. MEASUREMENTS AND RESULTS: TB, TC, and pharynx (TP) were measured continuously with thermocouples. During pSBC TB declined significantly from 36.9+/-0.67 degrees C to 33.1+/-1.23 degrees C. There was a trend towards lower TC during pSBC (from 36.9+/-0.70 to 36.4+/-1.2 degrees C). TP during pSBC was 29.1+/-2.19 degrees C. From the lowest achieved pSBC temperature TB rose during CO2 challenge by 1.22+/-0.67 degrees C (vs. 0.85+/-0.34 degrees C in non-SBC controls). From the lowest pSBC temperature during seizure activity TB rose by 2.08+/-0.35 degrees C (vs. 1.15+/-0.55 degrees C in non-SBC controls). CONCLUSIONS: Significant cooling of the cortex can be achieved by pSBC in a rat rodent model. Marked increases in TB with hypercapnia and with seizure activity were observed. These results may have implications for cooling methods in clinical settings. For example, pSBC may offer distinct advantages over alternative methods such as whole-body cooling and externally implemented SBC.

Outcome of coma in children.

Coma following a hypoxic-ischemic event is a serious condition and common reason for admission to the pediatric intensive care unit. Because coma has a high rate of mortality and morbidity in children, and the clinician may be unsure of the outcome very early in the course, it is important to have strategies to define prognosis. Although most studies have been conducted in adults, we review factors predicting outcome from coma of nontraumatic causes in infants and children. We consider the relation between physical findings, commonly accessible laboratory tools, and outcome, and comment on some newer techniques that may become more available for clinical purposes.

Brain temperature measured by 1H-NMR in conjunction with a lanthanide complex.

In vivo data on temperature distributions in the intact brain are scarce, partly due to lack of noninvasive methods for the region of interest. NMR has been exploited for probing a variety of brain activities in vivo noninvasively within the region of interest. Here we report the use of a thulium-based thermometric sensor, infused through the blood, for monitoring absolute temperature in rat brain in vivo by (1)H-NMR and validated by direct temperature measurements with thermocouple wires. Because the (1)H chemical shifts also demonstrate pH sensitivity, detection of multiple resonances was used to measure both temperature and pH simultaneously with high sensitivity. Examination of blood plasma and cerebral spinal fluid samples removed from rats infused with the thermometric sensor suggests that the complex, despite its negative charge, crosses the blood-brain barrier to enter the extracellular milieu. In the future, the thulium-based thermometric sensor may be used for monitoring temperature (and pH) distributions throughout the entire brain, examining response to therapy and evaluating changes induced by alterations in neuronal activity.

Complicated nosocomial pneumonia due to Legionella pneumophila in an immunocompromised child.

An immunocompromised child developed necrotizing pneumonia with BAL cultures growing Legionella pneumophila resistant to treatment, including erythromycin and rifampicin. Ciprofloxacin and clarithromycin reversed the clinical course; their use as first-line drugs is justifiable and a high index of suspicion for the occurrence of legionellosis is warranted.