Simulating the low-temperature, metastable electrochromism of Photosystem I: Applications to Thermosynechococcus vulcanus and Chroococcidiopsis thermalis.

Low-temperature, metastable electrochromism has been used as a tool to assign pigments in Photosystem I (PS I) from Thermosynechococcus vulcanus and both the white light and far-red light (FRL) forms of Chroococcidiopsis thermalis. We find that a minimum of seven pigments is required to satisfactorily model the electrochromism of PS I. Using our model, we provide a short list of candidates for the chlorophyll f pigment in FRL C. thermalis that absorbs at 756 nm, whose identity, to date, has proven to be controversial. Specifically, we propose the linker pigments A40 and B39 and two antenna pigments A26 and B24 as defined by crystal structure 1JB0. The pros and cons of these assignments are discussed, and we propose further experiments to better understand the functioning of FRL C. thermalis.

Rothia aeria vertebral discitis/osteomyelitis in an immunocompetent adult: Case report and literature review.

Rothia aeria is a gram-positive, pleomorphic bacteria forming part of human oral microflora usually only causing periodontal and dental infections. We describe the case of a 68-year-old immunocompetent male with lumbar vertebral discitis/osteomyelitis caused by R. aeria. A review of the literature demonstrated seventeen cases of non-dental R. aeria infection of which only six were in immunocompetent individuals. This is the first reported case of R. aeria vertebral discitis/osteomyelitis.

Tobramycin pharmacokinetics in patients with cystic fibrosis before and after bilateral lung transplantation.

STUDY OBJECTIVES: To compare the pharmacokinetics (PK) of tobramycin in patients with cystic fibrosis (CF) before and after bilateral lung transplantation, in order to evaluate optimal dosing practices post transplant. DESIGN: Retrospective, single-center, chart review study, in which tobramycin concentrations from CF patients were used to calculate PK parameters, including elimination rate constant, half-life, volume of distribution (Vd), area under the curve (AUC), and clearance before and after lung transplantation. SETTING: Medical school-affiliated teaching hospital. PATIENTS: Eight patients with CF, who received a bilateral lung transplant from January 1, 2005 through August 1, 2009 (4 males, 4 females; mean age 26.3 years). INTERVENTIONS: None. MAIN RESULTS: Sixty-nine sets of pre- (n=52) and post transplant (n=17) tobramycin concentrations were available. PK parameters were significantly altered post transplant. Elimination rate constant decreased 38% from 0.26±0.1 to 0.16±0.1 h(-1) (P<0.001), with a related increase of 200% in half-life from 2.8±0.8 to 8.4±8.7 h (P<0.001). Clearance decreased 25% post transplant from 67.3±32.3 to 50.2±15.9 mL/min (P=0.04). No statistically significant change occurred in AUC or Vd after transplant, although a trend was seen toward increased Vd. Dosage requirements after transplantation were significantly lower, 10.7±2.5 and 7.6±1.6 mg/kg/day, pre and post transplant, respectively (P<0.001). Concentrations were also evaluated in 2 time periods: 0-3 weeks and ≥6 weeks post transplant, based on available data. Clearance and Vd ≥6 weeks post transplant did not significantly differ from pre-transplant values (P=0.28 and 0.54, respectively), suggesting that these changes may be temporary. CONCLUSIONS: The results suggest that tobramycin PK are altered in patients with CF after bilateral lung transplantation, although no clear trend was seen owing to inter-patient variability. We propose that PK parameters should be reassessed during each treatment course post transplant.

Contributions of neuroimaging, balance testing, electrophysiology and blood markers to the assessment of sport-related concussion.

OBJECTIVE: To review the diagnostic tests and investigations used in the management of sports concussion, in the adult and paediatric populations, to (a) monitor the severity of symptoms and deficits, (b) track recovery and (c) advance knowledge relating to the natural history and neurobiology of the injury. DESIGN: Qualitative literature review of the neuroimaging, balance testing, electrophysiology, blood marker and concussion literature. INTERVENTION: PubMed and Medline databases were reviewed for investigations used in the management of adult and paediatric concussion, including structural imaging (computerised tomography, magnetic resonance imaging, diffusion tensor imaging), functional imaging (single photon emission computerised tomography, positron emission tomography, functional magnetic resonance imaging), spectroscopy (magnetic resonance spectroscopy, near infrared spectroscopy), balance testing (Balance Error Scoring System, Sensory Organization Test, gait testing, virtual reality), electrophysiological tests (electroencephalography, evoked potentials, event related potentials, magnetoencephalography, heart rate variability), genetics (apolipoprotein E4, channelopathies) and blood markers (S100, neuron-specific enolase, cleaved Tau protein, glutamate). RESULTS: For the adult and paediatric populations, each test has been classified as being: (1) clinically useful, (2) a research tool only or (3) not useful in sports-related concussion. CONCLUSIONS: The current status of the diagnostic tests and investigations is analysed, and potential directions for future research are provided. Currently, all tests and investigations, with the exception of clinical balance testing, remain experimental. There is accumulating research, however, that shows promise for the future clinical application of functional magnetic resonance imaging in sport concussion assessment and management.

The response of adenosine 3',5'-monophosphate to norepinephrine in the hypothalamus and pineal organ of female rats in proestrus or diestrus.

The response of cAMP to norepinephrine (NE) was measured in hypothalamic tissue and pineal glands of cycling female rats killed on the mornings of proestrus and diestrus (in 4-day cycles) or diestrus II (in 5-day cycles). The results from 4- or 5-day cycles were similar in all cases. The report of Weiss and Crayton that the response of adenylate cyclase in pineal homogenates to NE is reduced on proestrus was confirmed, and a similar but lesser reduction was also detected with intact pineal glands incubated in vitro. Chopped hypothalamic tissue incubated in vitro revealed a greater response of cAMP levels to NE on proestrus compared to diestrus in the anterior hypothalamic-preoptic area, but no significant changes in the middle or posterior hypothalamus. In an effort to reproduce the changes noted on proestrus, ovariectomized animals were injected with estradiol benzoate for 2 days, but no effects of the treatment on the cAMP response to NE were found. If the animals were also given reserpine, however, the estrogen was effective in reducing the response of pineal adenylate cyclase to NE. Possible explanations for these results and the potential significance of alterations in NE receptor systems for the control of gonadotropin release are discussed.

Norepinephrine is a possible neurotransmitter stimulating pulsatile release of luteinizing hormone-releasing hormone in the rhesus monkey.

The hypothesis that norepinephrine (NE) plays a facilitatory role in controlling the pulsatile release of LHRH was tested with a modified push-pull perfusion technique in conscious rhesus monkeys. The in vivo LHRH release in perfusate samples collected from the stalk-median eminence of ovariectomized females was pulsatile and synchronous with pulsatile LH release. Catecholamines measured in aliquots of perfusate samples revealed that in vivo NE release was also pulsatile and was synchronous with LHRH release. Local infusion of NE or methoxamine (an alpha 1-adrenergic stimulant) through a push cannula stimulated LHRH release, while iv injection of prazosin (an alpha 1-adrenergic blocker) suppressed LHRH release. It is concluded that NE is a possible neurotransmitter stimulating pulsatile LHRH release.

Neuroanatomical distribution of androgen and estrogen receptor-immunoreactive cells in the brain of the male roughskin newt.

Immunohistochemistry was used to investigate the neuroanatomical distribution of androgen and estrogen receptors in brains of adult male roughskin newts, Taricha granulosa, collected during the breeding season. Immunoreactive cells were found to be widely distributed in specific brain areas of this urodele amphibian. Androgen receptor-immunoreactive (AR-ir) cells were observed in the olfactory bulbs, habenula, pineal body, preoptic area, hypothalamus, interpeduncular nucleus, area acusticolateralis, cerebellum, and motor nuclei of the medulla oblongata. Estrogen receptor-immunoreactive (ER-ir) cells were found in the lateral septum, amygdala pars lateralis, pallium, preoptic area, hypothalamus, and dorsal mesencephalic tegmentum. This immunocytochemical study of the newt brain reveals AR-ir and ER-ir cells in several regions that have not been previously reported to contain androgen and estrogen receptors in non-mammalian vertebrates. Additionally, the distribution of AR-ir and ER-ir cells in the newt brain, in general, is consistent with previous studies, suggesting that the distribution of sex steroid receptor-containing neurons in some brain regions is relatively conserved among vertebrates.

Clinical pharmacokinetics in the 21st century. Does the evidence support definitive outcomes?

Clinical pharmacokinetics emerged as a clinical discipline in the late 1960s and early 1970s. Clinical pharmacokinetic monitoring (CPM) helped many pharmacists to enter the clinical arena, but the focus was more on the pharmacists and tools. With the widespread acceptance of pharmaceutical care and patient-focused pharmacy, we now must take a sobering look at how clinical pharmacokinetics fits into the pharmaceutical care process. The existing literature is laden with articles that evaluate the effect of CPM on surrogate end-points. Many pharmacists have also had personal experiences that attest to the usefulness of CPM. Decreased mortality, decreased length of treatment, decreased length of hospital stay, decreased morbidity, and decreased adverse effects from drug therapy have been examined in an effort to measure and evaluate the impact of CPM on patient outcomes. While many of these studies demonstrated significant positive outcomes, several showed that CPM did not have a significant impact on specific patient outcomes. A few studies even found a negative impact on specific patient outcomes. Ultimately, there is good evidence in only a few specific patient groups to support the benefit of CPM. Despite the limitations of data supporting the routine use of CPM in managing drug therapy in diverse populations, many pharmacists continue to expend considerable time and effort in this activity. We need to define those patients who are most likely to benefit from CPM and incorporate this into our provision of pharmaceutical care, while minimising the time and money spent on CPM that provides no value. In redefining the patients who will benefit from CPM, we need to critically re-evaluate clinical studies on the relationship between drug concentration and response. Similarly, we need to pay special attention to recent studies evaluating the impact of CPM on outcomes in specific subpopulations. In the absence of specific studies demonstrating the value of CPM in particular patients, we propose that a more comprehensive decision-making process be undertaken that culminates in the quintessential question: 'Will the results of the drug assay make a significant difference in the clinical decision-making process and provide more information than sound clinical judgement alone?' We also need to consider opportunities to expand the use of CPM for new drugs and where new evidence suggests benefit. Even when there is strong evidence that CPM is useful in managing therapy in particular patient groups, clinicians need to remember that the therapeutic range is no more than a confidence interval and, therefore, we need to 'treat the patient and not the level'. We need to incorporate the patient-specific and outcome-oriented principles of pharmaceutical care into our CPM, even as we utilise CPM as an essential tool in pharmaceutical care.

Absence of hyperactivity in lead-exposed developing rats.

It has been reported that postnatal lead treatment produces hyperactivity in rodents. Using rats, we attempted to extend these findings. Locomotor activity of offspring of lead-intubated and pair-fed control mothers was measured at 24-27 days of age, and no significant differences in reactivity or basal activity were found. Observational scoring of the animals at 28-29 and 35-36 days of age indicated that active behaviors were slightly reduced in the lead-treated rats. The brain lead concentrations of experimental animals were slightly reduced in the lead-treated rats. The brain lead concentrations of experimental animals were significantly elevated over controls. Estimates of statistical power indicated that behavioral effects of the magnitude reported in the literature would likely have been detected. The present results indicate that low-level lead exposure may not reliably produce hyperactivity in rodents. A review of the literature suggests that other data provide little support for a recently proposed rodent model of hyperactivity in children.

Pentobarbital inhibition of progesterone-induced behavioral estrus in ovariectomized guinea pigs.

Administration of pentobarbital inhibits the facilitatory effects of progesterone on the release of gonadotropins. In this experiment facilitatory effects of progesterone on lordosis behavior in guinea pigs were examined with pentobarbital anesthesia. Two major animal groups were subjects: one was short-term ovariectomized (2 weeks) and the other was long-term ovariectomized (several months). All animals received estradiol benzoate (6.6 mug s.c.) followed by progesterone (0.4 mg s.c.) 40 h later. Lordosis behavior was induced by the manual stimulation method of Young et al.29 Sodium pentobarbital (30 mg/kg) was injected 8,4 or 2 h before, simultaneously or 1, 2, 6, or 7 h after progesterone. Animals which received pentobarbital slept for 4.5-5 h with subsequent drowsiness for an additional 0.5-1 h. Pentobarbital injections given 8 h before progesterone had no effect on latency to the first lordosis or on other parameters of estrous behavior. However, pentobarbital delayed the onset of heat in estrogen treated ovariectomized guinea pigs when given 4 h before, 2 h before, or simultaneously with progesterone. The delay was directly related to the length of time the animals remained asleep after the progesterone injection, since estrous behavior was invariably displayed with the latency of controls after the animal awoke. Moreover, in animals which were awake for 1-2 h immediately after the progesterone injection before receiving pentobarbital, the latency of recovery from anesthesia to the first display of lordosis was about 1-1.5 h shorter than in the other pentobarbital groups. In contrast to the latency effects of pentobarbital, the duration of heat was unaffected by the anesthetic for all groups mentioned. In animals which received pentobarbital after they were already in heat, pentobarbital injection terminated heat and abolished it completely, since lordosis behavior was not displayed in the hours after recovery from anesthesia. Gross hypothalamic uptake of progesterone was not influenced by pentobarbital administration. Thus, it is tentatively concluded that an incubation period is necessary for progesterone to mediate the display of estrous behavior in the guinea pig in addition to the time necessary for neural uptake. The way in which pentobarbital interferes with the period of progesterone incubation is not currently known.

Prostaglandins, clonidine and sexual receptivity in the guinea pig.

Prostaglandins E1 and F2 alpha suppressed lordosis in ovariectomized guinea pigs brought into estrus with estradiol benzoate and progesterone. Pretreatment with clonidine prevented this action of the prostaglandins, but if the animals were first given prostaglandin and allowed to go out of estrus, then clonidine did not restore lordosis. In a previous study it was found that the abbreviation of estrus induced by copulation was also blocked by clonidine, again only if it were given before the inhibitory treatment. These results suggest tht prostaglandin, perhaps released from the female reproductive tract, could mediate the inhibitory effect of copulation, and radioimmunoassays of prostaglandin F2 alpha and its principal metabolite PGFM revealed substantial elevations in the concentrations of these materials in trunk blood after copulation. We discuss the possibility that prostaglandins may suppress sexual receptivity by interfering with an alpha-adrenergic mechanism.

Effects of ovarian steroids on serotonin metabolism within grossly dissected and microdissected brain regions of the ovariectomized rat.

Brain serotonin (5-HT) levels and accumulation rate within the dorsal raphe nucleus (DR) were elevated in ovariectomized (OVX) rats after ovarian steroid treatment, which consisted of estradiol benzoate (EB) followed by progesterone (P) 48 hr later. Some animals were also given the monoamine oxidase (MAO) inhibitor pargyline at designated times 10-40 min prior to sacrifice. Decapitation occurred 5 hr following the second steroid injection and 4-6 hr into the dark phase of a 14:10 light/dark cycle. Basal 5-HT levels and the rate of 5-HT accumulation (5-HTr) following MAO inhibition were estimated by radioenzymatic assay of brain tissue punched from frozen sections or dissected freehand. Within the DR, 5-HT levels and 5-HTr rates were respectively 13.8% (p less than 0.001) and 23.2% (p less than 0.025) higher in EB+P treated females compared with oil controls. Differences in basal 5-HT were found within the median raphe nucleus, but these were inconsistent from experiment to experiment. No differences were found in tissue immediately adjacent to these nuclear regions or within other brain regions including the ventral medial nucleus and suprachiasmatic nucleus of the hypothalamus. Increased levels of 5-HT were also found in grossly dissected tissue containing the mesencephalic raphe nuclei.

Concurrent adjacent meningioma and astrocytoma: a report of three cases and review of the literature.

Three patients presenting with an adjacent meningioma and astrocytoma are described. A review of the literature discusses several modes of neuroimaging and the difficulties in diagnosing simultaneous adjacent tumors. Aspects of the pathology and etiology of these tumors are also reviewed.

Biphasic effects of the antiserotonergic methysergide on lordosis in rats.

As also reported by other workers, the antiserotonergic drug methysergide was found to facilitate lordotic responding in estrogen primed, ovariectomized rats. A second dose of methysergide 24 hr after the first, however, failed to produce any increment in responding. Animals received daily estrogen injections in order to maintain a relatively constant level of priming. After several days of methysergide, a progesterone injection facilitated lordosis to the same degree as in controls receiving only saline and estrogen. When a second injection of progesterone was given 24 hr later, however, the animals failed to respond. In contrast, saline controls with this estrogen paradigm responded equally well to both progesterone injections. These results are discussed in terms of their bearing on possible serotonergic and non-serotonergic mechanisms by which progesterone may control lordosis.

The influence of alpha-receptors on lordosis in the female rat.

The alpha-adrenergic agonist clonidine suppressed lordotic responding in spayed female rats brought into heat by estrogen and progesterone. The suppression was blocked by the alpha-antagonist yohimbine, but not by phenoxybenzamine or pimozide. The suppression was blocked by the alpha-antagonist yohimbine, but not by phenoxybenzamine or pimozide. Phenoxybenzamine itself had no suppressive effect on lordosis, though yohimbine did under some conditions. These results argue against an important facilitatory influence of norepinephrine on lordosis in the rat. Further, in comparison with the quite different findings recently reported from the guinea pig, they offer support for the presence of two different kinds of alpha-adrenergic receptors in the brain with different physiological functions.

Copulation-induced abbreviation of estrus in the female guinea pig: block by clonidine.

In the female guinea pig, copulation produces a rapid inhibition of subsequent sexual receptivity. Injection of the alpha adrenergic agonist clonidine before mating blocked the early inhibitory effects of coital stimulation, while the serotonergic antagonist methysergide, and the dopaminergic antagonist pimozide were without effect. The effects of clonidine were prevented by pretreatment with the alpha adrenergic antagonist yohimbine. These results suggest that an adrenergic system is involved in the copulation-induced inhibition of receptivity and provide further evidence that such a system has an important facilitative role in the control of female sexual behavior in the guinea pig.

Comparison of creatinine clearance estimation methods in patients with trauma.

The abilities of a modified Cockcroft-Gault equation and the standard equation to estimate creatinine clearance (CLcr) in trauma patients were compared. The medical records of patients with stable renal function who had been treated for trauma and had had a 24-hour urine collection for creatinine measurement were reviewed. Creatinine concentrations in urine and serum were used to calculate the actual CLcr, which was normalized to 1.73 sq m. CLcr was estimated by the modified equation (which normalized body weight to 72 kg) and by the standard equation using ABW, IBW, and dosing body weight (DBW). Values derived with the standard equation were normalized to 1.73 sq m. The predictive performances of the modified and standard equations in estimating the actual CLcr were then compared. Fifty patients were enrolled. The standard equation using IBW or DBW produced estimates that differed significantly from the actual CLcr. The modified equation and the standard equation using ABW did not differ significantly in bias or precision, but both were significantly less biased than the standard equation using IBW or DBW. The only significant difference among equations in precision was between the modified equation (the more precise) and the standard equation using IBW. There were no clinically significant differences among methods in gentamicin dosing simulations. The modified Cockcroft-Gault equation can be used to estimate CLcr in trauma patients with stable renal function.

General versus subpopulation values in Bayesian prediction of aminoglycoside pharmacokinetics in hematology-oncology patients.

The predictive performance of Bayesian estimates incorporating pharmacokinetic values for hematology-oncology patients was compared with that of Bayesian estimates incorporating general population values. In study phase 1, medical records were reviewed for 50 adult patients with a hematologic or oncologic diagnosis who had received i.v. gentamicin or tobramycin. Aminoglycoside pharmacokinetic values were calculated for the patients by using a modified two-point Sawchuk-Zaske method, and the subpopulation mean for each variable was determined. In phase 2, data for 10 other hematology-oncology patients receiving aminoglycosides were entered into the Abbottbase Bayesian pharmacokinetics program. Aminoglycoside pharmacokinetic values and serum concentrations for each of these 10 patients were estimated, first using the program's general population values and then repeating the analysis using the subpopulation means for volume of distribution and renal clearance slope obtained in phase 1. The serum aminoglycoside concentrations predicted by each Bayesian method were compared with the actual peaks and troughs. Both the peak and trough predictions of the Abbottbase program using the subpopulation values for volume of distribution and renal clearance slope were significantly less biased than those predicted by the Abbottbase program incorporating the general population values. The methods did not differ significantly in precision. Use of subpopulation pharmacokinetic values in Bayesian predictions of serum aminoglycoside concentrations in hematology-oncology patients reduced bias significantly but had no significant effect on precision.

Referential cohesion and logical coherence of narration after right hemisphere stroke.

A group with right hemisphere dysfunction was compared to neurologically intact controls regarding the referential cohesion and logical coherence of narrative production. A somewhat varied sample of six stories was obtained with tasks of cartoon-elicited story-telling and auditory-oral retelling. We found deficits in the patient group with respect to referential cohesion, logical coherence, and accuracy of narration, but the occurrence of deficits depended on the condition in which narration was produced and, to some extent, on the particular story used in each condition. The primary implications of this study pertain to the attention given by researchers to the feature of discourse production being studied.

Accident reduction factors and causal inference in traffic safety studies: a review.

Accident reduction factors are used to predict the change in accident occurrence which a countermeasure can be expected to cause. Since ethical and legal obstacles preclude the use of randomized experiments when evaluating traffic safety improvements, empirical support for the causal effectiveness of accident countermeasures comes entirely from observational studies. Drawing on developments in causal inference initiated by Donald Rubin, it is argued here that the mechanism by which sites are selected for application of a countermeasure should be included as part of a study's data model, and that when important features of the selection mechanism are neglected, existing methods for estimating accident reduction factors become inconsistent. A promising, but neglected, way out of these difficulties lies in developing rational countermeasure selection methods which also support valid causal inference of countermeasure effects.