The control of alternative splicing by SRSF1 in myelinated afferents contributes to the development of neuropathic pain.

Neuropathic pain results from neuroplasticity in nociceptive neuronal networks. Here we demonstrate that control of alternative pre-mRNA splicing, through the splice factor serine-arginine splice factor 1 (SRSF1), is integral to the processing of nociceptive information in the spinal cord. Neuropathic pain develops following a partial saphenous nerve ligation injury, at which time SRSF1 is activated in damaged myelinated primary afferent neurons, with minimal found in small diameter (IB4 positive) dorsal root ganglia neurons. Serine arginine protein kinase 1 (SRPK1) is the principal route of SRSF1 activation. Spinal SRPK1 inhibition attenuated SRSF1 activity, abolished neuropathic pain behaviors and suppressed central sensitization. SRSF1 was principally expressed in large diameter myelinated (NF200-rich) dorsal root ganglia sensory neurons and their excitatory central terminals (vGLUT1+ve) within the dorsal horn of the lumbar spinal cord. Expression of pro-nociceptive VEGF-Axxxa within the spinal cord was increased after nerve injury, and this was prevented by SRPK1 inhibition. Additionally, expression of anti-nociceptive VEGF-Axxxb isoforms was elevated, and this was associated with reduced neuropathic pain behaviors. Inhibition of VEGF receptor-2 signaling in the spinal cord attenuated behavioral nociceptive responses to mechanical, heat and formalin stimuli, indicating that spinal VEGF receptor-2 activation has potent pro-nociceptive actions. Furthermore, intrathecal VEGF-A165a resulted in mechanical and heat hyperalgesia, whereas the sister inhibitory isoform VEGF-A165b resulted in anti-nociception. These results support a role for myelinated fiber pathways, and alternative pre-mRNA splicing of factors such as VEGF-A in the spinal processing of neuropathic pain. They also indicate that targeting pre-mRNA splicing at the spinal level could lead to a novel target for analgesic development.

The degree of acute descending control of spinal nociception in an area of primary hyperalgesia is dependent on the peripheral domain of afferent input.

Descending controls of spinal nociceptive processing play a critical role in the development of inflammatory hyperalgesia. Acute peripheral nociceptor sensitization drives spinal sensitization and activates spino-supraspinal-spinal loops leading to descending inhibitory and facilitatory controls of spinal neuronal activity that further modify the extent and degree of the pain state. The afferent inputs from hairy and glabrous skin are distinct with respect to both the profile of primary afferent classes and the degree of their peripheral sensitization. It is not known whether these differences in afferent input differentially engage descending control systems to different extents or in different ways. Injection of complete Freund's adjuvant resulted in inflammation and swelling of hairy hind foot skin in rats, a transient thermal hyperalgesia lasting <2 h, and longlasting primary mechanical hyperalgesia (≥7 days). Much longer lasting thermal hyperalgesia was apparent in glabrous skin (1 h to >72 h). In hairy skin, transient hyperalgesia was associated with sensitization of withdrawal reflexes to thermal activation of either A- or C-nociceptors. The transience of the hyperalgesia was attributable to a rapidly engaged descending inhibitory noradrenergic mechanism, which affected withdrawal responses to both A- and C-nociceptor activation and this could be reversed by intrathecal administration of yohimbine (α-2-adrenoceptor antagonist). In glabrous skin, yohimbine had no effect on an equivalent thermal inflammatory hyperalgesia. We conclude that acute inflammation and peripheral nociceptor sensitization in hind foot hairy skin, but not glabrous skin, rapidly activates a descending inhibitory noradrenergic system. This may result from differences in the engagement of descending control systems following sensitization of different primary afferent classes that innervate glabrous and hairy skin.

Magnolol causes alterations in the cell cycle in androgen insensitive human prostate cancer cells in vitro by affecting expression of key cell cycle regulatory proteins.

Prostate cancer, one of the most common cancers in the Western world, affects many men worldwide. This study investigated the effects of magnolol, a compound found in the roots and bark of the magnolia tree Magnolia officinalis, on the behavior of 2 androgen insensitive human prostate cancer cell lines, DU145 and PC3, in vitro. Magnolol, in a 24-h exposure at 40 and 80 µM, was found to be cytotoxic to cells. Magnolol also affected cell cycle progression of DU145 and PC3 cells, resulting in alterations to the cell cycle and subsequently decreasing the proportion of cells entering the G2/M-phase of the cell cycle. Magnolol inhibited the expression of cell cycle regulatory proteins including cyclins A, B1, D1, and E, as well as CDK2 and CDK4. Protein expression levels of pRBp107 decreased and pRBp130 protein expression levels increased in response to magnolol exposure, whereas p16(INK4a), p21, and p27 protein expression levels were apparently unchanged post 24-h exposure. Magnolol exposure at 6 h did increase p27 protein expression levels. This study has demonstrated that magnolol can alter the behavior of androgen insensitive human prostate cancer cells in vitro and suggests that magnolol may have potential as a novel anti-prostate cancer agent.

Protecting and connecting landscapes stabilizes populations of the Endangered savannah elephant.

The influence of protected areas on the growth of African savannah elephant populations is inadequately known. Across southern Africa, elephant numbers grew at 0.16% annually for the past quarter century. Locally, much depends on metapopulation dynamics-the size and connections of individual populations. Population numbers in large, connected, and strictly protected areas typically increased, were less variable from year to year, and suffered less from poaching. Conversely, populations in buffer areas that are less protected but still connected have more variation in growth from year to year. Buffer areas also differed more in their growth rates, likely due to more threats and dispersal opportunities in the face of such dangers. Isolated populations showed consistently high growth due to a lack of emigration. This suggests that "fortress" conservation generally maintains high growth, while anthropogenic-driven source-sink dynamics within connected conservation clusters drive stability in core areas and variability in buffers.

Design, synthesis, computational molecular docking studies of novel heterocyclics bearing 1,2,4-triazole, 1,3,4-oxadiazole conjugates as potent antibacterial and antitubercular agents.

Herein, we report the synthesis, and characterization of a new series of 1,3,4-oxadiazole and 1,2,4-triazole derivatives based on azaindole acetamides and assigned as potential antibacterial and antitubercular substances. The structures of these compounds were established by 1H NMR, 13C NMR, and HRMS spectral analysis. In preliminary antibacterial studies, analogues 6b, 6d, and 6e were found to be most effective against S. aureus with MIC of 12.5, 6.25, and 12.5 µg/mL, whereas 8d displayed excellent activity against S. aureus, B. subtilis, E. coli bacterial strains with zones of inhibition 12.5, 25, and 12.5 µg/mL respectively. Particularly, the prepared scaffolds 8c, 8d, and 8e showed remarkable antifungal activity with MIC value 12.5, 12.5, and 6.25 µg/mL against A. flavus and 6d, 6c producing an increase in the activity against C. Albicans with zones of inhibition 12.5 and 12.5 µg/mL respectively. Also, through the antitubercular studies, we found that compounds 6e and 8b have a strong activity with M. tuberculosis H37Rv with MICs 3.26, and 6.48 µg/mL, respectively. The protein stability, fluctuations of APO-Protein, and protein-ligand complexes were investigated through Molecular Dynamics (MD) simulations studies using Desmond Maestro 11.3, and potential lead molecules were identified. Our findings were further confirmed using molecular docking, revealing that azaindole based ligand 6e, 6f, and 8a has strong hydrophobic Tyr179, Trp183, Ile177, Ile445, and H-bondings interactions Arg151 and Arg454 through molecular dynamics simulation studies, making it potential biological compound. These compounds were further evaluated for their ADMET and physicochemical properties by using SwissADME.Communicated by Ramaswamy H. Sarma.

Cerebellar modulation of memory encoding in the periaqueductal grey and fear behaviour.

The pivotal role of the periaqueductal grey (PAG) in fear learning is reinforced by the identification of neurons in male rat ventrolateral PAG (vlPAG) that encode fear memory through signalling the onset and offset of an auditory-conditioned stimulus during presentation of the unreinforced conditioned tone (CS+) during retrieval. Some units only display CS+ onset or offset responses, and the two signals differ in extinction sensitivity, suggesting that they are independent of each other. In addition, understanding cerebellar contributions to survival circuits is advanced by the discovery that (i) reversible inactivation of the medial cerebellar nucleus (MCN) during fear consolidation leads in subsequent retrieval to (a) disruption of the temporal precision of vlPAG offset, but not onset responses to CS+, and (b) an increase in duration of freezing behaviour. And (ii) chemogenetic manipulation of the MCN-vlPAG projection during fear acquisition (a) reduces the occurrence of fear-related ultrasonic vocalisations, and (b) during subsequent retrieval, slows the extinction rate of fear-related freezing. These findings show that the cerebellum is part of the survival network that regulates fear memory processes at multiple timescales and in multiple ways, raising the possibility that dysfunctional interactions in the cerebellar-survival network may underlie fear-related disorders and comorbidities.

Anxiety disorders are a cluster of mental health conditions characterised by persistent and excessive amounts of fear and worry. They affect millions of people worldwide, but treatments can sometimes be ineffective and have unwanted side effects. Understanding which brain regions are involved in fear and anxiety-related behaviours, and how those areas are connected, is the first step towards designing more effective treatments. A region known as the periaqueductal grey (or PAG) sits at the centre of the brain's fear and anxiety network, regulating pain, encoding fear memories and responding to threats and stressors. It also controls survival behaviours such as the 'freeze' response, when an animal is frightened. A more recent addition to the fear and anxiety network is the cerebellum, which sits at the base of the brain. Two-way connections between this region and the PAG have been well described, but how the cerebellum might influence fear and anxiety-related behaviours remains unclear. To explore this role, Lawrenson, Paci et al. investigated whether the cerebellum modulates brain activity within the PAG and if so, how this relates to fear behaviours. Rats had electrodes implanted in their brains to record the activity of nerve cells within the PAG. A common fear-conditioning task was then used to elicit 'freeze' responses: a sound was paired with mild foot shocks until the animals learned to fear the auditory signal. In the rats, a subset of neurons within the PAG responded to the tone, consistent with those cells encoding a fear memory. But when a drug blocked the cerebellum's output during fear conditioning, the timing of the PAG response was less precise and the rats' freeze response lasted longer. Lawrenson, Paci et al. concluded that the cerebellum, through its interactions with the brain's fear and anxiety network, might be responsible for coordinating the most appropriate behavioural response to fear, and how long 'freezing' lasts. In summary, these findings show that the cerebellum is a part of the brain's survival network which regulates fear-memory processes. It raises the possibility that disruption of the cerebellum might underlie anxiety and other fear-related disorders, thereby providing a new target for future therapies.

North American cranberry (Vaccinium macrocarpon) stimulates apoptotic pathways in DU145 human prostate cancer cells in vitro.

Diets rich in fruits and vegetables have been shown to improve patient prognosis in a variety of cancers, a benefit partly derived from phytochemicals, many of which target cell death pathways in tumor cells. Cranberries (Vaccinium macrocarpon) are a phytochemical-rich fruit containing a variety of polyphenolic compounds. As flavonoids have been shown to induce apoptosis in human tumor cells, this study investigated the hypothesis that cranberry-mediated cytotoxicity in DU145 human prostate adenocarcinoma cells involves apoptosis. The results showed that induction of apoptosis in these cells occurred in response to treatment with whole cranberry extract and occurred through caspase-8 mediated cleavage of Bid protein to truncated Bid resulting in cytochrome-C release from the mitochondria. Subsequent activation of caspase-9 ultimately resulted in cell death as characterized by DNA fragmentation. Increased Par-4 protein expression was observed, and this is suggested to be at least partly responsible for caspase-8 activation. Proanthocyanidin-enriched and flavonol-enriched fractions of cranberry also increased caspase-8 and caspase-9 activity, suggesting that these compounds play a possible role in apoptosis induction. These findings indicate that cranberry phytochemicals can induce apoptosis in prostate cancer cells in vitro, and these findings further establish the potential value of cranberry phytochemicals as possible agents against prostate cancer.

Ursolic acid and its esters: occurrence in cranberries and other Vaccinium fruit and effects on matrix metalloproteinase activity in DU145 prostate tumor cells.

BACKGROUND: Ursolic acid and its cis- and trans-3-O-p-hydroxycinnamoyl esters have been identified as constituents of American cranberries (Vaccinium macrocarpon), which inhibit tumor cell proliferation. Since the compounds may contribute to berry anticancer properties, their content in cranberries, selected cranberry products, and three other Vaccinium species (V. oxycoccus, V. vitis-idaea and V. angustifolium) was determined by liquid chromatography-mass spectroscopy. The ability of these compounds to inhibit growth in a panel of tumor cell lines and inhibit matrix metalloproteinase (MMP) activity associated with tumor invasion and metastasis was determined in DU145 prostate tumor cells. RESULTS: The highest content of ursolic acid and esters was found in V. macrocarpon berries (0.460-1.090 g ursolic acid and 0.040-0.160 g each ester kg(-1) fresh weight). V. vitis-idaea and V. angustifolium contained ursolic acid (0.230-0.260 g kg(-1) ), but the esters were not detected. V. oxycoccus was lowest (0.129 g ursolic acid and esters per kg). Ursolic acid content was highest in cranberry products prepared from whole fruit. Ursolic acid and its esters inhibited tumor cell growth at micromolar concentrations, and inhibited MMP-2 and MMP-9 activity at concentrations below those previously reported for cranberry polyphenolics. CONCLUSION: Cranberries (V. macrocarpon) were the best source of ursolic acid and its esters among the fruit and products tested. These compounds may limit prostate carcinogenesis through matrix metalloproteinase inhibition.

Proanthocyanidins from the American Cranberry (Vaccinium macrocarpon) inhibit matrix metalloproteinase-2 and matrix metalloproteinase-9 activity in human prostate cancer cells via alterations in multiple cellular signalling pathways.

Prostate cancer is one of the most common cancers in the Western world, and it is believed that an individual's diet affects his risk of developing cancer. There has been an interest in examining phytochemicals, the secondary metabolites of plants, in order to determine their potential anti-cancer activities in vitro and in vivo. In this study we document the effects of proanthocyanidins (PACs) from the American Cranberry (Vaccinium macrocarpon) on matrix metalloproteinase (MMP) activity in DU145 human prostate cancer cells. Cranberry PACs decreased cellular viability of DU145 cells at a concentration of 25 µg/ml by 30% after 6 h of treatment. Treatment of DU145 cells with PACs resulted in an inhibition of both MMPs 2 and 9 activity. PACs increased the expression of TIMP-2, a known inhibitor of MMP activity, and decreased the expression of EMMPRIN, an inducer of MMP expression. PACs decreased the expression of PI-3 kinase and AKT proteins, and increased the phosphorylation of both p38 and ERK1/2. Cranberry PACs also decreased the translocation of the NF-κB p65 protein to the nucleus. Cranberry PACs increased c-jun and decreased c-fos protein levels. These results suggest that cranberry PACs decreases MMP activity through the induction and/or inhibition of specific temporal MMP regulators, and by affecting either the phosphorylation status and/or expression of MAP kinase, PI-3 kinase, NF-κB and AP-1 pathway proteins. This study further demonstrates that cranberry PACs are a strong candidate for further research as novel anti-cancer agents.

Five unit bolus oxytocin at cesarean delivery in women at risk of atony: a randomized, double-blind, controlled trial.

BACKGROUND: I.v. bolus oxytocin is used routinely during cesarean delivery to prevent postpartum hemorrhage. Its adverse hemodynamic effects are well known, resulting in a recent change in dose from 10 IU to 5. Whether a 5 IU bolus has any advantages over infusion alone is unclear. We tested the hypothesis that a 5 IU i.v. bolus of oxytocin before the initiation of a continuous infusion decreases the need for additional uterotonic drugs in the first 24 hours after delivery in women with risk factors for uterine atony undergoing cesarean delivery, compared with infusion alone. METHODS: A prospective, randomized, double-blind, controlled trial was conducted in 143 subjects undergoing cesarean delivery with at least 1 risk factor for uterine atony. Subjects received 5 IU bolus of oxytocin or normal saline i.v. over 30 seconds after umbilical cord clamping. All subjects received an infusion of 40 IU oxytocin in 500 mL normal saline over 30 minutes, followed by 20 IU in 1 L over 8 hours. The primary outcome was the need for additional uterotonics in the first 24 hours after delivery. Secondary outcomes included uterine tone as assessed by the surgeon (5-point Likert scale: 0 = "floppy," 4 = "rock hard"), estimated blood loss, side effects of bolus administration, and the oxytocin bolus-placental delivery interval. RESULTS: There was no difference in the need for additional uterotonic drugs in the first 24 hours between groups. There was a significant difference in uterine tone immediately after placental delivery (P < 0.01) (2.8 in the oxytocin group [95% confidence interval 2.6-3.0] vs 2.2 in the saline group [95% confidence interval 1.8-2.5]), which disappeared after 5 minutes. There were no differences in observed or reported side effects between groups. CONCLUSIONS: We found that a 5 IU i.v. bolus of oxytocin added to an infusion did not alter the need for additional uterotonic drugs to prevent or treat postpartum hemorrhage in the first 24 hours in women undergoing cesarean delivery with risk factors for uterine atony, despite causing an initial stronger uterine contraction. Our study was not powered to find a difference in side effects between groups. These results suggest that an oxytocin infusion may be adequate without the need for a bolus, even in high-risk patients.

Is there thermal benefit from preoperative warming in children?

AIM: We aimed to quantify the impact of a raised preoperative ambient temperature (T(ambient)) on core temperature (T(core)) after induction of anesthesia in children. BACKGROUND: It has been suggested that prewarming of patients before anesthesia induction reduces postinduction drop in T(core). Neither the prewarming temperature nor its duration is established for adults or children. Nevertheless, it remains common practice to either warm the operating theatre and induction room or employ radiant heaters prior to induction of anesthesia, particularly for infants and neonates. We aimed to quantify the benefit, if any, of this warming practice. METHODS: We conducted a prospective clinical study to assess T(core) behavior in children randomized to either raised or standard ambient temperature as a prewarming technique prior to induction and until the operation commenced. We have called this 'preoperative' warming. Well, children scheduled for elective surgery where presurgical anesthetic duration exceeded 20 min were randomized to a T(ambient) of either 26 or 21 degrees C. Esophageal temperature was monitored continuously until the operative procedure commenced. RESULTS: There were 30 children in each group. Those in the warmed group (26 degrees C) had a statistically significant higher initial T(core) (0.4 degrees C warmer) and less drop in their T(core) (0.18 degrees C benefit at 20 min). Although younger/lighter/shorter individuals were more likely to drop their T(core), a warmer T(ambient) had only 0.1 degrees C thermal benefit irrespective of age. CONCLUSIONS: There are statistically significant thermal advantages to preoperative environmental warming. This study provides data to assist the anesthetist in deciding when these are likely to be clinically relevant.

A systematic review of elephant impact across Africa.

Contradictory findings among scientific studies that address a particular issue may impede the conversion of science to management implementation. A systematic review of peer-reviewed studies to generate a single outcome may overcome this problem. The contentious topic of the impact that a megaherbivore such as the savanna elephant have for other species and their environment can benefit from such an approach. After some 68 years, 367 peer-reviewed papers covered the topic and 51 of these papers provided sufficient data to be included in a meta-analysis. We separated the direct impact that elephants had on trees and herbs from the indirect effects on other vertebrates, invertebrates, and soil properties. Elephants have an impact on tree structure and abundance but no overall negative cascading effects for species that share space with them. Primary productivity explained a small amount of variation of elephant impact on vegetation. Elephant numbers (density), study duration, rainfall, tree cover, and the presence of artificial water and fences failed to describe patterns of impact. We conclude that published information do not support the calls made for artificially manipulating elephant numbers to ameliorate elephant impact, and call for the management of space use by elephants to maintain savanna heterogeneity.

Inhibition of matrix metalloproteinase activity in DU145 human prostate cancer cells by flavonoids from lowbush blueberry (Vaccinium angustifolium): possible roles for protein kinase C and mitogen-activated protein-kinase-mediated events.

Regulation of the matrix metalloproteinases (MMPs) is crucial to regulate extracellular matrix (ECM) proteolysis which is important in metastasis. This study investigated the mechanism(s) by which three flavonoid-enriched fractions from lowbush blueberry (Vaccinium angustifolium) down-regulate MMP activity in DU145 human prostate cancer cells. Metalloproteinase activity was evaluated from cells exposed to "crude," anthocyanin-enriched (AN) and proanthocyanidin-enriched (PAC) fractions. Differential down-regulation of MMPs was observed. The activity of the endogenous tissue inhibitors of metalloproteinases (TIMPs) from these cells was also evaluated. Increases in TIMP-1 and TIMP-2 activity were observed in response to these fractions. The possible involvement of protein kinase C (PKC) and mitogen-activated protein (MAP) kinase pathways in the flavonoid-mediated decreases in MMP activity was observed. These findings indicate that blueberry flavonoids may use multiple mechanisms in down-regulating MMP activity in these cells.

Left ventricular filling in dilated cardiomyopathy: relation to functional class and hemodynamics.

Left ventricular systolic function does not correlate well with functional class in patients with dilated cardiomyopathy. To determine whether the correlation is better with Doppler indexes of left ventricular diastolic function, 34 patients with dilated cardiomyopathy (M-mode echocardiographic end-diastolic dimension greater than 60 mm, fractional shortening less than 25%, increased E point-septal separation) were studied. Patients were classified into two groups according to functional class. Group 1 consisted of 16 patients in New York Heart Association functional class I or II; group 2 included 18 patients in functional class III or IV. Left ventricular dimensions, fractional shortening, left ventricular mass, meridional end-systolic wall stress, peak early and late transmitral filling velocities and their ratio, isovolumetric relaxation period and time to peak filling rate were computed from pulsed wave Doppler and M-mode echocardiograms and calibrated carotid pulse tracings. Right heart catheterization was performed in 20 of 34 patients. No differences were observed between groups with regard to age, gender distribution, heart rate, blood pressure and M-mode echocardiographic-derived indexes of systolic function. Peak early filling velocity (72 +/- 13 versus 40 +/- 10 cm/s, p less than 0.001) was higher and atrial filling fraction (27 +/- 4% versus 46 +/- 8%, p less than 0.001) was lower in group 2 than in group 1. The ratio of early to late transmitral filling velocities was higher in group 2 patients (2.3 +/- 0.5 versus 0.7 +/- 0.2, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Delineation of myocardial viability with PET.

UNLABELLED: Relative flow and metabolic imaging (the "mismatch pattern") with PET have been proposed to identify the presence of viable myocardium in patients with ischemic left ventricular dysfunction. Yet, optimal criteria to identify dysfunctional but viable myocardium and predict significant functional improvement have not been fully defined. METHODS: Dynamic PET imaging with 13N-ammonia and 18F-deoxyglucose to assess absolute myocardial perfusion and glucose uptake was performed in 25 patients (20 men, 5 women; mean age 57 +/- 12 yr, range 30-72 yr) scheduled for coronary revascularization because of coronary artery disease, anterior wall dysfunction and mildly depressed left ventricular ejection fraction (49% +/- 11%). Global and regional left ventricular function was evaluated by contrast left ventriculography at baseline and after revascularization. RESULTS: As judged from the changes in end-systolic volume and resting anterior wall motion before and after revascularization, 17 patients with improved wall motion score and decreased end-systolic volume were considered to have viable myocardium, whereas 8 patients with either no change in regional wall motion or increased end-systolic volume were considered to have nonviable myocardium. Before revascularization, viable myocardium showed higher absolute myocardial blood flow (77 +/- 20 versus 51 +/- 9 ml (min.100 g)-1, p = 0.004) and absolute regional myocardial glucose uptake (36 +/- 14 versus 24 +/- 11 mumole (min.100 g)-1, p = 0.04) than nonviable myocardium. CONCLUSION: This study identified absolute myocardial blood flow and normalized glucose extraction as the most powerful predictors of the return of contractile function after coronary revascularization in patients with ischemic anterior wall dysfunction.

Noninvasive estimation of pulmonary arterial wedge pressure with Doppler transmitral flow velocity pattern in patients with known heart disease.

Pulmonary arterial wedge pressure (PAWP) is an important marker of cardiac function. Regrettably, it requires catheterization, which can occasionally result in serious complications. A noninvasive method of estimating PAWP would thus be helpful. Recent studies have indicated that the Doppler transmitral flow velocity pattern was strongly dependent on preload and could provide an estimate of PAWP. This study was therefore designed to evaluate the relation between doppler transmitral flow velocity indexes and measured PAWP in 91 patients (learning group: 73 men, mean age 57 +/- 13 years) with ischemic heart disease (n = 41), dilated (n = 29) or hypertrophic cardiomyopathy (n = 4), or aortic stenosis (n = 17). Multiple regression analysis was used to derive an equation for estimation of PAWP, which was subsequently tested in a separate group of 33 patients (testing group: 28 men, mean age 58 +/- 12 years) with similar cardiac conditions. PAWP ranged from 4 to 48 mm Hg in the learning group and from 7 to 40 mm Hg in the testing group. In the learning group, PAWP correlated with the E/A ratio (r = 0.95), atrial filling fraction (r = -0.80), peak E velocity (r = 0.79), isovolumic relaxation period (r = -0.75), and deceleration time (r = -0.61). In the learning group, PAWP was best predicted as PAWP = 18.4 + [17.1.In(E/A ratio)]. This equation allowed prediction of PAWP within 3 mm Hg of the measured value in 24 of 33 patients (73%) in the testing group. In 8 additional patients, the equation also accurately predicted the changes in PAWP induced by volume loading or intravenous nitrates (r = 0.98).(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of transmitral filling dynamics on continuous-wave Doppler assessment of aortic regurgitation by half-time methods.

The influence of transmitral filling dynamics on the evaluation of aortic regurgitation (AR) by continuous-wave Doppler pressure half-time was assessed in 30 consecutive patients in sinus rhythm with chronic moderate to severe AR. Pulsed-wave Doppler-derived regurgitant fraction (obtained from aortic and pulmonary stroke volumes) and color flow mapping relative regurgitant area (obtained from the parasternal short-axis view) were chosen as reference standards for the severity of AR. An excellent correlation was found between these 2 parameters (r = 0.98), while correlations were poor between pressure half-time and either regurgitant fraction (r = -0.74) or relative regurgitant jet area (r = -0.69). The ratio of early (E) to late (A) transmitral peak velocities was used to divide the study population into 2 groups: group A (n = 16) with E/A less than 1 and group B (n = 14) with E/A greater than 1. In patients with a similar degree of AR (estimated from Doppler regurgitant fraction or relative regurgitant jet area), the pressure half-time was found to be significantly shorter. Thus, the severity of AR in group A patients was overestimated (p less than 0.01). Compared to group B, group A patients were significantly shorter. Thus, the severity of AR in group A patients was overestimated (p less than 0.01). Compared to group B, group A patients were significantly older (p less than 0.02) and had a larger left ventricular mass (p less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Prolonged exercise induces left ventricular dysfunction in healthy subjects.

To determine the effects of a moderately prolonged exercise on left ventricular systolic performance, 23 healthy male subjects, aged 18 to 51 yr (mean 37 yr) were studied. The subjects exercised first on a treadmill (brief exercise) and completed, on a separate day, a 20-km run. M-mode, two-dimensional, and Doppler echocardiography, as well as calibrated carotid pulse tracings, were obtained at rest and immediately on completion of both brief and prolonged exercise. Left ventricular systolic function was assessed by end-systolic stress-shortening relationships. Heart rate increased similarly after brief and prolonged exercise (+30%). Mean arterial pressure decreased from 99 +/- 7 to 92 +/- 8 mmHg (P less than 0.001) after prolonged exercise, but it remained unchanged after brief exercise. Left ventricular end-diastolic volume was decreased after prolonged exercise (130 +/- 23 vs. 147 +/- 18 ml at rest, P less than 0.01). Both ejection fraction and rate-adjusted mean velocity of fiber shortening decreased after prolonged exercise [from 67 +/- 5 to 60 +/- 6% (P less than 0.001) and from 1.12 +/- 0.2 to 0.91 +/- 0.2 cm/s (P less than 0.001), respectively] despite a lower circumferential end-systolic wall stress (133 +/- 23 vs. 152 +/- 20 g/cm2). The relationship between ejection fraction (or mean velocity of fiber shortening adjusted for heart rate) and end-systolic wall stress was displaced downward on race finish (P less than 0.05). These changes were independent of the changes in left ventricular end-diastolic volume and hence those in preload. The data suggest that moderately prolonged exercise may result in depressed left ventricular performance in healthy normal subjects.

Assay of anti-HBs antibodies using a recombinant antigen and latex particle counting: comparison with five commercial tests.

An assay of anti-HBs antibodies based on agglutination of latex particles coated with recombinant HBs-antigen was compared with Abbott radioimmunoassay (Abbott-RIA), which uses a human plasma-derived antigen. The population examined consisted of 76 Abbott-RIA anti-HBs-negative prevaccinated subjects and 1044 serum samples anti-HBs found positive by Abbott-RIA, including 283 samples of subjects vaccinated either with a human plasma-derived vaccine (group A; n = 180) or with a recombinant vaccine (group B; n = 103). Correlation coefficients between the two techniques were respectively r = 0.89 for the whole population (n = 1044), r = 0.98 in group A and r = 0.74 in group B. Anti-HBs titres were higher with latex than with RIA in group B as shown by the regression slopes: latex = 508 + 1.11 RIA in group A and latex = -1138 + 3.97 RIA in group B, suggesting that some vaccinated subjects from group B produced antibodies against epitopes proper to the recombinant antigen. In the prevaccinated population and in group A, the latex results were compared with those of radioimmunoassays (Abbott, Sorin) and enzyme immunoassays (Behring, Roche, Pasteur). Only the Roche-EIA detected anti-HBs in the prevaccinated subjects. The correlation between the various immunoassays was r greater than 0.96 only for values higher than 100 IU/l.

Bone marrow micrometastasis might not be a short-term predictor of survival in early stages non-small cell lung carcinoma.

OBJECTIVE: To determine the presence of occult micrometastasis (OM) in a selected population of surgically resectable patients presenting with non-small cell lung carcinoma (NSCLC) and to evaluate its prognostic value on relapses and survival. METHODS: From February 1996 to December 1999, 99 patients undergoing surgical treatment for NSCLC were prospectively investigated for the presence of occult bone marrow micrometastasis. Tumor cells were detected with monoclonal primary antibodies directed against low molecular weight cytokeratins. RESULTS: Median follow-up time was 14.3 months (range 0.2-45.6 months). Overall prevalence of OM was 22.2% (22 out of 99). The presence of OM was not correlated to pathology, T status, or N status. In survival analysis, the only independent predictors of overall survival were N0 status and Stage I (P=0.016 and 0.004, respectively), while T1 was a predictor of disease-free survival (P=0.044). Metastasis and loco-regional recurrence were observed at follow-up in 18.2 (four out of 22) and 9% (two out of 22) of patients OM(+) and in 14.3 (11 out of 77) and 7.8% (six out of 77) of patients OM(-), respectively (P=not significant). OM was a predictor neither of overall survival nor of disease-free survival (P=0.52 and 0.97, respectively). In Stage I patients, 1-year overall survival and 1-year disease-free survival were 89 and 98% for OM(-) patients and 88 and 90% for OM(+) patients, respectively (P=0.57 and P=0.75). CONCLUSIONS: OM was present in >20% of surgically treated NSCLC patients and did not correlate to pathological variables. In contrast to previous published data, in this study the presence of OM had no influence on overall or disease-free survival.