Cosmology and fundamental physics with the ELT-ANDES spectrograph.

State-of-the-art 19th century spectroscopy led to the discovery of quantum mechanics, and 20th century spectroscopy led to the confirmation of quantum electrodynamics. State-of-the-art 21st century astrophysical spectrographs, especially ANDES at ESO's ELT, have another opportunity to play a key role in the search for, and characterization of, the new physics which is known to be out there, waiting to be discovered. We rely on detailed simulations and forecast techniques to discuss four important examples of this point: big bang nucleosynthesis, the evolution of the cosmic microwave background temperature, tests of the universality of physical laws, and a real-time model-independent mapping of the expansion history of the universe (also known as the redshift drift). The last two are among the flagship science drivers for the ELT. We also highlight what is required for the ESO community to be able to play a meaningful role in 2030s fundamental cosmology and show that, even if ANDES only provides null results, such 'minimum guaranteed science' will be in the form of constraints on key cosmological paradigms: these are independent from, and can be competitive with, those obtained from traditional cosmological probes.

Association between hamstring coactivation during isokinetic quadriceps strength testing and knee cartilage worsening over 24 months.

OBJECTIVE: This study aimed to determine longitudinal associations, including sex-specific differences, between greater knee flexor antagonist coactivation and worsening cartilage morphology in knees with or at risk for osteoarthritis (OA). DESIGN: Baseline measurements were collected at the 60-month visit of a longitudinal osteoarthritis study following community-dwelling participants (MOST). Knee flexor and extensor muscle activity were measured with surface electromyography during a maximal isokinetic knee extension task. MRI analyzed knee cartilage morphology at baseline and 24-month follow-up. Multivariable adjusted logistic regression models were used to assess associations between coactivation level and cartilage morphology worsening. RESULTS: Analysis of 373 women (mean ± SD age 67.4 ± 7.3 years and BMI 29.7 ± 5.0 kg/m2) and 240 men (66.5 ± 7.8 years and 29.9 ± 4.5 kg/m2) revealed that women had greater medial (P < 0.001), lateral (P < 0.001), and combined (P < 0.001) hamstring coactivation than men. In both sexes, combined hamstring coactivation was associated with patellofemoral cartilage morphology worsening [1.23 (1.02, 1.49)] and to a less significant degree with whole knee cartilage morphology worsening [1.21 (0.98, 1.49)]. In men, greater combined hamstring coactivation was associated with increased risk for whole knee [1.59 (1.06, 2.39)] and patellofemoral [1.38 (1.01, 1.88)] cartilage morphology worsening and point estimates suggested association between medial hamstring coactivation and medial tibiofemoral cartilage morphology worsening. No significant associations were detected between greater hamstring coactivation and cartilage morphology worsening in women. CONCLUSIONS: These findings suggest a longitudinal relationship between antagonist hamstring coactivation during isokinetic knee extensor testing and worsening of cartilage morphology over 24 months in men with or at risk for knee OA.

Clinical value of weight-bearing CT and radiographs for detecting patellofemoral cartilage visualized by MRI in the MOST study.

OBJECTIVE: The patellofemoral joint is frequently affected by osteoarthritis (PFOA) and is incompletely imaged on radiographs (XR). Weight-Bearing CT (WBCT) could offer advantages for visualization. This study determined the sensitivity, specificity, and accuracy of axial WBCT and lateral XR for detection of PFOA features in comparison with cartilage damage on MRI. DESIGN: A convenience sample of 60 right knees from the MOST cohort were analyzed. WBCT and XR were read for OARSI JSN score and MRI for MOAKS cartilage score by two experienced musculoskeletal radiologists blinded to participant. Using MOAKS scoring on MRI (referent standard), the sensitivity, specificity and accuracy of patellofemoral OARSI JSN scores based on WBCT and XR were compared. RESULTS: The mean ± SD age and BMI for the participants included (66.7% women) were 67.6 ± 9.8 years and 30.0 ± 5.3 kg/m2 respectively. WBCT demonstrated significantly greater sensitivity (0.85-0.97 on WBCT vs 0.47-0.57 on XR) and accuracy (0.85-0.92 on WBCT vs 0.48-0.57 on XR) for all parameters except lateral full-thickness cartilage loss (McNemar's test p-values all <0.001). There was moderate-to-strong and low-to-moderate agreement between PFOA findings on WBCT and XR, respectively, and semi-quantitative scores of PF cartilage on MRI. Inter-rater reliability for XR JSN [weighted kappa = 0.83 (0.64, 1.0)], WBCT JSN [kappa = 0.60 (0.48, 0.72)] and MRI MOAKS-CM [kappa = 0.70 (0.61, 0.79)] readings were good. CONCLUSION: WBCT demonstrates significantly greater sensitivity and accuracy than radiographs for identification of PFOA. Given the same Relative Radiation Level as XR and improved visualization, WBCT holds promise to improve understanding of the weight-bearing patellofemoral joint.

Constraint on a varying proton-electron mass ratio 1.5 billion years after the big bang.

A molecular hydrogen absorber at a lookback time of 12.4 billion years, corresponding to 10% of the age of the Universe today, is analyzed to put a constraint on a varying proton-electron mass ratio, µ. A high resolution spectrum of the J1443+2724 quasar, which was observed with the Very Large Telescope, is used to create an accurate model of 89 Lyman and Werner band transitions whose relative frequencies are sensitive to µ, yielding a limit on the relative deviation from the current laboratory value of Δµ/µ=(-9.5 ± 5.4(stat)± 5.3(syst))×10(-6).

Limits on a gravitational field dependence of the proton-electron mass ratio from H2 in white dwarf stars.

Spectra of molecular hydrogen (H2) are employed to search for a possible proton-to-electron mass ratio (µ) dependence on gravity. The Lyman transitions of H2, observed with the Hubble Space Telescope towards white dwarf stars that underwent a gravitational collapse, are compared to accurate laboratory spectra taking into account the high temperature conditions (T∼13 000 K) of their photospheres. We derive sensitivity coefficients Ki which define how the individual H2 transitions shift due to µ dependence. The spectrum of white dwarf star GD133 yields a Δµ/µ constraint of (-2.7±4.7stat±0.2syst)×10(-5) for a local environment of a gravitational potential ϕ∼10(4) ϕEarth, while that of G29-38 yields Δµ/µ=(-5.8±3.8stat±0.3syst)×10(-5) for a potential of 2×10(4) ϕEarth.

First constraint on cosmological variation of the proton-to-electron mass ratio from two independent telescopes.

A high signal-to-noise spectrum covering the largest number of hydrogen lines (90 H(2) lines and 6 HD lines) in a high-redshift object was analyzed from an observation along the sight line to the bright quasar source J2123-005 with the Ultraviolet and Visual Echelle Spectrograph on the European Southern Observatory Very Large Telescope (Paranal, Chile). This delivers a constraint on a possible variation of the proton-to-electron mass ratio of Δµ/µ=(8.5 ± 3.6(stat) ± 2.2(syst))×10(-6) at redshift z(abs) = 2.059, which agrees well with a recently published result on the same system observed at the Keck telescope yielding Δµ/µ=(5.6 ± 5.5(stat) ± 2.9(syst))×10(-6). Both analyses used the same robust absorption line fitting procedures with detailed consideration of systematic errors.

Indications of a spatial variation of the fine structure constant.

We previously reported Keck telescope observations suggesting a smaller value of the fine structure constant α at high redshift. New Very Large Telescope (VLT) data, probing a different direction in the Universe, shows an inverse evolution; α increases at high redshift. Although the pattern could be due to as yet undetected systematic effects, with the systematics as presently understood the combined data set fits a spatial dipole, significant at the 4.2 σ level, in the direction right ascension 17.5 ± 0.9 h, declination -58 ± 9 deg. The independent VLT and Keck samples give consistent dipole directions and amplitudes, as do high and low redshift samples. A search for systematics, using observations duplicated at both telescopes, reveals none so far which emulate this result.

Antipyretic potency of centrally administered alpha-melanocyte stimulating hormone.

Centrally administered alpha-melanocyte stimulating hormone is much more potent in reducing fever than the widely used antipyretic acetaminophen. This finding supports the hypothesis that the endogenous neuropeptide has a role in the limitation of fever and suggests that it may be clinically useful as an antipyretic.

alpha-MSH production, receptors, and influence on neopterin in a human monocyte/macrophage cell line.

alpha-Melanocyte-stimulating hormone (alpha-MSH), a tridecapeptide derived from pro-opiomelanocortin, has potent antiinflammatory activity in laboratory animals. alpha-MSH inhibits nitric oxide production by murine macrophages, an influence believed to reflect activation of an autocrine circuit in these cells, one that is based on production and release of alpha-MSH and subsequent stimulation of melanocortin receptors. We found that THP-1 cells, human monocytic cells, produced alpha-MSH; this production was increased by interleukin-6, tumor necrosis factor a, or concanavalin A. These cells also expressed the gene for the human alpha-MSH receptor MC1. Unlike murine macrophages, THP-1 cells produced little nitrite in response to interferon-gamma (IFN-gamma) and lipopolysaccharide, and a-MSH inhibited this production only slightly. However, production of neopterin, a presumed primate homologue of nitric oxide in lower animals, was increased in THP-1 cells stimulated with INF-gamma plus TNF-alpha and alpha-MSH significantly inhibited this production. The evidence indicates that an autocrine regulatory circuit based on alpha-MSH occurs in human monocyte/macrophages much as in murine macrophages. alpha-MSH-induced modulation of specific inflammatory mediators/cytotoxic agents appears to differ depending on the importance of the mediators in the myelomonocytic cells of different species.

A patient's recollection of pre-operative status is not accurate one year after arthroplasty of the hip or knee.

If patients could recall their physical status before total hip (THA) or knee arthroplasty (TKA) accurately it could have valuable applications both clinically and for research. This study evaluated the accuracy of a patient's recollection one year after either THA or TKA using the Oxford hip or knee scores (OHS and OKS). In total, 113 patients (59 THA, 54 TKA) who had completed the appropriate score pre-operatively were asked to complete the score again at a mean of 12.4 months (standard deviation (sd) 0.8) after surgery, recalling their pre-operative state. While there were no significant differences between the actual and recalled pre-operative scores (OHS mean difference 0.8, sd 6.21, 95% confidence interval (CI) -0.82 to 2.42, p = 0.329; OKS mean difference -0.11, sd 7.34, 95% CI -2.11 to 1.89, p = 0.912), absolute differences were relatively large (OHS, 5.24; OKS, 5.41), correlation was weak (OHS r = 0.7, OKS r = 0.61) and agreement between actual and recalled responses for individual questions was poor in half of the OHS and two thirds of the OKS. A patient's recollection of pre-operative pain and function is inaccurate one year after THA or TKA.

Detection of Kell blood groups: molecular methods in the diagnostic laboratory.

The introduction of molecular biology techniques to the field of transfusion medicine has allowed more detailed analysis of the basis for the expression of several blood-group antigens. The application of the polymerase chain reaction for the determination of red-cell blood-group genotype is a highly sensitive technique that can be used to determine the likelihood of a fetus being affected by haemolytic disease of the fetuses or newborn. This alone makes polymerase chain reaction based techniques highly desirable for such applications. The determination of the genetic basis for the Kell/Cellano polymorphism has enabled the development of polymerase chain reaction-based techniques for genotyping. Several other red-cell blood-group antigen polymorphisms can also be analysed in this way.

Beta-endorphin: effect on thermoregulation in aged monkeys.

In previous experiments small doses of the opiate morphine produced greater hyperthermia in aged than in younger sub-human primates. To test whether this augmented response is due to enhanced sensitivity of CNS opioid receptors with age, beta-endorphin (0.625-5 micrograms), an endogenous opioid peptide, was injected into the lateral cerebral ventricle (ICV) of young (less than 9 years) and aged (greater than 9 years) squirrel monkeys. Significantly greater hyperthermias developed in the older primates after each dose. In the aged monkeys, all but the smallest dose increased core temperature about 1.5 degrees C within 1 hr after injection. Mean rectal temperature in the younger animals rose 0.5-0.7 degrees after all but the largest dose (1-1.5 degrees C rise). Both groups maintained an elevated body temperature after central beta-endorphin throughout the 5 hr recording period. 1.25 micrograms beta-endorphin given ICV in a hot environment (30 degrees C) caused greater hyperthermia in older animals. This dose given in the cold (18 degrees C) caused large changes in temperature of the aged monkeys, either hyperthermia or marked decreases, whereas the young primates developed only moderate rises in body temperature. The same dose of morphine sulfate (1.25 micrograms) ICV produced similar changes in core temperature in the two age groups in each ambient temperature. These results indicate that: (1) stimulation of CNS opioid receptors influences thermoregulation and (2) aging increases responsiveness to such stimulation.

Prediction of thrombus-related mechanical prosthetic valve dysfunction using transesophageal echocardiography.

Identification of thrombus-related mechanical prosthetic valve dysfunction (MPVD) has important therapeutic implications. We sought to develop an algorithm, combining clinical and echocardiographic parameters, for prediction of thrombus-related MPVD in a series of 53 patients (24 men, age 52 +/- 16 years) who had intraoperative diagnosis of thrombus or pannus from 1992 to 1997. Clinical and echocardiographic parameters were analyzed to identify predictors of thrombus and pannus. Prevalence of thrombus and diagnostic yields relative to the number of predictors were determined. There were 22 patients with thrombus, 19 patients with pannus, and 12 patients with both. Forty-two of 53 masses were visualized using transesophageal echocardiography (TEE), including 29 of 34 thrombi or both thrombi and panni and 13 of 19 isolated panni. Predictors of thrombus or mixed presentation include mobile mass (p = 0.009), attachment to occluder (p = 0.02), elevated gradients (p = 0.04), and an international normalized ratio of < or = 2.5 (p = 0.03). All 34 patients with thrombus or mixed presentation had > or = 1 predictor. The prevalence of thrombus in the presence of < or = 1, 2, and > or = 3 predictors is 14%, 69%, and 91%, respectively. Thus, TEE is sensitive in the identification of abnormal mass in the setting of MPVD. An algorithm based on clinical and transesophageal echocardiographic predictors may be useful to estimate the likelihood of thrombus in the setting of MPVD. In the presence of > or = 3 predictors, the probability of thrombus is high.

Effects of alcohol on thermoregulation in aged monkeys.

Ethanol ingestion has been implicated in accidental hypothermia of the elderly, but there is no prior data on the relative sensitivity to alcohol of aged homeotherms that might account for disproportionate dysthermia in this age group. To assess their sensitivity, ethanol (0.5-2.0 g/kg) or H20 was given by gavage to squirrel monkeys less than 4 yrs old, 4-9 yrs of age and over 9 yrs old. Dose-related decreases in body temperature occurred in all three groups in a 25.5 degrees C environment, with the greatest decreases in the oldest animals. In an 18.5 degrees C environment the hypothermias caused by 0.5 and 1.0 g/kg ethanol were greatly augmented in old monkeys and in some cases their temperatures fell to potentially life-threatening levels. In a 30.5 degrees C environment, 1.0 g/kg ethanol given to monkeys caused approximately equal temperature reductions in the three groups. When determined after 1.0 g/kg ethanol, peripheral vasomotor tone increased significantly in animals of each age group in all three environments. Decreases in rectal temperature were associated with parallel decreases in oxygen consumption. These results indicate that: 1) aging is associated with an increased sensitivity to the hypothermic action of ethanol in thermoneutral and cold environments, 2) ethanol in the doses tested inhibits heat production mechanisms without suppressing compensatory vasoconstriction in response to decreased body temperature.

Peripheral administration of alpha-MSH reduces fever in older and younger rabbits.

In these experiments IV, ICV and intra-gastric administration of alpha-MSH reduced fever caused by injections of leukocytic pyrogen (LP). 2.5 micrograms alpha-MSH injected IV reduced fever caused by IV LP, more so in rabbits over 3 yrs old than in those under 2 yrs of age; 5 mg of acetaminophen given IV had no antipyretic effect in either age group. ICV administration of 25 ng alpha-MSH reduced fever caused by IV LP injection in the older but not in the younger rabbits, alpha-MSH given IV (2.5 micrograms) also lowered fever induced by ICV injection of LP in older but not in younger animals. Both older and younger rabbits showed reductions in fever evoked by IV LP after 2.5 mg alpha-MSH was given by gastric tube. The results indicate that this peptide which occurs naturally within the brain has potent antipyretic properties when given systemically, presumably as a result of a central antipyretic action. Greater sensitivity to central alpha-MSH in the older rabbits may account for the reduced febrile response seen in the aged. The findings support previous data which suggest that central alpha-MSH has a physiological role in the limitation of fever.

Effects of morphine on body temperature of squirrel monkeys of various ages.

Increased sensitivity to certain drugs is believed to contribute to dysthermia in the elderly. To learn whether the temperature-altering effects of an opiate are increased in aged primates, injections of morphine sulfate (0.5-4 mg/kg) were given SC in randomly assigned order to squirrel monkeys ranging in age from 3.5 to over 17 years. Hyperthermia was the predominant response with no clear relationship to age, although hypothermic and biphasic responses also occurred, most commonly after the highest dose. Lateral cerebral ventricular injections of 0.625 and 1.25 micrograms morphine sulfate evoked hyperthermia in monkeys over 8 years of age but did not affect the temperature of animals less than 5 years old. Doses of 2.5 and 5 micrograms usually elicited hyperthermia regardless of age, but 10 micrograms induced hypothermia in a majority of monkeys. Naloxone was given intraventricularly to several monkeys to limit the degree of hypothermia after high doses of morphine given peripherally or centrally. Thus in these primates, as in other species such as the rat, lower doses of morphine usually evoked hyperthermia, but sufficiently high doses caused body temperature to fall. Unlike the case in the squirrel monkey with diazepam and with endogenous substances such as leukocytic pyrogen and taurine, there was not a strong or consistent relationship between age and morphine-induced temperature changes.

The role of self-directed in vivo exposure in combination with cognitive therapy, relaxation training, or therapist-assisted exposure in the treatment of panic disorder with agoraphobia.

The effects of self-directed in vivo exposure in the treatment of panic disorder with agoraphobia were examined. Seventy-four chronic and severe agoraphobic subjects were randomly assigned to Cognitive Therapy plus graded exposure. Relaxation Training plus graded exposure, or therapist-assisted graded exposure alone. Treatment consisted of 16 weekly 2.5-hour sessions. All subjects received programmed practice instructions for engaging in self-directed exposure as a concomitant strategy to their primary treatment. All subjects were instructed to keep systematic behavioral diary recordings of all self-directed exposure practice. The diary data were analyzed across and within treatments and assessment phases. Statistically significant findings were obtained across all diary measure domains with powerful repeated measures effects observed across all treatments. Significant between group effects and treatment x repeated measures interactions were obtained across the diary measure domains. Multiple linear regressions of in vivo anxiety levels and, to a lesser extent, frequency of self-directed exposure practice were found to be significantly associated with global assessment of severity at posttreatment and 3-month follow-up assessments. Furthermore, depression and marital satisfaction were significantly associated with in vivo anxiety. These and other findings are discussed with regard to their conceptual and clinical implications.

What internists should know about amiodarone.

Amiodarone is a potent and versatile antiarrhythmic. Despite side effects involving the lungs, heart, thyroid, and other organs, it is effective in the treatment of refractory atrial and ventricular arrhythmias and it has unique safety in patients with coronary disease and left ventricular dysfunction. This review discusses the evolving indications for amiodarone and management of toxicities and drug interactions.

Signatures of cool gas fueling a star-forming galaxy at redshift 2.3.

Galaxies are thought to be fed by the continuous accretion of intergalactic gas, but direct observational evidence has been elusive. The accreted gas is expected to orbit about the galaxy's halo, delivering not just fuel for star formation but also angular momentum to the galaxy, leading to distinct kinematic signatures. We report observations showing these distinct signatures near a typical distant star-forming galaxy, where the gas is detected using a background quasar passing 26 kiloparsecs from the host. Our observations indicate that gas accretion plays a major role in galaxy growth because the estimated accretion rate is comparable to the star-formation rate.

Limits on variations in fundamental constants from 21-cm and ultraviolet Quasar absorption lines.

Quasar absorption spectra at 21-cm and UV rest wavelengths are used to estimate the time variation of x [triple-bond] alpha(2)g(p)mu, where alpha is the fine structure constant, g(p) the proton g factor, and m(e)/m(p) [triple-bond] mu the electron/proton mass ratio. Over a redshift range 0.24 < or = zeta(abs) < or = 2.04, (Deltax/x)(weighted)(total) = (1.17 +/- 1.01) x 10(-5). A linear fit gives x/x = (-1.43 +/- 1.27) x 10(-15) yr(-1). Two previous results on varying alpha yield the strong limits Deltamu/mu = (2.31 +/- 1.03) x 10(-5) and Deltamu/mu=(1.29 +/- 1.01) x10(-5). Our sample, 8 x larger than any previous, provides the first direct estimate of the intrinsic 21-cm and UV velocity differences 6 km s(-1).