Photo-induced high-temperature ferromagnetism in YTiO3.

In quantum materials, degeneracies and frustrated interactions can have a profound impact on the emergence of long-range order, often driving strong fluctuations that suppress functionally relevant electronic or magnetic phases1-7. Engineering the atomic structure in the bulk or at heterointerfaces has been an important research strategy to lift these degeneracies, but these equilibrium methods are limited by thermodynamic, elastic and chemical constraints8. Here we show that all-optical, mode-selective manipulation of the crystal lattice can be used to enhance and stabilize high-temperature ferromagnetism in YTiO3, a material that shows only partial orbital polarization, an unsaturated low-temperature magnetic moment and a suppressed Curie temperature, Tc = 27 K (refs. 9-13). The enhancement is largest when exciting a 9 THz oxygen rotation mode, for which complete magnetic saturation is achieved at low temperatures and transient ferromagnetism is realized up to Tneq > 80 K, nearly three times the thermodynamic transition temperature. We interpret these effects as a consequence of the light-induced dynamical changes to the quasi-degenerate Ti t2g orbitals, which affect the magnetic phase competition and fluctuations found in the equilibrium state14-20. Notably, the light-induced high-temperature ferromagnetism discovered in our work is metastable over many nanoseconds, underscoring the ability to dynamically engineer practically useful non-equilibrium functionalities.

Correlation between measures of hypoglycemia and glycemic improvement in sulfonylurea treated patients with type 2 diabetes in India: results from the OBSTACLE hypoglycemia study.

BACKGROUND: This study aimed to assess correlation between measures of hypoglycemia and glycemic control in patients with type 2 diabetes mellitus (T2DM) treated with sulfonylureas. MATERIALS AND METHODS: T2DM patients being initiated on a sulfonylurea (SU) on background of a failing oral antihyperglycemic regimen were followed up for 12 weeks. (HbA1c) was measured at baseline and end of follow-up. Hypoglycemia was assessed using Stanford Hypoglycemia Questionnaire at week 12. RESULTS: Of the total 1069 patients enrolled, 950 were considered evaluable. A weak negative correlation was observed between end of follow-up HbA1c values and hypoglycemia score, using both linear regression analysis (correlation coefficient -0.12; P = 0.0002) and negative binomial regression (ß slope -0.09; P = 0.0010). A similar correlation was also observed between change in HbA1c from baseline and hypoglycemia score (ß slope -0.07; P = 0.0048). Mean HbA1c reduction was lowest (0.65 ± 2.27%) in patients not reporting any hypoglycemia and highest (1.28 ± 2.40%) in patients with hypoglycemia score greater than median of 2 (P = 0.0031). There was no correlation between hypoglycemia frequency and end of follow-up HbA1c values (P = 0.4111). CONCLUSION: With addition of SU on a background of a failing oral anti-hyperglycemic regimen, the extent of glycemic control correlates directly with measures of patient reported hypoglycemia.

Control of structure and spin texture in the van der Waals layered magnet CrSBr.

Controlling magnetism at nanometer length scales is essential for realizing high-performance spintronic, magneto-electric and topological devices and creating on-demand spin Hamiltonians probing fundamental concepts in physics. Van der Waals (vdW)-bonded layered magnets offer exceptional opportunities for such spin texture engineering. Here, we demonstrate nanoscale structural control in the layered magnet CrSBr with the potential to create spin patterns without the environmental sensitivity that has hindered such manipulations in other vdW magnets. We drive a local phase transformation using an electron beam that moves atoms and exchanges bond directions, effectively creating regions that have vertical vdW layers embedded within the initial horizontally vdW bonded exfoliated flakes. We calculate that the newly formed two-dimensional structure is ferromagnetically ordered in-plane with an energy gap in the visible spectrum, and weak antiferromagnetism between the planes, suggesting possibilities for creating spin textures and quantum magnetic phases.

Nanoscale lattice dynamics in hexagonal boron nitride moiré superlattices.

Twisted two-dimensional van der Waals (vdW) heterostructures have unlocked a new means for manipulating the properties of quantum materials. The resulting mesoscopic moiré superlattices are accessible to a wide variety of scanning probes. To date, spatially-resolved techniques have prioritized electronic structure visualization, with lattice response experiments only in their infancy. Here, we therefore investigate lattice dynamics in twisted layers of hexagonal boron nitride (hBN), formed by a minute twist angle between two hBN monolayers assembled on a graphite substrate. Nano-infrared (nano-IR) spectroscopy reveals systematic variations of the in-plane optical phonon frequencies amongst the triangular domains and domain walls in the hBN moiré superlattices. Our first-principles calculations unveil a local and stacking-dependent interaction with the underlying graphite, prompting symmetry-breaking between the otherwise identical neighboring moiré domains of twisted hBN.

Sensitivity and specificity of screening tools and smear microscopy in active tuberculosis case finding.

SETTING: Community based five pulmonary tuberculosis (PTB) surveys among adults. OBJECTIVES: Estimate sensitivity and specificity of screening tools for PTB and sputum microscopy. METHODS: For each survey site, we estimated sensitivity and specificity of different screening criteria and microscopy against culture; pooled estimates were obtained using Random Effects Model. RESULTS: Sensitivity of cough alone, screening for any symptom (persistent cough ≥2 weeks, fever or chest pain ≥1 month, hemoptysis), any symptom or history of anti-TB treatment (h/o ATT) were 56.2%, 66% and 71.2% respectively; specificities were 95.3%, 93.8% and 92.7% respectively. X-ray when used alone for primary screening had sensitivity and specificity of 76.6% and 97.3% respectively. When used along with screening for cough, these figures were 94.3% and 93.1%, and 100% and 97.3% when used with any symptom and h/o ATT. When used for secondary screening, sensitivity and specificity of X-ray was 66.8% and 87.8% respectively after primary screening for cough, 65.0% and 89.8% after screening for any symptom, and 67.1% and 86.7% when used after screening for any symptom or h/o ATT. Pooled sensitivity and specificity of smear was 46.2% and 99.3% respectively. CONCLUSION: Program managers may use these estimates while evaluating algorithms for active case finding.

Sub-national TB prevalence surveys in India, 2006-2012: Results of uniformly conducted data analysis.

SETTING: Community based tuberculosis (TB) prevalence surveys in ten sites across India during 2006-2012. OBJECTIVE: To re-analyze data of recent sub-national surveys using uniform statistical methods and obtain a pooled national level estimate of prevalence of TB. METHODS: Individuals ≥15 years old were screened by interview for symptoms suggestive of Pulmonary TB (PTB) and history of anti-TB treatment; additional screening by chest radiography was undertaken in five sites. Two sputum specimens were examined by smear and culture among Screen-positives. Prevalence in each site was estimated after imputing missing values to correct for bias introduced by incompleteness of data. In five sites, prevalence was corrected for non-screening by radiography. Pooled prevalence of bacteriologically positive PTB was estimated using Random Effects Model after excluding data from one site. Overall prevalence of TB (all ages, all types) was estimated by adjusting for extra-pulmonary TB and Pediatric TB. RESULTS: Of 769290 individuals registered, 715989 were screened by interview and 294532 also by radiography. Sputum specimen were examined from 50 852 individuals. Estimated prevalence of smear positive, culture positive and bacteriologically positive PTB varied between 108.4-428.1, 147.9-429.8 and 170.8-528.4 per 100000 populations in different sites. Pooled estimate of prevalence of bacteriologically positive PTB was 350.0 (260.7, 439.0). Overall prevalence of TB was estimated at 300.7 (223.7-377.5) in 2009, the mid-year of surveys. Prevalence was significantly higher in rural compared to urban areas. CONCLUSION: TB burden continues to be high in India suggesting further strengthening of TB control activities.

Intrathecal 6-mercaptopurine: preclinical pharmacology, phase I/II trial, and pharmacokinetic study.

For over 30 years, oral 6-mercaptopurine (6-MP) has been a mainstay of systemic maintenance therapy for acute lymphoblastic leukemia. Despite its efficacy as an antileukemic agent, 6-MP has not been previously administered by the intrathecal (IT) route. In anticipation of a clinical trial of IT 6-MP, preclinical cytotoxicity and pharmacology studies were performed to define a safe, effective dose. The optimal concentration (greater than 1 microM) and duration of exposure (greater than 12 h) to 6-MP required for cytotoxicity were determined in vitro using human leukemia cell lines. The dose required to achieve the desired cerebrospinal fluid concentrations in humans was derived from pharmacokinetic parameters determined in rhesus monkeys. A phase I/II study was then performed in pediatric patients with refractory meningeal leukemia. Nine patients (aged 3.5 to 16 years) with chronic meningeal leukemia (2 to 6 central nervous system relapses) were entered onto the study. All had previously failed, at a minimum, IT methotrexate, IT cytarabine, and cranial (+/- spinal) radiation. A 10-mg IT dose of 6-MP (calculated to produce cytotoxic cerebrospinal fluid levels for 12 h) was administered twice weekly for 4 weeks. There were four complete responses and three partial responses. The duration of complete responses ranged from 7 to 22 weeks. Observed toxicities were not dose limiting and included mild headache (three patients) and minimal nausea (two patients). Pharmacokinetic studies performed in patients confirmed that cerebrospinal fluid concentrations of 6-MP were greater than 1 microM for 12 h. These results indicate that the IT administration of 6-MP is feasible, is not associated with significant toxicity, and has definite activity in patients with refractory meningeal leukemia.

Drug susceptibility of rapid and slow growing non-tuberculous mycobacteria isolated from symptomatics for pulmonary tuberculosis, Central India.

BACKGROUND: Non-tuberculous mycobacteria (NTM) are emerging as important pathogens. Their treatment also differs from that of Mycobacterium tuberculosis. In India, any datum on them is scarce as species identification and drug susceptibility are not performed in most laboratories. Susceptibility also differs from one geographic area to another, and in our country, there are no data even to guide the clinicians to start treatment empirically. METHODOLOGY: The present study endeavours to generate drug susceptibility data on NTM isolated from sputum samples collected and stored from 6445 symptomatics for pulmonary tuberculosis during a prevalence survey and from specimens received from the hospital. Isolates were not necessarily associated with the disease. Species were identified and antibiotic susceptibility was performed using micro-broth dilution technique as per the standard Clinical and Laboratory Standards Institute guidelines. RESULTS: A total of 65 NTM with 11 species were identified, of which 27 belonged to Mycobacterium fortuitum complex, 14 Mycobacterium gordonae, 9 Mycobacterium avium, 7 Mycobacterium flavescens, 4 Mycobacterium scrofulaceum and one each of others. Sensitivity to amikacin for M. fortuitum was 95.22% (20 out of 21), followed by ciprofloxacin (76.19%) and clarithromycin (71.42%). All the 9 M. avium isolates, 11 of M. gordonae (78.57%), 5 of M. flavescens and 2 of M. scrofulaceum were sensitive to clarithromycin. All NTM were resistant to first-line antitubercular drugs except 8, which were sensitive to streptomycin. CONCLUSIONS: Drug sensitivity of NTM varies from species to species. While amikacin was the best for rapidly growing mycobacteria, clarithromycin was the most active drug against M. avium and other slow growers.

Prevalence of tuberculous lymphadenitis in children in Wardha district, Maharashtra State, India.

SETTING: Rural area of Wardha district, Maharashtra State, Central India. OBJECTIVE: To determine the prevalence of tuberculous lymphadenitis in children aged 0-14 years in the study area and to assess factors that may contribute towards the prevalence. DESIGN: House to house survey of a population of 23,229 in 35 neighbouring villages with 7900 children aged 0-14 years from May 1993 to May 1994 and from March 1995 to February 1996. RESULTS: The prevalence of tuberculous lymphadenitis/1000 children was 4.43. The maximum prevalence was in the 5-9 years age group. The prevalence was 34 times higher in children with positive family history of tuberculosis than in those without a history. There was an association between prevalence and the living standards of the children, with a higher prevalence in families that belonged to an underprivileged social class living in thatched, improvised houses. Multiple cervical lymph nodes >2 cm and with matting and fluctuation were found to be characteristic clinical features. CONCLUSION: The prevalence of peripheral lymphadenopathy was 27.2/1000 children and that of tuberculous lymphadenitis was 4.43/1000. Positive history of contact in the family was a significant epidemiological indicator of tuberculous glands.

Clinical and biochemical effects of verapamil administration to schizophrenic patients.

We administered verapamil hydrochloride, a calcium channel antagonist, to seven chronically ill schizophrenic patients for five weeks under double-blind, placebo-controlled conditions. No therapeutic effect was noted. Worsening in hostile and uncooperative behaviors and a syndrome of heightened emotional tone was observed during verapamil treatment and during the postverapamil placebo period. Verapamil produced significant increases in cerebrospinal fluid (CSF) and plasma levels of homovanillic acid and in plasma levels of prolactin, as well as significant decreases in plasma levels of 3-methoxy-4-hydroxyphenethyleneglycol. Verapamil and its active metabolite, norverapamil, were partitioned into CSF with CSF/plasma ratios of 0.06 and 0.04, respectively. The lack of therapeutic effects of verapamil in schizophrenic patients differs from earlier reports of its usefulness in treating manic patients. The biochemical and clinical data from our study suggest the possibility that verapamil exerts behaviorally relevant central nervous system activity in schizophrenic patients.

Evaluation of variants of carbol fuchsin solution to stain acid-fast bacilli in-situ by the pot method.

BACKGROUND: Ziehl-Neelsen (ZN) staining requires heating, and pre-stained smears contain viable bacilli. OBJECTIVE: To evaluate four variants of carbol fuchsin solution by the pot method and compare the results with ZN staining, taking culture as gold standard. METHOD: Five hundred sputum samples from presumptive tuberculosis cases were homogenised and divided into two parts. One part was subjected to routine ZN staining and culture on solid medium, the other was equally distributed into four pots. Equal quantities of the basic fuchsin (BF) variant were added to each pot. Variant I contained 2% BF with 10% phenol and 4% ammonium sulphate (PhAS), while Variant II had 0.6% BF with PhAS; Variants III and IV contained respectively 2% and 0.6% BF with 10% phenol only. After 1 h, smears were made from each pot and culture was performed on Löwenstein-Jensen medium. Smear results were compared with the ZN results and evaluated against culture. RESULTS AND CONCLUSION: Variant III gave excellent results compared to ZN (κ = 0.97), with sensitivity, specificity, and positive and negative predictive values similar to those of ZN, taking culture as gold standard. Pot contents were negative for Mycobacterium tuberculosis culture.

Rifabutin absorption in humans: relative bioavailability and food effect.

The relative bioavailability of the capsule dose form (150 mg) and the effect of high-fat food were assessed in a randomized, three-way crossover trial of rifabutin in 12 healthy male volunteers. Each subject received a single 150 mg dose as a solution (treatment A, fasted) or a capsule with food (treatment B) and without food (treatment C), with a 2-week washout period. Serial plasma and urine samples were obtained for 168 and 48 hours, respectively, and rifabutin and its active metabolite, 25-O-deacetyl-rifabutin, quantitated by a validated HPLC procedure. The mean +/- SD maximum concentration for rifabutin in plasma was 238 +/- 65, 156 +/- 52, and 188 +/- 50 ng/ml, time to reach peak concentration was 2.5 +/- 0.4, 5.4 +/- 1.6, and 3.0 +/- 1.1 hours, and the area under the plasma concentration-time curve from zero to infinity [AUC(0-infinity)] was 2989 +/- 726, 2640 +/- 891, and 2516 +/- 601 ng.hr/ml for the solution and the capsule during the fed and fasted states, respectively. Percentage of dose excreted in the urine as unchanged rifabutin was 11.0% +/- 2.4%, 11.4% +/- 4.9%, and 9.1% +/- 2.1% for treatments A, B, and C, respectively. The corresponding AUC(0-infinity) values for the equiactive metabolite 25-O-deacetyl-rifabutin, were 400 +/- 184, 361 +/- 187, and 298 +/- 102 ng.hr/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Steady-state cerebrospinal fluid transfer of verapamil and metabolites in patients with schizophrenia.

Cerebrospinal fluid (CSF) and plasma levels of verapamil and its two metabolites, norverapamil and D-620, were measured in seven patients with schizophrenia under steady-state conditions. Simultaneous sampling of CSF and plasma just before the dose during week 4 of the trial showed that verapamil, norverapamil, and D-620 partition in the CSF and reflect 7%, 5%, and 12% of the corresponding levels in plasma, respectively. There was a significant decrease in the mean unbound fraction of verapamil in schizophrenic patients as compared with normal subjects (0.058 vs. 0.11; p less than 0.001). Estimates of the mean unbound fraction obtained from CSF/plasma verapamil concentrations and the pH partition hypothesis showed excellent agreement with that measured by equilibrium dialysis (0.055 vs. 0.058) in these patients. Although systemic pool protein concentrations in schizophrenic patients were within normal range, an excellent positive correlation was observed between the ratio of the bound/free verapamil concentration and alpha 1-acid glycoprotein levels (r = 0.86; p less than 0.05). Determination and development of correlations between plasma and CSF may enhance our understanding of the central nervous system effects of verapamil.

Quinidine saliva concentrations: absence of correlation with serum concentrations at steady state.

Serum and saliva quinidine concentrations were measured in eight subjects with cardiac arrhythmias on various dosage regimens. There was good correlation between serum and saliva quinidine concentration after a single dose, but there was no such relationship after repeated dosing. Comparison of the area under a hysteresis loop, obtained by plotting the saliva/serum quinidine concentration ratio as a function of serum quinidine concentration over a dosing interval, indicated an exponential increase with increasing mean serum quinidine concentration. Salivary quinidine concentration predictions based on the Henderson-Hasselbalch equation did not correlate with the serum quinidine concentration under the steady-state conditions. These data suggest that quinidine concentration in saliva is not a direct reflection of its serum concentration in cardiac patients on maintenance (steady-state) therapy and hence not useful for therapeutic drug monitoring.

Bretylium kinetics in renal insufficiency.

Bretylium kinetics were examined in patients with varying degrees of renal impairment after a single intravenous dose of bretylium tosylate. Maximum plasma concentrations achieved at the end of the infusion, when normalized to the dose, correlated strongly with creatinine clearance. Drug disposition from plasma was biexponential, with a short distributive phase, but drug elimination was reduced, especially in patients with creatinine clearance below 30 ml/min X 1.73 m2. There was reduction in renal and total clearance and prolongation of t 1/2, with deteriorating renal function. In one patient who was reevaluated after a year, there was 76% reduction in the total clearance, corresponding to 43% deterioration of renal function. The difference of 33% between these values is due to a reduction of nearly 36% in volume of distribution, caused by the further deterioration of the renal function. Six-hour hemodialysis procedure on two anephric patients, resulted in an apparent one- to threefold increase in the computed bretylium clearance during dialysis, but the fraction of the total body load eliminated during the same period was not proportionally significant. The strong linear relationships between renal and total clearance, beta, and the creatinine clearance, may be helpful in adjusting dosage regimens for bretylium in patients with renal dysfunction.

Vancomycin disposition: the importance of age.

We examined the influence of age on vancomycin kinetics in 12 normal healthy men (six young and six elderly) after an intravenous infusion of 6 mg/kg. Serial blood and urine samples were collected for up to 2 days after dosing and were assayed for unchanged drug by a specific radioimmunoassay. Serum concentrations of vancomycin after infusion declined in a multiphasic manner. Both serum and urinary excretion data were simultaneously fit by a three-compartment model with SAAM-27 computer programs. Estimates of mean t1/2 obtained from the terminal phase of the drug disposition profile showed the t1/2 to be longer in the elderly than in the young subjects (12.1 and 7.2 hr). Although there was no change in the initial distribution volume of the central compartment, total systemic and renal clearances were reduced in the elderly and did not correlate with renal function. The increase in the vancomycin volume of distribution at steady state was ascribed to enhanced tissue binding of drug in the elderly, since the mean fraction of vancomycin bound in systemic pool of the young and elderly did not differ (0.53 and 0.56). In-depth analysis of excretion data tends to support suggestions of vancomycin excretion solely by glomerular filtration. Our data strongly suggest the need for adjustment or modification of recommended vancomycin dosing schedules in the elderly.

Lidocaine and its active metabolites.

It has been shown that the antiarrhythmic and toxic effects of lidocaine may be in part dependent on its two active metabolites, monoethylglycylxylidide (MEGX) and glycylxylidide (GX). Presently available gas liquid chromatographic analytic methods require long and tedious steps or sophisticated equipment such as gas liquid chromatography-mass spectrometry. The assay method reported here with the use of high-performance liquid chromatography is rapid and allows accurate, precise determination of lidocaine, MEGX, and GX in biologic fluids. On the 3 patients studied extensively with the use of this assay, one patient had MEGX concentrations almost twice those of lidocaine. At 83% lidocaine potency, the contribution of MEGX in this patient was about 1.5 times that of lidocaine. The second patient studied on two consecutive days had a 20% increase in serum lidocaine concentration and an equivalent decrease in MEGX concentration on the second day. In the third patient lidocaine was stopped with a resulting half-life of 3.8 hr, which is consistent with previously reported values for patients on long-term lidocaine infusion. Urinary excretion of lidocaine and its metabolites is in agreement with previous work. These data suggest that much information still remains to be learned about the active metabolites of lidocaine as well as of lidocaine.

Evaluation of zimeldine in Alzheimer's disease. Cognitive and biochemical measures.

Neuropsychological and neurochemical effects of zimeldine, a relatively specific serotonin reuptake blocker, were examined in four patients with clinically diagnosed Alzheimer's disease, in a double-blind, placebo-controlled, crossover study. Individualized doses of zimeldine were administered to achieve target plasma zimeldine concentrations of approximately 50 (low) to 100 (high) ng/mL. Overall, there was no significant effect of zimeldine on memory or reaction time measures as compared with placebo. The drug significantly reduced (by up to 38%) 5-hydroxyindoleacetic acid concentrations in the cereobrospinal fluid and almost abolished (90% reduction) platelet serotonin uptake. Cerebrospinal fluid concentrations of 3-methoxy-4-hydroxy-phenylglycol, a major metabolite of norepinephrine, and homovanillic acid, the major metabolite of dopamine, were not altered. Our findings indicate that alterations in central and peripheral serotoninergic function by a serotonin reuptake blocker (zimeldine) are unaccompanied by measurable changes in memory and/or reaction time in patients presumed to have Alzheimer's disease.

Neuroendocrine, physiologic, and behavioral responses following intravenous nicotine in nonsmoking healthy volunteers and in patients with Alzheimer's disease.

In separate studies, nonsmoking nicotine-naive subjects (11 young and middle-aged normal volunteers and 11 nonsmoking patients with Alzheimer's disease) received up to three doses of intravenous nicotine bitartrate (0.125, 0.25, and 0.5 micrograms/kg/min) and placebo for 60 min. Measurement of plasma ACTH, cortisol, and prolactin showed that nicotine produced in both groups a dose-dependent increase in cortisol, with ACTH in both groups and prolactin in the Alzheimer's group significantly elevated only by the 0.5 micrograms dose. Physiologic measures showed dose-dependent increases that were consistent with previous reports of nicotinic cholinergic stimulation. Behavioral effects included increases in anxiety and decreases in mood, especially following the 0.5 micrograms dose. Physical side effects were modest. The results indicate that nicotinic cholinergic stimulation can activate pituitary hormonal secretion in the human and suggest that nicotinic cholinergic stimulation may constitute an important part of cholinesterase inhibitor-induced endocrine stimulation and behavioral activation.

Concentration-dependent protein binding of a novel oral thromboxane synthase inhibitor--FCE 22,178.

The protein binding of FCE 22,178 in humans was determined ex vivo by equilibrium dialysis using plasma samples obtained from a dose-ranging study in normal male volunteers. These data suggested that FCE 22,178 may exhibit concentration-dependent protein binding over an in vivo concentration range of .8 to 64 micrograms/mL. Increase in free fraction at higher plasma drug concentrations corresponded directly to the dose-dependent increase in renal drug clearance. Nonlinear parameter estimation showed that FCE 22,178 binds tightly to plasma proteins with an apparent equilibrium association constant of 1.44 x 10(5) mol/L. Predicted change in the free fraction is consistent with the observed changes in renal clearance.