Outcome of gestational trophoblastic neoplasia: experience from a tertiary cancer centre in India.

AIMS: Gestational trophoblastic neoplasms (GTN) comprise a spectrum of interrelated conditions originating from the placenta. With sensitive assays for human chorionic gonadotropin (ß-hCG) and current approaches to chemotherapy, most women with GTN can be cured with preservation of reproductive potential. The purpose of this analysis was to address the outcome of GTN from a developing country, as data are largely sparse from this region. MATERIALS AND METHODS: We undertook a retrospective review of GTN cases treated at our centre from 2001 to 2008. Patients of GTN were assigned to low-risk (score ≤ 6) or high-risk (score ≥ 7) categories as per the modified World Health Organization scoring system. The low-risk group was treated with single-agent methotrexate (MTX) and the high-risk group received the EMA/CO regimen. Salvage therapies were EMA/EP or BEP. Treatment was continued until serum ß-hCG values were normal for three consecutive chemotherapy cycles, after which the patients were kept on follow-up. RESULTS: In total, 70 GTN patients were treated at our institution during this period; 48 (68%) were low-risk and 22 (32%) were in the high-risk category. The median ß-hCG level was 50 000 IU/l. The lung was the most common site of metastasis, seen in 15 (21%) patients. Among 48 low-risk patients, 37 (77%) received chemotherapy, of whom 25 (68%) were treated with MTX and 24 (96%) achieved a complete response. Twelve low-risk patients (32%) received EMA/CO therapy; 10 (83%) achieved a complete response. The 22 high-risk patients received EMA/CO and of these 16 (73%) achieved a complete response, two (9%) progressed, two (9%) died of progressive disease and two (9%) were lost to follow-up. Grade 3/4 toxicities with MTX included mucositis in two (8%) and neutropenia in five (21%) patients. At a median follow-up of 16.6 months, overall survival in the low- and high-risk groups was 100 and 88.8%, respectively. CONCLUSION: Risk-stratified treatment of GTN was associated with acceptable toxicity and resulted in outcome that was comparable with international standards.

Minimally invasive resin infiltration of arrested white-spot lesions: a randomized clinical trial.

BACKGROUND: The authors conducted a randomized, single-masked clinical trial involving patients who had completed orthodontic treatment to assess changes in the appearance of white-spot lesions (WSLs) that were treated with resin infiltration. METHODS: The authors divided affected teeth into control and treatment groups. In the treatment group, they restored teeth with WSLs by using resin infiltration. They evaluated changes in WSLs photographically by using a visual analog scale (VAS) (0 = no change, 100 = complete disappearance) and area measurements (in square millimeters). The authors analyzed the data by using two-way analysis of variance. RESULTS: The mean VAS ratings for treated teeth demonstrated marked improvement relative to that for control teeth immediately after treatment (67.7 versus 5.2, P < .001) and eight weeks later (65.9 versus 9.2, P < .001). The results for treated teeth showed a mean reduction in WSL area of 61.8 percent immediately after treatment and 60.9 percent eight weeks later, compared with a -3.3 percent change for control teeth immediately after treatment and a 1.0 percent reduction eight weeks later. CONCLUSIONS: Resin infiltration significantly improved the clinical appearance of WSLs, with stable results seen eight weeks after treatment. PRACTICAL IMPLICATIONS: Resin infiltration, a minimally invasive restorative treatment, was shown to be effective for WSLs that formed during orthodontic treatment.

Kv7 potassium channel activation with ICA-105665 reduces photoparoxysmal EEG responses in patients with epilepsy.

PURPOSE: To assess the effects of ICA-105665, an agonist of neuronal Kv7 potassium channels, on epileptiform EEG discharges, evoked by intermittent photic stimulation (IPS), the so-called photoparoxysmal responses (PPRs) in patients with epilepsy. METHODS: Male and female patients aged 18-60 years with reproducible PPRs were eligible for enrollment. The study was conducted as a single-blind, single-dose, multiple-cohort study. Four patients were enrolled in each of the first three cohorts. Six patients were enrolled in the fourth cohort and one patient was enrolled in the fifth cohort. PPR responses to 14 IPS frequencies (steps) were used to determine the standard photosensitivity range (SPR) following placebo on day 1 and ICA-105665 on day 2. The SPR was quantified for three eye conditions (eyes closing, eyes closed, and eyes open), and the most sensitive condition was used for assessment of efficacy. A partial response was defined as a reduction in the SPR of at least three units at three separate time points following ICA-105665 compared to the same time points following placebo with no time points with more than three units of increase. Complete suppression was defined by no PPRs in any eye condition at one or more time points. KEY FINDINGS: Six individual patients participated in the first three cohorts (100, 200, and 400 mg). Six patients participated in the fourth cohort (500 mg), and one patient participated in the fifth cohort (600 mg). Decreases in SPR occurred in one patient at 100 mg, two patients receiving 400 mg ICA-105665 (complete abolishment of SPR occurred in one patient at 400 mg), and in four of six patients receiving 500 mg. The most common adverse events (AEs) were those related to the nervous system, and dizziness appeared to be the first emerging AE. The single patient in the 600 mg cohort developed a brief generalized seizure within 1 h of dosing, leading to the discontinuation of additional patients at this dose, per the predefined protocol stopping rules. SIGNIFICANCE: ICA-105665 reduced the SPR in patients at single doses of 100 (one of four), 400 (two of four), and 500 mg (four of six). This is the first assessment of the effects of activation of Kv7 potassium channels in the photosensitivity proof of concept model. The reduction of SPR in this patient population provides evidence of central nervous system (CNS) penetration by ICA-105665, and preliminary evidence that engagement with neuronal Kv7 potassium channels has antiseizure effects.

Study of optical band gap and FTIR spectroscopy of Li2O.Bi2O3.P2O5 glasses.

Glasses having composition (25+x)Li(2)O.(65-x)P(2)O(5).10Bi(2)O(3) (0< or =x< or =25 mol%) were prepared by normal melt quenching technique. The optical absorption spectra of the polished samples were recorded in spectral range from 200 to 3300 nm at room temperature. The optical absorption edge (lambda(cutoff)), optical band gap (E(g)) and Urbach energy (DeltaE) were determined from the absorption spectra. Variation in these optical parameters has been associated with the structural changes occurring in these glasses with increase in Li(2)O:P(2)O(5) ratio. Variation in density (D), molar volume (V(M)) and glass transition temperature (T(g)) has also been correlated with structural changes in the glass samples. The FTIR spectra have been recorded in the spectral range from 400 to 1400 cm(-1). The FTIR spectra show the rapid depolymerization of phosphate chains with increase in Li(2)O content and P-O-Bi bonds are formed.

Learning-dependent structural plasticity in the adult olfactory pathway.

Olfactory learning in humans leads to enhanced perceptual discrimination of odor cues. Examining mouse models of both aversive and appetitive conditioning, we demonstrate a mechanism which may underlie this adult learning phenomenon. Topographically unique spatial wiring of the olfactory system allowed us to demonstrate that emotional learning of odor cues alters the primary sensory representation within the nose and brain of adult mice. Transgenic mice labeled at the M71 odorant receptor (specifically activated by the odorant acetophenone) were behaviorally trained with olfactory-dependent fear conditioning or conditioned place preference using acetophenone. Odor-trained mice had larger M71-specific glomeruli and an increase in M71-specific sensory neurons within the nose compared with mice that were untrained, trained to a non-M71 activating odorant, or had nonassociative pairings of acetophenone. These data indicate that the primary sensory neuron population and its projections may remain plastic in adults, providing a structural mechanism for learning-enhanced olfactory sensitivity and discrimination.

Differential regional expression of brain-derived neurotrophic factor following olfactory fear learning.

We examined brain-derived neurotrophic factor (BDNF) mRNA expression across the olfactory system following fear conditioning. Mice received 10 pairings of odor with footshock or equivalent unpaired odors and shocks. We found increased BDNF mRNA in animals receiving paired footshocks in the multiple regions examined including the posterior piriform cortex (PPC) and basolateral amygdala (BLA). This was in contrast to the unpaired and odor-alone treatments, where BDNF mRNA was increased in the olfactory bulb (OB) and anterior piriform cortex (APC) only, but not the higher olfactory areas. We propose that odor exposure increases expression of BDNF in the OB and APC while the PPC and BLA increase BDNF mRNA only when associative learning occurs.

Specificity of olfactory receptor interactions with other G protein-coupled receptors.

Studies on olfactory receptor (OR) pharmacology have been hindered by the poor plasma membrane localization of most ORs in heterologous cells. We previously reported that association with the beta(2)-adrenergic receptor (beta(2)-AR) facilitates functional expression of the OR M71 at the plasma membrane of HEK-293 cells. In the present study, we examined the specificity of M71 interactions with other G protein-coupled receptors (GPCRs). M71 was co-expressed in HEK-293 cells with 42 distinct GPCRs, and the vast majority of these receptors had no significant effect on M71 surface expression. However, co-expression with three subtypes of purinergic receptor (P2Y(1)R, P2Y(2)R, and A(2A)R) resulted in markedly enhanced plasma membrane localization of M71. Agonist stimulation of M71 co-expressed with P2Y(1)R and P2Y(2)R activated the mitogen-activated protein kinase pathway via coupling of M71 to Galpha(o). We also examined the ability of beta(2)-AR, P2Y(1)R, P2Y(2)R, and A(2A)Rto interact with and regulate ORs beyond M71. We found that co-expression of beta(2)-AR or the purinergic receptors enhanced the surface expression for an M71 subfamily member but not for several other ORs from different subfamilies. In addition, through chimeric receptor studies, we determined that the second transmembrane domain of beta(2)-AR is necessary for beta(2)-AR facilitation of M71 plasma membrane localization. These studies shed light on the specificity of OR interactions with other GPCRs and the mechanisms governing olfactory receptor trafficking.

Structural, optical, physical and electrical properties of V2O5.SrO.B2O3 glasses.

The present work aims to study the structure and variation of optical band gap, density and dc electrical conductivity in vanadium strontium borate glasses. The glass systems xV2O5.(40-x)SrO.60B2O3 and xV2O5.(60-x)B2O3.40SrO with x varying from 0 to 20 mol% were prepared by normal melt quench technique. Structural studies were made by recording IR transmission spectra. The fundamental absorption edge for all the glasses was analyzed in terms of the theory proposed by Davis and Mott. The position of absorption edge and hence the value of the optical band gap was found to depend on the semiconducting glass composition. The absorption in these glasses is believed to be associated with indirect transitions. The origin of Urbach energy is associated with the phonon-assisted indirect transitions. The change in both density and molar volume was discussed in terms of the structural modifications that take place in the glass matrix on addition of V2O5. dc conductivity of the glass systems is also reported. The change of conductivity and activation energy with composition indicates that the conduction process varies from ionic to polaronic one.

Multicenter study to determine antibody concentrations and assess the safety of administration of INH-A21, a donor-selected human Staphylococcal immune globulin, in low-birth-weight infants.

Nosocomial or late-onset sepsis is a common complication among premature infants, with a frequency inversely correlated with birth weight. Increased susceptibility to infection is due in part to an immature humoral (antibody-mediated) immune response. This study investigated the pharmacokinetics (PKs) and safety of a donor-selected specific intravenous immune globulin (IVIG) preparation, INH-A21 (Veronate), for prevention of sepsis in premature infants. Thirty-six infants weighing between 500 and 1,250 g during the first postnatal week were eligible to begin a series of up to four intravenous infusions of 500 or 750 mg/kg of body weight INH-A21. Blood samples were analyzed for antibodies against the Ser-Asp dipeptide repeat G (SdrG) and clumping factor A (ClfA) surface proteins of staphylococci. Sparse sampling and population PK analyses were performed to derive PK parameters. Following administration of the 500- and 750-mg/kg doses, the estimated average steady-state levels of anti-ClfA were 6.1 U/ml and 9.2 U/ml, respectively, and those of anti-SdrG were 5.2 U/ml and 7.7 U/ml, respectively. The elimination half-lives for anti-ClfA and anti-SdrG were 719 h and 701 h, respectively, and the clearances were 0.18 ml/h and 0.21 ml/h, respectively. In the final model, the values of the PK parameters were independent of gestational age. Both doses of INH-A21 were well tolerated, and the safety profile was similar to those of other IVIG preparations. These results suggest that a shorter dosing interval should be utilized between the first and second doses to achieve and maintain higher titers of anti-ClfA and anti-SdrG antibodies. Further studies examining INH-A21 for the prevention of late-onset sepsis in infants within the weight range studied are warranted.

Study of EPR, optical properties and electrical conductivity of vanadyl doped Bi2O3.PbO.B2O3 glasses.

Heavy metal based oxide glasses having composition xBi(2)O(3).(0.30 - x)PbO.0.70B(2)O(3) have been prepared (0.00 < or = x < or = 0.15, mol%) containing 2.0mol% of V(2)O(5) by normal melt-quenching technique. Electron paramagnetic resonance (EPR), optical spectra and dc conductivity of these glasses have been studied. Spin Hamiltonian parameters (SHP) of VO(2+) ions, dipolar hyperfine parameter, P and Fermi contact interaction parameter, K, molecular orbital coefficients (alpha(2) and gamma(2)) and optical band gap have been calculated. It is observed that in these glasses, the tetragonal nature of V(4+)O(6) complex increases with Bi(2)O(3) content. Increase in Bi(2)O(3):PbO ratio results in the contraction of 3d(xy) orbit of the unpaired electron in the vanadium ion, and the SHP are dependent on the theoretical optical basicity, Lambda(th). In present glasses, the conductivity (activation energy) first decreases (increases) with increase in mol% of Bi(2)O(3) content upto x = 0.08 and then shows a maxima (minima) at x = 0.10 and then starts decreasing (increasing) upto x < or = 0.15 with mol% of Bi(2)O(3) content.

Olfactory-mediated fear conditioning in mice: simultaneous measurements of fear-potentiated startle and freezing.

This study demonstrates that mice display olfactory-cued fear as measured with both freezing and fear-potentiated startle. Following a preconditioning test to measure any unconditioned responses to odor, mice received 5 pairings of a 10-s odor with a 0.25-s, 0.4-mA footshock. The next day, startle and freezing were measured in the presence and absence of the odor. Both fear measures increased after training with amyl acetate (Experiment 1) and acetophenone (Experiment 2). The enhancement of startle did not occur when the same number of odors and shocks were presented in an unpaired fashion (Experiment 3). Furthermore, mice were able to discriminate between an odor paired with shock and a nonreinforced odor (Experiment 4).

A cyclopropane fragmentation approach to heterocycle assembly: a convergent synthesis of oxepanes.

[reaction: see text] A cyclopropanol fragmentation approach to the synthesis of oxepanes has been developed. This convergent strategy condenses cyclopropyl diols with aldehydes to form an acetal, which is subsequently rearranged to furnish a keto-oxepane. The reaction has been developed as a one-pot procedure, utilizing sequential addition of Al(OTf)3 and TiCl4. Yields range from 50 to 70% for the sequence. A Zimmerman-Traxler transition state disposing substituents in equatorial positions is consistent with the observed formation of strictly cis products.

Some current concepts on childhood tuberculosis.

As children acquire infection with Mycobacterium tuberculosis from adults in their environment, the epidemiology of childhood tuberculosis (TB) follows that in adults. While global burden of childhood tuberculosis is unclear, in developing countries the annual risk of tuberculosis infection in children is 2- 5 per cent. Nearly 8-20 per cent of the deaths caused by tuberculosis occur in children. It has been suggested that BCG vaccination is responsible for decrease in the occurrence of disseminated and severe disease. Localized forms of illness, e.g., intrathoracic lymphadenopathy, and localized CNS disease have been reported to occur with greater frequency in vaccinated children. Human immunodeficiency virus (HIV) infected children are at an increased risk of tuberculosis, particularly disseminated disease. Diagnosis of TB in children presents special problems as the sputum is generally not available for examination. Diagnostic algorithms include scoring system utilizing clinical parameters and results of investigations. Various diagnostic techniques such as improved culture techniques, serodiagnosis, and nucleic acid amplification have been developed and evaluated to improve diagnosis of childhood tuberculosis. Serodiagnosis is an attractive investigation but till date none of the tests showed desirable sensitivity and specificity. Tests based on nucleic acid amplification are a promising development. Relatively less experience in children, need for technical expertise and high cost are the limiting factors for their use in childhood tuberculosis. Short-course chemotherapy for childhood tuberculosis is well established. Treatment with intermittent regimens is comparable to daily regimens. Directly observed treatment strategy (DOTS) has also shown encouraging results. Pattern of drug resistance among children with TB tends to reflect those found among adults in the same population. The rates of drug resistance to any drug vary from 20 to 80 per cent in different geographic regions.

Category based treatment of tuberculosis in children.

BACKGROUND: Childhood tuberculosis is treated with multiple regimens for different clinical manifestations. World Health Organization has suggested a category-based treatment of tuberculosis that focuses on adult type of illness. To include children as DOTS beneficiaries, there is a need to assess the feasibility of classification and treatment of various types of childhood tuberculosis in different categories. METHODS: The study was conducted in the Pediatric Tuberculosis (TB) Clinic of a tertiary care hospital in North India. All children registered in the TB clinic were classified in four categories, similar to the categorization in World Health Organization's guidelines for treatment of tuberculosis in adults. All children with freshly diagnosed serious form of tuberculosis were included in category I. Category II included patients who had treatment failure, had interrupted treatment, relapse cases and those who were suspected to have drug resistant tuberculosis. Patients with primary pulmonary complex (PPC), single lymph node tuberculosis, minimal pleural effusion and isolated skin tuberculosis were included in category III. Category IV included patients who did not improve or deteriorated despite administration of 5 drugs (as per Category II) for at least 2 months. RESULTS: A total of 459 patients were started on antituberculosis drugs and were available for analysis. Pulmonary tuberculosis was the commonest followed by lymph node tuberculosis. Identification of AFB was possible only in 52 (11 percent) of the patients and was more commonly seen in lymph node tuberculosis. The mean age of the children was 93 months and sex distribution was almost equal. 323 patients were in category I, 12 in category II, 120 in category III and 4 in category IV. 365 (80 percent) children completed the treatment. Of these, 302 (82.7 percent) were cured with the primary regimen assigned to them in the beginning, 54 (14.8 percent) required extension of treatment for 3 months and 9 (2.5 percent) patients required change in the treatment regimen. Side effect in form of hepatotoxicity was observed in 12 (2.6 percent) patients and was significantly more in patients who were getting category IV treatment. CONCLUSION: It is feasible to classify and manage various types of tuberculosis in children in different categories similar to WHO guidelines for adult tuberculosis.

Effect of TiO2 on electron paramagnetic resonance, optical transmission and dc conductivity of vanadyl doped sodium borate glasses.

Glass systems with composition xTiO2.(30 - x)Na2O.70B2O3 (series I) and xTiO2.(70 - x)B2O3.30Na2O (series II) containing 2 mol% V2O5 have been prepared (0 < or = x < or = 7, mol%) by normal melt-quenching. The electron paramagnetic resonance (EPR) spectra of VO2+ ions have been recorded in the X-band (approximately 9.13 GHz) at room temperature. Spin Hamiltonian parameters, gparallel, gperpendicular, Aparallel, Aperpendicular, the dipolar hyperfine coupling parameter (P) and the Fermi contact interaction parameter (K) have been calculated. The increase in Deltagparallel/Deltagperpendicular with increase in TiO2 content in series I shows that the octahedral symmetry of V4+O6 complex is reduced, whereas in series II the octahedral symmetry is improved with increase in x. The decrease in P, in both the series, indicates that the 3dxy orbit expands with increase in mol% of TiO2. The molecular orbital coefficients, alpha2 and gamma2 have been calculated by recording the optical transmission spectra in the range 500-850 nm. alpha2 and gamma2 increase with increase in x in both the series, which indicates that, the covalency of the vanadium oxygen bonds decreases. The dc conductivity sigma, decreases and activation energy, W increases with increase in TiO2:Na2O ratio whereas with increase in TiO2:B2O3 ratio the variation in sigma and W is within experimental error.

Olfactory receptor surface expression is driven by association with the beta2-adrenergic receptor.

Olfactory receptors (ORs) comprise more than half of the large class I G protein-coupled receptor (GPCR) superfamily. Although cloned over a decade ago, little is known about their properties because wild-type ORs do not efficiently reach the cell surface following heterologous expression. Receptor-receptor interactions strongly influence surface trafficking of other GPCRs, and we examined whether a similar mechanism might be involved in OR surface expression. Olfactory neurons are known to express beta-adrenergic receptors (ARs), and we found that coexpression with beta(2)-ARs, but not any other AR subtypes, dramatically increased mouse 71 (M71) OR surface expression in human embryonic kidney 293 cells. A persistent physical interaction between M71 ORs and beta(2)-ARs was shown by coimmunoprecipitation and by cointernalization of the two receptors in response to their specific ligands. Also, coexpression of wild-type M71 ORs with beta(2)-ARs resulted in cAMP responses to the M71 ligand acetophenone. Finally, in situ hybridization studies showed extensive colocalization of M71 OR and beta(2)-AR expression in mouse olfactory epithelium. These data demonstrate the successful heterologous surface expression of a functional wild-type OR and reveal that persistent physical association with other GPCRs can control OR surface expression.

Tuberculosis in children--what has changed in last 20 years?

Several changes have been observed in the epidemiology, clinical manifestations, diagnostic modalities and treatment of tuberculosis. Emergence of HIV epidemic and drug resistance have posed significant challenges. With increase in number of diseased adults and spread of HIV infection, the infection rates in children are likely to increase. It is estimated that in developing countries the annual risk of tuberculosis infection in children is 2.5%. Nearly 8-20% of the deaths caused by tuberculosis occur in children. Lymph node tuberculosis has increased over last two decades. HIV infected children are at an increased risk of tuberculosis, particularly disseminated disease. In last two decades drug resistant tuberculosis has increased gradually. The rates of drug resistance to any drug varied from 20% to 80% in different geographic regions. Various diagnostic techniques such as improved culture techniques, serodiagnosis, and nucleic acid amplification have been developed and evaluated to improve diagnosis of childhood tuberculosis. Serodiagnosis is an attractive investigation but till date none of the tests have desirable sensitivity and specificity. Tests based on nucleic acid amplification are a promising advance. Relatively less experience in children, need for technical expertise and high cost are limiting factors for their use in children with tuberculosis. Short-course chemotherapy for childhood tuberculosis is well established. Treatment with intermittent regimens is comparable to daily regimens. Directly observed treatment strategy have shown encouraging result.