Metabolic effects of pamidronate in patients with metastatic bone disease

We have evaluated the value of specific bone resorption markers in monitoring metastatic bone disease to define the duration of action of a single high-dose pamidronate infusion. Twenty patients received a single infusion of pamidronate 120 mg for painful bone metastases. Ten out of these 20 patients also received a second infusion. They were evaluated at baseline, 2, 4 and 8 weeks after each infusion. A composite pain questionnaire, serum and urine tests were carried out at these time points. Bone resorption markers measured included urinary calcium, hydroxyproline and two new markers: pyridinoline and deoxypyridinoline. Reference values were defined by 20 healthy controls matched by age and sex. Pamidronate induced a profound fall in bone resorption with a maximal effect within the first month after therapy. Changes in urinary calcium levels were confounded by a rise of 100% in the parathyroid hormone levels. Before treatment, pyridinoline and deoxypyridinoline were increased in 70% of patients, while urinary calcium was increased in only 40% of them. Thirteen patients had a > or = 50% fall in deoxypyridinoline levels and were considered as biochemical responders. These patients had a mean reduction in pain score of about 30% of baseline levels, which was significantly higher than the seven non-biochemical responders. In conclusion, urinary calcium is not a precise marker of bone resorption. Deoxypyridinoline seems to be the most specific bone resorption marker in cancer patients. Biochemical responders have the most benefit from pamidronate in terms of pain relief. This suggests that patients may benefit from more potent or repeated infusions of bisphosphonates

Kerosene subsidies for household lighting in India: what are the impacts?

Kerosene subsidy reform is a key policy concern in India and other developing countries. As kerosene is widely used for lighting in India, any price change will likely have considerable public welfare impacts on the large fraction of the poor who do not have access to reliable electricity supply for lighting. In this study, we assess historic kerosene use for residential lighting across population groups separated by urban/rural, expenditure, and electricity service levels using data from India. Consumption trends are used to inform a service demand model and evaluate how changes in fuel price, electricity connection, and supply reliability influence environmental, health and economic outcomes. We find that users relying on kerosene for supplemental lighting—in combination ('stacked') with electricity—accounted for 64% of residential kerosene consumed for lighting in 2005. Tested scenarios that addressed service needs of supplemental users had the greatest welfare benefits, especially in the future. Scenarios reducing PM2.5 emissions from kerosene lighting can avert between 50 and 300 thousand disability adjusted life years relative to a baseline scenario in 2030. Lighting kerosene is highly price sensitive, resulting in a drop in demand of 97% in a scenario in which current subsidies are phased out by 2030. Deadweight loss of the subsidy in 2005 is estimated at $200–950 million, with three quarters attributable to supplemental kerosene lighting. Support for cleaner lighting technologies not reliant on fossil fuel subsidies would appear to be 'no regrets' or 'co-benefits' options for India, and could be implemented in parallel with subsidy removal

Self-organizing maps: a tool to ascertain taxonomic relatedness based on features derived from 16S rDNA sequence

Exploitation of microbial wealth, of which almost 95% or more is still unexplored, is a growing need. The taxonomic placements of a new isolate based on phenotypic characteristics are now being supported by information preserved in the 16S rRNA gene. However, the analysis of 16S rDNA sequences retrieved from metagenome, by the available bioinformatics tools, is subject to limitations. In this study, the occurrences of nucleotide features in 16S rDNA sequences have been used to ascertain the taxonomic placement of organisms. The tetra- and penta-nucleotide features were extracted from the training data set of the 16S rDNA sequence, and was subjected to an artificial neural network (ANN) based tool known as self-organizing map (SOM), which helped in visualization of unsupervised classification. For selection of significant features, principal component analysis (PCA) or curvilinear component analysis (CCA) was applied. The SOM along with these techniques could discriminate the sample sequences with more than 90% accuracy, highlighting the relevance of features. To ascertain the confidence level in the developed classification approach, the test data set was specifically evaluated for Thiobacillus, with Acidiphilium, Paracocus and Starkeya, which are taxonomically reassigned. The evaluation proved the excellent generalization capability of the developed tool. The topology of genera in SOM supported the conventional chemo-biochemical classification reported in the Bergey manual

Development of an in vitro model to study clot lysis activity of thrombolytic drugs

BACKGROUND: Thrombolytic drugs are widely used for the management of cerebral venous sinus thrombosis patients. Several in vitro models have been developed to study clot lytic activity of thrombolytic drugs, but all of these have certain limitations. There is need of an appropriate model to check the clot lytic efficacy of thrombolytic drugs. In the present study, an attempt has been made to design and develop a new model system to study clot lysis in a simplified and easy way using a thrombolytic drug, streptokinase. METHODS: Whole blood from healthy individuals (n = 20) was allowed to form clots in a pre-weighed sterile microcentrifuge tubes; serum was removed and clot was weighed. After lysis by streptokinase fluid was removed and remnants of clot were again weighed along with the tube. Percentage of Clot lysis was calculated on the basis of the weight difference of microcentrifuge tubes obtained before and after clot lysis. RESULTS: There was a significant percentage of clot lysis observed when streptokinase was used. On the other hand with water (negative control), minimal (2.5%) clot lysis was observed. There was a significant difference between clot lysis done by streptokinase and water. CONCLUSION: Our study could be a rapid and effective methodology to study clot-lytic effect of newly developed drugs as well as known drugs

Signal Transduction Pathways in the Pentameric Ligand-Gated Ion Channels

The mechanisms of allosteric action within pentameric ligand-gated ion channels (pLGICs) remain to be determined. Using crystallography, site-directed mutagenesis, and two-electrode voltage clamp measurements, we identified two functionally relevant sites in the extracellular (EC) domain of the bacterial pLGIC from Gloeobacter violaceus (GLIC). One site is at the C-loop region, where the NQN mutation (D91N, E177Q, and D178N) eliminated inter-subunit salt bridges in the open-channel GLIC structure and thereby shifted the channel activation to a higher agonist concentration. The other site is below the C-loop, where binding of the anesthetic ketamine inhibited GLIC currents in a concentration dependent manner. To understand how a perturbation signal in the EC domain, either resulting from the NQN mutation or ketamine binding, is transduced to the channel gate, we have used the Perturbation-based Markovian Transmission (PMT) model to determine dynamic responses of the GLIC channel and signaling pathways upon initial perturbations in the EC domain of GLIC. Despite the existence of many possible routes for the initial perturbation signal to reach the channel gate, the PMT model in combination with Yen's algorithm revealed that perturbation signals with the highest probability flow travel either via the β1-β2 loop or through pre-TM1. The β1-β2 loop occurs in either intra- or inter-subunit pathways, while pre-TM1 occurs exclusively in inter-subunit pathways. Residues involved in both types of pathways are well supported by previous experimental data on nAChR. The direct coupling between pre-TM1 and TM2 of the adjacent subunit adds new insight into the allosteric signaling mechanism in pLGICs. © 2013 Mowrey et al

Post traumatic vertebro basilar dissection: Case report and review of literature

Posterior circulation territory stroke following mild head injury is a known entity although rarely seen. Numerous case reports appear in literature from time to time highlighting this complication. Blunt trauma to the head and neck possibly causes injury to the vertebrobasilar system in the form of angiorrhexis, subintimal, intramural and perivascular hemorrhage which causes secondary narrowing of the injured vessel. These processes can be complicated by progressive thrombosis & vascular occlusion. Here we are reporting a case of post traumatic vertebra-basilar dissection causing bilateral cerebellar and brainstem infarct

Gating at the Mouth of the Acetylcholine Receptor Channel: Energetic Consequences of Mutations in the αM2-Cap

Gating of nicotinic acetylcholine receptors from a C(losed) to an O(pen) conformation is the initial event in the postsynaptic signaling cascade at the vertebrate nerve-muscle junction. Studies of receptor structure and function show that many residues in this large, five-subunit membrane protein contribute to the energy difference between C and O. Of special interest are amino acids located at the two transmitter binding sites and in the narrow region of the channel, where C↔O gating motions generate a low↔high change in the affinity for agonists and in the ionic conductance, respectively. We have measured the energy changes and relative timing of gating movements for residues that lie between these two locations, in the C-terminus of the pore-lining M2 helix of the α subunit (‘αM2-cap’). This region contains a binding site for non-competitive inhibitors and a charged ring that influences the conductance of the open pore. αM2-cap mutations have large effects on gating but much smaller effects on agonist binding, channel conductance, channel block and desensitization. Three αM2-cap residues (αI260, αP265 and αS268) appear to move at the outset of channel-opening, about at the same time as those at the transmitter binding site. The results suggest that the αM2-cap changes its secondary structure to link gating motions in the extracellular domain with those in the channel that regulate ionic conductance

Comparative transcriptome analysis identified candidate genes for late leaf spot resistance and cause of defoliation in groundnut

Late leaf spot (LLS) caused by fungus Nothopassalora personata in groundnut is responsible for up to 50% yield loss. To dissect the complex nature of LLS resistance, comparative transcriptome analysis was performed using resistant (GPBD 4), susceptible (TAG 24) and a resistant introgression line (ICGV 13208) and identified a total of 12,164 and 9954 DEGs (differentially expressed genes) respectively in A- and B-subgenomes of tetraploid groundnut. There were 135 and 136 unique pathways triggered in A- and B-subgenomes, respectively, upon N. personata infection. Highly upregulated putative disease resistance genes, an RPP-13 like (Aradu.P20JR) and a NBS-LRR (Aradu.Z87JB) were identified on chromosome A02 and A03, respectively, for LLS resistance. Mildew resistance Locus (MLOs)-like proteins, heavy metal transport proteins, and ubiquitin protein ligase showed trend of upregulation in susceptible genotypes, while tetratricopeptide repeats (TPR), pentatricopeptide repeat (PPR), chitinases, glutathione S-transferases, purple acid phosphatases showed upregulation in resistant genotypes. However, the highly expressed ethylene responsive factor (ERF) and ethylene responsive nuclear protein (ERF2), and early responsive dehydration gene (ERD) might be related to the possible causes of defoliation in susceptible genotypes. The identified disease resistance genes can be deployed in genomics-assisted breeding for development of LLS resistant cultivars to reduce the yield loss in groundnut

Transition between Two Regimes Describing Internal Fluctuation of DNA in a Nanochannel

We measure the thermal fluctuation of the internal segments of a piece of DNA confined in a nanochannel about 50100 nm wide. This local thermodynamic property is key to accurate measurement of distances in genomic analysis. For DNA in 100 nm channels, we observe a critical length scale 10 m for the mean extension of internal segments, below which the de Gennes' theory describes the fluctuations with no fitting parameters, and above which the fluctuation data falls into Odijk's deflection theory regime. By analyzing the probability distributions of the extensions of the internal segments, we infer that folded structures of length 150250 nm, separated by 10 m exist in the confined DNA during the transition between the two regimes. For 50 nm channels we find that the fluctuation is significantly reduced since the Odijk regime appears earlier. This is critical for genomic analysis. We further propose a more detailed theory based on small fluctuations and incorporating the effects of confinement to explicitly calculate the statistical properties of the internal fluctuations. Our theory is applicable to polymers with heterogeneous mechanical properties confined in non-uniform channels. We show that existing theories for the end-to-end extension/fluctuation of polymers can be used to study the internal fluctuations only when the contour length of the polymer is many times larger than its persistence length. Finally, our results suggest that introducing nicks in the DNA will not change its fluctuation behavior when the nick density is below 1 nick per kbp DNA

Search for a massive invisible particle X0X^0 in B+→e+X0B^{+}\to e^{+}X^{0} and B+→μ+X0B^{+}\to \mu^{+}X^{0} decays

We present a search for a non-Standard-Model invisible particle $X^0$ in the mass range $0.1\textrm{-}1.8 \,{\rm GeV}/{c^2}$ in $B^{+}\to e^{+} X^{0}$ and $B^{+}\to \mu^{+} X^{0}$ decays. The results are obtained from a $711~{\rm fb}^{-1}$ data sample that corresponds to $772 \times 10^{6} B\bar{B}$ pairs, collected at the $\Upsilon(4S)$ resonance with the Belle detector at the KEKB $e^+ e^-$ collider. One $B$ meson is fully reconstructed in a hadronic mode to determine the momentum of the lepton of the signal decay in the rest frame of the recoiling partner $B$ meson. We find no evidence of a signal and set upper limits on the order of $10^{-6}$.Comment: 8 pages, 4 figures, 3 table