Analyzing human knockouts to validate GPR151 as a therapeutic target for reduction of body mass index.

Novel drug targets for sustained reduction in body mass index (BMI) are needed to curb the epidemic of obesity, which affects 650 million individuals worldwide and is a causal driver of cardiovascular and metabolic disease and mortality. Previous studies reported that the Arg95Ter nonsense variant of GPR151, an orphan G protein-coupled receptor, is associated with reduced BMI and reduced risk of Type 2 Diabetes (T2D). Here, we further investigate GPR151 with the Pakistan Genome Resource (PGR), which is one of the largest exome biobanks of human homozygous loss-of-function carriers (knockouts) in the world. Among PGR participants, we identify eleven GPR151 putative loss-of-function (plof) variants, three of which are present at homozygosity (Arg95Ter, Tyr99Ter, and Phe175LeufsTer7), with a cumulative allele frequency of 2.2%. We confirm these alleles in vitro as loss-of-function. We test if GPR151 plof is associated with BMI, T2D, or other metabolic traits and find that GPR151 deficiency in complete human knockouts is not associated with clinically significant differences in these traits. Relative to Gpr151+/+ mice, Gpr151-/- animals exhibit no difference in body weight on normal chow and higher body weight on a high-fat diet. Together, our findings indicate that GPR151 antagonism is not a compelling therapeutic approach to treatment of obesity.

Predominance of MGMT promoter methylation among Pakistani glioblastoma patients.

BACKGROUND: Glioblastoma multiforme (GBM), the most prevalent subgroup of neuroepithelial tumors, is characterized by dismal overall survival (OS). Several studies have linked O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation to OS in GBM patients. However, MGMT methylation frequencies vary geographically and across ethnicities, with limited data for South Asian populations, including Pakistan. This study aimed to analyze MGMT promoter methylation in Pakistani GBM patients. METHODS: Consecutive primary GBM patients diagnosed ≥ 18 years-of-age, with no prior chemotherapy or radiotherapy history, were retrospectively selected. DNA was isolated from formalin-fixed-paraffin-embedded tissues. MGMT promoter methylation was analyzed using methylation-specific PCR. Clinical, pathological, and treatment data were assessed using Fisher's exact/Chi-squared tests. OS was calculated using Kaplan-Meier analysis in SPSS 27.0.1. RESULTS: The study included 48 GBM patients, comprising 38 (79.2%) males and 10 (20.8%) females. The median diagnosis age was 49.5 years (range 18-70). MGMT methylation was observed in 87.5% (42/48) of all cases. Patients with MGMT methylation undergoing radiotherapy or radiotherapy plus chemotherapy exhibited significantly improved median OS of 7.2 months (95% CI, 3.7-10.7; P < 0.001) and 16.9 months (95% CI, 15.9-17.9; P < 0.001), respectively, compared to those undergoing surgical resection only (OS: 2.2 months, 95% CI, 0.8-3.6). CONCLUSION: This is the first comprehensive study highlighting a predominance of MGMT methylation in Pakistani GBM patients. Furthermore, our findings underscore the association of MGMT methylation with improved OS across diverse treatment modalities. Larger studies are imperative to validate our findings for better management of Pakistani GBM patients.

Population assessment of the Endangered Kashmir Gray Langur (Semnopithecus ajax, Pocock 1928) using the double-observer method.

Primates are among the most threatened taxa globally, therefore, there is a need to estimate and monitor their populations. Kashmir Gray Langur Semnopithecus ajax is an endangered species for which there is no population estimate. We used double-observer method to estimate its population size in the Kashmir region of North-Western Himalaya. We walked 1284 km across 31 survey blocks spanning all three divisions of Kashmir viz., North, Central, and South Kashmir, covering an area of 411 km2. We counted a minimum of 1367 individual langurs from 27 groups. The detection probability for observer 1 (0.719) and observer 2 (0.656) resulted in a population estimate of 1496 (95% confidence interval [CI] 1367-1899) across 30 groups (with a mean group size of 51), giving a density estimate of 3.64 (3.33-4.62) langurs/km². We found double-observer surveys to be suitable for the population estimation of langurs, and we make recommendations on how to effectively conduct primate surveys, especially in mountainous ecosystems. Our records extend the species distribution range beyond stated by the International Union for Conservation of Nature. Our findings also highlight that the Kashmir Himalaya is a stronghold of the species, where conservation efforts should focus.

Design, Synthesis, Docking Studies and Molecular Dynamics Simulation of New 1,3,5-Triazine Derivatives as Anticancer Agents Selectively Targeting Pancreatic Adenocarcinoma (Capan-1).

On the basis of remarkable anticancer profile of s-triazine nucleus, a new series of 2-methoxy-4-(3-morpholino-5-(arylamino)phenoxy)benzaldehyde derivatives 11 a-u was prepared and evaluated for in vitro antiproliferative activity against eight diverse human cancer cell lines (Capan-1, HCT-116, LN229, NCI-H460, DND-41, HL-60, K562 and Z138). Compounds 11 o, 11 r and 11 s were the most potent anticancer agents on pancreatic adenocarcinoma (Capan-1) cell line with IC50 value of 1.4, 5.1 and 5.3 µM, respectively, while compounds 11 f, 11 g, 11 k, 11 l and 11 n displayed selective activity against the pancreatic adenocarcinoma (Capan-1) cell line with IC50 values of 7.3-11.5 µM. These results indicate that derivative 11 o may serve as a promising lead compound for the ongoing development of novel antiproliferative agents. The docking studies were conducted to predict the interactions of derivative 11 o with putative protein targets in pancreatic adenocarcinoma (Capan-1) cell line, specifically the prenyl-binding protein PDEδ. Furthermore, the analysis of the molecular dynamics simulation results demonstrated that complex 11 o promoted a higher stability to the prenyl-binding protein PDEδ.

Synthesis, structure and acetylcholinesterase inhibition activity of new diarylpyrazoles.

A variety of diarylpyrazole derivatives III-VI were synthesized and structurally characterized using FTIR, 1H and 13C NMR spectroscopy, and in case of compound VIb by X-ray single crystal analysis. The in vitro biological studies revealed that seven of the diarylpyrazole derivatives IIIa, IIIb, IIId, IIIe, IVa, IVb and IVd are highly potent inhibitors of acetylcholinesterase enzyme with IC50 values of 0.48 ± 0.092 µg/mL, 0.45 ± 0.093 µg/mL, 0.30 ± 0.014 µg/mL, 0.59 ± 0.072 µg/mL, 0.29 ± 0.084 µg/mL, 0.56 ± 0.010 µg/mL and 0.28 ± 0.096 µg/mL, respectively. All these seven products were more potent than the standard drug, donepezil (IC50 = 0.73 ± 0.015 µg/mL), while compounds IIIc (0.67 ± 0.099 µg/ml) and VIa (0.66 ± 0.069 µg/ml) are almost equipotent to the donepezil. Particularly, compounds IVa and IVd are highly active acetylcholinesterase enzyme inhibitors, demonstrating more than two-fold inhibitory activity than the reference inhibitor. Molecular docking studies were carried out to identify the possible binding modes of the diarylpyrazoles within the active pocket of the enzymes. The docking interactions of the synthesized compounds with acetylcholinesterase also provided high docking scores. These results clearly indicate the potential of these compound as powerful lead molecules for further investigations.

Synthesis, X-ray diffraction analysis, quantum chemical studies and α-amylase inhibition of probenecid derived S-alkylphthalimide-oxadiazole-benzenesulfonamide hybrids.

Sulphonamide and 1,3,4-oxadiazole moieties are present as integral structural parts of many drugs and pharmaceuticals. Taking into account the significance of these moieties, we herein present the synthesis, single-crystal X-ray analysis, DFT studies, and α-amylase inhibition of probenecid derived two S-alkylphthalimide-oxadiazole-benzenesulfonamide hybrids. The synthesis has been accomplished in high yields. The final structures of both hybrids have been established completely with the help of different spectro-analytical techniques, including NMR, FTIR, HR-MS, and single-crystal X-ray diffraction analyses. In an effort to confirm the experimental findings, versatile quantum mechanical calculations and Hirshfeld Surface analysis have been performed. α-Amylase inhibition assay has been executed to investigate the enzyme inhibitory potential of both hybrids. The low IC50 value (76.92 ± 0.19 µg/mL) of hybrid 2 shows the good α-amylase inhibition potential of the respective compound. Ultimately, the binding affinities and features of the two hybrids are elucidated utilising a molecular docking technique against the α-amylase enzyme.

Novel coumarin-isatin hybrids as potent antileishmanial agents: Synthesis, in silico and in vitro evaluations.

Leishmaniasis being one of the six major tropical diseases that affects nearly 0.7-1.3 million people annually, has so far limited and high toxic therapeutic options. Herein, we report the synthesis, in silico, and in vitro evaluations of novel coumarin-incorporated isatin hydrazones (Spf-1 - Spf-10) as highly potent and safe antileishmanial agents. Molecular docking was initially carried out to decipher the binding confirmation of lead molecules towards the active cavity of the target protein (Leishmanolysin gp63) of Leishmania tropica. Among all the docked compounds, only Spf-6, Spf-8, and Spf-10 showed high binding affinities due to a pattern of strong conventional hydrogen bonds and hydrophobic π-interactions. The molecular dynamics simulations showed the stable pattern of such bonding and structure-based confirmation with a time scale of 50 ns towards the top compound (Spf-10) and protein. These analyses affirmed the high stability of the system. Three out of ten compounds evaluated for their antileishmanial activity against Leishmania tropica promastigotes and amastigotes were found to be active at micromolar concentrations (IC50 range 0.1-4.13 µmol/L), and most importantly, they were also found to be highly biocompatible when screened for their toxicity in human erythrocytes.

Synthesis and evaluation of novel S-benzyl- and S-alkylphthalimide- oxadiazole -benzenesulfonamide hybrids as inhibitors of dengue virus protease.

Direct acting antiviral drugs (DAADs) are becoming therapeutics of choice for the treatment of viral infections. Successful development of anti HIV and HCV drugs by targeting the viral proteases has provided impetus for discovering newer DAADs. Dengue virus (DENV) protease, which is composed of two nonstructural proteins, NS2B and NS3pro, can be likewise exploited for discovering new anti-dengue therapeutics. In this study, we have linked together two pharmaceutically interesting motifs, namely 1,3,4-oxadiazole and benzenesulfonamide in two alternative series to develop novel S-benzylated and S-alkylphthalimidated hybrids. For the first series of hybrids, 4-aminobenzoic acid (1) was reacted with substituted benzenesulfonyl chlorides via its amino group, whereas the carboxylic acid side was elaborated to sulfonamido-1,3,4-oxadiazole-2-thiols (6a/b) in three steps. At this stage, the intermediates 6a/b were bifurcated to either S-alkylphthalimidated (8a-j) or S-benzylated (9a-c) hybrids by reacting with corresponding halides. For the alternative series of hybrids, the carboxylic acid group of probenecid (10) was similarly elaborated to sulfonamido-1,3,4-oxadiazole-2-thiols (13), and diverged to S-alkylphthalimidated (14a-f) and S-benzylated hybrids (15a-e). Bioactivity assays demonstrated that 8g and 8h are the most potent inhibitors among the synthesized analogs, exhibiting the IC50 values of 13.9 µM and 15.1 µM, respectively. Computational assessment predicted the binding of the inhibitors at an allosteric site developed in the open conformation of DENV2 NS2B/NS3pro. Taken together these findings point out that the synthesized hybrid inhibitors possess a great potential for further antiviral drug development.

Synthesis and computational studies of highly selective inhibitors of human recombinant tissue non-specific alkaline phosphatase (h-TNAP): A therapeutic target against vascular calcification.

In this study, we have discovered small druglike molecules as selective inhibitors of human tissue-nonspecific alkaline phosphatase (h-TNAP), an enzyme critical for the regulation of extracellular matrix calcification. The upregulation of h-TNAP is associated with various pathologies particularly the vascular calcification (VC). Selective inhibition of h-TNAP over h-NPP1 may serve as a useful therapeutic strategy against vascular calcification. A series of novel triazolyl pyrazole derivatives (10a-y) in which thiol bearing triazole moiety as the zinc binding functional group was introduced to a pyrazole based pharmacophore was synthesized and evaluated as potent and selective inhibitors of h-TNAP over h-NPP1. The biological screening against h-TNAP, h-IAP, h-NPP1 and h-NPP3 showed that many of the synthesized compounds are selective inhibitors of TNAP. Particularly, the compounds 10a-h, 10j, 10m-q, 10u, 10w and 10x displayed high potency and complete selectivity towards h-TNAP over h-NPP1. Compound 10q emerged as a highly potent inhibitor (IC50 = 0.16 µM or 160 nM) against h-TNAP with 127-fold increased inhibition compared to levamisole. On the other hand, compound 10e was found to be most selective inhibitor against the tested APs and NPPs (IC50 = 1.59 ± 0.36 µM). Binding sites architecture analysis, molecular-docking and molecular dynamics simulations (MDS), revealed the basis for h-TNAP and h-IAP ligand selectivity as well as selectivity towards h-TNAP over h-NPP1. These newly discovered inhibitors are believed to represent valuable lead structures to further streamline the generation of candidate compounds to target VC.

Probing the high potency of pyrazolyl pyrimidinetriones and thioxopyrimidinediones as selective and efficient non-nucleotide inhibitors of recombinant human ectonucleotidases.

With the aim to discover novel, efficient and selective inhibitors of human alkaline phosphatase and nucleotide pyrophosphatase enzymes, two new series of pyrazolyl pyrimidinetriones (PPTs) (6a-g) and thioxopyrimidinediones (PTPs) (6h-n) were synthesized in good chemical yields using Knoevenagel condensation reaction between pyrazole carbaldehydes (4a-g) and pharmacologically active N-alkylated pyrimidinetrione (5a) and thioxopyrimidinedione (5b). The inhibition potential of the synthesized hybrid compounds was evaluated against human alkaline phosphatase (h-TNAP and h-IAP) and ectonucleotidase (h-NPP1 and h-NPP3) enzymes. Most of the tested analogs were highly potent with a variable degree of inhibition depending on the functionalized hybrid structure. The detailed structure-activity relationship (SAR) of PPT and PTP derivatives suggested that the compound with unsubstituted phenyl ring from PPT series led to selective and potent inhibition (6a; IC50 = 0.33 ±â€¯0.02 µM) of h-TNAP, whereas compound 6c selectively inhibited h-IAP isozyme with IC50 value of 0.86 ±â€¯0.04 µM. Similarly, compounds 6b and 6h were identified as the lead scaffolds against h-NPP1 and h-NPP3, respectively. The probable binding modes for the most potent inhibitors were elucidated through molecular docking analysis. Structure-activity relationships, mechanism of action, cytotoxic effects and druglikeness properties are also discussed.

Densely substituted piperidines as a new class of elastase inhibitors: Synthesis and molecular modeling studies.

Elastase is the only enzyme that has the capability to degrade elastin and collagen, the two proteins essential for skin and bones. The synthesis of some densely substituted piperidines functionalized with the trifluoromethyl group (4a-j) was carried out. The newly prepared compounds were subjected to elastase enzyme inhibitory potential and antioxidant activity assays. Among the series, 4i (IC50 = 0.341 ± 0.001 µM) exhibited the maximum inhibition against elastase. Binding analysis delineated that the fluorine atom of ligand 4i showed hydrogen and hydrophobic bonds with Thr41 and Thr96, with bond distances of 3.84 and 5.631 Å, respectively. The obtained results indicate that these trifluoromethyl functionalized piperidine derivatives could be considered as potential candidates to treat skin disorders.

Synthesis of new chiral 1,3,4-thiadiazole-based di- and tri-arylsulfonamide residues and evaluation of in vitro anti-HIV activity and cytotoxicity.

A series of new chiral 1,3,4-thiadiazole-based bis-sulfonamides 4a-4w and tri-sulfonamide analogue 5 was synthesized and evaluated as anti-HIV agents. The reaction of chiral amino acids 1 with sulfonyl chlorides 2, followed by subsequent reaction of resultant N-protected amino acids 2a-2f with thiosemicarbazide in the presence of excess phosphorous oxychloride afforded N-(1-(5-amino-1,3,4-thiadiazol-2-yl)alkyl)-4-arylsulfonamides 3a-3f. Treatment of 2a-2f with substituted sulfonyl chlorides in portions furnished the target bis-sulfonamide analogues 4a-4w in good yields, together with the unexpected 5. The new compounds were assayed against HIV-1 and HIV-2 in MT-4 cells. Compounds 4s were the most active in inhibiting HIV-1 with IC50 = 9.5 µM (SI = 6.6), suggesting to be a new lead in the development of an antiviral agent. Interestingly, compound 5 exhibited significant cytotoxicity of > 4.09 µM and could be a promising antiproliferative agent.

Exploration of thioxothiazolidinone-sulfonate conjugates as a new class of aldehyde/aldose reductase inhibitors: A synthetic and computational investigation.

In the present study, the pharmacophore integration methodology provided an efficient access to a new library of thioxothiazolidinone-sulfonate conjugates (8a-r) from easily available synthetic precursors. The approach was excellently high yielding with flexible structural sites for chemical modifications. The designed hybrid scaffolds were assessed for aldehyde/aldose reductase inhibition activities. The results for the in vitro bioassays were promising with the identification of compound 8e as the lead and selective candidate for ALR2 inhibition with an IC50 value of 0.468±0.003µMas compared to 3.1±0.2µM for the standard (sorbinil), whereas compound 8o demonstrated high inhibitory potency for both ALR2 and ALR1 enzymes. Molecular modeling analysis of the potent compounds provided further insight into the biological properties where detailed binding mode analysis revealed that the conjugates (8a-r) were found stabilized in the active site of the enzymes through the development of a number of interactions with catalytic residues.

Synthesis, characterization and biological evaluation of some 5-methylpyrazine carbohydrazide based hydrazones.

Pyrazine carbohydrazide based hydrazones were synthesized starting from 5-methylpyrazine-2-carboxylic acid. The acid was first converted to its methyl ester, which on further treatment with hydrazine hydrate transformed to carbohydrazide. The carbohydrazide was treated with differently substituted aromatic carbonyl compounds giving hydrazones. Characterization of the synthesized compounds was carried out using modern spectroscopic techniques and unambiguously confirmed through X-ray crystallographic studies of compound 3d. The purity of the compounds was verified using elemental analysis. The target molecules were evaluated for urease inhibition, antioxidant and antimicrobial activity.

Neuronal expression of the intermediate conductance calcium-activated potassium channel KCa3.1 in the mammalian central nervous system.

The expression pattern and functional roles for calcium-activated potassium channels of the KCa2.x family and KCa1.1 have been extensively examined in central neurons. Recent work indicates that intermediate conductance calcium-activated potassium channels (KCa3.1) are also expressed in central neurons of the cerebellum and spinal cord. The current study used immunocytochemistry and GFP linked to KCNN4 promoter activity in a transgenic mouse to determine the expression pattern of KCa3.1 channels in rat or mouse neocortex, hippocampus, thalamus, and cerebellum. KCa3.1 immunolabel and GFP expression were closely matched and detected in both excitatory and inhibitory cells of all regions examined. KCa3.1 immunolabel was localized primarily to the somatic region of excitatory cells in cortical structures but at the soma and over longer segments of dendrites of cells in deep cerebellar nuclei. More extensive labeling was apparent for inhibitory cells at the somatic and dendritic level with no detectable label associated with axon tracts or regions of intense synaptic innervation. The data indicate that KCa3.1 channels are expressed in the CNS with a differential pattern of distribution between cells, suggesting important functional roles for these calcium-activated potassium channels in regulating the excitability of central neurons.

Conjugates of degraded and oxidized hydroxyethyl starch and sulfonylureas: synthesis, characterization, and in vivo antidiabetic activity.

Orally administered drugs usually face the problem of low water solubility, low permeability, and less retention in bloodstream leading to unsatisfactory pharmacokinetic profile of drugs. Polymer conjugation has attracted increasing interest in the pharmaceutical industry for delivering such low molecular weight (Mw) drugs as well as some complex compounds. In the present work, degraded and oxidized hydroxyethyl starch (HES), a highly biocompatible semisynthetic biopolymer, was used as a drug carrier to overcome the solubility and permeability problems. The HES was coupled with synthesized N-arylsulfonylbenzimidazolones, a class of sulfonylurea derivatives, by creating an amide linkage between the two species. The coupled products were characterized using GPC, FT-IR, (1)H NMR, and (13)C NMR spectroscopy. The experiments established the viability of covalent coupling between the biopolymer and N-arylsulfonylbenzimidazolones. The coupled products were screened for their in vivo antidiabetic potential on male albino rats. The coupling of sulfonylurea derivatives with HES resulted in a marked increase of the hypoglycemic activity of all the compounds. 2,3-Dihydro-3-(4-nitrobenzensulfonyl)-2-oxo-1H-benzimidazole coupled to HES10100 was found most potent with a 67% reduction in blood glucose level of the rats as compared to 41% reduction produced by tolbutamide and 38% by metformin.

Aß neurotoxicity depends on interactions between copper ions, prion protein, and N-methyl-D-aspartate receptors.

N-methyl-d-aspartate receptors (NMDARs) mediate critical CNS functions, whereas excessive activity contributes to neuronal damage. At physiological glycine concentrations, NMDAR currents recorded from cultured rodent hippocampal neurons exhibited strong desensitization in the continued presence of NMDA, thus protecting neurons from calcium overload. Reducing copper availability by specific chelators (bathocuproine disulfonate, cuprizone) induced nondesensitizing NMDAR currents even at physiologically low glycine concentrations. This effect was mimicked by, and was not additive with, genetic ablation of cellular prion protein (PrP(C)), a key copper-binding protein in the CNS. Acute ablation of PrP(C) by enzymatically cleaving its cell-surface GPI anchor yielded similar effects. Biochemical studies and electrophysiological measurements revealed that PrP(C) interacts with the NMDAR complex in a copper-dependent manner to allosterically reduce glycine affinity for the receptor. Synthetic human Aß(1-42) (10 nM-5 µM) produced an identical effect that could be mitigated by addition of excess copper ions or NMDAR blockers. Taken together, Aß(1-42), copper chelators, or PrP(C) inactivation all enhance the activity of glycine at the NMDAR, giving rise to pathologically large nondesensitizing steady-state NMDAR currents and neurotoxicity. We propose a physiological role for PrP(C), one that limits excessive NMDAR activity that might otherwise promote neuronal damage. In addition, we provide a unifying molecular mechanism whereby toxic species of Aß(1-42) might mediate neuronal and synaptic injury, at least in part, by disrupting the normal copper-mediated, PrP(C)-dependent inhibition of excessive activity of this highly calcium-permeable glutamate receptor.

Intermediate conductance calcium-activated potassium channels modulate summation of parallel fiber input in cerebellar Purkinje cells.

Encoding sensory input requires the expression of postsynaptic ion channels to transform key features of afferent input to an appropriate pattern of spike output. Although Ca(2+)-activated K(+) channels are known to control spike frequency in central neurons, Ca(2+)-activated K(+) channels of intermediate conductance (KCa3.1) are believed to be restricted to peripheral neurons. We now report that cerebellar Purkinje cells express KCa3.1 channels, as evidenced through single-cell RT-PCR, immunocytochemistry, pharmacology, and single-channel recordings. Furthermore, KCa3.1 channels coimmunoprecipitate and interact with low voltage-activated Cav3.2 Ca(2+) channels at the nanodomain level to support a previously undescribed transient voltage- and Ca(2+)-dependent current. As a result, subthreshold parallel fiber excitatory postsynaptic potentials (EPSPs) activate Cav3 Ca(2+) influx to trigger a KCa3.1-mediated regulation of the EPSP and subsequent after-hyperpolarization. The Cav3-KCa3.1 complex provides powerful control over temporal summation of EPSPs, effectively suppressing low frequencies of parallel fiber input. KCa3.1 channels thus contribute to a high-pass filter that allows Purkinje cells to respond preferentially to high-frequency parallel fiber bursts characteristic of sensory input.

THORACODORSAL ARTERY PERFORATOR FLAP FOR UPPER LIMB RECONSTRUCTION.

BACKGROUND: Thoracodorsal artery perforator flap (TAP) is a feasible option to reconstruct defects in upper limb where only skin and subcutaneous tissue is required. METHODS: This case series was carried out at department of Plastic and Reconstructive Surgery Combined Military Hospital Rawalpindi. A total of 5 patients with upper limb defects were reconstructed with thoracodorsal artery musculocutaneous perforator flaps. Among them, 3 were pedicled and two free TAP flaps. All flaps except one pedicled flap were raised on a single perforator pedicle. Recipient sites were one axilla, two shoulder regions and two hands. The soft tissue defects in the patients had resulted from burns, trauma, wide local excision of synovial sarcoma and surgery for hidradenitis suppurativa. Preoperative hand held Doppler ultrasound was used to locate and mark the perforator. RESULTS: All flaps survived without significant complications. All flaps were hyperemic in the immediate postoperative period. We designed and raised all the five flaps on eccentrically placed perforators. All the raised perforators originated from the descending branch of the thoracodorsal artery. The donor sites were closed primarily with linear scars in all cases except one, in which partial closure was accomplished with split thickness skin grafting (STSG). CONCLUSION: The thoracodorsal artery perforator flap has great potential for reconstructing large, relatively shallow, defects of upper limb because of its suitable skin quality, texture and appropriate thickness, as well as hidden donor site, a reliable pedicle and sparing of muscle unit.

Luteovirus: insights into pathogenicity.

Luteoviruses are economically important plant viruses, infecting almost all cereals throughout the world. Idiosyncrasies related to this virus group may be a strategic consequence of viral genome compression. However, many fundamental questions have yet to be resolved. This review summarizes selected findings covering molecular aspects of pathogenesis relating to plant-infecting RNA viruses in general, and luteoviruses in specific. These studies enhance our understanding of the replication structures and the virus infection pathways.