The human LMNA gene encodes the essential nuclear envelope proteins lamin A and C (lamin A/C). Mutations in LMNA result in altered nuclear morphology, but how this impacts the mechanisms that maintain genomic stability is unclear. Here, we report that lamin A/C-deficient cells have a normal response to ionizing radiation but are sensitive to agents that cause interstrand cross-links (ICLs) or replication stress. In response to treatment with ICL agents (cisplatin, camptothecin, and mitomycin), lamin A/C-deficient cells displayed normal γ-H2AX focus formation but a higher frequency of cells with delayed γ-H2AX removal, decreased recruitment of the FANCD2 repair factor, and a higher frequency of chromosome aberrations. Similarly, following hydroxyurea-induced replication stress, lamin A/C-deficient cells had an increased frequency of cells with delayed disappearance of γ-H2AX foci and defective repair factor recruitment (Mre11, CtIP, Rad51, RPA, and FANCD2). Replicative stress also resulted in a higher frequency of chromosomal aberrations as well as defective replication restart. Taken together, the data can be interpreted to suggest that lamin A/C has a role in the restart of stalled replication forks, a prerequisite for initiation of DNA damage repair by the homologous recombination pathway, which is intact in lamin A/C-deficient cells. We propose that lamin A/C is required for maintaining genomic stability following replication fork stalling, induced by either ICL damage or replicative stress, in order to facilitate fork regression prior to DNA damage repair.
Aortoesophageal fistulae (AEF) are rare and are associated with very high mortality. Foreign body ingestions remain the commonest cause of AEF seen in children. However in a clinical setting of tuberculosis and massive upper GI bleed, an AEF secondary to tuberculosis should be kept in mind. An early strong clinical suspicion with good quality imaging and endoscopic evaluation and timely aggressive surgical intervention helps offer the best possible management for this life threatening disorder. Our case is a 10-year-old boy who presented to the pediatric emergency with massive bouts of haemetemesis and was investigated and managed by multidisciplinary team effort in the emergency setting.
Aorto-esophageal fistula; children; tuberculosis
Frameshift is one of the three classes of recoding. Frame-shifts lead to waste of energy, resources and activity of the biosynthetic machinery. In addition, some peptides synthesized after frame-shifts are probably cytotoxic which serve as plausible cause for innumerable number of diseases and disorders such as muscular dystrophies, lysosomal storage disorders, and cancer. Hidden stop codons occur naturally in coding sequences among all organisms. These codons are associated with the early termination of translation for incorrect reading frame selection and help to reduce the metabolic cost related to the frameshift events. Researchers have identified several consequences of hidden stop codons and their association with myriad disorders. However the wealth of information available is speckled and not effortlessly acquiescent to data-mining. To reduce this gap, this work describes an algorithmic web based tool to study hidden stops in frameshifted translation for all the lineages through respective genetic code systems.
This paper describes SHIFT, an algorithmic web application tool that provides a user-friendly interface for identifying and analyzing hidden stops in frameshifted translation of genomic sequences for all available genetic code systems. We have calculated the correlation between codon usage frequencies and the plausible contribution of codons towards hidden stops in an off-frame context. Markovian chains of various order have been used to model hidden stops in frameshifted peptides and their evolutionary association with naturally occurring hidden stops. In order to obtain reliable and persuasive estimates for the naturally occurring and predicted hidden stops statistical measures have been implemented.
This paper presented SHIFT, an algorithmic tool that allows user-friendly exploration, analysis, and visualization of hidden stop codons in frameshifted translations. It is expected that this web based tool would serve as a useful complement for analyzing hidden stop codons in all available genetic code systems. SHIFT is freely available for academic and research purpose at http://www.nuccore.org/shift/.
Frameshift; Reading frames; Hidden stop codons; Codon usage
Crossed fused renal ectopia is a rare congenital malformation, which is reported to be usually asymptomatic but may have varied presentations. This survey was conducted to study the clinical profile and the challenges posed in the management of this entity.
Materials and Methods:
Retrospective analysis of 6 patients diagnosed to have crossed fused renal ectopia during 1997-2010. The diagnosis was confirmed during surgical exploration in one patient. In one patient it was detected on antenatal ultrasonography and in the other 4 patients it was detected during investigations for abdominal pain, abdominal mass, anorectal malformation and urinary tract infection.
The left moiety was crossed and fused with the right moiety in 4 cases. Ultrasonography was found to be a good screening investigation with useful diagnostic contributions from CT scans, radionuclide scintigraphy and magnetic resonance urography. Micturating cystourethrography revealed presence of VUR in 4 cases, 3 of whom have undergone ureteric reimplantation. Two patients required pyeloplasty for pelviureteric junction obstruction; in one of these patients the upper ureter was entrapped in the isthmus. In one patient, a non-functioning moiety resulted in nephrectomy. All children were asymptomatic at last follow-up with stable renal functions.
Crossed fused renal ectopia was detected in most patients during investigation for other problems. It was found more commonly in boys. The left moiety was crossed to the right in the majority of cases. Associated urological problems were found in most cases and required the appropriate surgical management.
Congenital anomalies of kidney; crossed fused renal ectopia; fusion anomalies of kidney
Bedside monitoring of cerebral metabolism in traumatic brain injury (TBI) with microdialysis is gaining wider clinical acceptance. The objective of this study was to examine the relationship between the fundamental physiological neuromonitoring modalities intracranial pressure (ICP), cerebral perfusion pressure (CPP), brain tissue oxygen (PbtO2), and cerebrovascular pressure reactivity index (PRx), and cerebral chemistry assessed with microdialysis, with particular focus on the lactate/pyruvate (LP) ratio as a marker of energy metabolism. Prospectively collected observational neuromonitoring data from 97 patients with TBI, requiring neurointensive care management and invasive cerebral monitoring, were analyzed. A linear mixed model analysis was used to account for individual patient differences. Perilesional tissue chemistry exhibited a significant independent relationship with ICP, PbtO2 and CPP thresholds, with increasing LP ratio in response to decrease in PbtO2 and CPP, and increase in ICP. The relationship between CPP and chemistry depended upon the state of PRx. Within the studied physiological range, tissue chemistry only changed in response to increasing ICP or drop in PbtO2<1.33 kPa (10 mmHg). In agreement with previous studies, significantly higher levels of cerebral lactate (p<0.001), glycerol (p=0.013), LP ratio (p<0.001) and lactate/glucose (LG) ratio (p=0.003) were found in perilesional tissue, compared to “normal” brain tissue (Mann-Whitney test). These differences remained significant following adjustment for the influences of other important physiological parameters (ICP, CPP, PbtO2, PbtCO2, PRx, and brain temperature; mixed linear model), suggesting that they may reflect inherent tissue properties related to the initial injury. Despite inherent biochemical differences between less-injured brain and “perilesional” cerebral tissue, both tissue types exhibited relationships between established physiological variables and biochemistry. Decreases in perfusion and oxygenation were associated with deteriorating neurochemistry and these effects were more pronounced in perilesional tissue and when cerebrovascular reactivity was impaired.
autoregulation; brain injury; CPP; ICP; microdialysis
A variety of psychiatric disorders including depression have been reported in patients suffering from incontinence. It is uncertain if the association between incontinence and depression is causal or is related to a third common factor. We report the case of a 48-year-old man who presented with incontinence of urine and faeces along with a severe depressive episode. No organic cause could be identified for the incontinence. The depressive symptoms as well as the incontinence resolved with treatment with reboxetine and aripiprazole. However, the patient developed a manic episode. This case supports the hypothesis that incontinence and depression may share a common pathogenesis. The authors review the literature to investigate this linkage. The combination of aripiprazole and reboxetine should be used cautiously when treating first episode depression as it can induce a manic switch. Previous reports of manic switch with aripiprazole and reboxetine are reviewed.
Backgrounds and Objectives:
Lumbar-to-thoracic advancement of epidural catheter is a safe alternative to direct thoracic placement in children. In this prospective randomized study, success rate of advancement of two different types and gauges of catheter from lumbar-to-thoracic space were studied.
Materials and Methods:
Forty ASA I and II children (up to 6 years) undergoing thoracic or upper-abdominal surgery were allocated to either Group I (18G catheter) or Group II (23G catheter). After induction of general anesthesia a pre-determined length of catheter was inserted. Successful catheter placement was defined as the catheter tip within two segment of surgical incision in radio-contrast study. Intra-operative analgesia was provided by epidural bupivacaine and intravenous morphine. Post-operative analgesia was provided with epidural infusion of 0.1% bupivacaine+1mcg/ml fentanyl.
Observations and Results:
Catheter advancement was successful in 3 cases in Group I and 2 cases in Group II. Five different types of catheter positions were found on X-ray. Negative correlation was found between age and catheter advancement [significance (2-tailed) =0.03]. However, satisfactory post-operative analgesia was obtained in 35 cases. Positive correlation was found between infusion rate, the number of segment of gap between desired level and the level reached [significance (2-tailed) =0.00]. 23G catheter use was associated with more technical complications.
Advancement of epidural catheter from lumbar to thoracic level was successful in only 10-15% cases but satisfactory analgesia could be provided by increasing the infusion rates.
Advancement of epidural catheter; children; lumbar to thoracic space
Salmonella enteric serovar Typhi Ty2 is a human specific pathogen and an etiological agent for typhoid fever. Most of Salmonella
serotypes produce glycogen which has a comparatively minor role in virulence and colonization, but has a more significant role in
survival. Enzymes present in glycolytic pathway of bacteria help bacteria to survive by activating other factors inside host.
Numerous pathogenic bacteria species intervene with the plasminogen system, and this plasminogen–enolase association may play
a critical role in the virulence of S. Typhi by causing direct damage to the host cell extracellular matrix, possibly by enzymic
degradation of extracellular matrix proteins or other protein constituents. In this study, molecular modelling of enolase of
Salmonella has been accomplished in silico by comparative modelling; we have then analyzed Human alpha enolase which is a
homodimer and serves on epithelial cells with our model. Both Structures were docked by D-tartronate semialdehyde phosphate
(TSP) and 3-aminoenolpyruvate phosphate (AEP) enolase inhibitors. Our study shows that salmonella enolase and human enolase
have different active sites in their structure. This will help in development of new ligands, more suitable for inhibiting bacterial
survival inside host as vaccines for typhoid fever are not fully protective. The study also confirmed that enolase Salmonella and
Human Plasminogen suggested direct physical interaction between both of them as the activation loop of plasminogen residues
showed conformational changes similar to the tissue type plasminogen activator. Various computational biology tools were used
for our present study such as Modeller, Molegro Virtual Docker, Grommacs.
Salmonella Ty2; TSP (D-tartronate semialdehyde phosphate); AEP (3-aminoenolpyruvate phosphate); Modelling; Docking
New drug discovery is facing serious challenges due to reduction in number of new drug approvals coupled with exorbitant rising cost. Advent of combinatorial chemistry provided new hope of higher success rates of new chemical entities (NCEs); however, even this scientific development has failed to improve the success rate in new drug discovery. This scenario has prompted us to come out with a novel approach of integrated drug discovery, where Ayurvedic wisdom can synergize with drug discovery from plant sources. Initial steps in new drug discovery involve identification of NCEs, which can be either sourced through chemical synthesis or can be isolated from natural products through biological activity guided fractionation. The sources of many of the new drugs and active ingredients of medicines are derived from natural products. The starting point for plant-based new drug discovery should be identification of the right candidate plants by applying Ayurvedic wisdom, traditional documented use, tribal non-documented use, and exhaustive literature search. Frequency analysis of the ingredients of the ancient documented formulations and analysis of their Ayurvedic attributes may provide an in-depth idea of the predominance of particular Ayurvedic characteristics based on which appropriate candidate plants may be selected for bioactivity-based fractionation. The integration of Ayurvedic wisdom with drug discovery also brings the need for a paradigm shift in the extraction process from sequential to parallel extraction. Bioassay-guided fractionation of the identified plant may lead to standardized extract or isolated bioactive druggable compound as the new drug. This integrated approach would lead to saving of cost and time, coupled with enhanced success rate in drug discovery.
Ayurveda; biological activity; drug discovery; extraction; fractionation; plant
In order to survive, cells have evolved highly effective repair mechanisms to deal with the potentially lethal DNA damage produced by exposure to endogenous as well as exogenous agents. Ionizing radiation exposure induces highly lethal DNA damage, especially DNA double-strand breaks (DSBs), that is sensed by the cellular machinery and then subsequently repaired by either of two different DSB repair mechanisms: (1) non-homologous end joining, which re-ligates the broken ends of the DNA and (2) homologous recombination, that employs an undamaged identical DNA sequence as a template, to maintain the fidelity of DNA repair. Repair of DSBs must occur within the natural context of the cellular DNA which, along with specific proteins, is organized to form chromatin, the overall structure of which can impede DNA damage site access by repair proteins. The chromatin complex is a dynamic structure and is known to change as required for ongoing cellular processes such as gene transcription or DNA replication. Similarly, during the process of DNA damage sensing and repair, chromatin needs to undergo several changes in order to facilitate accessibility of the repair machinery. Cells utilize several factors to modify the chromatin in order to locally open up the structure to reveal the underlying DNA sequence but post-translational modification of the histone components is one of the primary mechanisms. In this review, we will summarize chromatin modifications by the respective chromatin modifying factors that occur during the DNA damage response.
histone modifications; DNA repair
Congenital airway anomalies can be asymptomatic or may cause severe respiratory distress requiring immediate treatment. These anomalies can present early in life, or may be just incidental findings. It is important to recognize these entities to realize their clinical significance and to avoid false diagnosis. In this article, the various congenital airway anomalies and their imaging features by multidetector computed tomography (MDCT) are reviewed in order of occurrence during the embryological timeline. This pictorial essay reviews the various distinct congenital airway lesions and their MDCT manifestations. It also provides insight into the embryological basis of the congenital airway lesions encountered.
Airway; Anomalies; Computed tomography; Congenital
Thrombosis of superior ophthalmic veins (SOV) is a well known entity occurring secondary to varied etiologies. We describe diffusion restriction in thrombosed SOV in two cases of different etiologies- bilateral involvement in a patient with septic cavernous sinus thrombosis (CST) and another where embolisation of an indirect carotico-cavernous fistula (CCF) resulted in complete SOV thrombosis accompanied by clinical worsening. Our cases add to the limited literature on diffusion findings in SOV thrombosis.
thyroid abscess; suppurative thyroiditis; bacterial throat infection
To evaluate the outcome following transarterial chemoembolization (TACE) and to identify the predictors of survival in patients with unresectable hepatocellular carcinoma (HCC).
Material and Methods:
HCC patients reporting to our hospital (2001-2007) were subjected to clinical, biochemical, and radiological examination. TACE was performed in those who fulfilled the inclusion criteria. Follow-up assessment was done with multiphase CT scan of the liver at 1, 3, and 6 months. Tumor response and survival rate were estimated. Univariate and multivariate analyses were done for determinants of survival.
A total of 73 patients (69 males, 4 females; mean age 49±13.4 years) were subjected to 123 sessions of TACE. The Child's classification was: A – 56 patients and B – 17 patients. Barcelona Clinic staging was: A – 20 patients, B – 38 patients, and C – 15 patients. Tumor size was ≤5cm in 28 (38%) patients, >5–10 cm in 28 (38%) patients, and >10 cm in 17 (23%) patients. Median follow-up was for 12 months (range: 1–77 months). No significant postprocedure complications were encountered. Overall survival rate was 66%, 47%, and 36.4% at 1, 2, and 3 years, respectively. Tumor size emerged as an important predictor of survival.
TACE offers a reasonable palliative therapy for HCC. Initial tumor size is an independent predictor of survival.
Hepatocellular carcinoma; survival rate; transarterial chemoembolisation
Dental implants have long provided an excellent treatment option to restore edentulous spaces. Successful formation of a direct bone to implant interface is the goal in implant therapy. Immediate loading is an alternative to two stage surgical procedure. Improved surgical instrumentation implants design, and surface topography changes the concept of two stages surgical to one stage surgical procedure.
Bicortica-Schraube Roentgen Indikator; Bone graft material
Concentrations of unbound meropenem in the cerebral extracellular fluid (ECF) of two patients with acute brain injury were assessed by microdialysis. Brain ECF unbound-meropenem concentrations were lower than serum unbound-meropenem concentrations, with brain-to-serum area under the concentration-time curve ratios of 0.73 and 0.14. A pharmacokinetic model was developed to fit the experimental data adequately.
AIM: To highlight various patterns of nodal involvement and post treatment changes in pediatric chest tuberculosis based on contrast enhanced computed tomography (CECT) scans of chest.
METHODS: This was a retrospective study consisting of 91 patients aged less than 17 years, who attended Paediatrics OPD of All India Institute of Medical Sciences with clinically diagnosed tuberculosis or with chest radiographs suggestive of chest tuberculosis. These patients had an initial chest radiograph as well as CECT of the chest and follow up imaging after 6 mo, and in some cases 9 mo, of completion of anti-tubercular treatment (ATT). CECT of these patients was reviewed for the location and extent of nodal involvement along with determination of site, size, enhancement pattern and calcification.
RESULTS: Enlargement of mediastinal or hilar lymph nodes was found in 88/91 patients (96.7%), with the most common locations being paratracheal (84.1%), and subcarinal (76.1%). The most common pattern of enhancement was found to be inhomogenous. The nodes were conglomerate in 56.8% and discrete in 43.2%. In addition, perinodal fat was obscured in 84.1% of patients. In the post-treatment scan, there was 87.4% reduction in the size of the nodes. All nodes post-treatment were discrete and homogenous with perinodal fat present. Calcification was found both pre- and post-treatment, but there was an increase in incidence after treatment (41.7%). There was hence a reduction in size, change in enhancement pattern, and appearance of perinodal fat with treatment.
CONCLUSION: Tubercular nodes have varied appearance and enhancement pattern. Conglomeration and obscuration of perinodal fat suggest activity. In residual nodes decision to continue ATT requires clinical correlation.
Tuberculosis; Lymph nodes; Contrast enhanced computed tomography
The human MOF gene encodes a protein that specifically acetylates histone H4 at lysine 16 (H4K16ac). Here we show that reduced levels of H4K16ac correlate with a defective DNA damage response (DDR) and double-strand break (DSB) repair to ionizing radiation (IR). The defect, however, is not due to altered expression of proteins involved in DDR. Abrogation of IR-induced DDR by MOF depletion is inhibited by blocking H4K16ac deacetylation. MOF was found to be associated with the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a protein involved in nonhomologous end-joining (NHEJ) repair. ATM-dependent IR-induced phosphorylation of DNA-PKcs was also abrogated in MOF-depleted cells. Our data indicate that MOF depletion greatly decreased DNA double-strand break repair by both NHEJ and homologous recombination (HR). In addition, MOF activity was associated with general chromatin upon DNA damage and colocalized with the synaptonemal complex in male meiocytes. We propose that MOF, through H4K16ac (histone code), has a critical role at multiple stages in the cellular DNA damage response and DSB repair.
Designing a vaccine for a disease is one of the crucial tasks that involve millions and billions of dollars, several decades and yet there is no guarantee of
successful results. Several pharmaceutical companies are investing their money and time in such activities. Computational biology could be of great help
in these activities by proving a library of plausible candidates that might actually show some positive responses. MHC binding peptide prediction is one
such area where the immense power of computers could be used to get a breakthrough. In this direction several databases and servers have been
developed by many labs to predict the MHC binding peptides. These short peptides on the antigen surface are recognized by the MHC molecule and are
presented to the receptors of T-cells for further immune response. Peptides that bind to a given MHC molecule share sequence similarity. Here we present
a comparative study of servers that can predict the MHC binding peptides in a given protein sequence of the antigen. Based on this comparative analysis
on HIV data, we are able to propose a library of putative vaccine candidates for the env GP-160 protein of HIV-1.
MHC; MHC binding peptides; HIV-1; epitopic library; putative vaccine candidates
Abernethy malformation is an extremely rare anomaly of the splanchnic venous system. We describe multidetector computed tomography findings of an incidentally detected Abernethy malformation with portal vein aneurysm in a two-and-half-year old child. The computed tomography scan was performed for the evaluation of respiratory distress, poor growth, and loss of appetite.
Abernethy malformation; multidetector computed tomography; portal vein aneurysm
Congenital anomalies of the male urogenital tract are common. Some lesions like posterior urethral valve or anterior urethral diverticulum tend to present early in infancy and are often easily diagnosed on conventional contrast voiding cystourethrograms. Other conditions like posterior urethral diverticulum or utricle can be relatively asymptomatic and therefore present late in childhood. We present the spectrum of imaging findings of common and uncommon anomalies involving the male urethra. Since the pediatric radiologist is often the first to make the diagnosis, he or she should be well aware of these conditions.
Congenital urethral anomalies; intravenous urogram; voiding cystourethrogram
Use of a fixed threshold value for tumor volume delineation in positron emission tomography (PET) images will ignore the effect of size of the lesion and source to background ratio (SBR). The purpose of this Phantom study was to evaluate the effect of the size of the lesion and SBR on the threshold to be used for PET tumor volume delineation.
Materials and Methods:
Phantom used in the study comprised a sphere–cylinder assembly containing six spheres of different inner diameters (1.10, 1.35, 1.44, 1.50, 1.83 and 1.93 cm) with inner volumes of 0.70, 1.30, 1.50, 1.77, 3.22 and 3.82 cm3, respectively. The scans were acquired with SBR of 6:01, 7:01, 8:01 and 10:01. These SBRs were calculated from 42 patients with lymphoma to simulate clinical images. PET tumor volume was calculated using RT_Image software at different threshold values (40, 45, 50, 55, 60, 65, 70 and 75% of SUVmax) for each sphere at different SBRs. The threshold intensity value at which the calculated volume was nearly equal to actual volume of spheres was considered as the standardized threshold intensity (STI) value.
STI values depended on the diameter of the sphere and not on the SBR. It is found that 40% threshold is suitable for calculating the volume of any lesion with diameter greater than 1.83 cm, 60% for diameter greater than 1.35 cm but less than 1.83 cm, and 75% for diameter less than 1.35 cm.
Size-dependent thresholding is an accurate and reproducible method of tumor volume delineation on PET-computed tomography (CT).
Positron emission tomography—computed tomography; phantom thresholding; tumor volume
Congenital posterior urethral diverticulum is an uncommon anomaly, sometimes complicated by infection or calculi formation. A conventional voiding cystourethrogram (VCUG) is the most commonly used diagnostic modality. Dynamic magnetic resonance imaging (MRI) has not been frequently described in this entity. We describe a case of posterior urethral diverticulum complicated with secondary calculi, where the patient was evaluated using dynamic MRI and conventional VCUG.
Dynamic MRI; posterior urethral diverticulum; voiding cystourethrogram
This commentary considers some of the factors that affect cerebral glucose metabolism in patients with traumatic brain injury. A study recently reported in Critical Care suggested a blood glucose range that may optimize cerebral glucose utilization; the findings of this study are evaluated and discussed. Some of the mechanisms of cerebral glucose control are explored, including the impact of intensive insulin therapy on cerebral metabolism.