Botulinum toxin is a highly potent oral and inhalation poison, which means that the toxin must have an efficient mechanism for penetration of epithelial barriers. To date, three models for toxin passage across epithelial barriers have been proposed: (i) the toxin itself undergoes binding and transcytosis; (ii) an auxiliary protein, HA35, transports toxin from the apical to the basal side of epithelial cells; and (iii) an auxiliary protein, HA35, acts on the basal side of epithelial cells to disrupt tight junctions, and this permits paracellular flux of toxin. These models were evaluated by studying toxin absorption following inhalation exposure in mice. Three types of experiments were conducted. In the first, the potency of pure neurotoxin was compared with that of progenitor toxin complex, which contains HA35. The results showed that the rate and extent of toxin absorption, as well as the potency of absorbed toxin, did not depend upon, nor were they enhanced by, the presence of HA35. In the second type of experiment, the potencies of pure neurotoxin and progenitor toxin complex were compared in the absence or presence of antibodies on the apical side of epithelial cells. Antibodies directed against the neurotoxin protected against challenge, but antibodies against HA35 did not. In the final type of experiment, the potency of pure neurotoxin and toxin complex was compared in animals pretreated to deliver antibodies to the basal side of epithelial cells. Once again, antibodies directed against the neurotoxin provided resistance to challenge, but antibodies directed against HA35 did not. Taken collectively, the data indicate that the toxin by itself is capable of crossing epithelial barriers. The data do not support any hypothesis in which HA35 is essential for toxin penetration of epithelial barriers.
We hereby report a patient with seizure disorder who was on long term carbamazepine, admitted with features of thyrotoxicosis and cerebellar dysfunction. Anticonvulsant medications are cerebellar toxins; but in this case, reversal of cerebellar dysfunction was noted upon treatment of thyrotoxicosis with antithyroid drugs.
Ataxia; autoimmune; encephalopathy; thyrotoxicosis
Background and Objectives:
There has been a rapid expansion of the directly observed treatment short-term (DOTS) under the revised national tuberculosis control program throughout India in the last decade. Few reports exist detailing individual DOTS centers’ experiences with regard to extrapulmonary tuberculosis (EPTB) in a medical college hospital setting.
Materials and Methods:
This is a retrospective, record-based study of patients with the diagnosis of EPTB, in all age groups. Data on all consecutive EPTB cases diagnosed at the K. S. Hegde Medical College and Hospital, Deralakatte, Mangalore from 1 January 2005 to 31 December 2011 at the DOTS centre attached to this hospital were collected, analyzed by Mantel-Haenszel Chi square for linear trend and described in proportion or percentages.
Among 1267 cases registered for treatment of all forms of tuberculosis, 528 (41.67%) had EPTB. Around half of the cases of EPTB (269, 51%) were among adult age groups and the majority of cases (342, 64.77%) received Category-I treatment. Pleural TB was the commonest type of EPTB (n = 148, 28.03%), followed by lymph node TB (n = 131, 24.81%). Involvement of lymph nodes was the commonest manifestation among the less than 14 years’ age group (27, 58.7%), while involvement of pleura was more common among > 65 years’ age group (23, 45.1%). The difference in the occurrence of EPTB by site between males and females is statistically significant with a P value of <0.005. There is a significant increase in the number of cases of tuberculosis affecting bones and joints, and other forms of tuberculosis over the years.
The burden of EPTB is more among the productive age group. Increase in the trend of bone and joint tuberculosis, and other rare forms of EPTB is a point of concern highlighting the importance of strengthening the services towards this group.
Directly observed treatment short-course; Extrapulmonary tuberculosis; India; Revised national tuberculosis control program
In the title compound, C17H11BrN2O2, the five-membered isoxazole ring has an envelope conformation with the C atom bearing the phenyl ring as the flap. The pyran ring has a half-chair conformation. In the chromeno ring system, the dihedral angle between the mean plane of the pyran ring and the benzene ring is 4.68 (2)°. The dihedral angle between the mean planes of the chromeno ring system and the isoxazole ring is 13.79 (15)°. The latter forms a dihedral angle of 34.10 (17)° with the phenyl ring. In the crystal, molecules are linked by C—H⋯N hydrogen bonds, forming an undulating two-dimensional network parallel to the ab plane.
In the title compound, C20H19NO5, the dihedral angle between the mean plane of the pyran ring (which has a half-chair conformation) and the benzene ring of the chromeno ring system is 7.21 (7)°. The dihedral angle between the mean plane of the chromeno ring system and the isoxazole ring is 21.78 (6)°, while the isoxazole ring forms a dihedral angle of 72.60 (8)° with the attached phenyl ring. In the crystal, molecules are linked via pairs of C—H⋯O hydrogen bonds, forming inversion dimers with an R
2(10) ring motif. These dimers are linked via C—H⋯N hydrogen bonds, forming chains along .
In the title compound, C18H14N2O2, the pyran ring of the chromeno ring system has a half-chair conformation, and the dihedral angle between its mean plane and the benzene ring is 5.3 (2)°. The isoxazole ring forms a dihedral angle of 74.6 (2)° with the attached benzene ring and is inclined to the mean plane of the chromeno ring system by 15.06 (19)°. In the crystal, there are no significant intermolecular interactions.
In the title compound, C26H27ClN3O3P, the mean plane of the central pyrazole ring forms a dihedral angle of 71.37 (14)° with the chlorophenyl ring. In the crystal, molecules are linked by pairs of N—H⋯O hydrogen bonds, forming inversion dimers with R
2(10) ring motifs. The 3-phenyl ring is disordered with four C atoms occupying two sets of sites with an occupancy ratio of 0.748 (4):0.252 (4).
The evolution of surgical skills and advances in pediatric cardiac intensive care has resulted in Norwood procedure being increasingly performed in emerging economies. We reviewed the feasibility and logistics of performing stage one Norwood operation in a limited-resource environment based on a retrospective analysis of patients who underwent this procedure in our institution.
Retrospective review of medical records of seven neonates who underwent Norwood procedure at our institute from October 2010 to August 2012.
The median age at surgery was 9 days (range 5-16 days). All cases were done under deep hypothermic cardiopulmonary bypass and selective antegrade cerebral perfusion. The median cardiopulmonary bypass (CPB) time was 240 min (range 193-439 min) and aortic cross-clamp time was 130 min (range 99-159 min). A modified Blalock-Taussig (BT) shunt was used to provide pulmonary blood flow in all cases. There were two deaths, one in the early postoperative period. The median duration of mechanical ventilation was 117 h (range 71-243 h) and the median intensive care unit (ICU) stay was 12 days (range 5-16 days). Median hospital stay was 30.5 days (range 10-36 days). Blood stream sepsis was reported in four patients. Two patients had preoperative sepsis. One patient required laparotomy for intestinal obstruction.
Stage one Norwood is feasible in a limited-resource environment if supported by a dedicated postoperative intensive care and protocolized nursing management. Preoperative optimization and prevention of infections are major challenges in addition to preventing early circulatory collapse.
Emerging economy; Norwood procedure; pediatric cardiac intensive care
Molecules of the title compound, C21H24O4, are located on a twofold rotation axis running through the central methylene C atom. The aldehyde group is coplanar with the benzene ring [C—C—C—O = 175.7 (4) °].
In the title compound, C26H27BrN3O3P, the central pyrazole ring forms a dihedral angle of 71.7 (2)° with the bromophenyl ring. In the crystal, molecules are linked by pairs of N—H⋯O hydrogen bonds, forming inversion dimers with R
2(10) ring motifs. Four C atoms of the 3-phenyl ring are disordered over two sets of sites [site occupancies = 0.745 (6) and 0.225 (6)].
In the title compound, C13H14O4S, both C=C double bonds adopt an E conformation. In the crystal, molecules are linked into centrosymmetric R
2(14) dimers via pairs of C—H⋯O hydrogen bonds.
In the title compound, C18H17NO4, the hydroxyethanimine group is essentially coplanar with the ring to which it is attached [C—C—N—O torsion angle = 179.94 (14)°]. The molecules are linked into cyclic centrosymmetric R
2(6) dimers via O—H⋯N hydrogen bonds and the crystal packing is further stabilized by C—H⋯O interactions.
In the title compound, C18H16N2O2, the hydroxyethanimine group is essentially coplanar with the ring to which it is attached (C—C—N—O torsion angle = −176.9°). Molecules are linked into cyclic centrosymmetric R
2(6) dimers via O—H⋯N hydrogen bonds.
Oxidative stress leads to membrane lipid peroxidation, which yields products causing variable degrees of detrimental oxidative modifications in cells. Reactive oxygen species (ROS) are the key regulators in this process and induce lipid peroxidation in Escherichia coli. Application of nonthermal (cold) plasma is increasingly used for inactivation of surface contaminants. Recently, we reported a successful application of nonthermal plasma, using a floating-electrode dielectric-barrier discharge (FE-DBD) technique for rapid inactivation of bacterial contaminants in normal atmospheric air (S. G. Joshi et al., Am. J. Infect. Control 38:293-301, 2010). In the present report, we demonstrate that FE-DBD plasma-mediated inactivation involves membrane lipid peroxidation in E. coli. Dose-dependent ROS, such as singlet oxygen and hydrogen peroxide-like species generated during plasma-induced oxidative stress, were responsible for membrane lipid peroxidation, and ROS scavengers, such as α-tocopherol (vitamin E), were able to significantly inhibit the extent of lipid peroxidation and oxidative DNA damage. These findings indicate that this is a major mechanism involved in FE-DBD plasma-mediated inactivation of bacteria.
In the title compound, C27H30N3O3P, the pyrazole ring is essentially planar [maximum deviation = 0.002 (2) Å] and it forms dihedral angles of 9.3 (1) and 40.2 (1)°, respectively, with the phenyl rings attached to the N and C atoms. In the crystal, pairs of centrosymmetrically related molecules are linked into dimers by N—H⋯O hydrogen bonds.
Introduction and Aim:
Focussed cardiac intensive care is known to produce better outcomes. We have evaluated the benefits of a dedicated Pediatric Cardiac Intensive Care Unit (PCICU) in the early postoperative outcomes of patients undergoing surgery for congenital heart disease.
Prospectively collected data of 634 consecutive patients who underwent congenital heart surgery from September 2008 to September 2009 were analyzed. Midway through this period a dedicated PCICU was started. The patients who were treated in this new PCICU formed the study group (Group B, n = 318). The patients who were treated in a common postoperative cardiac surgery ICU formed the control group (Group A, n = 316). Early postoperative outcomes between the two groups were compared.
The two groups were comparable with respect to demographic data and intraoperative variables. The duration of mechanical ventilation in the dedicated pediatric cardiac ICU group (32.22 ± 52.02 hours) was lower when compared with the combined adult and pediatric surgery ICU group (42.92 ± 74.24 hours, P= 0.04). There was a shorter duration of ICU stay in the dedicated pediatric cardiac ICU group (2.69 ± 2.9 days vs. 3.43 ± 3.80 days, P = 0.001). The study group also showed a shorter duration of inotropic support and duration of invasive lines. The incidence of blood stream infections was also lower in the dedicated pediatric ICU group (5.03 vs. 9.18%, P = 0.04). A subgroup analysis of neonates and infants <1 year showed that the advantages of a dedicated pediatric intensive care unit were more pronounced in this group of patients.
Establishment of a dedicated pediatric cardiac intensive care unit has shown better outcomes in terms of earlier extubation, de-intensification, and discharge from the ICU. Blood stream infections were also reduced.
Pediatric cardiac intensive care; dedicated intensive care unit; intensivist
Several transcription factors determine the cell fate decision between granulocytes and monocytes, but the upstream signal transduction pathways that govern myelopoiesis are largely unknown. Based on our observation of aberrant myeloid cell representation in hematopoietic tissues of 12/15-lipoxygenase (12/15-LOX)-deficient (Alox15) mice, we tested the hypothesis that polyunsaturated fatty acid metabolism regulates myelopoiesis.
Multi-color flow cytometric analysis and methylcellulose assays were used to compare myelopoiesis and the differentiative capacity of progenitors from Alox15 and wild-type mice. Furthermore, we elucidated the mechanism by which 12/15-LOX is involved in regulation of myelopoiesis.
Granulopoiesis in Alox15 mice is increased while monopoiesis is reduced. Moreover, there is an accumulation of granulocyte-macrophage progenitors that exhibit defective differentiation. Mechanistically, we demonstrate that transcriptional activity of Irf8, which regulates myelopoiesis, is impaired in Alox15 progenitors and bone marrow-derived macrophages due to loss of 12/15-LOX-mediated redox regulation of Irf8 nuclear accumulation. Restoration of redox signaling in Alox15 bone marrow cells and GMP reversed the defect in myeloid differentiation.
These data establish 12/15-LOX-mediated redox signaling as a novel regulator of myelopoiesis and Irf8.
Carbon Nanotube/High Density Polyethylene (CNT/HDPE) composites were manufactured and tested to determine their wear behavior. The nanocomposites were made from untreated multi-walled carbon nanotubes and HDPE pellets. Thin films of the precursor materials were created with varying weight percentages of nanotubes (1%, 3%, and 5%), through a process of mixing and extruding. The precursor composites were then molded and machined to create test specimens for mechanical and wear tests. These included small punch testing to compare stiffness, maximum load and work-to-failure and block-on-ring testing to determine wear behavior. Each of the tests was conducted for the different weight percentages of composite as well as pure HDPE as the baseline. The measured mechanical properties and wear resistance of the composite materials increased with increasing nanotube content in the range studied.
The recombinant, catalytically active light chain of botulinum toxin type A was evaluated as a potential vaccine candidate. Previous studies have shown that the light chain can elicit protective immunity in vivo. , but the underlying basis for this observation was not determined. In the present study, antibodies directed against the light chain were shown to act at three different sites in the body to produce neutralization. Firstly, these antibodies acted to block toxin absorption into the body. This was demonstrated in vitro, in studies on binding and transport of toxin across epithelial monolayers, and in vivo, in studies on inhalation poisoning. Secondly, anti-light chain antibodies acted to promote clearance of toxin from the general circulation. This was demonstrated in vivo in studies on toxin levels in blood and in parallel studies on toxin accumulation in liver and spleen. Finally, anti-light chain antibodies acted to protect cholinergic nerves from botulinum toxin action. This was demonstrated in two types of in vitro assays: rate of paralysis of murine phrenic nerve-hemidiaphragm preparations and extent of binding to Neuro-2a cells. When taken together, these data show that anti-light chain antibodies can evoke three layers of protection against botulinum toxin.
Botulinum toxin; Botulism vaccine; Neutralization
Pediatric cardiac intensive care has evolved as a distinct discipline in well-established pediatric cardiac programs in developed nations. With increasing demand for pediatric heart surgery in emerging economies, a number of new programs are being established. The development of robust pediatric cardiac intensive care units (PCICU) is critical to the success of these programs. Because of substantial resource limitations existing models of PCICU care cannot be applied in their existing forms and structure. A number of challenges need to be addressed to deliver pediatric cardiac intensive care in the developing world. Limitations in infrastructure, human, and material resources call for a number of innovations and adaptations. Additionally, a variety of strategies are required to minimize costs of care to the individual patient. This review provides a framework for the establishment of a new PCICU program in face of resource limitations typically encountered in the developing world and emerging economies.
Congenital heart surgery; critical care; developing country
ADAMTS13, a reprolysin-like metalloprotease, limits platelet-rich thrombus formation in the small arteries by cleaving von Willebrand factor (vWF) at the Tyr1605-Met1606 peptide bond. Deficiency of plasma ADAMTS13 activity, due to either an inherited or an acquired etiology, may lead to a potentially lethal syndrome, thrombotic thrombocytopenic purpura (TTP). Molecular cloning and characterization of the ADAMTS13 gene have provided further insight into the structure-function relationships, biosynthesis, and regulation of the ADAMTS13 protease, in addition to understanding the pathogenesis of TTP and perhaps other thrombotic disorders. ADAMTS13 consists of a short propeptide, a typical reprolysin-like metalloprotease domain, followed by a disinte-grin-like domain, first thrombospondin type 1 (TSP1) repeat, Cys-rich domain, and spacer domain. The carboxyl terminus of ADAMTS13 has seven more TSP1 repeats and two CUB domains. ADAMTS13 is synthesized mainly in hepatic stellate cells, but also in vascular endothelial cells. Recognition and cleavage of vWF require the proximal carboxyl terminal domains, but not the middle and distal carboxyl terminal domains. Cleavage of vWF appears to be modulated by shear force, binding to platelet or platelet glycoprotein-1bα, heparin, inflammatory cytokine (interleukin-6), and chloride ion. At the site of thrombus formation, the ADAMTS13 may be inactivated by thrombin, plasmin, and factor Xa. Having a sensitive and specific assay for ADAMTS13 activity is not only critical to understand the basic biology of ADAMTS13 protease, but also to facilitate a more timely and accurate clinical diagnosis of TTP, and to initiate potentially life-saving plasma exchange therapy. Although many assays have been developed and tested for clinical applications, the fluorescent resonance energy transfer-vWF73 assay appears to be the simplest and most promising assay to date.
Thrombotic thrombocytopenic purpura (TTP); von Willebrand factor; microvascular thrombosis; ADAMTS13; metalloprotease; assays; clinical application
Background: Timely error detection including feedback to clinical staff is a prerequisite for focused improvement in patient safety. Real time auditing, the efficacy of which has been repeatedly demonstrated in industry, has not been used previously to evaluate patient safety. Methods successful at improving quality and safety in industry may provide avenues for improvement in patient safety.
Objective: Pilot study to determine the feasibility and utility of real time safety auditing during routine clinical work in an intensive care unit (ICU).
Methods: A 36 item patient safety checklist was developed via a modified Delphi technique. The checklist focused on errors associated with delays in care, equipment failure, diagnostic studies, information transfer and non-compliance with hospital policy. Safety audits were performed using the checklist during and after morning work rounds thrice weekly during the 5 week study period from January to March 2003.
Results: A total of 338 errors were detected; 27 (75%) of the 36 items on the checklist detected ⩾1 error. Diverse error types were found including unlabeled medication at the bedside (n = 31), ID band missing or in an inappropriate location (n = 70), inappropriate pulse oximeter alarm setting (n = 22), and delay in communication/information transfer that led to a delay in appropriate care (n = 4).
Conclusions: Real time safety audits performed during routine work can detect a broad range of errors. Significant safety problems were detected promptly, leading to rapid changes in policy and practice. Staff acceptance was facilitated by fostering a blame free "culture of patient safety" involving clinical personnel in detection of remediable gaps in performance, and limiting the burden of data collection.
Apoptotic host cell death is a critical determinant in the progression of microbial infections and outcome of resultant diseases. The potentially fatal human infection caused by Rickettsia rickettsii, the etiologic agent of Rocky Mountain spotted fever, involves the vascular endothelium of various organ systems of the host. Earlier studies have shown that survival of endothelial cells (EC) during this infection depends on their ability to activate the transcription factor nuclear factor κB (NF-κB). Here, we investigated the involvement of caspase cascades and associated signaling pathways in regulation of host cell apoptosis by NF-κB. Infection of cultured human EC with R. rickettsii with simultaneous inhibition of NF-κB induced the activation of apical caspases 8 and 9 and also the executioner enzyme, caspase 3, whereas infection alone had no significant effect. Inhibition of either caspase-8 or caspase-9 with specific cell-permeating peptide inhibitors caused a significant decline in the extent of apoptosis, confirming their importance. The peak caspase-3 activity occurred at 12 h postinfection and led to cleavage of poly(ADP-ribose) polymerase, followed by DNA fragmentation and apoptosis. However, the activities of caspases 6 and 7, other important downstream executioners, remained unchanged. Caspase-9 activation was mediated through the mitochondrial pathway of apoptosis, as evidenced by loss of transmembrane potential and cytoplasmic release of cytochrome c. These findings suggest that activation of NF-κB is required for maintenance of mitochondrial integrity of host cells and protection against infection-induced apoptotic death by preventing activation of caspase-9- and caspase-8-mediated pathways. Targeted inhibition of NF-κB may therefore be exploited to enhance the clearance of infections with R. rickettsii and other intracellular pathogens with similar survival strategies.
This paper presents the clinical features in 12 patients with the Madras pattern of motor neuron disease (MMND) seen over a period of 10 years. Ten of the patients were from other parts of South India, outside Madras. Young age at onset, sporadic occurrence, sensorineural deafness, bulbar palsy, diffuse atrophy with weakness of limbs and progressive but benign course were the striking features. Electromyography revealed chronic partial denervation. MMND formed 3.7% of all forms of motor neuron disease. Although isolated cases have been seen elsewhere in India, this is the first report of a large number of patients of MMND seen outside Madras (Tamil Nadu). Recognition of this clinical syndrome is of importance for prognostication and as well for search of possible aetiological factors.