A comparative study of NONOate based NO donors: spermine NONOate is the best suited NO donor for angiogenesis.

Nitric oxide (NO) is a known modulator of angiogenesis. The NONOate subfamily of NO donors has long been used in experimental and clinical studies to promote angiogenesis. However, no studies have been conducted yet to compare the angiogenesis potential of these NO donors in respect to their pattern of NO release. We hypothesize that having different pattern of NO release, each of the NO donors in NONOate subfamily can promote key stages of angiogenesis in differential manner. To verify our hypothesis, NO donors with half life ranging from seconds to several hours and having very different pattern of NO release were selected to evaluate their efficacy in modulating angiogenesis. Endothelial tube formation using EAhy926 cells was maximally increased by Spermine NONOate (SP) treatment. SP treatment maximally induced both ex vivo and in vivo angiogenesis using egg yolk and cotton plug angiogenesis models respectively. Experiment using chick embryo partial ischemia model revealed SP as the best suited NO donor to recover ischemia driven hampered angiogenesis. The present study elaborated that differential release pattern of NO by different NO donors can modulate angiogenesis differentially and also suggested that SP have a unique pattern of NO release that best fits for angiogenesis.

A Monte Carlo tool for evaluating VMAT and DIMRT treatment deliveries including planar detectors.

The aim of this work is to describe and validate a new general research tool that performs Monte Carlo (MC) simulations for volumetric modulated arc therapy (VMAT) and dynamic intensity modulated radiation therapy (DIMRT), simultaneously tracking dose deposition in both the patient CT geometry and an arbitrary planar detector system. The tool is generalized to handle either entrance or exit detectors and provides the simulated dose for the individual control-points of the time-dependent VMAT and DIMRT deliveries. The MC simulation tool was developed with the EGSnrc radiation transport. For the individual control point simulation, we rotate the patient/phantom volume only (i.e. independent of the gantry and planar detector geometries) using the gantry angle in the treatment planning system (TPS) DICOM RP file such that each control point has its own unique phantom file. After MC simulation, we obtained the total dose to the phantom by summing dose contributions for all control points. Scored dose to the sensitive layer of the planar detector is available for each control point. To validate the tool, three clinical treatment plans were used including VMAT plans for a prostate case and a head-and-neck case, and a DIMRT plan for a head-and-neck case. An electronic portal imaging device operated in 'movie' mode was used with the VMAT plans delivered to cylindrical and anthropomorphic phantoms to validate the code using an exit detector. The DIMRT plan was delivered to a novel transmission detector, to validate the code using an entrance detector. The total MC 3D absolute doses in patient/phantom were compared with the TPS doses, while 2D MC doses were compared with planar detector doses for all individual control points, using the gamma evaluation test with 3%/3 mm criteria. The MC 3D absolute doses demonstrated excellent agreement with the TPS doses for all the tested plans, with about 95% of voxels having γ <1 for the plans. For planar dosimetry image comparisons, we defined an acceptable pass rate of >90% of percentage pixels with γ <1. We found that over 90% of control points in the plans passed this criterion. In general, our results indicate that the simulation tool is suitable for accurately calculating both patient/phantom doses and planar doses for VMAT dose delivery. The tool will be valuable to check performance and advance the development of in vivo planar detectors for use in measurement-based VMAT dose verification. In addition, the tool can be useful as an independent research tool for VMAT commissioning of the TPS and delivery system.

Thalidomide attenuates nitric oxide-driven angiogenesis by interacting with soluble guanylyl cyclase.

BACKGROUND AND PURPOSE: Nitric oxide (NO) promotes angiogenesis by activating endothelial cells. Thalidomide arrests angiogenesis by interacting with the NO pathway, but its putative targets are not known. Here, we have attempted to identify these targets. EXPERIMENTAL APPROACH: Cell-based angiogenesis assays (wound healing of monolayers and tube formation in ECV304, EAhy926 and bovine arterial endothelial cells), along with ex vivo and in vivo angiogenesis assays, were used to explore interactions between thalidomide and NO. We also carried out in silico homology modelling and docking studies to elucidate possible molecular interactions of thalidomide and soluble guanylyl cyclase (sGC). KEY RESULTS: Thalidomide inhibited pro-angiogenic functions in endothelial cell cultures, whereas 8-bromo-cGMP, sildenafil (a phosphodiesterase inhibitor) or a NO donor [sodium nitroprusside (SNP)] increased these functions. The inhibitory effects of thalidomide were reversed by adding 8-bromo-cGMP or sildenafil, but not by SNP. Immunoassays showed a concentration-dependent decrease of cGMP in endothelial cells with thalidomide, without affecting the expression level of sGC protein. These results suggested that thalidomide inhibited the activity of sGC. Molecular modelling and docking experiments revealed that thalidomide could interact with the catalytic domain of sGC, which would explain the inhibitory effects of thalidomide on NO-dependent angiogenesis. CONCLUSION AND IMPLICATIONS: Our results showed that thalidomide interacted with sGC, suppressing cGMP levels in endothelial cells, thus exerting its anti-angiogenic effects. These results could lead to the formulation of thalidomide-based drugs to curb angiogenesis by targeting sGC.

Poster - Thurs Eve-33: Initial implementation of a novel, measurement-based IMRT QA method.

Current measurement-based QA for IMRT typically involves a composite dose delivery to a phantom. However, this approach does not allow a direct dosimetric evaluation of the delivered treatment with respect to the patient anatomy. In this work we implement a novel, measurement-based IMRT QA method which provides an accurate reconstruction of the 3D-dose distribution in the patient model. The RPC Head&Neck phantom and two clinical prostate cases have been examined to date. Step & shoot plans were developed satisfying required dose metrics. A 2D-array of dose chambers (MatriXX, IBA Dosimetry) was mounted on a linear accelerator to capture delivered fluence. The measurement data were read directly by the control software (COMPASS, IBA Dosimetry), which also provides the ability to import patient plan data from the TPS. The COMPASS software also includes a dose calculation engine and head fluence model and requires beam commissioning procedures analogous to those of a TPS. Reconstructed doses and DVHs were compared to those calculated by the TPS. The beam model in the COMPASS software was able to predict percentage depth dose and X and Y profiles for MLC-defined apertures ranging from 1×1-20×20 cm∧2 to within 1.5% (depth-dose), 2.0% (in-field profiles), and 2.5% (out-of-field profiles). Reconstructed doses in the test plans were mostly within 2% of those in the TPS. DVHs compared to <1.2%. Reconstructed doses were overlaid on CT data and contoured structures, to enable a clinically useful understanding of discrepancies as compared to the TPS plan. Research partially sponsored by IBA Dosimetry.

Anti-inflammatory activity of Justicia prostrata gamble in acute and sub-acute models of inflammation.

In this study, the aqueous (AQJP) and alcoholic (ALJP) extracts of the whole plant of Justicia prostrata Gamble (Acanthaceae) were screened for their acute and subacute anti-inflammatory activities using carrageenan-induced acute inflammation and cotton-pellet-induced granuloma (subacute inflammation), respectively, in rats. In the carrageenan-induced rat paw oedema model, both extracts were found to exhibit maximum reduction in paw volume at the first hour in a dose-dependent manner. At the dose of 500 mg/kg p.o., both extracts AQJP and ALJP showed maximum inhibition (51.39% and 62.5%, respectively) in rat paw oedema volume at the first hour of carrageenan-induced acute inflammation. In the cotton pellet granuloma assay, AQJP and ALJP at the dose of 500 mg/kg p.o. suppressed the transudative, exudative and proliferative phases of chronic inflammation. These extracts were able to (i) reduce the lipid peroxide content of exudates and liver and (ii) normalize the increased activity of acid and alkaline phosphatases in serum and liver of cotton pellet granulomatous rats. Preliminary phytochemical screening revealed the presence of lignans, triterpenes and phenolic compounds in ALJP, whereas phenolic compounds and glycosides in AQJP. The anti-inflammatory properties of these extracts may possibly be due to the presence of phenolic compounds. The anti-inflammatory effects produced by the extracts at the dose of 500 mg/kg, p.o. was comparable with the reference drug diclofenac sodium (5 mg/kg p.o.).

The plant vacuolar sorting receptor AtELP is involved in transport of NH(2)-terminal propeptide-containing vacuolar proteins in Arabidopsis thaliana.

Many soluble plant vacuolar proteins are sorted away from secreted proteins into small vesicles at the trans-Golgi network by transmembrane cargo receptors. Cleavable vacuolar sorting signals include the NH(2)-terminal propeptide (NTPP) present in sweet potato sporamin (Spo) and the COOH-terminal propeptide (CTPP) present in barley lectin (BL). These two proteins have been found to be transported by different mechanisms to the vacuole. We examined the ability of the vacuolar cargo receptor AtELP to interact with the sorting signals of heterologous and endogenous plant vacuolar proteins in mediating vacuolar transport in Arabidopsis thaliana. AtELP extracted from microsomes was found to interact with the NTPPs of barley aleurain and Spo, but not with the CTPPs of BL or tobacco chitinase, in a pH-dependent and sequence-specific manner. In addition, EM studies revealed the colocalization of AtELP with NTPP-Spo at the Golgi apparatus, but not with BL-CTPP in roots of transgenic Arabidopsis plants. Further, we found that AtELP interacts in a similar manner with the NTPP of the endogenous vacuolar protein AtALEU (Arabidopsis thaliana Aleu), a protein highly homologous to barley aleurain. We hypothesize that AtELP functions as a vacuolar sorting receptor involved in the targeting of NTPP-, but not CTPP-containing proteins in Arabidopsis.

Air leaks from the respiratory tract in mechanically ventilated children with severe respiratory disease.

Our objectives were to evaluate the frequency of air leaks (AL) from the respiratory tract (pneumothorax, pneumomediastinum, pneumoperitoneum, subcutaneous emphysema) in critically ill children on mechanical ventilation (MV) for severe respiratory diseases, and to examine whether AL could be correlated with specific clinical events or ventilator settings. The study constitutes a retrospective cohort of 80 consecutive critically ill children receiving MV for severe respiratory diseases between 1986 and 1993. Patients (mean age 2.9 +/- 0.6 years, 49 males and 31 females), were admitted to the Pediatric Intensive Care Unit (PICU) with acute respiratory syndrome (ARDS) (27%), asthma (15%), bronchiolitis (10%), pneumonia (21%), pulmonary congenital diseases (9%), or foreign body aspiration (18%). Patients were divided into two groups; those with AL (n=22) and those without air-leaks (non-AL) (n = 58). Air leaks developed in 22 of 80 patients or in 27.5%. Survival was significantly lower in the AL group, compared to the non-AL group (41% vs. 76%, P < 0.01). The odds ratio that a patient with multiple organ system failure (MOSF) or infection would develop AL was 2.96 and 2.19, respectively. Candida and Pseudomonas species were recovered with significantly higher frequency in the AL group compared with the non-AL group (P < 0.025). There was a strong positive correlation between the incidence of AL and high ventilatory pressures (PIP 36 vs. 29.7 cm H(2)O, P < 0.001), or large tidal volumes (V(T) 12 vs. 9 mL/kg, P < 0.05), suggesting that large volumes might elicit injury to the pulmonary epithelium. Multiple logistic regression analysis showed that only V(T) was independently associated with the development of AL in children with primary severe respiratory disease (r(2) = -0.38, P = 0.01). In conclusion, MV will produce AL, particularly when high peak airway pressures (barotrauma) or large tidal volumes (volotrauma) are delivered by the ventilator. Sepsis, MOSF, and lung superinfection with Pseudomonas or Candida species may be also important factors in the development of AL in critically ill children.

Basal ganglia calcification.

Basal ganglia calcification (BGC) is now being diagnosed with increasing frequency with widespread application of computed tomography (CT) in clinical practice and is no more considered a rarity. During the period 1987 to 1995, 42 patients were noted to have BGC and it constituted 0.93% of all CT scan of brain carried out during the relevant period. These patients presented with diverse neurological and endocrine disorders i.e., epilepsy (22 patients), mental retardation (five patients), extra-pyramidal syndromes (five patients), abnormal behaviour (three patients), stroke (two patients), raised intracranial tension without localizing signs (one patient), following radiotherapy (one patient), and with hypoparathyroidism (three patients). These patients were noted to have variable degree of calcification in different parts of brain i.e., basal ganglia (42 cases), cerebellum (12 cases) and cerebral cortex (nine cases). Family history of a neurological disorder was available in five patients. This study highlights the fact that calcification of basal ganglia and other parts of the brain is often a nonspecific finding on CT scan and it may not be possible to establish a clinicopathological correlation.

Eosinophilic gastroenteritis--an Indian experience.

Eosinophilic gastroenteritis is an uncommon disorder with varied presentation. Records of 7 patients (6 men) with eosinophilic gastroenteritis, presenting to a large referral hospital over a 10-year period, were analyzed. The patients were young adults (mean age 32 years) with short duration (median 2 months) of illness. Symptoms included abdominal pain and vomiting (100%), weight loss (57%), diarrhea (43%) and abdominal distension (43%). Peripheral eosinophilia was present in all the patients. The diagnosis was made at duodenal (2 patients) or cecal (1) biopsy or surgical full-thickness jejunal biopsy (4). Three patients had predominantly mucosal disease (Klein type I), whereas two patients each had predominantly muscular (type II) and submucosal (type III) disease. Surgical resection was curative in one patient with type II disease. The other six responded to prednisolone, with complete resolution in one patient.

Trends of smoking among medical students.

The overall smoking prevalence among male medical students between the years 1955 and 1988 in a medical college in South India was 39.51 per cent. The trends of smoking appeared to be in three phases. An initial phase comprising of a steady rise to a peak in the late sixties and seventies, followed by a plateau of the prevalence in the next ten years and ultimately a sharp fall in the last five years. Study based on a mailed-in questionnaire to ten batches of students selected randomly, to study the factors affecting initiation and quitting of smoking showed that the peak period of initiation seemed to be in the two years before and after joining the course. There was a significant relationship between the presence of a smoker in the family and picking up the habit. Conversely, no significant relationships were found with respect to quitting.

Albendazole therapy for neurocysticercosis.

Based on clinical evaluation and computed tomography (CT) of the brain, 30 cases of neurocysticercosis were diagnosed. Diagnosis was supported by presence of histopathologically proven subcutaneous cysticerci in 12 cases. Three primary neurological syndromes were established i.e. epilepsy in 22 cases, increased intracranial tension in 6 cases and meningoencephalitis in 2 cases. Albendazole was administered orally in a dose of 15 mg/kg bodyweight/day for 30 days without prophylactic steroids. Follow up CT study at 3 months and 12 months revealed complete regression of all lesions in 2 cases, partial regressions in 14 cases and change in morphology in 4 cases. Transient appearence of fresh subcutaneous cysticerci as a side effect of therapy was noted in 4 cases. Albendazole, though acting slow, is considered a suitable alternative to praziquantel in medical management of parenchymal neurocysticercosis.

The use of drugs in emergency airway management in pediatric trauma.

Most patients who require emergency airway control receive drugs to induce rapidly sufficient anesthesia for direct laryngoscopy and endotracheal intubation, but there are no protocols that outline the use of specific drugs in general use. Drugs should safely and rapidly produce (1) unconsciousness; (2) paralysis; and (3) blunt intracranial pressure (ICP) responses to airway procedures. Consequences to be considered include increased ICP, hemorrhagic shock, and a full stomach. To refine the use of drugs used for airway procedures in pediatric trauma patients, the authors reviewed all cases of emergency endotracheal intubation over a recent 12-month period (1) to see whether medications used met the goals of producing unconsciousness and paralysis and blunting ICP responses were met safely; and (2) to identify potential drug-related complications. From July 1, 1990, to June 30, 1991, 60 of 791 children (7.6%) required endotracheal intubation at the scene of injury, at the referring hospital, or in our emergency department (15; 25%). Ten patients died (16.7%). Three fourths were younger than 9 years of age. All except one suffered blunt injuries. Nearly all (95%) suffered head injuries, isolated in 39 of 57 (68.4%) and combined with injuries in other regions in 18 (31.6%). Fifteen patients were in apnea (25%); seven were both apneic and pulseless. Three fourths (45 of 60) had diminished levels of consciousness; one fourth (15 of 60) were awake. Immediate endotracheal intubation proceeded appropriately without drugs in all seven patients in cardiopulmonary arrest. Only eight of the remaining 53 patients (15.1%) received an optimal medication regimen. Many patients with head injury were inadequately protected against increases in ICP. Thiopental, an effective anesthetic agent that effectively lowers intracranial pressure, was not used in 25 of 35 stable patients with isolated head injury (71.4%). Intravenous lidocaine was not used in 38 of 50 head-injured patients in whom it would have been an appropriate adjunct to control increases in ICP (76%). Eight patients received paralyzing agents alone, without sedatives or narcotics. Medications were thought inadequate to relieve the pain and discomfort of laryngoscopy and endotracheal intubation in 32 of the 53 patients who should have received them (60.4%). No paralyzing agents were used in 36 of the 53 instances where it would have been appropriate (67.9%). In two of 11 instances (18.3%) where succinylcholine was administered, no prior nondepolarizing agent was used. Complications of a full stomach at the time of emergency endotracheal intubation became evident in 10 patients (16.7%) who vomited during procedures to control the airway. Two patients (3.3%) aspirated.(ABSTRACT TRUNCATED AT 400 WORDS)

Clinical spectrum of myasthenia gravis and problems of management.

Seventeen cases of myasthenia gravis, aged 20-79 years, including one case of ocular myasthenia gravis, seen over a 3 year period, were analysed. Dysphagia was the presenting symptom in two cases. One patient had ectopic thymus gland in relation to the cardiac border, which posed difficulty in diagnosis. A majority of the patients were on medical treatment, including neostigmine, prednisolone and azathioprim. Plasmapheresis was done in 4 cases during crisis, with significant benefit. One patient was put on intermittent ventilatory support for 14-16 hours a day for over 2 years; she died during a power failure. Seven patients were subjected to thymectomy.

Cysticercal meningoencephalitis.

Meningoencephalitic syndrome can be caused by many infective agents. Over a period of 13 years, 15 of 170 cases of neurocysticercosis (NCC) presented as meningoencephalitis. The basis of diagnosis of NCC was positive subcutaneous nodule histopathology (4), CT scan (9) and autopsy (3) findings. The age of the patients ranged from 7-68 years (mean 32). Fever was encountered in 12, altered sensorium in 7, seizures in 10 and abnormal behaviour in 3 cases. All cases had papilloedema. Focal neurological signs included optic atrophy, lateral rectus palsy, hemiplegia, internuclear ophthalmoplegia and cerebellar ataxia. Cerebrospinal fluid was abnormal in 8 of 13 cases, leading to a suspicion of tuberculous meningitis. Twelve patients improved with therapy. Three cases ended fatally and autopsy confirmed the diagnosis.

Computed tomographic spectrum of neurocysticercosis.

Computed tomography (CT) is a very sensitive modality for the diagnosis of neurocysticercosis. Fifty eight patients were evaluated by plain radiography and CT scans. The initial presentation was as seizure disorder (33), raised intracranial tension (19), meningoencephalitis (5) and psychiatric manifestation (1). Histologically confirmed subcutaneous nodules were seen in 20 cases and ocular cyst in 2 cases. CT scan showed multiple calcification in 8 cases, disc lesions in 30,ring lesions in 3, and a combination of disc and ring lesions in another 13 cases. Low attenuation lesions were seen in 4 cases in combination with disc/disc and ring lesions. All 58 cases had supratentorial lesions while 19 cases had infratentorial lesions in addition. Perifocal or generalised oedema was seen in 33 and 11 cases respectively. The ventricles were compressed in one case, large in 2 cases and normal in the rest. CT scan is valuable in the diagnosis of neurocysticercosis. Its significance is different in the various clinical and radiological groups.

Lumbosacral plexopathy following regional paracervical block anaesthesia.

We report a 35 year old lady who developed lumbosacral plexopathy immediately following regional paracervical block anaesthesia for medical termination of pregnancy. There was only partial recovery at one year. The neurological deficit and its mechanisms are discussed.

PIP: A case of permanent injury to the nerves of the lumbosacral plexus as a result of regional paracervical block anesthesia before dilatation and curettage for abortion at 8 weeks' gestation is presented. The woman, aged 35, para 2, was given xylocaine. During injection she complained of pain in the gluteal muscle and left leg. The pain intensified and numbness, tingling and paraesthesia developed over 24 hours. The pain radiated to the L5-S1 distribution on the left when she raised her lower limb. She had difficulty moving her lower leg, and by 9 days later had hypotonia and foot drop, with absent ankle reflexes. While she gradually improved over 2 months, her condition stabilized with hypoesthesia of the left foot, foot drop and absent left ankle jerk reflex. The cause of this neuropathy is unknown, but thought to be either hematoma, direct trauma, infection. Thorough knowledge of nerve structure in the area is essential when giving paracervical block.

Uncommon manifestation of human cysticercosis with muscular pseudohypertrophy.

A case of human cysticercosis presenting with symmetric painless enlargement of muscles and seizures is presented. The patient had multiple subcutaneous nodules but no features of raised intracranial pressure. Muscle biopsy revealed densely packed cysticerci in calf muscles. Subcutaneous nodule biopsy was also confirmatory. So far sixteen cases have been described in the world literature and only one from outside India.