ABSTRACT
Purpose: Transplant surgery is a demanding field in which the technical skills of the surgeon correlates with patient outcomes. As such, there is potential for simulation-based training to play an important role in technical skill acquisition. This study provides a systematic assessment of the current literature regarding the use of simulation to improve surgeon technical skills in transplantation. Methods: Data were collected by performing an electronic search of the PubMed and Scopus database for articles describing simulation in transplant surgery. The abstracts were screened using the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines. Three reviewers analyzed 172 abstracts and agreed upon articles that met the inclusion criteria for the systematic review. Results: Simulators can be categorized into virtual reality simulators, cadaveric models, animal models (animate or inanimate) and synthetic physical models. No virtual reality simulators in transplant surgery are described in the literature. Three cadaveric models, seven animal models and eight synthetic physical models specific to transplant surgery are described. A total of 18 publications focusing on technical skills simulation in kidney, liver, lung, pancreas, and cardiac transplantation were found with the majority focusing on kidney transplantation. Conclusions: This systematic review identifies currently reported simulation models in transplant surgery. This will serve as a reference for general surgery and transplant surgery professionals interested in using simulation to enhance their technical skills.
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Oral squamous cell carcinoma (OSCC) is the most commom cancer in the world. If remain untreated for several years, it may be fatal. Hence, it is important to prevent and treat OSCC at an early stage. In this study the effect of aqueous and dry leaves extract of Ocimum sanctum was observed on Ca9-22 cell line, which is an OSCC cell line. For this, Ca9-22 cell line was cultured and maintained. After 24 h, the cells were treated with aqueous and dry leaves extract of Ocimum sanctum plant. Viability of the cancerous cells were studied by 3-(4, 5-dimethythiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay and neutral red uptake (NRU) assay. Minimum inhibitory concentrations (MIC), lethal concentration25 (LC25), lethal concentration50 (LC50) and highest permissive concentration (HPC) was calculated by probit computational method. Experimentally, the MIC value was 5 mg/L, whereas the HPC was 30 mg/L of the plant extract in aqueous state. For the dry extract the MIC was 5 mg/L whereas the HPC was 35 mg/L for both MTT and NRU assays. For MTT assay LC values: 7.41 (LC25), 14.79 (LC50) and 26.91 mg/L (LC75) for aqueous extract and 12.58 (LC25), 20.89 (LC50), 29.51 mg/L (LC75) for dry extract. For NRU assay LC values were 10.23 (LC25), 14.79 (LC50) and 20.89 mg/L (LC75) aqueous extract, and 16.59 (LC25), 23.44 (LC50), 30.19 mg/L (LC75) dry extract of the plant. From the above study it was concluded that, Ocimum sanctum have anti-cancerous activity. It can further be used for therapeutic purposes.
ABSTRACT
We report a patient with COVID-19 infection presenting with acute pancreatitis. The diagnosis of pancreatitis was based on laboratory as well as radiological evidence, and all the usual etiologies were ruled out. The temporal association with COVID-19 is strongly suggestive of novel coronavirus induced pancreatic injury.
ABSTRACT
AIM OF STUDY: Breast conserving surgery (BCS) is the standard treatment for stage I and II breast cancer. Multiple studies have shown that recurrences after lumpectomy occur mainly in or near the tumor bed. Use of accelerated partial breast irradiation (APBI) allows for significant reduction in the overall treatment time that results in increasing patient compliance and decreasing healthcare costs. We conducted a treatment planning study to evaluate the role of intensity modulated radiation therapy (IMRT) with regards to three-dimensional conformal radiation therapy (3DCRT) in APBI. MATERIALS AND METHODS: Computed tomography planning data sets of 33 patients (20 right sided and 13 left sided) with tumor size less than 3 cm and negative axillary lymph nodes were used for our study. Tumor location was upper outer, upper inner, central, lower inner, and lower outer quadrants in 10, 10, 5, 4 and 4 patients, respectively. Multiple 3DCRT and IMRT plans were created for each patient. Total dose of 38.5 Gy in 10 fractions were planned. Dosimetric analysis was done for the best 3DCRT and IMRT plans. RESULTS: The target coverage has been achieved by both the methods but IMRT provided better coverage (P = 0.04) with improved conformity index (P = 0.01). Maximum doses were well controlled in IMRT to below 108% (P < 0.01). Heart V2 Gy (P < 0.01), lung V5 Gy (P = 0.01), lung V10 Gy (P = 0.02), contralateral breast V1 Gy (P < 0.01), contralateral lung V2 Gy (P < 0.01), and ipsilateral uninvolved breast (P < 0.01) doses were higher with 3DCRT compared to IMRT. CONCLUSION: Dosimetrically, IMRT-APBI provided best target coverage with less dose to normal tissues compared with 3DCRT-APBI.
Subject(s)
Breast Neoplasms/radiotherapy , Mastectomy, Segmental/methods , Radiotherapy, Conformal/methods , Radiotherapy, Intensity-Modulated/methods , Breast Neoplasms/diagnostic imaging , Breast Neoplasms/pathology , Breast Neoplasms/surgery , Female , Humans , Imaging, Three-Dimensional/methods , Radiotherapy Planning, Computer-Assisted/methods , Retrospective Studies , Tomography, X-Ray Computed/methodsABSTRACT
Uranium mine workers are exposed to ore dust containing uranium and its daughter products during different mining operations. These radionuclides may pose inhalation hazards to workers during the course of their occupation. The most significant among these radionuclides is (226)Ra. The measurement of radium body burden of uranium mine workers is important to assess their internal exposure. For this purpose, the radon-in-breath measurement technique has been used in the present paper. Workers at the Jaduguda mine, India, associated with different categories of mining operations were monitored between 2001 and 2007. The measurement results indicate that workers--depending on mining operation category--show (226)Ra body burdens ranging from 0.15 to 2.85 kBq. The maximum body burden was found for workers associated with timbering operations, with an average (226)Ra body burden of 0.85 ± 0.54 kBq. Overall, the average value observed for 800 workers was 0.76 ± 0.51 kBq, which gives rise to an average effective dose of 1.67 mSv per year for inhalation and 0.21 mSv per year for ingestion.
Subject(s)
Mining , Occupational Exposure/analysis , Radium/analysis , Uranium , Body Burden , Humans , IndiaABSTRACT
Coarser mill tailings used as backfill to stabilize the stoped out areas in underground uranium mines is a potential source of radon contamination. This paper presents the quantitative assessment of radon emanation from the backfilled tailings in Jaduguda mine, India using a cylindrical accumulator. Some of the important parameters such as (226)Ra activity concentration, bulk density, bulk porosity, moisture content and radon emanation factor of the tailings affecting radon emanation were determined in the laboratory. The study revealed that the radon emanation rate of the tailings varied in the range of 0.12-7.03 Bq m(-2) s(-1) with geometric mean of 1.01 Bq m(-2) s(-1) and geometric standard deviation of 3.39. An increase in radon emanation rate was noticed up to a moisture saturation of 0.09 in the tailings, after which the emanation rate gradually started declining with saturation due to low diffusion coefficient of radon in the saturated tailings. Radon emanation factor of the tailings varied in the range of 0.08-0.23 with the mean value of 0.21. The emanation factor of the tailings with moisture saturation level over 0.09 was found to be about three times higher than that of the absolutely dry tailings. The empirical relationship obtained between (222)Rn emanation rate and (226)Ra activity concentration of the tailings indicated a significant positive linear correlation (r = 0.95, p < 0.001). This relationship may be useful for quick prediction of radon emanation rate from the backfill material of similar nature.
Subject(s)
Radiation Monitoring , Radon/analysis , Soil Pollutants, Radioactive/analysis , Diffusion , India , Mining , Models, TheoreticalABSTRACT
This paper presents a comparative study of (222)Rn emanation from the ore and backfill tailings in an underground uranium mine located at Jaduguda, India. The effects of surface area, porosity, (226)Ra and moisture contents on (222)Rn emanation rate were examined. The study revealed that the bulk porosity of backfill tailings is more than two orders of magnitude than that of the ore. The geometric mean radon emanation rates from the ore body and backfill tailings were found to be 10.01 × 10(-3) and 1.03 Bq m(-2) s(-1), respectively. Significant positive linear correlations between (222)Rn emanation rate and the (226)Ra content of ore and tailings were observed. For normalised (226)Ra content, the (222)Rn emanation rate from tailings was found to be 283 times higher than the ore due to higher bulk porosity and surface area. The relative radon emanation from the tailings with moisture fraction of 0.14 was found to be 2.4 times higher than the oven-dried tailings. The study suggested that the mill tailings used as a backfill material significantly contributes to radon emanation as compared to the ore body itself and the (226)Ra content and bulk porosity are the dominant factors for radon emanation into the mine atmosphere.
Subject(s)
Mining , Radiation Monitoring , Radon/analysis , Soil Pollutants, Radioactive/analysis , India , UraniumABSTRACT
Estimation of radon emanation in uranium mines is given top priority to minimize the risk of inhalation exposure due to short-lived radon progeny. This paper describes the radon emanation studies conducted in the laboratory as well as inside an operating underground uranium mine at Jaduguda, India. Some of the important parameters, such as grade/(226)Ra activity, moisture content, bulk density, porosity and emanation fraction of ore, governing the migration of radon through the ore were determined. Emanation from the ore samples in terms of emanation rate and emanation fraction was measured in the laboratory under airtight condition in glass jar. The in situ radon emanation rate inside the mine was measured from drill holes made in the ore body. The in situ(222)Rn emanation rate from the mine walls varied in the range of 0.22-51.84 × 10(-3) Bq m(-2) s(-1) with the geometric mean of 8.68 × 10(-3) Bq m(-2) s(-1). A significant positive linear correlation (r = 0.99, p < 0.001) between in situ(222)Rn emanation rate and the ore grade was observed. The emanation fraction of the ore samples, which varied in the range of 0.004-0.089 with mean value of 0.025 ± 0.02, showed poor correlation with ore grade and porosity. Empirical relationships between radon emanation rate and the ore grade/(226)Ra were also established for quick prediction of radon emanation rate from the ore body.
Subject(s)
Radiation Monitoring , Radon/analysis , Soil Pollutants, Radioactive/analysis , Uranium/analysisABSTRACT
Rice and its relatives are a focal point in agricultural and evolutionary science, but a paucity of fossils has obscured their deep-time history. Previously described cuticles with silica bodies (phytoliths) from the Late Cretaceous period (67-65 Ma) of India indicate that, by the latest Cretaceous, the grass family (Poaceae) consisted of members of the modern subclades PACMAD (Panicoideae-Aristidoideae-Chloridoideae-Micrairoideae-Arundinoideae-Danthonioideae) and BEP (Bambusoideae-Ehrhartoideae-Pooideae), including a taxon with proposed affinities to Ehrhartoideae. Here we describe additional fossils and show that, based on phylogenetic analyses that combine molecular genetic data and epidermal and phytolith features across Poaceae, these can be assigned to the rice tribe, Oryzeae, of grass subfamily Ehrhartoideae. The new Oryzeae fossils suggest substantial diversification within Ehrhartoideae by the Late Cretaceous, pushing back the time of origin of Poaceae as a whole. These results, therefore, necessitate a re-evaluation of current models for grass evolution and palaeobiogeography.
Subject(s)
Evolution, Molecular , Fossils , Oryza/genetics , Poaceae/genetics , Oryza/classification , PhylogenyABSTRACT
PURPOSE: To present our clinical experience using SIB-IMRT Technique for Intact Breast cancer. MATERIALS AND METHODS: A retrospective review of 45 cases of Stage I-IV breast cancer patients treated with SIB-IMRT with respiratory gating after Conservative treatments from 25th November 2008 to 16th February 2010. The most common fractionation was 1.8 Gy to Ipsilateral Breast tissue and 2.2 Gy to the lumpectomy cavity giving whole breast dose as 50.4 Gy and Lumpectomy cavity dose as 61.6 Gy over 28 fractions concomitantly. Respiratory gating was done and CT-images were taken in inspiratory breath hold position. RESULTS: A total of 45 patients with breast cancer - stage I (17.7%), II (71%), III (8.9%), IV (2.2%) were treated with SIB- IMRT with respiratory gated radiotherapy. Out of 45 patients, 24 are of left sided breast cancer and 21 are of right sided breast cancer patients. The median, Dose maximum (D-max) in SIB-IMRT is 106.2% of prescribed lumpectomy site dose. The median isodose line prescribed to PTV-2 is 100%. The Conformity index (CI) is 0.9688 (median value) and Homogeneity index (HI) 1.06 (median). The median ipsilateral lung, mean dose is 21.66 Gy and V-20 is 37.4%. For left sided cases the median value of mean heart dose, V-30 and V-40 are 22.98 Gy, 23.45% and 9.45 % respectively. Acute skin toxicity was of Grade-I in 2.2 %, Grade-II in 64.4 %, Grade-III in 31.1 %, and Grade-IV in 2.2 %. The global Breast cosmoses were seen excellent in majority (93%) of case at median follow up of 8 months duration. CONCLUSIONS: Breast SIB-IMRT Technique is feasible and comparable with other treatment techniques with reduced treatment duration by six fractions. At median follow up of 8 months the skin toxicity and cosmoses are excellent in high percentage of cases.
Subject(s)
Breast Neoplasms/therapy , Mastectomy, Segmental , Radiotherapy, Intensity-Modulated/methods , Adult , Breast Neoplasms/pathology , Combined Modality Therapy , Female , Humans , Middle Aged , Neoplasm Grading , Radiation Dosage , Skin/radiation effectsABSTRACT
We report a case which is unique as this patient was diagnosed pathologically as adenocarcinoma of the endometrium but clinically progressed as germ cell tumor. This was evident by progressive and rapid raised tumor markers (BHCG & LDH) with the development of multiple bilateral lung metastases. She was treated by administrating low doses of systemic combination chemotherapy as per the literature. Unfortunately, she developed acute respiratory distress syndrome as the complication of treatment and died due to it.
Subject(s)
Lung Neoplasms/secondary , Neoplasms, Germ Cell and Embryonal/secondary , Respiratory Distress Syndrome/etiology , Female , Humans , Lung Neoplasms/drug therapy , Middle Aged , Neoplasms, Germ Cell and Embryonal/drug therapy , PrognosisABSTRACT
The potential neuroprotective efficacy of dynorphin A antiserum on BBB dysfunction, edema formation and brain pathology was examined in a closed head injury (CHI) model in the rat. The CHI was produced by an impact of 0.224 N on the right parietal bone under anesthesia by dropping a weight of 114.6 g on the skull from a height of 20 cm through a guide tube. This concussive brain injury resulted in profound BBB disruption as evidenced by leakage of Evans blue and radioiodine in the brain. Edema formation and swelling at 5 h were most pronounced in the contralateral cerebral hemisphere. Pretreatment with dynorphin A antiserum (1:20, monoclonal) infused into the left lateral cerebral ventricle (30 microL in PBS) either 30 min before or 30 min after CHI significantly attenuated BBB dysfunction, brain edema formation, volume swelling and brain pathology. However, no reduction in brain edema, BBB permeability or improved brain pathology was seen when the antiserum was given 60 min post-CHI. These observations are the first to suggest that antiserum to dynorphin when administered into the CSF during early phase of CHI is neuroprotective. Our work further indicates that dynorphin is actively involved in the cellular and molecular mechanisms of edema formation and BBB breakdown in CHI.
Subject(s)
Antibodies/pharmacology , Blood-Brain Barrier/drug effects , Brain Edema/etiology , Brain Edema/pathology , Dynorphins/immunology , Head Injuries, Closed , Analysis of Variance , Animals , Antibodies/therapeutic use , Blood-Brain Barrier/pathology , Brain Edema/drug therapy , Disease Models, Animal , Head Injuries, Closed/complications , Head Injuries, Closed/drug therapy , Head Injuries, Closed/pathology , Male , RatsABSTRACT
The possibility that drugs attached to nanowires enhance their therapeutic efficacy was examined in a rat model of spinal cord injury (SCI). Three Acure compounds AP-173, AP-713 and AP-364 were tagged with TiO(2)-based nanowires (50-60 nm) and applied over the traumatized cord either 5 or 60 min after SCI in rats produced by a longitudinal incision into the right dorsal horn of the T10-11 segments under equithesin anaesthesia. Normal compounds were used for comparison. After 5 h SCI, behavioral outcome, blood-spinal cord barrier (BSCB) permeability, edema formation and cell injury were examined. Topical application of nanowired compound AP-713 (10 microg in 20 microL) when applied either 5 or 60 min after injury markedly attenuated behavioral dysfunction at 2-3 h after SCI and reduces BSCB disruption, edema formation and cord pathology at 5 h compared to other compounds. Whereas normal compounds applied at 5 min after injury (but not after 60 min) had some significant but less beneficial effects compared to their nanowired combinations. On the other hand, nanowires alone did not influence spinal cord pathology or motor function after SCI. Taken together, our results indicate that the nanowired-drug-delivery enhances the neuroprotective efficacy of drugs in SCI and reduces functional outcome compared to normal compounds even applied at a later stage following trauma, not reported earlier.
Subject(s)
Drug Delivery Systems/methods , Edema/drug therapy , Nanowires/administration & dosage , Neuroprotective Agents/administration & dosage , Neuroprotective Agents/pharmacology , Recovery of Function/drug effects , Spinal Cord Injuries , Analysis of Variance , Animals , Behavior, Animal/drug effects , Capillary Permeability/drug effects , Disease Models, Animal , Edema/etiology , Male , Microscopy, Electron, Transmission/methods , Rats , Rats, Wistar , Recovery of Function/physiology , Spinal Cord/drug effects , Spinal Cord/pathology , Spinal Cord/ultrastructure , Spinal Cord Injuries/complications , Spinal Cord Injuries/drug therapy , Time FactorsABSTRACT
The Indian palaeoanthropological record, although patchy at the moment, is improving rapidly with every new find. This broad review attempts to provide an account of (a) the Late Miocene fossil apes and their gradual disappearance due to ecological shift from forest dominated to grassland dominated ecosystem around 9-8 Ma ago, (b) the Pliocene immigration/evolution of possible hominids and associated fauna, (c) the Pleistocene record of fossil hominins, associated fauna and artifacts, and (d) the Holocene time of permanent settlements and the genetic data from various human cultural groups within India. Around 13 Ma ago (late Middle Miocene) Siwalik forests saw the emergence of an orangutan-like primate Sivapithecus. By 8 Ma, this genus disappeared from the Siwalik region as its habitat started shrinking due to increased aridity influenced by global cooling and monsoon intensification. A contemporary and a close relative of Sivapithecus, Gigantopithecus (Indopithecus), the largest ape that ever-lived, made its first appearance at around 9 Ma. Other smaller primates that were pene-contemporaneous with these apes were Pliopithecus (Dendropithecus), Indraloris, Sivaladapis and Palaeotupia. The Late Pliocene and Early Pleistocene witnessed northern hemisphere glaciations, followed by the spread of arid conditions on a global scale, setting the stage for hominids to explore "Savanahastan". With the prominent expansion of grassland environments from East Africa to China and Indonesia in the Pliocene, monkeys and baboons dispersed into the Indian subcontinent from Africa along with other mammals. Though debated, there are several claims of the presence of early hominins in this part of the world during the Late Pliocene, based primarily on the recovery of Palaeolithic tools. Fossils of our own ancestor and one of the first globe-trotters, early Homo erectus, has been documented from the Early Pleistocene of East Africa, Western Asia and Southeast Asia, thus indirectly pointing towards Indian subcontinent as a possible migration corridor between these regions. The only definite pre-Homo sapiens fossil hominin remains come from the Central Narmada Valley and are thought to be of Middle to late Pleistocene age, and the cranium has been shown to be closely linked to archaic Homo sapiens/H. heidelbergensis of Europe. Around approximately 74,000 yrs ago, a super volcanic eruption in Sumatra caused the deposition of Youngest Toba Tephra, that covered large parts of the Indian peninsula. Just around this time anatomically-and-behaviorally modern humans or Homo sapiens possibly arrived into India as evidenced by the so called Middle and Upper Palaeolithic assemblages and associated symbolic evidence. The available genetic data reveals that the gene pool to which modern Indians races belong was extremely diverse and had variable mixed links with both European and Asian populations.
Subject(s)
Biological Evolution , Hominidae/anatomy & histology , Animals , Climate , Fossils , Hominidae/classification , Hominidae/physiology , Humans , India , Phylogeny , Tool Use BehaviorABSTRACT
A rapid and sensitive reverse phase high performance liquid chromatographic method is depicted for the qualitative and quantitative assay of letrozole in pharmaceutical dosage forms. Letrozole was chromatographed on a reverse phase C18 column with a mobile phase consisting of acetonitrile and phosphate buffer (pH 7.8) in the ratio of 70:30 v/v. The mobile phase was pumped at a flow rate of 1 ml/min. Acenaphthene was used as an internal standard and the eluents were monitored at 232 nm. The retention time of the drug was 3.385 min. With this method, linearity was observed in the range of 10-100 mug/ml. The LOD and LOQ were found to be 0.51 mug/ml and 1.52 mug/ml, respectively. The method was found to be applicable for analysis of drug in tablets. The results of the analysis were validated statistically.
ABSTRACT
The possibility that drugs attached to innocuous nanowires enhance their delivery within the central nervous system (CNS) and thereby increase their therapeutic efficacy was examined in a rat model of spinal cord injury (SCI). Three compounds--AP173 (SCI-1), AP713 (SCI-2), and AP364 (SCI-5) (Acure Pharma, Uppsala, Sweden)--were tagged with TiO(2)-based nanowires using standard procedure. Normal compounds were used for comparison. SCI was produced by making a longitudinal incision into the right dorsal horn of the T10-T11 segments under Equithesin anesthesia. The compounds, either alone or tagged with nanowires, were applied topically within 5 to 10 min after SCI. In these rats, behavioral outcome, blood-spinal cord barrier (BSCB) permeability, edema formation, and cell injury were examined at 5 h after injury. Topical application of normal compounds in high quantity (10 microg in 20 microL) attenuated behavioral dysfunction (3 h after trauma), edema formation, and cell injury, as well as reducing BSCB permeability to Evans blue albumin and (131)I. These beneficial effects are most pronounced with AP713 (SCI-2) treatment. Interestingly, when these compounds were administered in identical conditions after tagging with nanowires, their beneficial effects on functional recovery and spinal cord pathology were further enhanced. However, topical administration of nanowires alone did not influence trauma-induced spinal cord pathology or motor functions. Taken together, our results, probably for the first time, indicate that drug delivery and therapeutic efficacy are enhanced when the compounds are administered with nanowires.
Subject(s)
Drug Delivery Systems/instrumentation , Drug Delivery Systems/methods , Nanowires/therapeutic use , Neuroprotective Agents/administration & dosage , Recovery of Function/drug effects , Spinal Cord Injuries/drug therapy , Analysis of Variance , Animals , Blood-Brain Barrier/drug effects , Blood-Brain Barrier/physiopathology , Disease Models, Animal , Dose-Response Relationship, Drug , Indicators and Reagents , Male , Microscopy, Electron/methods , Nanowires/ultrastructure , Rats , Rats, Sprague-Dawley , Spinal Cord Injuries/pathologyABSTRACT
Closed head injury (CHI) often results in profound brain swelling and instant death of the victims due to compression of the vital centers. However, the neurochemical basis of edema formation in CHI is still obscure. Previous studies from our laboratory show that blockade of serotonin synthesis prior to CHI in a rat model attenuates brain edema, indicating a prominent role for serotonin in head injury. Thus, neutralization of endogenous serotonin activity and/or blocking of its receptors will induce neuroprotection in CHI. Since serotonin has more than 14 receptors and selective serotonin antagonists are still not available, we used serotonin antiserum to neutralize its in vivo effects before or after CHI in a rat model. CHI was produced by an impact of 0.224 N on the right parietal skull bone under Equithesin anesthesia by dropping a weight of 114.6 g from a height of 20 cm through a guide tube. This concussive brain injury resulted in blood-brain barrier (BBB) disruption, brain edema formation, and volume swelling at 5 h that were most pronounced in the contralateral cerebral hemisphere. The plasma and brain serotonin levels were increased several-fold at this time. Intracerebroventricular administration of serotonin antiserum (1:20, monoclonal) into the left lateral cerebral ventricle (30 microL in PBS) 30 min before or 30 min (but not 60 min) after CHI significantly attenuated BBB disruption, brain edema formation, volume swelling, and brain pathology. The plasma and brain serotonin levels continued to remain high. These observations are the first to suggest that antiserum to serotonin when administered into the CSF during the early phase of CHI are capable of inducing neuroprotection.
Subject(s)
Antibodies/therapeutic use , Blood-Brain Barrier/drug effects , Brain/pathology , Head Injuries, Closed , Serotonin/immunology , Analysis of Variance , Animals , Blood-Brain Barrier/physiopathology , Brain/metabolism , Disease Models, Animal , Head Injuries, Closed/drug therapy , Head Injuries, Closed/pathology , Head Injuries, Closed/physiopathology , Male , Rats , Serotonin/metabolismABSTRACT
The role of heme oxygenase (HO) in closed head injury (CHI) was examined using a potent HO and guanylyl cyclase inhibitor, zinc protoporphyrin (Zn-PP) in the rat. Blood-brain barrier (BBB) permeability to Evans blue and radioiodine, edema formation, and plasma and brain levels of serotonin were measured in control, CHI, and Zn-PP-treated CHI rats. CHI was produced by an impact of 0.224 N on the right parietal bone by dropping 114.6 g weight from a height of 20 cm in anesthetized rats. This concussive injury resulted in edema formation and brain swelling 5 hours after insult that was most pronounced in the contralateral hemisphere. The whole brain was edematous and remained in a semi-fluid state. Microvascular permeability disturbances to protein tracers were prominent in both cerebral hemispheres and the underlying cerebral structures. Plasma and brain serotonin showed pronounced increases and correlated with edema formation. Pretreatment with Zn-PP (10 mg/ kg, i.p) 30 minutes before or after CHI attenuated edema formation, brain swelling, plasma and brain serotonin levels, and microvascular permeability at 5 hours. Brain edema, BBB permeability, and serotonin levels were not attenuated when the compound was administered 60 minutes post-CHI suggesting that HO is involved in cellular and molecular mechanisms of edema formation and BBB breakdown early after CHI.
Subject(s)
Blood-Brain Barrier/physiopathology , Brain Concussion/drug therapy , Brain Concussion/physiopathology , Brain Edema/prevention & control , Brain Edema/physiopathology , Protoporphyrins/administration & dosage , Serotonin/metabolism , Animals , Blood-Brain Barrier/drug effects , Brain/drug effects , Brain/metabolism , Enzyme Inhibitors/administration & dosage , Heme Oxygenase (Decyclizing)/antagonists & inhibitors , Male , RatsABSTRACT
The role of histamine in edema formation, blood-spinal cord barrier (BSCB) permeability, and spinal cord blood flow (SCBF) following spinal cord injury (SCI) was examined using modulation of histamine H1, H2, and H3 receptors in the rat. Focal trauma to the spinal cord at the T10-11 level significantly increased spinal cord edema formation, BSCB permeability to protein tracers and SCBF reduction in the T9 and T12 segments. Pretreatment with histamine H1 receptor antagonist mepyramine (1 mg, 5 mg, and 10 mg/kg, i.p.) did not attenuate spinal pathophysiology following SCI. Blockade of histamine H2 receptors with cimetidine or ranitidine (1 mg, 5 mg, or 10 mg/kg 30 minutes before injury) significantly reduced early pathophysiological events in a dose dependent manner. The effects of ranitidine were far superior to cimetidine in identical doses. Pretreatment with a histamine H3 receptor agonist alpha-methylhistamine (1 mg and 2 mg/kg/i.p.), that inhibits histamine synthesis and release in the CNS, thwarted edema formation, BSCB breakdown, and SCBF disturbances after SCI. The lowest dose of histamine H3 agonist was most effective. Blockade of histamine H3 receptors with thioperamide (1 mg, 5 mg/kg, i.p.) exacerbated spinal cord pathology. These observations suggest that stimulation of histamine H3 receptors and blockade of histamine H2 receptors is neuroprotective in SCI.
Subject(s)
Edema/physiopathology , Receptors, Histamine/metabolism , Spinal Cord Injuries/physiopathology , Spinal Cord/blood supply , Spinal Cord/physiopathology , Animals , Blood Flow Velocity , Edema/etiology , Male , Permeability , Rats , Rats, Wistar , Spinal Cord Injuries/complicationsABSTRACT
Bioavailability and/or bioequivalence studies play a key role in the drug development period for both new drug products and their generic equivalents. For both, these studies are also important in the postapproval period in the presence of certain manufacturing changes. Like many regulatory studies, the assessment of bioavailability and bioequivalence can generally be achieved by considering the following three questions. What is the primary question of the study? What are the tests that can be used to address the question? What degree of confidence is needed for the test outcome? This article reviews the regulatory science of bioavailability and bioequivalence and provides FDA's recommendations for drug sponsors who intend to establish bioavailability and/or demonstrate bioequivalence for their pharmaceutical products during the developmental process or after approval.