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Background: The aim of this study was to assess the pattern of periurethral bacterial flora in uncircumcised boys and to evaluate the effect of circumcision on alteration of periurethral uropathogenic bacterial flora., Materials and Methods: Pattern of periurethral bacterial flora before and after circumcision was studied prospectively in 124 boys. The results were analysed to compare change in bacterial colonisation before and after circumcision., Results: The age range was 6 weeks to 96 months. Most (94.3%) of the boys had religious indication and 5.7% had medical indication for circumcision. E. coli, Proteus and Klebsiella were most common periurethral bacterial flora in uncircumcised subjects. Coagulase-negative staphylococcus and Staphylococcus aureus was most common periurethral bacterial flora in circumcised subjects. In 66.1% of circumcised subjects, no bacteria were grown from periurethral region., Conclusion: We conclude that presence of prepuce is associated with great quantity of periurethral bacteria, greater likelihood of the presence of high concentration of uropathogens and high incidence of urinary tract infection (UTI). This study provides circumstantial evidence supporting the idea that early circumcision may be beneficial for prevention of UTI.

Long term exposure of nanoparticles e.g., silica dust (SiO2) from desert environments, or engineered nanoparticles from metals viz., Cu, Al or Ag from industry, ammunition, military equipment and related products may lead to adverse effects on mental health. However, it is unclear whether these nanoparticles may further adversely affect human health in cardiovascular or metabolic diseases e.g., hypertension or diabetes. It is quite likely that in diabetes or hypertension where the body immune system is already compromised there will be greater adverse effects following nanoparticles exposure on human health as compared to their exposure to healthy individuals. Previous experiments from our laboratory showed that diabetic or hypertensive animals are more susceptible to heat stress-induced neurotoxicity. Furthermore, traumatic injury to the spinal cord in SiO2 exposed rats resulted in exacerbation of cord pathology. However, whether nanoparticles such as Cu, Ag or SiO2 exposure will lead to enhanced neurotoxicity in diabetic animals are still not well investigated. Previous data from our laboratory showed that Cu or Ag intoxication (50 mg/kg, i.p. per day for 7 days) in streptozotocine induced diabetic rats exhibited enhanced neurotoxicity and exacerbation of sensory, motor and cognitive function as compared to normal animals under identical conditions. Thus the diabetic animals showed exacerbation of regional blood-brain barrier (BBB) disruption, edema formation and cell injuries along with greater reduction in the local cerebral blood flow (CBF) as compared to normal rats. These observations suggest that diabetic animals are more vulnerable to nanoparticles induced brain damage than healthy rats. The possible mechanisms and functional significance of these findings are discussed in this review largely based on our own investigations.

Oxidative stress in the central nervous system is one of the key players for neurodegeneration. Thus, antioxidants could play important roles in treating several neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and aging-related brain disorders. This review is focused on the new developments in oxidative stress-induced neurodegeneration. Further, based on our own investigations, new roles of quercetin, an antioxidant compound in hypoxia and ischemia induced neuroprotection in relation to suppression of oxidative stress, improvement in behavioral function, reduction in infarct volume, brain swelling, and cellular injury in both in vivo and in vitro models are discussed. Our new findings clearly suggest that antioxidant compounds have potential role in therapeutic strategies to treat neurodegenerative diseases in clinical settings., (Copyright © 2012 Elsevier Inc. All rights reserved.)

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.

The possibility that cerebrolysin, a mixture of several active fragments of neurotrophic factors and peptides induces neuroprotection following nanoparticles induced exacerbation of brain damage in heat stroke was examined in a rat model. For this purpose, the therapeutic efficacy of Cerebrolysin (2.5 or 5 ml/kg) recommended for stroke treatment was used in comparison with other drugs in standard doses recommended for such therapy in clinical situations e.g., levetiracetam (44 mg/kg), pregabalin (200 mg/kg), topiramate (40 mg/kg,i.p.) and valproate (400 mg/kg). Rats subjected to 4 h heat stress in a biological oxygen demand (BOD) incubator at 38 degrees C (Rel Humid 45-47%; Wind vel 22.4 to 25.6 cm/sec) developed profound behavioral symptoms of heat stroke e.g., hyperthermia, profuse salivation, prostration and gastric ulcerations in the stomach. These rats also exhibited marked brain pathology at this time. Thus, breakdown of the blood-brain barrier (BBB) to proteins associated with brain edema formation could be seen in these heat stressed rats as compared to control groups. The edematous brain areas showed profound neuronal damage and/or distortion in large areas of the neuropil. These pathological symptoms were further exacerbated in Cu or Ag nanoparticles treated group (50-60 nm particle size, 50 mg/kg, i.p./day for 7 days) after identical heat stress on the 8th day. Pretreatment with cerebrolysin (2.5 ml/kg, i.v.) daily for 3 days in normal rats before heat stress significantly reduced the behavioral stress symptoms and the breakdown of the BBB function, edema formation and neuronal injuries. However, the magnitude and intensity of these neuroprotective effects were much less intense in all other drug treated rats after similar heat stress. On the other hand, almost double dose of cerebrolysin (5 ml/kg) was needed to achieve comparable neuroprotection in nanoparticles treated animals after heat stress. Whereas, double dose of all other compounds was much less effective in inducing neuroprotection in nanoparticles treated heat-exposed animals. These observations are the first to show that cerebrolysin exerts the most superior neuroprotective effects in heat stress as compared to other neuroprotective agents on brain pathology in normal and in nanoparticles treated group. Furthermore, cerebrolysin in double dose was the most effective in inducing neuroprotection in nanoparticles treated heat exposed rats on brain pathology as compared to double doses of other drugs. Taken together, our results show that cerebrolysin has the most superior neuroprotective effects on brain pathology in heat stroke in both normal and nanoparticles treated rats as compared to other contemporary neuroprotective agents, not reported earlier.

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.

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.

The ingestion of Indian carp gallbladder may result in transient hepatitis with subsequent acute renal failure. This case series also illustrates the importance of understanding the use and potential serious complications of alternative medicines. So fish gallbladder poisoning should be considered in unexplained acute renal failure in Chinese and Asian patients. We report four family members who developed acute renal failure and toxic hepatitis at the same time following ingestion of raw Indian carp (Labeo rohita) gall bladder.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article is being retracted at the request of the Authors. The authors provided the following reasons: 1. The first author of the paper omitted the name of one of the contributors and did not disclose that he had been involved in similar studies at another Center. The results of these studies were previously published in another journal, resulting in a striking similarity between the images in this article and that of Mishra V et al., 2010 Neuropharmacology https://doi.org/10.1016/j.neuropharm.2010.08.015 2. The authors were not able to reproduce the results of the Western blotting data given in the paper. It should be noted that the Editor-in-Chief has serious concerns about the fact that some images in these studies were previously published in unrelated studies in another journal., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Introduction: Injectable poly-l-lactic acid (PLLA) is a biocompatible and biodegradable polymer device indicated in Europe for correction of facial contour deficiencies, with a gradual onset of effect that is maintained for up to 25 months., Methods: In this single-centre, open-label study, 20 adult subjects seeking treatment for facial contour deficiencies were treated with injectable PLLA every 4-6 weeks for ≤6 months or until optimal correction (0 or 1 on nasolabial photonumeric wrinkle assessment scale [0 = no wrinkles; 5 = very deep wrinkles, redundant fold]). 3-D digital surface imaging and standardized 2-D photography were used to assess mid-face and nasolabial volumetric correction and clinical improvement, respectively., Results: Based on 3-D digital surface imaging, statistically significant increases in average mid-facial volume occurred with injectable PLLA after the first injection session and persisted through to the end of treatment. Investigator and subject ratings of 'much improved' or 'excellent' improvement were reported using 2-D photographs as a visual aid. Subjects reported high levels of satisfaction. No serious adverse events were reported., Discussion: In this study, injectable PLLA was found to be safe and effective for mid-face and nasolabial fold volumetric correction.

The possibility that pain perception and processing in the CNS results in cellular stress and may influence heat shock protein (HSP) expression was examined in a rat model of morphine dependence and withdrawal. Since activation of pain pathways result in exhaustion of growth factors, we examined the influence of cerebrolysin, a mixture of potent growth factors (BDNF, GDNF, NGF, CNTF etc,) on morphine induced HSP expression. Rats were administered morphine (10 mg/kg, s.c. /day) for 12 days and the spontaneous withdrawal symptoms were developed by cessation of the drug administration on day 13(th) that were prominent on day 14(th) and continued up to day 15(th) (24 to 72 h periods). In a separate group of rats, cerebrolysin was infused intravenously (5 ml/kg) once daily from day one until day 15(th). In these animals, morphine dependence and withdrawal along with HSP immunoreactivity was examined using standard protocol. In untreated group mild HSP immunoreaction was observed during morphine tolerance, whereas massive upregulation of HSP was seen in CNS during withdrawal phase that correlated well with the withdrawal symptoms and neuronal damage. Pretreatment with cerebrolysin did not affect morphine tolerance but reduced the HSP expression during this phase. Furthermore, cerebrolysin reduced the withdrawal symptoms on day 14(th) to 15(th). Taken together these observations suggest that cellular stress plays an important role in morphine induced pain pathology and exogenous supplement of growth factors, i.e. cerebrolysin attenuates HSP expression in the CNS and induce neuroprotection. This indicates a new therapeutic role of cerebrolysin in the pathophysiology of drugs of abuse, not reported earlier.

The possibility that diabetes aggravates nanoparticles induced blood-brain barrier (BBB) breakdown, edema formation and brain pathology was examined in a rat model. Engineered nanoparticles from metals Ag and Cu (50-60 mn) were administered (50 mg/kg, i.p.) once daily for 7 days in normal and streptozotocine induced diabetic rats. On the 8th day, BBB permeability to Evans blue and radioactive iodine (131I-sodium) was examined in 16 brain regions. In these brain regions alterations in regional CBF was also evaluated using radiolabelled (125I) carbonized microspheres (o.d. 15 +/- 6 microm). Regional brain edema and Na+, K+ and Cl- ion analysis were done in 8 selected brain regions. Histopathology was used to detect neuronal damage employing Nissl staining. Nanoparticles treatment in diabetic rats showed much more profound disruption of the BBB to Evans blue albumin (EBA) and radioiodine in almost all the 16 regions examined as compared to the normal animals. In these diabetic animals reduction in regional cerebral blood flow (CBF) was more pronounced than in normal rats. Edema development as seen using water content and increase in Na+ and a decrease in K+ ion were most marked in diabetic rats as compared to normal rats after nanoparticles treatment. Cell changes in the regions of BBB disruptions were also exacerbated in diabetic rats compared to normal group after nanoparticles treatment. Taken together, these observations are the first to show that diabetic rats are more susceptible to nanoparticles induced cerebrovascular reactions in the brain and neuronal damage. The possible mechanisms and significance of the present findings are discussed.

Introduction: Several studies confirm that botulinum toxins type A (BTX-A) are effective for reducing facial lines caused by hyperactive muscles. Two different commercial types of BTX-A currently available are BTX-A-1 (Botox) and BTX-A-2 (Dysport). This paper reports further comparison of dosing, efficacy and safety., Methods: Sites treated: glabellar, horizontal forehead lines and crow's feet. Different dilutions and dosages were studied with BTX-A-1 and BTX-A-2. The reduction of facial lines was evaluated by investigators and patients. Computerized photographic numerical assessment was also studied in determining the efficacy of BTX-A for crow's feet lines., Results: Study 1: Injecting glabellar lines at doses of BTX-A-1 (30 units) and BTX-A-2 (75 units) (2.5:1 ratio BTX-A2:BTX-A1) showed similar efficacy. Study 2: BTX-A-2 (256 units total) was significantly more effective than BTX-A-1 (64 units total) (i.e. a dose ratio of 4:1) for upper face lines. No differences in the side-effect profiles between the two toxins were observed in either study. Study 3: A computerized photographic numerical assay was an objective assessment of crow's feet severity. Using a dose ratio of BTX-A-2 to BTX-A-1 of 3:1 showed a trend towards BTX-A-2 superiority., Conclusion: Two different botulinum toxins type A were shown to be effective and safe for hyperfunctional facial lines. The choice of dose, dilution and placement is critical for each individual toxin. Computerized photography gave numerical severity scores of crow's feet severity.

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.

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.

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.

Silicon (SiO2) nanoparticles or silica dust is quite common form of exposure to soldiers engaged in gulf war that may influence their health and brain function. It is quite likely that traumatic injuries to the CNS may be influenced by exposure to these nanoparticles. However, the details of silicon nanoparticles on human health functions are still unknown. In this investigation we examined the effects of chronic silicon dioxide nanoparticles (SiO2, 40-50 nm) exposure on spinal cord injury (SCI) induced alterations on the functional outcome and the cord pathology in a rat model. Since nanoparticles induce oxidative stress, the influence of an antioxidant compound H-290/51 was also examined in these nanoparticles treated injured rats as well. Rats treated with SiO2 for 7 days did not show any significant alteration in behaviour on rota rod performances or on capacity angle tests. However, subjection of these nanoparticles exposed rats to SCI resulted in a profound deterioration in motor functions compared to normal rats with SCI. The magnitude of blood-spinal cord barrier (BSCB) disruption to Evans blue and radioiodine tracers and edema formation was much more aggravated following SCI in nanoparticles treated animals compared to untreated traumatized rats. Pretreatment with H-290/51 (50 mg/kg, p.o.) 30 min before SCI in nanoparticle treated rats did not alter spinal cord pathology or functional outcome, however, this dose of the compound was very effective in reducing pathophysiology of SCI in normal animals. These observations are the first to suggest that exposure of nanoparticles enhances the sensitivity of CNS to injuries and alter the effect of neuroprotective drugs.

Recently nano-drug delivery to the central nervous system (CNS) has been shown to be more effective than the parent compound by itself. An increased availability of the drug for longer periods to the brain or spinal cord and/or a decrease in the drug metabolism altogether could lead to potentiation of the pharmacological activity of the nano-delivered compounds. However, it is still unclear whether the nanocarriers used to deliver the drugs may itself has any potential neurotoxic activity. Although, nanodrug-delivery appears to be a quite promising therapeutic tool for the future clinical therapy, its advantages and limitations for the routine use of patients still needs to be elucidated. Our laboratory is engaged to study a plethora of potential neuroprotective novel compounds delivered to the CNS using nanowiring techniques following brain or spinal cord trauma. Our investigations show that nanowired drugs, if delivered locally following spinal cord injury achieve better neuroprotection than the parent compounds. This effect of nano-drug delivery appears to be very selective in nature. Thus, a clear differentiation based on the compounds used for nano-drug delivery can be seen on various pathological parameters in spinal cord injury. These observations suggest that nanowiring may itself do not induce neuroprotection, but enhance the neuroprotective ability of compounds after trauma. This review describes some recent advances in nano-drug delivery to the CNS in relation to novel neuroprotective strategies with special emphasis on spinal cord trauma based on our own observations and recent findings from our laboratory investigations.

Progress in the field of strain engineering is being made by identifying the genetic basis of complex phenotypes, engineering new phenotypes, and combining beneficial phenotypes in industrial hosts. Advances in genomics technologies including high-throughput sequencing and DNA microarrays have improved our ability to make genotype-phenotype correlations. Applications include the analyses of traits that have evolved in nature and traits that have been created in the laboratory. Additionally, newer tools such as Whole Genome Shuffling (WGS), Scalar Analysis of Library Enrichments (SCALEs), global transcription machinery engineering (gTME), and gene-disruption methods such as transposon insertion or site-specific homologous recombination are improving the construction of phenotypic libraries and the selection and analysis of cells with desirable traits. This review focuses on some of these current methods.

Background: Injectable poly-l-lactic acid (PLLA) has been used to correct age- or disease-related facial volume deficits., Objective: This single-center, retrospective survey evaluated PLLA for cosmetic use., Methods and Materials: A questionnaire was mailed to 281 patients treated with PLLA 6 months or more previously. PLLA was reconstituted 4 hours or more before injection with 5 mL of sterile water plus 1 mL of 1% xylocaine added before injection., Results: Two hundred twenty-one patients responded (210 female; average age 54.3; average treatments 3.3 per patient); the majority had received facial injections. Transient side effects included bruising, swelling, and discomfort. After treatment (1-6 months), 14/41 patients developed Grade 1 papules or nodules (slightly palpable, nonvisible; clinically nonrelevant; all resolved spontaneously), 15/41 developed Grade 2 papules or nodules (palpable, slightly visible; clinically nonrelevant; all resolved spontaneously), and 12/41 developed Grade 3 nodules (easily palpable, obviously visible [9 perioral; 3 periorbital or temple]; 5 resolved spontaneously; 7 were treated [5 intralesional corticosteroids; 2 surgery])., Conclusion: Patients treated with PLLA experienced duration of improvement of up to 24 months. Maximum improvement took several treatment sessions. Nodules occurred in perioral and periorbital regions, so incidence is reduced by avoiding these areas.

The oldest known fossil hominin in southern Asia was recovered from Hathnora in the Narmada Basin, central India in the early 1980's. Its age and taxonomic affinities, however, have remained uncertain. Current estimates place its maximum age at >236ka, but not likely older than the early middle Pleistocene. The calvaria, however, could be considerably younger. We report recent fieldwork at Hathnora and associated Quaternary type-sections that has provided new geological and archaeological insights. The portion of the exposed 'Boulder Conglomerate' within the Surajkund Formation, which forms a relict terrace and has yielded the hominin fossils, contains reworked and stylistically mixed lithic artifacts and temporally mixed fauna. Three mammalian teeth stratigraphically associated with the hominin calvaria were dated by standard electron spin resonance (ESR). Assuming an early uranium uptake (EU) model for the teeth, two samples collected from the reworked surface deposit averaged 49+/-1ka (83+/-2ka, assuming linear uptake [LU]; 196+/-7ka assuming recent uptake [RU]). Another sample recovered from freshly exposed, crossbedded gravels averaged 93+/-5ka (EU), 162+/-8ka (LU) or 407+/-21ka (RU). While linear uptake models usually provide the most accurate ages for this environment and time range, the EU ages represent the minimum possible age for fossils in the deposit. Regardless, the fossils are clearly reworked and temporally mixed. Therefore, the current data constrains the minimum possible age for the calvaria to 49+/-1ka, although it could have been reworked and deposited into the Hathnora deposit any time after 160ka (given the LU uptake ages) or earlier (given the RU ages). At Hathnora, carbonaceous clay, bivalve shells, and a bovid tooth recovered from layers belonging to the overlying Baneta Formation have yielded (14)C ages of 35.66+/-2.54cal ky BP, 24.28+/-0.39cal ky BP, and 13.15+/-0.34ky BP, respectively. Additional surveys yielded numerous lithics and fossils on the surface and within the stratigraphic sequence. At the foot of the Vindhyan Hills 2km from the river, we recovered a typologically Early Acheulean assemblage comprised of asymmetrical bifaces, large cleavers with minimal working, trihedral picks, and flake tools in fresh condition. These tools may be the oldest Acheulean in the Narmada Valley. Several lithics recovered from the Dhansi Formation may represent the first unequivocal evidence for an early Pleistocene hominin presence in India. In situ invertebrate and vertebrate fossils, pollen, and spores indicate a warm, humid climate during the late middle Pleistocene. High uranium concentrations in the mammalian teeth indicate exposure to saline water, suggesting highly evaporative conditions in the past. Late Pleistocene sediment dated between 24.28+/-0.39cal ky BP and 13.15+/-340ky BP has yielded pollen and spores indicating cool, dry climatic conditions corresponding to Oxygen Isotope Stage 2 (OIS 2). An early Holocene palynological assemblage from the type locality at Baneta shows evidence for relatively dry conditions and a deciduous forest within the region. The Dhansi Formation provisionally replaces the Pilikarar Formation as the oldest Quaternary formation within the central Narmada Basin. The Baneta Formation, previously dated at 70ka to 128ka, correlates with the late Pleistocene and early Holocene. Our results highlight the need for further Quaternary geological and paleoanthropological research within the Narmada Basin, especially because dam construction threatens these deposits.

Role of cocaine in influencing blood-brain barrier (BBB) function is still unknown. Available evidences suggest that cocaine administration results in acute hyperthermia and alterations in brain serotonin metabolism. Since hyperthermia is capable to induce the breakdown of the BBB either directly or through altered serotonin metabolism, a possibility exists that cocaine may induce neurotoxicity by causing BBB disruption. This hypothesis is discussed in this review largely based on our own laboratory investigations. Our observations in rats demonstrate that cocaine depending on the dose and routes of administration induces profound hyperthermia, increased plasma and brain serotonin levels leading to BBB breakdown and brain edema formation. Furthermore, cocaine was able to enhance cellular stress as seen by upregulation of heat shock protein (HSP 72 kD) expression and resulted in marked neuronal and glial cell damages at the time of the BBB dysfunction. Taken together, these observations are the first to suggest that cocaine-induced BBB disruption is instrumental in precipitating brain pathology. The possible mechanisms of cocaine-induced BBB breakdown and neurotoxicity are discussed.

Spinal cord injury (SCI) is a serious clinical problem for which no suitable therapeutic strategies have been worked out so far. Recent studies suggest that the SCI and its pathophysiological responses could be altered by systemic exposure to nanoparticles. Thus, SCI when made in animals intoxicated with engineered nanoparticles from metals or silica dust worsened the outcome. On the other hand, drugs tagged with titanium (TiO(2)) nanoparticles or encapsulated in liposomes could enhance their neuroprotective efficacy following SCI. Thus, to expand our knowledge on nanoparticle-induced alterations in the spinal cord pathophysiology further research is needed. These investigations will help to develop new strategies to achieve neuroprotection in SCI, for example, using nanodrug delivery. New results from our laboratory showed that nanoparticle-induced exacerbation of cord pathology following trauma can be reduced when the suitable drugs tagged with TiO(2) nanowires were administered into the spinal cord as compared to those drugs given alone. This indicates that nanoparticles depending on the exposure and its usage could induce both neurotoxicity and neuroprotection. This review discusses the potential adverse or therapeutic utilities of nanoparticles in SCI largely based on our own investigations. In addition, possible mechanisms of nanoparticle-induced exacerbation of cord pathology or enhanced neuroprotection following nanodrug delivery is described in light of recently available data in this rapidly emerging field of nanoneurosciences., (Copyright 2009 Elsevier B.V. All rights reserved.)

Background & Objective: In India, anaemia in pregnancy remains a major public health problem associated with increased risk of low birth weight deliveries. A study was carried out at an urban primary health institution in Delhi, to assess feasibility of screening all pregnant women attending antenatal clinic for anaemia, identifying those with moderate anaemia (haemoglobin between 5.0 - 7.9 g/dl), administering intramuscular (im) therapy to them in the out-patient department (OPD), and observing the impact on maternal haemoglobin (Hb) levels and birth weight of the infant., Methods: In the antenatal clinic all pregnant women were screened for anaemia. Women with Hb between 5.0- 7.9 g/dl were counselled and those who were willing, were given six intramuscular injections each consisting of iron sorbitol citric acid complex containing 150 microg elemental iron, 1500 microg folic acid, 150 microg hydroxocobalamine acetate (vitamin B1)). They were followed up through pregnancy and till delivery. Birth weight of infants of women who received therapy were compared with birth weight of infants born in DCMC., Results: Over 80 per cent of 3698 women who attended the antenatal clinic were anaemic; 745 (20.1%) had Hb between 5.0-7.9 g/dl. Of these, 419 women agreed to take im therapy as outpatients; 367 took all 6 injections. Metallic taste on the tongue, nausea, vomiting and pain at the injection site were the side effects reported. The mean Hb even 9 wk after completion of therapy was only 9.6 g/dl. Mean birth weight in 340 women who completed the treatment was 2.8 kg - significantly (P<0.001) higher than birth weight in women who had Hb <8.0 g/dl at the time of delivery, but lower than birth weight of infants born to non anaemic women., Interpretation & Conclusion: In urban primary health care institutions, it is possible to screen pregnant women for anaemia, identify those with Hb between 5.0 and 7.9 g/dl and give them im therapy as outpatients. Use of a preparation with fewer and milder side effects, counselling and support of women who develop side effect may result in high compliance rates; 900 mg of elemental iron as iron sorbitol citric acid was insufficient to raise mean Hb beyond 9.6 g/dl. The dosage has to be increased to achieve optimal results in relation to maternal haemoglobin levels and birth weight.

L-tyrosine (L-tyr) overproducing Escherichia coli strain derived from an L-phenylalanine (L-phe) overproducing strain is characterized in 10 L and 200 L scale fermentations. Deletion of the chromosomal region encoding for the pheA gene, chorismate mutase/prephenate dehydratase, its leader peptide (pheL) and its associated promoter resulted in significant increase in L-tyr production (Olson et al., 2007. Appl Microbiol Biotechnol 74(5):1031-1040). Further increase in titer was achieved by overexpressing tyrA, encoding chorismate mutase/prephenate dehydrogenase, from a strong non-native trc promoter (Olson et al., 2007. Appl Microbiol Biotechnol 74(5):1031-1040). Fermentation optimization studies include media component selection; glucose feed optimization, antifoam agent selection, and understanding fermentation parameters affecting foaming. Generational stability of the strain was evaluated along with rate, titer, and yield of tyrosine formation from glucose. L-tyr titer of 55 g/L in 48 h was demonstrated in 200 L batches, is the highest titer published till date. We have also evaluated two primary separations schemes to isolate and purify L-tyr from the fermentation broth. Physical separation of L-tyr crystals from biomass using a decanter type centrifuge, based on the density difference between the solids, is compared and contrasted with a strategy where L-tyr is first dissolved at pH 11.5 and then acid precipitated from clarified supernatants following removal of biomass using membrane filtration. L-tyr product purity of 98% with yields ranging from 90% to 95% is demonstrated., (Copyright 2007 Wiley Periodicals, Inc.)

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.

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.

This is a summary report of the International Pharmaceutical Federation/Board of Pharmaceutical Sciences (FIP/BPS) international conference, Bio-International 2005, which was held October 24-26, 2005 at the Royal Pharmaceutical Society, in London, UK. Bioequivalence (BE) issues related to multisource locally delivered topical dosage forms, oral inhalation drug products, highly variable drug products (HVDP), and endogenously occurring drugs were discussed. The conference also focused on alternate approaches to assess BE for some of these drug products. Pharmacokinetic (PK) approaches like, dermatopharmacokinetics (DPK) for dermatological topical dosage forms, scaled average BE (s-ABE) where within-subject variability is considered for estimation of 90% confidence intervals to document BE for highly variable drugs (HVD) were recommended. In addition, issues and difficulties related to the BE assessment of oral inhalation products, role, and appropriateness of metabolites in BE assessment, importance of base line correction in BE assessment of endogenously occurring drugs, and waiver of BE study requirements for certain drugs based on a Biopharmaceutics Classification System (BCS), were also discussed., ((c) 2006 Wiley-Liss, Inc.)

Background: Different formulations of botulinum toxin type A can behave differently. There has been little clinical research directly comparing formulations., Objective: We sought to compare the efficacy and tolerability of two botulinum toxin type A formulations-BoNTA1 and BoNTA2-in the treatment of moderate and severe glabellar lines., Methods: Sixty-two patients with moderate or severe glabellar lines at maximum contraction were randomly assigned to receive 20 U of BoNTA1 or 50 U of BoNTA2 (20% in the procerus muscle, 80% in the corrugator muscles)., Results: The incidence of 1-grade improvement or greater in glabellar line severity at maximum contraction was as follows: 77% (BoNTA1) versus 59% (BoNTA2) at week 12, 53% versus 28% at week 16. The estimated incidence of relapse was 23% (BoNTA1) versus 40% (BoNTA2) at week 16. Both formulations were similarly well tolerated., Limitations: Few male and non-Caucasian subjects were studied., Conclusion: BoNTA(1) offered more prolonged efficacy than BoNTA2 in the treatment of glabellar lines at the dose ratio of 2.5:1 (BoNTA2:BoNTA1) used in this study.

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.

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.

Background: Botulinum toxins have been proven effective for reducing facial lines. There are two commercial types of botulinum toxin type A available in many countries but no published comparison studies., Objective: To compare the efficacy and tolerability of Botox Cosmetic and Dysport 50 U in the treatment of glabellar lines (using 20 U of Botox Cosmetic, which is the dose approved by the US Food and Drug Administration for the treatment of glabellar lines, and 50 U of Dysport, which has been reported to be the optimal dose for this formulation)., Study Design: Parallel-group double-blind pilot study. Evaluation by observing physician, photographic, and patient evaluations., Conclusion: Botox 20 U provided better and more prolonged efficacy than Dysport 50 U in the treatment of glabellar lines.

Background: For many patients, injectable filling agents offer the promise of facial rejuvenation while offering reduced risks compared with more invasive surgery. With the increase in products available and the rise in the number of patients seeking this type of intervention, it is crucial that both the physician and the patient are fully cognizant of the risks involved with each product., Objective: To review the incidences and types of reaction to various commonly used injectable products., Methods: A literature review and personal experiences (gained largely in Europe over the past 8 years) of dermal fillers from 1996 to the present, including illustrative case reviews., Results: Reactions can be attributed to the procedure itself, the procedural technique, and the agent injected. Some of these reactions are preventable, whereas others are inevitable; most are mild and transient. Improving product formulations, altering the concentration of product injected, or changing the injection technique can dramatically reduce the incidence of adverse reactions. Since its reformulation in mid-1999, the biologically engineered hyaluronic acid filler Restylane (Medicis Pharmaceuticals, Scottsdale, AZ, USA) elicits less than one allergic reaction in 1600 treatments. Skin reactions with poly-L-lactic acid (New-Fill/Sculptra, Dermik Laboratories, Berwyn, PA, USA) are considerably less likely if a greater dilution and deeper injection technique are employed., Conclusion: Different injectable products have highly divergent properties, associated risks, and injection requirements. The dermasurgeon should be suitably experienced to select and use these products correctly.

Many systemic agents are used in the treatment of psoriasis. They provide good control of psoriasis in the majority of patients and have improved their life quality indices. Frequently, combination therapy is utilized to synergize the efficacy of these medications. Many dermatologists are hesitant in prescribing systemic agents because of their adverse effects. However, such potential toxicities arising from these medications can largely be avoided if proper patient selection and close monitoring are performed.

Background: Recent studies demonstrate that botulinum toxin type A (BTX-A) decreases palmar hyperhidrosis., Objective: To evaluate the efficacy and safety of BTX-A for palmar hyperhidrosis., Methods: Patients (n = 19) received injections of placebo (normal saline) in one hand and BTX-A in the other. Assessments included gravimetric measurement of sweat production and physician's and patient's rating of severity. Safety evaluations included measuring grip strength. Preliminary 28-day results are reported., Results: The mean percentage decrease in gravimetric measurement at day 28 was significantly greater with BTX-A versus placebo. One hundred percent of 17 patients rated the treatment as successful, while only 12% (2/17) rated placebo injection successful. Grip and hand strength were unchanged with either treatment. Only 21% (4/19) reported mild adverse events., Conclusion: BTX-A injections produce significant improvements in palmar hyperhidrosis without a concomitant decrease in grip or dexterity, or the occurrence of serious adverse events.

Fermentation-based bioprocesses rely extensively on strain improvement for commercialization. Whole-cell biocatalysts are commonly limited by low tolerance of extreme process conditions such as temperature, pH, and solute concentration. Rational approaches to improving such complex phenotypes lack good models and are especially difficult to implement without genetic tools. Here we describe the use of genome shuffling to improve the acid tolerance of a poorly characterized industrial strain of Lactobacillus. We used classical strain-improvement methods to generate populations with subtle improvements in pH tolerance, and then shuffled these populations by recursive pool-wise protoplast fusion. We identified new shuffled lactobacilli that grow at substantially lower pH than does the wild-type strain on both liquid and solid media. In addition, we identified shuffled strains that produced threefold more lactic acid than the wild type at pH 4.0. Genome shuffling seems broadly useful for the rapid evolution of tolerance and other complex phenotypes in industrial microorganisms.

Background: Facial lines resulting from hyperactivity can be misleading manifestations of negative emotions, fatigue and stress. They may also contribute to a perception of facial aging. A well established treatment is botulinum toxin type A (BTX-A). Recently, botulinum toxin type B (BTX-B) has become available for the treatment of cervical dystonia. There has been little comparison on the efficacy of the two different types of botulinum toxins, nor is there information on appropriate dosing of BTX-B for facial muscles., Objectives: The purpose of this pilot study was to observe the effects of BTX-B in comparison to BTX-A, on patients with brow furrows assessing initial efficacy and duration of effect., Methods: Patients were injected with BTX-B in two different dose conversions against BTX-A to the corrugator-procerus complex. Some patients received a conversion of 50 units of BTX-B (total of 1000 units) to one unit of BTX-A while others received a conversion of 100 units of BTX-B (total of 2000 units) to one unit of BTX-A. The patients treated with BTX-A received a total of 20 units. These patients were clinically assessed prior to treatment and 3 days, 1 week, 4 weeks, 12 weeks and 16 weeks after treatment., Results: Both types of botulinum toxin were effective at improving glabellar frown lines. The onset of actions occurred slightly sooner (2-3 days) with BTX-B than with BTX-A (3-7 days). Duration of effect with BTX-A was at least 16 weeks. With 1000 units of BTX-B, dose duration was 6-8 weeks and with 2000 units of BTX-B, duration was 10-12 weeks., Summary: Both types of botulinum toxin are effective at correcting deep glabellar furrows. At least with the doses used, BTX-B has a quicker onset of action and BTX-A has longer benefit for glabellar wrinkles. These data strongly suggest that further dose ranging studies of BTX-B are necessary and indicated in controlled double blind studies in a larger patient population.

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.

Purpose: To determine the relative bioavailability of two marketed, immediate-release methylphenidate tablets. The study used a replicated study design to characterize intrasubject variability, and determine bioequivalence using both average and individual bioequivalence criteria., Methods: A replicated crossover design was employed using 20 subjects. Each subject received a single 20 mg dose of the reference tablet on two occasions and two doses of the test tablet on two occasions. Blood samples were obtained for 10 hr after dosing, and plasma was assayed for methylphenidate by GC/MS., Results: The test product was more rapidly dissolved in vitro and more rapidly absorbed in vivo than the reference product. The mean Cmax and AUC(0-infinity) differed by 11% and 9%, respectively. Using an average bioequivalence criterion, the 90% confidence limits for the Ln-transformed Cmax and AUC(0-infinity), comparing the two replicates of the test to the reference product, fell within the acceptable range of 80-125%. Using an individual bioequivalence criterion the test product failed to demonstrate equivalence in Cmax to the reference product., Conclusions: The test and reference tablets were bioequivalent using an average bioequivalence criterion. The intrasubject variability of the generic product was greater and the subject-by-formulation interaction variance was borderline high. For these reasons, the test tablets were not individually bioequivalent to the reference tablets.

Purpose: The FDA has proposed replacing the current average bioequivalence criterion with population and individual bioequivalence criteria that consider variances in addition to the difference of averages. One of these variances in the individual bioequivalence criterion measures subject-by-formulation interaction, the extent to which the test-reference difference varies from person to person. This paper discusses conceptual and statistical issues raised in various publications and presentations with respect to the presence and estimation of such an interaction., Methods: We focus on the importance of subject-by-formulation interaction, an understanding of what is a large interaction, and the assessment of the magnitude of this interaction in bioequivalence studies. Simulation studies, examples from the literature, and data from FDA files are used to demonstrate the magnitude of the interaction and its distribution under various conditions., Results: The concept of a large interaction is tied to the concept of a large mean difference. We suggest that an interaction greater than 0.15 is a conservative criterion for a large interaction. Magnitudes of estimated interaction are affected by variability, sample size, and the selection of data sets that pass average bioequivalence., Conclusions: Examples of substantial interactions are beginning to appear. More data is needed before reaching definitive conclusions regarding the frequency and importance of observed interactions.

Role of histamine H2 receptors in blood-brain barrier (BBB) disturbances, cerebral blood flow (CBF), brain edema formation, and cell injury caused by heat stress in a rat model was examined using the pharmacological approach. Blockade of histamine H2 receptors by cimetidine or ranitidine significantly attenuated the BBB permeability to Evans blue albumin and [131]I-sodium extravasation, brain edema formation and cell injury following 4 h heat stress in rats at 38 degrees C. These drug treatments also restored the CBF to near normal values. These beneficial effects in heat stress were most marked in rats treated with ranitidine compared to cimetidine given in identical dosage. Our observations suggest that blockade of histamine H2 receptor is beneficial in hyperthermic brain injury and indicates that histamine is involved in the pathophysiology of heat stress induced brain dysfunction. Our study strongly suggests further need to develop more specific and sensitive histaminergic H2 receptor blockers for the treatment of neurological ailments.

A highly efficient Escherichia coli-based, batch in vitro protein synthesis system using circular plasmid DNA is described. Compared to a presently available commercial kit, this improved system produced several hundredfold greater yields of the rDNA human protein thrombopoietin (ca. 450 micrograms/mL). The system is capable of obtaining specific synthesis rates similar to those in vivo, approximately a 1000-fold increase compared to the original methods previously described. It compares favorably in rates and yields to the recently published semicontinuous methods but with the convenience of a true batch system.