An open-label study of pemigatinib in cholangiocarcinoma: final results from FIGHT-202.

BACKGROUND: Fibroblast growth factor receptor 2 (FGFR2) fusions and rearrangements are clinically actionable genomic alterations in cholangiocarcinoma (CCA). Pemigatinib is a selective, potent, oral inhibitor of FGFR1-3 and demonstrated efficacy in patients with previously treated, advanced/metastatic CCA with FGFR2 alterations in FIGHT-202 (NCT02924376). We report final outcomes from the extended follow-up period. PATIENTS AND METHODS: The multicenter, open-label, single-arm, phase II FIGHT-202 study enrolled patients ≥18 years old with previously treated advanced/metastatic CCA with FGFR2 fusions or rearrangements (cohort A), other FGF/FGFR alterations (cohort B), or no FGF/FGFR alterations (cohort C). Patients received once-daily oral pemigatinib 13.5 mg in 21-day cycles (2 weeks on, 1 week off) until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) in cohort A assessed as per RECIST v1.1 by an independent review committee; secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: FIGHT-202 enrolled 147 patients (cohort A, 108; cohort B, 20; cohort C, 17; unconfirmed FGF/FGFR alterations, 2). By final analysis, 145 (98.6%) had discontinued treatment due to progressive disease (71.4%), withdrawal by patient (8.2%), or adverse events (AEs; 6.8%). Median follow-up was 45.4 months. The ORR in cohort A was 37.0% (95% confidence interval 27.9% to 46.9%); complete and partial responses were observed in 3 and 37 patients, respectively. Median DOR was 9.1 (6.0-14.5) months; median PFS and OS were 7.0 (6.1-10.5) months and 17.5 (14.4-22.9) months, respectively. The most common treatment-emergent AEs (TEAEs) were hyperphosphatemia (58.5%), alopecia (49.7%), and diarrhea (47.6%). Overall, 15 (10.2%) patients experienced TEAEs leading to pemigatinib discontinuation; intestinal obstruction and acute kidney injury (n = 2 each) occurred most frequently. CONCLUSIONS: Pemigatinib demonstrated durable response and prolonged OS with manageable AEs in patients with previously treated, advanced/metastatic CCA with FGFR2 alterations in the extended follow-up period of FIGHT-202.

A multicenter, randomized phase 2 study to establish combinations of CBP501, cisplatin and nivolumab for ≥3rd-line treatment of patients with advanced pancreatic adenocarcinoma.

BACKGROUND: There is no standard of care for ≥ 3rd-line treatment of metastatic pancreatic adenocarcinoma (PDAC). CBP501 is a novel calmodulin-binding peptide that has been shown to enhance the influx of platinum agents into tumor cells and tumor immunogenicity. This study aimed to (1) confirm efficacy of CBP501/cisplatin/nivolumab for metastatic PDAC observed in a previous phase 1 study, (2) identify combinations that yield 35% 3-month progression-free survival rate (3MPFS) and (3) define the contribution of CBP501 to the effects of combination therapy. METHODS: CBP501 16 or 25 mg/m2 (CBP(16) or CBP(25)) was combined with 60 mg/m2 cisplatin (CDDP) and 240 mg nivolumab (nivo), administered at 3-week intervals. Patients were randomized 1:1:1:1 to (1) CBP(25)/CDDP/nivo, (2) CBP(16)/CDDP/nivo, (3) CBP(25)/CDDP and (4) CDDP/nivo, with randomization stratified by ECOG PS and liver metastases. A Fleming two-stage design was used, yielding a one-sided type I error rate of 2.5% and 80% power when the true 3MPFS is 35%. RESULTS: Among 36 patients, 3MPFS was 44.4% in arms 1 and 2, 11.1% in arm 3% and 33.3% in arm 4. Two patients achieved a partial response in arm 1 (ORR 22.2%; none in other arms). Median PFS and OS were 2.4, 2.1, 1.5 and 1.5 months and 6.3, 5.3, 3.7 and 4.9 months, respectively. Overall, all treatment combinations were well tolerated. Most treatment-related adverse events were grade 1-2. CONCLUSIONS: The combination CBP(25)/(16)/CDDP/nivo demonstrated promising signs of efficacy and a manageable safety profile for the treatment of advanced PDAC. CLINICAL TRIAL REGISTRATION: NCT04953962.

Geographic Variation in Racial Disparities in Mortality From Influenza and Pneumonia in the United States in the Pre-Coronavirus Disease 2019 Era.

BACKGROUND: In 2018, influenza and pneumonia was the eighth leading cause of death in the United States. Since 1950, non-Hispanic blacks (NHBs) have experienced higher rates of mortality than non-Hispanic whites (NHWs). Previous studies have revealed geographic variation in mortality rates by race. The identification of areas with the greatest disparity in influenza and pneumonia mortality may assist policymakers in the allocation of resources, including for the coronavirus disease 2019 pandemic. RESEARCH QUESTION: Does geographic variation in racial disparity in influenza and pneumonia mortality exist? STUDY DESIGN AND METHODS: The Centers for Disease Control and Prevention database for Multiple Cause of Death between 1999 and 2018 for NHB and NHW decedents ≥ 25 years of age with a Tenth Revision of the International Statistical Classification of Diseases and Related Health Problems code for influenza (J09-J11) and pneumonia (J12-J18) was used. Age-adjusted mortality rates (AAMRs) with 95% CIs were computed by race for Health & Human Services (HHS) regions and urbanization in NHBs and NHWs. RESULTS: In 1999 through 2018, there were 540,476 deaths among NHBs and NHWs 25 to 84 years of age. AAMRs were higher in NHBs than NHWs in each age group and in seven of 10 HHS regions. The greatest disparity was in HHS regions 2 (New York and New Jersey) and 9 (Arizona, California, Hawaii, and Nevada). In HHS region 2, NHBs (24.6; 95% CI, 24.1-25.1) were more likely to die than NHWs (15.7; 95% CI, 15.6-15.9). Similarly, in region 9, NHBs (23.2; 95% CI, 22.7-23.8) had higher mortality than NHWs (16.1; 95% CI, 15.9-16.2). Within these regions, disparities were greatest in the core of major metropolitan areas. A very high AAMR in NHBs was noted in large, central metropolitan areas of region 2: 28.2 (95% CI, 27.6-28.9). INTERPRETATION: In 1999 through 2018, the NHB-NHW disparity in AAMRs from influenza and pneumonia was greatest in central metropolitan areas of HHS regions 2 and 9.

Predictors of immunotherapy-induced immune-related adverse events.

Purpose: We aimed to elucidate predictive factors for the development of immune-related adverse events (iraes) in patients receiving immunotherapies for the management of advanced solid cancers. Methods: This retrospective study involved all patients with histologically confirmed metastatic or inoperable melanoma, non-small-cell lung cancer, or renal cell carcinoma receiving immunotherapy at the Cancer Centre of Southeastern Ontario. The type and severity of iraes, as well as potential protective and exacerbating factors, were collected from patient charts. Results: The study included 78 patients receiving ipilimumab (32%), nivolumab (33%), or pembrolizumab (35%). Melanoma, non-small-cell lung cancer, and renal cell carcinoma accounted for 70%, 22%, and 8% of the cancers in the study population. In 41 patients (53%) iraes developed, with multiple iraes developing in 12 patients (15%). In most patients (70%), the iraes were of severity grade 1 or 2. Female sex [adjusted odds ratio (oradj): 0.094; 95% confidence interval (ci): 0.021 to 0.415; p = 0.002] and corticosteroid use before immunotherapy (oradj: 0.143; 95% ci: 0.036 to 0.562; p = 0.005) were found to be associated with a protective effect against iraes. In contrast, a history of autoimmune disease (oradj: 9.55; 95% ci: 1.34 to 68.22; p = 0.025), use of ctla-4 inhibitors (oradj: 6.25; 95% ci: 1.61 to 24.25; p = 0.008), and poor kidney function of grade 3 or greater (oradj: 10.66; 95% ci: 2.41 to 47.12; p = 0.025) were associated with a higher risk of developing iraes. A Hosmer-Lemeshow goodness-of-fit test demonstrated that the logistic regression model was effective at predicting the development of iraes (chi-square: 1.596; df = 7; p = 0.979). Conclusions: Our study highlights several factors that affect the development of iraes in patients receiving immunotherapy. Although future studies are needed to validate the resulting model, findings from the study can help to guide risk stratification, monitoring, and management of iraes in patients given immunotherapy for advanced cancer.

Shelf-life enhancement of bio-inoculant formulation by optimizing the trace metals ions in the culture medium for production of DAPG using fluorescent pseudomonad R62.

Statistical experimental design was used to optimize the concentration of trace elements for production of antifungal compound, 2,4-diacetylphloroglucinol (DAPG), from fluorescent pseudomonad R62 in shake-flask cultivation. The selection of the trace metal ions, influencing DAPG production, was done using Plackett-Burman design (PBD). Only Zn(2+), Mn(2+) and MoO(4)(2-) were the most significant components (p<0.05). A quadratic model was used to fit the response. Application of response surface methodology (RSM) revealed that the optimum values of the salts of the trace elements Zn(2+) (ZnSO(4)·7H(2)O), Mn(2+) (MnCl(2)·4H(2)O), and MoO(4)(2-) (Na(2)MoO(4)·2H(2)O) were 83, 42 and 135µM, respectively, to achieve 125 mg/L of DAPG, which was nearly 13-fold more compared to its production in basal synthetic medium in shake flask. The studies in 14L bioreactor resulted in 135 mg/L of DAPG at the end of 36 h of cultivation. The culture broth containing 125 mg/L of DAPG was found to be sufficient for keeping the bio-inoculant viable in non-sterile talcum powder-based formulations (which contained 25µg DAPG/g carrier) when stored at 28°C for 6 months. The structure of the purified DAPG was confirmed using (1)H NMR and mass spectrometry.

Application of inorganic carrier-based formulations of fluorescent pseudomonads and Piriformospora indica on tomato plants and evaluation of their efficacy.

AIMS: Fluorescent pseudomonads are widely used as bioinoculants for improving plant growth and controlling phytopathogenic fungi. Piriformospora indica (Pi), a symbiotic root endophyte, also has beneficial effects on a number of plants. The present study focuses on the improvement of growth yields of tomato plants and control of Fusarium wilt using inorganic carrier-based formulations of two fluorescent pseudomonad strains (R62 and R81) and Pi. METHODS AND RESULTS: The inorganic carrier-based formulations of pseudomonad strains and Pi were tested for plant growth promotion of tomato plants under glass house and field conditions. In controlled glass house experiments, 8·8-fold increase in dry root weight and 8·6-fold increase in dry shoot weight were observed with talcum powder-based consortium formulation of R81 and Pi. Field trial experiments ascertained the glfass house results with a considerable amount of increase in plant growth responses, and amongst all the treatments, R81 + Pi treatment performed consistently well in field conditions with an increase of 2·6-, 3·1- and 3·9-fold increase in dry root weight, shoot weight and fruit yield, respectively. The fluorescent pseudomonad R81 and Pi also acted as biocontrol agents, as their treatments could control the incidence of wilt disease caused by Fusarium oxysporum f.sp. lycopersici in tomato plants under glass house conditions. CONCLUSIONS: The culture broths of pseudomonads R62, R81 and Pi were successfully used for development of talcum- and vermiculite-based bioinoculant formulations. In controlled glasshouse experiments, the talcum-based bioinoculant formulations performed significantly better over vermiculite-based formulations. In field experiments the talcum-based consortium formulation of pseudomonad R81 and Pi was most effective. SIGNIFICANCE AND IMPACT OF THE STUDY: This study suggests that the formulations of pseudomonad strains (R62 and R81) and Pi can be used as bioinoculants for improving the productivity of tomato plants. The application of such formulations is a step forward towards sustainable agriculture.

Optimization of chemically defined medium for recombinant Pichia pastoris for biomass production.

A chemically defined medium was optimized for the maximum biomass production of recombinant Pichia pastoris in the fermentor cultures using glycerol as the sole carbon source. Optimization was done using the statistical methods for getting the optimal level of salts, trace metals and vitamins for the growth of recombinant P. pastoris. The response surface methodology was effective in optimizing nutritional requirements using the limited number of experiments. The optimum medium composition was found to be 20 g/L glycerol, 7.5 g/L (NH4)2SO4, 1 g/L MgSO4.7H2O, 8.5 g/L KH2PO4, 1.5 mL/L vitamin solution and 20 mL/L trace metal solution. Using the optimized medium 11.25 g DCW/L biomass was produced giving a yield coefficient of 0.55 g biomass/g of glycerol in a batch culture. Chemostat cultivation of recombinant P. pastoris was done in the optimized medium at different dilution rates to determine the kinetic parameters for growth on glycerol. Maximum specific growth rate of 0.23 h(-1) and Monod saturation constant of 0.178 g/L were determined by applying Monod model on the steady state data. Products of fermentation pathway, ethanol and acetate, were not detected by HPLC even at higher dilution rates. This supports the notion that P. pastoris cells grow on glycerol by a respiratory route and are therefore an efficient biomass and protein producers.

Processing of vibrotactile inputs from hairy skin by neurons of the dorsal column nuclei in the cat.

The capacity of single neurons of the dorsal column nuclei (DCN) for coding vibrotactile information from the hairy skin has been investigated in anesthetized cats to permit quantitative comparison first with the capacities of DCN neurons responding to glabrous skin vibrotactile inputs and second with those of spinocervical tract neurons responding to vibrotactile inputs from hairy skin. Dynamically sensitive tactile neurons of the DCN the input of which came from hairy skin could be divided into two classes, one associated with hair follicle afferent (HFA) input, the other with Pacinian corpuscle (PC) input. The HFA-related class was most sensitive to low-frequency (<50 Hz) vibration and had a graded response output as a function of vibrotactile intensity changes. PC-related neurons had a broader vibrotactile sensitivity, extending to > or =300 Hz and appeared to derive their input from the margins of hairy skin, near the footpads, or from deeper PC sources such as the interosseous membranes or joints. HFA-related neurons had phaselocked responses to vibration frequencies up to approximately 75 Hz, whereas PC neurons retained this capacity up to frequencies of approximately 300 Hz with tightest phaselocking between 50 and 200 Hz. Quantitative measures of phaselocking revealed that the HFA-related neurons provide the better signal of vibrotactile frequency up to approximately 50 Hz with a switch-over to the PC-related neurons above that value. In conclusion, the functional capacities of these two classes of cuneate neuron appear to account for behavioral vibrotactile frequency discriminative performance in hairy skin, in contrast to the limited capacities of vibrotactile-sensitive neurons within the spinocervical tract system.

Vibrotactile coding capacities of spinocervical tract neurons in the cat.

The response characteristics and tactile coding capacities of individual dorsal horn neurons, in particular, those of the spinocervical tract (SCT), have been examined in the anesthetized cat. Twenty one of 38 neurons studied were confirmed SCT neurons based on antidromic activation procedures. All had tactile receptive fields on the hairy skin of the hindlimb. Most (29/38) could also be activated transynaptically by electrical stimulation of the cervical dorsal columns, suggesting that a common set of tactile primary afferent fibers may provide the input for both the dorsal column-lemniscal pathway and for parallel ascending pathways, such as the SCT. All but 3 of the 38 neurons studied displayed a pure dynamic sensitivity to controlled tactile stimuli but were unable to sustain their responsiveness throughout 1s trains of vibration at vibration frequencies exceeding 5-10 Hz. Stimulus-response relations revealed a very limited capacity of individual SCT neurons to signal, in a graded way, the intensity parameter of the vibrotactile stimulus. Furthermore, because of their inability to respond on a cycle-by-cycle pattern at vibration frequencies >5-10 Hz, these neurons were unable to provide any useful signal of vibration frequency beyond the very narrow bandwidth of approximately 5-10 Hz. Similar limitations were observed in the responsiveness of these neurons to repetitive forms of antidromic and transynaptic inputs generated by electrical stimulation of the spinal cord. In summary, the observed limitations on the vibrotactile bandwidth of SCT neurons and on the precision and fidelity of their temporal signaling, suggest that SCT neurons could serve as little more than coarse event detectors in tactile sensibility, in contrast to DCN neurons the bandwidth of vibrotactile responsiveness of which may extend beyond 400 Hz and is therefore broader by approximately 40-50 times than that of SCT neurons.

Vibrotactile frequency discrimination in human hairy skin.

The human capacity for vibrotactile frequency discrimination has been compared directly for glabrous and hairy skin regions by means of a two-alternative, forced-choice psychophysical procedure in five subjects. Sinusoidal vibratory stimuli, delivered by means of a 4-mm-diam probe, were first used to obtain detection threshold values for the two skin sites, the finger tip and the dorsal forearm, at four standard frequencies, 20, 50, 100, and 200 Hz. Values confirmed previous results showing detection thresholds were markedly higher on hairy skin than on glabrous skin. For the discrimination task, each standard frequency, at an amplitude four times detection threshold, was paired with a series of comparison frequencies, and discrimination capacity then was quantified by deriving from psychometric function curves, measures of the discriminable frequency increment (Deltaf) and the Weber Fraction (Deltaf/f), which, when plotted as a function of the four standard frequencies, revealed similar capacities for frequency discrimination at the two skin sites at the standard frequencies of 20, 100, and 200 Hz but an equivocal difference at 50 Hz. Cutaneous local anesthesia produced a marked impairment in vibrotactile detection and discrimination at the low standard frequencies of 20 and 50 Hz but little effect at higher frequencies. In summary, the results reveal, first, a striking similarity in vibrotactile discriminative performance in hairy and glabrous skin despite marked differences in detection thresholds for the two sites, and, second, the results confirm that vibrotactile detection and discrimination in hairy skin depend on superficial receptors at low frequencies but depend on deep, probably Pacinian corpuscle, receptors for high frequencies.

Mechanosensory perception: are there contributions from bone-associated receptors?

1. The identity of the receptors and afferent nerve fibres that mediate the sense of touch varies somewhat with body location. Those that have been most intensively characterized are associated with the distal glabrous skin of the limbs and, in primates, mediate the sense of touch in the fingertips and palms. In this glabrous skin region, there appear to be three or four principal classes of tactile sensory nerves that fall into two broad groups. One group, the so-called slowly adapting (SA) receptors and afferent fibres, is responsive to static mechanical displacement of skin tissues and is made up of two classes, the type I (SAI) fibres that innervate Merkel receptors and the type II (SAII) fibres that innervate Ruffini endings. The second broad group displays a pure dynamic sensitivity to tactile stimuli and also falls into two principal classes, the rapidly adapting (RA) tactile fibres that are associated with Meissner corpuscle receptors and the Pacinian corpuscle (PC)-associated class of tactile afferent fibres. 2. In other regions of the skin, such as the hairy skin of the arms, legs and trunk, there are similar functional classes of tactile sensory nerves, although the receptor endings differ somewhat from those of the glabrous skin. 3. Receptors in close association with the long bones of the limbs include groups of Pacinian corpuscles distributed along the interosseous membranes. These are highly sensitive to dynamic forms of mechanical stimuli, in particular vibrotactile disturbances. However, despite their close association with bone, these receptors probably cannot be legitimately considered 'osseoreceptors'. 4. Both the periosteum and the bone marrow are richly supplied by nerve fibres. However, much evidence indicates that these are largely or entirely in the fine-diameter category of nerve fibres, whose roles may be confined to either nociception or to the efferent autonomic regulation of bone-associated blood vessels. 5. In conclusion, it remains uncertain whether any aspects of our innocuous touch or kinaesthetic senses, in either the limbs or in orofacial regions, can be ascribed to 'osseoreceptors' located in the periosteum or within the bone marrow itself.

Compactin-a review.

Compactin, a hypocholesterolemic molecule, is a competitive inhibitor of 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase, which is a regulatory enzyme for cholesterol biosynthesis. The structural similarity and high affinity of the acid form of compactin and HMG, the natural substrate of enzyme, results in specific and effective inhibition of this enzyme. Inhibition results in reduced levels of mevalonic acid in the body, leading to pleiotropic effects. Various fungi have been used for the commercial production of compactin. Using different strategies for improving production levels, yields have been increased to around 900 times of the amount originally produced. Recently, the gene sequence responsible for compactin production has been cloned and sequenced. This review deals with the chemistry, mode of action, pharmacology, biosynthesis, and production of compactin. A comparative study of various reports dealing with the production of compactin is also included.

Tactile neural mechanisms in monotremes.

Monotremes, perhaps more than any other order of mammals, display an enormous behavioural reliance upon the tactile senses. In the platypus, Ornithorhynchus anatinus, this is manifest most strikingly in the special importance of the bill as a peripheral sensory organ, an importance confirmed by electrophysiological mapping that reveals a vast area of the cerebral cortex allocated to the processing of tactile inputs from the bill. Although behavioural evidence in the echidna, Tachyglossus aculeatus, suggests a similar prominence for tactile inputs from the snout, there is also a great reliance upon the distal limbs for digging and burrowing activity, pointing to the importance of tactile information from these regions for the echidna. In recent studies, we have investigated the peripheral tactile neural mechanisms in the forepaw of the echidna to establish the extent of correspondence or divergence that has emerged over the widely different evolutionary paths taken by monotreme and placental mammals. Electrophysiological recordings were made from single tactile sensory nerve fibres isolated in fine strands of the median or ulnar nerves of the forearm. Controlled tactile stimuli applied to the forepaw glabrous skin permitted an initial classification of tactile sensory fibres into two broad divisions, according to their responses to static skin displacement. One displayed slowly adapting (SA) response properties, while the other showed a selective sensitivity to the dynamic components of the skin displacement. These purely dynamically-sensitive tactile fibres could be subdivided according to vibrotactile sensitivity and receptive field characteristics into a rapidly adapting (RA) class, sensitive to low frequency (

Statistical medium optimization and production of a hyperthermostable lipase from Burkholderia cepacia in a bioreactor.

AIM: Statistical medium optimization for maximum production of a hyperthermostable lipase from Burkholderia cepacia and its validation in a bioreactor. METHODS AND RESULTS: Burkholderia cepacia was grown in shake flasks containing 1% glucose, 0.1% KH2PO4, 0.5% NH4Cl, 0.24% (NH4)2HPO4, 0.01% MgSO4.7H2O and 1% emulsified palm oil, at 45 degrees C and pH 7.0, agitated at 250 rev min(-1) with 6-h-old inoculum (2% v/v) for 20 h. A fourfold enhancement in lipase production (50 U ml(-1)) and an approximately three fold increase in specific activity (160 U mg(-1)) by B. cepacia was obtained in a 14 litre bioreactor within 15 h after statistical optimization following shake flask culture. The statistical model was obtained using face centred central composite design (FCCCD) with five variables: glucose, palm oil, incubation time, inoculum density and agitation. The model suggested no interactive effect of the five factors, although incubation period, inoculum and carbon concentration were the important variables. CONCLUSIONS: The maximum lipase production was 50 U ml(-1), with specific activity 160 U mg(-1) protein, in a 14 litre bioreactor after 15 h in a medium obtained after statistical optimization in shake flasks. Further, the model predicted reduction in time for lipase production with reduction in total carbon supply. SIGNIFICANCE AND IMPACT OF THE STUDY: Statistical optimization allows quick optimization of a large number of variables. It also provides a deep insight into the regulatory role of various parameters involved in enzyme production.

Enhanced expression of the recombinant lethal factor of Bacillus anthracis by Fed-Batch culture.

High cell density cultivation has been one of the most effective ways to increase cell as well as the product yields. The structural gene for the 90-kDa lethal factor (LF) isolated from Bacillus anthracis was expressed as fusion protein with 6x histidine residues under the transcriptional regulation of the T5 promoter in Escherichia coli. Various strategies were tried to scale up the expression of the recombinant lethal factor by bioprocess optimization using fed batch culture technique in a 14 litre fermentor. The media, a defined mixture of salts, trace elements, vitamins, etc. along with a specified carbon source was used for the growth. The pH of the media was maintained at 6.8 while the temperature was changed from 37 to 28 degrees C during the cultivation. During the growth and induction phases, the DO was maintained above 20% by automatic control of agitation. The specific growth rate was controlled by utilizing an exponential feeding profile determined from mass balance equations. As a result of control of specific growth rate at two different levels, there was about twenty five fold increase in biomass compared to the biomass in the shake flask. E. coli cells yielded a soluble cytosolic protein with an apparent molecular mass of 90 kDa. The protein was purified to homogeneity using metal chelate affinity chromatography, followed by anion exchange on FPLC using Mono-Q column. In solution, trypsin cleaved protective antigen bound to native and recombinant LF with comparable affinity. The recombinant LF resembled the LF purified from B. anthracis in the macrophage lysis assay, using a murine macrophage cell line J774A.1 sensitive to anthrax toxin. It was possible to achieve a yield of 50 mg of the purified protein from 1 litre culture broth.

Optimization of xylanase production by Melanocarpus albomyces IIS68 in solid state fermentation using response surface methodology.

Xylanase production by the thermophilic fungus, Melanocarpus albomyces IIS68, during solid state fermentation of wheat straw was studied and the effects of various variables were observed. Using the response surface methodology and the multivariant statistical approach, the optimum levels of the variables affecting xylanase production were determined. The optimum levels of the variables were 600-850 microm particle size, 43 h inoculum age, 1.37% Tween 80, 86% initial moisture content, 5.1% urea, 0.74% yeast extract and a harvest time of 96 h. Under these optimized conditions, xylanase activity of 7760 U/g initial dry substrate was obtained which was in very good agreement with the value predicted by the quadratic model (7890 U/g initial dry substrate).

Task related changes in ERP auditory vs visual tasks.

P3 component of event related potentials have been studied in relaxed state of mind. Changes in P3 latency and amplitude are expected if measured after a rigorous mental exercise. The event related potentials (ERP) were measured in 20 normal male subjects aged between 18 and 22 years. ERP was recorded twice in each subject before and after the administration of a mental task. The auditory mental task comprised of repeating in reverse order string of random digits read out to the subject at a uniform speed of 1 per second. The visual task comprised reading laterally inverted type written text. Each subject had to undergo 2 sessions in separate sittings. The latency and amplitude of P300 recorded before and after the task were compared statistically using Students' unpaired t-test. There was significant increase in P3 latency following both visual and auditory tasks (auditory task: before 330 +/- 24.43 msec and after 342.9 +/- 27.66 msec, similarly visual task: before 333.2 +/- 26.66 msec and after 345.65 +/- 26.56 msec). All other ERP waves latency and amplitude changes were insignificant.

Task related changes in contingent negative variation (CNV) response of endogenous evoked potentials.

Contingent negative variation (CNV) is a slow negative cortical potential shift, which occurs during a warned foreperiod reaction time paradigm. Most studies of evoked potentials have concentrated on components occurring during the first 300 msec, although there are important and recordable aspects of signal processing occurring well beyond 300 msec e.g. late negative slow wave. CNV has proven sensitive to a number of psychological variables, none of which can yet be singled out as a definitive or exclusive correlate. Changes are expected if measured after a rigorous mental exercise. CNV was measured in 20 normal male subjects aged between 18 and 20 years. CNV was recorded twice in each subject before and after the administration of a mental task. The auditory mental task comprised repeating in reverse order string of random digits read out to the subject at a uniform speed of 1 per second. The visual mental task comprised reading laterally inverted type written text. Each subject had to undergo 2 sessions in separate sittings. The latency and amplitude of waves N1, P3, orientation (O), expectancy (E), CNV, reaction time (RT) were recorded. These values recorded before and after the task were compared statistically using student's unpaired t-test. The significant latencies recorded before and after the auditory task were, N1: 88.00 +/- 11.96 and 100.00 +/- 21.52 msec, P3: 289.00 +/- 54.85 and 299.00 +/- 52.91 msec, reaction time (RT): 102 +/- 17.05 msec and 123 +/- 17.5 msec, and in case of visual task, N1: 88 +/- 13.16 msec and 99.00 +/- 16.51 msec, reaction time (RT): 107 +/- 11.74 msec and 127 +/- 13.42 msec respectively. All other CNV wave latencies and amplitude changes were insignificant. Hence task effects sensory perception as reflected by increased latency of the long latency response N1 and the cortical integrative processes resulting in increased reaction time.

A profile of cardiovascular disease in northern Ontario: public health planning implications.

Cardiovascular disease (CVD) is a leading cause of death in Northern Ontario and therefore considered an important issue. To this end, this paper examines CVD trends in Northern Ontario and the prevalence of known risk factors that give an insight into these trends. Ontario Health Survey 1990, Ontario Health Survey 1996, Canadian Institute for Health Information (1990-95) and Vital Statistics (1990-95) were examined. It was determined that CVD rates in Northern Ontario significantly exceeded those of the province. Further, high prevalence of modifiable risk factors, such as smoking, fat intake, physical inactivity and obesity are all experienced in Northern Ontario when compared to the province. Planning implications, as they relate to collaboration, delivery of services, determinants of health, multiple risk factors and monitoring and evaluation are also discussed.

Factors associated with seat belt use: an evaluation from the Ontario Health Survey.

This study examines the factors associated with seat belt use for drivers and passengers in Ontario. Using the 1990 Ontario Health Survey, a population-based survey of non-institutionalized Ontario residents, factors associated with seat belt use among drivers and passengers were identified and are reported as unadjusted and adjusted odds ratios (OR; 95% CI). Seat belt non-use in Ontario drivers was most strongly associated with younger age (p < 0.0001), high risk health behaviours (drinking and driving (OR: 2.43), speeding (OR: 2.04), smoking (OR: 1.66)), being male (OR: 1.87), living in northern (OR: 1.80) or rural (OR: 1.69) regions, and achieving lower education (OR: 1.46). Seat belt non-use in passengers was associated with younger age (p < 0.0001), smoking (OR: 1.62), being male (OR: 1.68), living in northern (OR: 1.63) or rural (OR: 1.46) regions, and low education (OR: 1.31). Vehicular trauma is a major public health problem and seat belt use has been shown to reduce injuries in the event of a crash. Any strategy to increase seat belt use in Ontario should be targeted to involve both drivers and passengers. Attention should be paid to increasing seat belt usage by younger adults, males, and especially those living in northern and rural regions.