Vascular phenotype identification and anti-angiogenic treatment recommendation: A pseudo-multiscale mathematical model of angiogenesis.

The development of anti-angiogenic drugs for cancer therapy has yielded some promising candidates, but novel approaches for interventions to angiogenesis have led to disappointing results. In addition, there is a shortage of biomarkers that are predictive of response to anti-angiogenic treatments. Consequently, the complex biochemical and physiological basis for tumour angiogenesis remains incompletely understood. We have adopted a mathematical approach to address these issues, formulating a spatially averaged multiscale model that couples the dynamics of VEGF, Ang1, Ang2 and PDGF, with those of mature and immature endothelial cells and pericyte cells. The model reproduces qualitative experimental results regarding pericyte coverage of vessels after treatment by anti-Ang2, anti-VEGF and combination anti-VEGF/anti-Ang2 antibodies. We used the steady state behaviours of the model to characterise angiogenic and non-angiogenic vascular phenotypes, and used mechanistic perturbations representing hypothetical anti-angiogenic treatments to generate testable hypotheses regarding transitions to non-angiogenic phenotypes that depend on the pre-treatment vascular phenotype. Additionally, we predicted a synergistic effect between anti-VEGF and anti-Ang2 treatments when applied to an immature pre-treatment vascular phenotype, but not when applied to a normalised angiogenic pre-treatment phenotype. Based on these findings, we conclude that changes in vascular phenotype are predicted to be useful as an experimental biomarker of response to treatment. Further, our analysis illustrates the potential value of non-spatial mathematical models for generating tractable predictions regarding the action of anti-angiogenic therapies.

Who's challenging who? Changing attitudes towards those whose behaviour challenges.

BACKGROUND: Although staff attitudes towards individuals with intellectual disability (ID) whose behaviour challenges may be an important part of a positive support culture, very little research has focused on the development of training specifically designed to change staff attitudes. Positive contact is hypothesised to be an effective way to change attitudes towards stigmatised groups. METHODS: We designed and developed a half day training package about the experiences of individuals whose behaviour challenges - Who's Challenging Who (WCW). The WCW package was delivered according to a manual by a trainer with ID and a professional without disability. Seventy-six staff from a variety of organisations participated in one of 10 WCW training sessions and provided data on their attitudes and empathy towards individuals whose behaviour challenges prior to the WCW training and immediately at the end of training. Staff also completed a post-training evaluation questionnaire. RESULTS: A training package was successfully developed collaboratively with individuals whose behaviour challenges, and received very positive evaluations from staff participants. Short-term positive change was shown for empowerment and similarity attitudes, and staff empathy and self-efficacy. These outcomes were associated with small to moderate effect sizes. CONCLUSIONS: Meaningful short-term positive staff attitude changes were found and the WCW training model was shown to be feasible. More robust research designs are needed for future evaluation. In addition, the function of an attitude change intervention such as WCW within organisations' training strategies requires further development.

Global taxonomic, functional, and phylogenetic diversity of bees in apple orchards.

An essential prerequisite to safeguard pollinator species is characterisation of the multifaceted diversity of crop pollinators and identification of the drivers of pollinator community changes across biogeographical gradients. The extent to which intensive agriculture is associated with the homogenisation of biological communities at large spatial scales remains poorly understood. In this study, we investigated diversity drivers for 644 bee species/morphospecies in 177 commercial apple orchards across 33 countries and four global biogeographical biomes. Our findings reveal significant taxonomic dissimilarity among biogeographical zones. Interestingly, despite this dissimilarity, species from different zones share similar higher-level phylogenetic groups and similar ecological and behavioural traits (i.e. functional traits), likely due to habitat filtering caused by perennial monoculture systems managed intensively for crop production. Honey bee species dominated orchard communities, while other managed/manageable and wild species were collected in lower numbers. Moreover, the presence of herbaceous, uncultivated open areas and organic management practices were associated with increased wild bee diversity. Overall, our study sheds light on the importance of large-scale analyses contributing to the emerging fields of functional and phylogenetic diversity, which can be related to ecosystem function to promote biodiversity as a key asset in agroecosystems in the face of global change pressures.

Integrating digital pathology and mathematical modelling to predict spatial biomarker dynamics in cancer immunotherapy.

In oncology clinical trials, on-treatment biopsy samples are taken to confirm the mode of action of new molecules, among other reasons. Yet, the time point of sample collection is typically scheduled according to 'Expert Best Guess'. We have developed an approach integrating digital pathology and mathematical modelling to provide clinical teams with quantitative information to support this decision. Using digitised biopsies from an ongoing clinical trial as the input to an agent-based mathematical model, we have quantitatively optimised and validated the model demonstrating that it accurately recapitulates observed biopsy samples. Furthermore, the validated model can be used to predict the dynamics of simulated biopsies, with applications from protocol design for phase 1-2 studies to the conception of combination therapies, to personalised healthcare.

The Iliotibial Band: A Complex Structure with Versatile Functions.

The development of a pronounced iliotibial band (ITB) is an anatomically distinct evolution of humans. The mechanical behaviour of this "new" structure is still poorly understood and hotly debated in current literature. Iliotibial band syndrome (ITBS) is one of the leading causes of lateral knee pain injuries in runners. We currently lack a comprehensive understanding of the healthy behaviour of the ITB, and this is necessary prior to further investigating the aetiology of pathologies like ITBS. Therefore, the purpose of this narrative review was to collate the anatomical, biomechanical and clinical literature to understand how the mechanical function of the ITB is influenced by anatomical variation, posture and muscle activation. The complexity of understanding the mechanical function of the ITB is due, in part, to the presence of its two in-series muscles: gluteus maximus (GMAX) and tensor fascia latae (TFL). At present, we lack a fundamental understanding of how GMAX and TFL transmit force through the ITB and what mechanical role the ITB plays for movements like walking or running. While there is a range of proposed ITBS treatment strategies, robust evidence for effective treatments is still lacking. Interventions that directly target the running biomechanics suspected to increase either ITB strain or compression of lateral knee structures may have promise, but clinical randomised controlled trials are still required.

Expression of D-serine and glycine transporters in the prefrontal cortex and cerebellum in schizophrenia.

The NMDA receptor co-agonists D-serine and glycine are thought to contribute to glutamatergic dysfunction in schizophrenia. They are removed from the synapse by specific neuronal and glial transporters, the status of which is clearly relevant to theories of D-serine and glycine function in the disorder. D-serine is primarily transported by Asc-1, and glycine by GlyT1 but maybe also by SNAT2. As a first step to addressing this issue, we studied Asc-1, GlyT1 and SNAT2 expression in dorsolateral prefrontal cortex and cerebellum of 18 subjects with schizophrenia and 20 controls, using immunoblotting and in situ hybridization. Asc-1 protein and SNAT2 mRNA were decreased in schizophrenia in both regions. GlyT1 mRNA and protein, and Asc-1 mRNA, were not altered. Antipsychotic administration for 14 days did not alter expression of the genes in rat brain. Unchanged GlyT1 suggests that glycine transport is not markedly affected in schizophrenia, and therefore that increased synaptic removal is not the basis for the putative deficit in glycine modulation of NMDA receptors in the disorder. Lowered Asc-1 in schizophrenia implies that D-serine reuptake is reduced, perhaps as a response to decreased synaptic D-serine availability. However, this interpretation remains speculative. Further investigations will be valuable in the evaluation of these transporters as potential therapeutic targets in psychosis.

Modeling Longitudinal Preclinical Tumor Size Data to Identify Transient Dynamics in Tumor Response to Antiangiogenic Drugs.

Experimental evidence suggests that antiangiogenic therapy gives rise to a transient window of vessel normalization, within which the efficacy of radiotherapy and chemotherapy may be enhanced. Preclinical experiments that measure components of vessel normalization are invasive and expensive. We have developed a mathematical model of vascular tumor growth from preclinical time-course data in a breast cancer xenograft model. We used a mixed-effects approach for model parameterization, leveraging tumor size data to identify a period of enhanced tumor growth that could potentially correspond to the transient window of vessel normalization. We estimated the characteristics of the window for mice treated with an anti-VEGF antibody (bevacizumab) or with a bispecific anti-VEGF/anti-angiopoietin-2 antibody (vanucizumab). We show how the mathematical model could theoretically be used to predict how to coordinate antiangiogenic therapy with radiotherapy or chemotherapy to maximize therapeutic effect, reducing the need for preclinical experiments that directly measure vessel normalization parameters.

Reversible changes in radiation response induced by all-trans retinoic acid.

PURPOSE: The aim was to establish a model of reversible radiosensitization in human tumor cell lines by all-trans retinoic acid without influencing cell cycle or differentiation. METHODS AND MATERIALS: Three human carcinoma cell lines (one bladder and two lung lines) were incubated in medium containing delipidized serum with or without varying concentrations of all-trans retinoic acid for a range of time periods, and their acute response to radiation measured by clonogenic assay. Cell phenotype was monitored using growth rates, morphology, and intermediate filament expression. RESULTS: Two of the three cell lines (those in which cell kill was predominantly through reparable damage beta in control cultures) showed an increase in radiosensitivity with retinoic acid, at a concentration with no discernable effect on phenotype (10(-7) M). No significant change in alpha values was observed. The values for beta increased from 0.057 to 0.109 and from 0.039 to 0.075, corresponding to dose modification factors of 1.59 and 1.67. When retinoic acid was removed prior to irradiation, cell survival returned to control levels by 48 h. CONCLUSION: Radiosensitization occurred at retinoic acid concentrations that did not otherwise perturb the cells; the effect may be due to inhibition of DNA repair in cells usually competent at repair. The model provides a method of altering radiosensitivity in selected cell lines without genetic mutation, which may enable investigation of DNA repair mechanisms.

Growth hormone and insulin-like growth factor-I accelerate PMSG-induced differentiation of granulosa cells.

To investigate the nature of the interactions between growth hormone (GH), insulin-like growth factor-I (IGF-I) and follicle stimulating hormone (FSH), their temporal and dose-related effects on steroidogenesis were studied in granulosa cells from stilboestrol-treated immature rats, stimulated in vitro with pregnant mare's serum gonadotropin (PMSG) or FSH. GH in the presence of PMSG enhanced aromatase activity and progesterone synthesis above that induced by maximally stimulating doses of PMSG alone, and accelerated PMSG-induced peak levels for both progesterone and aromatase activity. IGF-I also enhanced PMSG-induced aromatase activity and progesterone production, and accelerated their peak responses in a similar fashion to the effects observed for GH. The stimulatory actions of IGF-I could still be observed after the removal of FSH from the cultures, and appeared to be partly independent of cAMP. It is concluded that both GH and IGF-I act on FSH-induced granulosa cells to accelerate the differentiation of the follicular cell to a lutein cell.

Dosage of colloidal bismuth subcitrate in duodenal ulcer healing and clearance of Campylobacter pylori.

Sixty consecutive patients with endoscopically proven duodenal ulcers were given colloidal bismuth subcitrate tablets either as 120 mg q.d.s. or 240 mg b.d., in a randomized single-blind study. The efficacy of each regimen was determined by endoscopic examination and antral biopsy at 4 weeks; if the ulcer remained unhealed, treatment was continued and endoscopy repeated at 8 weeks. The ulcer-healing efficacy of the two regimens was identical; however, in the four times daily group only 27% remained Campylobacter pylori positive after 8 weeks of treatment compared with 58% of the twice-daily group. Similarly, only 21% of twice daily patients were free of histological gastritis compared with 42% of the four times daily patients.

Risperidone in the elderly: a pharmacoepidemiologic study.

BACKGROUND: The possibly limited adverse effects of risperidone encourage interest in its use in geriatric patients. METHOD: Medical records of 122 hospitalized psychogeriatric patients (> or = 65 years old) newly treated with risperidone were reviewed and scored for indications, doses, and effects of this novel neuroleptic. RESULTS: Subjects (83 women, 39 men), mean +/- SD age = 76.5 +/- 6.8 years (range, 65-95), were given risperidone for agitation or psychosis associated with dementia (53%), a major mood disorder (29%), or other disorders (18%). Most (77%) were also medically ill and received other psychotropic (76%) or cardiovascular agents (70%). Daily doses of risperidone averaged 1.6 +/- 1.1 mg (range, 0.25-8.0) (0.025 mg/kg body wt.); 78% received 2.0 mg. Risperidone appeared to be effective in 85% of cases, but 18% were discontinued due to intolerability (11%) or inefficacy (7%). Adverse events occurred in 32% of the patients (36% of those discontinued). These adverse events included hypotension (29%) or symptomatic orthostasis (10%), cardiac arrest (1.6%) with fatality (0.8%), and extrapyramidal effects (11%) or delirium (1.6%). Benefits were associated with younger age and male gender, but not risperidone dose. Adverse effects were associated with cardiovascular disease and its treatment, cotreatment with an SRI antidepressant or valproate, and relatively rapid dose increases. CONCLUSION: Risperidone appeared to be effective and may be safe for many elderly psychiatric patients with comorbid medical conditions provided that doses are low and increased slowly. Particular caution is advised in the presence of cardiovascular disease or cotreatment with other psychotropic agents.

Hyperkalemia in cardioplegic solutions causing increased cholesterol accumulation in vein grafts.

Hyperkalemic cardioplegic solutions are frequently infused through vein grafts during aorta-coronary bypass operations. Although some reports have suggested the potential for physical damage to grafts by such exposure, the effects of these solutions on graft atherogenesis have not been studied. We evaluated the influence of potassium and colloid content of cardioplegic solutions on graft cholesterol accumulation in our established animal model of graft atherogenesis. Fourteen cephalic vein grafts were interposed bilaterally in the femoral arteries of seven normolipemic stump-tailed macaque monkeys. Before grafting, each vein was distended at 350 torr for 1 minute with autologous blood. Half of each vein was then filled for 30 minutes with either balanced crystalloid solution or with balanced crystalloid plus albumin (5 mg/ml). The other half of the vein was filled with the same solution plus potassium chloride (27 mEq/L). Grafts were harvested at 12 weeks. Cholesterol content was significantly greater (p less than 0.01) in graft segments exposed to hyperkalemia than in their control counterparts. Onconicity had no effect on cholesterol content. In this animal model, prolonged exposure of vein grafts to hyperkalemic cardioplegic solutions caused increased lipid uptake. This finding may presage accelerated atheromatous degeneration.

Detection of human papillomavirus type 16 DNA in cervical swabs and formalin-fixed, paraffin-embedded squamous cell carcinomas of non-genital tissues using a synthetic oligodeoxynucleotide probe.

The potential of using a chemically synthesized oligodeoxynucleotide as a diagnostic probe to detect human papillomavirus type 16 (HPV-16) in genital infections was evaluated by comparing it with a cloned full-length HPV-16 probe in dot-blot DNA hybridizations. An oligonucleotide sequence, 20 bases in length from the E6 region of HPV-16 (E6 oligo) and different from the DNA sequences of HPV types 6, 11 and 18 by at least 2 base pairs, was chosen for chemical synthesis. The oligoprobe, which was 5'-end labelled with [32P]dATP, was found to be specific, but approximately ten times less sensitive than the full-length radiolabelled probe of HPV-16, in dot-blot hybridizations with the DNA of HPV-6, -11, -16 and -18, HPV positive and negative cell-lines. From 36 cervical or vulval scrapes two samples were found positive with both cloned HPV-16 and oligoprobe hybridization. Of 21 samples of formalin-fixed, paraffin-embedded squamous cell carcinomas originating from anus, oesophagus, penis, colon, breast and skin only 4 anal squamous cell carcinomas were positives when hybridized with cloned HPV-16 DNA or with the oligoprobe. This study confirms that HPV-16, which is frequently associated with squamous cell carcinoma of the cervix is also strongly associated with squamous cell carcinoma of the anus.

Pharmacokinetics of psychotropic drugs: what can it tell us?

1. Knowledge of basic pharmacokinetic parameters may help the clinician to optimize drug treatment regimen. 2. For some psychotropic drugs (e.g. lithium and some antidepressants) a good correlation exists between plasma levels and therapeutic or toxic effects. 3. "Optimum" steady state levels can now be predicted from single dose blood level data of some drugs (lithium, nortriptyline, desipramine). 4. Altered pharmacokinetics in elderly and children have to be taken into consideration in treatment with psychotropic drugs. 5. With development of suitable drug assays, plasma level control of therapy is becoming a part of a good clinical practice.

Paclitaxel in extensively pretreated nonseminomatous germ cell tumors.

Paclitaxel was given as a single agent to previously treated, cisplatin-refractory, and relapsed patients with metastatic nonseminomatous germ cell tumors (GCT). Fifteen patients received paclitaxel at 250 mg/m(2) as a 24-hour continuous intravenous infusion, repeated every 21 days. The regimen was premedicated to prevent hypersensitivity reactions. Patients were supported with granulocyte-colony stimulating factor until resolution of the neutropenia. Of 15 patients, I I patients had received at least three previous chemotherapy regimens; 80% of the patients were cisplatin-refractory at study entry. A total of 34 courses of paclitaxel were delivered. A serologic partial response and a partial remission for an overall response rate of 13.3% (95% C.I. 2-39%), with a median duration of 9.5 weeks, were achieved. Thirteen (86.6%) patients developed progressive disease. The toxicity of the regimen consisted of grade 3 4 neutropenia, with only one infectious complication and no life-threatening events. Nonhematologic toxicity was significant for progressive peripheral neuropathy in 8 patients. No hypersensitivity reactions or symptomatic cardiac toxicity occurred. In conclusion, paclitaxel in the dose and schedule given has minimal activity in this extensively treated, cisplatin-refractory group of patients with nonseminomatous GCT. Further investigation is warranted to find the role of paclitaxel in GCT by either selecting a better patient population and/or combining it with cisplatin, which would use the synergistic cytotoxicity that has been reported.

Psychosis, lithium-induced antipsychotic response, and seasonality.

Lithium alone has previously been shown to effect antipsychotic response in approximately one-quarter of mood incongruent psychoses. Such lithium-responsive psychoses and/or the antipsychotic effects of lithium appear to be seasonal, with maximal response rates occurring in the 3-month periods surrounding January and July peaks. Within patients, retrials of lithium in formerly lithium-responsive psychotic patients demonstrate a trend toward greater continued antipsychotic effects of lithium during the periods surrounding January and July (80% response rates) vs. the remaining 6 months of the year (33% response rates).

Analysis of structural requirements for the absorption of drugs and macromolecules from the nasal cavity.

An octapeptide and a protein, of molecular weights 800 and 34,000, respectively, were found to have nasal bioavailabilities of 73 and 0.6%, respectively, in the rat. This data, combined with reported values for 23 other compounds, indicated good availability without adjuvants for all molecules up to 1000 molecular weight (mean 70%, SD between compounds 26%, n = 15) with a decline in availability above this value. The relationship between absorption and molecular weight was modeled assuming competition between constant clearance from the nasal cavity and molecular weight-dependent transport through the mucosa. Deviations of absorption from values predicted by this model did not correlate with factors such as charge, hydrophobicity, or susceptibility to aminopeptidases, but the relative absorption of cyclic and cross-linked peptides and proteins was significantly greater than that of linear peptides. It is argued that the most likely route for transport is through junctions between cells and that surface-active adjuvants (MW 6000) which markedly enhance insulin uptake may act by rendering hydrophobic areas of contact of the junctional proteins temporarily hydrophilic. The nasal route is suitable for efficient, rapid delivery of many molecules of molecular weight less than 1000. With the use of adjuvants, this limit can be extended to at least 6000 and possibly much higher.

Effects of sodium 5-methoxysalicylate on macromolecule absorption and mucosal morphology in a vascularly perfused rat gut preparation in vivo.

The effect of sodium 5-methoxysalicylate on absorption was assessed by measurement of the appearance of test compounds in the portal blood output of a perfused rat gut model. The test compounds were a hexapeptide analogue of somatostatin, insulin, and horseradish peroxidase. Considerable amounts of sodium 5-methoxysalicylate were present in the portal blood 10 min after intraduodenal administration. When co-administered with sodium 5-methoxysalicylate (60 mg), a marked increase in the concentrations of the test substances occurred at t = 15 min which lasted for a further 15 min. Quantities of less than 60 mg had much reduced adjuvant effects. In control experiments with no adjuvant, the concentrations of the test substances remained low throughout the 1-h period of blood collection. After the administration of 60 mg of sodium 5-methoxysalicylate, slight mucosal damage was apparent at 10 min. This became progressively worse with time and, at 1 h, extensive mucosal stripping had occurred. The results suggest, although they do not prove, that apparent adjuvant effects in the small intestine may be a direct consequence of serious mucosal damage. This means that care must be taken in the investigation of adjuvant properties to exclude the possibility that an observed increase in transport is due to gross loss of integrity of the membrane.

Cloning bovine cytokine cDNA fragments and measuring bovine cytokine mRNA using the reverse transcription-polymerase chain reaction.

Bovine cytokine-specific primers and the reverse transcription-polymerase chain reaction (RT-PCR) were used to clone cDNA fragments that were specific for bovine IL-1 alpha, IL-1 beta, IL-2, and IFN-gamma. Specificity of the cDNA fragments was verified by sequence analysis based on known bovine IL-1 alpha, IL-1 beta, IL-2, and IFN-gamma gene sequences. In addition, RT-PCR was used to monitor cytokine mRNA expression in concanavalin A (Con A) and lipopolysaccharide (LPS)-stimulated bovine peripheral blood mononuclear cells (PBMC), and the results were compared with those obtained by measuring PBMC cytokine secretion using biologic assays. IL-1 activity in LPS-stimulated PBMC cultures was similar at 12 h and 24 h, although the activity decreased by approximately 40% at 48 h. IL-2 and IFN-gamma activity in supernatants of Con A-stimulated PBMC cultures was low at 12 h and reached maximum levels at 48 h. RT-PCR transcript analysis detected an increase in IL-1 alpha, IL-1 beta, IL-2, and IFN-gamma mRNA expression that was usually correlated with the detection of these soluble cytokines by the bioassays. These results indicate that RT-PCR is a sensitive and effective method of obtaining cDNA probes and that this technique can be used to monitor bovine cytokine mRNA expression.