Precision medicine for psychotic disorders: objective assessment, risk prediction, and pharmacogenomics.

Psychosis occurs inside the brain, but may have external manifestations (peripheral molecular biomarkers, behaviors) that can be objectively and quantitatively measured. Blood biomarkers that track core psychotic manifestations such as hallucinations and delusions could provide a window into the biology of psychosis, as well as help with diagnosis and treatment. We endeavored to identify objective blood gene expression biomarkers for hallucinations and delusions, using a stepwise discovery, prioritization, validation, and testing in independent cohorts design. We were successful in identifying biomarkers that were predictive of high hallucinations and of high delusions states, and of future psychiatric hospitalizations related to them, more so when personalized by gender and diagnosis. Top biomarkers for hallucinations that survived discovery, prioritization, validation and testing include PPP3CB, DLG1, ENPP2, ZEB2, and RTN4. Top biomarkers for delusions include AUTS2, MACROD2, NR4A2, PDE4D, PDP1, and RORA. The top biological pathways uncovered by our work are glutamatergic synapse for hallucinations, as well as Rap1 signaling for delusions. Some of the biomarkers are targets of existing drugs, of potential utility in pharmacogenomics approaches (matching patients to medications, monitoring response to treatment). The top biomarkers gene expression signatures through bioinformatic analyses suggested a prioritization of existing medications such as clozapine and risperidone, as well as of lithium, fluoxetine, valproate, and the nutraceuticals omega-3 fatty acids and magnesium. Finally, we provide an example of how a personalized laboratory report for doctors would look. Overall, our work provides advances for the improved diagnosis and treatment for schizophrenia and other psychotic disorders.

Towards precision medicine for anxiety disorders: objective assessment, risk prediction, pharmacogenomics, and repurposed drugs.

Anxiety disorders are increasingly prevalent, affect people's ability to do things, and decrease quality of life. Due to lack of objective tests, they are underdiagnosed and sub-optimally treated, resulting in adverse life events and/or addictions. We endeavored to discover blood biomarkers for anxiety, using a four-step approach. First, we used a longitudinal within-subject design in individuals with psychiatric disorders to discover blood gene expression changes between self-reported low anxiety and high anxiety states. Second, we prioritized the list of candidate biomarkers with a Convergent Functional Genomics approach using other evidence in the field. Third, we validated our top biomarkers from discovery and prioritization in an independent cohort of psychiatric subjects with clinically severe anxiety. Fourth, we tested these candidate biomarkers for clinical utility, i.e. ability to predict anxiety severity state, and future clinical worsening (hospitalizations with anxiety as a contributory cause), in another independent cohort of psychiatric subjects. We showed increased accuracy of individual biomarkers with a personalized approach, by gender and diagnosis, particularly in women. The biomarkers with the best overall evidence were GAD1, NTRK3, ADRA2A, FZD10, GRK4, and SLC6A4. Finally, we identified which of our biomarkers are targets of existing drugs (such as a valproate, omega-3 fatty acids, fluoxetine, lithium, sertraline, benzodiazepines, and ketamine), and thus can be used to match patients to medications and measure response to treatment. We also used our biomarker gene expression signature to identify drugs that could be repurposed for treating anxiety, such as estradiol, pirenperone, loperamide, and disopyramide. Given the detrimental impact of untreated anxiety, the current lack of objective measures to guide treatment, and the addiction potential of existing benzodiazepines-based anxiety medications, there is a urgent need for more precise and personalized approaches like the one we developed.

Surgical vs Non-surgical interventions for distal radius fractures: a quantitative analysis of Patient-Rated Wrist Evaluation measures.

Trials to assess differences in PRWE (Patient Related Wrist Evaluation) over time, for both surgical and non-surgical interventions post DRFs (distal radius fractures) are rare. The DASH (Disabilities of the Arm, Shoulder and Hand) questionnaire has been shown to be improved by a greater margin in the medium term for surgical interventions, than non surgical interventions. However, a study found that PRWE can be considered superior to the DASH questionnaire for DRFs, due to greater specificity to wrist pain and function. Conflicting data makes it difficult to determine surgical vs non-surgical superiority for DRF's over time with PRWE as a recovery metric. PubMed and Cochrane were searched for randomised controlled trials up to 31.8.23, reporting PRWE over 3, and 12 months. Data was extracted by 2 researchers. The differences in PRWE over time post surgical and non-surgical interventions was assessed using unpaired T testing. 1226 records were screened. 4 studies enrolling 817 participants met the eligibility criteria and were analysed. Significantly lower PRWE in surgical intervention has been identified at the 3 month mark (p<0.001). There was greater significant change in non-surgical intervention between months 3 and 12 (p<0.001). Change in PRWE over time may be a good indicator of functional outcomes in DRFs post surgical or non-surgical interventions. This could inform future clinical trial design and surgical decision-making. Further work is required to design even more user-friendly and digital patient- reported outcomes specifically for DRFs.

Precision medicine for mood disorders: objective assessment, risk prediction, pharmacogenomics, and repurposed drugs.

Mood disorders (depression, bipolar disorders) are prevalent and disabling. They are also highly co-morbid with other psychiatric disorders. Currently there are no objective measures, such as blood tests, used in clinical practice, and available treatments do not work in everybody. The development of blood tests, as well as matching of patients with existing and new treatments, in a precise, personalized and preventive fashion, would make a significant difference at an individual and societal level. Early pilot studies by us to discover blood biomarkers for mood state were promising [1], and validated by others [2]. Recent work by us has identified blood gene expression biomarkers that track suicidality, a tragic behavioral outcome of mood disorders, using powerful longitudinal within-subject designs, validated them in suicide completers, and tested them in independent cohorts for ability to assess state (suicidal ideation), and ability to predict trait (future hospitalizations for suicidality) [3-6]. These studies showed good reproducibility with subsequent independent genetic studies [7]. More recently, we have conducted such studies also for pain [8], for stress disorders [9], and for memory/Alzheimer's Disease [10]. We endeavored to use a similar comprehensive approach to identify more definitive biomarkers for mood disorders, that are transdiagnostic, by studying mood in psychiatric disorders patients. First, we used a longitudinal within-subject design and whole-genome gene expression approach to discover biomarkers which track mood state in subjects who had diametric changes in mood state from low to high, from visit to visit, as measured by a simple visual analog scale that we had previously developed (SMS-7). Second, we prioritized these biomarkers using a convergent functional genomics (CFG) approach encompassing in a comprehensive fashion prior published evidence in the field. Third, we validated the biomarkers in an independent cohort of subjects with clinically severe depression (as measured by Hamilton Depression Scale, (HAMD)) and with clinically severe mania (as measured by the Young Mania Rating Scale (YMRS)). Adding the scores from the first three steps into an overall convergent functional evidence (CFE) score, we ended up with 26 top candidate blood gene expression biomarkers that had a CFE score as good as or better than SLC6A4, an empirical finding which we used as a de facto positive control and cutoff. Notably, there was among them an enrichment in genes involved in circadian mechanisms. We further analyzed the biological pathways and networks for the top candidate biomarkers, showing that circadian, neurotrophic, and cell differentiation functions are involved, along with serotonergic and glutamatergic signaling, supporting a view of mood as reflecting energy, activity and growth. Fourth, we tested in independent cohorts of psychiatric patients the ability of each of these 26 top candidate biomarkers to assess state (mood (SMS-7), depression (HAMD), mania (YMRS)), and to predict clinical course (future hospitalizations for depression, future hospitalizations for mania). We conducted our analyses across all patients, as well as personalized by gender and diagnosis, showing increased accuracy with the personalized approach, particularly in women. Again, using SLC6A4 as the cutoff, twelve top biomarkers had the strongest overall evidence for tracking and predicting depression after all four steps: NRG1, DOCK10, GLS, PRPS1, TMEM161B, GLO1, FANCF, HNRNPDL, CD47, OLFM1, SMAD7, and SLC6A4. Of them, six had the strongest overall evidence for tracking and predicting both depression and mania, hence bipolar mood disorders. There were also two biomarkers (RLP3 and SLC6A4) with the strongest overall evidence for mania. These panels of biomarkers have practical implications for distinguishing between depression and bipolar disorder. Next, we evaluated the evidence for our top biomarkers being targets of existing psychiatric drugs, which permits matching patients to medications in a targeted fashion, and the measuring of response to treatment. We also used the biomarker signatures to bioinformatically identify new/repurposed candidate drugs. Top drugs of interest as potential new antidepressants were pindolol, ciprofibrate, pioglitazone and adiphenine, as well as the natural compounds asiaticoside and chlorogenic acid. The last 3 had also been identified by our previous suicidality studies. Finally, we provide an example of how a report to doctors would look for a patient with depression, based on the panel of top biomarkers (12 for depression and bipolar, one for mania), with an objective depression score, risk for future depression, and risk for bipolar switching, as well as personalized lists of targeted prioritized existing psychiatric medications and new potential medications. Overall, our studies provide objective assessments, targeted therapeutics, and monitoring of response to treatment, that enable precision medicine for mood disorders.

Risk factors for outbreaks caused by variant strain of Newcastle disease on environmentally controlled broiler chicken farms in Lahore, Pakistan.

Newcastle disease (ND) is a frequently reported disease in poultry among both vaccinated and non-vaccinated flocks in Pakistan. During 2011-2012 poultry industry in Punjab, mainly in Lahore region, faced fatal outbreaks of ND caused by a variant strain. An analytical study was conducted during outbreak period in Lahore region. A total of 114 environmentally controlled farms were selected with the help of convenient sampling method. A questionnaire was designed about the potential risk factors associated with the spread of ND outbreak. The bivariate relationships between ND status and independent variables were investigated by applying the Chi-square and Fisher's exact test. Multivariable logistic model was used to estimate the effect of each studied variable on the outcome by adjusting the other variables in the model. The variables which showed an association with ND outbreaks at commercial poultry farms were improper method for dead birds disposal (OR=4.96; 95% CI 1.63-15.12), use of same feed transporting vehicle at multiple poultry farms (OR=4.92; 95% CI 1.58-15.33), farm to farm distance of less than 1 km (OR=9.32; 95% CI(1.19-73.12), number of sheds at one farm (OR=2.31; 95% CI 0.93-5.69), labor type (OR=2.72; 95% CI 0.83-8.88) and biosecurity (OR= 4.47; 95% CI 0.56-35.66).

Convection enhanced delivery of panobinostat (LBH589)-loaded pluronic nano-micelles prolongs survival in the F98 rat glioma model.

BACKGROUND: The pan-histone deacetylase inhibitor panobinostat is a potential therapy for malignant glioma, but it is water insoluble and does not cross the blood-brain barrier when administered systemically. In this article, we describe the in vitro and in vivo efficacy of a novel water-soluble nano-micellar formulation of panobinostat designed for administration by convection enhanced delivery (CED). MATERIALS AND METHODS: The in vitro efficacy of panobinostat-loaded nano-micelles against rat F98, human U87-MG and M059K glioma cells and against patient-derived glioma stem cells was measured using a cell viability assay. Nano-micelle distribution in rat brain was analyzed following acute CED using rhodamine-labeled nano-micelles, and toxicity was assayed using immunofluorescent microscopy and synaptophysin enzyme-linked immunosorbent assay. We compared the survival of the bioluminescent syngenic F98/Fischer344 rat glioblastoma model treated by acute CED of panobinostat-loaded nano-micelles with that of untreated and vehicle-only-treated controls. RESULTS: Nano-micellar panobinostat is cytotoxic to rat and human glioma cells in vitro in a dose-dependent manner following short-time exposure to drug. Fluorescent rhodamine-labelled nano-micelles distribute with a volume of infusion/volume of distribution (Vi/Vd) ratio of four and five respectively after administration by CED. Administration was not associated with any toxicity when compared to controls. CED of panobinostat-loaded nano-micelles was associated with significantly improved survival when compared to controls (n=8 per group; log-rank test, P<0.001). One hundred percent of treated animals survived the 60-day experimental period and had tumour response on post-mortem histological examination. CONCLUSION: CED of nano-micellar panobinostat represents a potential novel therapeutic option for malignant glioma and warrants translation into the clinic.

Provincial elections and timing of cancer drug funding.

BACKGROUND: Concerns have been raised about the potential influence of political pressures on drug funding decisions. We evaluated the temporal relationship between cancer drug funding and provincial elections in 9 Canadian provinces. METHODS: New indications for cancer drugs between January 2003 and December 2012 were identified, and the dates of official provincial funding dates and election dates between 1 January 2003 and 31 December 2014 were retrieved. The probability of drug funding announcements in the 60-day period preceding a provincial election was evaluated using binomial probability distribution analysis. RESULTS: Data from 9 provinces (all Canadian provinces except Quebec) were available. During the period of interest, 69 new indications for 39 individual drugs were identified. Variation in the availability of funding dates was identified. At the time of data collection, 2 provinces did not have data available for all 69 indications. For the 9 provinces, the number of funded indications during the 60-day period preceding an election ranged from 0 to 3; however, no differences in the proportion of indications funded pre-election were identified. Additional analyses also failed to demonstrate any significant associations with the 90-day period before an election, or the 60- and 90-day periods after an election. CONCLUSIONS: We observed no clear temporal relationship between provincial election dates and funding decisions in this recent Canadian sample of new indications for cancer drugs.

Pulmonary arteriovenous malformations and their mimics.

Pulmonary arteriovenous malformations (PAVMs) are abnormal communications between the pulmonary arteries and veins, which result in a right-to-left (R-L) shunt with resultant hypoxemia, the severity of which will depend upon the size and number of lesions. Most PAVMs occur in individuals with hereditary haemorrhagic telangiectasia (HHT) and are a cause of serious morbidity and mortality largely related to cerebrovascular complications secondary to paradoxical embolization. The importance of their recognition and treatment by embolization, even in the absence of symptoms, is well known. Their appearances on chest radiographs are often, but not always, characteristic and the CT appearances are diagnostic; however, there are a number of both vascular and non-vascular diseases that can cause confusion. This review serves to highlight these PAVM "mimics".

Convection-enhanced delivery of AAV2 in white matter--a novel method for gene delivery to cerebral cortex.

BACKGROUND: Convection-enhanced delivery (CED) is currently under investigation for delivering therapeutic agents to subcortical targets in the brain. Direct delivery of therapies to the cerebral cortex, however, remains a significant challenge. NEW METHOD: We describe a novel method of targeting adeno-associated viral vector (AAV) mediated gene therapies to specific cerebral cortical regions by performing high volume, high flow rate infusions into underlying white matter in a large animal (porcine) model. RESULTS: Infusion volumes of up to 700 µl at flow rates as high as 10 µl/min were successfully performed in white matter without adverse neurological sequelae. Co-infusion of AAV2/5-GFP with 0.2% Gadolinium in artificial CSF confirmed transgene expression in the deep layers of cerebral cortex overlying the infused areas of white matter. COMPARISON WITH EXISTING METHODS: AAV-mediated gene therapies have been previously targeted to the cerebral cortex by performing intrathalamic CED and exploiting axonal transport. The novel method described in this study facilitates delivery of gene therapies to specific regions of the cerebral cortex without targeting deep brain structures. CONCLUSIONS: AAV-mediated gene therapies can be targeted to specific cortical regions by performing CED into underlying white matter. This technique could be applied to the treatment of neurological disorders characterised by cerebral cortical degeneration.

In vitro and in vivo testing of a novel recessed-step catheter for reflux-free convection-enhanced drug delivery to the brain.

INTRODUCTION: The optimisation of convection-enhanced drug delivery (CED) to the brain is fundamentally reliant on minimising drug reflux. The aim of this study was to evaluate the performance of a novel reflux-resistant CED catheter incorporating a recessed-step and to compare its performance to previously described stepped catheters. METHODS: The in vitro performance of the recessed-step catheter was compared to a conventional "one-step" catheter with a single transition in outer diameter (OD) at the catheter tip, and a "two-step" design comprising two distal transitions in OD. The volumes of distribution and reflux were compared by performing infusions of Trypan blue into agarose gels. The in vivo performance of the recessed-step catheter was then analysed in a large animal model by performing infusions of 0.2% Gadolinium-DTPA in Large White/Landrace pigs. RESULTS: The recessed-step catheter demonstrated significantly higher volumes of distribution than the one-step and two-step catheters (p=0.0001, one-way ANOVA). No reflux was detected until more than 100 ul had been delivered via the recessed-step catheter, whilst reflux was detected after infusion of only 25 ul via the 2 non-recessed catheters. The recessed-step design also showed superior reflux resistance to a conventational one-step catheter in vivo. Reflux-free infusions were achieved in the thalamus, putamen and white matter at a maximum infusion rate of 5 ul/min using the recessed-step design. CONCLUSION: The novel recessed-step catheter described in this study shows significant potential for the achievement of predictable high volume, high flow rate infusions whilst minimising the risk of reflux.

Robot-guided convection-enhanced delivery of carboplatin for advanced brainstem glioma.

BACKGROUND: Patients with diffuse intrinsic pontine glioma (DIPG) have a poor prognosis with median survival reported as 9 months. The failure of systemic chemotherapy to improve prognosis may be due to inadequate penetration of the blood-brain barrier (BBB). Convection-enhanced delivery (CED) has the potential to improve outcomes by facilitating bypass of the BBB. We describe the first use of carboplatin for the treatment of advanced DIPG using a robot-guided catheter implantation technique. METHODS: A 5-year-old boy presented with a pontine mass lesion. The tumor continued to progress despite radiotherapy. Using an in-house modification to neuroinspire stereotactic planning software (Renishaw Plc., Gloucestershire, UK), the tumor volume was calculated as 43.6 ml. A transfrontal trajectory for catheter implantation was planned facilitating the in-house manufacture of a recessed-step catheter. The catheter was implanted using a neuromate robot (Renishaw Plc., Gloucestershire, UK). The initial infusion of carboplatin (0.09 mg/ml) was commenced with real-time T2-weighted MRI, facilitating estimation of the volume of infusate distribution. Infusions were repeated on a total of 5 days. RESULTS: The catheter implantation and infusions were well tolerated. A total volume of 49.8 ml was delivered over 5 days. T2-weighted MRI on completion of the final infusion demonstrated signal change through a total volume of 35.1 ml, representing 95 % of the targeted tumor volume. Follow-up at 4 weeks revealed clinical signs of improvement and increased T2 signal change throughout the volume of distribution. However, there was tumor progression in the regions outside the volume of distribution. CONCLUSIONS: This case demonstrates the feasibility of accurately and safely delivering small-diameter catheters to the brainstem using a robot-guided implantation procedure, and real-time MRI tracking of infusate distribution.

Intermittent convection-enhanced delivery to the brain through a novel transcutaneous bone-anchored port.

Convection-enhanced delivery (CED) describes a novel method of drug delivery to the brain through intraparenchymal microcatheters. One of the barriers to effective translation of CED to clinical trials is the requirement for intermittent delivery over prolonged periods. This is particularly relevant for delivery of neurotrophins for the treatment of Parkinson's disease where chronic infusion of glial cell-line derived neurotrophic factor (GDNF) with subcutaneously implanted pumps has been associated with poor distribution and local toxicity due to point source accumulation. We have previously described the development of an implantable catheter for CED which facilitates repeated drug administrations at intervals of up to one month. The aim of this study was to determine the feasibility of implanting a transcutaneous bone-anchored port (TBAP) which facilitates chronic intermittent drug delivery to the brain. We describe the design and development of a titanium port which was implanted in Large White and NIH miniature pigs for periods of up to three months. By intermittently accessing the port with a needle administration set it was possible to repeatedly perform CED infusions at one month intervals. This study confirms the safety and feasibility of performing intermittent CED through a transcutaneous bone-anchored port. The use of a transcutaneous port has the potential to facilitate clinical translation of CED of therapeutics requiring intermittent delivery to achieve optimum efficacy whilst negating the need for subcutaneously implanted pumps.

Respiratory-aspirated 35-mm hairpin successfully retrieved with a Teflon® snare system under fluoroscopic guidance via a split endotracheal tube: a useful technique in cases of failed extraction by bronchoscopy and avoiding the need for a thoracotomy.

Respiratory foreign body aspiration (FBA) is a common global health problem requiring prompt recognition and early treatment to prevent potentially fatal complications. The majority of FBAs are due to organic objects and treatment is usually via either endoscopic or surgical extraction. FBA of a straight hairpin has been described as a unique entity in the literature, occurring most commonly in females, particularly during adolescence. In the process of inserting hairpins, the pins will typically be between the teeth with the head tilted backwards, while tying their hair with both hands. This position increases the risk of aspiration, particularly if there is any sudden coughing or laughing. To our knowledge, this is the first case report of a 35-mm straight metallic hairpin foreign body that has been successfully retrieved by a radiological snare system under fluoroscopic guidance. This was achieved with the use of a split endotracheal tube, and therefore avoided the need for a thoracotomy in an adolescent female patient.

Controlling soot formation with filtered EGR for diesel and biodiesel fuelled engines.

Although exhaust gas recirculation (EGR) is an effective strategy for controlling the levels of nitrogen oxides (NO(X)) emitted from a diesel engine, the full potential of EGR in NO(X)/PM trade-off and engine performance (i.e., fuel economy) has not fully been exploited. Significant work into the cause and control of particulate matter (PM) has been made over the past decade with new cleaner fuels and after-treatment devices emerging to comply with the current and forthcoming emission regulations. In earlier work, we demonstrated that engine operation with oxygenated fuels (e.g., biodiesel) reduces the PM emissions and extends the engine tolerance to EGR before it reaches smoke-limited conditions. The same result has also been reported when high cetane number fuels such as gas-to-liquid (GTL) are used. To further our understanding of the relationship between EGR and PM formation, a diesel particulate filter (DPF) was integrated into the EGR loop to filter the recirculated soot particulates. The control of the soot recirculation penalty through filtered EGR (FEGR) resulted in a 50% engine-out soot reduction, thus showing the possibility of extending the maximum EGR limit or being able to run at the same level of EGR with an improved NO(X)/soot trade-off.

Combined pedunculopontine-subthalamic stimulation in Parkinson disease.

OBJECTIVE: To assess the effect of deep brain stimulation (DBS) in the pedunculopontine nucleus (PPN) and caudal zona incerta (cZi)-both separately and in combination-on motor symptoms and regional cerebral blood flow (rCBF) in patients with Parkinson disease (PD). METHODS: Four patients with bilateral cZi and PPN DBS electrodes were rated with the Unified Parkinson's Disease Rating Scale motor subscale (UPDRS-III) when taking and withdrawn from medication. A block of 16 [(15)O]-H(2)O PET resting measurements of rCBF were performed in 4 different states with patients withdrawn from medication: 1) no stimulation, 2) cZi stimulation alone, 3) PPN stimulation alone, 4) combined PPN/cZi stimulation. RESULTS: When patients were medicated, combined PPN/cZi stimulation produced a statistically significant improvement in UPDRS-III score compared to cZi stimulation alone. In the "off" medication state, the clinical effect of combined stimulation was not significantly different from that induced by cZi stimulation alone. Concomitant PPN/cZi stimulation had a cumulative effect on levels of rCBF, effectively combining subcortical and cortical changes induced by stimulation of either target in isolation. CONCLUSIONS: These findings suggest that concomitant low frequency stimulation of PPN and cZi regions induces additive brain activation changes and provides improved control of PD symptoms when medicated. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that concomitant low frequency stimulation of PPN and cZI improves motor symptoms in patients with PD on dopamine replacement. It provides Class III evidence that concomitant low frequency stimulation of PPN and cZi induces additive rCBF changes in motor areas of brain.

The development of an implantable catheter system for chronic or intermittent convection-enhanced delivery.

Convection-enhanced delivery (CED) is a promising technique for the administration of therapeutic agents such as cytotoxics, neurotrophins and enzymes to the brain. In this study we describe the development of an implantable catheter system that is compatible with long-term intermittent CED. Catheters made from fused silica, PEEK or carbothane, and of various internal and external diameters were implanted in the striatum of rats and assessed for patency at 21 or 28 days. A high-rate of catheter blockage was observed with all fused silica and PEEK catheters. Carbothane catheters with an outer diameter of 0.6mm and an inner diameter of 0.35 mm had significantly lower rates of blockage (P≤0.01). Carbothane catheters were then implanted into 4 Large White/Landrace pigs and 4 NIH miniature pigs and infusions undertaken at monthly intervals to evaluate catheter patency and infusate distribution. Catheter patency was demonstrated for a maximum period of 163 days in one animal. Widespread and reproducible intraputamenal CED could be achieved with intermittent drug delivery at flow-rates as high as 5 µl/min. Problems were encountered using the pig model due to catheter distortion from rapid animal growth. In conclusion, it is possible to achieve intermittent high-flow CED with a chronic implanted carbothane catheter with a low rate of catheter blockage.

Analysis of foramen ovale with special emphasis on pterygoalar bar and pterygoalar foramen.

The foramen ovale is of great surgical and diagnostic importance in procedures like percutaneous trigeminal rhizotomy for trigeminal neuralgia, transfacial fine needle aspiration technique in perineural spread of tumour, and electroencephalographic analysis. This study presents the anatomic variations in dimensions, appearance, number of foramen ovale (FO), and presence of pterygoalar bar and pterygoalar foramen. For the present study ninety dry adult human skulls were utilised. Anterioposterior (length) and transverse (width) diameters of FO were measured, and the presence of pterygoalar bar and foramen were observed. The most common shape of FO observed was like a figure 'D'. The ranges of anteroposterior diameter of the right and left FO were 8.5-4.5 mm and 10-3 mm, respectively. The mean length of the right FO was 6.60 mm while that of the left FO was 6.26 mm. The ranges of transverse diameter (width) of both right and left foramen were 2.5-6 mm and 2-5 mm, respectively. The mean transverse diameter of the right FO was 3.70 mm and that of left was 3.34 mm. Bony spur in FO was seen in 6.66% of cases. A complete pterygoalar bar and foramen were observed in seven cases unilaterally, and in one case it was bilateral. Anteroposterior and transverse diameters of right FO were greater than left. Anatomical understanding, including the size, shape of FO, and presence of pterygoalar bar, has immense surgical and diagnostic importance.

Clonality assessment of lymphoproliferative lesions using the polymerase chain reaction: an analysis of two methods.

BACKGROUND: Lymphoid malignancies are a heterogeneous group of disorders which may be difficult to differentiate from reactive proliferations even after immunohistochemistry. Polymerase chain reaction (PCR) is believed to be a good adjunct tool for diagnosis. MATERIALS AND METHODS: We examined 24 cases of neoplastic and non-neoplastic lymphoproliferative lesions in this study and evaluated the PCR as an additional tool in the confirmation of the diagnosis. Two different PCR methodologies were evaluated. RESULTS: In the evaluation of the T-cell PCR, it was seen that the correlation using both the commercial kits and the custom-synthesized primers was highly significant at a P value of <0.05. In the evaluation of the B-cell PCR, it was seen that the correlation using both the commercial kits and the custom-synthesized primers was not significant using either method (P > 0.05). CONCLUSIONS: Both the methods showed an excellent concordance for T-cell γ gene rearrangements, However, the same was not seen in the B-cell receptor rearrangements. This may be because of the small sample size or the inability of consensus V primers to recognize complementary DNA sequences in all of the V segments.

Priorities for the head and neck cancer patient, their companion and members of the multidisciplinary team and decision regret.

AIMS: To compare the treatment outcome priorities of patients, their companions and members of the multidisciplinary team (MDT), and also to determine if the former two groups suffered from regret of their decision. MATERIALS AND METHODS: Patients were eligible if attending with a companion at least 6 months after radiotherapy for head and neck cancer given with curative intent. They were interviewed by two clinicians separately with questions from the Chicago Priority Scale and Ottawa Decision Regret Scale. RESULTS: In total, 30 patients, 30 companions and 25 members of the MDT were evaluated. 'Being cured of my cancer', 'living as long as possible', 'having no pain' and 'being able to swallow all foods and drinks' were the top four priorities for all three groups. Patients ranked 'having no pain' lower than either companions (P=0.003) and members of the MDT (P=0.006). Patients ranked 'keeping my appearance unchanged' as less important than members of the MDT (P=0.013) and 'keeping my normal sense of taste and smell' as more important than members of the MDT (P=0.013). The post-treatment regret score was 12.50 for patients and 10.33 for companions out of 100 (P value was not significant). CONCLUSIONS: There was a strong agreement between patients, their companions and members of the MDT with regards to priorities in head and neck cancer outcomes and low post-treatment regret for patients and their companions. These results suggest that the patients' companions and members of the MDT are able to exercise good judgment when it comes to supporting patients in decision making.

A role for endosomal proteins in alphavirus dissemination in mosquitoes.

Little is known about endosomal pathway proteins involved in arthropod-borne virus (arbovirus) assembly and cell-to-cell spread in vector mosquitoes. UNC93A and synaptic vesicle-2 (SV2) proteins are involved in intracellular transport in mammals. They show amino acid sequence conservation from mosquitoes to humans, and their transcripts are highly enriched in Aedes aegypti during arbovirus infection. Transient gene silencing of SV2 or UNC93A in mosquitoes infected with the recombinant alphavirus Sindbis MRE16-enhanced green fluorescent protein (SINV; family Togaviridae) resulted in the accumulation of viral positive- and negative-strand RNA, congregation of virus envelope antigen in intracellular networks, and reduced virus dissemination outside of the midgut. Further, UNC93A silencing, but not SV2 silencing, resulted in a 10-fold reduction in viral titres at 4 days post-infection. Together, these data support a role for UNC93A and SV2 in virus assembly or budding. Cis-regulatory elements (CREs) were identified at the 5'-ends of genes from the original data set in which SV2 and UNC93A were identified. Common CREs at the 5'-end genomic regions of a subset of enriched transcripts support the hypothesis that UNC93A transcription may be co-regulated with that of other ion transport and endosomal trafficking proteins.