Gamma knife capsulotomy for intractable OCD: Neuroimage analysis of lesion size, location, and clinical response.

Obsessive-compulsive disorder (OCD) affects 2-3% of the population. One-third of patients are poorly responsive to conventional therapies, and for a subgroup, gamma knife capsulotomy (GKC) is an option. We examined lesion characteristics in patients previously treated with GKC through well-established programs in Providence, RI (Butler Hospital/Rhode Island Hospital/Alpert Medical School of Brown University) and São Paulo, Brazil (University of São Paolo). Lesions were traced on T1 images from 26 patients who had received GKC targeting the ventral half of the anterior limb of the internal capsule (ALIC), and the masks were transformed into MNI space. Voxel-wise lesion-symptom mapping was performed to assess the influence of lesion location on Y-BOCS ratings. General linear models were built to compare the relationship between lesion size/location along different axes of the ALIC and above or below-average change in Y-BOCS ratings. Sixty-nine percent of this sample were full responders (≥35% improvement in OCD). Lesion occurrence anywhere within the targeted region was associated with clinical improvement, but modeling results demonstrated that lesions occurring posteriorly (closer to the anterior commissure) and dorsally (closer to the mid-ALIC) were associated with the greatest Y-BOCS reduction. No association was found between Y-BOCS reduction and overall lesion volume. GKC remains an effective treatment for refractory OCD. Our data suggest that continuing to target the bottom half of the ALIC in the coronal plane is likely to provide the dorsal-ventral height required to achieve optimal outcomes, as it will cover the white matter pathways relevant to change. Further analysis of individual variability will be essential for improving targeting and clinical outcomes, and potentially further reducing the lesion size necessary for beneficial outcomes.

Targeting the IL-22/IL-22BP axis enhances tight junctions and reduces inflammation during influenza infection.

The seasonal burden of influenza coupled with the pandemic outbreaks of more pathogenic strains underscore a critical need to understand the pathophysiology of influenza injury in the lung. Interleukin-22 (IL-22) is a promising cytokine that is critical in protecting the lung during infection. This cytokine is strongly regulated by the soluble receptor IL-22-binding protein (IL-22BP), which is constitutively expressed in the lungs where it inhibits IL-22 activity. The IL-22/IL-22BP axis is thought to prevent chronic exposure of epithelial cells to IL-22. However, the importance of this axis is not understood during an infection such as influenza. Here we demonstrate through the use of IL-22BP-knockout mice (il-22ra2-/-) that a pro-IL-22 environment reduces pulmonary inflammation during H1N1 (PR8/34 H1N1) infection and protects the lung by promoting tight junction formation. We confirmed these results in normal human bronchial epithelial cells in vitro demonstrating improved membrane resistance and induction of the tight junction proteins Cldn4, Tjp1, and Tjp2. Importantly, we show that administering recombinant IL-22 in vivo reduces inflammation and fluid leak into the lung. Taken together, our results demonstrate the IL-22/IL-22BP axis is a potential targetable pathway for reducing influenza-induced pneumonia.

IL-22Ra1 is induced during influenza infection by direct and indirect TLR3 induction of STAT1.

BACKGROUND: Influenza attacks the epithelium of the lung, causing cell death and disruption of the epithelial barrier leading to fluid buildup in the lung and impairment of gas exchange. Limited treatment options for severe influenza pneumonia prioritize the need for the discovery of effective therapies. IL-22 is a cytokine that promotes tissue integrity and has strong promise as a treatment option. While research has been focused on the cytokine itself, there is limited understanding of the regulation of the IL-22 receptor (IL-22Ra1) at the epithelial surface during infection. METHODS: IL-22Ra1 levels were measured by qRT-PCR, western blot and immunofluorescence following H1N1 influenza infection (A/PR/8/34 H1N1) or synthetic TLR3 mimetic, Poly (I:C). Regulation of the receptor was determined using STAT inhibitors (STAT1, STAT3 and PanSTAT inhibitors), TLR3 inhibition, and neutralization of interferon alpha receptor 2 (IFNAR2). Significance was determined by a p-value of greater than 0.05. Significance between two groups was measured using unpaired t-test and significance between more than two groups was measured using one-way ANOVA with Tukey Multiple Comparison Test. RESULTS: Here we show both in vivo and in vitro that IL-22Ra1 was induced as early as 24 h after influenza (H1N1 PR8) infection. This induction was triggered by toll-like receptor 3 (TLR3) as a TLR3 mimetic [Poly (I:C)] also induced IL-22Ra1 and inhibition of endosomal formation required for TLR3 function inhibited this process. This upregulation was dependent upon IFNß signaling through STAT1. Importantly, induction of IL-22Ra1 significantly increased IL-22 signaling as evidenced by pSTAT3 levels following IL-22 treatment. CONCLUSION: Collectively, these data suggest epithelial cells may optimize the beneficial effects of IL-22 through the induction of the IL-22 receptor during viral infection in the lung.

Polygenic risk score and heritability estimates reveals a genetic relationship between ASD and OCD.

Obsessive-compulsive disorder (OCD) and Autism spectrum disorder (ASD) are both highly heritable neurodevelopmental disorders that conceivably share genetic risk factors. However, the underlying genetic determinants remain largely unknown. In this work, the authors describe a combined genome-wide association study (GWAS) of ASD and OCD. The OCD dataset includes 2998 individuals in nuclear families. The ASD dataset includes 6898 individuals in case-parents trios. GWAS summary statistics were examined for potential enrichment of functional variants associated with gene expression levels in brain regions. The top ranked SNP is rs4785741 (chromosome 16) with P value=6.9×10-7 in our re-analysis. Polygenic risk score analyses were conducted to investigate the genetic relationship within and across the two disorders. These analyses identified a significant polygenic component of ASD, predicting 0.11% of the phenotypic variance in an independent OCD data set. In addition, we examined the genomic architecture of ASD and OCD by estimating heritability on different chromosomes and different allele frequencies, analyzing genome-wide common variant data by using the Genome-wide Complex Trait Analysis (GCTA) program. The estimated global heritability of OCD is 0.427 (se=0.093) and 0.174 (se=0.053) for ASD in these imputed data.

Note: Manganin foil sensor for small uniaxial stress.

We describe a simple manganin foil resistance manometer for uniaxial stress measurements. The manometer functions at low pressures and over a range of temperatures. In this design, no temperature seasoning is necessary although the manometer must be prestressed to the upper end of the desired pressure range. The prestress pressure cannot be increased arbitrarily; irreversibility arising from shear stress limits its range. Attempting larger pressures yields irreproducible resistance measurements.

Whole-genome association analysis of treatment response in obsessive-compulsive disorder.

Up to 30% of patients with obsessive-compulsive disorder (OCD) exhibit an inadequate response to serotonin reuptake inhibitors (SRIs). To date, genetic predictors of OCD treatment response have not been systematically investigated using genome-wide association study (GWAS). To identify specific genetic variations potentially influencing SRI response, we conducted a GWAS study in 804 OCD patients with information on SRI response. SRI response was classified as 'response' (n=514) or 'non-response' (n=290), based on self-report. We used the more powerful Quasi-Likelihood Score Test (the MQLS test) to conduct a genome-wide association test correcting for relatedness, and then used an adjusted logistic model to evaluate the effect size of the variants in probands. The top single-nucleotide polymorphism (SNP) was rs17162912 (P=1.76 × 10(-8)), which is near the DISP1 gene on 1q41-q42, a microdeletion region implicated in neurological development. The other six SNPs showing suggestive evidence of association (P<10(-5)) were rs9303380, rs12437601, rs16988159, rs7676822, rs1911877 and rs723815. Among them, two SNPs in strong linkage disequilibrium, rs7676822 and rs1911877, located near the PCDH10 gene, gave P-values of 2.86 × 10(-6) and 8.41 × 10(-6), respectively. The other 35 variations with signals of potential significance (P<10(-4)) involve multiple genes expressed in the brain, including GRIN2B, PCDH10 and GPC6. Our enrichment analysis indicated suggestive roles of genes in the glutamatergic neurotransmission system (false discovery rate (FDR)=0.0097) and the serotonergic system (FDR=0.0213). Although the results presented may provide new insights into genetic mechanisms underlying treatment response in OCD, studies with larger sample sizes and detailed information on drug dosage and treatment duration are needed.

Measuring the cost of care in benign prostatic hyperplasia using time-driven activity-based costing (TDABC).

BACKGROUND: Determining '"value'" in health care, defined as outcomes per unit cost, depends on accurately measuring cost. We used time-driven activity-based costing (TDABC) to determine the cost of care in men with benign prostatic hyperplasia (BPH) - a common urologic condition. METHODS: We implemented TDABC across the entire care pathway for BPH including primary and specialist care in both inpatient and outpatient settings. A team of expert stakeholders created detailed process maps, determined space and product costs, and calculated personnel capacity cost rates. A model pathway was derived from practice guidelines and calculated costs were applied. RESULTS: Although listed as 'optional' in practice guidelines, invasive diagnostic testing can increase costs by 150% compared with the standalone urology clinic visit. Of five different surgical options, a 400% cost discrepancy exists between the most and least expensive treatments. CONCLUSIONS: TDABC can be used to measure cost across an entire care pathway in a large academic medical center. Sizable cost variation exists between diagnostic and surgical modalities for men with BPH. IMPLICATIONS: As financial risk is shifted toward providers, understanding the cost of care will be vital. Future work is needed to determine outcome discrepancy between the diagnostic and surgical modalities in BPH.

Extinction retention and fear renewal in a lifetime obsessive-compulsive disorder sample.

Obsessive-compulsive disorder (OCD), like other illnesses with prominent anxiety, may involve abnormal fear regulation and consolidation of safety memories. Impaired fear extinction memory (extinction recall, ER) has been shown in individuals with current symptoms of OCD [1]. However, contrary to expectations, the only previous study investigating this phenomenon showed a positive correlation between extinction recall abilities and OCD symptomology (i.e., as OCD symptoms worsened, extinction memory improved). The purpose of the current study was to determine if patients with a lifetime diagnosis of OCD (not necessarily currently symptomatic) also demonstrate impairments in extinction memory, and the relationship between OCD symptomology and extinction memory in this type of sample. In addition, we also examined fear renewal, which has never been investigated in an OCD sample. We enrolled 37 patients with OCD, the majority of whom were on serotonin reuptake inhibitors, and 18 healthy control participants in a 2-day paradigm assessing fear conditioning and extinction (Day 1) and extinction retention and renewal (Day 2). Skin conductance responses (SCRs) were the dependent measure. Results, as in the prior study, indicated that the only between-group difference was impaired ER in OCD patients relative to controls. Contrary to our prediction, OCD symptom severity was not correlated with the magnitude of extinction recall. There were no differences in fear renewal between OCD patients and controls.

Genome-wide association study in obsessive-compulsive disorder: results from the OCGAS.

Obsessive-compulsive disorder (OCD) is a psychiatric condition characterized by intrusive thoughts and urges and repetitive, intentional behaviors that cause significant distress and impair functioning. The OCD Collaborative Genetics Association Study (OCGAS) is comprised of comprehensively assessed OCD patients with an early age of OCD onset. After application of a stringent quality control protocol, a total of 1065 families (containing 1406 patients with OCD), combined with population-based samples (resulting in a total sample of 5061 individuals), were studied. An integrative analyses pipeline was utilized, involving association testing at single-nucleotide polymorphism (SNP) and gene levels (via a hybrid approach that allowed for combined analyses of the family- and population-based data). The smallest P-value was observed for a marker on chromosome 9 (near PTPRD, P=4.13 × 10(-)(7)). Pre-synaptic PTPRD promotes the differentiation of glutamatergic synapses and interacts with SLITRK3. Together, both proteins selectively regulate the development of inhibitory GABAergic synapses. Although no SNPs were identified as associated with OCD at genome-wide significance level, follow-up analyses of genome-wide association study (GWAS) signals from a previously published OCD study identified significant enrichment (P=0.0176). Secondary analyses of high-confidence interaction partners of DLGAP1 and GRIK2 (both showing evidence for association in our follow-up and the original GWAS study) revealed a trend of association (P=0.075) for a set of genes such as NEUROD6, SV2A, GRIA4, SLC1A2 and PTPRD. Analyses at the gene level revealed association of IQCK and C16orf88 (both P<1 × 10(-)(6), experiment-wide significant), as well as OFCC1 (P=6.29 × 10(-)(5)). The suggestive findings in this study await replication in larger samples.

Separation anxiety disorder in adult patients with obsessive-compulsive disorder: prevalence and clinical correlates.

OBJECTIVE: Individuals with obsessive-compulsive disorder (OCD) and separation anxiety disorder (SAD) tend to present higher morbidity than do those with OCD alone. However, the relationship between OCD and SAD has yet to be fully explored. METHOD: This was a cross-sectional study using multiple logistic regression to identify differences between OCD patients with SAD (OCD+SAD, n=260) and without SAD (OCD, n=695), in terms of clinical and socio-demographic variables. Data were extracted from those collected between 2005 and 2009 via the Brazilian Research Consortium on Obsessive-Compulsive Spectrum Disorders project. RESULTS: SAD was currently present in only 42 (4.4%) of the patients, although 260 (27.2%) had a lifetime diagnosis of the disorder. In comparison with the OCD group patients, patients with SAD+OCD showed higher chance to present sensory phenomena, to undergo psychotherapy, and to have more psychiatric comorbidities, mainly bulimia. CONCLUSION: In patients with primary OCD, comorbid SAD might be related to greater personal dysfunction and a poorer response to treatment, since sensory phenomena may be a confounding aspect on diagnosis and therapeutics. Patients with OCD+SAD might be more prone to developing specific psychiatric comorbidities, especially bulimia. Our results suggest that SAD symptom assessment should be included in the management and prognostic evaluation of OCD, although the psychobiological role that such symptoms play in OCD merits further investigation.

Endoscopic endonasal approach for the treatment of schwannomas of the pterygopalatine fossa: case report and review of the literature.

INTRODUCTION: Pterygopalatine fossa (PPF) schwannomas are rare lesions most often arising from branches of the trigeminal nerve. Symptomatic lesions have been traditionally treated by conventional external approaches. However, the development of an expanded endonasal approach (EEA) enables skull base surgeons to reach these deeply seated lesions via a different route with its own advantages and drawbacks. METHODS: Case report and review of the literature. CASE DESCRIPTION: A 41-year-old woman presented with a 6-year history of right facial pain and numbness. Her symptoms had increased progressively over a year, and she recently had developed right-sided otalgia. MRI revealed a right PPF mass, hypointense on T1 and T2 sequences with homogeneous enhancement following the use of gadolinium. A biopsy, attempted at another institution, was considered non-diagnostic. We totally removed the lesion through an endoscopic endonasal transmaxillary approach. Final pathology confirmed the diagnosis of schwannoma. Post-operatively, the patient noted a significant improvement of her facial pain (V2 territory). CONCLUSION: The endonasal endoscopic transmaxillary approach provides adequate access to the PPF, thus enabling safe tumor removal with less morbidity than conventional routes.

Reducing nitrate loss in tile drainage water with cover crops and water-table management systems.

Nitrate lost from agricultural soils is an economic cost to producers, an environmental concern when it enters rivers and lakes, and a health risk when it enters wells and aquifers used for drinking water. Planting a winter wheat cover crop (CC) and/or use of controlled tile drainage-subirrigation (CDS) may reduce losses of nitrate (NO) relative to no cover crop (NCC) and/or traditional unrestricted tile drainage (UTD). A 6-yr (1999-2005) corn-soybean study was conducted to determine the effectiveness of CC+CDS, CC+UTD, NCC+CDS, and NCC+UTD treatments for reducing NO loss. Flow volume and NO concentration in surface runoff and tile drainage were measured continuously, and CC reduced the 5-yr flow-weighted mean (FWM) NO concentration in tile drainage water by 21 to 38% and cumulative NO loss by 14 to 16% relative to NCC. Controlled tile drainage-subirrigation reduced FWM NO concentration by 15 to 33% and cumulative NO loss by 38 to 39% relative to UTD. When CC and CDS were combined, 5-yr cumulative FWM NO concentrations and loss in tile drainage were decreased by 47% (from 9.45 to 4.99 mg N L and from 102 to 53.6 kg N ha) relative to NCC+UTD. The reductions in runoff and concomitant increases in tile drainage under CC occurred primarily because of increases in near-surface soil hydraulic conductivity. Cover crops increased corn grain yields by 4 to 7% in 2004 increased 3-yr average soybean yields by 8 to 15%, whereas CDS did not affect corn or soybean yields over the 6 yr. The combined use of a cover crop and water-table management system was highly effective for reducing NO loss from cool, humid agricultural soils.

Bacterial growth in red blood cell units exposed to uncontrolled temperatures: challenging the 30-minute rule.

BACKGROUND AND OBJECTIVES: The '30-min rule' requires discarding red blood cells (RBCs) exposed to uncontrolled temperatures for >30 min to ensure safe RBC transfusion. This study was aimed at determining whether multiple room temperature (RT) exposures promote bacterial growth. MATERIALS AND METHODS: Pooled and split RBC units were inoculated with ~1 CFU/ml of Serratia marcescens, Yersinia enterocolitica, Escherichia coli or Staphylococcus epidermidis. Control units remained in storage, while test units were exposed to RT for six 30-min or three 60-min intervals. Bacterial concentrations and endotoxin levels were determined after each exposure and at 42 days of storage. RBC core temperature and RT were monitored in mock units with Escort iLog temperature loggers. A mixed model was used for statistical analyses. RESULTS: Red blood cell core temperature reached 10.7 ± 0.4°C and 14.2 ± 0.2°C during 30- and 60-min exposures, respectively. Staphylococcus epidermidis and E. coli did not grow in either control or exposed RBCs. Yersinia enterocolitica concentration and endotoxin levels were similar in both control and test units. Serratia marcescens concentration and endotoxin levels were higher in exposed units; however, differences between units exposed for 30 min or 60 min were not observed. CONCLUSION: There is no added risk to RBC safety by increasing RT exposures to 60 min with each removal from storage for up to a total of 3 h during RBC shelf life. Therefore, extending the 30-min limitation in RBCs exposed to uncontrolled temperatures to 60 min should be considered by regulatory agencies.

Management of patients with aneurismal subarachnoid hemorrhage and associated symptomatic vasospasm on presentation.

Rebleeding and symptomatic vasospasm (VS) are the major causes of subsequent morbidity and mortality in patients surviving a subarachnoid hemorrhage (SAH). Although most patients present rapidly after the bleed, some may seek medical attention in a delayed fashion due to non-resolving or worsening headaches or new neurological deficits, requiring treatment during the period at risk for VS. Such patients may either present asymptomatic radiological VS on their diagnostic angiogram or present symptomatic VS confirmed on angiogram. A similar situation may occur in patients presenting within the first 48 hours after SAH with very early angiographic VS. Deciding on the optimal timing and modality of treatment in such patients with SAH and symptomatic VS on presentation is controversial. Only six observational studies that specifically assessed aneurysm treatment in the presence of symptomatic VS have been published to date. We reviewed the published literature on the management of ruptured intracranial aneurysms in the presence of symptomatic VS and suggest avenues for future studies.

Blister-like aneurysms of the internal carotid artery - management considerations.

Blood blister-like aneurysms (BBA) originate at non-branching sites of the internal carotid artery (ICA). These aneurysms present a fragile wall and a poorly defined broad-based neck. Recognition of the BBA is essential for proper management of these vascular lesions. Various surgical and endovascular strategies have been attempted for these heterogeneous lesions. These have been associated with significant morbidity and mortality including rebleeding, regrowth, ischemic and thromboembolic complications. The authors review the key elements important for diagnosis and management of BBA and review current treatment options.

Surgical strategies for aneurysms deemed unclippable and uncoilable.

Although most cerebral aneurysms can nowadays be successfully treated either by standard clipping or sole coiling, a subset of aneurysms may not be amenable to standard clipping or coiling and require alternative treatment options. Surgical options, other than clipping and/or endovascular options other than sole coiling, may be the optimal treatment plan for some complex aneurysms. Surgical strategies for such complex aneurysms include parent artery occlusion, revascularization procedures and flow redirection. In this article, we review which factors are predictive of failure of conventional aneurysm treatment options; summarize key information needed to orient treatment decision; and discuss surgical options for unclippable and uncoilable aneurysms.

The supraorbital approach for recurrent or residual suprasellar tumors.

BACKGROUND: Suprasellar tumors can be removed through a variety of approaches including conventional frontotemporal craniotomies, the transsphenoidal route, or the supraorbital (SO) eyebrow craniotomy. Herein we assess the utility of the SO route for recurrent or residual suprasellar tumors previously treated by an alternative route. MATERIAL AND METHODS: A retrospective analysis of all consecutive patients who underwent an SO approach for removal of a recurrent/residual tumor was undertaken. RESULTS: Between December 2007 and February 2010, 11 patients underwent an SO craniotomy for a recurrent or growing residual tuberculum sellae meningioma (n=7) or craniopharyngioma (n=4). All 11 patients had prior craniotomies, 5 had transsphenoidal surgery, 6 had radiation treatment, and 1 had chemotherapy. In the last 5 cases, the endoscope was used in addition to the microscope for intraoperative visualization. 3 patients underwent decompression of multicystic craniopharyngiomas and the remaining 8 patients had tumor debulking, all achieving 70% or more tumor removal. Of 9 patients with preoperative visual deterioration, 6 (67%) had improvement and no patient had visual worsening. No new adenohypophysis or neurohypophysis dysfunction was noted. One patient had a postoperative CSF leak requiring reoperation. CONCLUSION: The SO approach should be considered as a safe and effective alternative route for recurrent or residual suprasellar tumors previously treated by conventional craniotomy or TS surgery. It typically offers a simplified trajectory that minimizes scar tissue from prior approaches and provides excellent access for optic apparatus decompression. Endoscopy is helpful to visualize hidden tumor remnants and maximize safe tumor removal.

Endoscopic endonasal resection of the odontoid process as a standalone decompressive procedure for basilar invagination in Chiari type I malformation.

BACKGROUND: The expanded endonasal approach of the cranio-cervical junction provides comfortable working space while avoiding some of the disadvantages of the transoral route. We report a purely endonasal endoscopic resection of the odontoid process for basilar invagination in a patient with a Chiari type I malformation, without posterior decompression or fusion. CASE REPORT: A 54-year-old female patient presented with cranial nerve and brainstem deficits. CT and MRI showed a Chiari type I malformation and compression of the medulla by basilar invagination of the odontoid process. The tip of the latter was displaced up to the bulbo-pontine sulcus. The odontoid process was resected via the expanded endoscopic endonasal approach, without additional posterior decompression or fusion. The post-operative course was uneventful, including the absence of velopharyngeal insufficiency. Neurological deficits regressed rapidly. The preoperative cervical pain virtually disappeared. At 9 months follow-up, the patient had normal activity with minimal residual neurological deficits. Post-op dynamic radiography and CT showed stability of the cranio-cervical junction. CONCLUSION: Decompression of the bulbomedullary junction by purely endoscopic transnasal resection of the odontoid process is well tolerated and efficient. Immediate stabilization is not mandatory in all cases of congenital causes of basilar invagination.

Vidian nerve neurofibroma removed via a transpterygoid approach.

BACKGROUND: Lesions originating in the vidian canal are extremely rare. Most frequently, they are extensions from contiguous carcinomas. We present a rare case of a vidian nerve neurofibroma and discuss its surgical management. CASE REPORT: A 62-year-old woman with a history of a basal cell skin cancer was evaluated for bilateral tinnitus. Imaging revealed a left-sided lesion at the medial aspect of the pterygoid process base, over the vidian canal. Under image-guidance, an endonasal endoscopic transpterygoid approach was performed. The histopathological examination supported the diagnosis of neurofibroma. CONCLUSION: Benign nerve sheath tumors of the vidian nerve should be considered in the differential diagnosis of a vidian canal lesion. Given the propensity of more aggressive tumors, a tissue diagnosis should be warranted in order to coordinate appropriate subsequent treatment. The expanded endonasal transpterygoid approach offers a safe, less invasive, and effective route to perform the excisional biopsy of such a lesion.