The TIGR triangle of the pineal region: a virtual reality anatomic study.

BACKGROUND: In this morphometric study, we describe the anatomy of the TIGR triangle, which is bordered by the tentorial surface of the cerebellum, the internal cerebral vein and vein of Galen complex, and the vein of Rosenthal. These structures define the window, or deep keyhole, to access the pineal region in non-midline supracerebellar infratentorial approaches. METHODS: The posterior fossa anatomy of 16 patients was studied in virtual reality (VR), and the TIGR triangles were defined and measured with special attention on its angular orientation in the posterior fossa. The angular expanse of the posterior fossa was measured and recorded as the transverse-sigmoid junction (TSJ) angle. Because a perpendicular corridor through an anatomic aperture provides the best exposure, we studied the starting point along the TSJ angle that offers the best exposure of TIGR. RESULTS: In the 31 posterior fossa sides included in the study, the perpendicular trajectory through the TIGR triangle was on average 27.13° CI 95% (range: 5.97°-48.53°) from the midline. When comparing the SCIT variants, both the paramedian and lateral approaches provided near-perpendicular trajectory through the TIGR triangle in a majority of specimens. However, the modified paramedian approach, with starting point defined as TSJ angle/3, provided the most perpendicular path through the TIGR triangle. CONCLUSION: We studied the size, spatial orientation, and morphology of the TIGR triangle. Our data indicated that the best exposure of TIGR is through a modified paramedian SCIT approach, in which the starting point one third of the way from midline to the TSJ.

First-year complications after immediate breast reconstruction with a biological and a synthetic mesh in the same patient: A randomized controlled study.

BACKGROUND: Even though meshes and matrices are widely used in breast reconstruction, there is little high-quality scientific evidence for their risks and benefits. The aim of this study was to compare first-year surgical complication rates in implant-based immediate breast reconstruction with a biological mesh with that of a synthetic mesh, in the same patient. METHODS: This study is a clinical, randomized, prospective trial. Patients operated on with bilateral mastectomy and immediate breast reconstruction were randomized to biological mesh on one side and synthetic mesh on the other side. RESULTS: A total of 48 breasts were randomized. As the synthetically and the biologically reconstructed breasts that were compared belonged to the same woman, systemic factors were exactly the same in the two groups. The most common complication was seroma formation with a frequency of 38% in the biological group and 3.8% in the synthetical group (p = .011). A higher frequency of total implant loss could be seen in the biologic mesh group (8.5% vs. 2%), albeit not statistically significant (p = .083). CONCLUSIONS: In the same patient, a synthetic mesh seems to yield a lower risk for serious complications, such as implant loss, than a biological mesh.

Drain secretion and seroma formation after immediate breast reconstruction with a biological and a synthetic mesh, respectively: A randomized controlled study.

The aim of this study was to compare seroma production in breast reconstruction with a biological mesh with that of a synthetic mesh, in the same patient. The patients were randomized to biological mesh in one breast and synthetical in the other. Twenty-four breasts were included. The total drain production and the daily drain production were similar in the two groups. After drain removal, there were more seroma aspirations in the biological group. During the exchange to a permanent implant, there was significantly more seroma in the biological group. Seroma formation is different in synthetic and biological meshes.

The Use of Synthetic Mesh in Reconstructive, Revision, and Cosmetic Breast Surgery.

BACKGROUND: Recent evidence suggests that the use of acellular dermal matrices in prosthetic breast reconstruction, revision, or augmentation may be associated with an increased risk of complications. In this article we report our results of a potential alternative, using a new long-term resorbable synthetic matrix in these cases. METHODS: A retrospective study was performed evaluating 11 primary breast reconstructions (19 breasts), 43 secondary reconstructions (77 breasts), 3 augmentation/augmentation mastopexys (6 breasts), and 5 mastopexys (10 breasts) in 62 patients using TIGR® Matrix Surgical Mesh. RESULTS: Follow-up ranged from 9.4 to 26.1 months with an average follow-up of 16.5 months. Average age was 54 years. The number of patients who had prior radiation was 9 (14.5 %). Four patients (6.5 %) were smokers. Postoperative breast complications included necrosis of two flaps (1.8 %), two seromas requiring drainage (1.8 %), four infection/extrusions (3.6 %), two relapses of inframammary fold/malposition (1.8 %), and two with rippling (1.8 %). Other complications included six cases of asymmetry that required a corrective procedure. In a variety of breast surgery cases very good aesthetic results were achieved. CONCLUSION: The long-term absorbable synthetic matrix, TIGR® Matrix Surgical Mesh, shows potential when used as temporary reinforcement in patients undergoing breast reconstruction or breast surgery revisions and in primary aesthetic procedures, and it appears to be a viable alternative to the use of acellular dermal matrices. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors http://www.springer.com/00266 .

Redefining the Small Regulatory RNA Transcriptome in Streptococcus pneumoniae Serotype 2 Strain D39.

Streptococcus pneumoniae (pneumococcus) is a major human respiratory pathogen and a leading cause of bacterial pneumonia worldwide. Small regulatory RNAs (sRNAs), which often act by posttranscriptionally regulating gene expression, have been shown to be crucial for the virulence of S. pneumoniae and other bacterial pathogens. Over 170 putative sRNAs have been identified in the S. pneumoniae TIGR4 strain (serotype 4) through transcriptomic studies, and a subset of these sRNAs has been further implicated in regulating pneumococcal pathogenesis. However, there is little overlap in the sRNAs identified among these studies, which indicates that the approaches used for sRNA identification were not sufficiently sensitive and robust and that there are likely many more undiscovered sRNAs encoded in the S. pneumoniae genome. Here, we sought to comprehensively identify sRNAs in Avery's virulent S. pneumoniae strain D39 using two independent RNA sequencing (RNA-seq)-based approaches. We developed an unbiased method for identifying novel sRNAs from bacterial RNA-seq data and have further tested the specificity of our analysis program toward identifying sRNAs encoded by both strains D39 and TIGR4. Interestingly, the genes for 15% of the putative sRNAs identified in strain TIGR4, including ones previously implicated in virulence, are not present in the strain D39 genome, suggesting that the differences in sRNA repertoires between these two serotypes may contribute to their strain-specific virulence properties. Finally, this study has identified 66 new sRNA candidates in strain D39, 30 of which have been further validated, raising the total number of sRNAs that have been identified in strain D39 to 112.IMPORTANCE Recent work has shown that sRNAs play crucial roles in S. pneumoniae pathogenesis, as inactivation of nearly one-third of the putative sRNA genes identified in one study led to reduced fitness or virulence in a murine model. Yet our understanding of sRNA-mediated gene regulation in S. pneumoniae has been hindered by limited knowledge about these regulatory RNAs, including which sRNAs are synthesized by different S. pneumoniae strains. We sought to address this problem by developing a sensitive sRNA detection technique to identify sRNAs in S. pneumoniae D39. A comparison of our data set reported here to those of other RNA-seq studies for S. pneumoniae strain D39 and TIGR4 has provided new insights into the S. pneumoniae sRNA transcriptome.

Transcript profiling reveals that cysteine protease inhibitors are up-regulated in tuber sprouts after extended darkness.

Potato (Solanum tuberosum L.) tubers are an excellent staple food due to its high nutritional value. When the tuber reaches physiological competence, sprouting proceeds accompanied by changes at mRNA and protein levels. Potato tubers become a source of carbon and energy until sprouts are capable of independent growth. Transcript profiling of sprouts grown under continuous light or dark conditions was performed using the TIGR 10K EST Solanaceae microarray. The profiles analyzed show a core of highly expressed transcripts that are associated to the reactivation of growth. Under light conditions, the photosynthetic machinery was fully activated; the highest up-regulation was observed for the Rubisco activase (RCA), the glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and the Photosystem II 22 kDa protein (CP22) genes, among others. On the other hand, sprouts exposed to continuous darkness elongate longer, and after extended darkness, synthesis of chloroplast components was repressed, the expression of proteases was reduced while genes encoding cysteine protease inhibitors (CPIs) and metallocarboxypeptidase inhibitors (MPIs) were strongly induced. Northern blot and RT-PCR analysis confirmed that MPI levels correlated with the length of the dark period; however, CPI expression was strong only after longer periods of darkness, suggesting a feedback loop (regulation mechanism) in response to dark-induced senescence. Prevention of cysteine protease activity in etiolated sprouts exposed to extended darkness could delay senescence until they emerge to light.

Dynamic control of the mevalonate pathway expression for improved zeaxanthin production in Escherichia coli and comparative proteome analysis.

Engineered heterologous multi-gene metabolic pathways often suffer from flux imbalance and toxic metabolites, as the production host typically lacks the regulatory mechanisms for the heterologous pathway. Here, we first coordinated the expression of all genes of the mevalonate (MEV) pathway from Saccharomyces cerevisiae using the tunable intergenic regions (TIGRs), and then dynamically regulated the TIGR-mediated MEV pathway to prevent the accumulation of toxic metabolites by using IPP/FPP-responsive promoter. After introduction of the dynamically controlled TIGR-mediated MEV pathway into Escherichia coli, the content and concentration of zeaxanthin in shaker flask cultures were 2.0- and 2.1-fold higher, respectively, than those of the strain harboring the statically controlled non-TIGR-mediated MEV pathway. The content and concentration of zeaxanthin in E. coli ZEAX (pZSPgadE-MevTTIGR-MevBTIGRIS-2) reached 722.46mg/L and 23.16mg/g dry cell weight (DCW), respectively, in 5.0L fed-batch fermentation. We also comparatively analyzed the proteomes between E. coli ZEAX and E. coli ZEAX (pZSPgadE-MevTTIGR-MevBTIGRIS-2) to understand the mechanism of zeaxanthin biosynthesis. The results of the comparative proteomes demonstrate that zeaxanthin overproduction may be associated with increased precursor availability, increased NADPH availability, increased ATP availability, oxidative stress response, and increased membrane storage capacity for zeaxanthin due to changes in both cellular shape and membrane composition.

Progress in understanding the association between high myopia and primary open-angle glaucoma.

Many clinical and fundamental studies have shown that high myopia (HM) and glaucoma are closely associated. In particular, the occurrence and progression of primary open-angle glaucoma interact with the progression of HM. Two hypotheses have been proposed to explain the association between the two disorders: the hypertension gene theory and the collagen-related gene theory. HM and primary open-angle glaucoma patients show similar collagen changes and hypersensitive responses to glucocorticoids. Consequently, these common features may hold key information regarding their underlying mechanisms. Advances in life sciences, such as molecular genetics, provide opportunities for clarifying their association at the molecular level. This article reviews available research on the association between these two disorders from the perspectives of epidemiology, clinical manifestation, diagnosis and pathogenic mechanisms.

Surgical and Patient-Reported Outcomes After Mastectomy and Implant-Based Prepectoral Reconstruction Using TIGR® Synthetic Mesh.

Background Single-stage direct-to-implant (DTI) breast reconstruction after mastectomy has gained popularity over the last decade, thanks to the wide use of biological matrices and synthetic meshes. Despite their high cost, there is no evidence of superior outcome from the biological matrices compared to the synthetic meshes. In this study, we aimed to evaluate our experience with TIGR, a synthetic, long-term absorbable mesh, in mastectomy and immediate breast reconstruction (MIBR) with a focus on patient-reported outcomes (PROMs). Methods This was a single-trust prospective quality improvement study conducted between 2017 and 2019. The main objectives were complication rates including infection, implant loss, and other surgical complications in patients undergoing TIGR mesh-assisted MIBR in the prepectoral plane for either cancer or risk reduction. PROMs were measured using the validated European Organisation for Research and Treatment of Cancer (EORTC) breast questionnaire module. Clinical evaluations were conducted at one week, three weeks, and 12 months postoperatively. All patients provided written consent, and the audit was registered with the Quality Improvement Department of the organization. Results One hundred and twelve meshes were used in 93 patients with a mean age of 49 (24-75) years and a body mass index (BMI) of 23.4 (19.1-29.6). During the follow-up period, complications occurred in 26 patients (28%), including infection in four (4.3%), complete skin flap necrosis in one (1%), partial flap necrosis in three (3.2%), and implant loss in four (4.3%) patients. PROM data from 41 individuals indicated a moderate overall quality of life (82.7%), with high functional domain scores with relatively lower emotional functioning scores. Symptom domains generally scored poorly except for body image and sexual functioning. Conclusion Mastectomy and immediate prepectoral breast reconstruction using TIGR mesh is safe with low major complication rates. It is associated with high functional and quality of life scores but low scores in symptom domains which could be multifactorial. However, limitations due to study type and follow-up duration suggest caution in generalizing findings.

ASL MRI informs blood flow to chronic stroke lesions in patients with aphasia.

Introduction: Response to post-stroke aphasia language rehabilitation is difficult to anticipate, mainly because few predictors can help identify optimal, individualized treatment options. Imaging techniques, such as Voxel-based Lesion Symptom Mapping have been useful in linking specific brain areas to language behavior; however, further development is required to optimize the use of structural and physiological information in guiding individualized treatment for persons with aphasia (PWA). In this study, we will determine if cerebral blood flow (CBF) mapped in patients with chronic strokes can be further used to understand stroke-related factors and behavior. Methods: We collected perfusion MRI data using pseudo-Continuous Arterial Spin Labeling (pCASL) using a single post-labeling delay of 2,200 ms in 14 chronic PWA, along with high-resolution structural MRI to compute maps of tissue damage using Tissue Integrity Gradation via T2w T1w Ratio (TIGR). To quantify the CBF in chronic stroke lesions, we tested at what point spatial smoothing should be applied in the ASL analysis pipeline. We then related CBF to tissue damage, time since stroke, age, sex, and their respective cross-terms to further understand the variability in lesion CBF. Finally, we assessed the feasibility of computing multivariate brain-behavior maps using CBF and compared them to brain-behavior maps extracted with TIGR MRI. Results: We found that the CBF in chronic stroke lesions is significantly reduced compared to its homologue grey and white matter regions. However, a reliable CBF signal (although smaller than expected) was detected to reveal a negative relationship between CBF and increasing tissue damage. Further, the relationship between the lesion CBF and age, sex, time since stroke, and tissue damage and cross-terms suggested an aging-by-disease interaction. This relationship was strongest when smoothing was applied in the template space. Finally, we show that whole-brain CBF relates to domain-general visuospatial functioning in PWA. The CBF-based brain-behavior maps provide unique and complementary information to structural (lesion-based) brain-behavior maps. Discussion: Therefore, CBF can be detected in chronic stroke lesions using a standard pCASL MRI acquisition and is informative at the whole-brain level in identifying stroke rehabilitation targets in PWAs due to its relationship with demographic factors, stroke-related factors, and behavior.

Integrated immunoinformatics and subtractive proteomics approach for multi-epitope vaccine designing to combat S. pneumoniae TIGR4.

Streptococcus pneumoniae is one of the major precarious pathogens accountable for over 1.2 million fatalities annually. The key drivers for pneumococcal vaccine development involve high morbidity and mortality in over one million cases, especially in very young children and the elderly. In this study, immunoinformatics was integrated with subtractive proteomics to find antigenic proteins for designing a multi-epitope vaccine against S. pneumoniae. As prospective vaccine targets, the developed pipeline identified two antigenic proteins, i.e., penicillin-binding protein and ATP synthase subunit. Several immunoinformatics and bioinformatics resources were used to forecast T- and B-cell epitopes from specific proteins. By employing a mixture of five cytotoxic T-cell lymphocytes, six helper T-cell lymphocytes, and seven linear B-cell lymphocyte epitopes, a 392 amino acid-long vaccine was designed. To enhance immune responses, the designed vaccine was coupled with a cholera enterotoxin subunit B adjuvant. The designed vaccine was highly antigenic, non-allergenic, and stable for human usage. The stability of the vaccine with toll-like receptor-4 was evaluated by molecular docking and molecular dynamic simulation. In addition, immunological simulation was performed to test its real-world potency. The vaccine codon was then cloned in silico. Overall, this study paves the way for the development of a multi-epitope S. pneumoniae vaccine under laboratory conditions. Furthermore, the current findings warrant for the experimental validation of the final multi-epitope vaccine construct to demonstrate its immunological reinforcing capability and clinical applicability.

Increased Production of Riboflavin by Coordinated Expression of Multiple Genes in Operons in Bacillus subtilis.

Riboflavin is an essential vitamin widely used in the food, pharmaceutical, and feed industries. However, the insufficient supply of precursors caused by the imbalance of intracellular metabolic flow limits the riboflavin synthesis by industrial strains. Here, we increase riboflavin production by tuning multiple gene expression to balance intracellular metabolic flow. First, we tuned the expression of mCherry and egfp genes within operons by generating libraries of tunable intergenic regions (TIGRs) and confirmed the relative expression of the two reporter genes. The TIGR library can coordinate the expression ratio of reporter genes more than 180 times in Escherichia coli and more than 70 times in Bacillus subtilis. Next, we used this strategy to tune the expression of zwf, ribBA, and ywlf genes within operons through the TIGR library to increase the intracellular precursor pool for riboflavin biosynthesis. Based on the fluorescence characteristics of riboflavin, 96-well plates were used to screen the optimal combination mutants quickly. The best-engineered strain was selected from the library, which produced 2.7 g/L riboflavin, increasing by 64.35% in the shake flask. Finally, the riboflavin titer increased by 59.27% to 11.77 g/L in fed-batch fermentation. The strategy described here will contribute to the industrial production of riboflavin and related products by B. subtilis.

Prophylactic onlay mesh at emergency laparotomy: promising early outcomes with long-acting synthetic resorbable mesh.

BACKGROUND: Careful surgical strategy is paramount in balancing the prevention of fascial dehiscence, incisional hernia (IH) and fear of additional mesh-related wound complications post-laparotomy. This study aims to review early outcomes of patients undergoing an emergency laparotomy with prophylactic TIGR® mesh, used to reduce early fascial dehiscence and potential subsequent IH. METHOD: A retrospective, ethically approved review of 24 consecutive patients undergoing prophylactic TIGR® mesh placement during emergency laparotomies by a single surgeon between January 2017 and June 2021 at a University Hospital. A standardized approach included onlay positioning of the mesh, small-bite fascial closure, and a wound bundle. We recorded patient demographics, operative indications, findings, degree of peritonitis, postoperative complications, and mortality. RESULT: The study included 24 patients; 16/24 (66.6%) were female and median age was 72.5 (range 31-86); 14/24 patients were ASA grade III or greater; 4/24 patients (16.6%) developed six complications and 3/6 occurred in a single patient. Complications included subphrenic abscess, seroma, intrabdominal hematoma, enterocutaneous fistula leading to deep wound infection and small bowel perforation. Five (20.8%) patients died in hospital; central venous catheter sepsis (n = 1), fungal septicaemia (n = 1) and multiorgan failure (n = 3). Surgical site infection and seroma rates were low, occurring in 2/24 patients (4% each). CONCLUSION: This study has identified that prophylactic onlay mesh in patients undergoing an emergency laparotomy is not associated with significant wound infection or seroma when used with an active wound bundle. The wider use of TIGR® to prevent fascial dehiscence and potential long-term IH prevention should be considered.

Not All Lesioned Tissue Is Equal: Identifying Pericavitational Areas in Chronic Stroke With Tissue Integrity Gradation via T2w T1w Ratio.

Stroke-related tissue damage within lesioned brain areas is topologically non-uniform and has underlying tissue composition changes that may have important implications for rehabilitation. However, we know of no uniformly accepted, objective non-invasive methodology to identify pericavitational areas within the chronic stroke lesion. To fill this gap, we propose a novel magnetic resonance imaging (MRI) methodology to objectively quantify the lesion core and surrounding pericavitational perimeter, which we call tissue integrity gradation via T2w T1w ratio (TIGR). TIGR uses standard T1-weighted (T1w) and T2-weighted (T2w) anatomical images routinely collected in the clinical setting. TIGR maps are analyzed with relation to subject-specific gray matter and cerebrospinal fluid thresholds and binned to create a false colormap of tissue damage within the stroke lesion, and these are further categorized into low-, medium-, and high-damage areas. We validate TIGR by showing that the cerebral blood flow within the lesion reduces with greater tissue damage (p = 0.005). We further show that a significant task activity can be detected in pericavitational areas and that medium-damage areas contain a significantly lower magnitude of hemodynamic response function than the adjacent damaged areas (p < 0.0001). We also demonstrate the feasibility of using TIGR maps to extract multivariate brain-behavior relationships (p < 0.05) and show general agreement in location compared to binary lesion, T1w-only, and T2w-only maps but that the extent of brain behavior maps may depend on signal sensitivity as denoted by the sparseness coefficient (p < 0.0001). Finally, we show the feasibility of quantifying TIGR in early and late subacute stroke phases, where higher-damage areas were smaller in size (p = 0.002) and that lesioned voxels transition from lower to higher damage with increasing time post-stroke (p = 0.004). We conclude that TIGR is able to (1) identify tissue damage gradient within the stroke lesion across different post-stroke timepoints and (2) more objectively delineate lesion core from pericavitational areas wherein such areas demonstrate reasonable and expected physiological and functional impairments. Importantly, because T1w and T2w scans are routinely collected in the clinic, TIGR maps can be readily incorporated in clinical settings without additional imaging costs or patient burden to facilitate decision processes related to rehabilitation planning.

Comparison of inflammatory response and synovial metaplasia in immediate breast reconstruction with a synthetic and a biological mesh: a randomized controlled clinical trial.

The aim of this study was to compare inflammatory response and synovial metaplasia in implant-based immediate breast reconstruction with a biological mesh (Veritas®) with that of a synthetic mesh (TIGR® Matrix Surgical Mesh). We hypothesize that the inflammatory response and formation of synovial metaplasia might be different and the rate of capsular contracture therefore different. The patients were recruited from the Gothenburg TIGR®/Veritas® Study (ClinicalTrials.Gov identifier NCT02985073). All referrals for bilateral immediate breast reconstruction were assessed for inclusions. During the operation, the patients were randomized to which sides the biological and the synthetic mesh were going to be applied. During the implant exchange biopsies were taken. Biopsies were taken from 30 breasts in 15 patients. There seem to be more myofibroblast and neovascularization in the biological meshes than in the synthetic and the collagen fibers seem to be aligned in an irregular pattern with both parallel and vertical fibers. In the synthetic meshes, there were more giant cells and foreign body reaction and the collagen fibers were loosely and well aligned, oriented parallel to the surface of the implant. Synovial metaplasia was seen in the majority of both the biological and the synthetic meshes. The histological patterns in early capsules from biological and synthetic meshes vary considerably. Nonetheless, it is unknown what role different cell types have in capsular formation in the long run and there was no difference in clinical capsular contracture at the clinical follow-up in this study.

TIGR matrix for implant-based breast reconstruction - a long-term resorbable mesh.

The use of biological and synthetic meshes to aid implant coverage in implant-based breast reconstruction is well established. This technique allows single stage implant-based reconstruction compared to the traditional technique which required tissue expansion before permanent implant placement and therefore involved two operations for the patient. They can further be used for pre-pectoral implant reconstructions in a similar direct-to-implant strategy. This retrospective observational study by Pompei et al has evaluated the use of TIGR Matrix, a long-term resorbable mesh, in 49 patients with 60 operated breasts for both reconstructive and aesthetic cases. They have reported their operative method and followed up their cases for a mean of 12 months. They have reported a cumulative mesh complication rate of 5.4% and one implant was explanted due to infection. They identified a significant correlation between obesity and mesh-related complications. This study is significant as there remains little data regarding the long term outcomes of resorbable synthetic mesh for breast reconstruction. Their reported complication rates are consistent with those in other studies for synthetic meshes. As synthetic meshes can be significantly cheaper than their biological counterparts, this work could promote more widespread use.

The Use of TIGR Matrix in Breast Aesthetic and Reconstructive Surgery: Is a Resorbable Synthetic Mesh a Viable Alternative to Acellular Dermal Matrices?

The authors document their experience in the use of synthetic 100% bioresorbable surgical mesh (TIGR Matrix, Novus Scientific, Uppsala, Sweden) in breast reconstruction as well as in breast aesthetic surgery. They performed a retrospective review on patients who underwent implant-based breast reconstruction as well as patients who underwent breast reduction mammoplasty procedures with the use of TIGR Matrix Surgical Mesh. When compared with other synthetic but nonresorbable meshes, it appears to show a potentially lower seroma and infection rates, but most importantly, a lower rate of revisional and mesh explantation surgeries.

TIGR4 strain causes more severe disease than WU2 strain in a mouse model of Streptococcus pneumoniae meningitis: a common pathogenic role for interferon-γ.

Streptococcus pneumoniae (S. pneumoniae) meningitis causes debilitating neurological symptoms and acute fatalities in patients, and long-term neurological sequelae in some survivors. Current vaccines do not protect against all 94 known S. pneumoniae capsular serotypes, many of which are capable of causing pneumococcal meningitis (PM). We here compare the pathogenic outcomes of two clinically virulent isolates of S. pneumoniae, serotype 3 strain WU2 and serotype 4 strain TIGR4, in a murine model of PM. At an identical infectious dosage of 103 CFU administered via the intracerebroventricular route, significantly greater mortality, interleukin (IL)1ß and IL6 production, and blood-brain barrier dysfunction occurred in TIGR4-induced PM compared to PM caused by WU2. Higher bacterial counts in the cerebrospinal fluid and nitrite/nitrate in serum were observed 40 h post inoculation with TIGR4 compared to mice infected with WU2. Similar to our previous findings in WU2 PM, interferon-γ was an essential driver of the pathogenesis of TIGR4 PM, suggesting that this cytokine may be a common pathogenic agent across a range of pneumococcal meningitides and, thus, a potential therapeutic target for intervention.

Drilling of Hybrid Titanium Composite Laminate (HTCL) with Electrical Discharge Machining.

An experimental investigation was conducted to determine the application of die sinker electrical discharge machining (EDM) as it applies to a hybrid titanium thermoplastic composite laminate material. Holes were drilled using a die sinker EDM. The effects of peak current, pulse time, and percent on-time on machinability of hybrid titanium composite material were evaluated in terms of material removal rate (MRR), tool wear rate, and cut quality. Experimental models relating each process response to the input parameters were developed and optimum operating conditions with a short cutting time, achieving the highest workpiece MRR, with very little tool wear were determined to occur at a peak current value of 8.60 A, a percent on-time of 36.12%, and a pulse time of 258 microseconds. After observing data acquired from experimentation, it was determined that while use of EDM is possible, for desirable quality it is not fast enough for industrial application.

Interferon-γ from Brain Leukocytes Enhances Meningitis by Type 4 Streptococcus pneumoniae.

Streptococcus pneumoniae is the leading cause of bacterial meningitis. Pneumococcal meningitis is a life-threatening disease with high rates of mortality and neurological sequelae. Immune targeting of S. pneumoniae is essential for clearance of infection; however, within the brain, the induced inflammatory response contributes to pathogenesis. In this study we investigate the local inflammatory response and the role of IFN-γ in a murine model of pneumococcal meningitis induced by intracranial injection of type 4 S. pneumoniae. Lymphoid and myeloid cell populations involved in meningitis, as well as cytokine gene expression, were investigated after infection. Animals were treated with a monoclonal antibody specific for murine IFN-γ to evaluate its role in animal survival. Intracranial inoculation of 3 × 10(4) colony-forming units of type 4 strain TIGR4 caused 75% of mice to develop meningitis within 4 days. The amount of lymphocytes, NK cells, neutrophils, monocytes and macrophages in the brain increased 48 h post infection. IFN-γ mRNA levels were about 240-fold higher in brains of infected mice compared to controls. Pro-inflammatory cytokines such as IL-1ß and TNF-α, and TLR2 were also upregulated. In vivo treatment with anti-IFN-γ antibody increased survival of infected mice. This study shows that IFN-γ produced during meningitis by type 4 S. pneumoniae enhances bacterial pathogenesis exerting a negative effect on the disease outcome.