CT-guided pretreatment biopsy diagnosis in patients with thymic epithelial tumours: diagnostic accuracy and risk of seeding.

AIM: To investigate the diagnostic performance of computed tomography (CT)-guided percutaneous transthoracic needle biopsy (PTNB) for thymic epithelial tumours (TETs) and the complication rate after PTNB including seeding after PTNB. MATERIALS AND METHODS: This retrospective study identified PTNBs for anterior mediastinal lesions between May 2007 and September 2021. The diagnostic performance for TETs and complications were investigated. The concordance of the histological grades of TETs between PTNB and surgery was evaluated. The factors associated with pleural seeding after PTNB were determined using Cox regression analysis. RESULTS: Of 387 PTNBs, 235 PTNBs from 225 patients diagnosed as TETs (124 thymomas and 101 thymic carcinomas) and 150 PTNBs from 133 patients diagnosed as other than TETs were included. The sensitivity, specificity, and accuracy for TETs were 89.4% (210/235), 100% (210/210), and 93.5% (360/385), respectively, with an immediate complication rate of 4.4% (17/385). The concordance rate of the histological grades between PTNB and surgery was 73.3% (77/105) after excluding uncategorised types of thymomas. During follow-up after PTNB (median duration, 38.8 months; range, 0.3-164.6 months), no tract seeding was observed. Pleural seeding was observed in 26 patients. Thymic carcinoma (hazard ratio [HR], 5.94; 95% confidence interval [CI], 2.07-17.08; p=0.001) and incomplete resection (HR, 3.29; 95% CI, 1.20-9.02; p=0.02) were associated with pleural seeding, while the biopsy approach type (transpleural versus parasternal) was not associated (p=0.12). CONCLUSIONS: Pretreatment biopsy for TETs was accurate and safe and may be considered for diagnosing TETs, particularly when the diagnosis is challenging and histological diagnosis is mandatory.

Auditory cortex hyperconnectivity before rTMS is correlated with tinnitus improvement.

INTRODUCTION: Repetitive transcranial magnetic stimulation (rTMS) has been used as a potential treatment for tinnitus; however, its effectiveness is variable and unpredictable. We hypothesized that resting-state functional connectivity before rTMS may be correlated with rTMS treatment effectiveness. METHODS: We applied 1-Hz rTMS to the left primary auditory (A1) and dorsolateral prefrontal cortices (DLPFC) of 10 individuals with tinnitus and 10 age-matched controls. Resting-state functional magnetic resonance imaging (fMRI) studies were performed approximately one week before rTMS. Seed-based connectivity analyses were conducted for each individual, with seed regions as rTMS target areas. RESULTS: Compared to controls, the left superior temporal areas showed significantly increased positive connectivity with the left A1 and negative connectivity with the left DLPFC in the tinnitus group. The left frontoparietal and right cerebellar areas showed significantly increased negative connectivity with the left A1 and positive connectivity with the left DLPFC. Seed-based hyperconnectivity was correlated with tinnitus improvement (pre-rTMS vs. 2-week post-rTMS Tinnitus Handicap Inventory scores). Tinnitus improvement was significantly correlated with left A1 hyperconnectivity; however, no correlation was observed with left DLPFC connectivity. Positive rTMS outcomes were associated with significantly increased positive connectivity in bilateral superior temporal areas and significantly increased negative connectivity in bilateral frontal areas. CONCLUSIONS: Our results suggest that oversynchronisation of left A1 connectivity before rTMS of the left A1 and DLPFC is associated with treatment effectiveness.

Auditory cortex hyperconnectivity before rTMS is correlated with tinnitus improvement / Correlación entre hiperconectividad de la corteza auditiva antes del tratamiento con estimulación magnética transcraneal repetitiva y mejoría de los acúfenos

Introduction: Repetitive transcranial magnetic stimulation (rTMS) has been used as a potential treatment for tinnitus; however, its effectiveness is variable and unpredictable. We hypothesized that resting-state functional connectivity before rTMS may be correlated with rTMS treatment effectiveness. Methods: We applied 1-Hz rTMS to the left primary auditory (A1) and dorsolateral prefrontal cortices (DLPFC) of 10 individuals with tinnitus and 10 age-matched controls. Resting-state functional magnetic resonance imaging (fMRI) studies were performed approximately one week before rTMS. Seed-based connectivity analyses were conducted for each individual, with seed regions as rTMS target areas. Results: Compared to controls, the left superior temporal areas showed significantly increased positive connectivity with the left A1 and negative connectivity with the left DLPFC in the tinnitus group. The left frontoparietal and right cerebellar areas showed significantly increased negative connectivity with the left A1 and positive connectivity with the left DLPFC. Seed-based hyperconnectivity was correlated with tinnitus improvement (pre-rTMS vs. 2-week post-rTMS Tinnitus Handicap Inventory scores). Tinnitus improvement was significantly correlated with left A1 hyperconnectivity; however, no correlation was observed with left DLPFC connectivity. Positive rTMS outcomes were associated with significantly increased positive connectivity in bilateral superior temporal areas and significantly increased negative connectivity in bilateral frontal areas. Conclusions: Our results suggest that oversynchronisation of left A1 connectivity before rTMS of the left A1 and DLPFC is associated with treatment effectiveness.(AU)

Introducción: La estimulación magnética transcraneal repetitiva (EMTr) se ha utilizado como posible tratamiento para los acúfenos, aunque su efectividad es variable e impredecible. Planteamos la hipótesis de que existe una correlación entre la conectividad funcional en estado de reposo antes de aplicar EMTr y la efectividad de dicho tratamiento. Métodos: Aplicamos EMTr a 1 Hz sobre la corteza auditiva primaria (A1) y la corteza prefrontal dorsolateral (CPFDL) izquierdas de 10 pacientes con acúfenos y 10 controles del mismo rango de edad. Se realizaron estudios de resonancia magnética funcional (RMF) en estado de reposo de todos los pacientes aproximadamente una semana antes de la EMTr. En cada caso, se construyó un mapa de conectividad basado en las ROIs, en el que las ROIs eran las áreas que se tratarían con la EMTr. Resultados: La región temporal superior izquierda mostró una conectividad positiva significativamente mayor con el área A1 izquierda y mayor conectividad negativa con la CPFDL izquierda en los pacientes con acúfenos que en los controles. Además, las áreas frontoparietal izquierda y cerebelar derecha mostraron una conectividad negativa significativamente superior con el área A1 izquierda y mayor conectividad positiva con la CPFDL izquierda. La hiperconectividad de las ROIs se correlacionó con mejoría de los acúfenos según las puntuaciones pre-EMTr y 2 semanas post-EMTr en la escala Tinnitus Handicap Inventory. La mejoría de los acúfenos se correlacionó de manera significativa con la hiperconectividad del área A1 izquierda; sin embargo, no se encontró correlación con la conectividad de la CPFDL izquierda. El resultado favorable del tratamiento con EMTr se asocia con una mayor conectividad positiva en áreas temporales superiores de ambos hemisferios y con mayor conectividad negativa en áreas frontales bilaterales...(AU)

Localized conditional induction of brain arteriovenous malformations in a mouse model of hereditary hemorrhagic telangiectasia.

BACKGROUND: Longitudinal mouse models of brain arteriovenous malformations (AVMs) are crucial for developing novel therapeutics and pathobiological mechanism discovery underlying brain AVM progression and rupture. The sustainability of existing mouse models is limited by ubiquitous Cre activation, which is associated with lethal hemorrhages resulting from AVM formation in visceral organs. To overcome this condition, we developed a novel experimental mouse model of hereditary hemorrhagic telangiectasia (HHT) with CreER-mediated specific, localized induction of brain AVMs. METHODS: Hydroxytamoxifen (4-OHT) was stereotactically delivered into the striatum, parietal cortex, or cerebellum of R26CreER; Alk12f/2f (Alk1-iKO) littermates. Mice were evaluated for vascular malformations with latex dye perfusion and 3D time-of-flight magnetic resonance angiography (MRA). Immunofluorescence and Prussian blue staining were performed for vascular lesion characterization. RESULTS: Our model produced two types of brain vascular malformations, including nidal AVMs (88%, 38/43) and arteriovenous fistulas (12%, 5/43), with an overall frequency of 73% (43/59). By performing stereotaxic injection of 4-OHT targeting different brain regions, Alk1-iKO mice developed vascular malformations in the striatum (73%, 22/30), in the parietal cortex (76%, 13/17), and in the cerebellum (67%, 8/12). Identical application of the stereotaxic injection protocol in reporter mice confirmed localized Cre activity near the injection site. The 4-week mortality was 3% (2/61). Seven mice were studied longitudinally for a mean (SD; range) duration of 7.2 (3; 2.3-9.5) months and demonstrated nidal stability on sequential MRA. The brain AVMs displayed microhemorrhages and diffuse immune cell invasion. CONCLUSIONS: We present the first HHT mouse model of brain AVMs that produces localized AVMs in the brain. The mouse lesions closely resemble the human lesions for complex nidal angioarchitecture, arteriovenous shunts, microhemorrhages, and inflammation. The model's longitudinal robustness is a powerful discovery resource to advance our pathomechanistic understanding of brain AVMs and identify novel therapeutic targets.

Synthesis of Functionalized Triblock Copolyesters Derived from Lactic Acid and Macrolactones for Bone Tissue Regeneration.

Synthetic and functional grafts are a great alternative to conventional grafts. They can provide a physical support and the precise signaling for cells to heal damaged tissues. In this study, a novel RGD peptide end-functionalized poly(ethylene glycol)-b-poly(lactic acid)-b-poly(globalide)-b-poly(lactic acid)-b-poly(ethylene glycol) (RGD-PEG-PLA-PGl-PLA-PEG-RGD) is synthetized and used to prepare functional scaffolds. The PGl inner block is obtained by enzymatic ring-opening polymerization of globalide. The outer PLA blocks are obtained by ring-opening polymerization of both, l-lactide or a racemic mixture, initiated by the α-ω-telechelic polymacrolactone. The presence of PGl inner block enhances the toughness of PLA-based scaffolds, with an increase of the elongation at break up to 300% when the longer block of PGl is used. PLA-PGl-PLA copolymer is coupled with α-ω-telechelic PEG diacids by esterification reaction. PEGylation provides hydrophilic scaffolds as the contact angle is reduced from 114° to 74.8°. That difference improves the contact between the scaffolds and the culture media. Moreover, the scaffolds are functionalized with RGD peptides at the surface significantly enhancing the adhesion and proliferation of bone marrow-derived primary mesenchymal stem cells and MC3T3-E1 cell lines in vitro. These results place this multifunctional polymer as a great candidate for the preparation of temporary grafts.

Effect of supplementation of cryoprotectant solution with hydroxypropyl cellulose for vitrification of bovine oocytes.

BACKGROUND: Successful cryopreservation of bovine oocytes is very important for research and commercial applications. However, the survival and development rate of vitrified-thawed (VT) oocytes are lower than those of non-vitrified-thawed (non-VT) oocytes. OBJECTIVE: To investigate the effect of adding hydroxypropyl cellulose (HPC) to the vitrification solution for bovine oocytes. MATERIALS AND METHODS: For vitrification, bovine metaphase II oocytes were pretreated with a solution containing 10% ethylene glycol supplemented with 0, 10, 50, or 100 ug/mL HPC for 5 min, exposed to a solution containing 30% ethylene glycol supplemented with 0, 10, 50, or 100 ug/mL HPC for 30 s, and then directly plunged into liquid nitrogen. RESULTS: The survival rate of oocytes was significantly higher in the 50 HPC group than in the 0, 10, and 100 HPC groups. The reactive oxygen species level was lower in the non-VT and 50 HPC groups than in the other groups. The mRNA levels of proapoptotic genes (Bax) were lower in the non-VT, 0, and 50 HPC groups than in the other groups. The mRNA levels of antiapoptotic genes (BCl2) were higher in the non-VT than in the other groups. The development rates of embryos (day 8) obtained via parthenogenetic activation (PA) were determined in the non-VT, 0 HPC, and 50 HPC groups. The cleavage rate was significantly higher in the non-VT group. CONCLUSION: Supplementation of vitrification solution with HPC improves the survival of VT bovine oocytes and the development capacity of embryos derived from these oocytes via PA. doi.org/10.54680/fr23110110212.

BMP10 functions independently from BMP9 for the development of a proper arteriovenous network.

Hereditary hemorrhagic telangiectasia (HHT) is a genetic vascular disorder characterized by the presence of arteriovenous malformation (AVM) in multiple organs. HHT is caused by mutations in genes encoding major constituents for transforming growth factor-ß (TGF-ß) family signaling: endoglin (ENG), activin receptor-like kinase 1 (ALK1), and SMAD4. The identity of physiological ligands for this ENG-ALK1 signaling pertinent to AVM formation has yet to be clearly determined. To investigate whether bone morphogenetic protein 9 (BMP9), BMP10, or both are physiological ligands of ENG-ALK1 signaling involved in arteriovenous network formation, we generated a novel Bmp10 conditional knockout mouse strain. We examined whether global Bmp10-inducible knockout (iKO) mice develop AVMs at neonatal and adult stages in comparison with control, Bmp9-KO, and Bmp9/10-double KO (dKO) mice. Bmp10-iKO and Bmp9/10-dKO mice showed AVMs in developing retina, postnatal brain, and adult wounded skin, while Bmp9-KO did not display any noticeable vascular defects. Bmp10 deficiency resulted in increased proliferation and size of endothelial cells in AVM vessels. The impaired neurovascular integrity in the brain and retina of Bmp10-iKO and Bmp9/10-dKO mice was detected. Bmp9/10-dKO mice exhibited the lethality and vascular malformation similar to Bmp10-iKO mice, but their phenotypes were more pronounced. Administration of BMP10 protein, but not BMP9 protein, prevented retinal AVM in Bmp9/10-dKO and endothelial-specific Eng-iKO mice. These data indicate that BMP10 is indispensable for the development of a proper arteriovenous network, whereas BMP9 has limited compensatory functions for the loss of BMP10. We suggest that BMP10 is the most relevant physiological ligand of the ENG-ALK1 signaling pathway pertinent to HHT pathogenesis.

Margetuximab with retifanlimab as first-line therapy in HER2+/PD-L1+ unresectable or metastatic gastroesophageal adenocarcinoma: MAHOGANY cohort A.

BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-positive metastatic gastric and gastroesophageal adenocarcinoma (GEA) is globally treated with chemotherapy plus trastuzumab. Novel therapeutic strategies strive to not only optimize efficacy, but also limit toxicities. In MAHOGANY cohort A, margetuximab, an Fc-engineered, anti-HER2 monoclonal antibody (mAb) was combined with retifanlimab, an anti-programmed cell death protein 1 mAb, in the first-line HER2-positive/programmed death-ligand 1 (PD-L1)-positive GEA. PATIENTS AND METHODS: MAHOGANY cohort A part 1 is a single-arm trial to evaluate margetuximab plus retifanlimab in patients with HER2 immunohistochemistry 3+, PD-L1-positive (combined positive score ≥1%), and non-microsatellite instability-high tumors. Primary objectives for cohort A were safety/tolerability and the confirmed objective response rate (ORR). RESULTS: As of 3 August 2021, 43 patients were enrolled and received margetuximab/retifanlimab. Nine grade 3 treatment-related adverse events (TRAEs) were reported in eight (18.6%) patients and eight serious TRAEs in seven (16.3%) patients. There were no grade 4/5 TRAEs. Three patients discontinued margetuximab/retifanlimab because of immune-related adverse events. The ORR by independent assessment was 53% [21/40 (95% confidence interval (CI) 36.1-68.5)], with a median duration of response of 10.3 months (95% CI 4.6-not evaluable); disease control rate was 73% [29/40 (95% CI 56.1-85.4)]. The study sponsor discontinued the study in advance of the planned enrollment when it became apparent that the study design would no longer meet the requirements for drug approval because of recent advances in the treatment of GEA. CONCLUSIONS: The chemotherapy-free regimen of combined margetuximab/retifanlimab as first-line treatment in double biomarker-selected patients demonstrated a favorable toxicity profile compared with historical outcomes using chemotherapy plus trastuzumab. The ORR observed in this study compares favorably versus ORR observed with other chemotherapy-free approaches.

Brillouin light scattering in niobium doped lead zirconate single crystal.

Brillouin light scattering experiments were performed for lead zirconate single crystals doped with niobium. Special attention was paid to the elastic mode softening near phase transition temperatures. The results are compared with data obtained by Raman light scattering experiments. We observed that the interaction between acoustic and optic modes is responsible for symmetry breaking far above TC, leading to polar regions' appearance. No changes in the acoustic mode frequency and its damping are observed at TC, where ε(T) exhibits a maximum value. The absence of these changes and the central peak observed in Raman experiments suggest that the phase transition at TC is mainly of the order-disorder type. The origin of other phase transitions is discussed as well.

Emerging pathogenic mechanisms in human brain arteriovenous malformations: a contemporary review in the multiomics era.

A variety of pathogenic mechanisms have been described in the formation, maturation, and rupture of brain arteriovenous malformations (bAVMs). While the understanding of bAVMs has largely been formulated based on animal models of rare hereditary diseases in which AVMs form, a new era of "omics" has permitted large-scale examinations of contributory genetic variations in human sporadic bAVMs. New findings regarding the pathogenesis of bAVMs implicate changes to endothelial and mural cells that result in increased angiogenesis, proinflammatory recruitment, and breakdown of vascular barrier properties that may result in hemorrhage; a greater diversity of cell populations that compose the bAVM microenvironment may also be implicated and complicate traditional models. Genomic sequencing of human bAVMs has uncovered inherited, de novo, and somatic activating mutations, such as KRAS, which contribute to the pathogenesis of bAVMs. New droplet-based, single-cell sequencing technologies have generated atlases of cell-specific molecular derangements. Herein, the authors review emerging genomic and transcriptomic findings underlying pathologic cell transformations in bAVMs derived from human tissues. The application of multiple sequencing modalities to bAVM tissues is a natural next step for researchers, although the potential therapeutic benefits or clinical applications remain unknown.

Usefulness of Wave-CAIPI for Postcontrast 3D T1-SPACE in the Evaluation of Brain Metastases.

BACKGROUND AND PURPOSE: High-resolution postcontrast 3D T1WI is a widely used sequence for evaluating brain metastasis, despite the long scan time. This study aimed to compare highly accelerated postcontrast 3D T1-weighted sampling perfection with application-optimized contrasts by using different flip angle evolution by using wave-controlled aliasing in parallel imaging (wave-T1-SPACE) with the commonly used standard high-resolution postcontrast 3D T1-SPACE for the evaluation of brain metastases. MATERIALS AND METHODS: Among the 387 patients who underwent postcontrast wave-T1-SPACE and standard SPACE, 56 patients with suspected brain metastases were retrospectively included. Two neuroradiologists assessed the number of enhancing lesions according to lesion size, contrast-to-noise ratiolesion/parenchyma, contrast-to-noise ratiowhite matter/gray matter, contrast ratiolesion/parenchyma, and overall image quality for the 2 different sequences. RESULTS: Although there was no significant difference in the evaluation of larger enhancing lesions (>5 mm) between the 2 different sequences (P = .66 for observer 1, P = .26 for observer 2), wave-T1-SPACE showed a significantly lower number of smaller enhancing lesions (<5 mm) than standard SPACE (1.61 [SD, 0.29] versus 2.84 [SD, 0.47] for observer 1; 1.41 [SD, 0.19] versus 2.68 [SD, 0.43] for observer 2). Furthermore, mean contrast-to-noise ratiolesion/parenchyma and overall image quality of wave-T1-SPACE were significantly lower than those in standard SPACE. CONCLUSIONS: Postcontrast wave-T1-SPACE showed comparable diagnostic performance for larger enhancing lesions (>5 mm) and marked scan time reduction compared with standard SPACE. However, postcontrast wave-T1-SPACE showed underestimation of smaller enhancing lesions (<5 mm) and lower image quality than standard SPACE. Therefore, postcontrast wave-T1-SPACE should be interpreted carefully in the evaluation of brain metastasis.

Suppression of BMP signaling by PHD2 deficiency in Pulmonary Arterial hypertension.

BMP signaling deficiency is evident in the lungs of patients with pulmonary arterial hypertension. We demonstrated that PHD2 deficiency suppresses BMP signaling in the lung endothelial cells, suggesting the novel mechanisms of dysregulated BMP signaling in the development of pulmonary arterial hypertension.

Genetics and Emerging Therapies for Brain Arteriovenous Malformations.

Brain arteriovenous malformations (AVMs) are characterized by a high-pressure, low-resistance vascular nidus created by direct shunting of blood from feeding arteries into arterialized veins, bypassing intervening capillaries. AVMs pose a risk of spontaneous rupture because the vessel walls are continuously exposed to increased shear stress and abnormal flow phenomena, which lead to vessel wall inflammation and distinct morphologic changes. The annual rupture rate is estimated at 2%, and once an AVM ruptures, the risk of rerupture increases 5-fold. The ability of AVMs to grow, regress, recur, and undergo remodeling shows their dynamic nature. Identifying the underlying cellular and molecular pathways of AVMs not only helps us understand their natural physiology but also allows us to directly block vital pathways, thus preventing AVM development and progression. Management of AVMs is challenging and often necessitates a multidisciplinary approach, including neurosurgical, endovascular, and radiosurgical expertise. Because many of these procedures are invasive, carry a risk of inciting hemorrhage, or are controversial, the demand for pharmacologic treatment options is increasing. In this review, we introduce novel findings of cellular and molecular AVM physiology and highlight key signaling mediators that are potential targets for AVM treatment. Furthermore, we give an overview of syndromes associated with hereditary and nonhereditary AVM formation and discuss causative genetic alterations.

Filtration performance and breathing resistance of elastomeric half mask respirator P100 filter cartridges after repeated and extended use in healthcare settings.

In 2020, the Centers for Disease Control and Prevention recommended the use of the National Institute for Occupational Safety and Health-certified Elastomeric Half Mask Respirators equipped with N95 or P100 respirator filter cartridges for protection against the SARS-CoV-2 viral agent, as a viable alternative to N95 filtering facepiece respirators. Additionally, the Centers for Disease Control and Prevention recommendations stated that based on current practice, it was acceptable to repeatedly use these filter cartridges for up to 12 months as a contingency capacity strategy during anticipated respirator shortages. To validate this recommendation, an investigation was undertaken in which Elastomeric Half Mask Respirators equipped with P100 respirator filter cartridges were deployed and used by healthcare professionals in clinical settings (i.e., inpatient nursing units, operating rooms) for extended periods. These filter cartridges were subsequently tested to accurately quantify their filtration efficiency and breathing resistance to determine if they continued to meet National Institute for Occupational Safety and Health's performance requirements. Findings from this investigation confirmed that an Elastomeric Half Mask Respirator when equipped with a P100 filter cartridge continues to provide a high level of aerosol filtration performance (≥99.97%) and exhibits little change in breathing resistance even after 12 months of repeated use (i.e., wear, cleaning, and disinfection between patient use and at the end of work shift) in healthcare settings.

Learning curve of single-incision laparoscopic totally extraperitoneal repair (SILTEP) for inguinal hernia.

PURPOSE: Laparoscopic totally extraperitoneal hernia repair (TEP) is a widely used treatment for inguinal hernia. Single-incision laparoscopic TEP (SILTEP) has attracted the attention of several surgeons, given its superior cosmetic results and patient satisfaction, as well as comparable outcomes to multiport surgery. Nonetheless, no relevant studies have evaluated the learning curve (LC) of SILTEP in terms of both operation time (OT) and surgical failure. Therefore, we aimed to investigate the LC of SILTEP for inguinal hernia. METHODS: Medical records of 180 patients who underwent SILTEP performed by a single surgeon from a single institution between October 2012 and November 2017 were retrospectively reviewed. The LC was analyzed using the moving average method and cumulative sum control chart (CUSUM) for OT and surgical failure. Surgical failure was defined as the need for additional ports, open conversion, severe postoperative complications (Clavien-Dindo ≥ IIIa), and recurrence. Eight patients who underwent combined surgery or bilateral hernia repair were excluded from the OT analysis. RESULTS: From CUSUM graphs, the study period was divided into three phases: OT-phases 1 (1st-32nd), 2 (33rd-83rd), and 3 (84th-172nd) for OT and failure-phases 1 (1st-29th), 2 (30th-58th), and 3 (59th-180th) for surgical failure. Mean OTs were statistically different in the three OT phases (64.6 vs. 50.8 vs. 35.2 min; p < 0.001). Open conversion (31.0% vs. 0% vs. 2.5%) and additional port insertion (6.9% vs. 24.1% vs. 2.5%) stabilized consecutively at failure-phases 2 and 3 (p < 0.001). Surgical failure rates decreased to 5.7% by failure-phase 3 (37.9% vs. 24.1% vs. 5.7%; p < 0.001). CONCLUSION: For an experienced laparoscopic surgeon, we estimated that approximately 60 cases are needed to overcome the LC for SILTEP in terms of both reducing OT and achieving a surgical failure rate < 10%. Further proficiency could be achieved after approximately 85 SILTEP procedures with a stable OT of approximately 35 min.

Effects of military life on changes in body mass index of enlisted men: a cross-sectional study.

BACKGROUND: Obesity is a serious health problem with an incidence that is increasing rapidly. Enlisted men are a distinctive group characterised by 24-hour community-living and are likely to experience changes in body weight as a result of regular diet and exercise during enlistment. METHODS: This study reviewed data from the Second Military Health Survey. Changes in body mass index (BMI) before and during military service were analysed using paired t-test. We calculated OR and 95% CI for factors affecting weight improvement during military service through logistic regression. RESULTS: The mean BMI in the underweight group increased by 5.87 kg/m2 during service, while that in the normal weight group increased by 1.18 kg/m2. In contrast, the mean BMI in the overweight group decreased by 5.47 kg/m2 during service. The OR for an improved BMI in the subjective good health group compared with the subjective poor health group was statistically significant (OR=1.71, 95% CI 1.02 to 2.87). The OR for an improved BMI was significantly higher in the group with three or more times per week of strength training than in the group with one to two times per week of strength training, and was higher among the marines compared with the Army soldiers (OR=1.48, 95% CI 1.03 to 2.12 and OR=2.15, 95% CI 1.07 to 4.32, respectively). CONCLUSIONS: Strength training showed a statistically significant increase in BMI during military service. Furthermore, the BMI of men who were underweight before their service increased, while it decreased among those who were overweight.

Bone Marrow-Derived Alk1 Mutant Endothelial Cells and Clonally Expanded Somatic Alk1 Mutant Endothelial Cells Contribute to the Development of Brain Arteriovenous Malformations in Mice.

We have previously demonstrated that deletion of activin receptor-like kinase 1 (Alk1) or endoglin in a fraction of endothelial cells (ECs) induces brain arteriovenous malformations (bAVMs) in adult mice upon angiogenic stimulation. Here, we addressed three related questions: (1) could Alk1- mutant bone marrow (BM)-derived ECs (BMDECs) cause bAVMs? (2) is Alk1- ECs clonally expended during bAVM development? and (3) is the number of mutant ECs correlates to bAVM severity? For the first question, we transplanted BM from PdgfbiCreER;Alk12f/2f mice (EC-specific tamoxifen-inducible Cre with Alk1-floxed alleles) into wild-type mice, and then induced bAVMs by intra-brain injection of an adeno-associated viral vector expressing vascular endothelial growth factor and intra-peritoneal injection of tamoxifen. For the second question, clonal expansion was analyzed using PdgfbiCreER;Alk12f/2f;confetti+/- mice. For the third question, we titrated tamoxifen to limit Alk1 deletion and compared the severity of bAVM in mice treated with low and high tamoxifen doses. We found that wild-type mice with PdgfbiCreER;Alk12f/2f BM developed bAVMs upon VEGF stimulation and Alk1 gene deletion in BMDECs. We also observed clusters of ECs expressing the same confetti color within bAVMs and significant proliferation of Alk1- ECs at early stage of bAVM development, suggesting that Alk1- ECs clonally expanded by local proliferation. Tamoxifen dose titration revealed a direct correlation between the number of Alk1- ECs and the burden of dysplastic vessels in bAVMs. These results provide novel insights for the understanding of the mechanism by which a small fraction of Alk1 or endoglin mutant ECs contribute to development of bAVMs.

Novel experimental model of brain arteriovenous malformations using conditional Alk1 gene deletion in transgenic mice.

OBJECTIVE: Hereditary hemorrhagic telangiectasia is the only condition associated with multiple inherited brain arteriovenous malformations (AVMs). Therefore, a mouse model was developed with a genetics-based approach that conditionally deleted the causative activin receptor-like kinase 1 (Acvrl1 or Alk1) gene. Radiographic and histopathological findings were correlated, and AVM stability and hemorrhagic behavior over time were examined. METHODS: Alk1-floxed mice were crossed with deleter mice to generate offspring in which both copies of the Alk1 gene were deleted by Tagln-Cre to form brain AVMs in the mice. AVMs were characterized using MRI, MRA, and DSA. Brain AVMs were characterized histopathologically with latex dye perfusion, immunofluorescence, and Prussian blue staining. RESULTS: Brains of 55 Tagln-Cre+;Alk12f/2f mutant mice were categorized into three groups: no detectable vascular lesions (group 1; 23 of 55, 42%), arteriovenous fistulas (AVFs) with no nidus (group 2; 10 of 55, 18%), and nidal AVMs (group 3; 22 of 55, 40%). Microhemorrhage was observed on MRI or MRA in 11 AVMs (50%). AVMs had the angiographic hallmarks of early nidus opacification, a tangle of arteries and dilated draining veins, and rapid shunting of blood flow. Latex dye perfusion confirmed arteriovenous shunting in all AVMs and AVFs. Microhemorrhages were detected adjacent to AVFs and AVMs, visualized by iron deposition, Prussian blue staining, and macrophage infiltration using CD68 immunostaining. Brain AVMs were stable on serial MRI and MRA in group 3 mice (mean age at initial imaging 2.9 months; mean age at last imaging 9.5 months). CONCLUSIONS: Approximately 40% of transgenic mice satisfied the requirements of a stable experimental AVM model by replicating nidal anatomy, arteriovenous hemodynamics, and microhemorrhagic behavior. Transgenic mice with AVFs had a recognizable phenotype of hereditary hemorrhagic telangiectasia but were less suitable for experimental modeling. AVM pathogenesis can be understood as the combination of conditional Alk1 gene deletion during embryogenesis and angiogenesis that is hyperactive in developing and newborn mice, which translates to a congenital origin in most patients but an acquired condition in patients with a confluence of genetic and angiogenic events later in life. This study offers a novel experimental brain AVM model for future studies of AVM pathophysiology, growth, rupture, and therapeutic regression.