Evaluation of Immature Granulocyte Count as the Earliest Biomarker for Sepsis.

Background: Diagnosing sepsis early is important for its successful management. Various biomarkers are being used currently, but mostly they are either expensive or not readily available. This study aims to evaluate usefulness of automated immature granulocyte count (IG#) and immature granulocyte percentage (IG%) as early diagnostic markers of sepsis and compares it to other established predictive markers. Patients and methods: In this prospective observational study, 137 eligible, critically ill, nonseptic intensive care unit patients were analyzed for automated IG#, IG%, serum procalcitonin (PCT), and blood lactate (Lac), daily for 7 days after recruitment. Patients were followed for the development of sepsis, defined by the new Sepsis-3 criteria. The study was divided into four time periods of 24 hours each with respect to the day of developing organ dysfunction. Using area under receiver operator characteristic and diagnostic odds ratio (DOR) methods, the best biomarker for the prediction of sepsis in each time period was calculated. Results: IG# and IG% were the earliest biomarkers to have a significant discriminating value with area under the curve of 0.81 and 0.82, respectively, as early as 24 hours before clinical sepsis is diagnosed by Sepsis-3 criteria. Both IG# and IG% have a high DOR of 34.91 and 18.11, respectively, when compared to others like PCT and Lac having a DOR of 27.06 and 4.78, respectively. Conclusion: IG# and IG% are easily available, rapid, and inexpensive tools to differentiate between septic and nonseptic patients with high specificity and sensitivity. It is the earliest biomarker to show a significant rise in patients developing sepsis. How to cite this article: Bhansaly P, Mehta S, Sharma N, Gupta E, Mehta S, Gupta S. Evaluation of Immature Granulocyte Count as the Earliest Biomarker for Sepsis. Indian J Crit Care Med 2022;26(2):216-223.

Laboratory misdiagnosis of von Willebrand disease in post-menarchal females: A multi-center study.

Increased awareness of von Willebrand Disease (VWD) has led to more frequent diagnostic laboratory testing, which insurers often dictate be performed at a facility with off-site laboratory processing, instead of a coagulation facility with onsite processing. Off-site processing is more prone to preanalytical variables causing falsely low levels of von Willebrand Factor (VWF) due to the additional transport required. Our aim was to determine the percentage of discordance between off-site and onsite specimen processing for VWD in this multicenter, retrospective study. We enrolled females aged 12 to 50 years who had off-site specimen processing for VWF assays, and repeat testing performed at a consulting institution with onsite coagulation phlebotomy and processing. A total of 263 females from 17 institutions were included in the analysis. There were 251 subjects with both off-site and onsite VWF antigen (VWF:Ag) processing with 96 (38%) being low off-site and 56 (22%) low onsite; 223 subjects had VWF ristocetin co-factor (VWF:RCo), 122 (55%) were low off-site and 71 (32%) were low onsite. Similarly, 229 subjects had a Factor VIII (FVIII) assay, and 67 (29%) were low off-site with less than half, 29 (13%) confirmed low with onsite processing. Higher proportions of patients demonstrated low VWF:Ag, VWF:RCo, and/or FVIII with off-site processing compared to onsite (McNemar's test P-value <.0005, for all assays). These results emphasize the need to decrease delays from sample procurement to processing for VWF assays. The VWF assays should ideally be collected and processed at the same site under the guidance of a hematologist.

Potential of the Community Counts registry to characterize rare bleeding disorders.

INTRODUCTION: Rare bleeding disorders (RBDs) comprise of heterogeneous coagulation factor deficiencies and platelet disorders that are underreported worldwide. AIM: First report on RBD data from United States haemophilia treatment center network (USHTCN). METHODS: A national surveillance system for the federally recognized USHTCN developed in collaboration with the Centers for Disease Control and Prevention (CDC) and American Thrombosis and Haemostasis Network (ATHN) was queried for patients with RBDs. Patient counts were extracted from the HTC Population Profile (HTC PP) component including limited data on patients followed through the USHTCN, and from the Registry component, including patient authorized, detailed clinical data. The prevalence of RBDs in the United States was estimated based on the HTC PP data and compared to the expected national prevalence based on data extrapolated from Orphanet, an international registry. RESULTS: Based on the estimated prevalence of RBD in the overall 2017 US population, the cases in the HTC network were lower than expected for FI, FII, FX, and FV + FVIII deficiencies by 36%, 61%, 75% and 94%, respectively, and higher than expected for FXIII, FV, FVII, and FXI deficiencies by 7%, 14%, 33% and 185%, respectively. The proportion of RBD patients reported in the HTC PP, enrolled in the Registry, was 10.8%. CONCLUSIONS: There is a clear need to identify individuals with RBDs who could benefit from the comprehensive care provided in the USHTCN. In addition, increased enrolment of people with all RBDs in the Registry is needed to improve knowledge of treatment outcomes of patients with RBDs in the United States.

Thrombin and plasmin generation in patients with plasminogen or plasminogen activator inhibitor type 1 deficiency.

INTRODUCTION: Deficiencies of plasminogen and plasminogen activator inhibitor type 1 (PAI-1) are rare disorders of fibrinolysis. Current laboratory assays for analysis of activity of plasminogen and PAI-1 do not provide an accurate correlation with clinical phenotype. METHODS: The Nijmegen Hemostasis Assay (NHA) was used to simultaneously measure thrombin and plasmin generation in 5 patients with plasminogen deficiency (PLGD) and 10 patients with complete PAI-1 deficiency. Parameters analysed included: lag time ratio, thrombin peak time ratio, thrombin peak height, thrombin potential (AUC), fibrin lysis time, plasmin peak height and plasmin potential. Parameters were expressed as a percentage compared to a reference value of 53 healthy normal controls. RESULTS: Patients with PLGD demonstrated a short lag time and thrombin peak time, with normal thrombin peak height but an increased AUC. Plasmin generation was able to be detected in only one (23% plasminogen activity) of the five PLGD patients. All ten PAI-1 deficient patients demonstrated a short lag and thrombin peak time, low thrombin peak height with normal AUC. Plasmin generation revealed an increased plasmin peak and plasmin potential; interestingly, there was a large variation between individual patients despite all patients having the same homozygous defect. CONCLUSION: Patients with either PLGD or PAI-1 deficiency show distinct abnormalities in plasmin and thrombin generation in the NHA. The differences observed in the propagation phase of thrombin generation may be explained by plasmin generation. These results suggest that disorders of fibrinolysis also influence coagulation and a global assay measuring both activities may better correlate with clinical outcome.

Sustained release of a model water-soluble compound via dry powder aerosolizable acetalated dextran microparticles.

Objective: To design and characterize aerosol microparticles (MP) to provide sustained release of the water-soluble compound sulforhodamine B (SRB) and achieve effective aerosol dispersion. Significance: Modulating the release of water-soluble compounds remains a challenge in pulmonary drug delivery. Methods: SRB and water made up an aqueous solution, while acetalated dextran (Ac-Dex) and isopropyl alcohol made up an organic solution. The two solutions were mixed together, and the solution was spray dried to produce MP. MP were characterized for morphology, size, release kinetics, aerosol dispersion, and cellular interactions. Results: Ac-Dex MP exhibited corrugated morphology and aerodynamic diameters from 2.06 to 2.86 µm. MP deposited in all stages of a Next Generation Impactor, with >90% fine particle fraction. MP exhibited encapsulation efficiencies >129% with SRB loading values up to 16.7 µg SRB/mg MP. MP exhibited sustained release of SRB at pH 7 and fast release at pH 5. In vitro experiments showed minimal cytotoxicity, successful uptake of MP in epithelial cells, and no disruption to the integrity of epithelial monolayers. Conclusions: Ac-Dex MP systems demonstrated the ability to provide sustained the release of a water-soluble therapeutic in addition to effective aerosol dispersion for pulmonary applications.

Plasminogen Activator Inhibitor Type I Controls Cardiomyocyte Transforming Growth Factor-ß and Cardiac Fibrosis.

BACKGROUND: Fibrosis is the pathological consequence of stress-induced tissue remodeling and matrix accumulation. Increased levels of plasminogen activator inhibitor type I (PAI-1) have been shown to promote fibrosis in multiple organ systems. Paradoxically, homozygous genetic deficiency of PAI-1 is associated with spontaneous age-dependent, cardiac-selective fibrosis in mice. We have identified a novel PAI-1-dependent mechanism that regulates cardiomyocyte-derived fibrogenic signals and cardiac transcriptional pathways during injury. METHODS: Cardiac fibrosis in subjects with homozygous mutation in SERPINE-1 was evaluated with late gadolinium-enhanced cardiac magnetic resonance imaging. A murine cardiac injury model was performed by subcutaneous infusion of either saline or Angiotensin II by osmotic minipumps. We evaluated blood pressure, cardiac function (by echocardiography), fibrosis (with Masson Trichrome staining), and apoptosis (with TUNEL staining), and we performed transcriptome analysis (with RNA sequencing). We further evaluated fibrotic signaling in isolated murine primary ventricular myocytes. RESULTS: Cardiac fibrosis was detected in 2 otherwise healthy humans with complete PAI-1 deficiency because of a homozygous frameshift mutation in SERPINE-1. In addition to its suppressive role during spontaneous cardiac fibrosis in multiple species, we hypothesized that PAI-1 also regulates fibrosis during cardiac injury. Treatment of young PAI-1-/- mice with Angiotensin II induced extensive hypertrophy and fibrotic cardiomyopathy, with increased cardiac apoptosis and both reactive and replacement fibrosis. Although Angiotensin II-induced hypertension was blunted in PAI-1-/- mice, cardiac hypertrophy was accelerated. Furthermore, ventricular myocytes were found to be an important source of cardiac transforming growth factor-ß (TGF-ß) and PAI-1 regulated TGF-ß synthesis by cardiomyocytes in vitro as well as in vivo during cardiac injury. Transcriptome analysis of ventricular RNA after Angiotensin II treatment confirmed that PAI-1 deficiency significantly enhanced multiple TGF-ß signaling elements and transcriptional targets, including genes for extracellular matrix components, mediators of extracellular matrix remodeling, matricellular proteins, and cardiac integrins compared with wild-type mice. CONCLUSIONS: PAI-1 is an essential repressor of cardiac fibrosis in mammals. We define a novel cardiomyocyte-specific regulatory mechanism for TGF-ß production by PAI-1, which explains the paradoxical effect of PAI-1 deficiency in promoting cardiac-selective fibrosis. Thus, PAI-1 is a molecular switch that controls the cardiac TGF-ß axis and its early transcriptional effects that lead to myocardial fibrosis.

Clinical features of children, adolescents, and adults with coexisting hypermobility syndromes and von Willebrand disease.

We present five patients with coexistent von Willebrand disease (VWD) and Ehlers-Danlos syndrome and 21 with VWD and joint hypermobility. Females outnumbered males ten to three, Beighton scores were documented in 58% (15 of 26 patients), and several patients experienced moderately severe bleeding. We believe coexistent hypermobility disorder with VWD potentially affects bleeding severity and want to raise awareness among hematologists. Evaluation by geneticists is recommended because of the varying complexities observed across the disease spectrum, and the availability of new genetic tests should lead to more accurate diagnoses for the various hypermobility disorders.

Coadministration of a tumor-penetrating peptide improves the therapeutic efficacy of paclitaxel in a novel air-grown lung cancer 3D spheroid model.

Three-dimensional (3 D) cell culture platforms are increasingly being used in cancer research and drug development since they mimic avascular tumors in vitro. In this study, we focused on the development of a novel air-grown multicellular spheroid (MCS) model to mimic in vivo tumors for understanding lung cancer biology and improvement in the evaluation of aerosol anticancer therapeutics. 3 D MCS were formed using A549 lung adenocarcinoma cells, comprising cellular heterogeneity with respect to different proliferative and metabolic gradients. The growth kinetics, morphology and 3 D structure of air-grown MCS were characterized by brightfield, fluorescent and scanning electron microscopy. MCS demonstrated a significant decrease in growth when the tumor-penetrating peptide iRGD and paclitaxel (PTX) were coadministered as compared with PTX alone. It was also found that when treated with both iRGD and PTX, A549 MCS exhibited an increase in apoptosis and decrease in clonogenic survival capacity in contrast to PTX treatment alone. This study demonstrated that coadministration of iRGD resulted in the improvement of the tumor penetration ability of PTX in an in vitro A549 3 D MCS model. In addition, this is the first time a high-throughput air-grown lung cancer tumor spheroid model has been developed and evaluated.

Development of Aerosol Phospholipid Microparticles for the Treatment of Pulmonary Hypertension.

Pulmonary arterial hypertension (PAH) is an incurable cardiovascular disease characterized by high blood pressure in the arteries leading from the heart to the lungs. Over two million people in the USA are diagnosed with PAH annually and the typical survival rate is only 3 years after diagnosis. Current treatments are insufficient because of limited bioavailability, toxicity, and costs associated with approved therapeutics. Aerosol delivery of drugs is an attractive approach to treat respiratory diseases because it increases localized drug concentration while reducing systemic side effects. In this study, we developed phospholipid-based aerosol microparticles via spray drying consisting of the drug tacrolimus and the excipients dipalmitoylphosphatidylcholine and dipalmitoylphosphatidylglycerol. The phospholipid-based spray-dried aerosol microparticles were shown to be smooth and spherical in size, ranging from 1 to 3 µm in diameter. The microparticles exhibited thermal stability and were amorphous after spray drying. Water content in the microparticles was under 10%, which will allow successful aerosol dispersion and long-term storage stability. In vitro aerosol dispersion showed that the microparticles could successfully deposit in the deep lung, as they exhibited favorable aerodynamic diameters and high fine particle fractions. In vitro dose-response analysis showed that TAC is nontoxic in the low concentrations that would be delivered to the lungs. Overall, this work shows that tacrolimus-loaded phospholipid-based microparticles can be successfully created with optimal physicochemical and toxicological characteristics.

Variable bleeding phenotype in an Amish pedigree with von Willebrand disease.

Through a cross-sectional study design, the bleeding phenotype in the Amish in Indiana (IN) and Wisconsin (WI) was described using two different bleeding scores. von Willebrand factor (VWF) testing was performed and bleeding questionnaires from Centers for Disease Control and Prevention (CDC) and European MCMDM-1 (Tosetto bleeding score (BS)) were administered to the IN and WI cohort respectively. Seven hundred and seventy nine subjects were recruited, 17% were diagnosed with VWD based on Ristocetin cofactor, VWF:RCo < 30 IU/dl. Majority of the affected (AF), 67%, were tested and had a common mutation c.4120 C > T. The WI AF were much younger at a mean age 15 years vs 26 years in IN AF cohort. The AF subjects had a median VWF:RCo of 13IU/dl with a statistically significant higher median BS 1 versus 0 in the WI AF vs WI Unaffected (UA), 2 vs 1 in the IN AF vs IN UA, P < 0.01. Adults had a higher median BS compared to children in the WI and IN cohort, 2 vs 1 and 3 vs 1 respectively (P < 0.05) but there was no statistically significant difference in the BS between males and females in either cohort. The common symptoms reported were epistaxis and gingival oozing. BS ≥ 3 and BS ≥ 4 were observed in 46% of AF IN and 16.6% of AF WI, respectively. There was significant variability in the bleeding phenotype, with an overall low BS in the affected Amish with VWD, despite a unifying mutation. Am. J. Hematol. 91:E431-E435, 2016. © 2016 Wiley Periodicals, Inc.

Validation Study of the Composite Score to Identify Von Willebrand Disease in Children.

BACKGROUND: The diagnosis of type 1 von Willebrand disease (VWD) presents a diagnostic challenge in children. In fact, 25% or more of children with VWD may be diagnosed only after they experience postoperative bleeding. We previously described a 4-variable composite score that has 92.5% sensitivity and 95% specificity for diagnosing VWD in children with known VWD when 2 of 4 criteria are positive: (1) Tosetto bleeding score ≥ 1; (2) family history of VWD; (3) personal history of iron deficiency anemia; and/or (4) positive James early bleeding score. The purpose of this study was to prospectively validate a composite score of ≥ 2 for identifying children with VWD. PROCEDURE: Children without a previously diagnosed bleeding disorder presenting for hematology evaluation were enrolled. Sensitivity, specificity, positive, and negative predictive value of the composite score was determined. RESULTS: A total of 193 subjects were enrolled from 12 participating centers were included in the analysis. Forty-seven children had type 1 VWD, including 11 with von Willebrand Ristocetin Cofactor (VWF):RCo < 30 IU/dL, 14 subjects with a VWF:RCo 30 to 39 IU/dL, and 22 with a VWF:RCo 40 to 49 IU/dL. Including all 4 variables, a composite score of ≥ 2 had a sensitivity of 63.6% to 76.0%, specificity of 33.5% to 35.1%, negative predictive value of 76.9% to 93.8%, and positive predictive value of 5.5% to 25%. CONCLUSIONS: The negative predictive value of the composite score was robust, especially at lower VWF:RCo suggesting that VWD testing could be eliminated in nearly a third of children referred for VWD testing.

Effect of locosamide as an add-on therapy in the management of dissociative disorders.

The role of lacosamide (LCM) as add on treatment modality in dissociative disorders (DD) is of interest. It was a randomized control trial in which 300 patients diagnosed with dissociative disorders having treatment for the dissociative disorders were included. They were divided into two groups. Group one consisted of intervention group in which LCM was also administered along with conventional psychiatric medication for different dissociative disorders. Group two consisted of control group where the patients of dissociative disorders were found to have conventional medication. There was analysis of improvements in recovery of symptoms and quality of life. There was statistically significant increase in excellent, very good, good and fair quality of life and decrease in poor and satisfactory quality of life in intervention group after drug intervention. It was observed that symptoms of the patients improved in 50.67% cases in intervention group and 10.67% cases in control group. There was greater improvement in recovery of symptoms and quality of life in patients of DD in which LCM was administered as add on medication.

An Evaluation of the Changing Trends in Substance Use Behavior Among Patients in the Tertiary Care Setting After the Implementation of Liquor Prohibition in Bihar, India: A Cross-Sectional Study.

Background and objective Substance use disorders pose significant global public health challenges, with India being no exception. Bihar, one of India's most populous states, implemented alcohol prohibition in April 2016 to address the adverse effects of alcohol abuse. However, the impact of this policy on overall substance use behavior among patients in healthcare settings remains to be explored. This cross-sectional study aimed to evaluate the changing trends in substance use behavior among patients in the tertiary care setting following the prohibition of alcohol use in Bihar. Methods A total of 372 patients diagnosed with substance use disorders were recruited from tertiary care facilities in Bihar. Data on demographic characteristics, types of substances used, frequency and quantity of use, reasons for use, and awareness of prohibition laws were collected through structured interviews and reviews of medical records. Descriptive and inferential statistics were used for data analysis. Results The majority of the participants were male (n = 346, 93.01%), with a mean age of 38.5 years. While tobacco use remains stable, there are significant increases in opioid and cannabis consumption post-prohibition, highlighting unintended consequences (p-values - opioids: 0.008, cannabis: 0.021). Additionally, heightened daily and weekly substance use after prohibition is evident (p-values: daily: 0.008, weekly: 0.021), emphasizing the necessity for nuanced policy considerations. Reasons for substance use, including coping with stress and peer pressure, showed significant differences before and after the prohibition (p<0.05). Moreover, awareness of alcohol prohibition laws increased significantly after the implementation of the prohibition (p = 0.003). Conclusions Our findings suggest that while alcohol prohibition in Bihar did not significantly lead to any changes in terms of the types of substances used among patients in tertiary care settings, it did influence the frequency and quantity of tobacco and cannabis consumption. Increased awareness of prohibition laws underscores the importance of policy enforcement and public education initiatives in addressing substance use behavior.

The effect of secondary prophylaxis versus episodic treatment on the range of motion of target joints in patients with haemophilia.

This study prospectively compared the effect of secondary prophylaxis to episodic treatment on target joint (TJ) range of motion (ROM), number of joint haemorrhages and new TJ development in patients with moderate or severe haemophilia. Two-hundred and eighty-six males, 17% in prophylaxis, 83% in episodic treatment group, participating in the Centers for Disease Control and Prevention's Universal Data Collection project, fulfilled inclusion criteria: age >2 years at enrollment, free of TJs at enrollment, developed at least one TJ after enrollment, and received either prophylaxis or episodic treatment continuously for two follow-up visits after TJ development. The outcomes of interest - percentage change in TJ ROM, number of joint haemorrhages and new TJ development, were modelled using multivariate linear, Poisson and logistic regression techniques respectively. Individuals who received secondary prophylaxis in comparison to episodic treatment were younger at TJ development (P < 0.01); there was no difference in the decrease in TJ ROM between the two groups (P = 0.9). Factors significantly associated with a higher rate of haemarthroses included episodic treatment, severe haemophilia, age >5 years at TJ development, obesity and inhibitor negative status. Secondary prophylaxis significantly decreased haemarthroses but was not associated with a significant improvement in TJ ROM or with new TJ development.

High Serum Ferritin Levels among Blood Transfused Thalassemic Patients Admitted to the Department of Paediatrics in a Tertiary Care Centre: A Descriptive Cross-Sectional Study.

Introduction: Raised serum ferritin levels often indicate iron overload, but they are not specific as the levels are elevated in inflammatory disorders, liver diseases, alcohol excess, or malignancy. If regular transfusions are required for the patient with thalassemia, this doubles the rate of iron accumulation leading to earlier massive iron overload and iron-related damage. The aim of this study aimed to find out the prevalence of high serum ferritin levels among blood-transfused thalassemic patients admitted to the Department of Paediatrics in a tertiary care centre. Methods: A descriptive cross-sectional study was conducted at a tertiary care centre from 1 March 2022 to 31 December 2022. Ethical approval was taken from the Institutional Review Committee (Reference number: 078/79-017/HG). Children who were confirmed by haemoglobin electrophoresis on regular blood transfusion were included in the study. Those who did not gave consent were excluded from the study. Convenience sampling method was used. Point estimate and 90% Confidence Interval were calculated. Results: Out of 53 cases, the prevalence of high serum ferritin level was seen in 46 (88.79%) (80.30-97.28, 95% Confidence Interval). Among 46, 34 (73.91%) had serum ferritin levels of more than 1000 to 2500 ng/ml whereas 12 (26.09%) had more than 25000 ng/ml. Conclusions: The prevalence of high serum ferritin levels among blood transfused thalassemic patients admitted to the Department of Paediatrics in a tertiary care centre was found to be higher than in other studies done in similar settings. Keywords: blood transfusion; ferritin; thalassemia.

3D assessment of alveolar bone alterations in orthodontic movement among Indians.

Apical root resorption, which is characterised as a biological or abnormal phenomenon that shortens the length of the root apex, is additional typical iatrogenic impact of orthodontic tooth movement that may jeopardise the effectiveness of treatment and tooth lifespan. The main goals of the current retrospective investigation were to assess the dimensions of alveolar bone alterations that come along with orthodontic movement and to look into the frequency and extent of resorption of root in maxillary incisors across categories that were similarly managed with clear aligners (OCA) and fixed appliances (OFA) using CBCT. The study included 50 subjects who were divided into two categories with 25 study subjects in each category. Category OFA: Subjects receiving OFA (n=25). A CBCT scan was used to get three-dimensional pictures at the beginning of therapy as well as at the end of therapy. The overall resorption of root at apical region in OFA group was 0.63±0.21 mm. The overall resorption of root at apical region in OCA group was 0.32 ±0.36 mm. The difference in observation was statistically significant (p= 0.000) with reduced resorption of root at apical region in clear aligners. It was concluded that the decrease in thickness of alveolar bone was greater in orthodontic fixed appliances group as compared to clear aligners. The resorption of root at apical region was lesser in clear aligners group as compared to fixed appliances.

Quantifying the Release of Titanium From the Titanium Dioxide-Impregnated Composites Used in Orthodontic Bonding.

BACKGROUND: Previous literature data has extensively assessed the biocompatibility of various orthodontic adhesives and their components, where the results of most of the studies showed cytotoxic effects of different degrees owing to the unbound molecules released structurally from the cured components. AIM: The present in-vitro study was aimed to assess the release of titanium dioxide nanoparticles in the artificial saliva from the orthodontic composites impregnated with titanium dioxide nanoparticles of 5% w/w (weight/weight) and 1% w/w used for metal brackets bonding. METHODS: The study assessed 160 teeth extracted freshly during orthodontic treatment and divided into two groups of 80 samples, each that bonded to orthodontic brackets having 5% w/w and 1% w/w composites with titanium dioxide nanoparticles kept in the artificial saliva. Quantification was done for 5% w/w and 1% w/w composites having titanium nanoparticles with inductively coupled plasma mass spectroscopy at 24 hours, two, four, and six months. RESULTS: It was seen that in teeth with 1% titanium dioxide, the greatest titanium release was seen at two months, with non-significant release after two months. In teeth with 5% w/w titanium dioxide nanoparticles showed significant titanium release all the time. A significantly greater titanium dioxide release on increasing concentration from 1% to 5% was seen for the 5% w/w group at all the assessment times. CONCLUSION: The present study concludes that a higher release of titanium is seen in 5% w/w composite containing titanium dioxide nanoparticles, and the concentrations of 1% and 5% can be safely used and are considered to be within permissible limits.

Efficacy of Two Types of Noninvasive Nerve Stimulation in the Management of Myofascial Pain Caused by Temporomandibular Joint (TMJ) Disorders.

Background A range of diseases affecting the jaw muscles and/or temporomandibular joint are referred to as temporomandibular disorders (TMDs). Nearly 80% of the general population is affected by TMDs, and 48% of those people have trouble opening their mouths and have painful muscles. Aim To compare the effectiveness of transcutaneous electrical nerve stimulation (TENS) and microcurrent nerve stimulation (MENS) for the relief of masticatory muscle discomfort. Methods Groups I and II were further separated into two groups of 30 persons each (A and B), as well as subgroups C and D. Subjects in Group I received TENS treatment for 20 minutes at frequencies of 0-5 and 5-5 for subgroups A and B, and with visual analog scale (VAS) scores of 1-5 and 6-10 for subgroups C and D, respectively. Subjects in Group II received MENS for 20 minutes, with subgroups C and D receiving the same frequency and VAS score as subgroups A and B, respectively. All individuals underwent treatment with a comparable frequency and length of time every day for five days. Results For subgroup D treated with MENS, there was a considerable reduction in pain; however, for subgroups A and C, there was a comparable reduction in the VAS score for both groups treated with MENS and TENS therapy. Conclusion Compared to TENS, MENS provides quicker and more effective pain relief. Paresthesia and tingling are two adverse effects of TENS that are not present with MENS. However, MENS and TENS are equally helpful at treating masticatory muscle discomfort that is both acute and chronic, as well as improving mouth opening.

Intracellular tPA-PAI-1 interaction determines VLDL assembly in hepatocytes.

Apolipoprotein B (apoB)-lipoproteins initiate and promote atherosclerotic cardiovascular disease. Plasma tissue plasminogen activator (tPA) activity is negatively associated with atherogenic apoB-lipoprotein cholesterol levels in humans, but the mechanisms are unknown. We found that tPA, partially through the lysine-binding site on its Kringle 2 domain, binds to the N terminus of apoB, blocking the interaction between apoB and microsomal triglyceride transfer protein (MTP) in hepatocytes, thereby reducing very-low-density lipoprotein (VLDL) assembly and plasma apoB-lipoprotein cholesterol levels. Plasminogen activator inhibitor 1 (PAI-1) sequesters tPA away from apoB and increases VLDL assembly. Humans with PAI-1 deficiency have smaller VLDL particles and lower plasma levels of apoB-lipoprotein cholesterol. These results suggest a mechanism that fine-tunes VLDL assembly by intracellular interactions among tPA, PAI-1, and apoB in hepatocytes.