Cerebrospinal Creatine Kinase BB Isoenzyme: A Biomarker for Predicting Outcome After Cardiac Arrest.

BACKGROUND: Cerebrospinal fluid creatine kinase BB isoenzyme (CSF CK-BB) after cardiac arrest (CA) has been shown to have a high positive predictive value for poor neurological outcome, but it has not been evaluated in the setting of targeted temperature management (TTM) and modern CA care. We aimed to evaluate CSF CK-BB as a prognostic biomarker after CA. METHODS: We performed a retrospective cohort study of patients with CA admitted between 2010 and 2020 to a three-hospital health system who remained comatose and had CSF CK-BB assayed between 36 and 84 h after CA. We examined the proportion of patients at hospital discharge who achieved favorable or intermediate neurological outcome, defined as Cerebral Performance Category score of 1-3, compared with those with poor outcome (Cerebral Performance Category score 4-5) for various CSF CK-BB thresholds. We also evaluated additive value of bilateral absence of somatosensory evoked potentials (SSEPs). RESULTS: Among 214 eligible patients, the mean age was 54.7 ± 4.8 years, 72% of patients were male, 33% were nonwhite, 17% had shockable rhythm, 90% were out-of-hospital CA, and 83% received TTM. A total of 19 (9%) awakened. CSF CK-BB ≥ 230 U/L predicted a poor outcome at hospital discharge, with a specificity of 100% (95% confidence interval [CI] 82-100%) and sensitivity of 69% (95% CI 62-76%). When combined with bilaterally absent N20 response on SSEP, specificity remained 100% while sensitivity increased to 80% (95% CI 73-85%). Discordant CK-BB and SSEP findings were seen in 13 (9%) patients. CONCLUSIONS: Cerebrospinal fluid creatine kinase BB isoenzyme levels accurately predicted poor neurological outcome among CA survivors treated with TTM. The CSF CK-BB cutoff of 230 U/L optimizes sensitivity to 69% while maintaining a specificity of 100%. CSF CK-BB could be a useful addition to multimodal neurological prognostication after CA.

Sleep Health as a Determinant of Disparities in Stroke Risk and Health Outcome.

Sleep is essential to human survival and overall vascular health. Sleep health encompasses the objective and subjective qualities associated with one's daily pattern of sleep and wakefulness and has become a growing clinical and public health concern. Impaired sleep duration and quality can increase stroke risk and mediate the relationship between the physical aspects of an individual's environment and disparities in stroke incidence. Here, we review observational studies evaluating the association between sleep health and cerebrovascular disease. We assess the influence on sleep of the physical environment, including the ambient environment with noise levels and the built environment. We also describe the influences on sleep health and stroke risk of social determinants of health, including the chronic stressor of racial discrimination. Finally, we discuss how changes in historical neighborhood characteristics or societal policies can influence the social factors affecting sleep health and stroke risk among socioeconomically disadvantaged groups or ethnic and racial minorities. Given the regional and racial or ethnic differences in stroke risk across the United States, an understanding of novel vascular risk factors, such as the multifaceted role of sleep health, will be critical to develop effective public policies to improve population health.

Bringing Generalists to Global Health: a Missed Opportunity and Call to Action.

The credo of the generalist physician has always been the promotion of health for all, in every aspect: not just multiple vulnerable organ systems, but multiple social, cultural, and political factors that contribute to poor health and exacerbate health inequity. In recent years, the field of global health has also adopted this same mission: working across both national and clinical specialty borders to improve health for all and end health disparities worldwide. Yet within the Society for General Internal Medicine, and among American generalists, engagement in global health, both within and outside the USA, remains uncommon. We see this gap as an opportunity, because in fact generalists in America already have the skills and experience that global health badly needs. SGIM could promote generalists to global health's vanguard, with three core steps. First, we generalists must continue to integrate health for the vulnerable into our domestic work, generating care models applicable in low-resource settings around the globe. Conversely, we must also engage with and implement international ideas and solutions for universal access to primary care for vulnerable patients in the USA. And lastly, we must build platforms to connect ourselves with colleagues worldwide to exchange these learnings.

Do animal models of brain tumors replicate human peritumoral edema? a systematic literature search.

INTRODUCTION: Brain tumors cause morbidity and mortality in part through peritumoral brain edema. The current main treatment for peritumoral brain edema are corticosteroids. Due to the increased recognition of their side-effect profile, there is growing interest in finding alternatives to steroids but there is little formal study of animal models of peritumoral brain edema. This study aims to summarize the available literature. METHODS: A systematic search was undertaken of 5 literature databases (Medline, Embase, CINAHL, PubMed and the Cochrane Library). The generic strategy was to search for various terms associated with "brain tumors", "brain edema" and "animal models". RESULTS: We identified 603 reports, of which 112 were identified as relevant for full text analysis that studied 114 peritumoral brain edema animal models. We found significant heterogeneity in the species and strain of tumor-bearing animals, tumor implantation method and edema assessment. Most models did not produce appreciable brain edema and did not test for observable manifestations thereof. CONCLUSION: No animal model currently exists that enable the investigation of novel candidates for the treatment of peritumoral brain edema. With current interest in alternative treatments for peritumoral brain edema, there is an unmet need for clinically relevant animal models.

Mitochondrial Permeability Transition in Stem Cells, Development, and Disease.

The mitochondrial permeability transition (mPT) is a process that permits rapid exchange of small molecules across the inner mitochondrial membrane (IMM) and thus plays a vital role in mitochondrial function and cellular signaling. Formation of the pore that mediates this flux is well-documented in injury and disease but its regulation has also emerged as critical to the fate of stem cells during embryonic development. The precise molecular composition of the mPTP has been enigmatic, with far more genetic studies eliminating molecular candidates than confirming them. Rigorous studies in the recent decade have implicated central involvement of the F1Fo ATP synthase, or complex V of the electron transport chain, and continue to confirm a regulatory role for Cyclophilin D (CypD), encoded by Ppif, in modulating the sensitivity of the pore to opening. A host of endogenous molecules have been shown to trigger flux characteristic of mPT, including positive regulators such as calcium ions, reactive oxygen species, inorganic phosphate, and fatty acids. Conductance of the pore has been described as low or high, and reversibility of pore opening appears to correspond with the relative abundance of negative regulators of mPT such as adenine nucleotides, hydrogen ion, and divalent cations that compete for calcium-binding sites in the mPTP. Current models suggest that distinct pores could be responsible for differing reversibility and conductance depending upon cellular context. Indeed, irreversible propagation of mPT inevitably leads to collapse of transmembrane potential, arrest of ATP synthesis, mitochondrial swelling, and cell death. Future studies should clarify ambiguities in mPTP structure and reveal new roles for mPT in dictating specialized cellular functions beyond cell survival that are tied to mitochondrial fitness including stem cell self-renewal and fate. The focus of this review is to describe contemporary models of the mPTP and highlight how pore activity impacts stem cells and development.

Sorption behavior studies of Cs and its migration in soil samples around Visakhapatnam, India.

Meeting the requirement of high specific activity of radioisotopes and carrying out comprehensive research and development activities in the nuclear field, different nuclear facilities, including their waste disposal facilities, are going to be operational at Visakhapatnam, India. Due to environmental processes, the engineered disposal modules may lose their structural integrity and may release some radioactivity to the geo-environment. The subsequent migration of radionuclides reaching the geological environment will be governed by the distribution coefficient (Kd). Cs was chosen for the sorption study in two soil samples (soil-29 and 31) and to estimate the Kd in all the 40 soil samples through the laboratory batch method at the new campus of DAE, Visakhapatnam, India. Different soil chemical parameters like pH, organic matter, CaCO3, and cation exchange capacity were determined in 40 soil samples and their effect on Cs sorption was investigated. The effect of solution pH and initial concentration of Cs on sorption was also studied. The results show that the sorption of Cs increases with increasing pH. The Cs sorption was well explained by Freundlich and Dubinin-Radushkevich (D-R) isotherm models. Site-specific distribution coefficients (Kd) were also estimated and the values were found to vary from 75 ± 1 to 540 ± 12 L kg-1. The observed wide variation in Kd could be due to large variations in the physico-chemical properties of collected soil. The competitive ions effect study suggests that K+ has higher interference for Cs+ sorption as compared to Na+. The present study results will help assess the environmental impact due to Cs release in any unforeseen scenario and in planning effective remediation strategies.

Pediatric Primary Yolk Sac Tumour of the Kidney: Recommendations for Pretreatment Diagnosis.

Introduction Although nephroblastomas are frequently treated without prior biopsy, there are the occasional other pediatric renal tumors that require different management. In the literature, there are around 30 primary renal germ cell tumors (GCT), including four cases of Yolk sac tumor (YST). We present another primary renal YST.Case report: A five-year-old boy was diagnosed as Wilms tumor on radiology and needle biopsy. He received chemotherapy, with no response. The post-chemotherapy resection specimen revealed a YST.Conclusion: Renal YST may be indistinguishable from Wilms tumor clinically and radiologically. For pre-biopsy chemotherapy management protocols, serum tumor markers such as AFP may be recommended to identify the occasional GCT, including YST. Pre-chemotherapy needle biopsies may lead to misdiagnosis, and may require confirmation by an experienced pathologist or central review.

Clinico-Epidemiological profile of new leprosy cases detected in leprosy case detection campaign in North Maharashtra during 2018-2020.

Leprosy is a leading cause of disability in India. The percentage of disability and deformity can be reduced by diagnosing leprosy at an early stage. In order to detect the hidden leprosy cases, leprosy case detection campaigns, on line with Pulse Polio Campaign have been introduced specifically for high endemic districts, by the Central Leprosy Division. Records of cases from 2018 to 2020 were evaluated retrospectively to study the trend of new cases. The present study denotes the presence of hidden undiagnosed cases in the community and will require an intensification of leprosy control activities through contact tracing and active case detection. Continued quality surveillance is required for early detection, timely management, and prevention of the spread of the disease.

Robotic infraclavicular approach for minimally invasive neck dissection in head-neck cancers.

Background: In the recent years, there has been a rapid increase in the use of robot assisted neck dissection (RAND) as an alternative method for conventional neck dissection. Several recent reports have emphasized upon the feasibility and effectiveness of this technique. However, substantial technical and technological innovation is still essential in spite of the availability of multiple approaches for RAND. Materials and Methods: The present study describes a novel technique, i.e., Robotic Infraclavicular Approach for Minimally Invasive Neck Dissection (RIA MIND) used in head and neck cancers with the help of Intuitive da Vinci Xi Surgical System. Results: After RIA MIND procedure, the patient was discharged on the third post operative day. Also, the total wound size was less than 3.5 cm which enhanced the patient recovery time and required minimal post operative care. The patient was further reviewed 10 days after the procedure for the removal of sutures. Conclusion: RIA MIND technique was effective and safe for performing neck dissection for oral, head and neck cancers. However, additional detailed studies will be required for establishing this technique.

Device for Assessing Knee Joint Dynamics During Magnetic Resonance Imaging.

BACKGROUND: Knee assessment with and without load using magnetic resonance imaging (MRI) can provide information on knee joint dynamics and improve the diagnosis of knee joint diseases. Performing such studies on a routine MRI-scanner require a load-exerting device during scanning. There is a need for more studies on developing loading devices and evaluating their clinical potential. PURPOSE: Design and develop a portable and easy-to-use axial loading device to evaluate the knee joint dynamics during the MRI study. STUDY TYPE: Prospective study. SUBJECTS: Nine healthy subjects. FIELD STRENGTH/SEQUENCE: A 0.25 T standing-open MRI and 3.0 T MRI. PD-T2 -weighted FSE, 3D-fast-spoiled-gradient-echo, FS-PD, and CartiGram sequences. ASSESSMENT: Design and development of loading device, calibration of loads, MR safety assessment (using projectile angular displacement, torque, and temperature tests). Scoring system for ease of doing. Qualitative (by radiologist) and quantitative (using structural similarity index measure [SSIM]) image-artifact assessment. Evaluation of repeatability, comparison with various standing stances load, and loading effect on knee MR parameters (tibiofemoral bone gap [TFBG], femoral cartilage thickness [FCT], tibial cartilage thickness [TCT], femoral cartilage T2 -value [FCT2], and tibia cartilage T2 -value [TCT2]). The relative percentage change (RPC) in parameters due to the device load was computed. STATISTICAL TEST: Pearson's correlation coefficient (r). RESULTS: The developed device is conditional-MR safe (details in the manuscript and supplementary materials), 15 × 15 × 45 cm3 dimension, and <3 kg. The ease of using the device was 4.9/5. The device introduced no visible image artifacts, and SSIM of 0.9889 ± 0.0153 was observed. The TFBG intraobserver variability (absolute difference) was <0.1 mm. Interobserver variability of all regions of interest was <0.1 mm. The load exerted by the device was close to the load during standing on both legs in 0.25 T scanner with r > 0.9. Loading resulted in RPC of 1.5%-11.0%, 7.9%-8.5%, and -1.5% to 13.0% in the TFBG, FCT, and TCT, respectively. FCT2 and TCT2 were reduced in range of 1.5-2.7 msec and 0.5-2.3 msec due to load. DATA CONCLUSION: The proposed device is conditionally MR safe, low cost (material cost < INR 6000), portable, and effective in loading the knee joint with up to 50% of body weight. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 1.

Extrapancreatic Advanced Endoscopic Interventions.

As the field of interventional endoscopy advances, conditions that were once treated with surgery are increasingly being treated with advanced endoscopy. Endoscopy is now used for treatment of achalasia, bariatric procedures for obesity; resection of early-stage malignancies in the gastrointestinal tract; and placement of lumen-apposing metal stents in the treatment of biliary obstruction, gastric outlet obstruction, cholecystitis, and drainage of nonpancreatic-related fluid collections or abscesses. Knowledge of the novel terminology, procedural details, expected postintervention imaging findings, and potential complications is vital for radiologists because these procedures are rapidly becoming more mainstream in daily practice. These procedures include peroral endoscopic myotomy for the treatment of achalasia and other esophageal motility disorders; endoscopic sleeve gastroplasty and placement of an intragastric balloon for weight loss; endoscopic submucosal dissection in the resection of tumors of the gastrointestinal tract; and therapeutic endoscopic-guided procedures for the treatment of biliary obstruction, gastric outlet obstruction, acute cholecystitis, and drainage of nonpancreatically related fluid collections. Patients benefit from these minimally invasive procedures, with potential improvement in morbidity and mortality rates, decreased length of hospital stay, and decreased health care costs when compared with the surgical alternative. Complications of these procedures include leaks or perforations, infections or abscesses, fistulas, and occlusion and migration of stents. An invited commentary by Pisipati and Pannala is available online. ©RSNA, 2022.

Essential medicines for cardiovascular diseases in India: Rapid appraisal of policies and processes at the subnational level.

Background The burden of cardiovascular diseases (CVDs) and response to health systems vary widely at the subnational level in India. Our study aimed to assess the variation in state-level access to medicines for CVDs by comparing the essential medicines lists (EMLs) at the national and subnational levels in India and by rapid appraisal of the existing policies and processes of drug procurement. Methods We assessed the inclusion of six classes of medicines for CVDs in the recent and publicly available national and subnational EMLs from July to September 2018 in the states of Telangana and Madhya Pradesh. We examined the drug procurement and distribution policies and processes using documentary review and five key informant interviews between March and June 2018. Results The WHO's EML, India's national EML, and 21 of 28 publicly available (75%) Indian state and Union Territory EMLs included all six classes of essential medicines for CVDs. However, some medicines were not included in the policy packages of essential medicines meant for primary health centres. Both the states used centralized tendering and decentralized distribution as part of the public sector drug procurement process. The requirement was based on the previous year's consumption. The approximate time between procurement planning and distribution was 7-8 months in both the states. Conclusion Substantial variation exists in the selection of drugs for CVDs in EMLs at the subnational level in India. Improving forecasting techniques for requirement of medicines and reducing time lags between forecasting and distribution to health facilities may allow for better access to essential medicines.

Cerebral fat embolism syndrome at a single trauma center.

OBJECTIVES: Based on a 16-year case series, we sought lessons about diagnosis and treatment of cerebral fat embolism syndrome. MATERIALS AND METHODS: Using discharge codes at a Level 1 Trauma Center, we performed a retrospective chart review of clinical characteristics, diagnostic studies, treatments, and outcome in cerebral fat embolism syndrome. RESULTS: Thirty-nine (40%) of 97 patients with fat embolism syndrome were diagnosed with cerebral fat embolism syndrome, with 29 (74%) presenting with coma. All had abnormal brain magnetic resonance imaging, with scattered cytotoxic edema (starfield pattern) in 29 (74%). All but two of the 21 patients with dilated fundoscopy showed retinal embolism. Among 29 patients with transcranial Doppler, the presence of microembolic signals in 15 (52%) was associated with fever (p = 0.039), right-to-left intracardiac shunting (p = 0.046) and a trend towards initial coma. In 11 patients with serial transcranial Dopplers and treatment with high-intensity statin therapy, the frequency of microembolic signals tended to decrease after therapy was initiated. Of the 28 (72%) of the 39 patients discharged, 16 (57%) had mild to moderate disability at last follow up. CONCLUSIONS: The recognition of cerebral fat embolism syndrome may be improved with routine inclusion of brain magnetic resonance imaging, dilated fundoscopy, and transcranial Doppler. We share our empiric management algorithm for cerebral fat embolism syndrome using these studies and with consideration of experimental therapies in select patients to prevent ongoing cerebral injury.

Extraction of total antioxidants from Azadirachta indica (neem) using three phase partitioning and its process intensification using ultrasound.

The majority of the naturally occurring antioxidants are obtained from plant sources. The antioxidant activity is mostly exhibited by polyphenols present in the plant cells. Azadirachta Indica (Neem) leaves are renowned for their medicinal applications due to their anti-inflammatory, antimalarial, antifungal, antibacterial, antiviral, antioxidant, and anticarcinogenic properties. This work aims to optimize the extraction of Azadirachta Indica (Neem) leaf antioxidants using three-phase partitioning (TPP). The optimized conditions are operating time 15 minutes, slurry ratio 1:30 (g/mL), salt concentration 30% (w/v), aqueous to solvent ratio 1:1.5 (v/v), and stirring speed 400 rpm that infer 74.66% extraction yield. Additionally, ultrasonic pretreatment was also employed to increase the extraction yield up to 86.61%. Sonication pretreatment for 4 min operated at 30 W power, and 75% duty cycle was observed to offer maximum antioxidant extraction about 3.3 mg/g.

Engineering Resistance Against Viruses in Field Crops Using CRISPR- Cas9.

Food security is threatened by various biotic stresses that affect the growth and production of agricultural crops. Viral diseases have become a serious concern for crop plants as they incur huge yield losses. The enhancement of host resistance against plant viruses is a priority for the effective management of plant viral diseases. However, in the present context of the climate change scenario, plant viruses are rapidly evolving, resulting in the loss of the host resistance mechanism. Advances in genome editing techniques, such as CRISPR-Cas9 [clustered regularly interspaced palindromic repeats-CRISPR-associated 9], have been recognized as promising tools for the development of plant virus resistance. CRISPR-Cas9 genome editing tool is widely preferred due to high target specificity, simplicity, efficiency, and reproducibility. CRISPR-Cas9 based virus resistance in plants has been successfully achieved by gene targeting and cleaving the viral genome or altering the plant genome to enhance plant innate immunity. In this article, we have described the CRISPR-Cas9 system, mechanism of plant immunity against viruses and highlighted the use of the CRISPR-Cas9 system to engineer virus resistance in plants. We also discussed prospects and challenges on the use of CRISPR-Cas9-mediated plant virus resistance in crop improvement.

Journey towards National Institute of One Health in India.

BACKGROUND & OBJECTIVES: Issues such as emerging and re-emerging infectious diseases, antimicrobial resistance, food security, biosafety and biosecurity are associated with changes in land use, population growth, urbanization, global travel and trade and climate change. As a result, a trans-disciplinary approach among human, animal and environmental health disciplines gained support. The Indian Council of Medical Research (ICMR) and Indian Council of Agricultural Research (ICAR) decided to establish a National Institute of One Health at Nagpur, Maharashtra, India. In this context, two collaborative research projects, funded by the ICAR and ICMR were initiated to conduct the epidemiological surveillance of selected zoonotic diseases in Central India. METHODS: Disease surveillance and molecular detection employing standard techniques like enzyme linked immunosorbent assay (ELISA), immuno-fluroscent assay (IFA), standard tube agglutination test (STAT) , Rose Bengal plate test (RBPT) and polymerase chain reaction (PCR) were undertaken based on the disease to be screened. RESULTS: In animals, the seropositivities for listeriosis (7.66%) and brucellosis (11.69%) were recorded. The occurrence of tuberculosis (3.8%) and leptospirosis (6.33%) was detected by PCR. Through cross-sectional studies from suspected human population with associated risk factors for zoonotic diseases, the seropositivity of brucellosis (1.83-11%), listeriosis (1.01-10.18 %), leptospirosis (8.14-12.67%) and scrub typhus (1.78-20.34%) was recorded. The investigations on scrub typhus indicated bimodal pattern during the months of pre-monsoon and post-monsoon season with a peak in post-monsoon in human cases. Ornithonyssus bacoti mites were identified from the rodents as a vector harbouring Orientia tsutsugamushi. The bovine tuberculosis was detected in 1.43 per cent human cases employing molecular assay. INTERPRETATION & CONCLUSIONS: The data indicated the occurrence of important zoonotic diseases adversely affecting the livestock health and human wellbeing. The scientific collaboration between veterinary and medical faculties has set an example for effective implementation of One Health (OH) programme for the establishment of National Institute of OH.

The prevalence, severity, and risk factors for dry eye disease in Dubai - a cross sectional study.

BACKGROUND: The prevalence of dry eye disease is increasing globally and requires the attention of healthcare professionals as it worsens patients' quality of life. No published studies on the epidemiology of dry eyes have been found in Dubai. PURPOSE: To describe the epidemiology, prevalence, severity, and associated factors of dry eyes in Dubai, United Arab Emirates, in 2019. METHODS: This was an analytical, cross-sectional, survey-based study. An online survey was distributed by email to Mohammed Bin Rashid University students, staff, and faculty and to the staff at Mediclinic City and Parkview Hospitals in Dubai, United Arab Emirates, from April-June 2019. The survey included demographic questions and the Ocular Surface Disease Index (OSDI). RESULTS: The survey was completed by 452 participants; the majority were females (288/452; 63.7 %). The prevalence of dry eyes in Dubai was estimated to be 62.6 % (283/452), with severely dry eyes being the most prevalent (119/283; 42 %). Females, high daily screen time (> 6 h), and the use of contact lenses were found to be associated with dry eyes (P-value < 0.05, 95 % confidence interval). Age was found to be negatively correlated with prevalence of dry eyes. Exposure to smoking/shisha, history of eye injury/surgery, and nationality were not associated with dry eyes. CONCLUSIONS: This is the first cross-sectional study to investigate the prevalence of dry eyes in Dubai (62.6 %). The majority of participants had severe dry eyes symptoms. Severely dry eyes were more common among females and users of contact lenses.

Robotic-assisted breast-axillo insufflation thyroidectomy (RABIT): a retrospective case series of thyroid carcinoma.

OBJECTIVE: To evaluate the feasibility and safety of robotic-assisted breast-axillo insufflation thyroidectomy (RABIT) for differentiated thyroid cancer. METHODS: In this retrospective case series, patients with differentiated thyroid carcinoma were enrolled in our hospital from January 2018 to December 2018. All patients underwent indirect laryngoscopy to assess the status of vocal cord preoperatively. RABIT was performed with five separate breast-axillo incisions. All the procedures were performed using da Vinci Xi Robotic Surgical System, a single docking method using CO2 insufflation. RESULTS: Twelve patients completed RABIT, in which one case needed conversion to open thyroidectomy. The mean age was 30.25 ± 7 with male to female ratio being 1:1. Preoperative diagnosis showed papillary carcinoma (n = 9) and follicular neoplasm (n = 3). The mean operative time for RABIT was 140 ± 50.45 min and average blood loss during surgery was 22.92 ± 9 mL. Mean hospital stay was 4.42 ± 1.08 days. Final pathology confirmed classical papillary thyroid carcinoma (n = 10; 83.3%) and follicular variant of papillary carcinoma (n = 2; 16.7%). None of the cases reported injury or paralysis to the recurrent laryngeal nerves. CONCLUSION: RABIT is a safe and feasible approach for thyroidectomy. It has several advantages in that it provides similar symmetrical view to conventional open surgery and enables to maintain specimen integrity and use of assistant port permits better handling of the gland. Additionally, the largest operating angles with this technique prevent collision between the robotic arms and provide excellent cosmetic satisfaction due to very small, five separate breast-axillo incisions.

In vitro apoptotic effect on human lymphatic filarial parasite by piperidine derivatives and thymidine reversal study.

A novel library of synthetic piperidine derivatives was used to screen against human lymphatic filarial parasite Brugia malayi. Piperidine has earlier been reported to have effect against parasites including rodent filarial nematodes. Compounds with hydroxyl substitutions (4Q and 4H) showed marked antifilarial effect. Molecular docking of 4H derivative showed more favorable thermodynamic parameters against thymidylate synthase of B. malayi than human counterpart. A wide difference between IC50 and LD50 ensured the therapeutic safety of the candidates against the filarial parasites. Addition of thymidine to the treatment regimen led to a significant reversal of antifilarial effect of 4H that confirmed inhibition of thymidylate synthase as pharmacological rationale. Apoptosis induced in the parasite as a consequence of probable inhibition of thymidylate synthase was studied by acridine orange/ethidium bromide fluorescent staining and poly (ADP-ribose) polymerase activity inhibition. Involvement of mitochondria was confirmed by decreased 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) conversion and increased cytosolic cytochrome c level in 4H treated microfilariae, compared with the untreated microfilariae. Moreover, Michael adduct of chalcone targeting dihydrofolate reductase and piperidine targeting thymidylate synthase demonstrated synergistic effect on the parasite, indicating the importance of inhibition of DNA synthesis by combined effect. In conclusion, piperidine derivatives with hydroxyl substitution have a great therapeutic potential with an apoptotic rationale involving mitochondrial pathway, due to possible inhibition of parasitic thymidylate synthase.

What Regions of the Distal Clavicle Have the Greatest Bone Mineral Density and Cortical Thickness? A Cadaveric Study.

BACKGROUND: Osteosynthesis of distal clavicle fractures can be challenging because of comminution, poor bone quality, and deforming forces at the fracture site. A better understanding of regional differences in the bone structure of the distal clavicle is critical to refine fracture fixation strategies, but the variations in BMD and cortical thickness throughout the distal clavicle have not been previously described. PURPOSE: /questions (1) Which distal clavicular regions have the greatest BMD? (2) Which distal clavicular regions have the greatest cortical thickness values? METHODS: Ten distal clavicle specimens were dissected from cadaveric shoulders. Eight specimens were female and two were male, with a mean (range) age of 63 years (59 to 67). The specimens were selected to match known epidemiology, as distal clavicular fractures occur more commonly in older patients with osteoporotic bone, and clavicular fractures in older patients are more common in females than males. The clavicles were then imaged using quantitative micro-CT to create 3-D images. The BMD and cortical thickness were calculated for 10 regions of interest in each specimen. These regions were selected to represent locations where distal clavicular fractures commonly occur and locations of likely bony comminution. Findings were compared between different regions using repeated measures ANOVA with Geiser-Greenhouse correction, followed by Bonferroni method multiple comparison testing. Effect size was also calculated to estimate the magnitude of difference between regions. RESULTS: The four most medial regions of the distal clavicle contained the greatest BMD (anterior intertubercle space 887 ± 31 mgHA/cc, posterior intertubercle space 879 ± 26 mgHA/cc, anterior conoid tubercle 900 ± 21 mgHA/cc, posterior conoid tubercle 896 ± 27 mgHA/cc), while the four most lateral regions contained the least BMD (anterior lateral distal clavicle 804 ± 32 mgHA/cc, posterior lateral distal clavicle 800 ± 38 mgHA/cc, anterior medial distal clavicle 815 ± 27 mgHA/cc, posterior medial distal clavicle 795 ± 26 mgHA/cc). All four most medial regions had greater BMD than the four most lateral regions, with p < 0.001 for all comparisons. For the BMD ANOVA, η was determined to be 0.81, representing a large effect size. The four most medial regions of the distal clavicle also had the greatest cortical thickness (anterior intertubercle space 0.7 ± 0.2 mm, posterior intertubercle space 0.7 ± 0.3 mm, anterior conoid tubercle 0.9 ± 0.2 mm, posterior conoid tubercle 0.7 ± 0.2 mm), while the four most lateral regions had the smallest cortical thickness (anterior lateral distal clavicle 0.2 ± 0.1 mm, posterior lateral distal clavicle 0.2 ± 0.1 mm, anterior medial distal clavicle 0.3 ± 0.1 mm, posterior medial distal clavicle 0.2 ± 0.1 mm). All four most medial regions had greater cortical thickness than the four most lateral regions, with p < 0.001 for all comparisons. For the cortical thickness ANOVA, η was determined to be 0.80, representing a large effect size. No differences in BMDs and cortical thicknesses were found between anterior and posterior regions of interest in any given area. CONCLUSIONS: In the distal clavicle, BMD and cortical thickness are greatest in the conoid tubercle and intertubercle space. When compared with clavicular regions lateral to the trapezoid tubercle, the BMD and cortical thickness of the conoid tubercle and intertubercle space were increased, with a large magnitude of difference. CLINICAL RELEVANCE: Distal clavicular fractures are prone to comminution and modern treatment strategies have centered on the use of locking plate technology and/or suspensory fixation between the coracoid and the clavicle. However, screw pullout or cortical button pull through are known complications of locking plate and suspensory fixation, respectively. Therefore, it seems intuitive that implant placement during internal fixation of distal clavicle fractures should take advantage of the best-available bone. Although osteosynthesis was not directly studied, our study suggests that the best screw purchase in the distal clavicle is available in the areas of the conoid tubercle and intertubercle space, as these areas had the best bone quality. Targeting these areas during implant fixation would likely reduce implant failure and strengthen fixation. Future studies should build on our findings to determine if osteosynthesis of distal clavicular fractures with targeted screw purchase or cortical button placement in the conoid tubercle and intertubercle space increase fixation strength and decreases construct failure. Furthermore, our findings provide consideration for novel distal clavicular locking plate designs with modified screw trajectories or refined surgical techniques with suspensory fixation implants to reliably capture these areas of greatest bone quality.