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Abstract Background In a previous study, we reported that selective dorsal root ganglion stimulation (DRGSTIM) at DRG level L4 promoted a favorable outcome for complex regional pain syndrome (CRPS) patients along with DRGSTIM-related changes of inflammatory biomarkers in blood and saliva. The impact on somatosensation is largely unknown. Herein, we assessed the quantitative sensory profile to quantify L4-DRGSTIM effects in CRPS patients. Methods Twelve refractory CRPS patients (4 female; 8 male; mean age 69 ± 9 years) received standardized quantitative sensory testing (QST) protocol at baseline and after 3 months of unilateral L4-DRGSTIM assessing nociceptive and non-nociceptive thermal and mechanical sensitivity of the knee affected by CRPS and the contralateral non-painful knee area. Results At baseline, CRPS subjects showed significantly increased thresholds for warmth, tactile and vibration detection (WDT, MDT and VDT) and exaggerated pain summation (WUR). After 3 months of unilateral L4-DRGSTIM all pain parameters exhibited trends towards normalization of sensitivity accumulating to a significant overall normalization for pain sensitivity (effect size: 0.91, p 0.40). Notably, reduction of pain summation (WUR) correlated significantly with pain reduction after 3 months of L4-DRGSTIM. Conclusions Selective L4-DRGSTIM lowered ongoing pain in CRPS patients and evoked significant normalization in the pain domain of the somatosensory profile. Thermoreception and mechanoreception remained unchanged. However, larger randomized, sham-controlled trials are highly warranted to shed more light on effects and mechanisms of dorsal root ganglion stimulation on quantitative sensory characteristics. The study protocol was registered at the 15.11.2016 on German Register for Clinical Trials (DRKS ID 00011267). https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00011267

Rafia Shafqat, Yadira Flores-Montanez, Victoria Delbono, Stephanie J Nahas Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USACorrespondence: Stephanie J Nahas 900 Walnut St., Suite 200, Philadelphia, PA 19107-5509, USATel +1 215 955 1960Fax +1 215 906 0335Email stephanie.nahas@jefferson.eduAbstract: Dihydroergotamine (DHE) is an ergot alkaloid derivative of substances produced by rye fungus. Ergotamine was first used in the field of gynecology and obstetrics, then used for migraine treatment a few years later. DHE was developed as a derivative of ergotamine. DHE, when compared to ergotamine, demonstrates greater alpha-adrenergic antagonist activity, lower arterial vasoconstriction, less dopaminergic agonism, and lower emetic potential. DHE can be delivered via several routes including intravenous (IV), intramuscular (IM), subcutaneous (SC), intranasal (IN), oral, and orally inhaled (although the latter two are not available in the USA and the last remains experimental only). DHE can be used in an outpatient basis in infusion centers, emergency departments, and urgent care centers, as well as inpatient treatment for admitted patients. There are protocols for adults as well as pediatric migraine treatment. DHE and other ergot alkaloids are considered contraindicated in pregnant women as they decrease uterine blood flow and increase uterine muscle contractility predisposing to spontaneous abortion. DHE during lactation is also not recommended as it can lead to gastrointestinal distress and weakness in infants; it can also suppress milk production. Caution should be taken before administering DHE in patients with cardiovascular risk factors. DHE is an older drug with an interesting history, yet it is still clinically useful today for patients with migraine attacks not responsive to triptans, who have a greater burden from migraine, and in refractory migraine.Keywords: ergotamine, rye fungus, pregnant, lactating, cardiovascular risk factors, infusion, inpatient, pediatric

Abstract Background In our recent clinical trial, increased peripheral concentrations of pro-inflammatory molecular mediators were determined in complex regional pain syndrome (CRPS) patients. After 3 months adjunctive unilateral, selective L4 dorsal root ganglion stimulation (L4-DRGSTIM), significantly decreased serum IL-10 and increased saliva oxytocin levels were assessed along with an improved pain and functional state. The current study extended molecular profiling towards gene expression analysis of genes known to be involved in the gonadotropin releasing hormone receptor and neuroinflammatory (cytokines/chemokines) signaling pathways. Methods Blood samples were collected from 12 CRPS patients for whole-transcriptome profiling in order to assay 18,845 inflammation-associated genes from frozen blood at baseline and after 3 months L4-DRGSTIM using PANTHER™ pathway enrichment analysis tool. Results Pathway enrichment analyses tools (GOrilla™ and PANTHER™) showed predominant involvement of inflammation mediated by chemokines/cytokines and gonadotropin releasing hormone receptor pathways. Further, screening of differentially regulated genes showed changes in innate immune response related genes. Transcriptomic analysis showed that 21 genes (predominantly immunoinflammatory) were significantly changed after L4-DRGSTIM. Seven genes including TLR1, FFAR2, IL1RAP, ILRN, C5, PKB and IL18 were down regulated and fourteen genes including CXCL2, CCL11, IL36G, CRP, SCGB1A1, IL-17F, TNFRSF4, PLA2G2A, CREB3L3, ADAMTS12, IL1F10, NOX1, CHIA and BDKRB1 were upregulated. Conclusions In our sub-group analysis of L4-DRGSTIM treated CRPS patients, we found either upregulated or downregulated genes involved in immunoinflammatory circuits relevant for the pathophysiology of CRPS indicating a possible relation. However, large biobank-based approaches are recommended to establish genetic phenotyping as a quantitative outcome measure in CRPS patients. Trial registration The study protocol was registered at the 15.11.2016 on German Register for Clinical Trials (DRKS ID 00011267). https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00011267

Abstract Background Rising evidence indicate that oxytocin and IL-1β impact trigemino-nociceptive signaling. Current perspectives on migraine physiopathology emphasize a cytokine bias towards a pro-inflammatory status. The anti-nociceptive impact of oxytocin has been reported in preclinical and human trials. Cervical non-invasive vagus nerve stimulation (nVNS) emerges as an add-on treatment for the preventive and abortive use in migraine. Less is known about its potential to modulate saliva inflammatory signaling in migraine patients. The rationale was to perform inter-ictal saliva measures of oxytocin and IL-1ß along with headache assessment in migraine patients with 10 weeks adjunctive nVNS compared to healthy controls. Methods 12 migraineurs and 12 suitably matched healthy control were studied with inter-ictal saliva assay of pro- and anti-neuroinflammatory cytokines using enzyme-linked immuno assay techniques along with assessment of headache severity/frequency and associated functional capacity at baseline and after 10 weeks adjunctive cervical nVNS. Results nVNS significantly reduced headache severity (VAS), frequency (headache days and total number of attacks) and significantly improved sleep quality compared to baseline (p

Preclinical as well as human studies indicate that melatonin is essential for a physiological sleep state, promotes analgesia and is involved in immunometabolic signaling by regulating neuroinflammatory pathways. Experimental and clinical neuromodulation studies for chronic pain treatment suggest that neurostimulation therapies such as spinal cord stimulation, vagus nerve stimulation and dorsal root ganglion stimulation have an impact on circulating inflammatory mediators in blood, cerebrospinal fluid and saliva. Herein, we provide an overview of current literature relevant for the shared pathways of sleep, pain and immunometabolism and elaborate the impact of melatonin on the crossroad of sleep, chronic pain and immunometabolism. Furthermore, we discuss the potential of melatonin as an adjunct to neurostimulation therapies. In this narrative review, we addressed these questions using the following search terms: melatonin, sleep, immunometabolism, obesity, chronic pain, neuromodulation, neurostimulation, neuroinflammation, molecular inflammatory phenotyping. So far, the majority of the published literature is derived from experimental studies and studies specifically assessing these relationships in context to neurostimulation are sparse. Thus, the adjunct potential of melatonin in clinical neurostimulation has not been evaluated under the umbrella of randomized-controlled trials and deserves increased attention as melatonin interacts and shares pathways relevant for noninvasive and invasive neurostimulation therapies.

Leptin has been recognized as a potential tumor growth promoter in various cancers including cranial tumor pathologies such as pituitary adenomas, meningiomas and gliomas. Despite recent advances in adjunctive therapy and the established surgical resection, chemo- and radiotherapy regimen, glioblastoma multiforme remains a particular diagnostic and therapeutic challenge among the intracranial tumor pathologies, with a poor long-term prognosis. Systemic inflammation and immune-metabolic signaling through diverse pathways are thought to impact the genesis and recurrence of brain tumors, and glioblastoma multiforme in particular. Among the various circulating mediators, leptin has gained especial diagnostic and therapeutic interest, although the precise relationship between leptin and glioblastoma biology remains largely unknown. In this narrative review (MEDLINE/OVID, SCOPUS, PubMed and manual searches of the bibliographies of known primary and review articles), we discuss the current literature using the following search terms: leptin, glioblastoma multiforme, carcinogenesis, immunometabolism, biomarkers, metformin, antidiabetic medication and metabolic disorders. An increasing body of experimental evidence implicates a relationship between the development and maintenance of gliomas (and brain tumors in general) with a dysregulated central and peripheral immune-metabolic network mediated by circulating adipokines, chemokines and cellular components, and in particular the leptin adipokine. In this review, we summarize the current evidence of the role of leptin in glioblastoma pathophysiology. In addition, we describe the status of alternative diagnostic tools and adjunctive therapeutics targeting leptin, leptin-receptors, antidiabetic drugs and associated pathways. Further experimental and clinical trials are needed to elucidate the mechanism of action and the value of immune-metabolism molecular phenotyping (central and peripheral) in order to develop novel adjunctive diagnostics and therapeutics for newly diagnosed and recurrent glioblastoma patients.

Chronic pain is a devastating condition affecting the physical, psychological, and socioeconomic status of the patient. Inflammation and immunometabolism play roles in the pathophysiology of chronic pain disorders. Electrical neuromodulation approaches have shown a meaningful success in otherwise drug-resistant chronic pain conditions, including failed back surgery, neuropathic pain, and migraine. A literature review (PubMed, MEDLINE/OVID, SCOPUS, and manual searches of the bibliographies of known primary and review articles) was performed using the following search terms: chronic pain disorders, systemic inflammation, immunometabolism, prediction, biomarkers, metabolic disorders, and neuromodulation for chronic pain. Experimental studies indicate a relationship between the development and maintenance of chronic pain conditions and a deteriorated immunometabolic state mediated by circulating cytokines, chemokines, and cellular components. A few uncontrolled in-human studies found increased levels of pro-inflammatory cytokines known to drive metabolic disorders in chronic pain patients undergoing neurostimulation therapies. In this narrative review, we summarize the current knowledge and possible relationships of available neurostimulation therapies for chronic pain with mediators of central and peripheral neuroinflammation and immunometabolism on a molecular level. However, to address the needs for predictive factors and biomarkers, large-scale databank driven clinical trials are needed to determine the clinical value of molecular profiling.

Abstract Mutations in PINK1 and Parkin cause early-onset Parkinson’s Disease (PD). PINK1 is a kinase which functions as a mitochondrial damage sensor and initiates mitochondrial quality control by accumulating on the damaged organelle. There, it phosphorylates ubiquitin, which in turn recruits and activates Parkin, an E3 ubiquitin ligase. Ubiquitylation of mitochondrial proteins leads to the autophagic degradation of the damaged organelle. Pharmacological modulation of PINK1 constitutes an appealing avenue to study its physiological function and develop therapeutics. In this study, we used a thermal shift assay with insect PINK1 to identify small molecules that inhibit ATP hydrolysis and ubiquitin phosphorylation. PRT062607, an SYK inhibitor, is the most potent inhibitor in our screen and inhibits both insect and human PINK1, with an IC50 in the 0.5–3 µM range in HeLa cells and dopaminergic neurons. The crystal structures of insect PINK1 bound to PRT062607 or CYC116 reveal how the compounds interact with the ATP-binding pocket. PRT062607 notably engages with the catalytic aspartate and causes a destabilization of insert-2 at the autophosphorylation dimer interface. While PRT062607 is not selective for PINK1, it provides a scaffold for the development of more selective and potent inhibitors of PINK1 that could be used as chemical probes.

Background: As humans are gifted by a defense system, Plants also possess a specialized system of defense that helps them to combat attacking microorganisms and harsh environmental conditions. This defense system is in the form of secondary metabolites that are present in the form of antimicrobial peptides. Antimicrobial peptides are specialized cysteine rich residues that play their marked protective role in plant defense systems. Material methods: In this study, we have extracted antimicrobial peptides from seeds and roots of three medicinal plants Ricinus communis, Cassia fistula, and Acacia nilotica. Extraction was carried out in two pharmaceutical buffers Tris NaCl and PBS buffer. Results: Results indicated that the extracts with PBS buffer without freeze thaw yield more concentrations of 2353 μg/ml, 1508 μg/ml, and 1553 μg/ml of proteins in Cassia fistula roots, Ricinus communis (seeds), and Cassia fistula (seeds) respectively. These concentrations were higher than the proteins extracted by Tris NaCl and PBS buffer with freeze thaw cycles. Conclusion: Extraction of these peptides from important medicinal plants and incorporating them in other plants with lesser immunity, can boost the immune system of receptive plants.

Objectives: To determine the efficacy of open versus closed negative pressure wound therapy for contaminated and dirty surgical wounds in terms of time duration to full wound healing. Study Design: Quasi-experimental study. Place and Duration of Study: Department of General Surgery, Combined Military Hospital, Quetta Pakistan, from Oct 2021 to Apr 2022. Methodology: A total of 96 patients with surgical wounds requiring repair were included for study. All patients underwent their respective surgery followed by grouping. Patients in Group-A received closed negative pressure wound therapy while those in Group-B received open negative pressure wound therapy. All patients were followed up till complete healing of the wound or till the occurrence of complications. Results: Our study sample had a mean age of 44.16±12.66 years, with a slight female preponderance of 51(53.1%) participants. The mean total healing time for closed negative pressure wound therapy was 17.35±6.95 days, while it was 42.00±16.21 days with open negative pressure wound therapy, (p0.05). Conclusion: Closed negative pressure wound therapy results in faster wound healing, with a similar complication rate as open negative pressure wound therapy.

Introduction: Fractures in the distal femur are quite rare, comprising around 0.4% of all fractures and 3% of femoral fractures. Managing distal femur fractures has been a subject of debate, but recent developments favor indirect reduction and minimally invasive approaches. The objective is to find a harmonious equilibrium between the mechanical stability of the fractured segments and their biological viability. Given their elevated complication rate, achieving optimal restoration of functional anatomy and ensuring stable fixation is imperative for prompt recovery from distal femoral fractures. Comparison of less invasive stabilization system versus dynamic condylar screw fixation in treatment of distal femur fractures is subject of ongoing debate as to which one is better. Aims and Objectives: To compare the functional and radiological outcomes of distal femur fractures treated with less invasive stabilization system versus dynamic condylar screw fixation. Place and Duration of study: A randomized clinical trial was conducted in the Orthopedic Department of Sheikh Zayed Hospital, Lahore, from July 2, 2020, to January 1, 2021. Material and Methods: A randomized clinical trial was conducted at Sheikh Zayed Hospital in Lahore over a six-month duration. In total 104 patients who fulfilled the inclusion criteria were admitted to the Orthopedic Department via Emergency and OPD. Demographic data and medical histories were taken. The sample size consisted of 52 patients in each group, with random allocation to either the LISS (A) or DCS (B) groups determined by a lottery method. Follow-up appointments were scheduled for all patients at one month, three months, and six months post-surgery. Radiological outcome was evaluated at each follow-up visit while functional outcome assessed at sixth monthly follow up. Data analysis was performed using the SPSS: version 22, considering p ? 0.05 as significant. Results: Frequency of functional outcome was i.e. excellent (32.7%), good (14.4%), fair (2.9%) in group A and excellent (27.9%), good (31.7%), fair (7.7%) in group B (p-value>0.05). Mean fusion time was 18.67±3.04 in group A and 19.62±4.36 in group B (p-value>0.05). Conclusion: Our findings indicate no substantial distinction between the two groups. Using DCS or LISS, both methods yield favorable outcomes with negligible complications in the management of distal femoral fractures. Both systems effectively reduce soft tissue injury.

Abstract The past 10 years have seen remarkable progress in our capability of analyzing reflection features in the X-ray spectra of accreting black holes. Today X-ray reflection spectroscopy is a mature technique and a powerful tool for studying the accretion process around black holes, measuring black hole spins, and testing Einstein’s theory of General Relativity in the strong field regime. However, current reflection models still rely on a number of simplifications and caution is necessary when we derive very precise measurements. In this paper, we study the impact of the returning radiation on our capability of measuring the properties of black holes using X-ray reflection spectroscopy, and in particular on our capability of testing the Kerr black hole hypothesis. While the returning radiation alters the reflection spectrum of the disk, from the analysis of our simulations we find that models without returning radiation can normally recover well the correct black hole spin parameters and can test the Kerr metric.

This study undertakes an investigation into the fatigue life of carbon steel specimens with opposite semicircular edge notches using a combined approach based on experimental and numerical analysis. The study emphasises the determination of stress concentration factors (SCFs) for these notches based on S-N curves of carbon steel, employing a comprehensive method to evaluate their impacts on fatigue performance. Both experimental and numerical methods are applied to understand the influence of notches on fatigue characteristics, yielding insights into potential failure modes and opportunities for design enhancement. The research deepens our comprehension of fatigue mechanics in carbon steel structures, offering valuable perspectives regarding structural engineering and design refinement. The outcomes highlight the significance of integrating experimental testing and numerical simulations to carry out an exhaustive investigation of fatigue behaviour in notched specimens.

We present a new model to calculate reflection spectra of thin accretion disks in Kerr spacetimes. Our model includes the effect of returning radiation, which is the radiation that is emitted by the disk and returns to the disk because of the strong light bending near a black hole. The major improvement with respect to the existing models is that it calculates the reflection spectrum at every point on the disk by using the actual spectrum of the incident radiation. Assuming a lamppost coronal geometry, we simulate simultaneous observations of NICER and NuSTAR of bright Galactic black holes and we fit the simulated data with the latest version of relxill (modified to read the table of reflionx , which is the nonrelativistic reflection model used in our calculations). We find that relxill with returning radiation cannot fit well the simulated data when the black hole spin parameter is very high and the coronal height and disk’s ionization parameter are low, and some parameters can be significantly overestimated or underestimated. We can find better fits and recover the correct input parameters as the value of the black hole spin parameter decreases and the value of the coronal height increases.

Abstract Bumblebee gravity is one of the simplest gravity theories with spontaneous Lorentz symmetry breaking. Since we know a rotating black hole solution in bumblebee gravity, we can potentially test this model with the available astrophysical observations of black holes. In this work, we construct a reflection model in bumblebee gravity and we use our model to analyze the reflection features of a NuSTAR spectrum of the Galactic black hole EXO 1846-031 in order to constrain the Lorentz-violating parameter $$\ell $$ ℓ . We find that the analysis of the reflection features in the spectrum of EXO 1846-031 cannot constrain the parameter $$\ell $$ ℓ because of a very strong degeneracy between the estimates of $$\ell $$ ℓ and of the black hole spin parameter $$a_*$$ a ∗ . Such a degeneracy may be broken by combining other observations.

Objective: To compare the outcomes of early versus delayed postoperative oral feeding in patients undergoing resection and anastomosis of the gut. Study Design: Quasi-experimental study Place and Duration of Study: Surgical Department of Pak Emirates Military Hospital, Rawalpindi Pakistan, from Jun 2020 to May 2021. Methodology: A total of 30 patients fulfilling the selection criteria were enrolled after taking written informed consent and were randomly divided into two groups of equal numbers. Patients in Group-A received early oral feeding, and in Group-B had delayed oral feeding postoperatively, and the outcome measures were assessed till the patients were discharged. Results: The mean duration of hospital stay in Group-A versus Group-B was 50.94 days vs. 60.74 days (p=0.005), the mean time to passage of the first flatus was 30.61 days vs. 50.48 days (p

Proteins are the second most essential macromolecules after nucleic acids. This article aimed at the comparative analysis of extraction methods and nutritional benefits of milk and dairy products. Proteins form the body mass and perform several crucial tasks that include acting as a catalyst and carrying out different metabolic reactions in the body. Furthermore, protein acts as a transporter, transmits nerve impulses, provides mechanical support or immune protection, and controls growth. Several sources of proteins are present, but milk holds an important place due to its biological activities. The considerable health benefits of milk and its products are due to proteins. Yoghurt and cheese have significant importance among milk products. Proteins of milk and its products can be extracted by pH adjustment through homogenisation, centrifugation, and deproteinisation. There are several techniques for identifying and quantifying milk and product proteins. The Kjeldahl and spectrophotometric methods are the most widely used methods for quantifying proteins in milk and its products. Furthermore, these techniques include electrophoresis and chromatographic methods, including native gel electrophoresis, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), urea-PAGE, capillary electrophoresis, and isoelectric focusing. A few are chromatographic methods like reverse-phase high-performance liquid chromatography (RP-HPLC), size exclusion chromatography, and ion-exchange chromatography. Each technique has its advantages as well as disadvantages. The selection of the process depends upon the type of protein. The extracted proteins from milk and its products have many health or therapeutic effects that exhibit antimicrobial, antiproliferative, antioxidant, antihypertensive, anticancer, antiviral, and immunomodulatory effects. Yoghurt has prime importance among milk products because of its therapeutic effects and more protein.

Objective: To determine the diagnostic accuracy of Barium contrast enema for diagnosis of Hirsch-sprung disease, taking histopathology as the gold standard. Study Design: Cross-sectional validation study. Place and Duration of Study: Department of Paediatric Surgery, Pak Emirates Military Hospital, Rawalpindi Pakistan, from Nov 2019 to May 2021. Methodology: A total of 251 patients with symptoms of Hirsch-sprung disease were included. All patients were assessed with a Barium enema and full-thickness rectal biopsy. Barium enema was reported for the presence of contrast in the rectum after 24 hours, the presence or absence of transitional zone and a Recto Sigmoid Index less than 1. Full-thickness rectal biopsy was taken 2 cm above the dentate line, and histopathology was performed to see the ganglion cells in Meissner`s and Myenteric plexus. Results: Histo-pathologically confirmed cases were 120(true positive), where 12(false positive) had no Hirsch-sprung disease on histopathology. In Barium enema negative patients, 113 were true negatives while 06 were false negatives. Overall sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy of Barium contrast enema for diagnosis of Hirsch-sprung disease were 95.24%, 90.40%, 90.91%, 94.96% and 92.83%, respectively. Conclusion: We concluded that the diagnostic accuracy of Barium contrast enema for diagnosis of Hirsch-sprung disease is quite high, taking histopathology as the gold standard.

Green synthesis of metallic nanoparticles is an auspicious method of preparing nanoparticles using plant extracts that have lesser toxicity to animal cells and the host. In the present work, we analyzed the antibacterial activity of Citrullus colocynthis and Psidium guajava-mediated silver nanoparticles (Cc-AgNPs and Pg-AgNPs, respectively) against Aeromonas hydrophila (A. hydrophila) in an in vivo assay employing Labeo rohita (L. rohita). L. rohita were divided into six groups for both Cc-AgNPs and Pg-AgNPs treatments separately: Control, A. hydrophila infected, A. hydrophila + Ampicillin, A. hydrophila + Cc/Pg-AgNPs (25 µg/L), A. hydrophila + Cc/Pg-AgNPs (50 µg/L), and A. hydrophila + Cc/Pg-AgNPs (75 µg/L). Changes in different bio-indicators such as hematological, histological, oxidative stress, and cytokine analysis were observed. Interestingly, the infected fish treated with both types of AgNPs (Cc-AgNPs and Pg-AgNPs) exhibited a higher survival rate than the untreated infected fish and demonstrated signs of recovery from the infection, providing a compelling indication of the positive impact of phytosynthesized AgNPs. Disruptions in hematological and histological parameters were found in the infected fish. Both Cc-AgNPs and Pg-AgNPs showed recovery on the hematological and histological parameters. Analysis of oxidative stress and cytokine markers also revealed provoking evidence of the positive impact of Cc-AgNPs and Pg-AgNPs treatment against disease progression in the infected fish. The major finding of the study was that the higher concentrations of the nanoparticles (50 µg/L in the case of Cc-AgNPs and 75 µg/L in the case of Pg-AgNPs) were more effective in fighting against disease. In conclusion, our work presents novel insights for the use of green-synthesized AgNPs as economic and innocuous antibacterial candidates in aquaculture.

Polyvinyl Alcohol (PVA) is frequently applied as a support material in 3D printing, especially in the crafting of intricate designs and projecting elements. It functions as a water-soluble filament, often paired with materials like ABS or PLA. PVA serves as a momentary scaffold, supporting the jutting segments of a 3D model throughout the printing process. Subsequent to printing, the primary component can be effortlessly isolated by dissolving the PVA support using water. PVA, being a pliable and eco-friendly polymer, is susceptible to moisture. Its aqueous solubility renders it a prime selection for bolstering 3D print structures. In this investigation, equivalent-sized samples were 3D printed utilizing an Ultimaker 3D printer to assess the potency of PVA-generated specimens. Tensile examinations were executed on each sample employing a testing apparatus. The durability of the specimens was notably impacted by the input parameters, specifically the stratum width and stratum thickness. Strength dwindled as stratum width increased, whereas it rose with augmented stratum thickness. A few specimens with heightened stratum width and compromised quality displayed subpar performance during the tensile assessment. The findings unveiled a peak tensile strength of 17.515 MPa and a maximum load of 1600 N. Attaining an optimal degree of material utilization led to a decrease in filament consumption by 8.87 g, all the while upholding a MTS (maximum tensile strength) of 10.078 MPa.

The present study reports the green synthesis of silver nanoparticles from leaves’ extract of Mangifera indica (M. indica) and their antibacterial efficacy against Aeromonas hydrophila (A. hydrophila) in Cirrhinus mrigala (C. mrigala). The prepared M. indica mediated silver nanoparticles (Mi-AgNPs) were found to be polycrystalline in nature, spherical in shapes with average size of 62 ± 13 nm. C. mrigala (n = ±15/group) were divided into six groups i.e., G1: control, G2: A. hydrophila challenged, G3: A. hydrophila challenged + Mi-AgNPs (0.01 mg/L), G4: A. hydrophila challenged + Mi-AgNPs (0.05 mg/L), G5: A. hydrophila challenged + Mi-AgNPs (0.1 mg/L) and G6: A. hydrophila challenged + M. indica extract (0.1 mg/L). Serum biochemical, hematological, histological and oxidative biomarkers were evaluated after 15 days of treatment. The liver enzyme activities, serum proteins, hematological parameters and oxidative stress markers were found to be altered in the challenged fish but showed retrieval effects with Mi-AgNPs treatment. The histological analysis of liver, gills and kidney of the challenged fish also showed regaining effects following Mi-AgNPs treatment. A CFU assay from muscle tissue provided quantitative data that Mi-AgNPs can hinder the bacterial proliferation in challenged fish. The findings of this work suggest that M. indica based silver nanoparticles can be promising candidates for the control and treatment of microbial infections in aquaculture.

Abstract Aneurysmal subarachnoid hemorrhage (SAH) is associated with high morbidity and mortality. Devastating post-SAH complications, such as cerebral vasospasm (CVS), delayed cerebral ischemia or seizures to mention a few, are mainly responsible for the poor clinical outcome. Inflammation plays an indispensable role during early brain injury (EBI) and delayed brain injury (DBI) phases over which these complications arise. T helper cells are the major cytokine secreting cells of adaptive immunity that can polarize to multiple functionally unique sub-populations. Here, we investigate different CD4+ T cell subsets during EBI and DBI phases after SAH, and their dynamics during post-SAH complications. Peripheral venous blood from 15 SAH patients during EBI and DBI phases, was analyzed by multicolour flowcytometry. Different subsets of CD3+ CD4+ T cells were characterized by differential cell surface expression of CXCR3 and CCR6 into Th1, Th2, Th17, whereas Tregs were defined by CD25hiCD127lo. The analysis of activation states was done by the expression of stable activation markers CD38 and HLA-DR. Interestingly, compared to healthy controls, Tregs were significantly increased during both EBI and DBI phases. Different activation states of Tregs showed differential significant increase during EBI and DBI phases compared to controls. HLA-DR− CD38+ Tregs were significantly increased during DBI phase compared to EBI phase in SAH patients developing CVS, seizures and infections. However, HLA-DR− CD38− Tregs were significantly reduced during EBI phase in patients with cerebral ischemia (CI) compared to those without CI. HLA-DR− CD38− Th2 cells were significantly increased during EBI phase compared to controls. A significant reduction in Th17/Tregs and HLA-DR− CD38+ Th17/Tregs ratios was observed during both EBI and DBI phases compared to controls. While HLA-DR− CD38− Th17/Tregs and HLA-DR− CD38− Th1/Th2 ratios were impaired only during EBI phase compared to controls. In conclusion, CD4+ T cell subsets display dynamic and unique activation patterns after SAH and during the course of the manifestation of post-SAH complications, which may be helpful for the development of precision neurovascular care. However, to claim this, confirmatory studies with larger patient cohorts, ideally from different ethnic backgrounds, are required. Moreover, our descriptive study may be the grounds for subsequent lab endeavors to explore the underlying mechanisms of our observations.

Biofilm is a structured conglomeration of bacteria entrenched in a polymer matrix that is self-produced and contains DNA, polysaccharide, protein, and cause chronic infections. Pseudomonas aeruginosa lung infection is one of the well stated examples of pathogenic biofilms in cystic fibrosis patients. Due to mutating nature of the pathogens high antibiotic resistance will develop that make antibiotic treatment ineffective against repeated infections that are related to indwelling medical devices. Normally it was considered that nanoparticles are not larger than 100 nm, and their development to fight infection has gained popularity over the several decades. Different types of nanoparticles were introduced to treat biofilm infections in which silver nanoparticles were considered to be more efficient than all others. Maximum zone of inhibition in case of silver nanoparticles was found to be 40 mm against S.aureus, whereas maximum zone of inhibition with ZnO nanoparticles was 16 mm against Campylobacter jejuni, while in case of selenium nanoparticles and iron oxide nanoparticles zone of inhibition was time dependent and concentration dependent respectively. The order of antibacterial activity was like that Ag-Np>ZnO>CuO>Fe2O3. In this review article we discussed different biofilm producing pathogens that were isolated from different locations in latest research and to evaluate the role of nanoparticles in eradicating these pathogenic microbes.

Objective: To compare the incidence of post dural puncture headache with pencil point 25 gauge Whitacre verse cutting 25 gauge Quincke spinal needle in patients for C section under spinal anaesthesia. Study Design: Randomized controlled trial. Place and Duration of Study: Operation Theatre, Department of Anaesthesia, Combined Military Hospital Lahore, from Nov 2015 to May 2016. Methodology: All patients with ASA status-I or II, undergoing elective C section surgeries were included in the study. Patients assigned to Group W was administered spinal anesthesia by using 25 gauge Whitacre pencil point needle at the level of L3,L4 space while patients assigned to Group Q was administered spinal anesthesia by using 25 gauge Quincke needle at the level of L3, L4 space. Patients were observed for PDPH in the recovery room and then in the ward 6 hourly till 72 hours. All the data was entered and analyzed on SPSS version 10. Results: In our study the mean age of the patients was 24.29 ± 3.78 years. The PDPH was observed in 33 (19.41%) patients. The mean value of VRS score after 6th hour was 2.92 ± 2.29, after 12th hour its mean value was 2.93 ± 2.28, its mean value after 18th hour was 2.93 ± 2.29 and the mean value of VRS after 24th hour was 3 ± 2.35, the mean value of VRS score after 36th hour was 2.93 ± 2.385, after 48th hour its mean value was 2.89 ± 2.269..........

Mutations in Parkin and PINK1 cause early-onset familial Parkinson's disease. Parkin is a RING-In-Between-RING E3 ligase that transfers ubiquitin from an E2 enzyme to a substrate in two steps: (i) thioester intermediate formation on Parkin and (ii) acyl transfer to a substrate lysine. The process is triggered by PINK1, which phosphorylates ubiquitin on damaged mitochondria, which in turn recruits and activates Parkin. This leads to the ubiquitination of outer mitochondrial membrane proteins and clearance of the organelle. While the targets of Parkin on mitochondria are known, the factors determining substrate selectivity remain unclear. To investigate this, we examined how Parkin catalyses ubiquitin transfer to substrates. We found that His433 in the RING2 domain contributes to the catalysis of acyl transfer. In cells, the mutation of His433 impairs mitophagy. In vitro ubiquitination assays with isolated mitochondria show that Mfn2 is a kinetically preferred substrate. Using proximity-ligation assays, we show that Mfn2 specifically co-localizes with PINK1 and phospho-ubiquitin (pUb) in U2OS cells upon mitochondrial depolarization. We propose a model whereby ubiquitination of Mfn2 is efficient by virtue of its localization near PINK1, which leads to the recruitment and activation of Parkin via pUb at these sites.

Hereditary Multiple Exostoses is a skeletal dysplasia that is very rare and defined by formation of numerous cartilage capped benign tumours either pedunculated or sessile known as osteochondromas throughout skeleton especially around the growth plates of ribs, vertebrae, pelvis and long bones. Rarely it can present forearm problems such bowing deformity of radius, ulnar shortening and radiocapitellar dislocation or subluxation. We are presenting a case of 20 year old female who presented with left distal ulnar exostosis resulting in ulnar shortening and radial bowing with restricted supination and pronation range of movement. Other complaint was of multiple non tender bony hard lumps in both upper and lower limbs. Excision of distal ulnar exostosis was done which resulted in marked improvement in pronation and supination range of movement. Hereditary multiple exostoses with forearm deformities though very rare but can present and the treatment is conservative except if any bony swelling manifests any complications such as pain or associated deformity.

Abstract Background There are conflicting data regarding the risk of hepatocellular carcinoma (HCC) after direct-acting antiviral agent (DAA) treatment. Risk of HCC in HCV genotype-3 infected persons after DAA therapy is not well known. Methods We prospectively studied HCV infected persons initiated on a DAA regimen between October 2014 and March 2017 at two centers in Pakistan. All persons were free of HCC at study initiation. HCC was confirmed based on characteristic CT scan findings. Patients were followed for 12 months after the completion of therapy. Results A total of 662 persons initiated treatment. Median age (IQR) was 50 (41, 57) years and 48.8% were male. At baseline, 49.4% were cirrhotic, 91% were genotype 3 and 91.9% attained SVR. Treatment regimens used were: Sofosbuvir (SOF)/ribavirin (RBV)/pegylated interferon (PEG-IFN), 25.2%; SOF/RBV, 62.4%; SOF/RBV/daclatasavir (DCV), 10.6%; SOF/DCV, 2.0%. Incident HCC was detected in 42 patients (12.8%) in the 12-month period after treatment completion and was exclusively observed in those with cirrhosis. In multivariable Cox regression analysis, SVR was associated with a reduction in HCC risk (HR, 95% CI: 0.35, 0.14,0.85). In Kaplan-Meier plots by treatment regimen, those treated with SOF/RBV, SOF/RBV/DCV, or SOF/DCV regimens had a shorter HCC-free survival compared with those treated with a SOF/RBV/PEG-IFN regimen. Conclusion In a predominantly genotype 3 cohort, incident HCC occurred frequently and early after treatment completion, and exclusively in those with pre-treatment cirrhosis. SVR reduced the risk of HCC. Treating HCV infected persons before development of cirrhosis may reduce risk of HCC.

The present study investigated the biomedical potential of eco-friendly Citrullus colocynthis-mediated silver nanoparticles (Cc-AgNPs). The antibacterial efficacy of Cc-AgNPs was evaluated against two multidrug-resistant pathogenic bacterial strains, Escherichia coli and Pseudomonas aeruginosa. The antiproliferative and antilipidemic performance of the prepared particles was determined against the MCF7 cell line, a breast cancer cell line. The in vitro antibacterial assay revealed that Cc-AgNPs induced dose-dependent bactericidal activity, as a considerable increase in the zone of inhibition (ZOI) was noted at higher concentrations. Reduced proliferation, migration, spheroid size, and colony formation exhibited the substantial antiproliferative potential of Cc-AgNPs against MCF7 cells. Significant alterations in the expression of cell surface markers, apoptosis, and cell proliferation genes further confirmed the antiproliferative impact of Cc-AgNPs. Moreover, Cc-AgNPs exhibited antilipidemic activity by reducing cellular cholesterol and triglyceride levels and regulating key genes involved in lipogenesis. In conclusion, these results propose that Cc-AgNPs can be employed as a potent tool for future antibacterial and anticancer applications

Aneurysmal subarachnoid hemorrhage (aSAH), resulting majorly from the rupture of intracranial aneurysms, is a potentially devastating disease with high morbidity and mortality. The bleeding aneurysms can be successfully secured; however, the toxic and mechanical impact of the blood extravasation into the subarachnoid space damages the brain cells leading to the release of different damage-associated molecular pattern molecules (DAMPs). DAMPs upregulate the inflammation after binding their cognate receptors on the immune cells and underlies the early and delayed brain injury after aSAH. Moreover, these molecules are also associated with different post-aSAH complications, which lead to poor clinical outcomes. Among these DAMPs, HMGB1 represents a prototypical protein DAMP that has been well characterized for its proinflammatory role after aSAH and during different post-aSAH complications. However, recent investigations have uncovered yet another face of HMGB1, which is involved in the promotion of brain tissue remodeling, neurovascular repair, and anti-inflammatory effects after SAH. These different faces rely on different redox states of HMGB1 over the course of time after SAH. Elucidation of the dynamics of these redox states of HMGB1 has high biomarker as well as therapeutic potential. This review mainly highlights these recent findings along with the conventionally described normal role of HMGB1 as a nuclear protein and as a proinflammatory molecule during disease (aSAH).

Aneurysmal subarachnoid hemorrhage (aSAH) is a highly fatal and morbid type of hemorrhagic strokes. Intracranial aneurysms (ICAs) rupture cause subarachnoid hemorrhage. ICAs formation, growth and rupture involves cellular and molecular inflammation. Macrophages orchestrate inflammation in the wall of ICAs. Macrophages generally polarize either into classical inflammatory (M1) or alternatively-activated anti-inflammatory (M2)-phenotype. Macrophage infiltration and polarization toward M1-phenotype increases the risk of aneurysm rupture. Strategies that deplete, inhibit infiltration, ameliorate macrophage inflammation or polarize to M2-type protect against ICAs rupture. However, clinical translational data is still lacking. This review summarizes the contribution of macrophage led inflammation in the aneurysm wall and discuss pharmacological strategies to modulate the macrophageal response during ICAs formation and rupture.

High yielding varieties were introduced to overcome the problem of food insecurity. Net returns of hybrid and conventional varieties of rice were analyzed in the present study. The sample size of 120 respondents from farming community of tehsil Bhowana was selected to get information. The gross returns per acre for hybrid, basmati and irri rice were calculated to be 77973.97, 55602.15 and 49077.23 rupees respectively. The total costs per acre for hybrid, basmati and irri rice were calculated to be 48506.34, 39391.87 and 37394.97 rupees respectively. The net returns per acre for hybrid, basmati and irri rice were 29467.63, 16210.28 and 11682.26 rupees respectively. The average value of rice varietal diversity index for small, medium and large farmers was estimated to be 0.2172, 0.3943 and 0.5589 respectively. Government and policy maker should start some programs for training of farmers, in selected areas. The model plots should be introduced and on those plots state of art technologies and skills should be employed practically. [ABSTRACT FROM AUTHOR]