Study of paraCEST response on six-coordinated Co(II) and Ni(II) complexes of a pyridine-tetraamide-based ligand.

This study highlights the successful synthesis of a potential ligand, 2,2',2'',2'''-((pyridine-2,6-diylbis(methylene))bis(azanetriyl))tetraacetamide (PATA), along with its corresponding Co(II) and Ni(II) complexes for paraCEST-based agents. X-ray diffraction data confirmed that both the complexes are six coordinated with distorted octahedral geometries, but only the [Co(PATA)]2+ complex has a good structural feature to show paraCEST activity. After a thorough characterization of the ligand and both of its complexes, various studies, including solution-state magnetic properties, redox properties, temperature, and pH variation studies, were carried out. [Co(PATA)]2+ remained inert in the presence of competing ions, under acidic conditions, at high temperatures, and in the physiological pH range. The paraCEST response of [Co(PATA)]2+ has been measured in the presence of HEPES buffer medium, and a high paraCEST feature was discovered at both 37 and 25 °C. The pH variation paraCEST studies were carried out and the exchange rate constant of the probe at 37 and 25 °C was also determined. However, due to the fast exchange of water protons, the [Ni(PATA)(OH2)]2+ complex remained inactive in the CEST process.

Nuances in Growing Rod Surgery: Our Initial Experience and Literature Review.

Introduction: Growing rod construct is one of the most widely acknowledged treatment modalities for early-onset scoliosis around the world, but it is not without complications. Throughout the course of treatment, numerous planned and inadvertent surgical interventions are required, which increase the complexity of the treatment. We share our experience with case examples along with extensive literature search and review to get an insight and document the complications with growing rod treatment. Case Report: These cases underwent surgery with dual growing rod for thoracolumbar idiopathic scoliosis in the view of failed conservative treatment and progressive deformity. Superficial infection is in one case and recurrence of deformity was a common finding though correction of deformity and final fusion was achieved in the cases. Breakage of screws, autofusion of the spanned segments, and profuse bony growths over the implants are common finding to get. Fibrosis and scar tissue from the previous surgeries result in difficulty in the exposure and performing corrective osteotomy. Conclusion: Growing rod surgery has high complication rates. Repeated surgical and anesthesia exposure pose a great risk to the body and immature skeleton of the young patient. Previous studies have put forth many possible course of action to lower down the complication rates but have met with variable results. A better implant design and surgical efficacy are needed to cut down the number of complications and surgical interventions in growing rod surgeries.

Current standards of surgical management of gastric cancer: an appraisal.

PURPOSE: Gastric cancer (GC) is the fifth most common malignancy worldwide and portends a grim prognosis due to a lack of appreciable improvement in 5-year survival. We aimed to analyze the available literature and summarize the current standards of surgical care for curative and palliative intent treatment of GC. METHODS: We conducted a systematic search on the PubMed database for studies on the management of GC. RESULTS: Endoscopic resection is an acceptable treatment option for T1a tumors. The role of optimal resection margin for GC remains unclear. D2 lymph node dissection remains the standard of care with splenectomy needed selectively for splenic hilum involvement. A distal pancreatic resection should be avoided. The advantage of bursectomy and omentectomy in GC surgery is not clear. Multi-visceral resection may be considered for locally advanced GC in carefully selected patients. Minimally invasive approaches are non-inferior to open surgery. Surgery should be abandoned prior even in metastatic GC within the frame of multimodal therapy approach. CONCLUSION: Various trials have conclusively shown improved patient outcomes when well-established surgical standards are followed.

Predictors of Postoperative Outcome in Emergency Laparotomy for Perforation Peritonitis; a Retrospective Cross-sectional Study.

Introduction: Hollow viscus perforation is a significant cause of surgical mortality. Various attempts have been made to identify high-risk patients preoperatively and optimize and manage such patients more aggressively. This study aimed to evaluate the predictors of outcome in patients undergoing emergency laparotomy for perforation peritonitis. Methods: This retrospective cross-sectional study was conducted on perforation peritonitis cases admitted to the Department of General Surgery, All India Institute of Medical Sciences, Rishikesh, India. The association between preoperative patient variables with postoperative complications, anastomotic leaks, need for intensive care unit (ICU) admission, and 30-day mortality were evaluated. Results: Tachycardia at the time of admission (t = 2.443, p = 0.020), hypotension (χ2 = 18.214, p = <0.001), lower haemoglobin (t = -4.134, p = <0.001), higher blood urea nitrogen levels (W = 1967.000, p = 0.012), International Normalised Ratio (INR) ≥ 1.5 (χ2 = 17.340, p = <0.001), the mean albumin level 2.89 ± 0.77 g/dL (t = -2.348, p = 0.027), and delay in surgery (χ2 = 28.423, p = 0.008) were significant associate factors of mortality. The association between need for ICU admission and higher pulse rate on admission (W = 2782.500, p = 0.011), lower systolic blood pressure (W = 1627.500, p = 0.029), higher blood urea nitrogen (W = 2299.000, p = 0.030) and serum creatinine levels (W = 2192.500, p = 0.045), preoperative coagulopathy (χ2 = 6.773, p = 0.017), hypoalbuminemia (t = -2.515, p = 0.016), and delay in surgery (χ2 = 17.780, p = 0.016) was significant. Conclusion: Based on the results of this study, hypotension, azotaemia, coagulopathy, and delay in surgery, increase the risk of postoperative mortality of patients undergoing emergency laparotomy for perforation peritonitis. Tachycardia, hypotension, azotaemia, hypoalbuminemia, and pre-operative coagulopathy were good predictors of need for ICU admission. Shock at presentation, deranged renal function and coagulopathy were associated with an increased risk of postoperative complications.

Constant score in asymptomatic shoulders varies with different demographic populations: derivation of adjusted score equation.

BACKGROUND: In the present study, the age- and sex-adjusted Constant score (CS) in a normal Indian population was calculated and any differences with other population cohorts assessed. METHODS: The study participants were patients who visited the outpatient department for problems other than shoulder and healthy volunteers from the local population. Patients without shoulder pain/discomfort during activity were included in the study. Subjects with any problem that might affect shoulder function (e.g., cervical, thoracic spine, rib cage deformity, inflammatory arthritis) were excluded. Constant scoring of all participants was performed by trained senior residents under the supervision of the senior faculty. Shoulder range of movement and strength were measured following recommendations given by the research and Development Committee of the European Society for Shoulder and Elbow Surgery (2008). A fixed spring balance was used for strength measurement; one end was fixed on the floor and the other end tied with a strap to the wrist of the participant, arm in 90° abduction in scapular plane with palm facing down. RESULTS: Among the 248 subjects (496 shoulders), the average age was 37 years (range, 18-78 years), 65.7% were males (326 shoulders) and 34.3% females (170 shoulders). The mean CS was 84.6±2.9 (males, 86.1±3.0; females, 81.8±2.9). CS decreased significantly after 50 years of age in males and 40 years of age in females (p<0.05). The mean CS was lower than in previous studies for both males and females. Heavy occupation workers had higher mean CS (p<0.05). A linear standardized equation was estimated for calculating the adjusted CS for any age. CONCLUSIONS: Mean CS and its change with age differed from previous studies among various population cohorts.

Sequential Imaging Characteristics and Potential Role of F18 Fluorodeoxyglucose Positron Emission Tomography/CT in the Evaluation of Treatment Response in Cases of Spinal Tuberculosis Without Neurological Involvement: Results From a Pilot Study.

Purpose In this non-randomized study, we prospectively studied the sequential imaging properties of fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) and evaluated the role of FDG PET as a non-invasive imaging modality for identifying non-responders during anti-tubercular treatment (ATT) of spinal tuberculosis (TB). Methods Before starting anti-tubercular treatment, 25 patients with clinically and radiological suspected; pathologically confirmed spinal TB had a pretreatment contrast-enhanced whole-body FDG PET scan, followed by scans at six, 12, and 18 months. The maximum standardized uptake value (SUVmax) was computed, and the mean change in SUVmax was compared. The mean change in SUVmax was correlated with the clinicoradiological improvement.  Result In cases of spinal tuberculosis, the FDG PET scan can help identify extra-spinal and non-contagious involvement. In our 25 cases of spinal TB, the baseline peak SUVmax of lesions ranged from 6.3 to 28.5 (mean 14.8). Despite treatment, the condition progressed in two patients, and they had neurological deficits; in both cases, the SUVmax levels increased. The fall in SUVmax during the treatment course was statistically significant (p-value <0.05) and correlated well with the clinical improvement. Conclusion The inflammatory cells show increased uptake of F18 FDG, so uptake of radioactive tracer localizes and quantifies the disease activity; thus, FDG PET/CT holds a promising role as a sensitive non-invasive modality for the detection, staging, assessing disease activity, and monitoring therapy and deciding end point treatment in spinal TB.

Study of Diagnostic Delay among Symptomatic Breast Cancer Patients in Northern India: A Mixed-Methods Analysis from a Dedicated Breast Cancer Centre.

OBJECTIVE: We conducted this study to understand the factors that contribute to the delay in diagnosis of symptomatic breast cancer patients. METHODOLOGY: We did a prospective analytical study with both quantitative and qualitative components over 14 months. The total delay in diagnosis of breast cancer from first symptom onset was defined as diagnostic delay. Presentation delay was defined as the time duration between the first symptom and the first visit to a health care provider. Provider delay was defined as the time duration between the presentation to a health care provider and the final diagnosis. Three hundred female breast cancer patients with a diagnostic delay of at least 3 months were interviewed using a pre-tested semi-structured questionnaire. RESULTS: We found that more than 50% of patients with delayed presentation were between 30-50 years of age. Painless breast lump was the most common initial symptom. More than 70% of patients presented with locally advanced and metastatic disease. The patient-related delay was more common than provider delay. Breast cancer awareness (p = 0.040) and reasons for delay (p = 0.014) were found to significantly influence the delay. More than 70% of patients reported their symptoms to male members of their families. CONCLUSION: Breast cancer awareness is the single most important determinant influencing diagnostic delay among symptomatic patients.

Photoswitchable Epothilone-Based Microtubule Stabilisers Allow GFP-Imaging-Compatible, Optical Control over the Microtubule Cytoskeleton.

Optical methods to modulate microtubule dynamics show promise for reaching the micron- and millisecond-scale resolution needed to decrypt the roles of the cytoskeleton in biology. However, optical microtubule stabilisers are under-developed. We introduce "STEpos" as GFP-orthogonal, light-responsive epothilone-based microtubule stabilisers. They use a novel styrylthiazole photoswitch in a design to modulate hydrogen-bonding and steric effects that control epothilone potency. STEpos photocontrol microtubule dynamics and cell division with micron- and second-scale spatiotemporal precision. They substantially improve potency, solubility, and ease-of-use compared to previous optical microtubule stabilisers, and the structure-photoswitching-activity relationship insights in this work will guide future optimisations. The STEpo reagents can contribute greatly to high-precision research in cytoskeleton biophysics, cargo transport, cell motility, cell division, development, and neuroscience.

Lattice defects induced by microtubule-stabilizing agents exert a long-range effect on microtubule growth by promoting catastrophes.

Microtubules are dynamic cytoskeletal polymers that spontaneously switch between phases of growth and shrinkage. The probability of transitioning from growth to shrinkage, termed catastrophe, increases with microtubule age, but the underlying mechanisms are poorly understood. Here, we set out to test whether microtubule lattice defects formed during polymerization can affect growth at the plus end. To generate microtubules with lattice defects, we used microtubule-stabilizing agents that promote formation of polymers with different protofilament numbers. By employing different agents during nucleation of stable microtubule seeds and the subsequent polymerization phase, we could reproducibly induce switches in protofilament number and induce stable lattice defects. Such drug-induced defects led to frequent catastrophes, which were not observed when microtubules were grown in the same conditions but without a protofilament number mismatch. Microtubule severing at the site of the defect was sufficient to suppress catastrophes. We conclude that structural defects within the microtubule lattice can exert effects that can propagate over long distances and affect the dynamic state of the microtubule end.

Chemical Genetics Screen Identifies COPB2 Tool Compounds That Alters ER Stress Response and Induces RTK Dysregulation in Lung Cancer Cells.

Activating mutations in the epidermal growth factor receptor (EGFR) are common driver mutations in non-small cell lung cancer (NSCLC). First, second and third generation EGFR tyrosine kinase inhibitors (TKIs) are effective at inhibiting mutant EGFR NSCLC, however, acquired resistance is a major issue, leading to disease relapse. Here, we characterize a small molecule, EMI66, an analog of a small molecule which we previously identified to inhibit mutant EGFR signalling via a novel mechanism of action. We show that EMI66 attenuates receptor tyrosine kinase (RTK) expression and signalling and alters the electrophoretic mobility of Coatomer Protein Complex Beta 2 (COPB2) protein in mutant EGFR NSCLC cells. Moreover, we demonstrate that EMI66 can alter the subcellular localization of EGFR and COPB2 within the early secretory pathway. Furthermore, we find that COPB2 knockdown reduces the growth of mutant EGFR lung cancer cells, alters the post-translational processing of RTKs, and alters the endoplasmic reticulum (ER) stress response pathway. Lastly, we show that EMI66 treatment also alters the ER stress response pathway and inhibits the growth of mutant EGFR lung cancer cells and organoids. Our results demonstrate that targeting of COPB2 with EMI66 presents a viable approach to attenuate mutant EGFR signalling and growth in NSCLC.

Left Paraduodenal Hernia Presenting as Closed Loop Jejunal Obstruction in a Young Female: An Enigmatic and Perilous Differential of Acute Abdomen.

Internal hernia is a rare cause of intestinal obstruction, accounting for <2% of cases with paraduodenal type being the most common. An internal hernia, mostly acquired, develops due to protuberance of the intestine through a gap in the peritoneum or mesentery formed as a result of an antecedent abdominal operation such as gastric bypass or liver transplant, ischemic injury, peritonitis, or trauma. Paraduodenal hernias (PDHs) are congenital anomalies, secondary to a failed fusion of mesentery with parietal peritoneum along with rotational midgut errors, causing the evolution of potential space for herniation within the left paraduodenal fossa. Primary internal hernias can have a varied clinical presentation and cause significant mortality and morbidity if left untreated. We report the case of a 20-year-old female with chronic pain in abdomen and intestinal obstruction due to left PDH (LPDH). The prompt diagnosis led to timely exploration and reduction of entrapped jejunum, with prudent closure of the hiatus, while circumventing any injury to the adjacent mesenteric circulation. No postoperative ileus arose, and recovery was uneventful.

Delayed Slipped Capital Femoral Epiphysis Following Septic Arthritis of a Hip: A Case Report.

INTRODUCTION: Delayed slip of the capital femoral epiphysis is a rare entity in the setting of a septic hip. CASE REPORT: A 13-year-old male presented with an inability to walk and pain around right hip and knee region with fever. On imaging evaluation, a diagnosis of septic hip and knee arthritis was made and both the joints were drained under general anesthesia by anterior approach and an empirical antibiotic therapy was started. On the initial radiograph, there was no sign of slippage of the capital femoral epiphysis. Although the limb was kept in an immobilized position in the 1st week of the surgical debridement, yet it did not prevent the subsequent development of slipped capital femoral epiphysis (SCFE). Open reduction and screw fixation was done to stabilize the slippage. Healing took place with reduction of joint space with some restriction of the hip motion. CONCLUSION: SCFE is a disastrous complication in association with septic arthritis of a hip. Routine traction and immobilization may not prevent slippage. Disproportionate amount of pain on weight bearing in a post septic hip should raise the suspicion of SCFE. Prophylactic pinning may be considered in selective cases with antibiotic coverage.

The State of Perplexity During Management of Gall Bladder Malignancy in an Expectant Young Mother.

During pregnancy, diagnosed cancer causes a major disturbance in the life of a pregnant woman and her family. The advanced stage of illness requiring systemic treatment inevitably leads the treating practitioner, with two lives at risk, into an ethical dilemma. The unborn child can be affected by the application of cancer medication to the mother as it is exposed to fetotoxic drugs. On the other hand, withholding therapy to allow fetal maturity may make the disease of the mother metastatic. Gall bladder carcinoma is often diagnosed as an unresectable disease (metastatic or locally advanced) due to its nonspecific symptomatology and carries the worst prognosis of any gastrointestinal or hepatobiliary neoplasm. We report a case of locally advanced gall bladder cancer (GBC) diagnosed during late pregnancy wherein the mother opted to continue the pregnancy without any intervention. A review of literature has been done to investigate the role of female hormones in a pregnancy complicating GBC with emphasis on management dilemma and the associated pitfalls.

Gastric Perforation Secondary to Fungal Gastritis in an Immuno-Competent Adult.

Gastrointestinal (GI) tract perforation is a surgical emergency. The epidemiology and etiology of perforation vary considerably across geography. Lower GI tract perforations in the elderly predominate in the West compared to upper GI perforations in the younger population in the tropics. Fungi and viruses have been reported to cause GI perforations in immuno-compromised individuals but it is rare in immuno-competent individuals. We report a very rare case of gastric perforation secondary to fungal gastritis in an immuno-competent 35-year-old female who presented with features of peritonitis. At emergency laparotomy, gastric perforation was found which was repaired by the Cellan-Jones method. Perforation edge biopsy findings were consistent with fungal etiology. She responded well to Antifungal therapy. We conclude that fungal etiology can be considered in patients with gastric perforation without any history of peptic ulcer disease (PUD) or use of oral non-steroidal anti-inflammatory drugs.

Diagnostic and surgical challenges in disseminated tuberculosis presenting as acute abdomen during COVID-19 pandemic.

Due to the lack of much insight into the SARS-CoV-2 and overlapping symptoms and signs with other respiratory infections, diagnosis and management is often challenging in chest ailments particularly tuberculosis.

Postmenopausal Bleeding as a Late Sequela of Pelvic Fracture.

Postmenopausal bleeding is one of the common presenting complaints in the gynecological outpatient department. The common causes of which are atrophic endometritis, vaginitis, estrogen therapy, cancer endometrium, and cancer cervix. Hereby, we present a rare case of a 65-year-old female presented with postmenopausal bleeding who had history of trauma 1 year back with pelvic bone fracture. The cause of postmenopausal bleeding, in this case, is abnormal bony protrusion secondary to malunited pelvic fracture causing laceration of the right lateral vaginal wall. The case was managed by local osteotomy and vaginal wall repair.

Two Antagonistic Microtubule Targeting Drugs Act Synergistically to Kill Cancer Cells.

Paclitaxel is a microtubule stabilizing agent and a successful drug for cancer chemotherapy inducing, however, adverse effects. To reduce the effective dose of paclitaxel, we searched for pharmaceutics which could potentiate its therapeutic effect. We screened a chemical library and selected Carba1, a carbazole, which exerts synergistic cytotoxic effects on tumor cells grown in vitro, when co-administrated with a low dose of paclitaxel. Carba1 targets the colchicine binding-site of tubulin and is a microtubule-destabilizing agent. Catastrophe induction by Carba1 promotes paclitaxel binding to microtubule ends, providing a mechanistic explanation of the observed synergy. The synergistic effect of Carba1 with paclitaxel on tumor cell viability was also observed in vivo in xenografted mice. Thus, a new mechanism favoring paclitaxel binding to dynamic microtubules can be transposed to in vivo mouse cancer treatments, paving the way for new therapeutic strategies combining low doses of microtubule targeting agents with opposite mechanisms of action.

Pharmaceutical-Grade Rigosertib Is a Microtubule-Destabilizing Agent.

We recently used CRISPRi/a-based chemical-genetic screens and cell biological, biochemical, and structural assays to determine that rigosertib, an anti-cancer agent in phase III clinical trials, kills cancer cells by destabilizing microtubules. Reddy and co-workers (Baker et al., 2020, this issue of Molecular Cell) suggest that a contaminating degradation product in commercial formulations of rigosertib is responsible for the microtubule-destabilizing activity. Here, we demonstrate that cells treated with pharmaceutical-grade rigosertib (>99.9% purity) or commercially obtained rigosertib have qualitatively indistinguishable phenotypes across multiple assays. The two formulations have indistinguishable chemical-genetic interactions with genes that modulate microtubule stability, both destabilize microtubules in cells and in vitro, and expression of a rationally designed tubulin mutant with a mutation in the rigosertib binding site (L240F TUBB) allows cells to proliferate in the presence of either formulation. Importantly, the specificity of the L240F TUBB mutant for microtubule-destabilizing agents has been confirmed independently. Thus, rigosertib kills cancer cells by destabilizing microtubules, in agreement with our original findings.

Anatomical variation of the Psoas Valley: a scoping review.

BACKGROUND: This scoping review aimed to investigate the literature on the anatomy of the psoas valley, an anterior depression on the acetabular rim, and propose a unified definition of the anatomical structure, describe its dimensions, anatomical variations and clinical implications. METHODS: A systematic computer search of EMBASE, PubMed and Cochrane for literature related to the psoas valley was undertaken using Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Clinical outcome studies, prospective/retrospective case series, case reports and review articles that described the psoas valley and its synonyms were included. Studies on animals as well as book chapters were excluded. RESULTS: Of the 313 articles, the filtered literature search identified 14 papers describing the psoas valley and its synonyms such as iliopsoas notch, a notch between anterior inferior iliac spine and the iliopubic eminence, Psoas-U and anterior wall depression. Most of these were cross-sectional studies that mainly analyzed normal skeletal hips. In terms of anatomical variation, 4 different configurations of the anterior acetabular rim have been identified and it was found that the curved type was the most frequent while the straight type may be nonexistent. Additionally, the psoas valley tended to be deeper in males as compared with females. Several papers established the psoas valley, or Psoas-U in a consistent location at approximately 3 o'clock on the acetabular rim which may have implications with labral pathology. CONCLUSION: This review highlights the importance of the anatomy of the psoas valley which is a consistent bony landmark. The anatomy and the anatomical variations of the psoas valley need to be well-appreciated by surgeons involved in the management of young adults with hip pathology and also joint replacement surgeons to ensure appropriate seating of the acetabular component.