Role of bio-flavonols and their derivatives in improving mitochondrial dysfunctions associated with pancreatic tumorigenesis.

Mitochondria, a cellular metabolic center, efficiently fulfill cellular energy needs and regulate crucial metabolic processes, including cellular proliferation, differentiation, apoptosis, and generation of reactive oxygen species. Alteration in the mitochondrial functions leads to metabolic imbalances and altered extracellular matrix dynamics in the host, utilized by solid tumors like pancreatic cancer (PC) to get energy benefits for fast-growing cancer cells. PC is highly heterogeneous and remains unidentified for a longer time because of its complex pathophysiology, retroperitoneal position, and lack of efficient diagnostic approaches, which is the foremost reason for accounting for the seventh leading cause of cancer-related deaths worldwide. PC cells often respond poorly to current therapeutics because of dense stromal barriers in the pancreatic tumor microenvironment, which limit the drug delivery and distribution of antitumor immune cell populations. As an alternative approach, various natural compounds like flavonoids are reported to possess potent antioxidant and anticancerous properties and are less toxic than current chemotherapeutic drugs. Therefore, we aim to summarize the current state of knowledge regarding the pharmacological properties of flavonols in PC in this review from the perspective of mitigating mitochondrial dysfunctions associated with cancer cells. Our literature survey indicates that flavonols efficiently regulate cellular metabolism by scavenging reactive oxygen species, mitigating inflammation, and arresting the cell cycle to promote apoptosis in tumor cells via intrinsic mitochondrial pathways. In particular, flavonols proficiently inhibit the cancer-associated proliferation and inflammatory pathways such as EGFR/MAPK, PI3K/Akt, and nuclear factor κB in PC. Overall, this review provides in-depth evidence about the therapeutic potential of flavonols for future anticancer strategies against PC; still, more multidisciplinary human interventional studies are required to dissect their pharmacological effect accurately.

Third reported patient with RAP1B-related syndromic thrombocytopenia and novel clinical findings.

RAP1B is a RAS-superfamily small GTP-binding protein involved in numerous cell processes. Pathogenic gain-of-function variants in this gene have been associated with RAP1B-related syndromic thrombocytopenia, an ultrarare disorder characterized by hematologic abnormalities, neurodevelopmental delays, growth delay, and congenital birth defects including cardiovascular, genitourinary, neurologic, and skeletal systems. We report a 23-year-old male with a novel, de novo RAP1B gain-of-function variant identified on genome sequencing. This is the third reported case which expands the molecular and phenotypic spectrum of RAP1B-related syndromic thrombocytopenia.

MED12-related Hardikar syndrome: Two additional cases and novel phenotypic features.

Hardikar syndrome (HS) is a MED12-related ultra-rare multiple congenital malformation syndrome known to affect the gastrointestinal, cardiac, and genitourinary systems among other features including cleft lip/palate and pigmentary retinopathy. Only 10 patients affected with HS have been previously described in literature, of which seven were molecularly confirmed. We report a 20-year-old and a 13-month-old patient with HS diagnosed by exome sequencing bringing the total number of clinically diagnosed cases to 12 and MED12 associated to 9. We describe previously unreported molecular and clinical findings associated with HS and review all reported cases to permit prompt diagnosis, appropriate management, and genetic counseling of HS patients.

Rare presentation of FDX2-related disorder and untargeted global metabolomics findings.

We present the case of a 20-year-old male with a history of myopathy and multiple episodes of rhabdomyolysis, and lactic acidosis. He needed hemodialysis for severe rhabdomyolysis-related acute renal failure at the time of initial presentation (age 10 years). Exome sequencing detected a homozygous likely pathogenic variant in FDX2 (c.12G>T, p.M4I). The FDX2 gene encodes a mitochondrial protein, ferredoxin 2, that is involved in the biogenesis of Fe-S clusters. Biallelic pathogenic variants in FDX2 have previously been associated with episodic mitochondrial myopathy with or without optic atrophy and reversible leukoencephalopathy. Only two cases with FDX2-related rhabdomyolysis as a predominant feature have been reported in medical literature. Here, we report a third patient with FDX2-related recurrent, severe episodes of rhabdomyolysis and lactic acidosis. He does not have optic atrophy or leukoencephalopathy. This is the oldest patient reported with FDX2-related disorder and he has significantly elevated CK during episodes of rhabdomyolysis. In addition, we describe untargeted global metabolomic findings during an episode of metabolic decompensation, shedding light on the biochemical pathway perturbation associated with this ultra-rare genetic disorder.

Revisiting the surgical anatomy of the triangle of doom and the triangle of pain.

Better understanding of the surgical anatomy of the triangle of doom and the triangle of pain with fixed bony landmarks like the anterior superior iliac spine (ASIS) and the pubic symphysis (PS) can help in defining a safe location for trocar placement during laparoscopic surgeries and minimize neurovascular complications. Ten cadavers were dissected bilaterally to explore the surgical anatomy of both the triangles. ASIS and PS were evaluated in relation to the deep inguinal ring, external iliac artery, femoral nerve, and inferior epigastric artery. The deep inguinal ring was located at a depth of ~3 cm, about 4.9 ± 0.56 cm along the y-axis and 6.2 ± 0.94 cm along the x-axis, from the ASIS. The external iliac artery was located ~4.33 ± 0.6 cm along the y-axis and 7.29 ± 0.76 along the x-axis from the ASIS. The inferior epigastric artery was at ~4.31 ± 0.38 cm from the midline at the level of ASIS. This knowledge can help in the surface localization of both the triangles and prevent injury to the various neurovascular structures in relation to these triangles. In the current study, cranial to the ASIS lying at a distance of >5 cm from the midline was observed to be a safe zone for accessory trocar placement. The umbilical port has been observed to be safe for trocar placement. The mean angle between ductus deferens and testicular vessels was observed to be 43.5° ± 4.79°, which could help in determining their relative locations during various surgical procedures.

The anatomy of the cystic duct and its association with cholelithiasis: MR cholangiopancreatographic study.

The aims of this article are to detail the anatomy of the cystic duct in patients with and without gallstones as it relates to maneuvering of the duct during endoscopic transpapillary gallbladder cannulation, and to elucidate its role in the dynamics of bile flow during gallbladder contraction. One hundred MRCPs were retrieved from the prospectively maintained radiology data system to assess the configuration of the cystic duct and its confluence vis-a-vis the main biliary duct. The configuration of the cystic duct was broadly classified into four types: Angular (44%), Linear (40%), Spiral (11%), and Complex (5%). The level of emergence of the cystic duct from the bile duct was proximal in 29%, middle in 49% and distal in 20%. Its direction from the bile duct was to the right and angled upward in 69%, right and angled downward in 15%, left and angled upward in 13%, and left and angled downward in 1%. Its orifice was on the lateral surface of the bile duct in 50%, posterior in 19%, anterior in 15% and medial in 14%. In two cases, the cystic duct opened directly into the duodenum. Tortuous cystic ducts and non-lateral unions with the bile duct were significantly more prevalent in gallstone cases than the non-gallstone group (p = 0.02). The present study details the spatial anatomy of the cystic duct vis a vis the main biliary duct. This has not been well investigated to date but has become increasingly relevant with the advent of recent gallbladder interventions.

Osseous deficiencies, pockets, superfluous lateral border thickening in scapula: a rare occurrence.

BACKGROUND: Beyond the nutrient and suprascapular foramen, the other foramina, holes or osseous deficiencies, pockets has rarely been reported in scapula. If present, the bony holes or deficiencies may lead to radiolucent areas and may be mistaken for sites of osteolytic destruction related to skeletal metastases, multiple myeloma or others. CASE REPORT: In the present case of left scapula, unusual osseous deficiencies of different size and shape along with pockets were observed in the body of scapula. The maximum height and width of largest bony deficiency was 35.8 mm and 12.6 mm. There was abnormal osseous thickening beside the lateral border of scapula along with the presence of some spines. Five nutrient foramina, three on the costal and two on the dorsal surface were noticed. CONCLUSIONS: The present case reports the osseous deficiencies, pockets and extra osseous growth along the lateral border, multiple nutrient foramina altogether in one specimen. Thorough anatomical knowledge of these unusual osseous variations can provide the clinicians, radiologists and forensic experts with better clinical judgement and may add insight to the surgical planning by orthopaedic surgeons.

Novel and known miRNAs in zebu (Tharparkar) and crossbred (Karan-Fries) cattle under heat stress.

MicroRNAs (miRNAs) are small single-stranded non-coding RNAs that act as the master regulator of animal growth and development. RNA-RNA interaction is an important mechanism of gene regulation during biotic and abiotic stress. Heat stress (HS) is one of the most important abiotic factors which affect the growth, milk yield and reproductive health of the dairy animals. In the present investigation, we identified 387 known and 77 novel miRNAs from Tharparkar (TH) and Karan Fries (KF) cattle under HS condition. Family distribution analysis showed the identified miRNAs belong to more than 15 different families in which miR-2284 was the most abundant. We identified 42,350 targets for the known miRNAs reported in cattle. Pathway analysis of the identified targets showed most of the target genes were involved in cancer, mitogen-activated protein kinase (MAPK) signaling, calcium signaling, Ras signaling, and cAMP signaling pathways. Differential gene expression showed more than 344 miRNAs changed their expression significantly between control and HS condition. Heat map was generated for the top 20 most up and downregulated miRNAs. Ten miRNAs were validated using qRT-PCR to be heat responsive, based on read count value and differential gene expression. These novel miRNAs are new addition to the miRNA database of cattle. This study provides an overview of miRNA profile and their interaction with the target genes which leads to further understanding in deciphering the thermotolerance mechanism in cattle.

Myeloid-derived suppressor cells: Bridging the gap between inflammation and pancreatic adenocarcinoma.

Pancreatic cancer has been identified as one of the deadliest malignancies because it remains asymptomatic and usually presents in the advanced stage. Tumour immune evasion is a well-known mechanism of tumorigenesis in various forms of human malignancies. Chronic inflammation via complex networking of various inflammatory cytokines in the local tissue microenvironment dysregulates the immune system and support tumour development. Pro-inflammatory mediators present in the tumour microenvironment increase the tumour burden by causing immune suppression through the generation of myeloid-derived suppressor cells (MDSCs) and T regulatory cells. These cells, along-with myofibroblasts, create a highly immunosuppressive and resistant tumour microenvironment and are thus considered as one of the culprits for the failure of anti-cancer chemotherapies in pancreatic adenocarcinoma patients. Targeting these MDSCs using various combinatorial approaches might have the potential for abrogating the resistance and suppressive nature of the pancreatic tumour microenvironment. Therefore, there is more curiosity in studying the crosstalk of MDSCs with other immune cells during pathological conditions and the underlying mechanisms of immunosuppression in the current scenario. In this article, the possible role of MDSCs in inflammation-mediated tumour progression of pancreatic adenocarcinoma has been discussed.

IL-6 is associated with expansion of myeloid-derived suppressor cells and enhanced immunosuppression in pancreatic adenocarcinoma patients.

Chronic inflammation favours the expansion of myeloid-derived suppressor cells (MDSCs) by secreting pro-inflammatory mediators. The role of MDSCs in mediating immunosuppression in pancreatic adenocarcinoma and in defining a premalignant route from chronic pancreatitis remains unclear. We aimed to study the immunosuppressive potential of all subsets of MDSCs and their correlation with inflammatory cytokines in pancreatic adenocarcinoma and chronic pancreatitis. Relative frequencies of MDSCs, immunosuppressive markers arginase-1 (ARG-1), programmed death-ligand 1 (PD-L1), reactive oxygen species (ROS) and cytokines in circulation and surgically resected local pancreatic tissue of chronic pancreatitis and pancreatic adenocarcinoma patients were analysed by multicolour flow cytometry and cytokine bead array, respectively. Levels of cytokines involved in MDSCs activation were analysed by ELISA, and the immunosuppressive nature of MDSCs was confirmed by T-cell suppression assay. Frequencies of circulating MDSCs and ARG-1, PD-L1, and ROS were significantly higher in pancreatic adenocarcinoma than healthy controls and showed a significant positive correlation with MDSCs burden in cancer tissue. Serum levels of cytokines IL-6, IL-8 and IL-10 were significantly elevated in pancreatic adenocarcinoma. IL-6 serum levels showed a significant positive correlation with frequencies of circulating MDSCs in pancreatic adenocarcinoma patients, and MDSCs mediated suppression of T-cell proliferation in vitro was associated with elevated IL-6 levels in the cell culture medium. Collectively, our results suggest that IL-6 plays a crucial role in the expansion of MDSCs and activating their immunosuppressive nature in pancreatic adenocarcinoma. The relative frequency of MDSCs in circulation can be used as a potential diagnostic biomarker for pancreatic cancer.

Cobalamin J disease detected on newborn screening: Novel variant and normal neurodevelopmental course.

Cobalamin J disease (CblJ) is an ultra-rare autosomal recessive disorder of intracellular cobalamin metabolism associated with combined methylmalonic acidemia and homocystinuria. It is caused by pathogenic variants in ABCD4, which encodes an ATP-binding cassette (ABC) transporter that affects the lysosomal release of cobalamin (Cbl) into the cytoplasm. Only six cases of CblJ have been reported in the literature. Described clinical features include feeding difficulties, failure to thrive, hypotonia, seizures, developmental delay, and hematological abnormalities. Information on clinical outcomes is extremely limited, and no cases of presymptomatic diagnosis have been reported. We describe a now 17-month-old male with CblJ detected by newborn screening and confirmed by biochemical, molecular, and complementation studies. With early detection and initiation of treatment, this patient has remained asymptomatic with normal growth parameters and neurodevelopmental function. To the best of our knowledge, this report represents the first asymptomatic and neurotypical patient with CblJ.

Surgical anatomy of basal turn in relation to middle cranial fossa and round window as pertaining to middle fossa cochlear implant technique.

PURPOSE: The purpose of this investigation was to evaluate the relation of the basal turn of cochlea with middle cranial fossa and round window as pertaining to middle cranial fossa cochlear implant technique. METHODS: Fifty-four formalin preserved temporal bones were micro-dissected to expose the basal turn. The point (f) was marked on the basal turn of cochlea where there was minimum distance of basal turn of cochlea from the floor of middle cranial fossa (f1). The f-f1 distance, the angle (∠smf) and distance of point "f" from the round window (s-f) was measured. RESULTS: The mean minimum distance between basal turn of cochlea and floor of middle cranial fossa (f-f1) was 2.0 ± 0.7 mm.The point f was at mean distance (s-f) and angle (∠smf) of 14.7 ± 1.6 mm and 217° ± 13.7° from round window, respectively. CONCLUSIONS: The information may be helpful for designing appropriate electrode array for middle fossa technique especially for deciding the length of electrode array towards round window, as otherwise electrode may extend into vestibule of inner ear. In the cases where bone thickness between superior part of basal turn of cochlea and middle cranial fossa is < 1.5 mm, surgeon should be extra cautious.

Alleviation of heat stress by Chlorophytum borivilianum: impact on stress markers, antioxidant, and immune status in crossbred cows.

Eighteen crossbred Karan Fries (KF) cows in mid-lactation (av. 130 days) were selected from the livestock herd of the institute. The treatment for the experimental cows was as follows: no supplement (control), a low dose of Chlorophytum borivilianum (CB) at a dose rate of 40 mg/kg BW/day (T1, n = 6), and a high dose of CB at a dose rate of 80 mg/kg BW/day (T2, n = 6) for a period of 90 days in hot-humid season. Physiological responses like respiration rate (RR), pulse rate (PR), and rectal temperature (RT) were recorded in the morning (8.00 A.M.) and afternoon (2.30 P.M.) at weekly intervals. The expression of pro-inflammatory (IL-1ß and TNF-α) and anti-inflammatory cytokine (IL-10) in PBMCs, the plasma level of antioxidants (SOD, catalase, TBARS, and TAC), hormones (cortisol, prolactin), and energy metabolites (glucose, NEFA, urea, and creatinine) were determined. Dry and wet bulb temperatures and minimum and maximum temperatures were recorded, and the THI was calculated. The values of PR and RT were decreased (p < 0.01) in the T2 group in comparison to T1. Plasma glucose level was lower, and NEFA, urea, and creatinine level were higher (p < 0.01) in the control group as compared to T2 and T1 groups, respectively. Plasma cortisol and prolactin levels were significantly higher (p < 0.01) in the control group and were lower in T1 and T2 groups. Feeding of CB in high dose decreased (p < 0.01) plasma SOD, catalase, TBARS, and improved TAC levels in T2 over the T1 group. The dietary supplementation of CB at a dose rate of 80 mg/kg BW/day was more effective in lowering the stress level and augments the immunity by downregulating pro-inflammatory and anti-inflammatory cytokine levels. Therefore, dietary CB supplementation could be used as an effective heat stress ameliorator in dairy cows.

Anatomic variability of oval window as pertaining to stapes surgery.

PURPOSE: The purpose of the study is to study the details of dimensions and shape of oval window in different age groups, sides and genders and their clinical implications. The oval window is a key structure while performing surgeries in relation to stapes. An intricate knowledge of the shape and size of the oval window is important for the reconstruction and fitting of cartilage compatible with the native shape of the oval window. METHODS: Sixty normal wet cadaveric temporal bones of known age; gender and side were micro-dissected. The maximum height and width of the oval window was measured. The shape of the oval window was noticed. RESULTS: The mean value for maximum height and width of the oval window was 1.31 ± 0.28 mm and 2.67 ± 0.42 mm, respectively. The height and width of the oval window ranged between 1 mm and 1.5 mm and 2 mm and 3 mm in majority of the cases. he oval window was found to be oval shaped in 53.3% cases, other shapes such as kidney, D shape, rectangular or trapezoidal were also observed. CONCLUSIONS: The refined morphometric information of the oval window will help in preoperative assessment and surgical planning of various oval window-related surgical procedures. The knowledge may also help in designing and selecting proper cartilage shoe for the best outcome. Narrow oval window may cause procedural complications and surgeon discomfort in various stapes surgeries.

Reappraisal of the classical abdominal anatomical landmarks using in vivo computerized tomography imaging.

INTRODUCTION: With expanding scope of interventions it becomes mandatory to have correct and evidence-based knowledge of surface anatomy of internal abdominal structures. Information available in text books is derived from work done on cadaveric studies. Current study was designed to provide data of key abdominal surface anatomical landmarks and their variations in living subjects using CT imaging of adult population. MATERIALS AND METHODS: Cross-sectional study was conducted using 100 abdominopelvic CT scans of patients of Indian origin. RESULTS: Vertebral levels of origin of celiac trunk varied from T11 to L1/2 intervertebral disc, superior mesenteric artery from T12 to L2, inferior mesenteric artery from L2 to L4 and aortic bifurcation from L3 to L5. Origin of both renal arteries varied between T12 and L2 and the formation of inferior vena cava varied from L3 to L5. Vertebral levels of upper pole of both kidneys ranged from T11 to upper L3. Spleen was related to 9th to 11th ribs in 36% and 10th to 12th ribs in 34% scans. Most common vertebral levels of subcostal plane, planum supracristale and planum intertuberculare noticed were lower L2, L4 and lower L5, respectively. CONCLUSIONS: Data derived from imaging investigations of living subjects and variations from the conventional descriptions observed in the current study might be helpful for clinicians.

Chronic inflammation during osteoarthritis is associated with an increased expression of CD161 during advanced stage.

Increasing evidence suggests a role of inflammation during the pathogenesis of osteoarthritis (OA). The local and systemic inflammation was studied in 33 patients of different KL grades, grade2 (n = 11), grade3 (n = 6) and grade4 (n = 16). The levels of cytokines, adipokines and matrix metalloproteinases (MMPs) were measured in serum and synovial fluid (SF) by flow cytometry and ELISA, respectively. The frequency of T cells and CD161 expression was measured by flow cytometry. The levels of IL-1ß, IL-6 and IL-10 were significantly higher in sera and SF of patients with OA as compared to healthy control's serum. Higher levels of MMP9 and leptin and lower levels of adiponectin were observed in SF as compared to serum. The MMP9 in SF and MMP13 levels in serum and SF decreased in KL grade 4 cases. In these patients, higher levels of leptin and lower levels of adiponectin were observed in SF versus patients of lower grades. There was increased infiltration of CD8+ T cells in SF of OA cases with decreased frequency in grade 4 cases. The expression of CD161 on T cells was significantly higher in SF than peripheral blood with significant upregulation in grade 4 patients. The CD161 expression had significant positive correlation with IL-17 in the serum of patients. The ROC curves of CD161 expression significantly distinguished grade 2 and grade 4 patients. Collectively, an elevated CD161 expression on T cells in circulation and synovial compartment clearly distinguished lower and higher grade patients warranting studies to assess its role as a contributing factor towards OA progression.

No. 313-Menstrual Suppression in Special Circumstances.

OBJECTIVE: To provide a Canadian consensus document for health care providers with recommendations for menstrual suppression in patients with physical and/or cognitive challenges or those who are undergoing cancer treatment in whom menstruation may have a deleterious effect on their health. OPTIONS: This document reviews the options available for menstrual suppression, its specific indications, contraindications, and side effects, both immediate and long-term, and the investigations and monitoring necessary throughout suppression. OUTCOMES: Clinicians will be better informed about the options and indications for menstrual suppression in patients with cognitive and/or physical disabilities and patients undergoing chemotherapy, radiation, or other treatments for cancer. EVIDENCE: Published literature was retrieved through searches of Medline, EMBASE, OVID, and the Cochrane Library using appropriate controlled vocabulary and key words (heavy menstrual bleeding, menstrual suppression, chemotherapy/radiation, cognitive disability, physical disability, learning disability). Results were restricted to systematic reviews, randomized controlled trials, observation studies, and pilot studies. There were no language or date restrictions. Searches were updated on a regular basis and new material was incorporated into the guideline until September 2013. Grey (unpublished) literature was identified through searching websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. VALUES: The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1). BENEFITS, HARMS, AND COSTS: There is a need for specific guidelines on menstrual suppression in at-risk populations for health care providers.

Rare anatomic variations of the right hepatic biliary system.

PURPOSE: To report rare and clinically significant anatomic variations in the biliary drainage of right hepatic lobe. METHODS: Unique variations in the extra- and intrahepatic biliary drainage of right hepatic lobe were observed in 6 cadaveric livers during dissection on 100 formalin-fixed en bloc cadaveric livers. RESULTS: There was presence of aberrant drainage of right segmental and sectorial ducts in four cases and of accessory right posterior sectorial duct in two cases. CONCLUSIONS: We encountered some extensively complicated biliary drainage of right hepatic lobe, unsuccessful recognition of which can lead to serious biliary complications during hepatobiliary surgeries and biliary interventions.

Diminished Capsule Exacerbates Virulence, Blood-Brain Barrier Penetration, Intracellular Persistence, and Antibiotic Evasion of Hyperhemolytic Group B Streptococci.

Group B streptococci (GBS) are encapsulated, ß-hemolytic bacteria that are a common cause of infections in human newborns and certain adults. Two factors important for GBS virulence are the sialic acid capsular polysaccharide that promotes immune evasion and the hemolytic pigment that induces host cell cytotoxcity. These virulence factors are often oppositely regulated by the CovR/CovS two-component system. Clinical GBS strains exhibiting hyperhemolysis and low capsule due to pathoadaptive covR/S mutations have been isolated from patients. Given the importance of capsule to GBS virulence, we predicted that a decrease or loss of capsule would attenuate the virulence of covR/S mutants. Surprisingly, hyperhemolytic GBS with low or no capsule exhibit increased virulence, intracellular persistence, and blood-brain barrier penetration, which was independent of a Trojan horse mechanism of barrier penetration. Additionally, intracellular persistence enabled both hemolytic and hyperhemolytic GBS to evade antibiotics routinely used to treat these infections. The finding that diminished capsule expression promotes GBS virulence, intracellular persistence, and antibiotic evasion has important implications for sustained antibiotic therapy and efficacy of capsule-based vaccines.

Use of Audio Computer-Assisted Self-Interviews to Gather Information on Risk Behaviors in a Population of Pregnant Adolescents.

In a prospective study comparing the use of the Audio Computer-Assisted Self-Interview (ACASI) with a traditional clinical interview in 40 pregnant adolescents, there was significantly greater disclosure of violence with the ACASI method. Better identification of high-risk behaviors may help to optimize care and programing for pregnant adolescents.