Isolated Frontal Sinus Mucormycosis Post Covid 19-external Approaches Revisited!

Background: Isolated frontal sinus involvement in mucormycosis is seen very infrequently. Recent technological advances including image guided navigation and angled endoscopes have shifted paradigm towards minimally invasive surgeries. Open approaches are still relevant for the disease of frontal sinus with lateral extension where effective clearance cannot be obtained if approached endoscopically. Objectives: The objective of this study was to describe the presentation and management of patients of mucormycosis with isolated frontal sinus involvement with help of external approaches. Materials and methods: The available records of the patients were retrieved and analysed. The literature, the associated contributory clinical features and management techniques were reviewed. Results: 4 patients presented with isolated frontal sinus mucor involvement. 3 out of 4 patients had history of diabetes mellitus (75%). All patients had history of covid-19 infection (100%). 3 out of 4 patients had unilateral frontal sinus involvement and were operated by Lynch Howarth approach. Mean age of presentation was 46 years with male predominance. Bicoronal approach was used in one case with bilateral involvement. Conclusion: Although conservative endoscopic surgeries are preferred nowadays for frontal sinus clearance but the extensive bony destruction with lateral extension in our series of patients with isolated frontal sinus mucormycosis warranted the need for open procedures.

Epidemiological, Clinical and Radiological Profile of Patients with Foreign Body Oesophagus: A Prospective Study.

To analyse the patients with foreign body oesophagus in relation to the clinico-radiological and socio-economic profile. The present prospective study was conducted on 100 consecutive patients of all age groups who underwent oesophagoscopy for suspected foreign body ingestion in a tertiary care hospital. The most common age group affected was 0-5 years. The median age was 5 ± 14.37 years. There was preponderance in males as compared to females, male to female ratio was 2.23:1. Majority (70%) of the patients, both males and females, belonged to rural areas. Lower socio-economic group was more commonly affected (54%). The most commonly reported symptom was foreign body sensation (55%) followed by vomiting (54%) and difficulty in swallowing (51%). Foreign body ingestion was witnessed in only 19% cases by the family members. The mean time between ingestion of the foreign body and admission to the hospital was found to be 4.5 h. The majority (97%) of foreign bodies were radio-opaque. The most common site of lodgement was just below the cricopharynx (89%). The most common foreign body retrieved in our series were coins (65%). The majority of foreign bodies (68%) were retrieved in 20-40 min after induction of general anaesthesia. In 99% of the patients we did not encounter any complications. The majority (93%) of the patient's parents/relatives had curiosity to have a glimpse of the foreign body till they actually saw the retrieved foreign body. Foreign body lodgement is more common among children of lower socio-economic strata more so in rural areas. Rigid oesophagoscopy is a safe and effective procedure for removal of the foreign body. Early intervention makes it easier to extract the foreign body without complications.

Intermuscular Fibrolipoma of the Neck: A Rare Case Report.

Lipomas are slow growing tumors rarely found in children. We report a very rare case of an intermuscular fibrolipoma found deep within the posterior triangle of the neck. A 3 year old child was brought with the complaints of right sided neck mass and an inability to fully turn his head for two months. Ultrasound and computed tomography of the neck suggested a diagnosis of intermuscular lipoma. The patient was successfully managed by complete surgical resection of the mass. Histopathological examination confirmed the diagnosis as intermuscular fibrolipoma. Due to the rarity of the case, we are prompted to report it.

Nattokinase atherothrombotic prevention study: A randomized controlled trial.

BACKGROUND: Described to be antithrombotic and antihypertensive, nattokinase is consumed for putative cardiovascular benefit. However, no large-scale, long-term cardiovascular study has been conducted with nattokinase supplementation. OBJECTIVE: To determine the effect of nattokinase on subclinical atherosclerosis progression and atherothrombotic biomarkers. METHODS: In this double-blinded trial, 265 individuals of median age 65.3 years, without clinical evidence of cardiovascular disease (CVD) were randomized to oral nattokinase 2,000 fibrinolytic units or matching placebo. Primary outcome was rate of change in subclinical atherosclerosis measured by serial carotid ultrasound every 6 months as carotid artery intima-media thickness (CIMT) and carotid arterial stiffness (CAS). Additional outcomes determined at least every 6 months were clinical parameters including blood pressure and laboratory measures including metabolic factors, blood rheology parameters, blood coagulation and fibrinolysis factors, inflammatory markers and monocyte/macrophage cellular activation markers. RESULTS: After median 3 years of randomized treatment, annualized rate of change in CIMT and CAS did not significantly differ between nattokinase supplementation and placebo. Additionally, there was no significant effect of nattokinase supplementation on blood pressure or any laboratory determination. CONCLUSIONS: Results of this trial show that nattokinase supplementation has a null effect on subclinical atherosclerosis progression in healthy individuals at low risk for CVD.

Thyroglossal Duct Remnants: A Comparison in the Presentation and Management Between Children and Adults.

Seventy one patients (43 children and 28 adults) of thyroglossal duct remnants (TGDRs) presented at a tertiary care institute from January 2001 to September 2017 were retrospectively analysed. The mean age of presentation was 7.15 years in children and 26.85 years in adults. The male to female ratio was 1.9:1 among children and 1.8:1 among adults. The most common presentation in children was a thyroglossal fistula (53.48%) whereas it was a painless cystic neck swelling (89.29%) in adults. All the children underwent a Sistrunk's operation whereas 78.57% of the adult patients underwent simple excision of cyst/fistula using the modified incision (Yadav's incision). Recurrence developed in one child and one adult patient who underwent Sistrunk's operation and none in the modified incision, these cases were treated with a second stage procedure. In conclusion, compared with adults, more children presented with a discharging thyroglossal fistula. The thyroglossal duct remnants can be managed successfully by simple excision in adults.

Sharp 3-Ended Metallic Foreign Body in an Infant Hypopharynx.

Foreign body ingestion is common in infants and children, but they can pose a difficult situation and a diagnostic problem if the foreign body is embedded in the soft tissues of the pharynx. To the best of our knowledge, this is the first case reported with such an unusually shaped foreign body having three sharp ends embedded at two different locations in the hypopharynx of a kid such small in age giving rise to respiratory as well as feeding problem. Secondly, a sharp foreign body penetrating arytenoid causing its swelling and inflammation, thus compromising the glottic opening and producing stridor is a rare phenomenon. We present a case of a 9 months old male infant who presented in ENT emergency with complaints of vomiting, refusal to accept solid as well as liquid feed for 5 days and sudden onset of abnormal grunting sounds on breathing for 1 day. Chest examination revealed intercostal retractions with decreased air entry bilaterally and conducted sounds in chest on auscultation. Abdomen examination revealed no abnormalities, and routine blood and urine investigations were also within normal limits. A metallic foreign body with three sharp ends was visualized in the neck X-ray, the retrieval of which by rigid hypopharyngoscopy relieved the symptoms.

Cholesterol biosensors: A review.

Cholesterol is the most important sterol synthesized by most of the human cells majorly in the liver. It is a necessary constituent of cell membranes, it acts as a precursor for the synthesis of steroid hormones, vitamin D, and bile acids. Cholesterol is transported in plasma primarily in the form of low-density lipoproteins (LDL), the principal route for its removal from tissues to the liver is in high-density lipoproteins (HDL), followed by excretion in the bile. Cholesterol level is less than 200 mg/dL in healthy persons. 200 and 239 mg/dL is considered borderline high and 240 mg/dL and above is considered a biomarker for cardiovascular diseases, heart attack, strokes, peripheral arterial disease, type 2 diabetes and high blood pressure. Several methods are available for detection of cholesterol, among them, most are burdensome, time-consuming, require sample pre-treatment, high-cost instrumental set-up, and experienced personnel to operate. Biosensing approach overcomes these disadvantages, as these are highly specific, fast, easy, cost-effective, and highly sensitive. The review describes the various cholesterol biosensors. Cholesterol biosensors work ideally within 1 to 300 s, in pH range, 7.0-8.6, temperature 25-37 °C and cholesterol concentration range, 0.000025-700 mM, the detection limits being in the range, 0.000002-4 mM, with working potential -0.05 to 0.65 V. These biosensors measured cholesterol level in fruit juices, beverages, sera and urine samples and reused up to 200 times over a period of 15 to 50 days, while stored dry at 4 °C (Table 1). Future perspective for further improvement and commercialization of cholesterol biosensors are discussed.

Aural Polyp is not Always Due to Chronic Otitis Media (COM): Preoperative Computed Tomographic Scan is Good Pointer for Sinister Lesions.

Twenty five patients of aural polyp who underwent canal wall down mastoidectomy were analysed retrospectively. Histopathological examination revealed cholesteatoma in 22 (88%) patients. However, histopathological diagnosis in 3 of these patients was unusual and rare benign tumors of the middle ear cleft-meningioma, neurilemmoma and capillary hemangioma. Review of the preoperative High Resolution Computed Tomography (HRCT) temporal bone revealed an unusual picture in all of the three cases. Features noted were: widening of the jugular foramen (meningioma), destruction of the anterior wall of mesotympanum (neurilemmoma), enhancing soft tissue density lesion (capillary hemangioma). Further, there was only partial loss of pneumatisation of the mastoid air cells in all of the 3 cases. It was observed that though HRCT temporal bone is a commonly advised investigation in patients of chronic otitis media (COM) with aural polyp, meticulous interpretation may reveal unusual features pointing towards sinister diagnosis. Conclusion: Aural polyp with preservation of pneumatisation of mastoid air cells points towards diagnosis other than COM.

Treatment of Tympanic Membrane Retraction Pockets by Excision and Cartilage Tympanoplasty: A Prospective Study.

To assess the role of cartilage tympanoplasty in management of retraction pockets of the pars flaccida. This was a prospective study at a tertiary care centre. Twenty patients having grade III or grade IV retraction pockets were included in the study. Retraction pockets were treated by excision and cartilage tympanoplasty. Findings noted on follow-up were recorded and analysed. Graft was taken up in 18 (90%) cases with residual perforation in 2 (10%) cases. Recurrence of retraction pockets was observed in 6 (30%) cases. Hearing was improved up to 15 dB in 16 (80%) cases. It is concluded that grade III and IV retraction pockets can be well managed by excision and cartilage tympanoplasty.

Placenta growth factor mediated gene regulation in sickle cell disease.

Sickle cell anemia (SCA) is an autosomal recessive disorder caused by mutation in the ß-globin gene. Pulmonary hypertension (PH), a complication of SCA, results in severe morbidity and mortality. PH is a multifactorial disease: systemic vasculopathy, pulmonary vasoconstriction, and endothelial dysfunction and remodeling. Placenta growth factor (PlGF), an angiogenic growth factor, elaborated from erythroid cells, has been shown to contribute to inflammation, pulmonary vasoconstriction and airway hyper-responsiveness (AH) in mouse models of sickle cell disease. In this review, we summarize the cell-signaling mechanism(s) by which PlGF regulates the expression of genes involved in inflammation, PH and AH in cell culture and corroborate these findings in mouse models of SCA and in individuals with SCA. The role of microRNAs (miRNAs) in the post-transcriptional regulation of these genes is presented and how these miRNAs located in their host genes are transcriptionally regulated. An understanding of the transcriptional regulation of these miRNAs provides a new therapeutic approach to ameliorate the clinical manifestations of SCA.

Second Branchial Anomalies: A Study of 94 Cases.

Ninety-four patients with second branchial anomalies were retrospectively analysed at a tertiary care centre from January 2006 to September 2016 to determine the demographical data and management. Branchial sinus and fistula presented earlier as compared to branchial cyst. The mean age at presentation in case of branchial sinuses, fistulae and cysts was 5.07, 5.79 and 7.31 years respectively. There was preponderance in males as compared to females, more so in bilateral cases. Male to female sex ratio was 2.91:1. The branchial fistulae were the most common type of lesions, followed by the branchial sinuses. The branchial anomalies were more on the right side (65.96%) probably due to right handedness of the population. Only eight patients (8.51%) had bilateral anomalies. Four patients had familial association, it was seen in bilateral cases and they presented earlier than unilateral cases. Early and complete surgical excision is the treatment of choice. Preoperative sinogram/fistulogram and intraoperative methylene blue dye injection is not mandatory for excision of a branchial sinus/fistula. Post-operative wound infection was the most common complication (4.25%).

A controlled comparison of auditory steady-state responses and pure-tone audiometry in patients with hearing loss.

We performed a prospective interventional study to evaluate correlations between hearing thresholds determined by pure-tone audiometry (PTA) and auditory steady-state response (ASSR) testing in two types of patients with hearing loss and a control group of persons with normal hearing. The study was conducted on 240 ears-80 ears with conductive hearing loss, 80 ears with sensorineural hearing loss, and 80 normal-hearing ears. We found that mean threshold differences between PTA results and ASSR testing at different frequencies did not exceed 15 dB in any group. Using Pearson correlation coefficient calculations, we determined that the two responses correlated better in patients with sensorineural hearing loss than in those with conductive hearing loss. We conclude that measuring ASSRs can be an excellent complement to other diagnostic methods in determining hearing thresholds.

Results of endonasal dacryocystorhinostomy in pediatric patients.

We conducted a prospective interventional study to evaluate the role of endoscopic endonasal dacryocystorhinostomy in children. Our study population was made up of 20 patients-18 boys and 2 girls, aged 2 to 12 years (mean: 5.3)-who presented with signs and symptoms suggestive of nasolacrimal duct blockage that was refractory to conventional medical treatment. In all cases, blockage was confirmed by nasolacrimal duct syringing that demonstrated regurgitation from the opposite punctum. The primary outcome measures for success were resolution of symptoms and duct patency on lacrimal irrigation. At 6 months, 17 patients (85%) experienced complete symptomatic relief, 1 (5%) had partial relief, and 2 (10%) reported no relief. Moreover, the nasolacrimal duct was patent in 17 patients, partially patent in 2, and blocked in 1. We conclude that endoscopic endonasal dacryocystorhinostomy is a safe and effective procedure in children with nasolacrimal duct blockage when medical therapy and probing have been unsuccessful.

Activated Transcription Factor 3 in Association with Histone Deacetylase 6 Negatively Regulates MicroRNA 199a2 Transcription by Chromatin Remodeling and Reduces Endothelin-1 Expression.

Previous studies showed that high levels of placenta growth factor (PlGF) correlated with increased plasma levels of endothelin-1 (ET-1), a potent vasoconstrictor, in sickle cell disease (SCD). PlGF-mediated transcription of the ET-1 gene occurs by activation of hypoxia inducible factor 1α (HIF-1α) and posttranscriptionally by microRNA 199a2 (miR-199a2), which targets the 3' untranslated region (UTR) of HIF-1α mRNA. However, relatively less is known about how PlGF represses the expression of miR-199a2 located in the DNM3 opposite strand (DNM3os) transcription unit. Here, we show that PlGF induces the expression of activated transcription factor 3 (ATF3), which, in association with accessory proteins (c-Jun dimerization protein 2 [JDP2], ATF2, and histone deacetylase 6 [HDAC6]), as determined by proteomic analysis, binds to the DNM3os promoter. Furthermore, we show that association of HDAC6 with ATF3 at its binding site in this promoter was correlated with repression of miR-199a2 transcription, as shown by DNM3os transcription reporter and chromatin immunoprecipitation (ChIP) assays. Tubacin, an inhibitor of HDAC6, antagonized PlGF-mediated repression of DNM3os/pre-miR-199a2 transcription with a concomitant reduction in ET-1 levels in cultured endothelial cells. Analysis of lung tissues from Berkeley sickle (BK-SS) mice showed increased levels of ATF3 and increased expression of ET-1. Delivery of tubacin to BK-SS mice significantly attenuated plasma ET-1 and PlGF levels. Our studies demonstrated that ATF3 in conjunction with HDAC6 acts as a transcriptional repressor of the DNM3os/miR-199a2 locus.

Placenta growth factor augments airway hyperresponsiveness via leukotrienes and IL-13.

Airway hyperresponsiveness (AHR) affects 55%-77% of children with sickle cell disease (SCD) and occurs even in the absence of asthma. While asthma increases SCD morbidity and mortality, the mechanisms underlying the high AHR prevalence in a hemoglobinopathy remain unknown. We hypothesized that placenta growth factor (PlGF), an erythroblast-secreted factor that is elevated in SCD, mediates AHR. In allergen-exposed mice, loss of Plgf dampened AHR, reduced inflammation and eosinophilia, and decreased expression of the Th2 cytokine IL-13 and the leukotriene-synthesizing enzymes 5-lipoxygenase and leukotriene-C4-synthase. Plgf-/- mice treated with leukotrienes phenocopied the WT response to allergen exposure; conversely, anti-PlGF Ab administration in WT animals blunted the AHR. Notably, Th2-mediated STAT6 activation further increased PlGF expression from lung epithelium, eosinophils, and macrophages, creating a PlGF/leukotriene/Th2-response positive feedback loop. Similarly, we found that the Th2 response in asthma patients is associated with increased expression of PlGF and its downstream genes in respiratory epithelial cells. In an SCD mouse model, we observed increased AHR and higher leukotriene levels that were abrogated by anti-PlGF Ab or the 5-lipoxygenase inhibitor zileuton. Overall, our findings indicate that PlGF exacerbates AHR and uniquely links the leukotriene and Th2 pathways in asthma. These data also suggest that zileuton and anti-PlGF Ab could be promising therapies to reduce pulmonary morbidity in SCD.

Peroxisome proliferator-activated receptor-α-mediated transcription of miR-301a and miR-454 and their host gene SKA2 regulates endothelin-1 and PAI-1 expression in sickle cell disease.

Endothelin-1 (ET-1) and plasminogen activator inhibitor-1 (PAI-1) play important roles in pulmonary hypertension (PH) in sickle cell disease (SCD). Our previous studies show higher levels of placenta growth factor (PlGF) in SCD correlate with increased plasma levels of ET-1, PAI-1, and other physiological markers of PH. PlGF-mediated ET-1 and PAI-1 expression occurs via activation of hypoxia-inducible factor-1α (HIF-1α). However, relatively little is understood regarding post-transcriptional regulation of PlGF-mediated expression of ET-1 and PAI-1. Herein, we show PlGF treatment of endothelial cells reduced levels of miR-301a and miR-454 from basal levels. In addition, both miRNAs targeted the 3'-UTRs of ET-1 and PAI-1 mRNAs. These results were corroborated in the mouse model of SCD [Berkeley sickle mice (BK-SS)] and in SCD subjects. Plasma levels of miR-454 in SCD subjects were significantly lower compared with unaffected controls, which correlated with higher plasma levels of both ET-1 and PAI-1. Moreover, lung tissues from BK-SS mice showed significantly reduced levels of pre-miR-301a and concomitantly higher levels of ET-1 and PAI-1. Furthermore, we show that miR-301a/miR-454 located in the spindle and kinetochore-associated protein-2 (SKA2) transcription unit was co-transcriptionally regulated by both HIF-1α and peroxisome proliferator-activated receptor-α (PPAR-α) as demonstrated by SKA2 promoter mutational analysis and ChIP. Finally we show that fenofibrate, a PPAR-α agonist, increased the expression of miR-301a/miR-454 and SKA2 in human microvascular endothelial cell line (HMEC) cells; the former were responsible for reduced expression of ET-1 and PAI-1. Our studies provide a potential therapeutic approach whereby fenofibrate-induced miR-301a/miR-454 expression can ameliorate PH and lung fibrosis by reduction in ET-1 and PAI-1 levels in SCD.

Erythropoietin-mediated expression of placenta growth factor is regulated via activation of hypoxia-inducible factor-1α and post-transcriptionally by miR-214 in sickle cell disease.

Placental growth factor (PlGF) plays an important role in various pathological conditions and diseases such as inflammation, cancer, atherosclerosis and sickle cell disease (SCD). Abnormally high PlGF levels in SCD patients are associated with increased inflammation and pulmonary hypertension (PHT) and reactive airway disease; however, the transcriptional and post-transcriptional mechanisms regulating PlGF expression are not well defined. Herein, we show that treatment of human erythroid cells and colony forming units with erythropoietin (EPO) increased PlGF expression. Our studies showed EPO-mediated activation of HIF-1α led to subsequent binding of HIF-1α to hypoxia response elements (HREs) within the PlGF promoter, as demonstrated by luciferase transcription reporter assays and ChIP analysis of the endogenous gene. Additionally, we showed miR-214 post-transcriptionally regulated the expression of PlGF as demonstrated by luciferase reporter assays using wild-type (wt) and mutant PlGF-3'-UTR constructs. Furthermore, synthesis of miR-214, located in an intron of DNM3 (dynamin 3), was transcriptionally regulated by transcription factors, peroxisome proliferator-activated receptor-α (PPARα) and hypoxia-inducible factor-1α (HIF-1α). These results were corroborated in vivo wherein plasma from SCD patients and lung tissues from sickle mice showed an inverse correlation between PlGF and miR-214 levels. Finally, we observed that miR-214 expression could be induced by fenofibrate, a Food and Drug Administration (FDA) approved PPARα agonist, thus revealing a potential therapeutic approach for reduction in PlGF levels by increasing miR-214 transcription. This strategy has potential clinical implications for several pathological conditions including SCD.

MicroRNA 648 Targets ET-1 mRNA and is cotranscriptionally regulated with MICAL3 by PAX5.

Pulmonary hypertension (PHT) is associated with high mortality in sickle cell anemia (SCA). Previously, we showed that elevated levels of placenta growth factor (PlGF) in SCA patients correlate with increased levels of the potent vasoconstrictor endothelin-1 (ET-1) and PHT. Moreover, PlGF induced the expression of ET-1 via hypoxia-inducible factor 1α. Here, we show a novel example of ET-1 posttranscriptional regulation by PlGF via action of microRNA 648 (miR-648), which is subject to transcriptional coregulation with its host gene, MICAL3 (microtubule-associated monooxygenase, calponin, and LIM domain containing 3gene). PlGF repressed expression of miR-648 in endothelial cells. Luciferase reporter assays using wild-type and mutant ET-1 3' untranslated region (UTR) constructs, and transfection of miR-648 mimics showed that miR-648 targets the 3' UTR of ET-1 mRNA. Since miR-648 is located in a 5'-proximal intron of MICAL3, we examined which of three potential promoters was responsible for its expression. The MICAL3 distal promoter (P1) was the predominant promoter used for transcription of pre-miR-648, and it was under positive control by PAX5 (paired box protein 5) transcription factor, as demonstrated by the loss and gain of function of PAX5 activity, and chromatin immunoprecipitation analysis. These studies provide a novel link wherein PlGF-mediated downregulation of PAX5 attenuates miR-648 expression leading to increased ET-1 levels that are known to induce PHT in SCA.

Peroxisome proliferator-activated receptor-α-mediated transcription of miR-199a2 attenuates endothelin-1 expression via hypoxia-inducible factor-1α.

Endothelin-1, a potent vasoconstrictor, plays an important role in pulmonary hypertension (PH) in sickle cell disease (SCD). Our previous studies show that higher levels of placenta growth factor (PlGF), secreted by erythroid precursor cells, correlate with increased plasma levels of endothelin-1 (ET-1) and other functional markers of PH in SCD. PlGF-mediated ET-1 expression occurs via activation of hypoxia-inducible factor-1α (HIF-1α). However, relatively less is understood regarding how PlGF-mediated expression of HIF-1α and its downstream effector ET-1 are post-transcriptionally regulated. Herein, we show that PlGF treatment of endothelial cells resulted in reduced levels of miR-199a2, which targeted the 3'-UTR of HIF-1α mRNA and concomitantly led to augmented ET-1 expression. Plasma levels of miR-199a2 in SCD subjects were significantly lower with reciprocally high levels of plasma ET-1, unlike unaffected controls. This observation provided a molecular link between miR-199a2 and high levels of ET-1 in SCD. Furthermore, we show that miR-199a2 located in the DNM3os transcription unit was co-transcriptionally regulated by peroxisome proliferator-activated receptor α (PPARα). Binding of the latter to PPARα cis-elements in the promoter of DNM3os was demonstrated by promoter mutational analysis and ChIP. Additionally, we show that fenofibrate, a PPARα agonist, increased the expression of miR-199a2 and DNM3os; the former was responsible for reduced expression of HIF-1α and ET-1. In vivo studies of fenofibrate-fed Berkeley sickle mice resulted in increased levels of miR-199a2 and reduced levels of ET-1 in lung tissues. Our studies provide a potential therapeutic approach whereby fenofibrate-induced miR-199a2 expression can ameliorate PH by reduction of ET-1 levels.