Translation of novel inhalable therapies for respiratory diseases is hampered due to the lack of in vitro cell models that reflect the complexity of native tissue, resulting in many novel drugs and formulations failing to progress beyond preclinical assessments. The development of physiologically-representative tracheobronchial tissue analogues has the potential to improve the translation of new treatments by more accurately reflecting in vivo respiratory pharmacological and toxicological responses. Herein, advanced tissue-engineered collagen hyaluronic acid bilayered scaffolds (CHyA-B) previously developed within our group were used to evaluate bacterial and drug-induced toxicity and inflammation for the first time. Calu-3 bronchial epithelial cells and Wi38 lung fibroblasts were grown on either CHyA-B scaffolds (3D) or Transwell® inserts (2D) under air liquid interface (ALI) conditions. Toxicological and inflammatory responses from epithelial monocultures and co-cultures grown in 2D or 3D were compared, using lipopolysaccharide (LPS) and bleomycin challenges to induce bacterial and drug responses in vitro. The 3D in vitro model exhibited significant epithelial barrier formation that was maintained upon introduction of co-culture conditions. Barrier integrity showed differential recovery in CHyA-B and Transwell® epithelial cultures. Basolateral secretion of pro-inflammatory cytokines to bacterial challenge was found to be higher from cells grown in 3D compared to 2D. In addition, higher cytotoxicity and increased basolateral levels of cytokines were detected when epithelial cultures grown in 3D were challenged with bleomycin. CHyA-B scaffolds support the growth and differentiation of bronchial epithelial cells in a 3D co-culture model with different transepithelial resistance in comparison to the same co-cultures grown on Transwell® inserts. Epithelial cultures in an extracellular matrix like environment show distinct responses in cytokine release and metabolic activity compared to 2D polarised models, which better mimic in vivo response to toxic and inflammatory stimuli offering an innovative in vitro platform for respiratory drug development.
Effective restoration of extensive tracheal damage arising from cancer, stenosis, infection or congenital abnormalities remains an unmet clinical need in respiratory medicine. The trachea is a 10–11 cm long fibrocartilaginous tube of the lower respiratory tract, with 16–20 tracheal cartilages anterolaterally and a dynamic trachealis muscle posteriorly. Tracheal resection is commonly offered to patients suffering from short-length tracheal defects, but replacement is required when the trauma exceeds 50% of total length of the trachea in adults and 30% in children. Recently, tissue engineering (TE) has shown promise to fabricate biocompatible tissue-engineered tracheal implants for tracheal replacement and regeneration. However, its widespread use is hampered by inadequate re-epithelialisation, poor mechanical properties, insufficient revascularisation and unsatisfactory durability, leading to little success in the clinical use of tissue-engineered tracheal implants to date. Here, we describe in detail the historical attempts and the lessons learned for tracheal TE approaches by contextualising the clinical needs and essential requirements for a functional tracheal graft. TE manufacturing approaches explored to date and the clinical translation of both TE and non-TE strategies for tracheal regeneration are summarised to fully understand the big picture of tracheal TE and its impact on clinical treatment of extensive tracheal defects.
Purpose: Heart failure presents a huge burden for individual patients and the healthcare system as a whole. This study aims to assess the adherence to these core measures as identified by the Joint Commission on Accreditation of Healthcare Organizations (JCAHO)/ American Heart Association (AHA) by physicians of Pakistan. Materials and Methodology: We conducted a cross-sectional study in Shifa International Hospital, Islamabad, Pakistan from the period of April 2013 to April 2016. Patients with a primary diagnosis of heart failure were drawn from a coding section of hospital’s record department. Data was evaluated to assess how strictly doctors were following core measures identified by JCAHO/AHA for the given diagnosis. Inclusion criteria for this study were patients ≥ 17 years of age and patients with a primary diagnosis of heart failure according to New York Heart Association (NYHA) classification. Patients with congenital anomalies and structural heart wall problems, like sarcoidosis, hemochromatosis, and amyloidosis, were excluded from the study. Results: Mean ejection fraction (EF) was found to be 27.23 ± 11.72 percent. Symptoms assessment of heart failure was done in 16/421 (3.8%) patients according to NYHA classification and in 405/421 (96.2%) patients according to outpatient-based heart failure assessment based on physician's experience other than NYHA classification. Left ventricle ejection fraction (LVEF) was assessed in 411/421 (97%) patients. Out of these, 336/411 (81.7%) patients had EF < 40%. Mean EF was found to be significantly higher in females as compared to males (p < 0.001). Three hundred and thirty-six out of 411 (81.7%) patients with EF < 40% needed angiotensin converting enzyme inhibitors (ACEi) and beta-blocker (BB) prescriptions. ACEi were prescribed only to 230/336 (68.7%) patients and 248/336 (73.8%) patients were given BB with documented contraindication to ACEi and BB in 7.36% and 17% patients, respectively. There was no significant association between gender and mean duration of hospitalization (p = 0.411). No significant association was found between EF ≤ 40% and mean duration of hospitalization (p = 0.426). Conclusion: We found that symptom assessment of congestive heart failure (CHF) patients, according to NYHA guidelines, are strikingly low. Also, a significant percentage of patients who need ACEi and BB are not prescribed the required medications despite echocardiography showing low left ventricular function.
Despite the advancements in the prevention and treatment of cardiovascular diseases, sudden cardiac death (SCD) remains a leading cause of mortality and is accountable for approximately 15% of the total mortality in the USA. The prognosis after sudden cardiac arrest (SCA) varies significantly and depends largely on the underlying etiology and the rapidity and efficiency of resuscitation; however, the outcome remains poor for most of the patients. The main culprits for SCD are coronary heart disease (CHD) and heart failure with reduced ejection fraction (HFrEF). Patients with HFrEF and an ejection fraction (EF) of less than 35% are considered for an implantable cardioverter-defibrillator (ICD) placement if the EF does not improve. A wearable cardioverter defibrillator (WCD) commonly known as a life-vest is sometimes used as a bridging modality until an ICD is implanted. The indication and utility of WCD is still a controversial topic. The purpose of this article is to provide an up-to-date comprehensive review of literature for WCD utilization. Cardiol Res. 2022;13(4):185-189 doi: https://doi.org/10.14740/cr1387
Introduction: Although not common, lung tumor-induced achalasia will occasionally be encountered by gastroenterologists in patients with dysphagia and/or achalasia. Clinical features suggesting the possibility of malignancy as a cause of achalasia include: abrupt development of the dysphagia, significant unintentional weight loss in a short period of time ( >15 pounds), age > 55 years; and extensive smoking history ( >20 years). Case Description/Methods: A 67-year-old male with extensive smoking history presented to the hospital with complaints of difficulty tolerating foods and liquids with intermittent nausea and vomiting. Patient has to cut food into pieces to be able to go down. At presentation he had lost 25lbs in 2 weeks. CT abdomen showed abnormality at the gastroesophageal junction. EGD which showed a severely ulcerated esophagus with a stenotic mass effect in the distal third of the esophagus preventing the scope from advancing into the stomach (Figure). Discussion: Differentiating between idiopathic achalasia and pseudoachalasia is difficult and is often only possible when there is a diagnosis of other illnesses observed to have caused patients to experience achalasia symptoms with malignancy accounting for about 5% of these cases (Campo, 2013). Esophageal and gastric cancers tend to be the most common malignancies that cause pseudoachalasia, accounting for up to 70% of cases (Gockel et al., 2005). It is quite rare to come across a case of lung cancer causing pseudoachalasia and for that reason very little literature exists about the association between the 2 and its clinical expressions. In this particular case the ability for food to go down albeit in extreme difficulty indicated that there was some peristalsis which is seen often in pseudoachalasia but not in idiopathic achalasia (Kim et al., 2015). Another factor which helped in our diagnosis was the inability of the scope to advance past the mass unless moderate pressure was applied. In achalasia patients, the scope should be able to advance past the gastroesophageal junction with no more than light pressure applied (Eckardt & Eckardt, 2009). Existing literature indicates that in many cases, the presentation of achalasia symptoms precedes the diagnosis of cancer in pseudoachalasia sufferers. Therefore, testing and retesting may need to be done to rule out malignancy in patients who present with achalasia symptoms who are over the age of 60 years, have a history of smoking, and have experienced rapid weight loss in a short period of time (Tucker, 1978).Figure 1.: EUS showing the periesophageal mass.
Objective: To find the inter-rater reliability of dentists from various specialties regarding the observation and interpretation of angle of impacted third molars on the OPG. Methodology: A cross sectional comparative study was conducted in College of Dentistry, Sharif Medical and Dental College, Lahore after obtaining ethical clearance from ethical committee of Sharif Medical Research Centre (SMRC) in which dentists from four different specialties namely; Oral Pathology, Endodontics, Prosthodontics and Oral and Maxillofacial surgery were included as raters. The study was conducted from December 2020 to February 2021. A total of 21 Orthopantomograms were assigned to each rater for assessing the angle of the impacted third molar. The classification for angle of impaction used was Winter`s classification Results: The level of agreement regarding the angle of impacted third molars observed on the Orthopantomograms between rater 1 and rater 2 was very strong (κ=0.791,p≤0.001) but was moderate between rater 2 and rater 3 (κ=0.438, p≤0.001) and rater 2 and rater 4 (κ=0.577, p≤0.001) . Conclusion: The level of agreement regarding the angle of impacted third molars observed on the Orthopantomograms between rater 1 (oral pathologist) was very strong with rater 2 (Oral and Maxillofacial surgeon) while that of rater 2 with rater 3 (endodontist) and rater 4 (Prosthodontist) was moderate. Keywords: Inter-rater reliability, Orthopantomograms (OPG), impacted third molars, mesioangular, distoangular, vertical, horizontal
Introduction: Fuoroquinolones generally have good safety profile however, there are reported cased of Drug-induced liver injury (DALI) due to their use. Clinicians should be aware of this rare but serious adverse effect for early recognition in order to prevent catastrophic liver injury requiring liver transplant. Case Description/Methods: A 63 year old woman was hospitalized for pneumonia and started on Levofloxacin 750mg IV daily for treatment. On admission total bilirubin, AST, ALT, ALKP, CBC, alcohol and renal function tests were normal. On third day sudden onset of severe jaundice and scleral icterus was noted with no associated rash, fever, chills or abdominal pain. Repeat lab work revealed cholestatic pattern of liver injury with total bilirubin of 9.5mg/dL, direct bilirubin of 6.2mg/dl and only minimal hepatocellular injury with AST of 43 IU/L, ALT 52 IU/L, and normal ALKP, albumin, prothrombin time/INR, platelets, hemoglobin, haptoglobin and LDL levels. Viral hepatitis serology was negative and auto-immune hepatitis was ruled out with negative anti-nuclear antibody (ANA), anti-smooth muscle and anti-mitochondrial antibodies. Ultrasound liver/gallbladder and CT scan of abdomen did not show and intra or extrahepatic bile ducts dilatation or any other abnormalities. Levofloxacin was discontinued and patient was treated with IV fluids resulting in dramatic improvement in bilirubin levels from as high as 9.5mg/dL to 2mg/dL within three days. Discussion: DILI can present in hepatocellular, cholesteric or mixed liver injury patterns. Fluoroquinolones can cause idiosyncratic DILI due to unpredictable response in few patients even at therapeutic doses. It is important for clinicians to be cognizant of rare but potentially life threatening adverse effects of fluoroquinolones. Prompt recognition of the offending agent, Levofloxacin in this case, and to discontinue it early on prevents fulminant hepatic failure requiring transplant. Interestingly, in this case hepatocellular and synthetic functions remained normal, including ALKP and patient presented with very sudden and significant cholestatic jaundice only. Other causes of cholestatic jaundice including hematological disorder, infectious hepatitis, autoimmune and structural liver diseases need to be ruled out before blaming the drug as potential culprit of the liver injury. Offending drug should be discontinued and should never be administered to the patient again.
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