Comparative binding analysis of WGX50 and Alpha-M with APP family proteins APLP1 and APLP2 using structural-dynamics and free energy calculation approaches.

A.D. is a common disease among other neurodegenerative disorders primarily developing due to amyloid-ß (Aß) neurotoxicity derived from the amyloid-ß protein precursor (AßPP). The amyloid precursor-like proteins 1 and 2 (APP1 and APLP2) biochemically behave similarly in many aspects to AßPP. We, therefore, proposed to test WGX-50 and Alpha-M for their interaction mechanism with APLP1 and APLP2 because both these drug candidate compounds previously showed inhibition of Aß aggregation. We employed a comparative atomic investigation on Alpha-M and WGX-50 in complex with novel targets, i.e., APLP1 and APLP2, using biophysical and molecular simulation methods. The docking score was -6.83 kcal mol-1 for Alpha-M-APLP1, -8.41 kcal mol-1 for WGX-50-APLP1, -7.02 kcal mol-1 for Alpha-M-APLP2 and -8.25 kcal mol-1 for the WGX-50-APLP2 complex. Our results also elaborate that in the case of their interaction with both APLP1 and APLP2, the WGX-50 complex exhibits better stability than the APLP1/2-Alpha-M complexes during simulation. Furthermore, WGX50 in both APLP1 and APLP2 stabilized the internal flexibility upon binding in contrast to the Alpha-M complexes. The data showed that the BFE for Alpha-M-APLP1 was calculated to be -27.38 ± 0.93 kcal mol-1, for WGX-50-APLP1 -39.65 ± 0.95 kcal mol-1, for Alpha-M-APLP2 -24.80 ± 0.63 kcal mol-1 while for WGX-50-APLP2 the BFE was -57.16 ± 1.03 kcal mol-1 respectively. These results highlight that APLP2-WGX50 has greater binding energies in all four systems. PCA and FEL analysis further revealed variations in the dynamic behavior of these complexes. Overall, our findings demonstrate that WGX50 potentially acts as a more potent inhibitor for APLP1 and APLP2 than Alpha-M and thus shows the diverse pharmacological potential of WGX50. Due to its stable binding interaction, WGX50 might be a suitable candidate drug compound for targeting these precursors under pathological conditions.

Left ventricular outflow tract thrombus in a patient with COVID-19-a ticking time bomb: a case report.

Background: Coronavirus disease 2019 (COVID-19) is a manifestation of severe acute respiratory syndrome coronavirus 2, which results in many different complications including left ventricular (LV) thrombi. Case summary: We present a 30-year-old female presenting with chest pain and shortness of breath. Patient had an extensive history including heart failure with an ejection fraction 15-20% and COVID-19 2 months ago. Echocardiogram revealed a 3.3 cm × 1.7 cm LV thrombus which was not present 4 months ago before her diagnosis of COVID-19. The LV thrombus embolized resulting in an embolus extending from the distal infrarenal abdominal aorta to the common iliac arteries bilaterally. Repeat COVID pre-procedure was positive. She underwent bilateral femoral artery cutdown, bilateral iliac artery embolectomy, superficial femoral artery embolectomy, and bilateral lower extremity fasciotomy. An extensive workup for the aetiology of the LV thrombus turned out to be negative and COVID-19 was deemed to be the aetiology of the thrombus. The patient was bridged from apixaban to warfarin and was successfully discharged within a few weeks. Discussion: Hypercoagulability is a known complication of COVID-19 causing thrombi in various parts of the body including the LV. Early recognition with echocardiography, especially in patients with heart failure, and prompt treatment is key to avoid further complications such as embolization.

RV lead placement - A forgotten cause of right heart failure.

INTRODUCTION: Cardiac implantable electronic devices (CIEDs) have opened new doors, improving the quality, and increasing the duration of life by providing support of heart rate, atrioventricular and interventricular synchrony, thereby preventing sudden cardiac death. Nevertheless, these devices can pose some risks to the patients, including pacemaker-mediated cardiomyopathy and endocarditis. CASE PRESENTATION: We elucidate the case of a patient who had severe Tricuspid Regurgitation as a result of single chamber Implantable Cardioverter Defibrillator (ICD) placement which led to right heart failure (RHF). His chief complaints were generalized fatigability and difficulty climbing steps at home. He also had orthopnea but denies paroxysmal nocturnal dyspnea. Despite using home diuretic regimen (Torsemide 40 gm daily), his continued to increase. He did not respond well to intravenous diuretics that time so decision was made to start Aquapheresis to which he responded very well. DISCUSSION: TV dysfunction associated with CIED leads can be investigated and diagnosed using different techniques. These pillars of diagnostic tests include two-dimensional (2D), 3D, and Doppler echocardiography. Presence of holosystolic hepatic vein flow reversal is key in diagnosing severe TR, whereas normal antegrade systolic flow excludes the possibility of moderate and severe TR. CONCLUSION: CIED leads causing tricuspid valve impairment has become increasingly recognized over the recent times; however, the evidence underlying this trend has been derived primarily from retrospective analyses. In order to circumvent these issues, leadless pacemakers and subcutaneous ICD devices should be considered.

QT interval prolongation and rhabdomyolysis associated with diphenhydramine toxicity: a case report.

Diphenhydramine is a widely available, over-the-counter medication used for allergies and as a sleeping aid. When used in prescription doses, it is generally safe. Overdose of the medication has been associated with dangerous and life-threatening outcomes. Our case describes diphenhydramine toxicity manifesting with two rare but potentially life-threatening complications, rhabdomyolysis, and QT prolongation. Laboratory testing for diphenhydramine levels are not widely available. We recommend a high degree of suspicion for these complications when evaluating patients with diphenhydramine overdose, to adequately manage and prevent untoward outcomes.

A rare association of Takotsubo cardiomyopathy with neuroleptic malignant syndrome.

Neuroleptic malignant syndrome is a potentially fatal neurological condition secondary to antipsychotic medication. It is characterized by distinctive clinical findings and autonomic disturbances. NMS has not been associated with Takotsubo cardiomyopathy (TCM). TCM is an abnormal response to physiological stressors resulting from the autonomic abnormalities which at times can mimic myocardial infarction (MI). We present a unique case of a 54-year-old female with bipolar disease presenting with lithium and haloperidol-induced NMS complicated by TCM. The purpose of this case is to make clinicians aware of this rare association.

Atypical Clinical Presentation of Crohn's Disease as Diffuse Abdominal Lymphadenopathy and Venous Thrombosis: A Difficult to Diagnose Case.

Crohn's disease (CD) is an inflammatory bowel disease with clinical manifestations that are more variable than those of ulcerative colitis. It can manifest with a wide range of gastrointestinal as well as extra-intestinal symptoms and at times it becomes difficult to diagnose because of presenting variability. Here we present a case of a young male who presented with diffuse abdominal lymphadenopathy with abdominal vein thrombosis and found to have CD.

Is ivabradine a wonder drug for atypical POTS?

Syncope is a sudden loss and gain of consciousness. Traditionally, it is caused by the abnormalities of neurological, cardiac or vasovagal systems. We present a case of a 19-year-old woman presenting with recurrent syncopal episodes with no apparent cause. Examination and investigations were unremarkable for any aetiology except positive tilt tests for postural orthostatic tachycardia syndrome. The purpose of this report is to make physicians aware of the unique presentation of this rare aetiology with recurrent syncopal episodes and the novel management approach.

Garbled speech: a rare presentation of metronidazole-induced neurotoxicity.

Neurotoxicity is a rare but significant side effect of metronidazole. We present, here, a case of a 34-year-old man, presenting with garbled speech and word finding difficulty. He was taking metronidazole for the last 3 months for stage 4 decubitus ulcers. MRI of the brain showed abnormal signal intensities in the splenium of the corpus callosum and dentate nuclei of the cerebellum. The diagnosis of metronidazole-induced neurotoxicity was made based on MRI findings. The antibiotic was stopped leading to resolution of abnormal MRI findings. We advocate that metronidazole can be associated with severe neurotoxicity, but its prompt cessation leads to better outcome and prognosis.

Clot Mayhem: A Case of May-Thurner Syndrome.

May-Thurner syndrome (MTS), also known as the iliac vein compression syndrome, is an anatomic anomaly in which the compression of the left common iliac vein by an overlying right common iliac artery leads to blood stasis, which predisposes to deep venous thrombosis (DVT) in the iliofemoral venous system. We present a case of a female with a history of DVT and currently on warfarin with a therapeutic international normalized ratio (INR), admitted with left leg swelling, redness, and intractable pain. Venous Doppler scan confirmed a massive DVT from the level of the left common femoral vein to the popliteal vein. The clot recurred after an unsuccessful trial of argatroban, in-line pharmacokinetic thrombolysis with local catheter-based alteplase infusion, and interventional radiology (IR)-guided mechanical thrombectomy. Subsequently, the patient was diagnosed as MTS with overlying left common iliac vein compression, as evident on venous Doppler ultrasound. She was managed successfully by venous stent placement and ongoing systemic anticoagulation with fondaparinux.

Optimal Duration for Clopidogrel Suspension Prior to Coronary Artery Bypass Grafting.

BACKGROUND: American College of Cardiology (ACC) guidelines suggest clopidogrel (Plavix) suspension for 5 days before non-emergent cardiac surgery (class IIa, level B). It puts the patients with recent angioplasty and ongoing ischemia at a higher risk of stent thrombosis. We sought to determine the bleeding risk in patients who stopped clopidogrel at 3 and less than 3 days before coronary artery bypass grafting (CABG) as compared to the usual 5 days prior to CABG. METHODS: A retrospective single center study was performed; and a total of 90 patients were included. Forty patients were not on clopidogrel but underwent CABG and hence were used as a control group (group 3). Fifty remaining patients were divided into three groups. Patients in whom clopidogrel was stopped 3 days or less before CABG were included in group 1 (n = 25); group 2 included patients who followed the standard ACC guidelines and clopidogrel was suspended 5 days before the CABG (n = 17); and finally patients who had stopped clopidogrel 4 days prior to surgery were included in group 4 (n = 8). This was compared to controls. Postoperative hemoglobin drop was analyzed between subgroups using IBM SPSS version 25. RESULTS: The mean age of the included population was 69.9 years (46 - 88) with 65% of them being male and 35% female patients. The difference in the hemoglobin fall was compared amongst these groups using the one-way ANOVA. There were no outliers, as assessed by boxplot, the data were normally distributed for each group, as assessed by Shapiro-Wilk test (P > 0.05), and there was homogeneity of variances, as assessed by Levene's test of homogeneity of variances (P > 0.05). The fall in hemoglobin for the four different groups was analyzed. The fall in hemoglobin in group 1 (stopped clopidogrel 3 days or less before CABG) was (n = 25, 2.36 ± 1.24), the fall in group 2 (stopped clopidogrel 5 days prior to CABG) was (n = 17, 2.89 ± 1.22), the fall in hemoglobin in group 3 (patients not on clopidogrel) was (n = 40, 2.54 ± 1.35), and the fall in hemoglobin in group 4 (patients stopped clopidogrel 4 days prior to CABG) was (n = 8, 2.02 ± 1.31). ANOVA was subsequently performed on the patient data, which showed no statistical difference between all the four groups regarding the fall in hemoglobin during surgery (P = 0.41). CONCLUSIONS: Our study concludes that there was no significant difference in the hemoglobin drop of the patients who had clopidogrel stopped 3 days prior to the major procedure like CABG in comparison to the patients who stopped clopidogrel 5 days before surgery. We advocate, that early cessation of clopidogrel is posing a threat of thrombosis in high risk patients with no additional benefit of decreased bleeding risks. However, large population studies are needed to validate the results.

A Case of Fibroelastoma with Widespread Embolism to the Brain, Kidney, and Spleen.

Cardiac papillary fibroelastoma (CPF) is the second most common primary cardiac tumor, which is diagnosed incidentally or with embolic phenomena, mostly in the form of a transient ischemic attack (TIA) and stroke. We present a case of a 58-year-old female who presented with fatigue and low-grade fever and was found to have multiple systemic infarcts. Her blood cultures and transthoracic echocardiography (TTE) were negative, ruling out infective endocarditis. However, transesophageal echocardiography (TEE) revealed a mobile mass at the aortic valve. The mass was surgically removed, and the aortic valve was repaired. The histological examination of the mass finally revealed a papillary fibroelastoma. To our knowledge, this is the first reported case where fibroelastoma presented with splenic and renal infarcts in combination with the cerebral infarcts. Since cardiac fibroelastoma can cause embolization to the cerebral, splenic, and renal vessels, we, therefore, advocate that it should be considered as one of the possible causes of widespread embolism. We also stress upon the importance of doing TEE in case of a suspected cardiac mass, as the TTE is more likely to give false-negative results.

Acquired Hemophilia A: A Rare but Potentially Fatal Bleeding Disorder.

Acquired hemophilia A is a disorder of rare entity, resulting in spontaneous bleeding in individuals with no history of bleeding disorders. It is believed to be caused by spontaneous inhibition of clotting factor VIII by autoantibodies, and is usually associated with other autoimmune conditions. The hallmark of this condition is mucocutaneous bleeding leading to ecchymosis, melena, hematoma or hematuria. Our discussion revolves around the case of an elderly male with no history of anticoagulant use presenting with hematuria. Imaging showed left kidney hemorrhage, his labs were significant for a prolonged partial thromboplastin time (PTT), and subsequent tests revealed low factor VIII levels and high factor VIII inhibitor levels, which led to the diagnosis of acquired hemophilia A in the patient. He was managed with medications resulting in normalization of factor VIII levels.

ST-Segment Elevation Myocardial Infaction Alert During the Night Shift, A Misfortune for the Patient or an Overstatement?

BACKGROUND: Conflicting data exist regarding the outcomes of primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI) based on intervention timings. It is believed that short staffing at night hours may lead to a lapse in the delivery of effective, efficient and timely medical intervention. METHODS: A retrospective single-center study was performed, and a total of 436 patients were randomized into two groups. Group A had 279 patients who had the heart catheterization done during the daytime (between 6 am and 6 pm), while group B had 157 patients who had the same intervention performed at night (between 6 pm and 6 am). RESULTS: Door to balloon (DTB) time during the day was about 16 min shorter than the DTB time at night (81.29 ± 3.26 vs. 97.30 ± 8.54) with no statistical difference (P = 0.051). The mean troponin rise during the day was 1.94 ± 10.60 SEM (95% confidence interval (CI): -22.70 to 18.90) higher than night troponin levels (71.75 ± 7.18 vs. 69.80 ± 7.18), but P value was 0.85. The left ventricular ejection fraction (LVEF) fall for daytime was 0.93% vs. 0.90% for night time patients (P = 0.94). CONCLUSION: There is no significant difference in the mean DTB time, the rise in troponin, fall in LVEF, readmission rates, or mortality, and hence no negative effects on patient outcomes based on the patient's time of presentation between the two groups.

Great saphenous vein stump: a risk factor for superficial/deep venous thrombosis and an indication for prophylactic anticoagulation? - a retrospective analysis.

Background: Great saphenous vein (GSV) grafts are used for coronary artery bypass surgeries, but the remaining stump of the GSV may be the nidus for superficial and deep vein thrombosis. This study aims to determine the risk of thrombosis in the GSV stump in patients who developed lower extremity swelling following coronary artery bypass graft (CABG). Methods: We conducted a single-center retrospective analysis at Abington Jefferson Hospital of 100 patients who underwent CABG with GSV. Patients were monitored via follow-up for seven days for the development of saphenous vein thrombosis without any prophylactic anticoagulation for venous thrombosis. Risk factors including age, diabetes, hypertension, smoking, familial thrombophilia's, family history of thrombosis, malignancy, and confounding factor-like early mobilization that may potentially alter the results were recorded. Results: The mean age of included patients was 70 years, and 65% of participants were men, 35% were women. Fourteen percent of the patients developed pain, swelling and edema in a leg where the graft was taken. We included patients aged >50 years with coronary artery disease who underwent CABG with SVG and developed lower extremity symptoms concerning for thrombosis. These patients underwent duplex ultrasound for possible GSV stump thrombosis. Any patients with coronary artery disease but no CABG or no lower extremity edema were excluded from the study. We found no saphenous vein thrombosis in the stump of the GSV in patients with clinical symptoms of thrombosis in their lower extremities based on duplex imaging. Conclusion: Based on our findings, the postoperative risk of developing thrombosis at the GSV stump and its extension to the deep veins is low and does not warrant prophylactic anticoagulation for venous thromboembolism. However, we recommend that further prospective studies with larger samples for an extended duration are warranted for better assessment of the risk of venous thrombosis in the GSV stump with minimal confounding factors.

Importance of Basal Metabolic Index in the Diagnosis of Heart Failure With B-Type Natriuretic Peptide.

BACKGROUND: Increased basal metabolic index (BMI) is associated with decreased levels of B-type natriuretic peptide (BNP). This makes the diagnosis of the congestive heart failure challenging in the obese population. We sought to determine the association and strength of the relationship between the two variables. METHODS: The association between BMI and BNP was examined in 405 patients utilizing a retrospective chart review in a single center study. Pearson correlation and regression analyses were performed to identify trends. BNP trends were also correlated with age. RESULTS: The mean age of patients was 77 years with 45% men and 55% women. Mean BNP level was 1,158 standard deviation (SD) ± 1,537. Mean BMI was 33 SD ± 28. BNP levels were found to be inversely related to increasing BMI (P value < 0.001). Using a cut-off of 3,500 pg/mL, there was a linear negative correlation on the dotted graph. In regression analysis the measure of effect of BMI on BNP levels was -0.90 pg/mL. There was no significant association between age and BNP levels (P = 0.90). CONCLUSIONS: Irrespective of age, obese patients have lower BNP levels, complicating the diagnosis of heart failure exacerbation in such patients. Our results suggest that BNP levels in patients with BMI greater than 33 should be adjusted 9 pg/mL per unit increase in BMI.

Duration of in-hospital cardiopulmonary resuscitation and its effect on survival.

OBJECTIVE: This study aims to determine the correlation between the duration of cardiopulmonary resuscitation (CPR) and the return of spontaneous circulation (ROSC) in an in-hospital cardiac arrest cohort. METHODS: All patients (age ≥ 17 years) who underwent CPR at our institution from 2015 to 2017 were included. The primary endpoint was ROSC or death. A total of 88 patients were included in the study. The Pearson correlation of CPR duration with the establishment of ROSC was calculated using the IBM SPSS, version 25. RESULTS: In all, 88 patients who received CPR, 55% (n = 48) experienced ROSC and survived. The remaining 45% (n = 40) of the total and 56% (n = 27) of those with ROSC died during the same hospitalization (Fig. 1). Among the 48 patients with ROSC, the documented duration of their CPR was about 10 min on average in comparison with 27.5 min CPR for patients who did not achieve ROSC (Fig. 2). Among all the patients, there was a negative correlation between the duration of the CPR and the establishment of ROSC. This is shown in Fig. 3. CONCLUSION: Our study shows that CPR duration is inversely associated with the establishment rates of ROSC. Most of the benefits of CPR can be achieved in the first 15 min, and a further increase in the duration of CPR provides a minimal gain. Still, survival was achievable till 38 min in some cases, and the ideal duration of resuscitation should remain a bedside decision taking into consideration the whole clinical picture.

Role of echocardiography in diagnostic evaluation of patients admitted to observation unit.

BACKGROUND: Syncope is a transient loss of consciousness due to transient decrease in cerebral perfusion. Syncope accounts for a 3-6% of all emergency department visits. Etiology of syncope can be neural, cardiogenic, or vascular. Previous studies have evaluated the types and management of syncope. Echocardiography is a commonly used test in the evaluation of causes of syncope. Whether the benefit compared to financial burden of this diagnostic study is in all subsets of syncope cases remains unclear. AIM: To evaluate the impact of echocardiography in the diagnostic evaluation of syncope and to evaluate the subset of patients that would benefit more from this diagnostic imaging. METHODS: We performed a retrospective chart review of patients > 18 years of age with a primary diagnosis of syncope in a period of January 1st 2015-January 31st 2017. Our inclusion criteria included patients > 18 years of age who were admitted to the observation floor with the primary complaint as syncope, had a normal or abnormal physical examination for syncope, had a normal or abnormal electrocardiogram during admission, had an echocardiography performed at admission. Our exclusion criteria included patients with seizures, hypoglycemia, myocardial infarction, patients who didn't get echocardiography, and patients who had a positive marker of cardiac injury. RESULTS: A total of 369 patients were initially identified with a primary diagnosis of syncope, however only 120 of these patients fulfilled our inclusion and exclusion criteria. A total of n=25 of included patients had either an abnormal physical exam or abnormal echocardiography. Among this "high risk" group, 24% (n=6) of the patients had an abnormal finding on their transthoracic echocardiography. On the other hand, in the "low risk" group with a normal physical examination and electrocardiogram (EKG), 14 had a trans-thoracic echocardiography (TTE) positive for cause of syncope, that led to a change in medication, workup, or intervention in 6.7% (n=8) of the patients. CONCLUSION: The analysis of our study suggested that the diagnostic yield of transthoracic echocardiography in syncope is very limited in the absence of an abnormal physical exam or electrocardiogram, and it increase the health care cost burden with no additional benefits.

Thyroxine-induced periodic paralysis: a rare complication of nutritional supplements.

The consumption of daily nutritional supplements has risen dramatically all over the world. Many people believe that dietary supplements, if not useful, are at least safe to fulfil small dietary gaps. Many nutritional supplements have not been approved by Federal Drug Administration due to their unregulated active ingredients, but they are available as over the counter. One of the active ingredients, exogenous triiodothyronine (T3), has been reported in dietary supplements. We present a case of sudden onset of tetraparesis. Laboratory workup showed hypokalaemia, low thyroid-stimulating hormone and thyroxine (T4) but normal T3 and thyroglobulin levels. The radioiodine uptake scan also showed reduced uptake. After aggressive serum potassium correction and stopping supplements, his condition got improved. So the suspicion of exogenous T3-induced thyrotoxic periodic paralysis was confirmed.