In Silico Evaluation of the Potential Association of the Pathogenic Mutations of Alpha Synuclein Protein with Induction of Synucleinopathies.

Alpha synuclein (α-Syn) is a neuronal protein encoded by the SNCA gene and is involved in the development of Parkinson's disease (PD). The objective of this study was to examine in silico the functional implications of non-synonymous single nucleotide polymorphisms (nsSNPs) in the SNCA gene. We used a range of computational algorithms such as sequence conservation, structural analysis, physicochemical properties, and machine learning. The sequence of the SNCA gene was analyzed, resulting in the mapping of 42,272 SNPs that are classified into different functional categories. A total of 177 nsSNPs were identified within the coding region; there were 20 variants that may influence the α-Syn protein structure and function. This identification was made by employing different analytical tools including SIFT, PolyPhen2, Mut-pred, SNAP2, PANTHER, PhD-SNP, SNP&Go, MUpro, Cosurf, I-Mut, and HOPE. Three mutations, V82A, K80E, and E46K, were selected for further examinations due to their spatial positioning within the α-Syn as determined by PyMol. Results indicated that these mutations may affect the stability and function of α-Syn. Then, a molecular dynamics simulation was conducted for the SNCA wildtype and the four mutant variants (p.A18G, p.V82A, p.K80E, and p.E46K). The simulation examined temperature, pressure, density, root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), solvent-accessible surface area (SASA), and radius of gyration (Rg). The data indicate that the mutations p.V82A, p.K80E, and p.E46K reduce the stability and functionality of α-Syn. These findings highlight the importance of understanding the impact of nsSNPs on α-syn structure and function. Our results required verifications in further protein functional and case-control studies. After being verified these findings can be used in genetic testing for the early diagnosis of PD, the evaluation of the risk factors, and therapeutic approaches.

Reliability of the modified Frailty Index (mFI) for intervention and continued surveillance in elective infrarenal abdominal aortic aneurysm (AAA).

INTRODUCTION: Frailty has been proven to lead to higher morbidity and mortality rates in surgical patients, independent of age. The modified Frailty Index (mFI) is a validated means of assessing for frailty. AIM OF STUDY: The aim of this study is to ascertain if the mFI correlates with clinician experience in turning down patients for abdominal aortic aneurysm (AAA) surgery and/or AAA surveillance. METHODS: A contemporaneously recorded database of all AAA patients treated during 2017 at a large University Hospital was reviewed. Patients were categorised into the following groups; continued surveillance, turned down for surveillance, patient declined surveillance, patient offered surgery, patient turned down for surgery and patient declined surgery. RESULTS: One hundred and forty two patients were included. Twenty-eight patients <5.5 cm were turned down for surveillance with a mFI of 0.27. Forty-one patients <5.5 cm continued with surveillance, with a mFI of 0.09 (p < 0.0001). Eighteen patients >5.5 cm were turned down for surgical intervention with a median mFI of 0.36. Forty-two patients were offered surgical intervention had a median mFI of 0.09 (p < 0.0001). CONCLUSION: Frailty is associated with higher morbidity and mortality amongst frail patient cohorts. mFI is a valid and easy to use tool to predict perioperative outcomes in AAA intervention. It correlates well with senior, experienced clinicians' decision-making in relation to who should and who should not undergo elective AAA surgery and those patients who should have ongoing aneurysm surveillance.

Brain abscess burr hole aspiration in children with congenital heart disease in low facility centers: case series.

This is a prospective cross-sectional study on brain abscess burr hole aspiration in children with congenital heart disease (CHD) performed from January 2018 to March 2019. All patients were operated on through a burr hole, and then received intravenous antibiotics for 6 weeks and orally for 2 weeks either empirically or according to the results of abscess culture, if positive. The follow-up of cranial computed tomography or brain magnetic resonance image with contrast was obtained after 2 months (post-operatively) to assess the effectiveness of the procedure and to look for any residual or recurrent abscesses. Data were collected in a designed data collection sheet and analysed using Statistical Package for the Social Sciences-20. Thirteen patients were found to satisfy inclusion criteria. The most common presenting symptoms were fever (n = 11/13, 84.6%), vomiting (n = 7/13, 53.8%), headache (n = 6/13, 46.2%), convulsions (n = 6/13, 46.2%), focal weakness (n = 3/13, 23.1%), and impaired level of consciousness (n = 1/13, 7.7%). No bacterial growth was detected in two-thirds of the cases (69.2%), while the culture was positive in the remaining one-third (30.8%). The follow-up images showed complete resolution of the abscesses except in one case (n = 1/13, 7.7%), which required a second session of aspiration. One patient died (n = 1/13, 7.7%) on the 19th post-operative day due to severe pneumonia. Aspiration of brain abscess in children with CHD through a burr hole is a safe and effective procedure in terms of operative time, duration of anaesthesia and postoperative complications.

A large un-ruptured abdominal aortic aneurysm causing pulmonary embolism.

A 79 years old woman presented in a peripheral hospital with dyspnea, right-sided pleuritic chest pain and cough for 3 days. On examination, she was tachycardiac and tachypneic. She had reduced air entry bilaterally on auscultation. Computed tomography-pulmonary angiogram, performed in peripheral Hospital, confirmed the diagnosis of pulmonary embolism, and she was commenced on warfarin. Ultrasonography showed no evidence of deep venous thrombosis in legs; however, ultrasound of the abdomen revealed an aortic aneurysm. She was hemodynamically stable on transfer to vascular surgery department, and her complete clinical examination revealed a pulsatile mass in the central abdomen. Computed tomography angiogram of aorta showed 8.7-cm abdominal aortic aneurysm. Venogram performed during inferior vena cava (IVC) filter insertion showed that IVC was displaced and compressed due to this large aortic aneurysm, causing thromboembolism. An open repair of the aneurysm was performed with uneventful recovery.

An iatrogenic popliteal pseudoaneurysm masked under compartment syndrome of leg.

This case describes a 60-year-old gentleman who presented with a pulsating mass behind his knee. Before this, he had a fasciotomy for suspected compartment syndrome of leg following knee arthroscopy, but this failed to resolve his leg symptoms. He was hemodynamically stable on presentation. His left calf was swollen with a circumference of 3 cm greater than right. There was a large pulsating mass palpable in his left popliteal fossa. Distal neurovascular status of the leg was intact. He had a normal cardiovascular, respiratory, abdominal and neurological examination. Ultrasound showed a cystic mass in the popliteal fossa suggestive of aneurysm. CT angiogram demonstrated a 6 × 5 × 4 cm pseudoaneurysm compressing and displacing the left popliteal artery with satisfactory three-vessel run-off. An emergency repair was performed. An arteriotomy was identified at the proximal end of pseudoaneurysm and it was closed with a patch of small saphenous vein. It led to a good clinical outcome.

Links between Toll-like receptor 4 and breast cancer.

Toll-like receptors (TLRs) have generated an extraordinary amount of interest in cancer research since the last decade. TLRs are a family of pattern recognition receptors that is involved in the host defense against microbial infections. It is well known that the activation of TLRs leads to the production of biological factors that drive inflammatory responses and activate the adaptive immune system. More recently, TLR-mediated signaling pathways have been shown to support tumor cell growth in vitro and in vivo. In this review, we describe recently emerged links between TLR4 and breast cancer oncogenesis, and future perspectives for the targeting of TLR4 in breast cancer therapy.

Postoperative Complications following Nodal Dissection and Their Association with Melanoma Recurrence.

Background. Although postoperative complications are common after lymph node dissection, its association with disease recurrence has not yet been fully investigated. Methods. A retrospective review of a prospectively maintained database was conducted, looking at all malignant melanoma patients with sentinel nodes positive disease requiring axillary or inguinal dissection between 2002 and 2011. Results. A total of 124 patients required nodal clearance from 317 patients with stage I/II malignant melanoma who had undergone sentinel lymph node biopsy. Of these, 104 patients met the inclusion criteria and were divided into inguinal lymph node dissections (ILND; n = 63) or axillary lymph node dissections (ALND; n = 41). Immunohistochemical deposits had higher detection rate in ALND (P = 0.01). The ILND patients had a higher recurrence rate (84.1% versus 63.4%; P = 0.02) and mortality (68.3% versus 48.8%; P = 0.05) without a significant difference in complications. In patients whom complications developed, 75% of the ILND group and 71.4% of the ALND group had disease recurrence, but without reaching a statistical value as an independent predictor of melanoma recurrence. Conclusion. Complications are common following ILND and ALND; however there is no significant difference in complications rates between the groups with some associations with recurrence without reaching a significant difference.

The road map to better knowledge? Care pathways as an educational tool during surgical internship.

INTRODUCTION: Changes in medical practice have promoted a culture of standardized care. Care pathways have been proven to raise the quality of clinical care. Their effect as an educational tool has not been evaluated to date. AIMS: To examine the educational role of care pathways in elective surgical admissions during surgical internship and the effect of their introduction on interns' confidence in performing tasks. METHODS: A questionnaire survey was filled in by interns to determine their confidence in performing different tasks during elective surgical admission and postoperative care. Care pathways were then formulated for the commonest procedures within the Department of Colorectal Surgery. The same interns then repeated the same questionnaire after they were exposed to the care pathways. RESULTS: Thirty interns participated in the study with a 100% response rate. There was statistically significant improvement in tasks performed confidently in 20 out of 21 areas surveyed after the introduction of the care pathways. The percentage of tasks performed with no confidence decreased from 25% to 1% (p<0.001). CONCLUSION: Care pathways are an effective method to improve the efficiency and confidence of interns in different aspects of surgical care, thereby improving patient safety. They also function as a valuable educational tool to aid interns in the management of patients with complex surgical issues.

Silencing of TLR4 increases tumor progression and lung metastasis in a murine model of breast cancer.

BACKGROUND: Toll-like receptor 4 (TLR4) is a member of a family of pattern recognition receptors that are involved in the host defense against microbial infection. Little research has investigated the link between TLR4 and cancer. We thus addressed the effect of TLR4 in both the host immune system and cancer cells with regard to its effect on breast cancer progression and metastasis. METHODS: Adult female Balb/c mice aged 6-8 weeks were divided into three groups. In group 1, 15 each wild-type and TLR4(-/-) mice were inoculated with 4T1 cells; in group 2, wild-type mice were inoculated with 4T1 cells (n = 15), 4T1 cells transduced with TLR4 lentivirus (n = 15) or with control lentivirus (n = 15); and in group 3, 15 TLR4(-/-) mice were inoculated with 4T1 cells transduced with TLR4 lentivirus. Flank tumor volume was measured with calipers during weeks 2-5. Animals were then humanely killed and the number of macroscopic lung nodules counted. RESULTS: There was a significant increase in tumor volume in weeks 2, 3 and 4 after inoculation of TLR4(-/-) mice with 4T1 cells compared with wild-type mice (p < 0.05). The number of metastatic lung nodules was significantly higher in TLR4(-/-) mice (p < 0.05), and survival of tumor-bearing TLR4(-/-) mice was substantially reduced compared with wild-type mice (p = 0.004). Knockdown of TLR4 from the 4T1 cells led to a relative reduction in lung metastasis, although it did not reach statistical significance. CONCLUSIONS: TLR4 exerts both a defensive role at the host level and a negative role at the cancer cell level in this murine metastatic breast tumor model. Further evaluation of the role of TLR4 in breast cancer is warranted.