Toxicokinetics and molecular interaction of [14C]-formaldehyde in rats

The excretion, tissue distribution, and binding of [¹⁴C]-formaldehyde were studied at different time intervals in male rats following a single intraperitoneal injection of 72 mg CH₂O (14.7 Ci)/ kg body weight. Within 30 min, 10% of the total dose was recovered in expired air as¹⁴CO₂ and by the end of 72 hr, 41% of the administered dose was eliminated through expired air. The total elimination of¹⁴CH₂O activity in urine and feces in 72 hr was 15%. Erythrocytes retained significant amounts of radioactivity, even at the end of 72 hr. Substantial levels of radioactivity were detected in most tissues one hr after administration, indicating a fast absorption and rapid distribution. Subcellular fractionation of the tissues showed that the highest levels of relative percent binding was in the microsomal fraction, whereas cytosol fractions contained lowest levels of bound radioactivity. DNA, RNA, protein and lipid fractions of liver and spleen tissues showed significantly elevated levels of¹⁴C-incorporation as compared to other tissues. Thein vivo incorporation of¹⁴C-activity showed an increased association of¹⁴CH₂O with RNA in all the tissues. The maximum registration of radioactivity in RNA was at 48 hr after administration. Significantly higher amounts of¹⁴C-activity were registered in DNA of all tissues. The maximum registration of radiolabel in DNA of most tissues was at 12 hr after the¹⁴CH₂O administration. The liver DNA showed maximal levels at 3 hr with a second peak at 48 hr.Substantial amounts of bound radioactivity in nucleic acids of all the tissues were observed even 72 hr after dosing. The relationship between macromolecular association and formaldehyde toxicity has been discussed.     

Increased cancericidal activity of PTT.119; a new synthetic bis-(2-chloroethyl)amino-l-phenylalanine derivative with carrier amino acids

Summary A new synthetic tripeptide (p-F-Phe-m-bis-(2-chloroethyl)amino-Phe-Met ethoxy HCl), PTT.119, was demonstrated to have significant cancericidal activity against seven in vitro tumor cell lines of different origins and etiologies and against primary human AMML, ALL, and hairy cell leukemias. Viabilities of each murine tumor and rabbit, marmoset, and human leukemia and lymphoma line were significantly reduced by treatment with 1–50 g PTT.119 in media containing serum. Continuous 24-h exposure or pulse treatment as short as 15 and 30 min with the tripeptide resulted in irreversible damage to the tumor cells. Under identical treatment conditions, freshly isolated human leukemic cells, particularly ALL lymphoblasts, were even more susceptible to PTT.119 than any of the tested tumor cell models.Examination of the parameters of PTT.119 activity revealed that reductions of tumor cell survival were dependent on the concentration of the tripeptide. Prolongation of PTT.119 exposure from 15 min to 24 h increased the rates of tumor cell death but did not proportionally reduce the numbers of surviving cells. Assessment of tumor cell viabilities for 5 consecutive days following pulse exposure to PTT.119 demonstrated increasing reductions in tumor cell survival, which were greatest 5 days after treatment with the tripeptide.The cancericidal activity of PTT.119 was compared with its three parental components either as individual agents or as a mixture. Both the alkylator moiety, m-sarcolysin (m.L.SL) alone or together with p-fluoro-phenylalanine and l-methionine ethoxy HCl, and l-PAM (l-phenylalanine mustard), the p-isomer of m.L.SL, were 1.5- to 3-fold less cytotoxic to L1210 leukemia and MJY-alpha mammary tumor cells than PTT.119. Covalent linkage of the amino acid residues to m.L.SL yielded a molecule with greatly augmented cancericidal activity capable of acting against a broad spectrum of tumor cells.     

Does center or surgeon volume influence adoption of minimally invasive versus open pancreatoduodenectomy? A systematic review and meta-regression

BackgroundThere has been increasing uptake of minimally invasive pancreatoduodenectomy during the past decade, but it remains a highly specialized procedure as benefits over open pancreatoduodenectomy remain contentious. This study aimed to evaluate current evidence on minimally invasive pancreatoduodenectomy versus open pancreatoduodenectomy in terms of impact of center volume on outcomes.MethodsA systematic review of articles on comparative cohort and registry studies on minimally invasive pancreatoduodenectomy versus open pancreatoduodenectomy published until 31st December 2019 were identified, and meta-analyses were performed. Primary endpoints were International Study Group on Pancreatic Fistula grade B/C postoperative pancreatic fistula and 30-day mortality.ResultsAfter screening 7,390 studies, 43 comparative cohort studies (8,755 patients) with moderate methodological quality and 3 original registry studies (43,735 patients) were included. For the cohort studies, the median annual hospital minimally invasive pancreatoduodenectomy volume was 10. No significant differences were found in grade B/C postoperative pancreatic fistula (odds ratio: 0.98, 95% confidence interval: 0.78–1.23) or 30-day mortality (odds ratio: 1.14, 95% confidence interval: 0.65–2.01) between minimally invasive pancreatoduodenectomy when compared with open. No publication biases were present and meta-regression identified no confounding for grade B/C postoperative pancreatic fistula, center volume or 30-day mortality. Minimally invasive pancreatoduodenectomy was only strongly associated with significantly lower rates of postoperative pulmonary complications and surgical site infection, shorter length of stay, and significantly higher rates of R0 margin resections.ConclusionMinimally invasive pancreatoduodenectomy remains noninferior to open pancreatoduodenectomy for grade B/C postoperative pancreatic fistula but is strongly associated with significantly lower rates of postoperative pulmonary complications and surgical site infection. Minimally invasive pancreatoduodenectomy can be adopted safely with good outcomes irrespective of annual center resection volume.     

A Case of Large Calcifying Fibroma of Tendo-achilles Managed by En-block Resection and Tendon Reconstruction

Calcifying aponeurotic fibroma is a rare benign fibrous tumor with typical radiological and histopathological features seen in young children and adolescents. It commonly involves the extremities and is characterized by a very high chance of local recurrence. A complete excision of the tumor is considered to be the treatment of choice. We report a case of the tumor involving the substance of achilles tendon and extending up till its insertion in the calcaneum. To the best of our knowledge, this is the largest reported case of calcifying fibroma, with the tumor measuring 10 cm in its largest diameter. The tumor was excised in toto followed by reconstruction of the tendon defect with V-Y plasty of the native tendon and supplemented with semitendinosus and gracilis graft. There was no evidence of recurrence during the follow up period of 1 year.     

Principles of preoperative assessment and enhanced recovery optimization for thoracic anaesthesia

A comprehensive preoperative assessment is imperative for patients undergoing lung surgery, ideally by way of a multidisciplinary team approach. This not only allows for clinicians to risk stratify patients and gain informed consent, but also to explore avenues in optimizing patients prior to surgery and plan for the delivery of the most appropriate postoperative care. A tripartite risk assessment combining risks of operative mortality, perioperative adverse cardiac events and postoperative dyspnoea should be assessed and discussed with patients. Those patients who continue towards surgical management may then be optimized with patient education addressing nutritional status, smoking cessation and alcohol dependency as well as the management of anaemia and physiological prehabilitation. This article aims to review existing guidelines for preoperative assessment in thoracic surgery as well as the latest preoperative guidance for enhanced recovery specific to thoracic surgery.     

Dyslipidemia and its associated factors in patients with type 2 diabetes mellitus

Journal of Public Health - Dyslipidemia is a major risk factor known to be associated with diabetes and cardiovascular diseases. This study determined the frequency of lipid abnormalities among...     

Enolase 1 of Candida albicans binds human CD4+ T cells and modulates naïve and memory responses

To obtain a better understanding of the biology behind life-threatening fungal infections caused by Candida albicans, we recently conducted an in silico screening for fungal and host protein interaction partners. We report here that the extracellular domain of human CD4 binds to the moonlighting protein enolase 1 (Eno1) of C. albicans as predicted bioinformatically. By using different anti-CD4 monoclonal antibodies, we determined that C. albicans Eno1 (CaEno1) primarily binds to the extracellular domain 3 of CD4. Functionally, we observed that CaEno1 binding to CD4 activated lymphocyte-specific protein tyrosine kinase (LCK), which was also the case for anti-CD4 monoclonal antibodies tested in parallel. CaEno1 binding to naïve human CD4⁺ T cells skewed cytokine secretion toward a Th2 profile indicative of poor fungal control. Moreover, CaEno1 inhibited human memory CD4⁺ T-cell recall responses. Therapeutically, CD4⁺ T cells transduced with a p41/Crf1-specific T-cell receptor developed for adoptive T-cell therapy were not inhibited by CaEno1 in vitro. Together, the interaction of human CD4⁺ T cells with CaEno1 modulated host CD4⁺ T-cell responses in favor of the fungus. Thus, CaEno1 mediates not only immune evasion through its interference with complement regulators but also through the direct modulation of CD4⁺ T-cell responses.     

Endothelial lipopigment as an indicator of α-tocopherol deficiency in two equine neurodegenerative diseases

Two spontaneous neurodegenerative diseases of the horse, equine motor neuron disease (EMND) and equine degenerative myeloencephalopathy (EDM), have been associated with -tocopherol deficiency, and both were characterized by prominent accumulations of endothelial lipopigment in the small vessels of the spinal cord. These endothelial pigment deposits appear to be reversible. In EMND horses pasture-supplemented for 9 months or more after the progression of weakness and wasting had arrested, there was very little endothelial lipopigment. The origin and the potential effects of these endothelial lipopigment accumulations are discussed.