Challenges in the Management of Omphalocele at University Teaching Hospital, Zambia

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Conjoined (Siamese) twins in Zambia

The university Teaching hospital is the main referral centre for Zambia a country that  has a population of over 11 million people. Fourteen sets of conjoined twins have been  seen between 1970 and 1999. Of these fourteen sets of twins, three cases were  stillborn (21.43%). The remaining 11 (78.57%) sets were brought in alive. Five (35.71%) of these eleven sets had multiple congenital abnormalities; and were not  subjected to operation. All five died within a period of two weeks. Six (42.86%) sets were successfully separated. An attempt has been made to establish the incidence of conjoined twins in Zambia. Basic principles of management have been suggested and constraints likely to be encountered in a third world country like Zambia have been  discussed. Key words: Conjoined, Siamese and twin

Challenges in the management of Benign Oesophageal strictures in Zambians

Background: Benign Oesophageal structures are common in Zambians and pose great challenge in their management. Infants and, children are more affected than adults. Conservative and surgical treatments have been deployed in this institute and each of these methods have their advantages and disadvantages.Methods: Operative technique consisted of 32 adult patients (15.6%) using isoperistaltic transverse colonic segment the length of which can be extended from ascending to descending colon depending on the distance between lower thyroid cartilage and the stomach. The transverse colon was passed subcutaneously. The first stage was feeding colostomy, which was followed by definitive operation.Results: Two hundred and five Zambians with benign oesophageal stricture caused by ingestion of corrosive substances were seen in a period of 20 years from 1985 to 2005 inclusive. The majority (84.4%) were Zambian infants aged below 3 years. The remaining 32 patients (15.6%) were adults aged from the ages of 15 to 64 years giving a mean age of 41 years. Corrosives were taken accidentally in 84.9% while in the remaining 31 (15.1%) drank corrosives in suicidal attempt. All the babies were treated conservatively using bouginage and gastrostomy. Five infants who came in irreversible shock died. The 32 (15.6%) had gastrostomy for feeding the patients with failed attempted bouginage and got anterior sternal transverse colon oesophageal replacement. Morbidity was high but mortality was nil. We found this operation suitable for third world countries since there was no need for parental feeds. The operation restored ability to take food orally in 80% as compared to 26% of patients with bouginage.Conclusion: Confident vascularity depending on middle colic and left colic is guaranteed by low incidence of stenosis. The functional results are excellent as compared to minor complications which can be corrected early

Sexual ambiguity and malformation in Zambia: challenges in surgical management

A medical research article on the challenges of managing sexual ambiguities in sexually deformed patients in a hospital in Zambia.This article addresses the complexity in diagnosis, gender assignment and management in patients with sexual ambiguity and malformed sexual organs. Between 1984 and 1993, nine children and 10 adult patients with this ailment were treated in the University Teaching Hospital, Lusaka, Zambia. All children had clitorovaginoplasty and adults had different surgical procedures such as feminisation and masculinisation operations. Methods, means and the manner in which we manage these patients in the midst of a scarcity of expert manpower and sophisticated equipment are discussed. Need for a specialized clinic for better management, teaching and research of this unfortunate and highly sensitive congenital defect has been emphasized

A novel tankyrase inhibitor, MSC2504877, enhances the effects of clinical CDK4/6 inhibitors.

Inhibition of the PARP superfamily tankyrase enzymes suppresses Wnt/β-catenin signalling in tumour cells. Here, we describe here a novel, drug-like small molecule inhibitor of tankyrase MSC2504877 that inhibits the growth of APC mutant colorectal tumour cells. Parallel siRNA and drug sensitivity screens showed that the clinical CDK4/6 inhibitor palbociclib, causes enhanced sensitivity to MSC2504877. This tankyrase inhibitor-CDK4/6 inhibitor combinatorial effect is not limited to palbociclib and MSC2504877 and is elicited with other CDK4/6 inhibitors and toolbox tankyrase inhibitors. The addition of MSC2504877 to palbociclib enhances G 1 cell cycle arrest and cellular senescence in tumour cells. MSC2504877 exposure suppresses the upregulation of Cyclin D2 and Cyclin E2 caused by palbociclib and enhances the suppression of phospho-Rb, providing a mechanistic explanation for these effects. The combination of MSC2504877 and palbociclib was also effective in suppressing the cellular hyperproliferative phenotype seen in Apc defective intestinal stem cells in vivo. However, the presence of an oncogenic Kras p.G12D mutation in mice reversed the effects of the MSC2504877/palbociclib combination, suggesting one molecular route that could lead to drug resistance

Assessment of p.Phe508del-CFTR functional restoration in pediatric primary cystic fibrosis airway epithelial cells

© 2018 Sutanto et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background Mutations in the cystic fibrosis transmembrane regulator (CFTR) gene can reduce function of the CFTR ion channel activity and impair cellular chloride secretion. The gold standard method to assess CFTR function of ion transport using the Ussing chamber requires a high number of airway epithelial cells grown at air-liquid interface, limiting the application of this method for high throughput screening of potential therapeutic compounds in primary airway epithelial cells (pAECs) featuring less common CFTR mutations. This study assessed an alternative approach, using a small scale halide assay that can be adapted for a personalized high throughput setting to analyze CFTR function of pAEC. Methods Pediatric pAECs derived from children with CF (pAEC CF ) were established and expanded as monolayer cultures, before seeding into 96-well plates for the halide assay. Cells were then transduced with an adenoviral construct containing yellow fluorescent protein (eYFP) reporter gene, alone or in combination with either wild-type CFTR (WT-CFTR) or p.Phe508-del CFTR. Four days post transduction, cells were stimulated with forskolin and genistein, and assessed for quenching of the eYFP signal following injection of iodide solution into the assay media. Results Data showed that pAEC CF can express eYFP at high efficiency following transduction with the eYFP construct. The halide assay was able to discriminate functional restoration of CFTR in pAEC CF treated with either WT-CFTR construct or the positive controls syntaxin 8 and B-cell receptor-associated protein 31 shRNAs. Significance The current study demonstrates that the halide assay can be adapted for pediatric pAEC CF to evaluate restoration of CFTR function. With the ongoing development of small molecules to modulate the folding and/or activity of various mutated CFTR proteins, this halide assay presents a small-scale personalized screening platform that could assess therapeutic potential of molecules across a broad range of CFTR mutations

A novel treatment of cystic fibrosis acting on-target:cysteamine plus epigallocatechin gallate for the autophagy-dependent rescue of class II-mutated CFTR

We previously reported that the combination of two safe proteostasis regulators, cysteamine and epigallocatechin gallate (EGCG), can be used to improve deficient expression of the cystic fibrosis transmembrane conductance regulator (CFTR) in patients homozygous for the CFTR Phe508del mutation. Here we provide the proof-of-concept that this combination treatment restored CFTR function and reduced lung inflammation (P<0.001) in Phe508del/Phe508del or Phe508del/null-Cftr (but not in Cftr-null mice), provided that such mice were autophagy-competent. Primary nasal cells from patients bearing different class II CFTR mutations, either in homozygous or compound heterozygous form, responded to the treatment in vitro. We assessed individual responses to cysteamine plus EGCG in a single-centre, open-label phase-2 trial. The combination treatment decreased sweat chloride from baseline, increased both CFTR protein and function in nasal cells, restored autophagy in such cells, decreased CXCL8 and TNF-α in the sputum, and tended to improve respiratory function. These positive effects were particularly strong in patients carrying Phe508del CFTR mutations in homozygosity or heterozygosity. However, a fraction of patients bearing other CFTR mutations failed to respond to therapy. Importantly, the same patients whose primary nasal brushed cells did not respond to cysteamine plus EGCG in vitro also exhibited deficient therapeutic responses in vivo. Altogether, these results suggest that the combination treatment of cysteamine plus EGCG acts ‘on-target' because it can only rescue CFTR function when autophagy is functional (in mice) and improves CFTR function when a rescuable protein is expressed (in mice and men). These results should spur the further clinical development of the combination treatment

Gene-enhanced tissue engineering for dental hard tissue regeneration: (1) overview and practical considerations

Gene-based therapies for tissue regeneration involve delivering a specific gene to a target tissue with the goal of changing the phenotype or protein expression profile of the recipient cell; the ultimate goal being to form specific tissues required for regeneration. One of the principal advantages of this approach is that it provides for a sustained delivery of physiologic levels of the growth factor of interest. This manuscript will review the principals of gene-enhanced tissue engineering and the techniques of introducing DNA into cells. Part 2 will review recent advances in gene-based therapies for dental hard tissue regeneration, specifically as it pertains to dentin regeneration/pulp capping and periodontal regeneration

Increasing the bactofection capacity of a mammalian expression vector by removal of the f1 ori

Bacterial-mediated cancer therapy has shown great promise in in vivo tumour models with increased survival rates post-bacterial treatment. Improving efficiency of bacterial-mediated tumour regression has focused on controlling and exacerbating bacterial cytotoxicity towards tumours. One mechanism that has been used to carry this out is the process of bactofection where post-invasion, bacteria deliver plasmid-borne mammalian genes into target cells for expression. Here we utilised the cancer-targeting Salmonella Typhimurium strain, SL7207, to carry out bactofection into triple negative breast cancer MDA-MB-231 cells. However, we noted that post-transformation with the commonly used mammalian expression vector pEGFP, S. Typhimurium became filamentous, attenuated and unable to invade target cells efficiently. Filamentation did not occur in Escherichia coli-transformed with the same plasmid. Further investigation identified the region inducing S. Typhimurium filamentation as being the f1 origin of replication (f1 ori), an artefact of historic use of mammalian plasmids for single stranded DNA production. Other f1 ori-containing plasmids also induced the attenuated phenotype, while removal of the f1 ori from pEGFP restored S. Typhimurium virulence and increased the bactofection capacity. This work has implications for interpretation of prior bactofection studies employing f1 ori-containing plasmids in S. Typhimurium, while also indicating that future use of S. Typhimurium in targeting tumours should avoid the use of these plasmids