Louise Louw

Docosahexaenoic acid induces apoptosis in colorectal carcinoma cells by modulating the PI3 kinase and p38 MAPK pathways.

Numerous studies have shown that long-chain polyunsaturated fatty acids can kill cancer cells in vitro as well as in vivo, while normal cells remain unaffected. Unfortunately, the cellular and molecular mechanisms responsible for this phenomenon are still poorly understood. The aim of this study was to investigate the potential chemopreventative/antiproliferative potential of docosahexaenoic acid (DHA) in an adenocarcinoma cell line (CaCo2 cells) and to evaluate the signalling pathways modulated by it. DHA (5-50 microM) significantly inhibited cell viability in a dose-dependent manner in CaCo2 cells, while the viability of normal colon cells (NCM460 cells) was not compromised. DHA also induced apoptosis in CaCo2 cells, as indicated by increases in caspase-3 activation and poly-ADP-ribose polymerase cleavage. Signalling proteins, which include extracellular signal-regulated kinase, p38 mitogen-activated protein kinase (MAPK), Akt and p53 were analysed by Western blotting using phosphospecific and total antibodies. The protein inhibitors wortmannin (phosphoinositide 3 kinase inhibitor), PD 98059 (MEK inhibitor) and SB 203580 (p38 inhibitor) as well as silencing RNA [small interfering RNA (siRNA)] of the p38 MAPK protein, were used to investigate cross-talk between signalling pathways. DHA supplementation significantly suppressed Akt phosphorylation, which also correlated with decreased cell viability and increased apoptosis in CaCo2 cells. Furthermore, siRNA experiments suggested a possible role for p38 MAPK in the phosphorylation of p53 at Ser15, a site which is associated with DNA damage. DHA might thus exert its beneficial effects by means of increased apoptosis and suppression of the important survival-related kinase, Akt.

Comparison of the fatty acid compositions in intraepithelial and infiltrating lesions of the cervix: part I, total fatty acid profiles.

In the second part of this study, the emphasis is on the free fatty acids during cervical carginogenesis, since they may reflect active cell metabolism during this disease process. Lipids were extracted from biopsies of normal epithelial tissue (N) (n=36), cervical intraepithelial lesions (CIL) (n=47), and infiltrating lesions (Ca) (n=47) of the cervix. Samples, from which the free fatty acid compositions were determined, were saponified, methylated and analysed by GLC. In accordance with results obtained on total fatty acid compositions, essential fatty acid deficiency (EFAD) in the intraepithelial lesions, compared with normal tissue (linoleic acid, P< 0.01), and infiltrating lesions compared with intraepithelial lesions (linoleic acid and arachidonic acid, P< 0.01) were observed. High levels of oleic acid were also observed when infiltrating lesions were compared with normal tissue (P < 0.01). As previously mentioned by us in part I of this study, with regard to possible disturbances in metabolic pathways based on the total fatty acid profiles during stages of cervical cancer, EFAD is prevalent during cervical carcinogenesis. This EFAD in cancer cells may result in many defective cell mechanisms, since fatty acids are associated with biochemical events such as lipid peroxidation, signal transduction and immune responses. The high level of oleic acid in cancer cells is known to activate PKC and thus contribute to the continous growth stimulus thought to exist in malignant cells. From a therapeutic viewpoint, substantial changes in the fatty acid composition of the membranes can be produced in cancer cells by selective fatty acid supplementation strategies. At present, modifications of the fatty acid compositions of cell membranes represent an experimental model that has promoted increased understanding of lipid transportation, membrane remodelling, and the relationship between membrane lipids and membrane function. By addressing factors responsible for insufficient essential fatty acid levels, carginogenesis may be prevented or treated. The clinical feasibility of using modification of fatty acids in tumours or cancer by diet or perfusion as an adjunct to standard therapies should be tested.

Different ophthalmic artery origins: Embryology and clinical significance.

This retrospective study gives a summary of ophthalmic artery (OA) variations to serve as guidelines for surgical interventionists and trainees. Pubmed and Medline searches were conducted. The OA usually arises intradurally (superomedial, anteromedial, or rarely superolateral) from the internal carotid artery (ICA). Rare extradural origin (primitive dorsal OA) (PDOA) remnant and extremely rare interdural origin (primitive ventral OA) (PVOA) remnant are of significance when sectioning the dural ring. Rarely, a persistent PDOA with ICA origin, or a PDOA remnant with inferolateral trunk origin, enters the orbit via the superior orbital fissure (SOF) for sole or partial orbital supply. Extremely rare, the PDOA and PVOA persist and form double OAs that arise from the ICA and run via the SOF and optic foramen. Occasionally, the OA arises from the middle meningeal artery (MMA), when both the PDOA and VDOA regress and enter the orbit via the SOF. Sole orbital supply via the external carotid artery (ECA), i.e. meningo‐ophthalmic artery and/or MMA branches, or dual OAs (ECA and ICA origins) may occur. Other rare OA origins include anterior or posterior communicating artery; anterior or middle cerebral artery; basilar artery; posterior inferior cerebellar artery; and the carotid bifurcation. Primitive arteries (persistent or remnant), and/or abnormal anastomoses play pivotal roles in manifestations of OA variations. Of clinical importance are orbital collateral routes and dangerous extracranial‐intracranial anastomoses. Awareness of OA origins and collateral routes is imperative for transarterial embolizations or infusion chemotherapy in the ECA territory to prevent visual complications. Clin. Anat. 28:576–583, 2015.

Effects of conjugated linoleic acid and high oleic acid safflower oil in the treatment of children with HPV-induced laryngeal papillomatosis: a randomized, double-blinded and crossover preliminary study

BackgroundSurgery is the mainstay therapy for HPV-induced laryngeal papillomatosis (LP) and adjuvant therapies are palliative at best. Research revealed that conjugated-linoleic acid (CLA) may improve the outcome of virally-induced diseases. The effects of Clarinol™ G-80 (CLA) and high oleic safflower oil (HOSF) on children with LP (concomitant with surgery) were evaluated.DesignA randomized, double-blinded, crossover and reference-oil controlled trial was conducted at a South African medical university. Study components included clinical, HPV type/load and lymphocyte/cytokine analyses, according to routine laboratory methods.ParticipantsOverall: ten children enrolled; eight completed the trial; five remained randomized; seven received CLA first; all treatments remained double-blinded.InterventionChildren (4 to 12 years) received 2.5 ml p/d CLA (8 weeks) and 2.5 ml p/d HOSF (8 weeks) with a washout period (6 weeks) in-between. The one-year trial included a post-treatment period (30 weeks) and afterwards was a one-year follow-up period.Main outcome measuresChanges in numbers of surgical procedures for improved disease outcome, total/anatomical scores (staging system) for papillomatosis prevention/viral inhibition, and lymphocyte/cytokine counts for immune responses between baselines and each treatment/end of trial were measured.FindingsAfter each treatment all the children were in remission (no surgical procedures); after the trial two had recurrence (surgical procedures in post-treatment period); after the follow-up period three had recurrence (several surgical procedures) and five recovered (four had no surgical procedures). Effects of CLA (and HOSF to a lesser extent) were restricted to mildly/moderately aggressive papillomatosis. Children with low total scores (seven/less) and reduced infections (three/less laryngeal sub-sites) recovered after the trial. No harmful effects were observed. The number of surgical procedures during the trial (n6/available records) was significantly lower [(p 0.03) (95% CI 1.1; 0)]. Changes in scores between baselines and CLA treatments (n8) were significantly lower: total scores [(p 0.02) (95% CI −30.00; 0.00)]; anatomical scores [(p 0.008) (95% CI −33.00: -2.00)]. Immune enhancement could not be demonstrated.ConclusionsThese preliminary case and group findings pave the way for further research on the therapeutic potential of adjuvant CLA in the treatment of HPV-induced LP.

Comparison of the fatty acid compositions in intraepithelial and infiltrating lesions of the cervix: part III, saturated and unsaturated fatty acid profiles.

The purpose of the third part of this study is to construct a basic lipid model (this includes information regarding total and free saturated, monounsaturated and polyunsaturated fatty acid contents, as well as total and free fatty acid saturation and double bond indexes, and comparisons of total and free n-3, n-6, n-7 and n-9 fatty acids in normal epithelial tissue, and intraepithelial and infiltrating lesions of the cervix) which, together with the individual total and free fatty acid profiles given in parts I and II of this study, should provide an understanding of the turnover of total and free acids, especially essential fatty acids, during cervical carcinogenesis. Such information can serve as a sound basis for further studies in an attempt to access this disease process. We observed an increase in monounsaturated fatty acid values in cancer tissue compared with normal tissue and a decrease of saturated fatty acid values in cancer tissue compared with normal tissue. Based on our observations, we speculate that because of the depletion of polyunsaturated fatty acids, monounsaturated fatty acid are synthesized to compensate for this loss; a possible source for the monounsaturated fatty acids are the saturated fatty acids via elongation and/or desaturation. Of particular interest is the n-3 fatty acid docosahexaenoic acid, the most unsaturated lipid in the biological systems, detected in very small amounts only in cancer cells of the cervix.

Imaging of dual ophthalmic arteries: identification of the central retinal artery.

Identification of the origin of the central retinal artery (CRA) is imperative in tailoring angiographic studies to resolve a given clinical problem. A case with dual ophthalmic arteries (OAs), characterized by different origins and distinct branching patterns, is documented for training purposes. Pre-clinical diagnosis of a 9-year-old child who presented with a sharp wire in the left-side eyeball was primarily corneal laceration. For imaging, a selected six-vessel angiographic study with the transfemoral approach was performed. Embolization was not required and the wire could be successfully removed. Right-side OA anatomy was normal, while left-side dual OAs with external carotid artery (ECA) and internal carotid artery (ICA) origins were seen. The case presented with a left-side meningo-ophthalmic artery (M-OA) anomaly via the ECA, marked by a middle meningeal artery (MMA) (origin: Maxillary artery; course: Through foramen spinosum) with normal branches (i.e. anterior and posterior branches), and an OA variant (course: Through superior orbital fissure) with a distinct orbital branching pattern. A smaller OA (origin: ICA; course: Through optic foramen) with a distinct ocular branching pattern presented with the central retinal artery (CRA). The presence of the dual OAs and the M-OA anomaly can be explained by disturbed evolutionary changes of the primitive OA and stapedial artery during development. The surgical interventionist must be aware of dual OAs and M-OA anomalies with branching pattern variations on retinal supply, because of dangerous extracranial–intracranial anastomotic connections. It is of clinical significance that the origin of the CRA from the ICA or ECA must be determined to avoid complications to the vision.

Imaging of Unilateral Meningo-ophthalmic Artery Anomaly in a Patient with Bilateral Nasopharyngeal Angiofibroma.

A 12-year-old boy with epistaxis presented with a rare midline nasopharyngeal angiofibroma that extended lateral into the pterygoid and infratemporal fossae. Pre-operative angiography revealed bilateral prominent feeder arteries and two major anastomotic connections, and a rare left meningo-ophthalmic artery (M-OA) anomaly that was the sole path of supply to the eye. A literature search using Pubmed and Medline was conducted. For imaging, a six-vessel study (i.e. external and internal carotid and vertebral arteries on both sides) was selected. Embolization of prominent tumor feeder arteries was unsafe for tumor extirpation, but super-selective embolization of both sphenopalatine arteries was performed to control epistaxis. The M-OA anomaly that originated from the maxillary artery (MA) was marked by an ophthalmic artery (OA) variant with orbital and ocular divisions that coursed through the superior orbital fissure and optic foramen, respectively, each with distinct branching patterns, a middle meningeal artery (MMA) with normal branches (i.e. anterior and posterior branches), and two branch variations (i.e. lacrimal and meningeal branches) that originated from the anterior branch of the MMA. The lacrimal branch coursed through a cranio-orbital foramen, but the meningeal branch remained outside the orbit. The anatomy of the right OA was normal. The left M-OA anomaly was considered incidental and not tumor-related since the tumor was more prominent on the right side, and no intra-orbital infiltrations occurred. Of clinical significance is that proximal embolization of MA or MMA carries a high risk of visual impairment in cases where M-OA anomalies are the sole mode of supply to the eye.