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Gallbladder cancer (GBC) has a poor prognosis with a 5-year survival rate suggesting the need for more effective treatment strategies. Studying the cross-talk of several pathways involved in crucial cellular and biological processes such as cell growth, proliferation, migration and apoptosis would prove beneficial in identifying key players of GBC progression and targeting them. This review highlights several pathways known to be dysregulated in GBC onset and progression and describes known and potential targets. Within these pathways, there are proteins involved in the signalling cascade, which may be targeted as potential biomarkers and drug targets. Furthermore, the cross-talk of these pathways is investigated in the context of GBC and the implications thereof. A better understanding of the pathways involved in GBC pathogenesis will aid clinicians in the prognosis, diagnosis and treatment of patients. There are significant clinical implications of GBC pathway-based studies as they permit the understanding of onset and progression of the disease.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a characteristic dysregulated metabolism. Abnormal clinicopathological features linked to defective metabolic and inflammatory response pathways can induce PDAC development and progression. In this study, we investigated the metabolites and lipoproteins profiles of PDAC patients of African ancestry. Nuclear Magnetic Resonance (NMR) spectroscopy was conducted on serum obtained from consenting individuals (34 PDAC, 6 Chronic Pancreatitis, and 6 healthy participants). Seventy-five signals were quantified from each NMR spectrum. The Liposcale test was used for lipoprotein characterization. Spearman’s correlation and Kapan Meier tests were conducted for correlation and survival analyses, respectively. In our patient cohort, the results demonstrated that levels of metabolites involved in the glycolytic pathway increased with the tumour stage. Raised ethanol and 3-hydroxybutyrate were independently correlated with a shorter patient survival time, irrespective of tumour stage. Furthermore, increased levels of bilirubin resulted in an abnormal lipoprotein profile in PDAC patients. Additionally, we observed that the levels of a panel of metabolites (such as glucose and lactate) and lipoproteins correlated with those of inflammatory markers. Taken together, the metabolic phenotype can help distinguish PDAC severity and be used to predict patient survival and inform treatment intervention.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a characteristic dysregulated metabolism. Abnormal clinicopathological features linked to defective metabolic and inflammatory response pathways can induce PDAC development and progression. In this study, we investigated the metabolites and lipoproteins profiles of PDAC patients of African ancestry. Nuclear Magnetic Resonance (NMR) spectroscopy was conducted on serum obtained from consenting individuals (34 PDAC, 6 Chronic Pancreatitis, and 6 healthy participants). Seventy-five signals were quantified from each NMR spectrum. The Liposcale test was used for lipoprotein characterization. Spearman’s correlation and Kapan Meier tests were conducted for correlation and survival analyses respectively. In our patient cohort, the results demonstrated that levels of metabolites involved in the glycolytic pathway increased with the tumour stage. Raised ethanol and 3-hydroxybutyrate were independently correlated with a shorter patient survival time, irrespective of tumour stage. Furthermore, increased levels of bilirubin resulted in an abnormal lipoprotein profile in PDAC patients. Additionally, we observed that the levels of a panel of metabolites (such as glucose, lactate) and lipoproteins correlated with those of inflammatory markers. Taken together, the metabolic phenotype can help distinguish PDAC severity and be used in predicting patient survival and in informing treatment intervention.

Pancreatic cancer is one of the most deadly cancers, ranking amongst the top leading cause of cancer related deaths in developed countries. Features such as dense stroma microenvironment, abnormal signaling pathways, and genetic heterogeneity of the tumors contribute to its chemoresistant characteristics. Amongst these features, growth factors have been observed to play crucial roles in cancer cell survival, progression, and chemoresistance. Here we review the role of the individual growth factors in pancreatic cancer chemoresistance. Importantly, the interplay between the tumor microenvironment and chemoresistance is explored in the context of pivotal role played by growth factors. We further describe current and future potential therapeutic targeting of these factors.

Background: The heterogeneity of receptor profiles in breast cancer is well known. The differing receptor profiles of primary breast cancer and nodal metastases have been investigated and found to range between 10–50% depending on the hormone receptor tested. A study comparing the hormone status of primary breast cancers and the synchronous ipsilateral involved sentinel lymph node has not been performed in a South African population. Method: This is a prospective study where two specialist radiologists performed the simultaneous core needle biopsies of the primary breast cancer and the clinically positive axillary nodes. All receptor status analysis was conducted by one specialist histopathologist. Results: Of 141 patients who gave written informed consent for this study, 29 were excluded; 112 patients met the inclusion criteria. Anonymised demographics of age, clinical stage, HIV status and metastatic screening were recorded. The simultaneous biopsies and receptor measurements identified 10 patients with discordant receptor status in the positive axillary lymph nodes. In each case, the receptor profile of the axillary lymphatic metastases was more aggressive than that of the primary tumour. The luminal A subtype had a significantly greater risk of discordance than other subtypes (p = 0.02). Conclusion: Core needle biopsy and receptor analysis should be considered on the positive axillary nodes in breast cancer patients. Adjuvant treatment should be targeted to the receptor profile of the lymph node metastases.&nbsp

Background Growth factors and cytokines mediate complex interactions between cells within the breast tumour microenvironment. In advanced cancer, an excess of regulatory T (TREG) lymphocytes and lack of natural killer (NK) cells in tumour-infiltrating lymphocyte populations may reflect a shift to pro-tumorigenic adaptive immune mechanisms. To facilitate targeted assessment of the interactions between tumour and immune cells ex vivo, three-dimensional (3D) culture systems are able to better recapitulate the in vivo microenvironment, recreating the anatomy of tumours. Materials and methods We used 3D breast tumour models to determine morphological alterations, and the levels of secreted transforming growth factor-β (TGFβ) and induced cytokines. 3D luminal phenotype models and basal phenotype models were generated by culturing NK cells and CD4+CD25+ TREG cells with MCF-7 cells and MDA-MB-231 cells respectively, in growth factor-reduced Matrigel. TGFβ was qualitatively assessed by immunolocalisation and cytokine data from culture supernatant was acquired with a multiplex cytokine assay. Traditional statistical analysis and principal component analysis were employed to unravel the cytokine response. Results and conclusion We identified that an interleukin-6 (IL6)-chemokine axis associated with TGFβ is primarily responsible for differences detected between breast cancer models, with luminal and basal phenotype tumours responding differentially to immune mediation. Identified cytokines are implicated in facilitating tumour cell subversion of immune cell function to promote an invasive phenotype. Moreover, the disruption of the extracellular matrix and failure to form well-differentiated tumour masses/networks is indicative of enhanced malignancy. Tumour cells are implicated in promoting a pro-inflammatory microenvironment to attenuate NK cell function and in inducing a pro-tumorigenic profile that is facilitated by TREG lymphocytes.

Pancreatic cancer accounts for 2.8% of new cancer cases worldwide and is projected to become the second leading cause of cancer-related deaths by 2030. Patients of African ancestry appear to be at an increased risk for pancreatic ductal adenocarcinoma (PDAC), with more severe disease and outcomes. The purpose of this study was to map the proteomic and genomic landscape of a cohort of PDAC patients of African ancestry. Thirty tissues (15 tumours and 15 normal adjacent tissues) were obtained from consenting South African PDAC patients. Optimisation of the sample preparation method allowed for the simultaneous extraction of high-purity protein and DNA for SWATH-MS and OncoArray SNV analyses. We quantified 3402 proteins with 49 upregulated and 35 downregulated proteins at a minimum 2.1 fold change and FDR adjusted p-value (q-value) ≤ 0.01 when comparing tumour to normal adjacent tissue. Many of the upregulated proteins in the tumour samples are involved in extracellular matrix formation (ECM) and related intracellular pathways. In addition, proteins such as EMIL1, KBTB2, and ZCCHV involved in the regulation of ECM proteins were observed to be dysregulated in pancreatic tumours. Downregulation of pathways involved in oxygen and carbon dioxide transport were observed. Genotype data showed missense mutations in some upregulated proteins, such as MYPN, ESTY2 and SERPINB8. Approximately 11% of the dysregulated proteins, including ISLR, BP1, PTK7 and OLFL3, were predicted to be secretory proteins. These findings help in further elucidating the biology of PDAC and may aid in identifying future plausible markers for the disease.

Pancreatic cancer is an aggressive cancer, making it a leading cause of cancer‑related deaths. It is characteristically resistant to treatment, which results in low survival rates. In pancreatic cancer, immune cells undergo transitions that can inhibit or promote their functions, enabling treatment resistance and tumor progression. These transitions can be fostered by metabolic pathways that are dysregulated during tumorigenesis. The present review aimed to summarize the different immune cells and their roles in pancreatic cancer. The review also highlighted the individual metabolic pathways in pancreatic cancer and how they enable transitions in immune cells. Finally, the potential of targeting metabolic pathways for effective therapeutic strategies was considered.

Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest human malignancies with a dismal prognosis. During PDAC progression, the immune response is affected as cancer cells evade detection and elimination. Recently, there have been advances in the treatment of PDAC using immunotherapy, although a lot more work is yet to be done. In this review, we discuss these advances, challenges and potentials. We focus on existing and potential immune targets for PDAC, drugs used to target them, and some clinical trials conducted so far with them. Finally, novel targets in the tumour microenvironment such as stromal cells and other potential future areas to explore including bacterial therapy and the use of neoantigens in immunotherapy are highlighted.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancer types, and it is associated with a 5-year survival rate of

Although nitric oxide (NO) plays an important role in blood pressure (BP) control, whether variation of genes involved in regulating the synthesis of NO infl uences BP is uncertain. As the heritability of BP is stronger for ambulatory than it is for conventional BP, we assessed the independent association of the well described functional exon 7 Glu298Asp variant of the eNOS gene with the presence of hypertension in 511 randomly selected normotensive control participants and 503 hypertensives with a diagnosis of hypertension confi rmed with 24-hour ambulatory BP profiles whilst off therapy. We also assessed the relationship between eNOS genotype and 24 hour ambulatory BP. Comparisons of genotype and allele frequencies indicated a lack of association of the exon 7 Glu298Asp gene variant with hypertension (Odds ratio of genotype predicting the presence of hypertension=0.97, confidence interval=0.70-1.30, p=0.92). However, patients with the Glu/Glu genotype of the Glu298Asp variant (n=424) had increased 24-hour systolic and diastolic blood pressures (152±1/97±1 mm Hg) in comparison to patients heterozygous for the Glu298Asp variant or homozygous for the 298Asp allele (n=79) (145±1/94±1 mm Hg, p‹0.005 for systolic BP and p‹0.001 for diastolic BP after multiple adjustments including age, gender, body mass index and the presence of diabetes mellitus). Differences in systolic and diastolic BP between genotype groups were noted during the day as well as at night. The association of eNOS genotype with ambulatory BP translated into an increased risk of more severe grades of hypertension in patients with the Glu/Glu genotype (grade II and III vs. grade I, Odds ratio=2.20, confidence interval=1.34-3.59, p‹0.0002). In conclusion, a functional gene variant (Glu298Asp) at the eNOS locus contributes ~1.4-2.5% to the variation in ambulatory blood pressure within hypertensives, but is not associated with the presence of hypertension in patients in whom the diagnosis has been confirmed by 24-hour ambulatory BP values. The relationship between eNOS genotype and 24-hour ambulatory BP and the severity of hypertension warrants further study.

Background: Present on arrival infection is a common indication for admission of surgical patients initially managed at primary care level. We aimed to describe the demographic and disease profile of patients presenting with infection requiring surgical management, describe determinants of patients’ health-seeking behaviour, and identify barriers to care. Methods: A prospective descriptive questionnaire-based study was conducted at Edenvale General Hospital between February 2014 and October 2016. Minors were excluded. Results: Eighty-nine patients participated. Abscesses (26%), diabetic foot (22%), and cellulitis (16%) were the commonest categories of infection necessitating admission. The majority of patients were South African (88%), Black African (82%), males (58%), without medical aid (99%), who were not formally employed (58%), were from poor households (74%), inhabited some form of formal housing (90%), were in charge of decisions regarding personal health (80%), and first sought help at the primary care level (71%). Delay to presentation was noted in 69% of patients, and delay to referral in 46%. Age, race, history of diabetes, and main source of monthly income were significant variables in delayed presentation (p

Interleukin-21 (IL-21) is a cytokine associated with tissue inflammation, autoimmune and infectious diseases. Organ dysfunction and death can occur in patients with acute pancreatitis (AP) in two distinct clinical phases. Initially, a systemic inflammatory response syndrome may be followed by systemic sepsis from infected pancreatic necrosis, known as the "second hit." The expression and possible role of IL-21 in AP has not been established.Thirty-six patients with mild, moderate, and severe AP (SAP) were enrolled. Peripheral blood samples of patients were drawn on days 7, 9, 11, and 13. Reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay were performed to determine the expression and concentration of IL-21.Interleukin-21 mRNA levels increased significantly at day 9 in severe (P = 0.002) pancreatitis compared with both the mild and control patient groups. At the protein level, IL-21 was elevated in SAP patients compared with those with mild pancreatitis, although this was not significant. Furthermore, day 9 IL-21 was elevated in septic SAP patients and patients with pancreatic necrosis.Interleukin-21 is transiently elevated in SAP compared with the mild/moderate group, and hence IL-21 may contribute to the immune imbalance that occurs in AP.

Oral supplementation with the amino acid arginine, the precursor of the vasodilator nitric oxide (NO), is associated with a reduction in blood pressure (BP). However, it is uncertain whether a decreased plasma arginine concentration predicts increases in BP. We assessed the relationship between fasting plasma arginine or other amino acid concentrations and 24 hour ambulatory BP in 75 nevertreated participants recruited from the Johannesburg area, 55 of whom were male. Plasma amino acid concentrations were measured with high performance liquid chromatography-mass-spectrometry. Plasma arginine concentrations were not inversely correlated with ambulatory BP. However, plasma arginine concentrations were increased in 36 participants with a mean daytime systolic BP >140 mm Hg (61 ± 17 μmol/L) as compared to the remaining participants (54 ± 15 μmol/L, p‹0.05). Moreover, plasma arginine concentrations were positively correlated with 24-hour diastolic BP (r=0.26, p‹0.05). In males with a BMI‹30kg/m2, plasma arginine concentrations were positively correlated with both night diastolic (r=0.46, p‹0.005) and systolic (r=0.42, p‹0.005) BP. In a multivariate model with adjustments for age gender, body mass index, and other amino acid concentrations, plasma arginine concentrations were independently and positively associated with night diastolic BP (p‹0.05). In conclusion plasma arginine concentrations are positively associated with ambulatory BP in a group of participants of African descent in South Africa. These data do not support the notion that deficiencies of arginine, the amino acid substrate for NO, are related to increases in BP in groups of African ancestry living in South Africa. However, as with other ethnic groups, the positive relationship between plasma arginine concentrations and BP suggests a reduced capacity to utilise the amino acid substrate for NO synthesis.

Cardiovascular disease accounted for nearly 40 % of all deaths in the USA in 2000 (American Heart Association, Heart Disease and Stroke Statistics—2003 Update. American Heart Association, 2002). Hypertension, heart failure, and metabolic diseases such as obesity, type 2 diabetes mellitus, and hypercholesterolaemia have impaired endothelial function as a common feature (Bode-Boger et al., Pharmacol Therapeut 114:295–306, 2007). Endothelial dysfunction, arising from underlying reduced bioavailability of nitric oxide (NO), causes inflammation and oxidative stress to drive the atherosclerotic process (Tousoulis et al., Curr Vasc Pharmacol 10:4–18, 2012; Vita, Circulation 124:e906–e912, 2011).

High blood pressure (BP) or hypertension is the major risk factor for cardiovascular events including stroke as well as kidney and heart failure (Addo et al. Hypertension 50:1012–1018, 2007). An estimated 600 million persons worldwide are affected by hypertension (Vasdev and Gill. Int J Angiol 17:7–22, 2008) with the prevalence increasing rapidly in sub-Saharan Africa (Addo et al. Hypertension 50:1012–1018, 2007). Between 2011 and 2025, the projected cost of non-communicable disease to the economy of the United States was estimated at $7.28 billion with cardiovascular disease accounting for more than half of this cost (World Health Organisation. A global brief on hypertension. Document WHO/DCO/WHD/2013.2. www.apps.who/int/iris/bitstream/10665/1/WHO_DCO_WHD_2013.2_eng.pdf. Downloaded 12 Aug 2014). The prevalence of hypertension in South Africa is between 14.6 and 24.4 %, and in 1991, the cost to the economy was estimated at $400 million (R 4–5 billion) or 7.5 % of healthcare expenditure (Pestana et al. S Afr Med J 86:679–684, 1996; Dougherty et al. Cent Afr J Med 42:21–24, 1996). Of concern is that of patients on treatment, only 30 % have blood pressures adequately controlled, with patients inadequately controlled still at excess risk for adverse cardiovascular events (Addo et al. Hypertension 50:1012–1018, 2007). Furthermore, traditional risk factors do not fully account for the burden and risk for cardiovascular disease seen in patients.

Wound healing is required to effectively stabilise and repair injury (Sen et al. Wound Repair Regen 17:763–771, 2009; Enoch and Leaper. Surgery 23:37–42, 2005). In an optimal system, the process of wound healing occurs in an orderly and controlled series of phases: homeostasis, inflammation, proliferation and remodelling (Singer and Clark. N Engl J Med 341:738–746, 1999; Eming et al. J Invest Dermatol 127:514–525, 2007). However, complications including infection and inappropriate activation of the immune system can impair this process and result in delayed healing and the development of chronic wounds. Such complications impact significantly on health-care resources, and in 2010, the cost of treating and caring for wounds in the United States alone was estimated at $25 billion (Enoch and Leaper. Surgery 23:37–42, 2005). It is therefore important to determine factors that influence the wound healing process to optimise and facilitate appropriate healing.

Study Type – Symptom Prevalence (prospective cohort) Level of Evidence 2a What's known on the subject? and What does the study add? Nocturnal enuresis is a common childhood problem. Although its prevalence is known in many countries, no data are available from South Africa and it is difficult to extrapolate data from developed countries to a population with such diverse conditions and resource-poor settings. This study is the first to report on the 16% prevalence rate and the low level of parental knowledge of enuresis in South African children aged between 5 and 10 years. OBJECTIVES • To establish the prevalence of NE in 5–10 year old South African children in a cross-sectional study using a parent-completed questionnaire. • To establish the parental perception and associated factors of mono-symptomatic nocturnal enuresis (MNE) treatment and treatment success rates in 5–10 year old children from South Africa. PATIENTS AND METHODS • A total of 4700 questionnaires were distributed to children at 37 selected schools willing to participate from South Africa. Parents anonymously filled out the questionnaire. • Data were reported as frequencies and percentages of NE in tables according to different gender and age groups. • The Chi-square test compared proportions between groups and Fisher's Exact test corrected for small numbers of observations (n ≤ 5). Age differences were determined using Student's t-test. A P-value ≤0.5 was considered to be statistically significant. RESULTS • The questionnaire's response rate was 72.1%, with 3389 children included in the study. • The overall prevalence of NE was 16.0%–14.4% of children suffered from mono-symptomatic NE (MNE). The prevalence of NE in boys was double that in that in girls. • Only 28.3% had received some form of treatment, whereas 13.5% had been medically treated by a doctor. Parents’ awareness of treatment modalities available is outdated and most of the management of MNE was done by parents themselves, albeit with low success rates. • A positive family history was found in 50.5% of children suffering from MNE. • Constipation was a problem in 15.8% of children with enuresis. CONCLUSIONS • This is the first study to estimate the prevalence of NE and report on the parental perception and possible associated factors of enuresis in children from South Africa. The study showed that South African children have a similar prevalence rate of NE (16%) when compared with other countries. • The possible associated factors with MNE in South Africa include constipation and a family history of enuresis. • Finally, there are low levels of parental knowledge of treatment modalities of MNE, leaving many children untreated.

Objectives One year of antihypertensive therapy may normalise left ventricular (LV) structure in 51% of hypertensive patients of European descent. Whether similar effects can be achieved in patients of African descent, who have a high prevalence of concentric LV hypertrophy (LVH) and remodelling, is unknown. Methods In 103 hypertensive patients in the Baragwanath Hypertension study we evaluated the prevalence of residual LV structural changes (echocardiography) after four and 13 months of stepwise antihypertensive therapy. Results After 13 months of therapy, 24-hour blood pressure control was achieved in 47% of patients. At baseline, 51.5% of patients had concentric LVH, 19% eccentric LVH and 12% concentric LV remodelling. Despite changes in LV mass index (p < 0.01) and relative wall thickness (p < 0.05) with treatment, the proportion of patients with a normal LV mass or geometry increased only from 17.5 to 25% (p > 0.05), while 26% remained with concentric LVH (p < 0.001 compared to baseline), 25% with eccentric LVH and 23% with concentric LV remodelling (p < 0.05 compared to baseline). Residual structural changes were associated with 24-hour pulse pressure (p = 0.02), but not with 24-hour systolic or diastolic blood pressure or clinic blood pressure. Conclusions Even after a year of antihypertensive therapy, a high proportion (74%) of hypertensives of African ancestry retained residual LV structural changes, an effect that was associated with 24-hour pulse pressure but not systolic or diastolic blood pressures or clinic blood pressure in this ethnic group.

This trial was undertaken to assess the efficacy of a multimodality management regime used for the prevention of hypertrophic scars. It follows previous research and experience (A.D. Widgerow et al, Aesthetic Plast Surg, 24(3):227–234, 2000) with a similar program but with the addition of active agents with specific effects against prolonged inflammation and enhanced hydrative capacity. The modalities specifically targeted are tension on the scar, hydration of the scar, collagen maturation, and controlled inflammation. Tape was impregnated with a combination of agents providing an occlusive dressing aimed at combatting exaggerated scarring. Patients who had undergone surgery were stratified into four groups: Group 1, 60 patients/60 scars following simple skin excisions, 30 treated scars, 30 untreated scars; Group 2, 20 patients/40 scars, each patient with two excisions, one treated, one untreated; Group 3, 10 patients/20 scars following bilateral breast surgery, one side treated with tape alone, one side treated with tape and gel; Group 4, 30 patients with varying cosmetic procedures/50 scars, all treated and compared with historical outcomes for hypertrophic scarring. Thus, 170 scars were assessed in 120 patients. Results were assessed at 1, 2, and 6 months using a combination of accepted scar assessment techniques. By amalgamating the Vancouver, Manchester, and morphologic table systems together with Patient and Observer Scar Assessment analyses, a comprehensive assessment of scar outcomes was undertaken and comparisons were made with control groups. Treated groups showed improvement outcomes in all variations of assessment. Patient and observer assessments correlated well, and morphologic appearances of the scars following the final assessment at 6 months showed statistically significant positive scar outcomes in the treatment groups. The multimodality approach to scar control showed significant benefits in the patient groups tested in this series.

Objective Nonfunctional popliteal entrapment is due to embryologic maldevelopment within the popliteal fossa. Functional entrapment occurs in the apparent absence of an anatomic abnormality. Gastrocnemius hypertrophy has been associated with the latter. Both forms of entrapment may cause arterial injury and lower limb ischemia. This study assessed the attachment of the medial head of the gastrocnemius muscle in healthy occluders and healthy nonoccluders. Methods Provocative tests were used to identify 58 nonoccluders and 16 occluders. Ten subjects from each group underwent magnetic resonance imaging evaluation of the popliteal fossa. The medial head of the gastrocnemius muscle attachment was assessed in the supracondylar, pericondylar, and intercondylar areas. Results In the occluder group, significantly more muscle was attached towards the femoral midline (supracondylar), around the lateral border of the medial condyle (pericondylar), and within the intercondylar fossa. Conclusion The more extensive midline position of the medial head of the gastrocnemius in occluders is likely to be a normal embryological variation. Forceful contraction results in compression and occlusion of the adjacent popliteal artery. The clinical significance of these anatomic variations remains unclear. However, these new observations may provide insight for future analysis of the causes and natural history of functional compression and the potential progression to clinical entrapment.

Background Failed fusion surgery remains difficult to treat. Few published data on disc replacement surgery after failed fusion procedures exist. Our objective was to evaluate outcomes of junctional lumbar disc replacement after previous fusion surgery and to correlate outcome with radiological changes to parameters of sagittal balance. Methods Out of a single-center prospective registry of 290 patients with 404 lumbar disc replacements, 27 patients had had a previous lumbar fusion operation on 1 to 4 lumbar segments and had completed a mean follow- up of 33 months (range: 18–56). We correlated the clinical outcome measures (patient satisfaction, 10-point pain score, and Oswestry Disability Index [ODI] score) to parameters of spinal sagittal alignment (sacral tilt, pelvic tilt, pelvic incidence, and lumbar lordosis). Results Postoperative hospital stay averaged 3.3 days (range: 2–8). Previously-employed patients went back to their jobs with a mean of 32 days (range: 21–42) after the procedure. At the latest follow-up, 1 of the patients considered the outcome to be poor, 3 fair, 8 good, and 15 excellent. Twenty-four patients “would undergo the operation again.” Average pain score decreased from 9.1 ± 1.0 (SD) to 3.2 ± 2.1 (P < .01). Average ODI decreased from 50.2 ± 9.9 preoperatively to 21.7 ± 14.2 (P ≤ .01). We found the change in pelvic tilt to be an independent predictor of better clinical outcome by multivariate analysis (P < .05). Conclusions In patients with junctional failure adjacent to a previous posterolateral fusion, disc replacement at the junctional level(s), compared with osteotomy and fusion surgery, offers the advantage of maintaining segmental mobility and correcting the flat-back deformity through a single approach with less operative time and blood loss. Early- to intermediate-term results are promising. The influence of changes in spinal sagittal alignment on clinical outcome needs to be addressed in future research. Clinical Relevance This is the first study on “junctional disc replacement patients” correlating clinical outcome to changes in spinal/pelvic alignment.

BACKGROUND: The tallest animal on Earth, the giraffe (Giraffa camelopardalis) is endowed with a mean arterial blood pressure (MAP) twice that of other mammals. The kidneys reside at heart level and show no sign of hypertension related damage. We hypothesized that a species-specific evolutionary adaption in the giraffe kidney allows normal for size renal hemodynamics and glomerular filtration rate (GFR) despite a MAP double that of other mammals.METHODS: Fourteen anaesthetized giraffes were instrumented with vascular and bladder catheters to measure glomerular filtration rate (GFR) and effective renal plasma flow (ERPF). Renal interstitial hydrostatic pressure (RIHP) was assessed by inserting a needle into the medullary parenchyma. Doppler ultrasound measurements provided renal artery resistive index (RI). Hormone concentrations as well as biomechanical, structural, and histological characteristics of vascular and renal tissues were determined.RESULTS: GFR averaged 342±99 ml min(-1) and ERPF 1252±305 ml min(-1) . RIHP varied between 45 and 140 mmHg. Renal pelvic pressure was 39±2 mmHg and renal venous pressure 32±4 mmHg. A valve-like structure at the junction of the renal and vena cava generated a pressure drop of 12±2 mmHg. RI was 0.27. The renal capsule was durable with a calculated burst pressure of 600 mmHg. Plasma renin and AngII were 2.6±0.5 mIU/l and 9.1±1.5 pg/ml, respectively.CONCLUSION: In giraffes, GFR, ERPF and RI appear much lower than expected based on body mass. A strong renal capsule supports a RIHP which is >10-fold that of other mammals effectively reducing the net filtration pressure and protecting against the high MAP. This article is protected by copyright. All rights reserved.

Three-dimensional (3D) culture approaches to investigate breast tumour progression are yielding information more reminiscent of the in vivo microenvironment. We have established a 3D Matrigel system to determine the interactions of luminal phenotype MCF-7 cells and basal phenotype MDA-MB-231 cells with regulatory T lymphocytes and Natural Killer cells. Immune cells were isolated from peripheral blood using magnetic cell sorting and their phenotype validated using flow cytometry both before and after activation with IL-2 and phytohaemagglutinin. Following the establishment of the heterotypic culture system, tumour cells displayed morphologies and cell-cell associations distinct to that observed in 2D monolayer cultures, and associated with tissue remodelling and invasion processes. We found that the level of CCL4 secretion was influenced by breast cancer phenotype and immune stimulation. We further established that for RNA extraction, the use of proteinase K in conjunction with the Qiagen RNeasy Mini Kit and only off-column DNA digestion gave the best RNA yield, purity and integrity. We also investigated the efficacy of the culture system for immunolocalisation of the biomarkers oestrogen receptor-α and the glycoprotein mucin 1 in luminal phenotype breast cancer cells; and epidermal growth factor receptor in basal phenotype breast cancer cells, in formalin-fixed, paraffin-wax embedded cultures. The expression of these markers was shown to vary under immune mediation. We thus demonstrate the feasibility of using this co-culture system for downstream applications including cytokine analysis, immunolocalisation of tumour biomarkers on serial sections and RNA extraction in accordance with MIQE guidelines.

Giraffes – the tallest extant animals on Earth – are renowned for their high central arterial blood pressure, which is necessary to secure brain perfusion. The pressure which may exceed 300 mmHg has historically been attributed to an exceptionally large heart. Recently, this has been refuted by several studies demonstrating that the mass of giraffe heart is similar to that of other mammals when expressed relative to body mass. It remains enigmatic, however, how the normal-sized giraffe heart generates such massive arterial pressures. We hypothesized that giraffe hearts have a small intraventricular cavity and a relatively thick ventricular wall, allowing for generation of high arterial pressures at normal left ventricular wall tension. In nine anaesthetized giraffes (495±38 kg), we determined in vivo ventricular dimensions using echocardiography along with intraventricular and aortic pressures to calculate left ventricular wall stress. Cardiac output was also determined by inert gas rebreathing to provide an additional and independent estimate of stroke volume. Echocardiography and inert gas-rebreathing yielded similar cardiac outputs of 16.1±2.5 and 16.4±1.4 l min−1, respectively. End-diastolic and end-systolic volumes were 521±61 ml and 228±42 ml, yielding an ejection fraction of 56±4%, and a stroke volume of 0.59 ml kg−1. Left ventricular circumferential wall stress was 7.83±1.76 kPa. We conclude that, relative to body mass, a small left ventricular cavity and a low stroke volume characterizes the giraffe heart. The adaptations result in typical mammalian left ventricular wall tensions, but results in lowered cardiac output.

Giraffes are the tallest living animals and endowed with the highest arterial blood pressure of any animal on Earth. Here we present novel data on kidney function in this extraordinary animal obtained over the course of two major expeditions in 2010 and 2012. As expected, the anaesthetised giraffes had very high mean arterial blood pressure ranging between 150 and 300 mmHg. However, despite the high filtration pressure, the rate of glomerular filtration (GFR) was only 0.7 ± 0.2 ml/min/kg, which is approximately 40 % below similar-sized mammals. The renal blood flow of 3.1 l/min accounts for approximately 20 % of cardiac output, and the calculated filtration fraction (GFR/ERPF) was approximately 0.3, and hence within typical mammalian values. The normal kidney function of the giraffes appears due to very high interstitial pressures within the kidney, a feature that is possible due to the very thick and strong capsule surrounding the kidney in combination with a vascular valve at the entrance of the renal vein into the abdominal cava. These relatively simple structural modifications normalize the Starling forces driving filtration over the Bowman capsula.

Background In the treatment of hypertension in subjects of African origins, although hydrochlorothiazide (HCTZ) is not as effective as calcium channel blockers, indapamide is superior to HCTZ. In the present study we therefore compared the effects of slow release (SR) indapamide with the calcium channel blocker amlodipine, when used as initial therapy, on blood pressure (BP) and left ventricular mass (LVM) during 6 months of treatment in this group. Methods Patients with a mean daytime ambulatory diastolic BP ≥90 mm Hg and ≤110 mm Hg ( n = 125, aged 53 ± 11 years, 68% women) were randomized to receive open-label 1.5 mg of indapamide SR or 5 mg of amlodipine. If daytime ambulatory diastolic BP at 1 month was ≥90 mm Hg, 4 mg of perindopril was added to indapamide SR or the dose of amlodipine was increased to 10 mg. Results After 1 month of therapy, there was an equivalent decline in systolic and diastolic BP in both groups ( P n = 62) the daytime BP decreased from 153 ± 12/101 ± 6 mm Hg to 138 ± 15/92 ± 10 mm Hg and for amlodipine ( n = 58), it decreased from 152 ± 13/99 ± 5 mm Hg to 138 ± 12/91 ± 8 mm Hg. At 6 months daytime ambulatory BP decreased to 130 ± 15/86 ± 8 mm Hg and to 129 ± 11/85 ± 5 mm Hg for the indapamide SR ( n = 42) and amlodipine ( n = 44) treatment groups, respectively. Both groups showed equivalent regression of LVM index and relative wall thickness. Conclusions These data suggest that in hypertensive patients of African ancestry initiating therapy with 1.5 mg of indapamide SR and then adding 4 mg of perindopril is equally as effective as amlodipine therapy at reducing BP, and modifying target organ damage.

Background— Inflammatory immune activation commonly occurs in heart failure and may perpetuate this syndrome. We sought to determine whether the immunomodulating agent pentoxifylline enhances left ventricular function in patients with ischemic cardiomyopathy. We also investigated the effect of therapy on levels of brain natriuretic peptide (NT-pro BNP), C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), and the marker of apoptosis, Fas/Apo-1. Methods and Results— In a single-center, prospective, randomized, double-blind, placebo-controlled study, 38 patients with ischemic cardiomyopathy received pentoxifylline 400 mg TID or placebo in addition to standard therapy. Clinical assessment, radionuclide ventriculography, echocardiography, and blood analyses were performed at baseline and after 6 months. There were no differences in baseline characteristics between the groups. Five patients died (4 in the placebo group). Pentoxifylline treatment resulted in an improvement in functional class ( P P P Conclusions— In patients with heart failure due to ischemic left ventricular dysfunction, the addition of pentoxifylline to standard therapy results in improvements in clinical status and radionuclide ejection fraction, which are accompanied by reductions in plasma markers of inflammation, prognosis, and apoptosis.

Background The severity of hypertension has prognostic significance. Previous studies have assessed the relationship between renin-angiotensin-aldosterone system (RAAS) genotype and the severity of hypertension in either treated patients or those who have only recently discontinued treatment. Methods We assessed the impact of RAAS genotype on ambulatory and office blood pressure (BP) in 231 newly diagnosed hypertensive patients of African ancestry who had never received therapy. Subjects were genotyped for variants of the angiotensin-converting enzyme (insertion/deletion), angiotensinogen (M235T, −20A→C), and aldosterone synthase ( CYP11B2 )(−344C→T) genes. Results The CYP11B2 gene polymorphism was associated with systolic BP (SBP). In comparison to subjects with at least one copy of the −344C allele (n = 75), patients who were homozygous for the −344T allele (n = 156) had both higher ambulatory SBP (150 ± 1 v 144 ± 1 mm Hg, P = .002 before and P = .01 after adjusting for multiple genotyping) and office SBP (163 ± 2 v 156 ± 2 mm Hg, P = .01 before and P = .05 after adjusting for multiple genotyping). Neither the angiotensin-converting enzyme insertion/deletion nor the angiotensinogen gene polymorphisms were associated with ambulatory or office SBP or diastolic BP (DBP). The CYP11B2 gene variant also did not affect DBP. Conclusion A variant within the CYP11B2 locus has a clinically important impact on the severity of SBP changes in individuals with newly diagnosed hypertension who are of African ethnicity.

Background— The extent to which genes modify the relationship between risk factors for hypertension and blood pressure (BP) is unclear. As angiotensinogen is expressed in adipose tissue and angiotensinogen (AGT) gene promoter variants influence the production of angiotensinogen, we evaluated the role of AGT gene variants as potential modifiers of body size–BP relations. Methods and Results— Five hundred twenty-one hypertensives of African origin sampled from a group with a high mean body mass index (BMI) had 24-hour ambulatory BP (ABP) measurements determined off therapy and were genotyped for the AGT –6G→A, –532C→T, –20A→C, and 704T→C (M235T) gene variants. Genotypes were also determined in 547 control subjects of African origin who had a normal clinic BP. The –6A and –532C alleles were concordant with the M235T variant. Although AGT gene variants had no independent effects on either the presence of hypertension or ABP values in hypertensives, the –20A→C polymorphism had a marked influence on the relation between ambulatory systolic BP and BMI. This relation was present in patients homozygous for the –20A allele (n=399, r =0.23, P r =0.01, P =0.89). The M235T polymorphism did not impact on the BMI-BP relation. Specificity of the –20A→C polymorphism effect on the BMI-BP relation is further indicated by the lack of effect on the systolic BP–age relation. Conclusion— An AGT gene promoter region variant is an important modifier of the relation between body size and BP. Hence, these data corroborate the notion that genetic modifiers can produce a profound impact on BP-phenotypic relations.

We have reported previously that despite treatment with angiotensin-converting enzyme inhibitors and beta blockers, the outcome of patients with peripartum cardiomyopathy (PPC) remains unfavorable. Similar to other etiologies of left ventricular dysfunction, we found elevated levels of tumor necrosis factor-alpha (TNF-alpha) in this group of patients. In the present study we sought to evaluate the effects of pentoxifylline, a drug known to inhibit the production of TNF-alpha, on clinical status, left ventricular function, and circulating plasma levels of TNF-alpha, in patients with PPC. We followed prospectively 59 consecutive women with PPC. The first 29 patients (group 1) were treated with diuretics, digoxin, enalapril and carvedilol. The next 30 consecutive patients (group 2) received pentoxifylline 400 mg TID in addition to the previous therapy. Clinical evaluation, echocardiograms and TNF-alpha determinations were performed at baseline and after 6 months of treatment. Patients in the pentoxifylline group were older and had a higher E/A ratio. Nine patients died (eight in group 1, P = 0.009 between groups). A combined end-point of poor outcome defined as either death, failure to improve the left ventricular ejection fraction >10 absolute points or functional class III or IV at latest follow-up, occurred in 52% of patients in group 1 and 27% of patients in group 2 (P = 0.03). Treatment with pentoxifylline (P = 0.04) was the only independent predictor of outcome. In conclusion, the results of this study suggest that the addition of pentoxifylline to conventional treatment, improves outcome in patients with peripartum cardiomyopathy.

Background —We previously reported beneficial effects of pentoxifylline, a xanthine-derived agent known to inhibit the production of tumor necrosis factor-α, in patients with idiopathic dilated cardiomyopathy treated with diuretics, digoxin, and ACE inhibitors. Since then, 3 large clinical trials showed important clinical benefits of β-blockers in this population. Therefore, we designed the present study to establish whether in patients with heart failure already receiving treatment with ACE inhibitors and β-blockers, the addition of pentoxifylline would have an additive beneficial effect. Methods and Results —In a single-center, prospective, double-blind, randomized, placebo-controlled study, 39 patients with idiopathic dilated cardiomyopathy were randomized to pentoxifylline 400 mg TID (n=20) or placebo (n=19) if they had a left ventricular ejection fraction P =0.01), with an increment in exercise time from 9.5±5 to 12.3±6 minutes ( P =0.1). Left ventricular ejection fraction improved from 24±9% to 31±13%, P =0.03, in the treatment group. Conclusions —In patients with idiopathic dilated cardiomyopathy, the addition of pentoxifylline to treatment with digoxin, ACE inhibitors, and carvedilol is associated with a significant improvement in symptoms and left ventricular function.

Background. Intimate partner violence (IPV) is actual or threatened physical, sexual, psychological, emotional or stalking abuse by an intimate partner. Despite the high prevalence of IPV in South Africa (SA), there is a paucity of data on university students training in fields where they are likely to have to manage the after-effects of such events in their personal capacity in the future. Objectives. To ascertain the prevalence of IPV in an SA tertiary institution population with a diverse demographic profile. Methods. Students from the faculty of health sciences and the faculty of humanities, social work department, completed an anonymous questionnaire. Students were made aware of psychological counselling available to them. Results. Responses were obtained from 1 354 of 1 593 students (85.0%) (67.8% female, 45.9% black, 32.7% white, 16.6% Indian, 4.8% coloured). Of the respondents, 53.0% indicated that they were in a relationship. The prevalence of any type of IPV (sexual, physical or emotional abuse) among all respondents was 42.6%. Emotional abuse was reported by 54.9% of respondents, physical abuse by 20.0% and sexual abuse by 8.9%. Thirty-five females (6.5% of respondents who had suffered IPV) indicated that they had been emotionally, physically and sexually abused. Fourteen percent identified themselves as perpetrators of abuse, but only three perpetrators of sexual abuse reported having also been victims of sexual abuse. Most respondents (58.7%) knew where to get help. Conclusion. The extent of IPV among the medical and social work students sampled was found to be unacceptably high, both as victims and as perpetrators. As a result of their exposure to IPV, these individuals may have difficulty in managing patients who have been subjected to abuse.

OBJECTIVE—To investigate the contribution of apoptosis in the development of the skeletal myopathy in chronic heart failure. DESIGN—The electrophoretic pattern of myosin heavy chains (MHC), fibre cross sectional area, number of in situ nick end labelling (TUNEL) positive apoptotic myocyte nuclei, and the tissue levels of caspase-3, Bcl-2, and ubiquitin were determined in biopsies taken from the vastus lateralis muscle. The study involved nine patients with severe chronic heart failure caused by ischaemic heart disease and hibernating myocardium and five controls. RESULTS—In chronic heart failure patients the vastus lateralis showed a significant increase of MHC2a and MHC2b and a greater degree of fibre atrophy, as demonstrated by the decreased cross sectional area. There was also an increased number of TUNEL positive apoptotic myocyte nuclei. Tissue concentrations of Bcl-2 were decreased, while those of caspase-3 and ubiquitin were increased. Peak oxygen consumption (VO2) was negatively correlated with the number of TUNEL positive nuclei and the fibre cross sectional area. There was a correlation between the number of apoptotic nuclei and the fibre cross sectional area, but no correlation between myosin heavy chains and number of apoptotic nuclei. CONCLUSIONS—Myocyte apoptosis occurs in the skeletal muscle of patients with chronic heart failure, and its magnitude is associated with the severity of exercise capacity limitation and the degree of muscle atrophy. Muscle atrophy contributes to the limitation of exercise capacity, together with the increased synthesis of fast, more fatiguable myosin heavy chains. Keywords: apoptosis; chronic heart failure; exercise capacity; myosin heavy chains

In this study, using 24-hour ambulatory blood pressure (BP) monitoring, the authors assessed the potential for BP control using hydrochlorothiazide (HCTZ, 12.5 mg daily), given as a monotherapy over 12 months to 49 black South African patients with mild to moderate hypertension (mean day diastolic blood pressure [DBP]or = 90 and115 mmHg). Uncontrolled patients received fixed combination of quinapril/HCTZ 10/12.5, 20/12.5, and 20/25 mg, with dose titration at 3 monthly intervals if BP control was not achieved (day DBP90 mmHg). Overall, profound and sustained BP reduction was observed at the end of the study. The 24-hour BP decreased from 151 +/- 14/98 +/- 7 to 136 +/- 15/87 +/- 9 mmHg (p0.0001 at end of study vs. baseline); the mean day BP decreased from 155 +/- 14/104 +/- 7 to 140 +/- 15/91 +/- 10 mmHg (p0.0001 at end of study vs. baseline). The overall control (mean day DBP90 mmHg) and response (decrease in day DBPor = 10 mmHg) rates were 49% and 61%, respectively. At the end of the study, only 2 patients (4%) remained on treatment with HCTZ. Out of the initial 12 patients controlled on HCTZ at 3 months (12/49, 24%), 5 patients remained controlled at 6 months and only 1 patient at 12 months. In contrast, quinapril/HCTZ combinations maintained their antihypertensive effect up to 9 months, with a significant number of patients (22/49, 45%) requiring the highest dose of the combination (20/25 mg daily). In conclusion, low-dose HCTZ should not be recommended as monotherapy in black patients with mild to moderate hypertension due to the fact that the BP-lowering effect is attenuated already at 6 months of treatment, with most patients requiring the addition of the ACE inhibitor.

Study Type--Symptom Prevalence (prospective cohort) Level of Evidence 2a. What's known on the subject? and What does the study add? Nocturnal enuresis is a common childhood problem. Although its prevalence is known in many countries, no data are available from South Africa and it is difficult to extrapolate data from developed countries to a population with such diverse conditions and resource-poor settings. This study is the first to report on the 16% prevalence rate and the low level of parental knowledge of enuresis in South African children aged between 5 and 10 years.• To establish the prevalence of NE in 5-10 year old South African children in a cross-sectional study using a parent-completed questionnaire. • To establish the parental perception and associated factors of mono-symptomatic nocturnal enuresis (MNE) treatment and treatment success rates in 5-10 year old children from South Africa.• A total of 4700 questionnaires were distributed to children at 37 selected schools willing to participate from South Africa. Parents anonymously filled out the questionnaire. • Data were reported as frequencies and percentages of NE in tables according to different gender and age groups. • The Chi-square test compared proportions between groups and Fisher's Exact test corrected for small numbers of observations (n ≤ 5). Age differences were determined using Student's t-test. A P-value ≤ 0.5 was considered to be statistically significant.• The questionnaire's response rate was 72.1%, with 3389 children included in the study. • The overall prevalence of NE was 16.0%-14.4% of children suffered from mono-symptomatic NE (MNE). The prevalence of NE in boys was double that in that in girls. • Only 28.3% had received some form of treatment, whereas 13.5% had been medically treated by a doctor. Parents' awareness of treatment modalities available is outdated and most of the management of MNE was done by parents themselves, albeit with low success rates. • A positive family history was found in 50.5% of children suffering from MNE. • Constipation was a problem in 15.8% of children with enuresis.• This is the first study to estimate the prevalence of NE and report on the parental perception and possible associated factors of enuresis in children from South Africa. The study showed that South African children have a similar prevalence rate of NE (16%) when compared with other countries. • The possible associated factors with MNE in South Africa include constipation and a family history of enuresis. • Finally, there are low levels of parental knowledge of treatment modalities of MNE, leaving many children untreated.

Determining the kinetic constants of arginine uptake by endothelial cells mediated by more than one transporter from linearization of data as Eadie-Hofstee plots or modeling which does not include the concentration of trace radiolabeled amino acid used to measure uptake may not be correct. The initial rate of uptake of trace [3H]l-arginine by HUVECs and ECV304 cells in the presence of a range of unlabeled arginine and modifiers was used in nonlinear models to calculate the constants of arginine uptake using GraphPad Prism. Theoretical plots of uptake derived from constants determined from Eadie-Hofstee graphs overestimated uptake, whereas those from the nonlinear modeling approach agreed with experimental data. The contribution of uptake by individual transporters could be modeled and showed that leucine inhibited the individual transporters differently and not necessarily competitively. N-Ethylmaleimide inhibited only y+ transport, and BCH may be a selective inhibitor of y+L transport. The absence of sodium reduced arginine uptake by y+L transport and reduced the K m′, whereas reducing sodium decreased arginine uptake by y+ transport without affecting the K m′. The nonlinear modeling approach using raw data avoided the errors inherent in methods deriving constants from the linearization of the uptake processes following Michaelian kinetics. This study provides explanations for discrepancies in the literature and suggests that a nonlinear modeling approach better characterizes the kinetics of amino acid uptake into cells by more than one transporter.