Targeting gallbladder cancer: a pathway based perspective.

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.

The negative appendicectomy rate at Charlotte Maxeke Johannesburg Academic Hospital - a 10-year review.

BACKGROUND: The negative appendicectomy rate (NAR) is defined as the proportion of surgically removed appendices that are pathologically normal. The acceptable NAR has been a debated issue. Previously, a higher rate was accepted, whilst newer thinking favours a lower rate. Diagnosing appendicitis is often a clinical challenge and may require crosssectional imaging to assist in the diagnosis. METHODS: A retrospective review was conducted at the Charlotte Maxeke Johannesburg Academic Hospital. Appendix histopathological reports were retrieved for patients older than 18 years over a 10-year period. Reports of ultrasound (US) and/or computed tomography (CT) scans were analysed in the last 18 months. RESULTS: One thousand two hundred and seventeen appendicectomy specimens were included. The overall NAR was 19%. This demonstrated a significant downward trend over the period (p < 0.003). Per gender, the female NAR showed a significant decline (p = 0.002) while the male decline was not significant (p = 0.517). Reproductive-age females were found to have significantly higher NAR as compared to other age groups. The overall perforation rate was 17% which demonstrated a significant increase over the study period (p = 0.012). In the last 18 months, 240 appendicectomies were performed. One hundred and eleven patients underwent imaging (46%), of which 78 underwent ultrasound (70%), 14 CT (13%) and 19 US and CT (17%). CONCLUSION: The overall NAR declined significantly over the period. Females under the age of 45 were found to have significantly higher NARs. Further prospective studies are needed to determine the benefit and feasibility of preoperative CT in resource-limited settings, particularly in reproductive-age females to reduce the NAR.

A prospective study of receptor profiles in breast cancer and the ipsilateral axillary lymph node metastases measured simultaneously in treatment naïve cases.

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.

Proximal suture line support in open abdominal aortic aneurysm repair: a comparative study.

OBJECTIVES: The aim of this study was to determine whether the collar graft (standard dacron graft with a customized flexible collar attached to the proximal rim) decreased anastomotic bleeding and the overall clamp time. DESIGN: Prospective randomised single center study. METHODS: Between November 2003 and January 2006, 21 patients were treated with a collar graft and 19 with a standard dacron graft. Routine endoaneurysmorraphy was used. Only infra-renal aneurysms between 5.5cm and 6.5cm were included. Aneurysms were diagnosed by CT scans. The total number of bleeding points, the total clamp time, and the number of teflon felt pledgets, was determined. RESULTS: The total number of bleeding points; the number of aortic re-clamps and total clamp time (minutes) per patient were all significantly lower in the collar graft group (1.2 versus 2, p<0.04; 0.5 versus 2.0, p<0.001; 13.6 versus 20.1, p<0.003 respectively). The number of teflon felt pledgets and new sutures used was significantly lower in the collar graft group (p<0.001 and p<0.003 respectively). CONCLUSION: The collar graft resulted in fewer anastomotic bleeding points and a shorter clamp time.

Efficacy of different drug classes used to initiate antihypertensive treatment in black subjects: results of a randomized trial in Johannesburg, South Africa.

BACKGROUND: Thiazides are recommended to initiate antihypertensive drug treatment in black subjects. OBJECTIVE: To test the efficacy of this recommendation in a South African black cohort. METHODS: Men and women (N = 409), aged 18 to 70 years, with a mean ambulatory daytime diastolic blood pressure between 90 and 114 mm Hg, were randomized to 13 months of open-label treatment starting with the nifedipine gastrointestinal therapeutic system (30 mg/d, n = 233), sustained-release verapamil hydrochloride (240 mg/d, n = 58), hydrochlorothiazide (12.5 mg/d, n = 58), or enalapril maleate (10 mg/d, n = 60). If the target of reducing daytime diastolic blood pressure below 90 mm Hg was not attained, the first-line drugs were titrated up and after 2 months other medications were added to the regimen. RESULTS: While receiving monotherapy (2 months, n = 366), the patients' systolic and diastolic decreases in daytime blood pressure averaged 22/14 mm Hg for nifedipine, 17/11 mm Hg for verapamil, 12/8 mm Hg for hydrochlorothiazide, and 5/3 mm Hg for enalapril. At 2 months the blood pressure of more patients treated with nifedipine was controlled: 133 (63.3%, P

Comparison of acebutolol with and without hydrochlorothiazide versus carvedilol with and without hydrochlorothiazide in black patients with mild to moderate systemic hypertension.

In the present study, we assessed the antihypertensive efficacy of acebutolol 200 mg versus carvedilol 25 mg once daily, given as monotherapy for 3 months to 40 black patients (20 patients in each group, mean age 53+/-10 years, 24 women) with mean blood pressure (BP) during the day >90 and <110 mm Hg. Patients in whom blood pressure could not be controlled took medication, which was increased at 3-month intervals as follows: step 2, acebutolol 200 mg or carvedilol 25 mg plus hydrochlorothiazide 12.5 mg once daily; step 3, acebutolol 400 mg or carvedilol 50 mg plus hydrochlorothiazide 25 mg once daily. Overall, significant but modest BP reduction was achieved with both beta blockers at 3 months. In the acebutolol group, 24-hour BP decreased from 142+/-15/94+/-7 mm Hg to 138+/-16/89+/-8 mm Hg (p<0.005 for diastolic BP at 3 months vs baseline). Mean day BP decreased from 145+/-15/98+/-5 mm Hg to 140+/-14/93+/-7 mm Hg (p<0.05 for systolic BP and p<0.0005 for diastolic BP at 3 months vs. baseline). In the carvedilol group, 24-hour BP decreased from 145+/-11/93+/-6 to 138+/-16/87+/-9 mm Hg (p<0.05 for systolic BP and p<0.005 for diastolic BP at 3 months vs baseline). Mean day BP decreased from 149+/-10/99+/-5 to 141+/-16/91+/-87 mm Hg (p<0.05 for systolic BP and p<0.0005 for diastolic BP at 3 months vs baseline). At 12 months, most patients required combination therapy to achieve BP control. The control (mean day diastolic BP <90 mm Hg) and response (mean day diastolic BP decrease > or =10 mm Hg) rates at 12 months were 59% and 82% in the acebutolol and 78% and 78% in the carvedilol groups, respectively. In conclusion, acebutolol or carvedilol in combination with hydrochlorothiazide, rather than acebutolol or carvedilol alone, should be considered as first-line antihypertensive therapy in black patients with mild to moderate hypertension.

Association of left ventricular systolic performance and cavity size with angiotensin-converting enzyme genotype in idiopathic dilated cardiomyopathy.

The insertion-deletion (ID) polymorphism of the angiotensin-converting enzyme (ACE) gene is a marker linked to differences in plasma and cardiac ACE activity as well as to an increased mortality in patients with idiopathic heart failure. We examined the possibility that ACE gene ID variants are associated with differences in left ventricular (LV) systolic performance or internal LV dimensions in a high-risk cohort of patients with idiopathic dilated cardiomyopathy (IDC). The ACE genotype was determined in 171 patients selected with IDC in New York Heart Association functional class II to III heart failure and with a LV ejection fraction of < or = 40%. Left ventricular performance and dimensions were assessed using echocardiography (n = 161) and radionuclide ventriculography (n = 169). The frequency of ACE gene ID alleles was not different in the study versus non-age-matched (n = 171; odds ratio 0.94) and age-matched (n = 106, odds ratio 0.88) control groups. Ejection fraction was found to be worse in patients with the DD genotype (echocardiography, DD = 23.5 +/- 0.70, ID + II = 26.8 +/- 0.8, p = 0.009; ventriculography, DD = 21.7 +/- 0.9, ID + II = 25.3 +/- 0.8, p = 0.003). LV end-systolic and end-diastolic diameters were increased in patients with the DD genotype. Multifactor regression analysis showed the ACE genotype to be an independent predictor of both ejection fraction (echocardiography, p <0.02; ventriculography, p <0.03) and end-diastolic diameter (p <0.02). In conclusion, the results of this study indicate that the DD genotype of the ACE gene is independently associated with both a reduced LV systolic performance and an increased LV cavity size in patients with IDC.

Antihypertensive effect of low-dose hydrochlorothiazide alone or in combination with quinapril in black patients with mild to moderate hypertension.

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 and < 115 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 DBP < 90 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 (p < 0.0001 at end of study vs. baseline); the mean day BP decreased from 155 +/- 14/104 +/- 7 to 140 +/- 15/91 +/- 10 mmHg (p < 0.0001 at end of study vs. baseline). The overall control (mean day DBP < 90 mmHg) and response (decrease in day DBP > or = 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.

An anatomical and physiological model of the renal parenchyma--model development and parametric identification.

Renal function is often characterized by the activity/time curves obtained by imaging the aorta and kidney. Non-parametric deconvolution of the activity/time curves is clinically useful as a diagnostic tool in determining renal transit times. Typically non-parametric deconvolution is performed using a technique that does not require a priori information, e.g. matrix-based and Fourier-transform methods. Using data filtering and conservation of mass constraints, non-parametric deconvolution continues to exhibit noise in the deconvolved curves. This noise hampers the identification of renal transit times. Given the shortcomings of non-parametric deconvolution, a parametric model of the renal response has been developed. Our model is shown to be anatomically and physiologically plausible. In this paper, the parametric model structure is used, in conjunction with experimental data, to estimate renal physiological parameters. These parameters include the filtration fraction, renal blood transit time and urine transit times. The model parameters are then related to the minimum transit time (MinTT), mean transit time (MTT), glomerular filtration rate (GFR) and parenchymal transit time index (PTTI). As deconvolution techniques often produce negative artifacts, Fine et al developed a technique to determine an aorta background to minimize this effect. In this paper this work is extended to determine a reasonable renal background from aorta activity/time curves. Non-parametric deconvolution is used to provide initial estimates of model parameters. The model is then fitted to twelve healthy background-corrected kidneys by an iterative parameter-estimation technique. The normal values correspond to those reported in the literature. These normal values are then used to identify renal arterial stenosis in two renal hypertensive patients. The results suggest that parametric identification, based on a renal-retention-function model, may provide additional anatomical and physiological information that is not provided by conventional non-parametric methods.

The glomerular filtration rate, effective renal plasma flow, and renal blood flow in the adult male chacma baboon (Papio ursinus).

The radionuclide determination of glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) has been validated in man, but not in the primate. GFR, ERPF, and renal blood flow (RBF) were measured in a group of 12 adult male chacma baboons using radiopharmaceuticals. GFR was determined using 99mtechnetium-labelled diethylenetriamine-pentacetic acid. ERPF was measured with 131iodine-labelled hippuran. RBF, body surface area, and kidney weights were calculated using standard formulae. GFR was 49 +/- 11 ml/min and ERPF was 237.9 +/- 54.2 ml/min. Calculated RBF was 430.7 +/- 111.9 ml/min and 507.4 +/- 138.4 ml/min/100 g of renal tissue. The results are in agreement with those obtained using more laborious nonradioisotopic techniques such as para-aminohippurate (PAH) and creatinine clearance and could serve as baseline normal values in the adult male chacma baboon.

A method for creating reversible ureteric obstruction in the primate.

A technique has been developed for the establishment of a state of reversible, ureteric obstruction in the primate. Ten adult males had baseline 99mTc-DTPA renogram studies. A randomly selected ureter was totally occluded and obstruction confirmed on renogram. The occlusion was reversed and subsequent renograms confirmed recovery of activity in the obstructed kidneys of the eight animals who survived the reversal procedure. Seven were alive on conclusion of the study. Prevention of ureteric strictures was achieved with an intra-ureteric silastic tube. Autopsies demonstrated patency of every previously occluded ureter. This is the first study to be reported in primates, and the second overall, in which complete ureteric obstruction and its successful reversal has been confirmed on renogram using this surgical method. The technique is suitable for the study of the effect of reversible ureteric obstruction on renal function.

Myocardial stiffness is attributed to alterations in cross-linked collagen rather than total collagen or phenotypes in spontaneously hypertensive rats.

BACKGROUND: The relative contributions of increases in myocardial collagen, collagen cross-linking, and the ratio of type I to type III collagen to the stiff myocardium in hypertension were determined. METHODS AND RESULTS: We compared the action of hydralazine (0.07 mmol x kg(-1) x d(-1)) with that of captopril (0.22 mmol x kg(-1) x d(-1)) on the left ventricular end-diastolic (LVED) myocardial stiffness constant, k (g x cm(-2)) and LV myocardial interstitial characteristics in spontaneously hypertensive rats (SHRs) and Wistar Kyoto (WKY) control rats. LVED k (SHR, 27.9+/-1; WKY, 19.5+/-1.2; P<.01), myocardial hydroxyproline concentrations (HPRO; microg/mg dry wt) (SHR, 4.19+/-0.16; WKY, 3.17+/-0.09; P<.001), and collagen type I/III ratios (SHR, 7.1+/-0.7; WKY, 2.1+/-0.2; P<.001) were increased, whereas the percentage of myocardial collagen extracted after cyanogen bromide digestion (an index of cross-linked collagen) was decreased (SHR, 17+/-3; WKY, 41+/-4; P<.001) in SHRs compared with WKY controls. Captopril therapy reduced LVED k, myocardial HPRO, collagen type I/III, and augmented collagen solubility (43+/-4) in SHRs to values similar to those measured in WKY controls. Hydralazine therapy, despite a favorable effect on LVED k in SHRs (20.+/-1.6, P<.01 compared with untreated SHRs), failed to influence either myocardial HPRO (4.18+/-0.18) or collagen type I/III (8+/-1) but did improve collagen solubility (31+/-2). CONCLUSIONS: An association between alterations in LVED k and collagen solubility but not between changes in LVED k and total collagen or phenotype ratios after antihypertensive therapy in SHRs suggests that myocardial stiffness in hypertension is the consequence of an enhanced myocardial collagen cross-linking rather than of an increase in total collagen or type I phenotype concentrations.

Association study of eight candidate genes with renin status in mild-to-moderate hypertension in patients of African ancestry.

AIM: We evaluated whether any one variant of genes that encode for substances that could modulate renin-angiotensin-aldosterone (RAA) system activity can account for a substantial proportion of the variability of plasma RAA system profiles in black South African hypertensives (HTs). METHODS: Plasma renin activity (PRA) and aldosterone concentrations (ALD) were determined in 59 black subjects with mild-to-moderate HT off therapy on an ad libitum diet. Patients were genotyped for the angiotensin-converting enzyme (ACE) gene insertion/deletion, angiotensinogen (AGT) gene M235T, A-20C and G-6A, aldosterone synthase (CYP11B2) gene C-344T, G protein beta3-subunit (GNB3) gene C825T, G(s) protein gene C131T, atrial natriuretic peptide (ANP) gene exon 3 stop condon and intron 2, alpha-adducin gene Gly460Trp, and epithelial Na(+) channel (eNa(+) (c)) gene T594M polymorphisms. RESULTS: Risk genotype frequencies for the G(s) (7%), ANP intron 2 (0%), and eNa(+)(c)(7%) variants were too low for each to account for a substantial portion of the variability of plasma RAA profiles in the group studied. Moreover, assuming either recessive or dominant inheritance models, neither ACE, AGT, GNB3, CYP11B2, ANP exon 3 nor alpha-adducin polymorphisms were significantly associated with the variance of PRA, ALD or ALD/PRA. CONCLUSIONS: These results do not support a substantial individual role for the gene candidates studied in contributing to plasma RAA system profiles in black South African HTs. However, a potential small role for some loci may exist, and epistasis or genotype-phenotype interactions as well as alternative inheritance models and variants still need to be evaluated.