The Zwolle experience with left bundle branch area pacing using stylet-driven active fixation leads.

AIMS: Left bundle branch area pacing (LBBAP) is a novel physiological pacing modality and is regarded as a viable alternative to His bundle pacing. LBBAP has mostly been performed with the lumen-less permanent pacing lead (SelectSecure™ Model 3830, Medtronic, Inc.) with a fixed helix. The aim of this study was to compare the non-stylet driven lumen-less lead (LLL) (Medtronic 3830) with a standard stylet-driven active fixation lead (SDL) (Tendril™ STS Model 2088TC-38, Abbott Laboratories) in terms of lead parameters, procedural success and complication rates. METHODS: Patients receiving a LBBA pacemaker in the Isala Hospital, The Netherlands, were prospectively enrolled. The majority received a standard right ventricular (RV) lead as backup, the implanter chose between LLL and SDL for the LBBAP lead. RESULTS: The study included 94 patients with a mean follow-up of 30 weeks. 30/31 LLL procedures were successful, compared with 62/63 in the SDL group. Including the participants that lost LBBAP during follow-up resulted in success rates of 90.3% for LLL versus 96.8% for SDL, P = 0.199. Mean number of deployments was significantly lower in the SDL group compared with the LLL group (2 ± 2.3 versus 4 ± 3.4, P = 0.005), implantation and procedural times were comparable. Pacing thresholds were low and remained low in both groups (at last follow-up 0.8 ± 0.30 V for LLL versus 0.6 ± 0.20 V for SDL). Complication rates did not differ significantly between both groups, P = 0.805. CONCLUSION: LBBAP using SDL is feasible and has comparable success rates with lower number of deployments of the active fixation screw.

The effect of renal sympathetic denervation on nocturnal dipping in patients with resistant hypertension; observational data from a tertiary referral centre in the Republic of Ireland.

OBJECTIVE: Renal sympathetic denervation (RSD) is an emerging device based treatment for patients with resistant hypertension. Nocturnal dipping (ND) is defined as a decrease in BP of 10-20 % during sleep, and has been shown to be protective against cardiovascular disease. This study examined the effect of RSD on the 24 h BP profile of patients with resistant hypertension. METHODS AND RESULTS: The first 23 consecutive patients with resistant hypertension scheduled for renal denervation in a single centre were included. 24 h ambulatory blood pressure monitors (ABPM) were given to patients pre-procedure and 9 months post-procedure. RSD led to a statistically non-significant reduction in overall 24 h ABPM BP (150/85 ± 12/9 vs. 143/84 ± 15/11 mmHg; P > 0.05) despite a reduction in the number of antihypertensive medications (4.9 ± 1.2 vs. 4.3 ± 1.2; P = 0.001). There were improvements in systolic ND 1.7 ± 8 vs. 5.2 ± 8 %; P < 0.05), diastolic ND (5.2 ± 8 vs. 10.2 ± 9 %; P < 0.05) and mean arterial pressure (MAP) ND (4.2 ± 8 vs. 8.0 ± 8 %; P < 0.05). Non-significant changes in ND status were observed in systolic (17 vs. 43 % of participants; P > 0.05), diastolic (30 vs. 43 % of participants; P > 0.05) and MAP (22 vs. 39 % of participants; P > 0.05) measurements. CONCLUSIONS: These data suggest that RSD may lead to an improvement in nocturnal dipping in selected patients with resistant hypertension. This may have cardiovascular benefits even if reduction in BP is not achieved with RSD.

Response to national policy imperatives for nursing education: a Western Cape case study.

Since South Africa became a democratic country in 1994, the higher education sector has been faced with the challenge of transformation and restructuring. The Minister of Education in the Education White Paper 3 stated that "the higher education system must be transformed to redress the past inequities, to serve a new social order, to meet pressing national needs and to respond to realities and opportunities" (Department of Education, 1997:2). Higher education institutions were faced with the realities of impending mergers and collaborations across programmes and between universities and technikons. The Council on Higher Education (CHE) submitted a report to the Minister of Education in February 2002 which proposed the establishment of new institutional and organizational forms within regions (Department of Education, 2002: 7-8). The Minister announced changes in higher education based on his assessment of the proposals submitted by the CHE which resulted in the reduction of the number of higher education institutions from 36 to 21 (Department of Education, 2002:11-20). There were specific implications for nursing education in the Western Cape. In December 2002 the Minister of Education, Kader Asmal announced that with effect from 2005, the University of the Western Cape (UWC) and a new institution, the Cape Peninsula University of Technology (CPUT) would be the only enrolling institutions for undergraduate nursing education in the Western Cape. The Cape Higher Education Consortium (CHEC) instead proposed the establishment of a common teaching platform for nursing education in the region to meet the objectives of national and provincial government and to make optimal use of the combined strengths of the three universities and the technikon. This proposal was accepted by the minister and the common teaching platform, a unique form of collaboration, was established in 2005.

Managing ethical issues in sexual violence research using a pilot study.

Conducting research in the area of sexual violence has complex ethical and practical challenges for the researcher. Managing ethical issues in sexual violence is important and can be achieved through the use of pilot studies. The primary purpose of the pilot study was to identify and manage potential ethical and practical problems that could jeopardise the main study or violate the ethical and human rights of participants in the main study on women's journey of recovery from sexual assault. The secondary purpose was to collect preliminary data in order to determine the human, financial and time resources needed for a planned study. The methods and processes used in conducting the pilot study in the study on women's journey of recovery are discussed according to each of the objectives of the pilot study, methods used to achieve the objective, observations or findings made during the pilot study, and implications for the main study. This article aims to demonstrate how a pilot study was used to manage identified potential ethical and practical research issues during the recruitment of participants and data collection for the research that was conducted by the first author to investigate women's journey of recovery from sexual assault trauma within the first week following sexual assault.

Use of Ir192 interstitial brachytherapy for an equine malignant dermal schwannoma.

A 10-year-old Hanoverian mare was evaluated for a right buccal swelling that recurred 3 months following surgical resection. Ultrasonographic examination showed a broadly pedunculated subcutaneous mass at the level of 106-109 and 406-409 cheek teeth associated with an erosive mucosal lesion on the inside of the cheek. Histological examination of a biopsy specimen revealed a well-demarcated, malignant, dermal schwannoma. Following subcutaneous placement of platinum coated Ir192 wires under general anaesthesia, low-dose radiation of 5 gray per day was delivered for 14 days. Short-term complications included loss of patency of the right nasolacrimal duct, erythema, dermatitis, leukotrichia and left-sided deviation of the muzzle. Ten months later, there has been no tumour recurrence. Findings suggest that the use of interstitial brachytherapy should be considered for a malignant, dermal schwannoma that has recurred or is not amenable to surgery.

Research integrity and misconduct: a clarification of the concepts.

The commercialization of research and the ever changing scientific environment has led scholars to shift the focus from promoting research integrity to regulating misconduct. As a result, most literature explains research integrity in terms of avoidance of misconduct. The purpose of the paper is to stimulate reflection and discussion on research integrity and research misconduct. This article explores the meaning of research integrity and research misconduct, and how research integrity can be promoted to ensure safer research and scholarship. We believe that the discussion can help clarify some hazy areas in the research and publication processes, and appreciate some crucial aspects that they may have seen taken for granted. The purpose of this article is to share with the readers some clarification or analysis of the two concepts namely: research integrity and misconduct. The objectives are: (1) To explore and analyse the concepts of research integrity and research misconduct from the educational or developmental perspective and not the legal perspective as others in literature have done. (2) To stimulate the reflection and discussion on strategies to promote research integrity and thus prevent research misconduct Literature review and concept analysis was undertaken to clarify the two concepts. We argue that the two concepts can be viewed along a continuum, i.e. where research integrity ends, research misconduct starts. We also argue that it is the responsibility of the research community at large to always ensure that the scientific ethics balance is maintained throughout the research process to ensure research integrity and avoid research misconduct. We also argue that research integrity is interlinked with morality while misconduct is interlinked with immorality.

Gastrazole (JB95008), a novel CCK2/gastrin receptor antagonist, in the treatment of advanced pancreatic cancer: results from two randomised controlled trials.

Gastrin has been shown to be a growth stimulant in pancreatic cancer cells. Gastrazole is a potent and selective gastrin receptor antagonist. Two randomised blinded trials were conducted to assess the effect of gastrazole in advanced pancreatic cancer. Patients with biopsy-proven, inoperable pancreatic carcinoma were recruited. Trial A compared protracted venous infusion (PVI) gastrazole with PVI placebo, whereas trial B compared PVI gastrazole with PVI fluorouracil (5-FU). Eighteen patients were randomised in trial A. Gastrazole produced significantly better survival compared to placebo (median 7.9 months vs 4.5 months; 1-year survival: 33 vs 11%, respectively; log rank P=0.02). No difference in toxicity was seen between gastrazole and placebo, except central venous catheter and pump complications. Ninety-eight patients were randomised in trial B. No significant survival difference was detected between gastrazole and 5-FU (median: 3.6 vs 4.2 months; 1-year survival: 13.2 vs 26.2%, respectively; log rank P=0.42). Toxicity of gastrazole was mild with significantly less diarrhoea (P=0.03), stomatitis (P<0.001) and hand- foot syndrome (P<0.001) compared to 5-FU. Quality of life (QoL) assessment showed similar QoL between gastrazole and 5-FU at baseline and no significant differences occurred with treatment either between arms or within arms. Compared to placebo, patients with advanced pancreatic cancer treated with gastrazole appeared to live longer, albeit in a very small trial and will require confirmation with large-scale randomised data. However, it did not produce survival advantage over PVI 5-FU. Lack of toxicity for gastrazole may allow its combination with cytotoxic drugs.

Small molecule selectin ligand inhibition improves outcome in ischemic acute renal failure.

BACKGROUND: The pathophysiologic and potential therapeutic role of selectins in renal ischemia-reperfusion injury (IRI) is not fully understood, due in part to redundancy in the roles of individual selectins. We hypothesized that blockade of ligands for all three selectins using a novel small molecule (TBC-1269) would improve the course of renal IRI by overcoming redundancy issues. This was investigated in a rat model of renal IRI. METHODS: Rats were treated with TBC-1269 either during or post-IRI. The effects of TBC-1269 were investigated in two models of renal IRI: moderate IRI (30 minutes bilateral renal artery clamping) and severe IRI (45 minutes clamping). The combination of anti-E- and anti-P-selectin antibodies also was investigated in rats subjected to moderate IRI. Renal function, histological injury and mortality were assessed. RESULTS: Rats treated with TBC-1269 during moderate IRI showed significantly reduced serum creatinine (SCr) and tubular necrosis post-ischemia compared to control animals. By contrast, delayed treatment (post-IRI) did not show a reduction in SCr. In rats with severe IRI, TBC-1269 treatment during IRI significantly reduced mortality at 48 hours post-ischemia. Rats with moderate IRI and treated with the combination of anti-E- and anti-P-selectin antibodies showed significantly reduced SCr compared to control rats at 24 hours post-ischemia. CONCLUSIONS: Small molecule selectin ligand inhibition provides a novel and effective approach to attenuate ischemic acute renal failure. Timing of treatment is crucial to success.

Identification of the CD4(+) T cell as a major pathogenic factor in ischemic acute renal failure.

Leukocytes have been implicated in the pathogenesis of ischemic acute renal failure (ARF), but the roles of the individual cell types involved are largely unknown. Recent indirect evidence suggests that T cells may play an important role in a murine model of ARF. In the current study, we found that mice deficient in T cells (nu/nu mice) are both functionally and structurally protected from postischemic renal injury. Reconstitution of nu/nu mice with wild-type T cells restored postischemic injury. We then analyzed the contribution of the individual T cell subsets to postischemic injury and found that mice deficient in CD4(+) T cells, but not mice deficient in CD8(+) T cells, were significantly protected from ARF. Direct evidence for a pathophysiologic role of the CD4(+) T cell was obtained when reconstitution of CD4-deficient mice with wild-type CD4(+) T cells restored postischemic injury. In addition, adoptive transfers of CD4(+) T cells lacking either the costimulatory molecule CD28 or the ability to produce IFN-gamma were inadequate to restore injury phenotype. These results demonstrate that the CD4(+) T cell is an important mediator of ischemic ARF, and targeting this cell may yield novel therapies.

Pulmonary presentations of amyloidosis.

Respiratory tract involvement with amyloid is rare. We report eight cases of lower respiratory tract amyloidosis including a case of isolated pulmonary interstitial amyloidosis treated with chemotherapy, two cases of recurrent endobronchial amyloid with airway obstruction successfully treated with laser therapy and three cases of localized nodular pulmonary amyloidosis. The subjects with endobronchial and nodular amyloid demonstrated good long-term survival, while those with systemic or interstitial pulmonary amyloid had progressive disease and poor survival. Circulating monoclonal immunoglobulins were identified in five of the eight cases as the likely cause of the amyloid.

Pathophysiological role of T lymphocytes in renal ischemia-reperfusion injury in mice.

Mononuclear cell infiltrates are found in human renal ischemia-reperfusion injury (IRI), and peritubular T lymphocytes have been identified in experimental IRI. However, the role of T cells in the pathogenesis of renal IRI is unknown. We hypothesized that T cells are one of the important mediators of renal IRI. To test this hypothesis, we used an established mouse model of renal IRI, and evaluated mice with genetically engineered deficiency of both CD4+ and CD8+ T cells. At 48 h postischemia, CD4/CD8-knockout (KO) mice had marked improvement in renal function compared with control C57BL/6 mice (serum creatinine: 0.7 +/- 0.4 vs. 2.5 +/- 0.3 mg/dl, respectively; P < 0.05). Neutrophil infiltration into postischemic kidney was reduced in CD4/CD8 KO mice, compared with control mice, at both 24 h [polymorphonuclear neutrophils (PMNs)/10 high power fields: 714 +/- 354 vs. 3,514 +/- 660, respectively; P < 0.05] and 48 h (88 +/- 32 vs. 1,979 +/- 209, respectively; P < 0.05). Tubular necrosis score in CD4/CD8 KO mice, compared with control mice, was significantly less at 48 h (0.4 +/- 0.1 vs. 2.4 +/- 0.2, respectively; P < 0.05). Because adhesion between T cells and renal tubular epithelial cells (RTECs) may underlie the pathophysiological role of T cells in renal IRI, we also measured T cell adhesion to primary murine RTECs in vitro. Exposure of RTECs to 2 h of hypoxia followed by 1 h of reoxygenation increased T cell adhesion more than twofold. Phorbol ester treatment, which activates integrins, increased T cell adhesion threefold. These data suggest that T lymphocytes can mediate experimental renal IRI. Moreover, adhesion of infiltrating T cells to renal tubular cells may provide a potential mechanism underlying postischemic tubular dysfunction.

Patients presenting with fresh trauma after interpersonal violence. Part I. Alcohol and substance abuse.

BACKGROUND: Patients presenting with fresh trauma frequently have evidence of substance abuse. Nevertheless, few South African studies have measured the levels of both alcohol and other substances in patients presenting with fresh trauma after interpersonal violence. METHODS: A representative sample of patients presenting with fresh trauma to the Trauma Unit of Tygerberg Hospital was selected for study. Subjects were questioned about the nature of the trauma and breath alcohol concentrations were determined. Blood and urine samples for analysis of alcohol and other substances were obtained from approximately half the subjects. RESULTS: Alcohol was found to be present in a majority of patients who presented after interpersonal violence, while other substances were present less commonly. There was a high correlation between clinical history of alcohol use, breath analysis of alcohol and blood alcohol measurement. CONCLUSIONS: Alcohol use plays a significant role in trauma due to interpersonal violence. It is essential to screen victims of interpersonal violence for a history of alcohol and other substances. Breath analysis for alcohol is a useful adjunct to clinical screening.

Patients presenting with fresh trauma after interpersonal violence. Part II. Assault history.

BACKGROUND: Patients presenting with fresh trauma are frequently victims of interpersonal violence. Nevertheless, few South African studies have documented the history surrounding such assaults and their management. METHODS: Patients presenting with fresh trauma to the Trauma Unit of Tygerberg Hospital were selected in order to provide a representative sample. Where patients were victims of interpersonal violence, a history of the current and previous assault(s) was taken. RESULTS: Victims of interpersonal violence often reported that they had been involved in such violence on previous occasions. Nevertheless, these patients had rarely received management from psychosocial services. Patients with a previous history of having been assaulted had a number of distinct characteristics, including female gender and increased substance use. CONCLUSIONS: Trauma has justifiably been described as a recurrent disease. There is an urgent need for effective psychosocial services for victims of interpersonal violence; ideally, this would prevent future multiple hospital admissions.

The effects of N-methyl-D-aspartate agonists and antagonists on isolated bovine cerebral arteries.

This pharmacologic study examines the direct cerebrovascular effects of N-methyl-D-aspartate (NMDA) receptor agonists and antagonists to determine whether large cerebral arteries have NMDA receptors. Bovine middle cerebral arteries were cut into rings to measure isometric tension development in vitro. Two competitive agonists, L-glutamate and NMDA, each had negligible effects on ring tension in the absence of exogenous vasoconstrictors. L-glutamate (in high concentrations) produced direct relaxation of potassium (K+)-constricted arteries, but the relaxation was not selective for L-glutamate, D-glutamate, or mannitol. Relaxation with L-glutamate was abolished when it was isosmotically substituted in the K(+)-rich medium. NMDA (in the absence or presence of glycine) and two competitive antagonists, 2-amino-5-phosphopentanoic acid (AP5) and (+/-)-3-(s-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), each had little effect on the tone of arteries preconstricted with potassium or the stable thromboxane A2 analog U-46,619. Three noncompetitive antagonists (S(+)-ketamine, dizocilpine, and dextrorphan) and their steroeisomers (R(-)-ketamine, (-)MK-801, and levorphanol) each produced dose-dependent relaxation of K(+)- or U-46,619-constricted arteries; relaxation was not selective for the (+) or (-) stereoisomers. These results suggest that large cerebral arteries lack NMDA receptors mediating constriction or relaxation. All noncompetitive antagonists dilated cerebral arteries, but by mechanisms that were not stereospecific.

Hemopneumothorax in an intravenous drug abuser.

This article reports a case of an intravenous drug abuser who presented with a hemopneumothorax, which is a rare complication of jugular vein self-injection. The patient achieved an inadvertent subclavian arterotomy, causing tingling and numbness in the hand and arm, an unusual "high," and blood filling the pleura, collapsing the lung. With an increase in pulmonary complications among intravenous drug abusers from infections in the immunocompromised state, pulmonary complaints related to trauma sustained from their activity must not be overlooked.

Ketamine directly dilates bovine cerebral arteries by acting as a calcium entry blocker.

This in vitro study was performed to determine the role of calcium in ketamine-induced cerebral vasodilation. Isolated bovine middle cerebral arteries were cut into rings to measure isometric tension development or into strips to measure radioactive 45Calcium (45Ca) uptake. Ketamine produced direct relaxation of arterial rings; the relaxation was attenuated in Ca(2+)-deficient media. Ketamine produced dose-related relaxation of arteries preconstricted with potassium, a stable thromboxane A2 analogue, or endothelin. Endothelial stripping with Triton X-100 had no effect on subsequent ketamine-induced relaxation. In Ca(2+)-deficient media containing potassium or the stable thromboxane A2 analogue, ketamine produced competitive inhibition of subsequent Ca(2+)-induced constriction. Ketamine blocked potassium- and thromboxane A2-stimulated 45Ca uptake in a dose-dependent manner, but had no effect on basal 45Ca uptake, the externally bound 45Ca content, or the volume of the 3H-sorbitol space. These results indicate that ketamine can directly dilate cerebral arteries by acting as a calcium channel antagonist; ketamine inhibits 45Ca uptake through both potential-operated (potassium) and receptor-operated (thromboxane A2) channels in cerebrovascular smooth muscle.

Role of angiotensin in the renal vasoconstriction observed during the development of genetic hypertension.

Studies have examined renal function to determine the role of the kidney in the pathogenesis and maintenance phases of hypertension in the Okamoto-Aoki strain of spontaneously hypertensive rat (SHR). As compared to age-matched Wistar-Kyoto rats (WKY), 4- to 6-week old SHR are moderately hypertensive and have a reduced glomerular filtration rate (GFR) and renal blood flow (RBF), and an increased renal vascular resistance. Cross-breeding studies indicate the reduction in RBF and GFR in young SHR is genetically linked to the hypertension and thus may be of primary pathogenetic importance. The combination of an elevated vascular resistance and reduced RBF and GFR in young SHR implicates increased activity of a vasoconstrictor system(s), decreased activity of a vasodilator system(s), or both. Observations from several laboratories support the notion that endogenous angiotensin II contributes to the renal vasoconstriction in young SHR during the developmental phase of hypertension. Acute and chronic inhibition of angiotensin converting enzyme reduce arterial pressure, reduce renal vascular resistance and increase renal blood flow in young and adult SHR. Renal vascular tone in SHR is more dependent on angiotensin converting enzyme activity than that in WKY. The ability of angiotensin converting enzyme inhibitors to produce renal vasodilation may be responsible, at least in part, for its antihypertensive effects. Other studies indicate that renal vascular reactivity to angiotensin II is exaggerated in young SHR. The strain differences in renal reactivity to angiotensin II can be abolished by cyclooxygenase inhibition with indomethacin, indicating that endogenous prostanoids counteract some of the constrictor action of angiotensin II, with more pronounced buffering activity in WKY.(ABSTRACT TRUNCATED AT 250 WORDS)

Tubuloglomerular feedback kinetics in spontaneously hypertensive and Wistar-Kyoto rats.

The steady-state behavior of the tubuloglomerular feedback system has been studied in detail, but little is known about its dynamics. However, kinetic data can provide insight regarding the contribution of feedback to autoregulatory responses. Accordingly, experiments were conducted in anesthetized, euvolemic, spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats to characterize the time course of changes in proximal tubular stop-flow pressure after step changes in the rate of orthograde perfusion of Henle's loop. We studied the responses both to increase in perfusion rate, which produced preglomerular vasoconstriction, and decreases in perfusion rate, which produced preglomerular vasodilation. In both strains, the pattern of induced stop-flow pressure transients consisted of a pure delay followed by a monoexponential decay to a new steady state. In SHR rats, delay times were shorter than in WKY rats, but response time constants were not significantly different in the two strains. However, response time constants for dilation were longer than for constriction in both strains. The delay times and relatively large response time constants observed indicate that tubuloglomerular feedback cannot mediate rapid autoregulatory responses to fluctuations in renal perfusion pressure. The response time of tubuloglomerular feedback is probably limited by both the time lag associated with fluid transit through the loop of Henle and a relatively slow rate-limiting step in the signal transduction process at the macula densa.

Exaggerated renal vascular reactivity to angiotensin and thromboxane in young genetically hypertensive rats.

The objective of this study was to test the hypothesis that angiotensin II and thromboxane A2 (TxA2) contribute to the elevated renal vascular resistance observed during the development of genetic hypertension. In 6-wk-old anesthetized spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats, renal blood flow (electromagnetic flowmetry) and carotid arterial pressure were measured during bolus injections of different doses of angiotensin II and U46619 (stable receptor agonist of TxA2) into the renal artery before and during inhibition of prostaglandin synthesis by indomethacin. In all cases, arterial pressure remained unchanged at the pre-injection levels. Under control conditions, angiotensin II reduced renal blood flow in SHR almost twice as much as in WKY. This strain difference was abolished by inhibition of prostaglandin synthesis, suggesting that a deficiency in the action of endogenous vasodilator prostaglandins is responsible for the enhanced response to angiotensin II in SHR. Under control conditions, the TxA2-receptor agonist produced similar reductions of renal blood flow in SHR and WKY. However, after indomethacin, the agonist-induced vasoconstriction was twice as large in SHR as in WKY, suggesting that SHR kidneys have an increased vascular reactivity to TxA2, which is unmasked when indomethacin reduces elevated levels of endogenous TxA2. These findings indicate important strain differences between young SHR and WKY in the renal vascular response to angiotensin II and TxA2 that may contribute to the renal vasoconstriction observed during the development of genetic hypertension.