Iris Publishers- Open access Journal of Advances in Cancer Research & Clinical Imaging | Kaposiform Hemangioendothelioma Associated with Kasabach Merrit Phenomenon in A Child

 

Authored by Oscar E González*,

Abstract

Kaposiform hemangioendothelioma (KHE) is a rare, potentially life-threatening vascular tumor. More than 50% of cases are diagnosed within the first year of life and are often associated with a thrombocytopenic coagulopathy known as Kasabach-Merritt phenomenon (KMP). Approximately 10% of patients die because of this disease, either due to local growth or KMP. Given the rarity of the entity, there have been no prospective studies regarding the treatment of KHE or standardized outcome measures to outline a standard treatment. We describe the case of a female child diagnosed at three months of age with an intraabdominal KHE associated with KMP. She received continuous treatment with vincristine, propranolol, and prednisolone for 10 months until the disappearance of the lesion in images and resolution of the coagulopathy. As a result, she obtained complete remission and now, five years after finishing the treatment, she continues symptom-free.

Keywords: Hemangioendothelioma; Kasabach merritt phenomenon; Consumption coagulopathy; Childhood

Abbreviations: KHE: Kaposiform hemangioendothelioma; KMP: Kasabach merritt phenomenon, MRI: Magnetic resonance imaging

Introduction

Kaposiform hemangioendothelioma (KHE) is a rare benign vascular tumor but potentially fatal when associated with Kasabach- Merritt phenomenon (KMP). This phenomenon is characterized by the development of consumption coagulopathy secondary to this vascular malformation; a situation that predisposes to bleeding and other hemorrhagic complications [1]. KHE usually compromises skin and subcutaneous tissue. It typically appears on the lateral neck, axilla, groin, extremities, and trunk. However, numerous case reports have identified KHE in bone, mediastinum, and retroperitoneum [2]. Although they are usually solitary, particularly in the bone, they can present as multifocal lesions. In addition, the direct extension of retroperitoneal and mediastinal lesions in the pancreas, mesentery, pericardium, thymus, and lymph nodes has been reported. There are no significant sex or ethnicity associations, and there are no reports of familial cases underlying genetic mutations [1,2].

There are several treatment modalities such as angiography and embolization, surgical excision, and pharmacologic treatment, with some consensus practice standards towards KHE treatment, however, the low prevalence has limited the standardization of treatment and KMP makes the management problematic, demanding strict adherence and rigorous follow-up [1]. This report describes the case of a three-month-old female patient with an intraabdominal KHE associated with KMP; treatment involved vincristine, propranolol, and prednisolone for 10 months, achieving complete remission.

Case Presentation

A three-month-old female infant was admitted to the emergency room due to four days of irritability, hyporexia, recurrent crying, mild pallor, and petechiae in extremities. She only had a history of gastroesophageal reflux and colic of the infant. Without surgical, traumatic, or positive-allergic history. On admission, she was in an acceptable general state, active and reactive. Due to a tendency to desaturation during sleep supplemental oxygen by nasal cannula at 0.1-liter/minute was initiated. Vitals were within normal limits. At physical examination, she presented mild pallor, petechiae, and ecchymosis on the extremities.

Initial laboratory values showed severe thrombocytopenia (Platelet count 14,700/μL) and anemia (Hb 9,1) (Figure 1).

Infectious, immune, and rheumatologic diseases were ruled out. The initial diagnosis of primary immune thrombocytopenia was considered, and immunoglobulin G was initiated However, at 72 hours it presented an inadequate response with a platelet decrease to 6,000/μL. A bone marrow biopsy was performed after platelet transfusion. The studies in bone marrow revealed megakaryocytic hyperplasia, without blasts.

She continued with severe thrombocytopenia, mild anemia, with normal lactate dehydrogenase, negative direct and fractionated coombs. A wide differential diagnosis of thrombocytopenia in infants was performed [3]. She did not have positive studies for perinatal infections. There was no familiar history of thrombocytopenia. She never presented signs, except for thrombocytopenia and secondary purpuric syndrome, compatible with hemolytic uraemic syndrome or with thrombotic thrombocytopenic purpura. She had platelets of normal size and had no infectious history of albinism or rash that could have indicated a possible hereditary thrombocytopenia type May Hegglin anomaly, or Sebastian’s syndrome. There were no signs of dyserythropoietic or leukemia in the bone marrow and because of her sex, we ruled out thrombocytopenia linked to X. Von Willebrand disease was not suspected since in the variant IIb of this disease the thrombocytopenia usually is very mild. We ruled out storage pool disease because in these diseases the platelet count is normal, and we made a platelet electron microscopy study that didn´t show any abnormalities. Congenital Amegacariocytic Thrombocytopenia or Thrombocytopenia-absent radius syndrome were ruled out because there was no megakaryocytic hypoplasia nor there were alterations in the forearm bones in the x-ray images. We noted low fibrinogen (87.2 mg/dl) and increased D-dimer (> 10000 ng/mL), but there were not any apparent signs on physical examination that suggested vascular abnormalities, and the abdominal ultrasound was reported without any masses nor organomegaly.

On day fifteen of hospitalization, since she was clinically stable and the platelet count for that time was above 20,000/uL, the study continued ambulatory. After 22 days of discharge, she was readmitted on account of hematochezia with anemia (HB 7, 1g/dl) and thrombocytopenia (17,000/uL). Abdominal CT scan showed transmural thickening of the walls of the right colon, involving the right lateral aspect of the transverse colon, the hepatic angle, and the upper two-thirds of the ascending colon, associated with a lesion in the root of the mesentery, poorly defined, periduodenal, peripancreatic, with involvement of the ileocolic region; it showed heterogeneous enhancement after administration of contrast, compatible with a vascular malformation. Based on manifestations of consumption coagulopathy, KHE and associated Kassabach- Merrit phenomenon were diagnosed (Figure 2).

We initiated treatment with an oral prednisolone dose of 3 mg/kg/day divided into two doses per day, propranolol 1.5 mg/ kg/day divided into two doses per day, intravenous vincristine 0.05 mg/kg/weekly, and esomeprazole for gastric protection. The patient showed clinical improvement, without hematochezia or coagulopathy. At week 15 of treatment, platelets were within normal ranges, and fibrinogen and dimer D levels had normalized. Prednisolone was suspended at week 15 of treatment and she continued monotherapy with weekly vincristine. After 10 months of treatment, abdominal MRI showed almost complete remission of the lesion (Figure 3). Given the significant decrease in the size of the vascular malformation, it was decided to stop the treatment. Five years after, she continues without any signs of relapse (Figure 3).

Discussion

KHE is a rare vascular tumor that usually manifests during early childhood, potentially fatal when associated with KMP. This phenomenon is characterized by consumption coagulopathy due to vascular malformations, a situation that predisposes to bleeding and other hemorrhagic complications [2,4]. Even though the presence of KMP in young children is highly suggestive of KHE, reports indicate that KHE can occur without KMP in 29-43% of cases [2]. The management of complicated KHE has been founded on reviews of the available evidence, expert opinion, and clinical experience. However, the approach to treatment must be individualized [5]. Platelet transfusion must be avoided because it worsens the thrombocytopenia and increases the risk of visceral hemorrhage, further promoting tumor growth. It should only be done in cases of active bleeding or where surgical extraction is considered, always just before the surgical intervention, since they are consumed in a few hours [2]. In our patient, the platelet transfusion was made before discovering it was a KHE when it was decided to perform a bone marrow aspiration biopsy to rule out other etiologies as a cause of her thrombocytopenia. Complete surgical excision comes with a high risk of hemodynamic and hematological instability. Therefore, pharmacological therapy is the first line of treatment and surgical excision can be a second-line approach for tumors in which a complete and safe resection can be performed [6,7]. Several treatments have been studied including corticosteroids, ε-aminocaproic acid, pentoxifylline, dipyridamole, and anti-mitotic agents. In certain cases, when pharmacological treatments failed, arterial embolization or radiation therapy had moderate success, but not without long-term risks such as worsening of hematological parameters or development of angiosarcoma when exposed to radiation therapy [8]. Chemotherapy agents used to treat KHE associated with the KMP include intravenous vincristine (0.05mg/ kg/weekly dose is the recommended dose) and oral corticosteroids (prednisolone 2mg/kg/day). We were able to corroborate with our patient, that the combination of prednisolone with propranolol both days; and weekly vincristine is a very effective and safe treatment alternative. Patients with KMP should be treated aggressively with a combined regimen, and monotherapy is not recommended [9,10].

The goal is to wean the corticosteroid as soon as possible after 3 to 4 weeks of therapy if there has been a good clinical response and stabilization of the patient’s hematologic status. The intended length of vincristine therapy is typically 24 weeks [1] but should be individualized to each patient, following tumor response, and avoiding related toxicity. In the described case, 10 months of treatment were enough to achieve a complete and sustained long-term response. Successful treatment is also possible with a combination of vincristine at the dose noted plus aspirin: 10 mg/ kg/day and ticlopidine: 10mg/kg/day [11] or Interferon-alpha. Nonetheless, the use of interferon-alpha in children is limited by cost, and due to the subcutaneous administration route [8].

Sirolimus is a promising agent for KHE and some prospective studies have shown it is safe and efficient in this pathology. However, the evidence of sirolimus in children against KHE is still limited. It’s usually used in cases refractory to the combination of vincristine and steroids, given orally with close pharmacokinetic monitoring [12,13]. Residual tumor or fibrosis is common, especially in more aggressive lesions, and is not a reason to continue therapy if highrisk symptoms have resolved and the tumor is stable on serial imaging.

Despite the rare occurrence of KHE that makes it difficult to identify a standard therapy, steroids plus vincristine seem to be a good choice for first-line treatment, highly effective, economical, and with a relatively low side-effect rate. Further reports are necessary to strengthen our knowledge of these lesions.

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Iris Publishers-Open access Journal of Biology & Life Sciences | The Effects of Tinospora crispa Aqueous Extract on C-Reactive Protein Level and Development of Atherosclerotic Plaques

 

Authored by Zamree Md Shah*,

Abstract

Tinospora crispa or known as Patawali was reported to have anti- atherosclerotic effects and has great potential to be used in traditional medicinal, food supplement and pharmaceutical preparations. However, until to date there is insufficient literature documenting the effects of this plant on Creactive protein as an inflammatory marker and its anti-atherosclerotic effects in the event of hypercholesterolemia. Therefore, this study was aimed to examine this possibility by measuring the level of C-reactive protein continuing with a histological analysis of the aorta of hypercholesterolemic rabbits to further understand the possible mechanism contributing to the anti-atherosclerotic effects of tinospora crispa aqueous extract (TCAE). Results revealed that TCAE was found to inhibit the progression of atherosclerotic plaque development induced by dietary cholesterol. The antiatherosclerosis potential of TCAE was demonstrated by its ability in reducing the CRP levels, coverage area of atherosclerotic plaque and thickness of foam cells in the atherosclerotic lesions and preserves endothelial healing following arterial injury. Supplementation of 450 mg/kg of T. crispa extract was found to be the optimal concentration to be utilised towards the formulation of product for preventing hypercholesterolemia, atherosclerosis and reducing risk factors for coronary artery disease in the future.

Keywords: Tinospora crispa; Hypercholesterolemic rabbits; C-reactive protein; Athersoclerosis

Introduction

Emerging evidence suggests that elevated plasma levels of C-reactive protein (CRP) have become one of the strongest independent predictors in the development of atherosclerosis and coronary heart disease (CVD) [1]. CRP directly participates in the process of atherogenesis by modulating endothelial function and its concentration known to predict cardiovascular events [2]. Higher concentrations of CRP are associated with increased levels of serum triglycerides (TG) [3,4]. The CRP may, therefore, play a direct role in promoting the inflammatory component of atherosclerosis, and therapeutic CRP reduction might be a potential target for the treatment of atherosclerosis.

Elevated concentrations of plasma low density lipoprotein (LDL) cholesterol, low plasma high density lipoprotein (HDL) cholesterol and high plasma triglycerides (TG) or known as hypercholesterolemia are well- established risk factors for development of atherosclerosis and cardiovascular disease (CVD) [5]. Atherosclerosis, characterized by chronic inflammation in arteries, involves the accumulation of oxidized lipoproteins (OxLDL), an increased number of inflammatory cells (monocytes and lymphocytes), an infiltration of macrophages and degeneration of the arterial intima [6]. Accumulation of OxLDL and other substances, promotes the immune system cells [7] to migrate into the layers of the endothelium causes the breakdown of various substances and the attraction of LDL cholesterol particles to the site [8]. These LDL particles are further engulfed by monocytes, which then differentiate into macrophages (foam cells) leading to the formation of atherosclerotic lesions [9]. These lesions, known as atheromatous plaques, enlarge as cells and lipids accumulate in them, and begin to swell into the vessel lumen, consequent to the rupture of the plaque, thus causes lipid fragments and cellular debris released into the vessel lumen [10]. These particles are exposed to thrombogenic agents on the endothelial surface, resulting in the formation of a thrombus, or blood clot. If the thrombus is large enough to block circulation of coronary or cerebral blood vessels, this results in a heart attack or stroke [11]. Atherosclerosis complications often occur suddenly, and they can seriously jeopardize patients’ lives, and therefore any interventions aimed at reducing hypercholesterolemia are of great interest.

Tinospora crispa (L.) Hook f & Thomson, is a climber that can be found in primary rainforest of South East Asia including Malaysia, Indonesia, Thailand and Vietnam. Studies showed that the crude extracts and isolated compounds of T.crispa possessed a broad range of pharmacological activities such as cardioprotective, anti-diabetic, anti-inflammatory, antioxidant, immunomodulatory, cytotoxic and antimalarial activities [12]. Moreover, it was discovered that T. crispa possessed an anti- hypercholesterolemic activity and is beneficial in preventing the heart-related diseases. However, until to date there is insufficient literature documenting the effects of aqueous extract of Tinospora crispa on C-reactive protein and its anti- atherosclerotic effects in the event of hypercholesterolemia. Therefore, this study was aimed to measure the level of C-reactive protein as an inflammatory marker, continuing with a histological analysis of the aorta to further understand the possible mechanism contributing to the anti-atherosclerotic effects of tinospora crispa aqueous extract (TCAE).

Objectives

The objectives were to assess the role of CRP in the development of atherosclerosis and to assess the atherosclerotic plaque formation in hypercholesterolemic induced rabbits supplemented with TCAE.

Material and Methods

Collection of raw material and preparation of TCAE

About 10kg of fresh stem part of Tinospora crispa were collected from Forest Research Institute Malaysia (FRIM) at Kepong, Selangor. The plant was authenticated by FRIM botanist (Voucher number: SBID009/15). The stems were cleaned, washed, cut and dried using an oven dryer with operating temperatures of about 55°C. The weight of the samples was monitored every day until constant weight was obtained. Subsequently, the dried stems of the plant are ground to a particle size of about 1 to about 4 mm by using a 20 hp pilot scale grinder. The ground stem sample is kept at room temperature in a sealed environment prior to the extraction process.

The grounded stems of T. crispa were extracted with reverse osmosis water. The extraction processes used were 60° C temperature, 1:15 g/ml solvent to solid ratio and 1 hour of extraction time. The liquid extract then was filtered through Whatman No 1 filter paper (Whatman plc, Maidstone, UK). The filtrate was collected, and excess water was evaporated under reduced pressure using freeze dryer.

Animals and experimental procedures

Forty-two (42) healthy adult male New Zealand White rabbits (East Asia Rabbits, Malaysia) with initial mean weighting between 2.5 to 3.0 kg were used in the experiments. The animals were randomly houses in individual cages with free access to food and water with a regular light/dark cycle and under room temperature (28 ± 2°C, relative humidity 60-70 %) for 2 weeks for acclimatization before use. Following acclimatization, the animals were randomly segregated into six groups of seven rabbits each Table 1. The experiment was designed in order to evaluate the ability of TCAE at different concentrations, to prevent or delay the progression of atherosclerosis. Hence, the induction of experimental hypercholesterolemic rabbits were established by giving chow diet which were enriched with 0.5 % cholesterol for continuous 10 weeks to 5 groups of rabbits namely, group 1: Hypercholesterolemic-induced (H), group 2: Simvastatin control (SC), group 3: Low dosage of TCAE (200 mg/kg), group 4: Medium dosage of TCAE (450 mg/ kg), and group 5: High dosage of TCAE (600 mg/kg). In the Normal control (NC) group the rabbits were given with normal chow diet. Food and water were given ad libitum throughout the experiment. The STCAE and simvastatin were given via oral gavage while blood sampling was performed at week 0 and at week 10 of experimental period. The experimental protocol and animal handling throughout the study were in accordance with guidelines approved by the institution ethics committee with Certificate number: IACUC-FRIM/1 (2013)/07- 5.

C-Reactive protein

Human CRP was purchased from Sigma (solution in 0.02 mol/L Tris and 0.25 mol/L sodium chloride, pH 8.0). CRP was purified from human plasma by using Ca2+-dependent affinity of the protein to phosphorylcholine. Purity of the protein is ≥ 98 %, as determined by SDS-PAGE. The preparation displayed a single protein band of Mr ≈21 000. The physical state was examined by centrifuging 100 μg in 5 mL of a linear 10 % to 40 % (wt/vol) sucrose density gradient in 20 mmol/L Tris, 100 mmol/L NaCl, and 2 mmol/L Ca2+ buffer (50 000 rpm, vertical rotor VTi 65, 4 °C, 60 minutes, Beckman ultracentrifuge model L60). The protein sedimented in a symmetrical peak of ≈5.5S, and protein was not detected in higher Mr fractions (>19S). Thus, the CRP did not autoaggregate. During preparation, precautions were taken to avoid lipopolysaccharide contamination. The latter was excluded by Limulus endotoxin assay (Kinetic-QCL, BioWhittaker). Sensitivity of the assay is 0.015 to 400 IU/mL.

Histology study

Aorta preparation: At the end of the week 10, the rabbits were sacrificed. Midline thoracotomies were performed. Aorta tissue between its origin and bifurcation into the iliac arteries was taken gently, free of adhering tissues and washed with cold normal saline solution. The large part of origin was cut into 3 mm and was put into 10 % formalin for histology study (haematoxylin and eosin staining), whereas the ascending large part of aorta between its origin and bifurcation into the iliac arteries was opened longitudinally and prepared for plaque assay (Sudan IV staining).

Sudan IV Staining: Assessment of atherosclerotic plaque lesions: Atherosclerotic plaque areas were assessed by a previously described method. Briefly, the aortic strips were dissected from the ascending arch to the iliac bifurcation, and extraneous adipose tissue was removed. The aortas were opened longitudinally, rinsed several times with ice- cold saline and stretched onto a piece of cardboard. Then, it was fixed immersed in neutral 100 g/L buffered formalin solution for 24 h and then rinsed in 70 % alcohol. The tissue was then immersed in Herxheimer’s solution containing Sudan IV (5 g), ethyl alcohol (70 %, 500 mL) and acetone (500 mL) at room temperature for 15 min and washed in running water for 1 h. This staining allowed a clear depiction of the plaques due to their deep red colour.

Macroscopy study: The photographs of the intimal surface of the aorta were taken using digital camera (EOS Canon, Japan) and the intimal lipid lesions were determined quantitatively by estimation of the percentage of sudanophilic stained areas in the total aortic intimal area in photographs using Image Analysis Software. The total atherosclerotic area of the intimal surface of the aorta was measured in mm2. The extent of atherosclerosis was expressed as a percentage of the luminal surface that was covered by atherosclerotic plaques using the formula below:

Tissue blocking: An approximately 3mm of aortic arch were fixed in 10% formalin for a few days and prepared for light microscopy by dehydrating the tissue samples in an ascending series of alcohol dehydration, clearing with xylene and wax impregnation with paraffin wax for 14 h in an automatic tissue processor machine as shown in (Table 1).

Table 1: Tissue Dehydration in a Tissue Processor Machine (TP1020).

Tissue sectioning and staining: The tissues were embedded into block by paraffin wax at 62 °C and were cooled at 0 °C for 3 h to form solid block. This is followed by the sectioning process, whereas the tissues were trimmed and sectioned with the thickness of 4 to 5 μm ranges using a microtome machine. The tissues were then placed in the water bath, attached on glass slides and then were dried on a hot plate at 50 to 55 °C for 30 min and then kept at 37 °C. The tissues sections were then stained with Haematoxylin and Eosin (H&E) staining method using Autostainer Machine Table 2. The slides underwent processing, colorization and dehydration. After thoroughly dried from xylene, the slides were mounted with cover slips and mounted with DPX. The slides were then dried at room temperature for a few days before being analysed under light microscopy (Olympus CK2) (Table 2).

Table 2: Colouration with Haematoxylin and Eosin (H&E).

Table 3: Percentage of Atherosclerotic Plaques Coverage of All Groups.

Notes: Each value represents the mean + SD. Values with the asterisk (*) are significantly different (p < 0.05) compared to hypercholesterolemic model group. Values with # are significantly different (p < 0.05) compared to normal control group. NC, normal control; H, high cholesterol diet group; TCAE, T. crispa aqueous extracts.

Quantitative analysis of histological data: For each slide of aorta, the plaque accumulation was analysed for the average determination of the thickness of the foam cells by using an image analysis system consisted of a Macintosh lix computer (Apple) equipped with a Frame Gabber Card (Quick capture, data translation), a Sony high-resolution video camera and a Trinitron Super Mac 21 in. color monitor.

Statistical analysis

All data were expressed as mean ± standard deviation (SD). One way ANOVA was used to compare the statistical differences between the treatment groups and the control group using SPSS version 21. Turkey post-hoc test was used for multiple group comparison analysis. Significant different was set at p<0.05.

Results

C-Reactive protein

Figure 1 shows the results of CRP in all groups throughout the experimental period. At the beginning of the study period, there was no significant difference of CRP levels observed among all groups. However, feeding 0.5 % high cholesterol diet alone to the rabbits caused a significant increase (p<0.05) in the CRP levels at week 10 (1.61 mg/ml) compared to week 0 (1.14 mg/ml). In contrast to the H group, SC group showed a significant reduction (p<0.05) of CRP concentration throughout the experiment conducted with the CRP value 1.13 mg/L at week 0 and 0.88 mg/L week 10, respectively. Result also revealed that, the CRP level in rabbits supplemented with 200 mg/kg of STCAE was significantly increased (p<0.05) from week 0 to week 10 with the CRP value of 1.12 and 1.35 mg/L, respectively. On the other hand, it was observed that there was no significant different of the CRP concentration in rabbits supplemented with 450 mg/kg of STCAE from week 0 (1.14 mg/L) to week 10 (1.13 mg/L), respectively, in which the CRP level was significantly decrease (p<0.05) when compared to H group. Whereas, the CRP level in rabbits supplemented with 600mg/L at week 10 was significantly reduced (p<0.05) compared to week 0 and H group with the CRP concentration of 0.94 mg/L and 1.15 mg/L, respectively. Meanwhile, there was no significant difference observed in CRP level throughout the experiment conducted in the NC group (Figure 1).

Sudan IV staining of aorta

Photomicrograph of aorta with H&E staining

Effect of TCAE on atherosclerotic plaques coverage

Percentage of atherosclerotic plaques coverage for each treatment groups are shown in Table 3. Atherosclerotic plaques coverage of rabbits fed with the normal diet and rabbits supplemented with simvastatin and different concentration of TCAE measured using NC as a baseline. It was observed that almost no visible atherosclerotic plaques or lesion area in aorta of rabbits in the normal group. High cholesterol diet group showed marked increase of plaques coverage with 31.12 ± 2.18 % of coverage. Rabbits supplemented with 200, 450 and 600 mg/kg of TCAE showed marked reduction of atherosclerotic plaques coverage with 18.32, 50.87 and 66.25 % reduction respectively, when compared to hypercholesterolemic rabbit. Simvastatin reduced plaques coverage to a greater extent with 92.80 % of reduction (Table 3).

Effect of TCAE on thick of foam cells

The aorta’s atherosclerosis extension was further observed on its area of fatty region by using the detection of the formation of foam cells in the atherosclerotic lesions. Result found that there was no visible of foam cells observed in the thoracic aorta of rabbits fed with the normal diet and rabbits supplemented with simvastatin, 450 and 600 mg/kg of TCAE. The foam cells formation appeared much more severe in rabbits supplemented with high cholesterol diet than in rabbits supplemented with 200 mg/kg of TCAE. The thickness of tunica intima in the high cholesterol diet group and in the group supplemented with 200 mg/kg of TCAE were 186.50 ± 9.69 μm and 69.92 ± 4.82 μm respectively with significance different at p<0.05 (Figure 4).

Discussion

Dietary cholesterol has been reported to contribute significantly elevation of plasma cholesterol. Increased cholesterol levels in the diet has been reported to elevate serum and aortic tissue cholesterol which subsequently increase aortic atherosclerotic [13] due to endothelial dysfunction [14].

The genesis of atherosclerotic associated with an increase level in markers of inflammation such as CRP and characterized by inflammation of the endothelium of the coronary arteries [15]. Evaluation on the CRP levels could provide a rapid indicator for determining individual risk factors of atherosclerosis in which individuals with elevated levels of CRP have a risk about 2 to 3 times higher than the risk of those with low CRP levels [16].

From the result obtained, it revealed that feeding high cholesterol diet to the rabbits for 10 weeks resulted in a significant increase of CRP levels compared to rabbits in the normal control group, indicating the incidence of early progression of atherosclerosis. The finding was supported by Yu, et al. [17] who reported that the plasma CRP levels were significantly higher in the cholesterol- fed rabbits than those of the control rabbits after 28 weeks of experiment. Similar finding was reported by Sun, et al. [18] who stated that the elevated CRP levels in plasma were correlated with the severity of atherosclerosis and hypercholesterolemia in rabbits. The excess of LDL in the circulation in the hypercholesterolemic- induced rabbits will cause more LDL to be accumulated in the sub-endothelial matrix which may undergo oxidation [8,19], later mediates OxLDL uptake by macrophage [20]. According to Mehta, et al. [21], CRP reduces the expression of nitric oxide synthase and prostacyclin synthase, binds with LDL and promotes its uptake by macrophages thus caused inflammation of the endothelium during early development stage of atherosclerotic process. In addition, accumulation of inflammatory cells, especially macrophages can produce a variety of cytokines that may stimulate the hepatic expression of the CRP gene and CRP production by the liver [18].

In contrast, supplementation of simvastatin to the hypercholesterolemic- induced rabbits significantly decreased (p<0.05) the CRP levels when compared to rabbits feeding with high cholesterol diet alone. Similar finding was reported by Shrivastava, et al. [15], who found that statin reduces CRP levels in many patients primarily by lowering the LDL cholesterol. The reduction of LDL levels in the circulation means less substrate available to be oxidized to produce oxidized- LDL (oxLDL) [22]. The less oxLDL in the intima caused the reduction of CRP levels resulting less formation of atherosclerotic plaque in the aorta [3].

Meanwhile, it was observed that supplementation of different concentration of TCAE to the hypercholesterolemic-induced rabbits were able to decrease the CRP levels in dose dependent manner as compared to the group of rabbit fed with high cholesterol diet alone. Interestingly, no significant different in the CRP concentration observed between the groups supplemented with 600 mg/ kg of TCAE and the group supplemented with simvastatin. TCAE at 600 mg/kg and simvastatin reduce 41.7 and 45.4 % of CRP concentration respectively, compared to hypercholestrolemic group. These results demonstrated the beneficial effect of supplemen tation with TCAE in inhibiting the production of CRP and subsequently reducing the extent of atherosclerosis, therefore, provide evidence that TCAE may have anti-inflammatory effects in addition to its lipid-lowering effects.

According to Dave, et al. [23], plaque stabilization and plaque regression were considered among the current approaches in managing atherosclerosis. Plaque stabilizations focus on stabilizing the content of plaque and strengthening the overlying endothelium whereas plaque regression focuses on the overall reduction in plaque volume and to reverse the arterial endothelium to its normal functional state.

The basic idea of plaque stabilization is to make the plaques more fibrous and reduce their lipid content with interventions such as lipid-lowering, anti-thrombotic, and anti-coagulant agents [24]. Decreased macrophage counts and MMP expression, and increased interstitial collagen content had led to increase the plaque stability [25]. Plaque regression on the other hand, emphasizes on longterm therapy in removing lipids and necrotic material, restoring normal endothelial function and repair of uncovered areas to bring about changes beyond just stabilization of vulnerable plaques [23].

In the present study, histological examination of tissues from hypercholesterolemic-induced-rabbits after 10 weeks of study period showed a morphological change in the aorta indicating that daily intake of high cholesterol diets causes development of early atherosclerosis lesions which consistent with the previous reports [13,26]. It was revealed that, the percentage of atherosclerotic plaques in rabbits fed with high cholesterol diet were significantly higher (p<0.05) compared to rabbits in any other groups. Similar findings were reported by Yanni [27], who found that administration of 0.5 %, w/w amount of cholesterol diet to the rabbits initiated the development of early atherosclerosis lesions similar to those in humans. According to Zulkhairi, et al., atherosclerosis occurred concomitant with an increase of MDA level in serum and aorta, indicating an increase in oxygen radical. Increase of oxygen radicals level can contribute to the high incident of endothelial injury which represents a critical initiating event in the development of atherosclerosis [28].

Interestingly, it was observed that the morphological changes of the aorta can be reversed by oral administration of TCAE. The results obtained in the present study showed that, supplementation of different concentration of TCAE were able to reduce significantly (p<0.05) the atherosclerotic plaque in dose dependent manner with 18.32, 50.87 and 66.25 % reduction respectively, compared with rabbits fed with high cholesterol diet, indicating the plaque regression ability of TCAE in inhibiting the atherosclerotic plaque progression and restoring normal endothelial function in the aorta.

Meanwhile, supplementation of 1.2 mg/kg/day simvastatin to the hypercholesterolemic-induced rabbits was able to reduce the lowest percentages of atherosclerotic plaque when compared with rabbits fed with high cholesterol diet. This indicates that simvastatin, which are already in clinical use to reduce cholesterol levels, are indeed effective in atherosclerotic patients. Studies carried out by Kano, et al. [29] and Soma, et al. [30], demonstrated statins reverse or impede the progression of atherosclerosis in rabbits. Whereas, a study by Gaist, et al. [31] revealed that statins show a good safety profile in patients with high cholesterol levels and cardiovascular disease, however, statins may be potentially associated with development of many side effects including hepatic damage, myalgias or polyneuropathy [32].

The results were then supported with evidence of severe thickness formation of foam cells in the thoracic aorta of rabbits fed with high cholesterol diets following 10 weeks experimental period. It was observed that the thickness of foam cells in rabbits fed with high cholesterol diet was significantly higher (p<0.05) compared to any other group, in line with the previous reports [33].

Meanwhile, the data from histopathological examination of simvastatin treatment fed rabbits revealed the absence of foam cells comparable with rabbits fed with the basal diet. The findings was supported by Libby [34] and Sukhova, et al. [35] who reported that statin reduced significantly macrophage content, adhesion molecules, cytokines and tissue factor expression in the lesions, as compared with dietary intervention alone. Clinical studies of plaque stabilization therapy by statin have consistently demonstrated increase in fibrous tissue content and reductions in the plaque lipid pool, however statin showed only modest reductions in plaque volume [36].

On the other hand, result showed that the thickness of foam cells in hypercholesterolemic-induced rabbits supplemented with 200 mg/kg of TCAE was significantly lower (p<0.05) with the reduction of 65.52 % as compared to the group without supplementation. Remarkably, there were no presence of foam cells observed in the thoracic aorta of rabbits fed with the 450 and 600 mg/kg of TCAE respectively, comparable with rabbits in the normal control and in the simvastatin groups, indicating the plaque stabilization ability of TCAE in stabilizing the content of plaque by reducing its foam cell and improving the endothelial functional. Yu, et al. [17] reported, reduction in macrophage and increase in smooth muscle cells in advanced lesions may affect plaque stability in rabbits.

The finding was in accordance to Zulkhairi, et al. who found that supplementation of 450 mg/kg T.crispa water extract exhibited no presence of foam cells in aorta of rabbit fed with high cholesterol diet. The ability of this plant in attenuating aortic fatty streak development could be associated to its lipid lowering activity [37,38]. It was supported by Stanely, et al. [39], who stated that administration of an extract of T. cordifolia roots for 6 weeks resulted in a significant reduction in serum and tissue cholesterol, phospholipids and free fatty acids in alloxan diabetic rats. On the other hand, according to Kamarazaman, et al. [40], T. crispa inhibits the formation of macrophage foam cells by preventing the survival and differentiation of monocyte into macrophage, thus reduce the risk of atherosclerosis-related diseases.

The development of atherosclerosis has been associated with the oxidative modification of LDL [17]. Therefore, the numerous and abundant antioxidant components in T. cripsa including phenolics [3] and flavonoids namely catechin, luteolin, morin and rutin. Studies have shown that the consumption of flavonoid antioxidant is inversely related to the risk of developing coronary heart disease. Flavonoids reduce LDL oxidation and also inhibit the aggregation and adhesion of platelets in the blood [41].

Other than oxidation of LDL, atherosclerosis also associated with inflammation in the intima of arteries [42]. It was reported that, expression of adhesion molecules such as vascular adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) promote the recruitment of leucocytes to the site of injury and later contribute in the development of the pro-inflammatory state and atherosclerotic lesion [43,44]. The macrophage colonystimulating factor (MCSF) will promote the transition of monocytes to macrophages and foam cells [9]. Those adhesion molecules can be stimulated by pro-inflammatory agents including cytokine Tumor Necrosis Factor (TNF)-α and oxidative stress along with several well-established risk factors such as hypercholesterolemia, hyperglycemia and hypertension which play important roles in the pathogenesis of coronary artery disease [45]. It is therefore believable that suppression of the pro-inflammatory endothelial cell state will limit the atherosclerosis process thus benefited in inhibiting the development of atherosclerotic lesions [46,47].

Previous in vitro study by Kamarazaman, et al. [48] exhibited that, supplementation of T. crispa aqueous and methanol extracts significantly reduced (p<0.05) secretion of ICAM-1, VCAM-1 and M-CSF, while in contrast significantly increased (p<0.05) secretion of nitric oxide (NO) in TNF-α induced HUVEC compared to untreated HUVECs. Increase in NO secretion could promote vascular vasodilatory effect thus preventing from the development of atherosclerotic plaque. NO is a potent endogenous vasodilator which plays a pivotal role in vascular homeostasis [49]. A reduction in NO synthesis may contribute to the initiation and progressivity of atherosclerosis [50,51].

The protective effect of T. crispa from the secretion of adhesion molecules possibly contributed by the presence of syringin. According to Rao, et al. [52], the anti-inflammation mechanism of syringin associated with lowering TNF-α, iNOS, ICAM-1 and its’ mRNA expression which later showed improvement on the injury of the organs. The finding was supported by Wua, et al. [53] who demonstrated that, syringin reduces inflammation response of TNF-α thus protects the target organs by lowering the inflammatory factors’ expression in the heart, brain and kidney comparable with Benazepril; an antihypertensive drug commonly used in clinic [54].

According to Pandey and Rizvi [55] and Opie & Lecour [56-60], a significant mechanism to prevent the development of atherosclerosis is to reduce cholesterol levels, reduce the oxidation of LDL, protect the endothelium and repress the synthesis of proinflammatory cytokines and adhesion molecules. Improvement in lipid profiles and cholesterol levels, reductions in LDL oxidation and protection from inflammatory factors as well improvement on the injury of endothelium have all been demonstrated with the intake of TCAE. However, further investigations are necessary required to further understand the exact mechanism of action of this compound as well as T. crispa as an anti-atherosclerotic agent.

Conclusion

Supplementation of TCAE was found to inhibit the progression of atherosclerotic plaque development induced by dietary cholesterol. The anti- atherosclerosis potential of TCAE was demonstrated by its ability in reducing the CRP levels, coverage area of atherosclerotic plaque and thickness of foam cells in the atherosclerotic lesions and preserves endothelial healing following arterial injury. Supplementation of 450 mg/kg of T. crispa extract was found to be the optimal concentration to be utilised towards the formulation of product for preventing hypercholesterolemia, atherosclerosis and reducing risk factors for coronary artery disease in the future.

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Iris Publishers-Open access Journal of Complementary & Alternative Medicine | The Health and Safety of Nephrology Nurses and The Environments in Which They Work

 

Authored by Ashley Hussain*,

Abstract

The articles are divided into different sections. The first section presents an introduction to the topic. The introductory part presents the background to the topic under research. Some of the important information covered under the introductory paragraph of the article includes factors such as the increase in the quality of wellbeing among nurses. Some of the factors that are mentioned in the introductory part include the quality of the nursing environment. In connection with the nursing environment factor, the article shows some of the works that have been done, which establishes the relationship between the patient’s safety and the employee’s safety. The introduction also provides a comprehensive meaning of the term nursing safety, based on the ideas of different authors and organizations. The second part of the article covers the methods that were used in the research. One of the methods that were used in the data collection phase includes the survey method. The main survey that was involved in the collection based on the extensive literature review of the articles related to nurse’s health and safety. The article indicates that the participants in the survey were informed using different platforms such as Face book, Twitter, and RN websites. Survey Monkey was the tool that was used for data collection. The next section presents the results obtained during the study. The results indicate that there is a strong correlation between the working environments for the nurses and nurses’ safety and health. The last part of the article is the conclusion of the study. The conclusion provides an overview of the results obtained during the study and the significance of the study.

Keywords:Health, Safety, Nurses, Work Environment, Culture of Safety

Abbreviations: AACN: American Association of Critical-Care Nurses; ANA: American Nurses Association; ANNA: The American Nephrology Nurses Association; AONE: American Organization of Nurse Executives; CDC: Center of Disease Control; NNI: Nephrology News and Issues; NOA: Nursing Organizations Alliance; RN: Registered Nurse

Introduction

The study is based on the problem that is common in a healthcare organization. In the research, the problem that is under the study concerns the relationship between the workplace environment and the wellbeing of the nurses as well as the safety of patients within a healthcare organization. For a long time, cases such as medical errors within organizations have always been linked to the poor environment created within an organization. Some of the poor working conditions for nurses include long working hours, sexual harassment, and high exposure to risks among others. This study is much concerned about such conditions in their relation to the execution of the responsibilities of the nephrology nurses. This study examines major elements that are associated with workplace wellbeing. The study is important because it collects vital information that concerns the environment involving nurses. Basing on the issues that are identified in the study that can be used in solving the related problems to increase the safety of patients.

Discussion

Methods

The study involves a mixed method of data collection. Both the qualitative and the quantitative methods of data collection. The quantitative methods form an emphasis on objective measurement, and it involves the manipulation of the pre-existing data. Surveys were used as primary methods of data collection in this study. The items used in the survey were designed to meet different research techniques. To make this method of data collection more accurate, the researchers made constant references to the different works that have explored similar pieces of information. Moreover, it also involved the consultation of different nursing professionals through focus group discussions, in which the researchers asked relevant questions that they believed could help in the collection of more information. Different groups of researches mostly prefer the survey method of data collection due to its numerous advantages. The first advantage concerns the cost this method of data collection is less costly because of the online option of data collection. Again, the method is convenient because it is not subjected to manipulations and therefore the information collected through this method of data collection is accurate. Concerning this face of data collection, the timeline of surveys was enough, thus allowing more responses from different individuals to maximize the accuracy of data collected.

Results and Discussions

Under this section, a lot of information based on different elements related to wellbeing or the nursing environment was presented. Information collected based on these elements is vital in the collection of data that would help the researchers to draw a conclusion based on the correlation between the environment and the wellbeing nephrology of nurses. These elements are explored below.

Satisfaction

The results indicate that most of the individuals are satisfied with their job. According to the study findings, some were very satisfied with their jobs but others were somewhat satisfied. Basing on the level of satisfaction, the information indicates that the population of very satisfied individuals is almost equal to the population of the somewhat satisfied individuals. Still, under satisfaction, the information indicates that most of the RN nurses would definitely recommend pursuing the nursing concerns and the same population would probably recommend. Regarding where the job satisfaction is high; probably elements such as regular appreciations must be present within an organization. Such elements are highly dependent on the organizations’ Human resource management.

Considering the significance of motivation within the workplace, positive comments and recognition are major players that influence the level of motivation among workers. From the information, it is evident that RNs have different levels of satisfaction because they belong to different kinds of organizations. Those nurses that represent highly satisfied employees probably come from organizations that consider vital factors such as workplace reinforcement through positive comments, [1]. On the other hand, the proportions of nurses who are somewhat satisfied with their jobs belong to organizations which in one way or the other have some qualities that do not support workplace wellbeing. Lastly, the possible reason why most of the RNs would recommend pursuing a nursing career because of the high demand of the nurses on the job market as compared to other professions.

Mental and physical abuse

All forms of abuse are among the major factors that contribute to unhealthy working conditions such as psychological stress and depression [2]. Therefore, enacting policies related to workplace forms of abuse is one of the recommendations that can be used to promote a healthy workplace. The research identifies different forms of abuse in the workplace with sexual harassment being the most dominant factor among the nurses and the patients. Other forms of harassment include verbal and physical harassment. Regarding physical and mental abuse, it is upon the organization to establish policies that will prevent any form of abuse [3]. The most common policy among many organizations is zero-tolerance to all forms of abuse.

However, the information indicates the there are other instances where abuse is never reported at all. The study found that a high percentage of the organizations claim to have zero-tolerance to all forms of abuse within their organizations, but that is not the case. The zero-tolerance policy is essential in an organization setting as it protects the wellbeing of the nurses working in an organization. Most of the workers are not aware of the existence of policies that protect their wellbeing in an organization, thus end up suffering in silence. Therefore, it is the responsibility of organizations to provide employees with a good working environment that is free from all forms of abuse. Giving the nurses’ needs an appropriate rank on the Maslow’s hierarchy of human needs can improve the efficiency of an organization. To be more specific, security needs should be prioritized to enhance a safer healthcare facility [4]. By so doing, the employees will be in a better position to work hard to reach the self-actualization.

Long, intense hours and fatigue

Long hours on shift are one of the major causes of inefficiencies at work, [5]. The information under this study indicates that nurses work for longer hours. The study found that overtime at work is considered a voluntary activity but organizations treat it as a requirement for the nurses. It is arguable that overworking nurses not only exposes them to health-related problems but also increases the chances of occurrence of medical errors. [6] Listed some of the dangers that are associated with long working hours. Long shifts put the nurses at the risk of contracting cardiac diseases. They also establish that diseases such as hypertension and work-related stress disorders are among the common risk that individuals working long hours are exposed to.

Leadership

Leadership is one of the determinants of the working environment safety. In many organizations, poor leadership contributes to a high rate of turnover. Within the healthcare setting, the study found that the type of leadership greatly influences both the patient and the nurses’ wellbeing either directly or indirectly, [7]. For instance, a manager with good leadership skills will understand the effects of motivation among employees and the need to create a motivational environment. Once the leader understands that, then he or she will find ways to motivate the nurse who will then put the needs of patients before everything. The research done by [8] gives an excellent idea on working environments with poor leadership skills. They say that leadership skills have room for adjustment. This idea gives a clue about the significance of training programs within an organization. The introduction of training programs within an organization is one of the crucial steps that an organization can take to improve the wellbeing of the individuals working within a given facility.

Staffing and work that gets done

Having enough number of staff is one of the major factors that help in the reduction of healthcare-related problems. Some of the major indicators of rightful staffing include a reduction in nursing fatigue. This is because the high number of nurses will obviously reduce cases of long working hours and overtime. A rightful patient-nurse ratio also reduces cases that are usually associated with medical errors, which leads to high mortality rates. Therefore, if mortality rates are low, it means that the facility is equipped with the right number of nurses, [9]. According to the research [10], several negative outcomes are associated with the unbalanced patient to RN ratio in the dialysis treatments. Some of the negative impacts such a ration in dialysis treatments include skipping of the treatments, and increase in the cases of dialysis hypertension among others. Generally, it is clear that the high number of patients being attended to by a single nurse, the high the number of medical errors and therefore increasing risks on patient’s safety. This information, therefore, provides an important factor that should be examined in instances where there are high frequencies of medical errors.

Conclusion

The results section presents some of the vital factors that should be considered to heighten safety in healthcare units. Considering satisfaction, it is evident that job satisfaction is the major determent of worker’s retention. Another factor that determines workplace safety is security and this is based on Maslow’s hierarchy of human needs. Some of the main factors that contribute to unhealthy working conditions as indicated in the article include both physical and mental abuse. However, it is indicated that zero-tolerance is the main policy that helps in the reduction of cases of abuse. Leadership is another factor; leadership, as presented in the article, has two faces, good leadership, and poor leadership. The study indicates that good leadership provides a healthy working environment for the nurses and bad leadership might interfere with the working conditions. However, the study found that leadership can be adjusted through training. Lastly, rightful staffing provides good working conditions and increase the level of patient safety. The high patient-RNs ratio is prone to medical errors that may lead to death. It is therefore acceptable to say that factors explored under this study are vital in the promotion of RN wellbeing and which in turn increases patient safety.

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