Rates of Neonatal Morbidity and Mortality in the Neonatal Intensive Care Unit at Alexandria University Children's Hospital: one year study

Objectives: To determine the rates of neonatal morbidity and mortality in neonatal intensive care unit of Alexandria University Children's Hospital

Study Design: Hospital records of neonatal admissions at neonatal intensive care unit [NICU] of Alexandria University Children's Hospital [AUCH] from 1st January 2012-31[st] December 2012 were analyzed retrospectively. Percent neonatal mortality and morbidity were calculated from the record, along with the causes of neonatal morbidity. The data were collected and statistically analyzed

Results: Out of 2063 neonates, 1098 [53.2%] were males while 965 [46.8%] were females with a male to female ratio of 1.3: 1. Majority, 1633 out of 2063 [79.2%], of the neonates was admitted during the 1st day of their life, mean age 2 days. Of total neonates included in the study 635 neonates [30.8%] died during their hospital stay. Significant risk factors [P<0.05] associated with neonatal mortality were: Caesarean delivery, multiple births, maternal infection, neonatal respiratory distress, prematurity, and low birth weight [LBW]. The mortality rate decreased with the increase in birth weight, as well as gestational age. Prematurity, neonatal jaundice, Respiratory distress and sepsis were the most common causes of neonatal morbidities contributing 70.4%, 70%, 65.4% and 48.2% respectively. Overall mortality was 30.8%.Th e three most common causes of neonatal mortalities were Respiratory distress [29.2%], Prematurity [27.8%] and neonatal sepsis [23.1%]

Conclusion: Majority of patients were admitted in the first day of life which indicates that improvement in the prenatal, natal and nursery care as a whole can reduce the neonatal mortality and morbidity in preterm as well as full term neonates

Angiogenic output in viral hepatitis, C and B, and HCV-associated hepatocellular carcinoma

Angiogenesis is known to play a pivotal role in most of malignancy, including HCC, and in chronic inflammation. To investigate the angiogenic output in HCV and HBV infection and its implication in the development of HCV associated HCC. Blood samples were collected and grouped as; HS healthy subjects control group; HCC-HCV; chronic HCV infected patient group [HCV+ve] who are positive for serum anti-HCV antibodies and HCV-RNA; anti-HCV antibody positive and HCV-RNA negative patient group [HCV-ve]; patients with positive HBsAg and HBV-DNA group [HBV+ve]; and HBsAg positive and HBV-DNA negative patient group [HBV-ve]. Serum levels of vascular endothelial growth factor, angiopoietin-2, endostatin and angiostatin were assessed in different studied groups

Evaluation of the role of presepsin [soluble cd 14 subtype] in the diagnosis of neonatal sepsis in preterm newborns

Objective: The present study was conducted to evaluate the role of presepsin as an early and rapid predictor of bacterial infection in newborn infants

Methods: This study was carried out on 50 preterm newborn infants with clinically suspected early onset sepsis admitted to the neonatal intensive care unit at Alexandria University Maternity Hospital, All studied newborns were subjected to History taking, detailed physical examination and sepsis work -up, including complete blood count, blood culture, CRP, CSF analysis if indicated and quantitative measurement of preseason

Results: The mean birth weight of the studied newborn infants was 1520 g and the mean gestational age was 32.7 weeks with no statistically significant difference as regard the preseason results. Virginities was the main maternal risk factor for EOS, present in 80 % of the studied newborn infants. The majority of cases of positive culture for Klebsiella were negative for preseason, and this was statistically significant, Presence of toxic granules had the highest incidence among laboratory markers in the CBC in the studied group, Preseason was positive in 48% of newborns and the mean value of preseason was 1397.6 ng/L, Most cases with positive initial CRP readings were positive for preseason and this was statistically significant. There was no significant difference in preseason results as regard clinical score, total laboratory score and both laboratory and clinical scores. All cases that had meningitis were positive for preseason, and most cases that didn't have meningitis were negative for preseason and this was statistically significant. There was no statistically significant difference between preseason results and duration till admission, Apgar score or hospital stay

Conclusion: We concluded that preseason is a useful, quickly and easily performed marker for diagnosis of neonatal, sepsis. Its results are comparable to the CRP and seemed to be superior to conventional CBC tests. Furthermore, presepsin is a promising prognostic marker that could identify high risk newborns to severe sepsis, but it may not be elevated in response to infections caused by organisms like Klebsiella

Presence of Helicobacter spp. DNA in the gallbladder of Egyptian patients with gallstone diseases

Earlier reports on the detection of Heticobocter DNA in the gallbladder tissue of patients with biliary diseases have shown discordant results. This study aimed to detect the presence of Helicobacter in gallstone, gallbladder tissue and bile specimens from subjects with H. pylori-positive gastritis with cholelithiasis. The presence of H. pylori in antrum biopsies was confirmed by rapid urease test and/or histopathological examination. DNA was extracted from gallbladder, bile and gallstone samples from 50 patients undergoing cholecystectomy. The presence of Helicobacter genus-specific DNA [16S rRNA genes] was determined by nested polymerase chain reaction assay. Helicobacter DNA was detected in the gallbladder tissue and bile of 28% and 18% respectively of the patients, but was not detected in any of the gallstones. These results do not rule out the possibility of Helicobacter infection as a contributing agent or cofactor in the development of biliary diseases

Antioxidants and tumor necrosis factor-alpha in patients with pulmonary tuberculosis

Tuberculosis [TB], is one of the major common air born infectious bacteria! diseases whichremains a major worldwide health problem with global mortality. To evaluate the efficiency of serurr samples compared to sputum for the early diagnosis of TB, and to evaluate the levels of superoxide dismutase [SOD], catalase [CAT], total antioxidant status [TAS] and tumor necrosis factor-a [TNF-alpha] in patients witt pulmonary tuberculosis [PTB]. One hundred patients with clinically suspected PTB and 25 healthy individuals were enrolled in the study. According to the bacteriological results, 78 patients were diagnosed as having PTB infection. These cases were categorized into 69 culture positive cases [sputum anc serum PCR positive patients [n=42], sputum PCR positive and serum PCR negative patients [n=16] and sputurr and serurr. PCR negative patients [n=11]] and 9 culture negative and sputum PCR positive cases witi radiological lung abnormalities suggestive for PTB. For these 78 cases, erythrocyte SOD, CAT, serum TAS an? TNF-alpha were determined. Twenty two patients were culture negative and negative for both sputum and serun PCR. They had no PTB and were not involved in biochemical studies. In all 78 PTB patients erythrocyte SOD, CAT and serum TAS levels were statistically lower than controls [p<0.05], while TNF-alpha was highly significantly .increased [p=0.001]. There was a significant direct linear correlation between SOD and CA" and TAS [p<0.0001, r= 0.78; p<0.0001, r= 0.88; p<0.0001, r=0.80 respectively] and a significant reverse linea correlation between TNF-alpha and SOD, CAT and TAS level [p<0.0001 r=-0.55; p<0.0001, r=-0.51; p<0.0001, r= 0.65 respectively]. Although the sputum culture is still the gold standard for the diagnosis of patientt with PTB, sputum PCR is an efficient method that could be used as an alternative to the culture for the rapk identification of PTB cases. The lower levels of SOD, CAT and TAS may be improved by the antioxidant therap which may help in better prognosis. Also anti TNF-alpha therapy may help in decreasing the elevated level of TNF-alpha shown in all PTB patients

Therapeutic approaches to age-related dementias: rational search for effective drugs

Dementia of the Alzheimer's type is a disease associated with age. As the life expectancy of the world population increases, the incidence of dementia is predicted to increase. Currently, very few medications are available that can be used to mitigate the symptoms of the disease. This symptomatic therapy is not optimal and is associated with variable outcomes and side effects. Furthermore, none of these drugs have been clearly proven to stop or prevent the development of the disease. To begin to seriously address the current poor situation of pharmacotherapeutic management of these devastating diseases, more research is required to understand the pathological changes associated with dementia and to rationally design, synthesize and test compounds with potential for more efficacy and fewer side effects and possibly, disease modifying actions. The ideal compounds would be those which, in addition to providing symptomatic relief, also slow down disease progression with minimal side effects

Correlation between myometrial thickness and the latency interval in preterm premature rupture of membranes

In order to predict the time of labor in patients with preterm premature rupture of membrane [PPROM], different factors have been studied resulting in different detection rates. Recently, sonographic measurement of myometrial thickness [MT] has been introduced and studied as an applicable and noninvasive method in predicting the length of latency interval [LI] of labor [the period from PPROM to start of labor]. The objective of our study was to determine the correlation between MT and LI in pregnant women with PPROM led to oligohydramnios. This was a cross-sectional study on 24 cases with PPROM. The sonographic measurement of myometrial thickness and the latency interval of patients with PPROM without labor pain were recorded. Gestational age was between 26-34 weeks and amniotic fluid index [AFI] was less than 5 percentile. The data were analyzed using SPSS software. The mean +/- SD maternal age was 29.2 +/- 1.2 years. The AFI in all women was less than 5% percentile of normal fluid for that gestational age. The mean +/- SD of gestational age was 29.1 +/- 2.2 weeks. The mean +/- SD of MT was 6.5 +/- 1.5 mm interiorly, 7.9 +/- 4.2 mm fundal, 6.6 +/- 1.7 mm in the lower segment and 7.8 +/- 2.2 mm laterally. The mean LT was 545 +/- 4.7 hours. Our study showed that there is no significant correlation between MT and LI in pregnant women with PPROM and reduced AFI

use of intraperitoneal mersilene in the management of large ventral hernias

Large ventral hernias usually require prosthesis for a successful repair. Many prosthetic techniques have been described with extra-fascial, sub-fascial, and intra-peritoneal positioning. The present study was conducted to asses the value of Mersilene mesh intra-peritoneal placement in the management of large ventral hernias. This study included 15 female patients with large ventral hernias [myo-apponeurotic defect >/= 10cm in diameter]. Their ages ranged from 30 to 62 years with a mean of 42.8 years. Twelve patients had an incisional hernia, following midline incision [n=6], right subcostal incision [n=3], paramedian incision [n=2], and Mc Burney's incision [n=1]. Three patients had a huge paraumblical hernia. All patients were clinically evaluated, investigated and had their respiratory function tests assessed both pre-and post-operatively. Hernias were repaired using the intra-peritoneal technique of mesh [30x30 cm Mersilene] positioning with placement of the greater omentum between the mesh and the bowel whenever possible. Patients were followed-up for a mean of 11.5 months [range 8-18 months]. The size of the hernia defect at surgery ranged from 10x13 cm to 22x25 cm with a mean of 13x14 cm. The mean hospital stay was 8.5 days [range 7-10 days]. Post-operatively, one patient developed superficial wound infection and another developed a seroma. Both resolved spontaneously on conservative measures. None of the patients developed post-operative respiratory distress. No recurrence was encountered during the follow-up period. The technique of intra-peritoneal Mersilene mesh fixation in the treatment of large ventral hernias a'ppears to be simple, adequate and safe. It does not cause post-operative respiratory distress and does not necessitate dissection of the intermediate planes thus minimizing hematoma and seroma formation and the risk of sepsis

Comparative study of visual assessment of neonatal jaundice and laboratory estimation of total serum bilirubin in full-term newborn infants

Neonatal hyperbilirubinemia is the most common condition that requires medical attention in newborns. The assessment of jaundice can be carried out using several methods. The aim of this work is to compare visual assessment and laboratory estimation of TSB in full term newborn infants and to evaluate the accuracy of visual assessment of neonatal jaundice in guiding management decisions in the out-patient settings. The study was conducted in the out-patient clinic of Alexandria University Children's Hospital for a period of eight months. 57.2% of babies were male infants while 42.8% were females with a mean gestational age of 38.5 +/- 1.58 weeks and mean weight of 2.98 +/- 0.62 kg. The total agreement between the lab-based management decision and the clinically based decision was 84.2% out of 500 cases involved in the study. Sensitivity of visual assessment was 95.8% while specificity was 80.5%. The false positive rate was 39.2% and positive predictive value was 60.8%. False negative rate and negative predictive value were 1.6% and 94.8% respectively. Also, the Spearman correlation of dermal zones determined by visual assessment and lab TSB in the whole sample was 0.76 [p = 0.000]. It was highest in Infants < 3 days [0.94] and lowest in infants > 14 days [0.69]. In conclusion, visual assessment of neonatal hyperbilirubinemia is a useful clinical tool, if used correctly and by trained medical personnel in resource-poor countries, where there is little or no access to reliable laboratory-based diagnostic services

Anterior abdominal wall fistula: a clinicopathological challenge

Aim of the work was to study the anterior abdominal wall fistulae connected to the gut from etiological, clinical and therapeutic aspects regarding their incidence, presentations, response to conservative or surgical treatment and final outcome. This study was carried out on 30 patients with external fistulae connecting the anterior abdominal wall and Originating from the intestine, biliary radicles and the pancreas. All patients were admitted to Department of Surgery, Main Alexandria University Hospital There were 18 males and 12 females, the age ranged from 12 to 65 years with a mean value of 48.15 +/- 3.24 years. Eleven patients [36.7%] were of high output fistulae, 4 patients [13.3%] were of moderate output fistulae and 15 patients [50%] were of low output fistulae. The complications were sepsis in 10 patients [33. 3%], fever in 10 patients [33.3%], electrolyte depletion and weight loss in 4 patients [13.3%] and skin complications in 22 patients [73.3%]. Abdominal ultrasound and CT scans were done in all cases and revealed internal collection in 7 patients [23.3%], fistulogram was done in 7 cases [23.3%] and endoscopic retrograde cholangiopancreatography [ERCP] in one case. The origin of fistulae was the small intestine In 10 patients [33.3%], the colon in l6 patients [53.3%], from biliary- enteric anastomosis in 3 patients [10%] and from pancreatic duct in one patient [3.3%]. The etiological factors were gut carcinoma in 8 patients [26.7%], hernia repair in 10 patients [33.3%], neglected appendicitis in 3 patients [10%], post Whipple operation in 3 patients [10%], post pancreatic necrosectomy in one case [3.3%], iatrogenic trauma to sigmoid colon during gynaecological surgery in 2 cases [6.7%], rupture sigmoid diverticulitis in 2 patients [6.7%] and one case [3.3%] following typhoid perforation. Spontaneous closure was achieved in 25 patients [83.3%] by conservative treatment which included total parenteral nutrition, enteral nutrition, somatostatin analogue and antibiotics. Surgical intervention was required in spatients [16.7%] in the form of resection of the fistula- bearing segment and anastomosis of the two healthy ends. Five fistulae [16.7%] closed between 2 and 4 weeks, 8 fistulae [26.67%] between 4 and 8 weeks, 9 fistulae [30%] between 6 and 8 weeks and 8 fistulae [26.7%] closed after more than 8 weeks. Only one patient [3.3%] died from sepsis and multiple organ failure. spontaneous closure is depending on a number of factors which include anatomical site, distal obstruction, presence of inter current disease and whether or not the fistulous track is simple or complex. Sepsis in the peritoneal cavity is the major cause of mortality. The use of octreotide is highly recommended as It definitely converts high output to low output fistulae. The enterocutaneous fistulae that fail to resolve within 4 to 6 weeks under conservative treatment require surgical intervention

role of CT guided fine needle aspiration biopsy in the management of intra-abdominal masses

The evaluation of deep non-palpable abdominal masses or focal lesion is often difficult. Distinction between malignant and non-malignant lesions and particularly inflammatory lesions is vital for patient management, and is often suspected from imaging techniques; the diagnosis requires confirmation by biopsy. Fine needle aspiration cytology [FNAC] is a well established diagnostic technique. This study aimed at evaluation of CT guided FNAB in diagnosis of intra-abdominal masses and its impact on treatment planning. The study was conducted on thirty patients with intra-abdominal masses [clinically or radiologically diagnosed] admitted to the Department of Surgery, Faculty of Medicine, the Main University Hospital. FNAs were performed at the Radiology unit in the Main University Hospital with the pathologists assistance. Patients were subjected to surgical exploration according to the findings, aiming at resection of the mass. The impacts of CT and FNAB on the surgical decision were recorded The pathological findings of FNAB were compared with the final histo-pathological findings of the specimen. The study was carried but on 30 patients who had abdominal mass or masses. Each patient was subjected to CT guided FNAC. The age of the patients ranged between 18-70 years, with a mean of 48.57 +/- 13.69 years. with a male to female ratio 1:1. The Sensitivity for CT was 76% and for FNAB was 89%. Specificity for CT was 100% and for ENAB was 100%. Positive predictive value for CT was 90% while it was 95% for FNAB. Negative predictive value was 18% for CT and 40% for FNAB. CT guided FNAB is a relatively painless procedure. It is a safe method for obtaining a pathologic diagnosis. The overall accuracy of the CT guided FNA in intra-abdominal masses was 73.3%. CT guided FNAB helped in avoiding surgery in patients with metastatic or irresectable tumors. The accuracy was 100% in hepatic, pancreatic and pelvic masses. while it was less accurate in retroperitoneal and gastrointestinal masses. This accuracy increased with adenocarcinomas and benign tumors, but decreased with lymphomas, smooth muscle tumors, inflammatory and fibrotic lesions

Telomerase activity, cytokeratin 20 and cytokeratin 19 in urine cells of bladder cancer patients

This work aims to search for markers suitable for the screening of bladder cancer, which should be specific, sensitive, reproducible, non-invasive and at acceptable cost. The study included 50 patients diagnosed as bladder cancer [35 TCC, 15 SCC] of different stages and grades, 30 patients with various urothelial diseases, besides 20 apparently healthy subjects of matched age and sex to the malignant group. A random midstream urine sample was collected in a sterile container for the determination of telomerase by RT-PCR, keratin 19 by ELSA CYFRA 21-i IRMA kit, keratin 20 by RT-PCR and immunohistochemical staining, and urine cytology. For all parameters [telomerase, Ki9, K20 and cytology] the malignant group was significantly different from both the benign and the control groups. None of the four studied parameters was correlated to the stage of the disease, and when it comes to grade, only Ki9 showed a significant positive correlation with grade both in TCC and SCC. When ROC curves for all parameters were compared, Ki9 had the largest area under the curve, and then comes K20. K 19 may be used as a biological marker for the diagnosis of bladder cancer Ki9 could not be used for differential diagnosis of different types of bladder cancer, meanwhile it could be a marker for differentiation that decreases in less differentiated tumors. As a tumor marker, K20 reflects inability to differentiate tumor type or grade in TCC, while in SCC of the bladder it is correlated with the grade. As a method, RT-PCR is superior to immunostaining for the detection of bladder cancer, meanwhile K20 immunohistochemistry [IHC] results were much better than urine cytology as a bladder cancer screening test. Haematuria and inflammation reduced the specificity of telomerase assay, which reduced its validity as a tumor marker of bladder cancer. Ki9 and K20 are the best candidates as screening tests for the diagnosis of bladder cancer, representing the highest sensitivity and specificity, beside the radiological and histopathology. Meanwhile, telomerase, although it was a sensitive enough marker, it reflected a high false positive rate

Prevalence of TT virus infection among chronic hepatitis C patients

Much is still unknown about the clinical significance of TT virus [TTV] that has been reported as a candidate for non A-G hepatitis virus. The aim of this study was to clarify the clinical significance of TTV in healthy subjects and patients co-infected with TTV and hepatitis C virus [HCV]. Twenty four healthy subjects in addition to 40 chronic hepatitis C patients were involved in this study. TTVDNA was detected using polymerase chain reaction [PCR], HCVRNA was measured using real time PCR, and liver enzymes were also determined by RANDOX; EC 2.6.2 IFCC Kit. TTVDNA was detected in 32.5% and 37.5% of control and chronic hepatitis C patients respectively, which was not statistically significant [p>0.05]. No significant increase in serum SGPT, SGOT values was observed among TTV DNA positive and TTV DNA negative in both groups. No significant differences were found between TTV DNA positive and negative groups regarding gender and HCV RNA load. Among the healthy control group, only 2 [8.3%] out of 24 had elevated liver enzymes and they were TTV DNA positive, while out of the 40 chronic hepatitis C patients, [40%] had elevated SGPT and SGOT values respectively. Of these 5 [35.7%] were both TTV DNA and HCVRNA positive. HCVRNA viremia did not correlate with the presence of TTVDNA. In summary, this study does not indicate TTV as a causative agent of non-B, non-C chronic hepatitis cases studied

Immune modulation in polytrans fused Egyptian children with thalassemia

Fifteen children with beta thalassemia major, with no evidence of infection, were evaluated for their interleukin-2 [IL-2] production, complement [C[3]] level, as well as immune complex formation. Eight healthy children served as control subject. The study revealed a significant decrease in IL-2 production and a significant increase in immune complexes formation in thalassemic children. Regarding C[3] level, it shows marked decrease in children with thalassemia when compared to normal one. from the immunological point of view, the present work shows some interesting findings, that poly transfused beta-thalassemic children are presented by certain functional immune deficiency determined by a defect in T cell response, as denoted by reduction in IL-2 level. Decrease in C[3] level is also observed which is the result of the increase in immune complex formation obtained in children with thalassemia

Chronic unclassified arteritis, a non-arteriosclerotic arterio-occlusive disease with a distinct clinicohistopathological entity

9 patients with characteristic clinical and histopathological features which are different from the known types of arteritis in literature were described. All the patients were non-diabetic males [mean age = 42.2 years]. The commonly affected arterial segment was the ilio-common femoral and the femoro-popliteal segments, with otherwise angiographically healthy arterial tree. Angiographically normal run-off arteries were always present. Operatively, the arteries has a fleshy thick wall which was rather friable with a variable degree of periarterial fibrosis. Immunohistopathological findings included a thick internal and external elastic lamina with variable patterns of chronic inflammatory cell infiltration and immune deposits of IgG and complement [C3] mainly

Early results of russel-taylor interlocking nail femur

This work included 16 cases of diaphyseal femoral fracture treated by interlocking nail femur, 12 of them had recent fractures and 4 cases had non union because of failed other methods of internal fixation. The average age was 32 years. Our cases were followed up for 14 months. All cases had solid consolidation before 11 months. Grafting was used in 6 cases. Seven cases were dynamised. Only one case had deep infection because it was a puncture compound fracture. We concluded from this study that interlocking femoral fixation mainly in comminuted femural fractures has many advantages regarding union, rigid fixation and preservation of femoral length

Management of pathological subtrochanteric fractures of the femur by zickel nail

This study included 11 cases of pathological fractures of the subtrochanteric area of the femur [2 cases of impending fractures]. Our average age was about 68 years, 5 cases had closed zickel nailing while 6 cases had open nailing technique. All cases had biopsies taken before nailing. Methyl metha-acrylate bone cement was used to fill gaps in 2 cases with wide lesions. Radiation and/or chemotherapy were given postoperatively according to biopsy result. Cases were followed up for 2 years. We concluded from this study that, Zickel nail fixation proved to be a very reasonable method of fixation in these types of fractures, which helps to alleviate pain and to improve the life style of the patients

Nailing versus plating for biomechanically stable mid shaft femoral fractures

Fifty cases of biomechanically stable fractures of the femoral midshaft, divided equally between two groups, were treated by i.m. nailing or DC plating. The results were assessed as regards pain, weight bearing, walking ability, quadriceps function, knee motion, union alignment and occurrence of infection. The final results were satisfactory in 88% of the nailed group and in 80% of the plated one

Changes of rat brain neurotransmitters following phyrethroids treatment

The effects of two synthetic pyrethroids, cypermethrin and permethrin, on the levels of gamma-amino-butyric acid [GABA], glutamate and acetylcholine [ACh] in the rat fore- and hind-brain and on the levels of dopamine, norepinephrine and serotonin in the whole rat brain were assessed. Daily subcutaneous administration of cypermethrin [125 mg/kg] or permethrin [425 mg/kg] for four days resulted in a significant increase in the level of ACh in the fore-brain. However, the levels of ACh in the hind-brain and the levels of GABA and glutamate in the fore- and hind-brain were not significantly altered following treatment with either cypermethrin or permethrin. The levels of dopamine and norepinephrine were significantly decreased with cypermethrin intake; however the levels of norepinephrine and serotonin were significantly increased following permethrin treatment. The results were discussed in relation to the toxic excitatory symptoms produced by pyrethroids

Hepatotoxic effects of some synthesized aralkylamine compounds with possible dopaminergic activity

The effects of four aralkylamine compounds, synthesized as possible dopamine antagonists, were assessed on some biochemical parameters taken as markers for hepatotoxicity. For comparative purposes, apomorphine, metoclopramide and phencyclidine [PCP] were included in this study. Ketamine was also tested due to its close chemical structure to PCP. The investigated parameters were glutathione, lipid peroxidation, aspartate aminotransferase and alanine aminotransferase. Direct involvement of the hepatotoxicity was most apparent with apomorphine. The synthesized compounds I, II, III and IV showed much less hepatotoxic effects than the other known tested compounds. This lack of effect would make their clinical application quite attractive, depending on their intrinsic activity