Fluorescent nanoparticle probes for cancer imaging

Optical imaging technique has strong potential for sensitive cancer diagnosis, particularly at the early stage of cancer development. This is a sensitive, non-invasive, non-ionizing (clinically safe) and relatively inexpensive technique. Cancer imaging with optical technique however greatly relies upon the use of sensitive and stable optical probes. Unlike the traditional organic fluorescent probes, fluorescent nanoparticle probes such as dye-doped nanoparticles and quantum dots (Qdots) are bright and photostable. Fluorescent nanoparticle probes are shown to be very effective for sensitive cancer imaging with greater success in the cellular level. However, cancer imaging in an in vivo setup has been recently realized. There are several challenges in developing fluorescent nanoparticle probes for in vivo cancer imaging applications. In this review, we will discuss various aspects of nanoparticle design, synthesis, surface functionalization for bioconjugation and cancer cell targeting. A brief overview of in vivo cancer imaging with Qdots will also be presented.     

Transfected beta3- but not beta2-adrenergic receptors regulate cystic fibrosis transmembrane conductance regulator activity via a new pathway involving the mitogen-activated protein kinases extracellular signal-regulated kinases

We have shown previously that in a heterologous mammalian expression system A549 cells, beta3-adrenoceptor (beta3-AR) stimulation regulates the activity of cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. The present investigation was carried out to determine the signaling pathway involved in this regulation. A549 cells were intranuclearly injected with plasmids encoding human CFTR and beta3-AR. CFTR activity was functionally assessed by microcytofluorimetry. The application of 1 microM 4-[3-t-butylamino-2-hydroxypropoxy]benzimidazol-2-1 hydrochloride (CGP-12177), a beta3-AR agonist, produced a CFTR activation that was not abolished by protein kinase A inhibitors. In pertussis toxin-pretreated cells, the CFTR activation induced by CGP-12177 was abolished. The overexpression of beta-adrenoceptor receptor kinase, an inhibitor of betagamma subunits, abolished the CGP-12177-induced CFTR activation, suggesting the involvement of betagamma subunits of Gi/o proteins. The pretreatment of A549 cells with selective inhibitors of either phosphoinositide 3-kinase (PI3K), wortmannin, and 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride (LY294002), or extracellular signal-regulated kinases 1 and 2 (ERK1/2) mitogen-activated protein kinase (MAPK), 2'-amino-3'-methoxyflavone (PD98059), and 1,4-diamino-2,3-dicyano-1,4-bis(2-aminophynyltio)butadiene (U0126), abolished the effects of CGP-12177 on the CFTR activity. Immunohistochemical assays showed that only the cells expressing beta3-AR exhibited MAPK activation in response to CGP-12177. Furthermore, CFTR activity increased in cells pretreated with 10% fetal bovine serum both in A549 cells injected only with CFTR and in T84 cells, which endogenously express CFTR, indicating that CFTR activity can be regulated by the MAPK independently of the beta3-AR stimulation. In conclusion, we have demonstrated that CFTR is regulated through a Gi/o/PI3K/ERK1/2 MAPK signaling cascade dependently or not on an activation of beta3-ARs. This pathway represents a new regulation for CFTR.     

Profound hypothermia protects neurons and astrocytes, and preserves cognitive functions in a Swine model of lethal hemorrhage

BACKGROUND: Lethal injuries can be repaired under asanguineous hypothermic arrest (suspended animation) with excellent survival. This experiment was designed to test the impact of this strategy on neuronal and astroglial damage in a swine model of lethal hemorrhage. Furthermore, our goal was to correlate the histological changes in the brain with neurological outcome, and the levels of circulating brain specific markers. MATERIALS AND METHODS: Uncontrolled hemorrhage was induced in 32 female swine (80-120 lbs) by creating an iliac artery and vein injury, followed 30 min later by laceration of the thoracic aorta. Through a thoracotomy approach, organ preservation fluid was infused into the aorta using a roller pump. Experimental groups included normothermic controls (no cooling, NC), and groups where hypothermia was induced at three different rates: 0.5 degrees C/min (slow, SC), 1 degrees C/min (medium, MC), or 2 degrees C/min (fast, FC). Profound hypothermia (core temperature of 10 degrees C) was maintained for 60 min for repair of vascular injuries, after which the animals were re-warmed (0.5 degrees C/min) and resuscitated on cardiopulmonary bypass (CPB). Circulating levels of neuron specific enolase (NSE) and S-100beta were serially measured as markers of damage to neurons and astrocytes, respectively. Light microscopy and quantitative immunohistochemical techniques were used to evaluate hippocampal CA1 area and caudate putamen for neuronal injury and astrogliosis (astrocyte hyperplasia/hypertrophy). Surviving animals were observed for 6 weeks and neurological status was documented on an objective scale, and cognitive functions were evaluated using a technique based upon the concept of operant conditioning. RESULTS: Normothermic arrest resulted in clinical brain death in all of the animals. None of the surviving hypothermic animals displayed any neurological deficits or cognitive impairment. On histological examination, normothermic animals were found to have ischemic changes in the neurons and astrocytes (hypertrophy). In contrast, all of the hypothermic animals had histologically normal brains. The circulating levels of brain specific proteins did not correlate with the degree of brain damage. The changes in NSE levels were not statistically significant, whereas S-100beta increased in the circulation after CPB, largely independent of the temperature modulation. CONCLUSIONS: Profound hypothermia can preserve viability of neurons and astrocytes during prolonged periods of cerebral hypoxia. This approach is associated with excellent cognitive and neurological outcome following severe shock. Circulating markers of central nervous system injury did not correlate with the actual degree of brain damage in this model.     

Meta-analysis of survival models of lung cancer

Lung cancer is a common disease that is difficult to treat successfully. Despite the continuous improvement and development of diagnostic method, the disease is still diagnosed in advanced stages. The present study aimed to calculate the 5-years survival rate of patients with lung cancer, to construct different models of survival rates according to different factors and to perform a meta-analysis involving systematic statistical pooling of eligible studies concerning survival of lung cancer. A longitudinal retrospective study was conducted in the treatment centers of Faculty of Medicine and Gamal Abd-El Nasser Hospital. All available records of patients diagnosed and confirmed pathologically as lung cancer during the years 1992 to 2001,were reviewed, the total number amounted to 1099 patients, these patients were followed up for one year till the end of 2002. Life table revealed that the cumulative probability of survival was 18.7% and 16.7%, respectively at 36 -< 42 month and 42 -< 48 month. No one survived up to 5 years. The median survival time was 7.97 months .Kaplan-Meier survival curves yielded that the lowest probability of survival throughout the studied period was noticed among those aged 70 years or more, with stage IV and patients who were treated with radiotherapy alone. Cox regression delineated three significant predictors for survival within 5 years, which were age of patients, stage of tumor and grade of differentiation. Results of meta-analysis demonstrated that pooling the results of different studies yielded a trend toward a reduced relative risk of death by 22% among patients with stage I compared to stage II, and reduced relative risk of 33% for patients with stage I compared to stage III. It is essential to improve the strategies for prevention of smoking and health education program for cessation of smoking early for smokers. Diagnosis, staging and development of a management plan should be completed as quickly as possible. Focuses on the treatment of patients with lung cancer with chemotherapy and radiotherapy.     

Chronic renal failure in Kuwaiti children: an eight-year experience

Over an 8-year period (January 1996 to December 2003), a total of 171 patients below the age of 15 years were diagnosed with chronic renal failure. The mean incidence rate of CRF in Kuwaiti children was found to be 38.2 per million children per year, with a peak incidence of 55 per million children per year. While the mean age at diagnosis was 33±12 months (range: 1 month to 15 years), the male:female ratio was 2.7:1. Etiological factors for chronic renal failure included congenital urological malformation (61.9%), chronic glomerulopathies (5.2%), hereditary nephropathies (21%), multi-system disease (0.5%), chronic pyelonephritis (without VUR) (4.6%), tumors (0.6%), ischemic renal disease (1.1%) and unknown etiology (1.7%). Thirty percent of patients reached end-stage renal disease within a mean of 18 months following diagnosis. The overall mortality before reaching ESRD was reported to be 4%. Kuwait has one of the highest incidence and prevalence rates of CRF in children. It is likely that genetic and hereditary factors are the cause of these high rates.     

Impedance Cardiography: Noninvasive Assessment of Hemodynamics and Thoracic Fluid Content During Bariatric Surgery

Background: The effects of pneumoperitoneum (ppm) on hemodynamic parameters during bariatric surgery were investigated using the impedance cardiography monitor. Methods: 11 patients with BMI 46.5±10 kg/m² (range 38.9-60.8 kg/m²) underwent laparoscopic adjustable gastric banding under general anesthesia. Besides routine monitoring, the impedance cardiography (ICG) monitor was used to monitor cardiac output (CO), cardiac index (CI), systemic vascular resistance (SVR), and thoracic fluid content (TFC). Data were recorded at three stages: A) before ppm, B) during ppm, and C) after gas deflation. One-way analysis of variance (ANOVA) was used to analyze differences of the data before, during and after ppm, and post-hoc (Bonferoni test) for multiple comparisons of the data obtained. For all comparisons, P<0.05 was considered significant. Results: There were significant low mean values of heart rate (HR), CO and CI at stage B compared to stage A (P<0.05). The mean values of TFC at stages A, B, and C were 30.48 ± 4.69, 29.74 ± 2.86 and 31.72 ± 4.93 k/Ohm respectively, with a non-significant relationship (P>0.05). The mean values of SVR during the same stages A, B and C were 1299.18 ± 374.40, 1873.64 ± 276.26 and 1669.36 ± 537.92 dynes sec cm^-5 respectively, with significant high mean values at stages B and C compared to mean value at stage A (P<0.05). Conclusions: Morbid obesity and pneumoperitoneum have significant effects on hemodynamics. However, it appears that these changes were of marginal clinical significance.     

Febrile seizures. From molecular biology to clinical practice

Febrile seizures occur between the age of 3 months and 5 years with a temperature of 38 degrees C or higher, and are either simple or complex. Eight gene loci have been identified to be associated with certain cases of autosomal dominant familial febrile seizures, and 12 genes have been associated with some of the familial epilepsy syndromes that can start with febrile seizures. The mutations and the protein products are known for only some of these 20 genes. The risk of recurrence of convulsions in a further febrile illness is on average 30%, and of developing epilepsy is on average 6%, but both vary depending on the presence and number of risk factors in any given patient. The immediate treatment of a febrile convulsion is intravenous or rectal diazepam, but febrile status epilepticus requires intravenous Phenobarbital and possibly other medications. Long-term antiepileptic drugs are not recommended in most patients with febrile seizures. However, exceptions should be considered on an individual basis in patients with complex febrile seizures with multiple risk factors for development of later epilepsy.     

Seroepidemiological study on human brucellosis in Assiut Governorate

Brucellosis is the most important zoonotic disease constituting a public health problem in Assiut Governorate, hence this study was carried out to determine the prevalence of brucellosis among humans in Assiut Governorate. A total of 7154 peripheral blood samples were collected from patients with fever at Assiut Fever Hospital during the period from 2002-2003. A full detailed anamnestic and clinical assessment in the form of questionnaire was designed for each individual to determine the risk factors with specific emphasis to age, sex, residence and occupation. All serum samples were screened for Brucella antibodies by slide agglutination test. Positive sera were further analyzed by standared tube agglutination test. Enzyme linked immunosorbent assay (ELISA) was carried out to detect IgM and IgG Brucella antibodies. Statistical analysis was performed and correlation coefficient was done between all risk factors. Results declared that the prevalence of brucellosis was (1.29 +/- 0.004 %) and (1.22 +/- 0.002 %) as detected by agglutination and ELISA, respectively. IgM antibodies were estimated in 9.8 % of the examined patients, while IgG antibodies were found in 30.4 % of the examined patients, moreover both IgM and IgG antibodies were detected in 54.3 % of the examined patients. The prevalence of brucellosis was significantly (P < 0.05) affected by sex, where the rate of detection was higher among females (1.76 +/- 0.009 %) than males (1.05 +/- 0.004 %) as detected by agglutination test. On the other hand, the prevalence rate based on ELISA was (1.64 +/- 0.39 % and 1.01 +/- 0.89 %) for females and males, respectively. Prevalence of brucellosis was higher in rural areas (1.3 +/- 0.005 % & 1.25 +/- 0.009 %) than in urban areas (1.23 +/- 0.001% & 1.12 +/- 0.01 %) as detected by agglutination test and ELISA, respectively. The prevalence of brucellosis varied significanctly between different occupational and age groups. Public health impact of brucellosis is discussed and suggestive measures for control are explained.     

Intravenous immunoglobulin in neurological disorders: a mechanistic perspective

Intravenous immunoglobulin (IVIg) has been used in the treatment of primary and secondary antibody deficiencies for over 25 years. It is a safe preparation with no long-term side effects. IVIg was first demonstrated to be effective in autoimmune disorders, two decades ago, in the treatment of acute immune thrombocytopenia. Since then, the therapeutic efficacy of IVIg has been established in Guillain Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), myasthenia gravis (MG), dermatomyositis (DM), Kawasaki syndrome and the prevention of graft-versus-host disease in recipients of allogeneic bone marrow transplants and reported in a large number of other autoimmune and systemic inflammatory conditions.