Assessment of Antioxidant and Anticancer Activities of Microgreen Alga Chlorella vulgaris and Its Blend with Different Vitamins.

There is a very vital antioxidant extracted from microgreen alga. Chlorella vulgaris has major advantages and requires high yield worldwide. Some microalgae require vitamins for their growth promotion. This study was held to determine the impact of different vitamins including Thiamine (B1), Riboflavin (B2), Pyridoxine (B6), and Ascorbic acid (c) at concentrations of 0.02, 0.04, 0.06, and 0.08 mg/L of each. Each vitamin was added to the BG11 growth medium to determine the effect on growth, total carbohydrate, total protein, pigments content, antioxidant activities of Chlorella vulgaris. Moreover, antitumor effects of methanol extract of C. vulgaris without and with the supplement of thiamine against Human prostate cancer (PC-3), Hepatocellular carcinoma (HEPG-2), Colorectal carcinoma (HCT-116) and Epitheliod Carcinoma (Hela) was estimated in vitro. C. vulgaris supplemented with various vitamins showed a significant increase in biomass, pigment content, total protein, and total carbohydrates in comparison to the control. Thiamine was the best vitamin influencing as an antioxidant. C. vulgaris supplemented with thiamine had high antitumor effects in vitro. So, it's necessary to add vitamins to BG11 media for enhancement of the growth and metabolites.

Protective role of Chlorella vulgaris with Thiamine against Paracetamol induced toxic effects on haematological, biochemical, oxidative stress parameters and histopathological changes in Wistar rats.

Paracetamol is extensively consumed as an analgesic and antipyretic drug, but at a high dose level, it leads to deleterious side effects, such as hepatic and nephrotoxicity. This research aimed to estimate the prophylactic efficacy of Chlorella vulgaris and/or thiamine against paracetamol (P) induced hepatorenal and cardiac toxicity. Forty-eight female Wistar rats were randomly divided into eight equal groups (n = 6 rats). Group 1, normal control group. Group 2, Paracetamol group. Groups 3, 4 and 5 were treated with Silymarin drug, Chlorella vulgaris alga, Chlorella vulgaris alga supplemented with thiamine, respectively daily for 7 successive days, then all were administered Paracetamol (2gm/kg. bwt.). While, Groups 6, 7 and 8 were treated by Silymarin, Chlorella vulgaris alga, Chlorella vulgaris supplemented with thiamine, respectively daily for 7 successive days without paracetamol administration. Our results clarified that Paracetamol toxicity caused significant adverse effects on hematological, serum biochemical parameters, and oxidant -antioxidant status as well as histopathological picture of heart, liver, and kidney. However, in the Paracetamol intoxicated groups pretreatment either with Chlorella vulgaris alone or plus thiamine successfully improved the undesirable deleterious effects of paracetamol, and restored almost all variables to near their control levels. This study has finished to that oxidative stress participates in the pathogenesis of paracetamol-induced toxicity in rats and using Chlorella vulgaris alga either alone or plus thiamine alongside their health benefits can protect against oxidative harmful effects induced by paracetamol through their free radical scavenging and powerful antioxidant effects, and they can be used as propylactic agents against paracetamol-induced toxicity.

Patterns, risk factors and outcome predictors of posterior reversible encephalopathy syndrome in pediatric cancer patients.

The purpose of this study was to assess the clinical and radiological patterns and outcome predictors of posterior reversible encephalopathy syndrome (PRES) in pediatric cancer patients. A retrospective study included patients who developed PRES during their treatment at the Children's Cancer Hospital Egypt. A total of 50 patients developed PRES. Leukemia and lymphoma were the commonest diagnoses (64%). Regarding the MRI findings, occipital affection was the most common (92%), followed by frontal and temporal lobes involvement in 32% and 22% respectively and advanced PRES was described in 8 patients. Of the whole patients, 80% had complete clinical resolution and 60% showed complete radiological resolution at 2 weeks' evaluation and 2 patients died out of PRES. Unfavorable outcome was associated with those who had motor dysfunction, status epilepticus at presentation, frontal lobe and thalamic affection and atypical PRES. PRES might present in atypical sites with poor outcome including death.

Outcomes of allogenic hematopoietic cell transplantation for childhood chronic myeloid leukemia: Single-center experience.

BACKGROUND/OBJECTIVES: Despite the apparent efficacy and favorable toxicity profile of TKIs, allogeneic SCT remains the only curative treatment for CML especially in younger patients, but TRM should be considered. We evaluated the clinical outcomes of pediatric CML patients who had SCT in our center. METHODS: This retrospective study included children with CML, who received an allogeneic SCT at Children Cancer Hospital Egypt, 57357, from 2007 to 2017. All patients received myeloablative conditioning chemotherapy containing busulfan/cyclophosphamide followed by stem cell infusion from MRD. RESULTS: From 121 patients diagnosed with CML, 43 had available MRD and subjected to HSCT while 78 patients continued TKI therapy. The median time to transplant from diagnosis was 13 months. At initial diagnosis, there were 39 patients in CP and 4 had blastic crises. Bone marrow harvest was the stem cell source in 32 patients, while 11 cases received mobilized peripheral blood stem cells with average stem cell dose of 4.45 × 106 /kg. The probabilities of overall survival and event-free survival at 5 years were 97.4% and 79.8%, respectively. TRM at 100 days and TRM at 1-year post-transplant were 0%. The incidence of chronic GVHD was significantly higher in peripheral blood than bone marrow stem cell source (P = .004). CONCLUSION: Considering the excellent survival rates and very low TRM, HSCT is still a valid option for pediatric patients with newly diagnosed CML with best using marrow stem cell source to avoid a significant risk of cGVHD and its related complications.

The lumbar artery perforator flap: clinical review and guidance on image reporting.

The lumbar artery perforator (LAP) flap is a relatively new procedure that can be utilized to manage lumbosacral defects in addition to reconstructing distal body parts as well, such as breast reconstruction. This fasciocutaneous flap is designed based on the LAPs small arteries that emerge from the lumbar arteries then move superficially piercing overlying tissues to perforate the lumbar fascia and supply the skin and subcutaneous tissue; However, anatomical and clinical studies regarding the LAP flap and its perforators are sparse in the literature, and the results are even contradicting. This article will discuss the LAP flap, the anatomy of its perforators, and the clinical aspects about its usage. In addition, we explore its preoperative imaging evaluation, and deliver a guide on image reporting and radiological data that will benefit the surgeon most during the procedure.

Early Deaths in Pediatric Acute Leukemia: A Major Challenge in Developing Countries.

Children with acute leukemia may experience high treatment-related mortality, which often occurs early in the induction phase. The aim of the study was to assess the incidence and risk factors related to increased mortality during induction therapy of pediatric patients with acute leukemia. This is a retrospective study that included pediatric acute leukemia patients who presented to the National Cancer Institute, Cairo University, between January 2011 and December 2013. The study included 370 patients, 253 with acute lymphoblastic leukemia, 100 with acute myeloid leukemia, and 17 with mixed phenotype acute leukemia. The total and induction death rates were 40.5% and 19.2%, respectively. Most of the early deaths were attributed to infections (64.7%) and cerebrovascular accidents (18.3%). Using enhanced supportive care measures during 2013 had significantly reduced the overall and induction mortality rates (29% and 13.6%, respectively, in 2013 vs. 46% and 20.3% in 2011). Induction deaths in pediatric acute leukemia remain a major challenge in developing countries, and using enhanced supportive care measures is effective to improve the survival outcome in this group of patients.

Impact of Helicobacter pylori eradication on refractory thrombocytopenia in patients with chronic HCV awaiting antiviral therapy.

The possibility of delaying treatment of HCV due to severe thrombocytopenia is challenging. This study aimed to detect the prevalence of active helicobacter infection as a claimed cause of thrombocytopenia in a cohort of Egyptian patients with chronic active HCV awaiting combined anti-viral therapy. The study included 400 chronic HCV patients with thrombocytopenia. Laboratory investigations included liver function tests, real time quantitative PCR, reticulocytic count, ESR, ANA, bone marrow aspiration, measurement of anti-helicobacter antibodies, and helicobacter stool antigen. Positive cases for active H. pylori were given the standard triple therapy for 2 weeks. Helicobacter stool antigen was detected 4 weeks after termination of therapy and the change in platelet count was detected 1 month after eradication. A total of 248 out of 281 seropositive patients for H. pylori (88.3 %) showed positive stool antigen (p = 0.01). Eradication was achieved in 169 (68.1 %) patients with platelet mean count 114.9 ± 18.8 × 10(3)/µl with highly significant statistical difference from pretreatment value (49.7 ± 9.2 × 10(3)/µl, p = 0.000). Seventy-nine patients were resistant to conventional triple therapy and given a 7-day course of moxifloxacin-based therapy; 61 patients responded (77.1 %) with mean platelet improvement from 76.4 ± 17.4 × 10(3)/µl to 104.2 ± 15.2 × 10(3)/µl (p = 0.000). The non-responders showed no improvement in their platelet count (74.6 ± 20.5 vs. 73.6 ± 15.3 × 10(3)/ul, P = 0.5). Eradication of active H. pylori in HCV augments platelet count and enhances the early start of antiviral therapy.

Design of Chronomodulated Drug Delivery System of Valsartan: In Vitro Characterization.

The aim of the present study was to design and evaluate a chronomodulated time-clock pulsatile tablets of valsartan to release it after a certain lag time, independent of the gastrointestinal pH, in its absorption window to cope with the circadian rhythm of human body for blood pressure elevation. Core tablets were prepared by direct compression of a homogenous mixture of valsartan, Avicel PH101, croscarmellose sodium, magnesium stearate and Aerosil. The core tablets were then sprayed coated with a sealing layer formed of ethyl cellulose that was subsequently coated with a release-controlling layer. Three different aqueous dispersions namely; carnauba wax or beeswax or a mixture in a ratio of 2.5:1, respectively, were used to form five time-clock tablet formulations having the release controlling layer with different thickness {B5, B10, B20, BW5 and CW5}. Quality control testing were carried out to the core tablets. Differential scanning calorimetry was also performed to detect the possible drug excipient interaction in the core tablet formulation. The release was carried out, for the prepared time-clock tablet formulations, in 0.1 N hydrochloric acid for the first 2 h, followed by phosphate buffer (pH 6.8) for 4.5 h. The effect of pH on valsartan release was studied through a release study in 0.1 N hydrochloric acid for 6.5 h. Two phase dissolution study was performed to the selected time-clock tablet formulation to predict the drug permeation through the gastrointestinal tract. Stability study of the selected formula was performed at 25°/60% RH and at 40°/75% RH for 3 months. Results showed that a release-controlling layer composed of a mixture of carnauba wax and beeswax in a ratio of 2.5:1 showed a reasonable release lag time. The release lag time of the tablets increased with the increase of the coat thickness, thus B20>B10>B5 with corresponding lag time values of 4.5, 3 and 2.5 h, respectively. Selected B5 tablet formula exhibited a reasonable lag time after which the highest, complete % drug release at pH 6.8 was obtained. In addition, a good partitioning of valsartan, between the aqueous and organic phases in a ratio of 1:7, was observed. The selected formula was stable for at least 3 months under standard long-term and accelerated storage conditions. In conclusion, in vitro studies revealed that the novel time-clock system could be used successfully to deliver valsartan in a pulsatile pH-independent manner. It provided a desirable lag time followed by a rapid and complete drug release accompanied by an expected effective permeation through the biological membranes upon release in the duodenum; the window of absorption, as indicated by the two phase release study.

Preclinical report on allogeneic uterus transplantation in non-human primates.

STUDY QUESTION: Is it possible to perform allogeneic uterus transplantation (UTx) with a donation from a live donor in a non-human primate species and what immunosuppression is needed to prevent rejection? SUMMARY ANSWER: Allogeneic UTx in the baboon is a donor- and recipient-safe surgical procedure; immunosuppression with induction therapy and a triple protocol should be used. WHAT IS KNOWN ALREADY: UTx may become a treatment for absolute uterine factor infertility. Autologous UTx models have been developed in non-human primates with reports on long-term survival of the uterine grafts. STUDY DESIGN, SIZEAND DURATION: This experimental study included 18 female baboons as uterus donors and 18 female baboons as uterus recipients. The follow-up time was 5-8 weeks. PARTICIPANTS/MATERIALS, SETTING AND METHODS: Uterus retrieval was performed with extended hysterectomy including bilateral uterine and internal iliac arteries and ovarian veins. After UTx, with vascular anastomoses unilateral to the internal iliac artery and the external iliac vein, the uterus recipients received one of the following: no immunosuppression (n = 4); monotherapy (oral slow release tacrolimus) (n = 4) or induction therapy (antithymocyte globulin) followed by triple therapy (tacrolimus, mycophenolate, corticosteroids; n = 10). Surgical parameters, survival, immunosuppression and rejection patterns were evaluated. MAIN RESULTS AND THE ROLE OF CHANCE: The durations of uterus retrieval and recipient surgery were around 3 and 3.5 h, respectively. The total ischemic time was around 3 h. All the recipients and the donors survived the surgery. All the recipients presented rejection to some extent within the first weeks following UTx. In one recipient, the uterus was of normal appearance at the end of the study period. In spite of occasional high (>60 ng/ml) blood levels of tacrolimus, there was no evidence of nephrotoxicity. LIMITATIONS AND REASONS FOR CAUTION: This initial non-human primate allogeneic UTx study indicates that further research is needed to optimize immunosuppression protocols in order to avoid uterine rejection. WIDER IMPLICATIONS OF THE FINDINGS: The findings suggest that allogeneic UTx in primate species is feasible but continued work on this issue is needed. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the Swedish Research Council, ALF University of Gothenburg, Hjalmar Svensson Foundation and by Jane and Dan Olsson Research Foundation. The authors do not have any competing interest.

Uterus transplantation in a non-human primate: long-term follow-up after autologous transplantation.

BACKGROUND: Uterus transplantation (UTx) may provide the first available treatment for women affected by uterine infertility. The present study aimed to further develop a surgical technique for autologous UTx in a non-human primate species and to assess long-term function. METHODS: Female baboons (n= 16) underwent autologous transplantation of the uterus with the Fallopian tubes and ovaries, performed with a previously published surgical technique (n= 6, Group 1) or using a modified technique (n= 10; Group 2). The uterine arteries were dissected to the proximal end of the anterior branch (Group 1) or the entire (Group 2) internal iliac artery, and the ovarian veins were dissected to the crossing over the ureter (Group 1) or further cranially to include greater lengths and patches of the cava/renal vein (Group 2). Back-table preparation created common venous and arterial ends with arterial anastomosis either end-to-side to the left external iliac artery (Group 1) or end-to-end to the left internal iliac artery (Group 2). RESULTS: Overall short-time survival of the animals was 88% (66% in Group 1 and 100% in Group 2). Of all the operated animals, 75% (66% in Group 1 and 80% in Group 2) resumed ovarian cyclicity. Regular menstruation after UTx was demonstrated only in Group 2 (60%). Menstruating animals (n= 6) were each exposed to timed mating for ≥5 menstrual cycles, but pregnancy did not occur. Adhesions and tubal blockage were seen in post-mortem analysis. CONCLUSIONS: The modified UTx model of Group 2 is a safe procedure and shows resumed long-term uterine function in a majority of the animals, although pregnancy could not be demonstrated.

Fertility after autologous ovine uterine-tubal-ovarian transplantation by vascular anastomosis to the external iliac vessels.

BACKGROUND: Transplantation of the uterus has been suggested as a treatment of uterine factor infertility. This study investigates whether the sheep uterus can resume its capacity to harbour normal pregnancies after autotransplantation by vascular anastomosis. METHODS: From 14 ewes, the uterus, excluding one uterine horn, was isolated along with its oviduct and ovary and preserved ex vivo and then transplanted back with end-to-side anastomosis of the vessels of the graft to the external iliac vessels. After recovery, the ewes underwent surgical examination and serum progesterone measurements to ascertain healing and ovarian activity. Afterwards, five autotransplanted and five control ewes were placed with a ram for mating. Caesarean sections were performed before the estimated term of pregnancy and data on fetal measures were compared. RESULTS: Of the 14 ewes, seven survived surgery with ovarian activity intact and grafts showing normal appearance. Mating occurred in four of five transplanted ewes and in five out of five controls, and three transplanted animals and five control animals conceived. In one transplanted ewe, torsion of the uterus was observed after spontaneous initiation of labour. Foeti from transplanted mothers were comparable in size to those of controls. CONCLUSIONS: Despite the encountered complications, this is the first report to demonstrate fertility and pregnancies going to term after autotransplantation of the uterus in an animal of a comparable size to the human.

Development of implants for sustained release of 5-fluorouracil using low molecular weight biodegradable polymers.

Anticancer drugs have poor efficacy especially against solid tumors that hinder drug penetration into the tumor. Thus, the dose has to be increased, but toxicity is a limiting factor. Local administration of a polymeric biodegradable poly-L-lactic acid (PLA) and poly(L-lactic acid-co-glycolic acid) copolymer (PLGA) implant containing an anticancer drug may be an acceptable method of concentrating the drug near the tumor site. This work sought to synthesize low molecular weight PLA and PLGA by polycondensation to yield polymers with good physical properties to make them suitable for use in implantable therapy. The synthesized polymers were characterized by determining their molecular weight, melting point, and percentage crystallinity using DSC. Fourier transformationinfra red spectrum (FT-IR), nuclear magnetic resonance (NMR) and specific optical rotation measurement were also used to characterize the synthesized polymers. Morphological characteristics were assessed using scanning electron microscopy (SEM). Implants were manufactured using compression (C) and injection molding (IM) and were loaded with 12 mg 5-fluorouracil (5-FU) per 120 mg implant. In vitro release patterns of all implants were assessed in phosphate buffered saline pH 7.4 (PBS 7.4) at 37°C. Factors affecting the release of 5-FU from implants were the polymer species, manufacturing technique, drug particle size, drug concentration, implant dimensions, and coating of the implant. Implants prepared with PLGA had significantly faster release of 5-FU than those prepared with PLA. Those manufactured using compression had significantly faster drug release than those prepared by injection molding. A PLA implant that contained 12 mg 5-FU/120 mg with a diameter of 0.3 cm and that was loaded with a drug particle size smaller than 150 µm and prepared by injection molding and then subsequently coated with PLA had the longest release period of 45 days.

Synthesis and spectroscopic studies of CoII, NiII, FeIII and ThIV complexes derived from 2,2'-dihydroxy-3,3'-di(carboxymethyl)-1,1'-binaphthyl.

The synthesis of 2,2'-dihydroxy-3,3'-di(carboxymethyl)-1,1'-binaphthyl (H2L) and its novel metal complexes with Co(II), Ni(II), Fe(III) and Th(IV) salts are reported. The ligand and its metal complexes have been characterized on the basis of analytical, conductance, spectral (IR, UV-vis, 1H NMR, mass) and magnetic susceptibility measurements. The Mössbauer spectrum of the Fe(III) complex indicates a low-spin octahedral geometry around the Fe(III) ion. The IR and 1H NMR spectral data show that the ligand behaves in a dibasic bidentate fashion coordinating to two metal atoms through the two deprotonated naphthyl OH groups and acts in a dibasic tetradentate manner using both carbonyl oxygen's and the deprotonated naphthyl OH groups coordinating to two metal ions. Thermal studies (TGA, DTA) confirm the presence of solvents either inside or outside the coordination sphere and support the mechanism of the decomposition process. The value of [alpha]D20 for the ligand has been determined in DMSO.

Pharmacokinetic evaluation of oral fenofibrate nanosuspensions and SLN in comparison to conventional suspensions of micronized drug.

An increasing number of newly developed drugs show bioavailability problems due to poor water solubility. Formulating the drugs as nanosuspensions may help to overcome these problems by increasing saturation solubility and dissolution velocity. In the present study the bioavailability of the poorly soluble fenofibrate following oral administration was investigated in rats. Four formulations were tested: a nanosuspension type DissoCube(R), one solid lipid nanoparticle (SLN) preparation and two suspensions of micronized fenofibrate as reference formulations, one suspension in sirupus simplex and a second in a solution of hydroxyethy-cellulose in physiological saline. Both colloidal drug delivery systems showed approximately two-fold bioavailability enhancements in terms of rate and extent compared to the reference formulations. No significant differences were found in AUC(0-22 h) as well as in C(max) and t(max) between the two colloidal delivery systems. In conclusion, nanosuspensions may be a suitable delivery system to improve the bioavailability of drugs with low water solubility.

Clinical and therapeutic studies on mange in horses.

At Kafr El-Sheikh province, Egypt, out of 117 examined drafting horses, mites were detected in 20 (17.09%) horses. The recovered mites were 14 Chorioptes, four Psoroptes and two Sarcoptes whereas mites were not detected in four cases clinically showed typical mange lesions. Interestingly, neither the age nor the sex of the examined horses had a clear influence on the prevalence of the infection. Clinical signs observed in mange infested horses were in the form of irregular skin lesions, severe itching and sometimes biting of affected skin areas and decrease feed consumption. The skin lesions mainly start as erythematous area followed by developing of papules and crust formation. Skin scratches as a result of traumatized lesions usually occurred. Hair was lost on the affected parts developing irregular alopecic areas. Distribution of the lesions was varied according to the type of mite. Chorioptic mite was detected in para-anal fold, distal portion of legs and tail lesions, Psoroptic mite was detected in withers, mane, shoulder and flank lesions whereas Sarcoptic mite was isolated mainly from lesions on the head and neck. Complete clinical and parasitological cure for mite infestation were obtained within 2 weeks in both moxidectin and ivermectin treated groups with 100% recovery rate. Our results indicated that moxidectin oral gel is effective and good alternative for the treatment of chorioptic mange in horse to avoid drug resistance that may develop as a result of the intensive use of ivermectin alone for long periods.

Nanosuspension formulations for low-soluble drugs: pharmacokinetic evaluation using spironolactone as model compound.

Various particle sizes of spironolactone as a model low solubility drug were formulated to yield micro-and nanosuspensions of the type solid lipid nanoparticles and DissoCubes. Seven oral and one i.v. formulations were tested in an in vivo pharmacokinetic study in rats with the aim of characterizing the bioavailability of spironolactone on the basis of its metabolites canrenone and 7-alpha-thiomethylspirolactone. In addition, a dose escalation study was carried out using nonmicronized spironolactone suspension as well as a nanosuspension type DissoCubes. On the basis of AUC as well as Cmax ratios, three groups of formulations were distinguished. The biggest improvement was seen with a solid lipid nanoparticle formulation yielding a 5.7-fold increase in AUC for canrenone and a similar improvement based on the Cmax metric, followed by a group of three formulations containing nanosized, micronized, and coarse drug material and surfactant. The DissoCubes nanosuspension yielded highly significant improvements in bioavailability averaging 3.3-fold in AUC and 3.0-fold in terms of Cmax for canrenone. The third class encompasses all other formulations, which showed very little to no improvement in bioavailability. The results show that the particle size minimization was not the major determining factor in the bioavailability improvement. Rather, the type of surfactant used as stabilizer in the formulations was of greater importance. Improvement in drug solubility in the intestine as well as in dissolution rate of spironolactone are the most likely mechanisms responsible for the observed effect, although additional mechanisms such as permeability enhancement may also be involved.

Testicular torsion: a perspective from the Middle East.

OBJECTIVE: To report our experience in the management of testicular torsion with emphasis on seasonal variation, salvage rate and the status of the torted testis 3-6 months after orchidopexy. SUBJECTS AND METHODS: Seventy-five patients with a presumptive diagnosis of testicular torsion, who presented to our hospital between January 1999 and December 2002, were included in the study. Following scrotal exploration, 63 patients were found to have testicular torsion. Of these, 11 with nonviable testes had orchiectomy while 52 with viable testes had orchidopexy. Both groups of patients had simultaneous contralateral orchidopexy. Patients who had orchidopexy were followed up 3-monthly by testicular ultrasound to assess the volume of the affected testis. RESULTS: Sixty-three patients were confirmed to have testicular torsion. The average number of new cases in the winter was 6.7 compared to 4 in the summer. Fifty-two patients underwent orchidopexy to give an operative salvage rate of 82.5%. Of 51 patients in whom the duration of torsion was less than 24 h, 1 (2.0%) had a nonviable testis, whereas of 12 patients in whom the duration of torsion was more than 24 h, 10 (83.3%) had a nonviable testis. After a minimum follow-up of 3 months for patients who had orchidopexy, 7 (13.5%) developed testicular atrophy. The incidence rate was estimated to be 7.9 cases per 100,000 population. CONCLUSION: The highest incidence was during the cold season. The outcome of surgical management of testicular torsion was dependent on the duration of torsion.

Prospective analysis of premature mortality in schizophrenia in relation to health service engagement: a 7.5-year study within an epidemiologically complete, homogeneous population in rural Ireland.

While premature death in schizophrenia is well recognised, mortality risk has received little longitudinal study in relation to population representativeness and patient engagement with health services. Within a rural Irish catchment area of socioeconomic, ethnic and geographical homogeneity and low residential mobility, an epidemiologically complete population of 72 patients with schizophrenia was followed up over 7.5 years in order to quantify mortality prospectively. Information was obtained in relation to 99% of the cohort, with 94% of those surviving retained in engagement with psychiatric care. There were 25 deaths (35% of cohort). A relative risk of 2.06 (95% CI, 1.40-2.80; P < 0.001) among this epidemiologically complete population may constitute an estimate of risk for mortality inherent to schizophrenia when disengagement from health services, residential mobility and socioeconomic, ethnic and geographical diversity are minimised. On long-term prospective evaluation, risk for death in schizophrenia was doubled on a background of enduring engagement in psychiatric care with increasing provision of community-based services and introduction of second-generation antipsychotics.

Intestinal drug efflux: formulation and food effects.

The intestine, primarily regarded as an absorptive organ, is also prepared for the elimination of certain organic acids, bases and neutral compounds depending on their affinity to intestinal carrier systems. Several of the transport systems known to mediate efflux in the major clearing organs--liver and kidney--are also expressed in the intestine. Examples of secretory transporters in the intestine are P-glycoprotein, members of the multidrug resistance associated protein family, breast cancer resistance protein, organic cation transporters and members of the organic anion polypeptide family. In this communication, the P-glycoprotein mediated intestinal secretion of talinolol, a model compound showing metabolic stability, has been investigated in the jejunum, ileum and colon of rat intestine by single-pass perfusion. A model has been developed which demonstrates an increase in carrier-mediated secretion in the order jejunum

Pretreatment with potent P-glycoprotein ligands may increase intestinal secretion in rats.

The expression of P-glycoprotein is induced in cell cultures upon exposure to various inducers. Therefore, the aim of the present study was to evaluate the in-vivo relevance of this observation, i.e. the influence of chronic pretreatments with selected drugs -- all of which are ligands to P-glycoprotein (P-gp) as demonstrated in radioligand binding studies and all of which have some or a considerable effect on P-gp expression in Caco-2 cells -- on the effective intestinal permeabilities of the model compound talinolol in rats employing in-situ single-pass intestinal perfusion of three different gut segments. Talinolol was selected, because it shows high selectivity for one of the exsorptive transporters (P-gp) and its intestinal permeability is very sensitive to changes in exsorption when the perfusate concentration is low. Prior to the induction study the perfusion model was optimized regarding the type and concentration of a competitive inhibitor which may be used to block the exsorption-related permeability reduction (through intestinal exsorption) during an ongoing perfusion and would permit an intra-individual comparison of the effective permeability without and with blockade of exsorption. While repetitive verapamil and talinolol dosing had no statistically significant exsorption-inducing effect, vinblastine and rifampicin pretreatments resulted in decreased intestinal talinolol permeabilities in the three tested gut segments, duodenum, jejunum, and colon [e.g., S-talinolol in jejunum: control, 2.50 x 10(-4) cm/s; vinblastine induction, 1.48 x 10(-4) cm/s (P<0.05); rifampicin induction, 1.51 x 10(-4) cm/s (P<0.05)]. Addition of an efficient secretion inhibitor (vinblastine) to the perfusate permitted the determination of the impact of inhibitable secretory processes on the total effective permeabilities and an estimation of passive permeability in the respective individual. The inhibitable permeability fractions were higher for vinblastine than for any other pretreatment and the difference from control pretreatment was statistically significant for all intestinal segments (duodenum, 61.8%; jejunum, 63.1%; colon, 43,7%; S-talinolol). Statistically significant differences were also detected for rifampicin in the perfused duodenum and jejunum (33.1 and 27.5% increase in inhibitable fraction, respectively, for S-talinolol). These differences are explained by a significant induction of outside-directed transport in the intestinal enterocytes by vinblastine and rifampicin.