[Clinical aspects and chemotherapy of adenocarcinoma of the kidney].
The classic triad of hematuria, pain and presence of a palpable flank mass is found only in few patients with renal carcinoma. Hematuria, the main symptom, occurs in nearly the half of patients. Blood levels of erythropoetin and renin are often elevated and may be of value as biochemical tumor markers. Chemotherapeutic agents do not alter the course of metastatic renal carcinoma significantly. Vinblastine is the most effective available drug currently. Progestins or androgens cause tumor regression very seldom. If antioestrogens or immuntherapeutic regimens may improve therapeutic results, is not to be decided at present.


Genetic testing for a patient with suspected familial hypercholesterolaemia.
Familial hypercholesterolaemia (FH) is a genetic condition that results in elevated low-density lipoprotein (LDL) cholesterol (LDL-C) levels with consequent increased risk for premature cardiovascular disease events. Although it is considered an autosomal-dominant genetic condition, the underlying genetic causes of FH can be complex. Currently most guidelines rely on clinical criteria to diagnose FH. But this approach has some pitfalls. We present a patient who was not formally diagnosed with FH using commonly used and well-accepted clinical criteria but via genetic testing was found to have a mutation for this disorder. This case brings to fore the challenges clinicians face in diagnosing and managing such unusual cases optimally. Through this case report, we hope to stimulate a debate among clinicians as well as other stakeholders regarding the need to develop more efficient ways of selecting patients for genetic testing in response to elevated LDL levels.


Evaluation of therapeutic response using iodine-131-B72.3 monoclonal antibody in patients with ovarian carcinoma.
We used radiolabelled monoclonal antibodies (MoAbs) to prove disease persistence after treatment for ovarian carcinoma. Twelve patients with histologically confirmed ovarian carcinoma were studied. They received 5 mCi (1 mg) of iodine-131-B72.3 by intravenous injection before and after a complete course of chemotherapy. Images were obtained with a LFOV gamma camera 2 h after MoAb administration and daily up to 6 days. Before treatment 8 patients had a true positive scan. Questionable antibody uptake was observed in 2 patients while 1 had a true negative scan and 1 a false-negative examination. After treatment the therapeutic response was evaluated. Five patients had partial remission and antibody scan showed persistence of disease in all patients except 1. Four patients showed progression of the disease and 1 no change. The antibody scan was positive in 4 and questionable in 1. Two patients had complete remission and negative antibody scans. Computed tomography (CT) could not always discriminate postoperative fibrosis from tumour lesions, especially when the peritoneum was involved in the disease. High serum levels of tumour markers were constantly associated with the presence of tumour lesions, but normal values did not guarantee absence of disease. We conclude than the antibody scan is complementary to CT and serum tumor markers in the definition of therapeutic response.


Analysis of liver regeneration in mice lacking type 1 or type 2 tumor necrosis factor receptor: requirement for type 1 but not type 2 receptor.
We used KO mice lacking either TNF receptor 1 (TNFR-1) or receptor 2 (TNFR-2) to determine whether signaling at the start of liver regeneration after partial hepatectomy (PH) involves only one or both TNF receptors and to analyze in more detail the abnormalities caused by lack of TNFR-1 receptor, which is required for the initiation of liver regeneration. Lack of TNFR-2 had little effect on NF-kappaB and STAT3 binding, and no effect in interleukin-6 production after PH, but caused a delay in AP-1 and C/EBP binding and in the expression of c-jun and c-myc messenger RNA (mRNA). In contrast to mice lacking TNFR-1, which had deficient hepatocyte DNA synthesis and massive lipid accumulation in hepatocytes, TNFR-2 KO mice had normal liver structure and similar levels of hepatocyte DNA replication as those of wild type mice. We conclude that TNFR-1, but not TNFR-2, is necessary for liver regeneration, and that NF-kappaB and STAT3 binding are activated by signals transduced by TNFR-1. Inhibition of AP-1 and C/EBP binding and in the expression of c-jun and c-myc mRNA in the first 4 hours after PH, as well as the apparent lack of Fos in AP-1 complexes, had no effect on the timing or extent of DNA replication.


Retinoids stimulate fibrinogen production both in vitro (hepatocytes) and in vivo. Induction requires activation of the retinoid X receptor.
The in vitro effects of retinoids on fibrinogen synthesis were investigated in HepG2 cells and primary human hepatocytes. In vivo effects were studied in the rat. In HepG2 cells, maximal stimulation (twofold) of fibrinogen secretion was obtained when cells were incubated in the presence of 1 mumol/L all-trans retinoic acid (T-RA) for 24 hours. A comparable increase was observed for both de novo fibrinogen synthesis and fibrinogen beta chain mRNA level. In primary cultures of human hepatocytes, treatment with 1 mumol/L T-RA for 72 hours also gave a twofold increase in fibrinogen production. Furthermore, rats treated for 6 days with 100 mg.kg-1.d-1 T-RA presented increased fibrinogen plasma levels (110%). A selective retinoic X receptor (RXR) agonist, 4-[1-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)-ethenyl]benzoi c acid (3-methyl TTNEB), as well as 9-cis retinoic acid, a natural RXR ligand, mimicked the effects of T-RA on fibrinogen synthesis in vitro at lower concentrations. In contrast, a selective retinoic A receptor alpha (RAR alpha) agonist was a poor activator. The ED50 of the different retinoids on fibrinogen secretion by HepG2 cells was 25 nmol/L for T-RA, 4 nmol/L for 9-cis retinoic acid, 11 nmol/L for the synthetic RXR agonist, and > 500 nmol/L for the RAR alpha agonist. However, incubation of HepG2 cells with RXR agonist together with RAR alpha agonist resulted in a further increase in fibrinogen production. The secretion of two other acute-phase proteins, alpha-antichymotrypsin and caeruloplasmin, was also stimulated by retinoids in HepG2 cells but by a different regulatory mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)


An improved method for determining virucidal efficacy of a chemical disinfectant using an electrical impedance assay.
A major problem with the testing of virucidal efficacy using current protocols is that scoring of virus-induced cytopathic effect (CPE) is dependent on subjective visual interpretation using light microscopy. The current report details the use of an electrical impedance assay (xCELLigence, ACEA Biosciences) for its utility in virucidal efficacy testing. In this study, the xCELLigence system was used in a procedure developed from guidelines given by the Deutsche Vereiniging zur Bekämpfung der Viruskrankheiten (DVV) (German Association for the Control of Virus Diseases) in order to demonstrate the inactivation of infectious bursal disease virus using a commercial virucide. Although the modified DVV assay using the xCELLigence system yielded identical results (i.e. a 5-log10 reduction in viral infectivity) as the traditional DVV assay, the system allows virucidal efficacy and cytotoxicity to be measured in a more precise and reproducible fashion.


Job sharing in medical training: an evaluation of a 3-year project.
Job sharing has been introduced on a major scale in one deanery to help accommodate increasing demand for flexible (part-time) training. We arranged 37 job shares for 74 trainees between 1996 and 1999. Job shares lasted from 6 months to 2 years. Trainees in job shares were as satisfied with their training as those in supernumerary posts or in full-time training.


Referral patterns of patients with liver metastases due to colorectal cancer for resection.
Colorectal carcinoma accounts for 10% of cancer deaths in the Western World, with the liver being the most common site of distant metastases. Resection of liver metastases is the treatment of choice, with a 5-year survival rate of 35%. However, only 5-10% of patients are suitable for resection at presentation. To examine the referral pattern of patients with liver metastases to a specialist hepatic unit for resection. Retrospective review of patient's charts diagnosed with colorectal liver metastases over a 10-year period. One hundred nine (38 women, 71 men) patients with liver metastases were included, mean age 61 years; 79 and 30 patients had synchronous and metachronus metastases, respectively. Ten criteria for referral were identified; the referral rate was 8.25%, with a resection rate of 0.9%. Forty two percent of the patients had palliative chemotherapy; 42% had symptomatic treatment. This study highlights the advanced stage of colorectal cancer at presentation; in light of modern evidence-based, centre-oriented therapy of liver metastasis, we conclude that criteria of referral for resection should be based on the availability of treatment modalities.


Prediction of life expectancy in individuals in the United Kingdom using current cohort tables.
This paper provides updated cohort tables of life expectancy for individuals in the United Kingdom. Using 2008-based projections from the UK Office for National Statistics (ONS) cohort and period expectation of life tables (the Ogden tables); predicted future life expectancies were calculated for quintiles of age from 0-90 years in men and women with mortality ratios between 100% and 1000%. Period tables have been included to illustrate the differences between period and cohort life expectancy in men and women at various ages. These tables are not intended to predict specific life expectancy in individuals but may indicate the mean life expectancy of a cohort of similarly affected people in the UK.


Survivability of highly pathogenic avian influenza virus (H5N1) in naturally preened duck feathers at different temperatures.
Ducks are the "Trojan Horses" for Asian H5N1 avian influenza viruses (AIV) and attain carrier status without displaying overt infection. These birds help in the spread of the virus among the poultry and human population through direct or indirect contact. Preen oil is the secretion of preen gland of water birds such as ducks. In a process called preening, the water birds spread preen oil across their feather and body. Preen oil has been known to play a significant role in the accumulation of various pathogens including Highly Pathogenic Avian Influenza (HPAI) from water onto feathers. However, the studies are scarce on the role of preen oil in the survivability of HPAIV. We conducted a simulative study to analyse the effect of preen oil on the survivability of the HPAI virus (H5N1) on duck feathers. Duck feather samples along with relevant controls were spiked with the H5N1 virus at two different initial concentrations (104 EID50 and 106 EID50 ), stored at 37°C, 25°C and 10°C temperatures and tested at regular intervals for percent infectivity by egg culture method and qRT-PCR. The infectivity and viral load were significantly higher in naturally preened duck feathers in comparison to the three preen oil deficit controls at both low and high initial concentrations of virus (104 EID50 and 106 EID50 ). Maximum persistence was seen at 10°C in naturally preened duck feathers spiked with 106 EID50 concentration of viruses. It was also seen that depletion of preen oil from duck feathers reduced the persistence of the virus. These results demonstrate that preen oil plays a significant role in survivability and protection of HPAIV on duck feathers. This study herein will present new avenues in understanding one of the epidemiological niches of HPAIV.


High-performance size-exclusion chromatography of recombinant derived proteins and aggregated species.
The chromatographic behavior of some recombinant derived proteins and aggregated species was studied using high-performance size-exclusion chromatography (HPSEC). At neutral pH values, monomeric proteins exhibited non-ideal behavior while aggregated species were not eluted. As the pH was lowered below 5, both aggregated and monomeric species were eluted, with the amount of aggregated species increasing with decrease in pH. Final elution conditions selected for the simultaneous chromatography of monomeric and aggregated proteins were 0.1 M orthophosphoric acid, pH 2.5. The utility of the system was evaluated by determining the rates of protein degradation at elevated temperatures and comparing the results with those obtained using standard bioassay procedures. The rate of formation of aggregated species was also determined by HPSEC and corresponded to the rate of degradation of monomeric protein. The use of HPSEC with low pH eluent provides a rapid means for estimating protein stability under accelerated temperature conditions as well as for determining the existence and formation of aggregated species.


Mastering the art of delegation.
Delegation, an important, readily acquired management skill, promotes efficiency, increases productivity and improves time management. A four-step process guides the nurse manager through the art and science of delegation.


[FIRST EXPERIENCE OF APPLICATION OF TECHNOLOGY OF A TWO-STREAM LOW-FREQUENCY ULTRASOUND TECHNOLOGY IN ABDOMINAL SURGERY].
Biophysical peculiarities of action on tissues of a two-strem low-frequency ultrasound (TSLFU) technology, elaborated by "Arobella Medical LLC" (USA) firm, were studied. Capacity of ultrasound to separate a pathologically-changed and healthy tissues, to divide the structures in accordance to their bioacoustical parameters constitutes the technology peculiarities. The presence of such a biophysical effect permits to achieve high resectability (R0) in patients with oncological diseases. Antibacterial effect and stimulation of intraorgan microcirculation with ultrasound irradiation were noted. Biophysical peculiarities of TSLFU were successfully applied in surgical treatment of 48 patients, suffering inflammatory and oncological diseases of the abdominal cavity organs.


Sutureless vascular reconstruction with titanium clips.
Attempts to find alternatives to sutured vascular reconstruction techniques has continued for decades and include various forms of rings, tubes, endoluminal stents as well as gluing or welding techniques of large vessel anastomoses. One recently introduced technique uses nonpenetrating titanium clips for everted vessel approximation and closure. Experimental work on their use in various types of large vessel repairs and reconstructions has shown that the clips are easily applied with a short learning curve, create good conditions for vessel wall healing without causing excessive inflammation or fibrosis, and are considerably faster to apply when compared to standard suture techniques. Although there are some clinical reports of defective clipped closures causing postoperative bleeding complications, they are rare and most probably related to technical errors in applying the clips. The main disadvantages of the clips include the limited experience of their applicability in atherosclerotic vessels, lack of long term follow-up and cost. Potentially, the clips could be useful in the repair of multiple vascular injuries, in vessel repair or ligation performed in confined spaces, and in vascular procedures requiring the shortest possible cross-clamping time. Future applications could include endoscopic procedures as well as the use of a one-shot device which simultaneously applies up to a dozen clips to symmetrically everted and approximated vessel edges.


[Kidney transplants from donors burdened metabolic acidosis in the course of poisoning with methanol and carbon monoxide].
The question of obtaining organs from donors who died of methanol poisoning has been discussed in the medical literature for many years. The results of such transplants published so far are very optimistic. However, the possibility of permanent and significant injury to transplanted organs caused by poisons or its metabolites raises serious concerns regarding the procedure. The long-term effects of intensive treatment of poisoning need to be considered as well. Metabolic acidosis and high blood osmolality are agents with recognized damaging potential impairing organ function at cellular level. The study traced the fate of kidney transplants from 13 donors who died of methanol poisoning and one isoned with carbon monoxide. The donors group consisted of 12 men and 2 women, of mean age 49 years (SD +/- 7.93). The kidneys were transplanted 20 men and 8 women. The mean age of recipients was 50.29 years (SD +/- 12.9). At the time of admission to the Department of Toxicology all donors presented with profound metabolic acidosis and high plasma osmolality (mean 434.71 mOsm/kg H2O (SD +/- 73.29). Metabolic acidosis was treated high doses of sodium bicarbonate (mean infusion volume of was 409 ml) before the HD procedure. Blood methanol levels were between 125 and 470 mg% (mean 317.23 SD +/- 136.83). The carboxyhaemoglobin concentration of in the donor poisoned with carbon monoxide was 47.2%. Transplantation was performed after confirmation of the brain death, the period of cold ischemia (CIT) ranged from 6 to 22 hours (mean 16.06 hours; SD +/- 3.99). Kidneys have taken function immediately after transplantation in 21 recipients. In seven cases, patients required two or three HD procedures. A total of 16 dialysis were performed post-transplants. In the group of patients, the mean glomerular filtration rate (GFR) at 3 months after transplantation was 46.71 ml/min/1.73m2 (SD +/- 10.89). During the 18 months follow-up a constant upward trend to the mean GFR 50.55 was noticed. In the group of donors, the mean blood urea concentration (BUN) 3 months after transplantation was 61.43 mg/dL, including 7 patients with BUN within the range of 80-100 mg/dL. At 18 months post transplant, the average concentration was 42.36 mg/dL, with no cases exceeding 55 mg/dL. Similarly, serum creatinine level normalized with the mean value of 3.01 mg/dL at 3 months and 1.68 mg/dL at 18 months post the procedure. There was no case exceeding 2 mg/dL. One recipient died of a heart attack after a period of more than 18 months after transplantation. However, the transplant was efficiently active at all times (GFR 56-60 ml).


Association of the Ser9Gly polymorphism in the dopamine D3 receptor gene with tardive dyskinesia in Korean schizophrenics.
Tardive dyskinesia (TD) is usually regarded as one of the most serious side-effects of the long-term usage of neuroleptics due to its high prevalence and potentially irreversible nature. Previously, several genetic polymorphisms were investigated for an association with TD in various ethnic populations. Among them, the Ser9Gly variant in the MscI restriction site of the dopamine D3 receptor gene was reported to be associated with TD. We have investigated the association of Ser9Gly polymorphism of the dopamine D3 receptor gene with TD in Korean schizophrenics. The frequencies of the genotypes of Ser/Ser, Ser/Gly and Gly/Gly in 54 schizophrenic patients without TD were 21 (38.9%), 33 (61.1%) and 0 (0%), while the corresponding frequencies in 59 schizophrenic patients with TD were 25 (42.4%), 28 (47.5%) and 6 (10.1%). We have found a significant genotypic association of the Gly/Gly genotype with TD in Korean schizophrenics (P = 0.028, two-tailed Fisher's exact test). However, there was no significant allelic association of the Ser9Gly allele with TD (chi2 = 0.288, d.f. = 1, P = 0.591) and there was no significant difference in the Abnormal Involuntary Movement Scale score between the three genotypic groups (P = 0.071, anova). In conclusion, we suggest that Gly/Gly homozygotes in the MscI polymorphic site of the dopamine D3 receptor gene may cause some change in the function of the dopamine D3 receptor and may be involved the pathogenesis of TD.


Inequivalence of the two tyrosine ligands in the N-lobe of human serum transferrin.
Human serum transferrin N-lobe (hTF/2N) has four iron-binding ligands, including one histidine, one aspartate, and two tyrosines. The present report elucidates the inequivalence of the two tyrosine ligands (Tyr 95 and Tyr 188) on the metal-binding properties of hTF/2N by means of site-directed mutagenesis, metal release kinetics, and absorption and electron paramagnetic resonance (EPR) spectroscopies. When the liganding tyrosines were mutated individually to phenylalanine, the resulting mutant Y95F showed a weak binding affinity for iron and no affinity for copper, whereas, mutant Y188F completely lost the ability to bind iron but formed a stable complex with copper. Since other studies have demonstrated that mutations of the other two ligands, histidine and aspartate, did not completely abolish iron binding, the present findings suggest that the tyrosine ligand at position 188 is essential for binding of iron to occur. Replacement of Tyr 188 with phenylalanine created a favorable chemical environment for copper coordination but a fatal situation for iron binding. The positions of the two liganding tyrosines in the metal-binding cleft suggest a reason for the inequivalence.


Cognitive deterioration due to GH deficiency in patients with traumatic brain injury: a preliminary report.
To determine whether cognitive and behavioural disorders observed in TBI patients are due to hormonal deficits or to the brain injury itself. Transversal, between-group design. Studied 22 severe TBI patients (GCS < 8): 11 had isolated GH deficiency and 11 did not. Prepared detailed clinical reports on patients and performed physical examinations, standard biochemical and full blood count analysis. Patients underwent neuropsychological assessment and hormonal evaluation 6 months after TBI diagnosis. TBI patients with GH deficiency show greater deficits in attention, executive functioning, memory and emotion than those without GH deficiency. Results show GH-related cognitive impairment in patients who develop GH deficiency after TBI and suggest that treatment of GH deficiency would improve cognition. The clinical importance of these findings should be established to better understand the nature, magnitude and meaning of GH-related cognitive impairment in patients who develop GH deficiency after TBI.


The effects of adsorption of solutes on glassware and teflon in the calculation of partition coefficients for solid-phase microextraction with 1PS paper.
Solid-phase microextraction presents numerous advantages over traditional extraction techniques. However, the determination of partition coefficients is not as simple as it may appear. For very nonpolar compounds, such as polycyclic aromatic compounds, adsorption to the glass wall of the extraction vial and the Teflon coating of the stir bar may be quite significant. These interactions must be taken into account when calculating partition coefficients. Failing to do this may lead to large errors in the value of the partition coefficient, particularly for very nonpolar compounds. Three polar compounds and seven polycyclic aromatic hydrocarbons were partitioned individually between Whatman 1PS paper and water solutions of the compounds. The partition coefficiencts were calculated with two equations, and detailed mass balance data were acquired for the adsorption of the solute on the stir bar, glass vial, and 1PS paper. The mass data were compared with the partition coefficients, and important conclusions were made about the practical use of the partition coefficients.


Ultrastructural and histochemical study of the neuromuscular junctions in the denervated intrinsic laryngeal muscle of the cat.
Morphological changes and acetylcholinesterase (AchE) activity in the neuromuscular junctions (NMJ) of the normal and denervated posterior cricoarytenoid muscle (PCA muscle) of the cat were studied. Two days after denervation, the nerve terminals at the NMJ had almost disappeared. Six weeks after denervation, intensity of AchE activity at the former junctional site (FJS) was unchanged histochemically. At this stage, primary synaptic clefts were distorted and the Schwann's cells covered the FJS. Fourteen weeks after denervation, AchE activity at the FJS had decreased in contrast to that of the non-affected side. Calcitonin gene-related peptide (CGRP) was also investigated at the NMJ of the normal PCA muscles immunocytochemically. The present study shows that CGRP coexists with Ach in the nerve terminals of the PCA muscles and may be involved in the regulation of the contractile function of the intrinsic laryngeal muscle.


Palladium-Catalyzed Carbonylative Dearomatization of Indoles.
An interesting palladium-catalyzed dearomative carbonylation of N-(2-bromobenzoyl)indoles has been developed. The catalytic system is composed of commercially available Pd(OAc)2 and DPPP and uses alcohols and anilines as nucleophiles to afford moderate to good yields of the desired products. This method provides a straightforward access to diverse fused indoline esters and amides with good functional group tolerance. Remarkably, this is the first example of carbonylative dearomatization.


[Three-dimensional finite element initial analysis on the structure defect restoration of mandibular first molar under static and impact loads].
To make a mechanical analysis on three-dimensional finite element models of the mandibular first molar with the maximum distal occlusal (DO) structure defect after the root canal therapy and filling and crown restoration under static and impact loads and to provide a guideline for planning restoration for the clinic. The research adopted reverse engineering technology to build the model of three-dimensional finite element. The form of the intercuspal occlusion and cusp to cusp occlusion during the circulation of posterior teeth occlusion movement were simulated. Half-sine pulse/impact was chosen for the impact dynamic. The impact ratio was indicated to the stress change between impact loads and static loads. Under the two kinds of loads, the maximum Mohr stress values of the metal crowns were shown in all models. The restoration effects between the two kinds of models were compared, the maximum Mohr stress value of the crown metal and dentin was not obviously difference. The maximum Mohr stress values of dentin were all obviously smaller than the stretch limit strength of dentin. The impact ratio closed to 1. The impact loads accorded with the oral actual situation more than the static loads, but the suitable analysis of the static loads could be accepted. The restoration of metal crown is necessary. The effects between the amalgam filling and full crown restoration and composite resin filling and full crown restoration is not difference obviously.


Prenatal sonographic diagnosis of Malpuech syndrome.
Malpuech syndrome (MS) is a rare autosomal recessive syndrome featuring pre- and post-natal growth deficiency, mental retardation, facial dysmorphism, cleft lip and palate (typically midline or bilateral), caudal appendage, renal malformations and male genital abnormalities. A prenatal diagnosis of MS was made in this fetus based on the family history and a combination of conventional and 3D prenatal ultrasound findings. The family were consanguineous with an affected first child. Prenatal ultrasound in the second pregnancy demonstrated bilateral cleft lip and palate in association with intrauterine growth retardation on serial prenatal ultrasound scans. Dysmorphic facial features and a small penis consistent with the diagnosis were confirmed on 3D scanning. Post-natal examination of the neonate confirmed the diagnosis of MS. To the best of our knowledge, this is the first prenatal diagnosis of this syndrome.


Paracrine signalling of inflammatory cytokines from an in vitro blood brain barrier model upon exposure to polymeric nanoparticles.
Nanoparticle properties, such as small size relative to large highly modifiable surface area, offer great promise for neuro-therapeutics and nanodiagnostics. A fundamental understanding and control of how nanoparticles interact with the blood-brain barrier (BBB) could enable major developments in nanomedical treatment of previously intractable neurological disorders, and help ensure that nanoparticles not intended to reach the brain do not cause adverse effects. Nanosafety is of utmost importance to this field. However, a distinct lack of knowledge exists regarding nanoparticle accumulation within the BBB and the biological effects this may induce on neighbouring cells of the Central Nervous System (CNS), particularly in the long-term. This study focussed on the exposure of an in vitro BBB model to model carboxylated polystyrene nanoparticles (PS COOH NPs), as these nanoparticles are well characterised for in vitro experimentation and have been reported as non-toxic in many biological settings. TEM imaging showed accumulation but not degradation of 100 nm PS COOH NPs within the lysosomes of the in vitro BBB over time. Cytokine secretion analysis from the in vitro BBB post 24 h 100 nm PS COOH NP exposure showed a low level of pro-inflammatory RANTES protein secretion compared to control. In contrast, 24 h exposure of the in vitro BBB endothelium to 100 nm PS COOH NPs in the presence of underlying astrocytes caused a significant increase in pro-survival signalling. In conclusion, the tantalising possibilities of nanomedicine must be balanced by cautious studies into the possible long-term toxicity caused by accumulation of known 'toxic' and 'non-toxic' nanoparticles, as general toxicity assays may be disguising significant signalling regulation during long-term accumulation.


Comparison of two- and three-dimensional unenhanced and contrast-enhanced echocardiographies versus cineventriculography versus cardiac magnetic resonance for determination of left ventricular function.
Contrast enhancement has been shown to improve detection of regional wall motion abnormalities (RWMA) in 2-dimensional (2D) echocardiography. This study determined the use of contrast enhancement in the setting of 3-dimensional (3D) echocardiography for definition of left ventricular RWMA compared with 2D echocardiography, cineventriculography, and cardiac magnetic resonance (CMR). In 63 patients, unenhanced and contrast-enhanced (SonoVue; Bracco Imaging S.p.A., Milan, Italy) 2D and 3D echocardiographies, CMR, and cineventriculography were performed. Hypokinesia in ≥1 segment defined the presence of RWMA. Interreader agreement (IRA) between 2 blinded off-site readers on presence of RWMA was determined within each imaging technique. Intermethod agreement among imaging techniques was analyzed. A standard of truth for the presence of RWMA was obtained by an independent expert panel decision. IRA on presence of RWMA expressed as Cohen's κ coefficient was 0.27 for unenhanced 3D echocardiography, 0.40 for unenhanced 2D echocardiography, 0.57 for CMR, and 0.51 for cineventriculography. The use of contrast increased IRA on RWMA to 0.42 for 3D echocardiography and to 0.56 for 2D echocardiography. Agreement with CMR on RWMA increased for 3D echocardiography when contrast enhancement was used (κ 0.40 vs 0.22 for unenhanced 3D echocardiography). Similarly, agreement of 2D echocardiography with CMR on RWMA increased with contrast enhancement (κ 0.50 vs 0.32). Accuracy to detect expert panel-defined RWMA was highest for CMR (84%) followed by 2D contrast echocardiography (78%) and 3D contrast echocardiography (76%). It was lesser for 2D and 3D unenhanced echocardiographies. In conclusion, analysis of RWMA is characterized by considerable interreader variability even using high-quality imaging techniques. IRA on RWMA is lower with 3D echocardiography compared with 2D echocardiography. IRA on RWMA and accuracy to detect panel-defined RWMA improve with contrast enhancement irrespective of the 2D or 3D echocardiography use.


Absence of evidence or evidence of absence? A transfer and depletion study of Sudan I in eggs.
Sudan I is a carcinogenic industrial azo-dye, forbidden for use in food. However, it has been detected in food on several occasions, such as in paprika, used in animal husbandry to enhance egg yolk colour. Therefore, an animal experiment was designed to simulate the transfer of Sudan I to eggs after its unintentional administration to laying hens. A group of laying hens (n=18) received feed contaminated with Sudan I at the raising concentrations: 0.45mg/kg, 4.97mg/kg and 42.1mg/kg. Residues of Sudan I were detected in egg yolks (0.29±0.03µg/kg, mean±SD) only after the administration of the feed contaminated with the dye at the highest concentration. The determined concentrations were much lower than expected based on the compound's lipophilicity. In conclusion, the transfer of Sudan I to eggs was limited and strongly dependent on its concentration in feed.


A facile and versatile approach to design self-assembled monolayers on glass using thiol-ene chemistry.
This work describes an integrated approach for designing on demand Self-Assembled Monolayers (SAMs) on silicon oxides and particularly glass substrates for cell biology applications. Starting from commercially available compounds, the strategy relies on thiol-ene reaction and provides high quality SAMs exhibiting adhesive and anti-adhesive patterns.


S-1-induced, prolonged complete regression of lung metastasis from gastric cancer refractory to 5'-DFUR: a case report with pharmacokinetic study.
S-1 is an oral fluoropyrimidine reported to be most active for gastric cancer. However, few studies have documented a complete response (CR) of lung metastasis to S-1 treatment. We describe a 66-year-old woman in whom S-1 induced complete regression of lung metastasis from gastric cancer, that had been refractory to another oral fluoropyrimidine, 5'-deoxy-5-fluorouridine (5'-DFUR). After preoperative chemotherapy with a combination of etoposide, adriamycin and cisplatin and with methotrexate plus 5-fluorouracil, the patient underwent a total gastrectomy with lower esophagectomy for advanced diffuse-type gastric cancer with invasion of the esophagus in May 1993. She received postoperative adjuvant chemotherapy with 5'-DFUR (600 mg/day) for 3 years. However, a solitary metastasis to the left lung was detected in November 1996 and she underwent partial resection of the left lung. Chemotherapy with 5'-DFUR was reinitiated after operation, but re-metastasis to the left lung with elevation of the serum carcinoembryonic antigen (CEA) level was diagnosed in June 1999. Treatment with S-1 was started in August. S-1 was given orally in a dose of 100 mg/day for 28 consecutive days, followed by a 14-day recovery; treatment was repeated every 6 weeks. The metastatic lesion in the left lung completely regressed after two courses of S-1 and the serum CEA level returned to the normal range. The patient received a total of 10 courses of S-1. The dose of S-1 was reduced to 80 mg/day from the sixth course because of grade 2 skin rash. Pharmacokinetic studies after administration of S-1 revealed high and prolonged plasma 5-FU levels. Nearly 4 years have passed since complete regression of the lung metastasis. This may be the first report to document a prolonged complete response of lung metastasis from gastric cancer induced by single-agent chemotherapy with S-1.


Blood pressure studies in black children.
Blood pressure measurements were obtained under office conditions by auscultatory method, using appropriate cuff sizes, in 1,668 healthy black children (827 boys and 841 girls) ranging in age from 4 to 17 years. We found no significant difference between the mean systolic blood pressure of black children in our study and that of whites as reported in the literature. However, mean diastolic blood pressure was lower in black children. Some black children (3.6%) were found to have blood pressure more than 2 standard deviations above the mean for their age and should be closely observed for developing hypertensive cardiovascular changes.


Percoll-purified and photosynthetically active chloroplasts from Arabidopsis thaliana leaves.
The availability of the complete genome sequence of Arabidopsis thaliana and of large collections of insertion mutants paved the way for systematic studies of gene functions in this organism, thus requiring adapting biochemical and physiological tools to this model plant. For physiological analysis of photosynthesis, methods combining high level of chloroplast purity and preservation of the photosynthetic activity were missing. Here, we describe a rapid method (less than 1h) to obtain Percoll-purified and photosynthetically active chloroplasts from Arabidopsis leaves retaining almost 90% of the Vmax of photosynthesis measured in the starting leaves from plants grown under a light intensity of 150mumolphotonm(-2)s(-1) and 80% of their initial photosynthetic rate after 3h of storage.


Importance of interim restorations in the molar region.
Interim restoration protects abutment teeth and periodontal tissues until prosthetic treatment ends with the fabrication of a definitive prosthesis, restores and maintains the functions and morphology of the stomatognathic system, and preserves the occlusal contact relationship. Temporary prostheses are used for a short time, to confirm the diagnosis and treatment plan. However, because interim restorations are used only briefly, their importance in ensuring the success of definitive prostheses is often overlooked. This review includes a comprehensive literature review of interim restoration of molars and summarizes the current clinical understanding and status of this functionally important area. Peer-reviewed publications were identified by searching PubMed in November 2018. An interim restoration, even when used briefly, can help dentists evaluate many aspects of the treatment plan and contribute to accurate prognosis of prosthetic treatment.


Control of intestinal nematode infections by chemotherapy: mass treatment versus diagnostic screening.
There is increasing interest in the implementation of programmes to control nematodiases by chemotherapy, but no consensus on whether diagnostic screening before treatment is an essential component of such programmes. It is estimated that a screening component increases costs by a factor of 2-6 and may be beyond the economic and skill resources of endemic areas, but accords with accepted medical practice since only infected individuals are treated. In an attempt to examine this issue quantitatively, the relative risks of mass treatment and morbidity due to helminthiasis are compared. Age- and locality-targeting of mass treatment at populations at high risk of morbidity are proposed as procedures for further enhancing this risk differential. It is suggested that resolving the question of screening versus mass treatment requires more quantitative information than is currently available on the risk of side effects with treatment and the risk of morbidity with variable intensities of infection.


[The physiological functions of the epiphysis (the gerontological aspect)].
Hormones of the pineal gland play an important part in regulation of the organism biological rhythms. Age-dependent alterations of the epiphysis are essential for the processes of ageing of the organism. Its geroprotective effect involves participation of its hormones in the system of the organism antioxidant protection.


Identification of 14-3-3epsilon substrates from embryonic murine brain.
Mice deficient in 14-3-3epsilon exhibit abnormal neuronal migration and die perinatally. We report here the first large-scale analysis of 14-3-3 interacting partners from primary animal tissue, identifying from embryonic murine brain 163 14-3-3epsilon interacting proteins and 85 phosphorylation sites on these proteins. Phosphorylation of the deubiquitinating enzyme USP8 at serine 680 was found essential for its interaction with 14-3-3epsilon and for maintaining USP8 in the cytosol.


Protective effect of L-trans-pyrrolidine-2,4-dicarboxilic acid preload against cell death induced by oxygen/glucose deprivation in differentiated PC12 cells.
It has been postulated that cellular glutamate is released into the extracellular fluid when the energy supply of the brain is compromised (i.e., anoxia or oxygen/glucose deprivation), and there the amino acid triggers the so-called excitotoxic cascade, causing neuronal death. Several mechanisms for this release have been postulated, and, by using glutamate transporter inhibitors, several authors have established that reversed uptake is the major mechanism through which glutamate is released in acute oxygen/glucose deprivation. We have studied the effect of the slowly transported glutamate analogue L-trans-pyrrolidine-2,4-dicarboxilic acid (PDC) preload on glutamate release and cell death in an in vitro model of oxygen plus glucose deprivation with differentiated PC12 cells. As expected, we found that PDC preload inhibits glutamate release induced by oxygen/glucose deprivation, supporting the conclusion that it occurs via reverse transport. In addition, we show that PDC preload but not the nontransportable glutamate uptake inhibitor DL-threo-beta-benzyloxyaspartate (TBOA) protects cells against the death induced by oxygen/glucose deprivation, indicating that PDC entry into the cell is necessary for this protective effect. This protection does not correlate with the extracellular glutamate concentration or changes in proteins synthesis rate and eukaryotic initiation 2 phosphorylation. Oxygen/glucose deprivation induces a significant increase in glutathione levels in both unloaded and PDC-preloaded cells, but this increase is not due to up-regulation of glutamate cysteine ligase levels. Intracellular glutathione disulfide (GSSG) significantly increased after oxygen/glucose deprivation. It was also interesting that intracellular GSSG levels in PDC-preloaded cells under oxygen/glucose deprivation strongly correlate with the protection exerted by this compound against cell death.


Improving Oncology Clinical Trial Participation and Experience.
Cancer patients are underrepresented in clinical trial populations because of protocol-, physician-, and patient-related barriers. We engaged focus groups of patients who had participated in breast and ovarian cancer trials to identify concerns regarding their experiences. The lessons learnt are applicable to improving patient experience during future trials.


Recovery of function during inpatient rehabilitation for moderate traumatic brain injury.
This study evaluated the functional improvement of 189 patients with traumatic brain injury (TBI) who participated in a comprehensive rehabilitation program at a National Institute on Disability and Rehabilitation Research--designated Center for traumatic brain injury rehabilitation. Data were comprised of functional ratings reported by therapists in nine disciplines. Improvement in mobility, self-care, communicative, family, nursing, psychological, and recreation functions were observed. The relationship between functional level and length of stay, onset-admission interval, age, sex, education, and work history were examined. The benefits of rehabilitation are supported by this multidimensional study.


Numerical model estimating the capabilities and limitations of the fast Fourier transform technique in absolute interferometry.
Anumerical model was developed to emulate the capabilities of systems performing noncontact absolute distance measurements. The model incorporates known methods to minimize signal processing and digital sampling errors and evaluates the accuracy limitations imposed by spectral peak isolation by using Harming, Blackman, and Gaussian windows in the fast Fourier transform technique. We applied this model to the specific case of measuring the relative lengths of a compound Michelson interferometer. By processing computer-simulated data through our model, we project the ultimate precision for ideal data, and data containing AM-FM noise. The precision is shown to be limited by nonlinearities in the laser scan.


[Laughter and depression: hypothesis of pathogenic and therapeutic correlation].
Laughter is a very common behaviour in everyday life, nevertheless scientific literature is lacking in studies which examine closely its nature. The study aims are: to summarise the present knowledge about laughter and its relation with depression and to make hypotheses on its possible therapeutic function. In the first part of the review the main data existing about encephalic structures involved in laughter genesis, which show participation of cortical and subcortical regions, are reported and the effects of laughter on the organism physiologic equilibrium, particularly on the neuroendocrine and immune systems, are described. In the second part, scientific evidence about the influence of depression on the ability to laugh are referred, which suggests that reduction of laughter frequency is a symptom of the disease and that its increase may be used as a marker of clinical improvement. Finally, the main assumptions supporting the hypothesis of the therapeutic action of laughter on depression are examined: first of all, it has been demonstrated that laughter is able to improve mood directly and to moderate negative consequences of stressful events on psychological well-being; in addition, it is possible that the stimulation of particular cerebral regions, involved in depression pathogenesis, and the normalisation of the hypothalamic pituitary adrenocortical system dysfunctions, both mediated by laughter, can counteract efficiently depressive symptoms; finally, the favourable effects of laughter on social relationships and physical health may have a role in influencing the ability of depressed patients to face the disease.


Microarray applications in occlusive vascular disease.
Interventional cardiology procedures and drug therapy have been widely applied for the treatment of occlusive vascular disease. However, there remains a critical lack of understanding of the disease process at a molecular level. Microarray technology has the unique advantage in the ability to analyze thousands of genes simultaneously. So far, several studies based on microarray analysis have already provided valuable expression data in diseases such as atherosclerosis and in-stent stenosis. This review summarizes: a) latest microarray research indentifying gene-expression profiles; b) the methodological analysis of the available microarray studies; c) generation of biological processes or pathways; d) detection of better diagnostic and therapeutic targets in atherosclerosis and in-stent stenosis. Further improvements in microarray interpretation as well as in study design, combined with definition and evaluation in the clinical arena, will enhance our understanding of the causes and mechanisms contributing to occlusive vascular diseases, and therefore will help to improve treatment of patients suffering from these diseases.


alpha-Tocopherol Inhibits IL-8 synthesis induced by thrombin and high glucose in endothelial cells.
It has been reported that alpha-tocopherol, an antioxidant agent, may play a role in preventing diabetic angiopathy. However, there is little evidence to show the effect of alpha-tocopherol on the production of pro-inflammatory cytokines in endothelial cells. Therefore, we examined the effect of alpha-tocopherol on the regulation of IL-8 synthesis induced by high glucose and/or thrombin in endothelial cells. Thrombin alone markedly increased the IL-8 release. Furthermore, high glucose levels and thrombin combined had additive effects on IL-8 synthesis, and alpha-tocopherol diminished their effect; alpha-tocopherol also inhibited the phosphorylation of IkappaB-alpha induced by high glucose levels and/or thrombin. Our results suggest that the administration of alpha-tocopherol to diabetic patients may have a beneficial effect for the prevention of diabetic vascular complications by the inhibition of IL-8 synthesis from endothelial cells.


New meets old: a case study and review of novel therapeutics for the treatment of CLL in older patients.
The treatment of older or medically frail patients with chronic lymphocytic leukemia (CLL) presents unique challenges to clinicians attempting to maximize efficacy while avoiding significant toxicity. This case report presents a 75-year-old man with Rai stage II CLL complicated by massive splenomegaly, high-risk cytogenetics, and intolerance to first-line therapy recommended by the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Hodgkin's Lymphomas. A brief summary of his disease and treatment course accompanies a discussion of the special challenges associated with treating this patient population. In addition, emerging novel and targeted therapies, including next-generation monoclonal antibodies and small molecule inhibitors, are reviewed in the broader context of evolving standards of care and the NCCN Guidelines.


The third extracellular loop of G-protein-coupled receptors: more than just a linker between two important transmembrane helices.
GPCRs (G-protein-coupled receptors) are a large family of structurally related proteins, which mediate their effects by coupling with G-proteins. Despite responding to a range of very diverse stimuli, these receptors exhibit a conserved tertiary structure comprising a bundle of seven TM (transmembrane) helices linked by alternating ECLs (extracellular loops) and ICLs (intracellular loops). The hydrophobic environment formed by the cluster of TM helices is functionally important. For example, the 11-cis retinal chromophore of rhodopsin forms a protonated Schiff base linkage to a lysine in TM7, deep within the helical bundle, and small ligands, such as amine neurotransmitters and non-peptide analogues of peptide hormones, also bind within the corresponding region of their cognate receptors. In addition, activation of GPCRs involves relative movement of TM helices to present G-protein interaction sites across the intracellular face of the receptor. Consequently, it might be assumed that the ECLs of the GPCR are inert peptide linkers that merely connect important TM helices. Focusing on ECL3 (third ECL), it is becoming increasingly apparent that this extracellular domain can fulfil a range of important roles with respect to GPCR signalling, including agonist binding, ligand selectivity and receptor activation.


Sleep restriction attenuates amplitudes and attentional modulation of pain-related evoked potentials, but augments pain ratings in healthy volunteers.
The experiment investigated the impact of sleep restriction on pain perception and related evoked potential correlates (laser-evoked potentials, LEPs). Ten healthy subjects with good sleep quality were investigated in the morning twice, once after habitual sleep and once after partial sleep restriction. Additionally, we studied the impact of attentional focussing on pain and LEPs by directing attention to (intensity discrimination) or away from the stimulus (mental arithmetic). Laser stimuli directed to the hand dorsum were rated as 30% more painful after sleep restriction (49+/-7 mm) than after a night of habitual sleep (38+/-7 mm). A significant interaction between attentional focus and sleep condition suggested that attentional focusing was less distinctive under sleep restriction. Intensity discrimination was preserved. In contrast, the amplitude of the early parasylvian N1 of LEPs was significantly smaller after a night of partial sleep restriction (-36%, p<0.05). Likewise, the amplitude of the vertex N2-P2 was significantly reduced (-34%, p<0.01); also attentional modulation of the N2-P2 was reduced. Thus, objective (LEPs) and subjective (pain ratings) parameters of nociceptive processing were differentially modulated by partial sleep restriction. We propose, that sleep reduction leads to an impairment of activation in the ascending pathway (leading to reduced LEPs). In contradistinction, pain perception was boosted, which we attribute to lack of pain control distinct from classical descending inhibition, and thus not affecting the projection pathway. Sleep-restricted subjects exhibit reduced attentional modulation of pain stimuli and may thus have difficulties to readily attend to or disengage from pain.


The relationship between relative eye usage and ocular dominance shifts in cat visual cortex.
A novel modification of the alternate monocular deprivation paradigm was used to quantitatively define the relationship between relative eye usage and the shift in visual cortical ocular dominance toward the advantaged eye. Both eyes of cats were alternately occluded by contact lenses during daily visual exposure sessions with varying ratios of relative eye usage: 1:1, 1.7:1, 3:1, 7:1, 50:1, 100:0. Only 100:0 and 50:1 ratios produced an ocular dominance shift in favor of the more experienced eye. The ocular dominance shift in 100:0 cats occurred in all cortical layers but only in extragranular layers of 50:1 cats. A steep power function described the data, indicating that an extreme imbalance in relative eye usage (>90%) is required for an ocular dominance shift.


Direct visualization of organelle movement along actin filaments dissociated from characean algae.
A system has been developed in which organelle transport can be studied without the influence of an organized cellular cytoplasm. Binding and continuous unidirectional movement of organelles along isolated cellular transport cables were directly visualized by video light microscopy after the dissociation of the cytoplasm of characean algae cells in a Ca2+-free buffer containing adenosine triphosphate. Individual organelles had more than one attachment site and moved at mean rates of 11.2 or 62.1 micrometers per second along multiple parallel pathways on each cable. Electron microscopy of these cables after direct freezing demonstrated that they consist of compact bundles of actin filaments. Under these conditions, characteristics of organelle movement should reflect directly the underlying molecular processes of binding and force generation.


Collaborative group testing benefits high- and low-performing students.
We used collaborative group testing in a veterinary physiology course (65 students) to test the hypothesis that all students (e.g., high-performing and low-performing students of each group) benefit from collaborative group testing. In this format, students answered questions in the traditional format as individuals. Immediately after completing the exam as individuals, students answered the same questions in groups of two, and, finally, the same questions were discussed by the instructor and students. We measured two learning outcomes for every student: individual and group test scores. Based on individual test scores, students were categorized as "high performing" (students with higher individual scores) or "low performing" (students with lower individual scores). Finally, student evaluations of the format were collected. Collaborative group testing enhanced student performance. Specifically, group scores were higher than individual scores (P < 0.001). Importantly, the size of the collaborative testing effect was large for the population and for the low-performing students; however, the collaborative testing effect was small for the high-performing students. Finally, student evaluations of this testing format were very positive. In conclusion, collaborative group testing was beneficial for all students; however, collaborative testing was significantly more beneficial for low-performing students.


Lung function and morphology after bilateral hilar stripping in dogs.
Acute changes of lung function and morphology were studied in 3 groups of dogs: after bilateral hilar stripping by ipsilateral approach (group 1), after right-side hilar stripping and left pneumonectomy by left-sided approach only (group 2) and in a control group. All dogs of group 1 showed a syndrome corresponding to functional hilar stripping with absent Hering-Breuer and cough reflex, slow respiration with increased tidal volume and discharge of fluid from the airways. Alveolar ventilation and oxygen tension, dead space/tidal volume ratio and pulmonary shunting did not change. Cardiac output and arterial oxygen tension were decreased. The lungs were heavy and histological examination showed lymphostasis and interstitial edema. The dogs of group 2 did not show significant changes in comparison to the control group.


Comparative analysis of innate immune responses following infection of newborn calves with bovine rotavirus and bovine coronavirus.
Bovine rotavirus (BRV) and bovine coronavirus (BCV) are important causes of diarrhoea and death in newborn calves. Although these viruses belong to distinct viral classes, they both infect intestinal epithelial cells and induce similar clinical symptoms. Rotavirus usually causes an acute infection, but coronavirus infection can persist and reoccur in adults. Differences in viral structure and clinical outcome prompted us to postulate that innate mucosal immune responses would be markedly different following rotavirus and coronavirus infections. To address this hypothesis, gene expression following BRV and BCV infection was analysed in surgically prepared intestinal loops from 1-day-old colostrum-deprived calves. Gene expression was profiled at 18 h post-infection using bovine cDNA microarrays; the majority of differentially expressed significant genes were associated with the cell cycle and innate immune responses. A select group of these genes was validated by quantitative real-time PCR (qRT-PCR). The expression of genes associated with interferons (IFNs), cytokines and Toll-like receptors, which were not present on the microarray, was analysed further by qRT-PCR. Strong activation of TLR3, IL-6 and p65 was observed in BRV-infected host tissues, but not in tissues infected with BCV. Both viruses also downregulated IFN- and pro-inflammatory cytokine-associated pathways. In vitro studies confirmed that IFN inhibited viral replication. All of these results together suggested either that very early events of host responses at 18 h post-infection were being observed, or that both viruses have unique effective strategies to evade host immune responses.


[Characteristics of drinking water and coronary heart disease. An epidemiological experience (author's transl)].
Mortality for coronary heart disease (CHD) in two samples of men aged 40-59 at entry was rather different after the first 5 year follow-up, but became more and more similar - and substancially identical - after 15 year follow-up. In the community which showed the greatest relative increase of CHD mortality beyond the fifth year, a drastic change in the characteristics of drinking water had occurred, with a large reduction of hardness, and of calcium and magnesium concentration.


A 9-year follow-up study of the immunogenicity and long-term efficacy of plasma-derived hepatitis B vaccine in high-risk Chinese neonates.
The long-term immunogenicity of and protection provided by a plasma-derived hepatitis B vaccine was determined in a cohort of 98 susceptible Chinese neonates immunized in 1982-1983. Within 24 hours of birth, 89 infants received the first of three 30-micrograms doses of vaccine (at 0, 1, and 6 months) and were subsequently followed up by testing for serological markers of hepatitis B virus and by determining levels of alanine aminotransferase annually for 9 years. After the primary series of vaccine doses, 74 (83%) of 89 subjects developed antibody to hepatitis B surface antigen (anti-HBs). At the 9-year follow-up, 51% of vaccinees still had levels of antibody of > or = 10 mIU/mL, considered the protective level. Seven responders to vaccine (9.4% of 74 evaluable patients) developed antibody to hepatitis B core antigen, and in six of these responders, levels of anti-HBs increased transiently. None of the vaccinees developed chronic carriage of hepatitis B surface antigen or clinical hepatitis. Immunization of high-risk neonates with a plasma-derived hepatitis B vaccine can induce long-lasting protective immunity that can prevent or modify primary infection for at least 9 years. Booster doses are not necessary during this period.


Functional equivalence of autistic leading and communicative pointing: analysis and treatment.
Several studies have demonstrated that behavior problems can be reduced by teaching new, socially desirable responses that serve the same function as the undesirable behaviors being replaced. The present study was undertaken to extend this strategy systematically to a different area of child development, specifically, language disorder. A less desirable form of requesting, autistic leading, was treated by strengthening a more desirable form of requesting, pointing. The study was conducted using a multiple baseline design across four children with autism. Intervention included verbal and physical prompting of the pointing response as well as tangible reinforcement for child-initiated instances of that response. In a later phase, verbal requesting was also taught to accompany the pointing. Following intervention, response generalization was observed; that is, as pointing became frequent, leading became rare. In addition, stimulus generalization was observed; that is, pointing was exhibited in the presence of new adults, new settings, and new tangible objects. Results are discussed with respect to the principle that functional equivalence and response efficiency can be combined procedurally to treat a variety of undesirable behaviors in an educationally constructive manner.


Artificial synthesis of interspecific chimeras between tuber mustard (Brassica juncea) and cabbage (Brassica oleracea) and cytological analysis.
Interspecific chimeras between tuber mustard and red cabbage were obtained by in vitro graft-culture method. Before grafting, 6-day-old seedlings of tuber mustard and red cabbage were vertically half-cut and treated with different concentrations of 6-BA and NAA for 1 min, then, they were symmetrically fit together. As a result, sectorial chimeras were initially produced from the united shoot tips. The maximum frequency of chimeral bud formation reached 6.33% when the vertical sections of tuber mustard and cabbage were treated with 2 mg/l 6-BA and 1 mg/l NAA. When sectorial chimeras were propagated on MS medium containing 1 mg/l 6-BA, periclinal and mericlinal chimeras gradually developed. Chimeral shoots were rooted on half-strength MS medium containing 0.1 mg/l NAA. The rooted chimeras were acclimatized and transferred to the field for cytological and morphological analysis. The results showed that stomata density in the chimeras was significantly higher than that of their parents, while chloroplast size, starch grain size and number were intermediate between the two parents. The chimeras were further analyzed by flow cytometry, and the results indicated that they contained both sets of parental chromosomes. Moreover, chimeral plants possessed valuable characters from the two parents.


A custom-made neoprene thumb carpometacarpal orthosis with thermoplastic stabilization: an orthosis that promotes function and improvement in patients with the first carpometacarpal joint osteoarthritis.
Patients with mild to moderate first carpometacarpal joint osteoarthritis report pain, a reduction in pinch and grip strength and hand function. The purpose of this study was to analyze the effect of a custom-made neoprene thumb carpometacarpal orthosis with thermoplastic stabilization on pain, function, grip strength, and key pinch in these patients. A total of 11 volunteer patients participated in this study. All the above-mentioned parameters were evaluated at baseline and also 30, 60, and 90 days after using the splint. A decrease in pain was observed after 30 days, and this continued to improve during treatment with the splint. After 90 days of using the splint, grip strength was improved. Function and pinch strength also increased significantly and was maintained during the study period compared to baseline. A custom-made neoprene thumb carpometacarpal orthosis with thermoplastic stabilization may be a suitable conservative approach for the treatment of first carpometacarpal joint osteoarthritis.


[Critical review of mechanisms of action of second-generation antipsychotic drugs].
The advent of second-generation antipsychotics (SGA) in the wake of clozapine, the prototype for atypical antipsychotics, represents a breakthrough in the pharmacologic treatment of schizophrenia. There is growing evidence that most of the SGA can offer advantages over first-generation antipsychotics within the effective dose range, such as improvement in negative symptoms and cognitive impairment, fewer extrapyramidal side effects, and less hyperprolactinemia. However, the essential pharmacological properties that confer the different therapeutic effects of the SGA have remained elusive, and the search for novel antipsychotics without dopamine D2 receptor antagonism has not been successful to date, though numerous development strategies continue to be pursued, guided by various pathophysiologic hypotheses. This article provides a brief review and critique of the current predominant theories of mechanisms of action of SGA, including the serotonin-dopamine hypothesis, the "fast-off-D2 theory," and regional specificity. In addition, it focuses on the roles of N-methyl-D-aspartate receptors, dopamine DI receptors, and alpha-adrenergic receptors in the pharmacology of SGA.


Development of Dirofilaria repens in Aedes aegypti reared in contrasting habitat.
The susceptibility of Dirofilaria repens infection in Aedes aegypti adults reared in hay-infusion and tap-water during their larval stages was tested. Ae. aegypti reared in hay-infusion ingested a bigger amount of blood than those reared in tap-water but harboured fewer D. repens larvae (developing and arrested). The difference in the susceptibility of mosquitoes from the two treatments was correlated with the difference in the robustness of the mosquitoes.


[Surgical treatment of a subclavian artery aneurysm].
The article describes a rare clinical case of an atherosclerotic (poststenotic) aneurysm of the second segment of the subclavian artery, also involving the opening of the internal thoracic artery (ITA) in a male patient with CAD. The authors showed a possibility of preserving the ITA during resection of the aneurysm, in order to use it later on for surgical revascularization of the myocardium.


A polymorphism in endostatin, an angiogenesis inhibitor, predisposes for the development of prostatic adenocarcinoma.
We have performed association studies between a novel coding single nucleotide polymorphism (D104N) in endostatin, one of the most potent inhibitors of angiogenesis, and prostate cancer. We observed that heterozygous N104 individuals have a 2.5 times increased chance of developing prostate cancer as compared with homozygous D104 subjects (odds ratio, 2.4; 95% confidence interval, 1.4-4.16). Modeling of the endostatin mutant showed that the N104 protein is stable. These results together with the observation that residue 104 is evolutionary conserved lead us to propose that: (a) the DNA segment containing this residue might contain a novel interaction site to a yet unknown receptor; and (b) the presence of N104 impairs the function of endostatin.


Lethal short-bowel syndrome.
Infants with short-bowel syndrome are difficult to manage. Despite supportive measures with parenteral nutrition and surgery to lengthen remaining bowel or increase functional absorptive surface area, the outcome for many of these infants is poor. We have reviewed a series of seven infants diagnosed with severe short bowel. Causes included volvulus (3), multiple atresias (2), and total intestinal aganglionosis (2). Survival time ranged from 15 days to 8 months. During the hospital course, each infant underwent one to three operative procedures to diagnose and manage the short bowel and all received total parenteral nutrition (TPN) ranging from 10 days to 6 months. One infant died of liver failure and two others developed significant liver dysfunction secondary to TPN. Most infants remained hospitalized until their death. Death occurred at an average of 9 weeks following the diagnosis of short-bowel syndrome. This review suggests that infants with less than 6 cm of small bowel beyond the Ligament of Treitz will inevitably die of their disease or treatment complications. Until bowel transplant becomes a viable alternative, operative intervention and nutritional support may prolong survival but will not change the outcome of these infants and will only contribute to additional morbidity. A decision to withhold further therapy would be reasonable at the time the diagnosis is established.


Superficial CD34-positive fibroblastic tumor: Cytologic features, tissue correlation, ancillary studies, and differential diagnosis of a recently described soft tissue neoplasm.
Superficial CD34-positive fibroblastic tumor is a low-grade mesenchymal neoplasm of superficial soft tissues characterized by fascicles of spindle to epithelioid cells displaying nuclear pleomorphism and strong diffuse CD34 immunoreactivity. The intraoperative imprint cytology preparations (ICP) of a superficial CD34-positive fibroblastic tumor from a 50-year-old female are described. To the best of our knowledge, there is no report of the cytologic findings of superficial CD34-positive fibroblastic tumor in the English medical literature. The ICP, differential diagnosis, tissue correlation, and ancillary studies of this fascinating entity are discussed. Diagn. Cytopathol. 2016;44:926-930. © 2016 Wiley Periodicals, Inc.


Safety and immunogenicity of the tau vaccine AADvac1 in patients with Alzheimer's disease: a randomised, double-blind, placebo-controlled, phase 1 trial.
Neurofibrillary pathology composed of tau protein is a main correlate of cognitive impairment in patients with Alzheimer's disease. Immunotherapy targeting pathological tau proteins is therefore a promising strategy for disease-modifying treatment of Alzheimer's disease. We have developed an active vaccine, AADvac1, against pathological tau proteins and assessed it in a phase 1 trial. We did a first-in-man, phase 1, 12 week, randomised, double-blind, placebo-controlled study of AADvac1 with a 12 week open-label extension in patients aged 50-85 years with mild-to-moderate Alzheimer's disease at four centres in Austria. We randomly assigned patients with a computer-generated sequence in a 4:1 ratio overall to receive AADvac1 or placebo. They received three subcutaneous doses of AADvac1 or placebo from masked vaccine kits at monthly intervals, and then entered the open-label phase, in which all patients were allocated to AADvac1 treatment and received another three doses at monthly intervals. Patients, carers, and all involved with the trial were masked to treatment allocation. The primary endpoint was all-cause treatment-emergent adverse events, with separate analyses for injection site reactions and other adverse events. We include all patients who received at least one dose of AADvac1 in the safety assessment. Patients who had a positive IgG titre against the tau peptide component of AADvac1 at least once during the study were classified as responders. The first-in-man study is registered with EU Clinical Trials Register, number EudraCT 2012-003916-29, and ClinicalTrials.gov, number NCT01850238; the follow-up study, which is ongoing, is registered with EU Clinical Trials Register, number EudraCT 2013-004499-36, and ClinicalTrials.gov, number NCT02031198. This study was done between June 9, 2013, and March 26, 2015. 30 patients were randomly assigned in the double-blind phase: 24 patients to the AADvac1 group and six to the placebo group. A total of 30 patients received AADvac1. Two patients withdrew because of serious adverse events. The most common adverse events were injection site reactions after administration (reported in 16 [53%] vaccinated patients [92 individual events]). No cases of meningoencephalitis or vasogenic oedema occurred after administration. One patient with pre-existing microhaemorrhages had newly occurring microhaemorrhages. Of 30 patients given AADvac1, 29 developed an IgG immune response. A geometric mean IgG antibody titre of 1:31415 was achieved. Baseline values of CD3+ CD4+ lymphocytes correlated with achieved antibody titres. AADvac1 had a favourable safety profile and excellent immunogenicity in this first-in-man study. Further trials are needed to corroborate the safety assessment and to establish proof of clinical efficacy of AADvac1. AXON Neuroscience SE.


[Free radicals mediate cardiac toxicity induced by adriamycin].
Anthracycline antibiotics, including adriamycin (ADM), are widely used to treat various human cancers, but their clinical use has been limited because of their cardiotoxicity. ADM is especially toxic to heart tissue. The mechanisms responsible for the cardiotoxic effect of ADM have been very/extremely controversial. This review focuses on the participation of free radicals generated by ADM in the cardiotoxic effect. ADM is reduced to a semiquinone radical species by microsomal NADPH-P450 reductase and mitochondrial NADH dehydrogenase. In the presence of oxygen, the reductive semiquinone radical species produces superoxide and hydroxyl radicals. Generally, lipid peroxidation proceeds by mediating the redox of iron. ADM extracts iron from ferritin to form ADM-Fe3+, which causes lipid peroxidation of membranes. These events may lead to disturbance of the membrane structure and dysfunction of mitochondria. However, superoxide dismutase and hydroxyl radical scavengers have little effect on lipid peroxidation induced by ADM-Fe3+. Alternatively, ADM is oxidatively activated by peroxidases to convert to an oxidative semiquinone radical, which participates in inactivation of mitochondrial enzymes or including succinate dehydrogenase and creatine kinase. Here, we discuss the activation of ADM and the role of reductive and oxidative ADM semiquinone radicals in the cardiotoxic effect of this antibiotic.


Concomitant increase of IL-10 and pro-inflammatory cytokines in intraepithelial lymphocyte subsets in celiac disease.
Celiac disease (CD) is a small intestinal enteropathy caused by permanent intolerance to wheat gluten. Active disease is characterized by a prominent cytokine response of intraepithelial lymphocytes (IELs) to gluten-containing diet with concomitant increase in expression of pro-inflammatory IFN-gamma and down-regulatory IL-10 without increase in tumor necrosis factor-alpha (TNF-alpha) or transforming growth factor-beta1 (TGF-beta1). The aim was to understand the local immune reaction by determining which intraepithelial T cell subsets produce the different cytokines. The three major IEL-subsets gammadeltaIELs, CD4(+)alphabetaIELs and CD8(+)alphabetaIELs, as well as CD94(+)CD8(+)alphabetaIELs, selectively expanded in active CD, were retrieved from small intestinal biopsies of children with active CD and controls and analyzed quantitatively for cytokine mRNA expression. In active CD, CD8(+)alphabetaIELs showed a significant increase in expression levels of both IFN-gamma and IL-10. CD8(+)alphabetaIELs were also the IEL subset with highest expression level per cell of both cytokines and constituted the cellular source for almost all IFN-gamma and most IL-10. Expression levels of both cytokines were higher in CD94(-)CD8(+)alphabetaIELs than CD94(+)CD8(+)alphabetaIELs. TNF-alpha levels were only increased in CD4(+)alphabetaIELs, which also showed the highest expression level per cell and constituted the major source of this cytokine. Interestingly, IL-10 was increased also in CD4(+)alphabetaIELs. Cytokine levels were low in gammadeltaIELs. 'Classical' CD94(-)CD8(+)alphabeta T cells within the epithelium are responsible for the excessive production of IFN-gamma, believed to drive the formation of intestinal lesions in active CD. Production of IL-10 may be a common feature of IELs producing pro-inflammatory cytokines, thereby attempting to limit inflammation in an autocrine fashion.


Advantages of an ADHD diagnosis in adulthood: evidence from online narratives.
In this article we explore the impact of a diagnosis of adult attention-deficit hyperactivity disorder (ADHD) on coping among diagnosed adults. We use grounded theory to examine 71 biographical narratives, self-published on the Internet by adults with ADHD. The findings illuminate a three-stage temporal continuum. During the first stage, the narrators suffered from lack of self-confidence accompanied by functional difficulties, stress, and guilt feelings. During the second stage, which began after the diagnosis, they began to believe in their ability to lead meaningful and more manageable lives. During the third stage, an additional effect of the diagnosis emerged: the narrators' realization or belief that ADHD might affect them for the better. Some narrators stated that their traits as persons with ADHD helped them to cope better than others unaffected by this syndrome. Consequently, those who have an ADHD diagnosis seem able to defeat unnecessary negative emotions and self-blame.


Head computed tomography guidelines are being followed.
Several guidelines have been developed to direct the ordering of head computed tomography (CT) for patients, but most are clinical presentation-specific. Recently, an integrated guideline for ordering emergent head CT for patients who present to the ED of Western Hospital, Footscray, Victoria, Australia, was developed in response to concerns raised regarding perceived over-utilization of head CT for ED patients. Our aim was to determine compliance with the guideline. This was an explicit retrospective medical record review of patients who presented to the ED of Western Hospital between 1/04/2004 and 17/6/2004 and had a head CT as part of their assessment. Clinical information for these cases was compared with guideline recommendations. Data are described by descriptive statistics. Of the 231 cases that were included in the study, 65 (28.1%, 95% confidence interval 23-35%) had abnormal CT findings. Guidelines were adhered to in 217 (93.9%, 95% confidence interval 91-97%) cases. For the cases where the guidelines were not adhered to (14; [6.1%]), there was only one abnormal scan the clinical significance of which is not clear. The study found that compliance with head CT guideline was high. This suggests that the guideline is both clinically relevant and supported by ED doctors or conversely that the guideline is concordant with existing ordering practices of the ED.


Mesenchymal stem cells in myelodysplastic syndromes: phenotypic and cytogenetic characterization.
Bone marrow-derived mesenchymal stem cells (MSC) have been defined as primitive, undifferentiated cells, capable of self-renewal and with the ability to give rise to different cell lineages, including adipocytes, osteocytes, fibroblasts, chondrocytes, and myoblasts. MSC are key components of the hematopoietic microenvironment. Several studies, including some from our own group, suggest that important quantitative and functional alterations are present in the stroma of patients with myelodysplasia (MDS). However, in most of such studies the stroma has been analyzed as a complex network of different cell types and molecules, thus it has been difficult to identify and characterize the cell(s) type(s) that is (are) altered in MDS. In the present study, we have focused on the biological characterization of MSC from MDS. As a first approach, we have quantified their numbers in bone marrow, and have worked on their phenotypic (morphology and immunophenotype) and cytogenetic properties. MSC were obtained by a negative selection procedure and cultured in a MSC liquid culture medium. In terms of morphology, as well as the expression of certain cell markers, no differences were observed between MSC from MDS patients and those derived from normal marrow. In both cases, MSC expressed CD29, CD90, CD105 and Prolyl-4-hydroxylase; in contrast, they did not express CD14, CD34, CD68, or alkaline phosphatase. Interestingly, in five out of nine MDS patients, MSC developed in culture showed cytogenetic abnormalities, usually involving the loss of chromosomal material. All those five cases also showed cytogenetic abnormalities in their hematopoietic cells. Interestingly, in some cases there was a complete lack of overlap between the karyotypes of hematopoietic cells and MSC. To the best of our knowledge, the present study is the first in which a pure population of MSC from MDS patients is analyzed in terms of their whole karyotype and demonstrates that in a significant proportion of patients, MSC are cytogenetically abnormal. Although the reason of this is still unclear, such alterations may have an impact on the physiology of these cells. Further studies are needed to assess the functional integrity of MDS-derived MSC.


Evoked potentials in the management of patients with cochlear implants: research and clinical applications.
Evoked potential measures are integral to the treatment of patients with cochlear implants. In particular, these techniques are useful in the management of the pediatric patient. This brief report describes three categories of evoked potentials including clinical and research examples: electrically evoked auditory brain stem responses with transtympanic stimulation, middle-latency responses with cochlear implant stimulation, and cognitive evoked potentials elicited by speech stimuli.


Flexibility and fatigue evaluation of oblique as compared with anterior lumbar interbody cages with integrated endplate fixation.
This study was undertaken to quantify the in vitro range of motion (ROM) of oblique as compared with anterior lumbar interbody devices, pullout resistance, and subsidence in fatigue. Anterior and oblique cages with integrated plate fixation (IPF) were tested using lumbar motion segments. Flexibility tests were conducted on the intact segments, cage, cage + IPF, and cage + IPF + pedicle screws (6 anterior, 7 oblique). Pullout tests were then performed on the cage + IPF. Fatigue testing was conducted on the cage + IPF specimens for 30,000 cycles. No ROM differences were observed in any test group between anterior and oblique cage constructs. The greatest reduction in ROM was with supplemental pedicle screw fixation. Peak pullout forces were 637 ± 192 N and 651 ± 127 N for the anterior and oblique implants, respectively. The median cage subsidence was 0.8 mm and 1.4 mm for the anterior and oblique cages, respectively. Anterior and oblique cages similarly reduced ROM in flexibility testing, and the integrated fixation prevented device displacement. Subsidence was minimal during fatigue testing, most of which occurred in the first 2500 cycles.


A longitudinal cephalometric study of postorthodontic craniofacial changes.
Although the orthodontist focuses great efforts on diagnosis and treatment of the patient, less attention is paid to posttreatment changes that occur because of relapse and continued growth, especially over the long term. This cephalometric study describes 36 patients who were recalled x = 5.5 years after treatment and again x = 14.4 years after treatment. Most linear dimensions increased significantly from the end of treatment to first recall (ca. 16 to 21 years), presumably as a result of continued adolescent growth, but few changes achieved significance thereafter (ca. 21 to 30 years). Arch relationships (eg, ANB, NAP, AOBO, Y-axis) continued to improve after treatment, probably as a result of late growth of the mandible producing a more orthognathic profile. There was little change from first to second recall in any of the variables. Results suggest that if relapse occurs, it is likely to be evident soon after treatment and diminish thereafter and that continued craniofacial growth generally augments the orthodontic correction.


Developmental surveillance of infants and young children in pediatric primary care.
This article reviews the importance of appropriate developmental surveillance in early childhood, what is known about its effectiveness in current pediatric practice, and ways in which its delivery can be improved to optimize child outcomes. Many infants and young children with developmental delays or risk factors for poor developmental outcomes are not identified by pediatric practitioners in a timely manner. When they are identified, they are often not referred to appropriate early intervention services or early childhood development programs. They are therefore denied the opportunity to benefit from programs documented to have long-lasting benefits for children. Structuring developmental screening around the use of validated parent questionnaires improves the rates at which children with developmental needs are appropriately identified. At the same time, lowering thresholds for referral improves the rates at which children with identified needs receive appropriate services. Pediatric practitioners are uniquely positioned to improve children's developmental outcomes through early identification and referral of children with developmental delays or risk factors for poor developmental outcomes. Unfortunately, inappropriate screening practices, high thresholds for referral, misplaced concerns about causing parental anxiety, and unfamiliarity with local resources all diminish the effectiveness with which many practitioners conduct developmental surveillance. Recent studies show that small changes in screening and referral practices have the potential to greatly improve the effectiveness of developmental surveillance. This, in turn, has the potential to improve lifelong outcomes for children.


Mortality changes in a Polish rural community (1350--1972) and estimation of their evolutionary significance.
Changes in the mortality profiles of the population of 13 villages in central Poland have been studied for the medieval and nineteenth-century periods. Three measures, derived from the demographic data, were analyzed within an evolutionary context: (1) Im, the opportunity for selection through differential mortality, (2) Rpot, the potential gross reproductive rate, and (3) Ibs, the index of biological state. Changes in these indicators over time denote sharp differences in the opportunity for natural selection through differential mortality. The greatest changes are associated with technological and organizational transformations of the social system, especially during the first half of the nineteenth century.


Mechanism of inner-sphere electron transfer via charge-transfer (precursor) complexes. Redox energetics of aromatic donors with the nitrosonium acceptor.
Spontaneous formation of colored (1:1) complexes of various aromatic donors (ArH) with the nitrosonium acceptor (NO+) is accompanied by the appearance of two new (charge-transfer) absorption bands in the UV-vis spectrum. IR spectral and X-ray crystallographic analyses of the [ArH,NO+] complexes reveal their inner-sphere character by the ArH/NO+ separation that is substantially less than the van der Waals contact and by the significant enlargement of the aromatic chromophore. The reversible interchange between such an inner-sphere complex [ArH,NO+] and the redox product (ArH+.+ NO.) is quantitatively assessed for the first time to establish it as the critical intermediate in the overall electron-transfer process. Theoretical formulation of the NO+ binding to ArH is examined by LCAO-MO methodology sufficient to allow the unambiguous assignment of the pair of diagnostic (UV-vis) spectral bands. The MO treatment also provides quantitative insight into the high degree of charge-transfer extant in these inner-sphere complexes as a function of the HOMO-LUMO gap for the donor/acceptor pair. The relative stabilization of [ArH,NO+] is traced directly to the variation in the electronic coupling element H(AB), which is found to be substantially larger than the reorganization energy (lambda/2). In Sutin's development of Marcus-Hush theory, this inequality characterizes a completely delocalized Class III complex (which occupies a single potential well) according to the Robin-Day classification. The mechanistic relevance of such an unusual (precursor) complex to the inner-sphere mechanism for organic electron transfer is discussed.


Diurnal variations of IR-Met-enkephalin in the brain of pentylenetetrazol-kindled rats.
Pentylenetetrazol (PTZ) kindling was induced in male Wistar rats by daily i.p. injections of 40 mg/kg of the convulsant agent. Immunoreactive (IR)-Met-enkephalin was quantified in the amygdala, hippocampus and hypothalamus 17 days after the last stimulus, in groups of 6-7 rats, every 4 h, beginning at 08.00 h. IR-Met-enkephalin level displayed diurnal variations in brain regions of control animals. In the amygdala and the hippocampus the peptide peaked at 24.00 h and in the hypothalamus at 20.00 h; the troughs were at 08.00, 16.00 and 08.00 h, respectively. Diurnal variations were abolished in the amygdala and hypothalamus of kindled rats. In the amygdala the effect was characterized by an IR-Met-enkephalin increase at 04.00, 08.00 and 12.00 h; in the hypothalamus the peptide was enhanced at 08.00 and 12.00 h; in the hippocampus IR-Met-enkephalin increased at 12.00 h and showed a displacement of the peak during the dark phase. The results suggest that PTZ kindling in rats produces a long-lasting alteration on diurnal variations of IR-Met-enkephalin levels in limbic structures.


Regulation of c-Ret, GFRalpha1, and GFRalpha2 in the substantia nigra pars compacta in a rat model of Parkinson's disease.
Glial cell line-derived neurotrophic factor (GDNF) family members have been proposed as candidates for the treatment of Parkinson's disease because they protect nigral dopaminergic neurons against various types of insult. However, the efficiency of these factors depends on the availability of their receptors after damage. We evaluated the changes in the expression of c-Ret, GFRalpha1, and GFRalpha2 in the substantia nigra pars compacta in a rat model of Parkinson's disease by in situ hybridization. Intrastriatal injection of 6-hydroxydopamine (6-OHDA) transiently increased c-Ret and GFRalpha1 mRNA levels in the substantia nigra pars compacta at 1 day postlesion. At later time points, 3 and 6 days, the expression of c-Ret and GFRalpha1 was downregulated. GFRalpha2 expression was differentially regulated, as it decreased only 6 days after 6-OHDA injection. Triple-labeling studies, using in situ hybridization for the GDNF family receptors and immunohistochemistry for neuronal or glial cell markers, showed that changes in the expression of c-Ret, GFRalpha1, and GFRalpha2 in the substantia nigra pars compacta were localized to neurons. In conclusion, our results show that nigral neurons differentially regulate the expression of GDNF family receptors as a transient and compensatory response to 6-OHDA lesion.


Formal alkyne aza-prins cyclization: gold(I)-catalyzed cycloisomerization of mixed N,O-acetals generated from homopropargylic amines to highly substituted piperidines.
A new gold(I)-catalyzed cycloisomerization to access highly substituted piperidines has been developed. By combining a conceptually new way of generating iminium ions using cationic gold(I) complexes and an efficient cyclization reaction that can minimize a potentially competing aza-Cope rearrangement, the proposed reaction successfully circumvents a long-standing problem in the classical aza-Prins reaction. Synthetic utility of the catalytic reaction was demonstrated by a synthesis of optically active 2-alkyl-piperidin-4-one.


N-ethylmaleimide increases P-glycoprotein photoaffinity labeling with iodoaryl-azidoprazosin in multidrug resistant cells.
P-glycoprotein (P-gp) mediates a multidrug resistance (MDR) phenotype in tumor cell lines selected with lipophilic cytotoxic drugs. Transport studies using purified P-glycoprotein reconstituted into defined liposomes have shown energy-dependent drug efflux of structurally dissimilar drugs. In this report, we have examined the effects of N-ethylmaleimide, a potent inhibitor of the P-gp ATPase, on P-gp drug binding in intact MDR cells and in plasma membranes. Our results show that short term treatment of MDR cells with 1-50 microM N-ethylmaleimide led to a concentration dependent increase in P-gp photoaffinity labeling with iodoaryl-azidoparazosin (IAAP). In addition, N-ethylmaleimide increases [3H] vinblastine accumu-lation in drug-resistant but not in sensitive cells. Comparison of IAAP photolabeled P-gp from intact cells with or without N-ethylmaleimide treatment did not show differences in the pattern of IAAP photolabeled peptides. Thus, the observed increase in P-gp photolabeling with IAAP in N-ethylmaleimide treated cells is not due to photolabeling at different sites. Incubation of MDR cells with [14C] N-ethylmaleimide showed that P-gp is directly modified at several Cysteine residues, as found from a complete proteolytic digestion of [14C] Nethylmaleimide labeled P-gp. The comparison of V8 staphylococcus aureas peptides from [14C] Nethylmaleimide or IAAP modified P-gp showed some peptides to co-migrate on SDS PAGE. However, modification of plasma membranes from drug resistant cells treated with N-ethylmaleimide did not show a dose-dependent increase in P-gp photolabeling with IAAP as seen with intact MDR cells. Interestingly, N-ethylmaleimide increases P-gp phosphorylation by inhibiting the turnover of Pgp phosphates. However, inhibition of P-gp phosphorylation with calyculin A did not show an increase in P-gp photolabeling in MDR cells. Taken together, the results of this study suggest that N-ethylmaleimide potentiates P-gp photolabeling with IAAP by inhibiting P-gp ATPase thereby increasing the local concentration of IAAP in intact MDR cells. Furthermore, inhibition of P-gp ATPase by N-ethylmaleimide does not lead to conformational changes that affects P-gp drug binding.


Medicinal foods and beverages among Maasai agro-pastoralists in northern Tanzania.
Pastoralist Maasai populations of east Africa use several different wild plants as dietary and medicinal additives in beverages (soups and teas), yet little is known about how the plants used and the rationales for use compare and contrast across different Maasai beverages, including how gender specific dietary and health concerns structure patterns of intake. We investigated three Maasai beverages: almajani (tea or herbal infusion); motorí (traditional soup); and okiti (psychoactive herbal tea). In order to build knowledge about the cultural functions of these Maasai food-medicines and their incidence of use we also investigated use rationales and self-reported frequencies of use. We conclude by examining gender differences and the possible pharmacological antimicrobial activity of the most frequently used plants. Research was conducted in 2015, with a population of semi-nomadic agropastoralist Maasai residing in northern Tanzania. Data were collected using key informant interviews, plant collections, n = 32 structured surveys, and n = 40 freelist interviews followed by a literature review to determine the known antimicrobial activity of the most used plants. We identified 20 plants that Maasai add to soup, 11 in tea, and 11 in the psychoactive tea, for a total of 24 herbal additives. Seven plant species were used in all three Maasai beverages, and these clustered with 10 common ailments. Based on self-reports, women use the beverages less frequently and in smaller amounts than men. There were also several gender differences in the plants that Maasai add to motorí and their associated use rationales. There are several intersections concerning the plant species used and their associated rationales for use in almajani, motori, and okiti. Moving outward, Maasai beverages and their additives increasingly involve gender specific concerns. Female use of food-medicines, relative to men, is structured by concerns over pregnancy, birth, and lactation. The frequent consumption of herbal additives, many of which contain antimicrobial compounds, potentially helps modulate infections, but could have other unintentional effects as well.


Gordon Memorial Lecture. Chicken neoplasia--a model for cancer research.
1. The use of animal models has been immensely important for the advancement of our knowledge of the aetiology and pathogenesis of human diseases, including neoplasia. 2. Viruses, as oncogenic agents, were first described in the early 1900s when cell-free filtrates were used experimentally to transmit leukemias and sarcomas in chickens. In more recent years, studies with avian leukosis/sarcoma viruses have led the field in attempts to establish the genetic and molecular basis of viral oncogenesis. 3. Marek's disease of chickens was the first neoplasm proven to be caused by a herpesvirus and it remains the only neoplastic disease for which an effective vaccine has been developed and deployed. It serves as an elegant model as we seek an understanding of the pathogenesis of herpesvirus-induced lymphomas at both the cellular and molecular levels.


Sequential uniform designs for fingerprints development of Ginkgo biloba extracts by capillary electrophoresis.
A sequential procedure for the method of development of fingerprints based on a uniform design approach has been described in this paper. The sequential uniform design is used to reach the global optimum for a separation. The procedure is illustrated through developing the fingerprint of a Ginkgo biloba extract by capillary electrophoresis (CE) with diode array detection (DAD). The local overlap index (LOVI) is proposed as a criterion to evaluate the separation quality of two-dimensional hyphenated data in the optimization process. The successful application of the described techniques, including a sequential procedure, the CE-DAD hyphenated method and the LOVI criterion, shows their practicality in the fingerprint development of herbal medicines. However, some critical remarks on their use can also be made.