Effects of intravenous nitroglycerin on hemodynamics and ischemic injury in patients with acute myocardial infarction.
In 24 patients with acute myocardial infarction intravenous nitroglycerin in 2 different dosages was administered and the effect on hemodynamics and extent of myocardial ischemia was investigated. According to the initial left ventricular filling pressure (LVFP) the patients were divided in Group I: LVFP below 20 mm Hg (13 patients) and in Group II: LVFP above 20 mm Hg (11 patients). Following an infusion of 3 mg of nitroglycerin in the first and 6 mg in the second hour, a significant decrease (P less than 0.0001) in the filling pressure (in Group I from 15 +/- 4 to 9 +/- 3 (+/-1 SD) and in Group II from 28 +/- 11 to 16 +/- 7 mm Hg) was observed. The mean arterial pressure decreased in both groups by an average of 9 mm Hg. The changes in the heart rate were minimal. The cardiac output decreased in Group I from 4.4 +/- 1.0 to 3.9 +/- 0.8 1/min (P less than 0.005) whereas in the group with left ventricular failure it increased significantly from a lowered initial value (3.4 +/- 1.0 to 4.0 +/- 1.1 1/min) (P less than 0.001). By using precordial mapping for estimation of ischemic injury in 12 patient sigma ST elevation decreased from 14.6 +/- 11.9 to 12.2 +/- 9.8 mV at a dose of 3 mg/h (P less than 0.03). The dose of 6 mg/h, however, was less effective on the extent of myocardial ischemia than 3 mg/h. Thus, the dosage of nitroglycerin may be critical in respect to infarct size, despite the beneficial hemodynamic effects of the drug.


Design of compact absorbers for high-heat-load X-ray undulator beamlines at SPring-8.
A compact and high-heat-load absorber for the SPring-8 X-ray undulator beamline has been developed and installed. It consists of an upper heat-absorber part and a lower photon duct part, which are configured together in a water-cooled GlidCop body. The absorber part has a horizontal notch shape and the photon duct part forms a rectangular open channel under the absorber part. Two types of absorber are designed: one, with wire mesh channels, is 486 mm long, 70 mm high and 64 mm wide; the other, with smooth-bore channels, is 610 mm long, 75 mm high and 70 mm wide. Thermal and stress analyses show that they withstand the 12.3 kW heat load and the maximum heat flux of 940 W mm(-2) at normal incidence.


Effects of a diet deficient in the B complex vitamins on infectivity, growth and distribution of Echinostoma caproni in ICR mice.
The effects of a diet deficient in the B vitamins on infectivity, growth, and distribution of Echinostoma caproni in ICR mice were studied. The vitamin-deficient diet (experimental) was isocaloric to the control diet but lacked the B vitamins. Thirty-six female, 6- to 8-week-old ICR mice were each infected with 25 metacercarial cysts. From the day of infection to the day of necropsy, 18 mice were fed the experimental diet and the remaining mice received the control diet. Equal numbers of experimental and control mice were necropsied at 2, 3 and 4 weeks postinfection (p.i.). Mice on the experimental diet showed a significant loss in body weight between 2 and 4 weeks p.i. There was no significant difference in worm recovery at 2 to 4 weeks p.i. from mice on either diet. Worms from hosts on the experimental diet were more dispersed and located more posteriad in the small intestine than those from mice on the control diet. Worm dry weight was significantly less in hosts on the experimental diet at all weeks p.i. compared with that of hosts on the control diet. The body area of worms on the experimental diet was significantly less at 2 and 3 weeks p.i. than that of worms on the control diet. An isocaloric diet deficient in the B vitamins had a detrimental effect on the growth of E. caproni in ICR mice.


Identification and characterisation of a human calmodulin-stimulated phosphodiesterase PDE1B1.
A cDNA encoding a calmodulin-stimulated 3',5'-cyclic nucleotide phosphodiesterase (PDE) was isolated from a human brain cDNA library. The cDNA, designated HSPDE1B1, encoded a protein of 536 amino acids that shared 96% sequence identity with the bovine "63 kDa" calmodulin-stimulated PDE. The recombinant protein had cyclic nucleotide phosphodiesterase activity that was stimulated approximately 2-fold by Ca2+/calmodulin and preferred cGMP as substrate. In addition, the enzymatic activity of HSPDE1B1 was inhibited by phosphodiesterase inhibitors with potencies similar to that displayed toward the bovine PDE1 enzymes: IBMX approximately equal to 8-methoxymethyl-IBMX > vinpocetine approximately equal to zaprinast > cilostamide > rolipram. HSPDE1B1 mRNA was found predominantly in the brain. Lower mRNA levels were found in heart and skeletal muscle. In situ hybridisation of brain revealed expression of HSPDE1B1 predominately in neuronal cells of the cerebellum, hippocampus and caudate. The HSPDE1B1 gene was mapped to human chromosome 12. A partial genomic sequence of HSPDE1B1 was isolated and shown to contain two splice junctions that are conserved in the rat PDE4 and the Drosophila dunce genes.


Peroperative estimation of the size of the thyroid remnant.
A new method for estimation of the size of the remaining tissue after thyroid resection is described. The method has been tested on cadavers and during lobectomy in a series of patients. It is shown that intraoperative quantification of the thyroid remnant can be performed mostly with +/- 0.5 g for an individual thyroid lobe with a coefficient of variation of +/- 7.6%. In patients with toxic nodular goiter and calcifications, however, the error might be larger due to the varying homogeneity of the thyroid tissue. In 73 patients with negative antibody titers operated on for hyperthyroidism it was shown that the size of the thyroid remnant was negatively correlated to the delta TSH, determined 6 weeks after the operation.


Synthesis, spectroscopy, electrochemistry and thermal study of Ni(II) and Cu(II) unsymmetrical N2O2 Schiff base complexes.
The new tetradentate unsymmetrical N(2)O(2) Schiff base ligands, Ni(II) and Cu(II) complexes were synthesised and chracterized by IR, UV-vis, (1)H NMR and elemental analysis. The electrochemical properties of the Ni(II) complexes were investigated. The thermogravimetry of the Ni(II) and Cu(II) complexes were carried out in the range of 20-700 degrees C. Decomposition of synthesised complexes is related to the Schiff base characteristics.


Phase I clinical and pharmacokinetic trial of docetaxel and irinotecan administered on a weekly schedule.
Docetaxel and irinotecan are synergistic agents with a broad spectrum of activity but overlapping myelosuppression. The study was designed to maintain dose intensity while limiting myelosuppression. The objectives of this study were to determine the maximal tolerated dose (MTD) of the combination of docetaxel and irinotecan administered weekly for four consecutive weeks every 42 days, to describe toxicities of this regimen, and to perform a pharmacokinetic analysis to evaluate changes in drug disposition as a function of dose as well as repeated dosing. Adult patients with advanced solid tumors were treated with docetaxel followed by irinotecan. Doses of 30/50, 35/50, 35/66, 30/57, 30/65, 30/80 mg/m(2), respectively, were studied. Pharmacokinetics of docetaxel, irinotecan and SN-38 in plasma were determined on days 1 and 22 by a high-performance liquid chromatography (HPLC) assay. A total of 35 patients were treated. The MTD was docetaxel 30 mg/m(2) plus irinotecan 65 mg/m(2). Diarrhea was the dose-limiting toxicity; myelosuppression and other non-hematological toxicities were uncommon and mild. There were no significant differences in pharmacokinetic parameters between day 1 and day 22 (n=20). Five objective responses (breast, stomach and unknown primary) were observed among 30 evaluable patients. In addition, eight patients achieved stable disease. The combination of weekly docetaxel and irinotecan is a well tolerated regimen and should be explored in phase II trials. This schedule maintains dose intensity and has limited myelosuppression.


The public health significance of fat-modified ruminant foods.
The apparent consumption of dietary fat in Australia is 115 g/person/day, of which two-thirds is contributed by ruminant-derived foods. Consequently, the polyunsaturated fatty acid/saturated fatty acid ratio of the Australian diet is low, approximately 0.2. Recently a process has been developed which allows modification of the fatty acid composition of ruminant body fat, and a range of foodstuffs (fat-modified foods) which have a substantially higher polyunsaturated fatty acid/saturated fatty acid ratio than their conventional counterparts has been produced and marketed. In the clinical trials in which there was complete substitution of fat-modified ruminant foods for conventional ruminant products the fall in serum cholesterol was approximately 10%. In the trial in which there was only partial substitution the fall in serum cholesterol was insignificant. Using the equation developed by Keys, the predicted fall in serum cholesterol resulting from varying degrees of substitution of fat-modified ruminant meats for their conventional counterparts in the Australian diet is shown to be negligible. The fat-modified products were marketed at approximately twice the price of their conventional counterparts and it is claimed that this will limit the degree of substitution. It is concluded that the public health significance of fat-modified foods is limited.


Extraperitonealization of the anastomosis and sacral drain in restorative surgery for rectal carcinoma: a safety mechanism in the absence of a covering stoma.
A retrospective 10-year study was conducted on 473 patients who underwent rectal cancer surgery, to evaluate a surgical procedure which has been generally abandoned, but which we believe has a significant potential to reduce the incidence of the severe and often fatal complications caused by anastomotic breakdown following low anterior resection, especially when a covering stoma is absent. This procedure involves separating the anastomosis and sacral drain from the abdominal cavity by suturing the parietal peritoneum to the colon and mesocolon, and placing the sacral drain outside the peritoneal cavity, whereby contamination of the abdominal cavity is avoided should anastomostic leakage occur. Sphincter preservation was possible in 343 patients (72.5%) while 116 (24.5%) underwent abdominoperineal resection (APR). Of 331 patients who underwent sphincter-saving resection (SSR), 31 (9.4%) had primary protective colostomies. Radical RO-resection according to the International Union Against Cancer (UICC) was performed in 405 patients, and 65 (19.6%) underwent extended resections. Anastomotic leakage became clinically manifest in 33 patients (10%; or 11% when those with primary colostomies were excluded). Only 1 patient required relaparotomy while 32 were successfully treated with temporary loop colostomy in the right epigastrium. No deaths occurred following anastomotic leakage breakdown. Overall operative hospital mortality was 3.0%; 2.7% and 2.6% in the SSR and APR groups, respectively. The adjusted 5-year survival rates were 60% for APR and 72% for SSR.


Motor units in vastus lateralis and in different vastus medialis regions show different firing properties during low-level, isometric knee extension contraction.
Architectural differences along vastus medialis (VM) and between VM and vastus lateralis (VL) are considered functionally important for the patellar tracking, knee joint stability and knee joint extension. Whether these functional differences are associated with a differential activity of motor units between VM and VL is however unknown. In the present study, we, therefore, investigate neuroanatomical differences in the activity of motor units detected proximo-distally from VM and from the VL muscle. Nine healthy volunteers performed low-level isometric knee extension contractions (20% of their maximum voluntary contraction) following a trapezoidal trajectory. Surface electromyograms (EMGs) were recorded from VM proximal and distal regions and from VL using three linear adhesive arrays of eight electrodes. The firing rate and recruitment threshold of motor units decomposed from EMGs were then compared among muscle regions. Results show that VL motor units reached lower mean firing rates in comparison with VM motor units, regardless of their position within VM (P < .040). No significant differences in firing rate were found between proximal and distal, VM motor units (P = .997). Furthermore, no significant differences in the recruitment threshold were observed for all motor units analysed (P = .108). Our findings possibly suggest the greater potential of VL to generate force, due to its fibres arrangement, may account for the lower discharge rate observed for VL then either proximally or distally detected motor units in VM. Additionally, the present study opens new perspectives on the importance of considering muscle architecture in investigations of the neural aspects of motor behaviour.


Determinants of aspirin resistance in patients with type 2 diabetes.
Cardiovascular disease is a leading cause of mortality among patients with type 2 diabetes mellitus (T2DM). Numerous patients with T2DM show resistance to aspirin treatment, which may explain the higher rate of major adverse cardiovascular events observed compared with non-diabetes patients, and it has recently been shown that aspirin resistance is mainly related to accelerated platelet turnover with persistent high platelet reactivity (HPR) 24h after last aspirin intake. The mechanism behind HPR is unknown. The aim of this study was to investigate the precise rate and mechanisms associated with HPR in a population of T2DM patients treated with aspirin. Included were 116 consecutive stable T2DM patients who had attended our hospital for their yearly check-up. HPR was assessed 24h after aspirin intake using light transmission aggregometry (LTA) with arachidonic acid (AA) and serum thromboxane B2 (TXB2) measurement. Its relationship with diabetes status, insulin resistance, inflammatory markers and coronary artery disease (CAD) severity, using calcium scores, were investigated. Using LTA, HPR was found in 27 (23%) patients. There was no significant difference in mean age, gender ratio or cardiovascular risk factors in patients with or without HPR. HPR was significantly related to duration of diabetes and higher fasting glucose levels (but not consistently with HbA1c), and strongly related to all markers of insulin resistance, especially waist circumference, HOMA-IR, QUICKI and leptin. There was no association between HPR and thrombopoietin or inflammatory markers (IL-6, IL-10, indoleamine 2,3-dioxygenase activity, TNF-α, C-reactive protein), whereas HPR was associated with more severe CAD. Similar results were found with TXB2. Our results reveal that 'aspirin resistance' is frequently found in T2DM, and is strongly related to insulin resistance and severity of CAD, but weakly related to HbA1c and not at all to inflammatory parameters. This may help to identify those T2DM patients who might benefit from alternative antiplatelet treatments such as twice-daily aspirin and thienopyridines.


[The importance of predicted risk factors in developmental hip dysplasia: an ultrasonographic screening program].
To evaluate the role of the risk factors in the diagnosis of developmental hip dysplasia (DDH) by ultrasonographic screening. The hips of 327 newborns (151 females, 176 males) with identifiable risk factors including family history (n=20), congenital muscular torticollis (n=19), oligohydramniosis (n=2), breech presentation (n=51), multiple gestation (n=6), pes calcaneovalgus (n=74), clubfoot (n=152), and postural metatarsus adductus (n=3) were examined clinically on the first day of life and by ultrasonography within two weeks after birth. The hips were evaluated according to the Graf method. Clinical examination of 239 newborns were normal. Of these, sonographic abnormalities were found in 15 newborns (6.3%). On the other hand, out of 88 newborns who were found clinically abnormal, ultrasonography findings were normal in 24 cases (27%). According to the Graf method, of 654 hips, 550 were type 1, 81 were type 2a, 15 were type 2c, five were type D, two were type 3a, and one was type 4. Treatment was required for only 19 infants (5.8%), four of whom had been found normal on clinical examination. Our data suggest that risk factors are important for early diagnosis of DDH, and that, due to detection of abnormal ultrasonography findings among newborns who had been found normal on clinical examination, screening of all newborns with ultrasonography seems to be essential regardless of the presence of any risk factors.


Differential motivational responses to food and pleasurable cues in anorexia and bulimia nervosa: a startle reflex paradigm.
Abnormal perceptions of food and shape underpin the cognitive behavioural model of eating disorders (EDs). The aim of this study was to investigate motivational processing of disorder-specific and standard emotional cues in anorexia (AN) and bulimia nervosa (BN) using startle eyeblink modulation (SEM). SEM was used because it is sensitive to motivational states of approach (appetitive response) and withdrawal (aversive response), which are independent of conscious intentional control. Acoustically elicited SEM and subjective anxiety ratings were measured in 30 female patients with an ED (n=15 AN, n=15 BN) and 30 female control subjects while they viewed ED-relevant stimuli (food, female bodies) and standardized emotional pictures. BN subjects showed an appetitive response (startle inhibition) to food relative to neutral cues that differed significantly from AN subjects. By contrast, self-reports indicated significantly increased anxiety related to food cues across both ED groups. To female body picture (relative to neutral) cues, no significant between-group differences were found for SEM. ED subjects unexpectedly showed an aversive response (startle potentiation) to positive cues, in contrast to controls, who showed the established startle attenuation. These preliminary results suggest that BN patients demonstrated an exaggerated appetitive response to food but not to standardized positive cues, whereas SEM in AN patients points to a generalized failure to activate the appetitive motivational system. Differences in motivational salience to food cues are in line with distinctions between AN and BN in eating behaviour and food consumption and support differential treatment requirements.


Preparative separation of polyphenols from tea by high-speed countercurrent chromatography.
High-speed countercurrent chromatography (HSCCC) was applied to the separation of polyphenols from tea leaves (Camellia sinensis L.). The capability of HSCCC to isolate pure tea polyphenols from complex mixtures on a preparative scale was demonstrated for catechins, flavonol glycosides, proanthocyanidins, and strictinin from green and black tea. The purity and identity of isolated compounds was confirmed by (1)H NMR and HPLC-ESI-MS/MS. Gram quantities of polyphenols from tea can be isolated with the procedure described.


Cell-Mediated Immune Response to Influenza Using Ex Vivo Stimulation and Assays of Cytokine and Granzyme B Responses.
The antibody response to vaccination has been the industry and regulatory standard for evaluating influenza vaccine efficacy. Although antibodies are an important defense mechanism providing sterilizing immunity, in older adults, the cellular immune response is also needed for clinical protection against the serious complications of influenza. Thus, the demonstration of enhanced antibody responses as a strategy for advancing new influenza vaccines through the standard clinical development pipeline may fail to translate to enhanced protection in the older population. In peripheral blood mononuclear cells (PBMC) challenged with live influenza virus, an increase in the interferon-γ:interleukin-10 (IFN-γ:IL-10) ratio and the level of the cytolytic mediator, granzyme B (GrzB), correlates with protection against influenza in vaccinated older adults. This chapter provides detailed methods for measuring these cell-mediated immune responses, which have been validated according to the International Conference on Harmonisation (ICH) guidelines. These immune correlates could be combined with antibody responses to improve the prediction of enhanced protection in vaccine trials in the older population.


Steric factors direct Baylis-Hillman and aldol reactions in titanium tetrachloride mediated coupling between alpha-keto esters and cyclohex-2-enone derivatives.
The titanium tetrachloride mediated reaction of alpha-keto esters with 5,5-dimethylcyclohex-2-enone provides the corresponding Baylis-Hillman adducts exclusively whereas a similar reaction of alpha-keto esters with cyclohex-2-enone furnishes the corresponding aldol adducts (with high syn-diasteroeselectivity) as the major product (along with the Baylis-Hillman adducts as the minor product), thus clearly demonstrating the role of the steric factors in directing the reaction pathway.


Rapid method for simultaneous determination of ascorbic acid and zinc in effervescent tablets by capillary zone electrophoresis with contactless conductivity detection.
Ascorbic acid and zinc are essential nutrients that play important roles in nutrition, immune support, and maintenance of health. For this reason, both compounds are widely used as ingredients in dietary supplements. We report, for the first time, an analytical method for fast simultaneous determination of ascorbic acid and zinc. A single analysis run is possible every 80 s (45 injections/h). The method is based on capillary electrophoresis with capacitively coupled contactless conductivity detection using a fused silica capillary with 50 cm length (effective length of 10 cm). The separation was achieved by using a background electrolyte composed by 30 mmol/L of 2-(morpholin-4-yl)ethane-1-sulfonic acid and 30 mmol/L of histidine, pH 6.1. The detection limits were 10 and 20 μmol/L and recovery values for spiked samples were 101 and 100% for zinc and ascorbic acid, respectively. The results obtained with the developed procedure were compared to those obtained by titration (ascorbic acid) and flame atomic absorption spectroscopy (zinc), and no statistically significant differences were observed (95% confidence level).


Point-of-use water filtration reduces healthcare-associated infections in bone marrow transplant recipients.
Outbreaks of infection with gram-negative bacteria (GNB) have been linked to hospital water. We sought to determine whether point-of-use (POU) water filtration might result in decreased risk of infection in hospitalized bone marrow transplant (BMT) recipients in the absence of any recognized outbreak. Unfiltered water was sampled from taps in the BMT unit of a major US teaching hospital, and cultured at a reference laboratory. POU bacterial-retentive filters (0.2 mum) were installed throughout the unit, and replaced every 14 days. Infection rates were tracked over a 9-month period, and compared with rates for a 16-month period before POU filtration. Unfiltered water samples from 50% (2 of 4) outlets sampled grew P. aeruginosa (2 of 4) and Stenotrophomonas maltophilia (1 of 4). Clinical infection rates in the unit were significantly reduced from 1.4 total and 0.4 GNB infections per 100 patient days in the period before POU filtration to 0.18 total and 0.09 GNB infections per 100 patient days (P=0.0068 and 0.0431, respectively) in the 9-month period for which filters were in place. Infections during the POU filtration period were due to non-waterborne organisms. Point-of-use (POU) water filtration may significantly reduce infection rates in BMT recipients in the absence of any recognized outbreak.


Intralesional interleukin-2: A novel option to maximize response to systemic immune checkpoint therapy in loco-regional metastatic melanoma.
The management of metastatic melanoma has been transformed by the development of immune checkpoint inhibitors. However, disease control in patients with extensive locoregional metastases remains a significant challenge. In this context, intralesional interleukin 2 (IL-2) presents a useful therapeutic option to maximize intratumoural drug concentration and minimize systemic toxicity. The utility of combined intralesional IL-2 and systemic immune checkpoint therapy, particularly in loco-regional disease, is unknown. We report the clinical and cellular effects of combined anti-programmed death-1 blockade and intralesional IL-2 therapy in two patients with loco-regional metastatic melanoma. Combined intralesional and systemic therapy induced a lasting resolution of the injected skin tumors; maintained for up to 2 years. This impressive response was associated with increased PD-L1 expression and CD8 T cell infiltration. To our knowledge, this is the first report that raises the possibility of a synergistic effect between intralesional IL-2 and systemic checkpoint inhibition. The lasting remission of injected metastases may be in part due to an altered tumor microenvironment; characterized by increased PD-L1 expression and increased CD8 T cell infiltration. If this interesting and novel preliminary observation is confirmed in larger studies, combined local and systemic immunotherapy could highlight a novel treatment strategy for extensive loco-regional disease.


Effects of Breathing and Apnoea during Sustained Inflations in Resuscitation of Preterm Infants.
A sustained inflation (SI) at birth in preterm babies may be ineffective unless the infants breathe. Gain in lung volume is associated with breathing during delivery room non-invasive management. To describe the breathing patterns of preterm infants during an SI and correlate to a calculated gain in lung volume. Retrospective observational study. Data collected from a respiratory function monitor during SI (25 cmH2O for 15 s then PEEP at 5 cmH2O) through a face mask in preterm infants (gestational age [GA] ≤31 weeks). Spontaneous breaths, inspiratory time (TI), inspiratory/expiratory tidal volume (Vti/Vte), and gain in lung volume were determined. 30 SIs in 20 infants (mean GA 27 weeks; birth weight 825 g) were analysed and stratified in 2 groups according to spontaneous breathing: SIs without spontaneous breaths (apnoea: n = 11) and SIs with spontaneous breaths (breathing: n = 19). Mean GA was lower in the apnoea group versus the breathing group (25 vs. 27+5 weeks; p = 0.01). Mean birth weight was lower in the apnoea group versus the breathing group (683 vs. 860 g; p = ns). In the breathing group, the mean number of spontaneous breaths was 4 with a mean TI of 0.52 min, the mean Vti/kg was 5.9 mL/kg, and the mean Vte was 2.7 mL/kg. The calculated mean gain in lung volume was 7.5 mL/kg in the apnoea group and 17.8 mL/kg in the breathing group (p = 0.039). Actively breathing infants during an SI at birth showed a gain in lung volume higher than apnoeic infants. Spontaneous breathing during SI seems to be related to GA.


Intravitreal bevacizumab (Avastin) for age-related macular degeneration: a critical analysis of literature.
The current medical environment demands that quality health care is delivered at an affordable cost through the use of objective, unbiased clinical data. This study was undertaken to review the current literature on bevacizumab for age-related macular degeneration and its value in determining best clinical practice. Randomised controlled trials (RCTs) and observational studies that met the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) criteria were identified from the current literature for further analysis. Data concerning treatment dosing regimens, response to treatment, complications, and factors influencing outcome and safety were extracted and compiled into a database. As of January 2009, there were 5 RCTs that compared the outcomes of bevacizumab to other treatment options and 50 studies that met the STROBE criteria with similar visual and anatomical outcomes between RCTs and observational studies. Although the doses and dosing frequencies varied between the studies, the mean gain in vision at 3 months was +7.76+/-5.4 ETDRS letters (range +2 to +14.4); an effect that was maintained at 6 months in studies with longer follow-up. Predominantly classic lesions were the most responsive of all lesion subtypes. The complication profiles/rates were similar to those reported with other anti-vascular endothelial agents. There is sufficient scientific and statistical evidence to advocate the effective use of OCT-guided administration of intravitreal bevacizumab for neovascular AMD. This is reflected in our study outcome measures that are comparable to findings published from recent well-conducted RCTs on intravitreal ranibizumab at the same time point.


Construction of near-infrared photonic crystal glucose-sensing materials for ratiometric sensing of glucose in tears.
Noninvasive monitoring of glucose in tears is highly desirable in tight glucose control. The polymerized crystalline colloidal array (PCCA) that can be incorporated into contact lens represents one of the most promising materials for noninvasive monitoring of glucose in tears. However, low sensitivity and slow time response of the PCCA reported in previous arts has limited its clinical utility. This paper presents a new PCCA, denoted as NIR-PCCA, comprising a CCA of glucose-responsive sub-micrometered poly(styrene-co-acrylamide-co-3-acrylamidophenylboronic acid) microgels embedded within a slightly positive charged hydrogel matrix of poly(acrylamide-co-2-(dimethylamino)ethyl acrylate). This newly designed NIR-PCCA can reflect near-infrared (NIR) light, whose intensity (at 1722 nm) would decrease evidently with increasing glucose concentration over the physiologically relevant range in tears. The lowest glucose concentration reliably detectable was as low as ca. 6.1 μg/dL. The characteristic response time τ(sensing) was 22.1±0.2s when adding glucose to 7.5 mg/dL, and the higher the glucose concentration is, the faster the time response. Such a rationally designed NIR-PCCA is well suited for ratiometric NIR sensing of tear glucose under physiological conditions, thereby likely to bring this promising glucose-sensing material to the forefront of analytical devices for diabetes.


Hypocalcemic cataract.
A 19-year-old male with advanced renal failure developed bilateral cataracts indistinguishable from those considered characteristic of calcium deficiency. The biochemical findings during the dialysis treatment showed severe hypocalcemic episodes. A hypothetical mechanism to explain this kind of cataract is mentioned.


Selective Epidurography for the Assessment of Epidural Catheter Placement After Esophagectomy.
Adequate pain control immediately after esophagostomy is critical to patient recovery and may be compromised by uncertainty regarding correct epidural catheter placement. The aim of the current study was to determine the role of performing an epidurogram in selective patients to assess epidural placement after esophagectomy. Patients undergoing esophagectomy in a high-volume center were retrospectively reviewed to identify those in whom an epidurogram was performed less than 24 hours after surgery. Since 2012 epidurograms have been selectively performed in patients and have demonstrated features concerning for incorrect epidural catheter placement, including difficult/complicated insertion, negative sensory test, nonreassuring intraoperative hemodyamic response, and inadequate postoperative pain control. Fifty-two of 192 patients (27%; 43 men; age 65 ± 11 years) who underwent esophagostomy since 2012 had an epidurogram. Epidurograms were not associated with any adverse events. In 21 patients (40%) epidurogram findings led to a direct change in patient management, prompting either removal/replacement of an incorrectly sited catheter (n = 9), partial withdrawal of a catheter associated with unilateral contrast distribution (n = 2), or by endorsing a clinical decision to modify the analgesic regimen in a patient with a correctly sited epidural catheter (n = 10). Identifying and rescuing incorrect epidural catheter placement was not associated with longer intensive care unit/hospital stay or postoperative morbidity (p > 0.05) CONCLUSIONS: We reviewed selective epidurogram use in esophagectomy patients to determine its role in "rescuing" inadequate pain control through expediting clinical decision-making. Findings confirm that in selected patients epidurography is feasible and has the potential to directly contribute to patient care.


Bimodal effect of neuropeptide Y on feeding, and its antagonism by receptor blocking agents in rats.
Satiated rats received intracerebroventricular (icv.) injections of several doses of neuropeptide Y (NPY) and the food intake was measured in the following 4 h. The peptide exerted a dose-dependent biphasic effect; the 100 dose significantly suppressed the food intake, but doses of 1 microgram and 5 micrograms stimulated feeding. After the injection of 2 microliters NPY-antiserum (icv., 1:50 dilution), the cumulative food intake decreased significantly in the first 24 h. From the drugs tested the alpha-1-antagonist prazosine (4 micrograms icv.) and the opiate antagonist naloxone (NX, 0.5 micrograms, icv.) selectively inhibited the feeding-stimulatory effect a high icv. dose of NPY. The alpha-2-antagonist yohimbine (4 micrograms icv.) and the non-selective beta-antagonist propranolol (5 micrograms icv.) did not influence either effect of NPY on feeding. The results suggest the involvement of alpha-1-adrenergic and opiate receptors in the food intake-stimulatory effect of a large icv. dose of NPY. The food intake-inhibitory effect of a low icv. peptide dose was not selectively antagonized by the receptor blocking agents used.


Chirp echo Fourier transform EPR-detected NMR.
A new ultra-wide band (UWB) pulse EPR method is introduced for observing all nuclear frequencies of a paramagnetic center in a single shot. It is based on burning spectral holes with a high turning angle (HTA) pulse that excites forbidden transitions and subsequent detection of the hole pattern by a chirp echo. We term this method Chirp Echo Epr SpectroscopY (CHEESY)-detected NMR. The approach is a revival of FT EPR-detected NMR. It yields similar spectra and the same type of information as electron-electron double resonance (ELDOR)-detected NMR, but with a multiplex advantage. We apply CHEESY-detected NMR in Q band to nitroxides and correlate the hyperfine spectrum to the EPR spectrum by varying the frequency of the HTA pulse. Furthermore, a selective π pulse before the HTA pulse allows for detecting hyperfine sublevel correlations between transitions of one nucleus and for elucidating the coupling regime, the same information as revealed by the HYSCORE experiment. This is demonstrated on hexaaquamanganese(II). We expect that CHEESY-detected NMR is generally applicable to disordered systems and that our results further motivate the development of EPR spectrometers capable of coherent UWB excitation and detection, especially at higher fields and frequencies.


Association of the DF3/MUC1 breast cancer antigen with Grb2 and the Sos/Ras exchange protein.
The DF3/MUC1 mucin-like glycoprotein is aberrantly overexpressed in human breast carcinomas. Although the precise functional role of this protein remains unclear, the cytoplasmic tail contains potential tyrosine phosphorylation sites for binding to Src homology 2 (SH2) domains. In the present studies using human MCF-7 breast cancer cells, we show that tyrosine phosphorylated DF3 directly interacts with the SH2 domain of the adaptor protein Grb2. The findings indicate that a pYTNP site in DF3 is responsible for this interaction. The results also demonstrate that the DF3/Grb2 complex associates with the guanine nucleotide exchange protein Sos. Because Sos binds to the SH3 domains of Grb2 and, thereby, associates with Ras at the cell membrane, formation of a DF3/Grb2/Sos complex supports a role for DF3 in intracellular signaling.


[Update on rheuma-orthopedics - role and therapeutic options].
Orthopaedic treatment options for rheumatological patients have been further developed over recent years. For orthopaedic treatment, a range of different interventions are offered: orthoses and special technical aids as well as injections for joints and tendons, or surgery. Surgical interventions cover joint preservation, restitution and arthrodeses. Improvements in equipment and surgical procedures also make minimally invasive interactions possible for rheumatoid diseases. Thus, postoperative morbidity has been reduced significantly. Improvement in function, reduction of pain and prevention of recurrent local inflammation are primary. Considering these aims, arthrodeses are restricted to special indications. Joint preservation and restitution are the predominant measures used. The various procedures are discussed.


A rapid immunocytochemical assay for CMV detection in peripheral blood of organ-transplanted patients in clinical practice.
This study describes clinical experience with a rapid method for diagnosis of cytomegalovirus infection in organ-transplanted patients, based on the detection of CMV-specific antigens in peripheral polymorphonuclear cells with a mixture of monoclonal antibodies. This CMV-pp65 assay was formerly called the "CMV immediate early antigen assay." A group of 180 organ-transplanted patients were examined with this assay; 75 of them could be observed from the date of transplantation. These 75 patients consisted of two groups: 59 kidney transplant patients receiving no CMV hyperimmunoglobulin prophylaxis (group I), 13 heart-transplanted patients, and 3 liver transplanted patients receiving prophylaxis (group II). Group III consisted of 105 patients who had been transplanted ca. 2 years before starting this study. In group I, 26 (44%) were CMV-pp65-positive (13 primary and 13 secondary infections). Fifteen of these 26 (58%) positive patients showed clinical symptoms of CMV infection. Eleven of these 15 (73%) were primary infections. Symptomatic patients had significantly more CMV-pp65-positive cells than asymptomatic patients; 12 patients showed a high number of positive cells and 11 of them developed severe CMV illness. Thirty-three patients were CMV-pp-65-negative (22 CMV IgG-sero-positive, 11 CMV IgG-seronegative). None of them had symptoms of CMV infection. In all patients of group I there were 36 periods of graft dysfunction in which CMV infection had to be differentiated from transplant rejection. In 10 out of 36 there was a CMV-pp65-positive test result and subsequent seroconversion. Treatment of viral infection resulted in improvement of clinical problems. In the remaining 26 episodes no CMV-pp65-positive cells were detected: in 17 cases graft dysfunction was caused by rejection, in 9 cases by other complications. In group II, 13 of 16 patients (81%) were positive in the CMV-pp65 assay (6 primary infections, 7 secondary infections). However, none of them showed clinical signs of CMV infection, regardless of the number of positive cells. No CMV-related graft dysfunction was observed. In group III, CMV infections did not play an important role. The experiences described suggest that this test is a valuable tool in early CMV diagnosis and in differentiating CMV-dependent graft dysfunction from other graft dysfunctions. It allows prompt therapeutic intervention.


Gender Differences in the Prediction of Acute Stress Disorder From Peritraumatic Dissociation and Distress Among Victims of Violent Crimes.
Peritraumatic dissociation and distress are strong predictors of acute stress disorder (ASD) and posttraumatic stress disorder (PTSD) development. However, there is limited data concerning gender differences in these relations, particularly among victims of violent crimes (VVC). The objective of this study is to examine whether peritraumatic dissociation and distress predict the number of ASD symptoms differently for men and women VVC. In all, 162 adults (97 women, M age = 39.6 years), 63% of whom experienced physical assaults, completed the Acute Stress Disorder Interview, the Peritraumatic Dissociative Experience Questionnaire, and the Peritraumatic Distress Inventory. Analyses included t tests and multiple hierarchical regressions models controlling for known PTSD risk factors. The regression model showed dissociation and distress to be significant predictors of ASD for both men and women (β = .349 and β =.312 respectively; all p < .001). A significant three-way interaction was also observed between peritraumatic distress (PDI), past potentially traumatic experiences, and gender. In simple slopes analyses, the combination of high levels of PDI and of a high number of past potentially traumatic events were associated with greater risk of ASD in men only ( b = 3.78, p < .001). However, women experienced greater PDI, t(157) = 5.844, p = .005, than men, and elevated distress was associated with more ASD symptoms independently of past traumatic events. Gender differences were revealed as a function of past potentially traumatic experiences. There is a cumulative impact of past potential traumas and current distress that predicts ASD in men, while in women, it contributes to ASD via increased distress.


Mechanism of chloramphenicol-induced modulation of mouse ileal motility.
The effect of chloramphenicol (CAP) on the intestinal motility of mice was studied. Acute and chronic CAP treatment significantly increased the food transit time. CAP produced concentration-dependent inhibition of motility of the isolated ileum of mice. Prazosin, propranolol, atropine, ouabain and chlorpromazine all failed to modulate or counteract the CAP-induced inhibition of ileal motility. However, naloxone and hexamethonium slightly modified the inhibitory response of CAP. The inhibitory response of CAP was markedly counteracted by cystine, a guanylate cyclase inhibitor. CAP increased the activity of Ca(++)-ATPase in the ileum in all experiments. Our results suggest that the CAP-induced inhibition of the intestinal motility is not mediated through adrenergic, cholinergic and cAMP or through inhibition of the electrogenic pump. Compared to thiamphenicol (TAP), CAP, with a p-NO2 group in its structure, exhibited more pronounced alteration of both intestinal motility and Ca(++)-ATPase activity. We, therefore, suggest that greater inhibition of ileal motility induced by CAP is possibly a p-NO2-cGMP-Ca(++)-ATPase-mediated mechanism.


[Kinetics and Reactive Species Analysis of Dimetridazole Degradation by TiO2].
Dimetridazole is considered as an emerging pollutant in waterbodies, which can potentially impact ecosystem and human health. Heterogeneous photocatalytic decomposition of dimetridazole by TiO2 was investigated under 365 nm UV light and effects of initial pH, TiO2 content and dimetridazole concentration on photocatalytic process were discussed. The results indicated that the optimized experiment condition is that the TiO2 content of 1 g x L(-1), dimetridazole concentration of 40 mg x L (-1), pH of 11, dimetridazole can be removed 90%. The photocatalytic degradation kinetics of dimetridazole could be fitted to the quasi-first-order equation. Photocatalytic degradation of dimetridazole can take place via two pathways: oxidation by *OH and reduction by e -.


Cytokine expression in response to root repair agents.
To evaluate the expression of TNF-α, IL-6, IFN-γ, TGF-β, IL-4, IL-10, RANKL, RANK and OPG on mouse calvarial bone treated with MTA, Geristore® and Emdogain® . Bone wounds were made on the heads of C57BL/6 mice, breaking the periosteum and the cortical surface of the calvaria. Each repair agent was inserted into sectioned Eppendorf microtubes and placed on the bone wound, and soft tissues were sutured. At 14 and 21 days, animals were sacrificed and the treated region was dissected. The calvaria bone was removed, and RNA was extracted. mRNA expression of the aforementioned cytokines was assessed using real-time PCR. Data were analysed by nonparametric methods, including the Mann-Whitney and Kruskal-Wallis tests (P < 0.05). Following treatment with Emdogain® and MTA, mRNA expression of RANKL, RANK and OPG increased significantly (P < 0.05) between days 14 to 21. Geristore® did not alter the basal expression of these mediators during the same period of evaluation. Whilst treatment with Emdogain® did cause a significant increase in TNF-α mRNA expression between days 14 and 21 (P < 0.05), treatment with MTA did not alter the basal expression of this cytokine at either experimental time point. However, TNF-α mRNA expression was down-regulated significantly at day 21 (P < 0.05) when Geristore® was applied. A significant increase in the mRNA expression of IL-6, TGF-β, IL-10, IL-4 and IFN-γ was observed with Emdogain® and MTA treatment between days 14 to 21, whereas Geristore® reduced significantly the expression of IL-6, TGF-β and IL-4 (P < 0.05). The clinical indication of these repair agents depends on the root resorption diagnosis. Whilst MTA and Emdogain® induce a pro- and anti-inflammatory response early and late, respectively, Geristore® was not associated with an inflammatory reaction when compared with both repair agents.


A new, broad-spectrum azole antifungal: posaconazole--mechanisms of action and resistance, spectrum of activity.
Posaconazole, a new triazole antifungal, exerts principally the same mechanism of action as the other azole derivatives, i.e. it inhibits the ergosterol production by binding and inhibiting the lanosterol-14alpha-demethylase which is present in almost all fungi except Pneumocystis and Pythium. Posaconazole has an exquisitely high affinity to this target. Since posaconazole has a chemical structure different from fluconazole and voriconazole, it can interact with an additional domain of the target so that it may inhibit even mutated strains resistant to fluconazole and voriconazole. In addition posaconazole is a bad substrate for efflux pumps in fungi, so it can stay active when other azoles are already inactive. Furthermore, the spectrum of posaconazole is rather large including also some zygomycetes resistant to other azoles. In conclusion, posaconazole is actually the most potent azole derivative used in medicine. A combination of posaconazole with other groups of antifungals may have a favourable effect. There are several methods to test the in vitro activities of posaconazole including the E-test, though interpretive breakpoints are still lacking.


Fractal analysis of astrocytes in stroke and dementia.
The varied morphological forms in which astrocytes occur in brain of ischemic/hemorrhagic stroke and Alzheimer's disease (AD) patients are complex and the mechanisms that drive their formation are not yet properly understood. Subjective differences can be described between these pathologies in what it concerns astrocyte implication, but these have not been yet subjected to a morphometrical quantification. Here we apply a fractal dimension (FD) analysis algorithm to differentiate both between fibrous, protoplasmatic and activated astroglia; but also between the three pathological conditions studied. Analyzing more than 1000 astroglia, we show here first that FD can clearly differentiate between the three morphological subtypes. Second, we describe resemblances of the FD values for ischemic and hemorrhagic lesions, and significant differences when these are compared to AD patients. These results are further discussed and integrated in what it regards the preferential regions proved to be affected in these conditions, and which parallels our results. This work illustrates that fractal dimension analysis of astroglia is a useful method for quantitatively describing gliosis in different pathologies, and that it may offer more insight into the pathogenesis of brain diseases.


Tissue angiotensin converting enzyme (ACE) during changes in the renin-angiotensin system.
To establish if physiological manipulations of the renin-angiotensin system modulates tissue angiotensin converting enzyme (ACE), rats were fed low, normal, or high salt diets, or high salt and DOCA, for 3 weeks, and then plasma and tissue ACE levels were determined by radioinhibitor binding studies. Urinary sodium excretion (mmol/24 h) was 0.03 +/- 0.01 (low salt), 0.58 +/- 0.09 (normal salt), and 10.4 +/- 1.3 (high salt), and plasma angiotensin II (pg/ml) was 73.5 +/- 8.6 (low salt), 49.3 +/- 8.5 (normal salt), 32.2 +/- 8.5 (high salt), and 6.9 +/- 0.6 (high salt plus DOCA) in the third week of dietary treatment. ACE was studied by Scatchard analysis of radioinhibitor binding in plasma and tissue homogenates. [125I]MK351A bound to ACE was measured under standardized conditions in the presence of MK351A (10(-13) to 10(-5) M) and MK351A binding sites and equilibrium dissociation constant calculated. There were no significant changes in binding site concentration in plasma, lung, aorta, epididymus, brain, or kidney preparations across the range of salt states studied. The equilibrium dissociation constant appeared uniform within organs, but varied between organs. Further studies were undertaken with captopril, enalapril, and cilazoprilic acid in kidney and lung preparations. Concentration of inhibitor required for equal displacement of bound [125I]MK351A was consistently greater for kidney than for lung. Binding studies of rat ACE using [125I]MK351A showed that manipulation of salt status did not influence rat tissue ACE. Binding data suggest ACE from different tissues may have variations at the active site.


Combined genomic-metabolomic approach for the differentiation of geographical origins of natural products: deer antlers as an example.
The correct identification of the geographical origin of deer antlers is essential to quality control, as its positive physiological effects correlate with chemical components. In this study, we applied both genomics and metabolomics to the origin-identification of 101 samples from Canada, New Zealand, and Korea. The genomics identified deer species in each country but failed to categorize all the samples, due to the presence of identical species in different countries. For identical species, NMR-based metabolomics gave clean separations, compounds specific to each country were identified, and the validity was confirmed by prediction analysis. As the genomics provided unambiguous read-outs for different species, and the metabolomics cleanly distinguished among identical species from different countries, their combined use could be a robust method for origin-identification even in difficult cases. We believe the method to be generally applicable to many herbal medicinal products for which various species are grown internationally.


Why medicine residencies?
Over the last several decades the context of the medicine residency has changed. These changes are described and attributed in considerable degree to bureaucratic impositions. I consider it paradoxic that there is finally a move afoot to reverse the changing nature of medicine residencies, yet this effort appears in the form of yet another bureaucratic imposition.


Computed tomography in the diagnosis of lymphangiomas in infants and children.
The computed tomographic features in 14 children (age range = 2 days to 10 years) with cystic hygromas of the neck and lymphangiomas of the chest, abdomen, and extremities were studied. Computed tomography can determine the morphology of these masses, their exact locations and their relationship to other organs. Most lymphangiomas appear as cystic masses of low attenuation value with or without septations. The septations may be thin or thick and result in a conglomerate of cysts of irregular borders, varying in size from a few millimeters to several centimeters. Some of the septae show enhancement after a bolus injection of contrast material. Contrary to what has been reported, lymphangiomas may invade nearby tissues and organs.


Metabolic hormones regulate basal and growth hormone-dependent igf2 mRNA level in primary cultured coho salmon hepatocytes: effects of insulin, glucagon, dexamethasone, and triiodothyronine.
Igf1 and Igf2 stimulate growth and development of vertebrates. Circulating Igfs are produced by the liver. In mammals, Igf1 mediates the postnatal growth-promoting effects of growth hormone (Gh), whereas Igf2 stimulates fetal and placental growth. Hepatic Igf2 production is not regulated by Gh in mammals. Little is known about the regulation of hepatic Igf2 production in nonmammalian vertebrates. We examined the regulation of igf2 mRNA level by metabolic hormones in primary cultured coho salmon hepatocytes. Gh, insulin, the glucocorticoid agonist dexamethasone (Dex), and glucagon increased igf2 mRNA levels, whereas triiodothyronine (T(3)) decreased igf2 mRNA levels. Gh stimulated igf2 mRNA at physiological concentrations (0.25x10(-9) M and above). Insulin strongly enhanced Gh stimulation of igf2 at low physiological concentrations (10(-11) M and above), and increased basal igf2 (10(-8) M and above). Dex stimulated basal igf2 at concentrations comparable to those of stressed circulating cortisol (10(-8) M and above). Glucagon stimulated basal and Gh-stimulated igf2 at supraphysiological concentrations (10(-7) M and above), whereas T(3) suppressed basal and Gh-stimulated igf2 at the single concentration tested (10(-7) M). These results show that igf2 mRNA level is highly regulated in salmon hepatocytes, suggesting that liver-derived Igf2 plays a significant role in salmon growth physiology. The synergistic regulation of igf2 by insulin and Gh in salmon hepatocytes is similar to the regulation of hepatic Igf1 production in mammals.


Pushing the limits of catalytic C-H amination in polyoxygenated cyclobutanes.
A synthetic route to a new class of conformationally constrained iminosugars based on a 5-azaspiro[3.4]octane skeleton has been developed by way of Rh(ii)-catalyzed C(sp(3))-H amination. The pivotal stereocontrolled formation of the quaternary C-N bond by insertion into the C-H bonds of the cyclobutane ring was explored with a series of polyoxygenated substrates. In addition to anticipated regioselective issues induced by the high density of activated α-ethereal C-H bonds, this systematic study showed that cyclobutane C-H bonds were, in general, poorly reactive towards catalytic C-H amination. This was demonstrated inter alia by the unexpected formation of a oxathiazonane derivative, which constitutes a very rare example of the formation of a 9-membered ring by way of catalyzed C(sp(3))-H amination. A complete stereocontrol could be however achieved by activating the key insertion position as an allylic C-H bond in combination with reducing the electron density at the undesired C-H insertion sites by using electron-withdrawing protecting groups. Preliminary biological evaluations of the synthesized spiro-iminosugars were performed, which led to the identification of a new class of correctors of the defective F508del-CFTR gating involved in cystic fibrosis.


Dopamine D4 receptor exon III alleles and variation of novelty seeking in alcoholics.
A dysfunction of dopaminergic neurotansmission has been implicated in alcohol-seeking behavior. Recently, a significant association between the seven-repeat allele (DRD4*7R) of a 16 amino acid motif in the third exon of the dopamine D4 receptor gene (DRD4) and the personality trait of novelty seeking has been reported. Our population-based association study tested the hypothesis that the DRD4*7R variant predisposes to high levels of novelty seeking, which may underlie alcohol-seeking behavior. The genotypes of the expressed DRD4 exon III polymorphism were determined in 197 German controls and 252 German alcohol-dependent males, of whom 92 alcoholics completed the tridimensional personality questionnaire. We found no significant differences in the DRD4*7R frequencies between controls and alcoholics, including two subgroups (56 alcoholics with dissocial personality disorder according to ICD-10 and 89 alcoholics with severe withdrawal symptoms) with a high level of novelty seeking. The novelty-seeking scores did not differ significantly between alcoholics (including both subgroups) carrying long alleles with six or more repeats compared with those lacking long alleles. The present results do not provide evidence that the DRD4*7R allele contributes a common and relevant effect to alcohol-seeking behavior in our sample of alcoholics.


The time course of aneurysmal haemorrhage on computed tomograms.
We performed serial CT scans in a prospective series of 100 patients with a ruptured aneurysm who were first scanned within 2 days of the haemorrhage. In all patients the early CT scan showed evidence of extravasated blood. In 96 patients the source of bleeding was clearly at the base of the brain, and 32 of these had a haematoma. We estimated from the results of 139 repeat scans that the probability of recognizing an aneurysmal haemorrhage on CT is 85% after 5 days, 50% after 1 week, 30% after 2 weeks (mostly patients with haematomas), and almost nil after 3 weeks.


Anaplastic large-cell lymphoma: clinical and prognostic evaluation of 90 adult patients.
During the last few years, the application of CD30 monoclonal antibodies has led to the identification of a new lymphoma entity, termed anaplastic large cell lymphoma (ALCL). This tumor includes four distinct histologic subtypes, among which the Hodgkin's-like/Hodgkin's-related one (ALCL-HL) shares morphologic and phenotypic features with Hodgkin's disease (HD). From September 1988 to October 1993, 90 ALCL patients were treated with third-generation chemotherapy regimens (either vincristine, cyclophosphamide, fluorouracil, cytarabine, doxorubicin, methotrexate with leucovorin, and prednisone [F-MACHOP] or methotrexate with leucovorin, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin [MACOP-B]) during the course of an Italian multicentric randomized trial on high-grade non-Hodgkin's lymphomas (HG-NHL). In particular, 47 patients had ALCL of the common type (ALCL-CT) and 43 ALCL-HL. Null phenotype was the most common (39.8%), while T-cell, B-cell, and hybrid forms accounted for 35.5%, 22.2%, and 2.5%, respectively. Complete remission (CR) was achieved in 66 of 90 (73.5%) patients (33 of 47 [70%] with ALCL-CT and 33 of 43 [77%] with ALCL-HL). The majority of the patients in CR (56.5%) were alive and well at a median follow-up time of 38 months; no significant differences were observed between the two histologic groups, with the rate of complete responders being 49% and 65% in ALCL-CT and ALCL-HL, respectively. The probability of relapse-free survival (RFS), projected at 63 months, was 67% for ALCL-CT and 82% for ALCL-HL. The risk of lower CR and RFS rates was associated with the presence of bulky disease, advanced stage, and B symptoms. The data of the present study confirm that ALCL responds to third-generation chemotherapy regimens similarly to other aggressive malignant lymphomas in terms of both CR and RFS rates.


Time-related effects of enzymatic disaggregation on model human lung carcinomas.
Enzyme cocktails used to prepare tumor cell suspensions may influence yield, viability, and cytology, thus time-related cocktail effects on model human lung carcinomas were examined. A549, NCI-H125, and NCI-H460 carcinomas were completely disaggregated at 25 degrees C over 2 h with either (mg/ml) collagenase/DNAase (C/D, 1/0.1), collagenase/hyaluronidase/DNAse (C/H/D, 1/0, 1/0.1), or polymyxa protease/DNAse (PP/D, 3/0.1). Trypan blue viabilities, total yields, viable yields, and flow cytometric percent tumor cells (TC) were measured every 20-30 min (n = 4-7 per tumor type). The final percentages of TC, mononuclear cells (MN), polymorphonuclear cells (PMN), lymphocytes, and necrotic cells were determined by cytology (n = 4-5 per tumor type). The time-dependent measurements showed that 1) disaggregation was progressive and complete with all cocktails; 2) viability was stable or increasing with all cocktails; 3) percent TC was stable for all cocktails, but lower for PP/D than C/D in final suspensions; and 4) PP/D gave lower final total yields, higher final viabilities, but the same final viable yields as the C cocktails, suggesting selective elimination of dead cells by PP/D. Final cytology measurements showed that PP/D gave a lower percent MN and a higher percent PMN than C cocktails. Cocktail effects may importantly influence cell suspension properties.


Serotonergic signaling inhibits hyperalgesia induced by spinal cord damage.
Although dysesthesia is one of the most serious problems in patients with spinal cord injury, most of them being unresponsive to conventional treatments. In this study, we established a rat thoracic spinal cord mild-compression model that revealed thermal hyperalgesia in the hind limb. The thoracic spinal cord was compressed gently, using a 20 g weight for 20 min. The withdrawal latency of the thermal stimulation of the bilateral hind-limb was monitored using Hargreaves' Plantar test apparatus. In this model, thermal-hyperalgesia was observed for 1 week after the injury. The spinal cord injury-induced thermal-hyperalgesia was mimicked by the intrathecal application of metergoline, a non-selective 5-HT antagonist, 1-(2-methoxyphenyl)-4-[4-(2-phthalimido) butyl]-piperazine hydrobromide (NAN190), a selective 5-HT1 antagonist, and 3-tropanyl-3,5-dichlorobenzoate (MDL72222), a selective 5-HT3 antagonist. Intraperitoneal application of fluvoxamine maleate, a selective serotonin reuptake inhibitor, reduced the intensity of hyperalgesia induced by spinal cord injury. The inhibitory effect of fluvoxamine maleate on thermal hyperalgesia was prevented by the application of the aforementioned nonselective or selective 5-HT receptor antagonists. Intrathecal application of fluvoxamine maleate and selective 5-HT receptor agonists, i.e., 8-hydroxy-2-(di-n-proplyamino)-tetralin hydrobromide (8-OH-DPAT: 5HT-1 selective) and 2-methyl-5-hydroxytryptamine maleate (2-m-5-HT: 5HT-3 selective), inhibited the spinal cord injury-induced hyperalgesia. These results suggest that the change in the descending serotonergic signal plays an important role in hyperalgesia after the spinal cord injury, and that the application of selective serotonin reuptake inhibitors will be one of the candidates for new therapeutic methods against post-spinal cord injury dysesthesia.


Behavioural impairment in smoke environments.
When aircraft cabin occupants are exposed to fire effluent, the first hazard encountered is usually smoke, containing particulates and toxic gases, which cause immediate visual obscuration and painful irritation of the eyes and respiratory tract. This may be followed by incapacitation due to pain or asphyxia, if exposure continues. In smouldering or small, confined, in-flight fires, where the yields of organic irritants and acid gases are likely to be high and exposure times long, then the distressing effects of irritants, lung inflammation, and asphyxia induced by carbon monoxide (CO) are likely to be the main hazards. For post-crash fires, which tend to develop rapidly to flashover, the time available for escape is often limited to a few minutes before conditions become lethal due to the effects of toxic smoke and heat, so that survival depends upon a rapid egress. Visual obscuration and smoke irritancy are important during the early stages in that they may reduce the speed and efficiency of escape. People have been shown to be reluctant to enter smoke-logged areas if these are between them and an exit, and movement speeds are greatly reduced at optical densities above OD/m 0.5, and even more when the smoke is irritant. Once cabin lining and seating materials become heavily involved in the area opposite a cabin breach, then the concentrations of toxic gases, especially CO and hydrogen cyanide, can increase rapidly further down the cabin causing rapid incapacitation of any remaining cabin occupants. This is followed or accompanied by extreme heat, so that deaths result from asphyxia and/or heat shock. For in-flight fires, it is recommended that consideration should be given to reducing the hazard from irritants. For post-crash fires, measures aimed at delaying the involvement of cabin contents (such as spray mist systems) should be considered.


Quantitative DNA fingerprinting may distinguish new primary breast cancer from disease recurrence.
Approximately 10% of women with breast cancer develop a second breast tumor, either a new primary or a recurrence. Differentiating between these entities using standard clinical and pathologic criteria remains challenging. Ambiguous cases arise, and misclassifications may occur. We investigated whether quantitative DNA fingerprinting, based on allele imbalance (AI) or loss of heterozygosity (LOH), could evaluate clonality and distinguish second primary breast cancer from recurrence. We developed a scoring system based on the AI/LOH fingerprints of 20 independent breast tumors and generated a decision rule to classify any breast tumor pair as related or unrelated. We validated this approach on eight related tumors (cancers and synchronous positive lymph nodes). Finally, we analyzed paired tumors from 13 women (bilateral cancers, primary tumors and contralateral positive axillary lymph nodes, or two ipsilateral tumors). Each pair's genetic classification was compared with their clinical diagnosis and outcome. Each independent cancer had a unique fingerprint. Every tumor pair's relationship was quantifiable. Six of eight related tumor pairs were genetically classified correctly, two were indeterminate, and none were misclassified. Among the 13 women with two cancers, four of five clinically indeterminate pairs could be classified genetically. In three of 13 women, the pair's classification contradicted the clinical diagnosis. These women had bilateral cancers genetically classified as related and disease progression. This challenges the paradigm that bilateral cancers represent independent tumors. Overall, women with tumors genetically classified as related had poorer outcomes. Quantitative AI/LOH fingerprinting is a potentially valuable tool to improve diagnosis and optimize treatment for the growing number of second breast malignancies.


Homocysteine levels, haemostatic risk factors and patency rates after endovascular treatment of the common iliac arteries.
To investigate the impact of clinical risk factors, plasma homocysteine and haemostatic variables on the results after endovascular treatment of symptomatic atherosclerosis of the common iliac artery. Prospective observational study. University hospital. The study included 139 technically successful interventions in 103 patients. Technical success was defined as < or = 30% residual stenosis as seen on the post treatment angiogram. Blood samples for analyses of fasting plasma values of homocysteine, fibrinogen, D-dimer, activated protein C resistance were drawn upon admission. Median follow-up for all procedures was 22 months (range 0-55 months). Patency was defined as freedom from > or = 50% restenosis or reocclusion. The technical success rate for all procedures was 93%. The 1-year cumulative primary patency rate based on intention to treat was 85%. Multivariate analysis revealed a significant independent association between patency rates and levels of fibrinogen and homocysteine and the nature of the lesion treated (stenosis vs. occlusion). The aetiology of restenoses and reocclusions is probably multifactorial. Procoagulant activity, the nature of the lesion treated and homocysteine levels within and above the upper range of normal limits are important risk factors for failure after endovascular treatment of the common iliac arteries.


Elimination of aromatic surfactants from municipal wastewaters: comparison of conventional activated sludge treatment and membrane biological reactor.
Behaviour of anionic surfactants of linear alkylbenzene sulphonates (LAS) type and non-ionic surfactants of nonylphenol polyethoxylate (NPnEO) type was studied in the conventional mechanical/biological sewage treatment plant (STP) as well as using a membrane biological reactor (MBR). LAS and NPnEO were determined using high performance liquid chromatography (HPLC) equipped with spectrofluorimetric detection. Liquid chromatography/tandem mass spectrometry (LC/MS/MS) was used for identification and quantification of stable metabolites, including nonylphenol (NP), nonylphenol monoethoxylate (NP1EO), nonylphenol diethoxylate (NP2EO) and nonylphenoxy carboxylic acids (NPnEC). The study showed that aromatic surfactants belong to the most prominent constituents in the examined municipal wastewaters with typical LAS and NPnEO concentrations of 2-10 mg/L and 0.1-0.5 mg/L, respectively. The removal of aromatic surfactants in conventional STP showed well-known features reported in the literature, including an efficient microbial transformation of the parent molecules and formation of stable metabolic products. The elimination efficiency of aromatic surfactants using the MBR unit was higher than that in the conventional STP, while the composition of recalcitrant nonylphenolic residues in the effluent seems to be ecotoxicologically more favourable due to the lower contributions of the lipophilic metabolites.


[Bilateral genuine cholesteatoma--a case report].
We report on a patient who has been in otorhinolaryngological treatment for more than 24 years owing to recurrent infra-auricular fistulation. Early hospital admissions were due to suspected abscess-forming parotitis or lymphadenitis. As far as could be discerned, no sonographical or radiological diagnostics were conducted. Complications in the sense of meningitis or labyrinthitis were not reported. In the case of the aforementioned patient a bilateral anomaly in the area of the external auditory canal went hand in hand with the development of a bilateral genuine cholesteatoma. The auriculae were configurated normally. Corrective radical surgery was conducted on both sides, first the left, then the right side. What seems remarkable in this context is the fact that despite a over two decades old cholesteatoma there was no erosion of the osseous boundaries of the eardrum towards the labyrinth and cochlea and the osseous cover of the canalis facialis. The patient was diagnosed with a high degree loss of hearing. It was not possible to derive reproductive acoustic potentials intraoperatively, which pointed to deafness. Whether this deafness was congenital or developed in the course of time based on a growing sensory hearing loss could not be ascertained.


Estimation of the state of saturation of brushite and calcium oxalate in urine: a comparison of three methods.
The estimation of the degree of saturation of brushite and of calcium oxalate in urine of patients with disorders of calcium metabolism has been proved to be an effective tool in evaluating the patient's propensity to form renal stones. The methods used in three different laboratories have been compared and evaluated in 27 urine samples. Relative saturation ratio (ratio of activity product and thermodynamic solubility product of brushite) and activity product ratio (ratio of activity product of original sample and that obtained after incubation of sample with synthetic brushite) were determined. Similar studies were performed for calcium oxalate. The values for relative saturation ratio of brushite or calcium oxalate differed widely among the three techniques. However, nearly identical values for activity product ratio of brushite were obtained. The activity product ratios of calcium oxalate, obtained by different techniques, closely approximated each other except in sampels containing excessive amounts of calcium (greater than 5 mM) or oxalate (greater than 5 mM). The values for the relative saturation ratios for both brushite and calcium oxalate were usually higher than the corresponding values for activity product ratio. The results indicate that the use of activity product ratio provides a more simple and reliable estimate of the urinary state of saturation than does the relative saturation ratio.


Platelet proteomics.
Platelets are small cell fragments, produced by megakaryocytes, in the bone marrow. They play an important role in hemostasis and diverse thrombotic disorders. They are therefore primary targets of antithrombotic therapies. They are implicated in several pathophysiological pathways, such as inflammation or wound repair. In blood circulation, platelets are activated by several pathways including subendothelial matrix and thrombin, triggering the formation of the platelet plug. Studying their proteome is a powerful approach to understand their biology and function. However, particular attention must be paid to different experimental parameters, such as platelet quality and purity. Several technologies are involved during the platelet proteome processing, yielding information on protein identification, characterization, localization, and quantification. Recent technical improvements in proteomics combined with inter-disciplinary strategies, such as metabolomic, transcriptomics, and bioinformatics, will help to understand platelets biological mechanisms. Therefore, a comprehensive analysis of the platelet proteome under different environmental conditions may contribute to elucidate complex processes relevant to platelet function regarding bleeding disorders or platelet hyperreactivity and identify new targets for antiplatelet therapy.


Energy efficient COD and N-removal from high-strength wastewater by a passively aerated GAO dominated biofilm.
Conventional aerobic treatment of high-strength wastewater is not economical due to excessively high energy requirement for compressed air supply. The use of passive aeration avoids the use of compressed air and enables energy efficient oxygen supply directly from the air. This study evaluates a passively aerated simultaneous nitrification and denitrification performing biofilm to treat concentrated wastewater. The biofilm reactor was operated > 5-months under alternating anaerobic/aerobic conditions. For 4-times concentrated wastewater, > 80% COD (2307 mg L-1 h-1) and > 60% N (60 mg L-1 h-1) was removed at a hydraulic retention time (HRT) of 7 h. A double application in the same reactor enabled > 95% COD and 85% N-removal, at an overall HRT of 14 h which is substantially shorter than what traditional activated sludge-based systems would require for the treatment of such concentrated feeds. Microbial community analysis showed Candidatus competibacter (27%) and nitrifying bacteria (Nitrosomonas, and Nitrospira) as key microbes involved in COD and N-removal, respectively.


[Molecular Biology for Surgical Treatment of Lung Cancer].
Progress in lung cancer research achieved during the last 10 years was summarized. These include identification of novel driver mutations and application of targeted therapies, resistance mechanisms to targeted therapies, and immunotherapy with immune checkpoint inhibitors. Molecular biology also affects the field of surgical treatment. Several molecular markers have been reported to predict benign/ malignant or stable/growing tumors, although far from clinical application. In perioperative period, there is a possibility of atrial natriuretic peptide to prevent cancer metastasis. As adjuvant settings, although biomarker-based cytotoxic therapies failed to show clinical efficacy, several trials are ongoing employing molecular targeted agents (EGFR-TKI or ALK-TKI) or immune checkpoint inhibitors. In clinical practice, mutational information is sometimes used to distinguish 2nd primary tumors from pulmonary metastases of previous cancers. Surgery also has important role for oligo-progressive disease during molecular targeted therapies.


Uncommon, exceptional and atypical: a case of frontal lobe epilepsy due to cortical dysplasia.
We report a case of frontal lobe epilepsy due to focal cortical dysplasia that included three independent unusual features. The patient, a 45-year-old, right-handed woman, had her first seizure at age 29, well into adulthood. Seizures had been easily controlled with medication for 15 years, then without provocation they became medically intractable during a single, identifiable day. Resection of the dysplastic tissue in the posterior dorsolateral right frontal cortex rendered the patient seizure-free, but produced a significant, non-fluent, Broca type, crossed aphasia. In addition, the seizure semiology was striking and remarkable, a common finding in frontal lobe epilepsy. [Published with video sequences].


Effect of Isabgol husk supplementation on trace minerals (Zn, Cu, Mn) levels in adolescent girls.
The study was conducted on eleven healthy non-anaemic adolescent girls of 16 to 18 years of age. Balance studies were conducted in two trials of three weeks each on low and high fibre diets. High fibre diet contained 25 g Isabgol husk in addition to low fibre diet. The mean diet and nutrient intakes of the subjects were approximately the same during both trials. Addition of Isabgol husk to low fibre diet significantly (P less than or equal to 0.05) increased faecal excretion of zinc, copper and manganese and lowered their apparent retention. The serum levels of these trace minerals decreased significantly (P less than or equal to 0.05). Thus the high level of Isabgol has undesirable effect on trace minerals.


Molecular androgen memory in sex development.
Sex specific development in the human comprises irreversible sexual differentiation of the external genitalia during embryogenesis, sexual maturation of secondary sex characteristics during puberty (e.g., sex specific body proportions, pubertal voice change) and eventually sex specific development of extragenital tissues and organs, including the brain. The presence or absence of androgens acting via the androgen receptor plays a key role therein. At the single cell level, androgens cause reversible short term changes of gene transcription by activating the androgen receptor. From a developmental perspective, this often leads to irreversible long-term changes of anatomy (e.g., sex-specific differentiation of the external genitalia) and function (e.g., sex-specific play behavior in children). These observations are discussed in the context of recent genome-wide gene expression studies and first published experimental data at the epigenome level. In essence, there is evidence for a molecular androgen memory at both the transcriptome and the epigenome level.


TAVR for Failed Surgical Aortic Bioprostheses Using a Self-Expanding Device: 1-Year Results From the Prospective VIVA Postmarket Study.
The VIVA (Valve in Valve) trial was designed to systematically and prospectively collect data regarding the use of transcatheter aortic valve replacement in patients with failing surgical aortic bioprostheses at high-risk for reoperation. Surgical aortic valve replacement has been the standard of care in symptomatic patients with aortic valve disease. However, bioprosthetic valves degenerate over time, requiring redo surgery. VIVA is an international, observational, single-arm, postmarket study conducted at 23 sites that enrolled 202 patients with symptomatic degeneration of an aortic bioprosthesis eligible for elective treatment with a CoreValve or Evolut R self-expanding transcatheter aortic valve. Patients were elderly (mean age 79.9 years), 47.5% were men, and they had a mean Society of Thoracic Surgeons score of 6.6%. Although 41.8% of patients had surgical bioprostheses with labeled size ≤21 mm, valve hemodynamic parameters were markedly improved from baseline (mean aortic valve gradient 35.0 ± 16.3 mm Hg) to discharge (17.5 ± 8.6 mm Hg) and were sustained at 1 year (15.5 ± 7.5 mm Hg). At 1 year, total aortic regurgitation greater than mild was measured in 1.1% of patients. Clinical outcomes at 30 days demonstrated low mortality (2.5%), no disabling strokes, a 0.5% rate of acute kidney injury, and an 8.0% rate of new pacemaker implantation. At 1 year, the mortality rate remained low (8.8%), with 1 disabling stroke (0.6%). Five patients (2.5%) experienced coronary artery obstructions, 3 during and 1 immediately after the procedure and 1 several months later. Degenerated surgical bioprostheses can be safely treated with the CoreValve or Evolut R platform using the catheter-based valve-in-valve procedure. Excellent 1-year clinical and hemodynamic outcomes were achieved in this real-world patient population. (CoreValve VIVA Study Evaluation of the Clinical Outcomes of CoreValve in Degenerative Surgical Aortic Bioprosthesis; NCT02209298).


One- and 2-day mifepristone-misoprostol intervals are both effective in medical termination of second-trimester pregnancy.
Termination of pregnancy because of fetal anomaly requires the utmost clinical sensitivity and individualized patient care. This study compared the efficacy of a 1-day mifepristone and misoprostol interval in medical termination of second-trimester pregnancy performed because of fetal anomaly with that of the standard 2-day interval among the first 100 women in each group. A 200 mg dose of mifepristone was used; 0.4 mg of misoprostol was administered vaginally at 3-h intervals until abortion occurred. When calculated from ingestion of mifepristone, the time to abortion was 28 h 25 min (28:25 h) [23:10-50:40 h; median (range)] and 52:43 h (45:55-83:15 h) (P < 0.0001) in the 1- and 2-day mifepristone-misoprostol groups respectively. However, following initiation of misoprostol administration, the time to abortion [7:25 h (1:00-23:15 h)] was longer (P < 0.05) in the 1-day interval group than in the 2-day interval group [6:20 h (0:45-36:30 h)]; by 12 h, 82 and 87% (n.s.) respectively of the subjects had aborted. The proportions of cases undergoing surgical evacuation of the uterus were 64 and 45% (P < 0.001), in the 1- and 2-day interval groups respectively. Thus both 1- and 2-day mifepristone-misoprostol intervals are valuable in termination of second-trimester pregnancy.


Effect of topically administered epinephrine, norepinephrine, and acetylcholine on cerebrocortical circulation and the NAD/NADH redox state.
We investigated the effects of topically administered catecholamines and acetylcholine (ACh) on the cerebrocortical microcirculation and NAD/NADH redox state in chloralose-anesthetized cats. NADH fluorescence of the brain cortex and the volume of small intracortical vessels were measured by fluororeflectometry, and in most of the experiments the pial vessels were photographed simultaneously through a cranial window. Cerebrocortical vascular volume (CVV) and the diameter of the pial vessels were decreased, and NADH was oxidized by concentrations of epinephrine and norepinephrine as low as 3 x 10(-8) M. Pial veins constricted approximately twice as much as pial arteries. ACh dilatated pial arteries, slightly constricted pial veins, and increased CVV, but had no effect on the NAD/NADH redox state. Since pial and intracortical vessels were constricted markedly by catecholamines, and since these vascular reactions appeared at a lower concentration than is presumed to occur in the synaptic cleft, our results support the regulating role of these substances in cerebral circulation. NADH oxidation, obtained with catecholamines, was interpreted to be due to enhanced tissue respiration. The finding that ACh dilatated pial arteries and increased CVV, but failed to influence the NAD/NADH redox state, might indicate that the brain cortices of normal animals are bioenergetically nonhypoxic. If cortical microregions where the oxygen tension is close to zero were biochemically hypoxic, NADH oxidation should have occurred during ACh administration.


[Role of lymphokines in immune response in respiratory viral infections].
The present review deals with the analysis of lymphokine response in two main respiratory viral infections: influenza and respiratory syncytial (RS) infection. Immune response in these two diseases has great phenomenological differences. In particular, in RS infection the intensive response of macrophages and epithelial cells, accompanied mainly by the synthesis and secretion of tumor necrosis factor and interleukin 8, is observed. Due to this fact no protective immunity is formed in RS infection, in contrast to influenza. The specific features of immune and lymphokine response in RS infection make it difficult to develop protective vaccines. At the same time it is with RS infection that the development of chronic bronchopulmonary diseases is linked. The analysis of the role of lymphokine response in respiratory viral infections, particularly in influenza and RS infections, confirms the necessity of revising therapy both in the acute and subacute stages of these diseases.


Lobular cancerization: incidence and differential diagnosis with lobular carcinoma in situ of breast.
A series of 120 breast biopsies and mastectomy specimens originally diagnosed as carcinoma was reviewed in order to emphasize the differences between lobular carcinoma in situ and cancerization of lobules. Criteria for differential diagnosis between the two types of lobular lesion are proposed. In the reviewed material 15 (12.5%) cases of lobular carcinoma in situ and 64 (53.3%) of lobular cancerization were found. The carcinoma in situ usually co-existed with other types of breast carcinoma, such as intraductal carcinoma, cancerization and invasive carcinoma of different types.


Impaired function of GABA(B) receptors in tissues from pharmacoresistant epilepsy patients.
Effects of pre- and postsynaptic γ-aminobutyric acid B (GABA(B)) receptor activation were characterized in human tissue from epilepsy surgery. Slices of human cortical tissue were investigated in a submerged-type chamber with intracellular recordings in layers II/III. Parallel experiments were performed in rat neocortical slices with identical methods. Synaptic responses were elicited with single or paired stimulations of incrementing intervals. Neurons in human epileptogenic tissue exhibited usually small inhibitory postsynaptic potentials (IPSP) mediated by GABA(B) receptor, verified by the sensitivity to the selective antagonist CGP 55845A. The IPSP(B) conductance averaged 5.8 nS in neurons from epileptogenic tissues and 15.9 nS in neurons from nonepileptogenic tissues (p < 0.0001). Application of baclofen caused small conductance increases in human neurons, which were linearly related to IPSP(B) conductances. Paired-pulse stimulation revealed constant synaptic responses in human temporal lobe epilepsy (TLE) slices at all interstimulus intervals (ISIs). Pharmacologically isolated IPSP(A) in the human tissue exhibited a small paired-pulse depression (average 10% at 500 ms ISI). Bicuculline-induced paroxysmal depolarization shifts (PDSs) were transiently depressed by 24% in human TLE tissue; and by 74% in rat neocortical slices (200 ms ISI; p = 0.015). The depressions of bicuculline-induced PDSs were antagonized by CGP 55845A in both species. Staining for GABA(B) receptors revealed significantly smaller numbers of immunopositive dots in human epileptogenic neurons versus human control neurons. The small IPSP(B), baclofen-conductances, and paired-pulse depression of PDSs and IPSPs in human TLE tissue indicate a reduced density of post- and presynaptic GABA(B) receptors. The reduced efficacy of presynaptic GABA(B) receptors facilitates the occurrence of repetitive synaptic activity.


Attributes of mentors as perceived by orthopaedic nurses.
Mentoring in nursing is a concept that merits close scrutiny in today's chaotic health care environment. Mentors can shape a positive environment for nurses to nurture career development, satisfaction and leadership. One of the issues of mentoring is that there is no agreement as to the role and functions of a mentor. Most of the controversy deals with the similarities and differences between mentors and preceptors. The purposes of this study were to identify attributes of mentors as perceived by orthopaedic nurses and to identify who orthopaedic nurses feel are the most appropriate persons to serve as mentors. This may enable nursing leaders to develop specific programs and strategies to increase job satisfaction and nurse retention among orthopaedic nurses.


Evaluation of muscle strength and manual dexterity in patients with Charcot-Marie-Tooth disease.
Matched pair study. Differences in hand-muscle strength/dexterity between dominant (DH) and non-dominant (NDH) hand in Charcot-Marie-Tooth disease (CMT) are not well understood. To compare muscle strength/dexterity between DH and NDH and to correlate manual dexterity, strength and sensory function. Thirty CMT patients were studied using functional muscle testing (FMT) and strength (dynamometry), dexterity (the Nine Hole Peg Test [NHPT]), and Jebsen-Taylor Hand Function [JTT]), and sensory function (the Nottingham Sensory Assessment [NSA]). Scores were worse for DH than NDH on FMT (p = 0.043) and NHPT (p = 0.014) but not on JTT (p = 0.098), handgrip strength (p = 0.710) or tripod pinch (p = 0.645). NSA did not correlate significantly with any tests (p's0.05). In CMT disease, DH appears more impaired than NDH in terms of function and dexterity. Greater muscle weakness in DH may also emerge as CMT progresses. 3b.


Aripiprazole is effective for treatment of delayed sleep phase syndrome.
Delayed sleep phase syndrome (DSPS) comprises a persistent or recurrent pattern of sleep disturbances, sleep disruption that leads to insomnia and/or excessive daytime sleepiness, and impaired functioning in social, occupational, or other spheres. Aripiprazole (APZ), a second-generation antipsychotic, manifests a novel mechanism of action by serving as a partial agonist of both D2 and serotonergic 5-HT1A receptors and antagonist of 5-HT2A receptors. We have used APZ to treat DSPS. One reason it was effective may be that the insomnia induced by daytime APZ was effective in treating the patient's daytime sleepiness. Another reason may be APZ increases histamine release which controls sleep-wake cycles. Thus, APZ may be therapeutic for DSPS.


Treatment of postoperative nausea and vomiting after outpatient surgery with the 5-HT3 antagonist ondansetron.
Postoperative nausea and vomiting following outpatient surgery can significantly delay discharge. This study evaluates the safety and efficacy of ondansetron (a new 5-HT3 antagonist) in the treatment of postoperative nausea and vomiting in patients following outpatient surgery. Five hundred outpatient surgical patients (53 male and 447 female), receiving general endotracheal anesthesia, were studied at ten centers. Patients were stratified by gender and received, in a randomized, double-blind manner, 1, 4, or 8 mg ondansetron or placebo in response to nausea and/or vomiting postoperatively. Episodes of vomiting, nausea scores, adverse events, vital signs, and laboratory values were evaluated before and during the 24 h after study drug administration. Complete response to study medication (no vomiting and/or retching, and no rescue antiemetic over the initial 0-2-h period) was more frequent in the ondansetron groups (1 mg 57%, 4 mg 61%, and 8 mg 57%) than in the placebo group (30%, P < .001). For the 0-24-h study a complete response occurred in only 15% of the placebo group compared to 41%, 47%, and 47% of the 1-, 4-, and 8-mg ondansetron groups, respectively (P < .001 for all comparisons with placebo). Median nausea scores (range 0-10) during the initial observation period (0-2 h) were significantly lower for all doses of ondansetron (1.3, 0.8, 1.8 for 1, 4, and 8 mg, respectively) as compared with placebo (2.3). No significant differences occurred in hemodynamic stability, incidence of adverse events, or changes in laboratory values in the ondansetron groups compared to the placebo group. Ondansetron, in doses less than 8 mg, is a safe, effective antiemetic for treating postoperative nausea and vomiting.


Template-directed oligonucleotide ligation on hydroxylapatite.
Bernal, and subsequently other authors, have suggested that the prebiotic synthesis of the precursors of biopolymers could have occurred on a solid surface such as that provided by clay or some other mineral. The separation of products from the other components of the reaction mixture in such a system is reminiscent of modern solid-phase synthesis of polypeptides and polynucleotides. One such scheme envisages that growing polymers were localized by adsorption to a mineral surface where an activating agent or activated monomers were supplied continuously or cyclically. We have been trying to test this scheme using reactions which we believe may be related to those that occurred during prebiotic evolution. We have already reported that oligonucleotides adsorbed onto hydroxylapatite provide suitable templates for the oligomerization of (guanosine 5'-phosphor)-2-methylimidazolide (2-MeImpG). However, this is not a suitable test reaction, as 2-MeImpG oligomerization proceeds almost to completion in a single step. Here we report that a sequence of reactions in which initially formed oligo(G)s are reactivated by conversion to phosphorimidazolides in the presence of poly(C) and then allowed to ligate is ideal, in that repeated cycles can be carried out on the surface of hydroxylapatite, whereas in the liquid phase the cycle could be achieved only with considerable difficulty.


Intravenously administered pamidronate for treating refractory Paget's disease of bone.
To report our experience with the use of intravenously administered pamidronate in 16 patients with refractory Paget's disease of bone. We describe our treatment regimen and outline serum alkaline phosphatase levels at baseline and after pamidronate therapy in our study cohort. In addition, we summarize clinical symptoms and response to treatment. Although clinical experience with pamidronate in the treatment of Paget's disease of bone has been limited in the United States, elsewhere it has been shown to be an effective agent that inhibits the increased osteoclastic activity characteristic of this disease. Accordingly, in 16 patients with Paget's disease unresponsive to various other therapies, we administered pamidronate intravenously at a dose of 30 mg in 500 mL of 5% dextrose in water during a 4-hour period once weekly for 6 weeks. Serum alkaline phosphatase was determined at baseline and at regular intervals for at least 12 months after the onset of therapy. Many of these patients reported relief of pain and an increased flexibility or range of motion after treatment. The only adverse effect reported by these patients was an acute-phase reaction during the first infusion in two patients. In all patients, serum alkaline phosphatase levels declined, and significant (P = 0.0012) decreases from baseline were noted within 6 weeks after the initial infusion. Maximal responses were generally seen within 6 months after treatment, serum alkaline phosphatase levels decreasing as much as 91% from baseline. These data suggest that intravenous pamidronate therapy is an effective alternative to calcitonin and etidronate in the treatment of Paget's disease of bone, particularly in those patients refractory to such agents.


Label-free biochemical detection coupled on-line to liquid chromatography
The on-line coupling of a label-free optical biosensor to a HPLC system is described by combining the separation power of HPLC with the specificity of the biosensor system. A highly cross-reactive antibody against the pesticide isoproturon was used as model for affinity proteins. The binding strength of the antibody to the utilized pesticides was characterized with the biosensor, first. In the on-line coupling setup, the eluate of the HPLC was mixed continuously with the antibodies. The presence of antigens was detected by a reduction of the antibody binding to the transducer. This reduced binding was quantified by a differentiation of the sensor signal by applying a Savitzky-Golay algorithm. Limits of detection were found to be in the femtomole range without preconcentration, which is comparable to a study using fluorescence-based biochemical detection.


The Relationship Between Hypermobile Ehlers-Danlos Syndrome (hEDS), Postural Orthostatic Tachycardia Syndrome (POTS), and Mast Cell Activation Syndrome (MCAS).
In recent years, an association between hypermobile Ehlers-Danlos syndrome (hEDS), mast cell activation syndrome (MCAS), and postural orthostatic tachycardia syndrome (POTS) has garnered attention and patients are increasingly presenting with this triad. However, a real relationship between these entities is unclear due to a lack of scientific validity. We conducted an extensive review of the literature using two different search strategies. A narrower strategy included 88 searches of various combinations of terms for each of the three conditions, yielding 19 unique papers. A broader search included 136 searches of various combinations of terms but included all forms of EDS and yielded 40 unique papers. Of these, only four and nine papers from the narrower and broader search strategies were original research articles. None of these papers resulted from a combination of the search terms for the three conditions. All three clinical entities are controversial in either existence or pathogenesis. MCAS is a poorly defined clinical entity, and many studies do not adhere to the proposed criteria when establishing the diagnosis. Patients previously diagnosed with EDS hypermobility type may not meet the new, stricter criteria for hEDS but may for a less severe hypermobility spectrum disorder (HSD). The pathophysiology of POTS is still unclear. An evidence-based, common pathophysiologic mechanism between any of the two, much less all three conditions, has yet to be described. Our review of the literature shows that current evidence is lacking on the existence of MCAS or hEDS as separate or significant clinical entities. Studies proposing a relationship between the three clinical entities are either biased or based on outdated criteria. The reason behind the purported association of these entities stems from an overlapping pool of vague, subjective symptoms, which is inadequate evidence to conclude that any such relationship exists.