The concepts of disease.
Concepts of disease have often been influenced by mediaeval scholastic doctrines. Today these are best replaced by the premises of modern class logic. One of the basic problems then concerns the universal class of patients. Its solution depends on the answer to the question: What are the distinguishing attributes of this class? Scadding stipulated that these attributes must differ from the norm of a species and be associated with biological disadvantage. This paper argues that these attributes must be abnormal by the standards of a population and/or the norms of an individual, and must be associated with at least one of three criteria: (a) therapeutic concern for himself experienced by a person, (b) such concern for him experienced by his social environment, and (c) medical concern for him. This solution, though based on subjective criteria, seems to tally with the actual practice in diagnosing disease.


Plasma coenzyme Q10 reference intervals, but not redox status, are affected by gender and race in self-reported healthy adults.
Abnormal concentrations of coenzyme Q(10) have been reported in many patient groups, including certain cardiovascular, neurological, hematological, neoplastic, renal, and metabolic diseases. However, controls in these studies are often limited in number, poorly screened, and inadequately evaluated statistically. The purpose of this study is to determine the reference intervals of plasma concentrations of ubiquinone-10, ubiquinol-10, and total coenzyme Q(10) for self-reported healthy adults. Adults (n=148), who were participants in the Princeton Prevalence Follow-up Study, were identified as healthy by questionnaire. Lipid profiles, ubiquinone-10, ubiquinol-10, and total coenzyme Q(10) concentrations were measured in plasma. The method used to determine the reference intervals is a procedure incorporating outlier detection followed by robust point estimates of the appropriate quantiles. Significant differences between males and females were present for ubiquinol-10 and total coenzyme Q(10). Blacks had significantly higher Q(10) measures than whites in all cases except for the ubiquinol-10/total Q(10) fraction. The fraction of ubiquinol-10/total coenzyme Q(10) is a tightly regulated measure in self-reported healthy adults, and is independent of sex and racial differences. Different reference intervals for certain coenzyme Q(10) measures may need to be established based upon sex and racial characteristics.


[Intraventricular obstructions in dobutamine stress echocardiography: determinants of their development and clinical sequelae].
Dobutamine stress echocardiography (DSE) leads to strong hypercontraction, tachycardia, and peripheral vasodilatation. In previous studies systolic obstruction of the left ventricular outflow tract (LVOT) was observed as a result of these factors. To evaluate left ventricular function and morphology in patients (pts) with induced systolic LVOT obstruction, we used continuous wave (CW) doppler registrations in combination with quantitative 2-D-echocardiography in 100 pts during routinely performed DSE (5-40 micrograms/kg/min). In addition left ventricular wall thickness was measured. Symptoms were registered using a standardised questionnaire and cardiac arrhythmias were counted over a two minute interval at rest and during the maximal heart rate of each patient. During DSE dynamic flow acceleration with late systolic peak velocity above 2 m/second (s) was considered to represent LVOT obstruction in pts with normal flow profiles in the LVOT before infusion of dobutamine. For invasive studies pts were investigated with femoral catheterisation by the method of Judkins. A greater than 50% stenosis was judged to be significant. Examinations in 73 pts provided data of sufficient quality for echocardiographic and Doppler sonographic evaluations. 39 pts, 26 men, 13 women, mean age 64 +/- 8 years, developed late systolic flow velocities above 2 m/s and therefore formed the obstructive group (grp A). Grp B consisted of 34 pts, 26 men and 8 women, mean age 66 +/- 10 years, who showed normal time velocity integrals during DSE. In 41 pts invasive data provided information concerning the existence and severity of coronary artery disease. There were no significant differences in the increase of heart rate, the product of maximal systolic blood pressure and maximal heart rate or the percentage of pts, who reached their age corrected submaximal heart rate during DSE. Obstructive pts (group A) showed late systolic dynamic acceleration of systolic flow with a mean maximal speed of 315.4 +/- 139.8 cm/s, which peaked 0.12 +/- 0.04 s after the R-wave. From the velocities we calculated a mean pressure gradient of 47.5 +/- 39.7 mm Hg using the modified Bernoulli equation. Group B patients showed lower and earlier maximal speeds with a mean value of 158.2 +/- 37.6 cm/s, 0.09 +/- 0.04 s after the R-wave, corresponding to a pressure gradient of 10.6 +/- 4.9 mm Hg (p < 0.001). Ejection fractions were higher (p < 0.001) before the test in grp A: 68.2 +/- 8% compared to 55.7 +/- 10.4% in B. This difference increased during peak stress: 74.1 +/- 7.7% compared to 59.5 +/- 12.8%. End diastolic (EDVI) and end systolic volume indexes (ESVI) were lower in grp A (p < 0.001). During DSE, the decrease in ESVI was somewhat stronger for pts in grp A. Left ventricular hypertrophy was more often seen with obstruction. Septal thickness was increased in A: 1.45 +/- 0.34 cm compared to 1.13 +/- 0.27 cm in B (p < 0.001). Left ventricular posterior wall measured 1.03 +/- 0.28 cm in A and 0.83 +/- 0.23 cm in B (p < 0.01). 27 pts in grp B and only 9 in grp A had a history of previous myocardial infarction. Showing no difference at rest, wall motion score indexes raised under DSE in both groups and developed significantly higher scores in grp B at peak stress: 1.30 (1.0-1.90) compared to 1.18 (1.0-1.75) in A. We observed typical chest pain more often in grp B. Unspecific symptoms and arrhythmogenic complications were not statistically different, with the exception of ventricular bigeminy which was more often observed in grp B. A decline in the diastolic blood pressure was observed in pts with very severe obstruction (> 3.5 m/s, p < 0.05). Sensitivity of DSE was 84%, specificity 79%. No significant differences between pts with and without obstruction were observed. Intraventricular obstructions during DSE are often observed in pts with normal systolic function at rest and during peak stress, especially in the case of left ventricular hypertrophy. (ABSTRACT TRU


The neural basis of semantic memory: evidence from semantic dementia.
Semantic dementia (SD) is a syndrome of progressive impairment in semantic memory. Fifty-eight brain regions were measured in seven post mortem SD cases, ten normal controls and two disease controls (diagnosis frontotemporal dementia and motor neuron disease, FTD-MND). Manual segmentation of the whole brain has not previously been undertaken in a series of SD cases, either post mortem or during life. Widespread volume loss relative to controls was found in SD, with anterior temporal lobe regions bearing the brunt (>60% atrophy of temporopolar and perirhinal cortices bilaterally). Comparison of regional volumes in SD and FTD-MND found greater atrophy in SD only in temporopolar and perirhinal volumes. The sole region showing atrophy relative to controls in FTD-MND but not SD was motor cortex. Posterior temporal and frontal regions were not consistently affected and no significant asymmetry of atrophy was found. In summary, whole-brain regional evaluation in SD, in comparison with normal controls and FTD-MND, found anterior temporal atrophy encompassing the perirhinal cortex with relative sparing of adjacent posterior temporal regions.


Polarization changing and beam profile deformation of light during the isotropic Raman-nath acousto-optic interaction.
A spatial Fourier transform approach is used to study the phenomena of polarization changing and beam profile deformation of light during the Raman-Nath, acousto-optic interaction in isotropic media. Starting from the vector version of the well-known Raman-Nath interaction equation and using a spatial Fourier transform allows analytic solutions that encompass the effects of polarization changing and beam-profile deformation for the multiple scattered light to be found in the spatial-frequency domain. Two kinds of sound wave, longitudinal and shear, are assumed to be interacted with the light, whose transverse spatial profile and state of polarization are arbitrary. It is shown that, for light with an arbitrary spatial profile after interaction with the sound wave in the Raman-Nath regime, the spatial profiles of the scattered light are almost the same shape as those of the input light. For the polarization changing part, it is found that the state of polarization and the direction of rotation can alter, depending not only on the sound amplitude but also on the propagation mode of the sound wave. Simulation results are provided to confirm the validity of this approach.


Antioxidative action of royal jelly in the yeast cell.
Royal jelly is a bee product, secreted from the hypopharingeal and mandibular glands of worker bees. There are many reports on pharmacological activities of royal jelly in experimental animals, but there are few about its antioxidative properties connected to aging. The aim of the work was to investigate the antioxidative action of royal jelly in the cell of the yeast Saccharomyces cerevisiae as a model organism. Yeast was cultivated in YEPD medium enriched with different concentrations of royal jelly like 1, 2 and 5 g/L. Yeast growth was monitored by measuring optical density. At different time points cell energy metabolic activity was measured using the cell energy metabolism indicator resazurin, and 2',7'-dichlorofluorescein was applied to estimate intracellular oxidation. Additionally, protein profile of cell extract was analyzed by 2-D electrophoresis. Results showed that royal jelly decreased intracellular oxidation in a dose dependent manner. Additionally it affected growth and cell energy metabolic activity in a growth phase dependent manner. Protein profile analysis showed that royal jelly in the cell does not act only as a scavenger of reactive oxygen species, but it also affects protein expression. Differentially expressed proteins were identified.


Frontal cortical dysfunction in Parkinson's disease (PD): Comparison of memory-based smooth-pursuit and anti-saccade tasks, and neuropsychological and motor symptom evaluations.
We reported recently that during a memory-based smooth-pursuit task, most Parkinson's disease (PD) patients exhibited normal cue-information memory but impaired smooth-pursuit preparation and execution. A minority of PD patients had abnormal cue-information memory or difficulty in understanding the task. To further examine differences between these two groups, we assigned an anti-saccade task and compared correct rates with various neuropsychological and motor symptom evaluations. The anti-saccade task requires voluntary saccades in the opposite direction to a visual stimulus, and patients with frontal cortical impairments are known to exhibit reflexive saccades (errors). We classified PD patients into 2 groups: one with normal cue-information memory during memory-based smooth-pursuit (n = 14), and the other with abnormal cue-information memory or with difficulty in understanding the memory task (n = 6). The two groups had significantly different anti-saccade correct rates and frontal assessment battery (FAB) scores (P < 0.01). Anti-saccade correct rates of individual patients (n = 20) correlated significantly with FAB scores (P < 0.01) but not with age, Hoehn-Yahr stage, unified PD rating scale (UPDRS) part III or mini-mental state examination (MMSE) scores. Among FAB subtests, significant correlation was obtained only with motor programming scores. These results suggest that performance of memory-based smooth-pursuit and/or anti-saccades depend on frontal cortical function or dysfunction.


Mortality studies in psoriatic arthritis: results from a single outpatient center. II. Prognostic indicators for death.
To investigate prognostic factors associated with mortality in patients with psoriatic arthritis (PsA). Patients followed up at the Toronto PsA Clinic between 1978 and 1994 were included. Patients were reviewed at initial clinic entry and at 6-month intervals using a standard protocol. Data on deaths were collected in a prospective manner, and death certificates were used to identify the primary and antecedent cause(s) of death. All death information was recorded in the clinic's computerized database. Only factors that represented standard clinical measures of disease activity and progression were studied. The relationship between potential prognostic factors recorded at the time of the first clinic visit and the mortality rate was determined using the Cox relative risk regression model. There were 428 patients (234 men and 194 women), of whom 68% were known to be alive on September 1, 1994, 20% were lost to followup but assumed to be alive, and 12% had died. Multivariate analysis revealed that an erythrocyte sedimentation rate (ESR) > 15 mm/hour, medications used prior to initial clinic visit, radiologic damage, and the absence of nail lesions were associated with an increased overall mortality rate. There is some suggestion that prior medication use was least important for deaths associated with the circulatory system, while radiologic damage was particularly important for such deaths. A marked sex-associated effect was noted among deaths caused by injuries/poisoning, since 6 of the deaths occurred in men and only 1 was in a woman. Patients with PsA are at an increased risk of death compared with the general population. Evidence of previously active and severe disease, as manifested by the prior use of medications and by radiologic changes as well as an elevated ESR at presentation, are prognostic indicators for death. The presence of nail lesions appears to be a protective factor that has the most clinical importance in the context of previously active and severe disease.


Fetal magnetocardiography in the investigation of congenital heart defects.
To investigate the changes of the fetal magnetocardiography (FMCG), a new noninvasive diagnostic tool in the analysis of electrophysiologic changes of the heart, in cases of congenital heart defect (CHD). The FMCG was analysed and compared to the postnatal ECG in eight cases of CHD: atrial septal defect ASDII (three cases), a combination of atrioventricular-septal-defect (AVSD) and Tetralogy of Fallot (TOF) (one case ), complete transposition of great arteries (d-TGA) (two cases), coarctation of aorta (COA) (one case), stenosis of the pulmonary artery (PS) and right ventricular hypoplasia (one case). (1) The following FMCG changes were observed: a split R-wave (AVSD/TOF, ASDII), prolongation of QRS complex (COA, PS). (2) The notch of the R-wave could not be observed in the newborn with AVSD/TOF. (3) Neither the fetal FMCG nor the neonatal ECG revealed any changes in the cases of d-TGA. (4) All other neonatal ECGs were corresponding to the FMCG. The FMCG can unearth changes of the cardiac electrophysiologic activity in the case of CHD. The method provides additional information concerning the effect of a CHD on the cardiac conductory system. As in the neonate, the FMCG changes do not reflect the severity of the CHD. FMCG cannot serve as a primary diagnostic tool in the case of CHD as compared to echocardiography.


Endoscopic sensitivity in the detection of esophageal strictures.
Endoscopy was compared in 90 patients with a radiographic diagnosis of peptic esophageal stricture. Retrospectively, 78 strictures were classified as valid diagnoses giving a positive radiographic predictive value of 87%. Endoscopy diagnosed 74 (95%) of the 78 peptic strictures, detecting all 45 strictures under 10 mm in caliber, but failing to detect four (12%) of 33 broader strictures. Nine (75%) of the 12 radiographic false-positive errors involved misinterpretation of muscular or mucosal rings of the lower esophagus. We conclude that endoscopy and radiology are equally effective and complementary methods for evaluating patients with suspected peptic stricture.


Clinical significance of farnesoid X receptor expression in thyroid neoplasia.
To evaluate the clinical significance of farnesoid X receptor (FXR) in thyroid neoplasia. FXR expression was assessed immunohistochemically on 88 thyroid neoplastic tissues (benign = 44, malignant = 44). Enhanced FXR was more frequently observed in papillary carcinomas compared with hyperplastic nodules (p = 0.0489). In malignant lesions, elevated FXR was associated with capsular (p = 0.0004) and vascular invasion (p = 0.0056) and increased follicular cells' proliferative rate (p < 0.0001). Elevated FXR expression was also associated with larger tumor size (p = 0.0086), presence of lymph node metastases (p = 0.0239) and lymphatic invasion (p = 0.0086) and increased recurrence rate risk (p = 0.0239). FXR may be associated with tumor aggressiveness that affects patients' survival in thyroid neoplasia.


Disorders in trunk rotation during walking in patients with low back pain: a dynamical systems approach.
(1) To introduce an evaluation tool for the assessment of walking disorders in low back pain patients. (2) To investigate whether walking patterns in low back pain patients are different from those of control subjects. Relative phase measures of movement coordination are applied in the assessment of trunk function in a small group of patients with non-specific low back pain and in control subjects. Normal subjects change the coordination of pelvic and thoracic rotations from an in-phase to an out-of-phase pattern with increasing walking speed. Low back pain patients may have a reduced ability to counter rotate pelvis and thorax at higher walking speeds (from 1.0 m/s onwards) as a result of hyperstable coordination patterns. Six patients with non-specific low back pain and six healthy control subjects walked on a treadmill at comfortable walking speeds and during a systematic variation of the treadmill velocity. Coordination of arm and leg movements as well as of pelvic and thoracic rotations was analyzed using a relative phase algorithm. The comfortable walking speed was reduced in the patient group. In contrast to the control subjects, four of the six patients were not able to establish an out-of-phase coordination pattern between thorax and pelvis at higher walking speeds. This coincided with an increased stability of movement coordination, indicating guarded behavior. In addition, an increased asymmetry between the phase-relations of left and right side of the body was found in some of the patients.


Central European medicinal bryophytes in the 16th-century work by Caspar Schwenckfeld, and their ethnopharmacological origin.
Ubiquitous bryophyte species are reported from European, American and Asian ethnopharmacies. Some of their traditional medicinal uses are similar in distant and isolated cultures, and moreover, medicinal properties of some bryophytes are currently confirmed as justified by their chemical constituents. Aims of the work: we identify bryophytes listed in a medicinal and botanical work from 1600, and compare their medicinal applications (known in Europe between 1530-1600) with other ethnopharmacological data about these species and with modern pharmacological knowledge. This way we attempt to display origins of medicinal usage of bryophytes in Central Europe. Bryophyte species in bibliographical sources printed in Central Europe (starting from O. Brunfels' Herbarum vivae Eicones... Argentorati, 1530) were identified according to old and recent taxonomical references. Caspar Schwenckfeld's scientific output from 1600 was treated here as a summary of 16th-century knowledge about medicinal bryophytes. Central European pharmacy about the year 1600 was familiar with the following bryophytes: Marchantia polymorpha L., Polytrichum commune Hedw., P. formosum Hedw. and Funaria hygrometrica Hedw. Between 1530-1600 in Central Europe the number of medicinal bryophytes increased from 2 (Lichen sive Hepatica and Polytrichon) to 4. Pharmaceutical usage of them was similar as in other, distant ethnopharmacies. Further 2-4 mosses (Rhytidiadelphus loreus and Rh. squarrosus; Thuidium tamariscinum and Th. delicatulum) were recognised as non-medicinal.


Impact of Ultraviolet Germicidal Irradiation for No-Touch Terminal Room Disinfection on Clostridium difficile Infection Incidence Among Hematology-Oncology Patients.
OBJECTIVE To evaluate the impact of no-touch terminal room no-touch disinfection using ultraviolet wavelength C germicidal irradiation (UVGI) on C. difficile infection (CDI) rates on inpatient units with persistently high rates of CDI despite infection control measures. DESIGN Interrupted time-series analysis with a comparison arm. SETTING 3 adult hematology-oncology units in a large, tertiary-care hospital. METHODS We conducted a 12-month prospective valuation of UVGI. Rooms of patients with CDI or on contact precautions were targeted for UVGI upon discharge using an electronic patient flow system. Incidence rates of healthcare-onset CDI were compared for the baseline period (January 2013-December 2013) and intervention period (February 2014-January 2015) on study units and non-study units using a mixed-effects Poisson regression model with random effects for unit and time in months. RESULTS During a 52-week intervention period, UVGI was deployed for 542 of 2,569 of all patient discharges (21.1%) on the 3 study units. The CDI rate declined 25% on study units and increased 16% on non-study units during the intervention compared to the baseline period. We detected a significant association between UVGI and decrease in CDI incidence (incidence rate ratio [IRR], 0.49; 95% confidence interval [CI], 0.26-0.94; P=.03) on the study units but not on the non-study units. The impact of UVGI use on average room-cleaning time and turnaround time was negligible compared to the baseline period. CONCLUSIONS Targeted deployment of UVGI to rooms of high-risk patients at discharge resulted in a substantial reduction of CDI incidence without adversely impacting room turnaround. Infect Control Hosp Epidemiol 2016;1-6.


Temporal patterns of secretion of porcine uterine suppressor and stimulatory macromolecules.
Temporal secretory patterns of porcine uterine suppressor (>/=230 kD) and stimulatory (29 kD) macromolecules were evaluated within uterine luminal protein (ULP) secretions recovered during early pregnancy. The ULP was recovered by uterine flushing from four Landrace gilts each on Days 9, 12, 15 and 18 of pregnancy. Unfractionated and fractionated ULP (using Sephacryl S-200) was tested for suppression or stimulation of phytohemagglutinin-induced peripheral blood T-lymphocyte proliferation. For all days of pregnancy, unfractionated ULP suppressed (P<0.002 to 0.0001) lymphocyte proliferative responses, with the greatest (P<0.05) activity observed for ULP collected on Day 9 of pregnancy. Suppressor activity resulted from the >/=230 kD component, in which the activity was greater (P<0.05) for ULP from gilts on Day 9 than Days 12, 15 and 18 of pregnancy. The 29 kD component failed (P>0.05) to stimulate lymphocyte proliferation, although there was a nonsignificant stimulatory trend for 2 of 4 gilts each at Days 12 and 15 of pregnancy. These findings demonstrate a temporal secretory pattern for the >/=230 kD lymphocyte suppressor component, which may be requisite for the immunological survival of the conceptus during early pregnancy. The inconsistent appearance of the lymphocyte stimulatory factor (29 kD component) tends to minimize its biological significance relative to the immunology of pregnancy.


[Angioplasty and stenting in severe stenosis of basilar artery refractory to pharmacotherapy].
Stenoses in the posterior cerebral circulation often have a bad prognosis. There may be a high rate of morbi-mortality and recurrences of ischemic events in this territory. Currently we have no evidence or consensus about what the best pharmacological option is for these patients. We report a case of a 75 year old woman with sever stenosis of the proximal part of the basilar artery with recurrent transient ischemic events unresponsive to different combinations of antiagregant and anticoagulant treatments. A percutaneous transluminal angioplasty with the addition of a stent in the basilar artery was performed successfully. At present, there are few studies and a low number of patients treated by this technique. The results obtained are promising, with a low rate of morbi-mortality, the most frequent complications being embolization of the atherosclerotic lesion, dissection, rupture or restenosis.


Gene therapy for malignant pleural mesothelioma: present and future.
Malignant pleural mesothelioma is relatively rare in frequency but one of the intractable diseases linked with asbestos exposure. Clinical outcomes with the present treatment modalities are unsatisfactory and no effective prevention method has been reported. Growing numbers of the patients in the Western countries with a long latent period need development of a novel therapeutic strategy. Gene therapy is a candidate for mesothelioma treatment because of its easy accessibility of a vector-mediated gene medicine into the intrapleural cavity. Several preclinical studies demonstrated that the gene medicine produced antitumor effects, suggesting the feasibility in clinical settings. In this article, we review the current status of gene therapy and clinical trials targeting mesothelioma and address possible directions to improve the efficacy.


Detection of antifungal properties in Lactobacillus paracasei subsp. paracasei SM20, SM29, and SM63 and molecular typing of the strains.
Lactobacilli isolated from different food and feed samples such as raw milk, cheese, yoghurt, olives, sour dough, as well as corn and grass silage, were screened for their antifungal activities. Out of 1,424 isolates tested, 82 were shown to be inhibitory to different yeasts (Candida spp. and Zygosaccharomyces bailii) and a Penicillium sp., which were previously isolated from spoiled yoghurt and fruits. Carbohydrate fermentation patterns suggested that a substantial portion, 25%, belonged to the Lactobacillus casei group, including L. casei, L. paracasei, and L. rhamnosus. The isolates SM20 (DSM14514), SM29 (DSM14515), and SM63 (DSM14516) were classified by PCR using species-specific primers to target the corresponding type strains (L. casei, L. paracasei, and L. rhamnosus) as controls. Further molecular typing methods such as randomly amplified polymorphic DNA, pulsed-field gel electrophoresis, and sequencing analysis of the 16S rRNA gene allowed classifying strains SM20, SM29, and SM63 as L. paracasei subsp. paracasei in accordance with the new reclassification of the L. casei group proposed by Collins et al.


[How I treat...hidradenitis suppurativa].
Hidradenitis suppurativa is a chronic and debilitating inflammatory disease. It presents as recurrent abcesses, sinus tracts and scarring. The condition usually develops in the axillae and groins, and more rarely involves the breasts, perineum and buttocks. There are many myths around hidradenitis suppurativa including its origin and pathomechanisms. Some antibiotics as well as corticosteroids and other immune downregulators are poorly effective in this stubborn condition. By contrast, TNF-alpha antagonists appear promising. Radical surgery is another effective option.


Healing of human intrabony defects following regenerative periodontal therapy with an enamel matrix protein derivative alone or combined with a bioactive glass. A controlled clinical study.
The purpose of the present study was to compare clinically the treatment of deep intrabony defects with a combination of an enamel matrix protein derivative (EMD) and a bioactive glass (BG) to EMD alone. Thirty patients (16 females and 14 males) suffering from advanced marginal periodontitis were included in this prospective, controlled parallel design multicenter study. In each of the patients, one intrabony defect was randomly treated with either EMD+BG (test) or with EMD alone (control). Clinical measurements were recorded at baseline and at 1 year following therapy. No differences in any of the investigated parameters were observed at baseline between the two groups. Healing was uneventful in all patients. At 1 year after therapy, the test group showed a reduction in mean probing depth (PD) from 8.5+/-1.1 to 4.4+/-1.2 mm (p<0.001) and a change in mean clinical attachment level (CAL) from 10.4+/-1.5 to 7.1+/-1.5 mm (p<0.0001). In the control group, the mean PD was reduced from 8.5+/-1.5 to 4.0+/-1.6 mm (p<0.001) and the mean CAL changed from 10.2+/-2.1 to 6.3+/-2.2 mm (p<0.01). In the test group, 12 sites (80%) gained at least 3 mm or more of CAL, whereas in the control group a CAL gain of 3 mm or more was measured at 13 sites (87%). No statistically significant differences in terms of PD reduction and CAL gain were found between the test and the control treatment. Within the limits of the present study it can be concluded that: (i) at 1 year after surgery, both therapies resulted in significant PD reductions and CAL gains, and (ii) the combination of EMD+BG does not seem to additionally improve the clinical results.


Highly accurate method for ligand-binding site prediction in unbound state (apo) protein structures.
This article describes a new method for predicting ligand-binding sites of proteins. The method involves calculating the van der Waals interaction energy between a protein and probes placed on the protein surface, and then clustering the probes with attractive interaction to find the energetically most favorable locus. In 80% (28/35) of the test cases, the ligand-binding site was successfully predicted on a ligand-bound protein structure, and in 77% (27/35) was successfully predicted on an unbound structure. Our method was used to successfully predict ligand-binding sites unaffected by induced-fit as long as its scales were not very large, and it contributed to a significant improvement in prediction with unbound state protein structures. This represents a significant advance over conventional methods in detecting ligand-binding sites on uncharacterized proteins. Moreover, our method can predict ligand-binding sites with a narrower locus than those achieved using conventional methods.


Nephrotoxicity profiles and threshold dose values for [177Lu]-DOTATATE in nude mice.
In peptide receptor radionuclide therapy for neuroendocrine tumors the main dose-limiting tissue is found in the kidneys because of tubular reabsorption and retention of radioactivity. The aim of this study was to quantify late effects in renal cortex of nude mice exposed to high amounts of [(177)Lu]-DOTA-Tyr(3)-octreotate ([(177)Lu]-DOTATATE), and to determine whether a threshold dose value exists for these findings. Nude mice were exposed to 90, 120 or 150 MBq of [(177)Lu]-DOTATATE. Renal toxicity was evaluated up to 6 months after injection. Blood samples were collected to examine renal functional markers, and after sacrifice at 6 months changes in renal morphology were explored. Tissue damage was estimated by quantifying the relative area of the different subunits in the renal cortex using point counting. Additional morphological signs of radiation damage were also noted. The absorbed doses to the kidneys were estimated by previously determined kidney pharmacokinetics and Monte Carlo simulations for different assumptions regarding the activity distribution. Increased serum creatinine and urea values indicated long-term renal toxicity. The tissue area occupied by proximal tubules decreased with increasing doses of [(177)Lu]-DOTATATE, whereas the other subunits in cortex slightly increased. The mean absorbed dose in the renal cortex for [(177)Lu]-DOTATATE was estimated to be 35-58 Gy for the different groups of animals. A dose-response relationship was observed for proximal tubular damage, and a threshold dose value of 24 Gy (BED 37 Gy) was determined. Selective morphological changes in kidney cortex of nude mice were quantified and appeared in a dose dependent manner after injection of high amounts of [(177)Lu]-DOTATATE.


Structure of the Tetrahymena ribozyme: base triple sandwich and metal ion at the active site.
The Tetrahymena intron is an RNA catalyst, or ribozyme. As part of its self-splicing reaction, this ribozyme catalyzes phosphoryl transfer between guanosine and a substrate RNA strand. Here we report the refined crystal structure of an active Tetrahymena ribozyme in the absence of its RNA substrate at 3.8 A resolution. The 3'-terminal guanosine (omegaG), which serves as the attacking group for RNA cleavage, forms a coplanar base triple with the G264-C311 base pair, and this base triple is sandwiched by three other base triples. In addition, a metal ion is present in the active site, contacting or positioned close to the ribose of the omegaG and five phosphates. All of these phosphates have been shown to be important for catalysis. Therefore, we provide a picture of how the ribozyme active site positions both a catalytic metal ion and the nucleophilic guanosine for catalysis prior to binding its RNA substrate.


Use of a pattern recognition technique to control a multifunctional prosthesis.
Various kinds of command source can be used to control an above-elbow prosthesis. But none of them can be used to perform a specified task easily. The research is devoted to investigation of the potential effectiveness of applying the kinematic data of the shoulder joint to control an upper-limb prosthesis. Using these data as input signals, an appropriate signal processing technique, pattern recognition, is utilised to derive control commands. The purpose of the investigation is to use these commands to control a multifunctional prosthesis so that an amputee can perform a few tasks. For testing performance accuracy, a goniometer is worn by a subject with intact arm. It is also interfaced to a digital computer. Next, he is asked to do one of the predefined tasks for which the joint angle trajectories have already been derived and stored. Almost as soon as the shoulder joint angles are sampled and sent to the computer, the program calculates the elbow and wrist angles. These values are compared with actual elbow and wrist angles, which are monitored by the goniometer.


PM-IRRAS Determination of Molecular Orientation of Phosphonic Acid Self-Assembled Monolayers on Indium Zinc Oxide.
Self-assembled monolayers (SAMs) of phosphonic acids (PAs) on transparent conductive oxide (TCO) surfaces can facilitate improvement in TCO/organic semiconductor interface properties. When ordered PA SAMs are formed on oxide substrates, interface dipole and electronic structure are affected by the functional group properties, orientation, and binding modes of the modifiers. Choosing octylphosphonic acid (OPA), F13-octylphosphonic acid (F13OPA), pentafluorophenyl phosphonic acid (F5PPA), benzyl phosphonic acid (BnPA), and pentafluorobenzyl phosphonic acid (F5BnPA) as a representative group of modifiers, we report polarization modulation-infrared reflection-absorption spectroscopy (PM-IRRAS) of binding and molecular orientation on indium-doped zinc oxide (IZO) substrates. Considerable variability in molecular orientation and binding type is observed with changes in PA functional group. OPA exhibits partially disordered alkyl chains but on average the chain axis is tilted ∼57° from the surface normal. F13OPA tilts 26° with mostly tridentate binding. The F5PPA ring is tilted 23° from the surface normal with a mixture of bidentate and tridentate binding; the BnPA ring tilts 31° from normal with a mixture of bidentate and tridentate binding, and the F5BnPA ring tilts 58° from normal with a majority of bidentate with some tridenate binding. These trends are consistent with what has been observed previously for the effects of fluorination on orientation of phosphonic acid modifiers. These results from PM-IRRAS are correlated with recent results on similar systems from near-edge X-ray absorption fine structure (NEXAFS) and density functional theory (DFT) calculations. Overall, these results indicate that both surface binding geometry and intermolecular interactions play important roles in dictating the orientation of PA modifiers on TCO surfaces. This work also establishes PM-IRRAS as a routine method for SAM orientation determination on complex oxide substrates.


Developmental changes in fat body and midgut chromosomes of Drosophila auraria.
Changes in puffing activity of fat body (FB) and midgut (MG) chromosomes of Drosophila auraria during late larval and white prepupal development as well as after in vitro culture with or without ecdysterone were studied and compared with those of the salivary gland (SG). The Balbiani Rings characteristic of the SG chromosomes of D. auraria, are not formed in FB and MG. Most of the inverted tandem chromosomal duplications that have been found to be common to all three tissues showed differentiation of puffing activity of the bands considered to be homologous. The major early ecdysone puffs 73A and 73B (considered to be homologues of D. melanogaster puffs 74EF and 75B, respectively), together with other early ecdysone puffs were present in all three tissues. Clear intermoult and postintermoult puffs were not evident in FB and MG chromosomes. However, a small set of late ecdysone puffs could be scored in FB, while no late ecdysone puffs were abserved in MG. Other tissue-specific puffs were identified, but a very small number of them were limited to MG.


Bronchiectasis.
Bronchiectasis, which was once thought to be an orphan disease, is now being recognized with increasing frequency around the world. Patients with bronchiectasis have chronic cough and sputum production, and bacterial infections develop in them that result in the loss of lung function. Bronchiectasis occurs in patients across the spectrum of age and gender, but the highest prevalence is in older women. The diagnosis of bronchiectasis is made by high-resolution CT scans. Bronchiectasis, which can be focal or diffuse, may occur without antecedent disease but is often a complication of previous lung infection or injury or is due to underlying systemic illnesses. Patients with bronchiectasis may have predisposing congenital disease, immune disorders, or inflammatory disease. The treatment of bronchiectasis is multimodality, and includes therapy with antibiotics, antiinflammatory agents, and airway clearance. Resectional surgery and lung transplantation are rarely required. The prognosis for patients with bronchiectasis is variable given the heterogeneous nature of the disease. A tailored, patient-focused approach is needed to optimally evaluate and treat individuals with bronchiectasis.


Identification of the bacteria-binding peptide domain on salivary agglutinin (gp-340/DMBT1), a member of the scavenger receptor cysteine-rich superfamily.
Salivary agglutinin is encoded by DMBT1 and identical to gp-340, a member of the scavenger receptor cysteine-rich (SRCR) superfamily. Salivary agglutinin/DMBT1 is known for its Streptococcus mutans agglutinating properties. This 300-400 kDa glycoprotein is composed of conserved peptide motifs: 14 SRCR domains that are separated by SRCR-interspersed domains (SIDs), 2 CUB (C1r/C1s Uegf Bmp1) domains, and a zona pellucida domain. We have searched for the peptide domains of agglutinin/DMBT1 responsible for bacteria binding. Digestion with endoproteinase Lys-C resulted in a protein fragment containing exclusively SRCR and SID domains that binds to S. mutans. To define more closely the S. mutans-binding domain, consensus-based peptides of the SRCR domains and SIDs were designed and synthesized. Only one of the SRCR peptides, designated SRCRP2, and none of the SID peptides bound to S. mutans. Strikingly, this peptide was also able to induce agglutination of S. mutans and a number of other bacteria. The repeated presence of this peptide in the native molecule endows agglutinin/DMBT1 with a general bacterial binding feature with a multivalent character. Moreover, our studies demonstrate for the first time that the polymorphic SRCR domains of salivary agglutinin/DMBT1 mediate ligand interactions.


Early redistribution of thallium-201 after temporary ischemia.
To define the time course of redistribution of thallium-201 (201Tl), ischemia was induced in seven pigs by temporary occlusion of the circumflex coronary artery. After 1 1/2 min of occlusion 201Tl and labeled microspheres were injected into the left atrium. Flow was re-established 4 min after occlusion. Prior to reflow, the relative activities of 201Tl and microspheres in the ischemic area were similar, but as early as 5 min after reflow the relative 201Tl activity was considerably higher than the relative microsphere activity and from 15 to 105 min after reflow, relative 201Tl activity (averabe 69% of that in normal myocardium) continued to be higher than relative microsphere activity (average 6% of normal). Myocardial arteriovenous differences for 201Tl were followed sequentially after 201Tl injection in normal dogs and in dogs with temporary coronary occlusions. The results suggested both loss of 201Tl from normal myocardium beginning 10 min after 201Tl injection and increased extraction of 201Tl from the blood pool immediately after release of a transient occlusion. Redistribution of 201Tl therefore begins very soon after relief of myocardial ischemia and even a short delay in initiating myocardial imaging may decrease the sensitivity of the technique for detecting transient ischemia.


cDNA cloning and expression of UDP-glucose dehydrogenase from bovine kidney.
We have isolated a cDNA encoding UDP-glucose dehydrogenase from a bovine kidney cDNA-library, the first mammalian cDNA clone published. [After submission of the manuscript, a study appeared describing the molecular cloning and characterization of the human and mouse UDP-glucose dehydrogenase genes (Spicer et al., 1998).] The enzyme catalyzes the conversion of UDP-glucose to UDP-glucuronic acid, an essential precursor in glycosaminoglycan biosynthesis. The cDNA has an open reading frame of 1482 nucleotides coding for a 55 kDa protein. Expression of the enzyme in COS-7 cells showed a 3-fold increase in UDP-glucose dehydrogenase activity; also, the C-terminal 23 amino acids was shown not to be necessary for enzyme activity. Northern blots from human and mouse tissues reveal high expression in liver and low in skeletal muscle. Human tissues have a major transcript size of 3.2 kilobases and a minor of 2.6 whereas mouse tissues have a single 2.6 kilobase transcript. We have also developed a sensitive and direct assay using UDP-[14C]Glc as a substrate for detection of small amounts of UDPGDH activity.


Does nanotech have a gender?
Gender is less of an issue in nanotechnology than in other areas of science and technology but, as Chris Toumey explains, public attitudes to nanotech do depend on gender.


Ionic dependence of glycylsarcosine uptake by isolated chicken enterocytes.
Dipeptide transport was studied in chicken enterocytes and its properties compared with those of Na+-dependent sugar transport. Results showed that 1) isolated cells were capable of accumulating glycylsarcosine (Gly-Sar) against a concentration gradient (2.5- to 3.0-fold accumulation). This uptake was maximal at pH 6.0, and it was inhibited by Na+-free medium and by ouabain; 2) uptake of Gly-Sar was not affected by methionine and was competitively inhibited by carnosine, with a Ki of 12 mM; 3) the protonophore FCCP inhibited both Gly-Sar and 3-oxy-methyl-D-glucose (3-OMG) uptake by the cells; 4) amiloride, a well-known inhibitor of the Na+/H+ exchanger system stimulated 3-OMG uptake and inhibited Gly-Sar uptake, its effects being greater at pH 7.4; 5) and monensin prevents the effects of amiloride on both sugar and dipeptide uptake. In summary, Gly-Sar uptake depends on extracellular Na+ in an indirect manner via its effect on H+ efflux, and it appears to be dependent on an inward H+ gradient.


DNA-Protein crosslinks induced by nickel compounds in isolated rat renal cortical cells and its antagonism by specific amino acids and magnesium ion.
Suspensions of isolated renal cortical cells in modified Krebs-Henseleit buffer (pH 7.4) were incubated with nickel chloride, nickel acetate, nickel sulfate, and nickel subsulfide (0-2 mM) at 37 degreesC for 2 h. A significant increase (63%) in DNA-protein crosslinks was observed at 2 mM nickel sulfate, whereas nickel subsulfide induced a significant increase in such crosslinks beginning at 0.5 mM concentration and a maximum increase of 200% of the control value reached at 2 mM concentration. No significant reduction in viability of renal cortical cells (as measured by trypan blue exclusion) was observed due to these nickel compounds at any concentration used. In the second series of experiments, coincubation of nickel subsulfide (2 mM) with l-histidine (8 or 16 mM), l-cysteine (4 or 8 mM), or l-aspartic acid (8 or 24 mM) significantly reduced the DNA-protein crosslinks induced by 2 mM nickel subsulfide. Similarly Mg2+ (24 mM), but not Ca2+ (24 mM), was able to antagonize nickel subsulfide-induced increase in DNA-protein crosslinks. High extracellular levels of Mg2+ and these amino acids significantly decreased the accumulation of Ni2+ from nickel subsulfide in renal cortical cells. Furthermore, these amino acids at high concentrations significantly inhibited the binding of Ni2+ from nickel subsulfide to deproteinized DNA from renal cortical cells, whereas such inhibition due to Mg2+ was close to significant (0.1 > p > 0.05). In vitro exposures of renal cortical cells to nickel subsulfide (0-2 mM) increased the formation of reactive oxygen species in concentration-dependent manner. Furthermore, coincubation of 2 mM nickel subsulfide with either catalase, dimethylthiourea, mannitol, or vitamin C at 37 degreesC for 2 h resulted in a significant decrease of nickel subsulfide-induced formation of DNA-protein crosslinks, suggesting that nickel subsulfide-induced DNA-protein crosslink formation in isolated rat renal cortical cells is caused by the formation of reactive oxygen species. The potent protective effects of these specific amino acids and Mg2+ against nickel subsulfide-induced DNA-protein crosslink formation in isolated renal cortical cells are due to reduction of cellular uptake of Ni2+ and inhibition of the binding of Ni2+ to deproteinized DNA.


Organization of inhibitory feed-forward synapses from the dorsal to the ventral cochlear nucleus in the cat: a quantitative analysis of endings by vesicle morphology.
The main ascending, excitatory pathway from the cochlea undergoes synaptic interruption in the dorsal and ventral cochlear nuclei. The dorsal cochlear nucleus also forms a feed-forward circuit, which receives cochlear input and projects to the ventral cochlear nucleus by a tuberculo-ventral tract. This circuit may provide an inhibitory fringe (side bands) surrounding the center bands of the main ascending pathway. Biotinylated dextran injections into the dorsal cochlear nucleus anterogradely labeled the tuberculo-ventral tract and its endings in the anteroventral cochlear nucleus but also retrogradely filled cochlear nerve fibers and their terminals in the same regions. To distinguish tuberculo-ventral from cochlear nerve terminals, we used electron microscopy of the immunolabeled endings. Images were digitized and filter-enhanced, and the sizes and shapes of synaptic vesicles were used to construct quantitative profiles of the terminal types. The cochlear nerve endbulbs mapped to the same iso-frequency band of the injection site (main band). Flanking the main band were smaller labeled endings. About 45% of labeled terminals were pleomorphic and equally represented in the main band and side bands. Therefore, if there is an inhibitory fringe in the main projection pathway, it was not selective for tuberculo-ventral tract endings. Surprisingly, an excitatory category of round vesicles of intermediate size was labeled in the main band but not in the side bands. These intermediate endings may balance the feed-forward inhibition from the tuberculo-ventral tract. The quantitative method devised for classification of ending types by their vesicle profiles should be a generally useful tool for analysis.


Multidisciplinary Tumor Boards: An Opportunity for Radiologists to Demonstrate Value.
In response to healthcare reform, a necessary evolution of radiology has shifted from generating volume to demonstrating value. Multidisciplinary tumor boards provide a critical opportunity for radiologists to demonstrate their value to their clinical colleagues, their patients, administrations, and society.


Chronic inflammation during osteoarthritis is associated with an increased expression of CD161 during advanced stage.
Increasing evidence suggests a role of inflammation during the pathogenesis of osteoarthritis (OA). The local and systemic inflammation was studied in 33 patients of different KL grades, grade2 (n = 11), grade3 (n = 6) and grade4 (n = 16). The levels of cytokines, adipokines and matrix metalloproteinases (MMPs) were measured in serum and synovial fluid (SF) by flow cytometry and ELISA, respectively. The frequency of T cells and CD161 expression was measured by flow cytometry. The levels of IL-1β, IL-6 and IL-10 were significantly higher in sera and SF of patients with OA as compared to healthy control's serum. Higher levels of MMP9 and leptin and lower levels of adiponectin were observed in SF as compared to serum. The MMP9 in SF and MMP13 levels in serum and SF decreased in KL grade 4 cases. In these patients, higher levels of leptin and lower levels of adiponectin were observed in SF versus patients of lower grades. There was increased infiltration of CD8+ T cells in SF of OA cases with decreased frequency in grade 4 cases. The expression of CD161 on T cells was significantly higher in SF than peripheral blood with significant upregulation in grade 4 patients. The CD161 expression had significant positive correlation with IL-17 in the serum of patients. The ROC curves of CD161 expression significantly distinguished grade 2 and grade 4 patients. Collectively, an elevated CD161 expression on T cells in circulation and synovial compartment clearly distinguished lower and higher grade patients warranting studies to assess its role as a contributing factor towards OA progression.


Fibroblast activation protein: a serine protease expressed at the remodeling interface in idiopathic pulmonary fibrosis.
Fibroblast activation protein (FAPalpha) is a member of the cell surface dipeptidyl peptidase (DPP) family of serine proteases. In its dimer form, FAPalpha exhibits gelatinase, collagenase, and DPP activity in vitro. Reactive fibroblasts in healing wounds and stromal fibroblasts associated with epithelial tumors express FAPalpha. Idiopathic pulmonary fibrosis (IPF) is a disease of the lung characterized by progressive fibrosis with no clear etiology or molecular marker for disease activity. Recently, it has been shown that fibroblast FAPalpha expression is induced in liver cirrhosis, with an expression pattern distinct from alpha-smooth muscle actin (alpha-SMA). In this study, we determine whether FAPalpha expression is selectively induced in areas of ongoing tissue remodeling characterized by fibroblast foci in IPF. Human lung tissue was obtained from patients with IPF, centrilobular emphysema, and normal lung. Immunohistochemical studies were performed using anti-FAPalpha antibody and antibodies against alpha-SMA and CD26 (DPPIV), another member of the DPP family. We found that FAPalpha was not expressed in normal human lung tissue or tissue with evidence of centriacinar emphysema, but was induced in all patients with IPF and With a pattern distinct from that of CD26 found primarily on hyperplastic alveolar epithelium. Specifically, FAPalpha was detected in fibroblast foci and in fibrotic interstitium and not in the interstitium of adjacent architecturally normal lung. Alveolar/airway epithelium and vascular smooth muscle did not express FAPalpha. This is the first report of FAPalpha expression in IPF and our results suggest that FAPalpha is selectively induced in fibrotic foci, but not in normal or emphysematous lung. Future studies will address whether FAPalpha may be used as a marker for disease activity in IPF.


[Determination of cytochrome P450 3A4 activity with testosterone probe using high performance liquid chromatography].
A method was established for evaluating cytochrome P450 3A4 (CYP3A4) activity using testosterone in vitro by high performance liquid chromatography-ultraviolet detection (HPLC-UV). It employed a Phenomenex C18 column (4.6 mm x 150 mm, 5 microm) at 30 degrees C. The mobile phase consisted of (A) methanol-acetonitrile-0.05% phosphate solution (pH 2.45) (5:15:80, v/v) and (B) acetonitrile-0.05% phosphate solution (pH 2.45) (50:50, v/v) using a linear gradient elution of 100%A - 100%B at 0-18 min, then held for 5 min and returned to A. The flow rate was set at 1.0 mL/min and the ultraviolet detector was operated at 245 nm. Firstly, testosterone was incubated with rat liver microsomes in vitro and extracted by solid phase extraction (SPE). Then, the methanol eluant was obtained and evaporated to thoroughly dry with a mild stream of N2 at 37 degrees C. Finally, the residues were reconstituted with 200 microL 50% (v/v) methanol and further analyzed by HPLC. The retention time of 6beta-hydroxylated testosterone was 11.60 min, the linear range of the method was from 0.5 microg/mL to 32 microg/mL, and the detection limit was 0.02 microg/mL. The method recoveries were from 99.07% to 101.30% and the extraction recoveries were from 88.41% to 92.73%. The retention time of testosterone was 19.27 min, the linear range of the method was from 0.5-40 microg/mL, and the detection limit was 0.01 microg/mL. The method recoveries were from 96.50% to 98.03% and the extraction recoveries were from 89.59% to 92.66%. All of the intraday and interday relative standard deviations were less than 10%. The method is fast, accurate, sensitive and suitable for the evaluation of CYP3A4 activity and research of enzyme metabolism kinetics in vitro.


FeNO and Exercise Testing in Children at Risk of Asthma.
Exercise testing is the gold standard for diagnosing exercise-induced bronchoconstriction in children, but requires considerable cooperation and medical resources. Therefore, fraction of exhaled nitric oxide (FeNO) has been proposed as a tool to predict the need for exercise testing. The objective of this study was to investigate the relationship between FeNO, exercise test results, and a history of respiratory symptoms during exercise in children at risk of asthma. FeNO measurement, exercise testing, and interview about respiratory symptoms during exercise were completed in 224 seven-year-old children from the at-risk Copenhagen Prospective Studies on Asthma in Childhood2000 birth cohort. The associations between FeNO, exercise test results, and reported respiratory symptoms during exercise were analyzed adjusting for gender, respiratory infections, and inhaled corticosteroid treatment. The associations were also analyzed stratified by asthma and atopic status. Of the 224 children, 28 (13%) had an established asthma diagnosis and 58 (26%) had a positive exercise test (≥15% drop in forced expiratory volume in 1 second [FEV1] from baseline). FeNO and bronchial obstruction after exercise were linearly associated with a doubling of FeNO corresponding to a 2.4% drop in FEV1 (95% confidence interval, 0.8-4.1; P < .01). However, a receiver operating characteristic curve analysis showed that the best cutoff of FeNO for predicting exercise test outcome among children who reported respiratory symptoms during exercise was 17 ppb, which only had 74% negative predictive value. There was no association between FeNO and reported respiratory symptoms during exercise (odds ratio = 1.3 [0.8-1.9]; P = .29) or reported symptoms during exercise and exercise test results (odds ratio = 1.0 [1.0-1.1]; P = .12). A history of respiratory symptoms during exercise was not associated with either elevated FeNO or a positive exercise test in children at risk of asthma. FeNO and exercise test results were linearly associated traits, but FeNO could not reliably be used dichotomized to predict the need of exercise testing.


Multisite randomized controlled trials in health services research: scientific challenges and operational issues.
Although well-designed randomized controlled trials (RCT) provide the strongest evidence regarding causation, only relatively recently have they been used by health services researchers to study the organization, delivery, quality, and outcomes of care. More recent yet is the extension of multisite RCTs to health services research. Such studies offer numerous methodological advantages over single-site trials: (1) enhanced external validity; (2) greater statistical power when studying conditions with a low incidence or prevalence, small event rate in the outcome (eg, mortality), and/or large variance in the outcome (eg, health care costs); and (3) rapid recruitment to provide health care organizations and policy makers with timely results. This paper begins by outlining the advantages of multisite RCTs over single-site trials. It then discusses both scientific challenges (ie, standardizing eligibility criteria, defining and standardizing the intervention, defining usual care, standardizing the data collection protocol, blinded outcome assessment, data management and analysis, measuring health care costs) and operational issues (ie, site selection, randomization procedures, patient accrual, maintaining enthusiasm, oversight) posed by multisite RCTs in health services research. Recommendations are offered to health services researchers interested in conducting such studies.


Movement disorders and psychological tests of frontal lobe function in schizophrenic patients.
Neuropsychological tests of frontal lobe functions were undertaken in 46 chronic schizophrenic patients who were also rated for movement disorders. Tardive dyskinesia was found to have significant associations with most of these psychological tests. The possible mechanisms are discussed within the context of known neostriatal psychological functions.


Rumination as a predictor of drinking behaviour in alcohol abusers: a prospective study.
To investigate the role of depression and rumination in predicting drinking status (absence or presence of alcohol use) and level of alcohol use at 3, 6 and 12 months following a brief course of cognitive-behavioural therapy for alcohol abuse. A total of 80 out-patients with a diagnosis of alcohol abuse completed measures of depression (Beck Depression Inventory), rumination (Ruminative Responses Scale) and alcohol use (Quantity-Frequency Scale). These indicated that rumination predicted drinking status and level of alcohol use at 3-, 6- and 12-month follow-up. The contribution of rumination was independent of depression and initial level of alcohol use. The results confirm that rumination is an important prospective predictor of drinking status and level of alcohol use in alcohol abusers and highlight the potential relevance of targeting rumination in the treatment of alcohol abuse.


[The complex hygienic regulations relating to the conditions of the use of pesticides on protected ground].
Pesticide usage on protected grounds must be conducted with severe hygienic regulations. Its use must be minimised and in future replaced by biological plant protectors.


Effects of chronic low-dose cadmium exposure on selected biochemical and antioxidant parameters in rats.
The effects of long-term (1 yr) exposure to low doses of cadmium (Cd) dissolved in drinking water on selected biochemical and antioxidant parameters were studied in Wistar rats. Rats were divided into four groups: male control group (C-m), female control group (C-f), male Cd-exposed group (Cd-m), and female Cd-exposed group (Cd-f). Cd groups were exposed to Cd dissolved in drinking water (cadmium dichloride 4.8 mg CdCl2/L, i.e., 2.5 mg Cd/L, 500-fold of maximal allowable concentration for potable water). The experiment was terminated on d 370. In all groups, biochemical parameters (total protein [TP], albumin, alanine aminotransferase, aspartate aminotransferase, glucose, cholesterol, triacylglycerols, urea, and creatinine) and antioxidant parameters (glutathione peroxidase, superoxide dismutase, and total antioxidant capacity) were measured in the blood. Total protein and albumin concentrations were decreased significantly in the Cd-m group. Other biochemical parameters did not change in Cd groups compared to control groups. Superoxide dismutase fell significantly in both male and female Cd-exposed groups. Activity of glutathione peroxidase was markedly lower in Cd-exposed groups. Total antioxidant capacity increased significantly in Cd-f group. These results suggest that chronic low-dose oral Cd exposure induces oxidative stress.


Hand assisted laparoscopic radical cystectomy for cancer bladder.
To evaluate the efficacy, safety and feasibility of hand assistance in performing laparoscopic radical cystectomy and to describe our point of technique of hand assisted laparoscopic radical cystectomy (HALRC) with extra-corporeal ileal conduit reconstruction for muscle invasive bladder cancer. This is the second case report of HALRC in the world literature. A five-port transperitoneal laparoscopic approach with an indigenous hand port was used to perform the radical cystectomy in a patient with muscle invasive TCC of bladder. After specimen retrieval, ileal conduit reconstruction was performed extra-corporeally through the site of hand port incision. HALRC was successfully completed in 4.3 hrs and the patient was discharged on the 7th day. The blood loss was 500 ml, and patient was transfused 2 units of blood, as the pre operative hemoglobin was 9 gms%. The analgesic requirement was 350 mgs of Pethidine (equivalent to 35 mgs of Morphine) and 450 mgs of oral Diclofenac Sodium. It took about 23 days for patient to resume normal activity. The histopathology was reported as T3b, left perivesical margin was positive and 2/5 of left pelvic lymph nodes were also involved. However, 7 lymph nodes removed from the right side did not show any disease. In view of histopathology report patient was given 4 cycles of postoperative chemotherapy, At the current follow up of 25 months the patient is free of any recurrence of disease. This case demonstrates the applicability of hand port assistance in to the laparoscopic field inside the abdomen, which helps in retraction and performing blunt dissection coupled with tactile sensation. It is feasible to use hand during laparoscopic radical cystectomy. Its usefulness has to be weighed against the standard laparoscopic radical cystectomy and additional time required for set up and the added cost. The technical success rate currently for standard laparoscopic radical cystectomy clearly demonstrates that hand assistance is not necessary. But, just as its applicability is being investigated, its role should be assessed in larger series of laparoscopic radical cystectomy.


First Report of Verticillium Wilt Caused by Verticillium dahliae on Lettuce in Italy.
Lettuce (Lactuca sativa L.) is an important crop used for fresh and processing markets in Italy and is grown on more than 21,000 ha. During October and November of 2006, wilt symptoms were observed on field-grown lettuce, cv. Estelle, in Forlì, Emila Romagna (northeastern Italy) and on cv. Ballerina grown under plastichouses in Piedmont (northwestern Italy). Both lettuce cultivars were of a butterhead type. Affected plants were stunted and developed yellow leaves with brown or black streaks in the vascular tissue. Yellowing started from the external leaves. Discoloration was observed in the vascular tissue of roots, crown, and leaves. A fungus was consistently and readily isolated from symptomatic vascular tissue, previously disinfested in 1% sodium hypochlorite, when cultured on potato dextrose agar (PDA). Microscopic observations revealed hyaline hyphae with many ovoid, dark microsclerotia measuring 32 to 43 × 16 to 26 μm developing after 15 days of growth at 18°C in the dark. Conidiophores showed two verticils of three elements. Conidia were hyaline, elliptical, single celled, and measured 3.5 to 8.5 × 1.8 to 4.3 μm (average 5.5 × 2.5 μm). According to its morphological characteristics, the fungus was identified as Verticillium dahliae (2). Healthy, 20-day-old lettuce plants, cvs. Principessa and Maxima, both belonging to the butterhead type, were separately inoculated by root dip with a conidial suspension (106/ml) of two isolates of V. dahliae isolated, respectively, at Forlì and Torino. Noninoculated lettuce plants served as control treatments. Plants (10 per treatment) were grown in pots (10-liter vol.) in a steam-disinfested peat/perlite/sand (3:1:1 vol/vol) substrate and were maintained in a glasshouse at temperatures ranging between 17 and 22°C and relative humidity ranging between 60 and 70%. First wilt symptoms and vascular discoloration in the roots, crown, and veins developed 40 days after the artificial inoculation. Forty percent of the plants were affected in the case of cv. Maxima and 30% for cv. Principessa. Noninoculated plants remained healthy. The pathogenicity tests were repeated twice. To our knowledge, this is the first report in Italy of Verticillium wilt on lettuce. The disease has been previously reported in Greece (1) and the United States (3). Currently, Verticillium wilt of lettuce seems restricted in Italy to very few farms in the two locations; moreover, its incidence is very low (0.05%). References: (1) E. K. Ligoxigakis et al. Phytoparasitica 30:141, 2002. (2) G. F. Pegg and B. L. Brady. Verticillium Wilts. CABI Publishing, Wallingford, UK, 2002. (3) G. E. Vallad et al. Plant Dis. 89:317, 2005.


Preoperative Assessment of Muscle Mass Using Computerized Tomography Scans to Predict Outcomes Following Orthotopic Liver Transplantation.
Sarcopenia is an established risk factor predicting survival in chronically ill and trauma patients. We herein examine the assessment and clinical implication of sarcopenia in liver transplantation (LT). Computerized tomography scans from 172 patients waitlisted for LT were analyzed by applying 6 morphometric muscle scores, including 2 density indices (psoas density [PD] and skeletal muscle density [SMD]) and 4 scores based on muscle area (total psoas area, psoas muscle index, skeletal muscle area, and skeletal muscle index). The prevalence of sarcopenia in our cohort ranged from 7.0% to 37.8%, depending on the score applied. Only sarcopenia as defined by the density indices PD and SMD (but not total psoas area, psoas muscle index, skeletal muscle area, or skeletal muscle index) revealed clinical relevance since it correlates significantly with postoperative complications (≥Grade III, Clavien-Dindo classification) and sepsis. Furthermore, sarcopenia predicted inferior patient and graft survival, with low muscle density (PD: <38.5 HU or SMD: <30 HU) representing an independent risk factor in a multivariate regression model (P < 0.05). Importantly, the widely used Eurotransplant donor risk index had a predictive value in nonsarcopenic patients but failed to predict graft survival in patients with sarcopenia. Sarcopenia revealed by low muscle density correlates with major complications following LT and acts as an independent predictor for patient and graft survival. Therefore, the application of a simple computerized tomography-morphologic index can refine an individual recipient's risk estimate in a personalized approach to transplantation.


Imaging electroluminescence from individual nanoparticles in an array exhibiting room temperature single electron effect.
Electroluminescence (EL) from the monolayer of a network of a one-dimensional (1D) necklace of 10 nm Au particles (nano)cemented by CdS is imaged. The EL and photoluminescence (PL) spectra confirm the emission from CdS. The EL emission blinks and is highly specular. The position of the speckles from individual CdS cement sites is independent of magnitude and polarity of the applied bias. The EL is explained by field-assisted ionization of the cement due to high internal fields in the array caused by stationary local charging that also leads to robust single electron effect at room temperature.


Halohydrin analogues of cryptophycin 1: synthesis and biological activity.
The chloro-, bromo-, and iodo-derivatives 2-4 of the antimitotic drug cryptophycin 1 were synthesized by opening the epoxide ring. The biological activities of the compounds were tested in an in vitro microtubule assembly and a cell proliferation assay. The chloro-derivative 2 showed lower activity in the tubulin assay compared to 3 and 4, but they all showed similar inhibition in the proliferation assay.


Identification of a novel de novo mutation of CREBBP in a patient with Rubinstein-Taybi syndrome by targeted next-generation sequencing: a case report.
Rubinstein-Taybi syndrome (RSTS) is a rare autosomal dominant congenital disorder (prevalence, 1:125000-720000) characterized by broad thumbs and halluces, facial dysmorphism, psychomotor development delay, skeletal defects, abnormalities in the posterior fossa, and short stature. The purpose of this study was to use targeted exome sequencing to identify the genetic cause of RSTS in a 6.5-year-old girl presenting typical features of this condition. Targeted exome sequencing of the patient DNA revealed de novo transition c.1066C>T corresponding to a novel nonsense mutation p.Q356X in the CREB-binding protein gene, CREBBP, whose haploinsufficiency is responsible for 50% to 60% of the RSTS cases. Based on comparing the clinical manifestations of our patient with those of patients carrying similar mutations, we supposed that haploinsufficiency is the possible functional consequence of p.Q356X mutation by creation of a loss-of-function CREBBP allele due to a premature stop codon and RSTS phenotype. Our findings expand the spectrum of mutations associated with this condition.


Optical coherence tomography patterns of stent restenosis.
Stent restenosis is an infrequent but poorly understood clinical problem in the drug-eluting stent era. The aim of the study was to evaluate the morphologic characteristics of stent restenosis by optical coherence tomography (OCT). Patients (n = 24, 25 vessels) presenting with angiographically documented stent restenosis were included. Quantitative OCT analysis consisted of lumen and stent area measurement and calculation of restenotic tissue area and burden. Qualitative restenotic tissue analysis included assessment of tissue structure, backscattering and symmetry, visible microvessels, lumen shape, and presence of intraluminal material. By angiography, restenosis was classified as diffuse, focal, and at the margins in 9, 11, and 5 vessels, respectively. By OCT, restenotic tissue structure was layered in 52%, homogeneous in 28%, and heterogeneous in 20%. The predominant backscatter was high in 72%. Microvessels were visible in 12%. Lumen shape was irregular in 28% and there was intraluminal material in 20%. The mean restenotic tissue symmetry ratio was 0.58 +/- 0.19. Heterogeneous and low scattering restenotic tissue was more frequent in focal (45.5% and 54.5%, respectively) than in diffuse (0 and 11.1%) and margin restenosis (0 and 0%) (P = .005 for heterogeneous, P = .03 for low scattering). Restenosis patients with unstable angina symptoms presented more frequently irregular lumen shape (60 vs 6.7%, P = .007). Stents implanted </=12 months ago had more frequently restenotic tissue with layered appearance (84.6% vs 16.7%, P = .003). We demonstrate the ability of OCT to identify differential patterns of restenotic tissue after stenting. This information could help in understanding the mechanism of stent restenosis.


[Research on Japanese monograph of comprehensive dietetic materia medica, the Pao chu bei yong wo ming ben cao (Japanese Materia Medica Prepared for Kitchen)].
Japanese physicians of Edo Period (1603-1867) wrote many dietetic books, by combining the knowledge system (content and compiling style) and thoughts of diet therapy from China with local condition in Japan. Among them, the Pao chu bei yong wo ming ben cao(Japanese Materia Medica Prepared for Kitchen), written by Mukai Genshou, a physician in the early Edo, is the earliest comprehensive work of dietetic materia medica. In this book, the choice and usage of Japanese dietetic materia medica reveals obvious Japanese local color, including the name, morphology, cultivation, collection, identification, nature and flavor, and indication etc., reflecting the sprouting idea of edible herbal plant at the beginning of Edo period and the characteristic of absorbing Chinese diet thoughts by Japanese physician. This is the important first-hand historical material to understand the development of Japanese dietetic herbalism in early Edo and its dietotherapy culture.


[The problem of hygienic standardization of commercial electric and magnetic fields in Russia and other countries].
Review of standards show that many countries still have no hygienic regulations concerning the electric and magnetic fields of commercial frequencies. National standards have been developed by only a few countries. In a number of countries guidelines for protection from the electric fields have been elaborated with the magnetic component disregarded. National standards show a significant difference, too. In most cases the maximum admissible levels are approximate and ignore potential synergetic biological effects of the agents; many of them do not set an adequate coefficient of the hygienic margin or foresee possible carcinogenous risk.


Evaluation of the effect of haemodialysis on cardiac dysfunction in patients of chronic renal failure.
Thirty-eight patients with end stage renal disease who were on haemodialysis and had recurrent congestive cardiac failure were analysed. Echocardiographic findings were evaluated at start of haemodialysis and after 6 dialysis sessions. Seventeen cases (48%) had diastolic dysfunction, 11 (29%) systolic dysfunction 8 (18%) had normal echocardiogram and 2 (5%) had dilated left ventricle with normal ejection fraction. In the systolic dysfunction group the end diastolic diameter decreased after 6 dialysis sessions. In the diastolic dysfunction group the end diastolic diameter and ejection fraction decreased minimally. In the systolic dysfunction group 8 patients (42%) expired within 18 months with a mean survival of 5 months and in the diastolic dysfunction group 5 patients (28%) died within 18 months with a mean survival of 12 months.


[Experience with water births: a prospective longitudinal study of 9 years with almost 4,000 water births].
This prospective, longitudinal study spanning more than 9 years examines the influence of the birthing method, in particular water birth, on neonatal and maternal morbidity and mortality. Using questionnaires, maternal and neonatal data of 9,518 spontaneous singleton births with cephalic presentation, including 3,617 water births and 5,901 land births, were compared. Land births show significantly higher rates of episiotomies as well as third- and fourth-degree perineal tears. Waters births show a significantly higher rate of births 'without injuries', first- and second-degree perineal tears, vaginal and labial tears. The average loss of blood after water birth is -5.26 g/l; this is statistically significantly less than after land births at -8.08 g/l. In 69.7%, water births required no analgesic, compared to 30.3% for land births. Water and land births do not differ with respect to maternal and neonatal infections. After land births, there was a significantly higher rate of newborn complications with subsequent transfer to an external NICU. There were neither maternal nor neonatal deaths related to the birthing event. Water births are just as safe as land births if obstetrical guidelines are followed. Risks, such as preeclampsia, signs of infection, meconium-stained amniotic fluid and pathological CTG, are found more frequently in land births and indicate that a safe and prospective birth management is being followed.


[Breast prostheses and their complications].
In the past few years silicone breast implants have been a highly charged and controversial topic for psychologic, health and politico-legal reasons for patients and for surgical, medical and research concern for professionals. Both sides are interested in knowing about the complications encountered with these implants on one hand and to find the ideal device needed for mammary reconstruction on the other. Indeed silicone does not fulfill the characteristics initially expected for a synthetic soft-tissue substitute. The local cellular response leads to the formation of a capsule around the implant with frequently unsatisfying cosmetic results. The well described leakage occurring through the silicone envelope allows the silicone gel to diffuse to multiple anatomic areas in the body. Scientific works demonstrated that silicone gel acts as a potent immunologic adjuvant and can induce antibodies to silicone surface-associated antigens. Breast implanted women who present with systemic clinical symptoms can be included either in the group of well defined connective tissue diseases or in the atypical connective tissue disease-like syndrome. The largest epidemiologic studies have shown reassuring evidence against large hazards but have documented a low but statistically significant risk of connective-tissue diseases in women with silicone gel filled implants. Practitioners must manage these patients with the awareness that reliable objective tests to identify the useful problem are not yet available.


Fluorescence In Situ Hybridization to Maize (Zea mays) Chromosomes.
Fluorescence In Situ Hybridization (FISH) is the annealing of fluorescent DNA probes to their complementary sequences on prepared chromosomes and subsequent visualization with a fluorescent microscope. In maize, FISH is useful for distinguishing each of the ten chromosomes in different accessions (karyotyping), roughly mapping single genes, transposable elements, transgene insertions, and identifying various chromosomal alterations. FISH can also be used to distinguish chromosomes between different Zea species in interspecific hybrids by use of retroelement painting. © 2016 by John Wiley & Sons, Inc.


Paradoxical embolism with a patent foramen ovale and atrial septal aneurysm.
Patent foramen ovale (PFO) and atrial septal aneurysm have been cited as potential risk factors for cryptogenic stroke. We present two cases which we propose to directly illustrate paradoxical embolisation as a mechanism of cerebrovascular accident. The diagnosis of PFO is discussed and the literature reviewed.


Neuroprotection of glial cell line-derived neurotrophic factor in damaged spinal cords following contusive injury.
Glial cell line-derived neurotrophic factor (GDNF) acts as a potent survival factor for many neuronal populations, including spinal motoneurons, indicating the therapeutic promise of GDNF for neurological disorders. Injury to spinal cord (SCI) triggers processes destructive to ascending sensory and descending motor conduction and extends tissue loss, thereby leading to permanent behavioral dysfunction. In this study, we attempted to examine whether GDNF protects neurons from SCI and subsequently lessens locomotor deficit in SCI rats. We utilized the NYU weight-drop device developed at New York University to induce spinal cord contusion at the T9-10 spinal segment. After SCI, GDNF was administrated into the cord 1-2 mm rostral and caudal to the epicenter. Animals receiving GDNF treatment showed significant improvement over phosphate-buffered saline (PBS)-treated controls on the Basso Beattie Bresnahan (BBB) locomotor rating scale (P < 0.01-0.001). GDNF treatment increased the remaining neuronal fibers with calcitonin gene-related peptide, neurofilament, and growth-associated protein 43 immunoreactivity in injured spinal tissues compared with PBS-treated controls. Moreover, treatment with GDNF caused approximately 50% cell survival in the contused spinal cord tissues. Examination of signal transduction triggered by GDNF indicated that GDNF injection transiently induced activation of the mitogen-activated protein (MAP) kinase pathway in the spinal cord. Additionally, an up-regulation of anti-apoptotic Bcl-2 levels in the contusive center of the damaged spinal cord was observed 24 hr post-GDNF injection. Together our results show that GDNF exerts behavioral and anatomic neuroprotection following SCI. Additionally, GDNF-activated MAP kinase and Bcl-2 signaling may contribute to neuronal survival after spinal cord contusion.


Functional defecation disorders in children: comparing the Rome II with the Rome III criteria.
To evaluate the prevalence of pediatric functional defecation disorders (FDD) using the Rome III criteria and to compare these data with those obtained using Rome II criteria. A chart review was performed in patients referred to a tertiary outpatient clinic with symptoms of constipation and/or fecal incontinence. All patients received a standardized bowel questionnaire and physical examination, including rectal examination. The prevalence of pediatric FDD according to both Rome criteria sets was assessed. Patients with FDD (n = 336; 61% boys, mean age 6.3 ± 3.5 SD) were studied: 39% had a defecation frequency ≤ 2/wk, 75% had fecal incontinence, 75% displayed retentive posturing, 60% had pain during defecation, 49% passed large diameter stools, and 49% had a palpable rectal fecal mass. According to the Rome III criteria, 87% had functional constipation (FC) compared with only 34% fulfilling criteria for either FC or functional fecal retention based on the Rome II definitions (P < .001). Of the patients with a rectal fecal mass, 95% would also have been correctly identified as having FC without a rectal examination. Twenty-nine patients (11%) fulfilled the criteria for functional nonretentive fecal incontinence according to both the Rome II and Rome III criteria. The pediatric Rome III criteria for FC are less restrictive than the Rome II criteria. The Rome III criteria are an important step forward in the definition and recognition of FDD in children.


An in vitro model for investigating impedance changes with cell growth and electrical stimulation: implications for cochlear implants.
The impedance of stimulating electrodes used in cochlear implants and other neural prostheses often increases post-implantation, and is thought to be due to fibrous tissue encapsulation of the electrode array. Increased impedance results in higher power requirements to stimulate target neurons at set charge densities. We developed an in vitro model to investigate the electrode-tissue interface in a highly controlled environment. This model was tested using three cell types, with and without charge-balanced biphasic electrical stimulation. Under standard tissue culture conditions, a monolayer of cells was grown over the electrode surface. Electrode impedance increased in proportion to the extent of cell coverage of the electrode. Cell type was a significant factor in the amount of impedance increase, with kidney epithelial cells (MDCK) creating the greatest impedance, followed by dissociated rat skin fibroblasts and then macrophages (J774). The application of electrical stimulation to cell-covered electrodes caused impedance fluctuations similar to that seen in vivo, with a lowering of impedance immediately following stimulation, and a recovery to pre-stimulation levels during inactive periods. Examination of these electrodes suggests that the stimulation-induced impedance changes were due to the amount of cell cover over the electrodes. This in vitro technique accurately models the changes in impedance observed with neural prostheses in vivo, and shows the close relationship between impedance and tissue coverage adjacent to the electrode surface. We believe that this in vitro approach holds great promise to further our knowledge of the mechanisms contributing to electrode impedance.


The qualitative assessment of general movements in preterm, term and young infants--review of the methodology.
We describe the state of the art of Prechtl's method for the qualitative assessment of general movements as a diagnostic tool for early detection of brain dysfunction. After discussing the optimal technique for video recording general movements in preterm, term and young infants, attention is focused on the proper analysis of this spontaneous motor pattern. Recently, a group of active researchers in the field reached consensus on the various qualities of normal and abnormal general movements. These definitions are reported here in full. Since it is a newly introduced method careful investigation into its reliability is required. Various groups of investigators have obtained data which demonstrate the robust character of the method (interscorer agreement: 78-98%). Finally, we discuss the validity of this early assessment method on the basis of the reports published so far. While the method's sensitivity is similar in all age groups studied (preterm, term, first month, second month, and third month age epochs), and averages 94.5%, the specificity of the method is age-dependent. It is low during the early ages, increases gradually and reaches 82 to 100% at 3 months post-term. This phenomenon is explained by spontaneous recovery of early dysfunction. In contrast, consistent abnormalities of general movements are linked to neurological deficits found at the 2 year follow-up.


Autologous patch graft in tube shunt surgery.
To evaluate an alternate method of covering the subconjunctival portion of the tube in aqueous shunt surgery. Evidence of tube erosion, graft-related infection, graft melting, or other associated intraocular complications were evaluated. A retrospective study of 16 patients (17 eyes) who underwent tube shunt surgery at Wills Eye Hospital between July 1991 and October 1996 was conducted. An autologous either "free" or "rotating" scleral lamellar graft was created to cover the subconjunctival portion of the tube shunt. All patients were evaluated for at least 6 months, with a mean follow-up of 14.8 months (range 6-62 months). All eyes tolerated the autologous graft well, with no clinical evidence of tube erosion, or graft-related or intraocular complications. Autologous patch graft in tube shunt surgery appears--in selected cases--to be an effective, safe and inexpensive surgical alternative to allogenic graft materials. It also offers ease of availability, and eliminates the risk of transmitting infectious disease.


Translational regulation of ribosomal protein S15 drives characteristic patterns of protein-mRNA epistasis.
Do coding and regulatory segments of a gene co-evolve with each-other? Seeking answers to this question, here we analyze the case of Escherichia coli ribosomal protein S15, that represses its own translation by specifically binding its messenger RNA (rpsO mRNA) and stabilizing a pseudoknot structure at the upstream untranslated region, thus trapping the ribosome into an incomplete translation initiation complex. In the absence of S15, ribosomal protein S1 recognizes rpsO and promotes translation by melting this very pseudoknot. We employ a robust statistical method to detect signatures of positive epistasis between residue site pairs and find that biophysical constraints of translational regulation (S15-rpsO and S1-rpsO recognition, S15-mediated rpsO structural rearrangement, and S1-mediated melting) are strong predictors of positive epistasis. Transforming the epistatic pairs into a network, we find that signatures of two different, but interconnected regulatory cascades are imprinted in the sequence-space and can be captured in terms of two dense network modules that are sparsely connected to each other. This network topology further reflects a general principle of how functionally coupled components of biological networks are interconnected. These results depict a model case, where translational regulation drives characteristic residue-level epistasis-not only between a protein and its own mRNA but also between a protein and the mRNA of an entirely different protein.


[Cutaneous non-Langerhans cells histiocytoses as cause of central diabetes insipidus].
The histiocytoses are rare diseases caused by alterations in the monocyte-histiocytic series with several clinical findings. Among the cutaneous syndromes of non-Langerhans cells, xanthoma disseminatum is the only disease of this group that has been classically associated to the central diabetes insipidus (CDI). The case reported describes a 30-year-old man that two years after presenting with CDI developed non confluent disseminated cutaneous brown papular lesions throughout the body. The histopathology, immunohistochemistry, and electronic microscopy were compatible with the diagnosis of non-Langerhans histiocytoses, suggesting the diagnosis of juvenile xanthogranuloma. The endocrine-metabolic evaluation did not show other alterations besides CDI in a 10-year follow up. The magnetic resonance of hypophysis showed absence of the pituitary hyperintense sign (bright spot). The radiologic and scinthigraphic evaluation of the bones did not show the presence of osteolytic lesions. This case prints out the importance of skin examination in cases of CDI and its association with cutaneous non-Langerhans histiocytoses in a broader spectrum, rather then restricted to the cases of xanthoma disseminatum.


A comparison of mosquito predation by the fish Pseudomugil signifier Kner and Gambusia holbrooki (Girard) in laboratory trials.
Using larval Cx. annulirostris mosquitoes, this study compared the predation rate of Pseudomugil signifer and Gambusia holbrooki for four larval instars, three prey densities, and three vegetation densities. There was no significant difference in the quantity of first, second, and third instar larvae consumed by the two fish species after 24 h. There was a significant negative relationship between the predation rate and both larval instar and prey density for both fish species. In simulated vegetation trials, P. signifer performed marginally better than G. holbrooki in medium to high density vegetation (0.3 stems/cm 2 and 0.6 stems/cm2, respectively).


Imaging Acute Neuromuscular Explants from Thy1 Mouse Lines.
Because core facilities that generate transgenic founder mice for a reasonable fee are now available at most major research institutions, generating new Thy1-XFP transgenic animals (in which XFP stands for any fluorescent protein) is an option even for relatively small laboratories. Here, we provide a protocol for screening offspring of Thy1 transgenic founders. Acute neuromuscular explants are obtained from 3-wk-old F1 mice that have been produced by crossing Thy1 transgenic founders and commercially obtained inbred mice. Thy1-driven expression is detected by fluorescence microscopy.


Risk Prediction Models for Colorectal Cancer Incorporating Common Genetic Variants: A Systematic Review.
Colorectal cancer screening reduces colorectal cancer incidence and mortality. Risk models based on phenotypic variables have relatively good discrimination in external validation and may improve efficiency of screening. Models incorporating genetic variables may perform better. In this review, we updated our previous review by searching Medline and EMBASE from the end date of that review (January 2014) to February 2019 to identify models incorporating at least one SNP and applicable to asymptomatic individuals in the general population. We identified 23 new models, giving a total of 29. Of those in which the SNP selection was on the basis of published genome-wide association studies, in external or split-sample validation the AUROC was 0.56 to 0.57 for models that included SNPs alone, 0.61 to 0.63 for SNPs in combination with other risk factors, and 0.56 to 0.70 when age was included. Calibration was only reported for four. The addition of SNPs to other risk factors increases discrimination by 0.01 to 0.06. Public health modeling studies suggest that, if determined by risk models, the range of starting ages for screening would be several years greater than using family history alone. Further validation and calibration studies are needed alongside modeling studies to assess the population-level impact of introducing genetic risk-based screening programs.


Radiographic study of the size of the first metatarso-digital segment in feet with incipient hallux limitus.
The aim of this study is to confirm whether the absolute and relative lengths of the first metatarso-digital segment is greater than normal in incipient hallux limitus deformity. In a sample of 144 dorsoplantar radiographs under weightbearing conditions (94 of normal feet and 50 of feet with a slightly stiff hallux), measurements were made of the relative first metatarsal protrusion, the length and width of the first metatarsal and of the proximal phalanx of the hallux, the length of the distal phalanx of the hallux, and the total length of the hallux. There were significant differences between the two types of feet in the relative first metatarsal protrusion, the width of the first metatarsal, the length and width of the proximal phalanx of the hallux, the length of the distal phalanx, and the total length of the hallux. The size of the first metatarso-digital segment could be implicated in the development of hallux limitus deformity.


Dilated cardiomyopathy in non-specific aortoarteritis.
Out of 195 cases of Takayasu's arteritis who presented in our institute between January 1988 and December 1997, 12 (5.58%) had dilated cardiomyopathy. Age of these patients ranged from 10 to 30 years (17.25 +/- 5.30 years) and male-female ratio was 1:11. All the cases had cardiovascular system features (dyspnoea, oedema, palpitation, angina, etc. but without hypertension), three had central nervous system features (headache, vomiting, convulsion etc.) and all had general systemic features like weight loss, malaise, fever, arthralgia etc. Electrocardiography, chest X-ray and echocardiographic findings were consistent with dilated cardiomyopathy. Haemodynamic findings showed raised left ventricular end-diastolic pressure and pulmonary capillary wedge pressure in all; raised pulmonary artery pressure, pulmonary vascular resistance, right ventricular pressure and right atrial pressure in 6, 6, 4 and 2 cases, respectively; reduced left ventricular peak systolic pressure in 10 cases but central aortic pressure and systemic vascular resistance in all the cases were within normal limits. Angiography showed type I, II and III involvement in 7 (majority), 3 and 2 cases, respectively. Coronary and pulmonary angiography were normal and left ventricular angiography showed poor left ventricular systolic function in all the cases. Histopathological study (on 3 autopsy cases) showed non-specific inflammation of myocardium with lymphocyte/mononuclear cell infiltration and normal coronary vessels. So, dilated cardiomyopathy in Takayasu's arteritis is not rare, though not much reported, and can influence the prognosis of aortoarteritis cases.


Long-axis rotation: a missing degree of freedom in avian bipedal locomotion.
Ground-dwelling birds are typically characterized as erect bipeds having hind limbs that operate parasagittally. Consequently, most previous research has emphasized flexion/extension angles and moments as calculated from a lateral perspective. Three-dimensional (3D) motion analyses have documented non-planar limb movements, but the skeletal kinematics underlying changes in foot orientation and transverse position remain unclear. In particular, long-axis rotation of the proximal limb segments is extremely difficult to measure with topical markers. Here, we present six degree of freedom skeletal kinematic data from maneuvering guineafowl acquired by marker-based XROMM (X-ray Reconstruction of Moving Morphology). Translations and rotations of the hips, knees, ankles and pelvis were derived from animated bone models using explicit joint coordinate systems. We distinguished sidesteps, sidestep yaws, crossover yaws, sidestep turns and crossover turns, but birds often performed a sequence of blended partial maneuvers. Long-axis rotation of the femur (up to 38 deg) modulated the foot's transverse position. Long-axis rotation of the tibiotarsus (up to 65 deg) also affected medio-lateral positioning, but primarily served to either re-orient a swing phase foot or yaw the body about a stance phase foot. Tarsometatarsal long-axis rotation was minimal, as was hip, knee and ankle abduction/adduction. Despite having superficially hinge-like joints, birds coordinate substantial long-axis rotations of the hips and knees to execute complex 3D maneuvers while striking a diversity of non-planar poses.


Investigating cADPR and NAADP in intact and broken cell preparations.
The body of literature characterizing cyclic adenosine diphosphoribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP) as Ca2+-mobilizing second messengers is growing apace. However, their unique properties may, for the uninitiated, make them difficult to work with. This article reviews many of the available techniques (and associated pitfalls) for investigating these nucleotide messengers, predominantly focusing upon optical techniques using fluorescent reporters to measure Ca2+ in the cytosol as well as Ca2+ or pH within the lumen of intracellular organelles.


Selection of patients with hemoptysis for fiberoptic bronchoscopy.
One hundred ten hospitalized patients with hemoptysis were reviewed to identify factors that would characterize those with malignancy and to evaluate the usefulness of fiberoptic bronchoscopy (FB) in the diagnosis of hemoptysis. Seventy patients underwent FB. This procedure was diagnostic in 22/28 (79 percent) of the carcinoma patients and in 26/42 (62 percent) of the patients with a nonmalignant cause of hemoptysis. The following three characteristics indicate a high probability of malignancy: 1) age greater than 40 years, 2) any abnormality on the chest roentgenogram, 3) hemoptysis lasting greater than one week. If any of these factors are present, FB should be done. Other factors to be considered include presence of anemia, weight loss, persistent cough, long smoking history and risk of bronchoscopic complications.