Non-equilibrium effects of molecular motors on polymers.

We present a generic coarse-grained model to describe molecular motors acting on polymer substrates, mimicking, for example, RNA polymerase on DNA or kinesin on microtubules. The polymer is modeled as a connected chain of beads; motors are represented as freely diffusing beads which, upon encountering the substrate, bind to it through a short-ranged attractive potential. When bound, motors and polymer beads experience an equal and opposite active force, directed tangential to the polymer; this leads to motion of the motors along the polymer contour. The inclusion of explicit motors differentiates our model from other recent active polymer models. We study, by means of Langevin dynamics simulations, the effect of the motor activity on both the conformational and dynamical properties of the substrate. We find that activity leads, in addition to the expected enhancement of polymer diffusion, to an effective reduction of its persistence length. We discover that this effective "softening" is a consequence of the emergence of double-folded branches, or hairpins, and that it can be tuned by changing the number of motors or the force they generate. Finally, we investigate the effect of the motors on the probability of knot formation. Counter-intuitively our simulations reveal that, even though at equilibrium a more flexible substrate would show an increased knotting probability, motor activity leads to a marked decrease in the occurrence of knotted conformations with respect to equilibrium.

Phosphorescent iridium-containing nanomicelles: synthesis, characterization and preliminary applications in nanomedical imaging.

Diagnostic nanomedicine constantly requires the development of novel contrast agents with intrinsic imaging capabilities. Phosphorescent Ir(iii)-complexes represent good candidates when delivered through polymeric nanoparticles. In this work, we propose a biocompatible nanoparticle made from an intrinsically phosphorescent copolymer, synthesized directly with an imaging tag present on its backbone. Polymeric nanoparticles can be obtained with the exact amount of phosphorescent moieties needed to maximize their output signal. Complete characterization and ex vivo studies confirmed that this nanosystem is suitable as a future diagnostic tool.

Cardiorespiratory events in infants with gastroesophageal reflux symptoms: Is there any association?

BACKGROUND: Cardiorespiratory (CR) events (apnea, bradycardia, oxygen desaturation) and gastroesophageal reflux (GER) symptoms often coexist in infants admitted to Neonatal Intensive Care Unit, leading to over-prescription of drugs and delayed discharge. We aimed to evaluate the relationships between CR and GER events. METHODS: The temporal associations between CR and GER events were analyzed in symptomatic infants who underwent synchronized CR and pH-impedance monitoring. The symptom association probability (SAP) index was used to identify infants with a significant number of temporal associations. Gastroesophageal reflux characteristics and the chronological sequence of CR and GER events occurring within 30 seconds of each other were evaluated according to SAP index. KEY RESULTS: Of the 66 infants enrolled, aged 29 (18-45) days, 58 had CR events during monitoring. From these 58 patients, a total of 1331 CR events and 5239 GER (24% acidic) were detected. The SAP index was positive in seven (12%) infants. These infants had greater GER frequency, duration, and proximal extent (P < .05). The number of temporal associations was 10 times greater in the positive SAP group. Gastroesophageal reflux events preceded CR events in 83% of these associations. These GER events had a higher proximal extent (P = .004), but showed no differences in pH values. CONCLUSIONS & INFERENCES: The simultaneous evaluation of CR and GER events could be useful to identify infants with severe GER and significant temporal associations between these events. Treatment of GER could be indicated in these infants, but as the GER events involved are mainly non-acidic, empirical treatment with antacids is, often, inappropriate.

Straightforward synthesis of a novel ring-fused pyrazole-lactam and in vitro cytotoxic activity on cancer cell lines.

In this paper a straightforward synthesis of a novel pyrazole derivative is reported. Prominent feature of this synthetic process is a 1,3-Dipolar Cycloaddition of a suitable nitrile imine with an activated α,ß-unsaturated lactam to afford directly and regioselectively the corresponding ring-fused pyrazole. Having obtained the central core of the synthetic target, a double stepwise functionalization with a "side chain" characterized by a terminal cyclic aliphatic amine was carried out. This molecular structure was designed to interact strongly with typical biological residues, and indeed it showed potent anticancer capability: in vitro cytotoxicity test on five different cancer cell lines showed interesting IC50 values in the range of 15-60 µM for exposure time of 24-72 h, thus resulting comparable with commercially available and nowadays therapeutically exploited anticancer compounds, such as 5-FU and NVP-BEZ235.

Congenital esophageal stenosis diagnosed in an infant at 9 month of age.

Esophageal stenosis is a relatively uncommon condition in pediatrics and requires an accurate diagnostic approach. Here we report the case of a 9-month old female infant who presented intermittent vomiting, dysphagia and refusal of solid foods starting after weaning. She was treated for gastroesophageal reflux. At first, radiological investigation suggested achalasia, while esophagoscopy revelaed a severe congenital esophageal stenosis at the distal third of the esophagus. She underwent four endoscopic balloon dilatations that then allowed her to swallow solid food with intermittent mild dysphagia. After 17 months of esomeprazole treatment off therapy impedance-pH monitoring was normal. At 29 months of follow-up the child is asymptomatic and eats without problems.Infants with dysphagia and refusal of solid foods may have undiagnosed medical conditions that need treatment. Many disorders can cause esophageal luminal stricture; in the pediatric age the most common are peptic or congenital. Careful assessment with endoscopy is needed to diagnose these conditions early and referral to a pediatric gastroenterologic unit may be necessary.

Surface chemistry and entrapment of magnesium nanoparticles into polymeric micelles: a highly biocompatible tool for photothermal therapy.

A novel highly biocompatible nanosystem containing Mg nanoparticles is reported, characterized and tested as a suitable and non-toxic tool for photothermal therapy.

Gonadal and uterine function in female survivors treated by chemotherapy, radiotherapy, and/or bone marrow transplantation for childhood malignant and non-malignant diseases.

OBJECTIVE: To evaluate gonadal function and uterine volume in a cohort of female survivors treated by chemotherapy, radiotherapy, and/or stem cell transplantation (SCT) for childhood malignant and non-malignant diseases. DESIGN: An observational study. SETTING: S. Matteo Hospital, Pavia, Italy. POPULATION: A cohort of 135 female survivors. METHODS: A clinical, hormonal, and ultrasonographic evaluation. Thirty-three patients (24%) had non-malignant haematologic diseases (thalassaemia or sickle cell anaemia), 68 (50%) had leukaemia, 23 (17%) had lymphomas, and 11 (8%) had solid tumours. In total, 106 patients had received SCT, preceded by a conditioning regimen. MAIN OUTCOME MEASURES: Anti-Müllerian hormone (AMH) and Inhibin-B, and uterine volume. RESULTS: The median concentrations of AMH and Inhibin-B in the entire cohort were 0.12 ng/ml (interquartile range, IQR, 0.1-0.5 ng/ml) and 3.5 pg/ml (IQR 0.1-13.2 pg/ml), respectively. In a stepwise ordered logistic regression analysis, conventional chemotherapy for the treatment of malignancies, as opposed to total body irradiation (TBI), was the only oncologically significant predictor of increased AMH levels (OR 4.8, 95% CI 1.9-12, P < 0.001). Conditioning treatment before or after menarche did not influence AMH concentrations (P = 0.24). The best predictor of reduced uterine volume was TBI during the preparation for the allograft (OR 3.5, 95% CI 1.4-8.4, P = 0.006). Increasing age at treatment (OR 0.86, 95% CI 0.77-0.95, P = 0.04), chemotherapy, as opposed to other treatments (OR 0.09, 95% CI 0.03-0.28, P < 0.001), and solid tumours as opposed to either leukaemia/lymphomas or non-malignant diseases (OR 0.2, 95% CI 0.07-0.56, P = 0.002) were associated with larger uterine volumes. CONCLUSIONS: Conditioning therapies for SCT, including TBI, had the worst effects on uterine volume and gonadal reserve. Increasing age at treatment and conventional chemotherapy were associated with less detrimental effects on uterine volume.

Effects of uncomplicated vaginal delivery and epidural analgesia on fetal arterial acid-base parameters at birth in gestational diabetes.

AIM: To investigate the effects of uncomplicated vaginal delivery and epidural analgesia on fetal acid-base parameters in women with gestational diabetes (GDM) compared with controls. METHODS: A retrospective case-control study of 142 women with gestational diabetes and 284 controls. To evaluate the effect of diabetes and analgesia on acid-base status correcting for potential confounders we used ordered logistic equations including quartiles of fetal arterial acid-base parameters collected at birth as outcomes and categories of diabetes and epidural analgesia as explanatory variables. RESULTS: In the GDM group cord base deficit (-2.63 mmol/l, interquartile range [IQR]=4.2 to -0.65 mmol/l vs. -1.9 mmol/l, IQR=-3.3 to -0.2 mmol/l, p=0.009, odds ratio (OR)=1.51, 95% confidence interval (CI)=1.04-2.18) was lower and concentration of calcium higher (1.49 mmol/l, IQR=1.42-1.56 mmol/l vs. 1.47 mmol/l, IQR=1.41-1.51 mmol/l, p=0.009, OR=1.69, 95% CI=1.12-2.56) compared with controls. Epidural analgesia in the GDM group was associated with reduced cord concentration of glucose (84.0mg/dl [4.7 mmol/l], IQR=70-103.3mg/dl vs. 92.5mg/dl [5.1 mmol/l], IQR=76.5-121.8 mg/dl, p=0.004), lactate (2.65 mmol/l (IQR=1.80-4.20) vs. 3.70 mmol/l (IQR=2.90-5.55 mmol/l), p=0.002) and less pronounced base deficit (-2.05 mmol/l, IQR=-3.90 to -0.17 mmol/l vs. -2.8, IQR=-5.57 to -1.05 mmol/l, p=0.01, OR=0.7, 95% CI=0.49-0.99). CONCLUSIONS: In uncomplicated pregnancies and deliveries, well-controlled gestational diabetes mellitus has potentially significant detrimental effects on fetal acid-base status at birth. Epidural analgesia reduces cord arterial glucose and lactates.

Comparison of the magnetic, radiolabeling, hyperthermic and biodistribution properties of hybrid nanoparticles bearing CoFe2O4 and Fe3O4 metal cores.

Metal oxide nanoparticles, hybridized with various polymeric chemicals, represent a novel and breakthrough application in drug delivery, hyperthermia treatment and imaging techniques. Radiolabeling of these nanoformulations can result in new and attractive dual-imaging agents as well as provide accurate in vivo information on their biodistribution profile. In this paper a comparison study has been made between two of the most promising hybrid core-shell nanosystems, bearing either magnetite (Fe3O4) or cobalt ferrite (CoFe2O4) cores, regarding their magnetic, radiolabeling, hyperthermic and biodistribution properties. While hyperthermic properties were found to be affected by the metal-core type, the radiolabeling ability and the in vivo fate of the nanoformulations seem to depend critically on the size and the shell composition.

Specific muscle-tendon architecture in elite Kenyan distance runners.

The Achilles tendon moment arm (MA_AT) and foot lever ratio (FLR) can play important roles for force production and movement economy during locomotion. This notion has become more relevant, and suggestion has been given that the Kenyan runners belonging to the world elite would have specific anatomical, mechanical, and functional properties in their lower limbs and that this feature could be responsible for their high running economy. The present study aimed to characterize the AT of elite Kenyan distance runners as compared with Japanese ones, and to examine the potential relationship with their running performance. Ultrasonography was used to measure AT cross-sectional area and AT soleus and gastrocnemius lengths. MA_AT and FLR were calculated from the position of anatomical landmarks using sagittal plane photographs. MA_AT was significantly longer and the FLR lower in Kenyans than in Japanese. Independently of the group, the running performance was positively related to the MA_AT (r = 0.55, P < 0.001) and negatively to the FLR (r = -0.45, P = 0.002). These results suggest that longer MA_AT and lower FLR could be advantageous in elite Kenyan runners, by contributing to effective endurance running performance in a protective and economical way.

Muscle-tendon interaction and EMG profiles of world class endurance runners during hopping.

The present study examined the muscle-tendon interaction of ten international level Kenyan runners. Ultrasonography and kinematics were applied together with EMG recordings of lower limb muscles during repetitive hopping performed at maximal level. The ten Kenyans had longer gastro Achilles tendon at rest (p < 0.01) as compared with ten control subjects matched in height. Conversely, the stretching and shortening amplitudes of the tendinous tissues of the medial gastrocnemius (MG) muscle were significantly smaller in the Kenyans than in controls during the contact phase of hopping. This applied also to the fascicle length changes, which were smaller and more homogeneous among Kenyans. These limited musculo-tendinous changes resulted in higher maximal hopping height and in larger power despite their reduced body weight. The associated finding of a greater shortening to stretching ratio of the MG tendinous tissues during contact could imply that the Kenyan MG muscle-tendon unit is optimized to favor efficient storage and recoil of elastic energy, while operating at optimal muscle fascicle working range (plateau region).

Relationship between sleep/wakefulness and gastroesophageal reflux in symptomatic newborns.

The state of sleep/wakefulness is well known to influence esophageal acid exposure and the number of acid refluxes whereas it is uncertain whether the same is true of the non-acid refluxes that predominate in the newborns. To investigate the relationship between sleep/wakefulness and refluxes 45 newborns with gastroesophageal reflux symptoms were studied with combined multichannel intraluminal impedance and pH monitoring. We found that sleep/wakefulness influenced acid and weakly acidic reflux frequency (awake 2.6+/-0.8; asleep 2.1+/-1.1; p=0.006). A negative correlation was found between sleepness periods and the mean reflux duration for both acid (R=0.55;p < 0.001) and weackly acidic (R=0.51;p < 0.001) refluxes. This finding may raise some concerns about the over-prescription of antacid drugs in newborns.

Faecal microbiota in breast-fed infants after antibiotic therapy.

AIM: To evaluate modifications of gut microbiota after antibiotic therapy in breast-fed infants. STUDY DESIGN: Twenty-six exclusively breast-fed infants younger than 5 months hospitalized for pneumonia treated with ceftriaxone (50 mg per kilo per day administered intramuscularly) were recruited. Intestinal microbiota at day 0 - before starting antibiotic administration - at the end of the therapy (5 days after) and after 15 days after the stop was analysed. Stool samples were collected and immediately diluted and cultured on selective media to detect total bacteria, Enterobacteriaceae, enterococci and lactobacilli. Statistical analysis was performed by using Wilcoxon test. RESULTS: After 5 days of antibiotic therapy, we observed a significant reduction in total faecal bacterial count (p = 0.003) in Enterobacteriaceae (p = 0.001) and enterococci (p < 0.001), in comparison with day 0. After 5 days of therapy, lactobacilli are no longer detected. Conversely, bacterial count values for all bacteria detected after 15 days from the end of therapy are significantly increased and similar to day 0. CONCLUSION: Our findings showed that gut microbiota was significantly modified after 5 days of antibiotic therapy; exclusively, breast-feeding may be relevant in promoting the re-establishment of gut microbiota composition in early infancy.

[Advances on the effects of the compounds of a phytotherapic agent (COLIMIL) on upper gastrointestinal transit in mice]. / Effetto di estratti titolati di Matricariae recutita, Foeniculum vulgare e Melissa officinalis (COLIMIL) sul transito gastrointestinale nei topi in vivo.

AIM: Phytotherapic agents, such as herbal formulations containing Matricariae recutita flowers (chamomile) extract, Foeniculum vulgare fruit (fennel) extract and Melissa officinalis aerial parts (lemon balm) extract have beneficial effects on gastrointestinal tract in colicky infants. However, the mechanism is largely unexplored and, particularly, it is not clear if it affects intestinal motility. The aim of this experimental study was to evaluate the effect of different herbal formulations containing Matricariae recutita extract, Foeniculum vulgare extract and Melissa officinalis extract on upper gastrointestinal transit in mice in vivo. METHODS: Gastrointestinal transit was measured in male ICR mice and in croton oil-treated mice after the oral administration of herbal formulations containing chamomile, fennel and lemon balm (ColiMil) and chamomile and lemon balm (ColiMil experimental). RESULTS: The herbal formulations tested (0.4-0.8 mL/mouse) dose-dependently and significantly inhibited gastrointestinal transit both in control and in croton oil-treated mice. Chamomile extract and lemon balm extract reduced significantly intestinal motility, but not fennel. At similar concentration ColiMil evoked a more consistent response than ColiMil experimental. CONCLUSION: Our findings directly demonstrate in vivo the effect of a combination of herbal formulations on intestinal motility. The observed inhibitory effect might be studied with clinical studies to test the efficacy of these compounds in the treatment of colicky infants.

Video-electrographic and clinical features in patients with ictal asystole.

OBJECTIVE: Ictal asystole (IA) is a rare event mostly seen in patients with temporal lobe epilepsy (TLE) and a potential contributor to sudden unexplained death in epilepsy (SUDEP). Clinical and video-electroencephalographic findings associated with IA have not been described, and may be helpful in screening for high risk patients. METHODS: A database search was performed of 6,825 patients undergoing long-term video-EEG monitoring for episodes of IA. RESULTS: IA was recorded in 0.27% of all patients with epilepsy, eight with temporal (TLE), two with extratemporal (XTLE), and none with generalized epilepsy. In 8 out of 16 recorded events, all occurring in patients with TLE, seizures were associated with a sudden atonia on average 42 seconds into the typical semiology of a complex partial seizure. The loss of tone followed after a period of asystole usually lasting longer than 8 seconds and was associated with typical EEG changes seen otherwise with cerebral hypoperfusion. Clinical predisposing factors for IA including cardiovascular risk factors or baseline ECG abnormalities were not identified. CONCLUSION: Ictal asystole is a rare feature of patients with focal epilepsy. Delayed loss of tone is distinctly uncommon in patients with temporal lobe seizures, but may inevitably occur in patients with ictal asystole after a critical duration of cardiac arrest and cerebral hypoperfusion. Further cardiac monitoring in patients with temporal lobe epilepsy and a history of unexpected collapse and falls late in the course of a typical seizure may be warranted and can potentially help to prevent sudden unexplained death in epilepsy.

Adult polyglucosan body disease.

We describe a case of adult polyglucosan body disease with characteristic clinical symptoms of peripheral neuropathy, upper motor neuron signs, and bowel and bladder dysfunction. Sural nerve biopsy revealed diagnostic intra-axonal polyglucosan bodies. On electron microscopic examination, the inclusions were located mainly within myelinated nerve fibers and consisted of branched filaments that were 6 to 8 nm wide. The diagnosis of adult polyglucosan body disease was confirmed by a skin biopsy from the axilla showing similar inclusions in myoepithelial cells of apocrine glands. This report provides additional evidence that skin biopsy, to date advocated by a single case report only, may be a less invasive and simpler diagnostic alternative to sural nerve or brain biopsies.

MRI in vitamin B12 deficiency myelopathy.

BACKGROUND: Little is known about vitamin B12 deficiency myelopathy's magnetic resonance imaging (MRI) manifestations and their relationship to the onset, evolution, and resolution of neurologic signs and symptoms. METHODS: We present a case and review eleven additional reported cases of subacute combined degeneration of the spinal cord detected by MRI. RESULTS: Our patient had increased T2-weighted signal and gadolinium contrast enhancement of the posterior columns in the cervical and thoracic regions and enhancement of the lateral columns in the high cervical region. This is a case with imaging evidence for lateral column lesions. Two prior reports have shown posterior column enhancement. T1-weighted images may show decreased signal in the posterior columns and sometimes demonstrate reversible spinal cord swelling. MRI abnormalities typically improve after vitamin replacement therapy. However, clinical signs may persist despite resolution of imaging abnormalities, and these abnormalities do not always resolve completely. In addition, symptoms may precede the imaging abnormality. CONCLUSIONS: Vitamin B12 deficiency may produce an increased T2-weighted signal, decreased T1-weighted signal, and contrast enhancement of the posterior and lateral columns of the spinal cord, mainly of the cervical and upper thoracic segments. Because the symptoms may precede any imaging abnormality, it is clear that spinal cord MRI may not be a highly sensitive, early test for subacute combined degeneration.

Apomorphine responses in Parkinson's disease and the pathogenesis of motor complications.

We studied the contribution of basal ganglia circuitry downstream from the nigrostriatal dopaminergic system to the pathogenesis of levodopa associated motor complications by means of an apomorphine dose-response paradigm in 28 parkinsonian patients grouped according to their clinical response to levodopa therapy. With progression from the dopa-naive to the severely fluctuating dyskinetic state, apomorphine response duration shortened, the dose-response slope steepened, and the therapeutic window narrowed. Because apomorphine acts independently of the integrity of presynaptic dopaminergic neurons, our results suggest that postsynaptic alterations account mainly for the appearance of response complications. The present findings support the possibility, raised by animal model studies, that motor response complications arise as a consequence of altered signal transduction mechanisms in striatal medium-sized neurons.

Influence of different hepatitis C virus genotypes on the course of asymptomatic hepatitis C virus infection.

BACKGROUND & AIMS: The association of liver disease with hepatitis C virus (HCV) genotypes mainly refers to patients with serious liver damage; little information is available on symptomless carriers. The aim of this study was to investigate the correlation of genotypes with clinical course, risk factors for infection, and antibody to HCV reactivity in asymptomatic subjects. METHODS: One hundred nine viremic blood donors with at least 1 year of follow-up were studied; 41 underwent liver biopsy. Genotypes were determined by line-probe assay. RESULTS: Genotype 1 was found in 47 (43.1%), genotype 2 in 48 (44%), genotype 3 in 8 (7.3%), genotype 4 in 2 (1.8%), and coinfections in 4 (3.7%). The relative risk (RR) for a raised pattern of alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyltranspeptidase was 2.1 (confidence interval [CI], 1.4-3.2), 1.7 (CI, 1.2-2.4), and 2.8 (CI, 1.6-4.9) in subjects with genotype 1 vs. 0.4 (CI, 0.2-0.7), 0.4 (CI, 0.3-0.7), and 0.4 (CI, 0.2-0.8) in subjects with genotype 2. Chronic hepatitis was found in 68%; the RR of chronic hepatitis was similar for genotypes 1 and 2 (RR, 1.1 [CI, 0.8-1.7] vs. RR, 1.0 [CI, 0.7-1.6]). Reactivity to NS4-derived antigens was infrequent in type 2-infected subjects. CONCLUSIONS: Genotype 2 was as frequent as genotype 1 but associated with less liver function impairment. The high prevalence of chronic hepatitis should be considered in counseling viremic asymptomatic donors.