[Ischemia of the lower limbs as a symptom of acute dissection of the ascending aorta].
A 27-year-old man, two 54-year old men and a 64-year-old woman presented with aspecific symptoms: acute pain and tingling in the shoulders plus paraplegia; exertional dyspnoea and tingling in both feet for the past week; increasing shortness of breath and cold, pale legs and feet for the past week; acute retrosternal pain, incontinence and paraparesis. The cause was dissection of the ascending aorta (type A). Following the operation, the legs were amputated because of ischaemia. The 27-year-old man and one of the 54-year-old men died; the other two patients made a satisfactory recovery. Acute type-A aortic dissection is a life-threatening disease that must be recognised early because it is an absolute indication for emergency surgery. The initial manifestation of type-A dissection may be very aspecific. Post-operative lower limb ischaemia, as the first symptom of this disease, is rare and usually disappears after surgery for type-A dissection. In some cases, however, ischaemia persists and alters the post-operative course dramatically.


Active CMV infection in two patients with multiple sclerosis treated with alemtuzumab.
Alemtuzumab is a humanized monoclonal antibody targeting the surface molecule CD52, resulting in a rapid depletion of innate and adaptive immune cells. Infection rates in multiple sclerosis (MS) treatment trials were higher in alemtuzumab than in interferon beta-treated patients. We report two MS patients who developed cytomegalovirus disease within 1 month after the first 5-day cycle of alemtuzumab. Upon identification and appropriate treatment of the infection, each recovered completely. Neurologists should be aware of this serious but treatable complication.


User driven, evidence based experimental design; a new method for interface design used to develop an interface for clinical overview of patient records.
A novel method of interface design--user driven, evidence based experimental design--was developed which approximates the usual clinical way of maturing science and technology in the healthcare domain. The method is user-driven and the clinician remains in control of gathering and evaluating evidence of relevance to the project--as well as specifying the details of the user interface. Information not obtainable from the literature was gained experimentally and used to achieve a deeper understanding of the problem before the design phase. The design was subsequently validated experimentally by ordinary users with no connection to the software or design team. After applying this method to the problem of gaining a satisfactory clinical overview of a single patient's record, we recommend that clinical IT interfaces have clinical logic, sufficient complexity, and are well structured. Developers should use computer power to support "building blocks" such as anatomical problem lists and summaries of history, status and treatment, personal notes, and should support clinical browsing using text and graphics.


The anatomy of Cupid's bow in normal and cleft lip.
This is a gross and microscopic examination of the cutaneous-vermilion-mucosal region (Cupid's bow) in infants with normal lip as compared to cleft lip. Morphologic observations of lips in situ were made with magnification. Specimens for histology were from the normal upper lip of infants (n = 3) and adults (n = 4), and from redundant tissue made available during primary repair of cleft lip (n = 13) and cleft lip revision (n = 4). Tissues were analyzed with hematoxylin and eosin, Gomori trichrome, and Fontana-Masson stains. Immunoperoxidase stains were used to emphasize vascular endothelium and epithelial cytokeratins. Our observations support the hypothesis that the anterior projection of the pars marginalis of the musculus orbicularis oris gives rise to the normal cutaneous-vermilion junction ("white skin roll" of Gillies-Millard). The band of vellus hairs, found atop the vermilion-cutaneous junction, also highlights the rim of Cupid's bow. There was no abrupt alteration in vasculature, melanin, or cytokeratin content in the white roll. Proceeding caudally, the vermilion-mucosal region was characterized by progressively increasing epidermal thickness and size of rete ridges, decreasing melanin, more superficial capillaries, and an abrupt transition from keratinized to nonkeratinized squamous epithelium ("red line" of Noordhoff). In the cleft lip specimens, where white roll was absent, there was hypoplasia and disorientation of the underlying pars marginalis component of m. orbicularis oris. Vellus hair follicles were seen in the zone of presumptive white roll in clefts, just as in normal lip. Frequently, these pilar units contained disproportionately large sebaceous glands. In some cleft lip specimens, ectopic sebaceous glands were noted in the oral mucosa. We also observed a deficiency of vermilion width on the medial side of unilateral cleft lip, whereas the width of the vermilion at the crest of the bow was normal or slightly increased in the lateral cleft segment. A narrow vermilion band and exposed hypoplastic mucosa were characteristic of the prolabium in the bilateral complete cleft deformity. The findings of this study are pertinent to technical details for construction of the Cupid's bow and vermilion in unilateral and bilateral cleft lip.


[Clinical spectrum of a common and insidious pathogen: Streptococcus milleri].
We studied the clinical significance of S. milleri isolated in our hospital in 68 patients during a 18-month period. In 51 patients (median age: 43 years, no underlying diseases in 29 patients), the isolates were associated with significant infections. They were beta-hemolytic in 32 cases and non-hemolytic in 19. The primary infection sites were the head and neck area (21 cases), the lungs (5 cases of pneumonia), the gastrointestinal tract (12 cases), the urogenital tract (3 cases), the soft tissues (6 cases), and the heart (2 endocarditis). Two septicemias were of unknown origin. Head and neck infections and pneumonia were most often associated with beta-hemolytic strains, and bacteremia, gastrointestinal and urogenital tract infections with alpha-hemolytic strains. S. milleri was found in pure culture in 24 cases. Polymicrobial associated flora (27 cases) was more frequent in the abdominal infections (87%) than in supra-diaphragmatic infections (42%). Severe complications were observed in 12 head and neck infections (57%) (cerebral abscesses 3, lethal mediastinitis 2, osteitis 1, meningitis 1, other suppurative lesions 5). When abscesses were present (27 cases), surgery was required in all cases. Despite the high frequency and severity of local complications, the clinical outcome was usually favorable. However, deaths directly related to S. milleri infections occurred in 2 cases of mediastinitis complicating the course of apparently harmless primary infections. Owing to the possible occurrence of life-threatening complications, S. milleri infections require early identification, treatment and surgery when indicated.


Prostate cancer incidence rates have started to decrease in central Italy.
The widespread use of prostate-specific antigen (PSA) testing has dramatically changed the epidemiology of prostate cancer. Growing incidence rates have been documented in almost all western countries following the increased usage of PSA screening. In the United States after a period of huge increase in incidence, rates have decreased to values lower than those of the pre-PSA era. Similar changes have been documented also in the area of the Tuscany Cancer Registry, central Italy, where prostate cancer incidence rates doubled from the early 1990s to 2003 and afterwards decreased. This is the first evidence, to our knowledge, of a decline in prostate cancer incidence in Italy following the screening-related increase.


Assessing acute psychological distress in the immediate aftermath of stroke.
High acute stress may presage the development of subsequent cardiovascular ailments. Understanding how best to assess acute stress may inform early interventions seeking to prevent long-term morbidity/mortality following stroke. A mixed methods approach examined early post-stroke acute stress symptoms using the post-traumatic stress disorder checklist-5 (PCL-5) and the acute stress disorder scale (ASDS). A focus group of stroke survivors and/or their caregivers ( N=8) evaluated PCL-5/ASDS feasibility, and 20 patients hospitalized for acute stroke were interviewed 2-10 days post-stroke onset, using either the PCL-5 or the ASDS. Acute stress symptoms were present and measurable during acute stroke recovery. Assessment of acute stress in hospitalized patients with stroke is feasible; a briefer modified ASDS has advantages over the PCL-5. The ASDS is a viable and useful measure for assessing psychological distress during the acute post-stroke aftermath. Findings suggest that acute stress symptoms are present among patients with stroke, warranting greater attention to psychological responses in the early post-stroke period. Given that acute stress has serious potential long-term health consequences, additional research on stroke-related acute stress may prove useful for understanding post-stroke morbidity/mortality.


Pregnancy and postnatal outcome of mosaic isochromosome 20q.
Prenatally diagnosed mosaicism for isochromosome 20q is generally reported in association with a normal outcome at birth and is rarely confirmed postnatally. However, the origin of these abnormal cells is unclear and there are few reports of long-term outcomes. We present an additional case of prenatally detected isochromosome 20q, with normal outcome up to age 3.6 years. The abnormal cells, while present at high levels in the amniotic fluid, could not be confirmed in placenta or fetal blood. Nonetheless, based on a review of the literature, the level of isochromosome 20q cells found is associated with risk of abnormal outcome, suggesting a possible effect in some cases.


The effects of nicotinamide plus carbogen or pions for microscopic SCCVII tumors.
We evaluated the sensitizing effect of nicotinamide plus carbogen (N&C) and the relative biological effectiveness (RBE) of pions on microscopic tumors where necrotic tumor centers have not yet been established. Female C3H/He mice and SCCVII tumors were used. The irradiation started two days after tumor implantation. In experiment 1, the tumor beds were irradiated at various doses with 250 KVp photons in 5 fractions over 5 days. Nicotinamide (500 mg/kg/mouse/day in 0.2 ml) was injected intraperitoneally (i.p.) 60 min before irradiation, and carbogen (95% O2 + 5% CO2) was flushed at the rate of 10 l/min for 10 min before irradiation and throughout the entire irradiation procedure. In experiment 2, the tumor beds were irradiated at various doses with pions or 250 KVp photons in 10 fractions over 5 days. In both experiments, the mice were observed for 100 days. The rate of tumor appearance was evaluated and the 50% tumor control dose (TCD50) calculated. The sensitizing ratio (SR) of N&C obtained from the TCD50 assay was 1.46 and the RBE of pions was 1.24. The SR of N&C and the RBE of pions were lower for microscopic tumors than those previously reported for macroscopic tumors. These results were probably due to the absence or reduced presence of radiobiological hypoxic component in the microscopic lesion. However, N&C can be considered to provide an advantage for treatment of even clinical microscopic tumors.


Association between presenting motor symptoms and the risk of cognitive impairment in Parkinson's disease.
Neuropsychological data collected from two groups of patients with idiopathic Parkinson's disease (n = 50, 159) were analysed to investigate the association between presenting motor symptoms determined from retrospective chart review and the risk of cognitive impairment. Presenting motor symptoms were abstracted from the medical records and coded by type, location, and laterality. Longitudinal data on changes in the maximum speed of voluntary arm movements were available for a subsample of patients. Bilateral (v unilateral) presentation was associated with an increased risk of cognitive impairment an average of nine years after onset of disease as measured by memory tests and the mini-mental state examination. A higher rate of decline of arm movement speed was also predictive of greater memory dysfunction. The type, side (left v right), and location (lower v upper extremity) of the presenting symptoms were not, however, consistently associated with the risk of cognitive impairment later in the course of the disease.


Anchors as Semantic Primes in Value Construction: An EEG Study of the Anchoring Effect.
Previous research regarding anchoring effects has demonstrated that human judgments are often assimilated to irrelevant information. Studies have demonstrated that anchors influence the economic valuation of various products and experiences; however, the cognitive explanations of this effect remain controversial, and its neural mechanisms have rarely been explored. In the current study, we conducted an electroencephalography (EEG) experiment to investigate the anchoring effect on willingness to accept (WTA) for an aversive hedonic experience and the role of anchors in this judgment heuristic. The behavioral results demonstrated that random numbers affect participants' WTA for listening to pieces of noise. The participants asked for higher pay after comparing their WTA with higher numbers. The EEG results indicated that anchors also influenced the neural underpinnings of the valuation process. Specifically, when a higher anchor number was drawn, larger P2 and late positive potential amplitudes were elicited, reflecting the anticipation of more intensive pain from the subsequent noise. Moreover, higher anchors induced a stronger theta band power increase compared with lower anchors when subjects listened to the noises, indicating that the participants felt more unpleasant during the actual experience of the noise. The levels of unpleasantness during both anticipation and experience were consistent with the semantic information implied by the anchors. Therefore, these data suggest that a semantic priming process underlies the anchoring effect in WTA. This study provides proof for the robustness of the anchoring effect and neural evidence of the semantic priming model. Our findings indicate that activated contextual information, even seemingly irrelevant, can be embedded in the construction of economic value in the brain.


Thermal effects on photon-induced quantum transport in a single quantum dot.
We theoretically investigate laser induced quantum transport in a single quantum dot attached to electrical contacts. Our approach, based on a nonequilibrium Green function technique, allows us to include thermal effects on the photon-induced quantum transport and excitonic dynamics, enabling the study of non-Markovian effects. By solving a set of coupled integrodifferential equations, involving correlation and propagator functions, we obtain the photocurrent and the dot occupation as a function of time. Two distinct sources of decoherence, namely, incoherent tunneling and thermal fluctuations, are observed in the Rabi oscillations. As temperature increases, a thermally activated Pauli blockade results in a suppression of these oscillations. Additionally, the interplay between photon and thermally induced electron populations results in a switch of the current sign as time evolves and its stationary value can be maximized by tuning the laser intensity.


[Insufficient knowledge of the relationship between sex chromosome abnormalities and psychiatric diagnoses].
Sex chromosome abnormalities are among the most common genetic changes. The manifestations vary and may include growth abnormalities, specific appearance features, and other endocrinological and physical disorders, but also delayed psychomotor development, learning disabilities, and psychiatric conditions including ADHD and autism spectrum disorders. Increased knowledge about the relationship between sex chromosome abnormalities, development and psychiatric conditions would enable improved care of these patients.


Nuclear power for the artificial heart.
Studies showed that a totally implantable nuclear-powered artificial heart is practicable, and consequently a prototype system development program was initiated in July 1973. Basic testing of the prototype should be completed in 1977, with extensive studies to qualify the device for clinical use running at least into the early 1980s.


The Expression of RAC1 and Mineralocorticoid Pathway-Dependent Genes are Associated With Different Responses to Salt Intake.
Rac1 upregulation has been implicated in salt-sensitive hypertension as a modulator of mineralocorticoid receptor (MR) activity. Rac1 could affect the expression of oxidative stress markers, such as hemoxigenase-1 (HO-1) or nuclear factor-B (NF-κB), and the expression of neutrophil gelatinase-associated lipocalin (NGAL), a cytokine upregulated upon MR activation. We evaluated RAC1 expression in relation of high salt intake and association with MR, NGAL, HO-1, and NF-κB expression, mineralo- and glucocorticoids levels, and inflammatory parameters. We studied 147 adult subjects. A food survey identified the dietary sodium (Na) intake. RAC1 expression was considered high or low according to the value found in normotensive subjects with low salt intake. We determined the gene expression of RAC1, MR, NGAL, HO-1, NF-κB, and 18S, isolated from peripheral leukocytes. We measured aldosterone, cortisol, sodium, potassium excretion, metalloproteinase (MMP9 y MMP2), and C-reactive protein. We identified 126 subjects with high Na-intake, 18 subjects had high, and 108 low-RAC1 expression. The subjects with high-RAC1 expression showed a significant increase in MR (P = 0.0002), NGAL (P < 0.0001) HO-1 (P = 0.0004), and NF-κB (P < 0.0001) gene expression. We demonstrated an association between RAC1 expression and MR (R sp 0.64; P < 0.0001), NGAL (R sp 0.48; P < 0.0001), HO-1 (R sp 0.53; P < 0.0001), and NF-κB (R sp0.52; P < 0.0001). We did not identify any association between RAC1 and clinical or biochemical variables. RAC1 expression was associated with an increase in MR, NGAL, NF-κB, and HO-1 expression, suggesting that RAC1 could be a mediator of cardiovascular damage induced by sodium, and may also useful to identify subjects with different responses to salt intake.


3-O-methyl-D-glucose uptake in cultured bovine adrenal chromaffin cells.
The membrane transport of glucose was studied in bovine adrenal chromaffin cell cultures by following the cell/medium distribution of the nonmetabolizable glucose analog, 3-O-methyl-D-glucose. Uptake of this sugar in day-1 cultures that are undergoing rapid morphological change and differentiation had a Vmax of 138 nmol/(mg protein.min) and Km of 15 mM, and was only slightly increased by 50 mU/mL insulin. In day-5 cultures where morphological changes were essentially completed, Vmax and Km decreased to 51 nmol/(mg protein.min) and 9.5 mM, respectively, and the response to insulin was restored to the level found in freshly isolated cells; this effect was abolished in the nominal absence of Ca2+. Thus, saturation kinetics and insulin and Ca2+ sensitivity of 3-methylglucose uptake observed in freshly isolated cells were maintained in culture. However, the insulin response was almost absent during the initial period of rapid morphological change when sugar transport was strongly stimulated. Culture of chromaffin cells in the presence of dexamethasone did not inhibit the formation of processes, but decreased 3-methylglucose uptake in day-5 cultures by an apparently competitive effect.


Effect of Trichinella spiralis infection on the immune response to HBV vaccine in a mouse model.
Vaccination is the most effective and cost-effective way to treat hepatitis B virus (HBV) infection. Collective data suggest that helminth infections affect immune responses to some vaccines. Therefore, it is important to reveal the effects of helminth infections on the efficacy of protective vaccines in countries with highly prevalent helminth infections. In the present work, effects of Trichinella spiralis infection on the protective efficacy of HBV vaccine in a mouse model were investigated. This study demonstrated that the enteric stage of T. spiralis infection could inhibit the proliferative response of spleen lymphocytes to hepatitis B surface antigen (HBsAg) and lead to lower levels of anti-HBsAg antibodies, interferon-γ, and interleukin (IL)-2, along with higher levels of IL-4 and IL-5. However, these immunological differences are absent in the muscle stage of T. spiralis infection. The results suggest that the muscle stage of T. spiralis infection does not affect the immune response to HBV vaccination, while the enteric-stage infection results in a reduced immune response to HBsAg.


Intra-household clustering of hepatitis C virus infection in Karachi, Pakistan.
Transmission rates of hepatitis C virus (HCV) infection through non-sexual household contacts have been considered to be very low. This study evaluated intra-household clustering of cases of HCV infection in a low socio-economic community in Karachi, Pakistan. Serum samples from 341 household contacts of 86 thalassaemic HCV-seropositive children were evaluated for antibodies to HCV using an ELISA. Spatial analysis of data was carried out to test for intra-household clustering. Seventy of 341 (20.5%) household contacts were HCV-seropositive. Of the households studied, 44.2% (38/86) had one or more contacts who tested HCV-seropositive. Ecological analysis of variables at household level showed that in households where HCV-seropositive index thalassaemic children were male HCV tended to be transmitted to one or more familial contacts. Spatial analysis with an asymptotic score test of the null hypothesis of no extra within-family infectivity revealed that there was a significant tendency of HCV infection to cluster within a household (score statistic = 19.44, P=0.032). The results showed that non-sexual household exposure may play a role in efficient HCV spread to household contacts of HCV-infected persons and needs further evaluation.


Idiopathic Spontaneous Rupture of Renal Pelvis in a Single Functioning Kidney.
Spontaneous rupture of renal pelvis (SRRP) is a rare condition resulting in an extravasation of urine into retroperitoneal space. Due to the uncharacteristic symptoms, often mimicking renal colic, its diagnosis may be complicated. Herein, we report a case of a 73-year-old male with a solitary functioning kidney who presented with malaise and right-sided abdominal pain, rapidly followed by anuria. Laboratory tests showed the signs of AKI. Contrast-enhanced CT performed soon after the admission showed nonspecific abnormalities in the right middle abdomen suspected to be either inflammatory infiltration or surgical scarring. Symptomatic treatment was started, and an acute hemodialysis treatment was commenced. After a temporal improvement, the patient's general condition worsened significantly, with exacerbated pain and massive increase in plasma creatinine. A second contrast-enhanced CT was performed with an addition of urography phase, revealing the extravasation of the contrast media in the location suggesting the rupture of the renal pelvis. The patient was treated successfully by the placement of a double-J ureteral stent into the ureter. Usually, a clear etiology of SRRP can be determined, that is, urinary tract obstruction, but in this case, we could not find a definite cause. It is important to remember that in the presence of a nonspecific abdominal pain and laboratory signs of AKI, a rare cause like SRRP should be taken into consideration. Performing a contrast CT scan with urography phase can save time in establishing a diagnosis and enable immediate urological intervention.


Increased mosquito feeding on Rift Valley fever virus-infected lambs.
Experiments were conducted to determine whether or not mosquitoes exhibited an increase in feeding on Rift Valley fever (RVF) virus-infected lambs as compared to uninfected ones. Overall, when given a choice between a viremic lamb, or its uninfected twin, 65% (1,264/1,943) of the engorged female Culex pipiens obtained blood from the viremic lamb. This excess of feedings on viremic lambs was demonstrated regardless of the age of the lambs, or the time period between inoculation of the lambs and exposure to mosquitoes. With 3-day-old and 6- to 8-week-old lambs, 66% of the mosquitoes obtained blood from the viremic lamb. At 28, 48, and 52 hours after infection, the percentages of mosquitoes feeding on viremic lambs were 72, 68, and 64, respectively. Temperature, as measured by the difference in temperature of the viremic lamb minus that of the control lamb, was positively correlated with mosquito feedings on young lambs (3 days old), but not on older lambs (6 to 8 weeks old). When Cx. pipiens and Aedes taeniorhynchus were simultaneously given the opportunity to feed on 3-week-old lambs, a significantly higher percentage of engorged Cx. pipiens (94/108, 87%) fed on the viremic lamb than did engorged Ae. taeniorhynchus (187/350, 53%). The data generated by this study (e.g., an excess of feedings on the viremic lambs) warrant further study to determine the significance of this observation under field conditions.


BMP-2-enhanced chondrogenesis involves p38 MAPK-mediated down-regulation of Wnt-7a pathway.
The bone morphogenetic protein (BMP) family has been implicated in control of cartilage development. Here, we demonstrate that BMP-2 promotes chondrogenesis by activating p38 mitogen-activated protein kinase (MAPK), which in turn downregulates Wnt-7a/b-catenin signaling responsible for proteasomal degradation of Sox9. Exposure of mesenchymal cells to BMP-2 resulted in upregulation of Sox9 protein and a concomitant decrease in the level of b-catenin protein and Wnt-7a signaling. In agreement with this, the interaction of Sox9 with b-catenin was inhibited in the presence of BMP-2. Inhibition of the p38 MAPK pathway using a dominant negative mutant led to sustained Wnt-7a signaling and decreased Sox9 expression, with consequent inhibition of precartilage condensation and chondrogenic differentiation. Moreover, overexpression of b-catenin caused degradation of Sox9 via the ubiquitin/26S proteasome pathway. Our results collectively indicate that the increase in Sox9 protein resulting from downregulation of b-catenin/Wnt-7a signaling is mediated by p38 MAPK during BMP-2 induced chondrogenesis in chick wing bud mesenchymal cells.


Non-volatile memory devices based on polystyrene derivatives with electron-donating oligofluorene pendent moieties.
We report bistable non-volatile memory devices based on polystyrene derivatives containing pendent electron-donating mono-, di-, and tri(9,9-dihexylfluorene), which are denoted as poly(St-Fl), poly(St-Fl(2)), and poly(St-Fl(3)), respectively. The effects of the oligofluorene chain lengths and polymer surface structures on the memory characteristics were explored. Poly(St-Fl)-, poly(St-Fl(2))-, and poly(St-Fl(3))-based devices exhibited a flash memory characteristic with different turn-on threshold voltages of 2.8, 2.0, and 1.8 V, respectively, which was on the reverse trend with the highest occupied molecular orbital levels of -5.86, -5.80, and -5.77 eV. Moreover, the memory device showed a high ON/OFF current ratio of 2.5 x 10(4) and a long retention time of 10(4) s. The possible mechanism of the switching behavior was explained by the space-charge-limited-current theory and filamentary conduction. The larger aggregation domain size of the polymer thin film processed from the mixed solvent of chlorobenzene/N,N-dimethylformamide probably promoted the diffusion of the Al atoms into the polymer film and formed the conduction channel. Thus, it significantly reduced the turn-on threshold voltage on the studied polymer memory devices. The present study suggested that the polymer memory characteristics could be efficiently tuned through the pendent conjugated chain length and surface structures.


Neonatal screening for sickle cell diseases in Camberwell: results and recommendations of a two year pilot study.
The sickle cell diseases are a major health problem for Afro-Caribbean peoples. Neonatal detection and prophylactic management can reduce mortality and morbidity in childhood. A study was therefore conducted analysing the results of the first two years of cord blood screening in the Camberwell health area. Thirteen cases of sickle cell disease and two of haemoglobin (Hb)C disease were identified among 2202 non-white infants screened. The carrier state, sickle cell trait (HbAS), was present in 11.9% and HbC trait (HbAC) in 4.1% of Afro-Caribbean infants. The incidence of disease and of carrier states was much higher in West Africans than in Caribbeans. The wider implications of screening and the need for a comprehensive plan of care are emphasised.


Fatty acids in component of milk enhance the expression of the cAMP-response-element-binding-protein-binding protein (CBP)/p300 gene in developing rats.
Fatty acids in milk are thought to play an important role in intestinal maturation and gene expression in the rat small intestine during the suckling-weaning period. In the present study, we determined the jejunal mRNA level of the cAMP-response-element-binding-protein-binding protein (CBP)/p300, which is one of the chromatin remodelling factors and regulates histone acetylation, during the postnatal period in rats. The mRNA level of CBP/p300 was high during the suckling and middle of the weaning period (day 5 to 20) and then declined sharply to a low level at the end of the weaning period and after weaning. In situ hybridisation also showed that CBP/p300 mRNA levels in the villus as well as the basal membrane clearly decreased after weaning. Rat pups at age 17 d, weaned to a high-fat diet, showed higher levels of CBP/p300 mRNA than those weaned to a low-fat diet. Oral administration of caprylic acid, oleic acid and linoleic acid, which are major fatty acid components in milk, induced jejunal CBP/p300 gene expression. The present results suggest that fatty acids in components of milk enhance expression of the CBP/p300 genes in the small intestine.


[Contemporary aspects of using sildenafil].
Sildenafil has been thoroughly studied in 74 registered double-blind, placebo-controlled clinical trials assessing the efficacy and safety of the drug in a total of more than 16 000 men with erectile dysfunction (ED). However, practicing urologists have some questions regarding administering the drug in patients with multiple comorbidities. In this review, on a par with the now "classic" research, we outline the latest updates of meta-analyzes and comparative studies relating to the use of sildenafil in different groups of patients. We also discuss the problem of self-discontinuation of sildenafil therapy and the possible risks of using counterfeit phosphodiesterase type 5 inhibitors (PDE-5i).


Sex differences in response to miRNA-34a therapy in mouse models of cardiac disease: identification of sex-, disease- and treatment-regulated miRNAs.
MicroRNA (miRNA)-based therapies are in development for numerous diseases, including heart disease. Currently, very limited basic information is available on the regulation of specific miRNAs in male and female hearts in settings of disease. The identification of sex-specific miRNA signatures has implications for translation into the clinic and suggests the need for customised therapy. In the present study, we found that a miRNA-based treatment inhibiting miRNA-34a (miR-34a) was more effective in females in a setting of moderate dilated cardiomyopathy than in males. Furthermore, the treatment showed little benefit for either sex in a setting of more severe dilated cardiomyopathy associated with atrial fibrillation. The results highlight the importance of understanding the effect of miRNA-based therapies in cardiac disease settings in males and females. MicroRNA (miRNA)-34a (miR-34a) is elevated in the diseased heart in mice and humans. Previous studies have shown that inhibiting miR-34a in male mice in settings of pathological cardiac hypertrophy or ischaemia protects the heart against progression to heart failure. Whether inhibition of miR-34a protects the female heart is unknown. Furthermore, the therapeutic potential of silencing miR-34a in settings of dilated cardiomyopathy (DCM) and atrial fibrillation (AF) has not been assessed previously. In the present study, we examined the effect of silencing miR-34a in males and females in (1) a model of moderate DCM and (2) a model of severe DCM with AF. The cardiac disease models were administered with a locked nucleic acid-modified oligonucleotide (LNA-antimiR-34a) at 6-7 weeks of age when the models display cardiac dysfunction and conduction abnormalities. Cardiac function and morphology were measured 6 weeks after treatment. In the present study, we show that inhibition of miR-34a provides more protection in the DCM model in females than males. Disease prevention in LNA-antimiR-34a treated DCM female mice was characterized by attenuated heart enlargement and lung congestion, lower expression of cardiac stress genes (B-type natriuretic peptide, collagen gene expression), less cardiac fibrosis and better cardiac function. There was no evidence of significant protection in the severe DCM and AF model in either sex. Sex- and treatment-dependent regulation of miRNAs was also identified in the diseased heart, and may explain the differential response of males and females. These studies highlight the importance of examining the impact of miRNA-based drugs in both sexes and under different disease conditions.


Multiple guidance of light using asymmetric micro prism arrays for privacy protection of device displays.
With increasing use of mobile displays outdoors, privacy-related issues have come to the fore. Therefore, in this study, we proposed a novel concept using directionally guided light transmission using double-sided asymmetric prism arrays for fabricating a privacy protection film for digital displays. The proposed film allows only the user in front of the display to see its contents using dual refraction in a prism array. Otherwise, when the display is viewed at an angle, it is difficult to recognize the contents due to the overlap of different letters. The optical path was analysed through ray-tracing simulations, and the performance of the film was quantified using an optical character recognition (OCR) method. To further enhance the effectiveness of the film, a metal film was applied on the vertical face of the micro prism arrays using an oblique deposition method. This metal-coated double-sided prism array film showed superior privacy-protecting performance compared to a conventional method based on the micro-louver structure.


Use of GELSECTAN® in Patients with Irritable Bowel Syndrome (IBS): an Italian Experience.
Irritable bowel syndrome is a chronic functional gastrointestinal disorder characterized by recurrent chronic abdominal pain and impaired bowel habits, which affects daily activity and work productivity, and is associated with a significant healthcare economic burden as well as an impaired quality of life and psycho-affective profile. Management of patients is a great challenge for physicians; at the present, the therapeutic strategy aimed to treat the different symptoms, and no medical therapy is proven to modify the natural history of the disease. GELSECTAN® (xyloglucan, pea protein and tannins, xylo-oligosaccharides) is a medical device with both protective and prebiotic actions on the intestinal mucosa, able to restore intestinal permeability and to improve gastrointestinal symptoms, controlling diarrhoea, abdominal pain and bloating in adult patients with irritable bowel syndrome. We report and discuss four cases of different patients with irritable bowel syndrome successfully managed with Gelsectan in the real clinical practice. Literature data, as well as these case reports, show that this device is effective and safe in improving symptoms and bowel habits associated to irritable bowel syndrome; its efficacy and safety were confirmed for the long-term use too. Agents with film-forming protective properties, such as Gelsectan, represent a new alternative therapeutic option for the management of patients with irritable bowel syndrome.


Thrombectomy under Cardiopulmonary Bypass for Inferior Vena Cava Thrombosis Induced by Liver Injury.
Inferior vena cava thrombosis (IVCT) caused by liver injury is a rare and challenging condition. A 32-year-old man sustained a severe liver injury in a traffic accident. Emergent thromboembolic procedure for the affected hepatic arteries was performed for hemostasis, resulting in hemodynamic stabilization of the patient. One month later, however, computed tomography (CT) showed liver congestion caused by IVCT from the suprahepatic IVC to the bilateral common iliac veins. As liver function deteriorated quickly despite heparin administration, surgical thrombectomy was performed under hypothermic circulatory arrest through sternotomy and laparotomy. After this operation, the liver was decongested and its function improved rapidly.


Some age-related effects of the 1974 Brisbane floods.
Some age-related effects of the 1974 Brisbane floods are examined. The impact of the floods on health increased in those over 35 years of age probably because they were more likely to be householders. Women under 65 years of age had more psychiatric symptoms than men, but this sex difference disappeared in those over 65 years, perhaps because the working man is not constantly confronted with the damage to his home in the way that others are. The possibility that people over 75 years living in flood-affected suburbs experienced increased morbidity even though not themselves flooded cannot be excluded.


Recent Advances in Physical Post-Harvest Treatments for Shelf-Life Extension of Cereal Crops.
As a result of the rapidly growing global population and limited agricultural area, sufficient supply of cereals for food and animal feed has become increasingly challenging. Consequently, it is essential to reduce pre- and post-harvest crop losses. Extensive research, featuring several physical treatments, has been conducted to improve cereal post-harvest preservation, leading to increased food safety and sustainability. Various pests can lead to post-harvest losses and grain quality deterioration. Microbial spoilage due to filamentous fungi and bacteria is one of the main reasons for post-harvest crop losses and mycotoxins can induce additional consumer health hazards. In particular, physical treatments have gained popularity making chemical additives unnecessary. Therefore, this review focuses on recent advances in physical treatments with potential applications for microbial post-harvest decontamination of cereals. The treatments discussed in this article were evaluated for their ability to inhibit spoilage microorganisms and degrade mycotoxins without compromising the grain quality. All treatments evaluated in this review have the potential to inhibit grain spoilage microorganisms. However, each method has some drawbacks, making industrial application difficult. Even under optimal processing conditions, it is unlikely that cereals can be decontaminated of all naturally occurring spoilage organisms with a single treatment. Therefore, future research should aim for the development of a combination of treatments to harness their synergistic properties and avoid grain quality deterioration. For the degradation of mycotoxins the same conclusion can be drawn. In addition, future research must investigate the fate of degraded toxins, to assess the toxicity of their respective degradation products.


Modified resin-bonded design for stabilization of mobile teeth: technique and clinical observations.
A design modification of the tooth preparation and framework design is presented to further enhance stabilization of mobile teeth with resin-bonded splints. An appropriate shade of composite resin is placed to restore an esthetic contour, cover the incisal edge framework extensions, and provide occlusal function as indicated. Patient reviews are presented to demonstrate the principles of treatment, versatility, and limitations of this treatment modality.


The metabolism of inositol 4-monophosphate in rat mammalian tissues.
Rat brain soluble fraction contains an enzymatic activity that dephosphorylates inositol 1,4-bisphosphate (Ins(1,4)P2). We have used anion exchange h.p.l.c. in order to identify the inositol monophosphate product of Ins(1,4)P2 hydrolysis (i.e. Ins(1)P1, Ins(4)P1 or both). When [3H]Ins(1,4)P2 was used as substrate, we obtained an inositol monophosphate isomer that was separated from the co-injected standard [3H]Ins(1)P1. This suggested an Ins(1,4)P21-phosphatase pathway leading to the production of the inositol 4-monophosphate isomer. The dephosphorylation of [32P]Ins(4)P1 was measured in rat brain, liver and heart soluble fraction and was Li+-sensitive. Chromatography of the soluble fraction of a rat brain homogenate on DEAE-cellulose resolved a monophosphate phosphatase activity that hydrolyzed both [3H]Ins(1)P1 and [4-32P]Ins(4)P1 isomers.


A coherent phase diagram of the [(AuCu)0.86Ag0.14]1-XPtX pseudobinary section in Au-Cu-Ag-Pt quaternary system.
In order to determine a coherent phase diagram of the [(AuCu)0.86Ag0.14]1-XPtX pseudobinary system, phase identifications and analyses of the microstructural configurations were performed by means of transmission electron microscopy. Various phase regions were detected in the coherent phase diagram as follows; (1) alpha 0 (fcc) single phase region, (2) two-phase region (alpha 1 + alpha 2), (3) AuCu I (L10) + alpha 0, (4) AuCu I + alpha 2, (5) AuCu II (L10-S) + alpha 2, (6) AuCu I + AuCu II + alpha 2, (7) AuCu I single phase region. Microstructural features of these regions relating to the phase transformations were described.


Preparation of N-(2-alkoxyvinyl)sulfonamides from N-tosyl-1,2,3-triazoles and Subsequent Conversion to Substituted Phthalans and Phenethylamines.
Decomposition of N-tosyl-1,2,3-triazoles with rhodium(II) acetate dimer in the presence of alcohols forms synthetically versatile N-(2-alkoxyvinyl)sulfonamides, which react under a variety of conditions to afford useful N- and O-containing compounds. Acid-catalyzed addition of alcohols or thiols to N-(2-alkoxyvinyl)sulfonamide-containing phthalans provides access to ketals and thioketals, respectively. Selective reduction of the vinyl group in N-(2-alkoxyvinyl)sulfonamide-containing phthalans via hydrogenation yields the corresponding phthalan in good yield, whereas reduction with sodium bis(2-methoxyethoxy)aluminumhydride generates a ring-opened phenethylamine analogue. Because the N-(2-alkoxyvinyl)sulfonamide functional group is synthetically versatile, but often hydrolytically unstable, this protocol emphasizes key techniques in preparing, handling, and reacting these pivotal substrates in several useful transformations.


Cellular distribution of C-C motif chemokine ligand 2 like immunoreactivities in frontal cortex and corpus callosum of normal and lipopolysaccharide treated animal.
C-C motif chemokine ligand 2 (CCL2) is reported to be involved in the pathogenesis of various neurological and/or psychiatric diseases. Tissue or cellular expression of CCL2, in normal or pathological condition, may play an essential role in recruiting monocytes or macrophages into targeted organs, and be involved in a certain pathogenic mechanism. However, few studies focused on tissue and cellular distribution of the CCL2 peptide in brain grey and white matters (GM, WM), and the changes of the GM and WM cellular CCL2 level in septic or endotoxic encephalopathy was not explored. Hence, the CCL2 cellular distribution in the front brain cortex and the corpus callosum (CC) was investigated in the present work by using immunofluorescent staining. (1) CCL2 like immunoreactivity (CCL2-ir) in the CC is evidently higher than the cortex. When the measurement includes ependymal layer attached to the CC, CCL2-ir intensity is significantly higher than cortex. (2) Structures in perivascular areas, most of them are GFAP positive, contribute major CCL2-ir positive profiles in both GM and WM, but apparently more in the CC, where they are bilaterally distributed in the lateral CC between the cingulate cortex and ventricles. (3) The neuron-like CCL2-ir positive cells in cortex are significantly more than in the CC, and that number is significantly increased in the cortex following systemic lipopolysaccharide (LPS), but not in the CC. (4) In addition to CCL2-ir positive perivascular rings, more CCL2-ir filled cashew shape elements are observed, probably inside of microvasculature, especially in the CC following systemic LPS. (5) Few macrophage/microglia marker-Iba-1 and CCL2-ir co-labeled structures especially the soma is found in normal cortex and CC; the co-localizations are significantly augmented following systemic LPS, and co-labeled amoeba like somata are presented. (6) CCL2-ir and astrocyte marker GFAP or Iba-1 double labeled structures are also observed within the ependymal layer. No accumulation of neutrophils was detected. There exist differences in the cellular distribution of the CCL2 peptide in frontal cortex GM and subcortical WM-CC, in both the physiological condition and experimental endotoxemia. Which might cause different pathological change in the GM and WM.


Cellular localization of vasopressin V1a receptor messenger ribonucleic acid in adult male rat brain, pineal, and brain vasculature.
Vasopressin V1a receptor (V1aR) transcripts were localized in brain, pineal, and superficial brain vascular tissues of adult male rats using hybridization histochemistry and an [35S]riboprobe complementary to the messenger ribonucleic acid (mRNA) encoding the fifth to the midseventh transmembrane regions of the receptor. V1aR mRNA was extensively distributed throughout brain and was expressed in 1) superficial cells of the granule cell layers of the main olfactory bulb, hippocampal dentate gyrus, and cerebellum; 2) numerous anatomically distinct brain nuclei; 3) isolated cells dispersed throughout the central nervous system; 4) cells of the choroid plexus, occasional blood vessels in the olfactory bulb and interpeduncular nucleus, and extraparenchymal intracranial vasculature; and 5) some white matter structures. Numerous cells expressing V1aR transcripts were found in forebrain structures, including primary olfactory (piriform) cortex, the anterior and posterior olfactory nuclei; dorsal, intermediate, and ventral lateral septal nuclei; the septo-fimbrial nucleus and accumbens nucleus; and numerous hypothalamic regions with the most intense hypothalamic labeling in the arcuate, stigmoid, suprachiasmatic, and periventricular nuclei and the lateral hypothalamic area. Cells expressing V1aR transcripts were ubiquitous throughout the midbrain, pontine, and medullary regions. A lower intensity signal was found in cells of the parvocellular paraventricular and anteroventral nucleus of the thalamus, circumventricular organs including the pineal, and the subfornical organ. V1aR transcripts were not generally detected in parenchymal vasculature, but could be found over large blood vessels in the interpeduncular nucleus and medial olfactory bulb; transcripts were commonly detected in perivascular brain cells. V1aR mRNA was abundantly expressed by choroid plexus, endothelial cells of midline blood vessels between the main olfactory bulbs, and superficial vascular tissue on all brain surfaces. These data confirm the presence of the vascular/hepatic-type V1aR gene in brain tissue and document an extensive expression. The distribution of V1aR mRNA suggests that there are at least two types of vasopressin-responsive cells in brain: one type exemplified by lateral septal ara neurons innervated by classical axodendritic/somatic synaptic vasopressinergic terminals and a second, perivascular/vascular type that would facilitate humoral vasopressinergic signaling in the brain.


Limibaculum sediminis sp. nov., isolated from mangrove sediment.
A Gram-stain-negative, cream-coloured, aerobic, motile and ovoid- to rod-shaped bacterium, designated as FT325T, was isolated from mangrove sediment collected in Shenzhen, PR China. The taxonomic position of strain FT325T was established by phylogenetic, physiological, biochemical and chemotaxonomic analyses. Strain FT325T grew optimally at 37-40 °C and pH 6.0 in the presence of 0 % (w/v) NaCl. Results of 16S rRNA gene sequence analysis showed that strain FT325T was most similarly related to Limibaculum halophilum CAU 1123T (96.2 %), Phaeovulum vinaykumarii DSM 18714T (93.9%) and Amaricoccus solimangrovi HB 172011T (93.7 %). The major fatty acids (>10 %) were C18 : 1 ω7c (60.0 %) and 11-methyl C18 : 1 ω7c (16.7 %). The sole respiratory quinone was Q-10. The polar lipids were phosphatidylglycerol, one unidentified glycolipid, three unidentified aminolipids and three unidentified phospholipids. Its estimated genome size was 4 318 768 bp and the genomic DNA G+C content was 69.6 mol%. Based on its distinct phenotypic, chemotaxonomic and phylogenetic characteristics, strain FT325T represents a novel species of the genus Limibaculum, for which the name Limibaculum sediminis sp. nov. is proposed (=MCCC 1K07397T=KCTC 92313T).


BDNF splice variants from the second promoter cluster support cell survival of differentiated neuroblastoma upon cytotoxic stress.
The neurotrophin brain-derived neurotrophic factor (BDNF) is a key survival factor for neural cells. In particular, in neuroblastoma tumour cells, expression of the BDNF/TrkB autocrine signalling system promotes a more malignant phenotype and resistance to chemotherapy. The human BDNF gene contains two clusters of upstream exons encoding the 5'UTR (exon 1 to exon 3 and exon 4 to exon 9a), these are alternatively spliced to a common exon 9, which contains the coding region and the 3'UTR. At least 34 different BDNF mRNA transcripts can be generated, although their physiological role is still unknown. The purpose of this study is to determine which BDNF transcript is involved in cell survival of the human neuroblastoma cell lines SH-SY-5Y (single-copy MYCN) and SK-N-BE (amplified MYCN). Expression of human BDNF mRNAs encoding all possible isoforms was characterised in the two neuroblastoma cell lines. We then investigated whether selective silencing of the different BDNF mRNAs using specific siRNAs could reduce cell survival in response to serum deprivation or the anticancer drugs cisplatin, doxorubicin and etoposide. We found that three isoforms located in the second exon cluster are essential for neuroblastoma cell survival under cytotoxic stress. Notably, promoters of the second exon cluster, but not the first, are controlled by Ca(2+)-sensitive elements.


Zhaonella formicivorans gen. nov., sp. nov., an anaerobic formate-utilizing bacterium isolated from Shengli oilfield, and proposal of four novel families and Moorellales ord. nov. in the phylum Firmicutes.
A novel obligately anaerobic, thermophilic and formate-utilizing bacterium K32T was isolated from Shengli oilfield of China. Cells were straight rods (0.4-0.8 µm × 2.5-8.0 µm), Gram-stain-positive, non-spore-forming and slightly motile. Optimum growth occurred with pH of 7 and 0.5 g l-1 NaCl under temperature of 55-60 °C. Nitrate could be reduced into nitrite, syntrophic formate oxidation to methane and carbon dioxide occurred when co-culturing strain K32T and Methanothermobacter thermautotrophicus ΔH. The main cellular fatty acids were iso-C15 : 0 (24.0 %), anteiso-C15 : 0 (21.7 %), C16 : 0 (12.7 %) and C14 : 0 (10.8 %), and the main polar lipid was phosphatidylglycerol. The G+C content of the genomic DNA was 46.3 mol%. The 16S rRNA gene sequence of K32T shared ≤90.4 % of sequence similarity to closest type strains of Desulfitibacter alkalitolerans, Calderihabitans maritimus and members of the genus Moorella. Based on the phenotypic, biochemical and genotypic characterization, Zhaonella formicivorans gen. nov., sp. nov. is proposed with K32T (=CCAM 584T =DSM 107278T=CGMCC1.5297T) as the type strain, which is the first representative of Zhaonellaceae fam. nov. In addition, the order Thermoanaerobacterales and family Peptococcaceae were reclassified, and three novel families in the novel order of Moorellales ord. nov. were also proposed.


Expression of human apolipoprotein B90 in transgenic mice. Demonstration that apolipoprotein B90 lacks the structural requirements to form lipoprotein.
Lipoprotein(a) (Lp(a)) is a lipoprotein formed by the disulfide linkage of apolipoprotein(a) (apo(a)) to the apoB100 of a low density lipoprotein particle. Earlier site-directed mutagenesis studies of apo(a) demonstrated that apo(a) cysteine 4057 is required for the disulfide linkage; however, the cysteine residue within apoB100 that is involved in the disulfide bond has not been identified. We previously demonstrated that the apoB100 produced by human apoB transgenic mice binds to apo(a) and forms Lp(a) (Linton, M.F., Farese, R. V., Jr., Chiesa, G., Grass, D. S., Chin, P., Hammer, R. E., Hobbs, H.H., and Young, S.G. (1993) J. Clin. Invest. 92, 3029-3037). To further explore the structural features of human apoB that are required for the formation of Lp(a), we used a transposon-interrupted human apoB gene clone to develop transgenic mice that express high levels of a truncated form of human apoB, apoB90, which contains the amino-terminal 4084 amino acids of apoB. In vitro incubation of apo(a) with the plasma of human apoB90 transgenic mice did not yield Lp(a), as judged by Western blots of SDS-polyacrylamide gels or by a monoclonal antibody-based radioimmunoassay. In contrast, incubation of apo(a) with the plasma of a mouse that expressed an equivalent amount of the full-length apoB100 did yield Lp(a). In addition to these in vitro incubation studies, no Lp(a) could be detected in the plasma of a "double transgenic" mouse expressing both human apoB90 and apo(a). These data indicate that the carboxyl-terminal 10% of apoB100 contains amino acid sequences that are essential for the formation of Lp(a).


In vivo imaging of the systemic recruitment of fibroblasts to the angiogenic rim of ovarian carcinoma tumors.
Tumor-associated stroma, in general, and tumor fibroblasts and myofibroblasts, in particular, play a role in tumor progression. We previously reported that myofibroblast infiltration into implanted ovarian carcinoma spheroids marked the exit of tumors from dormancy and that these cells contributed to vascular stabilization in ovarian tumors by expression of angiopoietin-1 and angiopoietin-2. Ex vivo labeling of fibroblasts with either magnetic resonance or optical probes rendered them detectable for in vivo imaging. Thus, magnetic resonance imaging (MRI) follow-up was feasible by biotin-bovine serum albumin-gadolinium diethylenetriaminepentaacetic acid or iron oxide particles, whereas labeling with near-IR and fluorescent vital stains enabled in vivo visualization by near-IR imaging and two-photon microscopy. Using this approach, we show here that prelabeled fibroblasts given i.p. to CD-1 nude mice can be followed in vivo by MRI and optical imaging over several days, revealing their extensive recruitment into the stroma of remote s.c. MLS human epithelial ovarian carcinoma tumors. Two-photon microscopy revealed the alignment of these invading fibroblasts in the outer rim of the tumor, colocalizing with the angiogenic neovasculature. Such angiogenic vessels remained confined to the stroma tracks within the tumor and did not penetrate the tumor nodules. These results provide dynamic evidence for the role of tumor fibroblasts in maintenance of functional tumor vasculature and offer means for image-guided targeting of these abundant stroma cells to the tumor as a possible mechanism for cellular cancer therapy.


Sequencing cyclic peptides by multistage mass spectrometry.
Some of the most effective antibiotics (e.g. Vancomycin and Daptomycin) are cyclic peptides produced by non-ribosomal biosynthetic pathways. While hundreds of biomedically important cyclic peptides have been sequenced, the computational techniques for sequencing cyclic peptides are still in their infancy. Previous methods for sequencing peptide antibiotics and other cyclic peptides are based on Nuclear Magnetic Resonance spectroscopy, and require large amount (miligrams) of purified materials that, for most compounds, are not possible to obtain. Recently, development of MS-based methods has provided some hope for accurate sequencing of cyclic peptides using picograms of materials. In this paper we develop a method for sequencing of cyclic peptides by multistage MS, and show its advantages over single-stage MS. The method is tested on known and new cyclic peptides from Bacillus brevis, Dianthus superbus and Streptomyces griseus, as well as a new family of cyclic peptides produced by marine bacteria.


[Mediastinal lymphangioma].
47-year-old women was admitted to the clinic for diagnosis of an incidentally X-ray detected enlargement of the medistinum shadow. In the past, the patient had been operated for lymphangioma of the right forearm. Chest computer tomography (CT) showed an abnormal mass in the front mediastinum with spherical structures, which density could indicate high-protein contents. In the right mammarian gland an oval cyst (23-15 mm), similar in character to the lesion in the mediastinum was found. The lymphangiomatic character of the lesion with the extension up to the superior aperture of the thorax was confirmed with magnetic resonans imaging (MRI). Due to the extensive changes and lack of symptoms, the patient was disqualified for surgical treatment and remains under further observation.


Redox interactions of immune cells and muscle in the regulation of exercise-induced pain and analgesia: implications on the modulation of muscle nociceptor sensory neurons.
The mechanistic interactions among redox status of leukocytes, muscle, and exercise in pain regulation are still poorly understood and limit targeted treatment. Exercise benefits are numerous, including the treatment of chronic pain. However, unaccustomed exercise may be reported as undesirable as it may contribute to pain. The aim of the present review is to evaluate the relationship between oxidative metabolism and acute exercise-induced pain, and as to whether improved antioxidant capacity underpins the analgesic effects of regular exercise. Preclinical and clinical studies addressing relevant topics on mechanisms by which exercise modulates the nociceptive activity and how redox status can outline pain and analgesia are discussed, in sense of translating into refined outcomes. Emerging evidence points to the role of oxidative stress-induced signaling in sensitizing nociceptor sensory neurons. In response to acute exercise, there is an increase in oxidative metabolism, and consequently, pain. Instead, regular exercise can modulate redox status in favor of antioxidant capacity and repair mechanisms, which have consequently increased resistance to oxidative stress, damage, and pain. Data indicate that acute sessions of unaccustomed prolonged and/or intense exercise increase oxidative metabolism and regulate exercise-induced pain in the post-exercise recovery period. Further, evidence demonstrates regular exercise improves antioxidant status, indicating its therapeutic utility for chronic pain disorders. An improved comprehension of the role of redox status in exercise can provide helpful insights into immune-muscle communication during pain modulatory effects of exercise and support new therapeutic efforts and rationale for the promotion of exercise.


Nef neutralizes the ability of exosomes from CD4+ T cells to act as decoys during HIV-1 infection.
Nef is an HIV-1 accessory protein that promotes viral replication and pathogenesis. A key function of Nef is to ensure sustained depletion of CD4 and MHC-I molecules in infected cells by inducing targeting of these proteins to multivesicular bodies (MVBs), and ultimately to lysosomes for degradation. Nef also affects cellular secretory routes promoting its own secretion via exosomes. To better understand the effects of Nef on the exocytic pathway, we investigated whether this viral factor modifies the composition of exosomes released by T lymphocytes. We showed that both CD4 and MHC-I molecules are secreted in exosomes from T cells and that the expression of Nef reduces the amount of these proteins in exosomes. To investigate the functional role for this novel activity of Nef, we performed in vitro HIV-1 infection assays in the presence of distinct populations of exosomes. We demonstrated that exosomes released by CD4+ T cells, but not CD4- T cells, efficiently inhibit HIV-1 infection in vitro. Because CD4 is the main receptor for HIV-1 infection, these results suggest that CD4 molecules displayed on the surface of exosomes can bind to envelope proteins of HIV-1 hindering virus interaction with target cells and infection. Importantly, CD4-depleted exosomes released by CD4+ T cells expressing Nef have a reduced capacity to inhibit HIV-1 infection in vitro. These results provide evidence that Nef promotes HIV-1 infection by reducing the expression of CD4 in exosomes from infected cells, besides the original role of Nef in reducing the CD4 levels at the cell surface.


[A Rare Case of Cerebellar Hemangioblastoma Causing Taste Disorder].
Taste(gustation)is one of the five senses, and comprises the types: sweet, bitter, salty, sour, and umami. Taste disorders, such as dysgeusia and parageusia, are classified into 2 types: those with peripheral origin and those with central origin. The peripheral origin-type taste disorder is caused by zinc deficiency, mouth dryness, a side effect of radiotherapy or complication of systemic diseases such as, diabetes, hepatopathy, and nephropathy. The central origin-type taste disorder is reported to be caused due to demyelinating disease, pontine hemorrhage, pontine infarction, and thalamic infarction; it is very rarely caused by a brain tumor. We surgically treated a 69-year-old man with cerebellar hemangioblastoma who had developed taste disorder. The tumor compressed the solitary nucleus, which includes the taste tract in the central nervous system. On removal of the tumor, the taste disorder gradually improved.


The effect of effort and weight controllability on perceptions of obese individuals.
We examined the impact of offset controllability (capability of losing weight) and offset effort (efforts to lose weight) on judgments of an obese target. Participants (n = 216) read about an obese person whose body weight was controllable/uncontrollable, and who did/did not put in effort to eat healthily and exercise. Effort played a more important role than controllability in evaluations of the target. Targets who put in effort to be healthy were ascribed fewer obesity stereotypes, evoked less disgust, and were considered to have a more acceptable lifestyle. These findings extend attribution theory and have implications for strategies to reduce weight bias.


Rab5-regulated endocytosis plays a crucial role in apical extrusion of transformed cells.
Newly emerging transformed cells are often eliminated from epithelial tissues. Recent studies have revealed that this cancer-preventive process involves the interaction with the surrounding normal epithelial cells; however, the molecular mechanisms underlying this phenomenon remain largely unknown. In this study, using mammalian cell culture and zebrafish embryo systems, we have elucidated the functional involvement of endocytosis in the elimination of RasV12-transformed cells. First, we show that Rab5, a crucial regulator of endocytosis, is accumulated in RasV12-transformed cells that are surrounded by normal epithelial cells, which is accompanied by up-regulation of clathrin-dependent endocytosis. Addition of chlorpromazine or coexpression of a dominant-negative mutant of Rab5 suppresses apical extrusion of RasV12 cells from the epithelium. We also show in zebrafish embryos that Rab5 plays an important role in the elimination of transformed cells from the enveloping layer epithelium. In addition, Rab5-mediated endocytosis of E-cadherin is enhanced at the boundary between normal and RasV12 cells. Rab5 functions upstream of epithelial protein lost in neoplasm (EPLIN), which plays a positive role in apical extrusion of RasV12 cells by regulating protein kinase A. Furthermore, we have revealed that epithelial defense against cancer (EDAC) from normal epithelial cells substantially impacts on Rab5 accumulation in the neighboring transformed cells. This report demonstrates that Rab5-mediated endocytosis is a crucial regulator for the competitive interaction between normal and transformed epithelial cells in mammals.


Granulocyte macrophage colony-stimulating factor treatment results in recovery of motor function after white matter damage in mice.
Clinical stroke usually results from a cerebral ischaemic event, and is frequently a debilitating condition with limited treatment options. A significant proportion of clinical strokes result from specific damage to the subcortical white matter (SWM), but currently there are few animal models available to investigate the pathogenesis and potential therapeutic strategies to promote recovery. Granulocyte macrophage colony-stimulating factor (GM-CSF) is a cytokine that has been previously shown to promote neuroprotective effects after brain damage; however, the mechanisms mediating this effect are not known. Here, it is reported that GM-CSF treatment results in dramatic functional improvement in a white matter model of stroke in mice. SWM stroke was induced in mice by unilateral injections of the vasoconstrictor, endothelin-1 (ET-1). The results reveal that ET-1-induced stroke impairs skilled motor function on the single pellet-reaching task and results in forelimb asymmetry, in adult mice. Treatment with GM-CSF, after stroke, restores motor function and abolishes forelimb asymmetry. The results also indicate that GM-CSF promotes its effects by activating mammalian target of rapamycin signalling mechanisms in the brain following stroke injury. Additionally, a significant increase in GM-CSF receptor expression was found in the ipsilateral hemisphere of the ET-1-injected brain. Taken together, the present study highlights the use of an under-utilized mouse model of stroke (using ET-1) and suggests that GM-CSF treatment can attenuate ET-1-induced functional deficits.


Thyrotropin-releasing hormone (TRH) action in mouse thyrotropic tumor cells in culture: evidence against a role for adenosine 3',5'-monophosphate as a mediator of TRH-stimulated thyrotropin release.
It has been suggested that TRH stimulation of TSH release is mediated by the adenylate cyclase-cAMP system. To determine whether cAMP is a necessary intracellular messenger for TRH stimulation of TSH release, we have performed detailed studies of the TRH effect employing a nearly homogeneous population of mouse thyrotropic tumor cells in culture. Dibutyryl cAMP, methylisobutylxanthine, and cholera toxin caused an increase in TSH release which was additive to that of TRH. TRH stimulated TSH release in a dose-dependent fashion; half-maximal stimulation occurred at approximately 0.6 nM but had no effect on total intracellular cAMP levels measured in the presence or absence of methylisobutylxanthine. There was no correlation between total intracellular cAMP levels and TSH release after 1 h. Moreover, there was no effect of TRH on protein kinase-bound or total intracellular cAMP levels at 1, 5, or 60 min of incubation. Lastly, TRH had no effect on adenylate cyclase activity in homogenates of thyrotropic cells in the presence or absence of guanylylimidodiphosphate. These results suggest that stimulation of TRH release by TRH from these cells does not involve cAMP as an intracellular messenger.


Studies of the cellular mechanisms underlying the vasorelaxant effects of rutaecarpine, a bioactive component extracted from an herbal drug.
We conducted studies to investigate the nature and underlying mechanisms of the vascular effects of rutaecarpine (Rut), an alkaloid isolated from the Chinese herbal drug Evodia rutaecarpa. By using largely the effects on phenylephrine (PE)-induced contraction in the isolated rat aorta as the experimental index and by comparison with several known vascular muscle relaxants such as acetylcholine (ACh), histamine, and A23187, Rut relaxed PE-precontracted aorta in concentration-(10(-7)-10(-4) M) and endothelium-dependent manners. Studies with appropriate antagonists indicated that this was coupled to nitric oxide (NO) and guanylyl cyclase. Extracellular Ca2+ removal and treatment with the intracellular Ca2+ antagonist, 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate (TMB-8), suggested that influx of extracellular Ca2+ was the major factor contributing to the action of Rut. Pertussis toxin suppressed the relaxation potency of histamine but had no effects on the actions of Rut. NaF, the G proteins activator, attenuated the actions of ACh, but only minimally affected Na-NP, A23187, and Rut. 1-[6-{[17 beta-3-methoxyestra-1,2,3(10)-trien-17-yl]amino} hexyl]-1H-pyrrole-2,5-dione (U73122), the phospholipase C inhibitor, again suppressed the actions of ACh but had few effects on A23187 and Rut. Taken together, these results suggest that these vasorelaxants had different cellular mechanisms and that neither pertussis toxin-sensitive Gi protein, other G proteins, nor phospholipase C activation was involved in the cellular response to rutaecarpine.


Fate of bilateral renal lesions missed on preoperative imaging: a report from the National Wilms Tumor Study Group.
In children undergoing nephrectomy for Wilms tumor exploration of the contralateral kidney has been recommended to detect occult tumors missed on preoperative evaluation. In this review of the National Wilms Tumor Study (NWTS) 4 cases of bilateral Wilms tumors (BWT) we evaluate incidence and outcome of missed bilateral lesions. NWTS-4 enrolled 3,335 patients from August 1986 through September 1994. There were 188 patients with BWT or 5.6% of the total registered. The operative records, pathology and imaging reports were reviewed. In 11 cases synchronous BWT was diagnosed at surgical exploration, which represents 5.9% of the bilateral cases but only 0.3% of all NWTS-4 cases. Two patients did not undergo preoperative imaging and were excluded from analysis. The size of the missed lesions was less than 1 cm in 6 patients and 1 to 2 cm in 3. Computerized tomography was performed in all patients except one who entered early in the study. Management of missed lesions included enucleation in 2 cases, biopsy in 6 and no surgery in 1. No patient underwent irradiation. The postoperative chemotherapy regimen consisted of doxorubicin, dactinomycin and vincristine in 6 children, and dactinomycin and vincristine in 3. Median followup was 9 years. There were no recurrences in any kidney with a missed lesion. All 9 patients were alive and disease-free at last followup. Routine contralateral renal exploration will identify few occult tumors not detected on preoperative imaging. Omission of routine exploration will not likely affect the outcome or management of newly diagnosed Wilms tumor provided preoperative computerized tomography or magnetic resonance imaging is performed. The outcome in these patients was excellent.


Depressive symptoms are associated with impaired sleep, fatigue, and disease activity in women with rheumatoid arthritis.
To investigate the associations between sleep quality, fatigue, disease activity and depressive symptoms in women with rheumatoid arthritis (RA). Female patients with previous diagnosis of RA from a Rheumatology Outpatient Clinic at a tertiary referral centre, in Fortaleza, Brazil, were consecutively recruited into the study. Sleep quality was assessed by the Pittsburgh Sleep Quality Index (PSQI); fatigue by the Fatigue Severity Scale (FSS); daytime sleepiness by the Epworth Sleepiness Scale (ESS); and depressive symptoms by the Beck Depression Inventory II (BDI-II). RA activity was measured by the disease activity score (DAS28). One hundred ten women (mean age ± SD = 51.1 ± 13.0 y) were included in the study. On average, patients with depressive symptoms (BDI-II > 13), as compared to those without, showed poorer sleep quality (PSQI: 10.09 ± 4.1 vs 7.33 ± 3.55; p = 0.001 respectively), more fatigue (FSS: 4.69 ± 1.89 vs 3.34 ± 1.8; p = 0.001) and higher disease activity level (DAS28: 4.36 ± 1.53 vs 3.7 ± 1.39; p = 0,047). The logistic regression analysis showed that sleep quality is an independent predictor of depressive symptom severity. Depressive symptoms, impaired sleep and fatigue are common in women with RA. Poor sleep is associated with greater frequency and severity of depressive symptoms in these patients, suggesting that screening for sleep and mood problems may be relevant both in clinical research and routine patient care. Future studies investigating the impact of measures to promote healthy sleep on depressive symptom control in this patient population are warranted.


Association of attrition with mortality: findings from 11 waves over three decades of the Whitehall II study.
Attrition, the loss of participants as a study progresses, is a considerable challenge in longitudinal studies. This study examined whether two forms of attrition, 'withdrawal' (formal discontinued participation) and 'non-response' (non-response among participants continuing in the study), have different associations with mortality and whether these associations differed across time in a multi-wave longitudinal study. Participants were 10 012 civil servants who participated at the baseline of the Whitehall II cohort study with 11 data waves over an average follow-up of 28 years. We performed competing-risks analyses to estimate sub-distribution HRs and 95% CIs, and likelihood ratio tests to examine whether hazards differed between the two forms of attrition. We then applied linear regression to examine any trend of hazards against time. Attrition rate at data collections ranged between 13% and 34%. There were 495 deaths recorded from cardiovascular disease and 1367 deaths from other causes. Study participants lost due to attrition had 1.55 (95% CI 1.26 to 1.89) and 1.56 (1.39 to 1.76) times higher hazard of cardiovascular and non-cardiovascular mortality than responders, respectively. Hazards for withdrawal and non-response did not differ for either cardiovascular (p value =0.28) or non-cardiovascular mortality (p value =0.38). There was no linear trend in hazards over the 11 waves (cardiovascular mortality p value =0.11, non-cardiovascular mortality p value =0.61). Attrition can be a problem in longitudinal studies resulting in selection bias. Researchers should examine the possibility of selection bias and consider applying statistical approaches that minimise this bias.


A randomized trial to compare two dosing intervals of misoprostol following mifepristone administration in second trimester medical abortion.
The conventional timing of misoprostol administration after mifepristone for second trimester medical abortion is 36-48 h, but simultaneous administration, which may make the regimen more convenient, has not been studied. The objective of this randomized comparison study is to compare two intervals of administration of misoprostol after pretreatment with mifepristone for second trimester medical abortion. Eligible women with gestational age between 12 and 20 weeks were randomized to receive mifepristone 200 mg orally followed by 600 microg misoprostol vaginally either immediately or 36-38 h later, followed by 400 microg vaginal misoprostol every 3 h for a maximum of four doses. The primary outcome measure was the success rate at 24 h after the start of misoprostol treatment and the secondary outcome measures were the induction-to-abortion interval and the frequency of side effects. There was a significant difference in the success rate at 24 h (36-38 h: 100%; immediate: 91.5%). The median induction-to-abortion interval was significantly shorter in the 36-38 h regimen (4.9 h) compared with the immediate regimen (10 h). Side effects in terms of febrile episodes and chills/rigors were significantly higher in the immediate administration group. Simultaneous use of mifepristone and misoprostol for second trimester medical abortion is not as effective as the regimen using a 36-38 h dosing interval.


Non-Negligible Roles of Pore Size Distribution on Electroosmotic Flow in Nanoporous Materials.
Electroosmotic flow in nanoporous materials is of fundamental importance for the design and development of filtration membranes and electrochemical devices such as supercapacitors and batteries. Recent experiments suggest that ion transport in a porous network is substantially different from that in individual nanochannels due to the pore size distribution and pore connectivity. Herein, we report a theoretical framework for ion transport in nanoporous materials by combing the classical density functional theory to describe the electrical double layer (EDL) structure, the Navier-Stokes equation for the fluid flow, and the effective medium approximation to bridge the gap between individual nanopores and the network connectivity. We find that ion conductivity in nanoporous materials is extremely sensitive to the pore size distribution when the average size of micropores is comparable to the EDL thickness. The theoretical predictions provide an explanation of the giant gap between the conductivity of a single pore and that of a porous network and highlight the mechanism of ion transport through nanoporous materials important for numerous practical applications.


[Myocardial remodeling in chronic renal failure patients on hemodialysis].
Pathologic myocardial changes in is one of the main causes of death in patients with terminal chronic renal failure (CRF). The authors studied structural and functional condition of the myocardium and the effect of various CRF factors on cardiovascular complications. The study demonstrates positive correlation between systolic arterial pressure (AP) and left ventricular (LV) remodeling, as well as between the degree of anemia and LV remodeling in patients with CRF on program hemodialysis. Concentric LV hypertrophy (LVH) was revealed in 24 (65%) patients, eccentric LVH--in 7 (19%) patients. The results show that eccentric LVH with reduced ejection fraction in CRF patients on hemodialysis is associated with high systolic and pulse pressure.


Effects of caffeine consumption on pregnancy outcome. A review.
Caffeine's metabolism, mechanisms of action and effects on pregnancy outcome in laboratory animals and humans have been studied extensively. A review of those studies suggests that until more information is available, it might be prudent to limit caffeine intake to approximately 300 mg/d during pregnancy in view of decreases in birth weight that might occur at or above that level of consumption. That level might also be appropriate for nursing mothers since caffeine is known to enter breast milk.


The effect of continuous care on the recovery of patients with advanced colorectal cancer undergoing chemotherapy.
To explore the impact of continuous care on chemotherapy patients with advanced colorectal cancer. Six hundred forty patients who received chemotherapy from June 2015 to December 2022 were included in this retrospective study and divided into the observation group (n = 332) and control group (n = 308) based on different care methods that they received. The observation group patients were followed up using the continuous care team model, the control group patients using the traditional telephone follow-up model. A comparative analysis was conducted on the effects of 2 modes on patients self-care ability, treatment compliance, anxiety, depression, communication ability with nurses, level of hope, as well as the effects of toxic side effects and cancer-related fatigue. The self-care ability and treatment compliance of patients in the observation group were significantly better than those in the control group (P < .05), with lower anxiety and depression scores, toxic side effects, and cancer-related fatigue compared to the control group (P < .05). The communication ability and patient hope level of nurses in the observation group were also significantly stronger than those in the control group (P < .05). The application of continuous care can improve patients self-care ability and treatment compliance, effectively reduce anxiety and depression in in patients with advanced colorectal cancer undergoing chemotherapy, and improve nurses communication skills and patients hope level. Therefore, this practice is worth promoting clinically.


Exploring the impact of suicide on clinicians: a multidisciplinary retreat model.
We developed an every other year, scheduled retreat model for clinicians and trainees to explore emotional and professional reactions that they may face after a patient's suicide. Psychiatry ambulatory clinical staff, residents, and faculty participated in a halfday retreat, which consisted of an opening panel discussion, in which panel members related their experiences of patient suicide, break out groups, and a final panel discussion. Unlinked preand post-retreat surveys were electronically sent to all potential participants. The pre-retreat survey was completed by 103 clinicians; 20% of the respondents were trainees or fellows, and 47% reported that they had experienced a patient suicide. Text responses to the pre-retreat survey reflected the wish to obtain a better understanding of the impact of patient suicide on caregivers, to cope with the event from a personal and professional standpoint, and to get a clearer understanding of what supports are available within the department. The post-retreat survey was completed by 45 clinicians. Comments after the retreat reflected an increased awareness of both shortand long-term effects on clinicians after a patient suicide and the extensive impact that a patient suicide can have on providers within their ambulatory care department. An alldepartment ambulatory retreat model has value in providing clinicians with support and information in a structured, educational setting to help reduce the sense of stigma and provide an increased awareness of the magnitude of the impact on clinicians who experience the death of a patient by suicide.


Effects of pattern masks on the formation of perceptual grouping.
Mechanisms underlying perceptual grouping serve to bind stimulus components that are contained within grouped patterns. In order to examine the time course of grouping development, grids of spatially isolated dots were followed by pattern masks across a range of SOA. Subjects indicated the predominant perceived grouping of the dot patterns. Masks either spatially superimposed target elements (element mask), or superimposed elements as well as paths among elements (connection mask). Element masks thereby disrupted processing of target elements, while connection masks additionally disrupted representations in regions among elements. It was found that element masks disrupted grouping 12ms after target offset, after which masks had no effect. Connection masks disrupted grouping up to 47ms following target offset. Results suggest grouping mechanisms access the afferent signal for a brief period early in processing, after which binding formation proceeds for an addition 35ms. Shortening connection mask duration to 12ms enhanced performance during a brief temporal window within the interference period. For each set of conditions, target elements were visible during the time frame in which stimulus patterns could not be perceptually grouped. Full-field checkerboard masks degraded discrimination similarly as connection masks, although were more effective in disrupting discrimination with an SOA of 24 and 36ms. Degrading stimulus organization progressively extended the time scale for each masking effect. For the grouping of low-level stimulus features tested here, results support a model in which afferent signals are accessed early, followed by progressive binding among grouped elements. Effect of shortening connection masks may reflect incomplete disruption of target processing, or possibly re-entry of stimulus representations by feedback from higher processing areas.


Pulmonary-renal syndrome, diffuse pulmonary hemorrhage and glomerulonephritis, associated with Wegener's granulomatosis effectively treated with early plasma exchange therapy.
We present a case of a 38-year-old Japanese man with Wegener's granulomatosis complicated with pulmonary-renal syndrome, i.e., diffuse pulmonary hemorrhage and rapidly progressive renal glomerulonephritis. As this is a life-threatening condition, we promptly initiated plasma exchange with intravenous methylprednisolone therapy. Diffuse pulmonary hemorrhage and renal failure were markedly improved. This case merits presentation because there are few clinical studies of the treatment of Wegener's granulomatosis with pulmonary-renal syndrome, particularly with pulmonary hemorrhage.


Instability of the fragile X syndrome repeat in mice: the effect of age, diet and mutations in genes that affect DNA replication, recombination and repair proficiency.
Repeat expansion diseases such as fragile X syndrome (FXS) result from increases in the size of a specific tandem repeat array. In addition to large expansions, small changes in repeat number and deletions are frequently seen in FXS pedigrees. No mouse model accurately recapitulates all aspects of this instability, particularly the occurrence of large expansions. This may be due to differences between mice and humans in CIS and/or TRANS-acting factors that affect repeat stability. The identification of such factors may help reveal the expansion mechanism and allow the development of suitable animal models for these disorders. We have examined the effect of age, dietary folate, and mutations in the Werner's syndrome helicase (WRN) and TRP53 genes on FXS repeat instability in mice. WRN facilitates replication of the FXS repeat and enhances Okazaki fragment processing, thereby reducing the incidence of processes that have been suggested to lead to expansion. p53 is a protein involved in DNA damage surveillance and repair. We find two types of repeat instability in these mice, small changes in repeat number that are seen at frequencies approaching 100%, and large deletions which occur at a frequency of about 10%. The frequency of these events was independent of WRN, p53, parental age, or folate levels. The large deletions occur at the same frequency in mice homozygous and heterozygous for the repeat suggesting that they are not the result of an interallelic recombination event. In addition, no evidence of large expansions was seen. Our data thus show that the absence of repeat expansions in mice is not due to a more efficient WRN protein or p53-mediated error correction mechanism, and suggest that these proteins, or the pathways in which they are active, may not be involved in expansion in humans either. Moreover, the fact that contractions occur in the absence of expansions suggests that these processes occur by different mechanisms.


Effect of a single intravenous zoledronic acid administration on biomarkers of acute kidney injury (AKI) in patients with osteoporosis: a pilot study.
The pilot study was designed to evaluate the early effect of intravenous (i.v.) zoledronic acid (ZA) on renal function. Five mg i.v. ZA was administered to 23 patients with osteoporosis (17 women and 6 men, mean age 73 ± 7 SD years). Urinary NGAL, KIM-1, and MCP-1, plasma (p) MCP-1 and serum (s) IL-18, serum calcium (sCa), Creatinine clearance (CrCl), parathyroid hormone (PTH), plasma C-terminal FGF23 (pFGF23), serum (s) Klotho, calcium excretion (CaEx) and renal threshold phosphate concentration/GFR (TmPO4 /GFR) were assessed at baseline, 24 h and Day 30 after administration. There was a significant decrease in sCa and CaEx at 24 h (-4.1 ± 2.8%, P < 0.01 and -28 ± 59%, P < 0.05, respectively) and Day 30 (-3.9 ± 4%, P < 0.001 and -26 ± 43%, P < 0.01) and a significant increase in PTH (79.8 ± 95.8%) at Day 30 (P < 0.001) compared to baseline. TmPO4 /GFR decreased significantly at 24 h and Day 30 (-8.6 ± 15.9%, P < 0.05 and -11.3 ± 13.5%, P < 0.001) compared to baseline. We observed no difference in the concentration of pFGF23, sKlotho and urinary AKI biomarkers at any time points. Mean levels of sIL-18 and pMCP-1 increased significantly at 24 h (44 ± 88%; P < 0.01 and 198 ± 237%; P < 0.001) and returned to baseline at Day 30. Our pilot study suggests that there is no direct acute effect of ZA on kidney function. The increase in plasma MCP-1 and serum IL-18 concentration could be associated with the stimulation of immunity mechanisms occurring soon after the administration of the drug. Secondary hyperparathyroidism develops shortly after the infusion of ZA and is maintained even after 1 month.


Artificial intelligence (AI) and machine learning (ML) in precision oncology: a review on enhancing discoverability through multiomics integration.
Multiomics data including imaging radiomics and various types of molecular biomarkers have been increasingly investigated for better diagnosis and therapy in the era of precision oncology. Artificial intelligence (AI) including machine learning (ML) and deep learning (DL) techniques combined with the exponential growth of multiomics data may have great potential to revolutionize cancer subtyping, risk stratification, prognostication, prediction and clinical decision-making. In this article, we first present different categories of multiomics data and their roles in diagnosis and therapy. Second, AI-based data fusion methods and modeling methods as well as different validation schemes are illustrated. Third, the applications and examples of multiomics research in oncology are demonstrated. Finally, the challenges regarding the heterogeneity data set, availability of omics data, and validation of the research are discussed. The transition of multiomics research to real clinics still requires consistent efforts in standardizing omics data collection and analysis, building computational infrastructure for data sharing and storing, developing advanced methods to improve data fusion and interpretability, and ultimately, conducting large-scale prospective clinical trials to fill the gap between study findings and clinical benefits.


Nematic solvation of segmented polymer chains.
We examine the effect of polymer chain segmentation on the recently discovered ability of nematic solvents to elongate and align polymer chain solutes. Coordinated single molecule spectroscopy and beads-on-a-chain simulations are used to study the orientational and conformational order of a series of segmented conjugated polymers, dissolved in the nematic liquid crystal 5CB. The order parameters for alignment and elongation are both observed to decrease with increasing segmentation, reflecting an interplay among conformational entropy, solvation anisotropy, and bending energy of the chain.


18F-fluorodeoxyglucose positron emission tomography/computed tomography for primary thyroid langerhans histiocytosis: A case report and literature review.
Langerhans cell histiocytosis (LCH) is a rare clonal proliferative disease, with an incidence rate of 4.0-5.4/1 million individuals. LCH encompasses a spectrum of disorders with diverse clinical presentations ranging from a single organ to multiple organ involvement. LCH rarely involves the thyroid gland. We presented a case with LCH of thyroid gland. The patient had painless progressive neck enlargement and then diabetes insipidus. Ultrasonic scan and magnetic resonance imaging scan revealed nodular goiter and pituitary stalk enlargement, respectively. Histopathological analysis revealed features of histiocytoid cells. 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) was performed in order to rule out the presence of whole body infiltration. 18F-FDG PET/CT also demonstrated increased uptake in the thickening pituitary stalk and maxillofacial skin lesion, in addition to the bilateral thyroid nodules, CT showed the left lung nodule and the skull destruction without 18F-FDG uptake. This report emphasizes the role of 18F-FDG PET/CT in multiple organs involvement of patients with LCH.


Cost-Effectiveness of 30- Compared to 20-Milliliter Blood Cultures: a Retrospective Study.
The importance of blood culture (BC) volume for detection of bloodstream infections (BSIs) is documented. Recently, improved diagnostic sensitivity was demonstrated for 30- versus 20-ml BCs in adults (Cockerill FR, Wilson JW, Vetter EA, Goodman KM, Torgerson CA, Harmsen WS, Schleck CD, IIstrup DM, Washington JA, Wilson WR. Clin Infect Dis 38:1724-1730, 2004, http://dx.doi.org/10.1128/JCM.01314-11). Hospitals receive higher reimbursement for patients with documented septicemia. We determined the cost-effectiveness of 30-ml versus 20-ml BCs using results from our institution and previously published data. Positive BC results from 292 bacteremic episodes were reviewed. The costs of the reagents, equipment, phlebotomist, and technologist time were determined. The medical records department provided Medicare reimbursement (MR) data for patients with selected ICD-9 codes. These data provided an estimate of the annualized increase in MR versus costs associated with conversion to 30-ml BCs. MR for 464 annual primary BSIs was $24,808/episode. An expected 7.2% increase in BSIs detected using 30-ml BCs would add 34 additional cases annually and increase MR by $843,472. Comparative MR data for cases where septicemia complicated another diagnosis were available for 4 International Classification of Diseases, Ninth Revision (ICD-9) codes: laparoscopic cholecystectomy, biliary tract disorders, pneumonia, and cellulitis. The mean incremental MR was $9,667 per episode, which projected to a $483,350 revenue increase annually. The annual cost associated with conversion to 30-ml BCs was estimated to be $157,798. Thus, the potential net increase in hospital revenue would be $1,169,031 for 30-ml versus 20-ml BCs. Our results suggest that conversion to 30-ml BCs may not only improve patient care by detecting more BSIs but also increase hospital revenue substantially.


Bilateral Lower Cranial Nerve Palsy after Closed Head Injury: A Case Report and Review of Literature.
Paralysis of the lower cranial nerves is uncommon after closed head injuries. Most cases reported are unilateral and associated with base of skull fractures, usually involving the occipital condyles. Bilateral lower cranial nerve palsy is even less common, with only a handful of cases reported in literature. A 17-year-old girl presented to us after she was involved in a side-on collision with a car while driving a scooter. She sustained traumatic brain injury requiring mechanical ventilation. Detailed neurological evaluation revealed bilateral paralysis of the IXth, Xth, and XIIth cranial nerves with no evidence of a fracture of the base of skull or brain stem injury. A traction type of injury to the nerves arising from a whiplash mechanism may have led to paralysis of the lower cranial nerves in our patient. An exhaustive review of literature revealed 11 reports of bilateral lower cranial nerve palsy associated with closed head injuries; there were only four cases without underlying fracture of the occipital condyles. Our patient made a complete recovery over a period of 4 months. A traction type of injury to the lower cranial nerves may occur due to a whiplash mechanism. This type of injury may be associated with a favorable outcome.


Continuous Intestinal Absorption Model Based on the Convection-Diffusion Equation.
Prediction of the rate and extent of drug absorption upon oral dosing needs models that capture the complexities of both the drug molecule and intestinal physiology. We report here the development of a continuous intestinal absorption model based on the convection-diffusion equation. The model includes explicit enterocyte apical membrane and intracellular lipid radial compartments along the length of the intestine. Physiologic functions along length x are built into the model and include velocity, diffusion, surface areas, and pH of the intestine. Also included are expression levels of the intestinal active uptake transporter OATP2B1 and efflux transporter P-gp. Oral dosing of solution as well as solid (with a dissolution function) was modeled for several drugs. The fraction absorbed (FA) and concentration-time (C-t) profiles were predicted and compared with clinical data. Overall, FA was well predicted upon oral (n = 21) or colonic dosing (n = 11), with four outliers. The overall accuracy (prediction of the correct bin) was 81% with outliers and 90% without outliers. Of the nine solution dosing data sets, six drugs were very well predicted with an exposure overlap coefficient (EOC) > 0.9 and predicted Cmax and Tmax values similar to those observed. Of the six solid dose formulations evaluated, the EOC values were > 0.9 for all drugs except budesonide. The observed precipitation of nifedipine at high doses was predicted by the model. Most of the poor predictions were for drugs that are known to be transporter substrates. As proof of concept, incorporating OATP2B1 and P-gp markedly improved the EOC and predicted Cmax and Tmax for fexofenadine. Finally, the continuous intestinal model accurately recapitulated the known relationships between drug absorption and permeability, solubility, and particle size. Together, these results indicate that this preliminary intestinal absorption model offers a simple and straightforward framework to build in complexities such as drug permeability, lipid partitioning, solubility, metabolism, and transport for improved prediction of the rate and extent of drug absorption.