The triad of paragangliomas, gastric stromal tumours and pulmonary chondromas (Carney triad), and the dyad of paragangliomas and gastric stromal sarcomas (Carney-Stratakis syndrome): molecular genetics and clinical implications.
Carney triad (CT) describes the association of paragangliomas (PGLs) with gastrointestinal stromal tumours (GISTs) and pulmonary chondromas (PCH). A number of other lesions have been described in the condition including pheochromocytomas, oesophageal leiomyomas and adrenocortical adenomas; CT is a novel form of multiple endocrine neoplasia (MEN), a genetic condition with a female predilection. Inactivating mutations of the mitochondrial complex II succinate dehydrogenase (SDH) enzyme subunits SDHB, SDHC and SDHD have been found in familial and sporadic PGLs, and gain-of-function mutations of the oncogenes c-kit (KIT) and platelet-derived growth factor receptor A (PDGFRA) cause sporadic and familial GISTs. We recently reported an international series of patients with CT, 34 females and three males (median age of presentation 21 years) who did not carry SDHA, SDHB, SDHC, SDHD, KIT or PDGFRA gene mutations. Comparative genomic hybridization revealed a number of DNA copy number changes. The most frequent and greatest contiguous change was a deletion within the 1pcen13-q21 region, which harbours the SDHC gene. Another frequent change was loss of 1p. Although GISTs showed more frequent losses of 1p than PGLs, the pattern of chromosomal changes was similar in the two tumours despite their different tissue origin and histology; the findings were consistent with a common genetic aetiology of these two tumours in CT. In a separate condition, in which the association (or dyad) of GISTs with PGLs is inherited in an autosomal dominant manner (Carney-Stratakis syndrome, CSS), germline mutations of the SDHB, SDHC and SDHD genes (but not KIT or PDFGRA) were found; GISTs in this condition were caused by SDH deficiency. We conclude that CT is a novel MEN syndrome whose genetic defect remains elusive. CSS is caused by SDH defects, suggesting that sarcomas (GISTs) can be caused by defective mitochondrial oxidation, consistent with recent data implicating this enzyme in a variety of endocrine and other tumours. The above have clinical implications (i) for patients with GISTs that are cKIT- and PDGFRA-mutation negative: these tumours are usually resistant to treatment with currently available tyrosine kinase inhibitors and may be part of a syndrome such as CT or CSS; and (ii) for patients with an inherited PGL syndrome, family history should be explored to identify any other tumours in the family, and in particular other endocrine lesions and GISTs.


DESHARKY: automatic design of metabolic pathways for optimal cell growth.
The biological solution for synthesis or remediation of organic compounds using living organisms, particularly bacteria and yeast, has been promoted because of the cost reduction with respect to the non-living chemical approach. In that way, computational frameworks can profit from the previous knowledge stored in large databases of compounds, enzymes and reactions. In addition, the cell behavior can be studied by modeling the cellular context. We have implemented a Monte Carlo algorithm (DESHARKY) that finds a metabolic pathway from a target compound by exploring a database of enzymatic reactions. DESHARKY outputs a biochemical route to the host metabolism together with its impact in the cellular context by using mathematical models of the cell resources and metabolism. Furthermore, we provide the sequence of amino acids for the enzymes involved in the route closest phylogenetically to the considered organism. We provide examples of designed metabolic pathways with their genetic load characterizations. Here, we have used Escherichia coli as host organism. In addition, our bioinformatic tool can be applied for biodegradation or biosynthesis and its performance scales with the database size. Software, a tutorial and examples are freely available and open source at http://soft.synth-bio.org/desharky.html


Pituitary adenylyl cyclase-activating peptide: a pivotal modulator of glutamatergic regulation of the suprachiasmatic circadian clock.
The circadian clock in the suprachiasmatic nucleus (SCN) of the hypothalamus organizes behavioral rhythms, such as the sleep-wake cycle, on a near 24-h time base and synchronizes them to environmental day and night. Light information is transmitted to the SCN by direct retinal projections via the retinohypothalamic tract (RHT). Both glutamate (Glu) and pituitary adenylyl cyclase-activating peptide (PACAP) are localized within the RHT. Whereas Glu is an established mediator of light entrainment, the role of PACAP is unknown. To understand the functional significance of this colocalization, we assessed the effects of nocturnal Glu and PACAP on phasing of the circadian rhythm of neuronal firing in slices of rat SCN. When coadministered, PACAP blocked the phase advance normally induced by Glu during late night. Surprisingly, blocking PACAP neurotransmission, with either PACAP6-38, a specific PACAP receptor antagonist, or anti-PACAP antibodies, augmented the Glu-induced phase advance. Blocking PACAP in vivo also potentiated the light-induced phase advance of the rhythm of hamster wheel-running activity. Conversely, PACAP enhanced the Glu-induced delay in the early night, whereas PACAP6-38 inhibited it. These results reveal that PACAP is a significant component of the Glu-mediated light-entrainment pathway. When Glu activates the system, PACAP receptor-mediated processes can provide gain control that generates graded phase shifts. The relative strengths of the Glu and PACAP signals together may encode the amplitude of adaptive circadian behavioral responses to the natural range of intensities of nocturnal light.


Integration of osteoclastogenesis through addition of PBMCs in human osteochondral explants cultured ex vivo.
The preservation of tissue specific cells in their native 3D extracellular matrix in bone explants provides a unique platform to study remodeling. Thus far, studies involving bone explant cultures showed a clear focus on achieving bone formation and neglected osteoclast activity and resorption. To simulate the homeostatic bone environment ex vivo, both key elements of bone remodeling need to be represented. This study aimed to assess and include osteoclastogenesis in human osteochondral explants through medium supplementation with RANKL and M-CSF and addition of peripheral blood mononuclear cells (PBMCs), providing osteoclast precursors. Osteochondral explants were freshly harvested from human femoral heads obtained from hip surgeries and cultured for 20 days in a two-compartment culture system. Osteochondral explants preserved viability and cellular abundance over the culture period, but histology demonstrated that resident osteoclasts were no longer present after 4 days of culture. Quantitative extracellular tartrate resistant acid phosphatase (TRAP) analysis confirmed depletion of osteoclast activity on day 4 even when stimulated with RANKL and M-CSF. Upon addition of PBMCs, a significant upregulation of TRAP activity was measured from day 10 onwards. Evaluation of bone loss trough μCT registration and measurement of extracellular cathepsin K activity revealed indications of enhanced resorption upon addition of PBMCs. Based on the results we suggest that an external source of osteoclast precursors, such as PBMCs, needs to be added in long-term bone explant cultures to maintain osteoclastic activity, and bone remodeling.


Myricetin and naringenin inhibit human squamous cell carcinoma proliferation and migration in vitro.
In this study the potential anticancer effect of 2 flavonoids, myiricetin (MYR) and naringenin (NAR) has been evaluated on an oral squamous cell carcinoma (OSCC) cell line, SCC-25, and HaCaT cells. Both the flavonoids inhibited SCC-25 cell growth, although NAR selectively affected cancer cells without impairing HaCaT cell growth. The cell proliferation inhibition by MYR and NAR was not related to apoptosis induction, but on cell cycle impairment, because a G0/G1 and a G2/M blockage was highlighted following 24 h of treatment in SCC-25 and HaCaT cells, respectively. Western blot analysis showed that MYR induced a decrease of Cyclin D1 in SCC-25 and of Cyclin B1 in HaCaT cells, while NAR negatively modulated Cyclin D1 expression in SCC-25 cells. Wound-healing and cell invasion assays demonstrated that both the flavonoids were able to reduce motility on both SCC-25 and HaCaT cells. In conclusion the results of the present study show the anticancer potential of NAR and MYR on OSCC because they exert cytostatic effect by the impairment of cell cycle progression. Moreover both the flavonoids inhibit cell migration, thus highlighting their potential effect as antimetastatic agents. Therefore, MYR and NAR appear as promising candidate as oral cancer chemopreventive agents.


Relative Importance of Baseline Pain, Fatigue, Sleep, and Physical Activity: Predicting Change in Depression in Adults With Multiple Sclerosis.
To determine whether baseline levels of pain, fatigue, sleep disturbance, and physical activity measured at the initial assessment predicted the development of or improvement of depression 3.5 years later, while controlling for sex, age, and disease severity. Observational, longitudinal survey study. A community-based population sample. Adults with multiple sclerosis (MS) (N=489). Not applicable. Primary outcome was classification of depression group measured using a Patient Health Questionnaire-9 cutoff score ≥10, indicating probable major depression. Fatigue severity (odds ratio, 1.19; 95% confidence interval, 1.12-1.26; P<.0001) and sleep disturbance (odds ratio, 1.06; 95% confidence interval, 1.02-1.10; P=.001) predicted probable major depression 3.5 years later among those not depressed at the initial assessment. An effect of age (odds ratio, .96; 95% confidence interval, .92-.99; P=.008) was found among those who developed depression, indicating that younger adults were more likely to develop depression. Pain, fatigue, sleep, and physical activity at baseline were not significantly associated with recovery from depression among those depressed at the initial assessment. Fatigue and sleep may contribute to the development of depression. Clinical trial research targeting these variables to determine their influence on depression is warranted.


Patellar tendon rupture repair using Dall-Miles cable.
Ten patients underwent patellar tendon repair with end-to-end suture technique and medial and lateral retinacular repair, as well as reinforcement with a Dall-Miles cable through the patella and tibial tubercle. The cable was tensioned at 60 degrees of flexion to allow immediate range of motion to at least 100 degrees of flexion and to protect the repair from undue tension while healing. Accurate tendon length was obtained from a lateral radiograph of the noninvolved knee in 60 degrees of flexion. Patients were allowed to bear full weight as tolerated postoperatively. A knee immobilizer was worn for approximately 2 weeks when adequate muscular control of the leg was attained. The cable was removed 6-8 weeks postoperatively, at which time range of motion equal to the opposite extremity was sought. Full extension was obtained by 1 week postoperatively. Average postoperative knee flexion was 88 degrees at 2 weeks, 112 degrees at 1 month, 133 at 3 months, and 138 degrees at 6 months compared to flexion of 141 degrees in the noninvolved knee. Mean quadriceps muscle strength 1 year postoperatively was 72%+/-11% of the noninvolved leg. No patient had patella infera or rerupture after surgery. Repair of a patellar tendon rupture with end-to-end techniques reinforced with a Dall-Miles cable allows immediate rehabilitation without the need for prolonged immobilization. This technique allows restoration of full range of motion early postoperatively and enables patients to regain adequate quadriceps strength.


Ventral cochlear nucleus coding of voice onset time in naturally spoken syllables.
These experiments examined the coding of the voice onset time (VOT) of six naturally spoken syllables, presented at a number of intensities, by ventral cochlear nucleus (VCN) neurons in rats anesthetized with urethane. VOT is one of the cues for the identification of a stop consonant, and is defined by the interval between stop release and the first glottal pulse that marks the onset of voicing associated with a vowel. The syllables presented (/bot/, /dot/, /got/, /pot/, /tot/, /kot/) each had a different VOT, ranging between 10 and 108 ms. Extracellular recordings were made from single neurons (N=202) with a wide range of best frequencies (BFs; 0.66-10 kHz) that represented the major VCN response types - primary-like (67.8% of sample), chopper (19.8%), and onset (12.4%) neurons. The different VOTs of the syllables were accurately reflected in sharp, precisely timed, and statistically significant changes in average discharge rate in all cell types, as well as the entire VCN sample. The prominence of the response to stop release and voice onset, and the level of activity prior to the VOT, were influenced by syllable intensity and the spectrum of stop release, as well as cell BF and type. Our results suggest that the responses of VCN cells with BFs above the first formant frequency are dominated by their sensitivity to the onsets of broadband events in speech, and allows them to convey accurate information about a syllable's VOT.


Sociodemographic Factors Predicting Exclusive Breastfeeding in Ethiopia: Evidence from a Meta-analysis of Studies Conducted in the Past 10 Years.
To investigate the association between EBF and educational status, household income, marital status, media exposure, and parity in Ethiopia. PubMed, EMBASE, Web of Science, SCOPUS, CINAHL and WHO Global health library databases were searched using key terms for all studies published in English between September 2009 and March 2019. The methodological quality of studies was examined using the Newcastle-Ottawa Scale (NOS) for cross-sectional studies. To obtain the pooled odds ratio (OR), extracted data were fitted in a random-effects meta-analysis model. Statistical heterogeneity was quantified using Cochran's Q test, τ2, and I2 statistics. In addition, Jackknife sensitivity analysis, cumulative meta-analysis, and meta-regression analysis were conducted. Out of 553 studies retrieved, 31 studies fulfilled our inclusion criteria. Almost all included studies were conducted among mothers with newborn less than 23 months old. Maternal primary school education (OR 1.39; 95% CI 1.03-1.89; I2 = 86.11%), medium household income (OR 1.27; 95% CI 1.05-1.55; I2 = 60.9%) and being married (OR 1.39; 95% CI 1.05-1.83; I2 = 76.96%) were found to be significantly associated with EBF. We also observed an inverse dose-response relationship of EBF with educational status and income. However, EBF was not significantly associated with parity, media exposure, and paternal educational status. In this meta-analysis, we showed the relevant effect of maternal education, income, and marital status on EBF. Therefore, multifaceted, effective, and evidence-based efforts are needed to increase the national level of exclusive breastfeeding in Ethiopia.


Structural elucidation of the O-antigen of the Shigella flexneri provisional serotype 88-893: structural and serological similarities with S. flexneri provisional serotype Y394 (1c).
The structure of the repeating unit of the O-antigen polysaccharide from Shigella flexneri provisional serotype 88-893 has been determined. (1)H and (13)C NMR spectroscopy as well as 2D NMR experiments were employed to elucidate the structure. The carbohydrate part of the hexasaccharide repeating unit is identical to the previously elucidated structure of the O-polysaccharide from S. flexneri prov. serotype Y394. The O-antigen of S. flexneri prov. serotype 88-893 carries 0.7 mol O-acetyl group per repeating unit located at O-2 of the 3-substituted rhamnosyl residue, as identified by H2BC and BS-CT-HMBC NMR experiments. The O-antigen polysaccharide is composed of hexasaccharide repeating units with the following structure: →2)-α-L-Rhap-(1→2)-α-L-Rhap-(1→3)-α-L-Rhap2Ac-(1→3)[α-D-Glcp-(1→2)-α-D-Glcp-(1→4)]-β-D-GlcpNAc-(1→. Serological studies showed that type antigens for the two provisional serotypes are identical; in addition 88-893 expresses S. flexneri group factor 6 antigen. We propose that provisional serotypes Y394 and 88-893 be designated as two new serotypes 7a and 7b, respectively, in the S. flexneri typing scheme.


Degradation of glucagon in isolated liver endosomes. ATP-dependence and partial characterization of degradation products.
Endosomes have recently been identified as one major site of glucagon degradation in intact rat liver. In this study, a cell-free system has been used to assess the role of ATP-dependent acidification in endosomal glucagon degradation and identify the glucagon products generated. Percoll gradient fractionation of Golgi-endosomal fractions prepared 10-30 min after injection of [125I]iodoglucagon showed a time-dependent shift of the radioactivity towards high densities. Regardless of time, the radioactivity was less precipitable by trichloroacetic acid (Cl3Ac) at high densities than at low densities. Chloroquine treatment slightly increased the density shift of the radioactivity and decreased its Cl3Ac-precipitability throughout the gradient. Incubation of endosomal fractions containing [125I]iodoglucagon in 0.15 M-KCl at 30 degrees C resulted in a time- and pH-dependent generation of Cl3Ac-soluble radioactivity, with a maximum at pH 4 (t1/2, 7 min). At pH 5, 1,10-phenanthroline, bacitracin and p-chloromercuribenzoic acid partially inhibited [125I]iodoglucagon degradation. At pH 6-7, ATP stimulated [125I]iodoglucagon degradation by 5-10-fold and caused endosomal acidification as judged from Acridine Orange uptake. The effects of ATP were inhibited by chloroquine, monensin, N-ethylmaleimide and dansylcadaverine. Poly(ethylene glycol) (PEG) precipitation of the radioactivity associated with endosomes showed that lowering the pH below 5.5 caused dissociation of the glucagon-receptor complex, and that, regardless of incubation conditions, all degraded [125I]iodoglucagon diffused extraluminally. On h.p.l.c., at least three products less hydrophobic than [125I]iodoglucagon were identified in incubation mixtures along with monoiodotyrosine. Radiosequence analysis of the products revealed one major cleavage located C-terminally to Tyr-13 and two minor cleavages affecting Thr-5-Phe-6 and Phe-6-Thr-7 bonds. It is concluded that glucagon degradation in liver endosomes is functionally linked to ATP-dependent endosomal acidification and involves several cleavages in the glucagon sequence.


A novel algorithm for a multi-cavity Raman fiber laser.
In this paper a Raman Fiber Lasers (RFLs) with several embedded cavities are studied. A novel algorithm is proposed to solve the coupled equations describing the optical power evolution in a RFL. By using some invariant constants as the boundary condition at the output end, the problem of solving ordinary differential equations (ODEs) with guessing boundary value is translated into a two-boundary-condition ODE problem. The algorithm is based on Newton-Raphson method and proved rather fast and stable. Quantitative analysis is performed based on the algorithm.


The use of synthetic lysine in the diet of lactating sows.
We conducted an experiment to determine the proportion of the lysine requirement of lactating sows that can be met using L-lysine x HCl. A total of 247 Pig Improvement Company (PIC) sows (parity one to four) were randomly allotted to one of five experimental diets containing .79% apparently digestible lysine. The first four diets contained 0, .075, .150, and .225% L-lysine x HCl replacing the intact lysine, primarily derived from soybean meal. Dietary crude protein was reduced from 17.9 to 16.9, 15.8, and 14.8% respectively. The fifth diet contained .174% L-lysine x HCl (15.5% CP) with added synthetic methionine, threonine, and tryptophan to restore the ratios of these amino acids to lysine to those in the control diet with no synthetic amino acids. The average lactation length was 15.7 +/- .3 d. Diet did not affect ADFI, sow backfat loss, sow loin eye area loss, or weaning-to-mating interval. Sows consumed an average of 4.6 kg/d and were provided 36 g/d of digestible lysine. Replacing soybean meal with increasing levels of L-lysine x HCl did not affect sow weight change. The number of pigs weaned decreased and preweaning mortality increased linearly (P = .08) with increasing levels of L-lysine x HCl. Litters from sows fed the .174% L-lysine x HCl with added methionine, threonine, and tryptophan grew slower and had a higher mortality rate than litters from sows fed no synthetic amino acids (P < .05). The addition of synthetic methionine, threonine, and tryptophan to the .174% L-lysine x HCl diet did not improve litter growth rate, but it did increase preweaning mortality (P = .05) and decrease the number of pigs weaned (P = .06) compared to the .15% L-lysine x HCl with no additional synthetic amino acids. These additions also resulted in an increased sow weight loss (P = .10). These results suggest that when more than .075% L-lysine x HCl is used to meet the lysine requirement preweaning mortality is increased and the number of pigs weaned is decreased. Supplementation with methionine, threonine, and tryptophan failed to ameliorate the negative response associated with L-lysine x HCl, which suggests that other amino acids may be limiting.


Rotationally Resolved Vacuum Ultraviolet Resonance-Enhanced Multiphoton Ionization (VUV REMPI) of Acetylene via the G̃ Rydberg State.
We present a 1 + 1' resonance-enhanced multiphoton ionization (REMPI) scheme for acetylene via the linear G̃ 4sσ (1)Πu Rydberg state, offering partial rotational resolution and the possibility to detect excitation in both the cis- and trans-bending modes. The resonant transition to the G̃ state is driven by a vacuum ultraviolet (VUV) photon, generated by resonant four-wave mixing (FWM) in krypton. Ionization from the short-lived G̃ state then occurs quickly, driven by the high intensity of the residual light from the FWM process. We have observed nine bands in the region between 79 200 cm(-1) and 80 500 cm(-1) in C2H2 and C2D2. We compare our results with published spectra in this region and suggest alternative assignments for some of the Renner-Teller split bands. Similar REMPI schemes should be applicable to other small molecules with picosecond lifetime Rydberg states.


Neuropathologic Characterization of Pontocerebellar Hypoplasia Type 6 Associated With Cardiomyopathy and Hydrops Fetalis and Severe Multisystem Respiratory Chain Deficiency due to Novel RARS2 Mutations.
Autosomal recessive mutations in the RARS2 gene encoding the mitochondrial arginyl-transfer RNA synthetase cause infantile-onset myoencephalopathy pontocerebellar hypoplasia type 6 (PCH6). We describe 2 sisters with novel compound heterozygous RARS2 mutations who presented perinatally with neurologic features typical of PCH6 but with additional features including cardiomyopathy, hydrops, and pulmonary hypoplasia and who died at 1 day and 14 days of age. Magnetic resonance imaging findings included marked cerebellar hypoplasia, gyral immaturity, punctate lesions in cerebral white matter, and unfused deep cerebral grey matter. Enzyme histochemistry of postmortem tissues revealed a near-global cytochrome c oxidase-deficiency; assessment of respiratory chain enzyme activities confirmed severe deficiencies involving complexes I, III, and IV. Molecular genetic studies revealed 2 RARS2 gene mutations: a c.1A>G, p.? variant predicted to abolish the initiator methionine, and a deep intronic c.613-3927C>T variant causing skipping of exons 6-8 in the mature RARS2 transcript. Neuropathologic investigation included low brain weights, small brainstem and cerebellum, deep cerebral white matter pathology, pontine nucleus neuron loss (in 1 sibling), and peripheral nerve pathology. Mitochondrial respiratory chain immunohistochemistry in brain tissues confirmed an absence of complexes I and IV immunoreactivity with sparing of mitochondrial numbers. These cases expand the clinical spectrum of RARS2 mutations, including antenatal features and widespread mitochondrial respiratory chain deficiencies in postmortem brain tissues.


Population PK/PD modeling of low-density lipoprotein cholesterol response in hypercholesterolemic participants following administration of bococizumab, a potent anti-PCSK9 monoclonal antibody.
We sought to characterize the population pharmacokinetic/pharmacodynamic (PK/PD) relationship of bococizumab (RN316/PF-04950615), a humanized IgG2Δa monoclonal antibody that binds to secreted human proprotein convertase subtilisin kexin type 9 (PCSK9), using data derived from 16 phase I, II, and III clinical studies (36,066 bococizumab observations, 46,790 low-density lipoprotein cholesterol [LDL-C] measurements, 3499 participants). A two-compartment disposition model with parallel linear and Michaelis-Menten elimination and an indirect response model was used to characterize the population PK and LDL-C response of bococizumab. Potential model parameters and covariate relationships were explored, and visual predictive checks were used for model assessment and validation. Key covariates included the effect of anti-drug antibodies (ADAs) on exposure through impact on clearance and bioavailability; impact of statins on bococizumab elimination (maximal rate of metabolism); and impact of statins, Asian race, and male sex on LDL-C efficacy (maximum effect). ADAs and neutralizing ADAs did not have additional effects on LDL-C beyond the influence on bococizumab exposure. In conclusion, the population PK/PD model adequately describes bococizumab concentration and LDL-C efficacy. The covariate effects are consistent with the presumed mechanism of action of PCSK9 inhibitors. With increasing availability of antibody-based therapeutics, improved understanding of the effect of ADAs and statins on bococizumab PK/PD adds to the literature and enhances our pharmacological understanding of how immunogenicity and concomitant medications may impact the PK/PD of biotherapeutics.


Temporally non-regular patterns of deep brain stimulation (DBS) enhance assessment of evoked potentials while maintaining motor symptom management in Parkinson's disease (PD).
Traditional deep brain stimulation (DBS) at fixed regular frequencies (>100 Hz) is effective in treating motor symptoms of Parkinson's disease (PD). Temporally non-regular patterns of DBS are a new parameter space that may help increase efficacy and efficiency. To compare the effects of temporally non-regular patterns of DBS to traditional regularly-spaced pulses. We simultaneously recorded local field potentials (LFP) and monitored motor symptoms (tremor and bradykinesia) in persons with PD during DBS in subthalamic nucleus (STN). We quantified both oscillatory activity and DBS local evoked potentials (DLEPs) from the LFP. Temporally non-regular patterns were as effective as traditional pulse patterns in modulating motor symptoms, oscillatory activity, and DLEPs. Moreover, one of our novel patterns enabled recording of longer duration DLEPs during clinically effective stimulation. Stimulation gaps of 50 ms can be used to increase efficiency and to enable regular assessment of long-duration DLEPs while maintaining effective symptom management. This may be a promising paradigm for closed-loop DBS with biomarker assessment during the gaps.


Attenuation correction for three-dimensional PET using uncollimated flood-source transmission measurements.
An attenuation-correction method for three-dimensional PET imaging, which obtains attenuation-correction factors from transmission measurements using an uncollimated flood source, is described. This correction is demonstrated for two different phantoms using transmission data acquired with QPET, a rotating imaging system with two planar detectors developed for imaging small volumes. The scatter amplitude in the transmission projections was a maximum of 30%; to obtain accurate attenuation-correction factors the scatter distribution was first calculated and subtracted. The attenuation-corrected emission images for both phantoms indicate that their original uniform amplitudes have been restored. The attenuation correction adds only a small amount of noise to the emission images, as evaluated from the standard deviation over a central region. For the first phantom, with maximum attenuation of 48%, the noise added was 2.6%. The second phantom was attenuated by a maximum of 37%, and 1.9% noise was added. Because the transmission data are smoothed, some artifacts are visible at the edges of the phantom where the correction factors change abruptly within the emission image.


Intracranial spectral amplitude dynamics of perceptual suppression in fronto-insular, occipito-temporal, and primary visual cortex.
If conscious perception requires global information integration across active distant brain networks, how does the loss of conscious perception affect neural processing in these distant networks? Pioneering studies on perceptual suppression (PS) described specific local neural network responses in primary visual cortex, thalamus and lateral prefrontal cortex of the macaque brain. Yet the neural effects of PS have rarely been studied with intracerebral recordings outside these cortices and simultaneously across distant brain areas. Here, we combined (1) a novel experimental paradigm in which we produced a similar perceptual disappearance and also re-appearance by using visual adaptation with transient contrast changes, with (2) electrophysiological observations from human intracranial electrodes sampling wide brain areas. We focused on broadband high-frequency (50-150 Hz, i.e., gamma) and low-frequency (8-24 Hz) neural activity amplitude modulations related to target visibility and invisibility. We report that low-frequency amplitude modulations reflected stimulus visibility in a larger ensemble of recording sites as compared to broadband gamma responses, across distinct brain regions including occipital, temporal and frontal cortices. Moreover, the dynamics of the broadband gamma response distinguished stimulus visibility from stimulus invisibility earlier in anterior insula and inferior frontal gyrus than in temporal regions, suggesting a possible role of fronto-insular cortices in top-down processing for conscious perception. Finally, we report that in primary visual cortex only low-frequency amplitude modulations correlated directly with perceptual status. Interestingly, in this sensory area broadband gamma was not modulated during PS but became positively modulated after 300 ms when stimuli were rendered visible again, suggesting that local networks could be ignited by top-down influences during conscious perception.


World Health Organization-defined classification of myeloproliferative neoplasms: morphological reproducibility and clinical correlations--the Danish experience.
We examined inter- and intraobserver reproducibility and concordance between histological diagnosis and independently collected clinical findings in a large series of patients with the major subtypes of myeloproliferative neoplasms (MPNs) and controls. Seven hematopathologists reviewed 272 bone marrow biopsies including 43 controls. Diagnoses were determined according to the 2008 criteria of the World Health Organization (WHO). The participants were blinded to all clinical data except patient age. After initial evaluation all hematopathologists participated in a 3-day meeting with a leading clinician chaired by an expert hematopathologists. In cases with lack of consensus on fiber grading (n = 57), a new evaluation was performed. In cases with discordance on morphological diagnosis (n = 129), an additional nonblinded evaluation taking clinical data into consideration was carried out. For remaining cases with a lack of concordance between morphological diagnosis and clinical diagnosis (n = 33), a similar nonblinded evaluation was performed. Consensus on final histological diagnosis and concordance with clinical diagnosis were determined. Blinded histological evaluation resulted in a 53% consensus rate. After re-evaluation of fiber content, consensus was reached in 60% of cases. Adding clinical data increased the histological consensus to 83%. For cases with a histological consensus, we found a concordance of 71% with the clinician's diagnoses. This is the first study to present a larger cohort of MPN patients mimicking the diagnostic challenges that hematopathologists face in their daily practice. The results support the postulates of the WHO that both morphological and clinical findings are essential for a valid diagnosis


The trade-off between morphology and control in the co-optimized design of robots.
Conventionally, robot morphologies are developed through simulations and calculations, and different control methods are applied afterwards. Assuming that simulations and predictions are simplified representations of our reality, how sure can roboticists be that the chosen morphology is the most adequate for the possible control choices in the real-world? Here we study the influence of the design parameters in the creation of a robot with a Bayesian morphology-control (MC) co-optimization process. A robot autonomously creates child robots from a set of possible design parameters and uses Bayesian Optimization (BO) to infer the best locomotion behavior from real world experiments. Then, we systematically change from an MC co-optimization to a control-only (C) optimization, which better represents the traditional way that robots are developed, to explore the trade-off between these two methods. We show that although C processes can greatly improve the behavior of poor morphologies, such agents are still outperformed by MC co-optimization results with as few as 25 iterations. Our findings, on one hand, suggest that BO should be used in the design process of robots for both morphological and control parameters to reach optimal performance, and on the other hand, point to the downfall of current design methods in face of new search techniques.


Action of Pseudomonas fragi on the proteins of pig muscle.
Considerable salt-soluble protein degradation was observed in pork muscle inoculated with Pseudomonas fragi. During a 20-day incubation period at 10 C, the samples proceeded to rank spoilage or putrefaction. There was a large decrease in the salt-soluble protein fraction and a corresponding increase in nonprotein nitrogen. Disc gel electrophoretic patterns showed that breakdown of the salt-soluble proteins had occurred after incubation for 20 days. During incubation for 10 days at 10 C, P. fragi produced large amounts of extracellular proteolytic activity in ground pork. Most of the proteolytic activity appeared immediately after spoilage occurred. However, a significant increase in the ability to hydrolyze casein and a slight increase in the ability to hydrolyze denatured hemoglobin occurred prior to spoilage.


[The main directions of reforming the service of medical statistics in Ukraine].
Introduction: Implementation of new methods of information support of managerial decision-making should ensure of the effective health system reform and create conditions for improving the quality of operational management, reasonable planning of medical care and increasing the efficiency of the use of system resources. Reforming of Medical Statistics Service of Ukraine should be considered only in the context of the reform of the entire health system. The aim: This work is an analysis of the current situation and justification of the main directions of reforming of Medical Statistics Service of Ukraine. Material and methods: In the work is used a range of methods: content analysis, bibliosemantic, systematic approach. The information base of the research became: WHO strategic and program documents, data of the Medical Statistics Center of the Ministry of Health of Ukraine. Review: The Medical Statistics Service of Ukraine has a completed and effective structure, headed by the State Institution "Medical Statistics Center of the Ministry of Health of Ukraine." This institution reports on behalf of the Ministry of Health of Ukraine to the State Statistical Service of Ukraine, the WHO European Office and other international organizations. An analysis of the current situation showed that to achieve this goal it is necessary: to improve the system of statistical indicators for an adequate assessment of the performance of health institutions, including in the economic aspect; creation of a developed medical and statistical base of administrative territories; change of existing technologies for the formation of information resources; strengthening the material-technical base of the structural units of Medical Statistics Service; improvement of the system of training and retraining of personnel for the service of medical statistics; development of international cooperation in the field of methodology and practice of medical statistics, implementation of internationally accepted methods for collecting, processing, analyzing and disseminating medical and statistical information; the creation of a medical and statistical service that adapted to the specifics of market relations in health care, flexible and sensitive to changes in international methodologies and standards. Conclusions: The data of medical statistics are the basis for taking managerial decisions by managers at all levels of health care. Reform of Medical Statistics Service of Ukraine should be considered only in the context of the reform of the entire health system. The main directions of the reform of the medical statistics service in Ukraine are: the introduction of information technologies, the improvement of the training of personnel for the service, the improvement of material and technical equipment, the maximum reuse of the data obtained, which provides for the unification of primary data and a system of indicators. The most difficult area is the formation of information funds and the introduction of modern information technologies.


Autophagy suppresses age-dependent ischemia and reperfusion injury in livers of mice.
As life expectancy increases, there are greater numbers of patients with liver diseases who require surgery or transplantation. Livers of older patients have significantly less reparative capacity following ischemia and reperfusion (I/R) injury, which occurs during these operations. There are no strategies to reduce the age-dependent I/R injury. We investigated the role of autophagy in the age dependence of sensitivity to I/R injury. Hepatocytes and livers from 3- and 26-month-old mice were subjected to in vitro and in vivo I/R, respectively. We analyzed changes in autophagy-related proteins (Atg). Mitochondrial dysfunction was visualized using confocal and intravital multi-photon microscopy of isolated hepatocytes and livers from anesthetized mice, respectively. Immunoblot, autophagic flux, genetic, and imaging analyses all associated the increase in sensitivity to I/R injury with age with decreased autophagy and subsequent mitochondrial dysfunction due to calpain-mediated loss of Atg4B. Overexpression of either Atg4B or Beclin-1 recovered Atg4B, increased autophagy, blocked the onset of the mitochondrial permeability transition, and suppressed cell death after I/R in old hepatocytes. Coimmunoprecipitation analysis of hepatocytes and Atg3-knockout cells showed an interaction between Beclin-1 and Atg3, a protein required for autophagosome formation. Intravital multi-photon imaging revealed that overexpression of Beclin-1 or Atg4B attenuated autophagic defects and mitochondrial dysfunction in livers of older mice after I/R. Loss of Atg4B in livers of old mice increases their sensitivity to I/R injury. Increasing autophagy might ameliorate liver damage and restore mitochondrial function after I/R.


Childhood internalizing behaviour: analysis and implications.
The concept of 'internalizing behaviour' reflects a child's emotional or psychological state and typically includes depressive disorders, anxiety disorders, somatic complaints and teenage suicide. Genetic and environmental causes have been largely implicated, although research continues to explore social etiological factors. Some research suggests females may be especially vulnerable to internalizing disorders, while data across ethnicities are somewhat variable. Regarding treatment, cognitive-behavioural therapies and use of pharmacological approaches (i.e. selective serotonin reuptake inhibitors) have both shown great promise in reducing symptoms of internalizing disorders. However, given the role of the social environment, prevention programmes aimed at reducing exposure to drugs, violence/abuse and environmental toxins are highly important. Internalizing disorders are associated with a host of deleterious outcomes (e.g. school drop-out, substance use and potentially suicide) as well as psychopathological outcomes (e.g. co-morbid anxiety or depression, externalizing disorders - including suicide). Children with mental health problems suffer educationally and are more likely to become entangled in the justice and welfare systems. Clearly, early treatment and prevention programmes for internalizing disorders need to be a priority from a public health perspective as well as from a family and community perspective.


Factors influencing the presence of hemiparesis in chronic subdural hematoma.
Chronic subdural hematoma (CSDH) has a variety of clinical presentations, including hemiparesis. Hemiparesis is of the utmost importance because it is one of the major indications for surgical intervention and influences outcome. In the current study, the authors intended to identify factors influencing the presence of hemiparesis in CSDH patients and to determine the threshold value of hematoma thickness and midline shift for development of hemiparesis. The authors retrospectively reviewed 325 patients (266 with unilateral and 59 with bilateral hematomas) with CSDH who underwent surgical evacuation, regardless of presence or absence of hemiparesis. In univariate analysis, hematoma loculation, age, hematoma maximal thickness, and midline shift were significantly associated with hemiparesis. Moreover, patients with unilateral hematomas had a higher rate of hemiparesis than patients with bilateral hematomas. Sex, trauma history, anticoagulant and antiplatelet drug use, presence of comorbidities, Glasgow Coma Scale score, hematoma density characteristics on CT scan, and hematoma signal intensity on T1- and T2-weighted MRI were not associated with hemiparesis. In multivariate analysis, the presence of loculation and hematoma laterality (unilateral vs bilateral) influenced hemiparesis. For unilateral hematomas, maximal hematoma thickness of 19.8 mm and midline shift of 6.4 mm were associated with a 50% probability of hemiparesis. For bilateral hematomas, 29.0 mm of maximal hematoma thickness and 6.8 mm of shift were associated with a 50% probability of hemiparesis. Presence of loculations, unilateral hematomas, older patient age, hematoma maximal thickness, and midline shift were associated with a higher rate of hemiparesis in CSDH patients. Moreover, 19.8 mm of hematoma thickness and 6.4 mm of midline shift were associated with a 50% probability of hemiparesis in patients with unilateral hematomas.


Multi-substrate chromosome preparations for high throughput comparative FISH.
A modification of a standard method of fluorescence in situ hybridisation (FISH) is described, by which a combination of several substrates and probes on single microscope slides enables more accurate comparisons of the distribution and abundance of chromosomal sequences and improves the relatively low throughput of standard FISH methods. The utility and application of multi-colour, multi-substrate FISH is illustrated by the simultaneous physical mapping of retrotransposon sequences to three species of Avena, and single locus BAC (bacterial artificial chromosome) clones and rDNA probes to three species of Brachypodium, demonstrating how this would enable better understanding of complex phylogenetic relationships among some of the species belonging to these two genera. The results show that use of multi-substrate chromosome preparations significantly increases the utility of FISH in comparative analyses of the distribution and abundance of chromosomal sequences in closely related plant species.


Prenatal flutamide enhances survival in a myogenic mouse model of spinal bulbar muscular atrophy.
Spinal bulbar muscular atrophy (SBMA) is caused by a CAG repeat expansion mutation in the androgen receptor (AR) gene, and mutant AR is presumed to act in motoneurons to cause SBMA. However, we found that mice overexpressing wild-type (wt) AR solely in skeletal muscle fibers display the same androgen-dependent disease phenotype as when mutant AR is broadly expressed, challenging the assumptions that only an expanded AR can induce disease and that SBMA is strictly neurogenic. We have previously reported that AR toxicity was ligand dependent in our model, and that very few transgenic (tg) males survived beyond birth. We tested whether the AR antagonist flutamide could block perinatal toxicity. tg males were treated prenatally with flutamide and assessed for survival and motor behavior in adulthood. Prenatal treatment with flutamide rescued tg male pups from perinatal death, and, as adults, such perinatally rescued tg males showed an SBMA phenotype that was comparable to that of previously described untreated tg males. Moreover, tg males carrying a mutant endogenous allele for AR--the testicular feminization mutation (tfm)--and thus having functional AR only in muscle fibers nevertheless displayed the same androgen-dependent disease phenotype as adults. These mice represent an excellent model to study the myogenic contribution to SBMA as they display many of the core features of disease as other mouse models. These data demonstrate that AR acting exclusively in muscle fibers is sufficient to induce SBMA symptoms and that flutamide is protective perinatally.


Cleavage of E-Cadherin by Matrix Metalloproteinase-7 Promotes Cellular Proliferation in Nontransformed Cell Lines via Activation of RhoA.
Perturbations in cell-cell contact machinery occur frequently in epithelial cancers and result in increased cancer cell migration and invasion. Previously, we demonstrated that MMP-7, a protease implicated in mammary and intestinal tumor growth, can process the adherens junction component E-cadherin. This observation leads us to test whether MMP-7 processing of E-cadherin could directly impact cell proliferation in nontransformed epithelial cell lines (MDCK and C57MG). Our goal was to investigate the possibility that MMP-7 produced by cancer cells may have effects on adjacent normal epithelium. Here, we show that MMP-7 processing of E-cadherin mediates, (1) loss of cell-cell contact, (2) increased cell migration, (3) a loss of epithelial cell polarization and (4) increased cell proliferation via RhoA activation. These data demonstrate that MMP-7 promotes epithelial cell proliferation via the processing of E-cadherin and provide insights into the molecular mechanisms that govern epithelial cell growth.


The Kirkwood-Buff integrals for one-component liquids.
The Kirkwood-Buff integrals (KBIs) for one-component systems are calculated from either the pair correlation functions or from experimental macroscopic quantities. As in the case of mixtures, the KBIs provide important information on the local densities around a molecule. In the low density limit (rho-->0) one can extract from the KBI some information on the strength of the intermolecular forces. No such information may be extracted from the KBIs at higher densities. We used experimental data on densities and isothermal compressibilities to calculate the KBIs for various liquids ranging from inert molecules, to hydrocarbons, alcohols, and liquid water.


Mechanisms underlying TNF-alpha effects on agonist-mediated calcium homeostasis in human airway smooth muscle cells.
We have previously shown that tumor necrosis factor (TNF)-alpha, a cytokine involved in asthma, enhances Ca2+ responsiveness to bronchoconstrictor agents in cultured human airway smooth muscle (ASM) cells. In the present study, we investigated the potential mechanism(s) by which TNF-alpha modulates ASM cell responsiveness to such agents. In human ASM cells loaded with fura 2, TNF-alpha and interleukin (IL)-1 beta significantly enhanced thrombin- and bradykinin-evoked elevations of intracellular Ca2+. In TNF-alpha-treated cells. Ca2+ responses to thrombin and bradykinin were 350 +/- 14 and 573 +/- 93 nM vs. 130 +/- 17 and 247 +/- 48 nM in nontreated cells, respectively (P < 0.0001). In IL-1 beta-treated cells, the Ca2+ response to bradykinin was 350 +/- 21 vs. 127 +/- 12 nM in nontreated cells (P < 0.0001). The time course for TNF-alpha potentiation of agonist-induced Ca2+ responses requires a minimum of 6 h and was maximum after 12 h of incubation. In addition, cycloheximide, a protein synthesis inhibitor, completely blocked the potentiating effect of TNF-alpha on Ca2+ signals. We also found that TNF-alpha significantly enhanced increases in phosphoinositide (PI) accumulation induced by bradykinin. The percentage of change in PI accumulation over control was 115 +/- 8 to 210 +/- 15% in control cells vs. 128 +/- 10 to 437 +/- 92% in TNF-alpha-treated cells for 3 x 10(-9) to 3 x 10(-6) M bradykinin. The PI turnover to 10 mM NaF, a direct activator of G proteins, was also found to be enhanced by TNF-alpha. The percentage of change in PI accumulation over control increased from 280 +/- 35% in control cells to 437 +/- 92% in TNF-alpha-treated cells. Taken together, these results show that TNF-alpha can potently regulate G protein-mediated signal transduction in ASM cells by activating pathways dependent on protein synthesis. Our study demonstrates one potential mechanism underlying the enhanced Ca2+ response to bronchoconstrictor agents induced by cytokines in human ASM cells.


Retrospectively acquired cohort study to evaluate the long-term impact of two different treatment strategies on disability outcomes in patients with relapsing multiple sclerosis (RE.LO.DI.MS): data from the Italian MS Register.
The increase in disease-modifying drugs (DMDs) allows individualization of treatment in relapsing multiple sclerosis (RMS); however, the long-term impact of different treatment sequences is not well established. This is particularly relevant for MS patients who may need to postpone more aggressive DMD strategies. To evaluate different therapeutic strategies and their long-term outcomes, measured as relapses and confirmed disability progression (CDP), in MS 'real-world' settings. Multicentre, observational, retrospectively acquired cohort study evaluating the long-term impact of different treatment strategies on disability outcomes in patients with RMS in the Italian MS Register. We evaluated 1152 RMS-naïve patients after propensity-score adjustment. Patients included were receiving: interferon beta-1a (IFN-β1a) 44 µg switching to fingolimod (FTY; IFN-switchers; n = 97); FTY only (FTY-stayers; n = 157); IFN-β1a only (IFN-stayers; n = 849). CDP and relapses did not differ between FTY-stayers and IFN-switchers [HR (95% CI) 0.99 (0.48-2.04), p = 0.98 and 0.81 (0.42-1.58), p = 0.55, respectively]. However, IFN-stayers showed increased risk of relapses compared with FTY-stayers [HR (95% CI) 1.46 (1.00-2.12), p = 0.05]. The ideal treatment option for MS is becoming increasingly complex, with the need to balance benefit and risks. Our results suggest that starting with FTY affects the long-term disease outcome similarly to escalating from IFN-β1a to FTY.


Detection of occult pneumonia in a pediatric emergency department.
Many children undergo chest radiography (CXR) in their evaluation of a febrile illness. Pneumonia without signs of respiratory distress or ausculatory findings has been previously described (termed occult pneumonia [OP]). The objectives of this study were to determine the incidence of OP among children who have CXR performed and to identify clinical predictors of OP. A prospective observational study of children undergoing CXR for possible pneumonia was conducted. Standardized data forms were completed before the CXR. Univariate analysis and recursive partitioning were used to identify predictors of OP. Of 1866 patients enrolled, 308 had no evidence of respiratory distress or lower respiratory tract findings and were studied for OP. Twenty-one patients had radiographic OP (6.8%; 95% confidence interval [CI], 4.0%-10.6%). Age, height of fever, duration or quality of cough, and pulse oximetry were not associated with OP. A decision rule based on fever for 1 day or longer or with a combination of fever for less than 1 day but worsening cough identifies patients at greater risk for OP (likelihood ratio, 1.47; 95% CI, 1.21-1.77). No patient with fever for less than 1 day and without any cough or without worsening cough had pneumonia (likelihood ratio, 0.40; 95% CI, 0.19-0.84). Occult pneumonia was identified in 1 of 15 patients undergoing CXR without respiratory distress or ausculatory findings. Obtaining a CXR for the detection of OP in children without cough and with fever for less than 1 day in duration should be discouraged.


Latinos and Cancer Information: Perspectives of Patients, Health Professionals and Telephone Cancer Information Specialists.
Semi-structured interviews were conducted with 16 Latino cancer patients diagnosed in California; 10 health professionals from the San Francisco Bay Area and Fresno, California; and 10 Cancer Information Services (CIS) information specialists from the regional offices handling calls from Spanish-speakers. Interview guides were designed by the investigators to answer three main research questions: 1) How do Latinos obtain information about cancer and what types of information do they access?; 2) What sources of cancer information do they seek out and find credible?; and 3) What are the barriers and facilitators to Latinos obtaining cancer information? Stakeholders generally viewed health professionals as the most credible source of cancer information. All groups regarded family and friends as important sources of information. Patients and health professionals tended to differ on the value of print materials. Although patients found them generally useful, health professionals tended to view them as inadequate for meeting the informational needs of their Latino patients due to the challenge of low health literacy. Health professionals also tended to undervalue Internet resources compared to patients and CIS specialists. All stakeholders viewed language, ethnic discordance and the impact on patients of the initial diagnosis as barriers to effective communication of cancer information. Health professionals and CIS specialists, but not patients, mentioned low literacy as a barrier. Our findings underscore the importance of the physician-patient relationship as a point of intervention to address the unmet informational and psychosocial needs of Latino cancer patients.


[Significance of the functional activity of toll-like receptors and other receptors of the innate immune system of the kidney physiology].
The kidney needs to defend against microbial pathogens in order to maintain normal structure and function. This is achieved through innate and adaptive components of the immune system. For a long time, immunologists were concentrating on the adaptive immune system, which, as a result, was studied in detail; at the same time, the significance of the innate immune system was underestimated. This gap was partly filled in the recently, when the key role of the innate immune system in fighting microorganisms and in activating and regulating the adaptive immune system was convincingly established. In the first part of the present article, the sense apparatus of the innate immune system (the so-called pattern-recognition receptors) will be reviewed; particular attention will be paid to the toll-like receptors (TLRs), which bear the main burden of microorganism recognition. Signalling pathways that are activated by TLRs and result in the activation of effector mechanisms will also be reviewed. In the second part of the review, we will analyse available data on how these mechanisms of the innate immune system secure defence and normal functioning of the kidney.


Home infusion therapy meets managed care: confrontation or cooperation.
The relatively uncommon experience of patients using home infusion therapy but at relatively great expense has led to problems, sometimes confrontational, between managed care organizations and home infusion therapy providers. The principal barriers to smooth contracting relationships are described by the author, who also proposes ways to create a win-win environment.


The burden of drug resistant tuberculosis in a predominantly nomadic population in Uganda: a mixed methods study.
Emergence of drug resistant tuberculosis (DR-TB) has aggravated the tuberculosis (TB) public health burden worldwide and especially in low income settings. We present findings from a predominantly nomadic population in Karamoja, Uganda with a high-TB burden (3500 new cases annually) and sought to determine the prevalence, patterns, factors associated with DR-TB. We used mixed methods of data collection. We enrolled 6890 participants who were treated for tuberculosis in a programmatic setting between January 2015 and April 2018. A cross sectional study and a matched case control study with conditional logistic regression and robust standard errors respectively were used to the determine prevalence and factors associated with DR-TB. The qualitative methods included focus group discussions, in-depth interviews and key informant interviews. The overall prevalence of DR-TB was 41/6890 (0.6%) with 4/64,197 (0.1%) among the new and 37/2693 (1.4%) among the previously treated TB patients respectively. The drug resistance patterns observed in the region were mainly rifampicin mono resistant (68.3%) and Multi Drug-Resistant Tuberculosis (31.7%). Factors independently associated with DR-TB were previous TB treatment, adjusted odds ratio (aOR) 13.070 (95%CI 1.552-110.135) and drug stock-outs aOR 0.027 (95%CI 0.002-0.364). The nomadic lifestyle, substance use, congested homesteads and poor health worker attitudes were a great challenge to effective treatment of TB. Despite having the highest national TB incidence, Karamoja still has a low DR-TB prevalence. Previous TB treatment and drug stock outs were associated with DR-TB. Regular supply of anti TB medications and health education may help to stem the burden of TB disease in this nomadic population.


Acute Diverticulitis: A Rare Cause of Abdominal Pain.
There is an increasing incidence of diverticulosis and diverticulitis in the younger populations; and its occurrence in very young individual is concerning. Here we report a rare and interesting case of a 20-year-old man who presented with 3-day history of epigastric abdominal pain associated with diarrhea and nausea. His abdominal examination revealed mild tenderness in the right lower abdominal quadrant. Computed tomography (CT) scan of abdomen with intravenous contrast revealed scattered diverticula throughout the colon with focal thickening, pericolonic infiltrative changes suggestive of acute diverticulitis in the distal ascending colon. He was treated with intravenous hydration and antibiotics and discharged when his clinical status improved. He underwent colonoscopy 1 month later which showed pan diverticulosis. This case illustrates the importance of considering acute diverticulitis in the differential diagnosis of right lower quadrant pain when evaluating a young patient.


The clinical performance of one- and two-step self-etching adhesive systems at one year.
The author compared the clinical performance of a two-step self-etching adhesive system and a one-step self-etching adhesive system over one year. Thirty-five patients with noncarious cervical lesions were enrolled in the study. The author restored 163 lesions using a two-step (Clearfil Protect Bond, Kuraray, Osaka, Japan) or a one-step (Xeno III, Dentsply/DeTrey, Konstanz, Germany) self-etching adhesive system. Enamel margins were not beveled, and no mechanical retentions were placed. The author evaluted the restorations at baseline and at three, six, nine and 12 months after placement using modified Ryge criteria for color-matching ability, marginal discoloration, marginal adaptation, initial caries formation, anatomical form, postoperative sensitivity and retention loss. The author assessed the changes in the parameters using the Cochran Q test and the McNemar test at a significance level of .05. At one year, the retention rates for the restorations in the two-step group were 100 percent; they were 96 percent for the restorations in the one-step group. Of the retained 75 restorations from the one-step group, two had marginal discoloration and slight anatomical form problems. In both groups, color-matching ability and postoperative sensitivity remained excellent. The performance of both self-etching adhesive systems was excellent during this one-year clinical trial. However, the two-step system exhibited slightly better retention than the one-step system. The one- and two-step self-etching adhesive systems evaluated in this study provided excellent clinical retention in noncarious lesions without mechanical retention.


Inhibitory behavioral control: A stochastic dynamic causal modeling study comparing cocaine dependent subjects and controls.
Cocaine dependence is associated with increased impulsivity in humans. Both cocaine dependence and impulsive behavior are under the regulatory control of cortico-striatal networks. One behavioral laboratory measure of impulsivity is response inhibition (ability to withhold a prepotent response) in which altered patterns of regional brain activation during executive tasks in service of normal performance are frequently found in cocaine dependent (CD) subjects studied with functional magnetic resonance imaging (fMRI). However, little is known about aberrations in specific directional neuronal connectivity in CD subjects. The present study employed fMRI-based dynamic causal modeling (DCM) to study the effective (directional) neuronal connectivity associated with response inhibition in CD subjects, elicited under performance of a Go/NoGo task with two levels of NoGo difficulty (Easy and Hard). The performance on the Go/NoGo task was not significantly different between CD subjects and controls. The DCM analysis revealed that prefrontal-striatal connectivity was modulated (influenced) during the NoGo conditions for both groups. The effective connectivity from left (L) anterior cingulate cortex (ACC) to L caudate was similarly modulated during the Easy NoGo condition for both groups. During the Hard NoGo condition in controls, the effective connectivity from right (R) dorsolateral prefrontal cortex (DLPFC) to L caudate became more positive, and the effective connectivity from R ventrolateral prefrontal cortex (VLPFC) to L caudate became more negative. In CD subjects, the effective connectivity from L ACC to L caudate became more negative during the Hard NoGo conditions. These results indicate that during Hard NoGo trials in CD subjects, the ACC rather than DLPFC or VLPFC influenced caudate during response inhibition.


Nutrient regulation of post-heparin lipoprotein lipase activity in obese subjects.
This study examines the immediate effect of ingestion of oral carbohydrate and fat on lipoprotein lipase (LPL) activity post-heparin in six lean and six obese age-matched women. Subjects were given, on two separate occasions, 340 kcal carbohydrate or an equicaloric amount of fat, both in 300 ml of water. Post-heparin LPL activity (10,000 U) was measured on each occasion 120 minutes after ingestion of the meal. Following oral carbohydrate postprandial plasma insulin levels were significantly higher in obese subjects than in lean (p < 0.01). Impaired glucose tolerance was seen in the obese group. GIP secretion was similar in lean and obese subjects both during oral fat and carbohydrate ingestion. GLP-1 secretion post-carbohydrate was lower in obese subjects. Total LPL activity unadjusted for body weight was similar in the two groups after carbohydrate administration but was significantly lower when adjusted per kg body weight. Total LPL activity was lower in the lean group at 130 minutes after fat administration (p < 0.02). Fasting serum triglycerides were higher in the obese group and were inversely related to the post-carbohydrate LPL activity (r = - 0.65, p < 0.02). Intraluminal lipoprotein lipase activity is not increased in established obesity. Fat and carbohydrate nutrients may affect LPL activity differently in lean and obese subjects.


Effects of parental public health insurance eligibility on parent and child health outcomes.
Many states expanded their Medicaid programs to low-income adults under the Affordable Care Act (ACA). These expansions increased Medicaid coverage among low-income parents and their children. Whether these improvements in coverage and healthcare use lead to better health outcomes for parents and their children remains unanswered. We used longitudinal data on a large, nationally representative cohort of elementary-aged children from low-income households from 2010 to 2016. Using a difference-in-differences approach in state Medicaid policy decisions, we estimated the effect of the ACA Medicaid expansions on parent and child health. We found that parents' self-reported health status improved significantly post-expansion in states that expanded Medicaid through the ACA by 4 percentage points (p < 0.05), a 4.7% improvement. We found no significant changes in children's use of routine doctor visits or parents' assessment of their children's health status. We observed modest decreases in children's body mass index (BMI) of about 2% (p < 0.05), especially for girls.


Plant selection for ethnobotanical uses on the Amalfi Coast (Southern Italy).
Many ethnobotanical studies have investigated selection criteria for medicinal and non-medicinal plants. In this paper we test several statistical methods using different ethnobotanical datasets in order to 1) define to which extent the nature of the datasets can affect the interpretation of results; 2) determine if the selection for different plant uses is based on phylogeny, or other selection criteria. We considered three different ethnobotanical datasets: two datasets of medicinal plants and a dataset of non-medicinal plants (handicraft production, domestic and agro-pastoral practices) and two floras of the Amalfi Coast. We performed residual analysis from linear regression, the binomial test and the Bayesian approach for calculating under-used and over-used plant families within ethnobotanical datasets. Percentages of agreement were calculated to compare the results of the analyses. We also analyzed the relationship between plant selection and phylogeny, chorology, life form and habitat using the chi-square test. Pearson's residuals for each of the significant chi-square analyses were examined for investigating alternative hypotheses of plant selection criteria. The three statistical analysis methods differed within the same dataset, and between different datasets and floras, but with some similarities. In the two medicinal datasets, only Lamiaceae was identified in both floras as an over-used family by all three statistical methods. All statistical methods in one flora agreed that Malvaceae was over-used and Poaceae under-used, but this was not found to be consistent with results of the second flora in which one statistical result was non-significant. All other families had some discrepancy in significance across methods, or floras. Significant over- or under-use was observed in only a minority of cases. The chi-square analyses were significant for phylogeny, life form and habitat. Pearson's residuals indicated a non-random selection of woody species for non-medicinal uses and an under-use of plants of temperate forests for medicinal uses. Our study showed that selection criteria for plant uses (including medicinal) are not always based on phylogeny. The comparison of different statistical methods (regression, binomial and Bayesian) under different conditions led to the conclusion that the most conservative results are obtained using regression analysis.


Balance and mobility in geriatric patients : Assessment and treatment of neurological aspects.
Personal autonomy in advanced age critically depends on mobility in the environment. Geriatric patients are often not able to walk safely with sufficient velocity. In many cases, multiple factors contribute to the deficit. Diagnostic identification of single components enables a specific treatment. This article describes the most common neurological causes of imbalance and impaired gait that are relevant for a pragmatic approach for the assessment of deficits in clinical and natural environments taking into account the physiology of balance and gait control, typical morbidities in older people and the potential of innovative assessment technologies. Expert opinion based on a narrative review of the literature and with reference to selected research topics. Common neurological causes of impaired balance and mobility are sensory deficits (reduced vision, peripheral neuropathy, vestibulopathy), neurodegeneration in disorders with an impact on movement control and motoric functions (Parkinsonian syndromes, cerebellar ataxia, vascular encephalopathy) and functional (psychogenic) disorders, particularly a fear of falling. Clinical tests and scores in laboratory environments are complemented by the assessment in the natural environment. Wearable sensors, mobile smartphone-based assessment of symptoms and functions and adopted strategies for analysis are currently emerging. Use of these data enables a personalized treatment. Furthermore, sensor-based assessment ensures that effects are measured objectively.


Evaluation of the stability, bioavailability, and hypersensitivity of the omega-3 derived anti-leukemic prostaglandin: Δ(12)-prostaglandin J3.
Previous studies have demonstrated the ability of an eicosapentaenoic acid (EPA)-derived endogenous cyclopentenone prostaglandin (CyPG) metabolite, Δ(12)-PGJ3, to selectively target leukemic stem cells, but not the normal hematopoietic stems cells, in in vitro and in vivo models of chronic myelogenous leukemia (CML). Here we evaluated the stability, bioavailability, and hypersensitivity of Δ(12)-PGJ3. The stability of Δ(12)-PGJ3 was evaluated under simulated conditions using artificial gastric and intestinal juice. The bioavailability of Δ(12)-PGJ3 in systemic circulation was demonstrated upon intraperitoneal injection into mice by LC-MS/MS. Δ(12)-PGJ3 being a downstream metabolite of PGD3 was tested in vitro using primary mouse bone marrow-derived mast cells (BMMCs) and in vivo mouse models for airway hypersensitivity. ZK118182, a synthetic PG analog with potent PGD2 receptor (DP)-agonist activity and a drug candidate in current clinical trials, was used for toxicological comparison. Δ(12)-PGJ3 was relatively more stable in simulated gastric juice than in simulated intestinal juice that followed first-order kinetics of degradation. Intraperitoneal injection into mice revealed that Δ(12)-PGJ3 was bioavailable and well absorbed into systemic circulation with a Cmax of 263 µg/L at 12 h. Treatment of BMMCs with ZK118182 for 12 h resulted in increased production of histamine, while Δ(12)-PGJ3 did not induce degranulation in BMMCs nor increase histamine. In addition, in vivo testing for hypersensitivity in mice showed that ZK118182 induces higher airways hyperresponsiveness when compared Δ(12)-PGJ3 and/or PBS control. Based on the stability studies, our data indicates that intraperitoneal route of administration of Δ(12)-PGJ3 was favorable than oral administration to achieve effective pharmacological levels in the plasma against leukemia. Δ(12)-PGJ3 failed to increase histamine and IL-4 in BMMCs, which is in agreement with reduced airway hyperresponsiveness in mice. In summary, our studies suggest Δ(12)-PGJ3 to be a promising bioactive metabolite for further evaluation as a potential drug candidate for treating CML.


Genetic analysis of Dobrava-Belgrade virus from western Serbia--a newly detected focus in the Balkan Peninsula.
Dobrava-Belgrade virus (DOBV) is a hantavirus species that causes the most severe form of haemorrhagic fever with renal syndrome (HFRS) in Europe. DOBV has been detected in three Apodemus rodents: A. flavicollis, A. agrarius and A. ponticus. These emerging viruses appear throughout the Balkan Peninsula including Serbia as its central part. In this study, we examined the seroprevalence, molecular epidemiology and phylogenetics of DOBV from A. flavicollis captured at six Serbian localities. Furthermore, we applied microsatellite typing of host animal genome to analyse the role of host kinship in DOBV animal transmission. The overall IgG seropositivity rate over 3 years (2008-2010) was 11.9% (22/185). All seropositive samples were subjected to RT-PCR and DNA sequencing for S and L genome segments (pos. 291-1079 nt and 2999-3316 nt, respectively). DOBV was genetically detected in three samples from mountain Tara in western Serbia, a newly detected DOBV focus in the Balkans. No sequence data from human cases from Serbia are available for the studied period. However, collected DOBV isolates in this work phylogenetically clustered together with isolates from Serbian human cases dating from 2002, with 1.9% nucleotide divergence. We determined the level of kinship between seropositive and seronegative animal groups and found no significant difference, suggesting that horizontal virus transmission in the studied population was the same within and among the hatches. Our findings are the first genetic detection of DOBV in rodents in Serbia. We confirm wide and continuous hantavirus presence in the examined parts of the Balkans, underlying the necessity of continual monitoring of hantavirus circulation in A. flavicollis.


How perfectionism and ineffectiveness influence growth of eating disorder risk in young adolescent girls.
While perfectionism is widely considered to influence risk for eating disorders, results of longitudinal studies are mixed. The goal of the current study was to investigate a more complex model of how baseline perfectionism (both high personal standards and self-critical evaluative concerns) might influence change in risk status for eating disorders in young adolescent girls, through its influence on ineffectiveness. The study was conducted with 926 girls (mean age of 13 years), and involved three waves of data (baseline, 6- and 12-month follow-up). Latent growth curve modelling, incorporating the average rate at which risk changed over time, the intercept (initial status) of ineffectiveness, and baseline perfectionism, was used to explore longitudinal mediation. Personal standards was not supported as contributing to risk but results indicated that the higher mean scores on ineffectiveness over the three waves mediated the relationship between higher baseline self-critical evaluative concerns and both measures of eating disorder risk. The relationship between concern over mistakes and change in risk was small and negative. These results suggest the usefulness of interventions related to self-criticism and ineffectiveness for decreasing risk for developing an eating disorder in young adolescent girls.


Macrophage variants in oxygen metabolism.
Whereas phagocytic cells from normal individuals have the capacity to kill ingested bacteria and parasites, those from patients with several uncommon genetic deficiency diseases are known to be defective in bactericidal activity. Studies on neutrophils of these patients have revealed fundamental defects in their ability to reduce molecular oxygen and metabolize it to superoxide anion, hydrogen peroxide, and oxygen radicals. In the present experiments, we describe a clone of a continuous murine macrophage-like cell line, J774.16, that, upon appropriate stimulation, activates the hexose monophosphate shunt, and produces superoxide anion and hydrogen peroxide. With nitroblue tetrazolium to select against cells capable of being stimulated by phorbol myristate acetate to reduce the dye to polymer--formazan--which is toxic fot cells, we have selected for variants that are defective in oxygen metabolism. Four of these subclones have been characterized and found to be lacking in the ability (a) to generate superoxide anion, as measured by cytochrome c reduction; (b) to produce hydrogen peroxide, as measured by the ability to form complex I with cytochrome c peroxidase; and (c) to be stimulated to oxidize glucose via the hexose monophosphate shunt. These variants appear to represent a useful model for studying the molecular basis for macrophage cytocidal activity.


Treatment of drug-induced seizures.
Seizures are a common complication of drug intoxication, and up to 9% of status epilepticus cases are caused by a drug or poison. While the specific drugs associated with drug-induced seizures may vary by geography and change over time, common reported causes include antidepressants, stimulants and antihistamines. Seizures occur generally as a result of inadequate inhibitory influences (e.g., gamma aminobutyric acid, GABA) or excessive excitatory stimulation (e.g. glutamate) although many other neurotransmitters play a role. Most drug-induced seizures are self-limited. However, status epilepticus occurs in up to 10% of cases. Prolonged or recurrent seizures can lead to serious complications and require vigorous supportive care and anticonvulsant drugs. Benzodiazepines are generally accepted as the first line anticonvulsant therapy for drug-induced seizures. If benzodiazepines fail to halt seizures promptly, second line drugs include barbiturates and propofol. If isoniazid poisoning is a possibility, pyridoxine is given. Continuous infusion of one or more anticonvulsants may be required in refractory status epilepticus. There is no role for phenytoin in the treatment of drug-induced seizures. The potential role of ketamine and levetiracetam is promising but not established.


Incidence of the histologic types of ovarian tumors in Benghazi (Libya) and Poland.
The distribution of histological types of ovarian tumors in two communities with different reproductive experience was compared. 108 cases of ovarian neoplasms diagnozed in Benghazi and 2238 cases collected in Ovarian Tumors Registry in Poland were classified according to the WHO histological typing. The difference in the incidence of histologic types and malignancy was statistically evaluated. Unlike Poland series, in Benghazi germ cell tumors are the most common type of ovarian neoplasms (50% of all reported cases), while the percentage of epithelial tumors accounts for 33.3. This proportion of incidence of epithelial and germ cell tumors in Benghazi is similar to relative frequency of these tumor types noted in teenagers in Europe and the USA. The difference in incidence of the histologic types of ovarian tumors in Benghazi and Poland is probably due to the significantly higher rate of fertility among Libyan women as compared with Polish female population.


Estrogen receptor β upregulates FOXO3a and causes induction of apoptosis through PUMA in prostate cancer.
Estrogen receptor β (ERβ) is emerging as a critical factor in understanding prostate cancer biology. Although reduced in prostate cancer above Gleason grade 3, ERβ is a potential drug target at the initial stage of the disease. In human prostate cancer cells, we found that ERβ causes apoptosis by increasing the expression of pro-apoptotic factor p53-upregulated modulator of apoptosis (PUMA), independent of p53, but dependent on the forkhead transcription factor class-O family member, FOXO3a. FOXO3a has previously been shown to induce PUMA after growth factor withdrawal and inhibition of the Akt pathway. Surprisingly, the phosphorylation of FOXO3a remained unchanged, while the mRNA and total protein levels of FOXO3a were increased in response to ERβ expression or treatment of PC3, 22Rv1 and LNCaP cells with the ERβ-specific ligands 3β-Adiol (5α-androstane-3β,17β-diol), DPN (diarylpropionitrile) or 8β-VE2 (8-vinylestra-1,3,5 (10)-triene-3,17β-diol). Knockdown of FOXO3a or ERβ expression abolished the increase of PUMA in response to 3β-Adiol in LNCaP and PC3 cells, suggesting that FOXO3a mediates the apoptotic effect of 3β-Adiol-activated ERβ. Moreover, the ventral prostate of ERβ-/- mice had decreased expression of FOXO3a and PUMA compared with the ERβ+/+ mice, indicating a relationship between ERβ and FOXO3a expression. The regulation of FOXO3a by ERβ in normal basal epithelial cells indicates a function of ERβ in cell differentiation and maintenance of cells in a quiescent state. In addition, the expression of ERβ, FOXO3a and PUMA is comparable and higher in benign prostatic hyperplasia than in prostate cancer Gleason grade 4 or higher, where there is substantial loss of ERβ, FOXO3a and PUMA. We conclude that ERβ induces apoptosis of prostate cancer cells by increasing transcription of FOXO3a, leading to an increase of PUMA and subsequent triggering of apoptosis via the intrinsic pathway involving caspase-9. Furthermore, we conclude that ligands specifically activating ERβ could be useful pharmaceuticals in the treatment of prostate cancer.


Reprogrammed mouse astrocytes retain a "memory" of tissue origin and possess more tendencies for neuronal differentiation than reprogrammed mouse embryonic fibroblasts.
Direct reprogramming of a variety of somatic cells with the transcription factors Oct4 (also called Pou5f1), Sox2 with either Klf4 and Myc or Lin28 and Nanog generates the induced pluripotent stem cells (iPSCs) with marker similarity to embryonic stem cells. However, the difference between iPSCs derived from different origins is unclear. In this study, we hypothesized that reprogrammed cells retain a "memory" of their origins and possess additional potential of related tissue differentiation. We reprogrammed primary mouse astrocytes via ectopic retroviral expression of OCT3/4, Sox2, Klf4 and Myc and found the iPSCs from mouse astrocytes expressed stem cell markers and formed teratomas in SCID mice containing derivatives of all three germ layers similar to mouse embryonic stem cells besides semblable morphologies. To test our hypothesis, we compared embryonic bodies (EBs) formation and neuronal differentiation between iPSCs from mouse embryonic fibroblasts (MEFsiPSCs) and iPSCs from mouse astrocytes (mAsiPSCs). We found that mAsiPSCs grew slower and possessed more potential for neuronal differentiation compared to MEFsiPSCs. Our results suggest that mAsiPSCs retain a "memory" of the central nervous system, which confers additional potential upon neuronal differentiation.


[Clinical instrumental and immunological studies of multiple sclerosis in children].
The results of clinical examination, data of analysis of the visual evoked potentials, computer and magneto-resonance tomography allowed to diagnose a reliable multiple sclerosis in 25 children (16 girls and 9 boys). The age of the onset of the disease was from 4 to 14 years, the duration of the follow-up--from 1 to 12 years. Monosymptomatic onset, remittent course with frequent exacerbations and successful recovery of the functions during the remissions prevailed. Purposeful treatment allowed to achieve a stable remission in 2/3 of the cases, while a gradual increase of the neurologic deficit was observed in the other patients. Phenotyping by HLA-system revealed association of demyelinating diseases in children with HLA-B12 (RR = 6.0; p < 0.025), together with the absence of HLA-B18 antigen. The authors made a conclusion that multiple sclerosis may be diagnosed in childhood and that it has some clinical and immunologic peculiarities.


Defects in D-alanyl-lipoteichoic acid synthesis in Streptococcus mutans results in acid sensitivity.
In the cariogenic organism, Streptococcus mutans, low pH induces an acid tolerance response (ATR). To identify acid-regulated proteins comprising the ATR, transposon mutagenesis with the thermosensitive plasmid pGh9:ISS1 was used to produce clones that were able to grow at neutral pH, but not in medium at pH 5.0. Sequence analysis of one mutant (IS1A) indicated that transposition had created a 6.3-kb deletion, one end of which was in dltB of the dlt operon encoding four proteins (DltA-DltD) involved in the synthesis of D-alanyl-lipoteichoic acid. Inactivation of the dltC gene, encoding the D-alanyl carrier protein (Dcp), resulted in the generation of the acid-sensitive mutant, BH97LC. Compared to the wild-type strain, LT11, the mutant exhibited a threefold-longer doubling time and a 33% lower growth yield. In addition, it was unable to initiate growth below pH 6.5 and unadapted cells were unable to survive a 3-h exposure in medium buffered at pH 3.5, while a pH of 3.0 was required to kill the wild type in the same time period. Also, induction of the ATR in BH97LC, as measured by the number of survivors at a pH killing unadapted cells, was 3 to 4 orders of magnitude lower than that exhibited by the wild type. While the LTA of both strains contained a similar average number of glycerolphosphate residues, permeabilized cells of BH97LC did not incorporate D-[(14)C]alanine into this amphiphile. This defect was correlated with the deficiency of Dcp. Chemical analysis of the LTA purified from the mutant confirmed the absence of D-alanine-esters. Electron micrographs showed that BH97LC is characterized by unequal polar caps and is devoid of a fibrous extracellular matrix present on the surface of the wild-type cells. Proton permeability assays revealed that the mutant was more permeable to protons than the wild type. This observation suggests a mechanism for the loss of the characteristic acid tolerance response in S. mutans.


Language control in bilinguals: The adaptive control hypothesis.
Speech comprehension and production are governed by control processes. We explore their nature and dynamics in bilingual speakers with a focus on speech production. Prior research indicates that individuals increase cognitive control in order to achieve a desired goal. In the adaptive control hypothesis we propose a stronger hypothesis: Language control processes themselves adapt to the recurrent demands placed on them by the interactional context. Adapting a control process means changing a parameter or parameters about the way it works (its neural capacity or efficiency) or the way it works in concert, or in cascade, with other control processes (e.g., its connectedness). We distinguish eight control processes (goal maintenance, conflict monitoring, interference suppression, salient cue detection, selective response inhibition, task disengagement, task engagement, opportunistic planning). We consider the demands on these processes imposed by three interactional contexts (single language, dual language, and dense code-switching). We predict adaptive changes in the neural regions and circuits associated with specific control processes. A dual-language context, for example, is predicted to lead to the adaptation of a circuit mediating a cascade of control processes that circumvents a control dilemma. Effective test of the adaptive control hypothesis requires behavioural and neuroimaging work that assesses language control in a range of tasks within the same individual.


Conservative treatment for closed fifth (small finger) metacarpal neck fractures.
Subcapital fractures of the fifth metacarpal bone, meaning fractures just below the knuckle of the little finger, account for approximately 20% of all hand fractures. Currently, there is no consensus concerning the optimal management of these fractures. Traditionally, treatment consists of closed reduction and external splinting in a neutral position using plaster of Paris (POP), involving the metacarpal joint, the proximal interphalangeal joint and the carpo-metacarpal joint. An alternative treatment strategy is functional treatment using taping or bracing that does not restrict movement. To compare functional treatment with immobilization, and to compare different periods and types of immobilization, for the treatment of closed fifth metacarpal neck fractures in adults. We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialized Register (July 2004), the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3, 2004), OVID OldMEDLINE (1951 to 1965), OVID MEDLINE (1966 to July 2004), OVID MEDLINE In-Process (July 2004), EMBASE (1988 to 2004, week 29), the Internet, and reference lists of articles. No language restrictions were applied. All randomized and quasi-randomized controlled trials which compare functional treatment with immobilization or different types of immobilization for closed fifth metacarpal neck fractures. Two review authors assessed abstracts of all studies identified by the initial search, identified studies meeting the selection criteria, independently assessed the quality of the trial reports, and extracted and analysed the data. Five studies met the inclusion criteria including a total of 252 participants. Most studies were of poor quality. The primary outcome measure, function of the hand, was not used in any studies. There was no evidence that any of the treatment modalities was statistically significantly superior. No included studies reported our primary outcome measure of interest, validated hand function. There was heterogeneity between the studies, which were of limited quality and size. No single non-operative treatment regimen for fracture of the neck of the fifth metacarpal can be recommended as superior to another in result. Further research is definitely warranted.


Reconstructive Surgery Camp for Leprosy Deformities in a Tertiary Hospital: An Example of Service Delivery at Low Costs.
Seventy percent of all cases of leprosy in the world occur in India. 8,462 new cases of disability were reported in India between 2010-11. Reconstructive Surgery Camps (RSC) provide free of cost plastic surgical expertise to patients of leprosy with deformity. The aim of this article was to report the outcomes of a RSC in a tertiary level university hospital in India. We also described the types of deformities in the patient group and the cost of conducting such a camp. The RSC involved 130 patients with leprosy related deformities operated by a team of plastic surgeons in a tertiary university hospital over 5 days. Health workers of the National Leprosy Elimination Program identified patients at community level. The camp was funded by the central government of India and the patients were provided incentives for undergoing treatment. Plantar ulcer was the commonest deformity (51.5%) while lagopthalmos (9.2%) was the least common deformity in the patient group. The overall complication rate in our study was around 10.6% (n=11). The total cost of this camp was 730,000 rupees (£7029.9). Reconstructive surgery in a camp setup is a low cost alternative of correcting leprosy related deformity. It also provides valuable practical experience in reconstructive surgery to surgical trainees. Tertiary hospital based camps for conducting large-scale surgeries may be a cost effective alternative to reduce waiting lists in public health sectors. Long-term studies monitoring patients operated in a camp setting would be worthwhile.


Inhibitory mechanism of the nucleus of the solitary tract involved in the control of cardiovascular, dipsogenic, hormonal, and renal responses to hyperosmolality.
The nucleus of the solitary tract (NTS) is the primary site of visceral afferents to the central nervous system. In the present study, we investigated the effects of lesions in the commissural portion of the NTS (commNTS) on the activity of vasopressinergic neurons in the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei, plasma vasopressin, arterial pressure, water intake, and sodium excretion in rats with plasma hyperosmolality produced by intragastric 2 M NaCl (2 ml/rat). Male Holtzman rats with 15-20 days of sham or electrolytic lesion (1 mA; 10 s) of the commNTS were used. CommNTS lesions enhanced a 2 M NaCl intragastrically induced increase in the number of vasopressinergic neurons expressing c-Fos in the PVN (28 ± 1, vs. sham: 22 ± 2 c-Fos/AVP cells) and SON (26 ± 4, vs. sham: 11 ± 1 c-Fos/AVP cells), plasma vasopressin levels (21 ± 8, vs. sham: 6.6 ± 1.3 pg/ml), pressor responses (25 ± 7 mmHg, vs. sham: 7 ± 2 mmHg), water intake (17.5 ± 0.8, vs. sham: 11.2 ± 1.8 ml/2 h), and natriuresis (4.9 ± 0.8, vs. sham: 1.4 ± 0.3 meq/1 h). The pretreatment with vasopressin antagonist abolished the pressor response to intragastric 2 M NaCl in commNTS-lesioned rats (8 ± 2.4 mmHg at 10 min), suggesting that this response is dependent on vasopressin secretion. The results suggest that inhibitory mechanisms dependent on commNTS act to limit or counterbalance behavioral, hormonal, cardiovascular, and renal responses to an acute increase in plasma osmolality.


Electron microscope study of red cell membranes after experimental infection with the virus of foot-and-mouth disease.
Guinea pigs were inoculated with the Vallée O type strain of the virus of foot-and-mouth disease. 42 to 48 hours after inoculation red blood cells washed in saline were found to be infective for normal guinea pigs suggesting that erythrocytes carry virus entities at the height of generalization of the disease. This infection is no longer obtained at 92 hours after inoculation when general symptoms of the disease decline. A replica-transfer technique was developed with which hemolyzed blood smears could be observed under the electron microscope. By direct examination and also shadow-casting with palladium, normal red cell membranes show only a very fine structure on the surface. Rounded masses of high electron density appear in the ghosts between 24 and 72 hours after inoculation with virus. The number and particularly the density of these masses tend to increase from 24 to 42 and 72 hours. In some cases they are disposed preferentially in single lines forming ring figures; in other cases they are distributed at random. At 42 hours after inoculation it was possible to detect dense particles of 20 to 70 mmicro. within the masses. Measurements of 100 masses at 72 hours gave results ranging from 116 to 437 mmicro with a mean diameter of 246 mmicro. Results based on 105 electron micrographs and on thousands of cells demonstrate that practically all red cell membranes contained dense masses 24 to 72 hours after inoculation. 92 hours after inoculation, coinciding with the disappearance of infectivity of the erythrocytes, the masses could no longer be seen and the membranes looked entirely normal. Although the facts reported here may be suggestive of a relationship between the dense masses within the red cell membranes and the presence of virus entities in washed erythrocytes, no definite interpretation of these findings is postulated at present.


Novel SS18-NEDD4 gene fusion in a primary renal synovial sarcoma.
We report a primary renal synovial sarcoma with a novel gene fusion and unusual morphology. The patient was a 35-year-old female who was found to have a 5 cm hypocellular, myxoid spindle cell renal neoplasm that subtly permeated amongst native renal tubules. The tumor cells showed elongated hyperchromatic nuclei with ill-defined pale cytoplasm, lacking significant mitotic activity or necrosis. Based on its deceptively bland morphology, the differential diagnosis included mainly benign entities, such as metanephric stromal tumor, mixed epithelial stromal tumor (MEST), and myxoid peripheral nerve sheath tumors. A definitive diagnosis of synovial sarcoma was made only subsequently to RNA-sequencing, which revealed a novel SS18-NEDD4 gene fusion. These results were further confirmed by fluorescence in situ hybridization using custom design break-apart probes for both genes. This case illustrates the utility of targeted RNA-sequencing in the classification of challenging tumors with deceptive morphology and identification of novel gene fusion variants. Apart from the canonical SS18-SSX fusion, this is only the second alternative gene fusion variant described in synovial sarcoma to date, in addition to two cases harboring the SS18L1-SSX1 fusion.


The State of Mentorship and Pancreatic Research Among Trainees in Pancreatology: A Multinational Survey Study.
The recent decrease seen in pancreatic research and young investigator involvement may reflect inadequate mentorship. This study aimed to describe the current state of mentorship in pancreatic research and evaluate how mentorship is associated with research productivity. In this prospective study, a survey addressing mentorship and research was distributed to trainees worldwide. Survey responses were analyzed using descriptive statistics and logistic regression was used to describe the association between mentorship and trainee research productivity. A total of 137 trainees from 16 countries participated. Although two-thirds of trainees expressed interest in pancreatic research and had identified a mentor in the field, only 34.8% had published a manuscript. Barriers to pancreatic research included lack of research opportunities (58.3%), limited mentorship (23.3%), and inadequate institutional support (15%). Although having a single mentor was not associated with research productivity (odds ratio, 1.43; 95% confidence interval, 0.74-2.76), having a local mentor was significantly associated with publishing (odds ratio, 4.57; 95% confidence interval, 1.95-10.74). Although many trainees interested in pancreatology have access to a mentor, barriers including lack of research opportunities, mentorship, and institutional support hinder trainee productivity. Opportunities for mentorship, collaboration, and networking are needed.