Integrated Behavioral Health Implementation and Training in Primary Care: A Practice-Based Research Network Study.
Integrating behavioral health services into primary care has a strong evidence base, but how primary care training programs incorporate integrated behavioral health (IBH) into care delivery and training has not been well described. The goal of this study was to evaluate factors related to successful IBH implementation in family medicine (FM) residency programs and assess perspectives and attitudes on IBH among program leaders. FM residency programs, all which are required to provide IBH training, were recruited from the American Academy of Family Physicians National Research Network. After completing eligibility screening that included the Integrated Practice Assessment Tool (IPAT) questionnaire, 14 training programs were included. Selected practices identified 3 staff in key roles to be interviewed: medical director or similar, behavioral health professional (BHP), and chief medical officer or similar. Forty-one individuals from 14 FM training programs were interviewed. IPAT scores ranged from 4 (Close Collaboration Onsite) to 6 (Full Collaboration). Screening, outcome tracking, and treatment differed among and within practices. Use of curricula and trainee experience also varied with little standardization. Most participants described similar approaches to communication and collaboration between primary care clinicians and BHPs and believed that IBH should be standard practice. Participants reported space, staff, and billing support as critical for sustainability. Delivery and training experiences in IBH varied widely despite recognition of the value and benefits to patients and care delivery processes. Standardizing resources and training and simplifying and assuring reimbursement for services may promote sustainable and high quality IBH implementation.


Simple 3-D characterization of ultrashort laser pulses.
The space and time distribution of electromagnetic energy is essential information for any laser pulse applications that require precision. Although many instruments quantify the temporal profile of ultrashort laser pulses, they are generally limited to space-averaged measurement. In this work, we present an extremely simple technique to characterize the spatial distribution of fluence, pulse duration and chirp of ultrashort light pulses. This technique is based upon imaging the two-photon fluorescence distribution generated by the laser pulse as it propagates through a dispersive medium. It is expected that this technique will provide to less specialized users a precise in-situ analysis of their ultrashort laser beam.


Multidecadal stability in tropical rain forest structure and dynamics across an old-growth landscape.
Have tropical rain forest landscapes changed directionally through recent decades? To answer this question requires tracking forest structure and dynamics through time and across within-forest environmental heterogeneity. While the impacts of major environmental gradients in soil nutrients, climate and topography on lowland tropical rain forest (TRF) structure and function have been extensively analyzed, the effects of the shorter environmental gradients typical of mesoscale TRF landscapes remain poorly understood. To evaluate multi-decadal performance of an old-growth TRF at the La Selva Biological Station, Costa Rica, we established 18 0.5-ha annually-censused forest inventory plots in a stratified-random design across major landscape edaphic gradients. Over the 17-year study period, there were moderate differences in stand dynamics and structure across these gradients but no detectable difference in woody productivity. We found large effects on forest structure and dynamics from the mega-Niño event at the outset of the study, with subdecadal recovery and subsequent stabilization. To extend the timeline to >40 years, we combined our findings with those from earlier studies at this site. While there were annual to multiannual variations in the structure and dynamics, particularly in relation to local disturbances and the mega-Niño event, at the longer temporal scale and broader spatial scale this landscape was remarkably stable. This stability contrasts notably with a current hypothesis of increasing biomass and dynamics of TRF, which we term the Bigger and Faster Hypothesis (B&FHo). We consider possible reasons for the contradiction and conclude that it is currently not possible to independently assess the vast majority of previously published B&FHo evidence due to restricted data access.


The in situ isolated larynx for evaluating peripheral opiate receptor antagonists.
The in situ isolated rodent larynx preparation can be utilized for the detection of peripheral opiate receptor antagonists. Measurements of peripheral opioid-induced laryngospasm and central opioid-induced respiratory depression can be made in each preparation. Fentanyl citrate was used to stimulate both peripheral and central opiate receptors and [D-Ala2-Met5] enkephalinamide was used to stimulate only peripheral opiate receptors. Compounds that inhibit both laryngeal and respiratory effects of fentanyl, e.g., naloxone HCl, can be considered both central and peripheral opiate receptor antagonists. Compounds that inhibit only the peripheral laryngeal effects of fentanyl, e.g., naltrexone methylbromide, can be considered peripheral opiate receptor antagonists. The description of this preparation provides a simple and sensitive anesthetized animal model for the detection and characterization of compounds acting at peripheral and/or central opiate receptors.


Longterm fenoprofen therapy in patients with rheumatoid arthritis.
Fenoprofen, a new antirheumatic agent, was evaluated in 45 patients with rheumatoid arthritis in an open study design to simulate the conditions under which the drug will be used. No control agents were used. The effectiveness of fenoprofen was demonstrated by the per cent of patients who improved during fenoprofen therapy. Duration of therapy varied from one to 629 days. Pain was the first parameter to respond, followed by an anti-inflammatory effect, which was observed after four to six weeks of therapy. Side effects consisted mainly of minor gastro-intestinal symptoms.


Karyotype of the invasive species Pterois volitans (Scorpaeniformes: Scorpaenidae) from Margarita Island, Venezuela.
The genus Pterois includes nine valid species, native to the Red Sea and Indian Ocean throughout the Western Pacific. P. volitans and P. miles are native to the Indo-Pacific, and were introduced into Florida waters as a result of aquarium releases, and have been recently recognized as invaders of the Western Atlantic and Caribbean Sea (Costa Rica to Venezuela). Thus far, cytogenetic studies of the genus Pterois only cover basic aspects of three species, including P. volitans from Indo-Pacific Ocean. Considering the lack of more detailed information about cytogenetic characteristics of this invasive species, the objective of the present study was to investigate the basic and molecular cytogenetic characteristics of P. volitans in Venezuela, and compare the results with those from the original distribution area. For this, the karyotypic characteristics of four lionfish caught in Margarita Island, Venezuela, were investigated by examining metaphase chromosomes by Giemsa staining, C-banding, Ag-NOR, and two-colour-Fluorescent in situ hybridization (FISH) for mapping of 18S and 5S ribosomal genes. Comparing the sequences of the 16S gene of the specimens analyzed, with sequences already included in the Genbank, we corroborated that our specimens identified as P. volitans are in fact this species, and hence exclude the possibility of a misidentification of P. miles. The diploid number was 2n = 48 (2m + 10sm + 36a) with FN = 60. Chromosomes uniformly decreased in size, making it difficult to clearly identify the homologues except for the only metacentric pair, and the pairs number two, the largest of the submetacentric series. C-banding revealed only three pairs of chromosomes negative for C-band, whereas all remaining chromosomes presented telomeric and some interstitial C-positive blocks. Only two chromosomes were C-banding positive at the pericentromeric regions. Sequential staining revealed Ag-NOR on the tips of the short arms of chromosome pair number two and the FISH assay revealed that 18S rDNA and 5S rDNA genes are co-located on this chromosome pair. The co-localization of 5S rDNA and 45S rDNA is discussed. Both constitutive heterochromatin and NOR location detected in samples examined in this study, differ from those reported for P. volitans in previous analysis of specimens collected in Indian Ocean (Java), suggesting the occurrence of chromosome microrearrangements involving heterochromatin during the spread of P. volitans.


Immunolocalisation of crustacean-SIFamide in the median brain and eyestalk neuropils of the marbled crayfish.
Crustacean-SIFamide (GYRKPPFNGSIFamide) is a novel neuropeptide that was recently isolated from crayfish nervous tissue. We mapped the localisation of this peptide in the median brain and eyestalk neuropils of the marbled crayfish (Marmorkrebs), a parthenogenetic crustacean. Our experiments showed that crustacean-SIFamide is strongly expressed in all major compartments of the crayfish brain, including all three optic neuropils, the lateral protocerebrum with the hemiellipsoid body, and the medial protocerebrum with the central complex. These findings imply a role of this peptide in visual processing already at the level of the lamina but also at the level of the deeper relay stations. Immunolabelling is particularly strong in the accessory lobes and the deutocerebral olfactory lobes that receive a chemosensory input from the first antennae. Most cells of the olfactory globular tract, a projection neuron pathway that links deuto- and protocerebrum, are labelled. This pathway plays a central role in conveying tactile and olfactory stimuli to the lateral protocerebrum, where this input converges with optic information. Weak labelling is also present in the tritocerebrum that is associated with the mechanosensory second antennae. Taken together, we suggest an important role of crustacean-SIFamidergic neurons in processing high-order, multimodal input in the crayfish brain.


Dressed-state resonant coupling between bright and dark spins in diamond.
Under ambient conditions, spin impurities in solid-state systems are found in thermally mixed states and are optically "dark"; i.e., the spin states cannot be optically controlled. Nitrogen-vacancy (NV) centers in diamond are an exception in that the electronic spin states are "bright"; i.e., they can be polarized by optical pumping, coherently manipulated with spin-resonance techniques, and read out optically, all at room temperature. Here we demonstrate a scheme to resonantly couple bright NV electronic spins to dark substitutional-nitrogen (P1) electronic spins by dressing their spin states with oscillating magnetic fields. This resonant coupling mechanism can be used to transfer spin polarization from NV spins to nearby dark spins and could be used to cool a mesoscopic bath of dark spins to near-zero temperature, thus providing a resource for quantum information and sensing, and aiding studies of quantum effects in many-body spin systems.


[Valve-in-valve with Portico valve for a degenerative bioprosthetic surgical valve (Biocor)].
In the last years, a general shift toward the use of surgical bioprosthetic aortic valves rather than mechanical valves with subsequent less use of anticoagulant therapy has been observed. However, bioprosthetic valves have limited durability. Reoperation, the current standard of care for these patients, carries a high surgical risk, especially because patients are elderly and with numerous comorbidities. Recently, transcatheter aortic valve replacement within a failed bioprosthetic valve (valve-in-valve procedure) has proven feasible. We here describe a case of valve-in-valve procedure with a Portico valve placed in a purely insufficient bioprosthetic valve (Biocor).


Inverse Batschelet distributions for circular data.
We provide four-parameter families of distributions on the circle which are unimodal and display the widest ranges of both skewness and peakedness yet available. Our approach is to transform the scale of a generating distribution, such as the von Mises, using various nontrivial extensions of an approach first used in Batschelet's (1981, Circular Statistics in Biology) book. The key is to employ inverses of Batschelet-type transformations in certain ways; these exhibit considerable advantages over direct Batschelet transformations. The skewness transformation is especially appealing as it has no effect on the normalizing constant. As well as a variety of interesting theoretical properties, when likelihood inference is explored these distributions display orthogonality between elements of a pairing of parameters into (location, skewness) and (concentration, peakedness). Further, the location parameter can sometimes be made approximately orthogonal to all the other parameters. Profile likelihoods come to the fore in practice. Two illustrative applications, one concerning the locomotion of a Drosophila fly larva, the other analyzing a large set of sudden infant death syndrome data, are investigated.


Normative Data for the Hayling and Brixton Tests in an Italian Population.
The Hayling and Brixton tests constitute a short test battery that quickly assesses verbal and spatial inhibition and flexibility. This battery has shown high construct validity and strong reliability in clinical and experimental settings. The aim of this study was to develop an Italian version of the Hayling and Brixton tests and obtain normative values. We collected normative data from 301 healthy Italian participants aged between 16 and 94 years, taking into account all demographics. To maximize the sample size, we used the overlapping interval strategy. Adjusted scores for demographics were obtained by linear regression analysis. The performance on the Hayling and Brixton tests was influenced by age and education. In particular, age affected verbal accuracy and response time on the Hayling Sentence Completion Test, whereas education only affected the former. Differently, the spatial component, as measured by the Brixton Spatial Anticipation Test, was shaped only by age, which decreased the number of correct responses. Our study provides normative data that have been adjusted for relevant demographics and percentile grids in an Italian population. Our data support the use of the Hayling and Brixton tests as a valid instrument for performing neuropsychological evaluations and longitudinal analyses of executive functions in clinical practice and for research purposes.


Further studies on the substrate spectrum of phytanoyl-CoA hydroxylase: implications for Refsum disease?
Refsum disease is a peroxisomal disorder characterized by adult-onset retinitis pigmentosa, anosmia, sensory neuropathy, ataxia, and an accumulation of phytanic acid in plasma and tissues. Approximately 45% of cases are caused by mutations in phytanoyl-CoA hydroxylase (PAHX), the enzyme catalyzing the second step in the peroxisomal alpha-oxidation of 3-methyl-branched fatty acids. To study the substrate specificity of human PAHX, different 3-alkyl-branched substrates were synthesized and incubated with a recombinant polyhistidine-tagged protein. The enzyme showed activity not only toward racemic phytanoyl-CoA and the isomers of 3-methylhexadecanoyl-CoA, but also toward a variety of other mono-branched 3-methylacyl-CoA esters with a chain length down to seven carbon atoms. Furthermore, PAHX hydroxylated a 3-ethylacyl-CoA quite well, whereas a 3-propylacyl-CoA was a poor substrate. Hydroxylation of neither 2- or 4-methyl-branched acyl-CoA esters, nor long or very long straight-chain acyl-CoA esters could be detected. The results presented in this paper show that the substrate specificity of PAHX, with regard to the length of both the acyl-chain and the branch at position 3, is broader than expected. Hence, Refsum disease might be characterized by an accumulation of not only phytanic acid but also other 3-alkyl-branched fatty acids.


Zoledronic acid reduces skeletal-related events in patients with osteolytic metastases.
This study evaluated the dose-response relation for zoledronic acid, a new generation high potency bisphosphonate, given as a 5-minute infusion in patients with malignant osteolytic disease. Two-hundred eighty patients with osteolytic lesions due to metastatic breast carcinoma or multiple myeloma were randomized to double-blind treatment with either 0.4, 2.0, or 4.0 mg of zoledronic acid or 90 mg pamidronate. The primary efficacy endpoint was the proportion of patients receiving radiation to bone. Other skeletal-related events, bone mineral density (BMD), bone markers, Eastern Cooperative Oncology Group performance status, pain and analgesic scores, and safety also were evaluated. Zoledronic acid at doses of 2.0 and 4.0 mg and pamidronate at a dose of 90 mg each significantly reduced the need for radiation therapy to bone (P < 0.05) in contrast with 0.4 mg zoledronic acid, which did not. Skeletal-related events of any kind, pathologic fractures, and hypercalcemia also occurred less frequently in patients treated with 2.0 or 4.0 mg zoledronic acid or pamidronate than with 0.4 mg zoledronic acid. Increases in lumbar spine BMD (6.2-9.6%) and decreases in the bone resorption marker N-telopeptide (range, -37.1 to -60.8%) were observed for all treatment groups. Skeletal pain, fatigue, nausea, vomiting, and headache were the most commonly reported adverse events. Adverse events were similar in nature and frequency with zoledronic acid and pamidronate. A 5-minute infusion of 2.0-4.0 mg zoledronic acid was at least as effective as a 2-hour 90-mg pamidronate infusion in treatment of osteolytic metastases. A 0.4-mg dose of zoledronic acid was significantly less effective. Both zoledronic acid and pamidronate were well tolerated.


Dorsal defect of the patella with fracture in a teenager.
We report the case of a young boy who presented a dorsal defect of the patella (DDP) with fracture after a small sport trauma. The patient's parents (professional of health care) had been warned on a possible tumoral disease in a previous consultation and claimed for an accurate diagnosis. Although fracture is rarely reported in DDP, the radiographic image strongly suggested this condition; nevertheless, the diagnosis accuracy requested by the parents lead to indicate a biopsy that showed irregular fragments of laminar bone and hyaline cartilage islands similar to articular cartilage compatible with a non-specific developmental ossification defect. The lytic defect was filled with morselized cancellous bone graft, the fracture having a normal consolidation. With a follow-up of 4 years, the patient is asymptomatic, and the radiological morphology of the patella is normal. Although DDP is accepted to be a radiologically well-defined condition, images may perhaps not get accuracy enough for diagnosis and biopsy may be indicated by clinical and radiological features different than the typical ones. Although fracture is rarely reported in case of DDP, it has not to be considered as indicative of tumor or malignancy.


Staphylococcus aureus α-toxin modulates skin host response to viral infection.
Patients with atopic dermatitis (AD) with a history of eczema herpeticum have increased staphylococcal colonization and infections. However, whether Staphylococcus aureus alters the outcome of skin viral infection has not been determined. We investigated whether S aureus toxins modulated host response to herpes simplex virus (HSV) 1 and vaccinia virus (VV) infections in normal human keratinocytes (NHKs) and in murine infection models. NHKs were treated with S aureus toxins before incubation of viruses. BALB/c mice were inoculated with S aureus 2 days before VV scarification. Viral loads of HSV-1 and VV were evaluated by using real-time PCR, a viral plaque-forming assay, and immunofluorescence staining. Small interfering RNA duplexes were used to knockdown the gene expression of the cellular receptor of α-toxin, a disintegrin and metalloprotease 10 (ADAM10). ADAM10 protein and α-toxin heptamers were detected by using Western blot assays. We demonstrate that sublytic staphylococcal α-toxin increases viral loads of HSV-1 and VV in NHKs. Furthermore, we demonstrate in vivo that the VV load is significantly greater (P < .05) in murine skin inoculated with an α-toxin-producing S aureus strain compared with murine skin inoculated with the isogenic α-toxin-deleted strain. The viral enhancing effect of α-toxin is mediated by ADAM10 and is associated with its pore-forming property. Moreover, we demonstrate that α-toxin promotes viral entry in NHKs. The current study introduces the novel concept that staphylococcal α-toxin promotes viral skin infection and provides a mechanism by which S aureus infection might predispose the host toward disseminated viral infections.


Nocturnal Rapid Eye Movement Sleep Without Atonia can Be a Diagnostic Parameter in Differentiating Narcolepsy Type 1 From Type 2.
We aimed to compare rapid eye movement sleep without atonia (RSWA), tonic RSWA, and phasic RSWA indices during polysomnography as a potential biomarker between narcolepsy type 1 and type 2. Medical files, polysomnography, and multiple sleep latency tests of patients with narcolepsy were evaluated retrospectively. A total of three adolescents and 31 adult patients were included. We calculated the total number of rapid eye movement (REM) epochs with tonic and phasic activity in accordance with the American Academy of Sleep Medicine manual scoring rules, version 2.4. We defined tonic RSWA index as the ratio of total number of REM sleep stage epochs with only tonic activity to total REM sleep stage epochs, phasic RSWA index as the ratio of total number of REM sleep stage epochs with only phasic activity to total REM sleep stage epochs, and RSWA index as the ratio of total number of REM stage sleep epochs with RSWA to total REM sleep stage epochs on the polysomnography. Clinically and polysomnographically diagnosed 25 patients with narcolepsy type 1 and 9 patients with narcolepsy type 2 were included. The median age of the subjects was 30 (10, 61) and 36 (18, 64), respectively. Eleven narcolepsy type 1 patients (44%) and 4 narcolepsy type 2 patients (44.44%) were women. The RSWA index of ≥ 3% yielded a sensitivity of 76% and specificity of 88.9% (AUC = 0.77 (0.09), 95% confidence interval = 0.58 to 0.97, p = 0.01), and the tonic RSWA index of ≥ 2.2% yielded a sensitivity of 72% and specificity of 77.8% (area under the curve = 0.74 (0.1), 95% confidence interval = 0.54-0.94, p = 0.03). As an electrophysiological biomarker, RSWA and tonic RSWA indices can be sensitive and specific polysomnography parameters in distinguishing narcolepsy type 1 from narcolepsy type 2.


Genes reveal traces of common recent demographic history for most of the Uralic-speaking populations.
The genetic origins of Uralic speakers from across a vast territory in the temperate zone of North Eurasia have remained elusive. Previous studies have shown contrasting proportions of Eastern and Western Eurasian ancestry in their mitochondrial and Y chromosomal gene pools. While the maternal lineages reflect by and large the geographic background of a given Uralic-speaking population, the frequency of Y chromosomes of Eastern Eurasian origin is distinctively high among European Uralic speakers. The autosomal variation of Uralic speakers, however, has not yet been studied comprehensively. Here, we present a genome-wide analysis of 15 Uralic-speaking populations which cover all main groups of the linguistic family. We show that contemporary Uralic speakers are genetically very similar to their local geographical neighbours. However, when studying relationships among geographically distant populations, we find that most of the Uralic speakers and some of their neighbours share a genetic component of possibly Siberian origin. Additionally, we show that most Uralic speakers share significantly more genomic segments identity-by-descent with each other than with geographically equidistant speakers of other languages. We find that correlated genome-wide genetic and lexical distances among Uralic speakers suggest co-dispersion of genes and languages. Yet, we do not find long-range genetic ties between Estonians and Hungarians with their linguistic sisters that would distinguish them from their non-Uralic-speaking neighbours. We show that most Uralic speakers share a distinct ancestry component of likely Siberian origin, which suggests that the spread of Uralic languages involved at least some demic component.


Protection from oxidative stress by thioredoxin and superoxide dismutase of mouse embryos fertilized in vitro.
A low oxygen tension and superoxide dismutase (SOD) have been demonstrated to promote development of embryos in vitro. In this study, we evaluated the effects of thioredoxin (TRX), a powerful protein disulphide reductase, on the development of mouse embryos fertilized in vitro. Moreover, to clarify the difference between the embryo-protecting mechanisms of TRX and SOD, as well as the critical periods of their actions, we carried out experiments in which we transferred embryos among three different media: basic, TRX- and SOD-supplemented. The rates of 4-cell, blastocyst and expanded blastocyst formation in TRX- (53%, 40% and 34% respectively), or SOD- (59%, 29%, 22%) supplemented media were significantly higher than those (28%, 4%, 0%) in the basic medium. The results of the transfer of embryos using basic and TRX-supplemented media indicated an increase in the rate of expanded blastocysts when TRX was applied from 7 to 30 h, and especially from 18 to 24 h after insemination. In contrast, the results of the transfer of embryos using basic and SOD-supplemented media indicated that SOD, which was also most effective when applied from 7 to 30 h after insemination, had some effects after 30 h. These results indicate that TRX and SOD promote the in-vitro development of mouse embryos fertilized in vitro, which suggests that protection of embryos from oxidative stress is a prerequisite for their development in vitro. SOD and TRX provide protection from oxidative stress by different mechanisms.


Intraosseous ganglion of the glenoid.
Intraosseous ganglions in the glenoid are uncommon. This case report illustrates the management and outcome of this uncommon but symptomatic shoulder problem.


Sports dentistry in general practice.
The sports dentistry movement in the United States and worldwide is experiencing new momentum. Much of this is generated by general dentists working in conjunction with like-minded specialists as well as with dental hygienists, dental laboratory technicians, and dental assistants. This article explores several issues of relevance to stimulate the interest of general dentists to become involved in private practice and community service activities in sports dentistry.


Hybridized Zoonotic Schistosoma Infections Result in Hybridized Morbidity Profiles: A Clinical Morbidity Study amongst Co-Infected Human Populations of Senegal.
Hybridization of infectious agents is a major emerging public and veterinary health concern at the interface of evolution, epidemiology, and control. Whilst evidence of the extent of hybridization amongst parasites is increasing, their impact on morbidity remains largely unknown. This may be predicted to be particularly pertinent where parasites of animals with contrasting pathogenicity viably hybridize with human parasites. Recent research has revealed that viable zoonotic hybrids between human urogenital Schistosoma haematobium with intestinal Schistosoma species of livestock, notably Schistosoma bovis, can be highly prevalent across Africa and beyond. Examining human populations in Senegal, we found increased hepatic but decreased urogenital morbidity, and reduced improvement following treatment with praziquantel, in those infected with zoonotic hybrids compared to non-hybrids. Our results have implications for effective monitoring and evaluation of control programmes, and demonstrate for the first time the potential impact of parasite hybridizations on host morbidity.


Cohesin regulation: fashionable ways to wear a ring.
Cohesin is a multiprotein complex, conserved from yeast to humans, that mediates sister chromatid cohesion. Its ring-shaped structure first suggested that it may perform its task by embracing the sister chromatids. The interaction of cohesin with chromatin is tightly regulated throughout the cell cycle, and several proteins contribute to cohesin loading and mobilization along DNA, establishment of cohesin-mediated cohesion, and removal of cohesin during mitosis. Recent studies suggest that distinct cohesin populations exist in different chromosomal regions and have particular requirements in their dynamic interaction with chromatin. In this review, I briefly summarize these studies and discuss their implications for current and future models of cohesin behavior.


Shp2 is dispensable in the formation and maintenance of the neuromuscular junction.
SHP2, a protein tyrosine phosphatase with two SH2 domains, has been implicated in regulating acetylcholine receptor (AChR) gene expression and cluster formation in cultured muscle cells. To understand the role of SHP2 in neuromuscular junction (NMJ) formation in vivo, we generated mus cle-specific deficient mice by using a loxP/Cre strategy since Shp2 null mutation causes embryonic lethality. Shp2(floxed/floxed) mice were crossed with mice expressing the Cre gene under the control of the human skeletal alpha-actin (HSA) promoter. Expression of SHP2 was reduced or diminished specifically in skeletal muscles of the conditional knockout (CKO) mice. The mutant mice were viable and fertile, without apparent muscle defects. The mRNA of the AChR alpha subunit and AChR clusters in CKO mice were localized in a narrow central region surrounding the phrenic nerve primary branches, without apparent change in intensity. AChR clusters colocalized with markers of synaptic vesicles and Schwann cells, suggesting proper differentiation of presynaptic terminals and Schwann cells. In comparison with age-matched littermates, no apparent difference was observed in the size and length of AChR clusters in CKO mice. Both the frequency and amplitude of mEPPs in CKO mice were similar to those in controls, suggesting normal neurotransmission when SHP2 was deficient. These results suggest that Shp2 is not required for NMJ formation and/or maintenance.


Experimental study of high frame rate imaging with limited diffraction beams.
Limited diffraction beams have a large depth of field and have many potential applications. Recently, a new method (Fourier method) was developed with limited diffraction beams for image construction. With the method and a single plane wave transmission, both 2D (two-dimensional) and 3D (three-dimensional) images of a very high frame rate (up to 3750 frames/s for a depth of 200 mm in biological soft tissues) and a high signal-to-noise ratio (SNR) can be constructed with relatively simple and inexpensive hardware. If limited diffraction beams of different parameters are used in both transmission and reception and transducer aperture is shaded with a cosine function, high-resolution and low-sidelobe images can be constructed with the new method without montage of multiple frames of images [the image quality is comparable to that obtained with a transmit-receive (two-way) dynamically focused imaging system]. In this paper, the Fourier method was studied with both experiment and computer simulation for 2D B-mode imaging. In the experiment, two commercial broadband 1D array transducers (48 and 64 elements) of different aperture sizes (18.288 and 38.4 mm) and center frequencies (2.25 and 2.5 MHz) were used to construct images of different viewing sizes. An ATS539 tissue-equivalent phantom of an average frequency-dependent attenuation of 0.5 dB/MHz/cm was used as a test object. To obtain high frame rate images, a single plane wave pulse (broadband) was transmitted with the arrays. Echoes received with the arrays were processed with both the Fourier and conventional dynamic focusing (delay-and-sum) methods to construct 2D B-mode images. Results show that the quality (resolution and contrast) of constructed images is virtually identical for both methods, except that the Fourier method is simpler to implement. Both methods have also a similar sensitivity to phase aberration distortions. Excellent agreement among theory, simulation, and experiment was obtained.


[Induction of retarded exoerythrocytic schizonts by chloroguanide resulting in delayed parasitaemia of Plasmodium inui in Macaca mulatta].
Three Rhesus monkeys inoculated with a large number of sporozoites of Plasmodium inui dissected from the salivary glands of infected mosquitoes, Anopheles dirus. Two of the monkeys (inoculated with 8.06 x 10(5) and 1.3 x 10(7) sporozoites, respectively) were treated with chloroguanide base 6 mg/(kg.d) x 4 d starting from 24 h after the inoculations and the other one (inoculated with 5.93 x 10(6) sporozoites) was not treated with chloroguanide as control. The primary parasitaemia attacks occurred in the former 2 monkeys were 31 and 25 d respectively after inoculation, while in the control was 7.5 d. Liver biopsies were done in all of the 3 monkeys, normal schizonts were seen in the control monkey on d 8 after inoculation, while none were detected in the 2 monkeys treated with chloroguanide. However, the retarded exoerythrocytic schizonts were found by indirect fluorescent antibody test (IFAT) in liver sections of the monkey inoculated with 1.3 x 10(7) sporozoites. Therefore, it is evident that moderate doses of chloroguanide retarded the formation of schizonts and thus delayed the primary parasitaemia.


Pseudolaric acid B activates autophagy in MCF-7 human breast cancer cells to prevent cell death.
Pseudolaric acid B (PAB) has been demonstrated to exert antitumor effects in MCF-7 human breast cancer cells. The present study aimed to investigate the mechanism of resistance to PAB-induced cell death. Following incubation with 4 µM of PAB for 3 days, the majority of MCF-7 cells became senescent, while some retained the same morphology as control cells, as assessed using a senescence detection kit. Additionally, 36 h of treatment with 4 µM of PAB increased the positive staining of autophagy markers, as shown by monodansylcadaverine and acridine orange staining. Western blot analysis indicated that this treatment also increased expression of the autophagy-related proteins Beclin-1 and microtubule-associated protein 1 light chain 3. Furthermore, treatment with PAB and the autophagy inhibitor 3-methyl adenine significantly decreased the ratio of autophagy, as assessed by flow cytometric analysis of monodansylcadaverine staining density (P<0.001), and increased the ratio of cell death, as assessed by MTT analysis (P<0.001). This indicated that autophagy promotes cell survival as a resistance mechanism to PAB treatment. Additionally, the present study demonstrated that PAB treatment did not affect the mitochondrial membrane potential, which may be related to autophagy. Increased Bcl-2 expression may explain why PAB did not affect the mitochondrial membrane potential. A Bcl-2 binding test demonstrated that PAB treatment inhibits the binding of Bcl-2 and Beclin-1, which may free Beclin-1 to participate in autophagy. Therefore, the present study demonstrated that autophagy may be activated by PAB treatment in human breast cancer MCF-7 cells, contributing to resistance to cell death.


Evidence for the existence of a sulfhydryl group in the adenylate cyclase active site.
6-Cloro-9-beta-d-ribofuranosylpurine 5'-triphosphate (CIRTP) and 6-mercapto-9-beta-d-ribofuranosylpurine 5'-triphosphate (SRTP) irreversibly inhibit adenylate cyclase from rat brain. Adenosine 5'-[beta, gamma -imido] triphosphate protects the enzyme against inactivation by CIRTP and SRTP and acts as a competitive inhibitor with respect to ATP with the Ki value 2 X 10(-4) M. Study of the pH-dependence of the rate of the enzyme inactivation by CIRTP showed that pK for the group modified by this compound is equal to 7.45. Inactivation is first order with respect to the enzyme; the saturation effect is observed at the increased concentration of CIRTP. The k2 and KI values for irreversible inhibition of brain adenylate cyclase by CIRTP were 0.25 min-1 and 1.9 X 10(-4) M, respectively. Adenylate cyclase inhibition by SRTP is also time-dependent. Partial protection against the enzyme inactivation was observed. Dithiothreitol restores the activity of SRTP-inactivated adenylate cyclase. The results obtained indicate the presence of an -SH group in the purine amino group binding area of the enzyme active site.


Overexpression of protective antigen as a novel approach to enhance vaccine efficacy of Brucella abortus strain RB51.
Brucella abortus strain RB51 is an attenuated rough strain that is currently being used as the official live vaccine for bovine brucellosis in the United States and several other countries. We reasoned that overexpression of a protective antigen(s) of B. abortus in strain RB51 should enhance its vaccine efficacy. To test this hypothesis, we overexpressed Cu/Zn superoxide dismutase (SOD) protein of B. abortus in strain RB51. This was accomplished by transforming strain RB51 with a broad-host-range plasmid, pBBR1MCS, containing the sodC gene along with its promoter. Strain RB51 overexpressing SOD (RB51SOD) was tested in BALB/c mice for its ability to protect against challenge infection with virulent strain 2308. Mice vaccinated with RB51SOD, but not RB51, developed antibodies and cell-mediated immune responses to Cu/Zn SOD. Strain RB51SOD vaccinated mice developed significantly (P < 0.05) more resistance to challenge than those vaccinated with strain RB51 alone. The presence of the plasmid alone in strain RB51 did not alter its vaccine efficacy. Also, overexpression of SOD did not alter the attenuation characteristic of strain RB51.


Continuous combined estrogen/progestin hormone replacement therapy.
Women entering menopause should be informed of the benefits and risks of hormone replacement therapy and of the variety of regimens available. One option, a continuous combined regimen of conjugated equine estrogen 0.625 mg and medroxyprogesterone acetate 2.5 mg, maintains the beneficial effects of estrogen on cardiovascular risk factors, although its effects on high-density lipoprotein cholesterol levels are less pronounced than with estrogen alone. The addition of progestin does not affect carbohydrate metabolism except for a slight decline in glucose tolerance. Blood coagulation factors and blood pressure showed no clinically significant changes different from those resulting from unopposed estrogen. Bone mineral density is increased more with the continuous combined regimen than with the continuous combined regimen than with a cyclical regimen of the same hormones. The incidence of endometrial hyperplasia is substantially less than that observed with unopposed estrogen. The overall frequency of irregular bleeding is lower than with estrogen alone and diminishes with continuation of therapy, whereas the incidence of amenorrhea increases from 52.1% to 75.1% between cycles 2 and 11. Epidemiologic evidence linking any hormonal therapy with breast cancer remains inconsistent, possibly because the risk, if any, is small. The relative risk of breast cancer for the continuous regimen has not been extensively studied in large-scale studies.


Efficacy of dosing and re-dosing of two oral fixed combinations of indomethacin, prochlorperazine and caffeine compared with oral sumatriptan in the acute treatment of multiple migraine attacks: a double-blind, double-dummy, randomised, parallel group, multicentre study.
In this double-blind, double-dummy, randomised, parallel group, multicentre study, the efficacy of dosing and re-dosing of a fixed combination of indomethacin, prochlorperazine and caffeine (Indoprocaf) was compared with encapsulated sumatriptan in the acute treatment of two migraine attacks. Additionally, in the group taking Indoprocaf, two different oral formulations were tested: effervescent tablets and encapsulated coated tablets. Of 297 patients randomised (150 assigned to Indoprocaf and 147 to sumatriptan), 281 were included in the intention-to-treat efficacy analysis. The initial dosing of Indoprocaf and sumatriptan was similarly effective with pain-free rates higher than 30% (95% CI of odds-ratio: 0.57-1.28) and headache relief rates of about 60% (95% CI of odds-ratio: 0.82-1.84) with both the drugs. The efficacy of re-dosing of Indoprocaf as rescue medication was more effective than that of sumatriptan with pain-free values of 47% vs. 27% in the total attacks with a statistically significant difference in the first migraine attack in favour of Indoprocaf. The efficacy of re-dosing to treat a recurrence/relapse was very high without differences between the drugs (pain-free: 60% with Indoprocaf and 50% with sumatriptan in the total attacks). Indoprocaf and sumatriptan were well-tolerated. The study demonstrated that the efficacy of the initial dosing of Indoprocaf was not higher than that of sumatriptan, but that the strategy to use the lowest effective dose as soon as the headache occurred, followed by a second dose if the headache has not relieved or to treat a relapse, was very effective, especially with Indoprocaf.


Nested clade analysis of the freshwater shrimp, Caridina zebra (Decapoda: Atyidae), from north-eastern Australia.
The freshwater shrimp, Caridina zebra, is endemic to montane rainforest streams of the Atherton Tableland, north-eastern Australia. As the confluences of many of the headwater streams are in unsuitable habitat, dispersal is expected to be highly restricted. Results from a previous allozyme survey for this species suggested that historical dispersal between separate river drainages had occurred due to rearrangements of the drainage lines at some stage in the recent past. The aim of this study was to use temporal information from the mitochondrial cytochrome oxidase subunit I (CO-I) gene to determine whether the observed genetic structure was a result of historical processes, or alternatively, due to low levels of terrestrial dispersal. The mitochondrial DNA (mtDNA) data were analysed using nested clade analysis, which can differentiate between historical fragmentation and range expansion vs. contemporary restricted gene flow. The results displayed three divergent clades that were likely to have arisen in allopatry. One widespread clade, with individuals in more than one river drainage, reflected a pattern of restricted gene flow. This suggests that this species is capable of terrestrial dispersal.


Alchemical Transfer Approach to Absolute Binding Free Energy Estimation.
The alchemical transfer method (ATM) for the calculation of standard binding free energies of noncovalent molecular complexes is presented. The method is based on a coordinate displacement perturbation of the ligand between the receptor binding site and the explicit solvent bulk and a thermodynamic cycle connected by a symmetric intermediate in which the ligand interacts with the receptor and solvent environments with equal strength. While the approach is alchemical, the implementation of the ATM is as straightforward as that for physical pathway methods of binding. The method is applicable, in principle, with any force field, as it does not require splitting the alchemical transformations into electrostatic and nonelectrostatic steps, and it does not require soft-core pair potentials. We have implemented the ATM as a freely available and open-source plugin of the OpenMM molecular dynamics library. The method and its implementation are validated on the SAMPL6 SAMPLing host-guest benchmark set. The work paves the way to streamlined alchemical relative and absolute binding free energy implementations on many molecular simulation packages and with arbitrary energy functions including polarizable, quantum-mechanical, and artificial neural network potentials.


Barriers to Household Risk Management: Evidence from India.
Why do many households remain exposed to large exogenous sources of non-systematic income risk? We use a series of randomized field experiments in rural India to test the importance of price and non-price factors in the adoption of an innovative rainfall insurance product. Demand is significantly price sensitive, but widespread take-up would not be achieved even if the product offered a payout ratio comparable to U.S. insurance contracts. We present evidence suggesting that lack of trust, liquidity constraints and limited salience are significant non-price frictions that constrain demand. We suggest contract design improvements to mitigate these frictions.


[Epidemiological research, operational planning, and intervention measures in workers' health]
To improve intervention measures in workers' health involves the adoption of approaches aimed at implementing inspection of the workplace, using ethical interventions with impact on the Brazilian Health System. Instruments include risk assessment, information flows, and identification of workers' morbidity and mortality characteristics. Such measures are planned with four operational bases: trade unions, production sector, sentinel event, and microregion, establishing a new dynamic relationship between epidemiological investigations and health interventions aimed at changing the work process associated with occupational injuries and diseases.


Prevalence of latent tuberculosis infection and associated risk factors among 1557 nursing students in a context of low endemicity.
The risk of tuberculosis (TBC) in nurses is related to its incidence in the general population. Nursing students involved in clinical training could be exposed to occupational risks similar to those of healthcare workers (HCWs). To better understand the epidemiology of nosocomial TBC among nurses in a context of low endemicity, we recruited a cohort of young nursing trainees at the Second University of Naples. A screening programme for LTBI in nursing students was conducted between January 2012 and December 2013, at the Second University of Naples, with clinical evaluations, tuberculin skin test (TST) and, in positive TST student, the interferon-g release assays (IGRA). Putative risk factors for LTBI were assessed by a standardized questionnaire. 1577 nursing students attending the Second University of Naples have been submitted to screening programme for TBC. 1575 have performed TST as first level test and 2 Quantiferon test (QFT). 19 students were TST positive and continued the diagnostic workup practicing QFT, that was positive in 1 student. Of the 2 subjects that have practiced QFT as first level test only 1 was positive. In 2 students positive to QFT test we formulated the diagnosis of LTBI by clinical and radiographic results. The prevalence of LTBI among nursing students in our study resulted very low. In countries with a low incidence of TBC, the screening programs of healthcare students can be useful for the early identification and treatment of the sporadic cases of LTBI.


The evaluation of drug-plasma protein binding interaction on immobilized human serum albumin stationary phase, aided by different computational approaches.
The drug-human serum albumin binding interaction was evaluated on a stationary phase immobilized with human serum albumin using a mixture of phosphate buffer (pH 7.0) and acetonitrile modifier as mobile phase. The 33 compounds that have a wide structural and therapeutic diversity were analyzed by performing a large number of experiments. The interaction mechanism was interpreted based on: i) retention characteristics of structurally related compounds, ii) retention modeling, iii) quantitative structure retention relationship (QSRR), and iv) molecular docking. Small structural differences of related compounds (e.g., reflected in different lipophilicity and polarity) have been found to affect their different binding to human serum albumin. It was found that drug retention in HSA column can be successfully described by using the quadratic function. The isocratic (logk(14%)) and extrapolated (b0(LSS)) retention factors showed the highest correlation (r > 0.76) with the constant that defines the binding affinity for human serum albumin (ACD/I-Lab). Therefore, selected chromatographic parameters can demonstrate reliable applicability for rapid screening of drug-plasma protein binding in drug discovery. In QSRR study, the resulting SVM/logk(14%) and MLR/b0(LSS) models display high internal and external predictive power. The constitutional properties (double bonds, aromatic rings, benzyl, allyl, -amino and -sulfur containing functional groups) supported by the charged parts of surface area had a significant impact on human serum albumin-binding affinity, which was also confirmed with molecular docking study. The high structural diversity of the data set provides wide applicability of tested chromatographic conditions and constructed models for defining the pharmacokinetic profile and possible structural modifications that can increase plasma protein binding of newly synthesized, pharmaceutically important compounds.


17p allelic deletions and p53 protein overexpression in Barrett's adenocarcinoma.
Barrett's esophagus is a condition in which the stratified squamous epithelium of the esophagus is replaced by metaplastic columnar epithelium that predisposes to the development of esophageal adenocarcinoma. Allelic deletions of 17p and alterations of p53 including elevated p53 protein levels have been observed in many different tumors. To investigate the presence of 17p allelic deletions and p53 protein overexpression in Barrett's adenocarcinomas, we have combined the use of restriction fragment length polymorphism analysis, multiparameter flow cytometry, and DNA content cell sorting. The combined use of these methodologies permits the purification of aneuploid tumor cells for restriction fragment length polymorphism analysis of 17p allelic deletions and the evaluation of p53 protein expression by multiparameter flow cytometry in the same aneuploid tumor cell populations. We analyzed 15 aneuploid populations and one tetraploid populations from 13 Barrett's adenocarcinomas for 17p allelic deletions and p53 protein overexpression to determine whether both of these alterations are involved in carcinogenesis in Barrett's esophagus. Twelve of 13 tumors (92%) had 17p allelic deletions, and 8 of 13 tumors (62%) had p53 protein overexpression. Eight of the 12 tumors (67%) with 17p allelic deletions also had p53 protein overexpression. These data indicate that both 17p allelic deletions and p53 protein overexpression are frequently involved in carcinogenesis in Barrett's esophagus.


The national disaster life support programs: a model for competency-based standardized and locally relevant training.
With grant funding from the Department of Health and Human Services under the Bioterrorism Training and Curriculum Development Program, the Medical College of Georgia Center of Operational Medicine (MCG-COM) provided an integrated disaster medicine continuing education program for the state of Georgia. This educational program was based on the American Medical Association (AMA) National Disaster Life Support (NDLS) curricula. With supplemental funding, the MCG-COM developed and piloted a national training strategy for all-hazards disaster preparedness education. This strategy built upon the existing 47 training centers delivering NDLS curricula. State advisory committees were established in four model states, developing state-specific modules based on a Hazard and Vulnerability Assessment. These modules were piloted as a model for the deployment of a national curriculum with state and local integration. In addition, the AMA established an educational consortium for the purpose of continual curriculum revision. This consortium, currently consisting of more than 75 participating organizations and federal liaisons, is responsible for all curriculum updates for the NDLS courses. Under this model, multidisciplinary crosscutting disaster medicine competencies and a proposed educational framework were developed. The resulting competencies and framework have been published in the peer-reviewed literature and are being integrated into the NDLS curricula.


Genetic Analysis and Fine Mapping of the Fire Blight Resistance Locus of Malus ×arnoldiana on Linkage Group 12 Reveal First Candidate Genes.
Malus ×arnoldiana accession MAL0004 has been found to be resistant to moderately and highly virulent strains of the fire blight causal pathogen - the Gram-negative bacterium, Erwinia amylovora. Genetic analyses with an F1 segregating population derived from crossing the highly susceptible apple cultivar 'Idared' and MAL0004 led to the detection and mapping of the fire blight resistance locus of M. ×arnoldiana to linkage group (LG)12 (FB_Mar12). FB_Mar12 mapped at the distal end of LG12 below the apple SSR Hi07f01 in an interval of approximately 6 cM (Centimorgan), where both the fire blight resistance loci of M. floribunda 821 and 'Evereste' were located. We fine mapped the region containing FB_Mar12 using 892 progenies. Mining of the region of interest (ROI) on the 'Golden Delicious' doubled haploid genome (GDDH13) identified the presence of 2.3 Mb (megabases) in the homologous region. Of 40 primer pairs designed within this region, 20 were polymorphic and nine were mapped, leading to the identification of 24 significant recombinant individuals whose phenotypes were informative in determining the precise position of the locus within a 0.57 cM interval. Analyses of tightly linked marker sequences on the M. baccata draft genome revealed scaffolds of interest putatively harboring the resistance loci of M. ×arnoldiana, a hybrid between M. baccata and M. floribunda. Open reading frame (ORF) analyses led to the prediction of first fire blight resistance candidate genes with serine/threonine kinase and leucine-rich repeat domains, including homologs of previously identified 'Evereste' candidate genes. We discuss the implications of these results on breeding for resistance to fire blight.


Current trends in the management of schizophrenia.
Schizophrenia is a common and devastating illness. Patients with schizophrenia may develop many disabilities both due to the disease process as well as due to side effects of the medication used. There are many advances in the treatment of schizophrenia, which can effectively reduce many of these disabilities. Treatment of schizophrenia is a primary health care responsibility and thus all health care personnel need to equip themselves with the latest knowledge on management issues. This article outlines the current management issues in schizophrenia.


The autoimmune regulator PHD finger binds to non-methylated histone H3K4 to activate gene expression.
Mutations in the gene autoimmune regulator (AIRE) cause autoimmune polyendocrinopathy candidiasis ectodermal dystrophy. AIRE is expressed in thymic medullary epithelial cells, where it promotes the expression of tissue-restricted antigens. By the combined use of biochemical and biophysical methods, we show that AIRE selectively interacts with histone H3 through its first plant homeodomain (PHD) finger (AIRE-PHD1) and preferentially binds to non-methylated H3K4 (H3K4me0). Accordingly, in vivo AIRE binds to and activates promoters containing low levels of H3K4me3 in human embryonic kidney 293 cells. We conclude that AIRE-PHD1 is an important member of a newly identified class of PHD fingers that specifically recognize H3K4me0, thus providing a new link between the status of histone modifications and the regulation of tissue-restricted antigen expression in thymus.


Universal patterns of equilibrium cluster growth in aqueous sugars observed by dynamic light scattering.
Dynamic light scattering performed on aqueous solutions of three sugars (glucose, maltose and sucrose) reveal a common pattern of sugar cluster formation with a narrow cluster size distribution. In each case, equilibrium clusters form whose size increases with increasing sugar content in an identical power law manner in advance of a common, critical-like, percolation threshold near 83 wt % sugar. The critical exponent of the power law divergence of the cluster size varies with temperature, increasing with decreasing temperature, due to changes in the strength of the intermolecular hydrogen bond and appears to vanish for temperatures in excess of 90 °C. Detailed analysis of the cluster growth process suggests a two-stage process: an initial cluster phase formed at low volume fractions, ϕ, consisting of noninteracting, monodisperse sugar clusters whose size increases ϕ(1/3) followed by an aggregation stage, active at concentrations above about ϕ=40%, where cluster-cluster contact first occurs.


Efficacy and safety of dipeptidyl peptidase-4 inhibitors and metformin as initial combination therapy and as monotherapy in patients with type 2 diabetes mellitus: a meta-analysis.
This meta-analysis was performed to provide an update on the efficacy and safety of dipeptidyl peptidase-4 (DPP-4) inhibitors and metformin as initial combination therapy and as monotherapy in patients with type 2 diabetes mellitus (T2DM). We conducted a search on MEDLINE, Embase and Cochrane Collaborative database for randomized controlled trials (RCTs) of DPP-4 inhibitors and metformin as initial combination therapy or as monotherapy in patients with T2DM by the end of December 2012, using the key words 'alogliptin', 'dutogliptin', 'linagliptin', 'saxagliptin', 'sitagliptin', 'vildagliptin' and 'metformin'. RCTs were selected for meta-analysis if (1) they were RCTs comparing DPP-4 inhibitors plus metformin as initial combination therapy or DPP-4 inhibitor monotherapy to metformin monotherapy, (2) duration of treatment was ≥12 weeks and (3) reported data on haemoglobin A1c (HbA1c) change, fasting plasma glucose (FPG) change, weight change, adverse cardiovascular (CV) events, hypoglycaemia or gastrointestinal adverse events (AEs). A total of eight RCTs were included. Compared with metformin monotherapy, DPP-4 inhibitors monotherapy was associated with lower reduction in HbA1c level [weighted mean differences (MD) = 0.28, 95% confidence intervals (CIs) (0.17, 0.40), p < 0.00001], lower reduction in FPG level [MD = 0.81, 95% CI(0.60, 1.02), p <0.00001], lower weight loss [MD = 1.51, 95% CI (0.89, 2.13), p < 0.00001], but lower risk of adverse CV events [risk ratio (RR) = 0.36, 95% CI (0.15, 0.85), p = 0.02], lower risk of hypoglycaemia [RR = 0.44, 95% CI (0.27, 0.72), p = 0.001] and lower risk of gastrointestinal AEs [RR = 0.63, 95% CI(0.55, 0.70), p <0.00001]. Compared with metformin monotherapy, DPP-4 inhibitors plus metformin as initial combination therapy was associated with higher reduction in HbA1c level [MD = -0.49, 95% CI (-0.57, -0.40), p < 0.00001], higher reduction in FPG level [MD = -0.80, 95% CI (-0.87, -0.74), p < 0.00001], lower weight loss [MD = 0.44, 95% CI (0.22, 0.67), p = 0.0001]; but was not associated with a further reduction in adverse CV events [RR=0.54, 95% CI (0.25, 1.19), p = 0.13], nor the higher risk of hypoglycaemia [RR = 1.04, 95% CI (0.72, 1.50), p = 0.82], nor the prolonged risk of gastrointestinal AEs [RR = 0.98, 95% CI (0.88, 1.10), p = 0.77]. DPP-4 inhibitors, which are safe and effective in controlling the blood glucose, may possibly decrease the risk of CV events in patients with T2DM. It could be a credible alternative for T2DM patients who, for some reason, cannot use metformin, or are in high risk of CV exposure. High-quality, large sample and long-term follow-up clinical trails are needed to confirm the long-term conclusions.


Differential recovery rates of rat D2 dopamine receptors as a function of aging and chronic reserpine treatment following irreversible modification: a key to receptor regulatory mechanisms.
The density of D2 dopamine receptors identified by 3H-spiperone binding was significantly lower in the striatum of senescent (28-month-old) than in mature (4-month-old) Fischer 344 rats. The time course of recovery of 3H-spiperone binding to D2 dopamine receptors following irreversible receptor modification by a single injection of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) was significantly slower in senescent than in mature rats. The kinetics of D2 dopamine receptor repopulation could be adequately described by a model assuming a constant rate of receptor production and a rate of degradation that was dependent on receptor concentration. Both the production rate and degradation rate constant of D2 dopamine receptors were lower in the senescent rats compared to mature rats. The changes in receptor density that occur as a function of development and aging are the result of changes in both the receptor production rate and receptor degradation rate constant, which, while both are reduced, tend to maintain receptor density. That is, receptor density decreased by 26% from 4 to 28 months of age, although the receptor production rate and degradation rate constant decreased by 40-50%. Chronic treatment of rats with reserpine produced a 21% increase in the density of striatal D2 dopamine receptors of mature, but not senescent, rats, accompanied by an increase in the initial recovery rate of 3H-spiperone binding sites following EEDQ treatment. It might have been expected that the reduced formation of agonist-bound receptors would have lead to a decrease in the receptor degradation rate constant.(ABSTRACT TRUNCATED AT 250 WORDS)


Phytochemical screening of Alstonia scholaris leaf and bark extracts and their antimicrobial activities.
Alstonia sholaris is an evergreen tree commonly found in South East Asia. In traditional medicine pharmacological activities are attributed to the leaves and bark of this plant. The aim of this study is characterizing the chemicals present in A. sholaris leaves and bark extracts and study their antimicrobial activities. Solvent extractions with Soxhlet apparatus of leaves and bark were obtained using hexane, benzene, isopropanol, methanol, and water. The crude extracts were concentrated and screened for qualitative phytochemical analysis and thin layer chromatography, and the antibacterial, antifungal an antiviral activity of crude extracts were measured by in vitro methods. Isopropanol and methanol extracts showed significant antibacterial activity and it was more pronounced against Gram positive than against Gram negative bacteria. Hexane, benzene, isopropanol and methanol fractions of A. scholaris bark and leaf showed activity against Enterobacter cloacae. Isopropanol extract showed maximum activity against selected human pathogenic fungus. In conclusion, the leaves and bark of A. scholaris are rich in phytochemicals with antimicrobial activities against human pathogens, being the isopropanol fraction the one with the highest antibacterial, antifungal, antiviral and anti-mycobacterial activities.


Extreme Appraisals of Internal States and Duration of Remission in Remitted Bipolar Patients.
To identify dysfunctional attitudes seen in bipolar disorder (BPD) is important for the cognitive theories of BPD and corresponding psychosocial interventions. Cognitions are seen as vulnerability factors in the development and maintenance of BPD. The present study aims to contribute to the cognitive literature on BPD by examining depressive and hypomanic attitudes and their contribution to the prediction of BPD diagnosis as well as by exploring the relationship between dysfunctional cognitions and clinical features (types of episodes experienced, duration of illness, and duration of remission). One hundred and eighteen remitted bipolar patients and 103 healthy controls completed the Mood Disorder Questionnaire (MDQ), Turkish Brief-Hypomanic Interpretations and Positive Predictions Inventory (HAPPI), and Dysfunctional Attitudes Scale. The bipolar group had significantly higher depressive and hypomanic attitudes than the control group. No significant differences were found regarding the types of episodes experienced and duration of illness. However, both types of attitudes decreased as the duration of remission increased. They were also found to contribute to the prediction of bipolar diagnosis together with the screening of the MDQ. The results pointed out that dysfunctional cognitions may be utilized as possible indicators for the risk of relapse in clinical groups and vulnerability for BPD among other populations.


A strategy based on patient preference improves the adherence and outcomes of phosphate binders in hemodialysis .
Phosphate binders (PB) have to be taken with food, their interference with an individual's lifestyle and social habits influences treatment adherence. Several PBs are available, and patient preferences should not be ignored when prescribing. The purpose was to know the extent of intentional and unintentional nonadherence to PB in hemodialysis (HD) patients, and to evaluate the long-term results (adherence, serum phosphate levels, and cost) of a strategy of prescription of PB that takes into account patient preferences. A prospective open-label, single-arm study, conducted in all 130 prevalent HD patients of our unit. Each patient was compared with themselves before (baseline) and 6, 12, and 24 months after adopting the new strategy. Factors included in the decision tree to prescribe PB were patient preferences, cost, and security. Self-reported, intentional, and unintentional nonadherence, serum P levels, and cost were evaluated. Patients were instructed to request a change of PB if they had problems or did not like those prescribed. Results: After implementing the new strategy, the percentage of patients receiving calcium PB monotherapy increased (p < 0.001), while the percentage of those receiving noncalcium PB monotherapy (p < 0.001) and a combination of noncalcium PB (p < 0.01) decreased. Self-reported nonadherence (64.6%) and intentional nonadherence (38.4%) decreased significantly at 6 months and remained stable until the end of the study (50.6%; p < 0.05 and 24.9%; p < 0.01, respectively). Unintentional nonadherence did not change. Intentionally nonadherent patients at baseline showed a significant and maintained decrease of serum P levels (p < 0.05) and in the number of tablets/day of PB (p < 0.01). Implementing the protocol resulted in a significant reduction of costs expended in PB. Individualization of treatment that takes into account patient preferences improves the adherence and control of P levels at a lower cost. The most important changes after the new strategy were observed in intentionally nonadherent patients. .


Oral Anticoagulation and Adverse Outcomes after Ischemic Stroke in Heart Failure Patients without Atrial Fibrillation.
The safety and effectiveness of oral anticoagulation (OAC) after an ischemic stroke in older patients with heart failure (HF) without atrial fibrillation remains uncertain. Utilizing Get With The Guidelines Stroke national clinical registry data linked to Medicare claims from 2009-2014, we assessed the outcomes of eligible patients with a history of HF who were initiated on OAC during a hospitalization for an acute ischemic stroke. The cumulative incidences of adverse events were calculated using Kaplan-Meier curves and adjusted Cox proportional hazard ratios were compared between patients discharged on or off OAC. A total of 8,261 patients from 1,370 sites were discharged alive after an acute ischemic stroke and met eligibility criteria. Of those, 747 (9.0%) were initiated on OAC. Patients on OAC were younger (77.2±8.0 vs. 80.5±8.9 years, p<0.01). After adjustment for clinical covariates, the likelihood of 1 year mortality was higher in those on OAC (aHR: 1.22, 95% CI 1.05-1.41, p<0.01), while no significant differences were noted for ICH (aHR: 1.34, 95% CI 0.69-2.59, p=0.38) and recurrent ischemic stroke (aHR: 0.78, 95% CI 0.54-1.15, p = 0.21). The likelihood of all-cause bleeding (aHR: 1.59, 95% CI 1.29-1.96, p<0.01) and all-cause re-hospitalization (aHR: 1.14, 95% CI 1.02-1.27, p = 0.02) was higher for those on OAC. Initiation of OAC after an ischemic stroke in older patients with HF in the absence of atrial fibrillation is associated with death, bleeding and re-hospitalization without an associated reduction in recurrent ischemic stroke. If validated, these findings raise caution for prescribing OAC to such patients.


Genome-wide genetic associations with IFNγ response to smallpox vaccine.
Smallpox is a deadly and debilitating disease that killed hundreds of millions of people in the past century alone. The use of Vaccinia virus-based smallpox vaccines led to the eradication of smallpox. These vaccines are remarkably effective, inducing the characteristic pustule or "take" at the vaccine site in >97 % of recipients, and inducing a wide spectrum of long-lasting humoral and cellular immune responses. The mechanisms behind inter-individual vaccine-response variability are likely to involve host genetic variation, but have not been fully characterized. We report here the first smallpox vaccine response genome-wide association study of over 1,000 recent recipients of Dryvax(®). The data presented here focus on cellular immune responses as measured by both production of secreted IFNγ and quantitation of IFNγ secreting cells by ELISPOT assay. We identified multiple significant SNP associations in genes (RASA1, ADRA1D, TCF7L1, FAS) that are critical components of signaling pathways that directly control lymphocyte IFNγ production or cytotoxic T cell function. Similarly, we found many associations with SNPs located in genes integral to nerve cell function; findings that, given the complex interplay between the nervous and immune systems, deserve closer examination in follow-up studies.


Dilemma in post-IBD patients with IBS-D symptoms: A 2020 overview.
Inflammatory bowel disease (IBD) patients in apparent clinical remission who present with irritable bowel syndrome (IBS)-like symptoms pose a diagnostic and therapeutic dilemma that is called post-IBD IBS. When associated with a diarrheal IBS presentation, this clinical syndrome is known as post-IBD IBS-D. We review and describe the literature regarding the clinical overlap of IBD and IBS. We discuss prevalent theories regarding the pathophysiology of post-IBD IBS-D and whether this presentation represents coincident inherent IBS-D, IBS-D triggered by IBD, or an even more subtle level of IBD activity that is unrecognized by available laboratory modalities. We also discuss observations that post-IBD IBS-D patients harbor significantly increased colon mucosal eosinophils and appear to respond to a GI-hypoallergenic diet and budesonide therapy. The symptoms overlap between IBD and IBS complicates diagnosis and subsequent management of patients with post-IBD IBS-D. In addition to current theories regarding the pathophysiology of this condition such as alterations in mucosal inflammation, the microbiota, mucosal permeability, and gut-brain interactions. This new avenue of eosinophilic colopathy and therapy directed toward food-derived immune response in patients with post-IBD IBS-D deserves additional investigation.


Executive dysfunction predicts nonresponse to fluoxetine in major depression.
Functional brain imaging studies of major depression have consistently revealed hypometabolism or hypoperfusion in specific regions of the prefrontal cortex and basal ganglia. Studies of cognitive functioning in major depression have suggested that some but not all subjects exhibit cognitive deficits that are consistent with frontal-subcortical dysfunction, although the reasons for this heterogeneity are unclear. In this study, we explored this heterogeneity among depressed subjects by examining the relationship between cognitive functioning and treatment outcome. Subjects with major depression were administered a complete neuropsychological test battery prior to treatment with fluoxetine. There were no significant differences between responders and nonresponders to fluoxetine in terms of age, educational achievement, number of past episodes of depression, and estimated premorbid IQ. However, nonresponders performed significantly worse than responders on several pretreatment measures of executive functioning, after controlling for baseline group differences in depression severity. The results are based on a small sample of primarily female subjects, resulting in low statistical power and less generalizability to samples of male subjects with depression. The findings suggest that subtle prefrontal dysfunction in subjects with major depression may be predictive of poor response with particular medications. Assessment of the executive functions may play a particular role in pretreatment identification of subjects likely to respond to specific medications.


Phonological and semantic fluencies are mediated by different regions of the prefrontal cortex.
Verbal phonological and semantic fluencies were investigated in 24 patients with unilateral prefrontal lesions and 10 normal control subjects. Lesions were limited to small areas within either the dorsolateral (Brodmann's area 46/9) or ventromedial (posterior part of the gyrus rectus) cortices. In a phonological fluency task, patients with lesions to the left dorsolateral region were impaired. In semantic fluency, not only the left dorsolateral group but also the two right frontal damaged groups performed worse than the control group. In agreement with previous studies, our results show that the phonological fluency is mediated by the left dorsolateral prefrontal cortex. In contrast to this, performance on the semantic fluency task depends on a wider portion of the prefrontal cortex involving the left and right dorsolateral and the right ventromedial areas.


[Acute lung injury related to transfusion of fresh frozen plasma].
A 23-year-old woman with no relevant medical history required transfusion of 2 units of fresh frozen plasma before diagnostic laparoscopy. Following transfusion, serious bilateral pulmonary edema with hypoxia developed and resolved with 48 hours of mechanical ventilation. Immunological testing of blood from the 2 donors and the patient revealed the presence of anti-HLA DR-52 antibodies in the plasma of a donor and the presence of the corresponding antigen in the patient, confirming the diagnosis of fresh frozen plasma transfusion-related acute lung injury. Transfusion-related acute lung injury associated with plasma-containing blood products has an incidence of 1:5000 transfused units and a mortality rate of up to 10% of cases. Clinical suspicion should remain high in making the diagnosis and ruling out other causes of pulmonary edema, given that a firm diagnosis will come only after immunological testing. Transfusion-related acute lung injury is considered an under-diagnosed syndrome and must be included in the differential diagnosis of respiratory distress when a transfusion has been given.


[Clostridium septicum bacteremia in a diabetic patient (author's transl)].
This report concerns the clinical and bacteriological study of a female diabetic who presented with a febrile illness of sudden onset and acute toxemia. Physical examination at admission was unrewarding. A few hours after admission lesions characteristic of gas gangrene appeared in the right upper limb without prior trauma, and a clostridial infection was suspected. Bacteriological studies of the exudate and of the patient's blood led to the isolation of Clostridium septicum, thus confirming the clinical suspicion. The disease had a precipitous course and the patient died 12 hours after admission in spite of the administration of high doses of intravenous penicillin. While waiting for bacteriological data, early antibiotic treatment appears to be indicated in any diabetic patient with an acute toxic syndrome and absence of localized infection.


Gas Phase Protein Folding Triggered by Proton Stripping Generates Inside-Out Structures: A Molecular Dynamics Simulation Study.
The properties of electrosprayed protein ions continue to be enigmatic, owing to the absence of high-resolution structure determination methods in the gas phase. There is considerable evidence that under properly optimized conditions these ions preserve solution-like conformations and interactions. However, it is unlikely that these solution-like conformers represent the "intrinsic" structural preferences of gaseous proteins. In an effort to uncover what such intrinsically preferred conformers might look like, we performed molecular dynamics (MD) simulations of gaseous ubiquitin. Our work was inspired by recent gas phase experiments, where highly extended 13+ ubiquitin ions were transformed to compact 3+ species by proton stripping (Laszlo, K. J.; Munger, E. B.; Bush, M. F. J. Am. Chem. Soc. 2016, 138, 9581-9588). Our simulations covered several microseconds and used a mobile-proton algorithm to account for the fact that a H+ in gaseous proteins can migrate between different titratable sites. Proton stripping caused folding of ubiquitin into heterogeneous "inside-out" structures. The hydrophilic core of these conformers was stabilized by charge-charge and polar interactions, while hydrophobic residues were located on the protein surface. Collision cross sections of these MD structures were in good agreement with experimental results. The inside-out structures generated during gas phase folding are in striking contrast to the solution behavior which is dominated by the hydrophobic effect, i.e., the tendency to bury hydrophobic side chains in the core (instead of exposing them to the surface). We do not dispute that native-like proteins can be transferred into the gas phase as kinetically trapped species. However, those metastable conformers do not represent the intrinsic structural preferences of gaseous proteins. Our work for the first time provides detailed insights into the properties of intrinsically preferred gas phase conformers, and we unequivocally find them to have inside-out architectures.


Trauma networks: present and future challenges.
In England, trauma is the leading cause of death across all age groups, with over 16,000 deaths per year. Major trauma implies the presence of multiple, serious injuries that could result in death or serious disability. Successive reports have documented the fact that the current ad hoc unstructured management of this patient group is associated with considerable avoidable death and disability. The reform of trauma care in England, especially of the severely injured patient, has already begun. Strong clinical leadership is embraced as the way forward. The present article summarises the steps that have been made over the last decade that led to the recent decision to move towards a long anticipated restructure of the National Health Service (NHS) trauma services with the introduction of Regional Trauma Networks (RTNs). While, for the first time, a genuine political will and support exists, the changes required to maintain the momentum for the implementation of the RTNs needs to be marshalled against arguments, myths and perceptions from the past. Such an approach may reverse the disinterest attitude of many, and will gradually evolve into a cultural shift of the public, clinicians and policymakers in the fullness of time.


Development of the human hypogastric nerve sheath with special reference to the topohistology between the nerve sheath and other prevertebral fascial structures.
Semi-serial sections from the lumbosacral region of nine fetuses (8-25 weeks gestation) were examined to clarify the lumbar prevertebral fascial arrangement. The prevertebral fasciae became evident after 12 weeks of age. After 20 weeks of age, the hypogastric nerve (HGN) was sandwiched by two fascial structures; the ventral fascia which seemed to correspond to the mesorectal fascia, whereas the dorsal fascia corresponded to the presacral fascia. These fasciae or the HGN sheaths extended laterally along the ventral aspects of the great vessels and associated lymph follicles. The ventral fascia is, to some extent, fused with the mesocolon descendens on the left side of the body. Notably, the lateral continuation of these two fasciae also sandwiches the left ureter, but not the right ureter, presumably due to modifications by the left-sided fusion fascia. A hypothetical common sheath for the HGN and ureter (i.e., the ureterohypogastric or vesicohypogastric fascia) might thus be an oversimplification. Before retroperitoneal fixation, the morphology of the peritoneal recess along the mesocolon descendens and mesosigmoid suggested interindividual differences in location, shape, and size. Therefore, in adults the ease of surgical separation of the rectum and left-sided colon from the HGN seems to depend on interindividual differences in the development of the embryonic peritoneal recess. On the caudal side of the second sacral segment, fascial structures were restricted along and around the HGN, pelvic splanchnic nerve, and pelvic plexus. The rectal lateral ligament thus seems to represent a kind of migration fascia formed by mechanical stress.


Missed appointment in adolescent clinic; perspective from tertiary care hospital, Thailand.
To determine the missed appointment rate and evaluate the factors related to appointment adherence in adolescent patients, based on the patients' characters and services provided. All medical records in adolescent clinic at Siriraj Hospital between 2004 and 2009 were reviewed Patients that visited the clinic at least twice with the follow-up visit order were recruited. Data analyses were performed by Chi-square test and Fisher's exact test wherever appropriated. One hundred twenty six patients met the inclusion criteria. Patients'mean age were 14.3-year-old (SD = 2.7) and the majority (95%) were students. Seventy one point five percent of principle diagnosis related to behavioral problems while 90% had at least one risky behavior detected Comparing between missed and non-missed appointment, only the acute illness and the history of appointment cancellation were significant different characters between groups (p < 0.001). Of 429 visits, 409 (95.3%) got telephone reminder a few days prior the appointment date, 48 (11.2%) remained non-complying and 40 (9.7%) had rescheduled. Only 18 (4.2%) of the visits were the patients themselves made re-appointments, which all complied with the new visit. Having rescheduled after being reminded and having history of a missed previous appointment were the most significant predictors for next appointment adherence (p = 0. 01 and p = 0.02 respectively). In adolescents, appointment non-compliance is a challenging issue for clinicians. Predicting factors found in this study might help foster appointment adherence. Interestingly, services provided such as telephone reminder short waiting time, appointment time did not influence adherence in this population.


Biocompatible functionalization of polymersome surfaces: a new approach to surface immobilization and cell targeting using polymersomes.
Vesicles assembled from amphiphilic block copolymers represent promising nanomaterials for applications that include drug delivery and surface functionalization. One essential requirement to guide such polymersomes to a desired site in vivo is conjugation of active, targeting ligands to the surface of preformed self-assemblies. Such conjugation chemistry must fulfill criteria of efficiency and selectivity, stability of the resulting bond, and biocompatibility. We have here developed a new system that achieves these criteria by simple conjugation of 4-formylbenzoate (4FB) functionalized polymersomes with 6-hydrazinonicotinate acetone hydrazone (HyNic) functionalized antibodies in aqueous buffer. The number of available amino groups on the surface of polymersomes composed of poly(dimethylsiloxane)-block-poly(2-methyloxazoline) diblock copolymers was investigated by reacting hydrophilic succinimidyl-activated fluorescent dye with polymersomes and evaluating the resulting emission intensity. To prove attachment of biomolecules to polymersomes, HyNic functionalized enhanced yellow fluorescent protein (eYFP) was attached to 4FB functionalized polymersomes, resulting in an average number of 5 eYFP molecules per polymersome. Two different polymersome-antibody conjugates were produced using either antibiotin IgG or trastuzumab. They showed specific targeting toward biotin-patterned surfaces and breast cancer cells. Overall, the polymersome-ligand platform appears promising for therapeutic and diagnostic use.


[Skin reactions on exposure to the pine processionary caterpillar (Thaumetopoea pityocampa)].
The pine processionary caterpillar is the larval form of the Thaumetopoea pityocampa moth. Mediterranean forests regularly suffer plagues of this insect, which has been moving north as a result of global warming. When the small urticating hairs that develop during the last 3 larval stages are shed and can become airborne. If they come in contact with skin, they can cause a variety of reactions, notably contact urticaria and papular rashes. Irritation can also occur if the hairs lodge in the mucosa of the conjunctiva or in the respiratory tract. Several cases of anaphylactic reactions have been reported in recent years. Mechanical (irritative) mechanisms may be involved in the pathogenesis of lesions, or immunoglobulin E-mediated allergic hypersensitivity reactions may be implicated when the process is rapid, recurrent, and progressively more severe.


Three-Dimensional Analysis of Binding Sites for Predicting Binding Affinities in Drug Design.
Understanding the interaction between drug molecules and proteins is one of the main challenges in drug design. Several tools have been developed recently to decrease the complexity of the process. Artificial intelligence and machine learning methods offer promising results in predicting the binding affinities. It becomes possible to do accurate predictions by using the known protein-ligand interactions. In this study, the electrostatic potential values extracted from 3-dimensional grid cubes of the drug-protein binding sites are used for predicting binding affinities of related complexes. A new algorithm with a dynamic feature selection method was implemented, which is derived from Compressed Images For Affinity Prediction (CIFAP) study, to predict binding affinities of Checkpoint Kinase 1 and Caspase 3 inhibitors.


Current barrier membranes: titanium mesh and other membranes for guided bone regeneration in dental applications.
Research on guided bone regeneration (GBR) is still ongoing, with evidence mainly from preclinical studies. Various current barrier membranes should fulfill the main design criteria for GBR, such as biocompatibility, occlusivity, spaciousness, clinical manageability and the appropriate integration with the surrounding tissue. These GBR characteristics are required to provide the maximum membrane function and mechanical support to the tissue during bone formation. In this review, various commercially available, resorbable and non-resorbable membranes with different characteristics are discussed and summarized for their usefulness in preclinical studies. Membranes offer promising solutions in animal models; however, an ideal membrane has not been established yet for clinical applications. Every membrane type presents both advantages and disadvantages. Titanium mesh membranes offer superb mechanical properties for GBR treatment and its current efficacy in trials will be a focus in this review. A thorough understanding of the benefits and limitations inherent to various materials in specific clinical applications will be of great value and aid in the selection of an optimal membrane for GBR.


[The characteristics of the development of rural families morbidity].
The morbidity of mothers and fathers residing in the full, involved and incomplete rural families is analyzed. The gender and inter-type rural family differences in the disease rate are established. The characteristics of the formation of the age-related structure of morbidity among the fathers and mothers as the major causes of death among the rural population are determined.


[Pharyngeal tuberculosis: Case report].
Pharyngeal tuberculosis is a rare extrapulmonary manifestation. In Argentina, the number of cases of tuberculosis reported in children under 19 years in 2012 was 1752. Only 12.15% had extrapulmonary manifestation. A case of a 17 year old girl with pharyngeal tuberculosis is reported. The patient presented intermittent fever and swallowing pain for 6 months, without response to conventional antibiotic treatment. Chest X-ray showedbilateral micronodular infiltrate, so hospitalization was decided to study and treat. The sputum examination for acid-fast resistant bacilli was positive and treatment with four antituberculous drugs was started, with good evolution and disappearance of symptoms. Diagnostic confirmation with the isolation of Mycobacterium tuberculosis in sputum culture was obtained. The main symptoms of pharyngeal tuberculosis are sore throat and difficulty in swallowing of long evolution. It is important to consider tuberculosis as differential diagnosis in patients with chronic pharyngitis unresponsive to conventional treatment.


Interventions for replacing missing teeth: hyperbaric oxygen therapy for irradiated patients who require dental implants.
Dental implants offer one way to replace missing teeth. Patients who have undergone radiotherapy and those who have also undergone surgery for cancer in the head and neck region may particularly benefit from reconstruction with implants. Hyperbaric oxygen therapy (HBO) has been advocated to improve the success of implant treatment in patients who have undergone radiotherapy but this remains a controversial issue. To compare the success, morbidity, patient satisfaction and cost effectiveness of dental implant treatment carried out with and without HBO in irradiated patients. The following electronic databases were searched: the Cochrane Oral Health Group's Trials Register (to 17 June 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 5), MEDLINE via OVID (1946 to 17 June 2013) and EMBASE via OVID (1980 to 17 June 2013). No restrictions were placed on the language or date of publication when searching the electronic databases. We checked the bibliographies of relevant clinical trials and review articles for studies outside the searched journals. We wrote to authors of the identified randomised controlled trials (RCTs) and to more than 55 oral implant manufacturers; we used personal contacts and we made a request on an internet discussion group in an attempt to identify unpublished or ongoing RCTs. Randomised controlled trials (RCTs) of HBO therapy for irradiated patients requiring dental implants. Screening of eligible studies, assessment of the methodological quality of the trials and data extraction were conducted in duplicate and independently by two review authors. Results were analysed using random-effects models to determine mean differences for continuous outcomes and risk ratios for dichotomous outcomes, with 95% confidence intervals. Only one RCT, providing very low quality evidence, was identified and included. Thirteen patients received HBO therapy while another 13 did not. Two to six implants were placed in people with fully edentulous mandibles to be rehabilitated with bar-retained overdentures. One year after implant loading, four patients had died from each group. One patient, treated with HBO, developed an osteoradionecrosis and lost all implants so the prosthesis could not be provided. Five patients in the HBO group had at least one implant failure versus two in the control group. There were no statistically significant differences for prosthesis and implant failures, postoperative complications and patient satisfaction between the two groups. Despite the limited amount of clinical research available, it appears that HBO therapy in irradiated patients requiring dental implants may not offer any appreciable clinical benefits. There is a definite need for more RCTs to ascertain the effectiveness of HBO in irradiated patients requiring dental implants. These trials ought to be of a high quality and reported as recommended by the CONSORT statement (www.consort-statement.org/). Each clinical centre may have limited numbers of patients and it is likely that trials will need to be multicentred.


pH-dependent coordination of Ag(I) ions by histidine: experiment, theory, and a model for SilE.
Artificial implants and biomaterials lack the natural defense system of our body and, thus, have to be protected from bacterial adhesion and biofilm formation. In addition to the increasing number of implanted objects, the resistance of bacteria is also an important problem. Silver ions are well-known for their antimicrobial properties, yet not a lot is known about their mode of action. Silver is expected to interact on many levels, thus the development of silver resistance is very difficult. Nevertheless, some bacteria are able to resist silver, even at higher concentrations. One such defense mechanism of bacteria against heavy-metal intoxication includes an efflux system. SilE, a periplasmic silver-binding protein that is involved in this defense mechanism, has been shown to possess numerous histidine functions, which strongly bind to silver atoms, as demonstrated by ourselves previously. Herein, we address the question of how histidine binds to silver ions as a function of pH value. This property is important because the local proton concentration in cells varies. Thus, we solved the crystal structures of histidine-silver complexes at different pH values and also investigated the influence of the amino-acid configuration. These results were completed by DFT calculations on the binding strength and packing effects and led to the development of a model for the mode of action of SilE.


[Physicochemical and immunochemical properties of heavy chains of immunoglobulin G typical of malignant growth].
Molecular weight of heavy chains of immunoglobulin G typical of cancer is studied immunoglobulin and may be responsible for manifestation of certain anomalous acid and peptide composition of this protein heavy chains as compared with immunoglobulin G in blood serum of healthy people. Immunochemical methods helped detecting an antigenic determinant (or determinants) which is arranged in the heavy chains of the studied immunoglobulin and may be responsible for manifestation of certain anomalous properties of cancer-typical immunoglobulin G molecules. A set of bromo-cyanogenic fragments differing from the spectrum of these fragments in the heavy chains of normal immunoglobulin G is formed following a specific chemical effect of bromo-cyanogen on the heavy chains of immunoglobulin G typical of cancer. Essential differences are found in dancyl-fingerprints of the heavy chains of the compared proteins. Everything mentioned is a result of changes in the primary structure of the heavy chains of immunoglobulin G typical of cancer.


Small Intestinal Lymphangioma Presenting as an Acute Abdomen with Relevant Review of Literature.
Cystic lymphangioma of small bowel mesentery is rare with clinical features ranging from an asymptomatic abdominal lump to acute intestinal obstruction. We discuss two cases of lymphangioma of small bowel mesentery who presented to us as acute intestinal obstruction. In the first case exploratory laparotomy revealed a large multicystic lesion arising from small bowel mesentery just distal to the duodenojejunal junction having multiple small cysts filled with milky white fluid. The involved region of the bowel was excised. The second case had a large multicystic lesion involving the mesentery of proximal jejunum, dudenojejunal junction, encasing the entire superior mesenteric vessels. For this patient, debulking was done.


Transmission of hand-arm vibration to the head.
A "tooth impression" was devised to measure head vibration. The vertical head vibration of four subjects was measured with the tooth impression during exposure of the hand to vertical sinusoidal vibration at acceleration levels of 3.15, 10.0, and 31.5 m/s2 root mean square in the range of 8-200 Hz. While in a standing position, the subjects pulled the vibrating handle upward at a force of 5 kg with the elbow joint stretched during the tests. The measurement was repeated twice. The difference between the two measurements was within 3 dB, a level which suggests that this method has good reproducibility. The vibration transmitted to the head was the greatest in the range of 12.5-16 Hz, and the attenuation was about 20 dB. Head vibration decreased by approximately 15 dB per octave at frequencies above 20 Hz as the frequency increased. When the excitation level was increased by 10 dB, the head vibration increased by about 8 dB.