Seroconfirmed Typhoid Fever and Knowledge, Attitude, and Practices among Febrile Patients Attending at Injibara General Hospital, Northwest Ethiopia.
Typhoid fever (TF) is a febrile global health problem caused by Salmonella enterica serovar Typhi (S. Typhi) with relatively high prevalence in low- and middle-income countries including Ethiopia. Identifying local prevalence and gaps in knowledge, attitude, and practice (KAP) towards TF is recommended by the World Health Organization to implement preventive measures. Therefore, this study determined the prevalence of S. Typhi and KAP of febrile patients towards TF in Injibara General Hospital, Northwest Ethiopia. Hospital-based cross-sectional study was conducted from January to March 2020. A total of 237 patients were included conveniently. Data on KAP and demographic variables were collected using a structured questionnaire by face-to-face interview. After the interview, 5 ml venous blood was collected and processed using the Widal test following the manufacturer's instruction. Mean scores and percentages were used to determine the level of KAP. Multivariable analysis was done to correlate KAPs with TF. P value < 0.05 was considered statistically significant. The overall prevalence of S. Typhi was 25.7%. The highest seroprevalence was observed among the age group of 30-34 years (33.3%) and patients with no education. The majority of participants know the major ways of TF transmission (59.1-90.7%) and prevention (81.4%) methods. However, the misconception on the route of TF transmission was observed in 13.5-36.7% of participants. About 65.4% and 67.5% of study participants were considered knowledgeable and had good preventive practice towards TF, respectively. Being a student (AOR = 0.227, CI = 0.053 - 0.965) and considering mosquito bite as transmission routes (AOR = 2.618, CI = 1.097 - 6.248) were significantly associated with TF. High S. Typhi prevalence was observed in the study area. Moreover, the misconception on the transmission of typhoid fever and educational level was a risk factor for TF. Thus, health facilities should incorporate topics on typhoid fever as part of their health education system within health facilities and in the community.


Infarction in the territory of the medial branch of the posterior inferior cerebellar artery.
We report 10 cases of cerebellar infarction in the territory of the medial branch of the posterior inferior cerebellar artery (mPICA). Axial sections on MRI through the middle of the medulla and the cerebellum showed the infarction as a triangular area with a dorsal base and a ventral apex directed towards the fourth ventricle. The infarct also involved the lateral and dorsal medulla when the mPICA supplied all or part of these regions. Three clinical patterns were observed: 1) pseudolabyrinthine signs with or without dysmetria and ataxia when the medulla was spared; marked axial lateropulsion was present in most cases; 2) complete or incomplete Wallenberg's syndrome, when the medulla was involved; 3) silent infarction. These syndromes are precisely those previously attributed to PICA occlusion without distinction of the branch involved. No alteration of consciousness was recorded and spontaneous recovery was the rule. Cerebellar infarction in the distribution of the mPICA can be regarded as a benign condition with a good prognosis.


Prevention of Staphylococcus aureus infections among surgical patients: beyond traditional perioperative prophylaxis.
Health care-related infections cause significant patient morbidity and mortality rates and add excess costs that frequently are not reimbursed. Staphylococcus aureus has long been recognized as an important pathogen in human disease and is the most common cause of nosocomial infections. The objective of this review of the English language literature and a MEDLINE search was to describe recent advances in the prevention of S aureus health care-related infections that are attributable to patients' endogenous colonization. The ecologic niche of S aureus is the anterior nares and nasal carriage increases the risk of the development of a surgical-site, lower respiratory tract, or bloodstream infection. S aureus carriers have a 2- to 9-fold increased risk of the development of a surgical-site or intravenous catheter infection. Three treatment strategies may eliminate nasal carriage: locally applied antibiotics or disinfectants, systemic antibiotics, and bacterial interference. Among these strategies, locally applied or systemic antibiotics are used most commonly. Nasal ointments or sprays and oral antibiotics have variable efficacy, and their use frequently results in antimicrobial resistance among S aureus strains. Of the commonly used agents, mupirocin (pseudomonic acid) ointment has been shown to be 97% effective in reducing S aureus nasal carriage. In a recently published randomized, double-blind, placebo-controlled trial to determine whether intranasal mupirocin reduced the rate of S aureus-infected surgical-site and other S aureus health care-related infections; 4% of S aureus nasal carriers who received mupirocin acquired S aureus health care-related infections compared with 7.7% of S aureus nasal carriers who received placebo (P=.02). The S aureus surgical-site infection rate was not reduced significantly, but carriers who received mupirocin before cardiothoracic or general surgery operations had almost 50% fewer S aureus surgical-site infections than carriers who received placebo. In this setting resistance rarely has been reported. Given the importance of S aureus nosocomial infections and the increased risk of S aureus nasal carriage in patients with health care-related infections, investigators must study cost-effective strategies to further prevent certain types of health care-related infections or nosocomial infections that occur in specific settings. One potential strategy is to decrease or eliminate S aureus nasal carriage among certain patient populations or in certain healthcare settings.


Verwey transition as evolution from electronic nematicity to trimerons via electron-phonon coupling.
Understanding the driving mechanisms behind metal-insulator transitions (MITs) is a critical step toward controlling material's properties. Since the proposal of charge order-induced MIT in magnetite Fe3O4 in 1939 by Verwey, the nature of the charge order and its role in the transition have remained elusive. Recently, a trimeron order was found in the low-temperature structure of Fe3O4; however, the expected transition entropy change in forming trimeron is greater than the observed value, which arises a reexamination of the ground state in the high-temperature phase. Here, we use electron diffraction to unveil that a nematic charge order on particular Fe sites emerges in the high-temperature structure of bulk Fe3O4 and that, upon cooling, a competitive intertwining of charge and lattice orders arouses the Verwey transition. Our findings discover an unconventional type of electronic nematicity in correlated materials and offer innovative insights into the transition mechanism in Fe3O4 via the electron-phonon coupling.


What Factors Influence Symptom Reporting and Access to Healthcare During an Emerging Infectious Disease Outbreak? A Rapid Review of the Evidence.
During any emerging infectious disease outbreak, people with symptoms of the illness are asked to report to a health service immediately to facilitate contact tracing. Several factors may influence a person's willingness to report symptoms and their ability to access healthcare services. Understanding these factors has become urgent during the COVID-19 pandemic. To determine which factors influence symptom reporting during an emerging infectious disease outbreak, we conducted a rapid review of the evidence. Studies included in the review were based on primary research, published in a peer-reviewed journal, written in English, included factors associated with symptom reporting or accessing healthcare, and were related to a major public health incident involving an infectious disease outbreak. Five themes were identified as facilitators of symptom reporting or accessing healthcare: accurate and informative communication about the disease and the need to seek help, symptom severity, concern about disease exposure, ease of access to healthcare facilities, and relationship with the healthcare provider. Seven themes were identified as barriers to symptom reporting or accessing healthcare: lack of knowledge of the disease and its treatment, fear of the disease and fear of subsequent treatments or requirements, stigmatization attached to having a disease, invasion of privacy, low concern about symptoms, economic consequences of disease diagnosis, and challenges related to attending a healthcare facility. For contract tracing services to be effective, members of the public need to have the capability, opportunity, and motivation to use them. The themes identified should be used to evaluate information provided to the public to ensure as many people as possible with relevant symptoms report them to a healthcare provider.


Sensor materials for the detection of human neutrophil elastase and cathepsin G activity in wound fluid.
Human neutrophil elastase (HNE) and cathepsin G (CatG) are involved in the pathogenesis of a number of inflammatory disorders. These serine proteinases are released by neutrophils and monocytes in case of infection. Wound infection is a severe complication regarding wound healing causing diagnostic and therapeutic problems. In this study we have shown the potential of HNE and CatG to be used as markers for early detection of infection. Significant differences in HNE and CatG levels in infected and non-infected wound fluids were observed. Peptide substrates for these two enzymes were successfully immobilised on different surfaces, including collagen, modified collagen, polyamide polyesters and silica gel. HNE and CatG activities were monitored directly in wound fluid via hydrolysis of the chromogenic substrates. Infected wound fluids led to significant higher substrate hydrolysis compared with non-infected ones. These different approaches could be used for the development of devices which are able to detect elevated enzyme activities before manifestation of infection directly on bandages. This would allow a timely intervention by medical doctors thus preventing severe infections.


RDRio Mycobacterium tuberculosis infection is associated with a higher frequency of cavitary pulmonary disease.
Molecular genotyping has shown Mycobacterium tuberculosis lineages to be geographically restricted and associated with distinct ethnic populations. Whether tuberculosis (TB) caused by some M. tuberculosis lineages can present with a differential clinical spectrum is controversial because of very limited clinical data. We recently reported on the discovery of RD(Rio) M. tuberculosis, a Latin American-Mediterranean sublineage that is the predominant cause of TB in Rio de Janeiro, Brazil. To investigate the clinical attributes of TB caused by RD(Rio) strains, we studied a cohort of TB cases from Belo Horizonte, Brazil, in which clinical information recorded on a standardized questionnaire was collected at the time of microbiological testing. These patients were referred for culture and drug susceptibility testing because of the clinical suspicion of "complicated" TB, as demonstrated by high rates of multidrug resistance (12%) and cavitary TB (80%). We performed spoligotyping and RD(Rio) genotyping on the M. tuberculosis strains and analyzed the clinical data from these patients. RD(Rio) M. tuberculosis accounted for 37% of the total TB burden. Multivariate analysis found a significant association between TB caused by RD(Rio) strains and pulmonary cavitation and residence in Belo Horizonte. Since cavitary TB is associated with higher sputum bacillary load, our findings support the hypothesis that RD(Rio) M. tuberculosis is associated with a more "severe" disease as a strategy to increase transmission. Future studies are needed to confirm these observations and to better define the contribution of RD(Rio) M. tuberculosis to the global TB epidemic.


Chromobodies to Quantify Changes of Endogenous Protein Concentration in Living Cells.
Understanding cellular processes requires the determination of dynamic changes in the concentration of genetically nonmodified, endogenous proteins, which, to date, is commonly accomplished by end-point assays in vitro Molecular probes such as fluorescently labeled nanobodies (chromobodies, CBs) are powerful tools to visualize the dynamic subcellular localization of endogenous proteins in living cells. Here, we employed the dependence of intracellular levels of chromobodies on the amount of their endogenous antigens, a phenomenon, which we termed antigen-mediated CB stabilization (AMCBS), for simultaneous monitoring of time-resolved changes in the concentration and localization of native proteins. To improve the dynamic range of AMCBS we generated turnover-accelerated CBs and demonstrated their application in visualization and quantification of fast reversible changes in antigen concentration upon compound treatment by quantitative live-cell imaging. We expect that this broadly applicable strategy will enable unprecedented insights into the dynamic regulation of proteins, e.g. during cellular signaling, cell differentiation, or upon drug action.


Pathological progress and remission strategies of osteoarthritic lesions caused by long-term joint immobilization.
While joint immobilization is a useful repair method for intra-articular ligament injury and periarticular fracture, prolonged joint immobilization can cause multiple complications. A better understanding how joint immobilization and remobilization impact joint function and homeostasis will help clinicians develop novel strategies to reduce complications. We first determined the effects of long-term immobilization on joint pain and osteophyte formation in patients after an extraarticular fracture or ligament injury. We then developed a mouse model of joint immobilization and harvested the knee joint samples at 2, 4, and 8 weeks. We further determined the effects of remobilization on recovery of the osteoarthritis (OA) lesions induced by immobilization in mice. We found that the long-term (6 weeks) joint immobilization caused significant joint pain and osteophytes in patients. In mice, 2-week immobilization already induced moderate sensory innervation and increased pain sensitivity and infiltration in synovium without inducing marked osteophyte formation and cartilage loss. Long-term immobilization (4 and 8 weeks) induced more severe sensory innervation and inflammatory infiltration in synovium, massive osteophyte formation on both sides of the femoral condyle, and the edge of the tibial plateau and significant loss of the articular cartilage in mice. Remobilization, which ameliorates normal joint load and activity, restored to certain extent some of the OA lesions and joint function in mice. Joint immobilization caused multiple OA-like lesions in both mice and humans. Joint immobilization induced progressive sensory innervation, synovitis, osteophyte formation, and cartilage loss in mice, which can be partially ameliorated by remobilization.


Silica Inverse Opal Nanostructured Sensors for Enhanced Immunodetection of Extracellular Vesicles by Quartz Crystal Microbalance with Dissipation Monitoring.
Extracellular vesicles (EVs) are nanosized circulating assemblies that contain biomarkers considered promising for early diagnosis within neurology, cardiology, and oncology. Recently, acoustic wave biosensors, in particular based on quartz crystal microbalance with dissipation monitoring (QCM-D), have emerged as a sensitive, label-free, and selective EV characterization platform. A rational approach to further improving sensing detection limits relies on the nanostructuration of the sensor surfaces. To this end, inorganic inverse opals (IOs) derived from colloidal self-assembly present a highly tunable and scalable nanoarchitecture of suitable feature sizes and surface chemistry. This work systematically investigates their use in two-dimensional (2D) and three-dimensional (3D) for enhanced QCM-D EV detection. Precise tuning of the architecture parameters delivered improvements in detection performance to sensitivities as low as 6.24 × 107 particles/mL. Our findings emphasize that attempts to enhance acoustic immunosensing via increasing the surface area by 3D nanostructuration need to be carefully analyzed in order to exclude solvent and artifact entrapment effects. Moreover, the use of 2D nanostructured electrodes to compartmentalize analyte anchoring presents a particularly promising design principle.


The impact of ABCC11 polymorphisms on the risk of early-onset fluoropyrimidine toxicity.
A missense variant (c.1637C>T, T546M) in ABCC11 encoding the MRP8 (multidrug resistance protein 8), a transporter of 5-fluorodeoxyuridine monophosphate, has been associated with an increased risk of 5-fluorouracil-related severe leukopenia. To validate this association, we investigated the impact of the ABCC11 variants c.1637C>T, c.538G>A and c.395+1087C>T on the risk of early-onset fluoropyrimidine-related toxicity in 514 cancer patients. The ABCC11 variant c.1637C>T was strongly associated with severe leukopenia in patients carrying risk variants in DPYD, encoding the key fluoropyrimidine-metabolizing enzyme dihydropyrimidine dehydrogenase (odds ratio (OR): 71.0; 95% confidence interval (CI): 2.5-2004.8; Pc.1637C>T*DPYD=0.013). In contrast, in patients without DPYD risk variants, no association with leukopenia (OR: 0.95; 95% CI: 0.34-2.6) or overall fluoropyrimidine-related toxicity (OR: 1.02; 95% CI: 0.5-2.1) was observed. Our study thus suggests that c.1637C>T affects fluoropyrimidine toxicity to leukocytes particularly in patients with high drug exposure, for example, because of reduced fluoropyrimidine catabolism.


Influence of neonatal idiopathic respiratory distress syndrome on serum enzyme activities in premature healthy and asphyxiated newborns.
Elevated serum aspartate aminotransferase (ASAT), lactate dehydrogenase (LDH), and hydroxybutyrate dehydrogenase (HBDH) activities are highly predictive for the development of hypoxia-related neurologic disorders in asphyxiated newborns. Little is known about the influence of the idiopathic respiratory distress syndrome (IRDS) on the serum profile of these enzymes. In a prospective study we measured ASAT, LDH, and HBDH activities in asphyxiated newborns with (n = 12) and without (n = 12) IRDS as well as non-asphyxiated newborns with IRDS (n = 16). Blood samples were taken serially at five fixed times: 0 (cord), 12, 24, 72, and 144 hours postpartum. Whereas both study groups of asphyxiated newborns showed significantly elevated enzyme activities as compared with the non-asphyxiated controls, the fundamental influence of perinatal hypoxic-ischemic events on neonatal serum enzyme profiles and activities of all three enzymes was not significantly altered by the development of IRDS. Therefore, the predictive value of these enzymes for the development of neurologic disorders in asphyxiated newborns is not adversely affected by the development of an immediately and effectively treated IRDS. It is concluded that elevated ASAT, LDH, and HBDH activities can be used as predictors for neurologic disorders in asphyxiated newborns even in the presence of IRDS.


Effect of (E)-5-(2-bromovinyl)-2'-deoxyuridine on several parameters of Epstein-Barr virus infection.
The selective and potent anti-herpesvirus drug, (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVdU), has been examined for its inhibitory effects on several parameters of Epstein-Barr virus (EBV) infection in the lymphoblastoid cell lines Raji, P3HR-1, B-95-8 and P3 hybrid cells (a human embryo oropharyngeal cell line fused with a nasopharyngeal carcinoma cell line). At a dosage of 0.03 to 0.1 mM, BVdU caused a marked inhibition of (i) spontaneous viral capsid antigen (VCA) expression in B-95-8 and P3 hybrid cells, (ii) VCA expression and DNA synthesis in B-95-8 cells induced with croton oil and n-butyrate, (iii) early antigen (EA) expression and DNA synthesis in Raji cells superinfected with EBV, and (iv) VCA expression and DNA synthesis in B-95-8 cells superinfected with EBV. In its inhibitory effects on these various parameters of EBV infection, BVdU appears to be comparable to acyclovir [9-(2-hydroxyethoxymethyl)guanine], another selective anti-herpesvirus drug which has been previously recognized as an effective inhibitor of EBV replication.


Neurovascular latissimus dorsi free-flap transfer for reconstruction of a major abdominal-wall defect in a 13-month-old child: late follow-up.
The authors present a late follow-up of a pediatric case originally reported in the Journal, involving a newborn with a left gastroschisis, exposure of the stomach, jejunum, and left colon. Subsequent to placement of silicone mesh, the child developed a nosocomial infection, which led to necrosis of the skin, subcutaneous tissue, and muscle. Post infection control, the abdominal viscera were covered with only skin and subcutaneous tissue. At 13 months, the abdominal-wall defect was reconstructed with a free latissimus dorsi microneurovascular flap. A current late follow-up at 9.5 years demonstrates mean normal growth, good abdominal-wall resistance and contraction, and caudal scar migration, with little visibility.


Abnormal cortical processing of the syllable rate of speech in poor readers.
Children with reading impairments have long been associated with impaired perception for rapidly presented acoustic stimuli and recently have shown deficits for slower features. It is not known whether impairments for low-frequency acoustic features negatively impact processing of speech in reading-impaired individuals. Here we provide neurophysiological evidence that poor readers have impaired representation of the speech envelope, the acoustical cue that provides syllable pattern information in speech. We measured cortical-evoked potentials in response to sentence stimuli and found that good readers indicated consistent right-hemisphere dominance in auditory cortex for all measures of speech envelope representation, including the precision, timing, and magnitude of cortical responses. Poor readers showed abnormal patterns of cerebral asymmetry for all measures of speech envelope representation. Moreover, cortical measures of speech envelope representation predicted up to 41% of the variability in standardized reading scores and 50% in measures of phonological processing across a wide range of abilities. Our findings strongly support a relationship between acoustic-level processing and higher-level language abilities, and are the first to link reading ability with cortical processing of low-frequency acoustic features in the speech signal. Our results also support the hypothesis that asymmetric routing between cerebral hemispheres represents an important mechanism for temporal encoding in the human auditory system, and the need for an expansion of the temporal processing hypothesis for reading disabilities to encompass impairments for a wider range of speech features than previously acknowledged.


Comparative evaluation of anesthetic efficacy of Gow-Gates mandibular conduction anesthesia, Vazirani-Akinosi technique, buccal-plus-lingual infiltrations, and conventional inferior alveolar nerve anesthesia in patients with irreversible pulpitis.
Conventional inferior alveolar nerve block (IANB) has a poor success rate in inflamed pulps. Three alternative techniques of providing anesthesia to mandibular molars were evaluated and compared with conventional IANB. Ninety-seven adult volunteer subjects, actively experiencing pain, participated in this prospective, randomized, double-blinded study. Twenty-five patients received Gow-Gates mandibular conduction block anesthesia, 24 patients received "high" Vazirani-Akinosi inferior alveolar nerve block, 26 received only buccal-plus-lingual infiltrations, and 22 patients (control) received conventional IANB anesthesia. Endodontic access preparation was initiated after 15 minutes of anesthesia. Pain during treatment was recorded using a Heft-Parker visual analog scale. Success was recorded for "none" or "mild" pain. Statistical analysis using nonparametric McNemer tests showed that Gow-Gates gave a success rate of 52%, which was statistically higher than control IANB (36%) (P < .05). Vazirani-Akinosi and infiltrations gave 41% and 27% success rates, respectively, with no statistically significant differences from control IANB. Gow-Gates mandibular conduction anesthesia may increase the success rates in patients with irreversible pulpitis compared with conventional IANB. None of the techniques provided acceptable success rates.


Nanoparticles target intimal macrophages in atherosclerotic lesions.
Oxidized phosphatidylcholines (oxPCs) enriched on the oxidized LDL (oxLDL) surface are responsible ligands for binding oxLDL to the CD36 receptor of intimal macrophages in atherosclerotic lesions. We synthesized liposome-like nanoparticles (NPs) using soy phosphatidylcholine and incorporated 1-palmitoyl-2-(4-keto-dodec-3-enedioyl) phosphatidylcholine, a type of oxPCs, on their surface to make ligand-NP (L-NPs). The objectives of this study were to measure and compare their binding affinity to and uptake by primary mouse and THP-1 derived macrophages, and to determine their target specificity to intimal macrophages in aortic lesions in LDL receptor null (LDLr-/-) mice. All in vitro data demonstrate that L-NPs had a high binding affinity to macrophage CD36 receptor. L-NPs had 1.4-fold higher accumulation in aortic lesion areas than NPs. L-NPs co-localized with intimal macrophages and CD36 receptors in the aortic lesions. This target delivery approach may portend a breakthrough in molecular imaging and targeted treatment of atherosclerosis.


Cerebral intravascular oxygenation correlates with mean arterial pressure in critically ill premature infants.
Premature infants experience brain injury, ie, germinal matrix-intraventricular hemorrhage (GMH-IVH) and periventricular leukomalacia (PVL), in considerable part because of disturbances in cerebral blood flow (CBF). Because such infants are susceptible to major fluctuations in mean arterial blood pressure (MAP), impaired cerebrovascular autoregulation would increase the likelihood for the changes in CBF that could result in GMH-IVH and PVL. The objectives of this study were to determine whether a state of impaired cerebrovascular autoregulation could be identified reliably and conveniently at the bedside, the frequency of any such impairment, and the relation of the impairment to the subsequent occurrence of severe GMH-IVH and PVL. To monitor the cerebral circulation continuously and noninvasively, we used near-infrared spectroscopy (NIRS) to determine quantitative changes in cerebral concentrations of oxygenated hemoglobin (HbO(2)) and deoxygenated hemoglobin (Hb) from the first hours of life. Our previous experimental study showed a strong correlation between a measure of cerebral intravascular oxygenation (HbD), ie, HbD = HbO(2) - Hb, determined by NIRS, and volemic CBF, determined by radioactive microspheres. We studied 32 very low birth weight premature infants (gestational age: 23-31 weeks; birth weight: 605-1870 g) requiring mechanical ventilation, supplemental oxygen, and invasive blood pressure monitoring by NIRS from 1 to 3 days of age. MAP measured by arterial catheter pressure transducer and arterial oxygen saturation measured by pulse oximetry were recorded simultaneously. The relationship of MAP to HbD was quantitated by coherence analysis. Concordant changes (coherence scores >. 5) in HbD and MAP, consistent with impaired cerebrovascular autoregulation, were observed in 17 of the 32 infants (53%). Eight of the 17 infants (47%) developed severe GMH-IVH or PVL or both. Of the 15 infants with apparently intact autoregulation, ie, coherence scores <.5, only 2 (13%) developed severe ultrasonographic lesions. Thus, for the entire study population of 32 infants, 8 of the 10 with severe lesions exhibited coherence scores >.5. We conclude that NIRS can be used in a noninvasive manner at the bedside to identify premature infants with impaired cerebrovascular autoregulation, that this impairment is relatively common in such infants, and that the presence of this impairment is associated with a high likelihood of occurrence of severe GMH-IVH/PVL.


Distraction osteogenesis of the mandible for airway obstruction in children: long-term results.
To determine the long-term results of distraction osteogenesis of the mandible for upper airway obstruction in children with micrognathia. Case series with chart review. Tertiary care children's hospital. The records of a pediatric otolaryngology practice and tertiary children's hospital were searched for patients treated with bilateral mandibular distraction osteogenesis for upper airway obstruction. Patients were selected if greater than three years of follow-up data were available. Data were analyzed for airway and feeding outcomes, and long-term surgical complications were identified. Thirty-two patients met study criteria. Of the 11 patients who had tracheotomy prior to distraction, seven were decannulated after the procedure. Seventeen patients needed perioperative gastrostomy. Seven are now able to feed orally. Fifteen patients treated with mandibular distraction were able to avoid gastrostomy tube placement altogether. The complication of open bite deformity was experienced by nine patients (28%). Five of 32 patients (16%) had tooth malformation, tooth loss, or dentigerous cyst formation while an additional three patients (9%) had long-term facial nerve injury. Nineteen patients (59%) were under three months old at the time of their distraction. Only one of these patients (5.2%) required an additional distraction procedure. Long-term follow-up data on patients treated with mandibular distraction for upper airway obstruction show sustained airway improvement. Additionally, micrognathic children treated with distraction have improved outcomes in oral feeding with a relatively low rate of long-term complications. It remains important to follow these patients to monitor the need for secondary reconstructive procedures.


Impaired physiological responses to chronic hypoxia in mice partially deficient for hypoxia-inducible factor 1alpha.
Chronic hypoxia induces polycythemia, pulmonary hypertension, right ventricular hypertrophy, and weight loss. Hypoxia-inducible factor 1 (HIF-1) activates transcription of genes encoding proteins that mediate adaptive responses to hypoxia, including erythropoietin, vascular endothelial growth factor, and glycolytic enzymes. Expression of the HIF-1alpha subunit increases exponentially as O2 concentration is decreased. Hif1a-/- mouse embryos with complete deficiency of HIF-1alpha due to homozygosity for a null allele at the Hif1a locus die at midgestation, with multiple cardiovascular malformations and mesenchymal cell death. Hif1a+/- heterozygotes develop normally and are indistinguishable from Hif1a+/+ wild-type littermates when maintained under normoxic conditions. In this study, the physiological responses of Hif1a+/- and Hif1a+/+ mice exposed to 10% O2 for one to six weeks were analyzed. Hif1a+/- mice demonstrated significantly delayed development of polycythemia, right ventricular hypertrophy, pulmonary hypertension, and pulmonary vascular remodeling and significantly greater weight loss compared with wild-type littermates. These results indicate that partial HIF-1alpha deficiency has significant effects on multiple systemic responses to chronic hypoxia.


Family-based therapy for adolescent drug abuse: knowns and unknowns.
Family-based therapy is one of the most thoroughly studied treatments for adolescent drug abuse. Considerable empirical support exists for the efficacy of family-based therapy in curtailing adolescent drug use and cooccurring behavior problems. This article extends knowledge of the effects of family-based therapy for adolescent drug abuse by reviewing 16 controlled trials and 4 therapy process studies from a treatment development perspective. We articulate "knowns and unknowns" regarding the outcomes of treatment as well as the components, processes, mechanisms, moderators, and boundaries of effective family-based therapy for adolescent drug abuse. The review highlights areas of progress and future research needs within the specialty of family-based therapy for adolescent drug abuse.


[Computed tomography of intra-articular calcaneal fractures].
The increasing number of operations on intraarticular calcaneal fractures created the need for a fast, reproducible method to examine the weight-bearing posterior talo-calcaneal joint. High resolution CT scanning in an almost coronal plane without reformating was done in 25 calcaneal fractures. Joint alignment and fragment dislocation were demonstrated more precisely than would have been possible with conventional studies. Three typical fractures were found: The lambda type, the y type and the comminution type. Follow-up studies showed osteo-arthritis, intraarticular degenerative changes of the articular surface and impingement of personeal tendons as possible causes of pain.


Isolation and identification of the major concanavalin A binding glycoproteins from murine-lymphocytes.
The major glycoproteins which bind concanavalin A have been isolated and identified from murine spleen cells, thymocytes,and purified thymus-derived (T) lymphocytes, and from the spleen cells of congenitally athymic (nude) mice. The cells were radiolabeled by lactoperoxidase catalyzed 125I iodination or by culturing the cells in media containing [3H]leucine or [3H]fucose. The cell membrane was solubilized with Nonidet P-40 and the concanavalin A binding proteins were isolated by affinity chromatography and analyzed according to their mobility on polyacrylamide gel electrophoresis in sodium dodecyl sulfate. The major proteins from various lymphocyte preparations were identified by immunoprecipitation with specific antisera. The molecules coded by the histocompatibility-2 complex acted as concanavalin A binding proteins H-2K and H-2D were isolated from T lymphocytes, thymocytes, and bone marrow derived (B) lymphocytes. The Ia antigens were identified from B lymphocytes and tentatively identified from T lymphocytes. In addition to these H-2 complex proteins, immunoglobulin M and D on B lymphocytes also bound concanavalin A binding. All these glycoproteins have previously been identified as cell surface molecules. The presence of certain minor unidentified concanavalin A binding proteins on lymphoid cells is indicated.


Transitions to adulthood and psychological distress in young adults born 12 years apart: constraints on and resources for development.
Later transitions to adult roles and responsibilities have been linked with better psychological well-being yet psychological distress has risen despite young people making the transition to adulthood at older ages over recent years. We examine the role of structural constraints and adolescent resources in the relationship between the timing of transitions and psychological distress in early adult life in the 1958 National Child Development Study and the 1970 British Cohort Study. Graphical chain models were used to examine the influences on timing of four key transitions and their relationship with psychological distress (Malaise Inventory). The role of structural factors at birth (gender, social class) and adolescent resources (psychosocial problems, exam grades) were modelled. An earlier transition to adult roles was associated with an increased risk for psychological distress but so was failing to make some key transitions. Structural constraints had negative effects on successful development. Persistent social class and gender inequalities in psychological distress were evident in both cohorts. Social class constraints were mediated by educational resources whereas gender constraints were mediated by psychosocial resources. The influence of structural constraints on the timing of transitions to adult roles was more complex with evidence of positive and negative mediation and moderation effects. Delaying transition to adulthood promotes psychological health but failure of transition to independent living is associated with psychological distress. Life-course transitions are constrained by social origin and gender and possibly economic environment. Adolescent resources help young adults to make timely transitions to adult roles.


Immunolocalization and partial characterization of a nucleolar autoantigen (PM-Scl) associated with polymyositis/scleroderma overlap syndromes.
Precipitating anti-PM-Scl antibodies are present in sera from patients with polymyositis, scleroderma, and polymyositis/scleroderma overlap syndromes. By indirect immunofluorescence microscopy, anti-PM-Scl antibodies stained the nucleolus in cells of different tissues and species, suggesting that the antigen is highly conserved. By electron microscopy, anti-PM-Scl antibodies reacted primarily with the granular component of the nucleolus. Drugs that inhibit rRNA synthesis had a marked effect on the expression of PM-Scl antigen. In actinomycin D-treated cells, immunofluorescence staining by anti-PM-Scl was significantly reduced with residual staining restricted to the granular regions of nucleoli. Treatment with 5,6-dichloro-beta-D-ribofuranosylbenzimidazole (DRB) also selectively reduced nucleolar staining. On a molecular level, anti-PM-Scl antibodies precipitated 11 polypeptides with molecular weights (Mr) ranging from 110,000 to 20,000. The Mr 80,000 and 20,000 polypeptides were phosphorylated. Evidence suggests that the PM-Scl antigen complex may be related to a preribosomal particle.


Snakebite Mitigation Project of the Madras Crocodile Bank/Centre for Herpetology, India: background and a brief summary of activities.
Snakebite is a serious problem in rural India where several highly venomous species are commonly found in and around agricultural areas where prey such as rodents and amphibians are abundant. Four snake species, referred to as the Big Four, are responsible for the most serious and fatal bites: spectacled cobra (Naja naja), Russell's viper (Daboia russelii), common krait (Bungarus caeruleus) and saw-scaled viper (Echis carinatus). A polyvalent antivenom is made to treat these bites but public awareness and distribution of this life-saving drug is inadequate. The Madras Crocodile Bank and its partners are conducting a snakebite project which includes venom sampling and research, snake and snakebite treatment centre mapping, and a nationwide awareness campaign for snakebite mitigation.


Symmorphosis in the proximal pathway for oxygen in the leaf-eared mouse Phyllotis darwini.
In this report, we explore the matching of structures to functional needs by comparing previously reported data of maximal oxygen consumption and the development of the lung in the leaf-eared mouse Phyllotis darwini in warm and cold environments. We discuss whether the state of structural design is commensurate with functional needs from regulated morphogenesis as predicted by the hypothesis of symmorphosis. We found a close match between respiratory structures and functional needs during postnatal development, expressed as safety factors close to unity. However, in the adult stage the safety factors were greater than two, which suggests that adult animals acquired a structure greater than that required considering their maximum capacities. A high safety factor in the respiratory system of adult mice may be a consequence of the symmorphosis that operates during ontogeny and does not necessarily support a rejection of this hypothesis.


Stool calprotectin monitoring after small intestine transplantation.
Small intestine transplantation is the only life-saving therapy available for patients with intestinal failure and life-threatening complications of parenteral nutrition, but it is still plagued by high levels of early acute rejection. The ability to diagnose rejection noninvasively, ideally before pathologic manifestations, would be a major advance in the care of intestinal transplant patients. We measured calprotectin levels in 732 stool samples collected, analyzed over from 72 patients having undergone 74 total transplants, and correlated them with clinical indications, ostomy output, and pathologic findings. We found that overall patients with rejection have higher mean levels of stool calprotectin than those without, but because of significant interpatient variability, defining an effective general "cutoff" for the test is difficult. Each patient, in effect, has to act as their own control. Patients experiencing rejection episodes have greater fluctuations in calprotectin levels than those without, suggesting increased "reactivity" within the graft. Our most frequent clinical indicator for biopsy, an increase in ostomy output, had no real relationship to the discovery of rejection. Although more frequent prospective sampling could perhaps demonstrate an advantage in early indication of rejection, based on these data, routine stool calprotectin monitoring is not strongly supported.


Improving child protection: a systematic review of training and procedural interventions.
To synthesise published evidence regarding the effectiveness of training and procedural interventions aimed at improving the identification and management of child abuse and neglect by health professionals. Systematic review for the period 1994 to 2005 of studies that evaluated child protection training and procedural interventions. Main outcome measures were learning achievement, attitudinal change, and clinical behaviour. Seven papers that examined the effectiveness of procedural interventions and 15 papers that evaluated training programmes met the inclusion criteria. Critical appraisal showed that evaluation of interventions was on the whole poor. It was found that certain procedural interventions (such as the use of checklists and structured forms) can result in improved recording of important clinical information and may also alert clinical staff to the possibility of abuse. While a variety of innovative training programmes were identified, there was an absence of rigorous evaluation of their impact. However a small number of one-group pre- and post-studies suggest improvements in a range of attitudes necessary for successful engagement in the child protection process. Current evidence supports the use of procedural changes that improve the documentation of suspected child maltreatment and that enhance professional awareness. The lack of an evidence based approach to the implementation of child protection training may restrict the ability of all health professionals to fulfil their role in the child protection process. Formal evaluation of a variety of models for the delivery of this training is urgently needed with subsequent dissemination of results that highlight those found to be most effective.


Biomass cooking fuels and prevalence of tuberculosis in India.
To examine the relation between use of biomass cooking fuels (wood or dung) and prevalence of active tuberculosis in India. The analysis is based on 260,162 persons age 20 and over in India's 1992-93 National Family Health Survey. Logistic regression is used to estimate the effects of biomass fuel use on prevalence of active tuberculosis, as reported by household heads, after controlling for a number of potentially confounding variables. Persons living in households that primarily use biomass for cooking fuel have substantially higher prevalence of active tuberculosis than persons living in households that use cleaner fuels (odds ratio [OR] = 3.56; 95% confidence interval [CI] = 2.82-4. 50). This effect is reduced somewhat when availability of a separate kitchen, house type, indoor crowding, age, gender, urban or rural residence, education, religion, caste or tribe, and geographic region are statistically controlled (OR = 2.58; 95% CI = 1.98-3.37). Fuel type also has a large effect when the analysis is done separately for men (OR = 2.46; 95% CI = 1.79-3.39) and women (OR = 2. 74; 95% CI = 1.86-4.05) and separately for urban areas (OR = 2.29; 95% CI = 1.61-3.23) and rural areas (OR = 2.65; 95% CI = 1.74-4.03). The analysis also indicates that, among persons age 20 years and over, 51% of the prevalence of active tuberculosis is attributable to cooking smoke. Results strongly suggest that use of biomass fuels for cooking substantially increases the risk of tuberculosis in India.


Adipose tissue progenitor cells directly interact with endothelial cells to induce vascular network formation.
Adipose stromal cells (ASCs) express markers and functional properties of pericytes in vitro and, in combination with endothelial cells (ECs), are able to establish multilayer functional vessels in vivo. However, the factors that coordinate EC-ASC communications to promote migration of these cells toward one another, and their heterotypic assembly into vascular structures are not well defined. To understand the mechanisms of EC-ASC interaction, we developed an in vitro model of coculturing ECs with ASCs in a system containing serum but no additional exogenous cytokines or extracellular matrix (ECM) proteins. We demonstrated that ASCs have a profound potential to stimulate morphogenesis of ECs into branching networks of cord structures. The vascular networks developed in 6 days and were stable for at least 3 weeks. This process was associated with an increase in ECM protein production by ASCs and ECs, alpha-smooth muscle actin expression by ASCs, and increased CD31/platelet endothelial cell adhesion molecule-1 (PECAM-1) surface presentation by ECs. The vascular network formation (VNF) was dependent on matrix metalloproteinase activity and cell communications through vascular endothelial growth factor, hepatocyte growth factor, and platelet-derived growth factor-BB pathways. ASCs exhibited significantly higher potential to stimulate VNF than smooth muscle cells and fibroblasts. Media conditioned by ASCs promoted VNF by ECs cultured on smooth muscle cells and fibroblasts, but could not replace the presence of ASCs in coculture. The presence of ASCs in EC-fibroblast cocultures in a low fraction efficiently stimulated VNF. These findings demonstrate that the vasculogenesis-promoting potential of ASCs depends on interaction with ECs involving contact and likely bi-directional interaction, resulting in modulated secretion of cytokines and ECM proteins.


Approaches targeting the type III secretion system to treat or prevent bacterial infections.
The type III secretion system (T3SS) injectisome is an essential virulence mechanism used by many bacterial pathogens to inject host cells with effector proteins. Bacteria harboring T3SSs can cause significant disease in humans. As bacterial antibiotic resistance is a major concern, alternative prophylaxis and therapeutics are needed and T3SSs are a target for anti-virulence drugs. In this article, the authors review whole-cell-based high-throughput screens (HTSs), which have been the main approach used to identify small molecules inhibiting T3SSs. The authors review this in the context of particular characteristics of T3SSs. Furthermore, they also describe the follow-up approaches used to study the inhibitors found. The authors also highlight target-based approaches to find inhibitors of specific T3SS components. Finally, the authors briefly review strategies used to find inhibitors of effectors or of effector-activated host cell pathways, and approaches based on T3SSs for active or passive immunization and rational vaccine design. Future efforts targeting T3SS to prevent or treat bacterial infections should focus on deciphering the mode of action of inhibitors and on target-based approaches. The aim should not only be to find anti-T3SS drugs but also to develop novel or improved vaccines. Continuous efforts to understand many remaining fundamental questions about the structure and function of T3SSs will also be needed.


Staff Views of an Emergency Department Intervention Using Safety Planning and Structured Follow-Up with Suicidal Veterans.
The objective of this study is to summarize staff perceptions of the acceptability and utility of the safety planning and structured post-discharge follow-up contact intervention (SPI-SFU), a suicide prevention intervention that was implemented and tested in five Veterans Affairs Medical Center emergency departments (EDs). A purposive sampling approach was used to identify 50 staff member key informants. Interviews were transcribed and coded using thematic analysis. Almost all staff perceived the intervention as helpful in connecting SPI-SFU participants to follow-up services. A slight majority of staff believed SPI-SFU increased Veteran safety. Staff members also benefited from the implementation of SPI-SFU. Their comfort discharging Veterans at some suicide risk increased. SPI-SFU provides an appealing option for improving suicide prevention services in acute care settings.


CrossFit and the Epidemiology of Musculoskeletal Injuries: A Prospective 12-Week Cohort Study.
Despite the increasing international popularity of CrossFit, there is a paucity of scientific evidence on the risk of CrossFit-related musculoskeletal injuries (CRMIs). To investigate the incidence (cumulative incidence proportion [IP] and incidence density [ID]) of CRMIs and the association of CRMIs with personal and training characteristics. Descriptive epidemiology study. A prospective, 12-week descriptive epidemiology cohort study was conducted in a convenience sample of CrossFit facilities in a single Brazilian city. Printed baseline questionnaires were distributed to 13 CrossFit boxes. All participants who filled out the questionnaire and consented to participate in the study were invited to respond to an online follow-up questionnaire every 2 weeks to collect data on CrossFit training characteristics and CRMIs. A CRMI was defined as any self-reported musculoskeletal injury or pain that prevented an athlete from exercising for at least 1 day. The IP was defined as the number of new cases divided by the entire population at risk, while the ID was defined as new events divided by the total person-time exposure in hours. Logistic mixed models were developed to investigate the association of CRMIs with personal and training characteristics. A total of 515 CrossFit participants filled out the baseline questionnaire and provided informed consent, and 406 (78.8%) completed at least 1 follow-up measure. There were 133 participants who reported at least 1 CRMI during the study, and a total of 247 unique and new CRMIs were reported over a total estimated person-time exposure to CrossFit of 13,041 hours. The IP was 32.8% (95% CI, 28.4%-37.5%). The ID was 18.9 (95% CI, 16.6-21.3) per 1000 hours of CrossFit exposure. The shoulders (19.0%; n = 47) and lumbar spine (15.0%; n = 37) were most affected. Muscle injuries (45.3%; n = 112) and joint pain (24.7%; n = 61) were the most common CRMI types reported. Switching between prescribed and scaled down training loads (odds ratio [OR], 3.5 [95% CI, 1.7-7.3]) and previous injuries (OR, 3.2 [95% CI, 1.4-7.7]) were risk factors for a CRMI, while CrossFit experience was identified as a protective factor (OR, 0.7 [95% CI, 0.5-1.0]). In this 12-week prospective study, the ID was 18.9 CRMIs per 1000 hours of exposure; switching between training loads and previous injuries was associated with 3.5- and 3.2-fold higher odds, respectively, of sustaining CRMIs.


Site-directed mutagenesis of a Saccharomyces cerevisiae mitochondrial translation initiation codon.
We have used a generally applicable strategy for gene replacement in yeast mitochondria to mutate the translation initiation codon of the COX3 gene from AUG to AUA. The mutation, cox3-1, substantially reduced, but did not eliminate, translation of cytochrome c oxidase subunit III (coxIII). Strains bearing the mutation exhibited a leaky (partial) nonrespiratory growth phenotype and a reduced incorporation of radiolabeled amino acids into coxIII in vivo in the presence of cycloheximide. Hybridization experiments demonstrated that the mutation had little or no effect on levels of the COX3 mRNA. Residual translation of the cox3-1 mutant mRNA was dependent upon the three nuclearly coded mRNA-specific activators PET494, PET54 and PET122, known from previous studies to work through a site (or sites) upstream of the initiation codon to promote translation of the wild-type mRNA. Furthermore, respiratory growth of cox3-1 mutant strains was sensitive to decreased dosage of genes PET494 and PET122 in heterozygous mutant diploids, unlike the growth of strains carrying wild-type mtDNA. Some residual translation of the cox3-1 mRNA appeared to initiate at the mutant AUA codon, despite the fact that the 610-base 5'-mRNA leader contains numerous AUA triplets. We conclude that, while AUG is an important component of the COX3 translation initiation site, the site probably is also specified by other sequence or structural features.


[Effect of a "running" pulse magnetic field on certain humoral indicators and physical ability to work in patients with neurocirculatory hypo- and hypertension].
The influence of "running" impulse magnetic field in patients with neurocirculatory hypo- and hypertension was studied. It has been determined that magnetotherapy in all patients increased physical load tolerability and at the same time produced different effects on hemodynamics (lowering blood pressure in hypertension and increasing it in hypotension). In patients with neurocirculatory hypotension the slightly expressed positive clinical effect was obtained, that makes "running" impulse magnetic field therapy useless in this pathology. At the same time in patients with neurocirculatory hypertension "running" impulse magnetic field therapy resulted in significant improvement of physical tolerability, improvement of patients general condition, blood pressure decrease, lowering of pressor power generation concentration, correcting effect on aldosterone blood content. These data witness for the usefulness of this method in treatment of patients with neurocirculatory hypertension.


Long-term differential modulation of genes encoding orexigenic and anorexigenic peptides by leptin delivered by rAAV vector in ob/ob mice. Relationship with body weight change.
We investigated the long-term effects of physiological levels of leptin produced by gene therapy on body weight (BW) and expression of genes that encode orexigenic and anorexigenic peptides in the hypothalamus. Recombinant adeno-associated viral vector (rAAV), a non-pathogenic and non-immunogenic vector, encoding leptin (betaOb) was generated and administered iv to ob/ob mice lacking endogenous leptin. Whereas the lowest dose of rAAV-betaOb (6x10(9) particles) was ineffective, the middle dose (6x10(10) particles) curbed BW gain without affecting food consumption for 75 days of observation. A ten-fold higher dose (6x10(11) particles) resulted in increased blood leptin levels and suppressed both BW gain and food consumption throughout the duration of the experiment. rAAV-betaOb doses that either curbed BW without affecting food consumption or evoked BW loss and reduced food intake, decreased the expression of genes encoding the orexigenic peptides, neuropeptide Y and agouti-related peptide in the ARC, and the two doses were equally effective. Concomitantly, the expression of genes encoding the anorexigenic peptide, alpha-melanocyte stimulating hormone and cocaine-and-amphetamine regulatory transcript, was augmented with the latter gene displaying a dose-dependant response. These results document the efficacy of delivering biologically active leptin for extended periods by an iv injection of rAAV-betaOb and show that physiological leptin concentrations simultaneously exert a tonic inhibitory effect on orexigenic and a stimulatory effect on anorexigenic signaling in the hypothalamus. This intricate dynamic interplay induced by leptin regulates BW with or without an effect on food intake in leptin-deficient ob/ob mice. Further, these results suggest that gene therapy is an effective mode of delivery to the hypothalamus of those therapeutic proteins that cross the blood-brain barrier to ameliorate neuroendocrine disorders.


Myxobolus pseudowulii sp. n. (Myxozoa: Myxosporea), a new skin parasite of yellow catfish Tachysurus fulvidraco (Richardson) and redescription of Myxobolus voremkhai (Akhmerov, 1960).
Two species of Myxobolus Bütschli, 1882 were found in yellow catfish Tachysurus fulvidraco (Richardson). A species of Myxobolus infecting the gills was morphologically identified as Myxobolus voremkhai (Akhmerov, 1960) and it was characterised here with additional morphological and molecular data. The other species of Myxobolus infecting the host's skin did not conform to any known myxosporean species. It is characterised by the presence of round, black or milky white plasmodia with black spots. Myxospores are pyriform in frontal view and lemon-shaped in lateral view, measuring 12.9-16.2 μm (14.6 ± 0.7 μm) in length, 8.1-10.8 μm (9.4 ± 0.5 μm) in width, and 6.1-8.1 μm (7.0 ± 0.4 μm) in thickness. Two ampullaceous polar capsules are slightly unequal in size, larger polar capsule 7.2-9.5 μm (7.9 ± 0.4 μm) long by 3.0-3.9 μm (3.5 ± 0.2 μm) wide, smaller capsule 6.9-8.0 μm (7.4 ± 0.3 μm) long by 2.9-3.9 μm (3.4 ± 0.2 μm) wide. Polar filaments are coiled with seven to nine turns. Histologically, the plasmodia develop in the stratum spongiosum of skin dermis, resulting in epithelial cell shedding and immunological cell infiltration. Given the morphological and molecular differences between this species and other species of Myxobolus, we proposed the name of Myxobolus pseudowulii sp. n. for this parasite from the skin of yellow catfish. Interestingly, some spores of the new species possess Henneguya-like caudal appendages. Phylogenetically, M. pseudowulii sp. n. and M. voremkhai infecting yellow catfish group together in one clade with other parasites of Siluriformes, indicating that parasites clustering according to the fish host order may be an important factor affecting the evolution of species within the Myxobolus clade.


Genetics of polycystic ovarian syndrome.
Polycystic ovarian syndrome (PCOS) is a reproductive system disorder characterized by irregular menses, anovulation, clinical and/or biochemical signs of hyperandrogenism (hirsutism and/or acne), ovarian micropolycystic appearance and metabolic abnormalities, such as hyperinsulinaemia and obesity. The aetiopathogenesis of this syndrome is not well known. Several pathogenetic hypotheses have been proposed to explain the full array of symptoms and signs, but with elusive results. A genetic abnormality causing PCOS is supported by the observation that different members of the same family are often affected, and about half of the sisters of PCOS women have elevated serum testosterone concentrations. Therefore, the presence of gene abnormalities in women with PCOS has been widely explored in the attempt to establish whether their mutations or polymorphisms may cause PCOS. The main genes evaluated are those involved in steroidogenesis, steroid hormone effects, gonadotrophin release regulation and action, insulin secretion and action, and adipose tissue metabolism. Despite the vast body of literature produced, none of the genes evaluated seems to play a key role in PCOS pathogenesis. It is likely that PCOS may represent the final outcome of different, deeply inter-related genetic abnormalities that influence each other and perpetuate the syndrome.


Antigen competition: a paradox.
Immunization of mice with pig erythrocytes caused impairment of the antibody response to subsequent immunization with sheep erythrocytes, a phenomenon called "antigen competition." Paradoxically, spleen cells from mice previously injected with pig erythrocytes produced an increased response when immunized in vitro with sheep erythrocytes. Augmentation of the in vitro response is due to an increase in one of the interacting cell types. "Antigen competition" is not due to competition for cells. Cell transfer experiments provided evidence that "antigen competition" observed in animals is the result of a humoral factor, presumably antibody, present in the animal but eliminated during preparation of cells for culture.


Meta-analysis of dry cow management for dairy cattle. Part 2. Cure of existing intramammary infections.
The main goal of dry cow therapy (DCT) is to cure existing intramammary infections (IMI) at dry off. Although several published studies have estimated the cure rate of IMI after DCT, variation among studies is great, which makes it difficult to conduct a proper economic evaluation of DCT. The objective of the present meta-analysis of existing peer-reviewed literature was to provide a summary quantification of quarter IMI cure based on DCT. A meta-analysis relative risk (RR) was calculated per intervention and pathogen group when at least 4 studies were available for analysis per comparison from the 22 selected studies, according to the selection criteria. Results of the meta-analysis were examined using publication bias tests. Blanket DCT with a 95% confidence interval (CI) provided a 1.78 (1.51 to 2.10) times higher calculated cure rate from quarter IMI during the dry period up to 21 d postcalving, compared with no DCT. The RR of cure was similar when treatment was conducted for Streptococcus spp. IMI quarters compared with Staphylococcus spp. IMI quarters. The pooled RR with the 95% CI were 1.83 (1.48 to 2.35) and 1.65 (1.38 to 1.96), respectively. There was no significant difference between cloxacillin and other DCT products in the cure of quarter IMI during the dry period up to 21 d postcalving. The pooled RR with the 95% CI was 1.00 (0.92 to 1.09). Similarly, there was no significant difference between cloxacillin and other DCT products in the cure of quarter Staphylococcus spp. IMI. The pooled RR with the 95% CI was 1.00 (0.96 to 1.06). The pooled RR with the 95% CI of quarter IMI cure using selective DCT, compared with no DCT, was 1.76 (1.23 to 2.54).


[Chronic venous insufficiency. Results of duplex scanning of 205 lower extremities with varices: 106 not previously operated and 99 previously operated for varicose veins].
The aim of this study was to establish the value of color-duplex scanning in a group of patients with varicose veins and another group of patients with with recurrent varicose veins. During a 6-month period, 170 patients with varicose veins were examined: one group of 106 lower extremities and another group of 99 lower extremities previously operated for varicose veins. The material included 102 women and 68 men with a mean age of 48 years. The patients were classified according to oedema, lipodermatosclerosis, healed and active ulcer. A Diasonic Gateway 2 and 5 MHz scanner head were used for the examination of the patients in a standing position in the groin, midthigh and in the popliteal fossa. Reflux in the superficial and deep venous system, obstruction in the deep system and insufficient operation were recorded. In the non-operated group 84% of the varicose veins were classified as primary. Three of four ulcers belonged to that group. In the operated group 42% of the cases were due to insufficient treatment. In 33% new sites with reflux were classified. Five of six ulcers could be ascribed to deep venous insufficiency. Color-duplex scanning is applicable for the determination of the anatomic placement of the chronic venous insufficiency in patients with varicose veins, previously operated or non-operated. In this material 80% of lower extremities could be selected to a possible operation. Operation of the remaining cases would be worthless.


Association between perioperative hypotension and postoperative delirium and atrial fibrillation after cardiac surgery: A post-hoc analysis of the DECADE trial.
To test the hypotheses that in adults having cardiac surgery with cardio-pulmonary bypass, perioperative hypotension increases the risk of delirium and atrial fibrillation during the initial five postoperative days. Sub-analysis of the DECADE multi-center randomized trial. Patients who had cardiac surgery with cardiopulmonary bypass at the Cleveland Clinic. In the underlying trial, patients were randomly assigned 1:1 to dexmedetomidine or normal saline placebo. Intraoperative mean arterial pressures were recorded at 1-min intervals from arterial catheters or at 1-5-min intervals oscillometrically. Postoperative blood pressures were recorded every half-hour or more often. The co-primary outcomes were atrial fibrillation and delirium occurring between intensive care unit admission and the earlier of postoperative day 5 or hospital discharge. Delirium was assessed twice daily during the initial 5 postoperative days while patients remained hospitalized with the Confusion Assessment Method for the intensive care unit. Assessments were made by trained research fellows who were blinded to the dexmedetomidine administration. There was no significant association between intraoperative hypotension and delirium, with an adjusted odds ratio of 0.94 (95% CI: 0.81, 1.09; P = 0.419) for a doubling in AUC of mean arterial pressure (MAP) <60 mmHg. An increase in intraoperative AUC of MAP <60 mmHg was not significantly associated with the odds of atrial fibrillation (adjusted odds ratio = 0.99; 95% CI: 0.87, 1.11; P = 0.819). Postoperative MAP <70 mmHg per hour 1.14 (97.5% CI: 1.04,1.26; P = 0.002) and MAP <80 mmHg per hour 1.05 (97.5%: 1.01, 1.10; P = 0.010) were significantly associated with atrial fibrillation. In patients having cardiac surgery with cardio-pulmonary bypass, neither intraoperative nor postoperative hypotension were associated with delirium. Postoperative hypotension was associated with atrial fibrillation, although intraoperative hypotension was not.


Refining the assessment of contrast-induced acute kidney injury: the load-to-damage relationship.
Comparing the nephrotoxicity of individual contrast agents is challenging, as contrast-induced acute kidney injury (CI-AKI), a widely used trial endpoint, is unable to discriminate between contrast-related and contrast-unrelated causes of renal damage. We established a quantitative method to selectively evaluate the dose-dependent nephrotoxic effect of different contrast agents. We randomized 113 patients undergoing coronary procedures to either iodixanol 320 mg/ml or iobitridol 350 mg/ml. We calculated baseline creatinine clearance (CrCl) and postprocedural change in serum creatinine. We then calculated the regression of the individual iodine load against the creatinine maximum change [load-to-damage relationship (LDR)]. We assumed that its R estimates the predictive accuracy of contrast dose-dependent effects on renal function changes, and that the slope of the LDR characterizes the intrinsic nephrotoxicity of the contrast. We also performed a semi-quantitative evaluation of procedural complexity to assess its complementary role in postprocedural AKI. We found significant correlations between contrast load and creatinine changes for both iobitridol (R: 0.29; P <0.0001) and iodixanol (R: 0.15; P = 0.00028). The LDR slope was, however, significantly steeper for iobitridol compared with iodixanol (19.03 ± 4.02 vs. 14.50 ± 4.63 Cr*CrCl/I; P <0.001) and in diabetic compared with nondiabetic patients (24.35 ± 4.96 vs. 4.59 ± 3.25 Cr*CrCl/I; P <0.001). Adding the procedural complexity score to the contrast load significantly increased the predictive ability of the regression model for postprocedural renal function changes (P < 0.02 for the R increase in overall population), suggesting a role for procedural complexity in postprocedural renal function damage. The LDR slope is a promising method to evaluate the specific contrast-related fraction of postprocedural AKI.


[Assessing the results of the multimodal treatment of patients with combined jaw deformities].
The results of treatment of patients with congenital combined deformations of the jaws are assessed after 6 months to 8 years. The results are analyzed for 96 patients with maxillary micro- or retrognathia and mandibular macro- or prognathia, maxillary macro- or prognathia, and mandibular micro- or retrognathia. Remote results were assessed by clinical, x-ray, and functional methods of examination. Stable esthetic and functional results were attained in all patients, which were observed during both immediate and remote periods of follow-up. No signs of deformation relapses were observed in any case.


Dietary carotenoids and vitamins A, C, and E and risk of breast cancer.
Data on intake of specific carotenoids and breast cancer risk are limited. Furthermore, studies of vitamins A, C, and E in relation to breast cancer risk are inconclusive. We have conducted a large, prospective study to evaluate long-term intakes of these nutrients and breast cancer risk. We examined, by use of multivariate analysis, associations between intakes of specific carotenoids, vitamins A, C, and E , consumption of fruits and vegetables, and breast cancer risk in a cohort of 83234 women (aged 33-60 years in 1980) who were participating in the Nurses' Health Study. Through 1994, we identified 2697 incident cases of invasive breast cancer (784 premenopausal and 1913 postmenopausal). Intakes of beta-carotene from food and supplements, lutein/zeaxanthin, and vitamin A from foods were weakly inversely associated with breast cancer risk in premenopausal women. Strong inverse associations were found for increasing quintiles of alpha-carotene, beta-carotene, lutein/zeaxanthin, total vitamin C from foods, and total vitamin A among premenopausal women with a positive family history of breast cancer. An inverse association was also found for increasing quintiles of beta-carotene among premenopausal women who consumed 15 g or more of alcohol per day. Premenopausal women who consumed five or more servings per day of fruits and vegetables had modestly lower risk of breast cancer than those who had less than two servings per day (relative risk [RR] = 0.77; 95% confidence interval [CI] = 0.58-1.02); this association was stronger among premenopausal women who had a positive family history of breast cancer (RR = 0.29; 95% CI = 0.13-0.62) or those who consumed 15 g or more of alcohol per day (RR = 0.53; 95% CI = 0.27-1.04). Consumption of fruits and vegetables high in specific carotenoids and vitamins may reduce premenopausal breast cancer risk.


Sleep Phase Delay in Cystic Fibrosis: A Potential New Manifestation of Cystic Fibrosis Transmembrane Regulator Dysfunction.
Cystic fibrosis (CF) transmembrane regulator (CFTR) protein dysfunction causes CF. Improving survival allows detection of increasingly subtle disease manifestations. CFTR dysfunction in the central nervous system (CNS) may disturb circadian rhythm and thus sleep phase. We studied sleep in adults to better understand potential CNS CFTR dysfunction. We recruited participants from April 2012 through April 2015 and administered the Munich Chronotype Questionnaire (MCTQ). We compared free-day sleep measurements between CF and non-CF participants and investigated associations with CF survival predictors. We recruited 23 female and 22 male adults with CF aged 18 to 46 years and 26 female and 22 male volunteers aged 18 to 45 years. Compared with volunteers without CF, patients with CF had delayed sleep onset (0.612 h; P = .015), midsleep (1.11 h; P < .001), and wake (1.15 h; P < .001) times and prolonged sleep latency (7.21 min; P = .05) and duration (0.489 h; P = .05). Every hour delay in sleep onset was associated with shorter sleep duration by 0.29 h in patients with CF and 0.75 h in subjects without CF (P = .007) and longer sleep latency by 7.51 min in patients with CF and 1.6 min in volunteers without CF (P = .035). Among patients with CF, FEV1 % predicted, prior acute pulmonary exacerbations, and weight were independent of all free-day sleep measurements. CF in adults is associated with marked delays in sleep phase consistent with circadian rhythm phase delays. Independence from disease characteristics predictive of survival suggests that sleep phase delay is a primary manifestation of CFTR dysfunction in the CNS.


Soybean NIMA-Related Kinase1 Promotes Plant Growth and Improves Salt and Cold Tolerance.
NEK (NIMA-related kinase) is known as a family of serine/threonine kinases which mainly participate in microtubule-related mitotic events in fungi, mammals and other eukaryotes. Our previous studies found that Arabidopsis NEK6 plays an important role in plant response to abiotic stress. We further investigated roles of the NEK family in soybean and found that at least eight members can respond to abiotic stresses. Among them, only GmNEK1, a novel NEK member which is distantly related to Arabidopsis NEK6, enhanced plant growth and promoted salt and cold tolerance in transgenic Arabidopsis plants. The growth of soybean plants harboring GmNEK1-overexpressing hairy roots under saline condition was also improved. A series of stress-related genes including RH3, CORI3 and ALDH10A8 were found to be up-regulated in GmNEK1-overexpressing Arabidopsis plants and soybean hairy roots. Moreover, soybean plants with GmRH3-overexpressing hairy roots exhibited increased salt tolerance, while soybean plants with GmRH3-RNAi (RNA interference) roots were more sensitive to salt stress than the wild-type plants. Our study uncovers a novel role for GmNEK1 in promoting plant adaptive growth under adverse conditions at least partially through up-regulation of GmRH3. Manipulation of these genes in soybean or other crops may improve growth and production under stress conditions.


Sex-specific differences in coronary blood flow and flow velocity reserve in symptomatic patients with non-obstructive disease.
Reduced coronary flow velocity reserve (CFVR) is associated with adverse cardiovascular outcomes. Whether CFVR and coronary blood flow (CBF) are similar in men and women with chest pain and non-obstructive CAD remains unknown. We hypothesised sex differences in CFVR and CBF. A total of 1,683 patients with signs/symptoms of ischaemia and angiographically unobstructed coronary arteries (<40% angiographic stenosis) underwent coronary vasomotion evaluation. CFVR was measured as hyperaemic/resting average velocity in the LAD. Mid-LAD diameter was measured with quantitative angiography and CBF calculated at rest (rCBF) and hyperaemia (hCBF). Resting microvascular resistance (rMR) was calculated as mean arterial pressure/rCBF. Of the total number of patients, 1,096 (65%) were women, median age 51 [42, 59] years. Compared to men, women had lower median CFVR (2.7 [2.4, 3.2] vs 3.1 [2.7, 3.6], p<0.001), higher rCBF (49.7 [34.0, 71.1] vs 45.9 [31.8, 68.7] ml/min, p=0.04), lower hCBF (139.5 [93.0, 195.2] vs 147.1 [95.7, 218.6] ml/min, p=0.02), but similar rMR (p=0.82). Female sex was an independent predictor of lower CFVR, higher rCBF, and lower hCBF. Compared to men, women with signs/symptoms of ischaemia and non-obstructive CAD have lower CFVR, higher rCBF, and lower hCBF. Female sex is a predictor of these sex-specific differences. The clinical diagnostic and prognostic implications of sex differences in coronary physiology need further evaluation.


Controlling wettability of PECVD-deposited dual organosilicon/carboxylic acid films to influence DNA hybridisation assay efficiency.
Herein, plasma polymerisation of a dual-layer tetraethyl orthosilicate (TEOS) and acrylic acid (AA) film under a specific recipe is performed. Newly deposited films are found to retain a weakly-bound soft layer of partially polymerised acrylic acid (wbAA), which can be ultimately removed by washing. However, when on the surface, this soft layer is shown to be influential in manipulating the properties of a robust covalently-bound AA (cbAA) underlayer when treated appropriately. Specifically, treatment of the as-deposited dual-layer TEOS/AA films via timed incubation in a humidity-controlled environment results in changes in the water contact angle (WCA) of the cbAA, and ultimately the surface of the TEOS/AA, enabling tuning of the wettability of the acrylic acid layer. Through the use of a controlled incubation environment of the TEOS/AA, followed by washing, we have demonstrated that carboxylic-acid containing surfaces with a WCA between 85° and 10° can be routinely generated, using basic apparatus and simple methodology. Moreover, these surfaces not only retain their AA functionality, demonstrated by covalent-linking of amine-terminated single-stranded DNA, but also strongly inhibit non-specific binding of the DNA strands. The efficiency of these surfaces to be used in DNA direct-binding hybridisation assays has been demonstrated, with limits of detection of 1.11 and 1.66 nM being measured.


Recent developments in cardiac output determination by bioimpedance: comparison with invasive cardiac output and potential cardiovascular applications.
To describe recent developments in bioimpedance technique and its application in cardiovascular diseases. Cardiac output determination has been used selectively during recent years because of the need for invasive right heart catheterization. Hence, experience with its application in patients with cardiovascular diseases and especially heart failure is limited. Bioimpedance is a novel noninvasive technique determining changes in instantaneous (during one heartbeat) conductance of a small electrical current transferred through the body. By using different algorithms correcting for various body composition constants, it calculates the change in instantaneous arterial blood volume (that is, stroke volume) and cardiac output. Traditionally, bioimpedance cardiac output is determined using either thoracic or whole body techniques according to the location of the electrodes transmitting and receiving the small electrical current. Significant progress was achieved in recent years in cardiac output determination by bioimpedance. Newer algorithms using thoracic and whole body bioimpedance have demonstrated better correlation with invasive cardiac output determination. In a few preliminary studies bioimpedance-determined cardiac output was found useful in the diagnosis, risk stratification, and treatment titration of some cardiovascular conditions. Further, larger prospective studies are required to determine the true independent value of cardiac output measurement by bioimpedance for the evaluation of cardiovascular diseases and especially heart failure. Recently, significant improvement was achieved in cardiac output measurement by bioimpedance with both newer thoracic and whole body techniques. Preliminary studies imply that this measure may be of value in managing some cardiovascular disorders.


Roles of USF, Ikaros and Sp proteins in the transcriptional regulation of the human reduced folate carrier B promoter.
The hRFC (human reduced folate carrier) is ubiquitously but differentially expressed in human tissues and its levels are regulated by up to seven non-coding regions (A1, A2, A, B, C, D and E) and at least four promoters. For the hRFC-B basal promoter, regulation involves binding of Sp (specificity protein) transcription factors to a critical GC-box. By transiently transfecting HT1080 cells with 5'- and 3'-deletion constructs spanning 1057 bp of upstream sequence, a transcriptionally important region was localized to 158 bp flanking the transcriptional start sites. By gel shift and chromatin immunoprecipitation assays, USF (upstream stimulatory factor), Sp1 and Ikaros-related proteins were bound to consensus elements (one E-box, two GC-box and three Ikaros) within this region. The functional importance of these elements was confirmed by transient tranfections of HT1080 cells with hRFC-B reporter constructs in which they were mutated, and by co-transfections of Drosophila Mel-2 cells with wild-type hRFC-B promoter and expression constructs for USF1, USF2a, Sp1 and Ikaros 2 and 8. Both USF1 and Sp1 proteins transactivated the hRFC-B promoter. Sp1 combined with USF1 resulted in a synergistic transactivation. Identical results were obtained with USF2a. Ikaros 2 was a repressor of hRFC-B promoter activity whose effects were partly reversed by the dominant-negative Ikaros 8. In HT1080 cells, transfection with Ikaros 2 decreased endogenous hRFC-B transcripts, whereas USF1 and Sp1 increased transcript levels. Ikaros 2 also decreased reporter gene activity and levels of acetylated chromatin associated with the endogenous promoter. Collectively, these results identify transcriptionally important regions in the hRFC-B promoter that include multiple GC-box, Ikaros and E-box elements. Our results also suggest that co-operative interactions between transcription factors Sp1 and USF are essential for high-level hRFC-B transactivation and imply that these effects are modulated by the family of Ikaros proteins and by histone acetylation.


Validation of the World Health Organization Disability Assessment Schedule (WHO-DAS II) in Greek and its added value to the Short Form 36 (SF-36) in a sample of people with or without disabilities.
There is controversy and ongoing interest on the measurement of functionality in the personal and social level. (1) to validate the Greek version of the World Health Organization Disability Assessment Schedule (WHO DAS II) and (2) to determine its added value to the physical and psychological health subscales of the Short Form 36 (SF-36). In a cross-sectional design, data were collected between December 2014 and March 2015 by using three questionnaires (WHO DAS II, SF-36, PSS-14) in a sample of people with disabilities (n = 101) and without disabilities (n = 109) in Athens, Greece. WHO DAS II internal consistency, construct and criterion-related validity were assessed by Cronbach alpha, exploratory factor analysis and correlations; its added value by multivariable linear regression. Cronbach Alpha's were satisfactory for the WHO DAS II, PSS-14 and SF-36 (0.85, 0.88 and 0.96 respectively). Exploratory factor analysis confirmed the existence of one or two factors in people with or without disabilities, respectively. WHO DAS II score showed significant negative correlation with the physical and mental health scale of SF-36 score, especially strong for physical health while was positively related to PSS-14 score. In multivariate analysis mental health appraisal was related to perceived stress in both groups. This study support the validity of the Greek version of WHO DAS II and warranted its use in assessment and follow up of people with disabilities, contributing to the development of suitable policies to cover their needs and providing comparable data with other surveys using the same instrument.


Characterization of SMA actuator for applications in robotic neurosurgery.
Shape memory alloy has been proven to be MRI compatible and due to its unique microstructure and molecular characteristics, it possesses many unique properties. Additionally, internal resistive heating of the wires eliminates the need for bulky external heating mechanisms. These advantages make SMA actuators good candidates for a wide range of applications in robotic surgical systems when compared to conventional actuators. In this paper, we present our preliminary work towards the development of a SMA based miniature robot for neurosurgery which can be operated under MRI. In this robot, we use two antagonistic SMA wires as actuators for each joint, so that each joint can be operated separately. We also designed an experimental setup to test the SMA wires. The goal of this experiment is to develop a systematic test especially for this robot and to collect sufficient data to estimate the performance of the robot. This setup can also be used to test SMA wires themselves. The data from this experiment will be used to determine important material parameters that are required for analytical models, and then use those models to develop a control strategy to manipulate the SMA actuators.


Lamivudine monotherapy in children and adolescents: The devil is in the detail.
Although expanded access to antiretroviral therapy (ART), and starting lifelong ART as soon as possible after diagnosis of HIV, have dramatically improved survival and reduced morbidity in HIV-infected children and adolescents, ~20% of children will develop virological failure (VF). Children and adolescents may be at higher risk of VF and drug resistance for a number of reasons, including prevention of mother-to-child exposure, reliance on a caregiver to administer ART, poor palatability of paediatric drugs, tuberculosis/HIV co-treatment in protease inhibitor (PI) (mainly lopinavir/ritonavir)-based regimens, and adolescence being associated with poor adherence. In children with VF, if adherence issues are addressed and re-suppression is not achieved, a switch to second- or third-line drugs may be indicated, which is the gold standard in management. However, in the face of ongoing adherence challenges, with potential accumulation of resistance mutations, limited treatment options due to extensive resistance and limited approved paediatric formulations, other strategies have been used. These include continuing a failing PI regimen, switching to a holding regimen (one or more nucleoside reverse transcriptase inhibitors) or discontinuing ART. Lamivudine monotherapy is a common choice when holding regimens are used, on the premise that the lamivudine-associated M184V resistance mutation reduces viral replication and may maintain clinical and immunological stability compared with discontinuing treatment altogether. However, this strategy is generally associated with immunological, and in some cases clinical, decline after starting lamivudine monotherapy. We discuss the pros and cons of using this therapy in children. We also propose guidance for using lamivudine monotherapy, suggesting clinical and immunological criteria for its use. Close monitoring and adherence support are required with this approach. Given many new emerging ART drugs and strategies, lamivudine monotherapy should be administered temporarily, while efforts to improve adherence are implemented. It should not be considered a default option in children with VF.


Hemi-inattention and the recovery patterns of stroke patients.
A series of stroke patients (n = 31) were assessed at four stages: 4 weeks, 8 weeks, 12 weeks and 18 months post-trauma. Significant recovery was noted at 8 weeks, although a trend towards recovery continued throughout the assessment phases. Patients presenting with hemi-inattention at the 4-week assessment achieved significantly poorer levels of functional ability at the final assessment although in some cases the inattention had resolved on neuropsychological tests.


Effect of surfactant type on surfactant-maltodextrin interactions: isothermal titration calorimetry, surface tensiometry, and ultrasonic velocimetry study.
Isothermal titration calorimetry (ITC), surface tensiometry, and ultrasonic velocimetry were used to characterize surfactant-maltodextrin interactions in buffer solutions (pH 7.0, 10 mM NaCl, 20 mM Trizma base, 30.0 degrees C). Experiments were carried out using three surfactants with similar nonpolar tail groups (C12) but different charged headgroups: anionic (sodium dodecyl sulfate, SDS), cationic (dodecyl trimethylammonium bromide, DTAB), and nonionic (polyoxyethylene 23 lauryl ether, Brij35). All three surfactants bound to maltodextrin, with the binding characteristics depending on whether the surfactant headgroup was ionic or nonionic. The amounts of surfactant bound to 0.5% w/v maltodextrin (DE 5) at saturation were < 0.3 mM Brij35, approximately 1-1.6 mM SDS, and approximately 1.5 mM DTAB. ITC measurements indicated that surfactant binding to maltodextrin was exothermic. Surface tension measurements indicated that the DTAB-maltodextrin complex was more surface active than DTAB alone but that SDS- and Brij35- maltodextrin complexes were less surface active than the surfactants alone.


Multi-targeted tyrosine kinase inhibitor reverses resistance to immunotherapy in hepatic sarcomatoid carcinoma.
Hepatic sarcomatoid carcinoma (HSC) is characterized by its aggressive behavior and poor prognosis. As of now, no universally endorsed standard therapeutic approaches for HSC have been established. Herein, we describe the case of a 60-year-old individual diagnosed with HSC, subsequently presenting with multiple metastases postoperatively. Owing to the pronounced expression of programmed cell death protein 1 (PD-1), the individual was subjected to monotherapy utilizing sintilimab for a duration spanning 12 months. Following this regimen, a synergistic treatment approach comprising both anlotinib and sintilimab was instituted, culminating in an ensuing 11 months of efficacious therapeutic response. Throughout the course of treatment, the patient's quality of life remained satisfactory. This particular therapeutic strategy not merely reinforces the efficacy of PD-1 inhibitors in the realm of HSC management, but more pivotally, suggests that tyrosine kinase inhibitors (TKIs) might counteract resistance to PD-1 antagonists, thus offering a potentially augmented treatment paradigm for HSC.


An update on the drug safety of treating erectile dysfunction.
Introduction: Treatment options for erectile dysfunction (ED) have evolved over the last two decades, particularly after the introduction of phosphodiesterase type-5 inhibitors (PDE5Is). The path, however, has not been straightforward with issues raised regarding safety and toxicity following ED treatments. Areas covered: A literature review was conducted on current evidence related to the safety of PDE5Is, intracavernosal injections and various older forms of oral therapies. Relevant trials were identified through a literature search of PubMed from 1980 to 2019. Expert opinion: PDE5Is are now recommended as the first line therapy for the treatment of ED due to their efficacy and tolerable side effects. Comparison of the various PDE5Is on safety has not been supported by prime evidence, and consequently, the negative aspects of each inhibitor appear the same as defined in the literature. Other means of therapies for ED are still in the running, and these also present a different range of side effects. While intracavernosal injections have potential to cause priapism and penile fibrosis, intraurethral alprostadil may result in more systematic side effects. Alternative topical ED therapies are generally limited with their local side effects.


Role of follow-up CT scans in the management of traumatic pediatric epidural hematomas.
Management of pediatric epidural hematoma (PEDH) ranges from observation to emergent craniotomy. Guidelines for management remain poorly defined. More so, serial CT imaging in the pediatric population is often an area of controversy given the concern for excessive radiation as well as increased costs. This work aims to further elucidate the need for serial imaging to surgical decision-making. A prospectively maintained single-institution trauma database was reviewed at a level-1 trauma center to identify patients 18 years old and younger presenting with PEDH over a 10-year period. Selected charts were reviewed for demographic information, mechanisms of injury, neurologic exam, radiographic findings, and treatment course. Surgical decisions were at the discretion of the neurosurgeon on call, often in discussion with a pediatric neurosurgeon. Two hundred and ten records with traumatic epidural hematomas were reviewed. Seventy-three (35%) were taken emergently for hematoma evacuation. Of these, 18 (25%) underwent repeat imaging prior to surgery. One hundred and thirty-seven (65%) were admitted for observation. Seventy-two patients (53%) did not undergo repeat imaging. Sixty-five (47%) admitted for conservative management had at least one repeat scan during their hospitalization. Indications for follow-up imaging during conservative management included routine follow-up (74%), initial scan in our system following transfer (17%), neurological decline (8%), and unknown (1%). Thirteen patients (9%) were taken for surgery in a delayed fashion following admission. Twelve patients who went to surgery in a delayed fashion demonstrated progression on follow-up imaging; however, increase in hematoma size on repeat imaging was the sole surgical indication in only four patients (3%). There were no deaths related to the epidural hemorrhage or postoperatively, regardless of management, and all patients recovered to their pre-trauma baseline. Given that isolated hematoma expansion accounted for an exceptionally small proportion of operative indications, this data suggests changes seen on CT should not be solely relied upon to dictate surgical management. The benefit of obtaining follow-up imaging must be strongly considered and weighed against the known deleterious effects of excessive radiation in pediatric patients, let alone its clinical utility.


Sampling bias overestimates climate change impacts on forest growth in the southwestern United States.
Climate-tree growth relationships recorded in annual growth rings have recently been the basis for projecting climate change impacts on forests. However, most trees and sample sites represented in the International Tree-Ring Data Bank (ITRDB) were chosen to maximize climate signal and are characterized by marginal growing conditions not representative of the larger forest ecosystem. We evaluate the magnitude of this potential bias using a spatially unbiased tree-ring network collected by the USFS Forest Inventory and Analysis (FIA) program. We show that U.S. Southwest ITRDB samples overestimate regional forest climate sensitivity by 41-59%, because ITRDB trees were sampled at warmer and drier locations, both at the macro- and micro-site scale, and are systematically older compared to the FIA collection. Although there are uncertainties associated with our statistical approach, projection based on representative FIA samples suggests 29% less of a climate change-induced growth decrease compared to projection based on climate-sensitive ITRDB samples.


Monoterpene synthases from grand fir (Abies grandis). cDNA isolation, characterization, and functional expression of myrcene synthase, (-)-(4S)-limonene synthase, and (-)-(1S,5S)-pinene synthase.
Grand fir (Abies grandis) has been developed as a model system for studying defensive oleoresin formation in conifers in response to insect attack or other injury. The turpentine fraction of the oleoresin is a complex mixture of monoterpene (C10) olefins in which (-)-limonene and (-)-alpha- and (-)-beta-pinene are prominent components; (-)-limonene and (-)-pinene synthase activities are also induced upon stem wounding. A similarity based cloning strategy yielded three new cDNA species from a wounded stem cDNA library that appeared to encode three distinct monoterpene synthases. After expression in Escherichia coli and enzyme assay with geranyl diphosphate as substrate, subsequent analysis of the terpene products by chiral phase gas chromatography and mass spectrometry showed that these sequences encoded a (-)-limonene synthase, a myrcene synthase, and a (-)-pinene synthase that produces both alpha-pinene and beta-pinene. In properties and reaction stereochemistry, the recombinant enzymes resemble the corresponding native monoterpene synthases of wound-induced grand fir stem. The deduced amino acid sequences indicated the limonene synthase to be 637 residues in length (73.5 kDa), the myrcene synthase to be 627 residues in length (72.5 kDa), and the pinene synthase to be 628 residues in length (71.5 kDa); all of these monoterpene synthases appear to be translated as preproteins bearing an amino-terminal plastid targeting sequence. Sequence comparison revealed that these monoterpene synthases from grand fir resemble sesquiterpene (C15) synthases and diterpene (C20) synthases from conifers more closely than other monoterpene synthases from angiosperm species. This similarity between extant monoterpene, sesquiterpene, and diterpene synthases of gymnosperms is surprising since functional diversification of this enzyme class is assumed to have occurred over 300 million years ago. Wound-induced accumulation of transcripts for monoterpene synthases was demonstrated by RNA blot hybridization using probes derived from the three monoterpene synthase cDNAs. The availability of cDNA species encoding these monoterpene synthases will allow an understanding of the regulation of oleoresin formation in conifers and will ultimately permit the transgenic manipulation of this defensive secretion to enhance resistance to insects. These cDNAs also furnish tools for defining structure-function relationships in this group of catalysts that generate acyclic, monocyclic, and bicyclic olefin products.


Scenes from a marriage--of optics and electronics.
BALTIMORE-Exploring the common ground between optics and electronics, more than 6800 physicists, spectroscopists, and engineers gathered here from 21 to 26 May at the joint meetings of the Conference on Lasers and Electro-Optics and the Quantum Electronics and Laser Science conference. Participants unveiled new technologies that have sprung up on this common ground, such as an imaging technique that can gauge the chemical composition of materials. They also described ways to broaden that ground, such as a novel approach for integrating lasers and silicon chips-a challenge that has slowed progress toward a new generation of high-speed computers and communications.