Utilization of axillary brachial plexus block in the postoperative rehabilitation of intra-articular fractures of the distal humerus.
An effective rehabilitation program is essential to prevent joint stiffness and regain range of motion after surgical treatment of intra-articular fractures of the distal humerus. We evaluated the effect of a physiotherapy program on functional results, that involved passive resistive stretching exercises performed under axillary brachial plexus block after radiographic observation of bone union of intra-articular fractures of the distal humerus treated with open reduction and internal fixation. The study included 21 patients (7 females, 14 males; mean age 34+/-5 years; range 21 to 57 years) who underwent open reduction and internal fixation for intra-articular fractures of the distal humerus. All the patients had closed fractures. Six patients had AO type C1, six patients had C2, and nine patients had C3 fractures. Surgical treatment consisted of a posterior incision, olecranon osteotomy, and fixation of the metaphyseal fragments using two reconstruction plates placed medially and laterally. Active range of motion exercises were started on the third postoperative day. To prevent early development of heterotopic ossification, passive range of motion exercises were avoided. Active stretching exercises were initiated three weeks after surgery. Upon radiographic observation of bone union, axillary brachial plexus block was performed. The physiotherapy program involved passive stretching exercises during nerve block, and active weight exercises after recovery from motor block. The catheter remained in the axillary region for three months, during which functional rehabilitation was continued 2-3 times a week on an outpatient basis. Functional results were evaluated according to the criteria of Jupiter et al. after a mean follow-up period of 31 months (range 24 to 46 months). All fractures united within a mean of 11.9 weeks (range 9 to 17 weeks) except for one type C3 fracture. Functional results were excellent in 10 patients (47.6%), good in eight patients (38.1%), moderate in two patients (9.5%), and poor in one patient (4.8%). Two patients with a moderate outcome had associated multiple fractures in the ipsilateral extremity. Distribution of the functional results according to the type of fractures were 4 excellent, 2 good in type C1; 4 excellent, 2 good in C2; and 2 excellent, 4 good, 2 moderate, and 1 poor in C3 fractures. The mean loss of elbow extension was 16 degrees. The mean elbow flexion, pronation, and supination were measured as 131 degrees, 90 degrees, and 75 degrees, respectively. None of the patients had nonunion at the olecranon osteotomy site, superficial or deep infection, or heterotopic ossification. Three patients developed transient ulnar nerve neuropraxia that resolved spontaneously during the follow-up period. There were no complications related to axillary catheterization. Following surgical treatment of intra-articular fractures of the distal humerus, a regular and pain-free physiotherapy program performed under axillary brachial plexus block on an outpatient basis increases patient compliance and enables early return to daily activities.


[The role and importance of biochemical markers in diagnosis of alcoholic acute pancreatitis].
Alcoholic acute pancreatitis occurs in 10% of alcoholics, who take more than 80 g alcohol daily. Different biochemical markers are used to diagnose acute pancreatitis, and some of them may help in establishing etiology of acute pancreatitis. This study is a prospective review of 21 patients. All patients were hospitalized at the Department for Gastroenterology and Hepatology or at the Department for Surgery of the Clinical Centre of Nif in the period from August 1st 2009 to March 1st 2010 with diagnosis of acute alcoholic pancreatitis. Detailed anamnesis, clinical examination, biochemical analyses and ultrasonography of the upper abdomen were done in all patients. All patients provided data on alcohol abuse. The analysis of the corresponding biochemical parameters revealed a statistically significant correlation between the following values: serum amylase and serum lipase (R = 0.964674; p < 0.001), cholesterol and triglycerides (R = 0.93789; p < 0.001), total and direct bilirubin (R = 0.857899; p < 0.001) and between aspartate aminotransferase and alanine aminotransferase (R = 0.824461, p < 0.001) in patients with alcoholic acute pancreatitis. In addition, there was a statistically significant correlation between the values of serum amylase and urinary amylase (R = 0.582742, p < 0.001). The analysis of biochemical markers showed that some of them were significant for beforehand diagnosis of alcoholic acute pancreatitis, which is in accordance with other studies. Some biochemical parameters can be potential predictors of alcoholic acute pancreatitis (lipase/amylase ratio > 2, greater ratio of aspartate aminotransferase/alanine aminotransferase, enhanced triglycerides and values of mean corpuscular volume.


Multiphoton microscopy: applications in Urology and Andrology.
Multiphoton microscopy (MPM) enables real-time imaging of various cellular processes at submicron resolution. MPM is currently being used in neuroscience, oncology, and immunology. MPM has demonstrated promising results in urology. MPM has been used in the identification of spermatogenesis, evaluation of bladder cancer, and tissue identification in prostate cancer surgery. MPM has allowed the visualization of seminiferous tubules within the testis in a rat model and identified areas of spermatogenesis. MPM could potentially improve the efficacy of testicular sperm extraction. In bladder cancer evaluation, MPM has proven to be an effective imaging tool in identifying areas suspicious for malignancy. The imaging technology could be utilized in the future to provide urologists with an immediate impression of extracted bladder tissue, or as part of a cystoscopic device to evaluate the bladder in real time. Similarly, MPM has proven to be a useful imaging technique to evaluate prostate cancer. MPM could be utilized during a prostatectomy to help differentiate prostate from cavernous nerves that are closely adherent to the prostate. MPM uses a laser and safety studies will need to be performed prior to its utilization in the clinical setting.


Inhibition of Heidenhain pouch pepsin secretion by commercial cholecystokinin and duodenal fat in dogs.
In unanesthetized dogs with Heidenhain pouches and separated duodenal pouches, intravenous infusion of commercial cholecystokinin (1.0 IDU per min) produced a significant depression of pouch acid and pepsin secretion stimulated by pentagastrin (1.0 microg per min) or by methacholine (2.0 microg per min). Acid response to methacholine was temporarily augmented. Irrigation of the duodenal pouches with emulsified fat produced similar patterns of depression of acid secretion in response to pentagastrin and pepsin secretion in response to pentagastrin or methacholine. Acid secretion stimulated by methacholine was temporarily augmented after the irrigation. It is concluded that fat releases endogenous cholecystokinin from the duodenal mucosa and that cholecystokinin, or duodenal fat, powerfully depresses Heidenhain pouch pepsin secretion in dogs. The involvment of the gastric inhibitory polypeptide (GIP) cannot be assessed from the present experiments.


Inflammation and depression: why poststroke depression may be the norm and not the exception.
Ischaemic stroke often precedes the appearance of clinical depression. Poststroke depression in turn influences the prognostic outcome. In the interest of advancing our understanding of the biological mechanisms underlying the development of poststroke depression, this systematic review explores the immunological processes driving the development of inflammation-related cell death in mood-related brain regions. Particular attention has been paid to cytokine-driven intrinsic apoptosis factors, including intracellular calcium, glutamate excitotoxicity and free radicals that appear in the brain following ischaemic damage and whose presence significantly increases the likelihood of clinically defined depression.


The effectiveness and safety of low-intensity transcranial ultrasound stimulation: A systematic review of human and animal studies.
Low-intensity transcranial ultrasound stimulation (LITUS) is a novel non-invasive neuromodulation technique. We conducted a systematic review to evaluate current evidence on the efficacy and safety of LITUS neuromodulation. Five databases were searched from inception to May 31, 2023. Randomized controlled human trials and controlled animal studies were included. The neuromodulation effects of LITUS on clinical or pre-clinical, neurophysiological, neuroimaging, histological and biochemical outcomes, and adverse events were summarized. In total, 11 human studies and 44 animal studies were identified. LITUS demonstrated therapeutic efficacy in neurological disorders, psychiatric disorders, pain, sleep disorders and hypertension. LITUS-related changes in neuronal structure and cortical activity were found. From histological and biochemical perspectives, prominent findings included suppressing the inflammatory response and facilitating neurogenesis. No adverse effects were reported in controlled animal studies included in our review, while reversible headache, nausea, and vomiting were reported in a few human subjects. Overall, LITUS alleviates various symptoms and modulates associated brain circuits without major side effects. Future research needs to establish a solid therapeutic framework for LITUS.


Developing an online learning community for mental health professionals and service users: a discursive analysis.
There is increasing interest in online collaborative learning tools in health education, to reduce costs, and to offer alternative communication opportunities. Patients and students often have extensive experience of using the Internet for health information and support, and many health organisations are increasingly trying out online tools, while many healthcare professionals are unused to, and have reservations about, online interaction. We ran three week-long collaborative learning courses, in which 19 mental health professionals (MHPs) and 12 mental health service users (MHSUs) participated. Data were analysed using a discursive approach to consider the ways in which participants interacted, and how this contributed to the goal of online learning about using Internet technologies for mental health practice. MHSUs and MHPs were able to discuss issues together, listening to the views of the other stakeholders. Discussions on synchronous format encouraged participation by service users while the MHPs showed a preference for an asynchronous format with longer, reasoned postings. Although participants regularly drew on their MHP or MHSU status in discussions, and participants typically drew on either a medical expert discourse or a "lived experience" discourse, there was a blurred boundary as participants shifted between these positions. The anonymous format was successful in that it produced a "co-constructed asymmetry" which permitted the MHPs and MHSUs to discuss issues online, listening to the views of other stakeholders. Although anonymity was essential for this course to 'work' at all, the recourse to expert or lay discourses demonstrates that it did not eliminate the hierarchies between teacher and learner, or MHP and MHSU. The mix of synchronous and asynchronous formats helped MHSUs to contribute. Moderators might best facilitate service user experience by responding within an experiential discourse rather than an academic one.


Visceral sensitivity perturbation integration in the brain-gut axis in functional digestive disorders.
Chronic abdominal pain is the most distressing symptom in patients with functional digestive disorders (FDD). IBS is the most common gastrointestinal disorder seen in primary care and gastroenterology practice. IBS is a functional bowel disorder in which abdominal pain is associated with defaecation or a change in bowel habit, with features of disordered defecation and with distension. The underlying pathophysiology of IBS is unknown but a chronic visceral hyperalgesia, in the absence of detectable organic disease, is implicated. The exact location of abnormality of visceral pain processing is not known. Theories of its etiology have range widely from the original view that the disease represents a primary disturbance of gut mucosa to emerging conception of the syndrome as emanating from a complex disordered interaction between the digestive and nervous systems. Several lines of evidence suggest a strong modulatory or etiologic role of the central nervous system in the pathophysiology of IBS. A major advance in the understanding of the central mechanisms of pain processing has evolved from application of functional imaging techniques, as represented by positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). In humans, multiple components are involved in somato-visceral pain processings, including sensory-discriminative components, affective components, and cognitive components. Silverman et al, using PET, were the first to explore neural correlates of abdominal pain induced by rectal distension. If healthy subjects activated the ACC, the IBS patients did not while they presented an activation of the left PFC. These findings were consistent with an IBS model that includes both the exaggerated activation of a vigilance network (dorsolateral PFC) and a failure in pain inhibition network anterior cingulate cortex (ACC). In contrast, Mertz et al., using fMRI, observed that pain led to a greater activation of the ACC than did non-painful stimuli thus arguing for an up-regulation of afferent sensitivity to pain. Using fMRI, we also characterized cerebral loci activated by a rectal distension in healthy volunteers. The activation patterns presented a strong similarity with the central processing of somatic pain. In contrast, in a women predominant population of IBS patients, we did not observed any neuronal activation in locations activated in healthy volunteers (ACC, dorsolateral PFC) while a significant deactivation was observed in the IC and in the amygdala, a limbic structure with a role to assign emotional significance to a current experience related to anxiety and fear. Brain imaging techniques thus appear as useful tools to characterize normal and abnormal brain processing of visceral pain in patients with FDD. Reversal effects of chemical compounds targeting these abnormalities either at a peripheral or a central level should be of interest.


Sexual risk taking among young internet-using men who have sex with men.
We examined the characteristics of young Internet-using men who have sex with men (MSM) and risks associated with seeking sex online, offline, or through both strategies. Data were obtained from MSM aged 18 to 24 years who completed a 45-minute online survey regarding sex and Internet use in the preceding 3 months. Significantly more Internet-using MSM who had met sexual partners both online and offline (43%) reported unprotected anal intercourse than did those who had met sexual partners exclusively online (29%) or offline (34%). MSM who met sexual partners exclusively offline reported the fewest partners but the greatest proportion of partnerships involving unprotected anal intercourse (49%). Meeting sexual partners both online and offline (odds ratio [OR]=3.38-58.42) and being drunk (OR=1.57) or high (OR=2.24) increased the odds of having more sexual partners. The same factors increased the odds of having unprotected anal intercourse (online and offline sexual partners, OR=1.60; being drunk, OR=1.43; being high, OR=1.61). Risky sexual behavior was prevalent among all of the study subgroups. Our findings suggest that online sex seeking is associated with greater numbers of sexual partners but neither promotes nor discourages unprotected anal intercourse. Regardless of where sexual partners met, being drunk and high were significant risks for unprotected anal intercourse.


Minireview: NAD+, a circadian metabolite with an epigenetic twist.
A wide variety of endocrine, physiological, and metabolic functions follow daily oscillations. Most of these regulations are controlled at the level of gene expression by the circadian clock and, a remarkably coordinated transcription-translation machinery that exerts its function in virtually all mammalian cells. A large fraction of the genome is under control of the circadian clock, a regulation that is achieved through dynamic changes in chromatin states. Recent findings have demonstrated intimate connections between the circadian clock and epigenetic control. The case of nicotinamide adenine dinucleotide, which modulates the circadian activity of the deacetylase sirtuin 1, constitutes a paradigmatic example of the link between cyclic cellular metabolism and chromatin remodeling. Indeed, the clock transcriptional feedback loop is interlocked with the enzymatic loop of the nicotinamide adenine dinucleotide salvage pathway.


Hydrogen-Rich Saline Attenuates Acute Lung Injury Induced by Limb Ischemia/Reperfusion via Down-Regulating Chemerin and NLRP3 in Rats.
Limb ischemia/reperfusion (LI/R) injury is associated with high morbidity and mortality. The hypothesis of this study is that hydrogen-rich solution could attenuateacute lung injury and improve mortality via chemerin and NLRP3 after LI/R in rats. A rat model of LI/R was performed by clamping the bilateral femoral arteries for 3 h followed by reperfusion. Hydrogen-rich saline (HRS) was administered intraperitoneally (10 mL/kg or 2.5 mL/kg) when the atraumatic micro clips were released. The rats were euthanized at 2 h after reperfusion and then the arterial blood and lung specimens were harvested for further analyses. Meanwhile, survival rate was observed. The results showed that HRS improved the survival rate and attenuated pulmonary edema, injury, and apoptosis. HRS also decreased the levels of tumor necrosis factor-α, interleukin-6, myeloperoxidase and malondialdehyde, and increased the activity of superoxide dismutase in serum and lung after the LI/R event. HRS downregulated the expression of chemerin and NLRP3 in lung. The study demonstrated that chemerin and NLRP3 could serve as important response factors that were involved in the lung injury following LI/R. HRS could significantly attenuate LI/R-mediated acute lung injury, at least in part, by inhibiting the activated chemerin/NLRP3 signaling pathway.


Aberrant frequency of IL-10-producing B cells and its association with Treg/Th17 in adult primary immune thrombocytopenia patients.
Regulatory B cells (Breg) are a distinct B cell subset with immunoregulatory properties. Pivotal to Breg function is interleukin-10. This study was to investigate the role of IL-10-producing B cell (B10) and its association with Treg and Th17 subsets in immune thrombocytopenia (ITP) patients. Peripheral blood mononuclear cells from ITP patients and controls were stimulated with PMA, ionomycin, and Brefeldin A. The frequencies of CD19(+)IL-10(+) B cells, CD3(+)CD4(+)IL-17(+) Th17 cells, and CD4(+)CD25(hi)Foxp3(+) Treg cells were analyzed by flow cytometry. The mRNA expression of Foxp3 and RORγt was detected by real-time quantitative PCR. The number of B10 cells was elevated in ITP patients. After first-line therapies, it remained at high level in patients who achieved complete or partial response but decreased in those who acquired no response. There was a positive correlation between B10 cells and Tregs in ITP both before and after therapies. The ratio of Treg/Th17 decreased in ITP, and it strongly correlated with B10 cells. The frequency of B10 cells is elevated in ITP and it correlates with both the Tregs counts and the Treg/Th17 ratio. B10 cells to regulate functional T cell subsets might be impaired in patients with ITP.


Tendinous Tissue Adaptation to Explosive- vs. Sustained-Contraction Strength Training.
The effect of different strength training regimes, and in particular training utilizing brief explosive contractions, on tendinous tissue properties is poorly understood. This study compared the efficacy of 12 weeks of knee extensor explosive-contraction (ECT; n = 14) vs. sustained-contraction (SCT; n = 15) strength training vs. a non-training control (n = 13) to induce changes in patellar tendon and knee extensor tendon-aponeurosis stiffness and size (patellar tendon, vastus-lateralis aponeurosis, quadriceps femoris muscle) in healthy young men. Training involved 40 isometric knee extension contractions (three times/week): gradually increasing to 75% of maximum voluntary torque (MVT) before holding for 3 s (SCT), or briefly contracting as fast as possible to ∼80% MVT (ECT). Changes in patellar tendon stiffness and Young's modulus, tendon-aponeurosis complex stiffness, as well as quadriceps femoris muscle volume, vastus-lateralis aponeurosis area and patellar tendon cross-sectional area were quantified with ultrasonography, dynamometry, and magnetic resonance imaging. ECT and SCT similarly increased patellar tendon stiffness (20% vs. 16%, both p < 0.05 vs. control) and Young's modulus (22% vs. 16%, both p < 0.05 vs. control). Tendon-aponeurosis complex high-force stiffness increased only after SCT (21%; p < 0.02), while ECT resulted in greater overall elongation of the tendon-aponeurosis complex. Quadriceps muscle volume only increased after sustained-contraction training (8%; p = 0.001), with unclear effects of strength training on aponeurosis area. The changes in patellar tendon cross-sectional area after strength training were not appreciably different to control. Our results suggest brief high force muscle contractions can induce increased free tendon stiffness, though SCT is needed to increase tendon-aponeurosis complex stiffness and muscle hypertrophy.


A closed-loop artificial pancreas based on risk management.
Control algorithms that regulate blood glucose (BG) levels in individuals with type 1 diabetes mellitus face several fundamental challenges. Two of these are the asymmetric risk of clinical complications associated with low and high glucose levels and the irreversibility of insulin action when using only insulin. Both of these nonlinearities force a controller to be more conservative when uncertainties are high. We developed a novel extended model predictive controller (EMPC) that explicitly addresses these two challenges. Our extensions to model predictive control (MPC) operate in three ways. First, they explicitly minimize the combined risk of hypoglycemia and hyperglycemia. Second, they integrate the effect of prediction uncertainties into the risk. Third, they understand that future control actions will vary if measurements fall above or below predictions. Using the University of Virginia/Padova Simulator, we compared our novel controller (EMPC) against optimized versions of a proportional-integral-derivative (PID) controller, a traditional MPC, and a basal/bolus (BB) controller, as well as against published results of an independent MPC (IMPC). The BB controller was optimized retrospectively to serve as a bound on the possible performance. We tuned each controller, where possible, to minimize a published blood glucose risk index (BGRI). The simulated controllers (PID/MPC/EMPC/BB) provided BGRI values of 2.99/3.05/2.51/1.27 as compared to the published IMPC BGRI value of 4.10. These correspond to 73/79/84/92% of BG values lying in the euglycemic range (70-180 mg/dl), respectively, with mean BG levels of 151/156/147/140 mg/dl. The EMPC strategy extends MPC to explicitly address the issues of asymmetric glycemic risk and irreversible insulin action using estimated prediction uncertainties and an explicit risk function. This controller reduces the avoidable BGRI by 56% (p < .05) relative to a published MPC algorithm studied on a similar population.


Conductometric immunoassay of alpha-fetoprotein in sera of liver cancer patients using bienzyme-functionalized nanometer-sized silica beads.
A conductometric immunoassay protocol was designed for the sensitive detection of a liver cancer biomarker, alpha-fetoprotein (AFP), in biological fluids by using enzyme-conjugated nanometer-sized enzyme-doped silica beads. Initially, urease molecules were doped into nanosilica particles by using the reverse micelle method. Thereafter, arginase-labeled anti-AFP antibodies were covalently conjugated onto the surface of the synthesized nanoparticles. The immunoreaction was carried out in a monoclonal anti-AFP capture antibody-coated microplate with a sandwich-type assay format by using bienzyme-functionalized silica nanobeads as the recognition elements. Upon l-arginine introduction, the substrate was cleaved into urea and l-ornithine on the basis of the arginase enzymatic reaction, and the as-produced urea was then decomposed into ammonia (NH4+) and bicarbonate (HCO3-) ions by the doped urease, thus causing the variation in the local conductivity of the detection solution on an interdigitated conductometric transducer. Under optimal conditions, the developed immunosensing system exhibited good conductometric responses toward target AFP within a dynamic linear range of 0.01-100 ng mL-1 at a relatively low detection limit of 4.8 pg mL-1 based on the 3sB criterion. Importantly, good reproducibility, high specificity and acceptable method accuracy were acquired for the analysis of human serum specimens in liver cancer patients.


ICTV Virus Taxonomy Profile: Caliciviridae.
The family Caliciviridae includes viruses with single-stranded, positive-sense RNA genomes of 7.4-8.3 kb. The most clinically important representatives are human noroviruses, which are a leading cause of acute gastroenteritis in humans. Virions are non-enveloped with icosahedral symmetry. Members of seven genera infect mammals (Lagovirus, Norovirus, Nebovirus, Recovirus, Sapovirus, Valovirus and Vesivirus), members of two genera infect birds (Bavovirus and Nacovirus), and members of two genera infect fish (Minovirus and Salovirus). This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the family Caliciviridae, which is available at ictv.global/report/caliciviridae.


Culture-Negative Periprosthetic Joint Infection: An Update on What to Expect.
Culture-negative periprosthetic joint infection (PJI) is a challenging condition to treat. The most appropriate management of culture-negative PJI is not known, and there is immense variability in the treatment outcome of this condition. The purpose of this study was to elucidate the characteristics, outcomes, and risk factors for failure of treatment of culture-negative PJI. A retrospective review of 219 patients (138 hips and 81 knees) who had undergone surgery for the treatment of culture-negative PJI was performed utilizing a prospectively collected institutional PJI database. PJIs for which the results of culture were unavailable were excluded. An electronic query and manual review of the medical records were completed to obtain patient demographics, treatment, microbiology data, comorbidities, and other surgical characteristics. Treatment failure was assessed using the Delphi consensus criteria. The prevalence of suspected culture-negative PJI was 22.0% (219 of 996), and the prevalence of culture-negative PJI as defined by the Musculoskeletal Infection Society (MSIS) was 6.4% (44 of 688). Overall, the rate of treatment success was 69.2% (110 of 159) in patients with >1 year of follow-up. Of the 49 culture-negative PJIs for which treatment failed, 26 (53.1%) subsequently had positive cultures; of those 26, 10 (38.5%) were positive for methicillin-sensitive Staphylococcus aureus. The rate of treatment success was greater (p = 0.019) for patients who had 2-stage exchange than for those who underwent irrigation and debridement. The present study demonstrates that culture-negative PJI is a relatively frequent finding with unacceptable rates of treatment failure. Every effort should be made to isolate the infecting organism prior to surgical intervention, including extending the incubation period for cultures, withholding antibiotics prior to obtaining culture specimens, and possibly using newly introduced molecular techniques. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.


Matrix metalloproteinase-9 expression correlates with prognosis and involved in ovarian cancer cell invasion.
One of the most important characteristics of ovarian cancer is invasion and metastasis. Matrix metalloproteinases (MMPs) are known to play an important role in cancer cell invasion by mediating the degradation of extracellular matrix (ECM). The activities of MMPs are regulated by tissue inhibitors of metalloproteinases (TIMPs). In this study, we investigated the clinical significance of MMP-2, -7 and -9 and TIMP-1, -2 and -3 expression and MMP-9 functional role in cell invasion and adhesion in ovarian cancer. RT-PCR was used to determine mRNA expression of MMP-2, -7 and -9 and TIMP-1, -2 and -3 in ovarian tissues; ELISA was used to detect the serum level of MMP-9; RNA interference (RNAi) was performed to determine the function of MMP-9 in cell invasion and adhesion in ovarian cancer cells. mRNA expression of MMP-2, MMP-7, MMP-9, TIMP-2 and TIMP-3 and serum level of MMP-9 were significantly high in patients with ovarian cancer. MMP-9 expression was significantly high in patients with advanced ovarian cancer and correlated with poor prognosis. The ability of cells for invasion and adhesion was significantly reduced by treatment of cells with MMP-9 siRNA. Our results suggest that MMP-9 is a potential prognostic factor for ovarian cancer and could be a novel treatment target in ovarian cancer patients.


Perfusion imaging using arterial spin labeling.
Arterial spin labeling is a magnetic resonance method for the measurement of cerebral blood flow. In its simplest form, the perfusion contrast in the images gathered by this technique comes from the subtraction of two successively acquired images: one with, and one without, proximal labeling of arterial water spins after a small delay time. Over the last decade, the method has moved from the experimental laboratory to the clinical environment. Furthermore, numerous improvements, ranging from new pulse sequence implementations to extensive theoretical studies, have broadened its reach and extended its potential applications. In this review, the multiple facets of this powerful yet difficult technique are discussed. Different implementations are compared, the theoretical background is summarized, and potential applications of various implementations in research as well as in the daily clinical routine are proposed. Finally, a summary of the new developments and emerging techniques in this field is provided.


Short term complications from transurethral resection of bladder tumor.
The diagnosis and subsequent management of bladder cancer often involves transurethral resection of bladder tumor (TURBT). Risks of TURBT include perioperative complications such as bleeding, pain and perforation. We aimed to determine TURBT complication rates and risk factors in a contemporary series. From 2002 to 2011, 505 patients underwent TURBT either for suspected bladder cancer or during follow up at a single institution. Baseline patient characteristics and complications within 2 weeks of surgery were extracted from the electronic medical record for all TURBTs. Patient and tumor characteristics were evaluated for associations with complication using univariate analysis. A multivariable logistic regression was fit to further examine associations between TURBT related characteristics and complication. A total of 910 TURBTs were performed on 505 patients. Overall complication rate was 8.1%. The most common complications were pain or spasm (3.0%), retention (2.8%), and infection (2.1%), and 0.5% of TURBTs had perforation. Over 85% of complications were Clavien-Dindo grade I or II. Forty-three patients had a complication after their first TURBT, while 25 had complications after subsequent TURBTs. Prior complication and single tumor, but not other patient or tumor-related characteristics, were associated with complication. Only prior complication (p < 0.01) was associated with subsequent complication after TURBT on multivariable analysis. Complication rate after TURBT is 8.1% and complications are generally not severe in nature. Prior short term complication is likely associated with subsequent complication. Further studies are needed to validate these results and determine patient groups most at risk for intraoperative and post TURBT complications.


Radioimmunoassay and radioenzymatic assay of a new aminoglycoside antibiotic, netilmicin.
A radioimmunoassay and a radioenzymatic assay for netilmicin, a new aminoglycoside, were developed in our laboratories to assist in the study of the pharmacology of the drug and to establish values for use in its monitoring. The assays are sensitive, precise, and rapid, giving results that correlate (r = 0.90) with each other and with those of a microbiological assay in which Klebsiella pneumoniae is used as the test organism. Preliminary pharmacological studies show the drug to have a biological half-life of 135 min. which is comparable to that for other aminoglycosides.


Treatment of small cell lung cancer.
The prognosis for patients with small cell lung cancer has improved over the past ten years from a median survival of 2.5 months to 8 to 10 months for patients with extensive metastatic disease and 12 to 16 months for patients with limited disease. This progress has been primarily through advances in chemotherapy. A small percentage of patients are having prolonged disease-free survival. Methods of staging are reviewed. The best current chemotherapeutic programs are discussed, as well as the present role of radiation therapy in the management of small cell lung cancer.


Phylogeny, phylogeography, and evolution in the Mediterranean region: News from a freshwater mussel (Potomida, Unionida).
The Potomida genus (Bivalvia, Unionida) has a Circum-Mediterranean distribution and like other freshwater mussel species, its populations have suffered dramatic declines. Although this genus is currently considered as monotypic, it has a long history of taxonomic revisions and presently many aspects of its systematics and evolutionary history are unclear. We sampled a total of 323 individuals from 39 different sites across the Potomida genus distribution, and sequenced two mitochondrial (16S rDNA and Cytochrome c Oxidase Subunit I) and one nuclear (28S rDNA) genes to clarify its phylogeny and phylogeographic history. Our results show that the genus includes two well-supported clades, one comprising solely the western Mediterranean species Potomida littoralis, and the other including two eastern Mediterranean species, the Greek endemic P. acarnanica and the Anatolian and Middle Eastern P. semirugata. We suggest that Potomida started radiating during the upper Miocene, and that both vicariance and dispersal events shaped the diversification and distribution of the genus along the Mediterranean region. P. littoralis is further divided in two mitochondrial lineages, one restricted to Europe and the other occurring mostly in North Africa. Moreover, some European basins present both lineages in sympatry. The conservation status of the three recognized species should be reevaluated, particularly P. acarnanica, since it is restricted to two Greek river basins presenting a high risk of extinction. Overall, our results clarify some important gaps in knowledge concerning the phylogeny, phylogeography and evolution of the Potomida genus in the Mediterranean region with important taxonomical, ecological and conservational implications.


Genetic, farm, and lactation effects on behavior and performance of US Holsteins in automated milking systems.
Selecting for favorable behavior and performance could enhance the efficiency of production in automated milking systems (AMS). The objectives of this study were to describe AMS behavior and performance in Holsteins, estimate genetic parameters among AMS traits, and determine genetic relationships of AMS traits with other routinely recorded traits. The edited data included 1,101,651 individual milking records and 394,636 daily records from 2,531 lactations and 1,714 cows that resided on 3 farms; data were obtained from the Dairy Data Warehouse (Assen, Netherlands) cloud. Traits considered were individual milking and daily totals for milk yield, milking time, milk harvest rate (the ratio of milk yield to milking time), milk flow rate, electrical conductivity, machine kickoffs, incomplete milkings, and blood in milk; the number of milkings per day and 305-d mature-equivalent milk yield (305ME) were also evaluated. Individual milkings were evaluated with mixed models that included fixed effects of week of lactation, lactation group (1, 2, ≥3), hour of day, and farm; random effects included cow within lactation, lactation group by week of lactation, and interactions of farm with date, hour, week of lactation, and year-season of calving. Daily records were evaluated with 3-trait animal models that included 305ME and 2 AMS traits with random additive genetic and permanent environment effects. Estimated breeding values were extracted and correlated with yield, conformation, and udder health genetic evaluations. Farm specific robot access policies had notable effects on week of lactation patterns for milk yield and number of milkings. Mature cows had higher milk harvest rates (2.05 kg/min) than first-lactation cows (1.73 kg/min) with larger differences in early lactation. First-lactation cows were more likely to kick off the machine (15.04%) than mature cows (8.62%), particularly in early lactation. Heritability estimates were generally lower for behavior traits (0.03 for incomplete milkings and 0.08 for kickoffs) than for milk harvest rate (0.30) and flow rate (0.55). Udder conformation traits did not have favorable genetic correlations with AMS traits, with the exception that longer teats were correlated with fewer kickoffs (-0.34) and incomplete milkings (-0.49); increased milk harvest rate and flow rate were unfavorably associated with genetic merit for udder health. There is genetic variation for milking efficiency and behavioral traits, suggesting genetic selection to enhance efficiency in AMS systems is possible. Genetic associations with udder conformation indicate that selection for udder morphology is unlikely to substantially improve milking efficiency. This calls for more direct selection of traits related to AMS efficiency.


Modeling of time-variant coupling between left ventricle and aorta in cardiac cycle.
An analytical model is developed to study the interaction between the left ventricle and vascular system. Ventricular pressure is expressed as a function of the chamber volume, volumetric strain rate, and the degree of activation. A three-element Wind-kessel model is employed to represent the hydraulic properties of the vascular system. Conditions of interaction between the left ventricle and the vascular system are formulated in mathematical terms. Numerical solutions are obtained for the mechanical events occurring during a cardiac cycle as a function of time. The time variations of aortic pressure and ventricular volume predicted by the model compare well with the experimental results of Sunagawa and co-workers [Am. J. Physiol. 243 (Heart Circ. Physiol. 12): H346-H350, 1982, and Am. J. Physiol. 245 (Heart Circ. Physiol. 14): H773-H780, 1983]. Furthermore, the application of the present model to the experimental data has allowed the derivation of the intrinsic contractility parameters in these experiments. The unique features of this analytical model are that 1) it provides the time-variant pressure and volume curves of the left ventricle in relation to the aorta, 2) it generates information on the effects of heart rate on these hemodynamic parameters, and 3) it allows the derivation of intrinsic contractility parameters from experimental data.


An unusual retroperitoneal cystic tumor.
This report describes a case of textiloma (term given to an inflammatory swelling caused by a retained textile foreign body) in a 60-year-old patient who had undergone surgery for a perforated gastroduodenal ulcer 17 years earlier. On examination the presence of a large mass was detected on the left hypochondria. A CT scan confirmed a cystic tumor with images suggesting detritus or necrosis in its lower part, as well as calcifications. Transperitoneal midline laparotomy was performed with extension by thoracophrenolaparotomy. Splenectomy was necessary. Macroscopic examination showed a spherical mass. After opening the tumor, retained surgical gauze was found. The histopathological diagnosis was granulomatosis reaction to a foreign body.


The treatment of radial scars in the modern era--surgical excision is not required.
The clinical significance of isolated radial scars (RS) diagnosed on core needle biopsy (CNB) remains unclear. By determining the pathologic concordance rate, we sought to define the indications for surgical excision for RS diagnosed on CNB. Between January 1994 and December 2007, 38 RS were diagnosed by CNB. Twenty-eight underwent surgical excision with 27 (96%) patients having further benign diagnoses. One patient, who was found to have invasive cancer on CNB, was also found to have malignancy on open biopsy. Fourteen lesions were diagnosed by 8-gauge, 13 lesions by 11-gauge, and one lesion by 14-gauge biopsy needles. Seven studies met inclusion criteria for analysis; 341 lesions with follow-on surgical biopsy were identified. Sixteen (5%) radial'scars were found to harbor malignancy and all were percutaneously biopsied with 14-gauge needles. With the inclusion of the current study, none of the isolated radial scars diagnosed by the larger 11- or 8-gauge biopsy needles resulted in upgraded lesions on follow-on surgical biopsy. Based on the current review, histologic radial scars are infrequently associated with occult malignancy and do not mandate surgical excision. Indications for excision include the mammographic diagnosis of RS and specimens associated with atypia that would otherwise require open biopsy.


Identification of amino acid residues important for the arsenic resistance function of Arabidopsis ABCC1.
The Arabidopsis ATP-Binding Cassette (ABC) transporter ABCC1 sequesters arsenic (As)-phytochelatin conjugates into the vacuole, thereby conferring As resistance. Here, we report the results of a screen for phosphorylation-dependent regulation sites of AtABCC1. Variants of AtABCC1 harboring mutations that replaced amino acid residues Tyr682 , Tyr709 , Tyr822 , Ser846 , Ser1278 , or Thr1408 with alanine confer reduced resistance and decrease the intracellular As content relative to wild-type AtABCC1 when heterologously expressed in the SM7 yeast strain. This suggests that these mutations compromise the vacuolar sequestration of As by AtABCC1. Furthermore, through a phosphomimic mutant study, we found that phosphorylation of Ser846 is required for the As resistance function of AtABCC1. Our analysis provides a first clue as to the phosphorylation-mediated regulation of AtABCC1 activity.


The bottom-up solution to the triacylglycerol lipidome using atmospheric pressure chemical ionization mass spectrometry.
Presented here is an approach to representing the data from atmospheric pressure chemical ionization (APCI) mass spectrometry (MS) of triacylglycerols (TAG) using a set of one, two, or three Critical Ratios. These Critical Ratios may be used directly to provide structural information concerning the regioisomeric composition of the triacylglycerols (TAG), and about the degree of unsaturation in the TAG. An AAA-type, or Type I, TAG has only one Critical Ratio, the ratio of the protonated molecule, [M + H]+, to the DAG fragment ion, [AA]+. The Critical Ratio for a Type I TAG is [MH]+/Z[DAG]+, and the mass spectrum of a Type I TAG can be reproduced from only this one ratio. An ABA/AAB/BAA, or Type II, TAG has two Critical Ratios, the [MH]+/sigma[DAG]+ ratio and the [AA]+/[AB]+ ratio. The [AA]+/[AB]+ ratio for a single TAG or TAG mixture can be compared with the [AA]+/[AB]+ ratios of pure regioisomeric standards, and the percentage of each regioisomer can be estimated. The abundance of the protonated molecule and the abundances of the two [DAG]+ fragment ions can be calculated from the two Critical Ratios for a Type II TAG. To calculate the abundances, the Critical Ratios are processed through the Bottom-Up Solution to the TAG lipidome. First, Critical Limits are calculated from the Critical Ratios, and then the Critical Ratios are classified into Cases by comparison with the Critical Limits. Once the Case classification is known, the equation for the abundance of each ion in the mass spectrum is given by the Bottom-Up Solution. A Type III TAG has three different FA and three Critical Ratios. The [MH]+/Z[DAG]+ ratio is the first Critical Ratio, the [AC]+/([AB]+ + [BC]+) ratio is the second Critical Ratio, and the [BC]+/[AB]+ ratio is the third Critical Ratio. The second critical ratio for a Type III TAG can be compared with regioisomeric standards to provide an estimate of the percentage composition of the regioisomers. The three Critical Ratios for a Type III TAG can be processed through the Bottom-Up Solution to calculate the four ion abundances that make up the APCI-MS mass spectrum. The Critical Ratios constitute a reduced data set that provides more information in fewer values than the raw abundances.


Transcription-dependent cohesin repositioning rewires chromatin loops in cellular senescence.
Senescence is a state of stable proliferative arrest, generally accompanied by the senescence-associated secretory phenotype, which modulates tissue homeostasis. Enhancer-promoter interactions, facilitated by chromatin loops, play a key role in gene regulation but their relevance in senescence remains elusive. Here, we use Hi-C to show that oncogenic RAS-induced senescence in human diploid fibroblasts is accompanied by extensive enhancer-promoter rewiring, which is closely connected with dynamic cohesin binding to the genome. We find de novo cohesin peaks often at the 3' end of a subset of active genes. RAS-induced de novo cohesin peaks are transcription-dependent and enriched for senescence-associated genes, exemplified by IL1B, where de novo cohesin binding is involved in new loop formation. Similar IL1B induction with de novo cohesin appearance and new loop formation are observed in terminally differentiated macrophages, but not TNFα-treated cells. These results suggest that RAS-induced senescence represents a cell fate determination-like process characterised by a unique gene expression profile and 3D genome folding signature, mediated in part through cohesin redistribution on chromatin.


A new genus and species of acuarioid nematode (Acuariidae: Seuratiinae) in petrels Pterodroma externa and P. neglecta from the Juan Fernández Islands, Chile.
A new genus and species of Seuratiinae is described based on adults recovered from the Juan Fernández and Kermedec Petrels (Pterodroma externa and P. neglecta) from the Juan Fernández Islands of Chile (south Pacific). Navonia pterodromae n. gen., n. sp. is distinguished from the other genera and species in Seuratiinae by the combination of the following characters: (1) cordons arising from commissures of buccal lips originating a finely denticulate collarette divided into 2 lateral lobes, and detached from underlying cuticle; (2) inconspicuous simple to bicuspid deirids; (3) presence of area rugosa; and (4) presence of a large left spicule in the male. It is also distinguished from some genera and species in this subfamily by the presence of a lateral furrow. Seuratia shipleyi was also recorded from P. externa. These are the first records of helminths in these 2 hosts and the first records of Seuratiinae from Chile.


The effect of parental alcohol and drug disorders on adolescent personality.
The relationship of parental alcohol or drug diagnosis to offspring personality was examined in a population-based sample of 17-year-old twins (568 girls and 479 boys) participating in the Minnesota Twin Family Study. Whether offspring personality characteristics 1) are specific to the type of substance use disorder in parents (alcohol versus drug) and 2) are found in high-risk offspring without substance use disorders as well as in offspring with substance use disorders was investigated. Personality was assessed with the Multidimensional Personality Questionnaire; substance use disorders were assessed in person through diagnostic interviews. In both male and female offspring, parental history of alcohol dependence was associated with greater negative emotionality, aggression, stress reaction, and alienation but lower well-being; parental history of drug disorders was associated with lower constraint, control, harm avoidance, and traditionalism but higher social potency. Excluding offspring with a substance use disorder had virtually no effect on the statistical significance of these findings. In contrast to findings in some adult samples, personality characteristics associated with a family history of substance use disorders are found even in adolescent offspring who have not yet developed these disorders themselves, suggesting that personality might be one indicator of familial risk for substance use disorders during this developmental stage. Personality profiles of offspring of parents with substance use disorders also show some diagnostic specificity, with constraint associated with parental drug abuse and negative emotionality with parental alcoholism.


The relationship between cardiac dosimetry and tumour quadrant location in left sided whole breast and chest wall adjuvant radiotherapy.
Radiotherapy after breast surgery decreases locoregional recurrence and improves survival. This is not without risks from radiation exposure and could have implications in clinical practice. Our study investigates the correlation between tumour location and radiation dose to the heart. Left-sided breast cancer patients who had radiotherapy at Aberdeen Royal Infirmary in 2010 were identified. Tumour location was established from notes and imaging. Radiotherapy planning scans were reviewed, and cardiac doses calculated. The mean cardiac dose, maximum dose and volume of the heart in the field, along with V5-V40, were determined. 40 patients had mastectomies and 118 breast conserving surgery. The median percentage of the heart in the field and the Interquartile Range was 0.59% (0.03-1.74) for all patients, with the highest for lower inner quadrant (LIQ) tumours 1.20% (0.29-2.40), followed by mastectomy 0.94% (0.02-1.82). The mean heart dose showed a higher median for mastectomies 1.59 Gy (1.00-1.94), followed by LIQ tumours 1.58 Gy (1.31-2.28), with an overall median of 1.42 Gy (1.13-1.95). The median percentage of the heart in the field, the mean cardiac dose and V5-V30 did not reach statistical significance, however, V40 and the maximum dose did. The benefits of radiotherapy after breast cancer surgery are established, but with potential harm from cardiac exposure. Our cohort showed higher radiation exposure to the heart in patients with LIQ tumours and mastectomies but reached significance only for V40 and maximum dose. This highlights tumour location as a potentially important risk factor for cardiac exposure with breast radiotherapy.


Reduction of retinal ganglion cell death in mouse models of familial dysautonomia using AAV-mediated gene therapy and splicing modulators.
Familial dysautonomia (FD) is a rare neurodevelopmental and neurodegenerative disease caused by a splicing mutation in the Elongator Acetyltransferase Complex Subunit 1 ( ELP1 ) gene. The reduction in ELP1 mRNA and protein leads to the death of retinal ganglion cells (RGCs) and visual impairment in all FD patients. Currently, patient symptoms are managed, but there is no treatment for the disease. We sought to test the hypothesis that restoring levels of Elp1 would thwart the death of RGCs in FD. To this end, we tested the effectiveness of two therapeutic strategies for rescuing RGCs. Here we provide proof-of-concept data that gene replacement therapy and small molecule splicing modifiers effectively reduce the death of RGCs in mouse models for FD and provide pre-clinical data foundation for translation to FD patients.


Heparin sensitivity and resistance in the neonate: an explanation.
Based on in vitro tests, newborns are reported to be both sensitive and resistant to standard heparin (SH) compared to adults. The sensitivity to SH occurs in assays based on de novo thrombin generation, and SH resistance occurs in systems where exogenous thrombin is added to newborn plasma. We hypothesized that this apparent paradox is related to the antithrombin III to (pro) thrombin ratio associated with each test. Since SH catalyses the activity of antithrombin III, any imbalance in the antithrombin III/(pro)thrombin ratio in newborns compared to adults would be amplified by SH. If the ratio of antithrombin III/(pro)thrombin is defined as 1 in adults, in comparison newborns have a ratio of 1.5. We compared how various doses of SH (0.1 to 0.6 u/ml) inhibited the generation of endogenous thrombin in defibrinated newborn (N) and adult (A) plasma. Following contact activation and recalcification of each plasma, thrombin activity was measured using a chromogenic substrate and quantitated by measuring the area under the curve. In the presence of SH, newborn plasma was more sensitive to SH than adult plasma and generated relatively less thrombin (N:6.1 vs A:9.1% sec/u/ml; p less than 0.01). When the ratio of antithrombin III/(pro)thrombin in newborns was altered to 2.5 by exogenous antithrombin III, the SH sensitivity was increased. This plasma now generated no detectable thrombin in the presence of only 0.1 u/ml of SH. In contrast, when the ratio of antithrombin III/(pro) thrombin of the newborn was altered by exogenous prothrombin to 0.6, this plasma now became resistant to SH and generated more thrombin than adults in the presence of SH (N:11.6 vs A:9.1; p less than 0.01). Because of the potential use of low molecular weight heparins (LMWH) in newborns, a LMWH, Choay 222, was also tested in a similar fashion and gave similar results to SH. Thus, the ratio of antithrombin III/(pro)thrombin likely determines the in vitro sensitivity or resistance of newborn plasma to SH and LMWH. There are no clinical studies that determine if newborns require more or less SH than the adult to successfully treat thrombotic complications. Current practice is a simple extrapolation of therapeutic ranges from adults. We speculate that the efficacy and safety of SH in the newborn in vivo can be improved by altering the antithrombin III/(pro)thrombin ratio.


Incidence and clinical course of thrombotic thrombocytopenic purpura due to ticlopidine following coronary stenting. EPISTENT Investigators. Evaluation of Platelet IIb/IIIa Inhibitor for Stenting.
Thrombotic thrombocytopenic purpura (TTP) is a rare and often fatal disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, mental status changes, and renal dysfunction. Ticlopidine hydrochloride is 1 of several drugs that have been associated with this disorder and is currently used routinely in the approximately 500000 patients per year in the United States who undergo a percutaneous coronary intervention involving a stent. To determine the incidence and describe the clinical course of TTP due to ticlopidine therapy following stenting. Retrospective analysis of cohort of all patients undergoing coronary stenting at the Evaluation of Platelet IIb/IIIa Inhibitor for Stenting (EPISTENT) study sites. Sixty-three centers throughout the United States and Canada. A total of 43322 patients who underwent a percutaneous coronary intervention and received a coronary stent during a 1-year period from 1996 to 1997. Cases of TTP following stenting during the 1-year period to determine the incidence of TTP due to ticlopidine therapy following coronary stenting. Additional cases were collected from these and other centers across North America to further describe the clinical presentation and course of TTP due to ticlopidine therapy following stenting. Nine cases of TTP following stenting were recognized at the 63 centers during the specified period, giving an incidence of 1 case per 4814 patients treated (0.02%; 95% confidence interval, 1 case per 2533 to 1 case per 10 541 patients treated). Ten additional cases of TTP related to ticlopidine therapy following stenting were identified from other centers, were identified from the primary centers outside the pre-defined period, or involved a noncoronary stent. Four patients (21%) received ticlopidine for 2 weeks or fewer, 14 patients (74%) for 2 to 4 weeks, and 1 patient (5%) for 8 weeks. The mean time of ticlopidine treatment prior to TTP diagnosis was 22 days (range, 5-60 days). The overall mortality rate was 21% (4/19), with all 4 deaths occurring in patients not treated with plasmapheresis, whereas there were no deaths among the 13 patients who received plasmapheresis. The findings of a TTP incidence of 0.02% in our cohort of ticlopidine-treated patients following coronary stenting suggests that TTP occurs much more commonly in this population than the estimated incidence of 0.0004% in the general population. The mortality rate for this rare complication exceeds 20%. Limiting ticlopidine therapy to 2 weeks after stenting does not prevent the development of TTP. Rapid diagnosis and treatment that includes plasmapheresis are critical for improved survival.


Solvent-induced infrared frequency shifts in aromatic nitriles are quantitatively described by the vibrational Stark effect.
The physical properties of solvents strongly affect the spectra of dissolved solutes, and this phenomenon can be exploited to gain insight into the solvent-solute interaction. The large solvatochromic shifts observed for many dye molecules in polar solvents are due to variations in the solvent reaction field, and these shifts are widely used to estimate the change in the dye's dipole moment upon photoexcitation, which is typically on the order of ∼1-10 D. In contrast, the change in dipole moment for vibrational transitions is approximately 2 orders of magnitude smaller. Nonetheless, vibrational chromophores display significant solvatochromism, and the relative contributions of specific chemical interactions and electrostatic interactions are debated, complicating the interpretation of vibrational frequency shifts in complex systems such as proteins. Here we present a series of substituted benzonitriles that display widely varying degrees of vibrational solvatochromism. In most cases, this variation can be quantitatively described by the experimentally determined Stark tuning rate, coupled with a simple Onsager-like model of solvation, reinforcing the view that vibrational frequency shifts are largely caused by electrostatic interactions. In addition, we discuss specific cases where continuum solvation models fail to predict solvatochromic shifts, revealing the necessity for more advanced theoretical models that capture local aspects of solute-solvent interactions.


Improved protein quality in transgenic soybean expressing a de novo synthetic protein, MB-16.
To improve soybean [Glycine max (L.) Merrill] seed nutritional quality, a synthetic gene, MB-16 was introduced into the soybean genome to boost seed methionine content. MB-16, an 11 kDa de novo protein enriched in the essential amino acids (EAAs) methionine, threonine, lysine and leucine, was originally developed for expression in rumen bacteria. For efficient seed expression, constructs were designed using the soybean codon bias, with and without the KDEL ER retention sequence, and β-conglycinin or cruciferin seed specific protein storage promoters. Homozygous lines, with single locus integrations, were identified for several transgenic events. Transgene transmission and MB-16 protein expression were confirmed to the T5 and T7 generations, respectively. Quantitative RT-PCR analysis of developing seed showed that the transcript peaked in growing seed, 5-6 mm long, remained at this peak level to the full-sized green seed and then was significantly reduced in maturing yellow seed. Transformed events carrying constructs with the rumen bacteria codon preference showed the same transcription pattern as those with the soybean codon preference, but the transcript levels were lower at each developmental stage. MB-16 protein levels, as determined by immunoblots, were highest in full-sized green seed but the protein virtually disappeared in mature seed. However, amino acid analysis of mature seed, in the best transgenic line, showed a significant increase of 16.2 and 65.9 % in methionine and cysteine, respectively, as compared to the parent. This indicates that MB-16 elevated the sulfur amino acids, improved the EAA seed profile and confirms that a de novo synthetic gene can enhance the nutritional quality of soybean.


[High prevalence of genotype 1 in individuals with hepatitis C in Belo Horizonte, MG].
The hepatitis C virus is characterized by significant genetic heterogeneity. It is currently classified into six main genotypes and several subtypes. Determining the genotype of the virus is important in clinical practice for guiding the treatment for individuals with chronic hepatitis C. The prevalence of different genotypes and subtypes of the hepatitis C virus has not been fully studied in some regions of Brazil. In this study, 788 samples from patients with chronic hepatitis C who were attended at the Viral Hepatitis Reference Centers in Belo Horizonte were analyzed between 2002 and 2006. The genotyping of the virus was performed by direct sequencing of the 5 UTR region. Additionally, phylogenetic analysis was performed, including all of the genotypic variants obtained. High prevalence of genotype 1 (78.4%; 1b [40.4%], 1a [37.5%] and 1a/b [0.5%]) was observed, followed by genotypes 3a (17.9%) and 2b (3.1%). Three samples were identified as genotype 2a/c (0.4%) and two as genotype 4 (0.2%). The phylogenetic analysis showed the expected segregation of the sequences obtained, with regard to the reference sequences for genotypes 1, 2, 3 and 4, except for two samples of genotype 1a. The high prevalence of genotype 1 (78.4%) found in this population from Belo Horizonte was similar to previous reports from other cities such as Rio de Janeiro, but it was higher than what has been described in São Paulo and in the south of the country. The presence of rare atypical sequences from the 5 UTR region suggests that variants in the hepatitis C virus exist in this population.


[Assessment of an ELISA for the detection of antibodies against HIV-1 protein p24].
DAVIH AC p24 kit for detecting anti p24 antibodies of HIV-1, worked out by the National Laboratory of Reference of AIDS (Labor-1, Cuba) is assessed and results are compared to those of the Western Blot technique (DAVIH-Blot, Labor-1, Cuba). 191 samples from HIV positive patients at various stages of the disease were analyzed. 96% sensitivity; 100% specificity and 96.3% coincidence were found in both techniques. The anti p-24 ELISA-DAVIH system is a good alternative for the follow-up of HIV positive patients.


Cerebral MRI and EEG studies in the initial management of pediatric headaches.
High resolution imaging modalities and electroencephalographic studies (EEG) are used in the assessment of children with headaches. We evaluated the role of cerebral MRI (cMRI) and EEG in the initial assessment of children with headache as the chief complaint of initial presentation. A retrospective chart analysis was performed at a tertiary University Hospital. 209 patients were included in this study [mean age 11.3 years; male 91 (43.5%); female 118 (56.5%)]. The following types of headaches were seen: Unclassified headache: 23.4%; probable migraine 17.2%, migraine without aura 13.4%, complicated migraine 12.4%, migraine with aura 1.0%; tension-type 15.3%, and cluster headaches 0.5%, and secondary headaches 16.7%. In 93 children (44.5%) abnormal physical/neurological findings were noted (multiple entries possible). On cMRI studies the following findings were seen: Infection of sinuses (7.2%), pineal cysts (2.4%), arachnoidial cyst and Chiari malformation (1.9%), unspecified signal enhancement (1.0%), and pituitary enlargement, inflammatory lesion, angioma, cerebral ischaemia, and intra-cerebral cyst (each 0.5%). Electroencephalographic findings included both focal and generalised abnormal slowing (5.3%) and Spike-wave complexes (3.3%). Despite abnormal findings on neurological/physical examination in a substantial number of children with headaches, the yield of pathological cMRIs was low. The use of EEG recordings was not contributory to the diagnostic and therapeutic approach. More research is needed to better define those patients who are likely to have an intracranial pathology.


Altered structural connectivity and functional brain dynamics in individuals with heavy alcohol use.
Heavy alcohol use and its associated conditions, such as alcohol use disorder (AUD), impact millions of individuals worldwide. While our understanding of the neurobiological correlates of AUD has evolved substantially, we still lack models incorporating whole-brain neuroanatomical, functional, and pharmacological information under one framework. Here, we utilize diffusion and functional magnetic resonance imaging to investigate alterations to brain dynamics in N = 130 individuals with a high amount of current alcohol use. We compared these alcohol using individuals to N = 308 individuals with minimal use of any substances. We find that individuals with heavy alcohol use had less dynamic and complex brain activity, and through leveraging network control theory, had increased control energy to complete transitions between activation states. Further, using separately acquired positron emission tomography (PET) data, we deploy an in silico evaluation demonstrating that decreased D2 receptor levels, as found previously in individuals with AUD, may relate to our observed findings. This work demonstrates that whole-brain, multimodal imaging information can be combined under a network control framework to identify and evaluate neurobiological correlates and mechanisms of AUD.


The future is continuous quality improvement.
The SSM Health Care System is a Catholic, not-for-profit, multihospital health care system with headquarters in St. Louis, Missouri. Sister Mary Jean Ryan, FSM, the President and Chief Executive Officer, has led the implementation of continuous quality improvement (CQI) throughout the system since 1990. This article presents excerpts from a speech Sister Ryan delivered at the system's annual leadership conference in 1990. Sister Ryan delivered this speech at the conclusion of a retreat where the principles of CQI were introduced to the SSM Health Care System leadership. The editors believe this inspiring speech provides insight into the kind of leadership needed to successfully implement quality management.


Growth, carcass and palatability traits of intact males and steers implanted with zeranol or estradiol early and throughout life.
This study was conducted to assess the impact of implanting intact beef males with protein anabolic agents at varying intervals throughout life. Ninety-six intact males were assigned to three implant treatments: 1) not implanted, 2) implanted at 9 wk of age, weaning and at 56-d intervals thereafter with a 36-mg zeranol implant or 3) estradiol implant at 9 wk of age and 68 d post-weaning. During the 118-d, post-weaning growing period, eight animals per treatment (one replication) were castrated. After a 114-d finishing period, cattle were slaughtered (average age of 13 to 14 mo). Feedlot performance, carcass and palatability data were obtained. Average daily gains and feed efficiency did not differ (P greater than .05) between zeranol and estradiol-implanted intact males. Regardless of implant treatment, steers had lighter carcass weights (P less than .05) and higher (P less than .01) quality grades than intact males. Implanting either intact males or steers with zeranol or estradiol resulted in higher (P less than .05) numerical yield grades. Quality grades were higher in zeranol-implanted cattle than the non-implanted or estradiol-implanted cattle. Intact males implanted with zeranol were similar in carcass fatness to zeranol-implanted steers. No differences (P greater than .05) in tenderness or connective tissue were detected. Implanting intact males early and throughout life with zeranol made them similar to steers in fatness, while estradiol implantation had few effects on carcass and palatability traits of intact males or steers.


Computational solutions in redox lipidomics - Current strategies and future perspectives.
The high chemical diversity of lipids allows them to perform multiple biological functions ranging from serving as structural building blocks of biological membranes to regulation of metabolism and signal transduction. In addition to the native lipidome, lipid species derived from enzymatic and non-enzymatic modifications (the epilipidome) make the overall picture even more complex, as their functions are still largely unknown. Oxidized lipids represent the fraction of epilipidome which has attracted high scientific attention due to their apparent involvement in the onset and development of numerous human disorders. Development of high-throughput analytical methods such as liquid chromatography coupled on-line to mass spectrometry provides the possibility to address epilipidome diversity in complex biological samples. However, the main bottleneck of redox lipidomics, the branch of lipidomics dealing with the characterization of oxidized lipids, remains the lack of optimal computational tools for robust, accurate and specific identification of already discovered and yet unknown modified lipids. Here we discuss the main principles of high-throughput identification of lipids and their modified forms and review the main software tools currently available in redox lipidomics. Different levels of confidence for software assisted identification of redox lipidome are defined and necessary steps toward optimal computational solutions are proposed.


Transgender transitioning and change of self-reported sexual orientation.
Sexual orientation is usually considered to be determined in early life and stable in the course of adulthood. In contrast, some transgender individuals report a change in sexual orientation. A common reason for this phenomenon is not known. We included 115 transsexual persons (70 male-to-female "MtF" and 45 female-to-male "FtM") patients from our endocrine outpatient clinic, who completed a questionnaire, retrospectively evaluating the history of their gender transition phase. The questionnaire focused on sexual orientation and recalled time points of changes in sexual orientation in the context of transition. Participants were further asked to provide a personal concept for a potential change in sexual orientation. In total, 32.9% (n = 23) MtF reported a change in sexual orientation in contrast to 22.2% (n = 10) FtM transsexual persons (p = 0.132). Out of these patients, 39.1% (MtF) and 60% (FtM) reported a change in sexual orientation before having undergone any sex reassignment surgery. FtM that had initially been sexually oriented towards males ( = androphilic), were significantly more likely to report on a change in sexual orientation than gynephilic, analloerotic or bisexual FtM (p = 0.012). Similarly, gynephilic MtF reported a change in sexual orientation more frequently than androphilic, analloerotic or bisexual MtF transsexual persons (p =0.05). In line with earlier reports, we reveal that a change in self-reported sexual orientation is frequent and does not solely occur in the context of particular transition events. Transsexual persons that are attracted by individuals of the opposite biological sex are more likely to change sexual orientation. Qualitative reports suggest that the individual's biography, autogynephilic and autoandrophilic sexual arousal, confusion before and after transitioning, social and self-acceptance, as well as concept of sexual orientation itself may explain this phenomenon.


Telepsychiatry with rural American Indians: issues in civil commitments.
The use of live interactive videoconferencing to provide psychiatric care, telepsychiatry, has particular relevance for improving mental health treatment to rural American Indian reservations. There is little literature on civil commitments in telepsychiatry and none specifically addressing this topic among American Indians. This article reviews telepsychiatry in the mental health care of American Indians, civil commitments and telepsychiatry in general, and the current state of civil commitments in American Indian communities. We conclude by considering commitment through telepsychiatry in rural reservations and offering guidelines to assist practitioners in navigating this challenging landscape. Civil commitments of American Indian patients residing in rural reservations can be successfully accomplished through videoconferencing by thoughtful and informed clinicians. However, much more work is needed in this area, including research into the cultural attitudes and perspectives towards commitments and further inquiry regarding potential legal precedents, as well as case reports and examples of this work.


Nr2e3 is a genetic modifier that rescues retinal degeneration and promotes homeostasis in multiple models of retinitis pigmentosa.
Recent advances in viral vector engineering, as well as an increased understanding of the cellular and molecular mechanism of retinal diseases, have led to the development of novel gene therapy approaches. Furthermore, ease of accessibility and ocular immune privilege makes the retina an ideal target for gene therapies. In this study, the nuclear hormone receptor gene Nr2e3 was evaluated for efficacy as broad-spectrum therapy to attenuate early to intermediate stages of retinal degeneration in five unique mouse models of retinitis pigmentosa (RP). RP is a group of heterogenic inherited retinal diseases associated with over 150 gene mutations, affecting over 1.5 million individuals worldwide. RP varies in age of onset, severity, and rate of progression. In addition, ~40% of RP patients cannot be genetically diagnosed, confounding the ability to develop personalized RP therapies. Remarkably, Nr2e3 administered therapy resulted in reduced retinal degeneration as observed by increase in photoreceptor cells, improved electroretinogram, and a dramatic molecular reset of key transcription factors and associated gene networks. These therapeutic effects improved retinal homeostasis in diseased tissue. Results of this study provide evidence that Nr2e3 can serve as a broad-spectrum therapy to treat multiple forms of RP.


Soft Mango Firmness Assessment Based on Rayleigh Waves Generated by a Laser-Induced Plasma Shock Wave Technique.
Many methods based on acoustic vibration characteristics have been studied to indirectly assess fruit ripeness via fruit firmness. Among these, the frequency of the 0S2 vibration mode measured on the equator has been examined, but soft-flesh fruit do not show the 0S2 vibration mode. In this study, a Rayleigh wave is generated on a soft mango fruit using the impulse excitation force generated by a laser-induced plasma shock wave technique. Then, the flesh firmness of mangoes is assessed in a non-contact and non-destructive manner by observing the Rayleigh wave propagation velocity because it is correlated with the firmness (shear elasticity), density, and Poisson's ratio of an object. If the changes in the density and Poisson's ratio are small enough to be ignored during storage, then the Rayleigh wave propagation velocity is strongly correlated to fruit firmness. Here, we measure the Rayleigh wave propagation velocity and investigate the effect of storage time. Specifically, we investigate the changes in firmness caused by ripening. The Rayleigh wave propagation velocity on the equator of Kent mangoes tended to decrease by over 4% in 96 h. The Rayleigh wave measured on two different lines propagated independent distance and showed a different change rate of propagation velocity during 96-h storage. Furthermore, we consider the reliability of our method by investigating the interaction of a mango seed on the Rayleigh wave propagation velocity.


Effects of sodium nitroprusside on left ventricular diastolic pressure-volume relations.
The effect of sodium nitroprusside on the relationship between left ventricular pressure and volume during diastole was studied in 11 patients with congestive heart failure. Nitroprusside was infused to lower mean arterial pressure approximately 20-30 mm Hg. High fidelity left ventricular pressures were recorded in all patients simultaneously with left ventricular cineangiography (biplane in eight and single plane in three patients), allowing precise measurement of pressure and volume throughout the cardiac cycle. Left ventricular diastolic pressure-volume curves were constructed in each patient from data obtained before and during nitroprusside infusion. In 9 of 11 patients there was a substantial downward displacement of the diastolic pressure-volume curve during nitroprusside infusion, with left ventricular pressure being lower for any given volume with nitroprusside. Serial left ventricular cineangiograms performed 15 min apart in six additional subjects who did not receive sodium nitroprusside showed no shift in the diastolic pressure-volume relation, indicating that the shift seen with nitroprusside was not due to the angiographic procedure itself. A possible explanation for the altered diastolic pressure-volume relationships with nitroprusside might be a direct relaxant effect of nitroprusside on ventricular muscle, similar to its known relaxant effect on vascular smooth muscle. Alternatively, nitroprusside may affect the diastolic pressure-volume curve by affecting viscous properties or by altering one or more of the extrinsic constraints acting upon the left ventricle.


Recurrent hypoglycemia secondary to metformin toxicity in the absence of co-ingestions: a case report.
Metformin toxicity is well known to cause lactic acidosis. Multiple cases of hypoglycemia due to isolated metformin overdose have been reported. Increased glucose consumption secondary to anaerobic metabolism has been reported as a possible explanation. A 23-year-old Arabic woman took 30 g of metformin. In the emergency department, 4 hours after of the event, she was fatigued but vitally stable. During her hospitalization, she had severe lactic acidosis, hypotension corrected with fluid boluses and vasopressors, and multiple episodes of hypoglycemia (6.3 mg/dL, 38 mg/dL, and 42 mg/dL), requiring multiple 50% dextrose-water boluses. The three hypoglycemic episodes occurred coincident with severe lactic acidosis. She improved after 24 hours of continuous renal replacement therapy. Hypoglycemia can be induced by metformin toxicity in the absence of co-ingestants. A possible explanation of metformin-induced hypoglycemia is increased glucose consumption due to anaerobic metabolism, decreased oral intake, decreased liver glucose production, and decreased glucose absorption.


Copolymerization of epoxides and carbon dioxide. Evidence supporting the lack of dual catalysis at a single metal site.
The chromium tetramethyltetraazaannulene catalyst system, Cr(tmtaa)Cl in the presence of a quaternary organic salt, has been employed to further investigate the mechanism of polycarbonate formation between cyclohexene oxide and carbon dioxide. Although the features of the proposed mechanism are generally well-accepted, the question of whether polymer chain propagation occurs from one side of the catalyst in a mono catalytic single-site fashion or from both sides of the N(4)-ligand plane in a dual catalytic manner. To probe this behavior, the ligand architecture was altered by the addition of a sterically encumbering strap (Cr(stmtaa)Cl), which effectively blocks one side of the complex and limits polymer chain growth to a single side of the catalyst. For direct comparison, an electronically similar catalyst, Cr(s(m)tmtaa)Cl, was prepared to mimic the strap complex while not possessing the site-blocking steric restraints of the full strap. Infrared spectroscopy demonstrated an uptake of 2 equiv of PPNN(3) cocatalyst by the strap mimic catalyst, while only 1 equiv of azide was able to bind to the catalyst containing the full strap, supporting the design function of both complexes. Monitoring the formation of poly(cyclohexylene carbonate) from the reaction of cyclohexene oxide and carbon dioxide via in situ infrared spectroscopy for both Cr(stmtaa)Cl and Cr(s(m)tmtaa)Cl, under identical conditions, revealed copolymer formation at essentially equivalent rates. Analysis of the polycarbonate products found that Cr(stmtaa)Cl and Cr(s(m)tmtaa)Cl produced copolymers with turnover frequencies of 806.6 and 797.3 h(-1), molecular weights of 11,431 and 12,003 Da, and polydispersities of 1.108 and 1.048, respectively. These results strongly support the idea that this and other catalysts systems presumed to operate by a similar process, such as Cr(salen)X, catalyze the copolymerization of epoxides with carbon dioxide through a mono catalytic single-site mechanism.


Middle cerebral artery velocity during head-up tilt induced hypovolaemic shock in humans.
Middle cerebral artery mean velocity (Vmean) and pulsatility index (PI) were followed during head-up tilt induced hypovolaemic shock in nine subjects. Mean arterial pressure (MAP), heart rate (HR), central venous pressure (CVP) and thoracic (TI) electrical impedance were also recorded. Vmean, PI, and CVP did not change during head-up tilt to 50 degrees, while MAP increased from 92 (81-106) (median and range) to 100 (97-112) mmHg, HR from 63 (53-74) to 84 (68-89) beats min-1 and TI100kHz from 30 (27-36) to 32 (30-39) Ohm (P < 0.01) (n = 8). During maintained tilt, Vmean decreased from 52 (32-72) to 34 (16-59) cm s-1, whereas HR increased to 87 (52-108) beats min-1 and TI100 kHz to 33 (31-39) Ohm (P < 0.01). Presyncopal symptoms appeared after 33 (3-46) min and were associated with a MAP of 65 (32-84) mmHg (P < 0.01) and a HR of 58 (52-71) beats min-1 (P < 0.05). Vmean decreased to 25 (16-36) cm s-1, and cerebral conductance index (Vmean/MAPbrain) and PI increased (P < 0.01). Arterial collapse was observed (diastolic velocity of zero) in one subject at a brain (diastolic) blood pressure of 21 mmHg and he developed tachycardia (131 beats min-1) during presyncope. PaCO2 did not change. Maintained tilt resulted in central volume depletion reflected by changes in MAP, HR, and thoracic electrical impedance but not in CVP. Transcranial Doppler derived indices of cerebral perfusion demonstrated critically low values despite marked increase in conductance index.


Essential Attributes of Clear Aligner Therapy in terms of Appliance Configuration, Hygiene, and Pain Levels during the Pandemic: A Brief Review.
Fixed orthodontic treatment has been compromised at many levels during the pandemic period, as clinics underwent a prolonged lockdown and patients could not be treated regularly. With the end of the pandemic nowhere in sight, may be it is time to put newer tools, such as clear aligner therapy, for better use. Fixed orthodontic appliances by nature are not always self-limiting, which, if left unmonitored over a long period may cause undesirable side effects, pain, and discomfort. The undesired tooth movements that may occur with arch wire-guided mechanics in addition to problems with cut wires or removed brackets may be minimized with the use of aligners. While the benefits of using aligners are for all to see, they do require extensive planning and careful evaluation of the progress. This article reviews the advantages of using aligners during the pandemic period and how it can be beneficial in helping orthodontists resume their practice.


A single case of MRI-guided focused ultrasound ventro-oral thalamotomy for musician's dystonia.
Musician's dystonia (MD) is a type of focal hand dystonia that develops only while playing musical instruments and interferes with skilled and fine movements. Lesioning of the ventro-oral (Vo) nucleus of the thalamus (Vo-thalamotomy) using radiofrequency can cause dramatic improvement in MD symptoms. Focused ultrasound (FUS) can make intracranial focal lesions without an incision. The authors used MRI-guided FUS (MRgFUS) to create a lesion on the Vo nucleus to treat a patient with MD. Tubiana's MD scale (TMDS) was used to evaluate the condition of musical play ranging from 1 to 5 (1: worst, 5: best). The patient was a 35-year-old right-handed man with involuntary flexion of the right second, third, and fourth fingers, which occurred while playing a classical guitar. Immediately after therapeutic sonications of FUS Vo-thalamotomy, there was dramatic improvement in the MD symptoms. The TMDS scores before; at 0 and 1 week after; and at 1, 3, 6, and 12 months after MRgFUS Vo-thalamotomy were 1, 4, 4, 5, 5, 5, and 5, respectively. No complications were observed. Focused ultrasound Vo-thalamotomy can be an effective treatment for MD.


The Effect of a Federal Controlled Substance Act Schedule Change on Hydrocodone Combination Products Claims in a Medicaid Population.
In 2012, hydrocodone combination products (HCPs) were the most prescribed medications in the United States. Under the Controlled Substance Act of 1970, hydrocodone alone was classified as a Schedule II drug, while HCPs were classified as Schedule III, indicating a lower risk for abuse and misuse. However, according to a Drug Enforcement Agency analysis, the addition of nonopioids has not been shown to diminish abuse potential of hydrocodone. In response to concerns for drug abuse and overdose, the Drug Enforcement Agency rescheduled HCPs to Schedule II in October 2014, with the intent of limiting overprescribing and increasing awareness of their abuse potential. However, it is unknown whether this has affected the overall claims for HCPs in a Medicaid population. To (a) compare the trend in HCP prescription claims with select non-HCP (opioid and nonopioid) analgesic claims before and after the HCP schedule change in the Massachusetts Medicaid fee-for-service/Primary Care Clinician plan population and (b) identify if there was a change in HCP new start member and claim characteristics before and after the HCP schedule change. This quasi-experimental, retrospective study used enrollment and pharmacy claims data to evaluate all members in the study population 1 year before and after the HCP schedule change. The number of claims for HCPs and select non-HCP analgesics was reported as the monthly rate per total population, and an interrupted time series analysis compared the change in the monthly rate of claims across groups. Members with 1 or more pharmacy claims for a new HCP prescription during a 5-month period before or after the HCP schedule change were analyzed to determine member demographics (age, gender, and number of claims) and claim characteristics (average daily dose, average quantity per claim, and days supply). The rate of HCP claims increased before and decreased after the HCP schedule change. Controlling for the trend during the period before the HCP schedule change, the rate of HCP claims per 1,000 members per month decreased at a greater rate than non-HCP analgesics in the period after the HCP schedule change (P < 0.001). The percentage of HCP claims for new start members decreased after the HCP schedule change (44.9% vs. 34.1% of all HCP claims pre- to post-schedule change; P < 0.001). In the group of new starts, there was not a significant difference in the average daily dose (26.3 mg vs. 26.4 mg; P = 0.69), while there was a decrease in average number of tablets dispensed per claim (from 37.1 to 20.3 tablets; P < 0.001) and an increase in the percentage of claims for a shorter days supply (from 57.7% to 81.6%; P < 0.001). The findings of this study suggest that the HCP schedule change may have contributed to the decrease in claims for HCPs in a Medicaid population. After the HCP schedule change, there was a trend towards decreased HCP use among new starts. No outside funding supported this study. The authors have nothing to disclose. Study concept and design were contributed by all authors except for Arnold and Clements. Tran, Arnold, and Clements took the lead in data collection, along with Peristere, and data interpretation was performed by all the authors, except Arnold. The manuscript was written primarily by Tran, along with Lavitas, Stevens, and Greenwood, and revised by all the authors except Arnold and Peristere. A poster of this research project was presented at the Academy of Managed Care Pharmacy's 2016 Annual Meeting in San Francisco, California, April 2016.


Complete sequence and molecular epidemiology of IncK epidemic plasmid encoding blaCTX-M-14.
Antimicrobial drug resistance is a global challenge for the 21st century with the emergence of resistant bacterial strains worldwide. Transferable resistance to β-lactam antimicrobial drugs, mediated by production of extended-spectrum β-lactamases (ESBLs), is of particular concern. In 2004, an ESBL-carrying IncK plasmid (pCT) was isolated from cattle in the United Kingdom. The sequence was a 93,629-bp plasmid encoding a single antimicrobial drug resistance gene, blaCTX-M-14. From this information, PCRs identifying novel features of pCT were designed and applied to isolates from several countries, showing that the plasmid has disseminated worldwide in bacteria from humans and animals. Complete DNA sequences can be used as a platform to develop rapid epidemiologic tools to identify and trace the spread of plasmids in clinically relevant pathogens, thus facilitating a better understanding of their distribution and ability to transfer between bacteria of humans and animals.


Dieulafoy's lesion: an obscure cause of GI bleeding.
Dieulafoy's lesion is an uncommon cause of major gastrointestinal bleeding and may be difficult to recognise. It consists of an arteriole that protrudes through a tiny mucosal defect, usually within 6 cm of the gastroesophageal junction on the lesser curve of the stomach. Similar lesions have also been described in the distal oesophagus, small intestine, colon, and rectum. Awareness of the condition and experience in endoscopy are the mainstay of diagnosis. Therapeutic endoscopy is the first line of treatment. It is safe, effective and has very good long term results.


Rotational Control of Asymmetric Molecules: Dipole- versus Polarizability-Driven Rotational Dynamics.
We experimentally study the optical- and terahertz-induced rotational dynamics of asymmetric molecules in the gas phase. Terahertz and optical fields are identified as two distinct control handles over asymmetric molecules, as they couple to the rotational degrees of freedom via the molecular dipole and polarizability selectively. The distinction between those two rotational handles is highlighted by different types of quantum revivals observed in long-duration (>100 ps) field-free rotational evolution. The experimental results are in excellent agreement with random phase wave function (RPWF) simulations [Phys. Rev. A 91, 063420 (2015)] and provide verification of the RPWF as an efficient method for calculating asymmetric molecular dynamics at ambient temperatures, where exact calculation methods are practically not feasible. Our observations and analysis pave the way for orchestrated excitations by both optical and terahertz fields as complementary rotational handles that enable a plethora of new possibilities in three-dimensional rotational control of asymmetric molecules.


Advances in new targets for immunotherapy of small cell lung cancer.
Small cell lung cancer (SCLC) is one of the highly aggressive malignancies characterized by rapid growth and early metastasis, but treatment options are limited. For SCLC, carboplatin or cisplatin in combination with etoposide chemotherapy has been considered the only standard of care, but the standard first-line treatment only results in 10-month survival. The majority of patients relapse within a few weeks to months after treatment, despite the relatively sensitive response to chemotherapy. Over the past decade, immunotherapy has made significant progress in the treatment of SCLC patients. However, there have been limited improvements in survival rates for SCLC patients with the current immune checkpoint inhibitors PD-1/PD-L1 and CTLA-4. In the face of high recurrence rates, small beneficiary populations, and low survival benefits, the exploration of new targets for key molecules and signals in SCLC and the development of drugs with novel mechanisms may provide fresh hope for immunotherapy in SCLC. Therefore, the aim of this review was to explore four new targets, DLL3, TIGIT, LAG-3, and GD2, which may play a role in the immunotherapy of SCLC to find useful clues and strategies to improve the outcome for SCLC patients.


Development of an instrument to measure caring peer group interactions.
The purpose of this study was to develop psychometric properties of the Peer Group Caring Interaction Scale (PGCIS) designed to measure caring during informal peer interactions as experienced by undergraduate nursing students. The PGCIS has two subscales that address caring peer behaviors and interactional events during which students assist their peers in the resolution of specific needs. PGCIS psychometric properties were developed using data from 873 junior students enrolled at 87 BSN schools of nursing. Internal consistency reliability was demonstrated for the 9-item Caring Behaviors and the 7-item Giving Assistance subscales with a coefficient alpha of .91 for each. Findings from an exploratory factor analysis supported the two subscale structure of the PGCIS. The PGCIS scores correlated positively with scores on the Intimacy subscale of the Organization Climate Description Questionnaire (OCDQ) and the Peer Group Interaction Scale and inversely with scores on the OCDQ Disengagement subscale. The findings from this study provide beginning support for the PCGIS as a valid and reliable approach to the measurement of caring in academic settings. Additional studies are recommended to continue the psychometric evaluation of this instrument.


Association between renal vasculature changes and generalized atherosclerosis: an autopsy survey.
To examine the association between renal vasculature changes and generalized atherosclerosis using autopsy cases. We histologically examined 107 autopsy patients(mean age, 68.4 years; 64% men; 81% non-CVD) to investigate the association between renal vasculature changes and generalized atherosclerosis. We measured the intima/media(I/M) ratio for the renal, intrarenal and systemic arteries(coronary, cerebral, common carotid and common iliac), calculated the rates of arteriolar hyalinization and global glomerulosclerosis and evaluated the frequency of advanced lesions(AHA classification ≥IV) in the systemic arteries. The I/M ratios of the renal and intrarenal arteries and the rate of global glomerulosclerosis increased with age, while the rates of arteriolar hyalinization and global glomerulosclerosis were associated with diabetes and hypertension(all p<0.05). The I/M ratio of the coronary artery was independently associated with the rate of global glomerulosclerosis(p<0.05). The frequency of advanced atherosclerotic lesions in the coronary and cerebral arteries was also correlated with the I/M ratio of the renal artery and rates of arteriolar hyalinization and global glomerulosclerosis(all p<0.05). The frequency of advanced lesions in the cerebral and common carotid arteries was independently associated with the I/M ratio of the renal artery and the rate of renal arteriolar hyalinization(odds ratio(OR) with [95% confidence interval]; 5.09 [1.15-27.9] and 4.11 [1.38-13.9], respectively). The results of this study demonstrated that pathological changes in four portions of the renal vasculature differ. Renal vasculature changes except the intrarenal arteries were significantly associated with those observed in the cerebral, common carotid and coronary arteries.


Multivariate information-theoretic measures reveal directed information structure and task relevant changes in fMRI connectivity.
The human brain undertakes highly sophisticated information processing facilitated by the interaction between its sub-regions. We present a novel method for interregional connectivity analysis, using multivariate extensions to the mutual information and transfer entropy. The method allows us to identify the underlying directed information structure between brain regions, and how that structure changes according to behavioral conditions. This method is distinguished in using asymmetric, multivariate, information-theoretical analysis, which captures not only directional and non-linear relationships, but also collective interactions. Importantly, the method is able to estimate multivariate information measures with only relatively little data. We demonstrate the method to analyze functional magnetic resonance imaging time series to establish the directed information structure between brain regions involved in a visuo-motor tracking task. Importantly, this results in a tiered structure, with known movement planning regions driving visual and motor control regions. Also, we examine the changes in this structure as the difficulty of the tracking task is increased. We find that task difficulty modulates the coupling strength between regions of a cortical network involved in movement planning and between motor cortex and the cerebellum which is involved in the fine-tuning of motor control. It is likely these methods will find utility in identifying interregional structure (and experimentally induced changes in this structure) in other cognitive tasks and data modalities.