Lateral geniculate neurons in behaving primates. III. Response predictions of a channel model with multiple spatial-to-temporal filters.
1. For the experiments reported in these papers, we recorded the responses of lateral geniculate (LGN) neurons to a large set of two-dimensional, black and white patterns based on Walsh functions and to a set of test stimuli. In the first two papers we reported that these neurons encode stimulus-related information in both the strength and the shape of the response waveforms and that there are more than two independent components in the response. These results cannot be explained by existing models. This paper provides a model of LGN neurons that not only accounts for the foregoing observations, but also yields predictions confirmed by direct tests. 2. The model represents a neuron as a set of three parallel channels. The input to each channel is an array of pixel luminances. Each channel consists of an input nonlinearity cascaded into a linear spatial-to-temporal filter. The output of each channel is a basic waveform, a principal component. The response of the neuron is the sum of the outputs of the three channels. 3. The model accounted for much of the variance in the coefficients of the first three principal components of the neuronal responses to the set of Walsh stimuli. Using parameters derived from the responses of neurons to the Walsh stimuli only, the model also predicted the responses to "center-surround" annuli of different contrasts and mean luminances, as well as to superpositions of pairs of Walsh patterns. The model made statistically significant predictions of the coefficients of two of the principal components of these responses. 4. After the parameters of the model had been fit to reproduce the responses of neurons to the Walsh stimuli, we found that the input nonlinearity of the model was compressed at both the high and low luminance levels. This compression produced response saturation that closely resembled the response saturation of neurons reported in the first paper in this series. Although not absolutely smooth, the spatial filter for the first channel had a dominant excitatory or inhibitory center and an antagonistic surround. Thus this spatial filter accounted for both the center and the surround structures of previous models of LGN receptive fields. There was greater variety in the structures of the spatial filters for the second and third channels, but none had a center-surround organization. Many of the spatial filters for these higher channels contained oriented ridges or valleys. Other spatial filters were dominated by a bipolar pair of pixels. 5. The model of LGN neurons that we present in this paper represents an extension over previous models in four ways. First, the model is capable of explaining the responses of neurons to a wider range of luminances than previous models. Second, the model is capable of explaining the shapes of the response waveforms as well as their magnitudes. Third, the concept of a single receptive field is extended to a series of spatial-to-temporal filters. Fourth, the model suggests that LGN neurons provide a description of both the brightness and the form of a stimulus in their response waveforms.


A Model Electron Transfer Reaction in Confined Aqueous Solution.
Liquid water confined within nanometer-sized channels exhibits a strongly reduced local dielectric constant perpendicular to the wall, especially at the interface, and this has been suggested to induce faster electron transfer kinetics at the interface than in the bulk. We study a model electron transfer reaction in aqueous solution confined between graphene sheets with classical molecular dynamics. We show that the solvent reorganization energy is reduced at the interface compared to the bulk, which explains the larger rate constant. However, this facilitated solvent reorganization is due to the partial desolvation by the graphene sheet of the ions involved in the electron transfer and not to a local dielectric constant reduction effect.


Biofiltration of cyclic air emissions of alpha-pinene at low and high frequencies.
Biofiltration of periodically fluctuating concentrations of an alpha-pinene-laden waste gas was investigated to treat both high-frequency and low-frequency fluctuations. The effects of periodic concentration fluctuations on biofilter performance were measured. Controlled variables of periodic operation included cycle period and amplitude. The cycle period ranged from 10 min to 6 days, with the inlet alpha-pinene concentration fluctuating between 0 and 100 parts per million volume. At high-frequency concentration cycling (i.e., on the order of minutes), both cyclic and constant concentration biofilters maintained similar long-term performance with an average removal efficiency of 77% at an averaged loading rate of 29 g alpha-pinene/m3 bed/hr. A first approximation suggests kinetics that are time-independent, indicating that steady-state data can be used to predict transient behavior at this time scale. Cyclic biofilter operation with a cycle period of 24 hr (with equal on/off time) was achievable for biofilters without a significant loss in performance. At longer time scales, cyclic biofilter performance decreased at the restart of the ON cycle. The recovery time to previous levels of performance increased with increasing cycle period; the recovery time was less than 1 hr for a cycle period of 24 hr and between 6 and 8 hr for a cycle period of 6 days.


Predicting pediatric anxiety from the temporal pole using neural responses to emotional faces.
A prominent cognitive aspect of anxiety is dysregulation of emotional interpretation of facial expressions, associated with neural activity from the amygdala and prefrontal cortex. We report machine learning analysis of fMRI results supporting a key role for a third area, the temporal pole (TP) for childhood anxiety in this context. This finding is based on differential fMRI responses to emotional faces (angry versus fearful faces) in children with one or more of generalized anxiety, separation anxiety, and social phobia (n = 22) compared with matched controls (n = 23). In our machine learning (Adaptive Boosting) model, the right TP distinguished anxious from control children (accuracy = 81%). Involvement of the TP as significant for neurocognitive aspects of pediatric anxiety is a novel finding worthy of further investigation.


Analysis of arterial intimal hyperplasia: review and hypothesis.
Despite a prodigious investment of funds, we cannot treat or prevent arteriosclerosis and restenosis, particularly its major pathology, arterial intimal hyperplasia. A cornerstone question lies behind all approaches to the disease: what causes the pathology? I argue that the question itself is misplaced because it implies that intimal hyperplasia is a novel pathological phenomenon caused by new mechanisms. A simple inquiry into arterial morphology shows the opposite is true. The normal multi-layer cellular organization of the tunica intima is identical to that of diseased hyperplasia; it is the standard arterial system design in all placentals at least as large as rabbits, including humans. Formed initially as one-layer endothelium lining, this phenotype can either be maintained or differentiate into a normal multi-layer cellular lining, so striking in its resemblance to diseased hyperplasia that we have to name it "benign intimal hyperplasia". However, normal or "benign" intimal hyperplasia, although microscopically identical to pathology, is a controllable phenotype that rarely compromises blood supply. It is remarkable that each human heart has coronary arteries in which a single-layer endothelium differentiates early in life to form a multi-layer intimal hyperplasia and then continues to self-renew in a controlled manner throughout life, relatively rarely compromising the blood supply to the heart, causing complications requiring intervention only in a small fraction of the population, while all humans are carriers of benign hyperplasia. Unfortunately, this fundamental fact has not been widely appreciated in arteriosclerosis research and medical education, which continue to operate on the assumption that the normal arterial intima is always an "ideal" single-layer endothelium. As a result, the disease is perceived and studied as a new pathological event caused by new mechanisms. The discovery that normal coronary arteries are morphologically indistinguishable from deadly coronary arteriosclerosis continues to elicit surprise. Two questions should inform the priorities of our research: (1) what controls switch the single cell-layer intimal phenotype into normal hyperplasia? (2) how is normal (benign) hyperplasia maintained? We would be hard-pressed to gain practical insights without scrutinizing our premises.


Network Reconfiguration for Increasing Transportation System Resilience Under Extreme Events.
Evacuating residents out of affected areas is an important strategy for mitigating the impact of natural disasters. However, the resulting abrupt increase in the travel demand during evacuation causes severe congestions across the transportation system, which thereby interrupts other commuters' regular activities. In this article, a bilevel mathematical optimization model is formulated to address this issue, and our research objective is to maximize the transportation system resilience and restore its performance through two network reconfiguration schemes: contraflow (also referred to as lane reversal) and crossing elimination at intersections. Mathematical models are developed to represent the two reconfiguration schemes and characterize the interactions between traffic operators and passengers. Specifically, traffic operators act as leaders to determine the optimal system reconfiguration to minimize the total travel time for all the users (both evacuees and regular commuters), while passengers act as followers by freely choosing the path with the minimum travel time, which eventually converges to a user equilibrium state. For each given network reconfiguration, the lower-level problem is formulated as a traffic assignment problem (TAP) where each user tries to minimize his/her own travel time. To tackle the lower-level optimization problem, a gradient projection method is leveraged to shift the flow from other nonshortest paths to the shortest path between each origin-destination pair, eventually converging to the user equilibrium traffic assignment. The upper-level problem is formulated as a constrained discrete optimization problem, and a probabilistic solution discovery algorithm is used to obtain the near-optimal solution. Two numerical examples are used to demonstrate the effectiveness of the proposed method in restoring the traffic system performance.


Energy Restriction Enhances Adult Hippocampal Neurogenesis-Associated Memory after Four Weeks in an Adult Human Population with Central Obesity; a Randomized Controlled Trial.
Adult neurogenesis, the generation of new neurons throughout life, occurs in the subventricular zone of the dentate gyrus in the human hippocampal formation. It has been shown in rodents that adult hippocampal neurogenesis is needed for pattern separation, the ability to differentially encode small changes derived from similar inputs, and recognition memory, as well as the ability to recognize previously encountered stimuli. Improved hippocampus-dependent cognition and cellular readouts of adult hippocampal neurogenesis have been reported in daily energy restricted and intermittent fasting adult mice. Evidence that nutrition can significantly affect brain structure and function is increasing substantially. This randomized intervention study investigated the effects of intermittent and continuous energy restriction on human hippocampal neurogenesis-related cognition, which has not been reported previously. Pattern separation and recognition memory were measured in 43 individuals with central obesity aged 35-75 years, before and after a four-week dietary intervention using the mnemonic similarity task. Both groups significantly improved pattern separation (P = 0.0005), but only the intermittent energy restriction group had a significant deterioration in recognition memory. There were no significant differences in cognitive improvement between the two diets. This is the first human study to investigate the association between energy restriction with neurogenesis-associated cognitive function. Energy restriction may enhance hippocampus-dependent memory and could benefit those in an ageing population with declining cognition. This study was registered on ClinicalTrials.gov (NCT02679989) on 11 February 2016.


Peripheral nerve repair throughout the body with processed nerve allografts: Results from a large multicenter study.
Peripheral nerve damage resulting in pain, loss of sensation, or motor function may necessitate a reconstruction with a bridging material. The RANGER® Registry was designed to evaluate outcomes following nerve repair with processed nerve allograft (Avance® Nerve Graft; Axogen; Alachua, FL). Here we report on the results from the largest peripheral nerve registry to-date. This multicenter IRB-approved registry study collected data from patients repaired with processed nerve allograft (PNA). Sites followed their own standard of care for patient treatment and follow-up. Data were assessed for meaningful recovery, defined as ≥S3/M3 to remain consistent with previously published results, and comparisons were made to reference literature. The study included 385 subjects and 624 nerve repairs. Overall, 82% meaningful recovery (MR) was achieved across sensory, mixed, and motor nerve repairs up to gaps of 70 mm. No related adverse events were reported. There were no significant differences in MR across the nerve type, age, time-to-repair, and smoking status subgroups in the upper extremity (p > .05). Significant differences were noted by the mechanism of injury subgroups between complex injures (74%) as compared to lacerations (85%) or neuroma resections (94%) (p = .03) and by gap length between the <15 mm and 50-70 mm gap subgroups, 91 and 69% MR, respectively (p = .01). Results were comparable to historical literature for nerve autograft and exceed that of conduit. These findings provide clinical evidence to support the continued use of PNA up to 70 mm in sensory, mixed and motor nerve repair throughout the body and across a broad patient population.


Functional analysis of combinatorial mutants altered in a conserved region in loop E of the CP47 protein in Synechocystis sp. PCC 6803.
Regions in the large lumenally exposed region (loop E) of CP47 affect properties of the watersplitting system in photosystem II (PS II). To investigate the role of these regions, we developed a method for functional complementation of obligate photoheterotrophic mutants carrying a deletion in one such region. Using an obligate photoheterotrophic mutant that carries a short deletion (delta (D440-P447) in loop E of CP47, completely degenerate sequences of eight codons in length were introduced at the site of the deletion. Transformants that were complemented to photoautotrophic growth were selected, and 20 such mutants were studied. Sequence analysis revealed that, as expected, in each of them CP47 had been restored to its wild-type length. However, none of the amino acid residues in the deleted region were found to be critical for function. A negatively charged residue at position 440 and a positively charged one at position 444 were favored but not required. Photoautotrophic growth of mutants obtained varied from almost normal to significantly impaired. The mutants contained 20-100% of the amount of PS II present in the wild type, with PS II amounts correlating with the initial rates of oxygen evolution. The mutants had a high rate of photoinactivation, and many mutants showed an up to 1000-fold increase in chloride requirement for photoautotrophic growth. These phenotypic effects were a direct consequence of the CP47 mutations and were not caused by altered binding of one of the extrinsic proteins. No particular amino acid residues in positions 440-447 of CP47 were found to be indispensable for photoautotrophic growth, and many amino acid combinations in this region support PS II function. However, the mutagenized region is shown to interact with the oxygen-evolving site of PS II and appears to have a direct role in chloride binding.


Unusual numbers and distribution of Langerhans cells in skin with unique immunologic properties.
Epidermal Langerhans cells resemble macrophages/monocytes in several remarkable ways: both bear surface receptors for the Fc portion of immunoglobulin molecules and for the C3b complement component. They take up, process and present antigen to reactive lymphocytes in an extremely effective fashion. They display on their cell surfaces the alloantigenic determinants encoded by genes of the I region of the major histocompatibility complex. Using ATPase activity, Langerhans cell surface densities are abnormal in 3 cutaneous sites which exhibit unique immunologic properties: markedly reduced numbers in hamster cheek pouch; reduced numbers and uneven distributions in murine tail skin; no Langerhans cells occur within corneal epithelium. As a functional expression of the absence of Langerhans cells from murine corneas, allografts prepared from corneal epithelium fail to sensitize recipients to Ia antigens encoded by I region genes of the donor. Corneal grafts disparate from their hosts at only I region loci are accepted for at least 45 days. The absence of Langerhans cells from cornea may account in part for its property as an immunologically privileged tissue. Subthreshold numbers of Langerhans cells in cheek pouch epithelium may contribute significantly to the observations that the hamster cheek pouch is an immunologically privileged site. We infer that skin deficient in Langerhans cells may be consequently deficient in alloantigenicity. Equally important, Langerhans cell-poor skin may be lacking in certain essential functions relating to the induction and expression of immune reactivity.


Development of guidelines for skeletal survey in young children with fractures.
To develop guidelines for performing initial skeletal survey (SS) in children <24 months old with fractures, based on available evidence and collective judgment of experts from diverse pediatric specialties. Following the Rand/UCLA Method, a multispecialty panel of 13 experts applied evidence from a literature review combined with their own expertise in rating the appropriateness of performing an SS for 525 clinical scenarios involving fractures in children <24 months old. After discussion on the initial ratings, panelists re-rated SS appropriateness for 240 revised scenarios and deemed that SSs were appropriate in 191 scenarios. The panelists then assessed in which of those 191 scenarios SSs were not only appropriate, but also necessary. Panelists agreed that SS is "appropriate" for 191 (80%) of 240 scenarios rated and "necessary" for 175 (92%) of the appropriate scenarios. Skeletal survey is necessary if a fracture is attributed to abuse, domestic violence, or being hit by a toy. With few exceptions, SS is necessary in children without a history of trauma. In children <12 months old, SS is necessary regardless of the fracture type or reported history, with rare exceptions. In children 12 to 23 months old, the necessity of obtaining SS is dependent on fracture type. A multispecialty panel reached agreement on multiple clinical scenarios for which initial SS is indicated in young children with fractures, allowing for synthesis of clinical guidelines with the potential to decrease disparities in care and increase detection of abuse.


Network-assisted genetic dissection of pathogenicity and drug resistance in the opportunistic human pathogenic fungus Cryptococcus neoformans.
Cryptococcus neoformans is an opportunistic human pathogenic fungus that causes meningoencephalitis. Due to the increasing global risk of cryptococcosis and the emergence of drug-resistant strains, the development of predictive genetics platforms for the rapid identification of novel genes governing pathogenicity and drug resistance of C. neoformans is imperative. The analysis of functional genomics data and genome-scale mutant libraries may facilitate the genetic dissection of such complex phenotypes but with limited efficiency. Here, we present a genome-scale co-functional network for C. neoformans, CryptoNet, which covers ~81% of the coding genome and provides an efficient intermediary between functional genomics data and reverse-genetics resources for the genetic dissection of C. neoformans phenotypes. CryptoNet is the first genome-scale co-functional network for any fungal pathogen. CryptoNet effectively identified novel genes for pathogenicity and drug resistance using guilt-by-association and context-associated hub algorithms. CryptoNet is also the first genome-scale co-functional network for fungi in the basidiomycota phylum, as Saccharomyces cerevisiae belongs to the ascomycota phylum. CryptoNet may therefore provide insights into pathway evolution between two distinct phyla of the fungal kingdom. The CryptoNet web server (www.inetbio.org/cryptonet) is a public resource that provides an interactive environment of network-assisted predictive genetics for C. neoformans.


Adherence to cervical screening in the era of human papillomavirus vaccination: how low is too low?
Human papillomavirus vaccine prevents infection by two major oncogenic types of the virus. Continued screening is needed in vaccinated women to prevent cancers caused by high-risk types not included in the vaccine. An exaggerated sense of protection from the vaccine could lead to a decline in the rate of screening among vaccinated women, which in principle could lead to an increase in the incidence of cervical cancer. We present a simple mathematical model of vaccination, screening, and disease incidence, including an analysis of the effect of data uncertainties. For a population with opportunistic screening and 30% vaccine coverage, screening rates in vaccinated women would have to decline by at least 80% (median value of probabilistic uncertainty analysis) before the incidence of cervical cancer would increase in the era since the introduction of the vaccine. By comparison, the decline needed is at least 49% in a population with organised screening and 70% vaccine coverage. In populations that have highly effective cervical screening programmes, incidence of cervical cancer starts to increase after smaller, but still substantial, decreases in screening. Introduction of vaccine is unlikely to lead to an increased incidence of cervical cancer as a result of diminished screening.


Important role of adrenergic mechanisms in acute glucose counterregulation following insulin-induced hypoglycemia in type I diabetes. Evidence for an effect mediated by beta-adrenoreceptors.
During hypoglycemia induced by an i.v. insulin infusion for 60 min, rates of plasma glucose (PG) decrease and recovery, PG nadir, and plasma counter-regulatory hormone and free fatty acid responses were studied in eight type I uncomplicated diabetic subjects and eight nondiabetic subjects. Each subject was tested three times at two different rates of insulin infusion (25 and 32 mU/m2/min): (1) during infusion of saline, (2) during infusion of phentolamine + propranolol (combined alpha, beta-blockade), and (3) during infusion of propranolol alone (isolated beta-blockade) for 150 min. At the time of the studies, the diabetic subjects had been made euglycemic by an overnight i.v. insulin infusion. During infusion of insulin (25 mU/m2/min) and saline, the rates of PG decrease and recovery were slower (P less than 0.01) and PG nadir was delayed in the diabetic subjects. Moreover, their plasma glucagon response was blunted while plasma epinephrine, norepinephrine, growth hormone, and cortisol responses were similar in both groups. Infusion of insulin at 32 mU/m2/min caused larger decreases in PG than had been observed when insulin was infused at 25 mU/m2/min. Plasma glucagon responses increased in the nondiabetic subjects (P less than 0.05) but not in the diabetic subjects. However, in the diabetic subjects, plasma epinephrine increased more than in the nondiabetic subjects (P less than 0.05). There was an inverse correlation between the individual plasma epinephrine responses and the plasma glucagon responses in the diabetic subjects (r = -0.72) but not in the nondiabetic subjects. Alpha, beta-adrenergic blockade decreased the plasma glucose nadir and impaired the rate at which normoglycemia was restored in the diabetic subjects (P less than 0.005 vs. saline) but not in the nondiabetic subjects. Plasma catecholamine and growth hormone responses were increased and plasma FFA recovery was suppressed in both groups (P less than 0.05 vs. saline), while the cortisol responses were unaltered. During isolated beta-adrenergic blockade, changes in plasma glucose, counterregulatory hormones and FFA were essentially identical to those observed during combined alpha, beta-adrenergic blockade in both groups except that the augmented plasma norepinephrine responses were no longer apparent. although epinephrine is not essential for prompt restoration of normoglycemia in normal man following insulin-induced hypoglycemia, it plays a major role in glucose counterregulation in diabetics who have an impaired glucagon secretion in response to hypoglycemia. These counterregulatory effects of epinephrine are mediated by beta-adrenoreceptors.


Observations with the electron microscope on the solvation and reconstitution of collagen.
The course of events in the solvation and reconstitution of collagen obtained from rat tail tendon is described as seen with the electron microscope. Under the influence of 0.01 per cent acetic acid the collagen fibers swell and dissociate into submicroscopic filaments, the smallest of which are probably beyond the resolution of the electron microscope. These filaments can be made to reconstitute into fibers either by the addition of neutral salts to the acid solution or by raising the pH. The structural form of the resulting fibers is influenced by the concentration of the salt and by the pH of the solution employed. Saline-concentrations around 1 per cent and pH's ranging from 4.8 to 6.8 lead to the formation of needle-shaped crystals, or tactoids, showing the striated structure characteristic of collagen. Saline concentrations outside of this range (0.5 per cent and 5.0 per cent) lead to the formation of long fibrils without evidence of striations. pH's on the alkaline side of 6.8 bring about the formation of long slender fibers. Some of the possible reasons for these different fiber forms are discussed. Apparently fibers are formed in vitro by the lateral and longitudinal association of the filaments seen in the original solutions. Some of the fibers thus formed may in turn associate laterally and longitudinally to form the larger fibers. The formation of the needle-shaped crystals appears to be an orderly process since it leads to the formation of a periodicity in the fibers. The striations in the smaller fibers are uniform and regularly spaced at around 210 A. With continued growth of these fibers there is a simultaneous development of a more obvious and precise banding. It is evident that two out of each group of three regularly spaced striae are more prominent. This produces the macroperiod of collagen measuring around 640 A in length.


The protean visage of systemic autoinflammatory syndromes: a challenge for inter-professional collaboration.
Systemic autoinflammatory syndromes are a group of inherited and acquired disorders of the innate immunity characterized by recurrence of seemingly unprovoked febrile attacks of variable duration and multi-district inflammation of different severity. The vast majority of these conditions when observed in pediatrics is caused by mutations in genetic systems involved in the orchestration of inflammation and apoptosis. The group includes hereditary recurrent fevers, idiopathic febrile syndromes, hereditary pyogenic disorders, bone autoinflammatory diseases, immune-mediated granulomatous diseases, complement disorders, hemophagocytic and vasculitic syndromes. Diagnostic identification derives from the combination of genotype studies and clinical/bioumoral data showing the spontaneous activation of cells of the innate immunity in the absence of specific ligands, although diagnosis remains only clinical for idiopathic febrile syndromes such as systemic-onset juvenile idiopathic arthritis and PFAPA syndrome. Meeting the needs of patients with complex chronic diseases as systemic autoinflammatory syndromes requires the provision of collaborative multidisciplinary care and the expertise of a number of health care providers across varied health care settings.


[Inheritance of resistance to Heterodera glycines race 14 in Huibuzhi black bean].
Heterodera glycines is the most serious disease in the world soybean (Glycine max) production. Huibuzhi black bean from Xing County in Shanxi Province, China is one of the most important resistant resources. Using a set of host differentials for soybean cyst nematode and criterion of race classification as well as method of manual inoculation, race 14 was identified as a prevalent one in the soil population of the Experiment Station, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing. A sensitive variety #7 Jidou as a female donor crossed with Huibuzhi black bean. Their offsprings were investigated for resistance to race 14. Two of F1 seedlings demonstrated their resistant. Two populations in F2 including 116 seedlings and 78 seedlings in each one appeared their own separate ratio that was in common: 43R:21S. A genetic hypothesis was proposed that resistance to SCN race 14 in Huibuzhi black bean was controlled by three gene pairs arose. Gene reciprocity existed among them: one recessive epistasis gene pair and two dominant complementary gene pairs. Random 30 families in F3 including 10-15 tested seedlings in each family were screened for resistance to SCN race 14. The segregate ratio, 19R:38Seg.:7S, among F3 families confirmed that the presented genetic hypothesis was correct.


The effect of posture and pH on solid and liquid oesophageal emptying.
Oesophageal emptying of solids and liquids has been assessed in normal subjects using radionuclide techniques. The solid bolus comprised a 10 g disc of cooked minced beef which was labelled with 160 microCi; 99m Tc macro-aggregated albumin (MAA). The liquid bolus consisted of 15 ml of water labelled with 300 microCi; 99m Tc. Studies were performed in the upright and supine positions and repeated after ingestion of 30 ml of 0.1 M HC1 diluted to pH 1.6. Solid and liquid assessments were performed separately with a scintillation camera positioned posteriorly. Subjects were instructed to swallow at the commencement of the test and at 15 s intervals subsequently, until the bolus entered the stomach. Oesophageal emptying in the supine position was significantly slower than emptying in the upright position. This was true for both solid and liquid emptying, in the neutral and in the acidified oesophagus. Emptying of a solid bolus did not appear to be influenced by oesophageal pH. However, emptying of a liquid bolus was significantly slower when the oesophageal pH was acid, for both the supine and upright positions. We conclude that the supine posture delays both liquid and solid oesophageal emptying. The presence of acid in the oesophagus at a pH of 1.6 delayed liquid emptying, but not solid emptying, from the oesophagus.


Serum urea analysis using the Beckman BUN Analyzer.
A new instrument, the Beckman BUN Analyzer, has been produced for the estimation of urea in microvolume (0-01 ml) of serum or plasma. It requires only a simple two-point calibration for standardization and is suitable for a range of urea levels from zero to 70 mmol/l. The test procedure is simple. After the initial calibration the test sample is injected into the testing chamber and a digital result of the urea concentration is displayed. Serum urea measurements made by this method compared well with those obtained by the Technicon AutoAnalyzer method over the entire working range. The within-batch coefficient of variation of the method is 5-5%, and less at urea levels of 11 to 44 mmol/l. The between-batch coefficient of variation of the method is 6-9%, and less at urea concentrations of 10 to 47 mmol/l. The BUN Aanalyzer method is a quick and reliable alternative to conventional laboratory methods for serum or plasma urea estimation and is especially useful for urgent investigations of both adult and paediatric patients in the hospital wards and at the outpatient clinics.


An improved technique for mitosis counting.
Mitosis counting remains one of the most valuable prognostic indicators in tumor pathology; however, as currently carried out it is time consuming and not reproducible. In this study, 6 different pathologists, using different microscopes, arrived at widely different mitotic counts on the same slide, ranging from 4 to 16. These differences were mainly due to the different field areas of the various microscopes used and the method used for counting and recording. In evaluating the most active 10 HPF, the count ranged from 10 to 19. Instead, when an average of 40 fields was recorded, the range was 4-11. Using the mitosis/volume index, which expresses the number of mitotic figures per mm2 of viable tumor, the counts ranged from 8 to 10, a marked improvement. However, this method is complicated and not "user-friendly.'' We suggest a variation of the technique by which a 2 mm2 rectangle is drawn on a cover slip and mounted under the microscope, centered on the most mitotically active area of the tumor. The mitoses in that area are counted (=n) and the percent of viable tumor (=x%) is estimated under low magnification. The number of mitoses per mm2 of viable tumor (cs-MAI) is then calculated according to the formula Cs-MAI=100n/2x. Using this modified method, the range of mitoses counted by the different observers was very narrow (9 to 11), and the time required for the counting was only 5-10 minutes.


Involvement of adenosine A2A receptors in engulfment-dependent apoptotic cell suppression of inflammation.
Efficient execution of apoptotic cell death followed by efficient clearance mediated by professional macrophages is a key mechanism in maintaining tissue homeostasis. Removal of apoptotic cells usually involves three central elements: 1) attraction of phagocytes via soluble "find me" signals, 2) recognition and phagocytosis via cell surface-presenting "eat me" signals, and 3) suppression or initiation of inflammatory responses depending on additional innate immune stimuli. Suppression of inflammation involves both direct inhibition of proinflammatory cytokine production and release of anti-inflammatory factors, which all contribute to the resolution of inflammation. In the current study, using wild-type and adenosine A(2A) receptor (A2AR) null mice, we investigated whether A2ARs, known to mediate anti-inflammatory signals in macrophages, participate in the apoptotic cell-mediated immunosuppression. We found that macrophages engulfing apoptotic cells release adenosine in sufficient amount to trigger A2ARs, and simultaneously increase the expression of A2ARs, as a result of possible activation of liver X receptor and peroxisome proliferators activated receptor δ. In macrophages engulfing apoptotic cells, stimulation of A2ARs suppresses the NO-dependent formation of neutrophil migration factors, such as macrophage inflammatory protein-2, using the adenylate cyclase/protein kinase A pathway. As a result, loss of A2ARs results in elevated chemoattractant secretion. This was evident as pronounced neutrophil migration upon exposure of macrophages to apoptotic cells in an in vivo peritonitis model. Altogether, our data indicate that adenosine is one of the soluble mediators released by macrophages that mediate engulfment-dependent apoptotic cell suppression of inflammation.


Replication protein A interactions with DNA: differential binding of the core domains and analysis of the DNA interaction surface.
Human replication protein A (RPA) is a heterotrimeric (70, 32, and 14 kDa subunits), eukaryotic single-stranded DNA (ssDNA) binding protein required for DNA recombination, repair, and replication. The three subunits of human RPA are composed of six conserved DNA binding domains (DBDs). Deletion and mutational studies have identified a high-affinity DNA binding core in the central region of the 70 kDa subunit, composed of DBDs A and B. To define the roles of each DBD in DNA binding, monomeric and tandem DBD A and B domain chimeras were created and characterized. Individually, DBDs A and B have a very low intrinsic affinity for ssDNA. In contrast, tandem DBDs (AA, AB, BA, and BB) bind ssDNA with moderate to high affinity. The AA chimera had a much higher affinity for ssDNA than did the other tandem DBDs, demonstrating that DBD A has a higher intrinsic affinity for ssDNA than DBD B. The RPA-DNA interface is similar in both DBD A and DBD B. Mutational analysis was carried out to probe the relative contributions of the two domains to DNA binding. Mutation of polar residues in either core DBD resulted in a significant decrease in the affinity of the RPA complex for ssDNA. RPA complexes with pairs of mutated polar residues had lower affinities than those with single mutations. The decrease in affinity observed when polar mutations were combined suggests that multiple polar interactions contribute to the affinity of the RPA core for DNA. These results indicate that RPA-ssDNA interactions are the result of binding of multiple nonequivalent domains. Our data are consistent with a sequential binding model for RPA, in which DBD A is responsible for positioning and initial binding of the RPA complex while DBD A together with DBD B direct stable, high-affinity binding to ssDNA.


Adjuvant or neoadjuvant chemotherapy for NSCLC.
In functionally fit patients with localized disease surgical resection remains the treatment of choice. There is also good evidence to support the use of chemotherapy in stages II-III. However, whether to use neoadjuvant or adjuvant therapy has been the topic of much debate. With its strong evidence base, adjuvant chemotherapy has been adopted in the European Society of Medical Oncology clinical practice guidelines for early and locally advanced stages II-III non-small-cell lung cancer (NSCLC), with consideration of adjuvant therapy in those with stage IB but with tumours >4 cm in size. There are fewer trials comparing neoadjuvant therapy plus surgery with surgery alone. Even less has been carried out directly comparing neoadjuvant with adjuvant therapy. The NATCH trial demonstrated no difference in survival between adjuvant and neoadjuvant arms, whilst others have yet to be completed. Meta-analysis also demonstrates no appreciable difference between the two methods. With such a strong body of evidence, however, postoperative delivery of chemotherapy remains the timing of choice in NSCLC.


Current trends in management of Zenker diverticulum.
Zenker's diverticulum is a relatively common problem encountered by head and neck surgeons. Careful review of the available literature regarding its pathogenesis indicates that Zenker diverticulum likely occurs as a result of increased intrabolus pressures during swallowing secondary to cricopharyngeal spasm. Rational treatment for Zenker diverticulum therefore addresses cricopharyngeal spasm. The traditional approach to diagnosis and management of Zenker diverticulum has been based on standard techniques and principles. For example, diverticulectomy with concurrent cricopharyngeal myotomy is an acceptable form of treatment with a high success rate. However, recent advances in endoscopic stapling and carbon dioxide laser technologies have added new options to the therapeutic armament of the otolaryngologist. For appropriately selected patients, endoscopic staple-assisted diverticulostomy is a minimally invasive, safe, and effective procedure associated with shorter hospital stays, more rapid postoperative recovery, decreased time to resumption of oral intake, and high levels of patient satisfaction.


Attenuation of pulmonary vascular hypertension and cardiac hypertrophy with sitaxsentan sodium, an orally active ET(A) receptor antagonist.
Effects of sitaxsentan (TBC11251), an orally active, highly selective antagonist of endothelin A receptors, were examined on the development and maintenance of pulmonary hypertension, pulmonary vascular remodeling, and cardiac hypertrophy in the rat. The pulmonary vasoconstrictor response to acute hypoxia (10% O(2)for 90 min) was prevented with sitaxsentan (5 mg/kg infused iv 10 min prior to the onset of hypoxia) while BQ-788 (a specific endothelin B receptor antagonist) was without effect. The same dose of sitaxsentan delivered iv 50 min after the onset of hypoxia reversed the established pulmonary vasoconstriction. In a 2-week model of hypoxia using 10% O(2), treatment with sitaxsentan (15 mg/kg per day in drinking water) attenuated pulmonary hypertension and the associated right ventricular hypertrophy, and prevented the remodeling of small pulmonary arteries (50-100 microM) without affecting systemic arterial blood pressure or heart rate. Institution of sitaxsentan treatment (15 and 30 mg/kg per day in drinking water) for 4 weeks after 2 weeks of untreated hypoxia produced a significant, dose dependent reversal of the established pulmonary hypertension, right heart hypertrophy, and pulmonary vascular remodeling despite continued hypoxic exposure. Sitaxsentan blocked increased plasma endothelin levels in the prevention protocol but did not affect the established elevated levels in the intervention study. Sitaxsentan dose dependently (10 and 50 mg/kg per day in the drinking water) attenuated right ventricular systolic pressure, right heart hypertrophy, and pulmonary vascular remodeling observed 3 weeks after a single subcutaneous injection of monocrotaline. These findings support the hypothesis that endothelin-1 plays a significant role in the development of pulmonary hypertension, pulmonary vascular remodeling, and the associated cardiac hypertrophy, and further suggest that specific endothelin-A receptor blockade may be useful in the treatment of pulmonary hypertension of diverse etiologies.


Diagnosing dementia and normal aging: clinical relevance of brain ratios and cognitive performance in a Brazilian sample.
The main objective of the present study was to evaluate the diagnostic value (clinical application) of brain measures and cognitive function. Alzheimer and multi-infarct patients (N = 30) and normal subjects over the age of 50 (N = 40) were submitted to a medical, neurological and cognitive investigation. The cognitive tests applied were Mini-Mental, word span, digit span, logical memory, spatial recognition span, Boston naming test, praxis, and calculation tests. The brain ratios calculated were the ventricle-brain, bifrontal, bicaudate, third ventricle, and suprasellar cistern measures. These data were obtained from a brain computer tomography scan, and the cutoff values from receiver operating characteristic curves. We analyzed the diagnostic parameters provided by these ratios and compared them to those obtained by cognitive evaluation. The sensitivity and specificity of cognitive tests were higher than brain measures, although dementia patients presented higher ratios, showing poorer cognitive performances than normal individuals. Normal controls over the age of 70 presented higher measures than younger groups, but similar cognitive performance. We found diffuse losses of tissue from the central nervous system related to distribution of cerebrospinal fluid in dementia patients. The likelihood of case identification by functional impairment was higher than when changes of the structure of the central nervous system were used. Cognitive evaluation still seems to be the best method to screen individuals from the community, especially for developing countries, where the cost of brain imaging precludes its use for screening and initial assessment of dementia.


Multicomponent polymeric engineering materials.
The great advances made in polymeric structural materials over the past decade have led to their replacement of conventional materials in a wide range of uses including high-performance aerospace applications. This shift in choice of materials is based on economic advantages, simplified fabrication, freedom from corrosion, and lower weight. The trend toward use of polymeric materials will grow as the materials science of this new technology is developed. Better insight into such fundamental problems as the mechanisms by which forces are transferred to the polymer molecule, the surface interactions between polymer phases or polymer and fiber, and the molecular processes by which energy is absorbed during fracture will greatly stimulate the development of this field.


The Pseudomonas syringae phytotoxin coronatine promotes virulence by overcoming salicylic acid-dependent defences in Arabidopsis thaliana.
SUMMARY Successful pathogen infection likely involves the suppression of general antimicrobial host defences. One Pseudomonas syringae virulence factor proposed to act in this manner is coronatine (COR), a phytotoxin believed to function as an analogue of one or more jasmonates, a family of plant growth regulators. COR biosynthetic (COR(-)) mutants of P. syringae pv. tomato strain DC3000 exhibit reduced virulence on Arabidopsis thaliana and tomato. In the present study, three genetically and biochemically defined COR(-) mutants of DC3000 were used to explore potential effects of COR and its precursors, coronafacic acid (CFA) and coronamic acid (CMA), on defence signalling pathways in A. thaliana. Inoculation with wild-type DC3000 resulted in the accumulation of several jasmonate-responsive transcripts, whereas infection with a mutant strain that accumulates CFA, which is structurally similar to methyl jasmonate (MeJA), did not. Thus, COR, but not CFA, stimulates jasmonate signalling during P. syringae infection of A. thaliana. The ability of the COR(-) mutants to grow to high levels in planta was fully restored in A. thaliana lines deficient for salicylic acid (SA) accumulation. Although the COR(-) mutants grew to high levels in SA-deficient plants, disease symptoms were reduced in these plants. Collectively, these results indicate that COR is required both for overcoming or suppressing SA-dependent defences during growth in plant tissue and for normal disease symptom development in A. thaliana.


Isolation of Vi antigen and a simple method for its measurement.
Vi antigen was purified from saline extract of Citrobacter strain 5396/38 by enzymatic digestion, concentration with ethanol, and precipitation with hexadecyltrimethylammonium bromide. The Vi antigen prepared by this method was 18 and 230 times more protective in mice than two other preparations isolated by an earlier method utilizing acid hydrolysis. A sensitive and specific method of electroimmunodiffusion was described for measurement of Vi antigen.


Patterns of survival among patients with myeloproliferative neoplasms diagnosed in Sweden from 1973 to 2008: a population-based study.
Reported survival in patients with myeloproliferative neoplasms (MPNs) shows great variation. Patients with primary myelofibrosis (PMF) have substantially reduced life expectancy, whereas patients with polycythemia vera (PV) and essential thrombocythemia (ET) have moderately reduced survival in most, but not all, studies. We conducted a large population-based study to establish patterns of survival in more than 9,000 patients with MPNs. We identified 9,384 patients with MPNs (from the Swedish Cancer Register) diagnosed from 1973 to 2008 (divided into four calendar periods) with follow-up to 2009. Relative survival ratios (RSRs) and excess mortality rate ratios were computed as measures of survival. Patient survival was considerably lower in all MPN subtypes compared with expected survival in the general population, reflected in 10-year RSRs of 0.64 (95% CI, 0.62 to 0.67) in patients with PV, 0.68 (95% CI, 0.64 to 0.71) in those with ET, and 0.21 (95% CI, 0.18 to 0.25) in those with PMF. Excess mortality was observed in patients with any MPN subtype during all four calendar periods (P < .001). Survival improved significantly over time (P < .001); however, the improvement was less pronounced after the year 2000 and was confined to patients with PV and ET. We found patients with any MPN subtype to have significantly reduced life expectancy compared with the general population. The improvement over time is most likely explained by better overall clinical management of patients with MPN. The decreased life expectancy even in the most recent calendar period emphasizes the need for new treatment options for these patients.


Modification of radiation response.
Response modifiers have been defined and several examples of modification of response of tissues of laboratory animals or of theoretical models were presented. I have reviewed several efforts to assess the clinical value of serveral of the radiation response modifiers and described some major problems. A major and quantitatively undefined problem for clinical testing of response modifiers is the heterogeneity of clinical material. An area of laboratory and clinical investigation which has large potential is examination for indicators of response probability so as to identify individual patients who are likely to benefit by application of particular radiation response modifiers. There is a need for clinical trials to determine if the results of Henk and associates can be verified. Had Henk been able to publish such results in 1962 instead of 1977, it is virtually certain there would have been considerable effort to verify his results and to investigate numerous other sites. Further, there would have been greater stimulus to the laboratory to provide means to stratify patients according to evidence of hypoxic regions or failure to reoxygenate. Also efforts would have been made to increase the efficacy of hyperbaric oxygen, e.g., suppression of oxygen utilization. The disappointing results from studies with misonidazole should not discourage the testing of new sensitizers of hypoxic cells provided they can be administered at drug doses which achieve substantially higher ER values. New trials of the pyrimidine analogs against tumor which are surrounded by slowly or non-dividing normal tissue appear appropriate. Emphasis was placed on the practical clinical value of radiation protectors which can be applied topically or administered regionally.


Cerebral oxygenation in patients after severe head injury: monitoring and effects of arterial hyperoxia on cerebral blood flow, metabolism and intracranial pressure.
Early impaired cerebral blood flow (CBF) after severe head injury (SHI) leads to poor brain tissue oxygen delivery and lactate accumulation. The purpose of this investigation was to elucidate the relationship between CBF, local dialysate lactate (lact(md)) and dialysate glucose (gluc(md)), and brain tissue oxygen levels (PtiO2) under arterial normoxia. The effect of increased brain tissue oxygenation due to high fractions of inspired oxygen (FiO2) on lact(md) and CBF was explored. A total of 47 patients with SHI were enrolled in this studies (Glasgow Coma Score [GCS] < 8). CBF was first assessed in 40 patients at one time point in the first 96 hours (27 +/- 28 hours) after SHI using stable xenon computed tomography (Xe-CT) (30% inspired xenon [FiXe] and 35% FiO2). In a second study, sequential double CBF measurements were performed in 7 patients with 35% FiO2 and 60% FiO2, respectively, with an interval of 30 minutes. In a subsequent study, 14 patients underwent normobaric hyperoxia by increasing FiO2 from 35 +/- 5% to 60% and then 100% over a period of 6 hours. This was done to test the effect of normobaric hyperoxia on lact(md) and brain gluc(md), as measured by local microdialysis. Changes in PtiO2 in response to changes in FiO2 were analyzed by calculating the oxygen reactivity. Oxygen reactivity was then related to the 3-month outcome data. The levels of lact(md) and gluc(md) under hyperoxia were compared with the baseline levels, measured at 35% FiO2. Under normoxic conditions, there was a significant correlation between CBF and PtiO2 (R = 0.7; P < .001). In the sequential double CBF study, however, FiO2 was inversely correlated with CBF (P < .05). In the 14 patients undergoing the 6-hour 100% FiO2 challenge, the mean PtiO2 levels increased to 353 (87% compared with baseline), although the mean lact(md) levels decreased by 38 +/- 16% (P < .05). The PtiO2 response to 100% FiO2 (oxygen reactivity) was inversely correlated with outcome (P < .01). Monitoring PtiO2 after SHI provides valuable information about cerebral oxygenation and substrate delivery. Increasing arterial oxygen tension (PaO2) effectively increased PtiO2, and brain lact(md) was reduced by the same maneuver.


[Intra-cranial hemorrhage in infants due to vitamin K deficiency - report of 2 cases]
OBJECTIVE: Drive attention to the late form of the hemorrhagic disease of the newborn, secondary to vitamin K deficiency, as a cause of intracranial hemorrhage in young infants.METHODS: The authors describe and analyze two cases of late hemorrhagic disease of the newborn, secondary to vitamin K deficiency, producing intracranially hemorrhage during the second month of age. The most important publications on this subject are reviewed.RESULTS: Both infants had not received prophylaxis with vitamin K at birth. They were both being fed exclusively on breast milk. They developed intracranial hemorrhage, and the clotting defect was rapidly corrected with intramuscular vitamin K. At 3 and 4 years of age, one of them has showed normal psychomotor development, and the other has showed moderate developmental delay with microcephaly.CONCLUSION: Late hemorrhagic disease of the newborn must be considered in young infants, between 2 and 12 weeks of age, with intracranial hemorrhage, especially those fed exclusively on breast milk who did not receive vitamin K at birth. It may produce neurodevelopmental delay. The clotting defect is rapidly corrected with intramuscular vitamin K. This condition is preventable. The prophylaxis is recommended with 1 mg of intramuscular vitamin K to all newborns, at birth, even without risk factors.


New advances in wrist arthroscopy.
Wrist arthroscopy is a commonly used procedure that has undergone many modifications and improvements since it was first described. The advent of new portals (both dorsal and volar) means that the wrist joint can be viewed from virtually any perspective ("box concept"). Indications for wrist arthroscopy have continued to expand and include diagnostic and reparative procedures and, more recently, reconstructive, soft-tissue, and bony procedures. Arthroscopic grading of Kienböck's disease better describes articular damage compared with plain radiographs and can help guide surgical treatment options. Triangular fibrocartilage complex injury diagnosis, classification, and treatment can be performed arthroscopically, including distal ulna resection (wafer procedure). Assessment of fracture reduction of the distal radius and scaphoid is superior to that obtained with fluoroscopy, with the advantage of being able to look for associated soft-tissue and chondral injuries. Arthroscopic assessment of intercarpal ligament injuries and instability is now considered the gold standard by many authors. Arthroscopy can also aid us in the management of post-traumatic capsular contraction, resection of ganglia, and the relatively rare isolated ulna styloid impaction. Complications of wrist arthroscopy are relatively uncommon. With the ever-expanding list of indications and procedures that can be performed with this technique, it exists as an essential diagnostic and therapeutic tool for the orthopaedic surgeon.


Radiobiological Implications of Nanoparticles Following Radiation Treatment.
Materials with a high atomic number (Z) are shown to cause an increase in the level of cell kill by ionizing radiation when introduced into tumor cells. This study uses in vitro experiments to investigate the differences in radiosensitization between two cell lines (MCF-7 and U87) and three commercially available nanoparticles (gold, gadolinium, and iron oxide) irradiated by 6 MV X-rays. To assess cell survival, clonogenic assays are carried out for all variables considered, with a concentration of 0.5 mg mL-1 for each nanoparticle material used. This study demonstrates differences in cell survival between nanoparticles and cell line. U87 shows the greatest enhancement with gadolinium nanoparticles (2.02 ± 0.36), whereas MCF-7 cells have higher enhancement with gold nanoparticles (1.74 ± 0.08). Mass spectrometry, however, shows highest elemental uptake with iron oxide and U87 cells with 4.95 ± 0.82 pg of iron oxide per cell. A complex relationship between cellular elemental uptake is demonstrated, highlighting an inverse correlation with the enhancement, but a positive relation with DNA damage when comparing the same nanoparticle between the two cell lines.


A Review of Select Centralized Pain Syndromes: Relationship With Childhood Sexual Abuse, Opiate Prescribing, and Treatment Implications for the Primary Care Physician.
Pain can be broadly divided into 3 classes, including nociceptive or inflammatory pain (protective), neuropathic (pathological, occurring after damage to the nervous system), or centralized (pathological, due to abnormal function but with no damage or inflammation to the nervous system). The latter has been posited to occur when descending analgesic pathways are attenuated and/or glutamatergic transmission is facilitated. Additionally, this "pain prone phenotype" can be associated with early life trauma and a suboptimal response to opiates. This article will review the relationships between centralized pain syndromes (ie, fibromyalgia, chronic low back pain), childhood sexual abuse, and opiate misuse. Finally, treatment implications, potentially effecting primary care physicians, will be discussed.


Increasing burden and risk factors for bronchiolitis-related medical visits in infants enrolled in a state health care insurance plan.
The goals were to estimate the year-round burden of health care visits attributable to bronchiolitis and to identify risk factors for bronchiolitis in term healthy infants. We conducted a population-based, retrospective cohort study of 103 670 term, non-low birth weight infants enrolled in Tennessee Medicaid in 1995-2003. We monitored infants through the first year of life. Risk factors for bronchiolitis during infancy and rates of inpatient, emergency department, and outpatient visits during the study period were calculated by using claims data. Over the 9 study years, rates of bronchiolitis visits were 238 outpatient visits per 1000 infant-years, 77 emergency department visits per 1000 infant-years, and 71 hospitalizations per 1000 infant-years. Average annual rates of bronchiolitis visits increased 41%, from 188 visits per 1000 infant-years to 265 visits per 1000 infant-years, from 1996-1997 to 2002-2003. Analysis of the linear trend in 500-g increments demonstrated a negative association between increasing birth weight and bronchiolitis diagnosis. There was a significant negative trend between maternal age and infant bronchiolitis diagnosis. Compared with infants of mothers 20 to 29 years of age, infants of mothers 15 to 19 years of age had a small increase in risk of having a bronchiolitis visit, whereas infants of older mothers (30-39 or 40-44 years of age) were less likely to have a visit. The disease burden of bronchiolitis is substantial, with increasing rates of all types of visits among term, otherwise-healthy infants enrolled in Tennessee Medicaid between 1995 and 2003. Protective factors in this cohort of term infants included higher birth weight and older maternal age.


Optimality Principles in Human Point-to-Manifold Reaching Accounting for Muscle Dynamics.
Human arm movements are highly stereotypical under a large variety of experimental conditions. This is striking due to the high redundancy of the human musculoskeletal system, which in principle allows many possible trajectories toward a goal. Many researchers hypothesize that through evolution, learning, and adaption, the human system has developed optimal control strategies to select between these possibilities. Various optimality principles were proposed in the literature that reproduce human-like trajectories in certain conditions. However, these studies often focus on a single cost function and use simple torque-driven models of motion generation, which are not consistent with human muscle-actuated motion. The underlying structure of our human system, with the use of muscle dynamics in interaction with the control principles, might have a significant influence on what optimality principles best model human motion. To investigate this hypothesis, we consider a point-to-manifold reaching task that leaves the target underdetermined. Given hypothesized motion objectives, the control input is generated using Bayesian optimization, which is a machine learning based method that trades-off exploitation and exploration. Using numerical simulations with Hill-type muscles, we show that a combination of optimality principles best predicts human point-to-manifold reaching when accounting for the muscle dynamics.


Sleep in frontotemporal dementia is equally or possibly more disrupted, and at an earlier stage, when compared to sleep in Alzheimer's disease.
Conversely to other neurodegenerative diseases (i.e., Alzheimer's disease, AD), sleep in frontotemporal dementia (FTD) has not been studied adequately. Although some evidence exists that sleep-wake disturbances occur in FTD, very little is known regarding sleep macrostructure and/or primary sleep disorders. To investigate these issues in this population and compare them to similar issues in AD and in healthy elderly (HE). Twelve drug-naïve behavioral-variant FTD (bvFTD) patients (7 men/5 women) of mean age 62.5 ± 8.6 years were compared to seventeen drug-naïve AD patients (8 men/9 women) of mean age 69.0 ± 9.9 years and twenty drug-naïve HE (12 men/8 women) of mean age 70.2 ± 12.5 years. All participants were fully assessed clinically, through a sleep questionnaire, an interview, and video-polysomnography recordings. The two patient groups were comparably cognitively impaired. However, compared to FTD patients, the AD patients had a statistically significant longer disease duration. Overall, the sleep profile was better preserved in HE. Sleep complaints did not differ considerably between the two patient groups. Sleep parameters and sleep macrostructure were better preserved in AD compared to FTD patients, regardless of primary sleep disorders, which occurred equally in the two groups. With respect to AD, FTD patients had several sleep parameters similarly or even more affected by neurodegeneration, but in a much shorter time span. The findings probably indicate a centrally originating sleep deregulation. Since in FTD patients sleep disturbances may be obvious from an early stage of their disease, and possibly earlier than in AD patients, physicians and caregivers should be alert for the early detection and treatment of these symptoms.


Development and pilot testing of a decision aid for postmenopausal women with osteoporosis.
This study's aim was to develop and pilot test an evidence-based decision aid for postmenopausal women with osteoporosis who are considering options to prevent fractures. The aid was based on the Ottawa Decision Support Framework, and integrated evidence from our Cochrane systematic reviews. Following development by a panel of experts in osteoporosis and decision making, a user review panel of practitioners and women who had already made their decision about osteoporosis therapy reviewed the decision aid for acceptability. Then the decision aid was pilot tested using a before-after design in women at the point of decision making. Compared to baseline, there were statistically significant improvements in knowledge, realistic expectations and decreased decisional conflict. Our decision aid shows promise in preparing women for counseling about osteoporosis therapies. Long-term adherence to chosen therapy and quality of life will be evaluated in a randomized controlled trial.


Hedging to save face: a linguistic analysis of written comments on in-training evaluation reports.
Written comments on residents' evaluations can be useful, yet the literature suggests that the language used by assessors is often vague and indirect. The branch of linguistics called pragmatics argues that much of our day to day language is not meant to be interpreted literally. Within pragmatics, the theory of 'politeness' suggests that non-literal language and other strategies are employed in order to 'save face'. We conducted a rigorous, in-depth analysis of a set of written in-training evaluation report (ITER) comments using Brown and Levinson's influential theory of 'politeness' to shed light on the phenomenon of vague language use in assessment. We coded text from 637 comment boxes from first year residents in internal medicine at one institution according to politeness theory. Non-literal language use was common and 'hedging', a key politeness strategy, was pervasive in comments about both high and low rated residents, suggesting that faculty may be working to 'save face' for themselves and their residents. Hedging and other politeness strategies are considered essential to smooth social functioning; their prevalence in our ITERs may reflect the difficult social context in which written assessments occur. This research raises questions regarding the 'optimal' construction of written comments by faculty.


Mycotoxin-producing strains of Penicillium viridicatum: classification into subgroups.
Fifty-two isolates of Penicillium viridicatum Westling were divided into three groups based on ability to produce ochratoxin and/or citrinin, color, growth rate, type of growth, odor, and isolation source. Members of group I resemble one of the representative strains of P. viridicatum described in the literature; those belonging to group II differ from group I strains in several characteristics; group III is a heterogeneous series of highly variable isolates. Although three subgroupings can be recognized, retention of all isolates in the species P. viridicatum is deemed most appropriate at this time. Spore macerates of all isolates were examined for virus-like particles but none were detected.


Home Dialysis: A Majority Chooses It, a Minority Gets It.
When choosing a modality for outpatient renal replacement therapy, patients and medical providers have 3 options to choose from in-center hemodialysis (HD), home HD (HHD), and peritoneal dialysis (PD). In 2017, just over 10% of incident ESKD patients were on a home dialysis modality. We set out to determine outcomes of dialysis modality education in both pre-dialysis and dialysis patients. Moreover, we examined barriers that preclude patients from choosing home dialysis. This was a single-center, retrospective study looking at patients who were referred to the CKD educator for dialysis modality education between January 1, 2019, and March 31, 2020. Patient demographics, preferred language of communication, stage of renal disease, and reasons for patients' refusal to undertake a home dialysis modality were recorded. Patients' average household income and driving distance to our home dialysis unit were calculated using their home zip code. 167 patients were referred for CKD education. Mean age was 60 years, and 59% male, 42% African American, 22% White, 7% Asian, and 28% were Hispanic or Latino. Only 23% of the total cohort chose in-center HD, while 74% chose a home dialysis modality (59% PD and 15% HHD), and the remaining patients remained undecided. 56% of in-center HD patients chose a home dialysis modality. The most commonly cited barriers to home dialysis were lack of a care partner, lack of home space, and patient preference. Over 90% of our patients reside in NY City where home space is limited. We require in our home HD program that patients have a trained care partner present during their treatments. We cannot assume that all CKD stage-4 patients or higher were either referred for CKD education or followed through on the referral. A large discrepancy between informed patients' choices and the reality of the current dialysis landscape. Absence of a care partner, lack of home space, and patients not deemed appropriate surgical candidates were the main driving forces in their not opting for a home modality.


A novel de novo variant in POLR3B gene associated with a primary axonal involvement of the largest nerve fibers.
POLR3B gene encodes a subunit of RNA polymerase III (Pol III). Biallelic mutations in POLR3B are associated with leukodystrophies, but recently de novo heterozygous mutations have been described in early onset peripheral demyelinating neuropathies with or without central involvement. Here, we report the first Italian case carrying a de novo variant in POLR3B with a pure neuropathy phenotype and primary axonal involvement of the largest nerve fibers. Nerve conduction studies, sympathetic skin response, dynamic sweat test, tactile and thermal quantitative sensory testing and brain magnetic resonance imaging were performed according to standard procedures. Histopathological examination was performed on skin and sural nerve biopsies. Molecular analysis of the proband and his relatives was performed with Next Generation Sequencing. The impact of the identified variant on the overall protein structure was evaluated through rotamers method. Since his early adolescence, the patient presented with signs of polyneuropathy with severe distal weakness, atrophy, and reduced sensation. Neurophysiological studies showed a sensory-motor axonal polyneuropathy, with confirmed small fiber involvement. In addition, skin biopsy and sural nerve biopsy showed predominant large fibers involvement. A trio's whole exome sequencing revealed a novel de novo variant p.(Arg1046Cys) in POLR3B, which was classified as Probably Pathogenic. Molecular modeling data confirmed a deleterious effect of the variant on protein structure. Neurophysiological and morphological findings suggest a primary axonal involvement of the largest nerve fibers in POLR3B-related neuropathies. A partial loss of function mechanism is proposed for both neuropathy and leukodystrophy phenotypes.


Role of furin in granular acidification in the endocrine pancreas: identification of the V-ATPase subunit Ac45 as a candidate substrate.
Furin is a proprotein convertase which activates a variety of regulatory proteins in the constitutive exocytic and endocytic pathway. The effect of genetic ablation of fur was studied in the endocrine pancreas to define its physiological function in the regulated secretory pathway. Pdx1-Cre/loxP furin KO mice show decreased secretion of insulin and impaired processing of known PC2 substrates like proPC2 and proinsulin II. Both secretion and PC2 activity depend on granule acidification, which was demonstrated to be significantly decreased in furin-deficient beta cells by using the acidotrophic agent 3-(2,4-dinitroanilino)-3'amino-N-methyldipropylamine (DAMP). Ac45, an accessory subunit of the proton pump V-ATPase, was investigated as a candidate substrate. Ac45 is highly expressed in islets of Langerhans and furin was able to cleave Ac45 ex vivo. Furthermore, the exact cleavage site was determined. In addition, reduced regulated secretion and proinsulin II processing could be obtained in the insulinoma cell line betaTC3 by downregulation of either furin or Ac45. Together, these data establish an important role for furin in regulated secretion, particularly in intragranular acidification most likely due to impaired processing of Ac45.


[A patient with an angiomyolipoma of the liver in whom the course of enlargement could be confirmed].
The patients was a 54-year-old woman. In the liver, a high-echo phyma was detected. The lesion increased from 5 to 23mm over 2 years and 4 months. On CT and MRI, it was difficult to differentiate the phyma from hepatocellular carcinoma. However, angiography revealed early outflow to the hepatic vein. In the late CTHA phase of angio-CT, there was no ring-like dark staining reaction (corona), as observed in hepatocellular carcinoma patients, outside the tumor. Hepatectomy was performed, suggesting angiomyolipoma. The course of enlargement could be followed-up, and we present findings that may be useful for differentiating this tumor from hepatocellular carcinoma.


Developing Criteria and Associated Instructions for Consistent and Useful Quality Improvement Study Data Extraction for Health Systems.
The Agency for Healthcare Research and Quality (AHRQ) could devote resources to collate and assess quality improvement studies to support learning health systems (LHS) but there is no reliable data on the consistency of data extraction for important criteria. We identified quality improvement studies and evaluated the consistency of data extraction from two experienced independent reviewers at three time points: baseline, first revision (where explicit instructions for each criterion were created), and final revision (where the instructions were revised). Six investigators looked at the data extracted by the two systematic reviewers and determined the extent of similarity on a scale of 0 to 10 (where 0 represented no similarity and 10 perfect similarity). There were 42 assessments for baseline, 42 assessments for the first revision, and 42 assessments for the final revision. We asked two LHS participants to assess the relative value of our criteria. The consistency of extraction improved from 1.17 ± 1.85 at baseline to 6.07 ± 2.76 after revision 1 (P < 0.001) and to 6.81 ± 1.94 out of 10 for the final revision (P < 0.001). However, the final revision was not significantly improved over the first revision (P = 0.14). One key informant rated the difficulty in finding and using quality improvement studies a 6 (moderately difficult) while the other a 4 (moderately difficult). When asked how valuable it would be if AHRQ found and collated the demographic information about the health systems and the interventions used in published quality improvement studies, they rated it a 9 (highly valuable) and a 6 (moderately valuable). Creating explicit instructions for extracting data for quality improvement studies helps enhance the consistency of data extraction. This is important because it is difficult for LHS to vet these quality improvement studies on their own and they would value AHRQ's support in that regard.


Comparison of the Eragen Multi-Code Respiratory Virus Panel with conventional viral testing and real-time multiplex PCR assays for detection of respiratory viruses.
High-throughput multiplex assays for respiratory viruses are an important step forward in diagnostic virology. We compared one such assay, the PLx Multi-Code Respiratory Virus Panel (PLx-RVP), manufactured by Eragen Biosciences, Inc. (Madison, WI), with conventional virologic testing, consisting of fluorescent-antibody staining plus testing with the R-mix system and fibroblast tube cultures. The test set consisted of 410 archived respiratory specimens, mostly nasopharyngeal swabs, including 210 that had been positive by conventional testing for a balanced selection of common respiratory viruses. Specimens yielding discrepant results were evaluated using a panel of respiratory virus PCR assays developed, characterized, and validated with clinical specimens. PLx-RVP increased the total rate of detection of viruses by 35.8%, and there was a 25.7% increase in the rate of detection of positive specimens. Reference PCR assay results corroborated the PLx-RVP result for 54 (82%) of 66 discrepancies with conventional testing. Of the 12 specimens with discrepancies between PLx-RVp and the reference PCRs, 6 were positive for rhinovirus by PLx-RVP and the presence of rhinovirus was confirmed by nucleotide sequencing. The remaining six specimens included five in which the PLx-RVP failed to detect parainfluenza virus and one in which the detection of influenza A virus by PLx-RVP could not be confirmed by the reference PCR. Taking the results of the reference PCR assay results into account, the sensitivities of the PLx-RVP for individual viruses ranged from 94 to 100% and the specificities ranged from 99 to 100%. We conclude that PLx-RVP is a highly accurate system for the detection of respiratory viruses and significantly improves the rate of detection of these viruses compared to that by conventional virologic testing.


Leishmania tropica infections in travellers.
Oriental sore (acute cutaneous leishmaniasis) is usually a self-limited infection of the skin caused by the protozoan Leishmania tropica. This disease is endemic to the Mediterranean, Asia, Africa, and the Middle East, and is seen in this country among travellers and immigrants. We found four cases at the University of Michigan and diagnosed and treated the disorder. Some of the treatments currently recommended for this disease are potentially toxic, and none have been proved to be of real value. Uncomplicated, acute cutaneous leishmaniasis (L tropica) may best be managed by withholding treatment and observing the patient.


Prevalence of malnutrition in general medical patients.
Three, single-day nutritional surveys at weekly intervals were conducted in the general medical wards of an urban municipal teaching hospital. The techniques of nutritional assessment included anthropometric measures (weight/height, triceps skin fold, arm-muscle circumference, serum albumin, and hematocrit). The prevalence of protein-calorie malnutrition was 44% or greater by these criteria (weight/height, 45%; triceps skin fold, 76%; arm-muscle circumference, 55%; serum albumin, 44%; and hematocrit, 48%). These results were reproducible without significant variation between surveys. In 34% of patients, a lymphopenia of 1,200 cells/cu mm or less was found, a level likely to be associated with diminished cell-mediated immunity. Compared with a similar survey among surgical patients, the medical patients were more depleted calorically (weight/height, triceps skin fold) but had better protein status (arm-muscle circumference, serum albumin). Significant protein-calorie malnutrition occurs commonly in municipal hospitals in both medical and surgical services.


Efficacy and safety of combined Chinese and Western medicine in the treatment of knee osteoarthritis: a prospective, multicenter cohort study.
Purpose: To conduct a real-world evaluation of the efficacy and safety of combined Chinese and Western medicine in treating knee osteoarthritis (KOA). Methods: A multicenter, prospective cohort study design was employed, enrolling 450 KOA patients (Kellgren-Lawrence score of 3 or less). The patients were divided into a Western medicine treatment group (WM group) and a combined Western and traditional Chinese medicine treatment group (WM-CM group). A 6-week treatment plan was administered, and follow-up visits occurred at 2 weeks, 4 weeks, and 6 weeks after initiating treatment. The primary outcome indicator was the total Western Ontario and McMaster Universities Arthritis Index (WOMAC) score after 6 weeks of treatment. Secondary outcome indicators included WOMAC subscales for pain, stiffness, and joint function, visual analogue scale (VAS) score, physical component summary (PCS), mental component summary (MCS), and clinical effectiveness. The incidence of drug-related adverse events was used as a safety evaluation indicator. Results: A total of 419 patients were included in the final analysis: 98 in the WM group and 321 in the WM-CM group. The baseline characteristics of the two groups were comparable, except for the incidence of stiffness symptoms and stiffness scores. After 6 weeks of treatment, the WM-CM group exhibited superior results to the WM group in improving the total WOMAC score (24.71 ± 1.38 vs. 16.36 ± 0.62, p < 0.001). The WM-CM group also outperformed the WM group in WOMAC pain and joint function scores, VAS score, PCS score, MCS score, and clinical effectiveness (p < 0.05), which was consistent with the findings of the main evaluation index. Subgroup analysis indicated that the combined Chinese and Western medicine treatment showed more pronounced benefits in patients under 65 years of age and in those with a Kellgren-Lawrence (K-L) classification of 0-I. Throughout the study, no adverse effects were observed in either group. Conclusion: The combination of Chinese and Western medicine demonstrated superiority over Western medicine alone in relieving knee pain symptoms, improving knee function, and enhancing the quality of life for KOA patients with a K-L score of 3 or less. Moreover, the treatment exhibited a good safety profile. Clinical Trial Registration: (https://www.chictr.org.cn/), identifier (ChiCTR1900027175).


Comparative analysis reveals that polyploidy does not decelerate diversification in fish.
While the proliferation of the species-rich teleost fish has been ascribed to an ancient genome duplication event at the base of this group, the broader impact of polyploidy on fish evolution and diversification remains poorly understood. Here, we investigate the association between polyploidy and diversification in several fish lineages: the sturgeons (Acipenseridae: Acipenseriformes), the botiid loaches (Botiidae: Cypriniformes), Cyprininae fishes (Cyprinidae: Cypriniformes) and the salmonids (Salmonidae: Salmoniformes). Using likelihood-based evolutionary methodologies, we co-estimate speciation and extinction rates associated with polyploid vs. diploid fish lineages. Family-level analysis of Acipenseridae and Botiidae revealed no significant difference in diversification rates between polyploid and diploid relatives, while analysis of the subfamily Cyprininae revealed higher polyploid diversification. Additionally, order-level analysis of the polyploid Salmoniformes and its diploid sister clade, the Esociformes, did not support a significantly different net diversification rate between the two groups. Taken together, our results suggest that polyploidy is generally not associated with decreased diversification in fish - a pattern that stands in contrast to that previously observed in plants. While there are notable differences in the time frame examined in the two studies, our results suggest that polyploidy is associated with different diversification patterns in these two major branches of the eukaryote tree of life.


Primary envelopment of pseudorabies virus at the nuclear membrane requires the UL34 gene product.
Primary envelopment of several herpesviruses has been shown to occur by budding of intranuclear capsids through the inner nuclear membrane. By subsequent fusion of the primary envelope with the outer nuclear membrane, capsids are released into the cytoplasm and gain their final envelope by budding into vesicles in the trans-Golgi area. We show here that the product of the UL34 gene of pseudorabies virus, an alphaherpesvirus of swine, is localized in transfected and infected cells in the nuclear membrane. It is also detected in the envelope of virions in the perinuclear space but is undetectable in intracytoplasmic and extracellular enveloped virus particles. Conversely, the tegument protein UL49 is present in mature virus particles and absent from perinuclear virions. In the absence of the UL34 protein, acquisition of the primary envelope is blocked and neither virus particles in the perinuclear space nor intracytoplasmic capsids or virions are observed. However, light particles which label with the anti-UL49 serum are formed in the cytoplasm. We conclude that the UL34 protein is required for primary envelopment, that the primary envelope is biochemically different from the final envelope in that it contains the UL34 protein, and that perinuclear virions lack the tegument protein UL49, which is present in mature virions. Thus, we provide additional evidence for a two-step envelopment process in herpesviruses.


The clinical activity of mental health nurse lecturers.
Concerns have been expressed about the ability of mental health lecturers to prepare practitioners with the skills, knowledge and attitudes needed to implement the National Service Framework for mental health. Specifically mental health nurse lecturers have been criticized for lacking clinical competence and credibility, and for being out of touch with developments in service delivery. This paper presents a selection of findings from a recent review into the clinical activity of mental health lecturers in higher education institutions in England. The issues discussed include roles in practice, questioning the value of face-to-face clinical work, the benefits of being clinically active, the difficulties of clinical academic roles, barriers to maintaining clinical activity, questioning the quality of the clinical workforce, and finally strategies to facilitate clinical activity. Whilst there is support among mental health nurse lecturers for the need to engage with practice at some level, there are inconsistencies in the ways that this is being achieved. Lecturers are, however, getting together to debate how best to keep up with changes in mental health practice and delivery.


In Vivo Base Editing of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) as a Therapeutic Alternative to Genome Editing.
High-efficiency genome editing to disrupt therapeutic target genes, such as PCSK9 (proprotein convertase subtilisin/kexin type 9), has been demonstrated in preclinical animal models, but there are safety concerns because of the unpredictable nature of cellular repair of double-strand breaks, as well as off-target mutagenesis. Moreover, precise knock-in of specific nucleotide changes-whether to introduce or to correct gene mutations-has proven to be inefficient in nonproliferating cells in vivo. Base editors comprising CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats [CRISPR]-CRISPR-associated 9) fused to a cytosine deaminase domain can effect the alteration of cytosine bases to thymine bases in genomic DNA in a sequence-specific fashion, without the need for double-strand DNA breaks. The efficacy of base editing has not been established in vivo. The goal of this study was to assess whether in vivo base editing could be used to modify the mouse Pcsk9 gene in a sequence-specific fashion in the liver in adult mice. We screened base editors for activity in cultured cells, including human-induced pluripotent stem cells. We then delivered a base editor into the livers of adult mice to assess whether it could introduce site-specific nonsense mutations into the Pcsk9 gene. In adult mice, this resulted in substantially reduced plasma PCSK9 protein levels (>50%), as well as reduced plasma cholesterol levels (≈30%). There was no evidence of off-target mutagenesis, either cytosine-to-thymine edits or indels. These results demonstrate the ability to precisely introduce therapeutically relevant nucleotide variants into the genome in somatic tissues in adult mammals, as well as highlighting a potentially safer alternative to therapeutic genome editing.


Coronary Artery Calcification Is Related to Inflammation in Rheumatoid Arthritis: A Long-Term Follow-Up Study.
Objective. A long-term follow-up of patients with rheumatoid arthritis (RA) to evaluate factors related to coronary artery calcification (CAC). Methods. All 22 eligible patients (4 males/18 females, mean age 65 years, and RA-duration 30-36 years) from the original (baseline; n = 39) study of atherosclerosis were included. Inflammation, cardiovascular risk factors, and biomarkers were measured at baseline. At follow-up 13 years later, CAC was assessed by computed tomography (CT) and the grade of inflammation was measured. Multivariate analysis of differences between patients with low (0-10) and high CAC (>10) was done by orthogonal projection to latent structures (OPLS). Results. Ten patients had CAC 0-10 and 12 had >10 (range 18-1700). Patients with high CAC had significantly higher ESR (24.3 versus 9.9 mm/h) and swollen joint count (2 versus 0). The OPLS models discriminated between patients having high or low CAC. With only baseline variables, the sensitivity was 73% and the specificity 82%. The model that also included inflammatory variables from follow-up had a sensitivity of 89% and a specificity of 85%. Exclusion of baseline intima media thickness and plaque from the latter model modestly reduced the accuracy (sensitivity 80% and specificity 83%). Conclusions. CAC is related to inflammation in patients with RA.


Spatial transmission of H5N2 highly pathogenic avian influenza between Minnesota poultry premises during the 2015 outbreak.
The spatial spread of highly pathogenic avian influenza (HPAI) H5N2 during the 2015 outbreak in the U.S. state of Minnesota was analyzed through the estimation of a spatial transmission kernel, which quantifies the infection hazard an infectious premises poses to an uninfected premises some given distance away. Parameters were estimated using a maximum likelihood method for the entire outbreak as well as for two phases defined by the daily number of newly detected HPAI-positive premises. The results indicate both a strong dependence of the likelihood of transmission on distance and a significant distance-independent component of outbreak spread for the overall outbreak. The results further suggest that HPAI spread differed during the later phase of the outbreak. The estimated spatial transmission kernel was used to compare the Minnesota outbreak with previous HPAI outbreaks in the Netherlands and Italy to contextualize the Minnesota transmission kernel results and make additional inferences about HPAI transmission during the Minnesota outbreak. Lastly, the spatial transmission kernel was used to identify high risk areas for HPAI spread in Minnesota. Risk maps were also used to evaluate the potential impact of an early marketing strategy implemented by poultry producers in a county in Minnesota during the outbreak, with results providing evidence that the strategy was successful in reducing the potential for HPAI spread.


Mild cognitive impairment: a cross-national comparison.
The main aim of this collaborative study was to assess the comparability of the most commonly used criteria for mild cognitive impairment (MCI) by comparing the cognitive performance of patients with MCI from the Mayo Clinic (USA) and the Karolinska Institutet (Sweden). Standardised neuropsychological test scores were used to compare the two samples from the two institutions with regard to the number of cognitive domains in which performance was below 1.5 SD. Possible predictors for the conversion from MCI to Alzheimer's disease (AD) were assessed. When the two institutions were considered together in the Cox proportional hazard model, the number of affected cognitive domains below 1.5 SD was a significant predictor of time to AD diagnosis with age, education, and APOE epsilon4 genotype entered into the same model as covariates. The number of affected cognitive areas remained as a significant predictor when the institutions were considered separately. The logistic regression model of conversion to AD showed that only tests assessing learning and retention were predictors of developing AD. Differences in population as well as in methodology of case ascertainment as well as other aspects may account for the observed variability between samples of patients with MCI. The number of impaired cognitive factors at baseline can predict the progression from MCI to AD. Furthermore, tests assessing learning and retention are the best predictors for progression to AD.


[The inductive immunosuppressive activity of the nonspecific lipopolysaccharide fraction of virulent Shigella sonnei].
The influence of lipopolysaccharide (LPS) fraction (molecular weight 50-70 kD) of virulent Shigella sonnei on bacterium ability to suppress delayed-type hypersensitivity (DTH) to xenogenic test-antigen in mice has been studied. It is found that single injection of LPS-fraction or bacteria does not inhibit DTH. Intraperitoneal injection of LPS-fraction together with avirulent S. sonnei causes DTH inhibition in mice and at the same time the injection of LPS-fraction together with Staphylococcus or Pseudomonas (extracellular parasites) does not render influence on DTH levels. There is a possibility of LPS-fraction conversion from active to non-active state and back after treatment by trichloracetic acid, phenol or redox system. It is assumed that in Shigella sonnei infection avirulent enteroinvasive bacteria can be involved in immunopathological process due to activity of non-specific fraction of S. sonnei LPS.


Identifying target behaviors for weight management interventions for women who are overweight during pregnancy and the postpartum period: a qualitative study informed by the Behaviour Change Wheel.
Maternal overweight is increasing, and it is associated with several risk factors for both the mother and child. Healthy lifestyle behaviors adopted during pregnancy are likely to impact women's health positively after pregnancy. The study's aim was to identify and describe weight management behaviors in terms of the Capability, Opportunity and Motivation Behaviour (COM-B) -model to target weight management interventions from both the perspectives of women who are overweight and maternity care professionals. This qualitative, descriptive study was conducted between 2019 and 2020. Individual interviews with pregnant and postpartum women who were overweight (n = 11) and focus group interviews with public health nurses (n = 5) were undertaken in two public maternity clinics in Southwest Finland. The data were analyzed using deductive content analysis consistent with the COM-B model. In the capability category, the women and the public health nurses thought that there was a need to find consistent ways to approach overweight, as it had often become a feature of the women's identities. The use of health technology was considered to be an element of antenatal care that could be used to approach the subject of weight and weight management. Smart wearables could also support an evaluation of the women's lifestyles. The opportunity category highlighted the lack of resources for support during perinatal care, especially after birth. Both groups felt that support from the family was the most important facilitating factor besides motivation. The women also expressed a conflict between pregnancy as an excuse to engage in unhealthy habits and pregnancy as a motivational period for a change of lifestyle. Furthermore, the women wanted to be offered a more robust stance on weight management and discreet counseling. Our findings offer a theoretical basis on which future research can define intervention and implementation strategies. Such interventions may offer clear advice and non-judgmental support during pregnancy and after delivery by targeting women's capabilities, opportunities, and motivation. Health technology could be a valuable component of intervention, as well as an implementation strategy, as they provide ways during maternity care to approach this topic and support women.


Levels and correlates of internalized homophobia among men who have sex with men in Pretoria, South Africa.
This study examines levels and correlates of internalized homophobia among men who have sex with men (MSM) in Pretoria, South Africa. Using respondent-driven sampling, we recruited 324 MSM from February to August 2009. Results were adjusted using RDSAT analysis to yield population-based estimates. High levels of internalized homophobia exist among South African MSM: 10-15% reported "often/very often" and over 20% reported "sometimes" having feelings of internalized homophobia. A greater level of internalized homophobia was significantly associated with a lower level of education [Adjusted Odds Ratio = 2.2; 95% CI = 1.1-4.9], a higher level of HIV misinformation [AOR = 2.7; 95% CI: 1.3-5.3], bisexual identity (vs. homosexual) [AOR = 5.5; 95% CI: 2.5-12.0], and HIV-related conspiracy beliefs [AOR = 2.4; 95% CI: 1.02-5.8]. These findings contribute valuable information to our understanding of internalized homophobia in South Africa, highlighting the need to empower the gay community, promote self-acceptance of homosexual identity, and address conspiracy beliefs among MSM to reduce internalized homophobia and increase access to HIV prevention interventions.


Minocycline treatment for pulmonary Mycobacterium avium complex disease based on pharmacokinetics/pharmacodynamics and Bayesian framework mathematical models.
Our aim was to identify the pharmacokinetic/pharmacodynamic parameters of minocycline in the hollow-fibre system (HFS) model of pulmonary Mycobacterium avium complex (MAC) and to identify the optimal clinical dose. Minocycline MICs for 55 MAC clinical isolates from the Netherlands were determined. We also co-incubated primary isolated macrophages infected with MAC with minocycline. Next, we performed a 28 day HFS-MAC model dose-response study in which we mimicked pulmonary concentration-time profiles achieved in patients. The HFS-MAC model was sampled at intervals to determine the minocycline pharmacokinetics and MAC burden. We identified the AUC0-24/MIC ratios associated with 1.0 log10 cfu/mL kill below day 0 (stasis), defined as a bactericidal effect. We then performed 10000 Monte Carlo experiments to identify the optimal dose for a bactericidal effect in patients. The MIC for 50% and 90% of cumulative clinical isolates was 8 and 64 mg/L, respectively. Minocycline decreased MAC bacterial burden below stasis in primary isolated macrophages. In the HFS-MAC model, minocycline achieved a microbial kill of 3.6 log10 cfu/mL below stasis. The AUC0-24/MIC exposure associated with a bactericidal effect was 59. Monte Carlo experiments identified a minocycline susceptibility MIC breakpoint of 16 mg/L. At this proposed breakpoint, the clinical dose of 200 mg/day achieved the bactericidal effect exposure target in ∼50% of patients, while 400 mg/day achieved this in 73.6% of patients, in Monte Carlo experiments. Minocycline at a dose of 400 mg/day is expected to be bactericidal. We propose a clinical trial for validation.