How to Enable Participation until the End of Life? A Survey of German Occupational Therapists Working in Palliative Care.
In palliative care, the needs of people with life-limiting illnesses must be addressed with the support of a multidisciplinary team. Occupational therapy is a profession that focuses on activity and participation. In Germany, there are no surveys to date that demonstrate the work of occupational therapists in palliative care and which problems can occur in this field. The aim of this study is to describe the work and problems of occupational therapists in German palliative care. The survey consists of 17 questions and could be conducted anonymously. Descriptive statistics and a thematic analysis of the free text responses were used to analyze data. Respondents were German occupational therapists who are members of the "German Association of Occupational Therapy". A total of 281 valid responses were evaluated, of which 120 respondents work in the context of palliative care. Most of them provide needs-based therapies (74%), train relatives (69%), or help patients with positioning (69%) or relaxation therapy (66%). Four themes were developed in the free text responses that describe problems in the utilization of occupational therapy in palliative care. The evaluation shows that occupational therapy in palliative care offers a variety of possible applications and approaches. The findings urgently need to be implemented in daily practice to improve the status of occupational therapists. This requires appropriate billing modalities and clear guidelines. There is still a significant need for research and training in this area.


Rapid method for the examination of platelet morphology.
A simple, rapid method is described for preparing platelets of domestic animals for light and electron microscopic examinations. The method involves the isolation of the platelet rich plasma (PRP) by centrifugation of the whole blood for five minutes followed by recentrifugation of PRP in a Wintrobe tube at 4500 rpm for 20 minutes to separate the blood components into four distinct layers composed exclusively of plasma, leucocytes, platelets and erythrocytes. A short fixation (20 minutes) by replacing the plasma layer with glutaraldehyde before breaking the bottom of the tube with a glass cutter allows the cellular contents to be gently pushed out of the tube in the form of a cylindrical semisolid pellet, with a wooden applicator stick. A further three hour fixation of the pellet in fresh glutaraldehyde before cutting out the middle layer for routine processing for light and electron microscopy provides pure preparation of platelets with a minimum of morphological distortion.


Comparison of amikacin with fosfomycin as an add-on to ciprofloxacin for antibiotic prophylaxis in transrectal prostate biopsy: A single-center retrospective study.
To assess the effect of ciprofloxacin (CP) and fosfomycin compared with CP and amikacin in patients with a fluoroquinolone (FQ)-resistant rectal flora who have undergone transrectal ultrasound-guided prostate biopsy (TRUSPB). In total, 516 patients with FQ-resistant rectal flora based on rectal swab cultures were divided into two groups according to prophylactic antibiotics. Patients in both groups were administered CP (400 mg, intravenous [IV], twice daily) on the same day as TRUSPB and 1 day after biopsy. The amikacin group (n=260) was administered a single injection of amikacin (1 g, IV) 1 hour before TRUSPB, whereas the fosfomycin group (n=256) was administered fosfomycin (3 g, orally) the night before the procedure. The primary endpoint was the rate of infectious complications in the two groups. Overall, 13 patients (2.5%) reported infectious complications: 12 patients (4.62%) in the amikacin group compared with 1 patient (0.39%) in the fosfomycin group (risk ratio, 0.09; 95% confidence interval [CI], 0.01-0.65), respectively, which was a statistically significant difference (p=0.017). This corresponds to a number needed to treat of 24 patients (95% CI, 15-65) to prevent one infectious complication. In the multivariate analysis to assess variables related to infectious complications, prophylactic antibiotics with added fosfomycin was associated with infectious complications (odds ratio, 0.060; 95% CI, 0.008-0.459). In the era of FQ resistance, CP and fosfomycin may reduce the rate of infectious complications compared with CP and amikacin prophylaxis.


IL-10 release requires stronger toll-like receptor 4-triggering than TNF: a possible explanation for the selective effects of heterozygous TLR4 polymorphism Asp(299)Gly on IL-10 release.
The toll-like receptor 4 Asp(299)Gly polymorphism results in an inactive receptor. Heterozygosis is associated with reduced LPS-inducible IL-10 protein and IL-10 mRNA from blood leukocytes and isolated monocytes, while numerous other mediators are not affected. We could exclude that this effect is due to the differences in the kinetics of IL-10 release, in the expression of total surface TLR4 or in LPS-binding to monocytes between subjects heterozygous for the Asp(299)Gly polymorphism or homozygous carriers of the wild-type allele. Furthermore, we could show that IL-10 induction in general requires stronger LPS-triggering than TNF and is more sensitive to LPS inhibitors. The lower number of responsive wild-type TLR4 receptors on monocytes of heterozygotes may explain why only IL-10 release is affected.


Injury to the circuit of Papez: An overlooked cause of recurrent seizures.
Papez' circuit is a unique neural pathway in the limbic system that is correlated with seizure activity. Injuries affecting Papez' circuit are often small and unusual in location but can be identifiable in MRI and functional imaging modalities, which can be helpful in the workup of refractory epilepsy. The Papez circuit is a unique neural pathway in the limbic system of the brain. We review a patient presenting with recurrent seizures as the main manifestation of Papez' circuit pathology. The radiologic features of ischemia involving the mammillothalamic tract in Papez' circuit were correlated with the seizure activity.


Structural and functional studies on the G(o) protein.
Monoclonal antibodies were raised against purified bovine and human brain G-proteins. The epitopes recognized by three monoclonal antibodies (MONO, 3C2, and 3E7) were mapped by expressing defined parts of the bovine G(o) alpha-cDNA in bacteria, followed by immunoblotting. All three antibodies recognize the recombinant bovine alpha o-protein, but at distinct sites. The epitopes of MONO and 3C2 were mapped between alpha o amino acids 80 and 145, and both antibodies recognize alpha o exclusively. Heterotrimeric G(o)-proteins as well as guanosine 5'-3-O-(thio)triphosphate-liganded free alpha o-subunits are readily immunoprecipitated by these monoclonal antibodies. Binding of MONO or 3C2 does not affect ADP-ribosylation of the alpha o-subunit by pertussis toxin. Apparently, the antibodies do not bind to or induce large conformational changes in regions of the alpha o-subunit that are involved in association with beta gamma-subunits or ADP-ribosylation. 3E7 behaves as an anti common alpha-subunit antibody when used in immunoblots. However, under nondenaturing conditions, 3E7 recognizes alpha o exclusively. After binding of 3E7, the pertussis toxin-dependent ADP-ribosylation of alpha o is effectively blocked, while the ADP-ribosylation of the various alpha i-subunits is not affected. The epitope of 3E7 was mapped between alpha o amino acids 13-88, a region which has been implicated in the interaction between alpha- and beta gamma-subunits. Possibly, the inhibitory effect of 3E7 on ADP-ribosylation of G(o) is secondary to the loss of beta gamma-subunits that is observed upon binding of 3E7.


Evaluation of Systane Complete for the Treatment of Contact Lens Discomfort.
To understand if a new artificial tear, which is indicated for the treatment of both evaporative and aqueous deficient dry eye, is able to safely alleviate contact lens discomfort (CLD) in symptomatic soft contact lens (CL) wearers. This registered, investigator-masked, two-week, randomized clinical trial recruited adult subjects with symptomatic Contact Lens Dry Eye Questionanire-8 (CLDEQ-8 scores ≥ 12) scores. Subjects were randomized to use artificial tears (Systane Complete) before and after CL use or no treatment. Clinical signs (visual acuity, tear breakup time, corneal staining, Schirmer's test I, and meibum quality and expression) and symptoms (CLDEQ-8, Standardized Patient Evaluation of Eye Dryness (SPEED), self-reported) were evaluated at baseline and two weeks. This study recruited 22 subjects who were randomized to artificial tears and 24 subjects who were randomized to no treatment. Subjects in the artificial tears group had significantly better CLDEQ-8 scores (12.86 ± 6.40 vs. 17.92 ± 5.30; p = 0.006) but not SPEED scores (7.55 ± 4.31 vs. 9.29 ± 4.14; p = 0.17) at two weeks compared to the no treatment group. No significant between group differences were noted for any clinical signs at two weeks (all p > 0.29). No subject in either group reported any adverse events during the study. Systane Complete was found to safely and significantly improve CL comfort in symptomatic CL wearers. Additional work is needed to better understand the mechanism(s) leading to improved comfort since tested clinical signs were unchanged.


Clinical validity of plasma and urinary desmosine as biomarkers for chronic obstructive pulmonary disease.
Although an increased concentration of degraded elastin products in patients with chronic obstructive pulmonary disease (COPD) has been reported for many years, its clinical validity and utility remain uncertain due to technical difficulties, small study groups and the unknown relationship between exacerbation and elastin degradation. The objectives of this study were to determine the validity of urinary and blood total desmosine/isodesmosine in patients with COPD and asthma and to evaluate their relationship to exacerbation status and lung function. Urinary and blood desmosine levels were measured using validated isotopic dilution liquid chromatography-tandem mass spectrometry methods. 390 study participants were recruited from the following groups: healthy volunteers, stable asthma, stable and 'during an exacerbation' COPD. Compared with healthy non-smokers, we found increased urinary or blood desmosine levels in patients with COPD, but no differences in patients with asthma or healthy smokers. The elevation of urinary desmosine levels was associated with the exacerbation status in patients with COPD. Approximately 40% of patients with stable and 'during an exacerbation' COPD showed elevated blood desmosine levels. Blood desmosine levels were strongly associated with age and were negatively correlated with lung diffusing capacity for carbon monoxide. The results suggest that urinary desmosine levels are raised by exacerbations of COPD whereas blood desmosine levels are elevated in a subgroup of patients with stable COPD and reduced lung diffusing capacity. The authors speculate that a raised blood desmosine level may identify patients with increased elastin degradation suitable for targeted therapy. Future prospective studies are required to investigate this hypothesis.


The steady-state amino acid fluxes across the perfused choroid plexus of the sheep.
The steady-state flux of labelled amino acids was investigated across the isolated perfused choroid plexus of the sheep. The extraction of anionic, cationic, small and large neutral amino acids by the blood side of the choroid plexus was demonstrated. However, there was no uptake of the analogue MeAIB, confirming the absence of the 'A' carrier system on this side of the blood--CSF barrier. The direction of the net flux of amino acids across the tissue varied depending on the amino acid and its concentration. At a concentration of 0.01 mM the net movement for phenylalanine, serine, aspartate and glycine was from blood to CSF. When the concentration of amino acid was increased to 0.1 mM, the net flux of phenylalanine and serine remained from blood to CSF whereas the net flux of the transmitters, aspartate and glycine, was in the opposite direction, from CSF to blood. When the level was raised further, to 1 mM, all four amino acids showed a net CSF to blood flux. The concentration of amino acids is newly formed CSF was calculated from the blood to CSF fluxes and was found to be between 2 and 200 microM, similar to that found in mammalian bulk phase CSF.


Electrophoretic isolation and partial characterization of a glycoprotein of the submandibular glands of the mouse.
A protein has been isolated from the water-extract of the submandibular glands of the mouse, after Biogel P-300 column passage, followed by preparative polyacrylamide gel electrophoresis at pH 4.3 and subsequently at pH 8.9, designated the AM1 protein. The isolated protein was electrophoretically pure in 7.5, 10 and 15% polyacrylamide gels both at pH 4.3 and at pH 8.9. Likewise, by electrophoresis in 15% sodium dodecyl sulfate-polyacrylamide gel only one protein band could be detected. Of the total amount of the water-extractable submandibular proteins the recovery of this protein component comprised 3 to 5 per cent. The molecular weight was estimated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis to be 28 000, both in 7.5 and 15% gel. The isoelectric point was determined by isoelectric focusing in 4.8% polyacrylamide slabgel to be 4.85. The amino acid analysis showed that the ratio of acidic amino acids (Glx plus Asx) to basic amino acids (Lys plus Arg) is 2.3. The glycoprotein consists of protein for 77.4 per cent and of carbohydrate for 22.6 per cent. The molar ratio of the carbohydrates was GlcNH2:GalNH2:Man:Gal:Glc:Fuc:sialic acid = 22.0:1.3:3.0:1.7:10.0:2.6:0.3. The glycoprotein was not secreted from the submandibular glands by stimulation with cholinergic (acetylcholin) or adrenergic (noradrenalin) drugs both in vitro and in vivo. So, it appeared that this glycoprotein could be characterized as a cellular, non-secretory component of these salivary glands.


Two nonhomologus viruses of Cryphonectria (Endothia) parasitica reduce accumulation of specific virulence-associated polypeptides.
Double-stranded RNA responsible for transmissible hypovirulence of Cryphonectria (Endothia) parasitica affected the accumulation of specific polypeptides. Nonhomologous hypovirulence-causing double-stranded RNAs, originating in Europe or North America, affected accumulation of the same polypeptides. Fewer than 5% of detectable proteins were affected, indicating that hypovirulence is probably not the result of general debilitation of the fungus.


TACE/ADAM17-TNF-alpha pathway in rat cortical cultures after exposure to oxygen-glucose deprivation or glutamate.
The role of the tumor necrosis factor (TNF)-alpha convertase (TACE/ADAM17) in the adult nervous system remains poorly understood. The authors have previously demonstrated that TACE is upregulated in rat forebrain slices exposed to oxygen-glucose deprivation (OGD). They have now used rat mixed cortical cultures exposed to OGD or glutamate to study (1) TACE expression and localization, and (2) the effects of TNF-alpha release on cell viability. OGD-or glutamate-caused TNF-alpha release, an effect that was blocked by the TACE inhibitor BB3103 (BB) (0.1-1 micromol/L; control: 1.67 +/- 0.59; OGD: 6.59 +/- 1.52; glutamate: 3.38 +/- 0.66; OGD +/- BB0.1: 3.23 +/- 0.67; OGD +/- BB1: 1.33 +/- 0.22 pg/mL, n = 6, P < 0.05). Assay of TACE activity as well as Western blot showed that TACE expression is increased in OGD-or glutamate-exposed cells. In control cultures, TACE immunoreactivity was present in some microglial cells, whereas, after OGD or glutamate, TACE immunostaining appeared in most microglial cells and in some astrocytes. Conversely, BB3103 (0.1 micromol/L) caused apoptosis after glutamate exposure as shown by annexin and Hoechst 33342 staining and caspase-3 activity, an effect mimicked by the proteasome inhibitor MG-132 (caspase activity: glutamate: 5.1 +/- 0.1; glutamate + BB: 7.8 +/- 0.8; glutamate + MG: 11.9 +/- 0.5 pmol. min(-1) mg(-1) protein, n = 4, P < 0.05), suggesting that translocation of the transcription factor NF-kappaB mediates TNF-alpha-induced antiapoptotic effect. Taken together, these data demonstrate that, in rat mixed neuronal-glial cortical cultures exposed to OGD or glutamate, (1) TACE/ADAM17 activity accounts for the majority of TNF-alpha shedding, (2) an increase in glial TACE expression contributes to the rise in TNF-alpha, and (3) TNF-alpha release in this setting inhibits apoptosis via activation of the transcription factor NF-kappaB.


Transcranial color-coded sonography in basilar artery stenting.
Basilar artery (BA) stenting is an emerging technique with promising results in revascularization of severe arteriosclerotic stenoses. Because of the limitations associated with other noninvasive techniques, we applied transcranial color-coded sonography (TCCS) in the follow-up. Successful stent application in two cases of acute basilar occlusion caused by thrombosis on pre-existing severe midbasilar stenoses was initially confirmed by angiography. Later recanalization was controlled noninvasively by magnetic resonance angiography (MRA), computed tomographic angiography (CTA) and TCCS. Ultrasound (US) was performed through the transtemporal bone window; a contrast-enhancing agent had to be used in one case. TCCS showed an orthograde flow in the distal BA in both patients without signs of severe stenoses. Transtemporal TCCS was demonstrated to be a noninvasive bedside technique in monitoring the patency of the BA after stenting.


Treatment with GnRH agonists before myomectomy and the risk of short-term myoma recurrence.
Twenty-four women with symptomatic multiple uterine myomas were allocated randomly to treatment with buserelin, 1200 micrograms/day intranasally, for 3 months followed by myomectomy (n = 8) or to immediate myomectomy (n = 16). Pre-operative treatment with buserelin reduced the mean uterine volume from 432 (SD 165) to 242 (SD 82) ml (P less than 0.01) but intra-operative blood loss and postoperative morbidity were not significantly less in this group. Six months after operation, pelvic examination was normal in all the patients. However, ultrasonography with transvaginal probe demonstrated the presence of myomas of less than 1.5 cm in five women (63%) treated pre-operatively with the analogue and in two women (13%) who underwent immediate surgery (P less than 0.05). Induction of a period of hypo-oestrogenism before myomectomy seems to favour short-term recurrence of uterine myomas, limiting the efficacy of surgery.


Copper(II)-Thymine Coordination Polymer Nanoribbons as Potential Oligonucleotide Nanocarriers.
The direct reaction between copper nitrate, thymine-1-acetic acid, and 4,4'-bipyridine in water leads to the formation of a blue colloid comprising uniform crystalline nanoribbons (length >1 μm; width ca. 150-185 nm; diameter ca. 15-60 nm) of a coordination polymer. The polymer displays a thymine-based structure freely available for supramolecular interactions. These nanostructures show significant selective interaction with single-stranded oligonucleotides based on adenine. Remarkably, they present low cell toxicity in three cell lines-despite the copper(II) content-and can be used as nanocarriers of oligonucleotides. These results suggest the potential of these types of nanostructures in several biological applications.


Light adaptation of bacteriorhodopsin correlates with dielectric spectral kinetics in purple membrane.
The retinal protein, bacteriorhodopsin (bR), has several potential bioelectronic applications and it is considered as a model for G-protein coupled receptors. Its electrical parameters, therefore, deserve particular attention. Such parameters could be determined by virtue of studying its dielectric spectrum in the low frequency range (20 Hz-1 MHz). The kinetics of dark-light adaptation of bR is reported in terms of electrical parameters of the purple membrane (PM) containing bR. The data have exhibited sudden pronounced increase in the ac-conductivity, upon illuminating the dark-adapted bR (DA-bR), which may be considered in further implications of bR for biotechnological applications. These changes turned out to be composed of, at least, two growing exponential components: one relatively fast followed by slower one. Their lifetime ratio exhibited decreases with increasing the frequency; meanwhile, their amplitude ratio displayed very exciting behavior at significant frequencies. This may correlate the kinetics of light adaptation to relaxations in PM. Moreover, the light adaptation has been observed to cause initial fast and large decreases in dc-conductivity with subsequent slower and smaller decreases. Changing the conductivity during the time of light adaptation reflects changes in the surface charge of the PM. The lifetimes of these events, therefore, help follow the kinetics of the pathway of conformational changes that might be occurring during light adaptation. The dipole moment (permanent and induced) of PM, in addition to, its size showed one exponential growth of comparable lifetime (approximately 7 min) during the light adaptation. The variation in PM size from dark to light state should be in keeping with that diffusion may influence the three-dimensional data storage in data processing based on bR.


The simultaneous effect of soil-borne NaF and air pollutant SO2 on CO2-uptake and pollutant accumulation.
Spruce cuttings were potted in quartz sand. One half was watered with tap water, the other with deionized water containing 100 ppm F- as NaF, during winter till bud break. After flushing the plants were exposed continuously for five weeks (June/July) either to normal air or to air with 0.025 and 0.075 ppm SO2, respectively. CO2-uptake was measured in the laboratory (40,000 lux) with an IRGA.Even in the absence of visible symptoms of injury to last year's needles, root-applied fluoride did suppress CO2-uptake significantly. Also the fumigation with 0.075 ppm SO2 caused a depression of CO2-uptake, whereas 0.025 ppm SO2 remained without significant reaction within five weeks. Fluorides infiltrating through roots and airborne SO2 acting together may depress CO2-uptake synergistically.Soil applied fluoride accumulated particularly in roots and twigs, whereas very little was found in the stem. The F--accumulation even increased with increasing SO2-concentrations but was without effect on S-accumulation.


Rational disruption of the oligomerization of the mini-ferritin E. coli DPS through protein-protein interface mutation.
DNA-binding protein from starved cells (DPS), a mini-ferritin capable of self-assembling into a 12-meric nano-cage, was chosen as the basis for an alanine-shaving mutagenesis study to investigate the importance of key amino acid residues, located at symmetry-related protein-protein interfaces, in controlling protein stability and self-assembly. Nine mutants were designed through simple inspection, synthesized, and subjected to transmission electron microscopy, circular dichroism, size exclusion chromatography, and "virtual alanine scanning" computational analysis. The data indicate that many of these residues may be hot spot residues. Most remarkably, two residues, R83 and R133, were observed to shift the oligomerization state to ~50% dimer. Based on the hypothesis that these two residues constitute a "hot strip," located at the ferritin-like threefold axis, the double mutant was generated which completely shuts down detectable formation of 12-mer in solution, favoring a cooperatively folded dimer. The fact that this effect logically builds upon the single mutants emphasizes that complex self-assembly has the potential to be manipulated rationally. This study should have an impact on the fundamental understanding of the assembly of DPS protein cages specifically and protein quaternary structure in general. In addition, as there is much interest in applying these and similar systems to the templation of nano-materials and drug delivery, the ability to control this ferritin's oligomerization state and stability could prove especially valuable.


[Physical training as core component of multimodal treatment of older frail people-study protocol of a randomized controlled pilot study].
Clinical practice guidelines recommend a multimodal intervention based on standardized screening for the treatment of frailty, which includes physical exercise as the main component. This study protocol describes a planned randomized controlled pilot study to evaluate the feasibility of a main study and first assessment of the effects of a multimodal, resource-oriented intervention program on frailty in older people. A total of 50 community-dwelling older men and women with frailty, ≥65 years of age, will be randomly allocated to the intervention or control group. The intervention group receives usual care and a multimodal intervention program. This program consists of a multidimensional screening, verbal counselling, written instructions on individual functional and health status, a home-based physical exercise program (high-intensity functional exercise program, HIFE), and support related to cognition, mood, risk of falling, medication, nutrition and self-care as required. The control group participants will receive usual care only. The feasibility will be assessed by indicators for processes, resources and management (practicability), as well as for acceptance, safety and possible effects of the intervention. The frailty index and secondary clinical endpoints will be assessed before and after the 3‑month intervention, as well as after a 3-month follow-up to estimate the effects. Data will be analyzed according to the intention-to-treat principle. Ethical approval was obtained from the Ethics Committee of the German Physiotherapy Association (ref. number: 2017-02). Outcomes will be disseminated in a peer-reviewed journal and at specialist conferences. German Clinical Trial Register: DRKS00011831.


Droplet Degeneration of Hippocampal and Cortical Neurons Signifies the Beginning of Neuritic Plaque Formation.
Neuritic plaques contain neural and microglial elements, and amyloid-β protein (Aβ), but their pathogenesis remains unknown. Elucidate neuritic plaque pathogenesis. Histochemical visualization of hyperphosphorylated-tau positive (p-tau+) structures, microglia, Aβ, and iron. Disintegration of large projection neurons in human hippocampus and neocortex presents as droplet degeneration: pretangle neurons break up into spheres of numerous p-tau+ droplets of various sizes, which marks the beginning of neuritic plaques. These droplet spheres develop in the absence of colocalized Aβ deposits but once formed become encased in diffuse Aβ with great specificity. In contrast, neurofibrillary tangles often do not colocalize with Aβ. Double-labelling for p-tau and microglia showed a lack of microglial activation or phagocytosis of p-tau+ degeneration droplets but revealed massive upregulation of ferritin in microglia suggesting presence of high levels of free iron. Perl's Prussian blue produced positive staining of microglia, droplet spheres, and Aβ plaque cores supporting the suggestion that droplet degeneration of pretangle neurons in the hippocampus and cortex represents ferroptosis, which is accompanied by the release of neuronal iron extracellularly. Age-related iron accumulation and ferroptosis in the CNS likely trigger at least two endogenous mechanisms of neuroprotective iron sequestration and chelation, microglial ferritin expression and Aβ deposition, respectively, both contributing to the formation of neuritic plaques. Since neurofibrillary tangles and Aβ deposits colocalize infrequently, tangle formation likely does not involve release of neuronal iron extracellularly. In human brain, targeted deposition of Aβ occurs specifically in response to ongoing ferroptotic droplet degeneration thereby producing neuritic plaques.


Patients at high risk with atrial fibrillation: a prospective and serial follow-up during 12 months with transesophageal echocardiography and cerebral magnetic resonance imaging.
Patients with atrial fibrillation and echocardiographic risk factors have a relevant risk of cerebral embolism. However, there is little knowledge about the long-term fate and the rate of clinical silent cerebral embolism under continued oral anticoagulation. Our aims were to assess the prognosis of patients with atrial fibrillation and determine a high-risk group with an increased risk of cerebral embolism under oral anticoagulation. A total of 173 consecutive patients with persistent or permanent atrial fibrillation and left atrial (LA) thrombi, dense spontaneous echocontrast, reduced LA appendage peak emptying velocities, or a combination of these were included in the study. In all, 169 patients with atrial fibrillation and without echocardiographic risk factors served as control patients. We performed serial and prospective transesophageal echocardiography, cranial magnetic resonance imaging, and clinical examinations during a period of 12 months. During the follow-up period 7 (4%) of the patients at high risk had cerebral embolism with neurologic deficits. A total of 4 (2%) patients died because of embolic events and 19 (11%) patients had silent embolism as documented on magnetic resonance imaging. In the control group, 10 (6%) patients had embolic events documented on magnetic resonance imaging; one was clinically apparent. Study patients with an event had more often previous thromboembolism (P < .0001). Patients with persistent or permanent atrial fibrillation and LA thrombi, dense spontaneous echocontrast, or reduced LA appendage peak emptying velocities have an explicitly increased risk of cerebral embolism (17%) despite oral anticoagulation. Previous thromboembolic event is another important predictor for an event.


Progestin binding in mammary tissue of prepartum, nonlactating and postpartum, lactating cows.
Binding of [3H]R5020 (17,21-dimethyl-19-nor-4,9-pregnadiene-3, 20-=dione) to bovine mammary cytosol indicated the presence of progestin binding sites of high-affinity and low-capacity in tissue from prepartum, nonlactating and from postpartum, lactating cows. To prevent binding of [3H]R5020 to glucocorticoid binding sites, a 200-fold molar excess of nonradioactive cortisol was included during all incubations, thus specific binding was limited to progestin binding sites. Nonradioactive R5020 and progesterone effectively inhibited [3H]R5020 binding to progestin binding sites, while estradiol-17 beta, dihydrotestosterone (17 beta-hydroxy-5 alpha-androstan-3-one), dexamethasone (9-fluoro-11 beta, 17, 21-trihydroxy-16 alpha methyl-1,4-pregnadiene-3,20-dione) or additional cortisol were ineffective. Dissociation constants for especially bound [3H]R5020 in cytosol from mammary tissue of nonlactating and lactating cows were nearly identical, averaging 1.9 (+/- 0.3) and 0.8 (+/- 0.2) x 10(-9)M, respectively. However, binding capacities (fmol/mg cytosolic protein) were greater in cytosol from prepartum, nonlactating (179 +/- 53) than postpartum, lactating (41 +/- 15) cows. Specific binding components in cytosol from lactating cows sedimented iun the 6-7S region on linear sucrose density gradients. When subjected to isoelectric focusing, specific binders with isoelectric points (pI) of approximately 6.1, 7.9 and 8.3 were resolved. The decrease in number of binding sites during lactation was due to the virtual absence of the anionic binding species, suggesting that their presence is necessary for progesterone to inhibit milk secretion.


Scar recurrence of uterine sarcoma: a case report.
Uterine leiomyosarcoma is an aggressive tumor that has a propensity for recurrence. Most of the recurrences occur at either pelvic or distant sites, such as lung or liver. Recurrences in the laparotomy scar are extremely rare. A 52-year-old woman underwent hysterectomy for stage I, grade 2 uterine leiomyosarcoma. She did not receive any adjuvant treatment. She presented 2 years later with wound recurrence. She had no evidence of intraabdominal disease. She underwent radical resection with mesh repair. Pathology revealed high grade spindle cell sarcoma very similar to the previous cancer. After completion of 18 months of follow-up, she was disease free. Radical resection of isolated metastases may be of benefit for these patients.


Interferon treatment of adenoviral conjunctivitis.
We conducted a randomized, double-masked, placebo-controlled study to evaluate the efficacy of topical interferon in the treatment of adenoviral conjunctivitis. The study was designed to determine the efficacy of plasmid-derived alpha-2 interferon treatment with regard to the duration of clinical disease, virus shedding, and the occurrence of bilateral infection and subepithelial infiltrates. Interferon therapy was not found to have a statistically significant effect with regard to these factors in the 14 patients who completed 14 days of treatment in the study with interferon or a placebo. Interferon therapy was, however, associated with a tendency toward asymptomatic infection in the second eye when compared to the controls.


[Surgical tactics in sharp-point foreign bodies of the gastrointestinal tract].
The author reports his observations of 92 patients who swallowed sharp-pointed foreign bodies. It is concluded that the absence of the displacement after barium suspension administration should be considered an indication to surgical intervention in uncomplicated cases. The withdrawal of sharp-pointed objects by means of a fibrogastroscope is hazardous in case of their penetration in the gastric wall.


Purification and characterization of ovotransferrin from Crocodylus siamensis.
Ovotransferrin (OTf) is the major glycoprotein in reptile egg whites. However, knowledge concerning its functional and biological properties remains limited. In this study, OTf from Crocodylus siamensis was purified and characterized. The proteins were precipitated with 80 % ammonium sulfate and then purified by anion exchange chromatography followed by hydrophobic interaction chromatography. The purified crocodile ovotransferrin (cOTf) had a molecular weight of 79 kDa. Analysis by two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) indicated multiple isoforms of cOTf, which had isoelectric points ranging from 6.0 to 6.8. cOTf was N-linked glycosylated protein identified by using PNGase F deglycosylation technique. Optimal autoproteolysis of cOTf occurred under acidic conditions and pH values more than 5, which differs from that of OTf.


Automated data cleaning of paediatric anthropometric data from longitudinal electronic health records: protocol and application to a large patient cohort.
'Big data' in healthcare encompass measurements collated from multiple sources with various degrees of data quality. These data require quality control assessment to optimise quality for clinical management and for robust large-scale data analysis in healthcare research. Height and weight data represent one of the most abundantly recorded health statistics. The shift to electronic recording of anthropometric measurements in electronic healthcare records, has rapidly inflated the number of measurements. WHO guidelines inform removal of population-based extreme outliers but an absence of tools limits cleaning of longitudinal anthropometric measurements. We developed and optimised a protocol for cleaning paediatric height and weight data that incorporates outlier detection using robust linear regression methodology using a manually curated set of 6,279 patients' longitudinal measurements. The protocol was then applied to a cohort of 200,000 patient records collected from 60,000 paediatric patients attending a regional teaching hospital in South England. WHO guidelines detected biologically implausible data in <1% of records. Additional error rates of 3% and 0.2% for height and weight respectively were detected using the protocol. Inflated error rates for height measurements were largely due to small but physiologically implausible decreases in height. Lowest error rates were observed when data was measured and digitally recorded by staff routinely required to do so. The protocol successfully automates the parsing of implausible and poor quality height and weight data from a voluminous longitudinal dataset and standardises the quality assessment of data for clinical and research applications.


Decreased expression of glutamate transporters in genetic absence epilepsy rats before seizure occurrence.
In absence epilepsy, epileptogenic processes are suspected of involving an imbalance between GABAergic inhibition and glutamatergic excitation. Here, we describe alteration of the expression of glutamate transporters in rats with genetic absence (the Genetic Absence Epilepsy Rats from Strasbourg: GAERS). In these rats, epileptic discharges, recorded in the thalamo-cortical network, appear around 40 days after birth. In adult rats no alteration of the protein expression of the glutamate transporters was observed. In 30-day-old GAERS protein levels (quantified by western blot) were lower in the cortex by 21% and 35% for the glial transporters GLT1 and GLAST, respectively, and by 32% for the neuronal transporter EAAC1 in the thalamus compared to control rats. In addition, the expression and activity of GLAST were decreased by 50% in newborn GAERS cortical astrocytes grown in primary culture. The lack of modification of the protein levels of glutamatergic transporters in adult epileptic GAERS, in spite of mRNA variations (quantified by RT-PCR), suggests that they are not involved in the pathogeny of spike-and-wave discharges. In contrast, the alteration of glutamate transporter expression, observed before the establishment of epileptic discharges, could reflect an abnormal maturation of the glutamatergic neurone-glia circuitry.


Periprosthetic fractures of the greater trochanter through osteolytic cysts with uncemented MicroStructured Omnifit prosthesis: retrospective analyses pf 23 fractures in 887 hips after 5-14 years.
Periprosthetic fractures of the greater trochanter through osteolytic cysts are rare. The proper treatment and its influence on the prosthetic survival remains unknown. We retrospectively evaluated 887 hips with uncemented MicroStructured Omnifit total hip prostheses at a mean follow-up time of 11 (5-14) years. We found 23 (2.6%) fractures of the greater trochanter through a cystic lesion, occurring 4-11 years postoperatively. Nonoperative treatment healed 15 of the 17 fractures that were minimally displaced. At a mean follow-up of 3 (2-5) years after the fracture, 16 had had revision of the components because of excessive wear, loosening, or nonunion. We conclude that a periprosthetic fracture of the greater trochanter through an osteolytic lesion is usually stable and heals without treatment. However, it is associated with poor prosthetic survival because of excessive polyethylene wear.


Neuromuscular neutral zones response to static lumbar flexion: muscular stability compensator.
The impact of six sequential static loading and rest of the lumbar spine on the changes in the neuromuscular neutral zones and thereby on spine stability was assessed. Six 10 min sessions of static load of a moderate level each spaced by 10 min rest were applied to the in vivo feline model. Test cycles of 0.25 Hz and at the same moderate peak load were applied before and every hour after the static loading sequence up to 7h. Load, displacement and electromyographic activity of the lumbar multifidi muscles were recorded throughout. Displacement and tension neuromuscular neutral zones were defined as the displacement or tension, in the increase and decrease phases of each cycle, when the electromyogram initiated and ceased activity, respectively. Displacement neuromuscular neutral zones demonstrated significant (P<0.001) increase immediately post-static loading, followed by an exponential decrease to pre-loading baseline by the 7th hour. Tension neuromuscular neutral zones, however, demonstrated significant (P<0.001) increase in the 2h immediately after the static loading and a significant decrease (P<0.001) thereafter. Peak electromyogram decreased in the first 3h post-loading, but significantly (P<0.001) increased thereafter to the 7th hour. It was concluded that the first 2-3h post-static loading finds the spine with significant laxity in the viscoelastic tissues concurrently with deficient muscular activation and therefore exposed to the risk of instability. It is also evident that a neural control compensation mechanism exists where it enhances the activation of the musculature to earlier and at higher activation magnitude, 2-3h post-loading, increasing lumbar stability while the viscoelastic tissues are still lax.


Use of highly sensitive mitochondrial probes to detect microchimerism in xenotransplantation models.
Chimerism, defined as the co-existence of cells of different origin within the same organism, has received much attention in hematopoietic cell and organ transplantation because of the strict relationship between its establishment and the induction of specific tolerance. Traditional methods applied for chimerism detection, such as immunohistochemistry, cytogenetics, fluorescent-activated cell sorter analysis, and serological and biochemical testing, are limited by their sensitivity. We have established a highly sensitive molecular approach based on the amplification of the mitochondrial cytochrome B gene and tested its specificity and sensitivity level in six different mammalian species, including human, pig, mouse, rat, sheep and rabbit. Increased sensitivity of detection of specific amplification products was obtained by the non-radioactive Southern blot technique. This novel approach allows the detection of one cell against the background of 1 to 4 x 10(6) xenogenec cells and will be helpful for high-sensitivity analysis of donor cell engraftment after xenotransplantation procedures in these animal models.


Targeting Perceived Burdensomeness to Reduce Suicide Risk.
Perceived burdensomeness (PB), defined by an intractable perception of burdening others, often reflects a false mental calculation that one's death is worth more than one's life and has been supported as a significant risk factor for suicide. Because PB often reflects a distorted cognition, it may serve as a corrective and promising target for the intervention of suicide. More work on PB is needed in clinically severe and in military populations. Sixty-nine (Study 1) and 181 (Study 2) military participants at high baseline suicide risk engaged in interventions targeting constructs relating to PB. Baseline and follow-up measures (at 1, 6, 12, 18, and 24 months) of suicidal ideation were administered, and various statistical approaches-including repeated-measures ANOVA, mediation analyses, and correlating standardized residuals-explored whether suicidal ideation decreased specifically by way of PB. In addition to utilizing a larger sample size, Study 2 included an active PB-intervention arm (N = 181) and a control arm (N = 121), who received robust care as usual. In both studies, participants improved considerably regarding baseline to follow-up suicidal ideation. The results of Study 2 mirrored those of Study 1, corroborating a potential mediational role for PB in treatment-related improvements in suicidal ideation in military participants. Effect sizes ranged from .07-.25. Interventions tailored at decreasing levels of perceived burdensomeness may be uniquely and significantly effective in reducing suicidal thoughts.


PROMIS Correlates With Legacy Outcome Measures in Patients With Neck Pain and Improves Upon NDI When Assessing Disability in Cervical Deformity.
Retrospective cohort study. To evaluate the ability of patient reported outcome measurement information system (PROMIS) assessments to capture disability related to cervical sagittal alignment and secondarily to compare these findings to legacy outcome measures. PROMIS is a validated patient-reported outcome metric that is increasing in popularity due to its speed of administration relative to legacy metrics. The ability of PROMIS to capture disability from sagittal alignment and baseline health status in patients with neck pain has not been investigated. Patients presenting with a chief complaint of neck pain from December 2016 to July 2017 were included. Demographics and comorbidities were retrospectively collected. All patients prospectively completed the neck disability index (NDI), EQ-5D, visual analog scale (VAS) neck, VAS arm, PROMIS physical function, PROMIS pain intensity, and PROMIS pain interference metrics. Cervical sagittal alignment parameters were measured on standing X-rays. The correlations between outcome measures, health status indexes, psychiatric diagnoses, and sagittal alignment were analyzed. Two hundred twenty-six patients were included. The sample was 58.4% female with a mean age of 55.1 years. In patients with neck pain, PROMIS physical function correlated strongly with the NDI (r = -0.763, P < 0.01), EQ-5D (r = 0.616, P < 0.01), VAS neck pain (-0.466, P < 0.01), and VAS arm pain (r = -0.388, P < 0.01). One hundred seventy-seven patients (69.96%) were included in the radiographic analysis. 20.3% of the radiographic cohort had cervical deformity and in this group, less cervical lordosis correlated with PROMIS pain intensity and EQ-5D but not NDI. In patients without cervical deformity, no outcome metric was found to correlate significantly with cervical alignment parameters. PROMIS domains correlated strongly with legacy outcome metrics. For the whole cohort, sagittal alignment was not correlated with outcomes. In patients with sagittal cervical deformity, worsening alignment correlated with PROMIS pain intensity and EQ-5D but not NDI. 3.


Vaccination with endosomal unknown epitopes produces therapeutic response in rheumatoid arthritis patients and modulates adjuvant arthritis of rats.
Our previous results showed that intrasynovial Rifamycin SV caused the lysis of synoviocites and freed the autoantigens which in turn stimulated the immunoregulatory rather than autoreactive T cell response in rheumatoid patients. Here, we hypothesize that disruption in vitro of peripheral blood mononuclear cells, by freeze/thawing or by lytic action of Rifamycin SV, would induce the release of endosomal pathogenic autoantigens from APCs present in the circulation, which could then be isolated from degrading enzymes by ultrafiltration. The preparation of the ultrafiltrates are based on the rupture of PBMCs (5 × 10(6) cells/mL) by the addition of Rifamycin SV in culture (250 μg/mL), which causes the lysis of 90 % of the cells in 3 h, or by three cycles of freeze/thawing of the PBMC, from -80 °C to room temperature. The lysate and the fragmented cells were then centrifuged and ultrafiltered by passage through a filtration device with a cut-off of 10 kDa. Also the synovial fluid was subjected to ultrafiltration. At clinical monitoring of the 30th day, 22/58 (38 %) patients subcutaneously treated with the autologous ultrafiltrate prepared by the freeze/thawing of PBMCs reached an ACR20. Comparable results were obtained with the other two ultrafiltrates. Cell cultures The addition of ultrafiltrates to rheumatoid PBMCs cultures led to the upregulation of a marker for T-regulatory cells, and downregulation of a cell proliferation marker; changes that together have the meaning of a global immunomodulatory response and that only a specific antigen (ultrafiltrate UF-f/t) might induce in the rheumatoid patient, probably by activating pre-existing protective network. Experimental arthritis All the ultrafiltrates except that prepared by Rifamycin SV were able to modulate the adjuvant arthritis in rats. In particular, longlasting synovial fluid induced a significant reduction of the severity of subsequent arthritis (p < 0.01) while SF from recent RA effusion (5-10 days after a previous complete extraction) and knee osteoarthrosis were ineffective. It is reasonable to assume there are at least two unknown endosomal immunoactive epitopes; one developing its immunotherapeutic property in RA, and the other, related to the molecule of HSP60, reduces the severity of oncoming arthritis. Both epitopes are present in humans, have a molecular weight of ≤10 kDa and do not appear to be bystander antigens. Please see Additional file 1 for the abstract in Italian.


Interactive computer play as "motor therapy" for individuals with cerebral palsy.
The aim of the study was to evaluate the quality of evidence for interactive computer play (ICP) to improve motor performance (including motor control, strength, or cardiovascular [CVS] fitness) in individuals with cerebral palsy. A computer-assisted literature search was completed, focusing on ICP as a therapeutic modality to improve motor outcomes in individuals of all ages with cerebral palsy with a specific focus on upper and lower extremity motor outcomes and promotion of CVS fitness. Articles were classified according to American Academy of Neurology guidelines and recommendation classifications were given based on the levels of evidence. Seventeen articles underwent full-text review including 6 on upper extremity motor function, 5 on lower extremity motor function, 1 on CVS fitness, and 5 on studies with a combination of upper or lower extremity or CVS fitness focus or both. Overall, there was level B (probable) evidence for ICP interventions to improve lower extremity motor control or function. However, there was inadequate evidence (level U) for ICP interventions improving upper limb motor control or function or CVS fitness. Although promising trends are apparent, the strongest level of evidence exists for the use of ICP to improve gross motor outcomes. Additional evidence is warranted especially when evaluating the effect of ICP on upper limb motor outcomes and CVS fitness.


Overexpression of multiple epidermal growth factor like domains 11 rescues anoikis survival through tumor cells-platelet interaction in triple negative breast Cancer cells.
The aim of this study was to test the hypothesis that overexpression of the Multiple Epidermal Growth Factor Like Domains 11 (MEGF11) gene in TNBC cells increases tumor cell survival against anoikis via interaction with platelets. The role of MEGF11 was studied in human TNBC MDA-MB-231 and MDA-MB-468 cells by overexpressing MEGF11 (o/e MEGF11) using non-attached culture. Mouse wild type 4 T1 and Δmegf11-4 T1 cells were implanted into the mammary fat pad of BALB/c mice. Circulating tumor cells were isolated and cultured. Plasma platelets were added to these cell lines to carry out a platelet binding assay by confocal microscopy. Anoikis was observed by Live/Dead staining and a quantitative PBMC-specific cytotoxic assay (with/without platelets) was carried out to measure calcein release. The protein levels of MEGF11, Akt, and caspase 3 were assessed by Western blotting. Reduced number of circulating Δmegf11 4 T1 cells, and 4 T1-platelet clusters and reduced p-Akt expression, accompanied by increased specific calcein release, were observed in the Δmegf11 4T1group compared to the 4 T1 wild type group. There was significant increased cancer-platelet binding using the o/e MEGF11 MDA-MB-231/468 lines. Cell survival, caspase 3 activation and PBMC-specific cytotoxicity in the o/e MEGF11 MDA-MB-468 cells, but not in the MDA-MB-231 cells, could be rescued by platelet binding (+), compared to the platelet (-) group. We conclude that MEGF11 overexpression in TNBC cells rescues tumor cells from anoikis via interaction with platelets in mouse 4 T1 cells and human MDA-MB-468 cells.


Morphological and endocrine correlates of the reproductive cycle of the aplacental viviparous dogfish, Squalus acanthias.
Pregnant female spiny dogfish were captured off the coasts of Maine and Massachusetts and morphometric and gravimetric analyses of the liver, gonad, and reproductive tract correlated with the reproductive cycle. Plasma samples were taken and circulating steroids (progesterone, testosterone, and estradiol) were measured by radioimmunoassay. Clear-cut temporal variations in plasma steroid levels were observed, which correlated with the ovarian cycle. Testosterone and estradiol-17 beta levels were low (100-200 pg/ml plasma) in early pregnancy when ovarian follicles were small but increased to about 10 ng/ml as follicles grew and gestation progressed. By contrast, plasma progesterone was high (2-6 ng/ml) in early to mid-pregnancy when corpora lutea were active and declined toward term (less than 1.0 ng/ml).


The physiological ecology of two populations of Mytilus edulis L.
Seasonal cycles in the rates of oxygen consumption, feeding, absorption efficiency and ammonia-nitrogen excretion in two populations of Mytilus edulis were measured in the field under ambient conditions and related to body size, the gametogenic cycle, the concentration of suspended particulate matter in the water and temperature. Relationships between the various physiological variables are also considered and protein and energy budgets estimated. Both the "scope for growth" and the "relative maintenance cost" were seasonally variable, demonstrating a minimum capacity for growth in the winter and a maximum capacity in the summer. In one population subjected to abnormally high temperatures in the winter the scope for growth was negative for four or five months between January and May. These population differences are discussed and the potential for using physiological integrations in intra-specific comparisons of fitness is identified.


1,10-Phenanthroline reversibility inhibits proliferation of two human prostate carcinoma cell lines (PC-3 and DU145).
The metal chelator 1,10-phenanthroline reversibly inhibits proliferation of two human prostate carcinoma cell lines, PC-3 and DU145. Inhibition is dose-dependent, and persists for several days after removal of the chelator. The ability to induce reversible quiescence in human prostate carcinoma cells in vitro may facilitate the study of their growth cycle biochemistry.


Frequency and differentiation capacity of circulating LTC-IC mobilized by G-CSF or GM-CSF following chemotherapy: a comparison with steady-state bone marrow and peripheral blood.
The present study was designed to compare directly the frequency of circulating LTC-IC and E-LTC-IC mobilized in peripheral blood (PB) after chemotherapy supported by either G-CSF (PB-G) or GM-CSF (PB-GM) in comparison to steady-state bone marrow (BM) and PB (PB-ST) values in the same patients. Long-term cultures (LTC) were performed from 20 patients with malignant lymphoma at saturating cell concentrations to assess bulk progenitor cell production and by limiting dilution assay (LDA) to measure both frequency of LTC-IC and their proliferative and differentiation capacities. While CFC production in bulk LTC was higher at weeks 3-5 with PB-G than with PB-GM samples, week-5 LTC-IC and week-10 LTC-IC (E-LTC-IC) frequencies were not different using a LDA. However, the number of CFC derived from a single LTC-IC was higher in PB-G patients than in PB-GM patients (p = 0.01). Interestingly, the frequency of LTC-IC per 1 x 10(5) MNC in mobilized PB positively correlated with one-year marrow progenitor cell recovery, in contrast to the number of autografted CD34(+) cells and CFU-GM per kg. Both G-CSF and GM-CSF resulted in similar increases in LTC-IC and E-LTC-IC in PB at comparable levels to those present in BM. However, the differentiation capacity of LTC-IC was higher after mobilization with G-CSF than with GM-CSF, suggesting qualitative differences in LTC-IC mobilized with these growth factors.


A case of pancreatic duct stones treated with electrohydraulic lithotripsy through a duodenal ulcer.
Video 1Crush the large-sized stones directly using an electrohydraulic lithotripsy device.


Unusual case of desmotropy. Combined spectroscopy (¹H-¹⁴N NQDR) and quantum chemistry (periodic hybrid DFT/QTAIM and Hirshfeld surface-based) study of solid dacarbazine (anti-neoplastic).
Antineoplastic chemo-therapeutic drug 5-(3,3-dimethyl-1-triazenyl)imidazole-4-carboxamide (Dacarbazine, DTIC), has been studied experimentally in solid state by ¹H-¹⁴N NQDR double resonance at 295 K and theoretically by the Density Functional Theory (DFT)/Quantum Theory of Atoms in Molecules (QTAIM) and Hirshfeld surfaces analysis. Only one set of eighteen resonance frequencies was found in the experiment. This indicates the presence of six inequivalent nitrogen sites: -N(CH₃), -NH₂, -NH- and three -N= (of which one is a ring, two are from triazene) in the DTIC molecule. This contradicts the X-ray data which revealed the multiplication of nitrogen sites due to unusual desmotropism. The averaging of NQR frequencies caused by the fast in NQR time-scale exchange of protons in a double-well potential combined with the oscillations of twisted supramolecular synthons was proposed as a potential mechanism responsible for this apparent contradiction. An effective improvement in the quality of the spectrum reproduction was achieved when the calculations were performed assuming the periodic boundary conditions, BLYP functional, the DNP basis set and taking the 3×3×3 k-point separation. The ordering of the nitrogen sites according to the increasing quadrupole coupling constant (QCC): N(3)<N(2)<N(6)<N(1)<N(4)<N(5) reflects the metabolic pathway of DTIC. Two sites N(5) and N(4) with the highest QCC are responsible for the first step - conversion to MTIC (5-[3-methyl-triazen-1-yl]-imidazole-4-carboxamide) required for effective processes of binding dacarbazine to DNA (demethylation of N(5)), and the second step - fast conversion of MTIC to 5-amino-1H-imidazole-4-carboxamide (AIC; remove -N(4)-N(5)HCH3). N(5) does not participate in any, while N(4) participates in weak C(2)H⋯N(4) interaction which can be readily broken. The four remaining nitrogen atoms N(1), N(2), N(3) and N(6) participate in strong intermolecular N(1)H⋯N(2) and intramolecular N(3)-H⋯N(6) bonds, which stiffen the crystalline structure.


Co-creation of a post-traumatic brain injury sexuality information toolkit: a patient-oriented project.
Different studies and two clinical practice guidelines emphasize the necessity to provide patients undergoing rehabilitation with information about commonly occurring changes in sexuality following traumatic brain injury (TBI). The purpose of this study was to co-create information resources for individuals with moderate to severe TBI and their partners to consult during rehabilitation. An iterative user-centered design was used, combining focus group and individual interviews. A convenience sample of individuals with TBI and life partners was constituted. The needs and expectations of these participants in terms of form and content of an information toolkit on post-TBI sexuality were explored. The subjects that matched the interests and needs of participants were numerous and supported by the literature. Contrasting with existing written resources, the participants' views oriented the creation process toward the development of a toolkit including five audiovisual presentations, a double-sided information sheet, and a checklist. A similar approach of co-creation could be used to develop other information packs aimed at patients with other disabilities. The created material is expected to be a usable and useful tool for individuals with TBI, which can support clinicians in addressing the subject of sexuality.Implications for rehabilitationThe central role held by individuals with moderate to severe traumatic brain injury, in identifying the sexuality related topics to be addressed and the form of resources to be created, led to a better understanding of their needs.This patient-centered research brought solutions to difficulties related to the understanding of health information, prevalent among patients.This patient-oriented project highlights the necessity for adequacy between the health information provided by rehabilitation professionals and the capacity of their patients' to seek for, process, and understand its content.


Synthesis of phosphatidylinositol 3,4-bisphosphate but not phosphatidylinositol 3,4,5-trisphosphate is closely correlated with protein-tyrosine phosphorylation in thrombin-activated human platelets.
Synthesis of D-3-phosphorylated phosphoinositides and its correlation with protein-tyrosine phosphorylation were examined using human platelets. Thrombin stimulation of platelets resulted in time- and dose-dependent production of phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P2), which is absent from resting platelets. In contrast, phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) was detected in resting platelets, but remained unaffected by thrombin treatment. The production of PtdIns(3,4)P2 but not PtdIns(3,4,5)P3 was inhibited by pretreatment with staurosporine or dibutyryl cyclic adenosine monophosphate (dbcAMP). Protein-tyrosine phosphorylation, which is reportedly involved in generation of 3-phosphorylated phosphoinositides, was elicited in thrombin-activated platelets. The tyrosine phosphorylation was suppressed by pretreatment with staurosporine or dbcAMP. These observations suggest that synthesis of PtdIns(3,4)P2 but not PtdIns(3,4,5) P3 is closely correlated with protein-tyrosine phosphorylation in human platelets.


Peroxiredoxin II functions as a signal terminator for H2O2-activated phospholipase D1.
Phospholipase D1 (PLD1) is a signal-transduction regulated enzyme which regulates several cell intrinsic processes including activation of NAPDH oxidase, which elevates intracellular H2O2. Several proteins have been reported to interact with PLD1 in resting cells. We sought to identify proteins that interact with PLD1 after phorbol 12-myristate 13-acetate (PMA) stimulation. A novel interaction with peroxiredoxin II (PrxII), an enzyme that eliminates cellular H2O2, which is a known stimulator of PLD1, was identified by PLD1-affinity pull-down and MS. PMA stimulation was confirmed to promote physical interaction between PLD1 and PrxII and to cause PLD1 and PrxII to colocalize subcellularly. Functional significance of the interaction was suggested by the observation that over-expression of PrxII specifically reduces the response of PLD1 to stimulation by H2O2. These results indicate that PrxII may have a signal-terminating role for PLD1 by being recruited to sites containing activated PLD1 after cellular stimulation involving production of H2O2.


Association of asparagine concentration in wheat with cultivar, location, fertilizer, and their interaction.
The need to produce wheat with low asparagine concentration is of great importance as a measure to mitigate acrylamide concentration in wheat-based products. The association of asparagine concentration in Canadian bread wheat with cultivar, growing location, fertilizer and their interaction were investigated. Wheat cultivars (8) were grown in 2 locations under 4 fertilizer treatments in triplicate (which consisted of two nitrogen rates (90 or 120 lbs/acre) with or without 15 lbs sulphur per acre). The asparagine concentration ranged from 168.9 to 1050 µg/g and was significantly affected by cultivar, location, and their interaction but not fertilizer treatment. Location and cultivar were responsible for 80% and 14% of the variation, respectively. Some cultivars were not affected by location and maintained their low asparagine accumulation trait. Thus, breeding strategies should aim to identify cultivars that are low asparagine accumulating and are stable across different growing environments.


Palladium-catalyzed medium-ring formation for construction of the core structure of laurencia oxacycles: synthetic study of laurendecumallene B.
Palladium-catalyzed medium-ring formation from a cyclic propargyl carbonate via a ring-opening and -closing cascade proceeded at the central carbon atom of the propargyl unit to provide a tetrahydro-2H-oxocine derivative bearing the core structure of laurencia oxacycle. The synthetic application of this reaction to a possible laurendecumallene B precursor is also presented.


Ankylosing spondylitis with Kikuchi-Fujimoto disease: A case report with literature review.
We present the case of a patient diagnosed with ankylosing spondylitis (AS) along with Kikuchi-Fujimoto disease (KFD), possibly triggered by infection or autoimmunity. Both AS and KFD involved a similar immune pathway. Hence, clinicians should consider the possibility of KFD when lymphadenopathy is observed, especially in patients with infection or underlying autoimmune diseases.


Costs associated with the inappropriate route of administration of parenteral histamine2-receptor antagonists.
The objectives were to assess the parenteral route for cimetidine and ranitidine and to determine excess medication costs associated with inappropriate use. Criteria were based on clinical situations that do not permit oral therapy, result in questionable dry absorption, or require a more rapid onset of action. The parenteral route was assessed as appropriate, inappropriate, or questionable. During two months, parenteral therapy was prescribed for 199 adult inpatients. Initially, 63 percent received the parenteral form appropriately; only 16 percent continued to receive the parenteral form appropriately throughout therapy. Less than half of the parenteral doses were determined to be appropriate. A major reason appears to be that orders are not changed as patients' conditions improve. Excess medication costs attributed to inappropriate parenteral therapy for the study period amounted to $6796 or $8002, depending on whether questionable doses were considered appropriate or inappropriate, respectively. An annual projected savings of $40,776 or $48,012 could be achieved if oral doses had been administered in place of inappropriate parenteral therapy.


Selection for an optimal monovoltine life cycle in an unpredictable environment. Studies on the beetleCatops nigricans Spence (Col., Catopidae).
Catops nigricans reproduces in the autumn. Pre-imaginal development is temperature-dependent and takes place during the winter, followed by aestivation in the early adult stage. This summer diapause is obligatory and temperature independent. It synchronizes the monovoltine life cycle with the annual cycle. In three populations collected near Kiel (54°22' N, 10°6' E), Köln (50°54' N, 7°6' E), and Paris (49°25' N, 2°20' E), pre-imaginal development slowed and the duration of summer diapause decreased with increasing latitude. Synchronization of the critical breeding interval with the appropriate environmental conditions was achieved through temperature- and photoperiod-dependent sensitivity of ovipositing adults, through different thermal thresholds in eggs, larvae, and pupae, and through sensitivity to photoperiod in third-instars larvae.C. nigricans copes with the unpredictability of climatic conditions in different ways. The local populations have evolved a mean diapause length which probably adjusts the life cycle in most years to the optimal date for reproduction. The mean diapause length was 77 days for Kiel, 98 days for Köln and 138 days for Paris at 10°C, short-day (=SD).C. nigricans also spreads the risk by varying diapause length. Amongthe progeny of single females the range of diapause duration covered about 70% of the total range of the whole population. The oviposition rate of females confined to subterranean life was the same as females confined to subterranean life was the same as in those living under the influence of a varying photoperiod.C. nigricans should therefore be able to live both in the litter layer of forests and also in the nests and galleries of small mammals.


Behavioral and neural generalization: Hitting the right notes.
Successful generalization to novel stimuli is a core goal of learning and memory systems, but how do we do it? In this issue of Neuron, Miller et al.1 use a novel auditory structure learning task to reveal neural and behavioral signatures of generalization.


Germinal vesicle materials are requisite for male pronucleus formation but not for change in the activities of CDK1 and MAP kinase during maturation and fertilization of pig oocytes.
In amphibian oocytes, it is known that germinal vesicle (GV) materials are essential for sperm head decondensation but not for activation of MPF (CDK1 and cyclin B). However, in large animals, the role of GV materials in maturation and fertilization is not defined. In this study, we prepared enucleated pig oocytes at the GV stage and cultured them to examine the activation and inactivation of CDK1 and MAP kinase during maturation and after electro-activation. Moreover, enucleated GV-oocytes after maturation culture were inseminated or injected intracytoplasmically with spermatozoa to examine their ability to decondense the sperm chromatin. Enucleated oocytes showed similar activation/inactivation patterns of CDK1 and MAP kinase as sham-operated oocytes during maturation and after electro-stimulation or intracytoplasmic sperm injection. During the time corresponding to MI/MII transition of sham-operated oocytes, enucleated oocytes inactivated CDK1. However, penetrating sperm heads in enucleated oocytes did not decondense enough to form male pronuclei. To determine whether the factor(s) involved in sperm head decondensation remains associated with the chromatin after GV breakdown (GVBD), we did enucleation soon after GVBD (corresponding to pro-metaphase I, pMI) to remove only chromosomes. The injected sperm heads in pMI-enucleated oocytes decondensed and formed the male pronuclei. These results suggest that in pig oocytes, GV materials are not required for activation/inactivation of CDK1 and MAP kinase, but they are essential for male pronucleus formation.


Safety of preoperative carvedilol in a patient with recent atenolol-induced pheochromocytoma crisis and cardiomyopathy: A case report.
Beta-adrenergic blockade without adequate alpha blockade is an established trigger of pheochromocytoma crisis (PC). Carvedilol is a nonselective beta-adrenergic and alpha 1-adrenergic blocking agent, and its use for preoperative preparation of pheochromocytoma patients with prior cardiomyopathy secondary to PC resulting from unopposed beta-blocker therapy has never been reported. A 48-year-old woman was admitted to the Urology Department for evaluation of a huge right upper abdominal mass. She developed hypertensive crisis with acute pulmonary edema resulting in respiratory failure after administration of atenolol to treat hypertension and tachycardia. Transthoracic echocardiogram revealed global hypokinesia. The patient was managed with intravenous nicardipine, furosemide, and prazosin because of the clinical suspicion of pheochromocytoma that was subsequently confirmed by elevated plasma and urine catecholamine levels. Within 3 days of alpha-adrenergic blockers treatment, there was rapid amelioration of hypertension and pulmonary congestion, as well as normalization of left ventricular function by echocardiography. However, tachycardia persisted after 1 month of adequate alpha-adrenergic blockade. Given the benefit of beta-adrenergic blockers in patients with systolic dysfunction, we slowly titrated carvedilol while carefully monitoring the patient's condition in the intensive care unit. Tachycardia was controlled without inducing PC. Surgical resection was successful without perioperative complications. Clinicians should be cautious when prescribing beta-adrenergic blocker in patients with hypertension and upper quadrant mass of unknown etiology. The mass may be pheochromocytoma. Preoperative use of carvedilol after sufficient alpha-adrenergic blockade for control of tachycardia in a patient with prior cardiomyopathy associated with atenolol-induced PC is safe and effective.


The relationship between fiberoptic endoscopic evaluation of swallowing outcome and symptoms of anxiety and depression in dysphagic patients.
Affective complaints are involved in bothersome oropharyngeal dysphagia (OD). The aim was to determine the relationship between the severity of OD and affective symptoms. Prospective cohort study. One hundred seven patients underwent a standardized examination protocol including the Hospital Anxiety and Depression Scale and fiberoptic endoscopic evaluation of swallowing (FEES). Two observers independently assessed patient performance on four ordinal FEES-variables (for thin and thick liquid consistency, blindly assessed). The relationship between FEES outcome and the presence of clinically relevant symptoms of anxiety and depression was analyzed using binary logistic regression. Significant associations were found between clinically relevant symptoms of anxiety and two variables: piecemeal deglutition (thin liquid consistency only) (P = .026) and postswallow vallecular pooling (thick liquid consistency only) (P = .015). The probability of presenting with anxiety symptoms decreased as the severity of piecemeal deglutition and postswallow vallecular pooling increased. No significant association was found between clinically relevant symptoms of depression and any specific FEES variable. These data revealed few associations between anxiety symptoms and the measured FEES variables. However, the more severe the score on FEES variables, the less important the affective complaints were. Anxiety seems to play a role in OD, but no causal relationship was found, commensurate with a cross-sectional study design. The contribution of affective symptoms to the development and treatment of OD warrants longitudinal research. 2b Laryngoscope, 126:E199-E207, 2016.


Synthesis of three disaccharides for the preparation of immunogens bearing immunodeterminants known to occur on glycoproteins.
p-Nitrophenyl 2-acetamido-3,6-di-O-benzyl-2-deoxy-beta-D-glucopyranoside was condensed with 2,3,4,6-tetra-O-benzyl-alpha-D-galactopyranosyl bromide, the product deprotected, and the disaccharide glycoside converted into p-trifluoroacetamidophenyl 2-acetamido-2-deoxy-4-O-beta-D-galactopyranosyl-beta- D-glucopyranoside. p-Nitrophenyl 3-O-benzoyl-4,6-di-O-benzylidene-alpha-D-mannopyranoside was condensed with 3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-beta-D-glucopyranosyl bromide, and the product was deprotected, to yield p-nitrophenyl 2-O-(2-acetamido-2-deoxy-beta-D-glucopyranosyl)-alpha-D-mannopyranoside. p-Nitrophenyl 2-acetamido-3,4-di-O-benzoyl-2-deoxy-beta-D-glucopyranoside was condensed with 2,3,4-tri-O-benzyl-alpha-L-fucopyranosyl bromide, and, after reduction, trifluoroacetylation, and deprotection, p-trifluoroacetamidophenyl 2-acetamido-2-deoxy-6-O-alpha-L-fucopyranosyl-beta-D-glucopyranoside was obtained.


Crystal structure of Al2.95Cr0.59, a phase closely related to the η-phase in the binary Al-Cr system.
The monoclinic η-phase in the binary Al-Cr system was initially named by Bradley & Lu [Bradley & Lu (1937 ▸). J. Inst. Met. 60, 319-337] as having the composition Al11Cr2 (Al:Cr ratio = 5.5:1). Its crystal structure was later refined [Cao & Kuo (2008). J. Alloys Compd. 458, 30, 319-337] to have a slightly lower Al content (Al:Cr ratio = 5.16:1). In the present work, a monoclinic phase with composition Al2.95Cr0.59 (Al:Cr ratio = 5.04:1) was obtained by high-pressure sinter-ing (HPS) of a stoichiometric Al11Cr2 mixture. Structure analysis of this phase, hereafter named η', revealed a close relationship to the previously reported η-Al11Cr2 structure, but with different mixed-occupied sites. Five fully occupied sites exhibit refined site occupation factors of 0.899 (5), 0.984 (4), 0.977 (5), 0.946 (4) and 0.945 (4) for the corresponding Al atoms. Moreover, there are no split Al sites in the η'-structure as reported for the η-structure. The refined chemical composition of the η'-phase revealed that it comprises two Al atoms fewer and two Cr atoms more than the previously reported η-Al11Cr2 phase.


Oblique Lateral Interbody Fusion (OLIF) with Supplemental Anterolateral Screw and Rod Instrumentation: A Preliminary Clinical Study.
This study aimed to evaluate the technical details, clinical effectiveness, and complications of oblique lateral interbody fusion supplemented with anterolateral screw-rod instrumentation in managing degenerative lumbar diseases. The clinical data of 14 patients with lumbar degenerative diseases who underwent oblique lateral interbody fusion and anterolateral screw-rod instrumentation in the Department of Neurosurgery, Sichuan Provincial People's Hospital, from April 2015 to May 2018, were retrospectively analyzed. The duration of operation, estimated blood loss, radiological exposure, length of hospital stay, and complications were recorded. The visual analog scale score, Oswestry Disability Index, and radiologic parameters were evaluated before and after surgery. The diagnosis included degenerative/isthmic spondylolisthesis (grade I), degenerative lumbar stenosis, disc hernia with instability, and adjacent segment disease. The follow-up period was 12-45 months. The clinical symptoms improved significantly after the operation according to the visual analog scale and Oswestry Disability Index scores. The average operation time, blood loss, and length of hospital stay were 72.50 ± 21.46 minutes, 53.21 ± 19.07 mL, and 5.57 ± 2.21 days, respectively. The postoperative radiographic examination demonstrated increased intervertebral height and foramen area (P < 0.05). The radiologic fusion rate was 95% at the last follow-up; cage subsidence was found in 1 case. No major complications, such as vascular injury, ureteral injury, or infection, occurred. As an alternative method of instrumentation, anterolateral screw-rod fixation minimized the total operation time, blood loss, radiological exposure, and soft tissue disruption, and realized 1-stage intervertebral fusion and instrumentation through a single small incision.


Association between repeated intubation attempts and adverse events in emergency departments: an analysis of a multicenter prospective observational study.
Although repeated intubation attempts are believed to contribute to patient morbidity, only limited data characterize the association between the number of emergency department (ED) laryngoscopic attempts and adverse events. We seek to determine whether multiple ED intubation attempts are associated with an increased risk of adverse events. We conducted an analysis of a multicenter prospective registry of 11 Japanese EDs between April 2010 and September 2011. All patients undergoing emergency intubation with direct laryngoscopy as the initial device were included. The primary exposure was multiple intubation attempts, defined as intubation efforts requiring greater than or equal to 3 laryngoscopies. The primary outcome measure was the occurrence of intubation-related adverse events in the ED, including cardiac arrest, dysrhythmia, hypotension, hypoxemia, unrecognized esophageal intubation, regurgitation, airway trauma, dental or lip trauma, and mainstem bronchus intubation. Of 2,616 patients, 280 (11%) required greater than or equal to 3 intubation attempts. Compared with patients requiring 2 or fewer intubation attempts, patients undergoing multiple attempts exhibited a higher adverse event rate (35% versus 9%). After adjusting for age, sex, principal indication, method, medication, and operator characteristics, intubations requiring multiple attempts were associated with an increased odds of adverse events (odds ratio 4.5; 95% confidence interval 3.4 to 6.1). In this large Japanese multicenter study of ED patients undergoing intubation, we found that multiple intubation attempts were independently associated with increased adverse events.


The short and long-term impact of nonpharmaceutical interventions on the prevalence of varicella in Xi'an during the COVID-19 pandemic.
Varicella is a highly prevalent infectious disease with a similar transmission pathway to coronavirus disease 2019 (COVID-19). In the context of the COVID-19 pandemic, anti-COVID-19 nonpharmaceutical interventions (NPIs) have been implemented to prevent the spread of the infection. This study aims to analyze varicella's epidemiological characteristics and further investigate the effect of anti-COVID-19 NPIs on varicella in Xi'an, northwestern China. Based on the varicella surveillance data, search engine indices, meteorological factors from 2011 to 2021 in Xi'an, and different levels of emergency response to COVID-19 during the pandemic, we applied Bayesian Structural Time Series models and interrupted time series analysis to predict the counterfactual incidence of varicella and quantify the impact of varying NPIs intensities on varicella. From 2011 to 2021, varicella incidence increased, especially in 2019, with a high incidence of 111.69/100 000. However, there was a sharp decrease of 43.18% in 2020 compared with 2019, and the peak of varicella incidence in 2020 was lower than in previous years from the 21st to the 25th week. In 2021, the seasonality of varicella incidence gradually returned to a seasonal pattern in 2011-2019. The results suggest that anti-COVID-19 NPIs effectively reduce the incidence of varicella, and the reduction has spatiotemporal heterogeneity.


The effect of n-3 fatty acids on low density lipoprotein subfractions.
A predominance of small, dense low density lipoprotein (LDL) represents a significant source of increased risk for the development of coronary heart disease in Westernized countries. Dietary long-chain n-3 polyunsaturated fatty acids exert a potent triglyceride-lowering effect that redistributes LDL subfractions toward larger and lighter particles. These dietary fatty acids thus have a key role to play in providing protection against this particularly atherogenic type of LDL.


Activation of the ventral and mesial frontal cortex of the monkey by self-initiated movement tasks as revealed by positron emission tomography.
In order to investigate the neural mechanisms of movement initiation, we measured the regional cerebral blood flow (rCBF) of the monkey during self-initiated and visually-initiated hand movement tasks using positron emission tomography (PET). The orbitofrontal, cingulate, and anteromedial part of the dorsal premotor areas were preferentially activated by the self-initiated hand movement task (SELF). The pre-supplementary motor area and the cingulate motor area were also included in the active foci during the task. In the visually-initiated task (VISUAL), the V1, V2, V3, V3A, and V4 were activated, whereas the activity of the dorsolateral premotor and primary motor areas was not significantly different between the two tasks. These findings suggest that the orbitofrontal and mesial frontal cortices play an important role in the neural processes involved in self-initiation of movement and self-regulation of inner drives.


A comparison of blind nasotracheal and succinylcholine-assisted intubation in the poisoned patient.
In the patient obtunded by drug intoxication, the optimal method of airway protection prior to gastric emptying is not clear. We report a prospective randomized trial of two methods of intubation in this patient population. Fifty-two overdose patients with Glascow Coma Scale scores of 12 or less were intubated either orotracheally after succinylcholine administration or nasotracheally. Success rate, time to intubate, difficulty, and complications of intubation were compared for the two groups. We found a success rate of 100% (23 of 23) for succinylcholine assisted intubation (SAI) versus 65% (19 of 29) success with blind nasotracheal intubation (BNI). Mean time to intubate was 64 seconds and 276 seconds in the SAI and BNI groups, respectively. Eighty-six percent (19 of 22) of patients were intubated successfully in less than 120 seconds in the SAI group versus 37% (10 of 27) in the BNI group (P less than .005). In the SAI group, the mean number of attempts was 1.3 per patient, (range, one to three) with 96% (22 of 23) having two or fewer attempts. No complications were identified. In the BNI group, the mean number of attempts was 3.7 per patient, (range, one to 13) with 45% (13 of 29) having two or fewer attempts (P less than .005). Sixty-nine percent of the BNI group experienced epistaxis, 17% had vomiting, and 10% aspirated. We conclude that SAI is a safe and effective method of airway protection in the obtunded poisoned patient. Complications and difficulty in intubation were significantly less with SAI than with blind nasotracheal intubation.


Bioengineered perfused human brain microvascular networks enhance neural progenitor cell survival, neurogenesis, and maturation.
Neural progenitor cells (NPCs) have the capability to self-renew and differentiate into neurons and glial cells. In the adult brain, NPCs are found near brain microvascular networks (BMVNs) in specialized microenvironments called the neurovascular niche (NVN). Although several in vitro NVN models have been previously reported, most do not properly recapitulate the intimate cellular interactions between NPCs and perfused brain microvessels. Here, we developed perfused BMVNs composed of primary human brain endothelial cells, pericytes, and astrocytes within microfluidic devices. When induced pluripotent stem cell-derived NPCs were introduced into BMVNs, we found that NPC survival, neurogenesis, and maturation were enhanced. The application of flow during BMVN coculture was also beneficial for neuron differentiation. Collectively, our work highlighted the important role of BMVNs and flow in NPC self-renewal and neurogenesis, as well as demonstrated our model's potential to study the biological and physical interactions of human NVN in vitro.


The glomerular tip lesion: a distinct entity or not?
Howie and Brewer recently described a novel glomerulopathy: the glomerular tip lesion (GTL). The characteristic feature of this entity is a collection of intracapillary foam cells and marked vacuolization of the epithelial cells of the glomerular segment adjacent to the origin of the proximal tubule. Although this lesion resembles focal segmental glomerulosclerosis (FSGS), Howie and Brewer suggested that it constitutes a distinct entity, differing also clinically from FSGS, in that it would have a better response to steroid treatment. We treated five patients fulfilling the criteria of Howie and Brewer. However, neither corticosteroids (1.5 mg/kg/day for 1 month in five patients) nor cyclosporin-A (5 mg/kg/day for three months in four patients) caused a decrease in proteinuria to below 4 g/day. In two patients, renal function deteriorated and in one of them, recurrence of classical FSGS was found in the renal transplant. A sixth patient was observed in whose biopsy a combination of GTL with membranous glomerulopathy was present. We conclude that GTL is not a distinct entity and that in the clinical course and response to treatment it does not differ from FSGS.


Epidemic characteristics and related risk factors of occupational exposure for pediatric health care workers in Chinese public hospitals: a cross-sectional study.
Health care workers have a high risk of occupational exposure. However, the risk of occupational exposure for pediatric health care workers has not been acknowledged in previous studies. The purpose of this study was to investigate the occupational exposure rate of pediatric health care workers in Chinese public hospitals, to explore risk factors for occupational exposure, and to put forward corresponding countermeasures to reduce occupational exposure of pediatric health care workers and protect their physical and mental health. A cross-sectional study was conducted with pediatric health care workers in 43 hospitals in 15 provinces in eastern, central, and western China between July and October 2018. With this sample, we computed the descriptive statistics of the demographic characteristics, calculated the frequency of various types of occupational exposure, and tested risk factors for occupational exposure using a chi-squared test and binary logistic regression analysis. Most respondents were nursing staff (61.1%) and workers with a low-ranking professional title (50.5%). The most common style of occupational exposure in our sample was a hazard in the work environment (62.6%). Notably, physicians were less likely to experience occupational exposure than nurses (OR = 0.320, 95% CI = 0.241, 0.426). Meanwhile, pediatric health care workers who interpreted the doctor-patient relationship as harmonious (OR = 0.304, 95% CI = 0.152, 0.607) were less likely to suffer occupational exposure. Pediatric health care workers in Chinese public hospitals have a high occupational exposure risk and the risk factors are complex and diverse. The state, society, hospitals should acknowledge this issue and develop strategies to protect the physical and mental health of pediatric health care workers.


Some examples of a method for determining key factors from life table data.
The method of Manly (1977) for determining key factors in the life cycle of animal populations is illustrated on several sets of published data.


Acute modified Blalock-Taussing shunt obstruction successfully treated with urokinase and heparin.
Acute modified Blalock-Tuassig shunt obstruction due to thrombosis may be life-threatening. We report non-invasive relief of shunt obstruction with thrombolysis and heparinisation, a potentially life-saving intervention that is applicable in all settings, including outside tertiary paediatric cardiology centres.


Iminosugar-based inhibitors of glucosylceramide synthase prolong survival but paradoxically increase brain glucosylceramide levels in Niemann-Pick C mice.
Niemann Pick type C (NPC) disease is a progressive neurodegenerative disease caused by mutations in NPC1 or NPC2, the gene products of which are involved in cholesterol transport in late endosomes. NPC is characterized by an accumulation of cholesterol, sphingomyelin and glycosphingolipids in the visceral organs, primarily the liver and spleen. In the brain, there is a redistribution of unesterified cholesterol and a concomitant accumulation of glycosphingolipids. It has been suggested that reducing the aberrant lysosomal storage of glycosphingolipids in the brain by a substrate reduction therapy (SRT) approach may prove beneficial. Inhibiting glucosylceramide synthase (GCS) using the iminosugar-based inhibitor miglustat (NB-DNJ) has been reported to increase the survival of NPC mice. Here, we tested the effects of Genz-529468, a more potent iminosugar-based inhibitor of GCS, in the NPC mouse. Oral administration of Genz-529468 or NB-DNJ to NPC mice improved their motor function, reduced CNS inflammation, and increased their longevity. However, Genz-529468 offered a wider therapeutic window and better therapeutic index than NB-DNJ. Analysis of the glycolipids in the CNS of the iminosugar-treated NPC mouse revealed that the glucosylceramide (GL1) but not the ganglioside levels were highly elevated. This increase in GL1 was likely caused by the off-target inhibition of the murine non-lysosomal glucosylceramidase, Gba2. Hence, the basis for the observed effects of these inhibitors in NPC mice might be related to their inhibition of Gba2 or another unintended target rather than a result of substrate reduction.


Risk of Recurrence in Patients With HER2+ Early-Stage Breast Cancer: Literature Analysis of Patient and Disease Characteristics.
Human epidermal growth factor receptor 2 (HER2) overexpression occurs in 15% to 20% of patients with early-stage breast cancers (EBCs). Without HER2-targeted therapy, 30% to 50% of patients relapse within 10 years, many developing incurable metastatic disease. This literature review was designed to identify and validate patient- and disease-related factors associated with recurrence in patients with HER2+ EBC. Peer-reviewed primary research articles and congress abstracts were identified by searching MEDLINE. Articles published in English from 2019 to 2022 were included to identify contemporary treatment options. Results were analyzed for the relationship between risk factors and surrogates of HER2+ EBC recurrence to determine how identified risk factors affected HER2+ EBC recurrence. Sixty-one articles and 65 abstracts that assessed age at diagnosis, body mass index (BMI), tumor size at diagnosis, hormone receptor (HR) status, pathologic complete response (pCR) status, and biomarkers were analyzed. We confirmed the results of previously published reviews reporting residual cancer burden >0, non-pCR, and fewer tumor-infiltrating lymphocytes (TILs) as risk factors of recurrence. HR status remained an important risk factor for recurrence, with HER2+/HR+ disease more likely to recur. Two or more positive lymph nodes, higher BMI, larger primary tumor size, and low Ki67 were more commonly associated with HER2+ EBC recurrence. The identification of patient and disease factors frequently associated with HER2+ EBC recurrence in the literature provides insight into potential recurrence risk factors. Further investigation into the risk factors identified in this review could lead to improved treatments for patients at high risk for HER2+ EBC recurrence.


Cellular angiofibroma: analysis of 25 cases emphasizing its relationship to spindle cell lipoma and mammary-type myofibroblastoma.
Cellular angiofibroma represents a rare benign mesenchymal tumor, occurring mainly in the superficial soft tissue of the genital region. The involvement of 13q14 in some cases confirmed the morphological suggested link with spindle cell lipoma and mammary-type myofibroblastoma. We analyzed the clinicopathological and immunohistochemical features of 25 cases, and performed in a number of cases additional molecular studies. There were 17 female and 8 male patients (age ranged from 27 to 83 years); females tended to be younger. A marked predilection for the vulva (n=13) was observed, and neoplasms in males were predominantly located in the inguinal region (n=4), and one case each in the scrotum, perianal, the knee, and the upper eyelid. The tumors arose most commonly in the superficial soft tissue and were well circumscribed in all but two cases. The tumor size ranged from 1 to 9 cm. All lesions were composed of spindle-shaped cells associated with numerous small- to medium-sized blood vessels; however, a broad morphological variation with foci of lipogenic differentiation in nine cases and sarcomatous transformation in one case was found. By immunohistochemistry, 11 out of 22 cases expressed CD34. A focal reaction for α-smooth muscle actin was observed in 9 out of 22 cases, and two cases each stained weak and focally positive for epithelial membrane antigen and CD99. In all seven cases tested, a monoallelic deletion of RB1 was detected by FISH analysis. Follow-up, available in 14 patients, showed neither local recurrence nor metastasis. In conclusion, we affirm the link between cellular angiofibroma, spindle cell lipoma, and mammary-type myofibroblastoma, showing a spectrum of one entity with morphological variations dependent on anatomic location.


A Gap in Care Leads to Progression of Fibrosis in Eosinophilic Esophagitis Patients.
There are few data assessing disease progression in eosinophilic esophagitis (EoE) after diagnosis. We aimed to determine outcomes and assess for progression of fibrosis in patients with EoE with a gap in their regular care. In this retrospective cohort study of newly diagnosed patients with EoE, a "gap" in care was defined as ≥2 years without medical contact for EoE. For inclusion, a gap in care and both pre- and post-gap endoscopies were required. Patients with and without a gap were compared. Data were also compared in gap patients before the gap and after EoE care resumed, and progression of fibrosis and predictors were assessed. Of 701 patients with EoE, 95 (14%) had a gap in care (mean time without care, 4.8 ± 2.3 years). Post-gap, 12% presented with food impaction requiring emergency evaluation. Compared with pre-gap, patients post-gap had higher endoscopic severity (2.4 vs 1.5; P < .001) and smaller esophageal diameters (11.0 vs 12.7 mm; P = .04). Strictures were more prevalent with longer gap time (P < .05 for trend). Each additional year of gap time increased odds of stricture by 26%, even after accounting for pre-gap dilation. Additionally, of 67 patients without pre-gap fibrosis, 25 (37%) had at least one fibrotic feature (stricture, narrowing, or requiring dilation) post-gap. A gap in care of ≥2 years in patients with EoE was associated with signs of increased disease activity, and progression to fibrostenosis was noted, particularly with longer gaps in care. Because EoE can progress to fibrosis even after diagnosis, regular care in patients with EoE is required, perhaps at intervals <2 years.


Neuronal nitric oxyde synthase positive neurons in human indusium griseum.
The study was designed to analyze the nNOS positive neurons present in the indusium griseum by describing their distribution and morphology. To this purpose, sagittal serial sections from paraffin or frozen autopsy specimens of corpus callosum including the overlying indusium griseum were processed by immunohistochemistry and immunofluorescence, using an antibody against the neuronal form of the enzyme nitric oxyde synthase. To test the specificity of the antibody used, Western Blot was performed in the indusium griseum of the same specimens. The stainings revealed the presence of many neuronal nitric oxyde synthase-immunopositive neurons in human indusium griseum, located along both rostral-caudal and medio-lateral directions. In particular, they were more numerous 1 mm apart from the midline, and their number peaked over the body of the corpus callosum. They showed different morphologies; in some cases, they were located at the boundary between indusium griseum and corpus callosum, more densely packed in proximity to the pial arteries penetrating into the corpus callosum. The significant presence and distribution of neuronal nitric oxyde synthase-immunopositive neurons suggests that indusium griseum likely plays a functional role in the neurovascular regulation within the corpus callosum. Schematic representation of human adult IG and the neurovascular unit originating from sopracallosal artery (Sca) that branches into smaller arterioles (Br) (created in PowerPoint). The arterioles cross the three layers of IG (layers I, II and III) and penetrate into the CC separated from IG by the Virchow-Robin space (VRs). As the arterioles go deeper, this space disappears and the vascular basement membrane comes into direct contact with the astrocytic end-feets (intracallosal arterioles and capillaries). nNOS-immunopositive neurons (nNOSIP N) surround the arterioles and control the vasomotore tone secreting nitric oxyde (NO). Two morphological types of nNOSIP N can be appreciated by the use of different colors: fusiform (blue) and ovoidal (pink). Also NeuN-immunopositive neurons (N) and many astrocytes (As) are present, more numerous in IG than in CC.