Diagnostic stewardship: what impacts antibiotics use?
The aim of this study was to review recently published diagnostic stewardship studies of common clinical infectious syndromes and the impact on antibiotic prescribing. Diagnostic stewardship can be implemented within healthcare systems and tailored to infectious syndromes, including urinary tract, gastrointestinal, respiratory and bloodstream infections. In urinary syndromes, diagnostic stewardship can decrease unnecessary urine culturing and associated antibiotic prescribing. Diagnostic stewardship of Clostridium difficile testing can decrease antibiotics and test ordering with a reduction in healthcare-associated C. difficile infections. Respiratory syndrome multiplex arrays can decrease time to results and increase detection of clinically relevant pathogens but may not decrease antibiotics use, or worse, could increase over-prescribing if diagnostic stewardship of ordering practices is not exercised. Lastly, blood culturing practices can be improved by clinical decision support to safely decrease collection and broad-spectrum antibiotic use. Diagnostic stewardship decreases unnecessary antibiotic use in a way that is different from and complementary to antibiotic stewardship. Further studies are needed to quantify the full impact on antibiotic use and resistance. Future considerations should be to institutionalize diagnostic stewardship in patient care activities to leverage integration into systems-based interventions.


Commentary on selected aspects of cardioprotection.
Three aspects of cardioprotection are discussed in this article. The first is myocyte death as a function of the duration and severity of ischemia in experimental acute myocardial infarction in the dog heart. The short period of time during which reperfusion with arterial blood will salvage myocytes is demonstrated along with data showing that this period diminishes significantly if collateral flow is very low or absent. The second topic is a discussion of potential mechanisms underlying postconditioning. It begins with a review of the changes that lead to irreversible injury during acute ischemia in the dog heart along with a discussion of the genesis of contraction band necrosis and no reflow when myocardium is salvaged by unrestricted reperfusion with arterial blood in order to provide a basis to discuss the potential mechanisms underlying postconditioning, a situation in which reflow is intermittent and restricted. Postconditioning is reported to achieve greater myocyte salvage than unrestricted reflow. Potential explanations for this beneficial effect include: first, sufficient sarcolemmal repair occurring during the intermittent reflow (reoxygenation) to prevent cell death by explosive cell swelling, and second, prevention of the opening of the mitochondrial permeability transition pore, thereby preventing mitochondrial failure and cell death in the reperfused tissue. Since there is no way available to identify and specifically study the myocytes that would have died if not protected by postconditioning, direct demonstration of mechanisms is difficult or impossible. Finally, the third topic in this commentary is an analysis of the obstacles faced by investigators using small rodent hearts to establish cardioprotective mechanisms. Such studies provide valid data but the relationship of the changes and the proposed mechanisms underlying these changes are not necessarily directly transferable to ischemic large animal hearts including the heart of man.


Validation study on pfetin and ATP-dependent RNA helicase DDX39 as prognostic biomarkers in gastrointestinal stromal tumour.
This study aimed to validate two prognostic biomarkers, pfetin and adenosine triphosphate-dependent RNA helicase DDX39 (DDX39), in gastrointestinal stromal tumour. Prognostic biomarkers have long been required for the optimal use of kinase inhibitors in gastrointestinal stromal tumour. The expression level of pfetin was immunohistochemically examined in 72 gastrointestinal stromal tumour cases, being correlated with the clinicopathological parameters. Meta-analysis of the prognostic value of pfetin was performed in a total of 371 cases. The prognostic utility of the combination of pfetin and DDX39 was examined in the 72 gastrointestinal stromal tumour cases. Immunohistochemical study demonstrated the disease-free survival rate to be 94.7% for pfetin-positive patients and 20.0% for pfetin-negative patients among the 72 gastrointestinal stromal tumour cases (P < 0.0001). In the 371 cases, the disease-free survival rate was 93.8% for pfetin-positive patients and 40.6% for pfetin-negative patients (P < 0.0001). Both univariate and multivariate analyses revealed that pfetin expression was an independent prognostic factor (P< 0.0001). When evaluated in combination with pfetin and DDX39, the disease-free survival rates were 0.0% for the pfetin-negative and DDX39-strong patients. These results established the clinical utility of pfetin as a novel prognostic biomarker for gastrointestinal stromal tumour. The combined use of pfetin and DDX39 appeared to have powerful prognostic value. These biomarkers will be useful in deciding whether to administer adjuvant therapy after surgery.


Optical coherence tomography axial resolution improvement by step-frequency encoding.
A novel technique for axial resolution improvement of Optical Coherence Tomography (OCT) systems is proposed. The technique is based on step-frequency encoding, using frequency shifting, of the OCT signal. A resolution improvement by a factor of approximately 7 is achieved without the need for a broader bandwidth light source. This method exploits a combination of two basic principles: the appearance of beating, when adding two signals of slightly different carrier frequencies, and the resolution improvement by deconvolution of the interferogram with an encoded autocorrelation function. In time domain OCT, step-frequency encoding can be implemented by performing two scans, with different carrier frequencies, and subsequently adding them to create the encoded signal. When the frequency steps are properly selected, deconvolution of the resulting interferogram, using appropriate kernels, results in a narrower resolution width.


Fixing coccidian oocysts is not an adequate solution to the problem of preserving protozoan type material.
Fresh (36 days old) sporulated oocysts of Eimeria nieschulzi were divided into 7 groups. Control oocysts were maintained at 23 C in 2% aqueous (w/v) K2Cr2O7. The 6 experimental groups were mixed with either Bouin's solution, 10% aqueous (v/v) buffered formalin, Karnovsky's solution, glutaraldehyde, paraformaldehyde, or 70% aqueous (v/v) ethanol (EtOH). After 115 days, oocysts from all 7 groups were examined under oil immersion to determine the effect of fixation on their structural integrity. The parameters examined were lengths and widths of oocysts and sporocysts, percent sporulation (%S), and percent crenation (%C) of oocysts and sporocysts. The highest destruction (%S and %C) occurred in oocysts exposed to glutaraldehyde and Karnovsky's fixatives where 100% of both oocysts and sporocysts crenated and only 8% and 48%, respectively, remained sporulated. Of the oocysts in paraformaldehyde, 93% remained sporulated, but 95%of these oocysts and 100% of the sporocyst crenated. In Bouin's solution, 75% of the oocysts were intact structurally, but of these, only 60% were still sporulated with 70% of their sporocysts crenated. Oocysts preserved in 70% EtOH were 80% intact and 70% remained sporulated, but nearly 60% of their sporocysts collapsed even though the oocyst walls were intact. Oocysts preserved in 10% buffered formalin maintained structural integrity but had lower numbers of sporulated oocysts (84%) and greater numbers of crenated oocysts (18%) than control oocysts maintained in the dichromate solution (95% and 0%, respectively).


Investigating the cumulative effects of Δ9-tetrahydrocannabinol and repetitive mild traumatic brain injury on adolescent rats.
The prevalence of mild traumatic brain injury is highest amongst the adolescent population and can lead to complications including neuroinflammation and excitotoxicity. Also pervasive in adolescents is recreational cannabis use. Δ9-Tetrahydrocannabinol, the main psychoactive component of cannabis, is known to have anti-inflammatory properties and serves as a neuroprotective agent against excitotoxicity. Thus, we investigated the effects of Δ9-tetrahydrocannabinol on recovery when administered either prior to or following repeated mild brain injuries. Male and female Sprague-Dawley rats were randomly assigned to receive Δ9-tetrahydrocannabinol or vehicle either prior to or following the repeated injuries. Rats were then tested on a behavioural test battery designed to measure post-concussive symptomology. The hippocampus, nucleus accumbens and prefrontal cortex were extracted from all animals to examine mRNA expression changes (Bdnf, Cnr1, Comt, GR, Iba-1 and Vegf-2R). We hypothesized that, in both experiments, Δ9-tetrahydrocannabinol administration would provide neuroprotection against mild injury outcomes and confer therapeutic benefit. Δ9-Tetrahydrocannabinol administration following repeated mild traumatic brain injury was beneficial to three of the six behavioural outcomes affected by injury (reducing anxiety and depressive-like behaviours while also mitigating injury-induced deficits in short-term working memory). Δ9-Tetrahydrocannabinol administration following injury also showed beneficial effects on the expression of Cnr1, Comt and Vegf-2R in the hippocampus, nucleus accumbens and prefrontal cortex. There were no notable benefits of Δ9-tetrahydrocannabinol when administered prior to injury, suggesting that Δ9-tetrahydrocannabinol may have potential therapeutic benefit on post-concussive symptomology when administered post-injury, but not pre-injury.


Autocorrelation noise removal for optical coherence tomography by sparse filter design.
We present a reconstruction method to eliminate the autocorrelation noise (ACN) in optical coherence tomography (OCT). In this method, the optical fields scattered from the sample features are regarded as the response of a sparse finite impulse response (FIR) filter. Then the OCT reconstruction is formulated as one of identifying the parameters of a sparse FIR filter, which are obtained via an [script-l](1) optimization with soft thresholding. The experimental results show that the proposed method can obtain OCT reconstruction results with effective attenuation of ACN.


Recurrence after complete cryoablation of colorectal liver metastases: analysis of prognostic features.
This study critically evaluated the prognostic determinants for disease-free survival (DFS) after cryoablation for colorectal liver metastases. An observational cohort study of prospectively collected data on 135 patients who underwent cryoablation with or without resection for colorectal liver metastases was performed. Univariate and multivariate analyses were used to determine the prognostic factors for overall DFS, cryosite DFS, remaining liver DFS, and extrahepatic DFS. Overall, 115 patients (85%) developed recurrence at the cryosite (44%), and the remaining patients developed recurrence at the liver (62%) and extrahepatic site (71%). In univariate analysis, preoperative and postoperative carcinoembryonic antigen (CEA) were significant for overall DFS. Distribution of metastases, operation type, total number of metastases, number of cryotreated metastases, largest size of cryotreated metastasis, and postoperative CEA were significant for cryosite DFS. The number of cryotreated metastases and postoperative CEA were significant for remaining liver DFS. The largest size of cryotreated metastasis, and preoperative and postoperative CEA were significant for extrahepatic DFS. In multivariate analysis, resection plus cryoablation, < or =7 liver metastases and < or =3 cm cryotreated metastasis were independently associated with an improved cryosite DFS. Preoperative CEA of < or =5 ng/mL was independently associated with an improved overall and extrahepatic DFS. The role of CEA in colorectal metastasis is important. Resection plus cryoablation rather than cryoablation alone should be used for larger lesions.


Comparison between allogenic and autologous vascular conduits in the drainage of anterior sector in right living donor liver transplantation.
Congestion of the anterior sector may lead to graft failure in right lobe grafts. Selective drainage of the prominent segment 5 and/or 8 veins is proposed to overcome this problem. Different vascular conduits may be used during drainage of the anterior sector. In this study, we evaluated the efficiency of the vascular conduits. Between June 1999 and December 2005, 190 patients underwent living donor right lobe liver transplantation and reconstruction of segment 5 and/or 8 veins was performed in 48 patients (25.2%). Two groups were formed according to the types of vascular conduits. Cryopreserved cadaveric iliac artery (n = 28) and cryopreserved cadaveric iliac vein (n = 8) were used in group A. In group B, recipient saphenous vein (n = 6), recipient umbilical vein (n = 5) and recipient collateral omental vein (n = 1) were used for reconstruction. The graft-recipient weight ratio, mean duration of anhepatic phase and MELD scores between two groups were not significantly different. All of the conduits were found to be patent just after reperfusion and in the early postoperative period by Doppler ultrasonography. In follow-up period of 1 year, four (11%) patients died in group A, two patients (16%) in group B. One of these patients died because of sepsis started from the saphenous vein incision site. None of the patients dying in the two groups were lost due to venous outflow problems. This study proves the efficacy of drainage of segment 5 and/or 8 veins using cryopreserved cadaveric vascular conduits. Every effort should be employed to store cadaveric iliac vessels, otherwise, whole other additive surgical intervention to ensure vascular conduit may lead uninvited serious complication.


A dynamic force balance model for colloidal expansion and its DLVO-based application.
A force balance model that describes the dynamic expansion of colloidal bentonite gels/sols is presented. The colloidal particles are assumed to consist of one or several thin sheets with the other dimensions much larger than their thickness. The forces considered include van der Waals force, diffuse double layer force, thermal force giving rise to Brownian motion, gravity, as well as friction force. The model results in an expression resembling the instationary diffusion equation but with an immensely variable diffusivity. This diffusivity is strongly influenced by the concentration of counterions as well as by the particle concentration in the colloid gel/sol. The properties of the model are explored and discussed, exemplified by the upward expansion of an originally highly compacted bentonite tablet in a test tube. Examples are presented for a number of cases with ionic concentrations varying between very dilute waters up to several molar of counterions. The volume fraction of particles ranges from 40% to very dilute sols.


[The protective factors of suicide probability in religious male high school students].
This study was conducted to identify the protective factors that influence suicide probability in religious male high school students. The data was collected from Nov. 5 to Dec. 10, 2009. Data were collected by self-report questionnaire from 255 students selected from 2 religious male high schools in B city. The instruments for this study were the Suicide Probability Scale for Adolescence (SPS-A), Inventory Parents Peer Attachment-Revision (IPPA-R), Spiritual Well-being Scale (SWBS), and Ego-identity Scale. The data were analyzed using t-test, one-way ANOVA, Scheffe test, Pearson correlation coefficients and stepwise multiple regression with the SPSS 14.0 program. The protective factors of suicide probability in religious male high school students were identified as existential spiritual well-being (β= -.46, p<.001), self-identity (β= -.30, p<.001), and mother attachment (β= -.21, p<.001). These three factors explained 61.5% of the variance in suicide probability. The results suggest that improvement in spirituality, ego-identity, and mother attachment for religious male high school students is important to reduce the probability of suicide.


Activation of tobacco leaf polyphenol oxidase by sodium dodecyl sulfate.
The effect of sodium dodecyl sulfate (SDS) on purified tobacco leaf PPO (PPO II) was investigated at various pHs and temperatures. SDS increased the activity of PPO II due to the formation of SDS-PPO II complex, leading to conformational changes, thus making access to active center easier. The relationship between the activity and the molar ratio of SDS-PPO II to PPO II showed that the critical point reached a plateau of activity at the molar ratio of about 1.2. The pH had a significant effect on interaction between SDS and PPO II, as compared to PPO II. The optimum catalytic temperature of the complex rose by 10 degrees C, suggesting that stabilization of the structure had been improved by the formation of complex.


Cytomegalovirus esophagogastritis in a patient with acquired immunodeficiency syndrome.
Symptomatic cytomegalovirus involvement of the gastrointestinal tract has become increasingly recognized in patients with acquired immunodeficiency syndrome. This may take varying forms, often mimicking more well known entities. This is a report of a male intravenous drug abuser with documented acquired immunodeficiency syndrome, who developed dysphagia and evidence of distal esophagitis. Although this was initially thought to be related to reflux peptic disease, he subsequently was documented to have cytomegalovirus esophagitis and gastritis. His course was further complicated by small bowel perforation with cytomegalovirus found here as well. Cytomegalovirus infection, in general, and its increasingly recognized role in the morbidity of patients with acquired immunodeficiency syndrome, is discussed.


Guanine-nucleotide- and adenine-nucleotide-dependent regulation of phospholipase D in electropermeabilized HL-60 granulocytes.
We have characterized the regulation of phospholipase D (PLD) in electropermeabilized HL-60 granulocytes in which endogenous phospholipids were pre-labelled with [3H]oleic acid. Treatment of these permeabilized cells with the non-hydrolysable GTP analogues guanosine 5'-[gamma-thio]triphosphate (GTP[S]) and guanosine 5'-[beta gamma-imido]triphosphate induced a sustained (near-linear for up to 60 min) accumulation of phosphatidic acid (PA). In the presence of ethanol a sustained production of phosphatidylethanol (PEt) was also observed. With increasing concentrations of ethanol, PEt formation increased, whereas PA formation declined; this indicated involvement of a PLD-type effector enzyme. The ability of GTP[S] to stimulate this PLD activity was Mg(2+)-dependent and was inhibited by GDP and its non-hydrolysable beta-thio analogue. Ca2+, at concentrations less than or equal to nM, had no effect on the GTP[S]-dependent PLD activity. However, higher concentrations of Ca2+ produced a significant potentiation of this activity. Inclusion of MgATP (greater than or equal to 0.1 mM), but not other nucleoside triphosphates, also induced a large potentiation of GTP[S]-dependent PLD activation. In the absence of guanine nucleotides, MgATP elicited no significant activation of PLD. Significantly, this effect of ATP was not mimicked by adenosine 5'-[beta gamma-methylene]triphosphate, a non-hydrolysable ATP analogue. Rather, this analogue inhibited both basal and ATP-potentiated GTP[S]-dependent PLD activity. This suggests that the ability of ATP to potentiate GTP[S]-dependent PLD activity involves phosphotransferase action rather than simple allosteric effects induced by adenine nucleotide binding. The absolute magnitude of the GTP[S]-dependent PLD activity which could be potentiated by MgATP was decreased by 90% when the permeabilized cells were preincubated for various times before addition of these stimulatory agents. This time-dependent loss of MgATP-induced potentiation was prevented when the permeabilized cells were preincubated in the presence of GTP[S]. These results demonstrate that electropermeabilized HL-60 granulocytes can be used to discriminate synergistic roles for a GTP-binding protein(s) and an ATP-dependent process (kinase?) in the regulation of phospholipase D activity.


Mucosal Eosinophil Abundance in Non-Inflamed Colonic Tissue Is Associated with Response to Vedolizumab Induction Therapy in Inflammatory Bowel Disease.
Vedolizumab is used as a treatment for patients with inflammatory bowel disease (IBD), but induction therapy leads to clinical response and remission in approximately 55% and 30% of patients with IBD, respectively. In this study, we aimed to explore the predictive value of mucosal eosinophils and serum eotaxin-1 regarding response to vedolizumab induction therapy. Eighty-four (84) patients with IBD (37 Crohn's disease [CD], 47 ulcerative colitis [UC]) were included. For 24 patients with IBD, histopathology was assessed for eosinophil counts in non-inflamed colonic tissue prior to vedolizumab treatment. For 64 patients with IBD, serum eotaxin-1 levels were quantified prior to (baseline) and during vedolizumab treatment. Serum samples of 100 patients with IBD (34 CD, 66 UC) from the GEMINI 1 and 2 trials were used for external validation. Baseline mucosal eosinophil numbers in non-inflamed colonic tissue were significantly higher in responders to vedolizumab induction therapy when compared to primary non-responders (69 [34−138] vs. 24 [18−28] eosinophils/high-power field, respectively, p < 0.01). Baseline serum eotaxin-1 levels in the discovery cohort were significantly elevated in responders, compared to primary non-responders (0.33 [0.23−0.44] vs. 0.20 [0.16−0.29] ng/mL, p < 0.01). Prediction models based on mucosal eosinophil counts and serum eotaxin-1 showed an area under the curve (AUC) of 0.90 and 0.79, respectively. However, the predictive capacity of baseline serum eotaxin-1 levels could not be validated in the GEMINI cohort. Mucosal eosinophil abundance in non-inflamed colonic tissue was associated with response to vedolizumab induction therapy in patients with IBD. Future studies are warranted to further validate the potential value of mucosal eosinophils and serum eotaxin-1 as biomarkers for response to vedolizumab therapy.


Subjective and objective responses to PTNS and predictors for success: a retrospective cohort study of percutaneous tibial nerve stimulation for overactive bladder.
We investigated the objective improvements in overactive bladder (OAB) symptoms in patients undergoing percutaneous tibial nerve stimulation (PTNS) and predictive factors of patient satisfaction. In this single-center retrospective cohort study at a tertiary urogynecology center, we identified all female patients who underwent PTNS therapy from 1 October 2007 - 1 January 2016 and followed them from their initial visit through medication therapy and PTNS treatments. Patients who tried at least one medication prior to starting PTNS therapy and completed at least one PTNS visit were included. Baseline demographic data, urinary data, and details of medication and PTNS therapy sessions were collected from records through chart review. Paired or two-sample t-tests were used to compare changes over time or groups. Bivariate and multivariable logistic regression were performed. Two hundred thirteen patients underwent PTNS therapy and 183 patients met the criteria. Overall patients were able to decrease voiding frequency by 1 h, decrease nocturia episodes by 0.8, and decrease urge incontinence episodes with PTNS therapy by ten episodes per week (p = 0.02). Patients who continued OAB medications did not have additional improvements compared with patients who did not continue OAB medications during PTNS. Overall, 25.4% (43/169) patients reported ≥ 75% improvement during PTNS therapy, and 61.5% (104/169) reported ≥ 50% improvement. When evaluating predictive factors of ≥ 50% overall improvement, the number of PTNS sessions increased odds of subjective success (OR = 1.8, p = 0.004). Other factors were not significant predictors of subjective PTNS success. PTNS can provide both objective and subjective improvements for patients who do not respond to OAB medication therapy.


Evidence for superantigen involvement in cardiovascular injury due to Kawasaki syndrome.
Kawasaki syndrome (KS), the major cause of acquired heart disease in children, is an acute multisystem vasculitis frequently associated with the development of myocarditis and coronary artery abnormalities. Despite the widely held belief that KS is an infectious disease, its etiology has remained elusive. Recently, we and others have reported the selective expansion of V beta 2+ T cells in the peripheral blood of most patients in the acute, but not in the convalescent, phase of KS. These data were consistent with the concept that this illness is triggered by a bacterial superantigen. We report here that a patient who died of acute KS had selective expansion of V beta 2+ T cells in her myocardium and coronary artery. Sequence analysis of TCR beta-chain genes of V beta 2+ T cells from the myocardium showed extensive junctional region diversity. These observations, along with the demonstration of V beta 2 expansion in both the CD4+ and CD8+ T cell subsets, support the concept that the activation of infiltrating V beta 2+ T cells are involved in the cardiovascular damage associated with KS.


Contribution of BCR-ABL molecular variants and leukemic stem cells in response and resistance to tyrosine kinase inhibitors: a review.
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm generated by reciprocal chromosomal translocation, t (9; 22) (q34; q11) in the transformed hematopoietic stem cell. Tyrosine kinase inhibitors (TKIs) target the mature proliferating BCR-ABL cells, the major CML driver, and increase overall and disease-free survival. However, mutant clones, pre-existing or due to therapy, develop resistance against TKIs. BCR-ABL1 oncoprotein activates various molecular pathways including the RAS/RAF/MEK/ERK pathway, JAK2/STAT pathway, and PI3K/AKT/mTOR pathway. Stimulation of these pathways in TKI resistant CML patients, make them a new target. Moreover, a small proportion of CML cells, leukemic stem cells (LSCs), persist during the TKI therapy and sustain the disease in the patient. Engraftment of LSCs in the bone marrow niche and dysregulation of miRNA participate greatly in the TKI resistance. Current efforts are needed for determining the reason behind TKI resistance, identification, and elimination of CML LSC might be of great need for cancer cure.


Releasing cohesin from chromosome arms in early mitosis: opposing actions of Wapl-Pds5 and Sgo1.
The cohesin complex establishes sister chromatid cohesion during S phase. In metazoan cells, most if not all cohesin dissociates from chromatin during mitotic prophase, leading to the formation of metaphase chromosomes with two cytologically discernible chromatids. This process, known as sister chromatid resolution, is believed to be a prerequisite for synchronous separation of sister chromatids in subsequent anaphase. To dissect this process at a mechanistic level, we set up an in vitro system. Sister chromatid resolution is severely impaired upon depletion of Wapl from Xenopus egg extracts. Exogenously added human Wapl can rescue these defects and, remarkably, it can do so in a very short time window of early mitosis. A similar set of observations is made for Pds5, a factor implicated previously in the stabilization of interphase cohesion. Characteristic amino acid motifs (the FGF motifs) in Wapl coordinate its physical and functional interactions with Pds5 and cohesin subunits. We propose that Wapl and Pds5 directly modulate conformational changes of cohesin to make it competent for dissociation from chromatin during prophase. Evidence is also presented that Sgo1 plays a hitherto underappreciated role in stabilizing cohesin along chromosome arms, which is antagonized by the mitotic kinases polo-like kinsase (Plk1) and aurora B.


Total synthesis of (+)-sarain A.
This article describes the details of our synthetic studies toward the complex marine alkaloid sarain A. Various strategies were conceived, setbacks encountered, and solutions developed, ultimately leading to a successful enantioselective total synthesis. Our route to (+)-sarain A features a number of key steps, including an asymmetric Michael addition to install the C4'-C3'-C7' stereotriad, an enoxysilane-N-sulfonyliminium ion cyclization to set the C3 quaternary carbon stereocenter, and assemble the diazatricycloundecane core, a ring-closing metathesis to construct the 13-membered ring, an intramolecular Stille coupling to fashion the unsaturated 14-membered macrocycle, and a late-stage installation of the tertiary amine-aldehyde proximity interaction.


Efficacy of allogeneic cord blood platelet gel on wounds of dystrophic epidermolysis bullosa patients after pseudosyndactyly surgery.
Epidermolysis bullosa (EB) is a rare genetic disorder characterized by the formation of blisters and wounds in skin and mucous membranes; it is classified into four types and has various methods of treatment. Management of previous wounds and prevention of formation of new lesions are the most important strategies in the course of therapy to improve patient's quality of life; lack of wound management can lead to further complications such as infection. The current study investigated the therapeutic effects of allogeneic platelet gel (prepared from umbilical cord blood) in a group of children diagnosed with dystrophic epidermolysis bullosa (DEB) eligible for surgical correction of pseudosyndactyly in the hand. The post-surgical clinical outcome in this group was compared with the clinical outcomes of DEB patients receiving the standard treatment (paraffin gauze wound dressing and topical antibiotics) after corrective surgery. The current study results showed an increase in the rate of recovery and promotion of tissue granulation, complete wound healing, and a decrease in pain level and treatment period. The application of cord blood platelet gel topical dressing was not a conventional method of treatment in patients with DEB wounds and blisters. However, the current study results demonstrated that this gel dressing could effectively accelerate epithelialization and healing of the wounds and decrease patients' pain and post-surgical recovery period, which altogether leads to improvements in patients' overall quality of life.


Nucleolin, a novel partner for the Myb transcription factor family that regulates their activity.
To unravel the mechanisms of action of transcriptional regulation by the Myb family of transcription factors, we have set out to isolate their protein partners. We identify nucleolin as one of the nuclear polypeptides that interact specifically with the A-Myb and c-Myb, but not B-Myb DNA-binding domains. We show unambiguously that this interaction is direct and takes place in vivo, as demonstrated by co-immunoprecipitation of the endogenously and exogenously expressed proteins. The minimal DNA-binding domain containing only the R2R3 c-Myb repeats is sufficient for nucleolin binding. Computer analysis of the R2R3 three-dimensional structure, as well as extensive mutational analysis within this region, reveals that the Arg(161) residue, present in c-Myb and A-Myb, but not B-Myb, is crucial for this interaction. We show that the interaction of nucleolin with Myb is functional because co-transfection of nucleolin down-regulates Myb transcriptional activity. Nucleolin is a multifunctional phosphoprotein present in both nucleoplasm and more abundantly in the nucleolus and shows helicase and chromatin decondensing activities. This is the first demonstration of nucleolin binding to a transcription factor.


Left ventricular longitudinal strain in patients with type 2 diabetes mellitus is independently associated with glycated hemoglobin level.
Left ventricular and left atrial strain are sensitive and reliable markers for evaluating cardiac function in patients with type 2 diabetes mellitus (T2DM), with interactions between the two parameters. The present study aimed to analyze the correlation between global longitudinal strain (GLS) of the left ventricle and glycated hemoglobin (HbA1c) levels in patients with T2DM. A total of 292 patients clinically diagnosed with T2DM were selected and divided into three groups according to HbA1c level. The strains of the left atrium and left ventricle in the three groups of T2DM patients with different HbA1c levels were compared. Univariate and multivariate (including left atrial functional indicators) linear regression analyses were performed to assess the relationship between strain indicators and HbA1c levels. Generalized additive models were used to examine the relationship between strain indicators and HbA1c levels. There were significant differences among the three groups in terms of age, microalbuminuria, total cholesterol, fasting blood glucose, postprandial blood glucose, and HbA1c level, and left atrial conduit longitudinal strain (LAScd) and GLS (p < .05). Univariate and multivariate linear regression analyses revealed that, as HbA1c levels increased, the absolute value of GLS gradually decreased (p < .001). Curve fitting revealed a positive correlation between HbA1c level and GLS, which was not affected by left atrial function. Left ventricular GLS was independently correlated with HbA1c level in patients with T2DM and was not affected by left atrial function.


Management of benign skull base meningiomas: a review.
The optimal management of benign meningiomas of the skull base is reviewed. Elderly patients with small, asymptomatic tumors can be observed and treatment can be initiated if and when progression occurs. Patients with tumors that appear to be amenable to complete resection with an acceptable rate of morbidity are optimally treated with surgery. Decompression of more extensive tumors through conservative subtotal resection and preservation of the involved cranial nerves may result in improved neurological function. Either alone or after subtotal resection, radiosurgery is indicated for tumors that can be treated adequately with this modality. Larger, ill-defined tumors and those that abut radiosensitive structures such as the optic nerve(s) are optimally treated with radiotherapy. Extensive subtotal resections that sacrifice one or more cranial nerves are no more likely to enhance the probability of success of subsequent radiotherapy than more conservative procedures.


Characteristics of COPD smokers and effectiveness and safety of smoking cessation medications.
Smoking is the main cause of chronic obstructive pulmonary disease (COPD), and smoking cessation is the only treatment shown to be effective in arresting the progression of COPD. Different epidemiological and population-based studies have shown smokers with COPD to have specific smoking characteristics that differentiate them from the rest of smokers and which complicate smoking cessation. The main objective of this study is to analyze the effectiveness and safety of drug treatments for smoking cessation in smokers with severe or very severe COPD. Smokers with severe or very severe COPD (Global Initiative for Chronic Obstructive Lung Disease stages III and IV) received treatment for smoking cessation. The treatment program consisted of a combination of behavioral therapy and drug treatment. Patients were followed up at 1, 2, 4, 6, 8, 10, 12, 18, and 24 weeks after the quit date. Four hundred seventy-two patients were seen, 65% were male, and their mean age was 58.3 (9.8). They smoked an average of 29.7 (13.4) cigarettes/day, and their mean Fagerström test for nicotine dependence score was 7.4 (2.1). Continuous abstinence rate from 9 to 24 weeks (CAR 9-24) was 48.5%. According to type of treatment used, CAR 9-24 for nicotine replacement therapy (NRT), bupropion, and varenicline were 38.2%, 55.6%, and 58.3%, respectively. Varenicline was more effective than nicotine patches: 61% versus 44.1% (odds ratio: 1.98; 95% CI: 1.25-3.12; p = .003). NRT was the treatment producing the fewest adverse effects. The onset of psychiatric symptoms due to medication was rare and evenly distributed across groups. This study shows that smokers with severe or very severe COPD are predominantly males with a high degree of physical dependence upon nicotine. CAR 9-24 was 48.5%. Varenicline and bupropion yielded higher abstinence rates than NRT. Varenicline was more effective than nicotine patches: all types of treatments were safe.


Accelerating bioactive peptide discovery via mutual information-based meta-learning.
Recently, machine learning methods have been developed to identify various peptide bio-activities. However, due to the lack of experimentally validated peptides, machine learning methods cannot provide a sufficiently trained model, easily resulting in poor generalizability. Furthermore, there is no generic computational framework to predict the bioactivities of different peptides. Thus, a natural question is whether we can use limited samples to build an effective predictive model for different kinds of peptides. To address this question, we propose Mutual Information Maximization Meta-Learning (MIMML), a novel meta-learning-based predictive model for bioactive peptide discovery. Using few samples from various functional peptides, MIMML can sufficiently learn the discriminative information amongst various functions and characterize functional differences. Experimental results show excellent performance of MIMML though using far fewer training samples as compared to the state-of-the-art methods. We also decipher the latent relationships among different kinds of functions to understand what meta-model learned to improve a specific task. In summary, this study is a pioneering work in the field of functional peptide mining and provides the first-of-its-kind solution for few-sample learning problems in biological sequence analysis, accelerating the new functional peptide discovery. The source codes and datasets are available on https://github.com/TearsWaiting/MIMML.


Electrospun α-Lactalbumin Nanofibers for Site-Specific and Fast-Onset Delivery of Nicotine in the Oral Cavity: An In Vitro, Ex Vivo, and Tissue Spatial Distribution Study.
Nicotine replacement therapy (NRT) formulations for oromucosal administration induce a delayed rise in nicotine blood levels as opposed to the immediate nicotine increase obtained from cigarette smoking, this being a shortcoming of the therapy. Here, we demonstrate that α-lactalbumin/polyethylene oxide (ALA/PEO) electrospun nanofibers constitute an efficient oromucosal delivery system for fast-onset nicotine delivery of high relevance for acute dosing NRT applications. In vitro, nicotine-loaded nanofibers showed fast disintegration in water, with a weight loss up to 40% within minutes, and a faster nicotine release (26.1 ± 4.6% after 1 min of incubation) of the loaded nicotine compared to two relevant marketed NRT formulations with a comparable nicotine dose (i.e., 7.9 ± 5.1 and 2.2 ± 0.3% nicotine was released from a lozenge and a sublingual tablet, respectively). Model-fitting of the release data indicated that the release mechanism of nicotine from the hydrophilic nanofibers was possibly governed by more than one type of release phenomena. Remarkably, ex vivo studies using porcine buccal mucosa demonstrated a more efficient permeation of the nicotine released from the nanofibers [flux of 1.06 ± 0.22 nmol/(cm2·min)] compared to when dosing even a ten-fold concentrated nicotine solution [flux of 0.17 ± 0.14 nmol/(cm2·min)]. Moreover, matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI MS) imaging of ex vivo porcine buccal mucosa exposed to nicotine-loaded nanofibers clearly revealed higher amounts of nicotine throughout the epithelium, as well as in the lamina propria and submucosa of the tissue. Our findings suggest that nicotine-loaded ALA/PEO nanofibers have potential as a mucosal, fast-releasing, and biocompatible delivery system for nicotine, which can overcome the limitations of the currently marketed NRTs.


Plant secondary metabolites in cancer chemotherapy: where are we?
Nowadays we have a number of chemical and biological agents at our disposal to treat chronic pathologies such as cancer. Although most drugs display significant activity, thus improving the clinical outcome, side-effects and emergence of resistances cannot be looked down. From an historical point of view, higher plants have been very important in the search of new therapeutic agents and they were in the origin of the first medicines used in human health. The contribute of plants to treat pathologies such as cancer is far from being over, mainly due to the high number of new drugs that are currently being evaluated in clinical trials. Metabolomics-based studies have rendered several new chemical entities, some of them with remarkable complex chemistry, which sometimes results in novel mechanisms of action, higher potency and lower toxicity. In this review, we will focus the most important plant-derived classes of compounds in clinical use, as well as those currently in clinical trials, with special focus on vinca alkaloids, taxanes, combretastatins, podophylotoxins and camptothecins. The molecular mechanism of action and spectrum of activity will also be discussed.


In Silico Exploration of Phytoconstituents From Phyllanthus emblica and Aegle marmelos as Potential Therapeutics Against SARS-CoV-2 RdRp.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) worldwide has increased the importance of computational tools to design a drug or vaccine in reduced time with minimum risk. Earlier studies have emphasized the important role of RNA-dependent RNA polymerase (RdRp) in SARS-CoV-2 replication as a potential drug target. In our study, comprehensive computational approaches were applied to identify potential compounds targeting RdRp of SARS-CoV-2. To study the binding affinity and stability of the phytocompounds from Phyllanthus emblica and Aegel marmelos within the defined binding site of SARS-CoV-2 RdRp, they were subjected to molecular docking, 100 ns molecular dynamics (MD) simulation followed by post-simulation analysis. Furthermore, to assess the importance of features involved in the strong binding affinity, molecular field-based similarity analysis was performed. Based on comparative molecular docking and simulation studies of the selected phytocompounds with SARS-CoV-2 RdRp revealed that EBDGp possesses a stronger binding affinity (-23.32 kcal/mol) and stability than other phytocompounds and reference compound, Remdesivir (-19.36 kcal/mol). Molecular field-based similarity profiling has supported our study in the validation of the importance of the presence of hydroxyl groups in EBDGp, involved in increasing its binding affinity toward SARS-CoV-2 RdRp. Molecular docking and dynamic simulation results confirmed that EBDGp has better inhibitory potential than Remdesivir and can be an effective novel drug for SARS-CoV-2 RdRp. Furthermore, binding free energy calculations confirmed the higher stability of the SARS-CoV-2 RdRp-EBDGp complex. These results suggest that the EBDGp compound may emerge as a promising drug against SARS-CoV-2 and hence requires further experimental validation.


Assessment of mycoviral diversity in Pakistani fungal isolates revealed infection by 11 novel viruses of a single strain of Fusarium mangiferae isolate SP1.
An extensive screening survey was conducted on Pakistani filamentous fungal isolates for the identification of viral infections. A total of 396 fungal samples were screened, of which 36 isolates were found double-stranded (ds) RNA positive with an overall frequency of 9% when analysed by a classical dsRNA isolation method. One of 36 dsRNA-positive strains, strain SP1 of a plant pathogenic fungus Fusarium mangiferae, was subjected to virome analysis. Next-generation sequencing and subsequent completion of the entire genome sequencing by a classical Sanger sequencing method showed the SP1 strain to be co-infected by 11 distinct viruses, at least seven of which should be described as new taxa at the species level according to the ICTV (International Committee on Taxonomy of Viruses) species demarcation criteria. The newly identified F. mangiferae viruses (FmVs) include two partitivirids, one betapartitivirus (FmPV1) and one gammapartitivirus (FmPV2); six mitovirids, three unuamitovirus (FmMV2, FmMV4, FmMV6), one duamitovirus (FmMV5), and two unclassified mitovirids (FmMV1, FmMV3); and three botourmiavirids, two magoulivirus (FmBOV1, FmBOV3) and one scleroulivirus (FmBOV2). The number of coinfecting viruses is among the largest ones of fungal coinfections. Their molecular features are thoroughly described here. This represents the first large virus survey in the Indian sub-continent.


Molecular basis of myosin assembly: coiled-coil interactions and the role of charge periodicities.
Complementation of alternating zones of positive and negative charge in the myosin rod enables molecules to interact in a number of ways. This accounts for the complexity of the molecular organisation of thick filaments. However, directed mutagenesis of expressed LMM cDNA indicated that charge zone complementation is not a major driving force in myosin polymerisation. Instead, it probably serves to prevent unfavourable interaction geometries.


Aortic dissection induced by vascular endothelial growth factor inhibitors.
Vascular endothelial growth factor (VEGF) contributes to angiogenesis and vasculogenesis. The occurrence and progression of tumors are accompanied by angiogenesis. Vascular endothelial growth factor inhibitors (VEGFI) have been used in anti-tumor treatment. However, aortic dissection (AD) is one of the VEGFI-associated adverse reactions with cute onset, rapid progression, and high case fatality rate. We collected case reports of VEGFI related to aortic dissection in PubMed and CNKI (China National Knowledge Infrastructure) from inception to 28 April 2022. Seventeen case reports were selected. The medication included sunitinib, sorafenib, pazopanib, axitinib, apatinib, anlotinib, bevacizumab, and ramucirumab. This review discusses the pathology, risk factors, diagnosis, and treatment of AD. Vascular endothelial growth factor inhibitors are related to aortic dissection. Although current literature lacks clear statistical evidence on the population, we offer points to encourage further confirmation of the best methods of care for these patients.


[Progress of studies on molecular immunology of human platelets].
In autoimmune thrombocytopenic purpura (AITP) specific autoantibodies bind platelet GP via their Fab fragments. Both splenic CD5+ B and CD5- B cells produce platelet glycoprotein-specific antibodies. There is limited number of antigenic determinants, and the GP-specific autoantibodies are derived from a restricted number of B-cell clones in chronic AITP. Blocking co-stimulatory signals could induce platelet-specific T cell anergy. MMF could be used as a second line agent for the treatment of steroid-resistant AITP. Detection of plasma thrombopoietin levels play an important role in the differentiation of thrombocytopenic states caused by platelet destruction or due to bone marrow hypoplasia. Endogenous TPO level is also important on the differential diagnosis of ET and RT. Quinine- or heparin-dependent antibodies could induce thrombocytopenia. PCR-SSP is useful for the genotyping of the platelet-specific alloantigen HPA. Biotinylated platelets have an impaired response to agonists as evidenced by in vitro platelet aggregation tests.


Inhibition of intestinal tumorigenesis in Apcmin/+ mice by (-)-epigallocatechin-3-gallate, the major catechin in green tea.
The present study was designed to investigate the effects of two main constituents of green tea, (-)-epigallocatechin-3-gallate (EGCG) and caffeine, on intestinal tumorigenesis in Apc(min/+) mice, a recognized mouse model for human intestinal cancer, and to elucidate possible mechanisms involved in the inhibitory action of the active constituent. We found that p.o. administration of EGCG at doses of 0.08% or 0.16% in drinking fluid significantly decreased small intestinal tumor formation by 37% or 47%, respectively, whereas caffeine at a dose of 0.044% in drinking fluid had no inhibitory activity against intestinal tumorigenesis. In another experiment, small intestinal tumorigenesis was inhibited in a dose-dependent manner by p.o. administration of EGCG in a dose range of 0.02% to 0.32%. P.o. administration of EGCG resulted in increased levels of E-cadherin and decreased levels of nuclear beta-catenin, c-Myc, phospho-Akt, and phospho-extracellular signal-regulated kinase 1/2 (ERK1/2) in small intestinal tumors. Treatment of HT29 human colon cancer cells with EGCG (12.5 or 20 micromol/L at different times) also increased protein levels of E-cadherin by 27% to 58%, induced the translocation of beta-catenin from nucleus to cytoplasm and plasma membrane, and decreased c-Myc and cyclin D1 (20 micromol/L EGCG for 24 hours). These results indicate that EGCG effectively inhibited intestinal tumorigenesis in Apc(min/+) mice, possibly through the attenuation of the carcinogenic events, which include aberrant nuclear beta-catenin and activated Akt and ERK signaling.


Schwann cells revert to non-myelinating phenotypes in the deafened rat cochlea.
Loss of sensory hair cells within the cochlea results in a permanent sensorineural hearing loss and initiates the gradual degeneration of spiral ganglion neurons (SGNs) - the primary afferent neurons of the cochlea. While these neurons are normally myelinated via Schwann cells, loss of myelin occurs as a precursor to neural degeneration. However, the relationship between demyelination and the status of Schwann cells in deafness is not well understood. We used a marker of peripheral myelin (myelin protein zero; P0) and a marker of Schwann cells (S100) to determine the temporal sequence of myelin and Schwann cell loss as a function of duration of deafness. Rat pups were systemically deafened for periods ranging from 2 weeks to greater than 6 months by co-administration of frusemide and gentamicin. Cochleae were cryosectioned and quantitative immunohistochemistry used to determine the extent of P0 and S100 labelling within the peripheral processes, SGN soma and their central processes within the modiolus. SGN density was also determined for each cochlear turn. P0 labelling decreased throughout the cochlea with increasing duration of deafness. The reduction in P0 labelling occurred at a faster rate than the SGN loss. In contrast, S100 labelling was not significantly reduced compared with age-matched controls in any cochlear region until 6 months post-deafening. These results suggest that Schwann cells may revert to non-myelinating phenotypes in response to deafness and exhibit greater survival traits than SGNs. The potential clinical significance of these findings for cochlear implants is discussed.


Sentinel surveillance of imported dengue via travellers to Europe 2012 to 2014: TropNet data from the DengueTools Research Initiative.
We describe the epidemiological pattern and genetic characteristics of 242 acute dengue infections imported to Europe by returning travellers from 2012 to 2014. The overall geographical pattern of imported dengue (South-east Asia > Americas > western Pacific region > Africa) remained stable compared with 1999 to 2010. We isolated the majority of dengue virus genotypes and epidemic lineages causing outbreaks and epidemics in Asia, America and Africa during the study period. Travellers acted as sentinels for four unusual dengue outbreaks (Madeira, 2012-13; Luanda, 2013; Dar es Salaam, 2014; Tokyo, 2014). We were able to characterise dengue viruses imported from regions where currently no virological surveillance data are available. Up to 36% of travellers infected with dengue while travelling returned during the acute phase of the infection (up to 7 days after symptom onset) or became symptomatic after returning to Europe, and 58% of the patients with acute dengue infection were viraemic when seeking medical care. Epidemiological and virological data from dengue-infected international travellers can add an important layer to global surveillance efforts. A considerable number of dengue-infected travellers are viraemic after arrival back home, which poses a risk for dengue introduction and autochthonous transmission in European regions where suitable mosquito vectors are prevalent.


Ultrafast photodissociation dynamics of 2-ethylpyrrole: adding insight to experiment with ab initio multiple cloning.
The ultrafast photodissociation dynamics of 2-ethylpyrrole (2-EP) is simulated in a fully quantum manner on the S1 and S2 πσ* states by the ab initio multiple cloning (AIMC) method. AIMC treats electrons with accurate electronic structure methods "on the fly", and nuclear dynamics with wavefunction propagation via a basis set of Ehrenfest trajectory guided Gaussian wavepackets. Total kinetic energy release (TKER) spectra are produced, as well as velocity map images and N-H dissociation times. These are compared to results from time-resolved velocity map imaging studies, and the AIMC method is able to provide quantitative reproduction of experimental data, including dissociation times of 50-80 fs. Novel insight into the dissociation mechanism is then obtained, with the experimentally obtained time constant shown to be composed of two components. Firstly, there is a contribution in <50 fs from 2-EP molecules that have sufficient energy in the N-H stretch coordinate to dissociate almost immediately over the barrier, and this is followed by a second slower contribution from 2-EP molecules that must sample the potential energy surface before finding a way around the barrier to dissociate. This two component mechanism is not observed experimentally due to the temporal widths of the laser pulses obscuring the dynamics in the <50 fs window, and is shown for the first time via theory. Calculations are also performed on selectively deuterated 2-EP, demonstrating that AIMC is able to produce a kinetic isotope effect for the dissociation time constant, and correctly predict a shift to lower energy in the TKER spectrum. The S2 πσ* state is also shown to be unstable with respect to the S1 πσ* state, with the N-H dissociation proceeding along S1 when initially excited to S2. This work demonstrates that the combination of state of the art theory and experiments can provide unprecedented novel insight into the N-H dissociation mechanism, with the tantalising prospect of providing insight into more general heteroatom hydride bond dissociation.


Exploring Parental Incarceration, US Government Support Programs, and Child Health and Well-Being: A National Cross-Sectional Study.
To describe relationships between parental incarceration and child health and flourishing-a measure of curiosity, resilience, and self-regulation-and to identify government programs that moderate this relationship. Using the National Survey of Children's Health data from 2016 through 2019 for children 6-17 years old, we estimated associations with logistic regression between parental incarceration and overall health and flourishing, adjusting for child, caregiver, and household factors. We secondarily examined physical health (asthma, headaches), mental health (attention deficit disorder/attention deficit hyperactivity disorder, depression), developmental needs (learning disability, special educational plan use), and educational (missing ≥11 school days, repeated grade) outcomes. We performed interaction analyses to determine whether government program participation (eg, free/reduced lunch, cash assistance) moderated relationships between parental incarceration and child outcomes. Children with parental incarceration accounted for 9.3% of the sample (weighted n = 4 400 000). Black, American Indian/Alaska Native, and multiracial children disproportionately experienced parental incarceration. Parental incarceration was associated with worse health (aOR, 1.31; 95% CI, 1.11-1.55) and higher odds of not flourishing (aOR, 1.66; 95% CI, 1.46-1.89). Physical health, mental health, developmental issues, and educational needs were also associated with parental incarceration. Participation in free and reduced lunch moderated the relationships between parental incarceration and general health and flourishing, and cash assistance moderated the association between parental incarceration and flourishing. For each, parental incarceration had an attenuated association with health among people who participated in government programs. Parental incarceration is disproportionately experienced by Black and Indigenous children and associated with worse child health and well-being. Government support program participation may mitigate negative associations between parental incarceration and child outcomes.


Mucolipidosis Type III: A Rare Disease in Differential Diagnosis of Joint Stiffness in Pediatric Rheumatology.
Mucolipidoses are metabolic disorders with autosomal recessive inheritance caused by deficiency of N-acetylglucosamine- 1-phosphotransferase leading to accumulation of glycosaminoglycans and sphingolipids intracellularly. The differential diagnosis of mucolipidosis II or III is based on the age of onset, clinical findings and degree of severity. In this article, we present four pediatric patients with mucolipidosis III or pseudo-Hurler polydystrophy who admitted to our hospital with joint stiffness. They were from consanguineous families with characteristic radiographic findings. The joints were painless and the rheumatologic evaluation and inflammation markers were negative. Mucolipidosis is a rare disease in pediatric patients to remember in differential diagnosis of joint stiffness.


Optimal birth weight percentile cut-offs in defining small- or large-for-gestational-age.
It remains questionable what birth weight for gestational age percentile cut-offs should be used in defining clinically important poor or excessive foetal growth. We aimed to evaluate the optimal birth weight percentile cut-offs for defining small- or large-for-gestational-age (SGA or LGA). In a birth cohort-based analysis of 17 979 120 non-malformation singleton live births, U.S. 1995-2001, we assessed the optimal birth weight percentile cut-offs for defining SGA and LGA. The 25th-75th percentile group served as the reference. Primary outcomes are the risk ratios (RR) of neonatal death and low 5-min Apgar score (<4) comparing SGA or LGA versus the reference group. More than 2-fold risk elevations were considered clinically significant. The 15th birth weight cut-off already identified SGA infants at more than 2-fold risk of neonatal death at pre-term, term or post-term, except for extremely pre-term births <28 weeks (continuous risk reductions over increasing birth weight percentiles). LGA was associated with a reduced risk of low 5-min Apgar score at pre-term, but an elevated risk at term and post-term. The 97th cut-off identified LGA infants at 2-fold risk of low 5-min Apgar at term. The commonly used 10th and 90th birth weight percentile cut-offs for defining SGA and LGA respectively seem largely arbitrary. The 15th and 97th percentiles may be the optimal cut-offs to define SGA and LGA respectively.


Organocalcium-mediated nucleophilic alkylation of benzene.
The electrophilic aromatic substitution of a C-H bond of benzene is one of the archetypal transformations of organic chemistry. In contrast, the electron-rich π-system of benzene is highly resistant to reactions with electron-rich and negatively charged organic nucleophiles. Here, we report that this previously insurmountable electronic repulsion may be overcome through the use of sufficiently potent organocalcium nucleophiles. Calcium n-alkyl derivatives-synthesized by reaction of ethene, but-1-ene, and hex-1-ene with a dimeric calcium hydride-react with protio and deutero benzene at 60°C through nucleophilic substitution of an aromatic C-D/H bond. These reactions produce the n-alkyl benzenes with regeneration of the calcium hydride. Density functional theory calculations implicate an unstabilized Meisenheimer complex in the C-H activation transition state.


Reference-free and cost-effective automated cell type annotation with GPT-4 in single-cell RNA-seq analysis.
Cell type annotation is an essential step in single-cell RNA-seq analysis. However, it is a time-consuming process that often requires expertise in collecting canonical marker genes and manually annotating cell types. Automated cell type annotation methods typically require the acquisition of high-quality reference datasets and the development of additional pipelines. We demonstrate that GPT-4, a highly potent large language model, can automatically and accurately annotate cell types by utilizing marker gene information generated from standard single-cell RNA-seq analysis pipelines. Evaluated across hundreds of tissue types and cell types, GPT-4 generates cell type annotations exhibiting strong concordance with manual annotations, and has the potential to considerably reduce the effort and expertise needed in cell type annotation.


Efficacy of treatment of trochanteric bursitis: a systematic review.
Trochanteric bursitis (TB) is a self-limiting disorder in the majority of patients and typically responds to conservative measures. However, multiple courses of nonoperative treatment or surgical intervention may be necessary in refractory cases. The purpose of this systematic review was to evaluate the efficacy of the treatment of TB. A literature search in the PubMed, MEDLINE, CINAHL, and ISI Web of Knowledge databases was performed for all English language studies up to April 2010. Terms combined in a Boolean search were greater trochanteric pain syndrome, trochanteric bursitis, trochanteric, bursitis, surgery, therapy, drug therapy, physical therapy, rehabilitation, injection, Z-plasty, Z-lengthening, aspiration, bursectomy, bursoscopy, osteotomy, and tendon repair. All studies directly involving the treatment of TB were reviewed by 2 authors and selected for further analysis. Expert opinion and review articles were excluded, as well as case series with fewer than 5 patients. Twenty-four articles were identified. According to the system described by Wright et al, 2 studies, each with multiple arms, qualified as level I evidence, 1 as level II, 1 as level III, and the rest as level IV. More than 950 cases were included. The authors extracted data regarding the type of intervention, level of evidence, mean age of patients, patient gender, number of hips in the study, symptom duration before the study, mean number of injections before the study, prior hip surgeries, patient satisfaction, length of follow-up, baseline scores, and follow-up scores for the visual analog scale (VAS) and Harris Hip Scores (HHS). Symptom resolution and the ability to return to activity ranged from 49% to 100% with corticosteroid injection as the primary treatment modality with and without multimodal conservative therapy. Two comparative studies (levels II and III) found low-energy shock-wave therapy (SWT) to be superior to other nonoperative modalities. Multiple surgical options for persistent TB have been reported, including bursectomy (n = 2), longitudinal release of the iliotibial band (n = 2), proximal or distal Z-plasty (n = 4), osteotomy (n = 1), and repair of gluteus medius tears (n = 4). Efficacy among surgical techniques varied depending on the clinical outcome measure, but all were superior to corticosteroid therapy and physical therapy according to the VAS and HHS in both comparison studies and between studies. This systematic review found that traditional nonoperative treatment helped most patients, SWT was a good alternative, and surgery was effective in refractory cases.


Fates and spatial variations of accumulation mode particles in a multi-zone indoor environment during the HOMEChem campaign.
Studying the indoor dynamics that impact particles is crucial in order to understand indoor air chemistry and assess overall human exposure to particles. This work investigates spatial gradients in particle concentration, caused by indoor transport and loss mechanisms. We conducted a variety of cooking experiments during the House Observations of Microbial and Environmental Chemistry (HOMEChem) campaign in June 2018 that allowed us to probe these mechanisms. We measured size-resolved (0.06-1 μm and 0.13-3 μm) particle number concentrations from cooking experiments using optical instruments at four locations throughout the house simultaneously. The particle number concentration in the kitchen was 40 ± 10% and 70 ± 10% higher than the concentrations in the living room and the bedroom, respectively. There was a minor size dependence, with larger differences in the smaller sizes of the accumulation mode (0.1-2.5 μm) than the larger end of the range. Dilution accounts for the majority of these concentration differences. Surface deposition was the dominant fate of particles within a zone, with observed deposition velocities ranging from 0.1 to 0.6 m h-1.


Not traditional prognostic factors in human conventional renal carcinoma.
The evaluation of know prognostic factors is an essential step of the assessment of the patients affected by primary renal carcinoma. As long as the major biological mechanisms of renal carcinomas remain unknown, it will be impossible to achieve an accurate prognostic judgement. The TNM classification has always been the main source of information. Nevertheless, recently several investigations evaluated the prognostic power of serum and cellular markers. The aim of this study is to identify those markers which show statistical reliability and can be used in the clinical practice. A literature search was performed on MEDLINE to identify potential not traditional prognostic factors for patients with renal cell carcinoma edited from January 1997 through April 2000 using prognosis and clear cell carcinoma and kidney as keywords. We considered also articles cited in references of first selected manuscript. The analysis of serum and cellular prognostic markers does not allow the identification of specific factors, reliable, independent, easy to dose, widely useful and whose informations are repeatable. Currently classical prognostic factors (staging, grading, hystologic type, patient clinical conditions, anaemia, presentation modalities, etc.) represent the only useful elements after surgical time in RCC patients. Among serum prognostic factors, CRP and ferritin play a crucial role. These proteins appear ideal in monitoring the disease over time, due to simple test execution and specimens repeatability. Among RCC molecular markers, proliferation index result promising for their reliability and reproducibility, the easy dosage and high series number tested. Literature data suggest that the ideal marker for renal carcinomas has not been identified yet. However, C-reactive protein, ferritin and the proliferative activity indexes (Ki67 and AgNOR) appear to be, at present, the best prognostic tools. To confirm obtained results and to use biomolecolar markers on a routinary base further studies on wide surgical series will be required. The improvement of technical tool and costs reduction represent also a necessary step toward the identification of efficient prognostic markers in RCC.


[Laparoscopy in the non-palpable testicles. Is it always necessary?].
In order to know the role of diagnostic laparoscopy with non palpable testicles (NPT), 15 children with 16 NPT were studied. Middle age was 7 years (R: 2-12). The surgical procedure was: laparoscopy initially and open inguinal surgery (OIS) after that. Six NPT were discovered with laparoscopy (37.5%). With OIS inguinal hernia was present in 4 cases, with testicle into the inguinal sac in 3 cases; 12 cases had not inguinal hernia, and 6 of them showed spermatic vessel and vas deferent without testicle. Orquidopexy of the 6 located testicles and testicular prothesis implantation in the other 10 cases, were performed. Finding of laparoscopy and OIS were perfectly correlated. Laparoscopy made the diagnosis in 7 cases, which the OIS would have been unable to do it (43.7%). In the other 9 cases, the OIS would have been diagnostic enough (56.2%) without laparoscopy. For those results, the authors prefer to begin the surgical procedure with OIS and if the spermatic vessels are no located, then the laparoscopy is done under the same anesthesia.


Genetic structure of age classes in Camellia japonica (Theaceae).
Camellia japonica L. (Theaceae), an insect- and bird-pollinated, broad-leaved evergreen tree, is widely distributed in Japan and the southern Korean peninsula. The species has a relatively even age distribution within populations, which may influence the spatial genetic structure of different age classes relative to species with typical L-shaped age distributions. To determine whether the internal spatial genetic structure found in seedlings and young individuals carries over into adults, we used allozyme loci, F-statistics, spatial autocorrelation statistics (Moran's I), and coancestry measures to examine changes in genetic structure among seven age classes in a population (60-m x 100-m area) in southern Korea. In seedlings, weak but significant positive values of Moran's I-statistics and coancestry measures were found for distances less than 14 m, which is consistent with a mechanism of limited seed dispersal combined with overlapping seed shadows. This spatial structure, however, dissipates in older age classes, and in adults genetic variation has an essentially random spatial distribution. Morisita's index of dispersion of individuals in each age class showed that seedlings and juveniles are more highly clustered than are older individuals. These results suggest that self-thinning changes the spatial relationships of individuals, and thus genotypes. A multilocus estimate of FST (0.008) shows a small but statistically significant difference in allele frequencies among age classes. In summary, intrapopulation genetic structure within and among age classes of C. japonica was significant but weak. Despite presumably limited seed dispersal, weak spatial genetic structure in juveniles suggests overlapping seed shadows followed by self-thinning during recruitment. The present study also demonstrates that studies of spatial genetic structure focusing on limited numbers of generations may not be sufficient to reveal the entire picture of genetic structure in populations with overlapping generations.


High levels of tobacco-specific N-nitrosamines and nicotine in Chaini Khaini, a product marketed as snus.
Recently, a tobacco product, Chaini Khaini, identified as snus appeared in India. The product marketing emphasises its discreet nature and explicitly claims safety by referring to the existing evidence on Swedish snus. We analysed tobacco-specific nitrosamines and nicotine in 12 samples of Chaini Khaini purchased in 2013 at open markets in India. Samples were purchased twice: in March 2013 from Mumbai and in November 2013 from Mumbai and Ahmedabad. Chemical constituents were measured by our routine validated methods. Levels of carcinogenic nitrosamines NNN, NNK and NNAL averaged 22.9 (±4.9), 2.6 (±1.0) and 3.1 (±1.5) µg/g tobacco (wet weight), respectively. The levels of NAB, which is normally present in trace levels in tobacco products, ranged from 3.9 to 12.9 µg/g tobacco. Total nicotine levels in all samples averaged 10.0 mg/g tobacco and unprotonated nicotine accounted for an average 95.4% of the total nicotine content. Chaini Khaini, which is labelled as snus and is marketed as a safe alternative to other tobacco products contains very high levels of carcinogenic nitrosamines and biologically available nicotine. Interventions are urgently needed to educate current and potential consumers of this product.


Psychometric properties of the Fear-Avoidance Beliefs Questionnaire and Tampa Scale of Kinesiophobia in patients with neck pain.
To examine selected psychometric properties of these instruments in a cohort of patients with mechanical neck pain. Cohort design of 78 subjects completing self-report measures of pain, disability, and the Fear-Avoidance Beliefs Questionnaire Work (FABQW) and Physical Activity (FABQPA) subscales, as well as the Tampa Scale of Kinesiophobia (TSK) at baseline and a 2-day follow-up. Intraclass correlation coefficients were used to calculate test-retest reliability, and Cronbach's alpha was used to calculate internal consistency. Concurrent validity was analyzed between the FABQPA, FABQW, TSK, pain, and disability using Pearson correlation coefficients and hierarchical linear regression modeling. The FABQPA and FABQW subscales exhibited substantial test-retest reliability, whereas the TSK exhibited moderate reliability. Internal consistency was high for all measures. The FABQW subscale was the only measure that significantly contributed to the regression model for both pain and disability in this group of patients with neck pain. Whereas the reliability and internal consistency of all measures ranged between moderate and substantial, the results of this study suggest weaker relationships between measures of fear and avoidance beliefs and pain/disability among patients with mechanical neck pain than has been reported among patients with low-back pain.


A telephone-delivered intervention for patients with NIDDM. Effect on coronary risk factors.
To examine whether a telephone-delivered intervention (TDI), designed to improve glycemic control in patients with non-insulin-dependent diabetes mellitus (NIDDM), improved coronary risk factors in high-risk patients. This randomized controlled trial involved 275 veterans with NIDDM followed in a general medical clinic. Intervention (TDI) patients were telephoned at least monthly by a nurse. Calls emphasized compliance with the medical regimen (diet, medications, and exercise), encouraged behavioral changes, and facilitated referrals to a dietitian or smoking cessation clinic. Control patients received no such calls. Baseline and 12-month follow-up measurements included fasting lipid profiles, weight, smoking status (self-reported; cessation verified by measurement of exhaled CO), adherence to diet and exercise (self-reported), appointments, and medications (hospital computerized data base). After 12 months, equal numbers of obese patients in the two groups reported adhering to a diabetic diet and exercising, although more obese TDI patients had seen a dietitian (30 vs. 7%, P = 0.003). Weight loss was not seen in either group (-0.9 +/- 5.3 vs. -0.1 +/- 3.6 kg, P = 0.202). Hyperlipidemic TDI patients were more likely to see a dietitian (31 vs. 6%, P = 0.003) and receive lipid-lowering medications (22 vs. 9%, P = 0.096), but serum cholesterol reduction was similar between groups (-11.7 +/- 33.4 vs. -4.3 +/- 32.7 mg/dl, P = 0.270); comparable results were seen for high-density lipoprotein, low-density lipoprotein, and triglyceride levels. More TDI group smokers reported quitting (26 vs. 0%, P = 0.033), but the difference was not significant for CO-verified abstention (10 vs. 0%, P = 0.231). The TDI improved self-reported adherence to regimens that might reduce coronary risk, but had little effect on objective measures of risk.


Multifocal Clinical Performance Improvement Across 21 Hospitals.
Improving quality and safety across an entire healthcare system in multiple clinical areas within a short time frame is challenging. We describe our experience with improving inpatient quality and safety at Kaiser Permanente Northern California. The foundations of performance improvement are a "four-wheel drive" approach and a comprehensive driver diagram linking improvement goals to focal areas. By the end of 2011, substantial improvements occurred in hospital-acquired infections (central-line–associated bloodstream infections and Clostridium difficile infections); falls; hospital-acquired pressure ulcers; high-alert medication and surgical safety; sepsis care; critical care; and The Joint Commission core measures.


Light at night, clocks and health: from humans to wild organisms.
The increasing use of electric lights has modified the natural light environment dramatically, posing novel challenges to both humans and wildlife. Indeed, several biomedical studies have linked artificial light at night to the disruption of circadian rhythms, with important consequences for human health, such as the increasing occurrence of metabolic syndromes, cancer and reduced immunity. In wild animals, light pollution is associated with changes in circadian behaviour, reproduction and predator-prey interactions, but we know little about the underlying physiological mechanisms and whether wild species suffer the same health problems as humans. In order to fill this gap, we advocate the need for integrating ecological studies in the field, with chronobiological approaches to identify and characterize pathways that may link temporal disruption caused by light at night and potential health and fitness consequences.


Self-reinoculation with fecal flora changes microbiota density and composition leading to an altered bile-acid profile in the mouse small intestine.
The upper gastrointestinal tract plays a prominent role in human physiology as the primary site for enzymatic digestion and nutrient absorption, immune sampling, and drug uptake. Alterations to the small intestine microbiome have been implicated in various human diseases, such as non-alcoholic steatohepatitis and inflammatory bowel conditions. Yet, the physiological and functional roles of the small intestine microbiota in humans remain poorly characterized because of the complexities associated with its sampling. Rodent models are used extensively in microbiome research and enable the spatial, temporal, compositional, and functional interrogation of the gastrointestinal microbiota and its effects on the host physiology and disease phenotype. Classical, culture-based studies have documented that fecal microbial self-reinoculation (via coprophagy) affects the composition and abundance of microbes in the murine proximal gastrointestinal tract. This pervasive self-reinoculation behavior could be a particularly relevant study factor when investigating small intestine microbiota. Modern microbiome studies either do not take self-reinoculation into account, or assume that approaches such as single housing mice or housing on wire mesh floors eliminate it. These assumptions have not been rigorously tested with modern tools. Here, we used quantitative 16S rRNA gene amplicon sequencing, quantitative microbial functional gene content inference, and metabolomic analyses of bile acids to evaluate the effects of self-reinoculation on microbial loads, composition, and function in the murine upper gastrointestinal tract. In coprophagic mice, continuous self-exposure to the fecal flora had substantial quantitative and qualitative effects on the upper gastrointestinal microbiome. These differences in microbial abundance and community composition were associated with an altered profile of the small intestine bile acid pool, and, importantly, could not be inferred from analyzing large intestine or stool samples. Overall, the patterns observed in the small intestine of non-coprophagic mice (reduced total microbial load, low abundance of anaerobic microbiota, and bile acids predominantly in the conjugated form) resemble those typically seen in the human small intestine. Future studies need to take self-reinoculation into account when using mouse models to evaluate gastrointestinal microbial colonization and function in relation to xenobiotic transformation and pharmacokinetics or in the context of physiological states and diseases linked to small intestine microbiome and to small intestine dysbiosis. Video abstract.


Health education and the municipal health network: practices of nutritionists.
Health education must be seen as an instrument used to promote quality of life. The objective of this study was to evaluate health education practices of nutritionists in a municipal health network. This is a qualitative study using Grounded Theory. Interviews and observation of educational activities were carried out. The use of materials was evaluated, together with attempts to engage the service users. Five analysis categories were applied. The intention of raising awareness and changing habits highlights the preference of professionals toward actions that are articulated and consistent with reality. Productivity valorization, insufficient training, and lack of physical structure were mentioned as restrictions. Most respondents did not evaluate results; they believe in sharing knowledge as a process that transforms reality; and defend the multidisciplinary approach and care by putting the concepts of integrality and equity into practice. The nutritionists' concepts of health education guide their professional performance, as they reflect the perspectives of the educational practices adopted.


Power Frequency Magnetic Fields Affect the p38 MAPK-Mediated Regulation of NB69 Cell Proliferation Implication of Free Radicals.
The proliferative response of the neuroblastoma line NB69 to a 100 µT, 50 Hz magnetic field (MF) has been shown mediated by activation of the MAPK-ERK1/2 pathway. This work investigates the MF effect on the cell cycle of NB69, the participation of p38 and c-Jun N-terminal (JNK) kinases in the field-induced proliferative response and the potential involvement of reactive oxygen species (ROS) in the activation of the MAPK-ERK1/2 and -p38 signaling pathways. NB69 cultures were exposed to the 100 µT MF, either intermittently for 24, 42 or 63 h, or continuously for periods of 15 to 120 min, in the presence or absence of p38 or JNK inhibitors: SB203580 and SP600125, respectively. Antioxidant N-acetylcysteine (NAC) was used as ROS scavenger. Field exposure induced transient activation of p38, JNK and ERK1/2. The MF proliferative effect, which was mediated by changes in the cell cycle, was blocked by the p38 inhibitor, but not by the JNK inhibitor. NAC blocked the field effects on cell proliferation and p38 activation, but not those on ERK1/2 activation. The MF-induced proliferative effects are exerted through sequential upregulation of MAPK-p38 and -ERK1/2 activation, and they are likely mediated by a ROS-dependent activation of p38.


Symptomatic dry eye treatment with autologous platelet-rich plasma.
Autologous platelet-rich plasma (PRP) has been proven to be very effective on tissue regeneration and wound healing. Here we investigate the potential use of PRP in the treatment of symptomatic dry eye. Eighteen consecutive patients with symptomatic dry eye were treated with topical PRP and followed up for 1 month. Disappearance of subjective symptoms, increase in best corrected visual acuity, tear meniscus, tear breakup time, decrease in inflammation, fluorescein staining and improvement in impression cytology were measured. Symptoms improved significantly in 89% of the patients, 28% improved at least 1 line of best corrected visual acuity. A significant improvement on lachrymal meniscus and conjunctival hyperemia and a decrease or disappearance of corneal fluorescein staining were observed. Impression cytology revealed a significant increase in conjunctival goblet cells. Treatment of patients suffering from significant dry eye symptoms with autologous RPR proved to be very effective, improving both patient symptoms and major clinical signs.


Physical exercise improves functional recovery through mitigation of autophagy, attenuation of apoptosis and enhancement of neurogenesis after MCAO in rats.
Physical exercise improves functional recovery after stroke through a complex mechanism that is not fully understood. Transient focal cerebral ischemia induces autophagy, apoptosis and neurogenesis in the peri-infarct region. This study is aimed to examine the effects of physical exercise on autophagy, apoptosis and neurogenesis in the peri-infarct region in a rat model of transient middle cerebral artery occlusion (MCAO). We found that autophagosomes, as labeled by microtubule-associated protein 1A light chain 3-II (LC3-II), were evident in the peri-infarct region at 3 days after 90-minute MCAO. Moreover, 44.6% of LC3-positive cells were also stained with TUNEL. The number of LC3 positive cells was significantly lower in physical exercise group than in control group at 14 and 21 days after MCAO. Suppression of autophagosomes by physical exercise was positively associated with improvement of neurological function. In addition, physical exercise significantly decreased the number of TUNEL-positive cells and increased the numbers of Ki67-positive, a proliferative marker, and insulin-like growth factor-1 (IGF-1) positive cells at 7, 14, and 21 days after MCAO. The present results demonstrate that physical exercise enhances neurological function possibly by reduction of autophagosome accumulation, attenuation of apoptosis and enhancement of neurogenesis in the peri-infarct region after transient MCAO in rats.


The critical periods of cerebral plasticity: A key aspect in a dialog between psychoanalysis and neuroscience centered on the psychopathology of schizophrenia.
Through research into the molecular and cellular mechanisms that occur during critical periods, recent experimental neurobiological data have brought to light the importance of early childhood. These have demonstrated that childhood and early environmental stimuli play a part not only in our subjective construction, but also in brain development; thus, confirming Freud's intuition regarding the central role of childhood and early experiences of the environment in our psychological development and our subjective outcomes. "Critical periods" of cerebral development represent temporal windows that mark favorable, but also circumscribed, moments in developmental cerebral plasticity. They also vary between different cortical areas. There are, therefore, strictly defined temporal periods for learning language, music, etc., after which this learning becomes more difficult, or even impossible, to acquire. Now, research into these critical periods can be seen as having a significant part to play in the interdisciplinary dialog between psychoanalysis and neurosciences with regard to the role of early experiences in the etiology of some psychopathological conditions. Research into the cellular and molecular mechanisms controlling the onset and end of these critical periods, notably controlled by the maturation of parvalbumin-expressing basket cells, have brought to light the presence of anomalies in the maturation of these neurons in patients with schizophrenia. Starting from these findings we propose revisiting the psychoanalytic theories on the etiology of psychosis from an interdisciplinary perspective. Our study works from the observation, common to both psychoanalysis and neurosciences, that experience leaves a trace; be it a "psychic" or a "synaptic" trace. Thus, we develop a hypothesis for an "absence of trace" in psychosis; reexamining psychosis through the prism of the biological theory of critical periods in plasticity.


The tenets of intrathoracic packing during damage control thoracic surgery for trauma patients: a systematic review.
Although Damage Control Thoracic Surgery (DCTS) has become a provocative alternative to treat patients with chest injuries who are critically ill and physiologically depleted, the management approaches of chest-packing and the measurement of clinically relevant outcomes are not well established. In this paper, we systematically reviewed the available knowledge and evidence about intra-thoracic packing during DCTS for trauma patients. We furthermore inform on the management approaches, surgical strategies, and mortality associated with this intervention. We identified articles in MEDLINE and SCOPUS. We reviewed all studies that included trauma patients with chest injuries and managed with intrathoracic packing during DCTS. Studies were eligible if the use of intrathoracic packing in trauma populations was reported. We identified 14 studies with a total of 211 patients. Overall, intrathoracic packing was used in 131 trauma patients. Packing was most commonly used to arrest persistent coagulopathic bleeding or oozing either from raw surfaces or repaired structures and in conjunction with other operative techniques. Pneumonectomy was a deadly intervention; however, one study reported survivors when pneumonectomy was deferred. Packing is a feasible, reliable and potentially effective complementary method for hemorrhage control. Therefore, we recommend that packing can be used liberally as a complement to rapid lung-sparing techniques.


Effects of hypokalemia and hypomagnesemia on zidovudine (AZT) and didanosine (ddI) nephrotoxicity in rats.
Zidovudine (AZT) and didanosine (ddI) are antiretroviral drugs widely used in AIDS patients. Hypokalemia and hypomagnesemia are frequently encountered in AIDS patients using AZT and/or ddI. To verify the effects of AZT and ddI on rat renal function submitted to normal diet, low potassium diet and magnesium-free diet. Glomerular filtration rate and renal hemodynamic were measured in Wistar rats submitted to a normal or a potassium-depleted diet. The animals were given AZT, ddI for 15 days. Six groups of rats were studied: normal diet, normal diet + AZT, normal diet + ddI, low K diet, low K diet + AZT and low K diet + ddI. Three additional groups of rats submitted to magnesium depletion for 15 days were also studied: magnesium-free diet, magnesium-free diet + AZT and magnesium-free diet + ddI. AZT and didanosine did not modify renal function of rats on a normal diet. However, in hypokalemic rats, both drugs produced a decrease in glomerular filtration rate and in renal blood flow consequent to renal vasoconstriction and associated with alterations in tubular function (characterized by an increased fractional excretion of sodium). Hypomagnesemia induced a decrease in glomerular filtration rate and in renal blood flow only in AZT-treated rats. Our data suggest that hypokalemia predisposes to AZT and ddI nephrotoxicity, while hypomagnesemia predisposes only to AZT nephrotoxicity. Thus, chronic AZT and ddI administration may produce acute renal failure in AIDS patients with hypokalemia and/or hypomagnesemia. Serum K and Mg levels should be carefully monitored in these patients.


Symptoms, cognitive functioning, and adaptive skills in geriatric patients with lifelong schizophrenia: a comparison across treatment sites.
Although many geriatric patients with schizophrenia have been referred to nursing home care, little is known about their characteristics. Across nursing home and chronic hospital settings, the authors directly assessed poor outcome geriatric patients with schizophrenia and contrasted their cognitive, symptomatic, and adaptive functioning to that of acutely admitted patients with a better outcome over the lifetime course of the illness. The subjects were 97 chronically hospitalized patients with schizophrenia, 37 patients with chronic schizophrenia who lived in nursing homes, and 31 acutely admitted geriatric patients with schizophrenia. These patients were rated with the Positive and Negative Syndrome Scale, tested with a neuropsychological battery, evaluated with the Mini-Mental State examination, and rated on a scale of social and adaptive deficits, the Social Adaptive Functioning Evaluation scale. Each group of patients proved discriminable from the other two: nursing home patients displayed the most severe adaptive deficits, and acutely admitted patients were the least cognitively impaired. Cognitive impairment was the strongest predictor of adaptive deficits for all three groups, and negative symptom differences among the groups were smaller than differences in cognitive impairment. Nursing home patients had the least severe positive symptoms, and the acutely ill and chronic hospital patients did not differ on positive symptoms. Cognitive impairment is a predictor of both overall outcome and specific adaptive deficits. These data suggest that interventions aimed at cognitive impairment may have an impact on overall functional status. In comparison, positive symptom severity is less strongly correlated with overall adaptive outcome and is uncorrelated with specific deficits in adaptive skills.


Splenic function in alcoholic liver disease.
Splenic function was assessed in 42 patients with alcoholic liver disease by counting the percentage of erythrocytes with indentations or pits, seen by differential interference contrast microscopy. These pits represent cellular debris normally removed by the spleen. The findings were compared with 42 age and sex matched controls. Mean (SEM) pitted red cell counts in the patients was 2.7 (0.4)% and in the controls 0.7 (0.07)% (p < 0.001). In all of the eight reformed drinkers (five with biopsy proven cirrhosis), cell counts were normal. Six patients with alcoholic liver disease had had serious infections within the past year. Of these, one had had a recent pneumococcal pneumonia and another of the patients died from overwhelming pneumococcal septicaemia. Both of these patients had evidence of functional hyposplenism as judged by high pitted erythrocyte counts. A total of 18 patients were considered to have pitted red cell counts above the normal, and 11 of these had proven cirrhosis and/or gross ascites. This study is the first to show the presence of functional hyposplenism in alcoholic liver disease and provides further evidence of the predisposition that these patients have to infection. At present, it is unclear whether the hyposplenism is a direct toxic effect of alcohol or the result of cirrhosis; further studies are warranted.


ATP-dependent regulation of rabbit myocardial cytosolic calcium-independent phospholipase A2.
We report here that rabbit myocardial cytosolic calcium-independent phospholipase A2 exists as a high molecular weight complex comprised of catalytic and regulatory polypeptides whose activity and stability are influenced by specific interactions with ATP. Multiple lines of evidence document the functional significance of interactions between the catalytic complex and ATP including: 1) adenine nucleotide triphosphates attenuate the rate of thermal denaturation of native cytosolic phospholipase A2; 2) ATP augments the initial rate of phospholipid hydrolysis in a manner independent of the concentration, interfacial properties, and physical state of aggregated substrate; 3) adenine nucleotide triphosphates attenuate the reactivity of an essential thiol residue to covalent modification by 5,5'-dithiobis(2-nitrobenzoic acid); and 4) the catalytic complex specifically and reversibly binds to ATP affinity matrices, although the purified 40-kDa catalytic subunit neither binds to ATP affinity matrices nor is subject to ATP-dependent activation and stabilization. The catalytic and regulatory elements were functionally resolved by differential thermal inactivation and the ATP-regulatable phospholipase A2 catalytic complex was reassembled by reconstitution of highly purified catalytic and partially purified regulatory proteins. Thus, alterations in ATP concentration influence the activity and longevity of the myocardial cytosolic calcium-independent phospholipase A2 catalytic complex, thereby potentially modulating the release of lipidic second messengers and facilitating adaptive alterations in membrane physical properties.


Binaural integration of periodically alternating speech following cochlear implantation in subjects with profound sensorineural unilateral hearing loss.
In cochlear implant (CI) recipients with unilateral hearing loss (UHL) and normal hearing (NH) in the contralateral ear, the central auditory system receives signals of different auditory modalities, i.e. electrically via the CI ear as well as acoustically via the NH ear. The present study investigates binaural integration of bimodal stimulation in the central auditory system of 10 CI subjects with UHL by applying a modified version of the Rapidly Alternating Speech Perception (RASP) test to characterise speech recognition ability under monotic and dichotic listening arrangements. Subsequently, the results for each monotic and dichotic test condition were compared to quantify the binaural benefit from CI usage. The study results demonstrate significantly improved speech recognition under dichotic compared to monotic listening conditions, providing evidence that there is binaural integration of acoustically and electrically transmitted speech segments in the central nervous system at brainstem and cortical levels. In contrast to more commonly used tests of binaural integration, such as localisation, the RASP test provides the clinical option to investigate binaural integration involving structures at the cortical level.


Morphology and biomechanics of the pinniped jaw: mandibular evolution without mastication.
Pinnipeds (seals, sea lions, and walruses) underwent a shift in jaw function away from typical carnivoran mastication to more novel marine behaviors during the terrestrial-aquatic transition. Here we test the effect of aquatic prey capture and male-male combat on the morphological evolution of a mammal jaw that does not masticate. Nine three-dimensional landmarks were taken along the mandible for 25 species (N = 83), and corpus and symphysis external and cortical breadths for a subset of five species (N = 33). Principal components analysis was performed on size-corrected landmark data to assess variation in overall jaw morphology across pinnipeds. Corpus breadths were input to a beam model to calculate strength properties and estimated bite force of specific species with contrasting behaviors (filter feeding, suction feeding, grip-and-tear feeding, and male-male combat). Results indicate that, although phylogenetic signal in jaw shape is strong, function is also important in determining morphology. Filter feeders display an elongate symphysis and a long toothrow that may play a role in filtering krill. Grip-and-tear feeders have a long jaw and large estimated bite force relative to non-biting species. However, the largest estimated bite forces were observed in males of male-male combative species, likely due to the high selection pressure associated with male success in highly polygynous species. The suction feeding jaw is weak in biting but has a different morphology in the two suction feeding taxa. In conclusion, familial patterns of pinniped jaw shape due to phylogenetic relatedness have been modified by adaptations to specialized behavior of individual taxa.