A novel leishmanial copper P-type ATPase plays a vital role in parasite infection and intracellular survival.
Copper (Cu) is essential for all life forms; however, in excess, it becomes toxic. Toxic properties of Cu are known to be utilized by host species against various pathogenic invasions. Leishmania, in both free-living and intracellular forms, exhibits appreciable tolerance toward Cu stress. While determining the mechanism of Cu-stress evasion employed by Leishmania, we identified and characterized a hitherto unknown Cu-ATPase in Leishmania major and established its role in parasite survival in host macrophages. This novel L. major Cu-ATPase, LmATP7, exhibits homology with its orthologs at multiple motifs. In promastigotes, LmATP7 primarily localized at the plasma membrane. We also show that LmATP7 exhibits Cu-dependent expression patterns and complements Cu transport in a Cu-ATPase-deficient yeast strain. Promastigotes overexpressing LmATP7 exhibited higher survival upon Cu stress, indicating efficacious Cu export compared with Wt and heterozygous LmATP7 knockout parasites. We further explored macrophage-Leishmania interactions with respect to Cu stress. We found that Leishmania infection triggers upregulation of major mammalian Cu exporter, ATP7A, in macrophages, and trafficking of ATP7A from the trans-Golgi network to endolysosomes in macrophages harboring amastigotes. Simultaneously, in Leishmania, we observed a multifold increase in LmATP7 transcripts as the promastigote becomes established in macrophages and morphs to the amastigote form. Finally, overexpressing LmATP7 in parasites increases amastigote survivability within macrophages, whereas knocking it down reduces survivability drastically. Mice injected in their footpads with an LmATP7-overexpressing strain showed significantly larger lesions and higher amastigote loads as compared with controls and knockouts. These data establish the role of LmATP7 in parasite infectivity and intramacrophagic survivability.


The economic context of drug and non-drug reinforcers affects acquisition and maintenance of drug-reinforced behavior and withdrawal effects.
The focus of this review is to examine the effect of non-drug alternative reinforcers on drug-reinforced behavior. An increasing number of animal laboratory as well as human clinical studies have demonstrated the effectiveness of non-drug reinforcers in reducing steady-state levels of drug self-administration. One goal of this review was to determine what behavioral economic conditions are optimal for reducing drug-reinforced behavior. Variables such as price of the drug and non-drug reinforcer have been manipulated by changing fixed-ratio (FR) value of these commodities. Income has been changed by limiting the amount of access to the commodities or by changing session length. Substitution was evaluated by determining whether decreased demand for a drug (due to increased price) was related to increased demand for a non-drug reinforcer. A second goal of this review was to investigate transition states in the drug addiction process with respect to the role of alternative non-drug reinforcers. Animal models of acquisition and withdrawal were examined to identify behavioral economic conditions under which acquisition may be prevented or withdrawal effects (and potential for relapse) may be alleviated.


Modulation of esophageal contractions by distension in vitro.
Stimulation of the intrinsic nerves of the esophageal body leads to a twitch of the circular muscle after the end of the stimulation (the esophageal off-response), and the twitch spreads in the distal direction because of a latency gradient in the onset of the off-response between the proximal and the distal esophagus. We investigated the possibility that local input can modulate the basic off-response through intrinsic mechanisms and make it resemble more closely the sequential ring contractions that move boluses in the esophagus of intact animals (esophageal peristalsis). The esophagus up to the aortic arch and down to the gastroesophageal junction was removed from opossums and suspended in an organ bath containing 2 liters of Krebs solution at 36 degrees C. The mechanical activity of the esophagus was recorded by force transducers on the serosal surface of the esophagus 2, 4, and 6 cm above the LES. The intramural nerves of the proximal esophagus were stimulated by electrical pulses with and without distension of the esophagus by inflation of a luminal balloon. Balloon distension increased the latency of the off-response in the distal esophagus, thereby reducing the velocity at which the circular muscle contraction spread through the esophagus. In addition, balloon distension increased the amplitude and the duration of the esophageal circular muscle contraction (both off- and on-responses), and decreased the amplitude of the longitudinal muscle contraction (duration response) and LES response (relaxation response). Similar changes in the esophageal contraction responses were produced by radial stretch of an open preparation of the esophagus from which the mucosa had been removed.(ABSTRACT TRUNCATED AT 250 WORDS)


Achieving energy balance with a high-fat meal does not enhance skeletal muscle adaptation and impairs glycaemic response in a sleep-low training model.
What is the central question of this study? Does achieving energy balance mainly with ingested fat in a 'sleep-low' model of training with low muscle glycogen affect the early training adaptive response during recovery? What is the main finding and its importance? Replenishing the energy expended during exercise mainly from ingested fat to achieve energy balance in a 'sleep-low' model does not enhance the response of skeletal muscle markers of early adaptation to training and impairs glycaemic control the morning after compared to training with low energy availability. These findings are important for optimizing post-training dietary recommendations in relation to energy balance and macronutrient intake. Training with low carbohydrate availability (LCHO) has been shown to acutely enhance endurance training skeletal muscle response, but the concomitant energy deficit (ED) in LCHO interventions has represented a confounding factor in past research. This study aimed at determining if achieving energy balance with high fat (EB-HF) acutely enhances the adaptive response in LCHO compared to ED with low fat (ED-LF). In a crossover design, nine well-trained males completed a 'sleep-low' protocol: on day 1 they cycled to deplete muscle glycogen while reaching a set energy expenditure (30 kcal (kg of fat free mass (FFM))-1 ). Post-exercise, low carbohydrate, protein-matched meals completely (EB-HF, 30 kcal (kg FFM)-1 ) or partially (ED-LF, 9 kcal (kg FFM)-1 ) replaced the energy expended, with the majority of energy derived from fat in EB-HF. In the morning of day 2, participants exercised fasted, and skeletal muscle and blood samples were collected and a carbohydrate-protein drink was ingested at 0.5 h recovery. Muscle glycogen showed no treatment effect (P < 0.001) and decreased from 350 ± 98 to 192 ± 94 mmol (kg dry mass)-1 between rest and 0.5 h recovery. Phosphorylation status of the mechanistic target of rapamycin and AMP-activated protein kinase pathway proteins showed only time effects. mRNA expression of p53 increased after exercise (P = 0.005) and was higher in ED-LF at 3.5 h compared to EB-HF (P = 0.027). Plasma glucose and insulin area under the curve (P < 0.04) and peak values (P ≤ 0.05) were higher in EB-HF after the recovery drink. Achieving energy balance with a high-fat meal in a 'train-low' ('sleep-low') model did not enhance markers of skeletal muscle adaptation and impaired glycaemia in response to a recovery drink following training in the morning.


Kimura Disease-A Case Report.
Kimura Disease, an eosinophilic hyperplastic granulomatous disease of idiopathic origin is most commonly seen in young males. It mostly presents with deep subcutaneous tissue swelling along with enlargement of salivary glands and regional lymphadenopathy. Diagnosis is mainly based on histopathological findings and raised serum IgE and hypereosinophilia. The radiological investigation of choice is Magnetic Resonance Imaging. Management strategy includes surgery and steroid therapy. Chemotherapeutic agents are also frequently used by some centres. Relapse and recurrence stands to be a common problem with management of this disease process. The online version contains supplementary material available at 10.1007/s12070-023-03817-y.


Carotid artery surgery: high-risk patients or high-risk centers?
Carotid angioplasty and stenting has been proposed as an alternative to carotid endarterectomy (CEA) in patients deemed as at high risk for this surgical procedure. To date, definitely accepted criteria to identify "high-risk" patients for CEA do not exist. Our objective was to assess the relevance of numerous supposed high-risk factors in our experience, as well as their possible effect on our early postoperative results. A retrospective review of 1,033 consecutive CEAs performed during a 5.6-year period at a single institution was conducted (Vascular Surgery Department, St. Etienne University Hospital, France). Early results in terms of mortality and neurologic events were recorded. Univariate and multivariate analyses for early risk of stroke, myocardial infarction, and death were performed, considering the influence of age, sex, comorbidities, clinical symptoms, and anatomic features. The cumulative 30-day stroke and death rate was 1.2%. A total of 10 strokes occurred and resulted in three deaths. The postoperative stroke risk was significantly higher in the subgroup of patients treated for symptomatic carotid artery disease: 2,6% (P = 0,004). Univariate analysis and logistic regression did not show statistical significance for 30-day results in any of the considered variables. Patients with significant medical comorbidities, contralateral carotid occlusion, and high carotid lesions can undergo surgery without increased complications. Those parameters should not be used as exclusion criteria for CEA.


Translation, cross-cultural adaption, validity and reliability of a composite physical function scale for adults aged 65 + years in a Danish context.
To prevent or postpone dependence on help in everyday activities, early identification of adults aged 65 + years at risk of functional decline or with progressing functional decline is essential. The American Composite Physical Function (CPF) scale was developed to detect and prevent this age-conditioned decline. In this study, the aim was to translate and adapt the scale into a Danish version and assess the validity and reliability in Danish adults aged 65 + years. A forward-backward translation procedure was used, followed by an expert panel review to finalise the Danish version of the CPF scale. In the subsequent pre-test, three-step cognitive interviews and hypotheses testing were performed to evaluate the validity, and a test-retest was done to assess reliability. In the pre-test, 47 adults participated in three-step cognitive interviews, and 45 adults answered an online version of the scale. In terms of content validity, the scale was relevant and easy to answer, although many informants skipped the instruction to the questionnaire, which may negatively impact face validity. Construct validity showed a significant difference in CPF scores in adults aged 65 + years by residence and activity level and a decreasing CPF score with increasing age. The reliability test showed an excellent kappa (0.92). The scale covering daily activities helps to identify adults aged 65 + years with reduced physical functions or at risk of loss of independence. Further research is needed to assess the CPF predictive value for adults aged 65 + years at risk of or with a progressing physical decline.


Post-operative spindle cell nodule of the vulva.
A case of post-operative spindle cell nodule arising in the vulva of a 33-year old woman is reported and the relevant literature reviewed. This is an uncommon, benign lesion which develops soon after a surgical procedure and which is composed of mitotically active spindle cells, causing possible confusion with sarcoma. Knowledge of the clinical history and an awareness of the existence of such lesions is necessary in order to avoid misinterpretation.


Rapid improvement of auditory verbal hallucinations in schizophrenia after add-on treatment with transcranial direct-current stimulation.
Treatment of nonresponsive auditory hallucinations in schizophrenia have been reported to improve with transcranial direct-current stimulation. This case description illustrates the use of add-on transcranial direct-current stimulation for rapid amelioration of auditory hallucinations in schizophrenia during the acute phase. Because transcranial direct-current stimulation is safe, largely well tolerated, and relatively inexpensive, this add-on treatment option is worth exploring through further rigorous studies.


Contraluminal transport of hexoses in the proximal convolution of the rat kidney in situ.
In order to study contraluminal hexose transport, concentration and time-dependent influx of 3H-2-deoxy-D-glucose from the interstitium into cortical tubular cells has been measured. The influx curves fit to a two parameter kinetics (Km 1.3 +/- 0.2 mmol/l, Jmax 0.67 +/- 0.16 pmol/s X cm) plus an additional diffusion term (with P = 6 X 10(-8) cm2/s) and a distribution ratio extracellular to intracellular amount of 2-deoxy-D-glucose of 1:0.6. Since the extracellular to intracellular free water space as estimated from morphological data was 1:2, one must conclude that glucose has only free access to 1/3 of the cell water. The intracellularly accessible space was augmented when the tubules were preperfused for 10 s with hypotonic saline. Thereby an increase of the compartment into which diffusion occurs was revealed and a final rupture of this intracellular compartment at 1/4 isotonic solutions was observed. Total replacement of ions in the peritubular perfusate by mannitol did not change 2-deoxy-D-glucose influx, indicating that it is Na+-independent. By adding isotonic concentrations of the respective sugars to the capillary perfusate, three degrees of inhibition of 2-deoxy-D-glucose influx could be revealed: strong inhibition by D-glucose, methyl-beta-D-glucoside, D-mannose, 3-O-methyl-D-glucose, 2-deoxy-D-galactose, methyl-beta-D-galactoside and 6-deoxy-D-glucose, moderate inhibition by D-galactose, L-glucose, L-mannose and D-fructose, no or borderline inhibition by methyl alpha-D-glucoside, 2-deoxy-methyl-alpha-D-galactoside, 1-thio-beta-D-glucose, 1-thio-beta-D-galactose, 5-thio-alpha-D-glucose, myo-inositol and mannitol.(ABSTRACT TRUNCATED AT 250 WORDS)


Cochlear inner hair cell ribbon synapse is the primary target of ototoxic aminoglycoside stimuli.
The ribbon synapses of inner hair cells (IHCs) play an important role in sound encoding and neurotransmitter release. However, it remains unclear whether IHC ribbon synapse plasticity can be interrupted by ototoxic aminoglycoside stimuli. Here, we report that quantitative changes in the number of IHC ribbon synapses and hearing loss occur in response to gentamicin treatment in mice. Using 3D reconstruction, we were able to calculate the number of IHC ribbon synapses after ototoxic gentamicin exposure. Mice were injected intraperitoneally with a low dose of gentamicin (100 mg/kg) once a day for 14 days. Double immunostaining was used to identify IHC ribbon synapses; histopathology and scanning electron microscopy were used to observe the morphology of cochlear hair cells and spiral ganglion neurons (SGNs), the hearing threshold shifts were recorded by auditory brainstem response examinations. Our study shows that the maximal number of IHC ribbon synapses appeared at the 7th day after treatment, followed by a significant reduction after the 7th day regardless of ongoing treatment. Correspondingly, the maximal elevation of hearing threshold was observed at the 7th day after treatment. Meanwhile, additional cochlear components included OHCs, IHCs, and SGNs were unaffected, suggesting that IHC ribbon synapses are more susceptible to ototoxic aminoglycoside stimulation. Our study indicated that quantitative changes in the number of IHC ribbon synapses is critical response to lower dose of ototoxic stimulation, and may contribute to moderate hearing loss. Additionally, our data indcated that ribbon synaptic plasticity may require the quantitative changes to play self-protective role adapted to ototoxic aminoglycoside stimuli.


Molecular tectonics: control of pore size and polarity in 3-D hexagonal coordination networks based on porphyrins and a zinc cation.
In the crystalline phase, porphyrin derivatives based on two 4-pyridyl units at the 5 and 15 meso positions and two 4-aryl moieties bearing various groups (CN, OMe, OH and CF(3)) at the 10 and 20 meso positions lead, in the presence of a zinc dication, to the formation of robust 3-D networks presenting hexagonal channels: both the size and the polarity of the pores were tuned by the nature of the substituents attached to the two aryl groups.


Lysosomes and pancreatic islet function. Time course of insulin biosynthesis, insulin secretion, and lysosomal transformation after rapid changes in glucose concentration.
The aim of this study was to estimate the time course of lysosomal transformations associated with crinophagy, i.e., the degradation of insulin within lysosomes, in the beta-cells of pancreatic islets. Primary and secondary lysosomes were identified in mouse islet beta-cells and subjected to ultrastructural morphometry. Islets from an in situ preparation were compared with isolated islets incubated in vitro. Under the in vitro conditions, the islets were initially exposed to 28 or 3.3 mM glucose for 24 h. Then the glucose concentration was rapidly changed to 3.3 and 28 mM glucose, respectively, and the islets were incubated for up to an additional 24 h. The beta-cell lysosomes were analyzed and related to alterations in insulin biosynthesis and secretion and islet insulin content after the rapid change in glucose concentration. In vivo, the beta-cell lysosomal population was predominantly composed of secondary lysosomes, which frequently contained secretory granule cores. After the initial 24-h period at 3.3 mM glucose, the volume density and the average volume of the secondary beta-cell lysosomes were increased, suggesting increased crinophagic activity. The mean diameter of the primary beta-cell lysosomes was decreased after 24 h at either 28 or 3.3 mM glucose. The change in glucose from 28 to 3.3 mM resulted in alterations in insulin biosynthesis and secretion, leading to an accumulation of insulin within the beta-cells. Lysosomal transformations suggestive of increased crinophagy were observed 24 h after the alteration in glucose concentration. The change from 3.3 to 28 mM glucose resulted in a parallel increase in insulin biosynthesis and secretion without a change in islet insulin content.(ABSTRACT TRUNCATED AT 250 WORDS)


TGF-beta2-induced cell surface tissue transglutaminase increases adhesion and migration of RPE cells on fibronectin through the gelatin-binding domain.
Migration and adhesion of dislocated retinal pigment epithelial (RPE) cells to a fibronectin-rich extracellular matrix is an initial step in proliferative vitreoretinopathy (PVR). In the present study, the functional role of cell surface tissue transglutaminase (tTG) in adhesion and migration of RPE cells on fibronectin (Fn) and collagen type I (Col I) after stimulation with TGF-beta2 was investigated. Cultured human RPE cells were treated with 1.0 ng/mL TGF-beta2 for 24 hours. Cell surface tTG expression was determined by cell fraction analysis. Attachment on Col I, full-length Fn, and its 45-kDa gelatin-binding and 110-kDa cell-binding fragment was measured with an MTT assay. Migration of RPE cells was measured by a Boyden chamber assay, and cell spreading was determined. Experiments were performed in the presence or absence of anti-tTG antibodies and anti-integrin alpha5 and beta1 antibodies. TGF-beta2 markedly induced expression of cell-surface tTG on RPE cells and increased attachment and migration on Fn and Col I. Blocking cell surface tTG inhibited attachment, migration, and spreading on Fn and its 45-kDa gelatin-binding fragment, whereas no effect was seen on Col I and the 110-kDa cell-binding Fn fragment. In contrast, blocking of integrin alpha5 and beta1 suppressed adhesion and migration on full-length Fn and the 110-kDa Fn fragment. These data demonstrate that TGF-beta2 increases expression of cell surface tTG, which in turn strengthens adhesion, migration, and spreading of RPE cells on Fn through the 45-kDa gelatin-binding Fn fragment. At the onset of PVR, this mechanism may help RPE cells to attach and migrate on Fn-containing matrices.


Periodic feeding of SCN-lesioned pregnant rats entrains the fetal biological clock.
Destruction of the maternal suprachiasmatic nuclei (SCN) early in gestation disrupts maternal communication of time-of-day information to the rat fetus. In the present study, we demonstrated that periodic feeding (food cue) to SCN-lesioned pregnant rats entrains the fetal biological clock. The phase of the drinking behavior rhythm was examined in pups reared in constant darkness, beginning at weaning. In several control (uncued) litters, pup phases at weaning were scattered. In other control litters where within-litter coordination of phase was observed, the average litter phase was unpredictable. In contrast, drinking rhythms of pups whose dams had received food cue during gestation were synchronized within- and between-litters, suggesting that prenatal food cue entrained the fetuses. The effect of food cue occurs prenatally, as similar results were obtained when offspring of SCN-lesioned, cued dams were fostered to lesioned, uncued dams on the day of birth. The present results, along with data from this and other laboratories, suggest that redundant mechanisms communicate time-of-day information to the fetus.


Conventional Image-Guided Procedures for Painful Spine.
This article reviews image-guided approaches for the treatment of common spine pain generators. The following treatment targets are discussed: epidural space (interlaminar and transforaminal approaches), facet joint, sacroiliac joint, and synovial cysts.


Helicopter Emergency Medical Services Response to a Major Incident.
Major incidents account for a vast number of consequences, whether it be individual morbidity and mortality or economic disruption and expense. Because of the infrequent nature, it poses a variety of unique risks and challenges for individual emergency medical services systems. Air ambulances are usually dispatched based on the clinical presentation of an individual patient who needs emergent critical care intervention. The response to a major incident is unusual and infrequent, but the benefit of tasking air ambulances to such incidents has been described by various authors. Here, such a response is described in a low- to middle-income country that saw the immediate tasking of 2 separate air ambulances to a single, multivehicle collision with multiple injured patients that occurred near a small, rural hospital not capable of treating critically ill patients. The benefits of tasking of the air ambulance in the sense of additional expertise as well as potential other nonclinical benefits are discussed and described here.


An emerging simple and effective approach to increase the productivity of thraustochytrids microbial lipids by regulating glycolysis process and triacylglycerols' decomposition.
The oleaginous microorganism Schizochytrium sp. is widely used in scientific research and commercial lipid production processes. However, low glucose-to-lipid conversion rate (GLCR) and low lipid productivity of Schizochytrium sp. restrict the feasibility of its use. Orlistat is a lipase inhibitor, which avoids triacylglycerols (TAGs) from hydrolysis by lipase. TAGs are the main storage forms of fatty acids in Schizochytrium sp. In this study, the usage of orlistat increased the GLCR by 21.88% in the middle stage of fermentation. Whereas the productivity of lipid increased 1.34 times reaching 0.73 g/L/h, the saturated fatty acid and polyunsaturated fatty acid yield increased from 21.2 and 39.1 to 34.9 and 48.5 g/L, respectively, indicating the advantages of using a lipase inhibitor in microbial lipids fermentation. Similarly, the system was also successful in Thraustochytrid Aurantiochytrium. The metabolic regulatory mechanisms stimulated by orlistat in Schizochytrium sp. were further investigated using transcriptomics and metabolomics. The results showed that orlistat redistributed carbon allocation and enhanced the energy supply when inhibiting the TAGs' degradation pathway. Therefore, lipase in Schizochytrium sp. prefers to hydrolyze saturated fatty acid TAGs into the β-oxidation pathway. This study provides a simple and effective approach to improve lipid production, and makes us understand the mechanism of lipid accumulation and decomposition in Schizochytrium sp., offering new guidance for the exploitation of oleaginous microorganisms.


Determinants of Breast-Conserving Therapy in Early-Stage Breast Cancer Patients: A Nationwide Study.
Evidence from previous studies and treatment guidelines suggested that breast-conserving therapy (BCT) is the treatment of choice for early-stage breast cancer. However, in the last decades, surgeons have noticed a high percentage of mastectomies done in this population. The aim of this study is to explore the factors associated with not choosing BCT among eligible patients with early-stage breast cancer. This study uses a retrospective cohort design. Demographic and clinical characteristics derived from The Taiwan Cancer Registry Database, the National Health Insurance Database and the Death File Database from January 1, 2004 to December 31, 2014. Patients were followed until December 31, 2015. To explore the associated factors related to BCT, we used univariate and multivariate logistic regression analysis. A total sample of 25,967 stage I breast cancer patients was included. Among them, 12,191 underwent BCT and 13,776 underwent mastectomy as their primary treatment. The logistic regression analysis reveals that age, pay-for-performance (P4P) program participation, number of affected lymph nodes, tumor size and location, were determinants of BCT. Interestingly enough, histological type did not reach the significance level. This study shows that personal and clinical characteristics influence the treatment choice in stage 1 breast cancer patients.


Quantitative comparison of coronary artery flow and myocardial perfusion in patients with acute myocardial infarction in the presence and absence of recent cocaine use.
Numerous factors have been implicated in the pathogenesis of cocaine associated myocardial infarction (CAMI). However, the relative contributions each of these mechanisms provide to the pathogenesis of CAMI have not been well defined. We hypothesized that significant angiographic differences exist between CAMI patients vs thrombotic AMI patients (TAMI) and normal controls. The TIMI Flow Grade, corrected TIMI Frame Count (CTFC), TIMI Myocardial Perfusion Grade (TMPG), presence of triple-vessel disease, stenosis severity, and presence of angiographically apparent thrombus were compared in patients who sustained CAMI to TAMI patients and normal controls. 2495 angiograms were analyzed (CAMI = 57, TAMI = 2403, Controls = 35). Impairment in both epicardial and microvascular flow in patients with CAMI was intermediate between TAMI and controls. Compared to TAMI patients, CAMI patients were less likely to have 3 vessel disease (8.9% vs. 19.1%; p < 0.05), epicardial stenosis was less severe (14.9+/-30.2 vs. 72.6+/-18.6; p < 0.0001), less thrombus was present (6.5% vs. 33.1%; p < 0.001) and TIMI grade 3 flow was observed more frequently (76% vs. 59%). Normal TMPG 3 perfusion was significantly impaired in both CAMI and TAMI patients when compared to controls without AMI (TMPG 3 was 40% and 26.6% vs. 100% respectively; p < 0.001 for both). The majority of patients in both AMI groups had diminished or absent tissue level perfusion (TMPG 0 flow, CAMI 53.9 vs. TAMI 56.8%). Both epicardial and microvascular flow is impaired in CAMI. While epicardial flow among CAMI patients is slightly better than TAMI patients, the incidence of little or severely impaired tissue level perfusion is nearly identical.


Across-muscle coherence is modulated as a function of wrist posture during two-digit grasping.
The purpose of this study was to investigate the extent to which correlated neural inputs, quantified as EMG-EMG coherence across intrinsic and extrinsic hand muscles, varied as a function of wrist angle during a constant force precision grip task. Eight adults (5 males; mean age 29 years) participated in the experiment. Subjects held an object using a two-digit precision grip at a constant force at a flexed, neutral, and extended wrist posture, while the EMG activity from intrinsic and extrinsic hand muscles was recorded through intramuscular fine-wire electrodes. The integral of z-transformed coherence computed across muscles pairs was greatest in the flexed wrist posture and significantly greater than EMG-EMG coherence measured in the neutral and extended wrist posture (P < 0.01 and 0.05, respectively). Furthermore, EMG-EMG coherence did not differ statistically between the extrinsic and intrinsic muscle pairs, even though it tended to be greater for the extrinsic muscle pair (P ≥ 0.063). These findings lend support to the notion of a functional role of correlated neural inputs to hand muscles for the task-dependent coordination of hand muscle activity that is likely mediated by somatosensory feedback.


Thirty minute transcutaneous electric acupoint stimulation modulates resting state brain activities: a perfusion and BOLD fMRI study.
Increasing neuroimaging studies have focused on the sustained after effects of acupuncture, especially for the changes of brain activities in rest. However, short-period stimuli have mostly been chosen in these works. The present study aimed to investigate how the resting state brain activities in healthy subjects were modulated by relatively long-period (30 min) acupuncture, a widely used modality in clinical practice. Transcutaneous electric acupoint stimulation (TEAS) or intermittent minimal TEAS (MTEAS) were given for 30 min to 40 subjects. Functional MRI (fMRI) data were collected including the pre-stimulation resting state and the post-stimulation resting state, using dual-echo arterial spin labeling (ASL) techniques, representing both cerebral blood flow (CBF) signals and blood oxygen-dependent level (BOLD) signals simultaneously. Following 30 min TEAS, but not MTEAS, the mean global CBF decreased, and a significant decrease of regional CBF was observed in SI, insula, STG, MOG and IFG. Functional connectivity analysis showed more secure and spatially extended connectivity of both the DMN and SMN after 30 min TEAS. Our results implied that modulation of the regional brain activities and network connectivity induced by thirty minute TEAS may associate with the acupuncture-related therapeutic effects. Furthermore, the resting state regional CBF quantified by ASL perfusion fMRI may serve as a potential biomarker in future acupuncture studies.


The effects of surgery on locomotion in elderly patients with cervical spondylotic myelopathy.
This study aimed to evaluate the effects of surgery on locomotor ability in patients with cervical spondylotic myelopathy (CSM) and compare the results between elderly and younger patients. A total of 369 consecutive patients who underwent expansive laminoplasty for CSM were prospectively analysed. Patients were divided into two age groups of ≥ 75 years (elderly group, 76 patients) and <75 years (younger group, 293 patients). Locomotor ability was estimated using part of the functional independence measure (FIM). The sum of gait and stairs items [functional independence measure (locomotion), FIM-L; possible scores, 2-14] and neurological status were estimated using the Japanese Orthopaedic Association (JOA) score (possible score, 0-17). Pre-operative neurological anamnesis was reviewed, and the surgical results of elderly patients with or without co-existing neurological history were evaluated to determine the origin of locomotor disability. Peri-operative FIM-L and JOA scores were significantly lower in the elderly group than in the younger group, and the opposite was true for improved FIM score. Cerebral infarction and previous lumbar surgery were identified as neurological co-morbidities in the elderly group. However, there was no significant difference in surgical results between elderly patients with and without co-existing neurological disorders. Decompression surgery can improve locomotor ability and decrease nursing care requirements among elderly patients with CSM. However, other neurological diseases can co-exist in elderly patients, making it difficult to diagnose the origin of locomotor disability. Therefore, detailed peri-operative work-up and timely decompression should be given priority to avoid progression towards fixed locomotor disability.


Nitrite as a candidate substrate in microbial fuel cells.
Current generation using nitrite as substrate (pH 6.9, 40 mgN l(-1)) in a nitrite-fed microbial fuel cell was investigated under anaerobic and aerobic anodic conditions as an alternative to the biological nitrite oxidation process. Cell current, coulombic efficiency (CE) and power generation of 0.04 mA, 30 ± 2 % and 19.3 ± 3.3 μW m(-2), respectively, were observed under anaerobic conditions while complete nitrite degradation (no current) was obtained under aerobic conditions. Switching from aerobic to anaerobic anode enhanced the CE and power generation (39 ± 1 % and 29 ± 4.3 μW m(-2)).


Genetic diversity and chemical profiling of different populations of Convolvulus pluricaulis (convolvulaceae): an important herb of ayurvedic medicine.
Convolvulus pluricaulis Choisy, commonly known as "Shankhpushpi", is an ayurvedic medicinal plant recommended as a brain tonic to promote intellect and memory, eliminate nervous disorders and to treat hypertension. Because of increasing demand of the drug, this plant species has been over-exploited. As a consequence, many unrelated plants are being sold by the crude drug dealers in India in the name of "Shankhpushpi". Information on its existing gene pool is currently lacking. We developed molecular (Random Amplification of Polymorphic DNA) and chemical (high performance liquid chromatography) markers that could distinguish the genuine plant species from its adulterants. Molecular characterization confirmed higher genetic variation at inter-zonal level as compared to intra-zonal populations. A total of 37 reproducible amplicons were generated of which 22 were polymorphic. The number of amplicons was in the range of 6-11 and genetic distance for the studied primers ranged from 0.07 to 0.34. Fifty nine per cent polymorphism was obtained across different geographical locations. Dendrogram studied through unweighted pair group method of arithmetic analysis differentiated all the genotypes into two major clusters, Cluster I had the single population of Rajasthan and Cluster II was represented by genotypes of Delhi, Haryana, Madhya Pradesh and Rajasthan. The Kaempferol content ranged from 0.07 to 0.49 mg/g and Delhi population was the highest accumulator.


Detection of dermatophytes in human nail and skin dust produced during podiatric treatments in people without typical clinical signs of mycoses.
Pedicures are the most common cosmetic foot treatment. Many pedicurists and podiatrists suffer from respiratory infections and diseases such as asthma, sinusitis, chronic cough and bronchitis. Skin and nail dust may play an important role in the development of occupational diseases and the transmission of mycosis to other clients. To examine the presence of dermatophytes in nail and skin dust produced during podiatric treatments of people without typical symptoms of mycosis and to assess the epidemiological hazards of tinea pedis for podiatrists as well as other clients. Seventy-seven samples underwent direct microscopy and culture. The results of direct microscopy were positive in 28/77 samples (36.36%) and doubtful in 3/77 (3.9%). Fungi were cultured from 36/77 samples (46.75%), including 8/77 (10.3%) positive for dermatophytes (Trichophyton rubrum-6 isolates and Trichophyton mentagrophytes-2). Material collected during podiatric treatments is potentially infected by pathogenic fungi; thus, there is a need to protect both workers who perform such treatments, as well as other clients, to prevent the transmission of pathogens in the Salon environment. Exposure to this occupational hazard may increase not only the risk of respiratory infections but also increase asthmatic or allergic reactions to Trichophyton.


Beta-2-microglobulin as a marker of malignant epithelial tumors of the skin.
Twenty-seven formalin-fixed, paraffin-embedded skin samples were examined to determine the usefulness of the loss of beta-2-microglobulin (B2m) in determining the malignancy of the epithelial cells of skin tumors. Our results confirm that there is loss of B2m from the cell surface in certain malignant lesions whereas the cells in the clearly benign lesions retain B2m on their cell membrane. Variable staining in the low-grade malignant and premalignant lesions renders B2m as an unreliable cell surface marker for differentiating borderline lesions.


Early Recognition of Pediatric Sepsis Simulation Checklist - An Exploratory Study.
To report on the modification and exploration of a 21-item Early Detection of Pediatric Sepsis Assessment Checklist aimed at improving nursing students' recognition of key factors that contribute to early detection of sepsis in pediatric patients through clinical simulation. One hundred and thirty-one undergraduate, pre-licensure nursing students were evaluated using the adapted 21-item Early Detection of Pediatric Sepsis Assessment Checklist in simulation using high-fidelity manikins. Categorical Principle Component Analysis was used to evaluate for factor structure, with items accounting for <0.20 of the variance were dropped from the loadings. Two factors emerged from the analysis: assessment and deterioration, accounting for 68% of the variance. Factor one, assessment, contained nine items (α = 0.77; λ = 3.36). Factor two, deterioration, contained seven items (α = 0.72; λ = 2.85). Five items did not load and were dropped from the factor structure, resulting in a 16-item checklist. Two factors emerged from the analysis which is key to improving the early detection of pediatric sepsis. Assessment, factor one, accounted for the nursing students' central skills of recognizing baseline vital signs and timely medication administration. Deterioration, factor two, contained items reflecting the recognition of changes from baseline that require action. Conceptually, these factors reflect the most central points in the early detection of signs in pediatric patients at risk for sepsis. This checklist forms a valuable tool to assess the knowledge of pre-licensure students and may possibly be extended as a tool to assess the clinical readiness and performance of new graduates through the safety and supervision allotted by simulation.


Anchoring ZnO on spinel cobalt ferrite for highly synergic sono-photo-catalytic, surfactant-assisted PAH degradation from soil washing solutions.
In this study, the photocatalytic activity of ZnO was effectively improved via its combination with spinel cobalt ferrite (SCF) nanoparticles. The catalytic performance of ZnO@SCF (ZSCF) was investigated in coupling with UV irradiation and ultrasound (US), as a heterogeneous sono-photocatalytic process, for the decontamination of phenanthrene (PHE) from contaminated soil. Soil washing tests were conducted in a batch environment, after extraction assisted by using Tween 80. Several characterization techniques such as XRD, FESEM-EDS, BET, TEM, UV-vis DRS, PL and VSM were utilized to determine the features of the as-prepared catalysts. ZSCF showed an excellent catalytic activity toward degradation of PHE in the presence of US and UV with a significant synergic effect. It was found that more than 93% of PHE (35 mg/L) and 87.5% of TOC could be eliminated by the integrated ZSCF/US/UV system under optimum operational conditions (pH: 8.0, ZSCF: 1.5 g/L, UV power: 6.0 W and US power: 70 W) within 90 min of reaction. After five times of use, ZSCF illustrated good reusability in the decontamination of PHE (87%) and TOC (79%). Quenching tests revealed the contribution of h+, HO• and e- species during PHE degradation over ZSCF/UV/US and an S-scheme photocatalytic mechanisms was proposed for the possible charge transfer routes under the ZSCF system. This study provides the important role of SCF in enhancing the ZnO photocatalytic activity due to its high performance, easy recovery and excellent durability, which it make an efficient and promising catalyst in environmental clean-up applications.


Valence band offset of β-Ga2O3/wurtzite GaN heterostructure measured by X-ray photoelectron spectroscopy.
A sample of the β-Ga2O3/wurtzite GaN heterostructure has been grown by dry thermal oxidation of GaN on a sapphire substrate. X-ray diffraction measurements show that the β-Ga2O3 layer was formed epitaxially on GaN. The valence band offset of the β-Ga2O3/wurtzite GaN heterostructure is measured by X-ray photoelectron spectroscopy. It is demonstrated that the valence band of the β-Ga2O3/GaN structure is 1.40 ± 0.08 eV.


Effects of light and circadian clock on the antiviral immune response in zebrafish.
The circadian clock mechanism, which is evolutionarily conserved across various organisms, plays a crucial role in synchronizing physiological responses to external conditions, primarily in response to light availability. By maintaining homeostasis of biological processes and behavior, the circadian clock serves as a key regulator. This biological mechanism also coordinates diurnal oscillations of the immune response during infections. However there is limited information available regarding the influence of circadian oscillation on immune regulation, especially in lower vertebrates like teleost fish. Therefore, the present study aimed to investigate the effects of light and the timing of infection induction on the antiviral immune response in zebrafish. To explore the relationship between the timing of infection and the response activated by viral pathogens, we used a zebrafish model infected with tilapia lake virus (TiLV). Our findings demonstrated that light availability significantly affects the antiviral immune response and the functioning of the molecular clock mechanism during TiLV infection. This is evident through alterations in the expression of major core clock genes and the regulation of TiLV replication and type I IFN pathway genes in the kidney of fish maintained under LD (light-dark) conditions compared to constant darkness (DD) conditions. Moreover, infection induced during the light phase of the LD cycle, in contrast to nocturnal infection, also exhibited similar effects on the expression of genes associated with the antiviral response. This study indicates a more effective mechanism of the zebrafish antiviral response during light exposure, which inherently involves modification of the expression of key components of the molecular circadian clock. It suggests that the zebrafish antiviral response to infection is regulated by both light and the circadian clock.


Common occurrence of zoonotic pathogen Cryptosporidium meleagridis in broiler chickens and turkeys in Algeria.
Only a small number of birds have been identified by molecular techniques as having Cryptosporidium meleagridis, the third most important species for human cryptosporidiosis. In this study, using PCR-RFLP analysis of the small subunit (SSU) rRNA gene, we examined the ileum of 90 dead chickens from 23 farms and 57 dead turkeys from 16 farms in Algeria for Cryptosporidium spp. C. meleagridis-positive specimens were subtyped by sequence analysis of the 60 kDa glycoprotein gene. Cryptosporidium infection rates were 34% and 44% in chickens and turkeys, respectively, with all positive turkeys (25) and most positive chickens (26/31) having C. meleagridis. All C. meleagridis specimens belonged to a new subtype family. The frequent occurrence of C. meleagridis in chickens and turkeys illustrates the potential for zoonotic transmission of cryptosporidiosis in Algeria.


Ferroptosis contributes to ethanol-induced hepatic cell death via labile iron accumulation and GPx4 inactivation.
Alcohol abuse is a significant cause of global morbidity and mortality, with alcoholic liver disease (ALD) being a common consequence. The pathogenesis of ALD involves various cellular processes, including oxidative stress, inflammation, and hepatic cell death. Recently, ferroptosis, an iron-dependent form of programmed cell death, has emerged as a potential mechanism in many diseases. However, the specific involvement and regulatory mechanisms of ferroptosis in ALD remain poorly understood. Here we aimed to investigate the presence and mechanism of alcohol-induced ferroptosis and the involvement of miRNAs in regulating ferroptosis sensitivity. Our findings revealed that long-term ethanol feeding induced ferroptosis in male mice, as evidenced by increased expression of ferroptosis-related genes, lipid peroxidation, and labile iron accumulation in the liver. Furthermore, we identified dysregulation of the methionine cycle and transsulfuration pathway, leading to severe glutathione (GSH) exhaustion and indirect deactivation of glutathione peroxidase 4 (GPx4), a critical enzyme in preventing ferroptosis. Additionally, we identified miR-214 as a ferroptosis regulator in ALD, enhancing hepatocyte ferroptosis by transcriptionally activating the expression of ferroptosis-driver genes. Our study provides novel insights into the involvement and regulatory mechanisms of ferroptosis in ALD, highlighting the potential therapeutic implications of targeting ferroptosis and miRNAs in ALD management.


Impact of delays in definitive treatment on overall survival: a National Cancer Database study of patients with Hodgkin lymphoma.
The purpose of this large observational study was to examine outcomes in patients with Hodgkin lymphoma (HL) by timing to definitive chemotherapy (TTC) using standard and propensity score (PS)-adjusted Cox proportional hazards models. From 1998-2011, 56,457 patients with stage I-IV HL were studied, with a median follow-up of 6.0 years (median age=39). Median TTC was 26 days from diagnosis. The cohort of "early" (<60 days from diagnosis) TTC patients included 45,307 (80.3%) patients and "late" (≥60 days) TTC was 11,150 (19.7%). Patients were more likely to experience early TTC if they were of a younger age, at an advanced stage, with "B" symptoms, favorably insured, favorable socioeconomic status, and treated at comprehensive cancer center (all p<0.05). Ten-year overall survival for patients with early TTC was 73.2% vs. 70.0% for those with late TTC (HR=0.87; 95%CI, 0.83-0.92, p<0.0001). After PS-matching for co-variates, early TTC was not associated with overall survival (HR=0.96; 95%CI, 0.85-1.08, p=0.51). This represents the only study to evaluate overall survival by time to definitive treatment for HL.


The safety of early discharge following transfemoral transcatheter aortic valve replacement under general anesthesia.
There is growing evidence of the safety of same-day discharge for low-risk conscious sedated TAVR patients. However, the evidence supporting the safety of early discharge following GA-TAVR with routine transesophageal echocardiography (TEE) is limited. To assess the safety of early discharge following transcatheter aortic valve replacement (TAVR) using General Anesthesia (GA-TAVR) and identify predictors for patient selection. We used data from 2,447 TEE-guided GA-TAVR patients performed at Cedars-Sinai between 2016 and 2021. Patients were categorized into three groups based on the discharge time from admission: 24 h, 24-48 h, and >48 h. Predictors for 30-day outcomes (cumulative adverse events and death) were validated on a matched cohort of 24 h vs. >24 h using the bootstrap model. The >48 h group had significantly worse baseline cardiovascular profile, higher surgical risk, low functional status, and higher procedural complications than the 24 h and the 24-48 h groups. The rate of 30-day outcomes was significantly lower in the 24 h than the >48 h but did not differ from the 24-48 h (11.3 vs. 15.5 vs. 11.7%, p = 0.003 and p = 0.71, respectively). Independent poor prognostic factors of 30-day outcomes had a high STS risk of ≥8 (OR 1.90, 95% CI 1.30-2.77, E-value = 3.2, P < 0.001), low left ventricle ejection fraction of <30% (OR 6.0, 95% CI 3.96-9.10, E-value = 11.5, P < 0.001), and life-threatening procedural complications (OR 2.65, 95% CI 1.20-5.89, E-value = 4.7, P = 0.04). Our formulated predictors showed a good discrimination ability for patient selection (AUC: 0.78, 95% CI 0.75-0.81). Discharge within 24 h following GA-TAVR using TEE is safe for selected patients using our proposed validated predictors.


Avian predation upon a mixed community of common voles (Microtus arvalis) and wood mice (Apodemus sylvaticus).
Pellets of diurnal avian predators (mainly kestrels and buzzards) were analysed to prove the hypothesis of selective predation for a mixed population of small rodents. It was found that voles heavily predominated as prey over mice (up to a factor of 19 during winter). Within both prey species, predation focussed on distinct parts of the populations: during winter the heaviest specimens were preferentially captured, during summer the subadults were in an exposed position. In the voles, an additional predominance of males occurred (up to a factor of 5.2 during summer). These findings verify the assumption of Errington (1956) that speciments of a low social rank are susceptible to the highest risk of predation.


Inhibition of COXs and 5-LOX and activation of PPARs by Australian Clematis species (Ranunculaceae).
The species of Clematis (Ranunculaceae) have been traditionally used for inflammatory conditions by indigenous Australians. We have previously reported that the ethanol extract of Clematis pickeringii inhibited COX-1. In this study, we examined the ethanol extracts and fractions of three Clematis species, Clematis pickeringii, Clematis glycinoides and Clematis microphylla, on cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX). We further examined the activating effects on the protein expression of peroxisome proliferator-activated receptor alpha (PPARalpha) and gamma (PPARgamma) in HepG2 cells. The ethanol extracts of three Clematis species inhibited the activities of COX-1, COX-2 and 5-LOX in the different extents. The stem extract of Clematis pickeringii showed the highest inhibitory activities among the three species on COX-1, COX-2 and 5-LOX with the IC(50) values of 73.5, 101.2 and 29.3 microg/mL. One of its fractions also significantly elevated PPARalpha expression by 173, 280 and 435% and PPARgamma expression by 140, 228 and 296% at 4, 8 and 16 microg/mL, respectively.


Enhancing potential impact of hospital discharge interventions for patients with COPD: a qualitative systematic review.
Patients with chronic obstructive pulmonary disease (COPD) are frequently readmitted to hospital resulting in avoidable healthcare costs. Many different interventions designed to reduce hospital readmissions are reported with limited evidence for effectiveness. Greater insight into how interventions could be better designed to improve patient outcomes has been recommended. To identify areas for optimisation within previously reported interventions provided to reduce COPD rehospitalisation to improve future intervention development. A systematic review was conducted by searching Medline, Embase, CINAHL, PsycINFO, and CENTRAL in June 2022. Inclusion criteria were interventions provided to patients with COPD in the transition from hospital to home or community. Exclusion criteria were lack of empirical qualitative results, reviews, drug trials, and protocols. Study quality was assessed using the Critical Appraisal Skills Programme tool and results were synthesised thematically. A total of 2,962 studies were screened and nine studies included. Patients with COPD experience difficulties when transitioning from hospital to home. It is therefore important for interventions to facilitate a smooth transition process and give appropriate follow-up post-discharge. Additionally, interventions should be tailored for each patient, especially regarding information provided. Very few studies specifically consider processes underpinning COPD discharge intervention implementation. There is a need to recognise that the transition itself creates problems, which require addressing, before introducing any new intervention. Patients report a preference for interventions to be individually adapted-in particular the provision of patient information. Whilst many intervention aspects were well received, feasibility testing may have enhanced acceptability. Patient and public involvement may address many of these concerns and greater use of process evaluations should enable researchers to learn from each other's experiences. The review was registered in PROSPERO with registration number CRD42022339523.


Is head injury a risk factor for schizophrenia?
The few studies that have examined whether head injury is a risk factor for later schizophrenia have had important methodological problems. We examined the rates of head injury among 8288 persons in the 15 years up to their first admission with schizophrenia and compared them with 82880 age- and gender-matched controls. We used hospitalization for concussion or severe head injury as a definition of head injury. We controlled for any generally altered accident proneness prior to schizophrenia by also comparing the groups with respect to exposition to fractures not involving the skull or spine. Males with schizophrenia had significantly reduced exposure to concussion (OR = 0.864, p = 0.024), whereas females had significantly increased exposure (OR = 1.322, p = 0.025). No differences were found as regards severe head injury. Males had significantly reduced risk of other fractures (OR = 0.616, p < 0.0001), whereas the risk in females did not differ from controls (OR = 1.154, p = 0.189). After adjusting head injury with the risk for other fractures, both concussion and severe head injury were significantly increased in males (OR = 1.501, p < 0.001 and OR = 1.516. p < 0.001, respectively) but not in females (OR = 1.15, p = 0.413 and OR = 0.819, p = 0.442, respectively). Our results do not exclude that for males, head injury may contribute to the risk for schizophrenia in a limited number of cases. This relation may also exist for females, but it is paralleled by an increased liability to traumas in general. Premorbid general accident proneness requires consideration when studying this association.


Poverty, income inequality, and health care consumption in Thailand.
The Thai economy has grown rapidly during the past three decades of modern industrialization. The structure of the economy has been changing from an agricultural to manufacturing based. Because industrial development policies has been biased toward Bangkok and surrounding provinces, regional income disparities have been widening. Despite the high growth record, Thailand has failed to distribute the benefits of economic growth equitably. This problem of income distribution could have many important consequences of relevance to the health of population.


Chemical speciation and human health risk of trace metals in urban street dusts from a metropolitan city, Nanjing, SE China.
The modified BCR (the European Community Bureau of Reference) sequential extraction procedure was applied for partitioning and evaluating the mobility, availability and persistence of trace metals (Al, Cd, Co, Cr, Cu, Ni, Pb, Sr, V and Zn) in urban street dusts collected from different areas of Nanjing, China. The mobility sequence based on the sum of the BCR sequential extraction stages was: Sr (91.65%)>Pb (79.16%)>Zn (74.26%)>Cu (68.53%)>Co (45.98%)>Al (40.01%)≈V (38.45%)≈Ni (37.88%)>Cr (29.35%)>Cd (22.68%). Almost every trace metal had its highest total concentrations in the industrial area, except for Sr which had its highest concentration in the commercial area. Contamination factors (Cf), risk assessment code (RAC) and enrichment factor (Ef) were then calculated to further assess the environmental risk and provide a preliminary estimate of the main sources of trace metals in street dusts. Non-carcinogenic effects and carcinogenic effects due to exposure to urban street dusts were assessed for both children and adults. For non-carcinogenic effects, ingestion was the main route of exposure to street dusts for these metals, followed by dermal contact and inhalation. Hazard index values for all studied metals were lower than the safe level of 1, and Pb exhibited the highest risk value (0.125) in the case of children. The carcinogenic risk for Cd, Co, Cr and Ni were all below the acceptable level (<10(-6)).


NLRC4 promotes the cGAS-STING signaling pathway by facilitating CBL-mediated K63-linked polyubiquitination of TBK1.
TANK-binding kinase 1 (TBK1) is crucial in producing type Ⅰ interferons (IFN-Ⅰ) that play critical functions in antiviral innate immunity. The tight regulation of TBK1, especially its activation, is very important. Here we identify NLRC4 as a positive regulator of TBK1. Ectopic expression of NLRC4 facilitates the activation of the IFN-β promoter, the mRNA levels of IFN-β, ISG54, and ISG56, and the nuclear translocation of interferon regulatory factor 3 induced by cGAS and STING. Consistently, under herpes simplex virus-1 (HSV-1) infection, knockdown or knockout of NLRC4 in BJ cells and primary peritoneal macrophages from Nlrc4-deficient (Nlrc4-/- ) mice show attenuated Ifn-β, Isg54, and Isg56 mRNA transcription, TBK1 phosphorylation, and augmented viral replications. Moreover, Nlrc4-/- mice show higher mortality upon HSV-1 infection. Mechanistically, NLRC4 facilitates the interaction between TBK1 and the E3 ubiquitin ligase CBL to enhance the K63-linked polyubiquitination of TBK1. Our study elucidates a previously uncharacterized function for NLRC4 in upregulating the cGAS-STING signaling pathway and antiviral innate immunity.


Label-free LC-MS/MS proteomics analyses reveal proteomic changes in oxidative stress and the SOD antioxidant strategy in TM cells.
Treatment for glaucoma has traditionally been limited to reducing intraocular pressure (IOP). Inhibiting oxidative stress in the trabecular meshwork (TM) is regarded as a new treatment for glaucoma; however, the effects do not meet expectations. Exploring the mechanism by which oxidative stress and antioxidant stress occur in TM cells will offer clues to aid the development of new treatments. In our study, we cultured TM cells and used H2O2 and SOD to induce and inhibit oxidative stress, respectively. Label-free LC-MS/MS quantitative proteomic analysis was conducted to analyze the differentially expressed proteins and relevant signaling pathways. A total of 24 upregulated proteins and 18 downregulated proteins were identified under oxidative stress. PTGS2, TGFβr2 and ICAM-1 are the key proteins. The PTGS2/NF-ĸb pathway, TGF-β/Smad signaling pathway and AGE-RAGE signaling pathway in diabetic complications may be the major signaling pathways under conditions of ROS-induced damage in TM cells. Seventy-eight proteins were upregulated and 73 proteins were downregulated under antioxidant stress in TM cells. The key protein was ICAM-1, which participates in the African trypanosomiasis pathway, one of the most important pathways under antioxidant stress. Combining the results of the Venn diagram with protein-protein interactions (PPIs), ICAM-1 was identified as the major protein. Cell Counting Kit-8 (CCK-8) and western blotting (WB) were used to reveal that suppressing the expression of ICAM-1 would improve the survival of TM cells. Key proteins and signaling pathways play important roles in the mechanisms of oxidative stress and antioxidant strategies in TM cells. ICAM-1 knockdown can suppress the apoptosis of TM cells induced by H2O2, which may reveal new therapeutic targets and biomarkers for glaucoma.


The effect of different oral hygiene treatments on the occurrence of ventilator associated pneumonia (VAP) in ventilated patients.
We compared the incidence of ventilator associated pneumonia (VAP) among patients treated with comprehensive oral care to those treated with conventional methods of oral care. We conducted a prospective, controlled study in an intensive care unit of 90 ventilated patients. Patients in the study group received a comprehensive oral hygiene treatment regimen that involved tooth brushing, suctioning, sodium bicarbonate, rinsing with an antiseptic solution containing 1.5% hydrogen peroxide and a mouth moisturiser. Patients in the control group received a more conventional treatment that included cleaning with a sponge and atraumatic clamp, and rinsing with a 0.2% solution of chlorhexidine gluconate. Among the 90 patients admitted to the ICU, 8.9% of the study group developed VAP compared with 33.3% of the control group (p< 0.004). The development of VAP per 1,000 ventilation days was 10.2 in the study group, and 29.5 in the control group (p< 0.06). The mean number of ventilation days and the mean number of hospitalisation days were also lower in the study group. In patients who are ventilated, a comprehensive oral hygiene treatment regimen that includes tooth brushing, suctioning and rinsing with an antiseptic is more effective in preventing VAP than more conventional protocols.


Anti-inflammatory activity of oleoresin from Brazilian Copaifera.
The oleoresin from Brazilian Copaifera species yielded copalic acid and sesquiterpenes and showed marked anti-inflammatory activity using various experimental models in rats. The oleoresin significantly inhibited carrageenin-induced pedal edema following oral doses from 0.70 to 2.69 ml/kg, but was somewhat less effective than 50 mg/kg calcium phenylbutazone. Repeated administration of the oleoresin at a dose of 1.26 ml/kg for a 6-day period reduced granuloma formation with a response comparable to that of 20 mg/kg of calcium phenylbutazone. This same dose of oleoresin also reduced the vascular permeability to intracutaneous histamine. The LD50 value of the oleoresin in rats was estimated to be 3.79 (3.21-4.47) ml/kg.


Dynamics of hepatic gene expression profile in a rat cecal ligation and puncture model.
Sepsis remains a major clinical challenge in intensive care units. The difficulty in developing new and more effective treatments for sepsis exemplifies our incomplete understanding of the underlying pathophysiology of it. One of the more widely used rodent models for studying polymicrobial sepsis is cecal ligation and puncture (CLP). While a number of CLP studies investigated the ensuing systemic inflammatory response, they usually focus on a single time point post-CLP and therefore fail to describe the dynamics of the response. Furthermore, previous studies mostly use surgery without infection (herein referred to as sham CLP, SCLP) as a control for the CLP model, however, SCLP represents an aseptic injurious event that also stimulates a systemic inflammatory response. Thus, there is a need to better understand the dynamics and expression patterns of both injury- and sepsis-induced gene expression alterations to identify potential regulatory targets. In this direction, we characterized the response of the liver within the first 24 h in a rat model of SCLP and CLP using a time series of microarray gene expression data. Rats were randomly divided into three groups: sham, SCLP, and CLP. Rats in SCLP group are subjected to laparotomy, cecal ligation, and puncture while those in CLP group are subjected to the similar procedures without cecal ligation and puncture. Animals were saline resuscitated and sacrificed at defined time points (0, 2, 4, 8, 16, and 24 h). Liver tissues were explanted and analyzed for their gene expression profiles using microarray technology. Unoperated animals (Sham) serve as negative controls. After identifying differentially expressed probesets between sham and SCLP or CLP conditions over time, the concatenated data sets corresponding to these differentially expressed probesets in sham and SCLP or CLP groups were combined and analyzed using a "consensus clustering" approach. Promoters of genes that share common characteristics were extracted and compared with gene batteries comprised of co-expressed genes to identify putatative transcription factors, which could be responsible for the co-regulation of those genes. The SCLP/CLP genes whose expression patterns significantly changed compared with sham over time were identified, clustered, and finally analyzed for pathway enrichment. Our results indicate that both CLP and SCLP triggered the activation of a proinflammatory response, enhanced synthesis of acute-phase proteins, increased metabolism, and tissue damage markers. Genes triggered by CLP, which can be directly linked to bacteria removal functions, were absent in SCLP injury. In addition, genes relevant to oxidative stress induced damage were unique to CLP injury, which may be due to the increased severity of CLP injury versus SCLP injury. Pathway enrichment identified pathways with similar functionality but different dynamics in the two injury models, indicating that the functions controlled by those pathways are under the influence of different transcription factors and regulatory mechanisms. Putatively identified transcription factors, notably including cAMP response element-binding (CREB), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and signal transducer and activator of transcription (STAT), were obtained through analysis of the promoter regions in the SCLP/CLP genes. Our results show that while transcription factors such as NF-κB, homeodomain transcription factor (HOMF), and GATA transcription factor (GATA) were common in both injuries for the IL-6 signaling pathway, there were many other transcription factors associated with that pathway which were unique to CLP, including forkhead (FKHD), hairy/enhancer of split family (HESF), and interferon regulatory factor family (IRFF). There were 17 transcription factors that were identified as important in at least two pathways in the CLP injury, but only seven transcription factors with that property in the SCLP injury. This also supports the hypothesis of unique regulatory modules that govern the pathways present in both the CLP and SCLP response. By using microarrays to assess multiple genes in a high throughput manner, we demonstrate that an inflammatory response involving different dynamics and different genes is triggered by SCLP and CLP. From our analysis of the CLP data, the key characteristics of sepsis are a proinflammatory response, which drives hypermetabolism, immune cell activation, and damage from oxidative stress. This contrasts with SCLP, which triggers a modified inflammatory response leading to no immune cell activation, decreased detoxification potential, and hyper metabolism. Many of the identified transcription factors that drive the CLP-induced response are not found in the SCLP group, suggesting that SCLP and CLP induce different types of inflammatory responses via different regulatory pathways.


Season of birth in Japanese patients with schizophrenia.
A number of North American and European studies have observed a higher proportion of winter births in schizophrenia patients. Fewer studies have investigated this issue in Asian populations, and the findings are not as consistent as in the studies of Western populations. A statistically significant excess of winter births has not been observed in Japanese or Korean studies, while some of the studies found a decreased number of summer births among their patients. We further investigated the issue in Japanese patients with schizophrenia (n=2985). No significant excess of winter births was observed. Spearman correlation between schizophrenia births and ambient temperature was not significant. However, a decrease in the summer births was found, consistent with most of the previous Japanese studies. When analyzed by gender, a decrease in summer births was found in males, but not in females. In addition, a trend towards an increase in winter births was observed and Spearman correlation between low ambient temperature and schizophrenia births was significant in male subjects. More significant seasonality of birth in male patients than in female patients might be related to more susceptibility to pre- or perinatal disturbances in neurodevelopment in males than in females.


Objective Quantification of Lens Opacity in Posterior Subcapsular Cataracts Using IOL Master 700 and CASIA-2.
To objectively quantify the lens opacity of posterior subcapsular cataracts (PSCs) using the swept-source optical coherence tomography (SS-OCT)-based devices including IOL Master 700 and CASIA-2. Prospective cross-sectional study. A total of 101 eyes of 101 patients with PSCs were enrolled in Zhongshan Ophthalmic Center from 2021 to 2022. The IOL Master 700 and CASIA-2 were used to obtain lens images. The average posterior subcapsular density (APSD) and the maximum posterior subcapsular density (MPSD) within the pupil area (radius: 3 or 5 mm) were measured by Image J. Spearman and Pearson correlation analysis were performed to assess the associations. APSD-3mm, APSD-5mm, MPSD-3mm, and MPSD-5mm had positive correlations with best corrected visual acuity (BCVA; r = 0.658, 0.641, 0.583, and 0.572, P < .001, respectively), all of which were higher than the correlation between LOCS-III P score and BCVA (r = 0.548, P < .001). Particularly, the APSD-3mm showed the highest correlation with BCVA. APSD could distinguish severe PSCs (LOCS-III P score ≥ 5) with an area under the receiver operating characteristic curve (AUC) of 0.836 (95% CI 0.743-0.930) for APSD-3mm and with AUC 0.758 (95% CI 0.643-0.873) for APSD-5mm, highlighting the better performance of APSD-3mm. The APSD-3mm of IOL Master 700 correlated strongly with that of CASIA-2 (r = 0.789, P < .001). This study presented an objective method for quantifying PSCs using IOL Master 700 and CASIA-2. APSD-3mm can be used as a new accurate and objective index for the quantitative assessment of PSCs.


Biopsychosocial predictors of pain among women recovering from surgery for endometrial cancer.
This study investigated post-surgical changes in pain among endometrial cancer patients, as well as the extent to which emotional distress and inflammatory and regulatory cytokine levels were associated with pain. Women (N=71) who underwent surgery for endometrial cancer completed questionnaires assessing pain intensity and interference, depression, and anxiety at 1week, 4weeks, and 16weeks post-surgery. Participants also provided a blood sample for the analysis of a panel of 7 cytokines at the same time points. Participants showed significant declines in pain intensity and pain interference from 1week to 4weeks post-surgery, after which pain remained stable. After adjusting for time since surgery, surgery type, adjuvant therapy, disease stage, age, and BMI, mixed-effects linear regression models indicated that greater depression and anxiety were associated with both greater pain intensity and interference. Higher levels of circulating IL-6 were also correlated with greater pain intensity, but not interference. Fixed-effects linear regression models indicated that temporal variation in depression, anxiety, and IL-6 within individual patients was associated with corresponding changes in pain. Pain symptoms were maximal when anxiety, depression, and IL-6 were highest. No other cytokines were associated with changes in pain. These findings indicate that depression, anxiety, and IL-6 may exacerbate pain during the recovery period following surgery for a gynecologic malignancy. Targeting these psychological processes and the proinflammatory cytokine IL-6 in women with more severe and persistent pain may help to reduce suffering and improve post-surgical recovery.


Time dependency of CSF cell count, lactate and blood-CSF barrier dysfunction after epileptic seizures and status epilepticus.
This retrospective observational study was conducted to examine the temporal relationship between increased cell count, lactate concentration in cerebrospinal fluid (CSF) and blood-CSF barrier dysfunction and the onset of a seizure event. Patients with a seizure event who underwent lumbar puncture for CSF analysis during diagnostic work-up (interindividual analysis) and those with at least one follow-up CSF analysis (intraindividual analysis) were studied. Pathologically altered parameters, such as cell count, lactate concentration, and blood-CSF barrier dysfunction as indicated by the albumin quotient (QAlb=CSF albumin/serum albumin), were examined with regard to the changes over time after seizure onset. An increased CSF cell count (>4/µl) was shown in 3% of our patients, whereas pathological lactate concentrations were found in 24% after single seizures and 28% after status epilepticus (SE)/recurring seizures. However, lactate levels showed a marked decrease with increasing time after an isolated seizure (p<0.0001) but not after SE/recurring seizures. Lactate levels were most frequently and significantly elevated within the first six hours after a single seizure (p<0.0001). Blood-CSF barrier dysfunction was detected in 34% after isolated seizures and in 47% after SE/recurrent seizures. Blood-CSF barrier dysfunction showed no association with latency between seizure onset and time of CSF collection. Changes in lactate and CSF protein concentrations are common after epileptic seizures. In contrast, CSF pleocytosis is uncommon and should prompt careful investigation for the presence of intrathecal infection or autoimmune CNS disease. Elevated lactate levels more than 6 h after the seizure event may indicate ongoing epileptic activity.


Perineal descent does not imply a more severe clinical disorder.
There is poor consensus in the literature about measuring perineal descent. We aimed to assess symptoms and quality of life in constipated patients with abnormal perineal descent. Constipated patients were categorized into those with obstructed defaecation, colonic inertia, mixed disorders and irritable bowel syndrome constipation types. Anal physiology was performed. KESS score, Irritable Bowel Syndrome Quality of Life and SF-12 questionnaires were completed. The position of the perineum was measured by defaecography. Patients were divided into two groups according to the position of the perineal descent at rest: group 1 (normal < 3.5 cm) and group 2 (abnormal > 3.5 cm). Fifty-eight patients were identified, 23 (40%) in group 1 and 35 (60%) in group 2. Patients in group 2 were older (P = 0.007), had a higher body mass index (BMI; P = 0.003), a higher rate of hysterectomy (P = 0.04) and more vaginal deliveries (P = 0.001). Obstructed defaecation was the predominant subtype of constipation. Group 1 had more difficulty in initiating defaecation and group 2 presented more cases with intussusception and enterocele (P = 0.03 for both). Group 2 had a lesser degree of perineal descent between rest and straining. Rectal compliance was greater in group 2 (P = 0.03). Symptoms and quality of life scores were similar between the groups. Radiologically determined excessive perineal descent is not indicative of worse symptoms or quality of life. This radiological finding does not warrant further investigation.


Ambiguity and nonidentifiability in the statistical analysis of neural codes.
Many experimental studies of neural coding rely on a statistical interpretation of the theoretical notion of the rate at which a neuron fires spikes. For example, neuroscientists often ask, "Does a population of neurons exhibit more synchronous spiking than one would expect from the covariability of their instantaneous firing rates?" For another example, "How much of a neuron's observed spiking variability is caused by the variability of its instantaneous firing rate, and how much is caused by spike timing variability?" However, a neuron's theoretical firing rate is not necessarily well-defined. Consequently, neuroscientific questions involving the theoretical firing rate do not have a meaning in isolation but can only be interpreted in light of additional statistical modeling choices. Ignoring this ambiguity can lead to inconsistent reasoning or wayward conclusions. We illustrate these issues with examples drawn from the neural-coding literature.


A dedicated BI-RADS training programme: effect on the inter-observer variation among screening radiologists.
The Breast Imaging Reporting and Data System (BI-RADS) was introduced in the Dutch breast cancer screening programme to improve communication between medical specialists. Following introduction, a substantial variation in the use of the BI-RADS lexicon for final assessment categories was noted among screening radiologists. We set up a dedicated training programme to reduce this variation. This study evaluates whether this programme was effective. Two comparable test sets were read before and after completion of the training programme. Each set contained 30 screening mammograms of referred women selected from screening practice. The sets were read by 25 experienced and 30 new screening radiologists. Cohen's kappa (κ) was used to calculate the inter-observer agreement. The BI-RADS 2003 version was implemented in the screening programme as the BI-RADS 2008 version requires the availability of diagnostic work-up, and this is unavailable. The inter-observer agreement of all participating radiologists (n=55) with the expert panel increased from a pre-training κ-value of 0.44 to a post-training κ-value of 0.48 (p=0.14). The inter-observer agreement of the new screening radiologists (n=30) with the expert panel increased from κ=0.41 to κ=0.50 (p=0.01), whereas there was no difference in agreement among the 25 experienced radiologists (from κ=0.48 to κ=0.46, p=0.60). Our training programme in the BI-RADS lexicon resulted in a significant improvement of agreement among new screening radiologists. Overall, the agreement among radiologists was moderate (guidelines Landis and Koch). This is in line with results found in the literature.


Quisqualate agonists occlude kainate-induced current in cultured striatal neurons.
We employed the whole cell patch-clamp technique to examine the ionic currents induced via activation of kainate/quisqualate receptors on striatal neurons in primary culture when N-methyl-D-aspartate receptors were blocked by selective antagonists. Bath perfusion of 10 microM-1 mM each of quisqualate, glutamate, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (a selective quisqualate agonist) or kainate, induced only a sustained current, but more rapid application by pressure ejection of each of the first three agonists (but not kainate) also activated a rapidly desensitizing current. The current induced by a near-saturating concentration of kainate (1 mM) was, on average, 16-fold larger than the maximum sustained current induced by quisqualate (10 microM), or 7.5-fold larger than that induced by alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (100 microM) or glutamate (100 microM). When kainate (100 microM-10 mM) was co-applied with each of the agonists (1 microM-1 mM), the sustained current was not the algebraic sum of the currents activated by kainate or the other agonist alone; rather, the kainate-induced current was increasingly occluded by co-application with increasing concentrations of another agonist. The potency to occlude kainate-induced current had a rank order of quisqualate greater than alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate approximately glutamate; although at sufficiently high concentrations all three agonists could occlude the kainate-induced current completely. When kainate and quisqualate were co-applied during the continued presence of quisqualate, the onset of the kainate-induced sustained current was dramatically slowed. However, the steady-state occlusion by quisqualate could be abolished when the ratio kainate to quisqualate was raised to 100:1; therefore, the occlusion appears to involve a competition between kainate and quisqualate at some shared receptor binding sites which have a higher affinity for quisqualate than kainate.


Regulation of long-term depression by increases in [guanosine 3',5'-cyclic monophosphate] in the hippocampal CA1 region of freely behaving rats.
A role for guanosine 3',5'-cyclic monophosphate (cGMP) and the protein kinase G (PKG) pathway in synaptic long-term depression (LTD) in the hippocampal CA1 region has been proposed, based on observations in vitro, where, for example, increases of [cGMP] result in short-term depression (STD) coupled with a reduction in presynaptic glutamate release. To date, no evidence exists to support that LTD in the intact, freely behaving animal involves these mechanisms. We examined the effect of increases of [cGMP] on basal transmission and electrically-induced STD at hippocampal CA1 synapses in vivo. We found that elevating [cGMP] dose-dependently caused a chemically-induced STD which occluded electrically-induced STD. Repeated administration of Zaprinast, an inhibitor of cGMP-degrading phosphodiesterase, resulted in persistent LTD (>24 h). Paired-pulse analysis supported a presynaptic mechanism of action. Application of an inhibitor of soluble guanylate cyclase prevented LTD induced by low-frequency stimulation (LFS), and impaired LFS-STD elicited in the presence of Zaprinast. These data suggest the involvement of cGMP in LTD in the CA1 region of freely behaving adult rats.


A unique amphiphilic triblock copolymer, nontoxic to human blood and potential supramolecular drug delivery system for dexamethasone.
The drug delivery system (DDS) often causes toxicity, triggering undesired cellular injuries. Thus, developing supramolecules used as DDS with tunable self-assembly and nontoxic behavior is highly desired. To address this, we aimed to develop a tunable amphiphilic ABA-type triblock copolymer that is nontoxic to human blood cells but also capable of self-assembling, binding and releasing the clinically used drug dexamethasone. We synthesized an ABA-type amphiphilic triblock copolymer (P2L) by incorporating tetra(aniline) TANI as a hydrophobic and redox active segment along with monomethoxy end-capped polyethylene glycol (mPEG2k; Mw = 2000 g mol-1) as biocompatible, flexible and hydrophilic part. Cell cytotoxicity was measured in whole human blood in vitro and lung cancer cells. Polymer-drug interactions were investigated by UV-Vis spectroscopy and computational analysis. Our synthesized copolymer P2L exhibited tuned self-assembly behavior with and without external stimuli and showed no toxicity in human blood samples. Computational analysis showed that P2L can encapsulate the clinically used drug dexamethasone and that drug uptake or release can also be triggered under oxidation or low pH conditions. In conclusion, copolymer P2L is nontoxic to human blood cells with the potential to carry and release anticancer/anti-inflammatory drug dexamethasone. These findings may open up further investigations into implantable drug delivery systems/devices with precise drug administration and controlled release at specific locations.


Identification of microRNA-mRNA-TF regulatory networks in periodontitis by bioinformatics analysis.
Periodontitis is a complex infectious disease with various causes and contributing factors. The aim of this study was to identify key genes, microRNAs (miRNAs) and transcription factors (TFs) and construct a miRNA-mRNA-TF regulatory networks to investigate the underlying molecular mechanism in periodontitis. The GSE54710 miRNA microarray dataset and the gene expression microarray dataset GSE16134 were downloaded from the Gene Expression Omnibus database. The differentially expressed miRNAs (DEMis) and mRNAs (DEMs) were screened using the "limma" package in R. The intersection of the target genes of candidate DEMis and DEMs were considered significant DEMs in the regulatory network. Next, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted. Subsequently, DEMs were uploaded to the STRING database, a protein-protein interaction (PPI) network was established, and the cytoHubba and MCODE plugins were used to screen out key hub mRNAs and significant modules. Ultimately, to investigate the regulatory network underlying periodontitis, a global triple network including miRNAs, mRNAs, and TFs was constructed using Cytoscape software. 8 DEMis and 121 DEMs were found between the periodontal and control groups. GO analysis showed that mRNAs were most significantly enriched in positive regulation of the cell cycle, and KEGG pathway analysis showed that mRNAs in the regulatory network were mainly involved in the IL-17 signalling pathway. A PPI network was constructed including 81 nodes and 414 edges. Furthermore, 12 hub genes ranked by the top 10% genes with high degree connectivity and five TFs, including SRF, CNOT4, SIX6, SRRM3, NELFA, and ONECUT3, were identified and might play crucial roles in the molecular pathogenesis of periodontitis. Additionally, a miRNA-mRNA-TF coregulatory network was established. In this study, we performed an integrated analysis based on public databases to identify specific TFs, miRNAs, and mRNAs that may play a pivotal role in periodontitis. On this basis, a TF-miRNA-mRNA network was established to provide a comprehensive perspective of the regulatory mechanism networks of periodontitis.


Contrasting role of NLRP12 in autoinflammation: evidence from a case report and mouse models.
To explore at the molecular level the phenotype of a patient suffering an autoinflammatory syndrome which was diagnosed as familial cold autoinflammatory syndrome type 2 (FCAS-2). To explore the functions of Nlrp12 in inflammation using mouse models. Whole exome sequencing and Nlrp12 targeted resequencing were performed on DNA isolated from the patient and her family members. In vivo and ex vivo models of inflammation (urate crystals-dependent acute joint inflammation and urate crystals-induced peritonitis) were analysed in Nlrp12-deficient and Nlrp12-competent mice. A rare missense NLRP12 variant (c.857C>T, p.P286L) was identified in the patient and her healthy relatives. Nlrp12-deficient mice exhibit reduced systemic inflammation and neutrophilic infiltration. Nlrp12 mediates proinflammatory functions in mice. In humans, the identification of Nlrp12 variants must be cautiously interpreted depending on clinical and paraclinical data to diagnose FCAS-2.


Deconstructing and reconstructing behaviour relevant to mental health disorders: The benefits of a psychological approach, with a focus on addiction.
RUTHERFORD, L.G. and Milton, A.L. Deconstructing and reconstructing behaviour relevant to mental health disorders: The benefits of a psychological approach, with a focus on addiction. NEUROSCI BIOBEHAV REV XX(X)XXX-XXX, 2021. - Current treatments for mental health disorders are successful only for some patients, and there is an unmet clinical need for new treatment development. One challenge for treatment development has been how best to model complex human conditions in animals, where mechanisms can be more readily studied with a range of neuroscientific techniques. We suggest that an approach to modelling based on associative animal learning theory provides a suitable framework for deconstructing complex mental health disorders such that they can be studied in animals. These individual simple models can subsequently be used in combination to 'reconstruct' a more complex model of the mental health disorder of interest. Using examples primarily from the field of drug addiction, we explore the 'psychological approach' and suggest that in addition to facilitating translation and backtranslation of tasks between animal models and patients, this approach is also highly concordant with the concept of triangulation.


Craniofacial osseous restoration with osteoinductive proteins in a collagenous delivery system.
Implants fabricated from mixtures of extracted bovine bone proteins and highly purified human type I collagen have been tested for efficacy in the restoration of osseous defects. Experimental implants composed of osteoinductive proteins and collagen, and control implants composed of collagen alone were placed in 15 x 15 mm cranial defects in New Zealand white rabbits. Implants harvested at 10, 12 and 14 week intervals were subjected to histological evaluation as well as quantitative analysis utilizing a computer morphometric planimeter. Defects filled with control implants displayed highly variable repair with a mean of 31% bony healing. Experimental implants were consistently effective in inducing significant bony regeneration with a mean of 91% repair within the time range of the study. In light of these results, it is apparent that an osteoinductive-collagenous implant system represents an efficacious treatment modality in osseous reconstruction and augmentation.


Usability of Iranian Primary Vitiligo Patient Registry (IPVPR): A Pilot Study.
Usability is essential for the acceptance and success of vitiligo patient registry system. Poor usability could decrease system efficiency and effectiveness, and have a negative impact on using the system and providing services. This study aims to evaluate the usability of vitiligo patient registry system. This pilot study was conducted in 2021. In total, 17 users who were working in the vitiligo ward participated in the study. System usability scale (SUS) was used to evaluate the usability of vitiligo patient registry system. In the usability evaluation stage, the mean score of the system usability scale was obtained as 77.79. Developing vitiligo patient registry system with high usability and making decisions based on the registered data could provide better understanding of this disease and facilitate research in this field. Application of this system and its acceptance by users could decrease costs and increase effectiveness and quality of services.


On the difficulties of fitting the double Michaelis-Menten equation to kinetic data.
The double Michaelis-Menten equation describes the reaction kinetics of two independent, saturable uptake mechanisms. The use of this equation to describe drug uptake has been reported several times in the literature, and several methods have been published to fit the equation to data. So far, however, confidence intervals on the fitted kinetic parameters have not been provided. We present a grid-search method for fitting the double Michaelis-Menten equation to kinetic uptake data, and a Monte-Carlo procedure for estimating confidence intervals on the fitted parameters. We show that the fitting problem is extremely ill-conditioned, and that very accurate data are required before any confidence can be placed in the fitted parameters.


Neuroleptic malignant syndrome: case report and review.
A patient with neuroleptic malignant syndrome is reported. The clinical features, complications and management are discussed and literature reviewed.


A new method of preclotting fabric prostheses. A preliminary report.
A new method of preclotting arterial fabric prostheses is described. The preclotting process depends on infusion of blood into a polyethylene bag containing the prosthesis. Massage of the bag aids permeation of the graft, and a second infusion of blood over a 1 minute period seals the fraft completely. Rapid preclotting and asepsis are the unique features of this method.


Delivering prenatal pertussis vaccine through maternity services in England: What is the impact on vaccine coverage?
Prenatal pertussis vaccination was introduced in 2012 in England and is primarily delivered through general practice. Since 2017 some maternity services are commissioned to offer it too. We aimed to describe the maternity service delivery of prenatal pertussis vaccination and its impact on vaccine uptake. We described the proportion of maternity services in England commissioned to offer pertussis vaccination to pregnant women in 2017/18 and the proportion of women vaccinated in this setting using a self-administered survey of NHS commissioners. We categorised clinical commissioning groups (CCGs) in England into "implementing" and "non-implementing" pertussis vaccination in maternity services. We identified CCGs where vaccination data was reliably transferred from maternity services to primary care records (source of routine data on vaccine uptake) and among those compared changes in vaccine uptake in implementing vs non-implementing CCGs between March 2016 (before implementation) and March 2018 (after). Of 141 maternity service units in England, 61% delivered prenatal pertussis vaccine in 2017/18. Of those 57.0% of maternity services immunized less than 10% of pregnant women and only 7.1% of maternity services immunized more than 40% of pregnant women. Between March 2016 and March 2018, coverage increased by 19.6% among non-implementing CCGs compared with 17.8% among all implementing CCGs (difference -2.2, p = 0.48) and 28.2% among implementing CCGs with reliable methods of data transfer (difference 8.6, p = 0.04). This difference translated to a difference of 1.6 percentage points in absolute terms. Delivering pertussis vaccine through maternity services has a moderate but important impact on vaccine uptake. There is a need to improve data transfer on vaccines administered in maternity service units to primary care. Maternity services should offer the vaccine to improve coverage and thus optimise protection for young infants. Barriers to effective programme implementation should be investigated and addressed.


Discovery and characterization of novel inhibitors of the sodium-coupled citrate transporter (NaCT or SLC13A5).
Citrate is a key regulatory metabolic intermediate as it facilitates the integration of the glycolysis and lipid synthesis pathways. Inhibition of hepatic extracellular citrate uptake, by blocking the sodium-coupled citrate transporter (NaCT or SLC13A5), has been suggested as a potential therapeutic approach to treat metabolic disorders. NaCT transports citrate from the blood into the cell coupled to the transport of sodium ions. The studies herein report the identification and characterization of a novel small dicarboxylate molecule (compound 2) capable of selectively and potently inhibiting citrate transport through NaCT, both in vitro and in vivo. Binding and transport experiments indicate that 2 specifically binds NaCT in a competitive and stereosensitive manner, and is recognized as a substrate for transport by NaCT. The favorable pharmacokinetic properties of 2 permitted in vivo experiments to evaluate the effect of inhibiting hepatic citrate uptake on metabolic endpoints.


Dandy-Walker syndrome with bilateral choanal atresia: A case report.
Dandy-Walker syndrome is a rare congenital brain malformation characterized by cerebellar vermis agenesis or hypoplasia, cystic dilatation of the fourth ventricle and a large posterior fossa causing upward displacement of tentorium and torcula. In this paper, we present a case of bilateral choanal atresia with Dandy-Walker Syndrome in a female newborn. We present a case of a female patient who was born at 38th weeks of gestation via emergency cesarean section due to non-reassuring cardiotocography and abnormal antenatal ultrasounds findings. The imaging revealed the presence of Dandy-walker malformation. The patient presented with cyanosis and respiratory distress. Bedside flexible nasoendoscopy revealed bilateral choanal atresia which is confirmed by computed tomography of sinuses. Endoscopic bilateral choanal atresia repair was performed. On postoperative follow up, nasal endoscopy showed bilateral intact flap and patent neochoana. Dandy-Walker syndrome is a congenital disorder that can be diagnosed prenatally. The syndrome is associated with multiple anomalies. However, there are few published reports of bilateral choanal atresia in Dandy-Walker Syndrome. Bilateral choanal atresia is considered a life-threatening condition in newborns that requires early surgical intervention.


[Haemodialysis in patients with pre- andpostoperative acute renal failure (author's transl)].
Treatment and management of patients with renal insufficiency before and after surgery is often complicated. Early interdisciplinary cooperation between intensive care specialist, surgeon, gynaecologist, urologist and nephrologist is necessary. The mortality rate of patients with acute renal failure is still high (50 to 60%). The increase in patients with chronic renal failure who are in need of haemodialysis involves more surgical procedures in this group even in future.


Correlation of coronary arteriography after acute myocardial infarction with predischarge limited exercise test response.
This study of post-acute myocardial infarction (AMI) patients compared the extent and distribution of coronary narrowings and left ventricular dysfunction in 45 patients who had greater than or equal to 1 mm ST-segment depression on a predischarge low-level exercise test (positive-result group) with those found in 78 patients who had less than 1 mm ST depression (negative-result group). Cardiac catheterization was done 50 +/- 20 days (mean + standard deviation) after AMI. Patients with positive responses more often had multivessel coronary artery disease (80 vs 47%, p = 0.001) and a greater than or equal to 75% narrowing in the left anterior descending (LAD) (87 vs 62%, p = 0.003) and left circumflex (71 vs 37%, p = 0.001) arteries, as well as in the proximal LAD segment before the first septal branch (58 vs 29%, p = 0.002). Among patients with positive responses 93% had normal or hypokinetic wall motion in the vascular territory of a severely diseased coronary artery (viable but potentially ischemic myocardium) while 63% of the negative-result group had these findings (p = 0.001). No difference in ejection fraction could be identified between the 2 groups (54 +/- 15% vs 54 +/- 16%). Prior studies of AMI patients have shown that ST-segment depression on a predischarge low-level exercise test will identify patients at higher risk of subsequent cardiac death. Our observations have identified differences in cardiac angiographic findings between patients with positive and negative responses to this test that may explain this difference in outcome.