Apnoea after the 2-month immunisation in extremely preterm infants: what happens with the 4-month immunisation?
To describe the outcome of the 4-month immunisation in a cohort of extremely preterm babies who had clinically significant apnoea after their 2-month immunisation. A retrospective audit was conducted from January 2001 to January 2011 at Flinders Medical Centre (FMC). Suspected apnoeic reactions to the 2-month immunisation in preterm infants ≤28 weeks + 6 days gestation were identified from the Neonatal Unit database. The medical records of babies with reactions then reviewed. We classified apnoeic reactions using predefined criteria into likely, possible or unlikely. The outcomes for subsequent immunisations were determined either when babies were specifically readmitted to FMC for immunisation and cardiorespiratory monitoring, or from the SA Health Immunisation Unit database. There were 203 extremely preterm babies at FMC over the study period who received their 2-month immunisation as inpatients. Clinically significant apnoea post immunisation occurred in 17 (8.4%) babies (likely in 12 and possible 5). The subsequent (4-month) immunisation was given with inpatient cardiorespiratory monitoring in nine babies (seven with likely and two with possible reactions), and no instability was identified. There were eight babies not readmitted to FMC for the subsequent immunisation. No reported adverse events were recorded on the SA Health Immunisation Unit database for these babies. Apnoea following the 2-month immunisation in extremely preterm infants is not likely to be repeated with the subsequent immunisation. Prospective surveillance using standardised case definitions and monitoring protocols in this population are required to guide uniform practice.


[Pseudochoreoathetosis as manifestation of cervical cord lesion. Case report].
The involuntary movements of choreoathetotic type are commonly regarded as a sign of basal ganglia lesion. However, such movements can also occur in pathological processes involving the cervical spinal cord. This condition is referred to as pseudochoreoathetosis. Involuntary movements can be related to lack of proper coordination between agonist and antagonist muscles, their simultaneous activation due to impairment of reciprocal inhibition. The characteristic feature of pseudochoreoathetosis is proprioceptive sensory loss. In this paper we present 4 patients who developed various involuntary limb movements in early stage of the disease. Lesions in the cervical spinal cord were confirmed by MRI. In case 1 the cause was astrocytoma, in cases 2 and 3--demyelination, in case 4 the precise character of the lesion could not be established. Pseudochoreoathetosis is a rare condition which often remains unrecognized. The presented cases emphasise the importance of early and correct diagnosis leading to proper therapeutical procedure.


Ninjinyoeito ameliorated cigarette smoke extract-induced apoptosis and inflammation through JNK signaling inhibition in human lung fibroblasts.
Cigarette smoke is a major risk factor for various lung diseases, such as chronic obstructive pulmonary disease (COPD). Ninjinyoeito (NYT), a traditional Chinese medicine, has been prescribed for patients with post-illness or post-operative weakness, fatigue, loss of appetite, rash, cold limbs, and anemia. In addition to its traditional use, NYT has been prescribed for treating frailty in gastrointestinal, respiratory, and urinary functions. Further, NYT treatment can ameliorate cigarette smoke-induced lung injury, which is a destructive index in mice; however, the detailed underlying mechanism remains unknown. The purpose of this study was to investigate whether NYT ameliorates cigarette smoke-induced cell injury and inflammation in human lung fibroblasts and determine its mechanism of action. We prepared a cigarette smoke extract (CSE) from commercially available cigarettes to induce cell injury and inflammation in the human lung fibroblast cell line HFL1. The cells were pretreated with NYT for 24 h prior to CSE exposure. Cytotoxicity and cell viability were measured by lactate dehydrogenase (LDH) cytotoxicity assay and cell counting kit (CCK)-8. IL-8 level in the cell culture medium was measured by performing Enzyme-Linked Immuno Sorbent Assay (ELISA). To clarify the mechanisms of NYT, we used CellROX Green Reagent for reactive oxygen species (ROS) production and western blotting analysis for cell signaling. Exposure of HFL1 cells to CSE for 24 h induced apoptosis and interleukin (IL)-8 release. Pretreatment with NYT inhibited apoptosis and IL-8 release. Furthermore, CSE exposure for 24 h increased the production of ROS and phosphorylation levels of p38 and JNK. Pretreatment with NYT only inhibited CSE-induced JNK phosphorylation, and not ROS production and p38 phosphorylation. These results suggest that NYT acts as a JNK-specific inhibitor. NYT treatment ameliorated CSE-induced apoptosis and inflammation by inhibiting the JNK signaling pathway. Finally, these results suggest that NYT may be a promising therapeutic agent for patients with COPD.


S100A4 influences cancer stem cell-like properties of MGC803 gastric cancer cells by regulating GDF15 expression.
Many studies have revealed that S100A4 is involved in cancer progression by affecting a variety of biological functions. Our previous study showed that S100A4 influences many biological properties of gastric cancer cells; however, the underlying mechanisms are far from clear. In this study, we used cDNA microarray analysis to investigate the global alterations in gene expression in MGC803 gastric cancer cells after siRNA-mediated S100A4 inhibition. Among the total genes investigated, 179 differentially expressed genes (38 upregulated and 141 downregulated) were detected in S100A4-siRNA transfected MGC803 cells compared with NC-siRNA transfected cells. We focused on the GDF15 gene, which was significantly downregulated after S100A4 inhibition. ChIP studies showed that the S100A4 protein binds to the GDF15 promoter, implicating S100A4 in GDF15 regulation at the transcriptional level. GDF15 overexpression promoted CSC-like properties of MGC803 cells, such as spheroid and soft-agar colony forming abilities. S100A4 inhibition suppressed the CSC-like properties of the cells, whereas, GV141-GDF15 vector transfection reversed these effects. Our results suggest that S100A4 influences the CSC-like properties of MGC803 gastric cancer cells by regulating GDF15 expression.


Reinstated episodic context guides sampling-based decisions for reward.
How does experience inform decisions? In episodic sampling, decisions are guided by a few episodic memories of past choices. This process can yield choice patterns similar to model-free reinforcement learning; however, samples can vary from trial to trial, causing decisions to vary. Here we show that context retrieved during episodic sampling can cause choice behavior to deviate sharply from the predictions of reinforcement learning. Specifically, we show that, when a given memory is sampled, choices (in the present) are influenced by the properties of other decisions made in the same context as the sampled event. This effect is mediated by fMRI measures of context retrieval on each trial, suggesting a mechanism whereby cues trigger retrieval of context, which then triggers retrieval of other decisions from that context. This result establishes a new avenue by which experience can guide choice and, as such, has broad implications for the study of decisions.


Remotely Guided Breast Sonography for Long-Term Space Missions: A Case Report and Discussion.
Space radiation can cause different types of cancers in crewmembers, especially during long-term space missions. To date, a complete bilateral breast ultrasound has not been performed at the International Space Station (ISS). A breast screening imaging technique could be a useful tool for early identification of breast cancer in astronauts. We hypothesized that breast ultrasound performed by a crewmember while being remotely guided by a specialist from the ground could be an essential tool for medical diagnosis in space. This project aimed to test an ultrasound screening protocol for breast tissue using real-time remotely guided telemedicine techniques. One female volunteer, with no previous medical experience, performed a self-scanned bilateral breast ultrasound exam guided by a remote sonographer. Dynamic ultrasound images were collected using a 25 mm broadband linear array transducer. To simulate fluid shift on the volunteer during microgravity, the bed was tilted -6°. Recorded ultrasound images were analyzed by radiologists, comparing the findings with a gold standard. The experiment demonstrated that real-time remotely guided sonography exam is feasible and can yield meaningful clinical results. This case study showed that remotely guided breast ultrasound can be performed and might become an important tool for diagnosis of breast cancer in space missions. The results cannot be generalized based on one subject, and additional research is warranted in this area in addition to its validation on the ISS. This technique, however, has potential for use as part of preventive medicine procedures for long-term space missions at the ISS, and eventually for human settlements on the Moon and Mars.


Chronic kidney disease is one of the most serious complications of diabetes. One of the challenges in the follow-up of patients with diabetes is to discover signs of kidney disease. Recent research shows that several drugs have renal protective effects. In this clinical review article we present markers used in the follow-up of patients with diabetes and chronic kidney disease, and new treatment options.


The loneliness of a long-distance runner. A ten-year survey of a patient diagnosed with Gorham-Stout syndrome at the occipitocervical junction.
This case study presents a 47-year-old male who was diagnosed with Gorham-Stout syndrome (GSS) 10 years ago in the occipitocervical junction. The pathology caused the resorption of the suboccipital bone, clivus, foramen magnum, and C1-C3 laminae. After his first fusion attempt in 2010 using occipital plate-cervical lateral mass screws, he needed many revision surgeries either for the progression of the pathology or for instrumentation failure and wound healing problems. Eventually, a new occipital plate and cervical pedicle screws were applied to obtain the exact solution. The involvement of the craniovertebral junction in GSS may be challenging for spinal surgeons due to the inadequate bone reserve for stabilization. As lateral mass screws cannot provide a strong pull-out force, cervical pedicular screws may be used as the first choice for unstable cervical GSS cases.


Severe preeclampsia and postpartum eclampsia associated with placenta previa and cesarean and hysterectomy: a case report.
Several prior studies have demonstrated that the presence of placenta previa protects against the development of preeclampsia. Also, there are no reported cases of eclampsia following cesarean section and hysterectomy. However, we encountered a patient with total placenta previa and accreta who developed severe antepartum preeclampsia followed by the onset of eclamptic seizures after a cesarean section and a subtotal hysterectomy. This case confirms that severe preeclampsia may occur in patients with placenta previa and demonstrate that severe preeclampsia may occur after placental removal and even after subtotal hysterectomy, which removed most of the trophoblastic tissue.


Free radial artery grafts: surgical technique and results.
In the search for alternative conduits, the use of radial artery (RA) grafts has found renewed interest. This study sought to evaluate prospectively the perioperative morbidity, including the postoperative complications in the donor forearm, and mortality in the routine use of RA grafts in coronary artery bypass surgery. Data were obtained prospectively on 200 consecutive patients who underwent coronary revascularization using at least one RA graft from January 1995 to April 1997. The mean age of the patents was 61.9+/-10.5 years (mean+/-standard deviation [SD]). The RA was obtained from one forearm in 197 patients and both forearms in 3 patients. Two patients (1%) required exploration for donor site hematomas, 4 patients (2%) had temporary perioperative dysesthesias in the region of the lateral cutaneous nerve of the forearm, and none had donor site wound infection. Two patients (1%) had a myocardial infarction with electrocardiographic changes in the areas grafted by the RA in the immediate postoperative period, indicating graft failure. The two deaths in the series were due to comorbid factors. Our data suggest that the RA is a safe and suitable conduit for coronary revascularization, and it provides good clinical results. Long-term follow-up of these patients is necessary to confirm the patency of RA conduits. Free RA grafts have the potential for use in other areas of surgery where a conduit is necessary for revascularization procedures.


Update in collecting duct carcinoma: Current aspects of the clinical and molecular characterization of an orphan disease.
Collecting duct renal cell carcinoma (cdRCC), which until recently was thought to arise from the collecting ducts of Bellini in the renal medulla, is a rare and aggressive type of non-clear renal cell carcinoma (ncRCC), accounting for 1% of all renal tumors and with nearly 50% of patients being diagnosed with Stage IV disease. The median overall survival in this setting is less than 12 months. Several regimens of chemotherapies had been used based on morphologic and cytogenetic similarities with urothelial cell carcinoma described previously, although the prognosis still remains poor. The use of targeted therapies also did not result in favorable outcomes. Recent works using NGS have highlighted genomic alterations in SETD2, CDKN2A, SMARCB1, and NF2. Moreover, transcriptomic studies have confirmed the differences between urothelial carcinoma and cdRCC, the possible true origin of this disease in the distal convoluted tubule (DCT), differentiating from other RCC (e.g., clear cell and papillary) that derive from the proximal convoluted tubule (PCT), and enrichment in immune cells that may harbor insights in novel treatment strategies with immunotherapy and target agents. In this review, we update the current aspects of the clinical, molecular characterization, and new targeted therapeutic options for Collecting duct carcinoma and highlight the future perspectives of treatment in this setting.


Radiation Oncologist Characteristics and their Association with Outcomes in Patients with Head and Neck Cancer.
Intensity modulated radiation therapy (IMRT) is widely used in the treatment of head and neck cancers (HNC). There is not enough evidence to suggest that some radiation oncologists (ROs) are associated with better outcomes in patients with HNC. We conducted a cross-sectional analysis to evaluate the effect of ROs' characteristics on outcomes in patients with HNC treated with IMRT. The study used the Surveillance Epidemiology and End Results-Medicare linked database to identify patient characteristics. Physician records were obtained from the American Medical Association. Logistic regression models with propensity scores were analyzed to look for an association between RO characteristics and patient outcomes. RO characteristics showed that approximately 30% of ROS completed their training in or after the year 2000 (recently trained), and 17% were in top decile of treatment volume (high volume). Less than 3% of ROs work in academic settings. We found that ROs who were recently trained have higher odds (odds ratio [OR]: 1.10; 95% confidence interval [CI], 1.011-1.191) compared with those who were not. In addition, ROs who were treating high volumes of patients have higher odds (OR: 1.08; 95% CI, 1.010-1.165) compared with those treating low volumes of an event of adverse effect of IMRT or death among patients. ROs who work in academic settings have a protective effect (OR: 0.72; 95% CI, 0.569-0.925). ROs who were recently trained and had a high treatment volume are associated with poorer outcomes among patients with HNC who receive IMRT treatment.


Systemic mast cell disease: a clinical and hematopathologic study of 26 cases.
Systemic mast cells disease (SMCD) is an uncommon disorder that constitutes approximately 10% of all mastocytoses. Diagnosis requires a substantial degree of clinical suspicion, which may not be present if characteristic skin lesions of urticaria pigmentosa are not observed. Lack of well-defined histopathologic features for the disease have delayed or prevented the diagnosis of SMCD. An initial diagnosis of "myeloproliferative disorder," chronic granulocytic leukemia, or myelofibrosis is frequently made. Study of the clinical and pathologic features of 26 cases of SMCD indicated that affected patients are generally middle aged and may have had urticaria pigmentosa for many years. Gastrointestinal symptoms are common, and splenomegaly and hepatomegaly along with radiographic evidence of generalized bone disease are usually noted. Hematologic factors are highly variable. Characteristic histopathologic features of SMCD are described for bone marrow, lymph nodes, liver, and spleen. The authors consider tissue fixation and staining methods to help identify mast cell lesions.


The little finger ulnar palmar digital artery perforator flap: anatomical basis.
The aim of this study was to explore the cutaneous vascularization of the hypothenar region and investigate the anatomical basis for perforator propeller flaps for coverage of the flexor aspect of the little finger. The area between the pisiform and the base of the little finger was studied in 14 hands of fresh cadavers injected with red latex. An oval flap 1.5 cm large was raised along the axis between these two points. Perforators going into the flap were dissected up to their origin from the ulnar palmar digital artery of the little finger, and their distance from the proximal edge of the A1 pulley was recorded. The mean number of perforator arteries entering the flap was 5.8 (range 4-8). A constant sizeable perforator was identified within 0.7 cm from the proximal margin of the A1 pulley in all 14 specimens. In the majority of cases (64 %), the most distal perforator was located at this level. Dissection of the flap was carried out suprafascially on the most distal perforator and 180° rotation allowed the flap to reach the flexor surface of the fifth finger. The donor site was closed primarily. Distal perforators of the ulnar palmar digital artery of the little finger are constantly found. Our anatomical findings support the possibility of raising a propeller perforator flap from the hypothenar region for coverage of the flexor aspect of the little finger. Its clinical application could provide a quick and straightforward single-stage option with a negligible donor-site morbidity for reconstruction of such defects.


A prospective randomized controlled study of hamstring and bone-free quadriceps tendons autografts in arthroscopic ACL reconstruction.
Anterior cruciate ligament (ACL) reconstruction is one of the most common surgical procedures worldwide. However, the ideal graft source is still debatable. This study compared hamstring (HT) and bone-free quadriceps (QT) tendon autografts in terms of muscle strength and patient-reported outcomes. Between June 2018 and December 2019, 46 patients were enrolled in the study and randomly assigned to one of two groups for the ACL reconstruction surgery-the HT autograft group or the QT autograft group. An experienced examiner performed preoperative and postoperative examinations. The HUMAC NORM isokinetic machine (Computer Sports Medicine International-CSMI, 2004) was used to assess flexor and extensor thigh muscle strength. Both groups received the same surgical technique and fixation method. All patients were examined after three, six, nine, and 12 months. The final evaluations were performed at the 24-month follow-up. Patients' scores on the International Knee Documentation Committee (IKDC) evaluation form and the Lysholm Knee Scoring Scale were used to evaluate patient-reported outcomes. The two groups were also compared in terms of postoperative complications and activity levels. The difference between preoperative and postoperative knee flexor peak torques (FPT) was lower in the QT group than in the HT group. The average difference between preoperative and postoperative knee extensor peak torque (EPT) was higher in the QT group than in the HT group. As a result, the HT group had a lower postoperative H/Q ratio (flexor strength normalized to body mass divided by extensor strength normalized to body mass) than the QT group (p < 0.001). The mean IKDC scores for the HT and QT groups were 90.13 ± 6.99 and 87.12 ± 6.61, respectively. The scores of the two groups postoperatively were close, and both groups showed significant improvement. The average graft size in the QT group was significantly greater than that in the HT group. Saphenous nerve palsy was the most common complication in the HT group (22%). Thigh hematomas were observed in two patients in the QT group and required urgent intervention (12%). After ACL reconstruction, we found a significant decrease in strength at the donor sites in both techniques, with similar patient-reported measures and stability outcomes. The H/Q strength ratio was higher in the QT group postoperatively, which may have a protective effect on the reconstructed ligament. Level of Evidence I It is a randomized controlled trial.


Probiotics: mechanism of action, health benefits and their application in food industries.
Probiotics, like lactic acid bacteria, are non-pathogenic microbes that exert health benefits to the host when administered in adequate quantity. Currently, research is being conducted on the molecular events and applications of probiotics. The suggested mechanisms by which probiotics exert their action include; competitive exclusion of pathogens for adhesion sites, improvement of the intestinal mucosal barrier, gut immunomodulation, and neurotransmitter synthesis. This review emphasizes the recent advances in the health benefits of probiotics and the emerging applications of probiotics in the food industry. Due to their capability to modulate gut microbiota and attenuate the immune system, probiotics could be used as an adjuvant in hypertension, hypercholesterolemia, cancer, and gastrointestinal diseases. Considering the functional properties, probiotics are being used in the dairy, beverage, and baking industries. After developing the latest techniques by researchers, probiotics can now survive within harsh processing conditions and withstand GI stresses quite effectively. Thus, the potential of probiotics can efficiently be utilized on a commercial scale in food processing industries.


Experimental calculations of droplet diffusion in a low-pressure cloud chamber.
A low-pressure cloud chamber was used for several years to display the tracks created by the passage of ionizing particles through vapors of interest. The spatial distributions of the ions that were formed were of special interest, but the accuracy with which these distributions could be determined was reduced by the presence of diffusion. This meant that the droplets, when photographed, had moved significantly away from the point of creation of the parent ion. In the present investigation photographs obtained by previous workers have been analyzed in an attempt to quantify the extent to which the droplets had diffused. The results suggest that the diffusion, when converted to standard density (1000 kg/m3), was independent of the pressure inside the cloud chamber and the mixture used. It could be represented by a one-dimensional root-mean-square diffusion distance whose value was calculated to be 2.42 +/- 0.04 nm. Values for the diffusion of thermalized electrons (< approximately 4 eV) before capture to form negative ions were also calculated. They appeared to lie in the range 3.5-5.0 nm, and were again independent of the pressure and nature of the mixture. The magnitude of the diffusion was large enough to mask any measurable prediffusion structure for a distance in the region of 10 nm radially around the track path of the alpha-particle and proton tracks analyzed.


Relocalized p27Kip1 tumor suppressor functions as a cytoplasmic metastatic oncogene in melanoma.
The p27 tumor suppressor negatively regulates G1 cell cycle progression. However, human malignancies rarely select for deletion/inactivation of p27, a hallmark of tumor suppressor genes. Instead, p27 is degraded or relocalized to the cytoplasm in aggressive malignancies, supporting the notion that p27 sequestration from its nuclear cyclin:cyclin-dependent kinase (cdk) targets is critical. However, emerging cell biology data suggest a novel cdk-independent cytoplasmic function of p27 in cell migration. Here, we find cytoplasmic p27 in 70% of invasive and metastatic melanomas. In contrast, no cytoplasmic p27 was detected in noninvasive, basement membrane-confined melanoma in situ, suggesting a late oncogenic role for cytoplasmic p27 in metastasis. Targeted cytoplasmic expression of wild-type or non-cdk-binding p27 at subphysiologic levels induced melanoma motility and resulted in numerous metastases to lymph node, lung, and peritoneum. These observations point to a prominent role of cytoplasmic p27 in metastatic disease that is independent of cyclin:cdk regulation or mere nuclear loss.


Role of ultrasound scan in prenatal diagnosis of cloacal exstrophy.
Cloacal exstrophy is a rare and complex ventral abdominal wall defect. Prenatal diagnosis is possible with the use of detailed ultrasound scanning. Prenatal diagnosis of an anomalous fetus helps the parents and their families in making informed decisions. This write-up is to report a case of cloacal exstrophy diagnosed during the prenatal period using an ultrasound scan. The pregnant mother presented at 35 weeks of gestation underwent a detailed ultrasound scanning and note the findings; a large defect on the ventral surface of the anterior abdominal wall extending from the umbilicus to the inferior pelvis, with a large mass protruding through the defect, umbilical cord arising from the proximal part of the mass, with another tubular mass protruding from the inferior aspect of the larger mass giving an appearance of "elephant trunk," absent urinary bladder, absent anal dimple, and scrotum was seen inferior to the mass but failed to appreciate the phallus. Both kidneys were normal, and there was no spinal defect. In addition, pubic bones were widely separated, and there was splaying of the iliac bone. Based on the ultrasound scan findings, a prenatal diagnosis of cloacal exstrophy was made. The pregnant mother and their families were counseled about the anomalous fetus, and they decided to continue the pregnancy. At birth, the abnormalities present in the baby were consistent with the prenatal ultrasound scan findings. On postnatal day 5, the baby underwent a complete primary surgical repair of the defect which comprised of closure of the abdominal wall defect, repair of bladder defect, pelvic osteotomies, and creation of a colostomy. The abnormalities of cloacal exstrophy detected by the ultrasound scan during the prenatal diagnosis period were consistent with the abnormalities detected at birth. This concludes that an ultrasound scan is a reliable tool to diagnose cloacal exstrophy during the prenatal period.


[Molecular identification of Armillaria gallica by PCR-RFLP analysis].
Armillaria gallica is a symbiotic fungus in the cultivation process of Gastrodia elata and Polyporus.The rhizomorph of A. gallica invades the stalk of the G. elata or the Sclerotium of the Polyporus,and is digested and utilized by the latter,becoming their important source of nutrition. Different nature of A. gallica affects the growth of G. elata and Polyporus. The authors collected A. gallica from 13 commercially available regions and screened two A. gallica,A and B,at the genetic and metabolic levels,in order to distinguish between the two A. gallica market. We have established convenient and effective DNA molecular identification method.By comparing the sequence differences between the A. gallica type A and type B invertase genes,PCR-RFLP primers were designed based on differential fragment. Primer ZTM.F/ZTM.R can amplified A. gallica type A and B,producing a band of about 304 bp in length. The restriction endonuclease EcoR V could recognize the difference sequence of A and B types of A. gallica. The type B was digested to form two fragments,thereby specifically identifying the A. gallica as type B. The established methods of PCR-RFLP is an accurate identification method for A. gallica. Therefore,in the cultivation process of G. elata and Polyporus,suitable strains can be selected according to different needs of variety,growth stage and ecological environment,and the yield and quality can be improved according to local conditions.


MICA exon 5 microsatellite typing by DNA heteroduplex analysis: a new polymorphism in the transmembrane region.
MICA (MHC class I chain-related gene A) is localized 47 kb upstream from HLA-B on the short arm of chromosome 6. It has been postulated that MICA protein folds similarly to the class I chain and may have the capacity to bind short ligands. Short tandem repeats (STR) within the transmembrane (TM) region of this gene have been described and five alleles consisting of 4 to 9 GCT codons, each encoding an alanine residue have been defined. We have applied DNA heteroduplex analysis to type MICA trinucleotide repeats in order to develop a simple and reliable method for their identification. This approach allowed the characterization of all MICA alleles. Moreover, a new polymorphism within the TM region was identified.


Effect of mild increase of physical activity on microvasculary reactivity in obese subjects with diabetes mellitus type 2.
Microangiopathy, well known in diabetic patients as a cause of late complications, develops mainly due to chronic exposition to elevated glucose and triglyceride level. Physical training acts as a protective factor even if no changes in metabolic parameters are observed. It's supposed, that lifestyle modification leads to the improvement of endothelial dysfunction and microvasculary reactivity, in healthy subjects it has already been proven experimentally. Determine if mild, short time and metabolically indifferent increase of physical activity changes microvasculary reactivity in obese diabetic patients and how long these findings persist after return to habitual lifestyle. In 8 patients with type 2 diabetes mellitus was measured microvasculary reactivity and perfusion of skin in lower limbs by laser-doppler flowmetry and transcutaneous oximetry. First before the study, second after 3-week's period of habitual physical activity, third after 3-week's period of mild increased physical activity and finally after next 3-week's period of habitual activity. Training intensity was objectified (non sport-practiced subjects) by pedometers. Results were evaluated by Friedman and pair Wilcoxon test. After mild aerobic activity (walk about 800 [560-1400] meters/day) microvasculary reactivity was increased in both tests (increase after heating from 4,9x [4,4 D 5,4] to 6,1x [5,7 D 6,8], p<0.01, shorten half time to reach maximum perfusion from 4,1 [2,7 D 5,4] s to 3,1 [2,4 D 4,0] s, p<0.05. The increased perfusion lasted after following four weeks of habitual activity in smaller extent (microvascular reactivity increase after heating 5.2 [4.8 D 6.1] s, half time to reach maximum perfusion 3.8 [2.7 D 5.0], this increase was not significant in comparison with habitual activity in the first period). Metabolic and anthropometric parameters and transcutaneous oxygen tension didn't change significantly.


Chronic prescription of antidepressant medication in patients with chronic kidney disease with and without kidney replacement therapy compared with matched controls in the Dutch general population.
Chronic kidney disease (CKD) is associated with a higher prevalence of depression, neuropathic pain and insomnia. These conditions are often treated pharmaceutically. In this study we aimed to determine the prevalence of chronic antidepressant use among CKD patients with and without kidney replacement therapy (KRT). By using the Dutch health claims database, we were able to determine the prevalence, type and dosage of chronic antidepressant prescriptions in patients with CKD Stage G4/G5 without KRT (n = 14 905), patients on dialysis (n = 3872) and patients living on a functioning graft (n = 8796) and compared these to age-, sex- and socio-economic status (SES)-matched controls from the general population. Our data show that the prevalence of chronic antidepressant prescription is 5.6%, 5.3% and 4.2% in CKD Stage G4/G5, dialysis and kidney transplant patients, respectively, which is significantly higher than in matched controls. Although our data revealed more prescriptions in female patients and in the age category 45-64 years, our data did not show any association between antidepressant prescriptions and SES. Selective serotonin reuptake inhibitors were the most prescribed drugs in all patient groups and controls. Tricyclic antidepressants were more often used in patients compared with controls. This nationwide analysis revealed that chronic antidepressant prescription in the Netherlands is higher in CKD patients with and without KRT than in controls, higher in middle-aged patients and women, unrelated to socio-economic status and lower than chronic use reported in other countries.


[Monocarboxylate transporter 1 enhances the sensitivity of breast cancer cells to 3-bromopyruvate in vitro].
To investigate the role of monocarboxylate transporter 1 (MCT1) in enhancing the sensitivity of breast cancer cells to 3-bromopyruvate (3-BrPA). The inhibitory effect of 3-BrPA on the proliferation of breast cancer cells was assessed with MTT assay, and brominated propidium bromide single staining flow cytometry was used for detecting the cell apoptosis. An ELISA kit was used to detect the intracellular levels of hexokinase II, lactate dehydrogenase, lactate, and adenosine triphosphate, and Western blotting was performed to detect the expression of MCT1. MDA-MB-231 cells were transiently transfected with MCT1 cDNA for over-expressing MCT1, and the effect of 3-BrPA on the cell proliferation and adenosine triphosphate level was deteced. 3-BrPA did not produce significant effects on the proliferation and apoptosis of MDA-MB-231 cells, and the cells treated with 200 µmol/L 3-BrPA for 24 h showed an inhibition rate and an apoptosis rate of only 8.72% and 7.8%, respectively. The same treatment, however, produced an inhibition rate and an apoptosis rate of 84.6% and 82.3% in MCF-7 cells, respectively. In MDA-MB-231 cells with MCT1 overexpression, 200 µmol/L 3-BrPA resulted in an inhibition rate of 72.44%, significantly higher than that in the control cells (P<0.05); treatment of the cells with 25, 50, 100, and 200 µmol/L 3-BrPA for 6 h resulted in intracellular adenosine triphosphate levels of 96.98%, 88.44%, 43.3% and 27.56% relative to the control level respectively. MCT1 can enhance the sensitivity of breast cancer cells to 3-BrPA possibly by transporting 3-BrPA into cells to inhibit cell glycolysis.


Pairing between gypsy insulators facilitates the enhancer action in trans throughout the Drosophila genome.
The Suppressor of the Hairy wing [Su(Hw)] binding region within the gypsy retrotransposon is the best known chromatin insulator in Drosophila melanogaster. According to previous data, two copies of the gypsy insulator inserted between an enhancer and a promoter neutralize each other's actions, which is indicative of an interaction between the protein complexes bound to the insulators. We have investigated the role of pairing between the gypsy insulators located on homologous chromosomes in trans interaction between yellow enhancers and a promoter. It has been shown that trans activation of the yellow promoter strongly depends on the site of the transposon insertion, which is evidence for a role of surrounding chromatin in homologous pairing. The presence of the gypsy insulators in both homologous chromosomes even at a distance of 9 kb downstream from the promoter dramatically improves the trans activation of yellow. Moreover, the gypsy insulators have proved to stabilize trans activation between distantly located enhancers and a promoter. These data suggest that gypsy insulator pairing is involved in communication between loci in the Drosophila genome.


The birth of innate immunity.
Modern immunology has seen an apparent revolution with the recognition that human immune defense is not only the responsibility of bone marrow-derived leucocytes, but also dependent on a coordinated network of many cell types including epithelial cells, fibroblasts and neural elements. This classic paper by Alexander Fleming and V.D. Allison (British J of Exp Path, 111, 1922, 252) was largely forgotten for 75 years and describes the discovery that epithelia produce a protein with direct antimicrobial activity. Thus, this paper represents the birth of the field now referred to as innate immunity and first describes an antimicrobial protein (AMP).


DAS28-CRP and DAS28-ESR cut-offs for high disease activity in rheumatoid arthritis are not interchangeable.
In most patients with rheumatoid arthritis (RA), Disease Activity Score 28-joint count C reactive protein (DAS28-CRP) is lower than DAS28 erythrocyte sedimentation rate (DAS28-ESR), suggesting that use of the DAS28-ESR cut-off to assess high disease activity (HDA) with DAS28-CRP may underestimate the number of patients with HDA. We determined the DAS28-CRP value corresponding to the validated DAS28-ESR cut-off for HDA. Baseline data were pooled from 2 clinical studies evaluating etanercept (ETN) plus methotrexate (MTX) or MTX in early RA; DAS28-CRP and DAS28-ESR were obtained, allowing the determination of the DAS28-CRP HDA value best corresponding to the DAS28-ESR cut-off of >5.1. At baseline, as expected, fewer patients had HDA by DAS28-CRP than DAS28-ESR; DAS28-CRP>5.1 and DAS28-ESR>5.1 had only modest agreement (κ coefficients 0.45-0.54). Mean DAS28-CRP and DAS28-ESR were 5.7 and 6.2, respectively, in the ETN+MTX group (n=571), and 6.0 and 6.5 in the MTX group (n=262). A DAS28-CRP cut-off of 4.6 corresponded to a DAS28-ESR cut-off of 5.1. We have shown that a DAS28-CRP of 4.6 corresponds to 5.1 for DAS28-ESR. Since this is substantially lower than the DAS28-ESR cut-off of 5.1, using 5.1 as the cut-off for DAS28-CRP underestimates disease activity in RA. NCT00195494; NCT00913458.


Pre-discharge and early post-discharge management of patients hospitalized for acute heart failure: A scientific statement by the Heart Failure Association of the ESC.
Acute heart failure is a major cause of urgent hospitalizations. These are followed by marked increases in death and rehospitalization rates, which then decline exponentially though they remain higher than in patients without a recent hospitalization. Therefore, optimal management of patients with acute heart failure before discharge and in the early post-discharge phase is critical. First, it may prevent rehospitalizations through the early detection and effective treatment of residual or recurrent congestion, the main manifestation of decompensation. Second, initiation at pre-discharge and titration to target doses in the early post-discharge period, of guideline-directed medical therapy may improve both short- and long-term outcomes. Third, in chronic heart failure, medical treatment is often left unchanged, so the acute heart failure hospitalization presents an opportunity for implementation of therapy. The aim of this scientific statement by the Heart Failure Association of the European Society of Cardiology is to summarize recent findings that have implications for clinical management both in the pre-discharge and the early post-discharge phase after a hospitalization for acute heart failure.


The plant mannose-binding lectin NTL preserves cord blood haematopoietic stem/progenitor cells in long-term culture and enhances their ex vivo expansion.
Ex vivo expansion of haematopoietic stem and progenitor cells in cytokine combinations is effective in promoting differentiation and proliferation of multilineage progenitor cells, but often results in reduction of self-renewable stem cells. This study investigated the effect of a mannose-binding lectin, NTL, purified from Narcissus tazetta var. chinensis, on prolonged maintenance and expansion of cord blood CD34+ cells. Our results showed that the presence of NTL or Flt-3 ligand (FL) significantly preserved a population of early stem/progenitor cells in a serum- and cytokine-free culture for 35 d. The effect of NTL on the ex vivo expansion of CD34+ cells in the presence of stem cell factor, thrombopoietin (TPO) and FL was also investigated. NTL-enhanced expansion of early progenitors (CD34+, CD34+CD38-, mixed colony-forming units and CFU-GEMM) and committed progenitor cells (granulocyte CFU, erythroid burst-forming units/CFU and megakayocyte CFU) after 8 and 12 d of culture. Six weeks after transplanting 12 d-expanded cells to non-obese diabetic severe combined immunodeficient mice, increased engraftment of human CD45+ cells was observed in the bone marrow of animals that received NTL-treated cells. The dual functions of NTL on long-term preservation and expansion of early stem/multilineage progenitor cells could be developed for applications in various cell therapy strategies, such as the clinical expansion of CD34+ cells for transplantation.


SWOG 0514: a phase II study of sorafenib in patients with unresectable or metastatic gallbladder carcinoma and cholangiocarcinoma.
Gallbladder and cholangiocarcinomas represent a heterogeneous group of malignant diseases that commonly present at an advanced stage and have limited therapeutic options. Based on the role of the Ras-Raf-Mek-Erk pathway and the VEGF axis in biliary carcinomas, we conducted a phase II study of sorafenib in patients with advanced biliary cancers. Eligible patients had no prior therapy for metastatic or unresectable disease. Sorafenib was administered at 400 mg po twice daily continuously. The study was terminated after the first stage of accrual due to failure to meet the primary objective. A confirmed response rate of 0% (0%-11%) was observed. Thirty-nine percent of patients demonstrated stable disease (including 2 with unconfirmed PR). PFS was 3 months (95% CI: 2-4 months) and OS 9 months (95% CI: 4-12 months). The most common grade 3 and 4 toxicities included hand-foot skin reaction (13%), bilirubin elevation (13%), venous thromboembolism (10%), AST/ALT elevation (10%) and elevated alkaline phosphatase (10%). While treatment with sorafenib did not result in objective responses, patients with biliary cancers receiving this drug had some therapeutic benefit. Additional studies with sorafenib in combination with chemotherapy or other targeted agents may be warranted.


Construction and identification of human glial cell-derived neurotrophic factor gene-modified Schwann cells from rhesus monkeys.
The objective of this study was to construct stable rhesus monkey Schwann cells (SCs) modified with the human glial cell-derived neurotrophic factor (hGDNF) gene. hGDNF gene amplification was performed with pUC19-hGDNF as templates, and then the coding sequence of hGDNF was inserted into the eukaryotic expression vector pBABE-puro to obtain the recombinant vector pBABE-puro-hGDNF. The recombinant vector pBABE-puro-hGDNF was identified with restriction enzyme, and then underwent DNA sequencing. SCs from rhesus monkeys were transfected with the recombinant vector pBABE-puro-hGDNF, and then the expression levels of mRNA and protein of the hGDNF gene were determined with real-time fluorescence quantitative PCR and Western blot, respectively, in the transfected SCs. The biological activity of GDNF gene-modified SCs (GDNF-SCs) was assessed by MTT assay. The length of the hGDNF coding sequence of PCR products was 569 bp. After the recombinant eukaryotic expression vectors were digested with restriction enzyme, there was a specific segment of 596 bp. The results of DNA sequencing of the specific segment of 596 bp were the same as that of hGDNF in GenBank, suggesting that the hGDNF gene was successfully inserted into the recombinant retrovirus vectors. The expression levels of mRNA and protein were significantly higher in transfected SCs as compared to nontransfected SCs (p<0.05). MTT assay indicated that the OD value was significantly higher in GDNF-SCs group than in SCs and DMEM groups (p<0.05). hGDNF-SCs can steadily and efficiently release hGDNF. This study provides a basis for cell therapy of nerve injury.


Gene delivery by lipoplexes and polyplexes.
Gene therapy has emerged as a promising approach for the treatment or prevention of acquired and genetic diseases. At the present time, major somatic gene transfer approaches employ either viral or non-viral vectors. Viral vectors show high gene transfer efficiency, but are deficient in several areas, including the induction of a host inflammatory and immune response. Some of these problems can be circumvented by employing non-viral vehicles, such as cationic liposomes or polymers. The complexes they form with DNA are defined as "lipoplexes" or "polyplexes, respectively, and constitute the most promising alternative to the use of viral vectors for gene therapy. Here we review the interactions between the vectors and DNA leading to complex formation, the supramolecular structures of lipoplexes and polyplexes, and their mechanisms of DNA transfer. Our objective is to provide a framework for the future design and synthesis of optimal non-viral vectors for gene therapy. The structure, charge and formulation of these vehicles are also related to the stability, and consequently to the efficiency of gene transfection. While lipids that facilitate transformation of lipoplexes to non-bilayer phases mediate high transfection activity in vitro, lipids, like cholesterol, that confer stability in serum, are more suitable for gene delivery in vivo. The efficiency of polyplex-mediated transfection depends on the ability of the polymer to condense DNA, while allowing it to dissociate once inside the cell.


Exosome-coated polydatin nanoparticles in the treatment of radiation-induced intestinal damage.
This study aimed to develop an exosome-coated polydatin (PD) nanoparticles (exo-PD) for improving the water solubility and bioavailability of polydatin and explore its salutary effects on intestinal radiation injury. Exosomes (exo) were extracted from the medium of human amniotic fluid stem cells (hAFSc). Mice were divided into control group, irradiation (IR) group, irradiation+PD (IR+PD) group, irradiation+exo (IR+exo) group and irradiation+exo-PD (IR+exo-PD) group. The results of characterization of protein markers, particle size, morphology and cellular uptake ability confirmed that exosomes were effectively isolated using ultracentrifugation. Compared with the IR group, exo-PD improved cell viability, prolonged survival of mice, improved leukocyte count and reduced diarrhea rate. Histological results showed that the exo-PD group had significant improvements in small intestinal villus length and crypt number and less crypt cell damage. exo-PD could reduce IL-1α and IL-6 levels, reduced γ-H2AX expression, increased mitochondrial membrane potential, enhanced oxidative phosphorylation, and delayed cellular senescence. exo-PD could alleviate intestinal injury by improving mitochondrial function through PI3K-AKT pathway. The exo-PD was able to reduce radiation damage to intestinal cells and could be a potential candidate for salvage of intestinal radiation damage.


Prevalence of Non-alcoholic Fatty Liver Disease (NAFLD) in Saudi Arabia: Systematic Review and Meta-analysis.
Liver disease is fast emerging as a global health priority. Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in Western countries, with an increasing prevalence associated with the rising prevalence of diabetes mellitus and obesity. The worldwide prevalence of NAFLD may be in the order of 25%, but in the Middle East, it may be even higher. This study aimed to estimate the prevalence of NAFLD in the Kingdom of Saudi Arabia (KSA). A systematic review and meta-analysis were undertaken. Electronic searches were carried out through Medline, EMBASE, CINAHL, Web of Science, and Google Scholar, for articles from inception to April 2020. Studies conducted on adult populations in any setting reporting NAFLD prevalence were included. Pooled proportions and associated 95% confidence intervals (CIs) were presented in forest plots using a random effect model. Eight studies, including 4045 participants, were included. The pooled prevalence of NAFLD among all adult populations in KSA was 16.8% (11.1%-22.5%). Amongst those with type 2 diabetes, the prevalence was 58.0% (45.0%-70.9%). There were no true general population studies of the prevalence of NAFLD in KSA available. This review suggests that NAFLD is common in the KSA, and that type 2 diabetes is a risk factor in KSA as identified elsewhere in the world.


A new, distinctly coloured species of Lysmata Risso, 1816 (Malacostraca: Decapoda: Lysmatidae) from the south-central Atlantic.
A new species of the caridean shrimp genus Lysmata Risso, 1816 is described from St. Helena and Ascension Island in the south-central Atlantic. Lysmata napoleoni sp. nov. is part of the so-called "long-branch group" of the genus and shows a strong morphological similarity with the eastern Atlantic L. seticaudata Risso, 1816, from which it can be distinguished by details of the accessory branch of the antennular flagellum. The new species also displays a unique and bright colour pattern and therefore can be easily recognised in the field. Furthermore, it is typically found in proximity of sea anemones, Telmatactis cricoides (Duchassaing), and appears to be an occasional fish cleaner.


Can Platelet Indices Be New Biomarkers for Subjective Tinnitus?
Mean platelet volume (MPV) is one of the platelet function indices that reflect the platelet production rate and functions. The MPV levels are increased by vascular occlusion, acute or chronic syndromes, and vasculitis, whereas infections, autoimmune diseases, and inflammatory situations reduce these levels. In this study, the authors investigated whether there was a relationship between platelet indices and subjective tinnitus. In this retrospective study, the authors evaluated platelet indices in subjective tinnitus patients. One hundred patients with subjective tinnitus and 100 healthy, age and sex-matched subjects were enrolled to the study. Audiometer and laboratory results were recorded. Comparative multivariate analyses between indicator factors and hearing outcomes were conducted. Mean platelet volume is significantly lower in subjective tinnitus group (P < 0.001). Platelet count and platelet distribution width are higher in the subjective tinnitus than control group (P < 0.001, P < 0.003, respectively). The authors' findings indicate that subjective tinnitus appears to be characterized by autoimmune and inflammatory events. Considering the decreasing MPV levels, MPV may be used to evaluate subjective tinnitus as an helper indicator.


Periodic arrays of interfacial cylindrical reverse micelles.
We report an approach for the fabrication of periodic molecular nanostructures on surfaces. The approach involves biomimetic self-organization of synthetic wedge-shaped amphiphilic molecules into multilayer arrays of cylindrical reverse micelles. The films were characterized by atomic force microscopy and X-ray reflectivity. These nanostructured films self-assemble in solution but remain stable upon removal and exposure to ambient conditions, making them potentially suitable for a variety of dry pattern transfer methods. We illustrate the generality of this approach by using two distinct molecular systems that vary in size by a factor of 2.


The Prognosis and Immune Checkpoint Blockade Efficacy Prediction of Tumor-Infiltrating Immune Cells in Lung Cancer.
The high morbidity and mortality of lung cancer are serious public health problems. The prognosis of lung cancer and whether to apply immune checkpoint blockade (ICB) are currently urgent problems to be solved. Using R software, we performed Kaplan-Meier (K-M) analysis, Cox regression analysis, functional enrichment analysis, Spearman correlation analysis, and the single-sample gene set enrichment analysis. On the Tumor IMmune Estimation Resource (TIMER2.0) website, we calculated the abundance of tumor-infiltrating immune cells (TIICs) of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) patients. B cell and myeloid dendritic cell (DC1) were independent prognostic factors for LUAD and LUSC patients, respectively. Enrichment analysis confirmed that genes highly related to B cell or DC1 were closely related to the immune activation of lung cancer patients. In terms of adaptive immune resistance markers, CD8A, CD8B, immunomodulators (immunostimulants, major histocompatibility complex, receptors, and chemokines), immune-related pathways, tumor microenvironment score, and TIICs, high B cell/DC1 infiltration tissue was inflamed and immune-activated and might benefit more from the ICB. Genes most related to B cell [CD19, toll-like receptor 10 (TLR10), and Fc receptor-like A (FCRLA)] and DC1 (ITGB2, LAPTM5, and SLC7A7) partially clarified the roles of B cell/DC1 in predicting ICB efficacy. Among the 186 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, there were three and four KEGG pathways, which partially explained the molecular mechanisms by which B cell and DC1 simultaneously predicted the prognosis and efficacy of immunotherapy, respectively. Among five immune subtypes, the abundance of B cell/DC1 and expression of six hub genes were higher in immune C2, C3, and C6. B cell and DC1 could predict the prognosis and ICB efficacy of LUAD and LUSC patients, respectively. The six hub genes and seven KEGG pathways might be novel immunotherapy targets. Immune C2, C3, and C6 subtypes of lung cancer patients might benefit more from ICB therapy.


Prenatal diagnosis of pentalogy of Cantrell.
Ten cases of prenatal diagnosis of Pentalogy of Cantrell are reported. A uniformly fatal outcome was found confirmed by a review of similar cases prenatally diagnosed by other authors. This is at variance with the data derived from the pediatric literature. Implications in obstetrical management and parental counseling are discussed.


Professional socialization to a research role: interest in research among graduate students in nursing.
This study was conducted to determine whether graduate coursework in research methods and statistics resulted in socializing graduate students in nursing into a research role. Two cohorts, each of about 60 female graduate students in nursing, completed self-administration questionnaires at three different times during their 6 month coursework in research methods and statistics. Subjects indicated significantly more interest in research methods than in statistics (p less than .01), although they rated statistics as valuable to nursing. At the beginning of graduate work, subjects with more work experience in nursing were significantly more interested (p less than .05) in conducting research. Graduate coursework in research methods and statistics produced no significant change in students' interest in doing research in their future nursing careers.


Effects of mealworm larva composition and selected process parameters on the physicochemical properties of extruded meat analog.
Mealworm larva (Tenebrio molitor), the most promising edible insect species with low cost and less environmental pollution, can fulfill the flavor and nutrition which are deficient in soy-based meat analog. Consumers who might have the sensitivity and reluctance to the intact form of edible insect could be offered the high-quality extruded meat analog. Therefore, this study aimed to investigate the effects of different mealworm larva contents and extrusion process parameters using twin-screw extruder on the physicochemical properties of the extruded meat analog. Mealworm larva was added to the base formulation at the rate of 0, 15, and 30%. Extrusion process parameters were varied as die temperature (140°C and 150°C) and moisture content (40% and 50%). The integrity index, texture profile analysis, and oxidation activity (TBARS) of extruded meat analog decreased with increase in mealworm larva content. However, water holding capacity, nitrogen solubility index, protein digestibility, and DPPH radical scavenging activity significantly increased (p < .05) as the mealworm content increased. Lower die temperature and higher moisture content enhanced the textural properties, but reduced nitrogen solubility index and protein digestibility. At higher die temperature, DPPH activity increased but TBARS showed the opposite result. After extrusion cooking, the total amino acid levels of extruded meat analog were 585.21 g/kg in 30% mealworm larva content that level was lower than 591.43 g/kg in raw mixture while the sulfur-containing amino acids and glutamic acid were higher than that of raw mixture. In conclusion, addition of mealworm larva could improve the nutritional value, antioxidant functionality, and taste of extruded meat analog under controlled extrusion process conditions.


Paediatric oral sensorimotor interventions for chewing dysfunction: A scoping review.
Chewing dysfunction can have adverse effects on growth, development and quality of life. There is a lack of evidence-based consensus guidelines for sensorimotor intervention. To address this, we need to understand the current state of the science in clinical sensorimotor interventions for paediatric chewing dysfunction and systematically plan a research agenda and priorities for the field. The purpose of this scoping review was to examine the extent, range and nature of evidence for oral sensorimotor interventions for paediatric chewing dysfunction. This scoping review entailed five phases that included: identification of the research question; identification of relevant studies; study selection; data charting; and collation, summarization and report of the results. Treatment studies that were peer-reviewed and written in English were included. All studies involved a paediatric population and included an oral sensorimotor and/or chewing intervention. Information regarding study design, population, intervention, comparator, outcome measures and findings were extracted. Of the 21 studies included in this scoping review, 53% were specific to children with cerebral palsy. All interventions were multi-component in nature and the treatment studies included a range of study designs, but few were controlled trials with comparators. A wide variety of outcomes measures were used within and across studies to determine treatment effectiveness. The findings suggest that in a small number of studies, sensorimotor interventions provide preliminary evidence for effectiveness in specific populations. These and other treatment protocols must be trialled in additional clinical populations and settings to improve the evidence base for sensorimotor treatment of paediatric chewing dysfunction. This review also serves to help prioritize research agendas and further motivates the need for consensus-based clinical guidelines for paediatric chewing treatment. What is already known on the subject Paediatric feeding disorders are highly prevalent and children often have chewing dysfunction that results in significant negative consequences. We lack evidence-based sensorimotor treatment approaches for chewing dysfunction, which directly impacts the care clinicians can provide children. What this study adds to existing knowledge This scoping review is the first step in examining the literature to understand the current state of the science for oral sensorimotor interventions for paediatric chewing dysfunction. Few randomized controlled studies were identified and a majority included children with cerebral palsy. Most of the interventions were multi-component and included a variety of treatment approaches. What are the potential or actual clinical implications of this work? The results of this scoping review can be used as an initial reference for clinicians selecting treatment approaches for chewing dysfunction. It also serves to help prioritize research agendas and further motivates the need for consensus-based clinical guidelines for paediatric chewing treatment.


A new Caenorhabditis elegans model of human huntingtin 513 aggregation and toxicity in body wall muscles.
Expanded polyglutamine repeats in different proteins are the known determinants of at least nine progressive neurodegenerative disorders whose symptoms include cognitive and motor impairment that worsen as patients age. One such disorder is Huntington's Disease (HD) that is caused by a polyglutamine expansion in the human huntingtin protein (htt). The polyglutamine expansion destabilizes htt leading to protein misfolding, which in turn triggers neurodegeneration and the disruption of energy metabolism in muscle cells. However, the molecular mechanisms that underlie htt proteotoxicity have been somewhat elusive, and the muscle phenotypes have not been well studied. To generate tools to elucidate the basis for muscle dysfunction, we engineered Caenorhabditis elegans to express a disease-associated 513 amino acid fragment of human htt in body wall muscle cells. We show that this htt fragment aggregates in C. elegans in a polyglutamine length-dependent manner and is toxic. Toxicity manifests as motor impairment and a shortened lifespan. Compared to previous models, the data suggest that the protein context in which a polyglutamine tract is embedded alters aggregation propensity and toxicity, likely by affecting interactions with the muscle cell environment.


Unilateral digital clubbing in a hemodialysis patient.
We present an unusual case of a chronic hemodialysis patient with moderate diffuse acrocyanosis and prominent unilateral clubbing of his right hand fingers, with classic physical features of hypertrophic osteoarthropathy. The patient's left hand, which had a functioning arteriovenous fistula, did not show any evidence of clubbing. We briefly discuss the different theories in regards to the pathogenesis of clubbing, and the potential role of arteriovenous fistula in preventing its occurrence.


Association of Trauma Center Level and Patient Volume with Outcomes for Penetrating Thoracic Trauma.
We investigated the potential link between trauma center American College of Surgeons verification level and institutional volume of penetrating thoracic trauma with outcomes for patients with penetrating thoracic trauma. Penetrating thoracic injuries were identified in the National Trauma Data Bank from 2013 to 2016. Primary exposures were trauma center American College of Surgeons verification level and annual penetrating trauma caseload by center. Cox models were used to evaluate the association between primary exposures and mortality. Poisson regression was used to evaluate admission and outcome rate differences by trauma center status. Of 68,727 patients identified, 38% were treated at level I centers, 18% at level II centers, and 44% at other centers. Only 3.1% required major surgery for thoracic injury (3.1% at level I, 2.6% at level II, and 3.2% at other). Overall, annual volume of penetrating thoracic trauma was not associated with mortality. For specific injuries, level I centers had superior outcomes for injuries to the thoracic aorta and vena cava compared with other centers. Level I centers also showed improved outcomes for lung/bronchus injuries compared with level II centers. Level I centers had less sepsis/acute respiratory distress syndrome, but more surgical site infection, venous thromboembolism, and unplanned operation compared with non-level I centers. There was no identified impact of penetrating thoracic trauma volume or trauma center verification level on overall mortality. However, level I verification did correlate with improved outcomes for some specific injuries. Further study to identify factors that improve outcomes in patients with high-risk penetrating thoracic mechanisms is warranted.


[Dose-dependent pellagroid skin reaction caused by carbamazepine].
A 11-year-old girl suffering from grand mal epilepsy underwent antiepileptic therapy with carbamazepine (600 mg/daily). Two weeks after increasing the dose (900 mg/day) she suddenly developed relatively sharply limited, sunburn-like brown reddish macular lesions with central scaling and partly hyperkeratotic areas on the hands, feet, face, knees, gluteal and axillar regions. Otherwise no health disorders were found; in particular no neurological or gastrointestinal symptoms occurred. After reduction of the doses (450 mg/day) these skin lesions faded away. With exception of elevated serum levels of carbamazepine, nicotinamide and vitamin B6, all blood tests were in normal range. Interactions of carbamazepine with the vitamin B6- nicotinamide metabolism are the reason for these previously undescribed cutaneous side effects in connection with carbamazepine therapy. The present case demonstrates a toxic, non-allergic reaction during carbamazepine treatment with pellagroid skin symptoms.


The effects of superior ovarian nerve sectioning on ovulation in the guinea pig.
The effects on spontaneous ovulation associated with the unilateral or bilateral sectioning of the superior ovarian nerves (SON) were analyzed in guinea pigs at different time intervals of the estrous cycle. Day 1 of the estrous cycle was defined as the day when the animal presents complete loss of the vaginal membrane (open vagina). Subsequent phases of the cycle were determined by counting the days after Day 1. All animals were autopsied on the fifth day of the estrous cycle after surgery. Sectioning the right, left, or both SONs on day 5 (early luteal phase) resulted in a significant increase in the number of fresh corpora lutea. Ovulation increased significantly when the left SON (L-SON) was sectioned during late follicular phase (day 1) and medium luteal phase (day 8). When surgery was performed on days 1 or 8, neither sectioning the right SON (R-SON) nor sectioning the SON bilaterally had an apparent effect on ovulation rates. Similarly, ovulation rates were not affected when unilateral (right or left) or bilateral sectioning of the SON was performed during late luteal phase two (day 12). Unilateral or bilateral sectioning of the SON performed during the early luteal phase (day 5) was associated with a significant decrease in uterine weight. A comparable effect was observed when the L-SON was sectioned during late follicular phase (day 1), or medium luteal phase (day 8). No effects on uterine weight were observed when unilateral or bilateral sectioning of the SON was performed during late luteal phase. Our results suggest that in the guinea pig the SON modulates ovulation, and that the degree of modulation varies along the estrous cycle. The strongest influence of the SONs on ovulation occurs during early luteal phase, and decrease thereafter, being absent by late luteal phase. In addition, sectioning the left or the right SON caused different responses by the ovaries of adult guinea pigs. This paper discusses the mechanisms by which ovulation increased when the SON was surgically cut.


Mode of action of long-term low-dose macrolide therapy for chronic sinusitis in the light of neutrophil recruitment.
Chronic sinusitis is a common inflammatory upper respiratory tract disease. One of the prominent features of this disease is persistent purulent effusion containing numerous emigrated neutrophils in the paranasal sinuses. Recent advances in sinusitis research have revealed two positive feedback mechanisms that explain the chronic neutrophil accumulation in the sinus. First, interleukin (IL)-1beta secreted by monocytes, macrophages and fibroblasts upregulates the expression of E-selectin and intercellular adhesion molecule-1 (ICAM-1) in vascular endothelial cells, and thereby induces the extravascular transmigration of neutrophils. The emigrated neutrophils then secrete IL-1beta, which amplifies the expression of E-selectin and ICAM-1, resulting in further neutrophil infiltration. Second, chemoattractants including IL-8 in the sinus effusion initiate neutrophil exudation. Emigrated neutrophils then secrete IL-8, which elicits further neutrophil accumulation in the sinus effusion. Long-term low-dose macrolide therapy was first introduced for the treatment of diffuse panbronchiolitis in the 1980's. In the 1990's it was also shown to be an effective treatment for chronic sinusitis. The inhibitory effect of macrolides on neutrophil infiltration in inflammatory sites has been well documented in these diseases. Several lines of evidence indicate that macrolides do not function simply as a bactericide. In vitro studies have demonstrated various effects of macrolides on immunocompetent cells, inflammatory cells and airway epithelial cells. It has been shown that macrolides inhibit the production of IL-8 and IL-1beta and the expression of ICAM-1, suggesting that macrolides block the aforementioned dual positive feedback system of neutrophil recruitment and thereby exert their clinical efficacy in the treatment of chronic sinusitis. The inhibitory effects of macrolides on multiple steps in the process of neutrophil recruitment are presumably mediated by the inhibition of transcription factors such as nuclear factor-kB and activator protein-1. Further investigation of the mode of action of macrolides at the molecular level would lead to the development of safer and more effective drugs for the treatment of chronic sinusitis. In addition, the possible risk of this therapy such as the occurrence of resistant strains have to be carefully surveyed hereafter.


Increases of quadriceps inter-muscular cross-correlation and coherence during exhausting stepping exercise.
The aim of this study was to examine the change of the intermuscular cross-correlation and coherence of the rectus femoris (RF), vastus medialis (VM) and vastus lateralis (VL) during exhausting stepping exercise. Eleven healthy adults repeated the stepping exercise up to their individual endurance limits (RPE score reached 20), and the cross-correlation and coherence were assessed by surface electromyography (EMG) recordings. The coefficient and time lag of cross-correlation and the coherence areas in the alpha (8-12 Hz), beta (15-30 Hz), gamma (30-60 Hz) and high-gamma (60-150 Hz) bands among the three muscle pairs (RF-VM, RF-VL and VM-VL) were calculated. As muscle fatigue, RF-VM and VM-VL showed increases of coefficients and the shortening of time lags. RF-VM and RF-VL showed increases of beta-band coherence in the ascent and descent phases, respectively. The increased intermuscular cross-correlation and beta-band coherence may be a compensatory strategy for maintaining the coordination of knee synergistic muscles during fatigue due to the fatigue-related disturbance of the corticospinal transmission. Therefore, the intermuscular cross-correlation and beta-band coherence may be a potential index for assessing muscle fatigue and monitoring the central control of motor function during dynamic fatiguing exercise.


Renin-angiotensin system in cultured human arterial smooth muscle cells.
Angiotensin converting enzyme (ACE) inhibitors were evaluated from their effects on human arterial smooth muscle cells in culture. [3H]ramipril binding has been determined in two different cell lines exhibiting ACE(+) and ACE(-) phenotypes. Specific binding occurred only in ACE(+) cells, was saturable, and displayed a Kd of 1 nM with a beta max value of 3.5 fmol/10(6) cells. Ramipril specific binding did not significantly modulate PGI2 synthesis in ACE(+) cells. By contrast, ramipril and, to a lesser extent, captopril appeared as weak inhibitors of PGI2 synthesis in ACE(-) cells. These data indicate that human arterial SMCs may express several phenotypes of the renin-angiotensin system under culture conditions and that ACE inhibitors may exert a non-renin-angiotensin-mediated pharmacological effect on eicosanoid synthesis.


Assertion training with adolescents.
A month-long assertion training program for adolescents was instituted and evaluated in a middle-school setting. A group of 23 adolescents who received the treatment was compared to a group of 23 adolescents who did not receive the treatment. Although there were no significant differences between the groups prior to the program, the group who received the training significantly improved their scores on the Piers -Harris Children's Self-Concept Scale and the Intellectual Achievement Responsibility Questionnaire by the termination of the program. The group who did not receive any special program showed no change in their scores on these scales. These differences were still present at a seven-week follow-up.


Activities of herpes simplex virus type 1 (HSV-1) ICP4 genes specifying nonsense peptides.
Synthetic oligonucleotide linkers containing translational termination codons in all possible reading frames were inserted at various positions in the cloned gene encoding the herpes simplex virus type 1 (HSV-1) immediate-early regulatory protein, ICP4. It was determined that the amino-terminal 60 percent of the ICP4 gene was sufficient for trans-induction of a thymidine kinase promoter-CAT chimera (pTKCAT) and negative regulation of an ICP4 promoter-CAT chimera (pIE3CAT); however, it was relatively inefficient in complementing an ICP4 deletion mutant. The amino-terminal ninety amino acids do not appear to be required for infectivity as reflected by the replication competence of a mutant virus containing a linker insertion at amino acid 12. The size of the ICP4 molecule expressed from the mutant virus was consistent with translational restart at the next methionine codon corresponding to amino acid 90 of the deduced ICP4 amino acid sequence.


Cross-Reactive Fluorescent Sensor Array for Discrimination of Amyloid Beta Aggregates.
It has been hypothesized that misfolding and misassembly of proteins into various aggregation states contribute to several neurodegenerative diseases. For instance, amyloid beta (Aβ) aggregation is considered a major factor in Alzheimer's disease pathogenesis. Herein, a fluorescent sensor array for detecting Aβ aggregates was fabricated using two probe pairs of conjugated polyelectrolytes and organic dye molecules, PPE1-Thioflavin T (ThT) and PPESO3-Nile Red (NR). Pattern recognition was achieved by linear discriminant analysis and hierarchical clustering analysis algorithms. As a result of distinguishing among monomers and three pure aggregate species, namely oligomers, protofibrils, and fibrils, the cross-reactive sensor array was also able to monitor aggregation kinetics in various aggregate forms and distinguish between on- and off- aggregate pathways. Our study provides a convenient approach for simultaneous detection of Aβ aggregates in mixtures, which may also be applied to the analysis of other disease-related proteins that are prone to aggregates.


Ion-ion correlation attraction in a molecular solvent.
We have performed Monte Carlo simulations for two like-charged infinite plates with counterions and solvent in between. The solvent is described at the primitive model (PM) level and also as a Stockmayer fluid. Both descriptions share the same qualitative ion correlation picture. At sufficiently high coupling, the pressure between the plates shows an attractive minimum, which is lost or reduced upon decreasing counterion valency, surface charge density, or increasing the screening. The pressure profiles become more oscillatory with higher density, which masks the ion-ion correlation attraction. An interpretation in terms of interaction free energies rather than pressures clarifies the picture. Analyzing the different contributions to the pressure gives further support to the conclusions; the same components are responsible for the same effect in the PM and in the molecular solvent.


Prostatic urethral lift: a novel approach for managing symptomatic BPH in the aging man.
Benign prostatic hyperplasia (BPH) is an obligate disorder of the aging male prostate with close associations to other metabolic conditions of aging including obesity. Clinical manifestations of this chronic disorder increase as men age suggesting that a growing number of older men will require intervention for progressive voiding symptoms or bladder dysfunction. The Prostatic Urethral Lift (PUL) procedure represents a new endoscopic approach in which small permanent intraprostatic implants are positioned to correct bladder outlet obstruction without tissue destruction. An overview of the treatment modality, review of recent literature, and analysis of data in the context of cost considerations is presented. The mean symptom score improvement of the prospective, sham controlled, pivotal trial was 11 points, 88% greater than sham controls. Multiple studies have confirmed symptom score improvement of at least 52%. Durability has been established out to 3 years. A randomized comparison between PUL and transurethral resection of the prostate (TURP) established PUL as superior to TURP in terms of a composite BPH6 endpoint which incorporated symptom relief, quality of recovery, erectile function preservation, ejaculatory function preservation, continence preservation, and safety. The National Institute for Health and Care Excellence of the United Kingdom conducted an analysis that found PUL is less costly than TURP. Earlier management with PUL may even reduce overall cost for those patients managed with medication. Current reports have demonstrated rapid voiding symptom improvement with a low risk of adverse events suggesting that this procedure represents a safe and cost effective new paradigm for the early therapy for BPH/ LUTS.


Epidemiological profile of malaria in the state of Tocantins, Brazil, from 2003 to 2008.
This study describes the epidemiological profile of malaria in the State of Tocantins, in the period 2003-2008, investigates the association between the frequency of malaria and population growth, classifies the cases by 'autochthonous' and 'imported', reports the indices of the disease and analyses the distribution of the cases by Plasmodium species, age and gender. The retrospective study was based on secondary data, stored in SIVEP-malaria and analyzed using the software Epi-Info 3.5.1. and Bioestat 5.0. 19,004 samples were investigated for malaria, 19% of them were positive, 73.32% with Plasmodium vivax, 21.80% with Plasmodium falciparum, 4.79% with mixed infections and only 0.08% with Plasmodium malariae. Male individuals accounted for 76.95% and predominated in all years and age groups, especially in the 15 to 49 years old group. From the overall cases, 34.27% were autochthonous and 65.73% were imported (χ2 = 356.8, p = 0.0001). The frequency of malaria decreased significantly during the entire series (rp = 0.96, p = 0.002) and the number of municipalities with autochthonous transmission also diminished. It was found that malaria is predominantly imported, related to land activities, which confirms the need for effective measures to maintain vigilance throughout the state and enhance educational activities in order to guide the population towards early treatment-seeking.


[Disasters and public health: an approach from the theoretical framework of epidemiology].
Throughout the 1990-2000 period, disasters (catastrophes) caused an average of 75,000 deaths yearly, injuring an average of 256 million people a year and causing economic losses totaling more than 650 billion euros. The magnitude of this problem, its impact on public health and on the degree of development of the populations involved are of such major importance as to warrant special interest from the public health standpoint, especially as a result of what are known as complex emergencies. The objective of this study is that of reviewing the definitions, the main concepts and the basic characteristics of disaster epidemiology. An analysis is also made of the risk factors involved in disasters, the impacts on public health of the main types of disasters and the main preventive strategies in terms of the different stages of the disaster cycle.


Characterization of a panel of monoclonal antibodies recognizing specific epitopes on GFAP.
Alexander disease (AxD) is a neurodegenerative disease caused by heterozygous mutations in the GFAP gene, which encodes the major intermediate filament protein of astrocytes. This disease is characterized by the accumulation of cytoplasmic protein aggregates, known as Rosenthal fibers. Antibodies specific to GFAP could provide invaluable tools to facilitate studies of the normal biology of GFAP and to elucidate the pathologic role of this IF protein in disease. While a large number of antibodies to GFAP are available, few if any of them have defined epitopes. Here we described the characterization of a panel of commonly used anti-GFAP antibodies, which recognized epitopes at regions extending across the rod domain of GFAP. We show that all of the antibodies are useful for immunoblotting and immunostaining, and identify a subset that preferentially recognized human GFAP. Using these antibodies, we demonstrate the presence of biochemically modified forms of GFAP in brains of human AxD patients and mouse AxD models. These data suggest that this panel of anti-GFAP antibodies will be useful for studies of animal and cell-based models of AxD and related diseases in which cytoskeletal defects associated with GFAP modifications occur.


Interferon-gamma polymorphisms correlate with duration of survival in pancreatic cancer.
Despite progress in diagnosis and staging, pancreatic cancer still has a poor prognosis and it remains difficult to predict duration of survival in advanced pancreatic cancer. Nutritional decline, or cachexia, is a contributory factor to decreased survival in advanced pancreatic carcinoma, and it has been demonstrated that proinflammatory cytokines give rise to cachexia. Interferon (IFN)-gamma is a proinflammatory cytokine whose administration increases survival outcomes in a variety of cancers. The human IFN-gamma gene has a variable length CA-repeat sequence, the length that has been shown to influence IFN-gamma production. The current study was performed to ascertain whether polymorphisms of the IFN-gamma gene would influence survival of individuals with advanced pancreatic cancer. The study demonstrated that the presence of allele 2 (12 CA repeats) was consistently associated with increased duration of survival after confirmation of nonresectable pancreatic carcinoma. We therefore propose that the presence of allele 2 may be a useful marker for patient outcome.


Dynamics of a qubit as a classical stochastic process with time-correlated noise: minimal measurement invasiveness.
So far it has been shown that the quantum dynamics cannot be described as a classical Markov process unless the number of classical states is uncountably infinite. In this Letter, we present a stochastic model with time-correlated noise that exactly reproduces any unitary evolution of a qubit and requires just four classical states. The invasive updating of only 1 bit during a measurement accounts for the quantum violation of the Leggett-Garg inequalities. Unlike in a pilot-wave theory, the stochastic forces governing the jumps among the four states do not depend on the quantum state but only on the unitary evolution. This model is used to derive a local hidden variable model, augmented by 1 bit of classical communication, for simulating entangled Bell states.


Hold the Chemo! Leukostasis, a Presentation of Brown Recluse Spider Bite: A Case Report.
Brown recluse spiders, also known as Loxosceles reclusa, are endemic to the Southwest and Central Midwestern United States. A bite from this spider can cause a range of clinical manifestations, anywhere from a painless papular lesion to life-threatening reactions. We report a possible spider bite presenting as leukostasis initially suspected to be acute leukemia. A 22-year-old female patient presented to the emergency department with confusion and right upper arm pain, redness, and swelling after a suspected spider bite. Initial labs showed WBC count of 103.5x10e3/µL, hemoglobin of 3.3 g/dL, positive Direct Coombs' test, creatinine of 1.8 mg/dL, transaminitis, and lactic acid of 20 mmol/L. Acute leukemia with leukostasis was suspected. She was started emergently on hydroxyurea in conjunction with prophylaxis for tumor lysis syndrome. However, peripheral smear showed left-shifted granulocytosis with lymphocytosis, monocytosis, and no blast cells or evidence of myelodysplasia. Bone marrow aspirate showed mildly hypercellular marrow with myeloid hyperplasia and no myelodysplasia. Flow cytometry analysis confirmed a left-shifted myeloid maturation pattern with 0.3% myeloblasts. BCR-ABL1 and JAK2 testing was negative. Hence, she had no evidence of leukemia but rather had leukostasis from a spider bite. Hydroxyurea was stopped and follow-up labs normalized. Sphingomyelinase D in the brown recluse spider venom is unique to Loxosceles and Sicarius and may be responsible for the unique clinical presentation of loxoscelism. The presentation of hyperleukocytosis complicated by shock with an unclear history poses a diagnostic challenge. In diagnostic uncertainty, consider delaying chemotherapy until a diagnosis can be confirmed to avoid potential harm.


Association of hypertriglyceridaemia with pre-eclampsia, preterm birth, gestational diabetes and uterine artery pulsatility index.
We aimed to determine whether high plasma triglyceride levels in the second trimester of pregnancy are associated with adverse pregnancy outcomes including preterm birth, gestational diabetes mellitus, pre-eclampsia and high uterine artery pulsatility index. This prospective cohort study was done between 2008 and 2010. Plasma levels of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglyceride were measured after 8 hours of overnight fasting. We compared the outcomes of 45 pregnant women who had high triglyceride levels (>195 mg/dl) with 135 pregnant women with triglyceride levels <195 mg/dl. The main outcome measures were the incidence of preterm birth, gestational diabetes, pre-eclampsia and uterine artery pulsatility index. Eight women with high triglyceride levels had preeclampsia (17.8% v. 3.7% in the control group, p<0.004), preterm birth occurred in 24.4% and 5.9% in the high triglyceride group and the control group, respectively (OR 5.1,95% CI 1.9-13.8, p<0.0001). The incidence of gestational diabetes in the high triglyceride group was significantly higher than that in the control group. There was no difference in uterine artery Doppler ultrasound between the two groups. There is a positive relation between hypertriglyceridaemia and pre-eclampsia, preterm birth and gestational diabetes.


Identification of astilbin metabolites produced by human intestinal bacteria using UPLC-Q-TOF/MS.
Astilbin, mainly isolated from a commonly used herbal medicine, Smilax glabra Roxb (SGR), exhibits a variety of pharmacological activities and biological effects. It is metabolized by intestinal bacteria after oral administration which leads to the variation of ethnopharmacological profile of this traditional medicine. However, little is known on the interactions of this active compound with intestinal bacteria, which would be very helpful in unravelling how SGR works. In this study, different pure bacteria from human feces were isolated and were used to investigate their conversion capability of astilbin. Ultra-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF/MS) technique combined with Metabolynx(TM) software was used to analyze astilbin and its metabolites. The parent compound and two metabolites (quercetin and eriodictyol) were detected in the isolated bacterial samples compared with blank samples. Quercetin was present in Enterococcus sp. 8B, 8-2 and 9-2 samples. Eriodictyol was only identified in Enterococcus sp. 8B sample. The metabolic routes and metabolites of astilbin produced by the different intestinal bacteria are reported for the first time. This will be useful for the investigation of the pharmacokinetic study of astilbin in vivo and the role of different intestinal bacteria in the metabolism of natural compounds.


Reduced structural connectivity in non-motor networks in children born preterm and the influence of early postnatal human cytomegalovirus infection.
Preterm birth is increasingly recognized to cause lifelong functional deficits, which often show no correlate in conventional MRI. In addition, early postnatal infection with human cytomegalovirus (hCMV) is being discussed as a possible cause for further impairments. In the present work, we used fixel-based analysis of diffusion-weighted MRI to assess long-term white matter alterations associated with preterm birth and/or early postnatal hCMV infection. 36 former preterms (PT, median age 14.8 years, median gestational age 28 weeks) and 18 healthy term-born controls (HC, median age 11.1 years) underwent high angular resolution DWI scans (1.5 T, b = 2 000 s/mm2, 60 directions) as well as clinical assessment. All subjects showed normal conventional MRI and normal motor function. Early postnatal hCMV infection status (CMV+ and CMV-) had been determined from repeated screening, ruling out congenital infections. Whole-brain analysis was performed, yielding fixel-wise metrics for fiber density (FD), fiber cross-section (FC), and fiber density and cross-section (FDC). Group differences were identified in a whole-brain analysis, followed by an analysis of tract-averaged metrics within a priori selected tracts associated with cognitive function. Both analyses were repeated while differentiating for postnatal hCMV infection status. PT showed significant reductions of fixel metrics bilaterally in the cingulum, the genu corporis callosum and forceps minor, the capsula externa, and cerebellar and pontine structures. After including intracranial volume as a covariate, reductions remained significant in the cingulum. The tract-specific investigation revealed further reductions bilaterally in the superior longitudinal fasciculus and the uncinate fasciculus. When differentiating for hCMV infection status, no significant differences were found between CMV+ and CMV-. However, comparing CMV+ against HC, fixel metric reductions were of higher magnitude and of larger spatial extent than in CMV- against HC. Preterm birth can lead to long-lasting alterations of WM micro- and macrostructure, not visible on conventional MRI. Alterations are located predominantly in WM structures associated with cognitive function, likely underlying the cognitive deficits observed in our cohort. These observed structural alterations were more pronounced in preterms who suffered from early postnatal hCMV infection, in line with previous studies suggesting an additive effect.


bHLH transcription factors in neural development, disease, and reprogramming.
The formation of functional neural circuits in the vertebrate central nervous system (CNS) requires that appropriate numbers of the correct types of neuronal and glial cells are generated in their proper places and times during development. In the embryonic CNS, multipotent progenitor cells first acquire regional identities, and then undergo precisely choreographed temporal identity transitions (i.e. time-dependent changes in their identity) that determine how many neuronal and glial cells of each type they will generate. Transcription factors of the basic-helix-loop-helix (bHLH) family have emerged as key determinants of neural cell fate specification and differentiation, ensuring that appropriate numbers of specific neuronal and glial cell types are produced. Recent studies have further revealed that the functions of these bHLH factors are strictly regulated. Given their essential developmental roles, it is not surprising that bHLH mutations and de-regulated expression are associated with various neurological diseases and cancers. Moreover, the powerful ability of bHLH factors to direct neuronal and glial cell fate specification and differentiation has been exploited in the relatively new field of cellular reprogramming, in which pluripotent stem cells or somatic stem cells are converted to neural lineages, often with a transcription factor-based lineage conversion strategy that includes one or more of the bHLH genes. These concepts are reviewed herein.


CacyBP/SIP, a calcyclin and Siah-1-interacting protein, binds EF-hand proteins of the S100 family.
Recently, a human ortholog of mouse calcyclin (S100A6)-binding protein (CacyBP) called SIP (Siah-1-interacting protein) was shown to be a component of a novel ubiquitinylation pathway regulating beta-catenin degradation (Matsuzawa, S., and Reed, J. C. (2001) Mol. Cell 7, 915-926). In murine brain, CacyBP/SIP is expressed at a high level, but S100A6 is expressed at a very low level. Consequently we carried out experiments to determine if CacyBP/SIP binds to other S100 proteins in this tissue. Using CacyBP/SIP affinity chromatography, we found that S100B from the brain extract binds to CacyBP/SIP in a Ca2+-dependent manner. Using a nitrocellulose overlay assay with 125I-CacyBP/SIP and CacyBP/SIP affinity chromatography, we found that this protein binds purified S100A1, S100A6, S100A12, S100B, and S100P but not S100A4, calbindin D(9k), parvalbumin, and calmodulin. The interaction of S100 proteins with CacyBP/SIP occurs via its C-terminal fragment (residues 155-229). Co-immunoprecipitation of CacyBP/SIP with S100B from brain and with S100A6 from Ehrlich ascites tumor cells suggests that these interactions are physiologically relevant and that the ubiquitinylation complex involving CacyBP/SIP might be regulated by S100 proteins.


Bayesian inference and attentional modulation in the visual cortex.
The responses of neurons in cortical areas V2 and V4 can be significantly modulated by attention to particular locations within an input image. We show that such effects emerge naturally when perception is viewed as a probabilistic inference process governed by Bayesian principles and implemented in hierarchical cortical networks. The proposed model can explain a rich variety of attention-related responses in cortical area V4 including multiplicative modulation of tuning curves, restoration of neural responses in the presence of distracting stimuli, and influence of attention on neighboring unattended locations. Our results suggest a new interpretation of attention as a cortical mechanism for reducing perceptual uncertainty by combining top-down task-relevant information with bottom-up sensory inputs in a probabilistic manner.


Factors influencing reconstitution by bone marrow transplantation.
Reconstitution of levels of pheripheral blood cells following bone marrow transplantation is dependent on the engraftment of the pluripotent hemopoietic stem cells of the transplant. In the case of allogeneic transplants, a successful engraftment carries a high risk of the development of GvHD, which is a serious and often life-threatening complication. T cell depletion of the allogeneic bone marrow graft can completely prevent GvHD provided a sufficient degree of depletion is achieved. Experiments with laboratory animals and clinical experience have shown that the higher rate of graft failure that occurs with T cell depleted marrow grafts can be avoided by increasing the conditioning dose of TBI with approximately 2 Gy. Experiments with T cell depleted autologous bone marrow grafts and with grafts of autologous purified stem cells in monkeys demonstrate that the decreased engraftment of T cell depleted bone marrow cannot be ascribed to a trophic function of T lymphocytes, e.g. via production of hemopoietic growth factors. Using sublethally irradiated Rhesus monkeys, the effect of post-irradiation treatment with GM-CSF or with Rhesus monkey r IL-3 was studied. Enhancement of blood cell regeneration was only recorded within a relatively small TBI dose range. When the dose of TBI induces more than approximately a 3-log stem cell kill, treatment with growth factors becomes ineffective. Comparable results are obtained when supralethally irradiated monkeys given relatively small grafts of T cell depleted autologous bone marrow were treated with the hemopoietic growth factors.


The MPB64 immunochromatography assay: an analysis of doubtful results.
Culture remains the gold standard for tuberculosis (TB) diagnosis, and the mycobacteria growth indicator tube (MGIT), endorsed by the World Health Organization (WHO), is widely used. Further identification of a positive culture is done with the help of an immunochromatography assay, which often shows faint bands that are difficult to interpret. We analysed 125 BACTEC MGIT culture positive results, of which 11/16 (68.7%) of the doubtful assays, analysed by MGIT™ TBc Identification test (TBcId), were positive for Mycobacterium tuberculosis complex (MTBC), the remaining being non-tuberculous mycobacteria as determined by an in-house duplex polymerase chain reaction and line probe assay. Guidelines on faint or doubtful bands in immunochromatography assays are important so as not to overlook true-positive cases of TB.